Simeonova
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A p p ro v e d
b y th e M in istry o f P u b lic H ealth
a n d th e M in istry o f S c ie n c e
a n d E d u c a tio n o f U k ra in e as a
te x tb o o k fo r stu d e n ts o f h ig h e r
m e d ic a l e d u c a tio n a l in stitu tio n s
o f th e III—IV a c c re d ita tio n lev els
Kyiv
AUS m edicine Publishing
,5я73
f» 092(075.8)
14
Л и т о р:
IIK (Чмеонова - доцент кафедри патоф1зюлоги Нацюнального медич-
ого ушверситету iM e u i О.О. Богомольця, кандидат медичних наук, лауреат
(ержанноУ npcMii Украши в галуз1 наук
11 а у к о в и й р е д а к т о р :
II I Mixuboe, член-кореспондент НацюнальиоУ академп медичних наук
кроши, професор
V е ц с н i e н г и:
I / Гчжспко, заслужений ;пяч науки i техшки Украши, професор, зав.
лфсари laianbimi iiarojioiii i KniHhiHOi патоф1зюлоги Одеського державного
1сдичшт> уи1|*среитсту;
I Н Кубишк1н, професор, зав. кафедри патоф1зюлогп Кримського держав
о ю медпчного у 11i не рс тхг*гу, головней кафедри з викладання англомовним
г у д е т им;
IM KUwhhim'M<at проф есор, 1нститут ф гнологи iMeui О .О . Богом ольця
fiKinicMiY наук У краш и;
laiiioH.i ii.noi
П< Лесино, ■Iо к гор медичних наук, (нститут ф1зюлоги iMeui 0 . 0 . Б ого-
ю н.нн 11ац1онш1ЫЮ1 aK.iaeMif наук У краш и
PREFACE...........................................................................................................................................................................10
Part 1
GENERAL PATHOPHYSIOLOGY
( 'hapter 1. Subejct, Method and Aim of Pathophysiology. Concept of Disease. Etiology and
P athogenesis............................................................................................................................................................. 11
Experiment as the Basic M ethod o f Pathophysiology.............................................................................. 12
Concept o f Disease.................................................................................................................................................12
Concept o f E tiology.............................................................................................................................................. 15
Concept o f P athogenesis..................................................................................................................................... 16
Principles o f Treatm ent........................................................................................................................................18
Tests and Tasks........................................................................................................................................................ 19
з
Ik
к Inflammation ....................................................................................................................120
•im.il Signs o f Inllnm m ation....................................................................................................................... 120
>l«*n ............................................................................................................................................... 121
honenesis ....................................................................................................................................................121
Alteration ...................................................................................................................... 121
Intbimimitory ( ells ...................................................................................................................... 121
H \ s Kole in Inflammation. Inllammation M ediators........................................................................ 123
MkitH'Irculilllon Disorder............................................................................................................................ 123
I 4iul.ni.4i, I migration, and Phagocytosis.............................................................................................. 125
Pmhi. мной iiiul Regeneration....................................................................................................................126
I Jisnnlri of MrtabollNin ...........................................................................................................................127
iiiiinuitIon .uni Organism Reactivity..........................................................................................................127
I' inU ( hange-. in Inflammation................................................................................................................. 128
niti« . i m o l Inllammation ..........................................................................................................................128
is and I a sks ...................................................................................................................... 128
A naplasia............................................................................................................................................................. 150
Systemic M anifestations o f N eop lasia...................................................................................................... 153
Malingnant Tumor and Organism Reactivity...............................................................................................153
M echanisms o f Protection against Tum or..................................................................................................... 153
I umor Influence on Organism Clinical M anifestations o f N eop lasia.................................................155
Tests and Tasks........................................................................................................................................................ 155
< hapter 13. Pathology of Energy Balance and Basal M etabolism ..................................................................187
I >isorders o f M etabolism R egulation...............................................................................................................188
I nergy Production Increase............................................................................................................................... 191
Energy Production D ecrease..............................................................................................................................193
Pathology o f Basal M etabolism ......................................................................................................................... 195
Tests and Tasks........................................................................................................................................................ 197
...
Ills
Part 2
SPECIAL (SY STEM IC) PATHOPHYSIOLOGY
Digestive Disorders Connected with Impairment o f Bile and Pancreatic Juice S ecretion ..........425
Intestinal Digestion Disorders........................................................................................................................... 425
I urge Intestine D isorders....................................................................................................................................428
Intestinal Impassabillty.........................................................................................................................................428
Impairment o f Ineretory (Hormonal) Function o f Digestive System ..................................................430
Tests and Tasks........................................................................................................................................................430
tpter 2H, Pathophysiology of Liver........................................................................................................................434
(tio lt)g y ..................................................................................................................................................................... 436
I’lit In g e n e s is ............................................................................................................................................................ 437
Cholestatic Hepatic Insufficiency..................................................................................................................... 438
Acholic (H ypocholic) Syndrom e....................................................................................................... 439
C holem ic Syndrome (C h o le m ia )...................................................................................................... 440
Mechanical (Posthepatic) Jaundice.................................................................................................. 441
Hepatocellular (Parenchymatous) Hepatic Insufficiency.................................................................. 442
Metabolic Syndrom e..............................................................................................................................443
Syndrome o f Antitoxic Function Impairment.............................................................................. 446
liepatic C om a..........................................................................................................................................447
Parenchymatous Hepatic Jaundice....................................................................................................449
Iiepatovascular Insufficiency...................................................................................................................... 450
Syndrome o f Portal H ypertension.....................................................................................................451
Jaundice...................................................................................................................................................................452
Hemolytic Jaundice....................................................................................................................................... 453
Tests and Tasks...................................................................................................................................................... 454
i
C ontents
INDEX 538
К К FACE
( h ap te r I
SUBJECT, METHOD AND AIM OF PATHOPHYSIOLOGY.
CO N C EPT OF DISEASE. ETIOLOGY AND PATHOGENESIS
CONCEPT OF DISEASE
12
t 'lljiH r i I Subject, M ethod and Aim of Pathophysiology. C oncept o f DKenNC. l-Uolo^y and .
1)isease is a unity o f two opposite tendencies — dam age and defense, which are
in <onstant coordination and confrontation.
All physiological patterns m ay be changed in the course o f any disease. How-
• Vi i. disease is not a sum o f quantitative changes, but a qualitatively new pheno
menon,
I >isease reveals a new understanding o f the optim al level o f physiological func-
i и иг. I or exam ple, in the course o f in
i' <non l he optim al body tem perature I ) is ease a s =
IV a phylosophical generidization
i ihove 37°C (3 8 -3 9 °C and m ore),
i-ui i lie body tem perature o f 36.6°C
/
и not optim al. During inflam m ation D isease as a typical
r; III
fin Increased am ount o f leukocytes in pathological process
ih* blood (up to 15—20 G /l instead o f
7ПТП
I У ( i/I) is optim al. D uring hypoxia D i s e a s e a s a n o 'I " 1
in im leased respiratory rate and an in-
1 1 eased num ber o f erythrocytes are o p
timal Analyzing the patient’s q uantita Disease in a patient
diagnosis
tive patterns, a physician must com pare
iln in not only with the physiological
Mumlaidfl, but also with the ones con /•>>:. I Levels of a disease (IV I)
s id e red optim al for this disease. .iiul relation ol abstract and concrete
Part I <»iiic n il I ' iiIIio | i IivsIo Iok.v
Classification of Diseases
Periods of Disease
M any diseases (infectious and som e others) develop in such four periods:
I Latent (has no clinical signs).
Л Prodromal (there appear first clinical sym ptom s, which are com m on in
m any diseases).
\ Г/w period o f pronounced manifestations and expressed clinical signs (which
aie specific o f this disease).
•I ()utcome.
I Ins four-staged periodization o f diseases was suggested in the past for acute
lull i lious diseases, hut m any diseases (cardiovascular, endocrine, allergic) are gov^
• 1 1 it'd by o th er laws, and the m entioned periodization is not applicable to them .
I h e s e diseases develop in three periods:
I beginning.
) Гhe st age o f disease proper.
I Outcome.
I Msease outcom e depends on the force o f the harm ful factor, organism reac-
1 1 vи\ and the ability to develop self-protective reactions. There are three types of
*11 • r.r o u tc o m e : recovery (c o m p le te , in c o m p le te), tra n sfo rm a tio n into a chro n ic
Ii*iih 01 pathological state, d e a th w ith p reagony, agony, clinical a n d th e n biological
death,
Pievalence o f defense reactions leads to recovery. Incom plete com pensation
leads to disease turning into a chronic form. Exhaustion o f adaptive reactions leads
lo death.
Г m m the pathophysiological point o f view m any diseases undergo two peri
ltd*
I Stage o f compensation (ability to work is preserved);
) Stage o f decompensation (ability to work is lost).
Manifestations of Disease
CONCEPT OF ETIOLOGY
I Hologlcal factors are divided into exogenous (external) and endogenous (inter
n il) as well as acquired and congenital ones,
I ( iriH’l 111 Ги|1|о||1п ч1«»1оц>
CONCEPT OF PATHOGENESIS
17
I'.it I I (ieiieral Pathophysiology
PRINCIPLES O F TREATMENT
I Isually a physician records p atien t’s com plaints, subjective and objective m ani
festations o f a disease, which are called sym ptom s. A physician may treat a certain
IM
( ImpkT I Subject, M ethod and Aim of l*ttlhophy>tology« C oncept o f Disease. ICtlology in u l.
vm ptom (pain) and alleviate the patient’s suffering. This is symptomatic therapy,
the worst type o f treatm ent.
I lie real cure is elim ination o f the disease cause (for exam ple, infection treat
M i l lit with antibiotics). This is etiological therapy. However, som etim es elim ina
1. A patient has pulm onary tuberculosis and is infected. K och’s bacillus has
been revealed in the mucus. W hat is the role o f K och’s bacillus in disease
developm ent? It plays the role of:
A. C ondition.
B. Pathogenesis.
C. M ain link o f pathogenesis.
I). Etiological factor.
II. G enetic factor.
2 . The m ain pharm aceutical agent for radiation disease treatm ent is the use
o f antioxidants against active form s o f oxygen, w hich determ ine the m ain
pathophysiological changes and clinical m anifestations. W hat is the role of
active forms o f oxygen? They are:
A. Etiological factor.
B. C ondition.
C. Main link o f pathogenesis.
I). C om pensatory reaction.
I’. M anifestation.
4. A stom atologist has found som e carious teeth in a 32-year-old w om an. W hat is
the proper nosological term to determ ine this state?
A. Pathological reaction.
B. Pathological process.
C\ Remission.
I). Illness.
I . C om pensatory reaction.
> C om pile a schem e o f viral influenza etiology taking the schem e I from this
ch ap ter as a rpodel,
i h u p ter 2
l*V! IKKJKNIС EFFECT OF ENVIRONMENTAL FACTORS
Y/ujft* of ( ompensation
posite direction signals reach the organs and systems, w hich participate in body
tem perature m aintenance. Along the m otor nerves im pulses reach the muscles;
therm oregulatory m uscle tone rises and m uscle trem bling develops. Along the sym
pathetic nerves im pulses reach the adrenal m edulla. A drenaline secretion increases
(adrenaline effects the vessels, m obilizes glycogen from the liver and muscles, stim u
lates oxidation). The pituitary gland stim ulates (by tropic horm ones) the thyroid
gland (thyroxin intensifies m etabolism , activates m itochondria biogenesis) and the
adrenal cortex (glucocorticoids stim ulate form ation o f carbohydrates from n oncar
bohydrate products and form the condition o f stress).
Stage o f Decompensation
Stage o f Compensation
The stage o f com pensation is a period o f hypertherm ia, when defense reactions
prevail, and norm al body tem perature is m aintained.
Compensatory reactions consist in heat em ission increase by activation o f c o n
vection, radiation, perspiration and evaporation. T he peripheral vessels are dilated.
If the tem perature o f the environm ent is above 30°C, convection is inhibited. U nder
the condition o f high air hum idity evaporation is lim ited as well.
Stage o f Decompensation
The stage o f decom pensation is a period o f hypertherm ia, when com pensatory
reactions are exhausted and body tem perature rises
C h a p te r 2 Pathogenic Effect of Environment ill Iju lo rs
Hum develops as a result o f the local effect o f high tem perature and is m ani
I* .led by skin destruction and systemic disorders in the organism .
I S pen d in g on the intensity o f local dam age, the following degrees o f burn are
distinguished:
I redness o f the skin (erythem a), a weak inflam m atory reaction w ithout skin
И* i ruction;
II acute exudative inflam m ation o f the skin, form ation o f blisters, and epi
ili mils scaling;
III partial skin necrosis and ulceration;
IV transcpiderm al necrosis.
In extensive burns system ic disorders predom inate over local ones. It goes
•Iмин Imiin disease.
< Tinical m anifestations o f burn disease are connected with the developm ent o
h«H I. toxem ia, infection, and dehydration.
Hum shock is the m ost severe post-burn effect. It is a result o f pain and exccs
- • iilleient im p u ta tio n to the central nervous system. T he regulation o f vascular
«••in inspiration and heart contraction is im paired. T he circulating blood volume
di i »• .ises. dehydratation and acute renal insufficiency develop.
Intoxication significantly contributes to the developm ent o f shock. Endotoxins
и- fin nicd as a result o f disbolism ; a large quantity o f toxins is liberated in the /o n e
"• damage C ritical disorders in protein m etabolism are noted; total protein disiti
и jiifitiou is observed D enatured proteins and toxic products o f their en/.yrnal lysis
мн. i ihe blood A critical disorder o f nitrogen m etabolism takes place.
Infection is a constant com plication o f burn disease and aggravates intoxiea
Пин I In* source ol infection is the dam aged surface and bowels (autoinlection).
f J*«i only llie bum area ilsell is colonized by bacteria but the entire skin surface ol
IX
Г.ill 1. ( . r u n a l I’al l i u fi l n s i o l o t ’v
I In* patient. Increased perm eability o f blood vessel walls leads to massive infection
and bacteriem ia. Sepsis resulting from burn w ound infection is the m ost im portant
cause o f death in seriously burned patients. U nder the effect o f proteolytic enzymes,
which are liberated from the dam aged cells, proteins m ay change, and antigens
becom e the reason for autoim m une aggression.
Dehydration is a severe com plication o f burn. It relates to the massive o u t
pouring o f exudate. T he burn area becom es reddened as sm all blood vessels dilate,
a norwards one observes increased capillary perm eability with protein-rich fluid exu
dation. Burn implies an open w ound, from which an enorm ous am ount o f plasm a
proteins may be lost through the dam aged surface. T he loss o f liquid induces hypo
volemia and hem oconcentration. Increased blood viscosity disrupts blood circula
tion and heart function. The w ater-m ineral balance breaks down. T he dam aged
tissues retain sodium (cellular hyperhydration develops) and lose potassium (the
blood co n ten t o f potassium increases, hyperkaliem ia develops).
Exhaustion (cachexia) is the final stage o f the disease. T he following p ath o
logical disorders are observed — edem a, anem ia, dystrophic changes in the organs,
pneum onia, glom erulonephritis, and adrenal glands insufficiency. All these disor
ders equally with pulm onary transudation striking and pulm onary edem a becom e
the cause o f death.
If burn disease takes a favorable course, recovery begins. D efects are filled with
granulation; w ounds are epithelized.
Thus, severely burned patients confront not only local injury repair but, even
m ore im portantly, its serious systemic consequences.
Etiology
M h I
Biological Effect of a Single Whole-Body Exposure to Various Doses
of Ionizing Radiation on Man
Imm (Koeiitgens) Biological Effect
10 No detectable somatic effects. Detectable morphologic and func
tional alterations in specific subpopulations of lymphocytes; prob
able chromosomal abnormalities
100 Mild form of the disease in some persons with nausea, vomiting and
transient leukopenia
1000 Affection of the bone marrow with leukopenia, thrombocytopenia
and anemia; necrosis of the gastrointestinal mucosa; severe radiation
disease; death within 30 days
10000 Death within hours
100000 Death of most types of mammalian cells
Pathogenesis
I hr energy o f ionizing radiation exceeds the energy o f intram olecular and intra
iinniu bonds. A bsorbed by a m acrom olecule, it may m igrate in th e cell realizing
hi ih« mosi vuln erable places. It results in io n izatio n , excitatio n a n d break o f
ь v> .(able b o n d s, tearin g of!' radicals, w hich are called free.
So, I lie initial links o f pathogenesis consist in ionization and excitation o f atom s
нм I molecules. C hem ical transform ation o f substances and form ation o f active in-
н mi. «lull- products caused by radiation are called radiolysis. Radiation dam age is
• ««пи.»led with direct and indirect action o n im portant biological molecules.
Direct effect o f radiation energy is a dam age o f m acrom olecules by radiation
и * И I veutually, intram olecular changes take place. Any type o f m olecules may be
а пни, i organic m acrom olecules such as DNA , lipids, phospholipids, enzymes,
pi*и* ms, vitam ins, hem oprotein, etc.
Indirect action is a dam age o f m acrom olecules by water radiolysis products.
\S h. i m olecu le io n izatio n is th e m ost sig n ifican t o f all p rim ary rad io c h em ical
i ю н .i«nm illions, I he first products are ionized water m olecules 11,0' and 11,0
Пн и lнм- hydrogen and hydroxyl radicals are form ed (II, O H ), which initiate a
• H uh i »l flirt he i reactions and new products are formed (hydrogen peroxide 11,0,,
h .impt ioside 1И),, atom ic oxygen O, etc.). W ater radiolysis products biochem i
t nilч ui‘ very active and cause extensive nonen/ym alie o x id atio n .
Purl I ( h' iuthI pHlltophysioloK.v
Biochemical Disorders
Later, the oxidizers attack organic m olecules, and new active radicals are
formed. C hem ical and biochem ical reactions rapidly increase, acquiring the nature
o f branching reactions. Such reactions develop m ore aggressively in a lipid m edium
and peroxide oxidation o f lipids is initiated.
fu rth e rm o re, radiotoxins are form ed. U n s a tu ra te d fatty ac id s a n d p h e n o ls
n r o x id ized re su ltin g in th e fo rm a tio n o f lipid (lipid peroxides, epoxides, a l
d ehyd es) a n d q u in o n e ra d io to x in s (precursors o f quinone radiotoxins are tyrosine,
tryptophan, serotonin, catecholam ines). R ad io to x in s in h ib it n u cleic ac id s y n th e
sis, in flu en ce D N A as c h e m ic a l m u ta g e n s, c h a n g e en zy m e activ ity , d am ag e
In tra c e llu la r m e m b ra n e s.
Enzymes are damaged directly (as a target) and indirectly (by w ater radiolysis
products and radiotoxins). Thiolic enzymes (they contain SH groups) have increased
radiosensitivity and are oxidized easily. Some enzymes, on the contrary, are activated,
particularly the ones released from dam aged lysosomes. Subsequently enzymal reac
tions are intensively intensifying — disintegration o f proteins and nucleic acids is acti
vated, synthesis is reduced, phosphorylation and antioxidant activity are damaged.
N itrogen balance becom es negative. G lobin synthesis is reduced. A ntibody
synthesis is suppressed.
It is necessary to pay a special attention to the dam age o f a unique D N A m ol
ecule. Its intram olecular bonds are the m ost vulnerable target for direct and indirect
radiation effect. F ree radicals an d peroxides dam age th e ch em ical stru ctu re o f
D N A . P y rim idine o x id atio n an d p u rin e bases d e a m in a tio n are observed in n u -
clcic acids so lu tio n s a fte r ra d ia tio n influence. T he change o f th e D N A structure
is called m utation, thus ionizing radiation relates to physical m utagens.
Thereby, p rim ary ra d io c h e m ic a l re a c tio n s co n sist o f d ire c t an d in d ire c t
injury o f th e m o st im p o rta n t b io c h e m ic a l cell c o m p o n e n ts — nu cleic acids,
p ro tein s, an d enzym es. L ate r o n , en zy m al re a c tio n s are v io le n tly c h a n g e d —
en zy m al lysis o f p ro te in s an d n u c le ic ac id s is a c tiv a te d , D N A sy n th esis is
in h ib ite d , b io sy n th esis o f p ro te in s a n d en z y m e s is su p p ressed .
Any cellular structure may becom e a target for radiation energy, active oxidiz
er., radiotoxins and activated enzymes. T h e above m en tio n ed physical, chem ical
and bio ch em ical ch an g es d istu rb all m a n ife sta tio n s o f c e llu la r vital activity.
I herefore, all biological processes in cells m ay be dam aged.
The signs o f radiation injury o f the nucleus (swelling, pycnosis, lysis) are c o n
firmed histologically. O ne can see signs o f ra d ia tio n in ju ries o f th e n u c le u s
u n d e r th e e le c tro n ic a n d light m icro sco p e s. C hrom osom al a b e rra tio n s (breaks,
d e le tio n , fra g m e n ta tio n ) an d m o re su b tle d iso rd e rs o f th e g e n e tic a p p a ra tu s
(yeno m u tatio n s) may change the synthesis o f D N A , specific p ro tein s and sub
sequently hereditary properties of cells.
All othei cell organoids are dam aged too.
C h a p in ’ Ри Н ю д си к' Krrecl of Environmental Factors
hi | mi« o f the fact that radiosensitivity o f the nucleus is not higher than that
III itllii i nijr.moids, its dam age is m ore evidently m anifested in the vital activity of
I I'll-:
I !m i. lore, it is not hard to understand the relative radiosensitivity o f tissues. In
|h m Ml и lies are sensitive to radiation energy in direct proportion to m itotic ae-
iM lv iin I 111 inverse proportion to the level o f differentiation. Thus, the tissues with
к ЫН» i-»ie o f cellular renovation dem onstrate the greatest radiosensitivity: these
ан Ии hm p h o id , hem opoietic, epithelial tissues (particularly the epithelium o f the
I и » aiul sex glands) and endothelium o f vessels. T he fibrous, bone, m uscular,
itiiH и* n o u s t ells are less radiosensitive. T he nervous cells are destructed under the
ф Пон oi high overdose radiation (interphase destruction).
iii I he peripheral blood, progressive atrophy o f the lym ph nodes, bone m arrow
and spleen. A decreased quantity o f all types o f blood cells and depression o f
their function are observed. Lym phocytes are the m ost vulnerable ones. Therefore
lym phopenia develops from the very beginning. Lym phocytes break down in the
lymph nodes and blood. Later, throm bocytopenia, granulocytopenia and eventually
anem ia develop.
Hemorrhage Syndrome
Immunodepressive Syndrome
i ЫшемЫЫ Syndrome
* r n f 't t il S y n d ro m e
ими и mil i hanges ol the nervous cells occur in case o f higher radiation doses.
Him* vi i inn dual changes do not always correspond to the functional ones.
• i *• hi ill syndrom e confirm s nervous system sensitivity to any influenced, in
imimij i.нищItin Nervous receptors le a d to mdiolysis products almost immcdi
h u t I (ii'i tem l rullio|tliysioluK,v
ately. Changes o f the bioeleetrieal activity o f the brain can be registered within first
minutes. At first excitation is recorded. So, neuroreflectory activity is observed b e
fore o th e r typical sym ptom s o f radiation disease appear.
T he lethal dose o f ionizing radiation provokes th e cerebral form o f acute disease
(see below) due to direct dam age o f the nervous tissue.
I he endocrine gland epithelium can be dam aged by direct and indirect radia
tion. In addition to this, the endocrine system is affected by stress.
All signs o f stress are obvious (hyperfunction o f the pituitary gland and adrenal
cortex, lym phopenia). In the endocrine system organs, the initial signs o f increased
activity are replaced by endocrine gland inhibition. Eventually, the endocrine sys
tem is exhausted.
Special atten tio n m ust be paid to radioisotopes. Thus, radioactive iodine affects
the thyroid gland most o f all.
Defense Reactions
30
C h a p te r Л P iH liogeiilc Mffecl o f I .iiv iro n m c n lu l F a c to r*
i .и п . . i o n l y the radiation dose, but also organism reactivity determ ine I lie
н ниI d tn aiio n ol radiation disease. In schem e 3 the m echanism s o f DNA
* и*.I и p a n a iv sum m arized.
I In III|< 1)1
*ih'|iMlll4 lo i'
Иг1|||м)нмц
|**i * III ШИ
iHtihnliini
они iiitv
Repait factors
II
I1 art I (iimiitn! Pathophysiology
All m entioned disorders o f hem opoiesis, function o f the nervous and alim en
tary system s are m arked in all form s o f radiation disease. But the degree o f injury,
developm ent rate and prognosis depend on the absorbed dose o f total radiation.
T hree clinical forms o f acute radiation disease are distinguished — m edullary, |
gastrointestinal and cerebral.
Medullary Form
> I'i.M. « !•m i . neoplasia, prem ature aging) and genetic (instability o f hereditary
<i r " Нм ,u » um tilation o f gene dam ages, leukem ia, diseases o f posterity).
l in j M.iiom tcstinal form o f acute radiation disease develops if the dose makes
i" n cm as I и iilt o f extensive destruction o f the intestinal epithelium . The
m i ... mi Hi. iniesimal mucosa becom es dam aged and prom otes infection penetra
Mi in
Ни disease m anifests itself through nausea, vom iting, pain in the bowels,
Mood м leaked stool and diarrhea. The loss o f fluids and electrolytes leads to dehy
Й о то й i. dm non in circulating blood volum e, vascular collapse. There develops
i n .1 п. ..h iruction o f the intestines and peritonitis due to the im paired barrier
Мни Ион ol the intestinal wall.
Mi*и I i possible tlue to the effect o f toxic substances o f m icrobial and tissue
mMiMh пи- toxemic form is observed in 20—80 G r radiation). M itotic division o f the
imi i HI ни I epithelium stops. Massive interphase destruction o f the digestive tract
* t M iik* plii* e I oss o f proteins and electrolytes, increased body tem perature and
г mm im Hi* intestines m ust be added.
I и nil »nun's w ithin X 12 days (or earlier). Lethality is 100 %.
I f l t l t l t i l I 'o i III
The third degree o f the disease m anifests itself through deep dystrophy o f tissues
and irreversible organ changes. The function o f the pituitary gland and suprarenal
glands is exhausted. Hem opoiesis is suppressed, vessel tone is lowered, vessel per
m eability is increased. N ecrotic defects o f the m ucous m em branes are observed.
Infection and inflam m ation take a necrotic course.
C h ronic radiation disease o f any form underlies late pathological alterations.
G ene disorders might cause neoplasia. The organism that has undergone small ir
radiation doses grows old prem aturely.
Man is exposed to decreased barom etric (atm ospheric) pressure at high altitude
(in the m ountains, on a nonherm etic aircraft and during a spacecraft crash, when
barom etric pressure equals zero). U nder laboratory conditions, hypobaria is m od
eled m ;i special test low-pressure (hyperbaric) cham ber.
I lie pathological changes that develop in the situation o f reduced barometric
pressure are caused by two etiological factors: a) low partial oxygen pressure (pO,)
.14
( Iw ip lc i <’ 1*н<li<>K 4*iili' IC JTecI o f E n v i r o n m e n t a l I ' a c t o r s
and pulse slow dow n, circulating blood volume decreases, as well as erythrocyte and
hem oglobin content (due to blood depositing), the brain vessels contract.
U n d er increased pressure oxygen acts toxically, but its toxic effect is realize*
later, at the stage o f decompensation. The condition o f tissue asphyxia develops. Ii
has the following explanation: tissues use oxygen that is physically dissolved in the
plasma, but not the one connected with hem oglobin (oxyhemoglobin). At increase!
pressure, the content o f oxygen dissolved in the blood increases. I f the quantity d
dissolved oxygen corresponds to the norm al consum ption o f oxygen by tissues, oxy
hem oglobin does not dissociate. In o th er words, hem oglobin becom es blocked hi
oxygen (hem oglobin is in the form o f oxyhem oglobin not only in the arterial but
also in the venous blood) and loses the ability to transport carbon dioxide ( C 0 2)
Since oxyhem oglobin is a stronger acid than the restored one, acidosis develops. I
U nder increased pressure, oxygen acts as a strong oxidizer causing oxidatior
o f lipids, proteins, nucleic acids. T he toxic effect o f high oxygen concentration ii
sim ilar to th at o f radiation. In both cases form ation o f free radicals and peroxide
with strong oxidative abilities causes affection o f D N A and tissue enzymes.
Sensitivity o f the organism to toxic action o f oxygen is determ ined by the levd
o f tissue antioxidants (tocopherols, glutathione, etc.). They can be used for th e treatj
m ent an d prophylaxis o f oxygen action on th e organism u n d er high pressure.
Table 2
Symptoms o f Nervous D isorder in M an Depending on Immersion Depth
To prevent the toxic effect o f oxygen and nitrogen, a gas m ixture with a lovJ
co n ten t o f oxygen an d nitrogen m ust be supplied into the underw ater breathin
apparatus. The optim al concentration o f oxygen in the inspired air is calculated fo
every im m ersion depth. For example, oxygen concentration in the gas m ixture ■
about 2 % while diving at 100 m depth. N itrogen is substituted with helium .
W hile returning from depth to the norm al atm ospheric conditions a new val
riety o f decompression syndrome is observed. An excessive quantity o f dissolved gal
is released through the blood and lungs (desaturation). D ecom pression m ust bJ
perform ed slowly. If it is not so (rapid ascent), the rate o f gas bubble formation!
exceeds the ability o f the lungs to release them . Bubbles o f air occlude blood veal
sels, press on cells and irritate receptors (gas embolism). C linical m anifestations ard
determ ined by bubble localization (subcutaneous em physem a, pain in the joints!
itch). In serious cases such m anifestations are possible impalrH«*nt and loss o f vi
36
C h a p te r Pathogenic Effect o f I'.nvlroiiiiii'iiiul Factors
tit » j* Mdl\ -1 m en tal disorders, loss o f conscio usn ess a n d o th e r sings o f brain and
( mhI ■им I Injury (even c o m a ). Placing the patient into a c o m p re ssio n c h a m b e r,
iftiM 14 ibhli", ,м c c o m pletely dissolved, p ro m p tly relieves th e se sym ptom s.
ELECTROTRAUMA
Etiology
Pathogenesis
Ни Ih II.ivmm)' events underlie the injury electrical en ergy tran sfo rm atio n into
it!(il i Ihmm n hi t null, m e c ha n ic al a n d che m ic a l).
I Im ми и \ ju .laii/es a to m s a n d m olecules, changes o rie n ta tio n o f particles an d
Ц Н м ) # iIn И iiiovement. T h u s electrical energy tran sfo rm s into the th e rm a l one
H pfftifi/ »/m /) Skin b u tn m ay occur.
I I и. ш р и м с and ho ne fractures are m anifestations ol the m echanical effect,
A i» • Hi. it i и mi o f electricity is called electrolysis (electrochemical effect). Posi
i Ihiitfi 'I ions пн id reaction) are c o n c e n tr a te d near c a th o d e , negatively charged
llltii mH Him и и n o n ) n e a r a n o d e . In biological m e d ia , electrolysis ciiusos ion
ИИЙЫНЬмМпм . Ii.mini's biological potentials a n d the state o f voltage d e p e n d e n t ion
17
1*1111 I. (tODOrttl I’ullmpliysiolony
Manifestations
H u i Im.mIImm
ia
Chapin Л I'ailioKcnic I^fToct o f Environmental Factors
i* M i«h«>*.rnsitivily o f the bone tissue is less than that o f the derm al epithe
Hum
t M иlii» r ir.it ivity o f the hem opoietic system is the highest.
A mmh who worked in a thick uniform in sum m er, m anifested body tem perature
о * •i■. pne.i tachycardia, dizziness, cram ps. T hen he lost consciousness. What
i** Hi. . .him ot this serious state?
\ I ......... heat pro duction .
H Im. tea I icd heat prod uctio n.
• lniritMflcd heat emission.
I * И н к aseil heat emission.
i il- a em ission equals heat production.
4 While clim bing a m ountain for several days at an altitude o f 3,500 m a m ountain-
clim ber had tachypnea, tachycardia, headache and dizziness. W hat are these
sym ptom s caused by?
A. D ecrease o f barom etric air pressure.
B. D ecrease o f the fractional pressure o f oxygen in the air.
C. Hypoventilation.
D. G as em bolism.
E. Decrease o f atm ospheric tem perature.
42
( Iwipin Гниющ ий- K ffi'd of MiivlronmonlHl Kmctors
A h »l* * i »I» inn i .iMiully to u c h e d a b a re d electricity cable with both han ds and
ihi .i VVIiiii was the* cause o f d e a th ?
а ч т и luadycardia.
И >ммi tin hycaidia.
* I il *i 11Lit It in ol the heart.
I • ‘ <niipli u heart blockade.
I i ti.li.H tam ponade.
(I I ni im.I ihI Ion disease tre a tm e n t a physician m ust know th e pathog en esis o f the
... ни . luiii al sy ndrom es discovered by m o d e rn scientific researches.
Pathogenesis o f hemorrhage syndrome is:
I l linim hni yle m a tu ra tio n in the b o n e m arrow is inhibited.
’ Им ability o f th ro m b o c y te s to aggregate is n o t im paired.
i l ii alii* *1у sis activity is not ch an ged .
I I|н л hi Ih . o f p ro coagu lan t p ro tein s in the liver is decreased.
is
43
( hapter 3
ROLE OF HEREDITY AND CONSTITUTION
IN PATHOLOGY
to g eth er with environm ental pathogenic factors, the genetic ones play a sig
nificant role in the developm ent o f diseases.
Hie diseases caused by genetic factors are called genetically determ ined. T heir
liansm ission to d escendants m ay be lim ited in case o f im paired reproductive
capacity o f the patient. I f diseases are tran sm itted to next generations, they are
ta ile d hereditary. A close n o tio n is congenital diseases. Such diseases declare
them selves right after birth. T hose diseases, w hich are caused by environm ental
lactors and have a clinical picture sim ilar to know n h ereditary diseases, are called
phenocopies.
M UTATION
( '«uses
I liological factors, which cause m utations, are term ed mutagens. They are di
vided into physical, chem ical and biological as well as exogenous and endogenous.
A m ong physical mutagens ionizing radiation is the strongest. It dam ages the
fc n etic apparatus directly o r by radiolysis products. M utation m ay be caused by
io n i/in g radiation in such a m inim al dose, w hich does n o t cause radiation dis
ease.
I he most potent chem ical mutagens are the analogs o f purine and pyrim idine
ba-.cs Hie chem ical com pounds o f carbon (polycyclic arom atic hydrocarbons) and
m hogcii (nitrosam ines) refer to mutagens.
/liological mutagens are D N A - and R N A -containing viruses. They som etim es
behave as m utagens in patients with measles, chickenpox, m um ps, infectious m ono
nucleosis. Rubella infection in pregnant w om en is associated with congenital infan
tile m alform ations. The products o f the vital activity o f som e fungi (e.g. aflatoxin)
also belong to m utagens. Oncoviruses are the strongest biological mutagens.
Ix o genous m utagens can induce endogenous mutagens (a< live forms o f oxygen,
free tadu ills, nulioloxins, etc.). Such m utagens may be induced in disbolism.
( luipliT R o lf o f l lc m llty and C o n stitu tio n in Pathology
i i jh
r Ini п и т .не divided into useful and harm ful, spontaneous and induced. The
Hhim. и* \ 1*1 spontaneous m utations is low in com parison with th e induced ones.
Swimth im itations (in som atic cells) disappear from the population after the
|и i *!• iih and arc not transm itted from generation to generation. G erm m uta-
|И>н пи г- пн cells) affect heredity o f descendants.
I »r prill liny, on the degree o f destruction, m utations are divided into gene and
Н и н и н xniil ones.
tu mutation is a change o f the structure o f only one gene, nam ely, the spe-
I(ti. tuiiri 1 1 | purine and pyrim idine bases in the D N A m olecule (the so-called point
' -и 11 u snlts in a change o f the order o f am ino acids in the protein m olecule.
Ih* »....... i»l possible gene m utations is enorm ous (both in structural and regu-
|§H - i* n* s) In germ cells gene m utations m ay happen in any gene (dom inant,
f§*§ 0 1 sex-linked).
i htomosomal mutation is a m ore vast destruction o f the hereditary apparatus
liml * * hiiim t n i/ed by changes o f the chrom osom e structure (break, deletion, in-
H ttin n . hiinslocation and fragm entation) or quantity (increased or decreased). The
tfiMniM iii%. i hnnges o f chrom osom es result from nondisjunction o f hom ologous
i. |н и 111 *»%•111 h’s during gam etogenesis o r at the early stage o f zygote splitting.
Exonuclease
--------------------- /-Ч —
и 111,1" 0 -~ (г--------------------- 4. Further cleavage
I lvndonuclease
_____ - v — P°lymerase
Ik itM U i >11 ) N A ...........................................................5. Synthesis --------------------- VWWA
of normal DNA
I ximuelcase I Ligase
l||ii|lt i( ii --------- f - B m d i n g o l a n e w --------------------------------------
—--------------------------------- D N A liagm cnl
In : R epair o l u d a m a g ed D N A c h a in by repair e n z y m e s
I'in I I G eneral Pathophysiology
The im m une system has im portant defense m echanism s. A nom alous proteins
and m utant som atic cells m ay be elim inated by hum oral and cellular im m une reac
tions. B-lym phocytes produce im m une globulins for the elim ination o f anom alous
proteins and cytotoxic antibodies, which destroy m utant cells by cytolysis (with the
aid o f a com plem ent). T-killers can destroy m utant cells with the aid o f lym phok-
mes Phagocytosis participates in im m une response.
Mechanisms of Germ Cells Protection. It is unknow n w hether m utant germ
cells are controlled by the antioxidant system and im m une m echanism s. They may
lose the im pregnation ability. If im pregnated, m utant genes are inherited by M en
d el’s genetic laws, some o f w hich prevent clinical m anifestation or gene spread in
population.
Recessive m utant genes are expressed only in the hom ozygous state (the re
cessive type o f inheritance) and are n o t m anifested in the heterozygous one. In the
latter case the m utant gene carrier is clinically healthy (however, it is a conductor
o f m utant genes in population).
Sex-linked m utant genes are inherited depending on the sex o f the host. About
60 pathological signs are connected with the X -chrom osom e, and m ost o f them arc
recessive ones. It m eans th at w om en, carriers o f such gene, are healthy, becausc
a norm al X -chrom osom e com pensates the presence o f an X -chrom osom e with a
dam aged gene (X -chrom osom e pathology in m en is not com pensated).
Most physiological patterns (arterial pressure, blood glucose level, im m unolo
gical reactivity, etc.) are determ ined n o t by one, but several genes (the polygenic type
o f inheritance). M anifestation o f the m utant gene o f these gene systems depends on
tin- environm ent (the so-called multifactorial diseases).
Such phenom ena as penetrance (the probability o f th e phenotypic m anifesta
tion o f a m utant gene) and expressiveness (the degree o f clinical m anifestation) arc
an im portant m echanism o f protection. P enetrance never reaches 100 %.
I )o m inant m utant genes are transm itted directly from parents to th eir children
and are m anifested in the first generation (the dom inant type o f inheritance). But
in this case protection shows at the level o f population as natural selection. The
carriers o f chrom osom al anom alies and dangerous dom inant genes do not survive
(because o f problem s in the em bryo) o r lose reproductive capacity.
In addition, it should be added that m any m utations o f germ cells have no con
sequences. C hildbirth is not so frequent during life. In spite o f m utation frequency
increase with age, the reproductive function is depressed and reproductive cells arc
rarely im pregnated.
Etiology
PATHOGENESIS
NlmlHMih ul Disorders
( Vllular Disorders
At the cellular level, hereditary diseases are m anifested by changes in cell func
tion an d form (sickle, spheroidal and target-like erythrocytes, which are typical of
lieieditary hem olytic anem ia). M embranopathy is a genetic defect o f the cellular
m em brane. As a variant o f m em branopathy it is a pathology o f membrane recep
tors l.rythrocytopathy is also a variety o f m em branopathy (spectrin deficiency in the
erythrocyte m em brane results in the im pairm ent o f m em brane elasticity, and eryth-
rocytcs are deform ed as in hem olytic m icrospherocytic anem ia). Trombocytopathy
is .1 genetically determ ined throm bocyte dysfunction. Lymphopathy is a genetically
determ ined disorder o f lym phocyte m aturation and functional activity w hich leads
to Immunopathy (immunodeficiency).
At the level o f the whole organism the pathogenesis o f hereditary diseases de
pends on the nature o f disbolism and the type, structure and function o f im paired
cells Som etim es the genetic defect limits the reproductive ability. T he carrier o f the
most dangerous m utation dies in the wom b (as an em bryo).
M any patients with hereditary pathology survive and lepm duee posterity. Il
leads to m utant gene accum ulation at the level o f population
C hapter ' Holt* o f Heredity and C onstituition in Pathology
Itomlfitint Disorders
^ • sf~. 1*
Fig. 3. Polydactylia crinopathy), agammaglobulinei
(im m unodeficiency), glyct
storage disease, galactosem ia, phenylketonuria, and m uscular dystrophy.
Polygenic Disorders
in к к о п а к у p k i c d i s p o s i t i o n
|H
h i huktHllltf)
Щ $ Р Hi- n .\ 0 \H\ ol Ih e s e diseases depends on the interaction o f genetic and
HpiiidMm tii'ii iiilhii i h rs Bv changing living conditions and avoiding risk factors it
р р м ы * ь» ни h( the developm ent o f m ultifactorial diseases.
:i iм»иtм- . «мi,11 mm.ii mu dam ages a greater part o f the genetic apparatus and
итт. i и ui-, disorder than gene m utation. C hrom osom al aberrations may
Ц ШшHimI I hit ,il-. deletion, inversion, translocation, fragm entation) and quanti
Ш я i* ml' *'| iioiulisjunclion o f hom ologous chrom osom es).
ItiH i p.iih иг ап- оПсп stciile and therefore do not transfer the disease to de
I h« iHiMrnt' parents are healthy.
hut I ( hihdiI hilhophvslologv
Etiology
Etiological factors are m utagens o f physical, chem ical and biological origin.
T he peculiarities o f chrom osom al disease etiology are the following:
• An etiological factor affects parents, but disease develops in a descendant.
• l)e novo a chrom osom al m utation in a germ cell takes place in a healthy adultj
person, and if this cell is not im pregnated, m utation has no consequences.
• fam ily predisposition to chrom osom e nondisjunction has been revealed.
• The disorders o f gam etogenesis and chrom osom e nondisjunction are m ore fre-]
quent in elderly people, but their germ cells are im pregnated less frequently.
Pathogenesis
T he initial pathogenetic link is chrom osom al m utation in the sex cell o f one
parent. The vitality o f this cell is seriously im paired. It usually dies o r loses im preg
nation ability. If it is im pregnated, the em bryo could die. C hrom osom al anom alies
cause 40 % o f spontaneous abortions and about 6 % o f stillbirths. If chrom osom al)
im balance is com patible with life, the host is seriously ill or dies in the immediate]
postnatal period. Som atic and m ental developm ent is deranged, the reproductive'
ability is lost. After the d eath o f such a patient the m utation disappears from popu
lation. If the reproductive function is preserved (in 3—5 % cases), posterity inherits]
the chrom osom al anom aly.
52
C h u p tc t ' Hole of llc m lily and C onstitution in ГиНиИоку
M utation in the 23rd (sex) pair o f chrom osom es affects the carrier’s viability
К л I o f all. T he quantitative changes o f this pair o f chrom osom es frequently d o not
Iи« w in ch ild ’s life. Clinical syndrom es are well described. T he patients have very
■nous physical and m ental disorders. T he karyotype 45,YO is lethal.
Hi-low we give som e exam ples o f chrom osom al diseases, w hen the carrier sur-
v Iv c n ,
Multi X Syndrome
In m ulti-X syndrom e a female has the 4 7 ,XXX karyotype. M ost patients are
•i. olutely norm al. Som etim es triple-X fem ales do not have any evident clinical
inninlestations and som e o f them have children. But m ore frequently, this syn
t o n i c declares itself through hypogonadism , am enorrhea or o th er m enstrual ir-
*» Mul.irities. Affected w om en have two or m ore B arr’s bodies (sex chrom atin) in the
Hituiilc cells.
M int'filter's Syndrome
ho m i \ Syndrome
Очи n \ Syndrome
i .и i и-is o f trisom ia 21 are the most viable am ong all carriers o f autosom al tri-
...... in I lie lotal num ber o f chrom osom es equals to 47, XY, 21+. There is a variety
wiili If» » hrom osom es if one 2 Iм chrom osom e is fused via its centrom ere with an-
Milii i .и m ccntric chrom osom e. This abnorm al chrom osom e is called R obertsonian
n.»i,.i<it ill Ion and can som etim es be inherited.
In th r typical form o f the disease m en are sterile, w om en may have children.
Им h u m * o! the dom inant type o f inheritance, 50 % o f children are healthy, but half
•«I i In in have the sam e disease.
Part I G eneral Pathophysiology
The disease is m anifested by developm ent delay, grow th inhibition and m ental
ictardation, prem ature aging, neuralgic disorders, cataract, increased purine synthe
sis, am yloidosis, on co p rotein production, a high frequency o f leukem ia, activation
ol free-radical oxidation. The visible signs are characteristic facial and dysm or
phic features such as brachycephaly, epicanthal folds, small ears, transverse palm ar
creases. Inhibition o f vertical grow th is m oderate, and m ost adults with D ow n’s
syndrom e are shorter th an the m ajority other people. In contrast to this, patients
with D ow n’s syndrom e gain m ore weight com pared to other population, and most;
adults with D ow n’s syndrom e are overweight. A pproxim ately 50 % o f affected chil-j
dren have congenital heart diseases th at declare them selves in the early perinatal
period because o f cardiorespiratory problems.
Im m une problem s are typical in the form o f im m unodeficiency. Laboratory
abnorm alities can be detected in both hum oral and cellular im m unity. A ntithyroid:
antibodies predispose to disturbance o f gam etogenesis and nondisjunction o f the
21 1 pair o f chrom osom es. C onsequently, the hypofunction o f the thyroid gland is
a risk factor. Increased susceptibility to infections is a com m on clinical feature at!
all ages.
There is a considerable range in the degree o f m ental retardation in adults w ith
D ow n’s syndrom e, and m any affected individuals can live sem i-independently.
W om en older than 35—39 years and m en older th a n 55 years have a higher risk
o f giving birth to a child with D ow n’s syndrom e.
CONGENITAL D ISEASES
Congenital disease is such a disease, which manifests itself right after birth.
C ongenital diseases are som etim es connected w ith genetic apparatus p ath o
logy.
C ongenital diseases m ay result from pathological pregnancies, intrauterine in-l
loci ion. Examples o f such congenital diseases are toxoplasm osis and congenital !
syphilis. They are not genetically determ ined and, naturally, are n o t inherited.
I he diseases caused by environm ental factors w ith a clinical picture sim ilar to
known hereditary diseases are called phenocopies.
If hereditary diseases declare them selves im m ediately after birth (polydactylia),
(hey are also term ed congenital.
GENETIC EXAMINATION
Significance
I о provide appropriate treatm ent one should know the cause o f a disease. Th
role o f genetic and environm ental factors must be established.
M any acqu ired diseases arc clinically sim ilar to the hereditary ones. F o r e x
am ple, hyp othy ro id ism , w h ich is caused by iodine deficiency in the e n v iro n m e n t, is
clinically sim ilar to the genetically d e te rm in e d lack o f thyroid h o im o n e , but treat
men! and prognoses arc different (p h e n o c o p ie s are not i n h n i l r d )
| hiiplei t Hole of H eredity and C o n stitu tio n in Pathology
Q u a n t i t a t i v e changes of c h r o m o s o m e s
в s '* * "
li ft H ii Si К П П O & q fr
№
и а и и ия м дt 6-12
4-5
1
h и и и u u и
6 7 8 9 10 11 12
А* М Ai XX ЛХ II
ш ш
П -15 16 17 18 ~1зУ)5
II АД ЯД
16 17 18
20 21 22 XXXYY Ш
19-20 21-22 XXX
=4
ill I I ( H'ticnil I'silliopliysioluKy
Ictliods
M cl hot Is o f genetic exam ination are num erous and are constantly improved.
Statistical m ethod consists in the com parison o f disease incidence in a family
ltd hum an p opulation (according to m edical statistics). This m ethod m akes it pos-
hlc | о establish the genetic n atu re o f a fam ily disease. I f the type o f inheritance is
nown (from literature), a physician m ay prognosticate morbidity.
Genealogical method reveals the type o f inheritance. It enables a physician to
i.tblish the probability o f disease repetition in the following generations.
biochem ical m ethod d etects enzym opathy (for exam ple, phenylketonuria) even
i a new born baby. F o r ex am ination it is enough to take the urine o r a drop o f
lood.
Morphological (cytological) method is investigation o f the p atien t’s karyotype,
nine diseases are karyotype-dletectable. C hrom osom es are visible under the light
ticroscope in the m ultiplying cells (at the stage o f m etaphase). It is possible to
hscrve quantitative and stru ctural m utations o f chrom osom es (fig. 4).
S ex Chromatin (B a rr’s Body) Analysis. Sex chrom atin is a spiral X -chrom o-
>me present in the interphase nuclei if there are two o f them in the chrom o-
imc set. N aturally, healthy w om en have sex chrom atin. If a cell contains several
chrom osom es, the quantity o f Barr’s bodies equals the quantity o f X -chrom o-
jtncs m inus one. B arr’s bodies can be easily detected in the oral m ucosa cells.
Genetic analysis uses co n tem porary m ethods o f m olecule D N A study.
th e twin m ethod (exam ination o f identical and fraternal twins) gives a possibili-
/ lo distinguish the role o f heredity and environm ent (table 3).
We 3
Disease Incidence of Another Twin in a Pair of Twins
Disease Incidence
Disease of Another Twin, %
In Identical Twins In Fraternal Twins
1uherculosis 66.7 23
tlincy, imbecility, debility 97 37
Manic depressive psychosis 96 19
Schizophrenia 69 10
piicpsy 56 10
»uthcies mellitus 65 18
L’ongcnitiil pylorostenosis 67 3
H i Up 33 5
Uilemic goiter 71 70
By tlu* n i c l l t o d o f u ltra so u n d m o r p h o l o g i c a l d e f e c t s o h m e m b r y n ( m i c r o c e p h a
tydrocephaly) may be detected.
( hiiplri 1 Mnlr of Heredity and C onstitution in Pathology
especially harmful in childhood. Beyond doubt, social and hygienic factors, such
as everyday conditions, food habits etc. have a great significance. T he teaching o f
constitution confirm s the law that the course o f any disease, its prognosis and trea t
ment depend not only on the character and severity o f the pathogenic factor, but
a ls o on the individual peculiarities o f the patient.
( '(institution Classification
a b
I ig. 6. K r e tsc h m e r ’s c la s sific a tio n o f c o n stitu tio n a l ty p es
</ asthenic, b — athletic, с — picnic
son, a hyposthenic one suffers from arterial hypotension, reduced intestinal absorp
tion, and elevated m etabolism . P atients o f th e hypersthenic type have the following
peculiarities: a higher level o f arterial pressure, slow m etabolic processes, reduced
carbohydrate to lerance, predisposition to ischem ic heart disease, m yocardial in
farction, obesity and diabetes mellitus.
William Sheldon based his classification on the developm ent o f the ectoderm ,
endoderm and m esoderm .
0 .0 . Bohomolets studied the role o f the connective tissue in the structural and
functional peculiarities o f the hum an body. H e presented a point o f view th at the
connective tissue unites the organism as a whole and form s the basis for constitu
tion. H ence, he based his classification on the peculiarities o f the active m esenchy-
ma. The scholar differentiated the following types — asthenic, fibrous, lipom atous,
and pastose. The asthenic type is characterized by predom inantly thin and tender
connective tissue. The fibrous type has denser connective tissue. T he lipomatous
type has ab u n d an t adipose tissue; the m esenchym al elem ents are predisposed to
latty infiltration and lipoid decom position (atherosclerosis). The pastose type has
edem atous connective tissue.
1.P. Pavlov considered that it is the nervous system, w hich unites the organism
■is a whole and ensures its reactivity and balance with th e environm ent. The charac
teristics o f higher nervous activity (force o f excitation and inhibition, th eir mobility
and balance) were taken as the basis o f classification. These types are sim ilar to
H ippocrates’ ones. The strong, mobile and unbalanced type (with the prevalence of
excitem ent) is choleric; the strong , mobile and balanced type is sanguine; the strong
hut slow type (inertia o f the m ain nervous processes) is phlegm atic; the weak type
(weakness o f both nervous excitem ent and inhibition with a relative prevalence of
Inhibition) is m elancholic.
G erm an hom eopathist Hahnemann classified patient types depending on their
sensitivity to m edicines. This idea is quite practical and underlies the use o f small
doses o f m edicines.
Studying the constitutional types m akes it evident that only som e people can
he referred to pure types, and most o f them are mixed ones.
Г hi I ( k i u t u I Pathophysiology
Significance o f Constitution
Diathesis
I he child looks norm al or pastose. Inflam m atory processes develop easily with
exudate form ation and a tendency to a hyperergic course. The following atopic
leatures o f im m unological reactivity are revealed — a tendency to excessive IgE and
IgC i production, increased kinin system activity. T he im m ediate (anaphylactic) type
ol allergy develops easily, sensitivity to serotonin and histam ine is increased. T heir
are eosinophils in the blood. Clinical m anifestations include bronchial asthm a,
hives, Q uincke’s edem a, croup, and anaphylactic shock.
I ymphohypoplastic Diathesis
>'■ , и» <1 On the o th er hand, there is hypoplasia o f t l he adrenal, thyroid and sexual
11 Hi.i . early exhaustion o f the reparative properties . o f the m esenchym a. Som atic
h i «I mental infantilism , pastosity, paleness, and weaWkly developed m uscles charac-
I» и . siu'h a child. Angina and pharyngitis arise frequiiently. Adrenal gland dysfunc
п««и i iv.ociated with a decreased resistance to stress s. Sudden death may be caused
In in insignificant reason.
ihmk a/ some points fo r comparison and fill in a c o m p a riso n table o f the common
(Viihttes and differences between molecular genethic and chromosomal diseases
Гимн nl C o m p a r is o n M olecular G enetic D i s e a s e s C hrom osom al Diseases
i'.n l I ( ioili‘m l I ’iilhopliysioloKv
I ?. A wom an with signs o f m ental retardation gave birth to a child (girl). A genet i*
pathology and its possible transm ission is supposed. W hat concepts must gui<U»
a physician? How m ust the child be exam ined?
Such diseases are sex-linked:
1. D ow n’s syndrom e.
2. Enzym opathy.
If the karyotype is examined, such characteristics
are typical o f certain syndromes:
3. A patient with K linefelter’s syndrom e is a girl.
4. A patient with T u rn er’s syndrom e is a boy.
5. I he am ount o f chrom osom es in a patient with D ow n’s syndrom e is 45,
6. T he am ount o f chrom osom es in a patient with T u rn er’s syndrom e is 45,
7. D ow n’s syndrom e - XO.
8. Turner's syndrom e - XXX.
Sex chrom atin (B arr's body) is absent in pat n u ts with Turner's л и-
drom e.
10 A patient with uuilti X syndrom e has no \« s <hiom ittln (B a n ’s body).
i hapter 4
OUCiANISM REACTIVITY AND RESISTANCE
C O N C E PT O F REACTIVITY
I Ih* course o f any disease depends not only on the force o f the etiological fac-
i■и hnl also on organism reactivity. In practical m edicine, the notion o f reactivity
h. ip in evaluate the adaptive potentialities o f the organism.
Reactivity is an ability o f the organism to change its activity and develop reac-
iions (mainly adaptive) in response to normal and pathogenic influences.
Reactivity m echanism s m anifest them selves at different levels o f biological or-
iniii/ation:
• Molecular (enzym e-substrate reaction, reaction o f hem oglobin to gas com po
sition in the blood, transform ation o f biologically active substances, etc.).
■ Cellular (phagocytosis, reaction o f B- and T -lym phocytes to antigens, mast
cell degranulation).
• Tissue (connective tissue reaction in inflam m ation).
• Organ (activation o f heart pulsation in response to overload).
• Physiological systems (arterial blood pressure rise in response to pain, hy
poxia, etc.).
• Organism as a whole.
• Population (form ation o f passive im m unity in children during the first year
o f life by transm ission o f im m une antibodies from m others to new borns via
the placenta and breast milk).
I he following systems significantly contribute to reactivity — genetic (constitu-
M*hi), nervous (central and vegetative), endocrine, connective tissue (which forms
biological barriers and provides im m une m echanism s).
Reactivity depends on sex and age. Low reactivity is typical o f early childhood
•in. hi underdevelopm ent o f the nervous, endocrine and im m une systems, im per-
I* • i к mi o f the external and internal barriers. T he highest reactivity is noted in adults,
lliiiiln.tlly descending to the old age.
D erangem ent o f reactivity is an im portant link in the pathogenesis o f every
•It • • . Reactivity disorder reduces the adaptive capacity o f the organism . At the
мин nine, any pathological process changes organism reactivity.
Types o f Reactivity
Reactivity is divided into prim ary (specific or biological) and secondary (ac-
(I under pathological influences o f the environm ent or developed in the
ими e oi a disease), group and individual. In addition, it is subdivided into norm al
inmmrrgy), increased (hyperergy), decreased (hypoergy) and qualitatively changed.
Physiological reactivity em braces reactions o f a healthy organism under favorable
In 11 ih conditions. Pathological reactivity m anifests itself uiulei the effect o f pat ho-
Pill! I (icm -nil I’alliophvsiolo^y
nenic factors (reactivity o f a sick person). The latter can manifest itself through
uncom m on reactions (allergy, shock).
Depending on its m echanism s, reactivity m ay be divided into nonspecific and
tpcclflc.
Nonspecific reactivity em braces reactions, which are not strictly dependent
>n a certain etiological factor and m ay occur in a variety o f conditions. All the
lelense reactions m entioned above (changes o f heat production and em ission in
»sponse to low and high am bient tem perature, vasodilatation, tachycardia and
typerventilation) relate to nonspecific reactivity. N onspecific defense reactions are
universal and econom ical. N onspecific organism reactions to infection (phagocy
o .i , form ation o f biologically active substances) should be also referred to this
m m o f reactivity
Specific reactivity em braces reactions, which are strictly dependent o n a certain
•liological factor. Only im m unological reactivity satisfies this requirem ent, when a
Id mite im m une antibody is form ed in response to a definite m icroorganism (an
ij'vn). Specific reactivity provides resistance to infection and form ation o f specific
m m unity. Specific defense reactions are m ore energy-dependent and are easily
lamagcd by unfavorable influences on the organism .
C O N C E P T O F R ESISTA N C E
M E C H A N IS M S O F REACTIVITY
Hiylo and ontogenesis dem onstrate th at organism reactivity form ation is con»
и* • iril with the level o f nervous and endocrine system developm ent.
I he functional state o f the central and autonom ic (vegetative) nervous systems
•l»in mines decreased reactivity in narcosis and shock. D ystrophy develops after
‘ » non o f the som atic and vegetative nerves.
II vpei function o f the thyroid gland stim ulates reactivity while hypofunction
м л и is it. Diabetes m ellitus is associated w ith reactivity decrease. A drenaline and
MMikotropin (adenohypophyseal horm one) prom ote adaptive reactions. Adrenal
• in lex horm ones also influence reactivity. Thus, glucocorticoids inhibit inflam m a-
i"i\ leactions, an d m ineralocorticoids stim ulate inflam m ation.
I ikrainian scientist O.O. B ohom olets developed the concept o f the physiologi-
• >1 system o f the connective tissue, which plays an im portant role in reactivity and
n i.i.mce. T ogether with support and plastic functions, it accom plishes the fol-
Ihwiiih ones — trophic, defense (form ation o f barriers, phagocytosis and im m une
inn hanism s), reparative.
I he connective tissue system includes: biological barriers, bone m arrow , lym-
phiu vies and lym ph nodes, m icro- and m acrophages (neutrophils, m onocytes, his-
Hih vU's o f the connective tissue), reticular cells o f the liver, spleen, kidneys, lungs.
In perform its functions the connective tissue uses non-specific (barriers, phagocy-
Im h) and specific (form ation o f im m une response) m echanism s.
I or connective tissue stim ulation 0 . 0 . Bohom olets offered to use a serum
M in i antireticular cytotoxic serum (ACS). It contains antibodies against co n n e c
t s tissue elem ents. This serum is produced by injecting elem ents o f the hum an
1 1 inflective tissue to anim als. A small dose o f ACS stim ulates functions o f the con-
Biological Barriers
llular hom eostasis and protcct organs from infection. I lie main structural ole
с ills o f internal barriers are the blood capillaries — endothelium , basal m em brane
id perivascular connective tissue.
Barrier perm eability may be changed under the influence o f m any factors,
ii leased perm eability is obtained under the effect o f ionizing radiation, acetyl-
inline, histam ine, kinins, hyaluronidase. T he opposite effect is produced by cate
lolam ines, salts o f calcium , vitam in PP. Barrier perm eability is changed undei
e m lluence o f different pathologic processes, such as traum a, inflam m ation, viral
loci ion. Barrier perm eability makes an organ m ore sensitive to infection, poisons
id intoxication.
I ach tissue has its own m edium and barrier. The com m on term for such bar
is is histo/icmatic.
I ach histohem atic barrier has its selective perm eability. In som e organs il
-.1lengthened by additional structures and receives a new nam e. These are the
ailed specialized barriers. It is a particular group o f barriers, w hich defend or
ins with weak local im m unity m echanism s (antibody form ation and phagocytosis),
нч lalized barriers arc hematoencephalic, hematoophthalmic, hematolabyrinthic, he
atotesticular, hematothyroid, and placenta.
The hem atoencephalic barrier (blood-brain barrier) has the m ost com plex or
m i/at ion. Besides the endothelium and basal m em brane, it has also argyroplnl
uilenal and astrocytes. M icroorganism s, toxins and antibodies do not penetrate
ito the brain under physiological conditions (the m orphology o f the hem atoen
•phalic barrier and its role in pathology are described o n p. 518 in chapter 31
’athophysiology o f nervous system»). As to m etabolites, horm ones and biological
active substances, the barrier acts selectively regulating the penetration o f these
laterials into the brain cells.
Hie placental barrier is vitally im portant for fetal developm ent as it protects
ie Ictus during pregnancy. Barrier perm eability im pairm ent harm fully influences
nbryonic developm ent and results in different types o f postnatal pathology.
Specialized barriers protect organs from infection and large m olecules, which
e circulating in the blood. But, on the o th er hand, these very organs are isolated
nin the im m une system in the em bryo, and physiological im m unological tolerance
> them (see below) is not form ed. Specialized barrier injury leads to autoim m une
egression against these organs.
Phagocytosis
IHwrders
- .— — - .........— .... **
I'illI I ( i H l f r u l l'ullio|»liysioloK >
Manifestations
70
C h a p te r 4. <)гци1|1м11 R eactivity and Resistance*
71
Г , III I ( iC IllM U l 1’|Н1ю|>||уч1о1оКУ
Itlood proteins
Fibroblast
proliferation
b p ith e lio c y te
o f the liver
Antibodies
Lym phokins
Fig. 7. I n t e r l e u k i n - 1 ( I L - 1 ) a n d its ta rg e ts
In the cen ter o f the figure th ere is a m acrophage, w hich produces IL-1 after
activation. IL-1 influences its targets: cells o f the bone m arrow , liver, hypothalam us,
lym phocytes, fibroblasts
It tS o f Plasma Origin
I his type o f BAS consists o f a com plem ent system and proteolytic enzymes,
which are found in the blood plasm a in the inactive form.
The complement system consists o f som e protein com ponents (denoted C l,
( ' СЧ, C5, C 6, C7, C8, C 9), which are in the blood serum in the inactive state
An activated com plem ent has a lot o f regulative and enzymal properties — proper
h e . of esterase and protease — activates phagocytosis and various BAS, provides
bacteric idal action o f the blood, destroys m icrobes by perforating their m em brane
I his system is activated (as a cascade) after the beginning o f im m une reaction (by
uitibodies and im m une com plexes) and takes part in infection elim ination. T he ae
:ive com plem ent destroys the im m une com plex and thus finish* antigen inactiva
Ion C om plem ent system disorder may be acquired and mh* h i * <1 Blockade o f the
n
C h a p t e r 4. O rg an ism R eactiv ity and R e sista n ce
vhi in -,is o f any com plem ent com ponent m ay be caused in pathology. Loss o f the
l> н I* in ulal action o f the blood, im m unity depression and developm ent o f serious
«И * r.rs arc the consequences.
\i tlvated //axeman factor stim ulates blood coagulation, activates the com ple-
mh hi s y s t e m and proteolytic blood enzymes.
I'hitcolytic blood enzymes are present in the blood in the form o f plasm inogen
м.. I l .1 111 к rei nogen. They are activated by o th er BAS (H agem an factor, com ple-
Hhini microbes and im m une com plexes. Kallikrein (activated kallikreinogen) is
...........in enzym e o f the kallikrein-kinin system. K inins are form ed from the blood
I'Imт . i protein (kininogen, which is a globulin).
I he kallikrein-kinin system is engaged in vasoactive substance (kinin) produ
IIhii *In»* to a cascade o f biochem ical reactions, w hich begins with H agem an factor
№ и v it ion (schem e 4). Bradykinin and kallidin refer to this system.
Ml m echanism s o f BAS form ation activate each other.
Scheme 4. System of Plasma Kinins
H agem an factor
T ripsin
K allikrein
F ibrinolysin
1
A ctivation o f
J
A ctivation o f A ctivation o f the
coagulation prekallikrein fibrinolytic system
I
Fibrin F ibrinolysin
Prekallikrein ► K allikrein
K ininase
I
Inactivated peptides
H is i fleet ( ontrol
I Reactivity and resistance are not synonym s. Analyze th eir relations filling the
table and finding proper examples for each situation
Situation Examples
1 T reactivity leads to T resistance A —hibernation
2. t reactivity leads to i resistance В —training in a pressure chamber
V 1 reactivity leads to T resistance С —sensibilization (allergy)
4. 1 reactivity leads to I resistance D —chronic diseases
1A
C liaptci I < >i ;■.1111 111 R e a c tiv ity a n d R e s is ta n c e
Pharm acologists propose different drugs for the treatm ent o f inflam m atory and
allergic diseases. This therapy is based on BAS inactivation. W hat knowledge
about BAS should guide pharm acologists?
Blood kallikrein-kinin system activation is accompanied by formation
o f such BAS:
1. histam ine,
2. serotonin,
3. prostaglandins,
4. bradykinin,
5. eicosanoids,
6. heparin,
7. leukotrienes.
The following BAS are o f cellular origin:
8. com plem ent,
9. proteolytic enzym es from neutrophil lysosomes.
Such BAS are released from tissue basophiles:
10. histam in,
11. heparin,
12. serotonin,
13. kinins,
14. kallidin.
( liaptcr 5
IMMUNOLOGICAL REACTIVITY AND ITS PATHOLOGY
76
С h a p t c r 5. Iiiiiiiiiii€il<>|jili‘iil R e a c tiv ity a n d I ts P a th o lo g y
and secrets. I hey can be absorbed by som e cells (m ast cells, epithelium ,
sm ooth muscles).
■ Г-lym phocytes provide cellular mechanisms o f immunity. They ruin patho
logical cells by lym phokines and perforin (elim inate b o d y ’s own m utant
cells and foreign cells), provide cooperation betw een all the cells o f the
im m une system.
* li lym phocytes do not distinguish body’s own proteins from the foreign
ones (are not tolerant to body’s own antigens).
• I lym phocytes distinguish body’s own proteins from the foreign ones (are
tolerant to body’s own antigens).
• Im m unoglobulin varieties are A, D , G , M , E (they are called im m une ant
1мн|)гч) T heir peculiarities are the following: IgE and IgG en ter tissues and m ay be
ih m bed by the som atic cells, IgG and IgM have precipitating properties, IgA arc
h! n id o ry type, IgD penetrate the placenta.
- Im m une response may be prim ary (after the first entry o f an antigen; the im
tmnir system m em orizes the results) and secondary. The latter is accom plished after
и | и иotl entrance o f the sam e antigen and proceeds m ore quickly and actively.
I lie m odern definition o f im m unological reactivity is the following.
hiiinuiiological reactivity is a com plex o f hum oral and cellular reac tio n s o f the
•<4 iiiKiii in response to antigens and specific to them .
So, the basic function o f im m unological reactivity is controlling the antigen
M.mposition o f the organism and m aintaining its antigen hom eostasis. B- and
\ hm phocytes (with the aid o f other systems) fulfil this function.
C lassification o f A ntigens
Antigens are m acrom olecular agents, m ainly o f protein nature. They are di-
■nl. t! mto infectious and noninfectious, natural and artificial, molecular and cellular,
complete and incomplete (haptens).
11tuler natural conditions antigens are m icroorganism s (bacteria, viruses, fungi).
I iиIt*i pathological conditions there w ork o th er types o f antigens (artificial, incom -
|il> i< non-protein, w hich will be discussed in chapter 6 while studying allergy).
In analyze im m unity m echanism s and im m une response disturbances it is
hii|M»ii;mt to keep in m ind that som e antigens (like cocci and m icrobial toxins) cir-
*ul ih in the blood, but others do not (viruses and fungi are located inside cells).
M E C H A N IS M S O F IM M U N E R E S P O N S E
77
Hurt I (id io m I I’iillmphvsioloKv
СVllular M echanisms
C ellular m echanism s o f im m unity are activated if the hum oral ones are not
siillieient. The type o f antigen also m atters. C ellular m echanism s have the following
characteristics.
• Antigens do not circulate in the blood.
• U nm oral antibodies (im m unoglobulins) are no t formed.
• C ellular m echanism s develop:
• for elim ination o f body’s own m utant cells;
• in case o f intracellular localization o f a foreign antigen (virus, m ycobacterium
o f tuberculosis, T reponem a pallidum in lues, brucella, histoplasma, etc.);
• as a response to incom plete antigen.
• M acrophages represent antigens to T-effectors, which transform into T-kill
ere.
• I killers react with antigens directly. Lym phocytes infiltrate the locus with
antigens. I killers destruct the cells by cytolysis with the aid o f lym phokines and
perforin.
• Phagocytosis and BAS are involved in im m une reactions.
• I helpers and T-suppressors take part in the process as well.
All variants o f im m une response are regulated. It m eans balancing the stimuli!
tlon and inhibition m echanism s. Its relevance m atter, in itniininologica! disorders,
which have a disregullitivc character (allergy).
( l u i p l c r S. lniiiiiiiioloK ic;il K e a c tiv ily a n d Its P a th o lo g y
Im m unity is divided into natural and artificial (form ed for the purpose of
piHphylaxis and treatm ent). In their turn, each type is subdivided into active and
t«i r.lve.
Natural active im m unity appears after an infectious disease.
Natural passive im m unity form s by antibody transm ission from a m other to her
bub\ with the m o th er’s milk and through the placenta.
Artificial active im m unity (active immunization) is form ed by injection o f vac-
\ in* , containing weak or dead m icroorganism s.
I'.ill I ( i n ie r a l I’lillioplivsloloKy
IM M U N O L O G IC A L TOLERA N CE
IM M U N O L O G IC A L REACTIVITY PATHOLOGY
Disorders o f the im m une system may manifest them selves as hyper/unction and
iypo/unction. As to the participation o f the gene m echanism s, im m unological reac
iv itv pathology is divided into acquired and hereditary
Classification o f im m unological reactivity pathology is given in schem e 5.
0
( liiiplci S. IiniiK iiiolo^ical K ra c tiv ity a n d U s P a th o lo g y
IM M U N O D E P R E S S IO N
1 1й40|ку
Nilm genesis
uI
Г.u I I <.m o r a l P iillin p liysloloi'v
M anifestations
IM M U N O D E F IC IE N C Y
G enetic defects may concern any stage o f the form ation and m aturation ol
И and Г lymphocytes. In m any cases im m unopathy is based on enzymopathy
(ien e and especially chrom osom al anom alies in the organism predispose to immu
nodefliciency and consequently to allergy (p. 89), neoplasia (p. 148) and leukemia
Ф 4.1) Hie pathogenesis and clinical m anifestations o f im m unodeficiency depend
on the type o f lymphocytes, whose function is im paired most o f all. There are three
forms ol immunodeficiency: B-lym phocytic, T-lym phocytic and the com bined type
It I viiiplioeytie Im m unodeficiency
H2
C h a p t e r 5. Im m u n o lo g ic a l Reactivity a n d Its P a th o lo g y
I I viuphocytic Immunodeficiency
( linical manifestations are severe. All the m echanism s o f im m unity are limited.
I и n the vaccines used for im m unization may provoke diseases and death. Predis-
|in ,iiinn to allergy and neoplasia is observed. C linical exam ples are W iskott-A ldrich
nvndrome, L ouis-B ar syndrom e (with skin telangiectasia) and Swiss-type agamma-
tti"hullnemia.
Phagocytosis, BAS, and com plem ent are functionally connected with the im
imme system. I heir disorders essentially decrease the effectiveness o f im m une rear
i m mi . imd, first o f all, resistance to infections.
Purl I <»enenil Pathophysiology
Phagocytosis disorders have been analyzed in every detail in ch ap ter 4 (p. 69),
Phagocytosis is supposed to be the main m echanism o f resistance to saprophytiJ
infections. So, all the reasons, which decrease the am o u n t o f leukocytes (ionizing
radiation, cell division inhibitors, etc.) or disturb their functions (genetic reasons,
neoplastic transform ation in leukem ia, intoxication, horm onal disorders, avitamm
osis), result in disorder o f im m unological reactivity.
All the BAS m entioned and analyzed in ch ap ter 4 (p. 70) influence the activ
ity o f im m unocytes, their division and m aturation. Im m unocytes perform then
functions with the aid o f m onokines, lym phokines, etc. So, genetic and acquired
problem s in the BAS system essentially im pair im m unological reactivity.
A special role in im m unological reactivity belongs to the com plem ent sys
tern, which is activated by antibodies and im m une com plexes. Active comple
m ent possesses a lot o f regulative and enzym atic properties. It has esterase nntl
protease properties, provides bactericidal action o f the blood, ruins the microbial
m em brane, com pletes antigen elim ination by im m une com plex proteolysis, activa
lion o f phagocytosis and o th er BAS. Some grave clinical situations (genetic anal
acquired) take place w hen the synthesis o f one o r an o th er com plem ent com ponent
(C l, C2, C3, C 5, C6, C7, C8 deficiency) is im paired. It leads to serious clinical
derangem ents: predisposition to m icrobial and viral infections, developm ent o f dift
fuse diseases o f the connective tissue (collagenoses), autoim m une diseases (chronii
glom erulonephritis, autoim m une joint dam age), repeated infections o f the respiru
lory system. Most o f them m anifest them selves in early childhood. It is a com m on
cause o f early death.
Not only decreased, but also pathologically increased com plem ent activity may
cause a disease. A deficiency o f com plem ent inhibitors underlies it. An example in
angioneurotic Q uincke’s edem a caused by genetic deficiency o f C l inhibitor, which
leads to pathological activation o f the com plem ent system.
Since many diseases proceed with or due to decreased im m unological reactivity
n is an actual problem o f m odern m edicine finding possibilities to effect it positive
!v l or this purpose the so-called im m unom odulators are devised by pharm acolo
j'is ts In this connection attention should be paid to a natural process, which works
.is ,i stim ulator o f im m unological reactivity. It goes about fever (will be described
m ch ap ter 9, p. 134).
Im m une system hypofunction, as well as im m unodepression and immunodefl*
i iencу have been discussed in this chapter. As to its hyperfunction, the next chaplcr
(«•Allergy») dwells on it.
84
( h a u le r \ I iiiiiiu iio Iok Ich I K v u ctlv ity am i Its P a th o lo g y
I \ girl, 8 years old, began to walk late. At 1 year she was ill w ith a serious
Ini m o f pneum onia. Later telangiectasia appeared on the skin and conjunctiva.
IgA are absent, the am ount o f T-lym phocytes is reduced. W hat type o f
im m unodeficiency is present?
A. DiGeorge.
H. W iskott-A ldrich.
< B ruton’s agam m aglobulinem ia.
I ). Swiss-type com bined.
I Louis-Bar.
I I Ini m onotherapy is necessary for autoim m une reaction depression after organ
11 nr,plantation. W hat horm ones are used in such a case?
A Som atotropin.
H M ineralocorticoids.
» Pharm acologists devise m edical drugs for the treatm ent o f im m unological
system disorders. W hat scientific knowledge should guide them ?
Lymphokines have the following properties:
1. T hey are released from T-lym phocytes after contacting an antigen.
2. T hey regulate the function o f all lym phocyte populations.
3. T hey do not influence granulocytes.
Antibodies are characterized by the following features:
4. They get into the organism from the outside.
5. T hey are form ed from album ins.
6. Antibodies are im m unoglobulins.
7. T hey provide the hum oral m echanism o f im m unity.
8. They freely circulate in the blood and organism liquids.
Immunoglobulins have the following types and properties:
9. lgE can be absorbed by tissue basophiles.
10. T here are 3 classes o f im m unoglobulins.
11. T hey inhibit com plem ent activity.
12. Im m unoglobulins can pass through the placenta and form active natural
im m unity in the newborn.
13. IgE can pass through the placenta.
( hapter 6
ALLERGY
Allergic diseases are an actual problem o f m edicine. They are widespread am ong
people, and there are m any reasons prom oting allergy expansion in population.
Allergy is a disorder o f immunological reactivity in the form o f increased and
i|iialilatively changed immune response, which dam ages the organism by immune
mechanisms.
A question arises, why in some cases im m une reactions result in health and
im m unity (im m unization), but in o th er cases the sam e im m une reactions result in
pathology in the form o f allergy (sensitization, o r allergization) and even death.
Why does allergy co n tin ue to expand in population?
C O M P A R IS O N O F IM M U N IT Y AND ALLERGY
IM M U N ITY
M J l ’RGY
The sam e im m unological reactions (hum oral and cellular) underlie allergy, but
*auses, conditions and final effects are entirely different.
I here are two principal ways o f allergy developm ent:
* In an initially healthy organism.
* In an organism with im m une system pathology.
I he cause o f this type o f allergy is located outside the organism and is d ete
mined by peculiarities o f the antigen (its origin, dose, frequency and interval o f
' lit IV).
«iit I (iciieral l^iihophyilology
I he role o f genetic factors in allergy developm ent has been confirm ed statist!-
Uy.
I lie structure and properties o f im m unocytes are genetically determ ined as
II a s the system o f BAS control. M ore often hereditary predisposition to allergy
delerm ined polygenetically.
I he following reasons and m echanism s are possible.
I In* m ost com m on cause o f allergy is T -lym phocytic o r com bined im m unodefi
ciency. In T-suppressive m echanism deficiency the function o f lym phocytes be
c o m e s unregulated and excessive. This deficiency m ay lead to the loss o f physio
logical im m unological tolerance and autoallergy developm ent.
Piedisposition to IgE form ation (w hich are cytophilic and fixed on the m ast
cells) may be genetically determ ined. A healthy organism has a m echanism
inhibiting IgE synthesis. This balance is genetically determ ined and m ay be dis-
u ranged. Г-suppressor deficiency and high IgE tite r are noted in m ost allergic
lisenses.
HAS inhibitor deficiency, which regulates pathochem ical events in allergy, may
>o genetically determ ined.
Deficiency o r excessive activity o f com plem ent underlie m any forms o f allergic
llieases.
)isorders o f the barrier function o f the respiratory and gastrointestinal tract m u
ons m em branes may be genetically determ ined and provide the entry o f foreign
m itcins (allergens) inside the organism .
• ЛИ chrom osom al syndrom es (see ch ap ter 5) are associated with serious distur
bances o f im m unological reactivity, predisposition to im m unodeficiency (p. 54)
and allergy.
• Diatheses are exam ples o f hereditary im m unological pathology.
ETIOLOGY
Etiological factors o f allergy are antigens (they got the nam e allergens) th a t lead
Iо sensitization (allergization) o f the organism instead o f im m unization.
ix ogenous Allergens
I ndogenous Allergens
A llerg e n s
E x o g en ous E ndogenous
P A T H O G E N E S IS
T Y PE S O F ALLERGY
ivi and parkinsonism if they arc blocking. A drenoreceptoi antibodies have been
Iso discovered.
M any allergic diseases are com bined as to their m echanism s.
W hen antigens are o f endogenous origin (autoantigens, autoallergens), we speak
bout autoallergy (autoimmune aggression).
In addition, allergy (sensibilization) is divided into active and passive.
ictive sensibilization develops under experim ental conditions after injecting an
Kens lo Ilie organism. Antibodies and im m une lym phocytes are form ed inside the
iganism.
Passive sensibilization develops under experim ental conditions after injectinr
nm unr antibodies o r sensibilized lym phocytes (injecting the blood plasma or lym
hold cc 1Is o f an actively sensitized d o n o r to an intact recipient).
STA G ES O F ALLERGY
nsiti/ed lym phocytes and is finished by form ation o f im m une com plexes a fte r a
pealed entry o f the allergen.
2. P u llio c h cm ica l stage consists o f BAS form ation.
I. P ath o p h y sio lo g ic a l stage appears as m orphological and functional distni
m vs, which underlie clinical m anifestations.
Various types o f allergy have special features o f pathogenesis.
IM M E D IA T E ALLERGY
Anaphylactic Allergy
н м iи)1 1 . c) insufficient control over BAS form ation and destruction. H istam ine,
in p.nin, and serotonin are released from mast cell granules and stim ulate eico-
tiMHHtl form ation (prostaglandins, leukotrienes, SRS) from m em brane lipids. T hen,
•I» n i ascade, all systems o f BAS form ation are activated — the kallikrein-kinin
м ...„I system (form ation o f bradykinin and other BAS), proteolytic blood enzym es
HiY|eanogen, profibrinolysin) and com plem ent (schem e 7).
I I - physiological system o f BAS inhibition and destruction does not work in
k
•Ii* situation. BAS involve the entire organism and initiate the next stage o f al-
Ьчцу.
/ *athophysiological stage is m anifested by local and general (system ic) chang-
• Vasodilatation, local reddening, skin eruption, itch, burning, pain are local
m anifestations representing an acute inflam m ation. Acute and chronic local allergic
f<l> ms arc a result o f increased perm eability o f vessels. Since eosinophils are a rich
мни c o f BAS inhibitors (histam inase, arylsulfatase as eicosanoid annihilation en-
fvme) I heir increased co u n t is observed in allergic diseases (eosinophilic leukocytosis,
I* U)4).
( icneral m anifestations o f allergy are m ore dangerous. Spasms o f the sm ooth
ишsi Ies o f the internal organs are clinically m anifested by bronchospasm (cough,
• 4 "' 't‘>ry breathlessness), spasm o f the gastrointestinal tract m uscles (spasm odic
p un m the abdom en, nausea, vom iting, diarrhea), spasm o f the uterus in w om en.
NpiHtic phenom ena are aggravated by edem a o f the m ucous, which covers the inter-
Vi h>me 7. Formation of BAS in Allergic Reactions
SRS
u i I (io itm il I’jHliophysioloKy
.«I organs. Larynx edem a manifests itself as asphyxia. Hem ostasis disorder consists
i sim ultaneous activation o f coagulation, anticoagulation and fibrinolysis. C lini-
illy il is m anifested by hypocoagulation in the aorta and large arteries (hemorrhage
ndrome), and hypercoagulation (thrombosis) in the capillaries. A rterial blood pres-
irc decrease, loss o f consciousness are the gravest m anifestations o f allergy. There
•v e lo p s shock, which is called anaphylactic.
m ini D isease
Scrum disease is a clinical exam ple o f anaphylactic allergy. This disease arises
hen an im m une serum containing antibodies against a certain infectious agent is
»ed lor passive im m unization o f a patient (see artificial passive immunity on p. 80).
iw ether with a therapeutic or preventive effect, the serum itself sensitizes a patient,
ul a repeated injection o f the same serum is very dangerous; it m ust be injected
small repeated doses (specific desensitization, p. 99). If it is injected w ithout pre-
ninary desensitization, acute renal insufficiency with anuria develops due to renal
ter dam age by im m une com plexes (p. 472).
A nother clinical exam ple o f anaphylactic allergy is the so-called pollinosis
.ilients suffer from itch and burning sensation in the eyes, lacrim ation, nasal
scharge).
C ytotoxic Allergy
( ytotoxic reactions refer to im m ediate allergy. They are called cytotoxic be-
use antibodies cause lysis o f cells.
Immunological Stage. T he pathogenic effect o f chem ical substances (usually
dicines, e.g. pyram idone), viruses and m icrobes plays a role. These etiological
tors m ay change body’s own antigen structure o f cellular m em branes. A ntibodies
formed against foreign o r body’s own cells (if they acquire autoallergen proper-
s). Antibodies belong to IgG and IgM and are called cytotoxic.
Pathochemical Stage. It em braces BAS activation. The m ain m ediators arc
m plcm ent and activated enzymes. BAS activate phagocytosis and N-killers.
Pathophysiological Stage. Cell lysis is provided by activated com plem ent and
k i l l e r s together with phagocytosis o f the cells covered with antibodies.
( finical Manifestations. A clinical exam ple is hem olysis o f d o n o r’s erythrocytes
e i m ism atched hem otransfusion (including rhesus incom patibility). The eryth-
v i e s undergo im m ediate cytolysis. A nother exam ple is autoim m une aggression
inisi body’s own blood cells (erythrocytes, leukocytes or throm bocytes) if th eir
linen properties are changed after dam age by m icrobes or m edicines (hemolytic
rmiu, leukopenia and thrombocytopenia). Cytotoxic im m une sera are widely used
experim ents for selective dam age o f certain cells and pathology m odeling. If cy-
ohic antibodies are form ed against the dam aged basal m em brane ol renal glom e-
rs, it causes acute glomerulonephritis.
C hap ter 6. Allergy
Im m une com plex diseases develop if im m une com plexes form insoluble m i
croprecipitates.
Immunological Stage. M any dissolved allergens (exogenous and endogenous,
com plete and incom plete) after binding with antibodies form insoluble im m une
com plexes in the form o f m icroprecipitates. Here belong drugs (penicillin, sulfa-
nilam ides), vaccines, food products (m ilk, eggs), inhaled allergens (dom estic dust,
fungi). In such cases IgG and IgM (with precipitate properties) are produced. Im
m une com plexes form m icroprecipitates in the tissues or in the blood and attach to
the basal m em branes.
Pathochemical Stage. U nder the effect o f im m une com plexes the following
m ediators are form ed — com plem ent, lysosomal factors o f leukocytes, kinins, su-
peroxide radicals.
Pathophysiological Stage. Im m une com plexes are usually attached to the basal
m em branes o f vessels. M icrocirculation is dam aged by BAS. An inflam m ation with
alteration, exudation and proliferation develops. Phagocytosis is activated. Leuko
cytic infiltration results in allergic productive inflam m ation. Throm bosis occurs in
the vessels. Inflam m ation m ay lead to ulceration and hem orrhages.
Clinical manifestations depend on the place o f im m une com plex fixation and
the kind o f the dam aged tissue. If im m une com plexes are fixed in the vessels,
hem orrhagic vasculitis develops. In case o f th eir localization in the kidneys (basal
mem branes o f glom erules), acute glom erulonephritis develops (80 % o f all form s o f
glom erulonephritis). Allergic derm atitis is an exam ple o f im m une com plex allergy
on the skin. If m icroprecipitates are located in the lungs, alveolitis arises. Some
autoallergic diseases (rheum atoid arthritis, system ic lupus erythem atosus) as well as
dom estic and food allergies are o f this type. In case o f massive com plem ent activa
tion anaphylactic shock and bronchial asthma may develop.
DELAYED ALLERGY
Delayed allergy develops in response to antigens, which are cells (foreign trans
plant o r dam aged body’s ow n cells). These reactions are realized n o t by hum oral
antibodies, but by cellular im m une reactions.
( ontact Dermatitis
C o n tact derm atitis also belongs to the delayed type o f allergy. It is a result ol
dei ina dam age after contacting everyday, industrial, m edical and other substances,
which play the role o f hapten and form com plex antigens w ith derm a proteins
M acrophages represent (by IL-1) the dam aged cells to T -helpers, which involve
I killers into skin damage.
AUTOALLERGY
Etiology
I very protein, cell and tissue o f the organism may serve as an antigen (autoan
liy.ens, autoallergens) and may becom e an object o f autoim m une aggression.
Pathogenesis
• I )rugs may play the role o f haptens and form com plex antigens with b o d y ’s
own proteins. A utoantibodies belong to IgG and IgM and dam age cells by cy-
inly.is I killers are involved into cell dam age. T he factors o f physical nature
и old, high tem perature, ionizing radiation) are capable o f changing pro p er antigen
.mu lilies by disclosure o f hidden and form ation o f new antigenic determ inants.
\< iivated com plem ent, phagocytic enzym es and superoxide radicals are the m ain
m ed iators.
• I )amage o f specialized biological barriers creates a situation, w hen the tissues,
which arc located beyond, becom e an object o f autoim m une aggression (this situ a
t i o n was discussed on p. 68).
M anifestations
A utoim m une diseases m anifest them selves depending on the protein or cells
dam aged by im m une aggression. An inflam m ation o f the native tissues develops
under an effect o f BAS.
A utoim m une aggression may concern any tissue, but most o f all the connective
и Iи* (basal m em branes, blood cells and joints). As clinical exam ples, glom erulone-
i»i11 ms, autoim m une version o f hem olytic anem ia, leukopenia and throm bocytope-
iii.i, allergic vasculitis, and rheum atoid arthritis m ust be noted. Im m unocom petent
i i- мu s ( I -lym phocytes, im m unoglobulins, lym ph nodes and b one m arrow) m ay
I- an object o f autoim m une aggression as well. F orm ation o f antibodies against
j*anmia globulin in patients with rheum atoid arthritis m ay also be m entioned as an
- чample. A utoim m une thyroiditis is an exam ple o f such pathology. C ardiopathy in
H iМЧlow’s disease is caused by anti-cardiac autoantibodies. D iabetes m ellitus o f the
in .1 type is referred to autoim m une diseases.
Л large group o f dem yelinating nervous system diseases (p. 521) are a u to
im mune (dissem inated sclerosis am ong them ). In postvaccinal and postinfectious
- if ■phalom yelitis im m unoglobulin, cellular and im m une com plex autoim m une re-
......... to C N S antigens (m yelin in particular) have been revealed. They are pro-
'••Ь «I by viral and bacterial infections in predisposed (to allergy) patients.
I hr pathogenesis o f m any autoim m unopathies is underlain by receptor d am -
4 " t receptor diseases have been m entioned on p. 91 — som e forms o f hyper- and
IN F E C T IO U S-A L L E R G IC D ISE A SE
Etiology
Exogenous etiological factors are m icrobes with antigen determ inants sim ilar
> hum an. There are a lot o f such exam ples (som e m icrobes and connective tis-
u*. streptococcus and sarcolem m a o f cardiom yocytes, album ins o f cow ’s m ilk and
isylin, etc.). Due to parallel evolution, m any m icrobes have obtained m olecular
m ilarity with m olecules o f m acroorganism s.
More often this situation occurs if a-hem olytic streptococcus is the etiological
ii to r Its polysaccharide antigens are sim ilar to glycoproteids o f the connective tis-
le, cardiac valves, and basal m em branes (o f nephrons). Viruses may cause allergy
. well Fungi, which are present in the inhaled air, are widespread allergens. Vac-
nes (dead or attenuated m icroorganism s) may also be an initial factor.
P atho g en esis
M anifestations
Such allergic diseases appear as a com plication o f the infectious ones. Clinical
m anifestations depend on the type o f tissue, w hich gets dam aged by autoim m une
aggression.
R heum atoid carditis, rheum atoid vasculitis and glom erulonephritis m ay arise as
a com plication o f p u rulent tonsillitis and scarlet fever caused by hem olytic strepto
coccus. A utoim m une dam age o f the nervous system (both central and peripheral)
may develop in predisposed to allergy patients as a com plication o f viral infections
and vaccination (postvaccinal and postinfectious encephalom yelitis).
P R IN C IP L E S O F P R E V E N T IO N AND T R E A T M E N T O F ALLERGY. D E S E N S IT IZ A T IO N
The knowledge o f allergy etiology and pathogenesis provides the base for its
prevention and therapy.
Etiological therapy (prophylaxis) is prevention o f potential allergen entrance
into the organism.
Pathogenetic therapy is directed tow ard im m unological o r pathochem ical
m echanism s o f allergy. H orm onotherapy (injection o f im m unodepressants, gluco
corticoids — hydrocortisone and prednisolone) blocks antibody and BAS form a
tion and is used for (auto)im m une reaction depression. G lucocorticoids have an
anti-inflam m atory effect stim ulating lipocortin production in tissues - it suppresses
the activity o f phospholipase A ^ therefore prostaglandins and leukotrienes are not
formed.
BAS inhibitors are used to alleviate pathochem ical reactions (antihistam ine
drugs).
If a disease appears to be o f the infectious-allergic type and is accom panied by
inllam m ation, together with antibacterial drugs im m unodepressants are used.
Desensitization is divided into specific and nonspecific.
Specific desensitization is carried out w ith the aid o f the sam e allergen, which
has caused sensitization. F or this purpose the allergen is introduced in small fre-
<|uent doses. The effect is achieved by form ation o f sm aller portions o f im m une
*omplexes. U n d er these conditions the pow er o f BAS inhibitors proves to be suf
ficient to alleviate pathochem ical and pathophysiological m anifestations. If after a
prophylactic injection o f an im m une serum its repeated injection is necessary, the
serum might be introduced by fractional sm all doses. T he same approach is used as
a sensitivity test before any serum usage.
Nonspecific desensitization is achieved by m edicines, w hich m inim ize the influ
ence o f BAS.
Symptomatic therapy consists in the usage o f m edicines, which decrease such
sym ptom s as spasm, pain, itch, edem a.
Г.ill I (ic n c rill I'lltllophysloloK.y
PSEU DOALLERGY
I here are m any diseases with clinical sym ptom s sim ilar to the allergic ones
irtklening o f the skin, eruption, itch, dyspnea and the state sim ilar to anaphylactic
•.hock However, there are no im m unological m echanism s, which underlie any true
allergy,
Such diseases m ay be caused by the following external factors - cosm etic and
everyday substances, detergents, industrial products (rubber, glue, plastic, wood),
Inod (m ilk, eggs, berries, tom atoes, citrus fruits), pollen and m edicines.
Som etim es such m orbid co n d itio n s are interpreted as allergy, but it is true
only in the cases, w hen im m unological events are detected - participation o f T
lym phocytes, form ation o f antibodies, an increased level o f IgE, a decreased level
o f co m p lem en t, a possibility o f specific desensitization. V irtually, the m entioned
substances may behave as allergens (haptens) w ith com plex antigen form ation
with organism proteins. But in th e cases, w hen im m unological events are absent,
и is not an allergy. Such diseases m ust be interpreted as individual intolerance
to a substance (it is not a synonym o f allergy). T he term pseudoallergy»is suitable
and may be used.
U nderstanding o f this problem is im portant for the treatm ent and prophylaxis
ol Mich diseases. N one o f the m ethods m entioned above is effective — neither im
m unodepression nor specific desensitization by fractional repeated doses o f the
•..une substance. A single m easure is avoidance o f the substance causing the morbid
condition and sym ptom atic therapy.
Pseudoallergy has the following m echanism s o f pathogenesis.
• I hese substances m ay dam age tissues and activate the sam e BAS, w hich are
form ed in true allergy. They are called histamine liberators (cause degranulation
of mast cells). T he clinical m anifestations are sim ilar to the allergic ones.
* 11 factors, which cause a disease, are foodstuffs (m ore often these are exotic prod
nets), enzym opathy m ay underlie individual intolerance.
• II m edicines cause a disease, it is necessary to take into consideration that drug
m etabolism is individual and genetically determ ined. T he products o f drug me
labolism may be a reason for BAS form ation.
* Some patients have such derm al m ast cells, w hich are easily dam aged by natu
tal environm ental factors (sun rays, cold, clothes friction). Local sym ptom s are
sim ilar to allergic inflam m ation.
1 Give the characteristics o f the 1st stage o f the im m ediate type o f allergy.
1. It is a pathochem ical stage.
2. It is a stage o f BAS form ation.
3. Sensibilization o f the organism is form ed during this stage.
4. O ne antibody m olecule is form ed on one m olecule o f the antigen.
5. This stage begins after the second dose o f the antigen.
6. It is finished after im m une com plex (antigen+ antibody) form ation.
7. Sensibilization o f the organism may be active only.
8. Sensibilization consists in distribution o f hum oral antibodies in the organ
ism and th eir fixation on tissue basophils and other som atic cells.
9. The period o f antibody form ation is 3—5 days.
10. The period o f sensitization form ation is 1—2 weeks.
i I here are m any autoim m une (autoallergic) diseases. They are based on the loss
o f physiological im m unological tolerance and form ation o f antibodies against
body’s own tissues.
ini I ( . r m r a l I'lHliuplivM oloKv
' Before antitetanic serum injection a high sensitivity o f the patent to this serum
was discovered. W hat substance is used for specific desensibilization?
A. An allowed dose o f antitetanic serum .
B. G lucocorticoids.
С\ Small doses o f antitetanic serum.
I). A ntihistam ine drugs.
I Im m unodepressants.
() A patient had leukopenia after treatm ent with pyram idon. Antileukocytic
antibodies have been found. W hat type o f allergic response according to
( oom bs and G ell’s classification takes place in such a case?
A. Anaphylactic.
И Cytotoxic.
C. Stim ulating.
I) D elayed-type hypersensitivity.
I Im m une complex.
7, А И year old patient used eye drops with penicillin In a couple o f mi nut e*
skin Itch, edem a o f the lips and eyelids, cough appeared, arterial pressure began
to decrease What type o f im m unoglobulins lake pan m the developm ent <»|
this allergic response?
C h a p t e r ft. ЛПсгку
8. A 14-year-old girl with congenital heart and thyroid gland defects suffers from
viral and fungal diseases. Im m unological investigation revealed T -lym phocytes
decrease. W hat disease o f the im m une system arises in such a case?
A. C om bined im m unodeficiency.
B. B ru to n ’s agam m aglobulinem ia.
C. Hypoplasia o f the thym us gland.
D. T u rn er’s syndrom e.
E. Inherited com plem ent deficiency.
9. A 7-year-old boy, like his grandfather, suffers from pneum onias and purulent
skin diseases. Significant decrease o f B-lym phocytes num ber has been revealed.
W hat type o f im m unological pathology takes place?
A. Inherited deficiency o f the com plem ent system.
B. H ypoplasia o f the thym us gland.
C. C om bined im m unodeficiency.
D. T u rn er’s syndrom e.
E. B ruton’s agam m aglobulinem ia.
10. An injection o f a large dose o f antibodies against the basal m em brane o f the
renal glom eruli o f an experim ental anim al leads to acute glom erulonephritis
developm ent. W hat type o f allergic response according to C oom bs and C e ll’s
classification provokes this pathology?
A. Anaphylactic.
B. Cytotoxic.
C. Im m une com plex.
D. D elayed-type hypersensitivity.
E. Stim ulating.
11. A patient with proteinuria, hem aturia, edem as and arterial hypertension was di
agnosed with acute glom erulonephritis. W hat type o f allergic response accord
ing to C oom bs and G ell’s classification is the cause o f a glom erulonephritis in
80 % o f cases?
A. A naphylactic.
B. Cytotoxic.
C. Im m une com plex.
D. D elayed-type hypersensitivity.
E. Stim ulating.
Pan I (intend Г)1 (||0 |)||уч|0 |»К.У
12 Allergic diseases are widespread am ong people .md Ihen num ber is constanllv
increasing. A physician must know that there h illeiHie predisposition, which
is determ ined genetically.
1. Allergic predisposition is inherited as a dom inate type.
2. Allergic predisposition is inherited as a polygenetic type.
The mechanisms o f allergic predisposition m ay he the following:
3 I im m unodeficiency.
4. Increased perm eability o f the m ucous m em branes for foreign proteins.
5. Surplus o f T-suppressors.
6 I suppressors deficit.
7. Predisposition to IgE production.
К Deficiency o f BAS inhibitors production.
9. Adrenal cortex hyperfunction and surplus o f glucocorticoids production.
I V I very physician m eets in his m edical practice a lot o f patients with allergic
diseases. W hat are the m ethods o f th eir prevention and treatm ent?
1. Isolation o f the organism from potential allergens is the best prophylactic
measure.
Use o f remedies with the following effect:
2. BAS inactivators, w hich block the first stage o f allergy.
3. Im m unodepressants, w hich block th e second stage o f allergy.
4. Drugs with antihistam inic effect.
5. Stim ulators o f T -lym phocyte production (im m unom odulators).
Glucocorticoids, which are commonly used to treat such patients,
have the following effects:
6. Inhibition o f antibody production.
7. Protection o f target cells from the effect o f BAS.
I I C om pare im m unity and allergy. Find points o f com parison reflecting com m on
features and differences. C om pile a com parison table.
1.
2.
Differences
3.
TYPICAL PATHOLOGICAL PROCESSES
Typical pathological processes are those, w hich have com m on features and
laws o f developm ent regardless o f the localization, nature o f th e causative factor
and organism evolutionary organization. T he following processes refer to them
inicrocirculation disorders, inflam m ation, fever, neoplasia, hypoxia, and starvation
i\s well as typical pathology o f m etabolism .
( hapter 7
PATHOPHYSIOLOGY OF PERIPHERAL BLOOD
CIRCULATION
ARTERIAL H Y PE R E M IA
Significance
V E N O U S H Y PE R E M IA
Etiology
Etiological factors o f venous hyperem ia are those, w hich narrow the lum en or
decrease the tonus o f veins. T hey m ay be exogenous and endogenous. They are:
• obstruction o f veins with a throm bus or an em bolus;
• com pression o f veins by a tum or, enlarged internal organ (for exam ple, uterus),
exudate in the region o f inflam m ation;
• com pression o f veins by exudative pleuritis, hem othorax, pneum osclerosis, em
physem a;
• cardiac left- o r right-ventricular failure;
• professional overloading (m aintaining vertical position for a long tim e);
• genetic predisposition to venous congestion (weakness o f the venous elastic ap
paratus, low to n u s o f the sm ooth m uscle elem ents o f the vascular wall).
Pathogenesis
closely related to edem a developm ent. Therefore, congestion and edem a com m only
o ccur together (venous edema). C ongestion leads to introvascular throm bosis.
Prolonged venous congestion results in the excessive growth o f the connective
tissue, which substitutes the parenchym a (so-called cirrhosis).
M anifestations
Significance
In most cases venous hyperem ia has a negative effect. It leads to tissue dis-
holism and causes atrophic and dystrophic changes. Organ functioning is disordered
due to hypoxia, dystrophy, and cirrhosis.
However, during inflam m ation venous hyperem ia is o f great significance pro
viding leukocyte em igration (see ch ap ter 8 «Inflam m ation», p. 125).
ISC H E M IA
Ischem ia is divided into com pressive, obstructive and angiospastic. Every type
ol im henna lias its own etiology and pathogenesis.
C h a p te r 7 . P athophysiology o f P e rip h era l Blood C ircu la tio n
Etiology
Various agents can cause ischem ia. Angiospastic ischem ia develops as a re
sult o f stim ulation o f the vasoconstrictor apparatus o f vessels o r their reflex spasm
caused by: a) physical factors (cold, m echanical and o th er injuries); b) chemical
agents; c) biological factors (bacterial toxins); d) emotional factors (fear, pain, rage)
and pathologic reflexes.
The duration and consequences o f ischem ia depend on such conditions, which
can m odify the effect o f etiological factors: a) tim e o f harm ful effect; b) type of
ischem ia; c) localization; d) condition o f collateral circulation; e) functional state
o f the organ or tissue.
Pathogenesis
M anifestations
Significance
Stasis is deceleration or com plete stop o f blood flow in capillaries, small arteries
and veins.
I he following types o f stasis are distinguished: true (capillary), ischemic (co m
plete stop o f blood inflow), and venous.
True Stasis
Thrombosis is lifetime formation o f a m ass containing blood elem ents (cells and
coagulated proteins) on the internal surface o f vessels.
T he final mass is term ed thrombus.
D epending on the com ponents, throm bi can be white (form ed o f platelets,
leukocytes and a sm all am ount o f plasm a proteins), red (contain erythrocytes), and
mixed (have alternating white and red layers).
Etiology
Pathogenesis
Significance
E M B O L IS M
I niholisni is formalion and carrying along the blood How o f a mass, which is not
typical of normal hlood com position.
112
C h a p te r 7. P a t h o p h y s i o l o g y o f P e r i p h e r a l B lood C i r c u l a t i o n
This mass is called embolus. The blood carries it to a site distant from its point
o f origin.
An em bolus m ay be solid, liquid o r gaseous.
A bout 99 % o f all em boli originate from throm bi. Indeed, throm bosis and em
holism are closely interrelated (throm boem bolism ).
Rare forms o f em boli are: a) foreign bodies such as bullets; b) droplets o f fat
(in case o f bone fracture); c) bits o f tum or; d) fragm ents o f bones or bone m arrow:
e) bubbles o f air (gas em bolism in caisson disease, p. 36), nitrogen or an o th er gas.
Inevitably, em boli get stuck in vessels too small to perm it th eir further passage.
It results in com plete vessel occlusion. Emboli m ay slow dow n and stop anywhere
within the cardiovascular system producing different clinical effects.
Significance. Em bolism always has a negative effect. T oday throm boem bolism
and infarctions constitute the m ain clinical problem s. Throm boem bolism o f the
pulm onary artery (the clinical picture: dyspnea, acute pain in th e chest, cyanosis,
swelling o f the cervical veins) is a frequent cause o f death in hospitalized patients.
Heart disease (m yocardial infarction, rheum atic heart disease, arrhythm ia) increase
the risk o f em bolism.
I A 38-year-old m an com plains o f pain in the heart, which arises after negative
em otions. A d o cto r diagnosed ischem ic illness (stenocardia). What m echanism
o f ischem ia is the most probable?
P a ri I. ( t e n e r u l P a t h o p h y s i o l o g y
Л. A ngiospastic.
B. Obturative.
C. Compressive.
I). M echanical.
E. Occlusive.
2. Л p atient with a closed fracture o f the hum eral bone had a plaster bandage
applied. The next day the hand swelled, becam e cyanotic and cold. W hat kind
o f pathology o f peripheral circulation took place?
A. G as em bolism.
B. Air em bolism.
C. Ischemia.
D. Venous hyperem ia.
E. Arterial hyperem ia.
After exercising a patient with throm bophlebitis o f the lower extrem ities has
dyspnea, acute pain in the chest, cyanosis, swelling o f the cervical veins. W hat
kind o f circulation pathology took place?
A. Throm boem bolism o f the m esenteric vessels.
B. T hrom boem bolism o f the coronary vessels.
C. T hrom boem bolism o f the brain vessels.
1). Throm boem bolism o f the pulm onary artery.
E. Throm boem bolism o f the v. porta.
5. A small N aC l crystal was placed near the m esenteric vein o f a frog during an
experim ent. This operation leaded to the form ation o f a blood clot. W hat is the
initial point in throm bogenesis?
A. Blood flow deceleration.
B. Activation o f coagulation.
( ’. A ctivation o f throm bocyte adhesion.
I). D am age o f the vascular wall.
I D ecreased activity o f anticoagulants.
(>. I inbolism o f the small circle o f circulation occurred «Пег a fem ur fracture.
What kind o f em bolism took place?
A. I at.
И I h m m bonnbolism
С h iip lc i / P a t h o p h ysio lo g y o f P e r i p h e r a l Hlood C i r c u l a t i o n
C. Cellular.
D. Gas.
E. Air.
20. ( ilobal warm ing prom otes exacerbation o f som e diseases. W hen air tem perature
was 34°C, a 42-year-old healthy patient had a heat stroke. His body tem pera
ture is 39°C, consciousness is dim m ed, the face is red, respiration is labored.
T he reason is arterial hyperem ia o f the brain. Give th e characteristics o f arterial
hyperem ia, which developed in this case.
1. The term hyperem ia m eans increased blood volum e in the affected tissue
o r organ.
2. Arterial hyperem ia o f the brain developed due to increased arterial in
flow.
3. As to pathogenesis, it is working.
4. It is characterized by local hypotherm ia.
5. It is always accom panied with organ swelling.
6. Pulsation is unpleasant subjective sensation.
7. It is always accom panied with brain edem a.
8. Arterial hyperem ia is especially useful for the brain.
The microscopic picture is characterized by:
9. Hlood flow acceleration.
10. Opening o f inactive capillaries.
I A 4 V year old patient suffers from ischem ic heart disease' I |e has severe attacks
of heart pain, Give the characteristics o f p atien t’s pathology
C h a p te r 7. P a th o p h y s io lo g y o f P e r ip h e r a l Itlo o d C ir c u la tio n
22. In a 58-year-old patient with obesity (body weight 105 kg), atherosclerosis of
vessels and arterial hypertension, m yocardial infarction developed. Throm bosis
o f the coronary vessels was a causative factor. Explain the reasons and m echa
nism s o f p atien t’s state developm ent.
1. Throm bosis is a lifetime form ation o f a mass containing blood elem ents
(cells and coagulated proteins) on the internal surface o f the vessels.
2. The etiological factors o f throm bosis m ay be endogenous and never exo
genous.
3. Infarction is the term inal stage o f throm bosis.
4. T he plasm atic stage is the first.
5. T he cellular stage is the second.
6. A therosclerosis predisposes to throm bosis.
7. Obesity increases predisposition to throm bosis, and arterial hypertension
prevents it because arterial pressure increase accelerates blood flow.
8. Obesity increases predisposition to throm bosis because heparin inhibits
lipolysis.
9. Throm bosis in this case has a defensive character.
Tin(I points o f comparison and compile a comparison table o f common features and
differences between arterial and venous hyperemia
4 )in ts o f C o m p a r is o n A rteria l H yperem ia Venous H yperem ia
С hapter 8
INFLAM M ATION
In llam m atio n is the most widespread pathological process. Inflam m atory diseases
arc the largest group o f diseases (gastritis, myocarditis, tonsillitis, hepatitis, etc.).
Inflam m ation is a typical pathological process, which is characterized by a com
plex o f m orphological, biochemical and functional changes, a reaction o f microcircu-
lation and conn ective tissue in response to tissue damage.
C elsus a n d G alenus described the local signs o f inflam m ation in ancient times.
Inflam m ation is a predom inantly local process, but the whole organism becom es
Involved.
I.oral signs o f inflam m ation are the following (fig. 10):
• Tumor (swelling).
• Rubor (redness).
• Calor (h e at).
• Do lor (p ain ).
• Funrtio teasa (functional disorder).
System ic signs o f inflam m ation are fever, leukocytosis, stim ulation o f the bone
m arrow , im m unological reactivity, hepatic function (synthesis o f new proteins),
la*ling sick (h ead ach e, insom nia, loss o f appetite and working capacity).
Tii• Id C ardinal sings o f Inllam m ation according («* < <bn uul Clnlcnus
C h a p t e r 8. In fla m m a tio n
ETIO LO G Y
Etiological factors o f inflam m ation are called flogogens. They are exogenous
and endogenous.
Exogenous flogogens are divided into physical (m echanical and therm al traum as,
electrical injury, ionizing and ultraviolet radiation), chemical (acids, alkalis, chem i
cal poisons) and biological (bacteria, viruses, fungi).
Endogenous flogogens are form ed in the organism as a result o f o th er diseases
(throm bosis, em bolism , allergy, form ation o f biliary and urinary calculi). Im m une
com plexes are the m ost potent endogenous flogogens and cause allergic inflam m a
tion.
P A T H O G E N E SIS
Stages o f Inflammation
Inflammatory Cells
In the focus o f inflam m ation it is possible to see a lot o f cells. Some o f them
• migrate from the blood (neutrophils, m onocytes, eosinophils, throm bocytes and
P u rl I (il'IU 'IJll Pillho|lllVslol<>Ky
lym phocytes), som e o f them have a local origin (tissue basophiles or m ast cells,
tissue m acrophages, fibroblasts). So, inflam m atory c ells are o f histiogenic and he
m atogenic origin. They perform im portant functions in the focus o f inflam m ation.
Hie defensive function is the most im portant one (phagocytosis, BAS form ation).
I lie most im portant role belongs to neutrophils and m onocytes (table 4). At the
same tim e, they are the factors o f secondary alteration.
ТаЫе 4
In fla m m a to ry C e lls
Neutrophils get into the focus o f inflam m ation from the blood and move to
he cen ter o f inflam m ation. Phagocytosis is th eir m ain function. M any neutrophils
lie liberating active hydrolytic enzym es from lysosomes. These enzym es are so n u
nc m us (about 60 — protease, amylase, lipase, phosphatase, collagenase, elastase,
IN A ase, DNAase, m yeloperoxidase, lactoferrin, lysosomal) th at neutrophils are
netaphoricaliy called a «mobile laboratory». BAS from neutrophils play an im -
lorianl role in the purification o f the inflam ed focus and at the .same tim e they
re harmful factors. Like o ther BAS, they can activate all o th er systems o f BAS
Munition.
Monocytes are a source o f a large quantity o f BAS (com plem ent, collagenase,
lastase, m onokines, interferon, transferrin, prostaglandins, throm boxane, leuko
icucs). One o f them is interleukin-1, which is liberated .il the very beginning of
illum ination It produces many effects (see fig. 7 on p. 7)), скрегinlly in the acute
Chapter 8. Inflammation
phase of inflammation. All systems, which are responsible for inflammation, are
sensitive to interleukin-1. The bone marrow is activated, an additional quantity
of’ leukocytes appears in the blood. Many cells have interleukin-1 receptors and
are its target — hepatocytes, fibroblasts, endotheliocytes, synoviocytes, nerve cells.
Ilepatocytes synthesize new proteins, including ceruloplasmin, S-reactive protein,
and fibrinogen. The synthesis of albumins and globulins for the blood is activated,
fibroblasts provide proliferation by collagen synthesis. Interleukin-1 influences
(he endothelium of capillaries and provides leukocyte adhesion. Endotheliocytes
form prostaglandins and coagulation factors. Collagenase production is increased
m chondrocytes (cartilage destruction and pain in the joints are noted). Proteolysis
is activated in the muscles (pain in the muscles). One of IL-1 effects is influence
on the hypothalamus and fever development. Loss of appetite, disturbance of the
central nervous system also refer to IL-1 effects.
, ,
Mast cells eosinophils thrombocytes and lymphocytes participate in inflamma
tion and are a source of BAS. From cellular membrane prostaglandins are formed.
I hey cause numerous and various manifestations of inflammation.
The BAS, which play a role in inflammation, are called mediators o f inflam m a
tion. They provide all the manifestations of inflammation (beginning from alteration
up to proliferation and reparation). All biologically active substances are common
for the normal reactivity (see pp. 70—73 and scheme 4 on p. 73) as well as for the
mechanisms of immunity, allergy and inflammation. However, there are some dif-
lerences. Lymphocytes play the main role in immunological reactions (p. 76), mast
cells — in allergy. As to inflammation, neutrophilic granulocytes and monocytes, as
phagocytes, are the main source of BAS together with other cells, which participate
in inflammation.
The BAS, which are formed in the first place, activate, as a cascade, all systems
of BAS formation, which are responsible for secondary alteration, microcirculation
disturbance, vascular permeability increase, edema, leukocyte migration, phagocy
tosis, proliferation. BAS involve the whole organism into inflammation, stimulate
the bone marrow, activate protein synthesis in the liver, increase body tempera
lure. There are no phenomena in inflammation, to which BAS would not have a
relation. Antipyretic medicines (e.g. aspirin) are directed against BAS, especially
prostaglandins. Table 5 gives all kinds of BAS, their origin and effects in the focus
of inflammation.
Local vascular reaction begins immediately after flogogen action and leads I о
I he development of the second stage of inflammation.
Cohnheim discovered the dynamics of local vascular reactions. It is easy to
observe it on the frog mesentery after its damage (fig. 12).
Local vascular reaction proceeds in four stages:
I. Short term spasm of arterial vessels.
*lUl I (•Climil Ги11|0|>1ил1о||>Ц)
labl* 5
Inflammation Mcdiaton»
2. Arterial hyperemia.
У Venous hyperemia.
4. Stasis.
I lu* named four forms of microcirculation disorder correspond to those de-
nhcd in chapter 7 «Pathophysiology of Peripheral Blood Circulation». However,
u*\ have some peculiarities. In particular, all of them have features of defense.
Arterial Hyperemia
Venous Hyperemia
Venous hyperemia inevitably follows the arterial one. The bloodstream decelera
tes, and leukocytes occupy the boundary position near the vascular wall. It means that
chemotactic substances, which are formed in the center of inflammation, influence
the leukocytes located in the bloodstream. Adhesive proteins, which are formed in the
endothelium, make the surface of endotheliocytes and leukocytes more sticky.
Stasis
Stasis (stop of blood flow in the capillaries) provides leukocyte release from
vessels into the center of inflammation. Vascular permeability to plasma proteins
and leukocytes considerably rises. Without blood flow deceleration, boundary posi
tion of leukocytes and permeability increase, the leukocyte emigration and further
phagocytosis are impossible.
I hiring the third stage the center of inflammation becomes free from microor
ganisms, necrotized tissues, foreign and toxic substances.
In the damaged tissue proliferation (multiplication) of the viable cells begins
I lie degree of reparation depends on regeneration ability. The cells of the cornice
live tissue, epidermis, and mucosal epithelium have the best regenerative ability
I he cells of the liver and kidneys possess smaller regeneration capability. The cells
ol the muscular and nerve tissues possess weak regeneration capability.
II ihe quantity of viable cells in the parenchyma is Insignificant, an organ is
restored by the connective tissue, f ibroblasts mulliplv and produce collagen, which
forms a scai m the /one of inlliuniuatioii
Chapter 8. Inflammation
Forms of Inflammation
D ISO R D ER OF M ET A B O LISM
Ilya Mechnikov, a great scientist and Nobel Prize winner, studied inflamma
ii"ii in animals of different organization. He revealed that inflammation develops in
Hi« process of evolution and has more simple forms. Frogs (heterothermal animals)
il« nionsirate vascular reactions and phagocytosis during inflammation, but do not
hrtvi .my increase of local and general temperature. Investigating inflammation in
M ilr.li (an invertebrate without the vascular system), Mechnikov discovered the
pin nomcnon of phagocytosis without vascular reactions. So, Mechnikov made a
•п т In мои that phagocytosis is the earliest and most principal event in inllammation
htH I. (ii'iicrul Pathophysiology
It is known that duration of any pathological process depends not only on the
lorce of the etiological factor, but also on organism reactivity. This law refers to in
flammation as well. Children and newborns demonstrate a violent (badly regulated)
and sometimes dangerous course of inflammation. Elderly persons have inactive
inflammation.
Depending on individual reactivity, inflammation may be divided into normer-
Hie (proceeds optimally), hypoergic (weak), and hyperergic (excessive).
Reactivity decrease (hypothermia, narcosis, effect of immunodepresants, ad
vanced age) diminishes manifestations of inflammation, which may take on a
chronic form without essential fever.
Allergic inflammation has some grave forms - acute erosive, acute exudative,
acute edematous, chronic productive (rheumatism).
С Local acidosis.
I) Influence of chcmotactic substances.
I Decrease of hydrostatic pressure in vessels.
A patient suffers from pleuritis. Pleural cavity puncture showed exudate. What
is the initial mechanism of exudation?
A. Increase of vessel permeability.
B. Increase of blood pressure.
C. Hypoproteinemia.
I ). Aggregation of erythrocytes.
I Decrease of oncotic pressure in tissues.
In some hours after burn in the site of hyperemia and edema a focus of necrosis
appeared. What is the main mechanism, which intensified destructive processes
in the focus of inflammation?
A. Emigration of lymphocytes.
B. Primary alteration.
С\ Secondary alteration.
I) I migration ofcrythrocytes.
I Proliferation of fibroblasts.
Chapter 9
FEVER
There are several terms close in meaning, which define the phenomenon of
increased body temperature. However, the cause, pathogenesis and significance are
completely different in each case.
Hyperthermia is the most common term for body temperature rise.
Overheating is a rise of body temperature due to a high ambient temperature
(this process was studied earlier, described on p. 22, pay special attention to defen
sive changes in thermoregulation).
Fever (from Latin febris) has a special place. It formed in the process of evolu
tion as an organism reaction to infection. The present chapter deals with this very
phenomenon.
Fever is a typical pathological process characterized by thermoregulation reorga
nization and an increase of body temperature in response to pyrogens.
Under clinical conditions (in an infected patient) it is impossible to assess fe
ver and distinguish it from infectious intoxication. One gets a mistaken impression
that a patient suffers from elevation of body temperature and wants to bring the
temperature down. Only under experimental conditions it is possible to model pure
fever and study it.
There are several methods of experimental modeling of pure fever, for example,
by injecting pure pyrogens. Hypothalamus perfusion with blood of different tempera
ture allows achieving an increase of body temperature of any degree. Such experi
ments made it possible to get information about fever etiology and pathogenesis.
ETIOLOGY
PA TH O G ENESIS
Changes in Hypothalamus
132 .. » i
____________________________________________________________________ Chapter 9. Fever
After the fixed point reaches an adequate level, the hypothalamus sends regula
tory impulses to proper organs, and additional heat is formed for body warming.
Stages of Fever
IU
Г.ill I (iciicml I'iilhoiiiivsioloKv
.14
Chapter 9. F e w
ORGAN CHANGES
In the course of infectious fever clinical symptoms are numerous, but there is
no strict correlation between them and the fever degree. The symptoms depend on
infectious intoxication, pyrogen effect and IL-1.
Experiments with pure pyrogens show changes in the organs, connected with
body temperature increase. They are milder than in infectious diseases and have
mainly protective value.
Stim ulation o f immunological reactivity (see above).
Blood circulation is activated. Pulse is accelerated (as a result of the local
warming of the cardiac pacemaker and activated sympathetic nervous influences).
Systolic and cardiac output increase. Arterial blood pressure (at the first stage) may
rise. Vasoconstriction is characteristic of the first stage, and vasodilatation of the
\eeond and third ones. If body temperature is reduced critically (at the third stage),
collapse may develop with vasodilatation in the background. Loss of water and hy
povolemia may develop. Significant changes of systemic blood circulation, which
are observed in infectious diseases result from intoxication, not fever.
Рим I, (li’IUTIll I’ullinphvsloloHv
Fig. 16. Curves of body temperature, pulse and respiration in febris conti
nua (croupous pneumonia)
I’ll 11 I ( | 1‘|10Г в 1 l * i ll ll O | » li y s l o l o ^ V
ilghci fever than it is adequate for a certain infection. If a child endures fever badly,
mdy temperature must be brought down. There are many antipyretic medicines,
'lit the truth is that physicians sometimes abuse them, clumping normal reactivity
uto a decreased one.
138
C h a p te r Fever
I'ig. 18. Dynamics of body temperature and pulse curves in a recurrent typhus patient
Artificial fever can be used to treat some diseases because of its ability to stimu
late immunological reactivity. Pure pyrogens (pyrogenal is of bacterial origin) are
used in case of lues, gonorrhea, osteotuberculosis and arterial hypertension (of renal
genesis, when vasodilatation is achieved and renal blood supply is improved). They
cause body temperature rise for 6—9 hours. Nowadays, IL-1 and other cytokines are
used in the clinical practice for this purpose. Their advantage in comparison with
pyrogens of bacterial origin consists in the absence of side effects.
In addition to fever, there are other forms of body temperature rise, which are
not as beneficial for the organism as fever.
Blood transfusion, injection of proteins and lipids for the purpose of parenteral
feeding may cause elevation of body temperature.
Primary pyrogens may be produced inside the organism independently from
infectious agents (in bone fractures, myocardial infarction, hemolytic crisis). These
substances are produced as a result of body’s own tissue destruction and influence
the organism as exogenous pyrogens.
Hyperthermia caused by overheating significantly differs from fever. The final
irsult is the same — body temperature increase, but the etiology, pathogenesis and
significance are different. The etiological factor is of physical origin (high ambient
1 A woman fell ill with acute pneumonia. There is fever up to 39°C, general
weakness, dry cough appeared. What inflammation mediator has the properties
of an endogenous pyrogen?
A. Thromboxane
B. Interleukin-1.
C. Histamine.
D. Serotonin.
E. Bradykinin.
2. A patient has a fever. Body temperature rises and keeps high from 1 till 3 a.m.
and then decreases to the normal level. Such fever is observed every fourth day.
What type of temperature curve is it?
A. Febris intermittens.
B. Febris continua.
C. Febris reccurens.
D. Febris hectica.
E. Febris remittens.
3. After overcooling the patient’s body temperature increased to 39.7°C and rose
from 39°C to 39.8°C in 3 days. What type of temperature curve is it?
A. Febris hectica.
B. Febris reccurens.
C. Febris continua.
D. Febris intermittens.
E. Febris remittens.
I'ind points o f comparison and compile a comparison table o f common features and
differences between fever and overheating due to high ambient temperature
1
2.
1
4.
141
Chapter 10
NEOPLASIA
I o distinguish one typical pathological process from another one should note
their cardinal sings. For neoplasia they are:
• endless growth (absence of the so-called limit of division, immortality);
• independence o fgrowth, autocrine (own) regulation (tumor grows from itself,
from one single transformed cell) infiltrating healthy tissues;
• unaplasia, reversion to a simpler, less differentiated form (like embryonic
state);
• metastatic expansion.
CLASSIFICATION
Induction
Transplantation
Implantation
E T IO LO G Y
Etiological factors, which cause malignant tumors, are called cancerogens. The
agents intensifying the effect of cancerogens but not causing tumors themselves are
i ailed cocancerogens. Cancerogens, which have all these effects, are called syncan
4 ‘rogens.
Cancerogens may be exogenous (physical, chemical and biological) and en
dogcnous.
Physical Factors
The physical factors are ionizing and ultraviolet radiation, radioactive isotopes
d»l iodine, radium) and ultrasound. They may cause neoplasia in such small doses,
which do not cause radiation disease.
'nil I («t'licml Pathophysiology
hemieal Cancerogens
lilologlcal Cancerogens
Endogenous Cancerogens
PA T H O G E N E S IS (C A N C E R O G E N E S IS )
N EO PLASTIC TRANSFORMATION
I his theory is proved by the fact that all the etiological factors are mutagens.
I Ih* essence of this theory consists in the assumption that mutation (damage of the
genes responsible for cellular division) is a cause of malignization. The process of
cellular division loses inhibition and becomes endless. Since mutation is irrever
sible, neoplasia is also irreversible. Mutation of the gene P53leads to apoptosis block
and thus cells avoid death.
The normal human genome has been proved to have genes similar to viral
oncogens (the scientific term for these genes is protooncogens). The real function
o! these genes is participation in embryogenesis regulating cellular sensitivity to
growth factors. During a normal postembryonic period these genes are inactive
(repressed).
I he essence of this theory is the assumption that these genes can become ex-
* essively active, and different etiological factors (including physical and chemical
mutagens) play a role in this activation. DNA-copies of oncoviruses may play the
promotor role. An activated protooncogen is called active cellular oncogen. It is that
which leads to neoplastic cell transformation.
Active cellular protooncogen expression leads to increased oncoprotein (tumor
protein) synthesis. It is supposed that:
• oncoproteins act as growth factors;
• o n c o p r o t e i n s b in d with c e llu la r g r o w th fa c t o r t n r p i n r . and g e n e ra te signals
lo r cell division;
Chapter 10. Neoplnsiu
Cohnheim was the first to pay attention to the similarity between malignant
and embryonic cells and offered an oncogenesis theory named the theory o f em
bryonic rests. According to it, neoplasm develops as an atypical embryo in atypical
place. Thus, malignization is embryonalization and oncogenesis is blocked embryo-
genesis. Nowadays this conception received further development.
The similarity between malignant and embryonic cells consists in the follow
ing.
• Common m arkers (markers are substances, which provide the growth, de
velopment and function of tissue - hormones, enzymes, activators, inhibitors, as
well as immunoregulatory, transport, receptor and structural proteins). In fact, all
cancer markers are found in the embryonic tissue. It determines common biological
properties — implantation ability, invasive growth, autocrine regulation.
• Im m unological tolerance to the presence in the organism of foreign genetic
information. Due to these mechanisms in a pregnant woman a half-foreign embryo
is not rejected but preserved («protection of something foreign within the organ
ism»). The mechanisms are the following — masking of foreign antigens, blocking of
lymphocytic aggression by antibodies, activation of T-suppressors (markers possess
ing suppressive activity). The same mechanisms are found in the organism with a
neoplasm. On the one hand, neoplastic antigens are immunogenic for the organism
itself; on the other hand, an oncospheroid can escape from immune supervision.
I he causes of escape are low immunogenicity of malignant cells, adsorption of
blocking antibodies on their surface and their defense against the cytotoxic effect
of macrophages and T-lymphocytes. It is supposed, that the trigger role belongs to
antigens, which are common for a neoplasm and an embryo.
• Parthenogenetic division and multiplication of one single fertilized egg and
one signal malignant cell after transformation. Neoplasm is not a group of simple
copies of a primary transformed cell; it is a heterogenic population of cells. Similar
lo blastocyst formation, an oncospheroid has three germ layers with their own spe-
eilic functions — differentiated somatic cells (determine various histological types
of tumors - melanoma, neuroma, sarcoma, etc.), oncotrophoblastic and germ cells
(oncogerminative). Then, similarly to blastocyst, an oncospheroid provides further
development. In an embryonic anlage every germinal layer harmoniously develops
according to its function. Contrary to this, a tumor anlage has abortive embryonal
development. So, oncogenesis is a blocked embryogenesis. An oncospheroid de
vclops in the direction of a progressive decrease of the quantity of differentiated
•His, which are substituted by germ and trophoblastic cells (neoplastic progression,
see below).
I'liil I. ( n i i m i l I ’lilliopliyslolou.v
148
anomalies predispose to neoplasia development (this predisposition was noted in
chapter 1, p. 52) as well as immunodeficiency (this predisposition was noted on
p. 82).
Hereditary predisposition is proved statistically. The phenomenon of «canccr
families» has been described. High- and low-cancer lines of experimental animals,
which have increased or decreased resistance to cancerogens, are created under
experimental conditions.
Genetic factors determine the mechanisms of organism reaction to cancero
gens and defense against tumors. The genetically determined disturbance in the
immune system considerably increases the frequency of neoplasia. T-lymphocytic
and combined immunodeficiency increases the risk of neoplasia.
Men are more frequently affected with stomach cancer while women more
frequently have tumors of the sexual and mammary glands.
PE C U LIA R IT IE S OF TU M O R GROWTH
liiO
Г . Ill I . ( • 4*tl(* I'll I I'lld lo p llY sln lo K V
N E O P L A S IA M A N IFEST A T IO N S
ANAPLASIA
Morphological Anaplasia
ISO
( h a p lc i I" Neoplasia
151
Purl I PlKlloploNiolo^V
Somciimcs malignant tumor synthesizes such proteins, which arc not typical of
tissues before their transformation (for example, hormones).
Physicochemical Anaplasia
Some physical and chemical indices are changed in malignant tumors towards
the embryonic state.
• Quantity of water is increased.
• ( ilycolysis activation together with an increased amount of K +leads to lactic acid
accumulation and intracellular acidosis development (cell pH is reduced to 6.4).
Hut in the blood alkalosis develops due to compensatory mechanisms.
• ( outent of potassium is increased.
• ( outent of calcium and magnesium is reduced.
• I leetrical conductivity increases.
• I'he surface tension of the cellular membrane is reduced (due to a decreased
amount of Ca2+). Intracellular adhesion is reduced, and malignant cells easily
move into the surrounding normal tissues in invasive growth.
• ( olloid viscosity is reduced.
• Malignant cells have a negative charge. Due to the negative charge of leukocytes,
the latter do not approach malignant cells.
I lie dilfusion of metabolic substances into cells and of their products — outside
cells is stimulated.
Malignant cells are intensively dyed.
inelioual Anaplasia
2
Chapter 10. Neoplasia
The functions of malignant cells are simplified. Malignant cells lose those spe
cific functions (secretion, formation of mediators and hormones, excitability, etc.)
that were typical to them before transformation. Secretion of the gastric juice in
■.loinach cancer (achylia) and bile formation in liver cancer are suppressed. Tumor
of the pancreas cells causes hyperglycemic conditions and even coma.
In addition, functional metaplasia may consist in production of substances,
which are unusual for this organ. For example, malignant tumor of the pancreas
sometimes synthesizes gastrin; thyroxin was revealed in a malignant tumor of renal
origin; synthesis of a thyroid gland hormone (calcitonin) was revealed in breast
«.mcer; hormones of the pituitary gland (A D H , A C T H ) are synthesized in lung
i .nicer. Uncontrollable synthesis of hormones (hormone-producing tumors) may
occur.
S Y ST EM IC M ANIFESTATIONS OF NEOPLASIA
The law, according to which the course of any pathological process depends
not only on the etiological factor, but also on organism reactivity, refers to neopla
sia as well.
Examining the patient it is possible to see reactivity depression, however, it
is difficult to assess defense reactions. An experiment allows conducting such an
Investigation.
The method of transplantation shows that transplanted malignant cells do not
always multiply. A small quantity of malignant cells cannot be transplanted.
Successful transplantation requires sterility. If inflammation develops in the
place of transplantation, the transplant can die. Even after providing all necessary
conditions (sufficient mass of malignant cells, sterility) transplantation may not be
successful in 100 % cases.
Appearance of tumor cells in the organism does not necessarily result in the
development of a tumor process. The immune tissue controls antigen homeostasis
m I lie organism (a clone of cells with any antigenic differences is eliminated by
immunological reactions). It refers to tumor cell clones. The immune system is the
main system of protection against tumors.
II is a function of T-killers to eliminate mutant somatic cells involving phago
cytosis and complement. This mechanism is also extended onto mutant malignant
t ells. Isolated malignant cell-mutants are as a rule recognized and eliminated by
I killers, cytolysis and phagocytosis mechanisms. Since malignant cells have some
new antigens (viral), B-lymphocytes can form antibodies. Interferon is an inhibitor
of nucleic acids of viral origin.
These mechanisms of immune protection against malignant tumors have been
well studied under experimental conditions in healthy animals, to which malignant
cells were transplanted.
().(). Bohomolets proclaimed that the development of a malignant tumor is
theoretically impossible if the connective tissue is healthy. The transformed cells
aie destroyed in such a case, and therefore clinical manifestations of tumors are
noted less frequently than neoplasia occurrence. Consequently, malignant tumor
development is possible only against the background of reduced immunological
reactivity.
Investigation of patients with malignant tumors shows that their immune reac-
tions are depressed.
Causes o f immunodepression are: a) effect of etiological factors (all cancerogens
suppress immune reactions); b) overload of the immune system with a tumor of a
large mass.
Malignant tumors have their own mechanisms o f escaping from immune supervi
sion. They arc:
• antigen simplification of malignant tumor;
•appearance of fetal antigens, to which the organism has immunological toler
anee;
• masking of tumor antigens (for example, chorionepithelioma cells have a
neutral polysaccharide capsule);
• a negative charge of tumors and leukocytes.
A surprising phenomenon was described in an experiment Antibodies, which
.ue formed in response lo tumor antigens, do not destroy .1 minor, but, on the con
trary, protect il. I hey are fixed on malignant cells and him к tin cytotoxic effect of
I killers ami macrophages. In some tumors there are sevcml antigen determinants,
155
'. I l l I. ( i i 'I H T H l P m l i o p l i v s i o l o K )
Chemical cancerogens:
5. They are compounds of carbon (polycyclic aromatic hydrocarbons
PAHs) and nitrogen (nitrosamines).
6. There are no PAH in the environment.
7. PA H have a predominantly organotropic effect.
8. Nitrosamines have a local effect.
Endogenous cancerogens are:
9. Bilic acids.
10. Steroid hormones (folliculin) never act as cancerogens.
4. Pathogenesis of neoplasia.
1. Neoplasia pathogenesis proceeds in three stages.
2. Neoplastic progression is the first stage.
3. Neoplastic promotion is the second stage.
4. Neoplastic transformation is the third stage.
5. The malignant cell genome remains stable during malignization.
6. A transformed cell begins to multiply under the additional effect of pro
motors.
7. A malignant cell may produce only malignant cells.
8. A malignant cell does not transmit new properties to descendant cells.
9. The process of cellular division loses intercellular contact inhibition and
becomes endless.
/, A man has been working for a long time in the petroleum-refining industry.
What classes of carcinogenic agents did he contact?
A. Nitrosamines.
B. Aminonitrocompounds.
C. Polycyclic aromatic hydrocarbons.
Г .111 I (.meritI I'jiIIioiiIivsIoIoky
10. Anemia and a malignant tumor of the uterus were diagnosed in a 58-year-old
woman, who suffers from pain in the abdomen and uterine hemorrhage. What
are the systemic manifestations of neoplasia?
1. Neoplasm is a local manifestation of a systemic disease.
2. At old age the risk of neoplasia diminishes.
3. Uncontrolled synthesis of hormones sometimes occurs.
4. Independently from the localization of malignant tumors, anemia deve
lops.
5. Systemic manifestations of neoplasia are a peculiarity of growth and quali
tative changes in malignant cells (anaplasia).
6. Systemic manifestations of neoplasia result from interrelation between the
organism and a malignant tumor (influence of the organism on the tumor
and vice versa).
7. The organism does not influence tumors.
8. There are no defense reactions of the organism against malignant tu
mors.
9. Only in the organism with depressed reactivity the development of malig
nant tumors is possible.
C hapter I I
HYPOXIA
Hypoxia is one of the most widespread pathological processes. All the diseases
from birth till death have a hypoxic component.
Hypoxia is a typical pathological process developing due to insufficient oxygen
supply to tissues or impaired oxygen use resulting in energy (in the form of A TP)
production disorder.
Lack of oxygen and energy (A T P) leads to disorders of metabolism and energy-
linked functions of the organism.
CLASSIFICATION
ET IO LO G Y
Hypoxic Hypoxia
Respiratory Hypoxia
Ilemic Hypoxia
Hemic hypoxia is caused by the factors, which impair oxygen capacity of the
blood. Hemic hypoxia is subdivided into anemic hypoxia and hypoxia caused by
hemoglobin inactivation.
Anemia as a cause of hypoxia is discussed in chapter 20 «Pathophysiology of
I rythrocytes. Anemia». It has hemic hypoxia as the main pathophysiological mani
Irstation (p. 278). Hemorrhage as a cause of hemic hypoxia is discussed in chapter
19 devoted to blood loss (p. 269).
As to hemoglobin inactivation, in pathologic conditions such hemoglobin com
pounds are formed, which are not able to perform the respiratory function. It is
airboxyhemoglobin, formed from hemoglobin and CO (carbon monoxide, whose
affinity for hemoglobin is 300 times more than for oxygen); this kind of hemoglobin
ran not bind oxygen; the iron-containing enzymes are also inactivated. Methemo
globin is formed during poisoning with nitrates and some drugs with an oxidizing
capacity. In this form of hemoglobin trivalent iron does not bind oxygen.
Circulatory Hypoxia
Ilistic Hypoxia
Histic hypoxia is caused by the factors, which disturb oxygen utilization and
energy (in the form of A T P) formation. Oxygen supply to tissues may be sufficient,
but biological oxidation is impaired.
A classical example of histic hypoxia is poisoning with cyanides (they inaeti
vate cytochrome oxidase). Large doses of alcohol, narcotics and some drugs inhibit
dehydrogenases of the Krebs cycle. The antibiotic oligomycin damages the enzyme
Ii lU fiM . 161
I ’,ill I ( . e n n u i Ги11|ор||уч1о1оцу
Combined Hypoxia
PA T H O G E N ESIS
hy, 19. Changes of the oxyhemoglobin dissociation curve {a, b, c) in the process ofnigtin
ism adaptation i<
>hypoxia
Г.i l l I ( i f i in u l Ги11н1||||)ч1о1ою
( oniliiiieil Hypoxia
PATHOGENESIS
lift ll> Changes o f I he oxyhemoglobin dissociation curve ( a , h, <-) in the process ol oiyan
ism adaptation to hypoxia
I ’i i i I I ( • r u n ill 1'и1Ьо||||уч||||<1к>
u-.tilies to a decreased affinity of hemoglobin for oxygen in tissues; so, tissues get
more oxygen.
PATHOLOGICAL CHANGES
H«orders of Metabolism
i 'iiclcr (heir influence, hemoglobin is transformed into metHb and membranes arc
Mili/cd. The intermediate products of protein metabolism are accumulated. The
in.unity of ammonia increases, of glutamine — decreases. The negative nitrous hul-
imu- is established.
rhosphoprotein and phospholipid metabolism becomes disturbed. Their synthesis
in the liver gets reduced.
As the membrane canals are an important A T P consumer, the active transport
.</ ions through the biological membranes gets disturbed. The content of intraccl
ini.и potassium is decreased. Calcium accumulation in the cytoplasm is one of the
Iumc links in the pathogenesis of the hypoxic damage of cells (p. 262).
Synthesis of neuromediators and hormones is reduced. It leads to nervous and
mlocrine regulatory mechanism impairment.
Morphological Changes
I lie observed biochemical disorders in the cell cause the structural ones.
At the cellular level, an ultrastructure lesion is marked as hyperchromatosis and
■it ' (imposition of the nucleus, swelling and degradation of mitochondria.
Increased acidity, membrane destruction and energy deficit lead to lysosome
л,image. Active proteolytic enzymes are released and damage the cellular structure.
Cell division gets suppressed.
lops, is protective; as a result, the nervous system becomes less sensitive to oxygen
Hiciency I he decrease of body temperature may be interpreted in the same wav
II is a damage that induces compensatory adaptation. Thus, it is a decrease ol
>(),, in the blood that initiates chemoreceptor stimulation and mobilization ol ex
eiiial respiration and blood circulation. It is A T P deficit that induces mitochondna
nogenesis,
U S E OF HYPOXIA IN M E D IC IN E
Paradoxically, hypoxia is used in clinical practice for treatment. For this pin
ри л pressure chambers are used. While training in hypoxic conditions, the organ
i in becomes more resistant to various unfavorable factors, in particular, physi» il
load, infection, poisoning and ionizing radiation. Immune reactions are activated
It is used in the treatment for bronchial asthma, anemia and other chronic disease,
in whose pathogenesis hypoxia is a leading mechanism.
In some diseases, oxygen under an increased pressure is used (hyperoxi;») Ii
■trales oxygen reserves in the blood and tissues. It is used in poisoning with carbon
monoxide and operations on the «dry» heart (without blood supply).
1 An unconscious man was taken to the hospital alter poisoning with carbon
monoxide. Appearance of what substance in the blood provokes hypoxia?
A. Carboxyhemoglobin.
H Met hemoglobin.
C. Carbohemoglobin.
I). Oxyhemoglobin,
li. Lactate.
I A S0-year old man was taken from a closed room full of smoke from a fire. I Ic
was unconscious. What kind of hypoxia did the victim develop?
A. Hypoxic.
M Respiratory.
C. Hemic.
I). 11istic.
I . Circulatory.
<
> Л patient demonstrates a decreased amount of erythrocytes and hemoglobin
in the blood, reduced color index, low concentration of iron in the serum,
microanisocytosis, poikilocytosis. These changes are accompanied by hypoxia
development. What kind of hypoxia is observed in this case?
Л. Exogenous.
B. Hypoxic.
C. Circulatory.
D. Hemic.
E. Respiratory.
s Л patient had a lung surgery. The heart stopped. Its regular contractions were
restored only in 10 minutes. What organ suffered from hypoxia most of all?
A. Spleen.
B. Heart.
C. Liver.
D. Kidneys.
E. Brain cortex.
HI I'liree experimental animals — a snake, a frog and a rat — were put into .1
pressure chamber to study hypoxia. After decompression a difference between
1hem was noted. What is the difference and how is it explained?
The following immediate compensatory reactions are necessary
fo r survival in acute hypoxia development:
1. Acceleration of heart rate.
2. Development of additional capillaries in organs.
3. Stimulation of erythropoiesis in the bone marrow.
4. Activation of glycolysis.
5. Myocardial hypertrophy.
(>. Hyperplasia of the bone marrow.
I'tirl I (irlHTMl Рй1||0|>||)ч|0|»К>
7. Hyperventilation.
S. Decrease of arterial blood pressure.
Results o f the experiment are the following:
9. The snake dies the first.
10. The frog has the best active resistance.
11. The rat lives the longest time.
Resistance o f the organism to acute hypoxia may be increased by:
12. Decrease of body temperature.
13. Increase of body temperature.
14. Narcotic substances.
15. Caffeine.
16. Antioxidants.
11 A chronic inflammation of the lungs (chronic pneumonia) was diagnosed in .i
patient of 59 years old. He suffers from sickness, cough, dyspnea (respiratory
insufficiency). During a year his body temperature periodically rises to 37.2'(
I he leukocyte content in the blood is not increased.
What is the patient’s organism reactivity?
1. Normal.
2. Increased.
3. Decreased.
What compensatory reactions are characteristic
to chronic hypoxia o f respiratory type?
4 Hyperventilation.
5. Tachycardia.
(>. Hyperplasia of the bone marrow.
7. Increase of the respiratory capacity of the lungs.
X. Erythrocytes leaving the depot.
W lial disorders o f metabolism are typical o f chronic hypoxia?
9. Activation of the basal metabolism.
10. Inhibition of synthetic processes.
II Inhibition of oxidation.
12. PO L activation.
IV Positive nitrogen balance.
14. Increase of the glycogen content in the muscles.
1 Myocardial infarction was diagnosed in a 44-year-old patient. He was с а т Ы
to the hospital in a grave state.
What type o f hypoxia developed in the patient?
1. Acute.
2. Chronic.
3. Hypoxic.
4 Circulatory.
5. Hemic.
<
> Respiratory.
7. Tissue.
К ( Dinbini'il
( hapU'i 1 1 . II.Y |H > \iu
2. Txcitation (connected with sensiition «>i luingei nnd active hunting for
lood).
.1 Suppression (the most prolonged period).
4. Terminal, or the period of paralysis and death (3-4 days).
Restoration comes if starvation is stopped before the terminal period and nour
ishment is restored.
In people fasting deliberately with a serious motivation, excitation and suppres-
II >n may not take place.
Pathophysiological Periods. Three pathophysiological periods of complete star
vation are distinguished on the basis of changes of metabolism and energy con-
.umption. fhe respiratory quotient is used as an index. They are:
/. Uneconomical use of energy (2—4 days in man, respiratory quotient increases
to I ).
2. Maximal adaptation (40—50 days in man, respiratory quotient decrease to
0.7).
f. Tissue decay, intoxication and death (3—5 days, respiratory quotient equals
O.K).
Pathophysiological periods of complete starvation correspond to those of stress
(sec chapter 30 «Pathophysiology of Endocrine System», p. 506).
PA TH O G EN ESIS
IIR S T PERIO D
( hanges in Metabolism
S H ONI) PERIO D
I lie second period is the most prolonged one. Together with the first period, it
is а Маце o f compensation but regulated by other mechanisms. The second stage is a
si age of maximal adaptation. It is a period of economical utilization of substances
.iiul energy. The second period determines practically the whole course of starva
lion. Its duration depends on many factors mentioned above. In men it is 30-4(1
days and more.
Adaptation is provided at the level of metabolism. Adaptive reactions are real
i/.ed by: a) more economical use of nutrients; b) use of lipids as nutrition reserves;
c) basal metabolism reduction; d) changes in the enzyme activity and isoenzyme
systems I hey are given below with more details.
( hanges in Metabolism
i in
1‘iiH I (•rncrul Гй11ш||||уч1о||>к>
I lie third period is a period of decompensation, the terminal one. Its duration is
■и ne days (about 3—5 days). It is a period of tissue decay, intoxication and death
<Ii.nines in Metabolism
Fat depots 97 %
I'lie respiratory quotient in Spleen 60 %
i ' reuses in comparison with the Liver 53.7 %
previous period and equals 0.8. It Testis 40 %
m eans that proteins are used as a Muscles 30.7 %
source o f energy. There is an in Blood 26 %
creased lysis not only of the pro- Kidneys 25.9 %
lei ms that are easily mobilized Skin 20.6 %
(blo o d proteins) but also of the Intestine 18 %
slitblc proteins of the muscles. The Lungs 17.7 %
Pancreas 17 %
decrease of body mass is acceler
Bones 13.9%
ated again reflecting the destruc
Nervous tissue 3.9
tiv e processes.
Heart 3.6 °«
Ihere appear destructive
changes in (he mitochondria. The 0 20 40 60 80 100%
le ve l ol oxidative phosphorylation 21 l lio ileiiu-c ol mass loss by organs and tis
decreases hi cells, A disorder ol the s,,cs complete starvation
Chapter 12. Starvation
i nzymal systems, which are destructed in the process of starvation, provokes deep
ilisbolism.
The blood glucose level is less than 3 mmol/1.
Excretion of nitrogen, potassium and phosphorus in the urine increases. Their
ialio in the urine is the same as in the protoplasm.
Metabolic acidosis becomes decompensated (p. 246).
RESTORATION
M ED IC A L STARVATION (FASTING)
The regularities observed in the course of the scientific study of complete star
vation without water deprivation serve as approval of its therapeutic use as fasting. It
is based on the idea that such starvation does not cause dystrophy but only atrophy,
which can be completely restored.
Nowadays fasting is used as a non-specific method of some diseases treatment
including allergic, cardiovascular, digestive, dermal, diseases of the joints, obesity
and even mental ones. Dosed fasting (from 1—7 to 15—35 days but before the tlnul
|x*riod starts) increases the processes of dissimilation and promotes discharge of ex
ccssive metabolic waste. During the so-called endogenous nourishment the organism
uses its own pathological and dystrophic tissues and proteins fat depots, metabolie
I'lllt I < l'nllio|ilivsloliiK>
Complete starvation with water deprivation has the same periods as complete
starvation without water deprivation, but it is severer and shorter (3—6 days).
II water does not come from the outside, it is taken from the tissues. It is oxida
live water. The largest quantity of water is produced by fat oxidation — 100 g lipids
r ive 112 g of water, protein and carbohydrate oxidation provides half that quantity.
I lu- metabolic products, which are formed, require more water for their excretion
and thus a vicious circle is formed, which approximates death. Catabolic processes
.не excessively activated, tissue decay products are accumulated, and intoxication
develops.
IN C O M P L E T E STARVATIO N
Etiology
Г liological factors are those, which cause partial limitation of food intake by
i lie organism or difficulties in its utilization. They can be exogenous and endo
notions.
lyogenous causes are: a) insufficient amount of food, b) the factors, which
damage the digestive tract resulting in the limitation of food intake by the organism,
с ) the factors, which cause diseases of the digestive tract with a disturbance o f food
utilization. Etiological factors are physical (trauma), chemical (poisoning, which
causes constant vomiting), biological (infectious, psychogenic factors, which cause
anorexia) and social (undernourishment in poverty unci unemployment).
r.ndoRcnous causes are diseases of the digestive system, which limit food intake
by the organism (morphological delects), or diseases, which make it difficult to
Chapter 12. SltirvMlioii
Pathogenesis
Incomplete starvation is a chronic situation, which may last for a long time.
In food deficit, the organism spends energy resources very economically. Body
mass decreases more slowly than in complete starvation, but it is often masked by
edema.
Basal metabolism decreases considerably, more significantly than in complete
starvation without water deprivation (by 30-35 % instead of 10—20 % ). The respi
ratory quotient decreases insignificantly.
Contrary to complete starvation, when no dystrophy is observed, incomplete
starvation shows severe signs of dystrophy. Degenerative processes develop in tis
sues. They are graver than in complete starvation because of a longer duration.
As a result of plastic material (protein) deficit synthetic processes are sup
pressed. Oncotic blood pressure decreases due to a decrease of the content of pro
teins in the blood. Osmotic pressure in tissues rises due to chloride accumulation.
As a result water retention is observed.
Starvation may cause many diseases (in some chapters of this textbook it is
mentioned as an etiological factor).
Manifestations
Qualitative starvation develops when Ihc conlenl ol one oi some nutrient com
ponents (proteins, lipids, carbohydrates, minerals, vitamins, and electrolytes) in
food is insufficient. The energy value o f food is normal. Qualitative starvation is
often com bined with the quantitative one.
Clinical manifestations are specific and depend on insufficient intake o f certain
substances.
In carbohydrate deficiency the liver becom es poor in glycogen resulting in ke
logeiiesis due to lipid transport into the liver.
I)eliciency o f fats in food is easily compensated by carohydrates and proteins
used as a source o f energy. However, to provide the plastic function o f lipids, the
organism should be necessarily supplied with indispensable fatty acids — arachi
donic, linoleic and linolenic. It is also important to take into consideration th.ii
absorption o f vitamins A, D, К is connected with lipids (liposoluble vitamins) and
avitaminosis develops in fat starvation.
Protein starvation is the most serious. Prolonged malnutrition with a primaiv
deficit o f proteins in food leads to protein calorie deficiency. It causes severe ah
uicntary dystrophy. In children it develops quicker than in adults as they have an
increased need in proteins (Kwashiorkor disease). It harmfully influences the de
vclopincnt o f the nervous system in early childhood, when the nervous cells grow
intensively. Depression o f the synthesis o f nucleoproteids, proteins and decreased
си /у iibil activity accompany prolonged protein insufficiency. The quantity o f cells is
diminished and atrophic processes develop in organs. The growth and development
o l bones is suppressed. Avitaminosis develops. It is a basis for anemia developmeni
H.14.1I metabolism is decreased. Hepatic lipid degeneration occurs. The pancrens
u u d e ig o e s hyalinosis and fibrosis. Dystrophic changes o f the heart and kidneys take
place. Ii often leads to death. Only rational nourishment can save a child.
Mineral starvation manifests itself through a deficit o f important ions — polas
nun (nervous and muscle excitability is depressed), calcium (osteoporosis and teta
in.i develop), iron (hypochromic anemia develops), cobalt (hem opoiesis disorder),
iodine (endemic goiter and hypothyroidism), fluorine (bone formation disorder).
I itamin insufficiency (avitaminosis and hypovitaminosis) can be exogenous (as
.1 lesuli o f the absence or a low content o f vitamins in food) or endogenous. Vila
iniiis B,, Bh, Bl2 and PP are important for the nervous system, vitamins Bh, B^ and
I lor the endocrine system, vitamin Bl2 — for hemopoiesis, vitamins B, and PP
lot the digestive system.
Here are some example o f avitaminosis:
• Beriberi (deficit o f vitamin B, is manifested as polyneuritis and dystrophic chany
es in Ihe nervous fibers and myelin layers).
• Pellagra (deficit o f vitamin PI* is manifested a s dermatitis, damage o f the mucous
membranes ol the digestive tract with diarrhea).
• Rachitis (deficit o f vitamin I), is manifested as a tlinordei ol the absorption •>)
calcium and phosphorus in Ihc small intestine and lentil tubules with a disordn
ol hone mine rail/at Ion).
( h u p te i 12. .M arvulion
I lie basal metabolism o f a rat after 48 h o f starvation without water deprivat ion
has decreased by 20 %. The respiratory quotient is 0.7; there is lipemia, nega
live nitrous balance. What period o f com plete starvation is it (according to the
pathogenetic classification)?
A. Uneconom ical energy expenditure.
Ii. Maximal adaptation.
C. Terminal.
I). Indifference.
Ii. Excitement.
5. During starvation the mass o f organs and tissues as a rule decreases. What or
gan loses more mass?
A. Brain.
B. Kidneys.
C. Liver.
D. Heart.
E. Muscles.
(hapter 13
PATHOLOGY OF ENERGY BALANCE AND BASAL
METABOLISM
D IS O R D E R S O l M E I AIM II IS M Н М Л I \ I ION
I very kind o f work needs energy. Every defense reaction and hyperfunction
tn i ils energy as well.
A macrooiganism is a system, which produces energy for itself. Probably we do
n u t know all types o f biological energy, nevertheless, it is known that dehydrogena
imii (detachment o f H ') is a mechanism o f energy release (like proton fuel). Ii is
pioiluccd with the aid o f oxygen as an acceptor o f electrons. G lucose, fatly acids,
пиши) acids serve as substrates for energy production. In brief, for energy produc
linn t h e cells need substrates, enzym es and as a rule oxygen. Then Ihc energy takes
two forms:
• thermal energy in the form o f heal calorics;
• biological energy in the form o f high-energy phosphate bonds (AI I'l.
■
I'llll I I . r u n ill l'u(llo|ilivsiiil<iKV
The first form o f energy is needed to maintain normal body temperature. The
second form is needed for all biological energy-dependent processes — contraction,
secretion, ion channel functioning, substance synthesis, cell division, etc. ATP is
a specific form o f biological energy, which is accumulated in the organism in this
reserved form. There are two main metabolic processes o f energy production — oxi
dation and phosphorylation.
The hypothalamus regulates the balance o f thermal energy. Mitochondria arc
the place o f energy production. Oxidation (with participation o f 0 2) is a more effec-
live way o f energy production in the form o f ATP than glycolysis (different variants
o f oxygen deficiency form different types o f hypoxia, chapter 11, pp. 160—162).
Energy imbalance underlies most functional and organic disorders in organs
and tissues. It may develop at all stages o f energy transformation due to a) absence
oi lack o f substrates; b) oxygen deficit; c) change in the amount or activity o f en
zymes (o f respiratory chains, Krebs cycle, glycolysis); d) damage o f the regulatory
systems; e) genetic defects.
The respiratory quotient reflects preferred oxidation o f certain substrates. The
normal respiratory quotient is 0.9. It rises to 1.0 if carbohydrates are oxidized
predominantly; it decreases to 0.7 if lipids are mainly oxidized. The respiratory
quotient equals 0.8 if proteins are used for energy production. (It helps to distin
guish the pathophysiological periods o f com plete starvation on the basis o f energy
consumption as it was described on p. 176).
Two processes are tightly connected (coupled) in mitochondria — oxidation and
phosphorylation. They are regulated and depend on the state o f mitochondria anil
hormonal regulation. The organism manipulates with this connection. If the or
ganism needs additional heat, these processes may be uncoupled, free oxidation
predominates, ATP formation is temporarily limited. If the organism needs an ad
ditional amount o f ATP (hyperfunction) then oxidation and phosphorylation may
be coupled more tightly.
Contemporary methods o f investigation make it possible to determine the
amount o f ATP and estimate the state o f mitochondria. Their swelling results in
Ihc spatial removal o f the enzymes transporting electrons via the respiratory chain
from the enzymes o f the phosphorylation system. It leads to uncoupling o f oxida
(ion and phosphorylation. ATP formation decreases, energy becom es dispersed as
free heat, the specific functions o f cells are impaired (it is described as a variant
of histic hypoxia on p. 161). Many factors, which have the effect o f uncoupling,
are o f clinical interest because o f phosphorylation disorder. Some microorganism',
produce this effect. Diphtheria toxin as well as live and dead aurococcus cultures
produce it. Poisoning with some chemical agents (a-dinitrophenol, which damages
mitochondria) uncouples oxidation and phosphorylation resulting in hyperthermia,
which has no defense value (p. 140).
As to thyroxin, this hormone together with adrenaline is the most potent regu
lator o f energy production. It increases the permeability o f mitochondria, stimulates
oxidation, phosphorylation and energy formation Energy production in the form
ol heat increases. Its calorigcnic effect is nol explained by uncoupling o f oxidation
and phosphorylation because mitochondria are not swollen Imt enlarged Oxidative
( li.ipl ci I ■ I ’ .iiliiiln;’ v o f K i w r g y Balancr iintl l . i il Metabolism
Ih at Calories
Systemic increase o f heat production occurs under the influence o f low ambi
• nl temperature (for the maintenance o f normal body temperature) and in fever
Ilor organism warming and body temperature increase). In these cases the defense
ir.ictions are very well regulated. The thermoreceptors and a special nervous ccnlcr,
which is located in the hypothalamus (the center o f thermoregulation), control the
thermal balance.
It is important to understand the strategy o f biological adaptive mechanisms in
i i <h situations because it differs from that in non biological objects. In the lattei
I ’. l l l I «.I III I .11 I 'l l l l l l i p l l N M I l l l i p
As a defense As a result o f
reaction m etabolism
JL d iso rd er
H eat
calories ^A T P l 'f ' C atabolic
Л --- .------- horm one
I M echanism s |-
Thermo T O xidation secretion
regulation /f' O xidation and T oxic effect
-| M echanism s
phosphorylation o f uncoupling
activation
coupling substances
I 4O xidation
4 / H eat em ission
i-l'l4 H eat production
O xidation and - T H eat em ission
p hosphorylation R esults |- E xhaustion o f
uncoupling
nervous and
endocrine system s
M aintenance
o f body /T> Plastic
tem perature processes
on exposure -| R esults |-
to cold Pregnancy
ATP
Energy production decrease (both in the form o f heat and ATP) always has .i
negative meaning (schem e 10). It may occur at all stages o f energy production and
may result from:
• deficit o f substrates;
• deficit o f oxygen;
• deficit or damage o f enzymes;
• damage o f mitochondria;
Г.и I I (•ciK ia l I’alhnplnMoloK)
Carbohydrates are an important energy source lor cells, and for some o f them
(nervous) carbohydrates are essential.
Го master the pathology o f carbohydrate metabolism one should know several
lernis:
• glyccmia — blood glucose level, an integral index o f carbohydrate metabolism,
,i standard measure is 3.3—5.5 mmol/1;
• hyperglycemia and hypoglycemia - increased and decreased blood glucose
levels;
• glycolysis — anaerobic glucose oxidation to pyruvate;
• glycogenesis — glycogen formation from glucose;
• glycogenolysis — splitting o f glycogen into glucose;
• glyconeogenesis — carbohydrate formation from non-carbohydrate products
amino acids - under the effect o f glucocorticoids o f the adrenal cortex and from
I'ally acids;
• glycogenosis - pathological storage o f glycogen in the liver and muscles;
• glycosuria - presence o f glucose in the urine.
Carrier proteins that transport glucose into cells are termed GLUT (G LU T-4
is Ihe insulin-regulated glucose transporter found in the adipose tissues and striated
muscles (skeletal and cardiac); G L U T -2 is the Na-dependent transmembrane car
m i protein that enables passive glucose movement across cell membranes into Ihc
cells o f the digestive tract and kidneys).
Pathology o f carbohydrate metabolism consists in disorders o f anabolism and
catabolism.
Disorders o f carbohydrate metabolism may take place at any point o f carbo
hydialc balance — digestion and absorption, maintenance o f the blood sugar level,
intermediate metabolism, formation o f reserves in the form o f glycogen, correlation
with other types o f metabolism.
I he main indices, which characterize carbohydrate metabolism, are the follow
imk blood sugar level and tolerance to carbohydrates. In pathology there are several
additional indices: the amount o f glucose in the urine, the amount o f intermediate
products o f carbohydrate metabolism (ketone bodies, other products).
I he main disease, which is connected with carbohydrate metabolism disordei,
is diabetes mcllitus.
Carbohydrates are digested and absorbed in the stomach and intestine. Disoi
dcrs o f carbohydrate digestion and absorption may be acquired and congenital.
Amylolytic enzyme deficit in the alimentary Irad is observed in case o f in
(lamination o f the intestinal mucosa. Nevertheless, .uquired enzymal splitting ol
( li.iplfi 1-4 l'iilli» l» K > o f < a r h o l i y t l r i i l c M c I u I h iI is iii
(tlvi'i»genosis
Nervous Mechanisms
Hormonal Mechanisms
Thyroxin stim ulates glucose absorption in the intestines, activates liver phos
pliorylase and lim its organism tolerance to carbohydrates. H yperfunction o f the
ihvroid glands is characterized by a decreased tolerance to carbohydrates.
(Hucocorticoids (horm ones o f the zona fasciculata o f the adrenal cortex) raise
tin blood glucose level by glyconeogenesis activation (glucose synthesis from am ino
к id s). T hey induce the synthesis o f m atrix R N A , w hich is responsible for the
• n/ym es o f glyconeogenesis form ation. They decrease the cellular m em brane pei
ми ability for glucose and inhibit the rate o f hexokinase reaction and hexose-6
phosphate form ation.
Corticotropin acts similarly to glucocorticoids because it stim ulates th eir secre
non. It activates glyconeogenesis and inhibits hexokinase activity.
Somatotropin (the horm one o f grow th produced in the adenopituitary gland)
impairs tolerance to carbohydrates, causes hyperglycem ia, ensures hyperplasia o f
iIn- u-cells o f th e pancreatic islets, stim ulates glucagon synthesis, activates liver
iir.ulinase, lipolysis and glyconeogenesis (from fatty acids).
11 is only insulin (secreted by pancreatic p-cells) that decreases the blood glu-
i use level and provides balance.
Such dissim ilarity o f horm onal participation in blood sugar level regulation has
(wo consequences: (a) the first line o f horm ones is called contrainsulin although
ili< и physiological action is synergic to insulin, (b) insulin deficiency significantly
■illn is the blood sugar level, raises it (fig. 22).
Го m aster the m aterial o f this chapter one should know in detail the m echa
nr m s o f insulin effect.
Glycemia
5 .5 5
hr Norm al regulation o f carbohydrate m etabolism and its possible disord eis hi him "i
h i altered correlation betw een insulin and h orm on e antagonists
Pllfl I < H 'l l r l ill l 'u l l l < l |l l i y s i o l o K .V
Ih c m ain с fleet o f insulin consists in lowerti i# the 1>1<нн1 \ицчг level It is achieved
by increasing glucose utilization by target cells and acciunulaliiiK carbohydrate re
serves. Insulin provides the m em brane transport o f glucose, am ino acids and certain
ions. So, insulin is the main anabolic (trophotropic) horm one in the organism .
Insulin realizes these effects by such m echanism s:
• Raises target cell perm eability for glucose by increasing in the cell m em branes
the am ount o f glucose carriers (G L U T -4 ) and the rate o f hexokinase reaction
resulting in increased form ation o f gIucose-6-phosphate as the m ain m etabolic
substrate for interm ediate glucose m etabolism .
• Activates the Krebs cycle (the enzym e citrate synthase).
• Activates glycogenesis, prom otes glycogen storage in the liver and muscles.
• Inhibits glycogenolysis by stopping phosphorylase activity.
• Activates lipogenesis (conversion o f 10 % glucose into lipids).
• Induces synthesis o f protein, R N A and DNA.
• Regulates such intracellular indices: adenylate cyclase (w hich regulates the intra
cellular cA M P level), guanylate cyclase and c G M P production, N a-K -A M P ase
activity, sodium -calcium flux.
• Provides penetration o f potassium into cells.
• Inhibits glyconeogenesis.
• Has m itotic activity (sim ilar to grow th factors).
• Influences the genetic apparatus o f target cells and induces the corresponding
enzymes.
T he effect o f insulin on target cells depends on the am ount and affinity o f
insulin receptors. T hey have been identified on fat cells, hepatocytes, fibroblasts,
m onocytes, thym ic lym phocytes.
A com parison between the effect o f insulin and contra-insulin horm ones 0 1 1
carbohydrate m etabolism is given in schem e 11.
HYPOGLYCEMIA
( iiusos
M anifestations
h\|H>glycemia.
lachycardia develops due to adrenaline hyperproduction. H unger (excitation
■■I the ventrolateral nuclei o f the hypothalam us), trem or, weakness, irritability and
li и are the clinical sym ptom s. C onvulsions develop. If the glucose level is below
1 1 m m ol/1 hypoglycemic coma develops.
HYPERGLYCEMIA
It is known that all the blood glucose is filtered in the renal glomerules into
Ihc primary urine. Then glucose is com pletely reabsorbed into the blood from the
primary urine via the epithelium o f the proximal tubules. Carrier proteins (N a-de-
pendent G L U T -2) and enzymes (hexokinase) provide glucose reabsorption. Energy
and proper N a-K pump regulation are necessary for it.
I hc renal threshold is the maximal level o f glycemia (normally 8.8 mmol/1),
which is not accompanied by appearance o f glucose in the final urine.
II blood glucose concentration is high (hyperglycemia), some glucose is ex
a c te d m Ihc urine (glycosuria).
In some cases glycosuria develops without hyperglycemia, i.e. when transport
\ .(cms in (he kidneys are impaired. Acquired and hereditary pathology o f the
proximal lubules as well as Na-balance disorder have the same result. In these cases
one- speaks about renal threshold decrease and the so-called renal diabetes.
TOLERANCE TO CARBOHYDRATES
Depending on the reason and degree o f problems with insulin, its insufficiency
i . divided into two forms — absolute and relative. Depending on cause localization,
it is divided into pancreatic and extrapancreatic. These two classifications actually
<omcide.
Absolute (pancreatic) insulin insufficiency is a result o f decreased insulin biosyn
ih.ms or secretion.
Relative (extrapancreatic) insulin insufficiency refers to the situation, when in
м11111 production is normal, but metabolic disturbances and clinical picture are l lie
пне as in absolute insulin deficit.
I he causes and pathogenesis o f these two forms are different.
Metabolic Disorders
Interm ediate glucose m etabolism is im paired in all possible ways, nam ely:
• G -6 -P form ation decrease as well as its participation in glycolysis, pentose
phosphate cycle and glycogen synthesis;
• inhibition o f m etabolic capacity o f the Krebs cycle;
• accum ulation o f interm ediate acid m etabolites and m etabolic acidosis devc
lopm ent;
• A TP form ation decrease;
• glycogenesis suppression;
• glycogenolysis activation;
• glyconeogenesis activation;
• glycogen reserve depletion in the liver and muscles;
• suppression o f glucose conversion into lipids.
As a result, such an integration pattern as tolerance to carbohydrates fails.
Hyperglycemia
(ilycosuria induces osmotic diuresis and thus polyuria, causing a loss not only
■•I water but also electrolytes (N a, K, Mg, P). In addition, insulin insufficiency
ntuates in limitation o f membrane transport o f certain ions and increased pen
• l nil ion o f sodium into the cells. Disorders o f water balance result in:
• dehydration due to increased loss o f water in the urine;
• elevation o f blood osmotic pressure.
Pathophysiological Disorders
• C onstant loss o f glucose in the urine overloads .ill horm onal m echanism s
o f blood sugar level support (secretion o f glucocorticoids and o th er contra
insulin horm ones). O verloading o f horm onal m echanism s leads to their ex
haustion.
• Atherosclerosis acquires a generalized form.
• Excessive synthesis o f glyco- and m ucoproteids leads to the developm ent ol
vessel hyalinosis, w hich is accom panied by autoim m une inflam m ation and
aggravates atherosclerotic dam age. Vascular pathology (angiopathy) is the
m ain reason for invalidity and death.
• I ipid infiltration o f the parenchym atous organs (liver, m yocardium ) lead-,
to failure o f these organs and aggravates pathophysiological disorders with
various clinical sym ptom s.
• (ilycosuria prom otes osm otic diuresis, which can reach 1 0 -1 2 1/day. Loss
o f w ater leads to dehydration. A lthough patients com pensate it by drinking,
electrolytes (N a, K, M g, P) are lost in the urine. Loss o f w ater results in
hyperosm olarity and thirst.
• G lycolization o f various proteins (H b, enzym es, collagen, etc.) has different
consequences depending on the type o f dam aged proteins.
• f orm ation o f im m une antibodies is suppressed. It results in decreased resis
lance o f the organism to infection (im m unodepression).
• Regenerative and plastic processes are suppressed resulting in decreased
wound healing. Any traum a is accom panied by incapability o f regeneration
and frequently results in form ation o f the so-called trophic ulcers, whose
developm ent is prom oted by atherosclerosis.
• G row th retardation is observed in children.
DIABETES MELLITUS
E TIO LO G Y
I liological factors, causing D M , are physical, chem ical and biological, whose
general property is the ability to cause insulin insufficiency. D epending on genet it
m echanism participation, DM is divided into acquired and genetically determ ined
C lu ip tc r 14. I’alholuKV of < a rb o h y d ra tc M i-laliulisin
ll< rrditary insufficiency o f the pancreatic islets can be detected under the effect of
pmvoking exogenous etiological factors.
Physical factors are not very relevant. They are traumas o f the pancreas (in
• liulmg surgical) and ionizing radiation. Environmental influences raise the risk o f
ii,ise development (if predisposition is present).
Chemical factors are р-cytotropic chem ical substances (alloxan, dithizone,
irrptozotocin and nitrosamines are p-cell cytotoxic agents inducing a diabetes
lik«- condition in experimental animals). Some pharmacological agents (diurct
и ■ oral contraceptives, p-adrenergic drugs) inhibit insulin secretion in man and
m induce the disease. The mode o f nutrition matters a lot. The factors, which
иii rease the load on the insulin apparatus (overeating, excessive consumption o f
iibohydrates and fats) provoke DM manifestations in patients with genetic pre-
•lr position.
Biological factors are o f infectious, immune and psychogenic origin.
Infectious factors are р-cytotropic viruses (Coxsackie, agents o f whooping
ищцИ, measles, German measles, hepatitis, influenza), agents o f scarlet fever, lues
•iiiil tuberculosis.
I he value o f immune factors is confirmed by the possibility o f experinien-
i it DM reproduction by injection o f heterogeneous antibodies against insulin or
|t cells.
Emotional overstrain can provoke the development o f DM (if genetic predis
I i t ion exists). Stress aggravates the diabetic condition and acts through steroid-
tuiluced glyconeogenesis or increased catecholamine secretion.
Pregnancy plays a role o f a biological factor. Predisposition is often importani
Thus, genetic predisposition is the main endogenous cause o f DM .
P A T H O G E N E S IS
ncclion o f the disease with the ABO system antigens has been noted (patients with
the A blood group are alTccted more often).
Mutation o f the genes, which participate in the functioning o f the insulin ap
p;i ml us and peripheral effect o f insulin, underlie hereditary predisposition to DM
Several mutant genes, which determine DM development, have been revealed
( ienetic defects o f p-cell membranes, insulin synthesis and secretion, insulin an
tagonist content, and insulin receptor structure may be inherited.
Types o f inheritance include autosomal dominant, autosomal recessive and
polygenetic ones. DM reference to the category o f multifactorial diseases reflecis
the value o f genetic factors together with the role o f the environment.
(ien etic predisposition is the basis, on which causative exogenous etiological
lactors (chemical, immune, infectious, psychic, overeating, etc.) lead to the devel
opnicnt o f DM . They unmask hereditary predisposition.
Secondary diabetes can develop in chromosomal syndromes (Klinefelter’s.
D own’s).
Thus, the disease depends on the interplay o f genetic and environmental influ
ences.
M etabolic Changes
I hc metabolic changes concern all pathways <>l metabolism as it has been dis
cussed above. In spite o f essential limitation o lsu gai use with food, a patient has a
liiK-h blood glucose level because o f glyconeogenesis Intermediate glucose mctnho
C h a p te r 14. I'alholoK ) of C a rb o h y d ra te M e tab o lism
ii in is disordered. So, insulin, as a drug, is used no t only to reduce the blood sugar
level, but mostly to correct interm ediate m etabolic pathways.
I he m etabolic m anifestations o f D M are detected by laboratory investigations.
• lunges in laboratory indices are: hyperglycem ia, acetonem ia, ketonem ia, lactaci
•innia, hyperlipem ia, hypercholesterolem ia and glycosuria.
Hyperglycemia som etim es reaches 25 m m o l/1 , glycosuria — up to 555 666
niinol/1 (100—120 g /d ay and m ore), the level o f lactic acid (lactocidem ia) exceeds
IIК m m ol/1 (N 0.033—0.078 m m o l/1 ), hyperlipem ia — up to 50—100 g /l (N 3.5
n к/ I ) , ketonem ia (by determ ination o f ketone bodies) — up to 5200 m c m o l/l
(N < 517 m c m o l/l).
Clinical Manifestations
Diabolic Ciми.i
I lie most violent com plication o f DM is com atose slate. I lie m anifestations
o f com a are th e following: loss o f consciousness, arterial hypotension, Kussm aul’n
disorder o f respiration, a smell o f acetone from the m outh.
Ih ere are several types o f diabetic com a. They are:
Acidotic (lactacidemic), w hich is a result o f lactic acid accum ulation and blond
p ll reduction.
Ketonemic, w hich is a result o f the toxic effect o f ketone bodies.
Hyperosmolar, which is a result o f high hyperglycem ia.
Hypoglycemic, w hich is a com m on result o f insulin overdose.
I hc clinical and m etabolic m anifestations o f DM m entioned above as well as
the etiology and pathogenesis vary in different types o f D M m entioned below.
D M C L A SS IFIC A T IO N
IN S U L IN -D E P E N D E N T D M
(type 1; juvenile-onset; ID D M )
D am age o f p-cells,
change o f th eir antigen properties
Secondary (Symptomatic) DM
I M atch the term s, w hich are used in the study o f carbohydrate m etabolism p a
thology, and th eir definitions.
Term Definition
1 (iiv e the characteristics o f the peripheral effect o f insulin and its disorders.
I. It is the m ain cause o f absolute insulin insufficiency.
I'iiil I <ie n rr a l I‘mIIi<i|)Ii >\I<iIok >
(i Л 12-year-old teenager grew thin. The level o f glucose in the blood w;is
50 mmol/1. Later com a developed. W hat was the m ain m echanism o f com a?
A. Ketonem ic.
B. Hypoglycemic.
C. H yperosm olar.
D. Lactacidem ic.
E. Hypoxic.
A patient with type 1 diabetes was injected insulin. Later he suffered from
sickness, irritability, sweating. W hat is the basic m echanism o f hypoglycem ia,
which developed?
A. Intensifying o f ketogenesis.
B. Intensifying o f glycogenolysis.
C. C arbohydrate starvation o f the brain.
D. Intensifying o f lipogenesis.
E. Depressing o f glyconeogenesis.
5. The reference o f DM to the category <•! niiiliilactoi i;il diseases reflects the
value o f genetic factors together with the role ol pathogenic influences ol
the environment.
6. G enetic predisposition is a basis, on which different etiological factors
may cause DM .
Proofs o f the role o f genetic mechanisms are the following:
7. Existence o f «family» diabetes, when the disease is recorded in several
members o f one family.
8. The concordance rate in ID D M is about 50 % and approaching 100 % for
twins having N ID D M .
Compile a comparison table o f the normal influence o f insulin on the blood sugar
level and its disorder in insulin insufficiency
Normal Influence of Insulin Disorder of Blood Sugar Level
on Blood Sugar Level in Insulin Insufficiency
(not less than 10 mechanisms) (pathogenesis of hyperglycemia)
1.
2.
3.
I 'ind points o f comparison and compile a comparison table o f differences between type
I and type 2 DM
Points of Comparison Type 1 DM Type 2 DM
1.
2.
3.
4.
<luipter 15
PATHOLOGY OF LIPID METABOLISM
Ihere are anim als (rabbits, horses) that do not get fats with food, but develop
......ilim entary deficit o f lipids. 10 % o f carbohydrates are converted into lipids tin
•In physiological conditions with the aid o f insulin.
As to lipid absorption in the bowels, there are som e causes o f disorder:
• lack o f bile (liver insufficiency, calculous cholecystitis), which emulsifies
lipids by bile acids and exposes them to pancreatic lipase;
• inflam m ation o f the bowel m ucosa;
• pancreatic insufficiency (the pancreas is the m ain source o f lipase in the
bowels).
II lipids are not absorbed in the bowels, they appear in feces (steatorrhea).
Absorption o f fat-soluble vitam ins (A, D, К , E) is connected with lipid absorp
...... C orresponding clinical m anifestations o f a- and hypovitam inosis (bleeding,
i n Intis. vision and endocrine system im pairm ent) develop in case o f insufficient
.ii • ni pt ion o f lipids and vitam ins.
S our clotted milk, m ineral w ater, laxatives intensify cholesterol excretion from
the intestine. Physical training prevents accum ulation o f endogenous cholesterol.
The m edicines, w hich block endogenous cholesterol synthesis at the level o f
и i tic acid, have been created. How ever, they block steroid horm one synthesis.
Linder physiological conditions, ketone bodies (w hich are form ed in the pro-
• oss o f p-oxidation o f fatty acids) provide the organism with energy, com peting
with glucose.
Ketogenesis intensification is a serious disorder o f interm ediate lipid m etabo
lism. In glucose deficiency o r im possibility o f its utilization as a source o f energy,
iipolysis and ketoacidosis get increased. U n d er pathological conditions, w hen lipo
lysis in the adipose tissue gets intensified, the liver does not utilize all fatty acids for
m^lyceride synthesis, and part o f them are included into p-oxidation and ketogcne
м It is th e m echanism o f ketoacidosis in starvation (p. 178) and D M (m ore details
••ii p. 210). Significant accum ulation o f ketone bodies in the blood (m ore than 0.1
and up to 20 m cm ol/1) is
dangerous for life resulting
in metabolic acidosis.
Disorders of Lipid
Accumulation and
Deposition
Lipids m ay be ac
cum ulated in a specific
ndipose tissue and in o th er
ones. T he first variant is
tailed obesity. The second
is lipoid degeneration (in-
llltration, decom position).
N curohum oral regulation
ol lipid deposition and
mobilization is represent
ed in figure 24.
OBESITY
Specialized cells o f the connective tissue (adipocytes) can contain alm ost un- I
limited quantity o f fat drops.
Obesity is an excessive accumulation of lipids in the adipose tissue.
Obesity is an actual m odem problem not from the point o f view o f esthetics,
but as a risk factor o f the developm ent o f such pathological processes as D M , athc- I
rosclerosis, arterial hypertension and throm bosis. It becom es clear that obesity is
related to m any diseases and prem ature aging.
TYPES
ETIOLOGY
Etiological factors, which cause obesity, are divided into exogenous and endo- I
genous, as well as acquired and genetic.
An exogenous factor is overeating. Increased consum ption o f food is one o f the
m ain causes o f obesity. The latter includes m o th er’s nutrition during pregnancy, I
child feeding in early childhood, family and national traditions, way o f life, pros I
perity and food accessibility. C ertain diets predispose to overeating and obesity, j
Overeating causes alimentary obesity. W hat kind o f food leads to obesity most of
all? It is carbohydrates. Patients should be recom m ended to limit consum ption of
farinaceous food, potato and sweet.
C hronic stress usually changes eating habits o f people and provokes overeal
ing.
H ypodynam ia is an o th er exogenous factor. If sensitivity o f the alim entary cen
ter and constitution are norm al, energy im balance is created by the way o f lilt*
without m o to r activity.
T he endogenous factors o f obesity are nervous and endocrine system d is o rd e r
as well as the pathological constitution. M any patients com plain that in spite ol
norm al appetite and lim itation o f high-calorie product consum ption, their weiglii
increases and they are obese. Suppressed catabolism underlies such a situation.
G en etic factors (m etabolism peculiarities, enzym e activity) also refer to Ih e ,
endogenous ones. A peculiarity o f obesity etiology consists in the fact that Ih e j
lipomatous constitution (according b) O.O. Rohoinolcls, p. 59) plays Ihe role o f «
decisive condition.
Chapter I S. Pathology o f I jp id M etabolism
PATHOGENESIS
I lie role o f genetic factors and constitution has been confirm ed statistically. It
ii i been observed th at obesity develops in som e generations o f one family (consti
tutional obesity). However, this inform ation is not a direct evidence o f the role ol
h a rd ily , as one can not exclude the influence o f the sam e environm ent, the same
luibits concerning the kinds o f food and the way o f life.
More convincing inform ation has been received under experim ental condi
lions.
Л subpopulation o f m ice with congenital obesity has been artificially created in
i laboratory. The pathology is inherited as an autosom al recessive trait.
The role o f constitution in obesity is obvious. O.O. B ohom olets distinguished
ih.- lipom atous type o f constitution together with fibrous, pastose and asthenic (the
i .1 1 . 1 has no obesity in any case).
Prim ary (constitutional) obesity is observed in 55—65 % o f all cases. T he gene
"I obesity and its product leptin are being investigated.
The structure and function o f the systems, w hich regulate alim entary behavior
.nil lipid m etabolism peculiarities can be inherited — adipose tissue peculiarities,
. lipocyte quantity and size. All these factors m ust be taken into account in obesity
1 'iiliogenesis. In general, obesity is inherited polygenetically. In m eans that il is
il« iri m ined by genetic, environm ental factors and acquired diseases.
T ogether w ith the nervous system the endocrine one accom plishes regulation of
fat m obilization and deposition. A drenaline and insulin have the m ost potent influ
ence but in the opposite direction. A drenaline stim ulates lipolysis. Insulin stimu
lates lipogenesis by the synthesis o f neutral fats from glucose and fatty acids, inhibit
lipolysis, decreases the blood sugar level, stim ulates appetite. Figure 25 represent
the role o f insulin and adrenaline in lipid m etabolism in the lipocytes and correla
tion o f lipogenesis and lipolysis.
All conditions, w hich decrease the blood glucose level, stim ulate pancreatic
island function and are accom panied by hunger provoking overeating.
T here is a variant o f obesity, w hich is characterized by hyperinsulinism , insulin
resistance and hyperglycem ia. T he basic dam ages are at the level o f target cells. Л
decreased quantity o f insulin receptors on the surface o f adipose cells leads to in
sulin resistance and com pensatory hyperinsulinism . Obesity com bines with D M in
Adrenaline В Adrenaline
Scheme 13. Relation between obesity, DM, atherosclerosis, arterial hypertension, thrombosis
and myocardial infarction
G enetic predisposition (not connected w ith HLA system antigens)
H eparin
deficiency
D ecrease o f insulin
receptor am ount
Relative insulin
insufficiency
I
P-Cell
dysfunction
|| 1 . 1 1 A b s o lu te in su lin
---------------- -------------------
e x h a u s t io n iiwullU itncy
C h a p te r IS. Га11|»1»ю o f Lipid M e tab o lism
LIPOID DEGENERATION
4. D uring the second period o f com plete starvation w ithout w ater deprivation Ihc
level o f lipids in the blood o f an experim ental anim al has increased. Wlial form
o f hyperlipem ia is observed in this case?
A. Transport.
B. N utritional
( lu p in I' Г ;Н ||(||оц\ o f I .ipid M cliiliolisin
D. Productional.
E. Combined.
P roteins play a central role in the vital activity o f the organism . They determ ine
the structure and function o f any organ. Each organ has its specific proteins
structural proteins, enzym es, receptors, transport proteins, etc.
F or this very reason protein m etabolism pathology is an im portant com ponent
o f the pathogenesis o f all pathologic processes w ithout exception. The pathogenesi
o f any pathology at the m olecular level includes dam age o f the protein m olecules
T here are no reserves o f proteins in the organism , and only food is a source ol
am ino acids. T he dynam ics o f protein balance has the following order:
• entry o f proteins with food;
• digestion o f proteins in the digestive tract into am ino acids;
• absorption o f am ino acids into the blood;
• intracellular anabolism and catabolism ;
• excretion o f final products.
Disorders o f the protein balance m ay occur at every stage o f the transform ation
o f proteins received with food.
Regulation of Protein M etabolism . Anabolism and catabolism o f proteins an
regulated by horm ones. T he latter serve as a signal for the activating o r inhibti
ing effect on the processes o f transcription in the genom e. T hen, w ith the aid ol
enzym es, m any functional proteins (the structural and receptor proteins, etc.) аи-
synthesized. So, it is a classical schem e: horm one — gene — enzym e.
Anabolic effect o f horm ones consists in activation o f the processes o f protein
synthesis in com parison with their disintegration. T he following horm ones have
such an effect.
Somatotropic hormone is a horm one o f growth. It activates protein synthesis
It activates lipid oxygenation and neutral lipid m obilization and thus leads to stil
ficicnt release o f energy, which is necessary for protein synthesis.
Insulin provides transm ission o f am ino acids through the cellular m em brane
into cells and thus provides protein synthesis and inhibits gluconeogenesis. Lack ol
insulin leads to protein synthesis decrease.
Sex hormones (testosterone, progesterone) refer to anabolics and activate protein
synthesis.
Catabolic effect o f horm ones consists in activation o f protein disintegration in
com parison w ith protein synthesis. T he following horm ones have such an effect.
Thyroxin increases the am ount o f active sulfhydric groups in the structure ol
som e enzymes. Tissue cathepsins are activated and th eir proteolytic effect gets in
creased. It increases the activity o f som e am inooxydases thus desam ination ol
som e am ino acids is increased.
Glucocorticoids (cortisol) activate protein disintegration Protein expenditure in
creases gluconeogenesis. Protein synthesis is deccleialed
C h a p te r l(>. Га11к||»к> o f I’ro lcin M etabolism
Q uantitative and qualitative disorders o f blood protein com position reflect van
ous pathologic processes. T hey are m anifested by changes in the organism durii,u
infection, neoplasia, allergy, inflam m ation, etc.
Hyperproteinemia is always relative, caused by hem oconcentration. Its absolut
variety is observed in some types o f leukem ia with form ation o f anom alous proteii
(paraproteins).
Hypoproteinemia is, as a rule, absolute and occurs during starvation, neoplasi
diseases o f the liver (decreased production o f proteins) and kidneys (increased pro
tein loss in the urine), disorder o f protein absorption in the digestive tract.
Dysproteinemia is a im balance betw een the co n ten t o f album ins, globulins and
o th er proteins in the blood.
T he entry o f proteins into the organism is im paired in com plete o r partial (pro
tein) starvation (see chapter 10, p. 184).
Im paired protein digestion in the digestive tract into am ino acids happens in
case o f a decrease o r absence o f digestive proteolytic enzym es (pepsin from th
stom ach, tripsin and hem otripsin from the pancreas). In decreased gastric acidi
ty, the activity o f peptidases (pepsin, chem osin) m ay be disordered. A complci
arrest o f pepsin secretion in the gastric juice does not affect the degree o f protein
splitting in the intestine but essentially influences its rate. In achylia o r subtotal
stom ach resection the form ation o f tyrosine and tryptophan is disordered. In chonic
pancreatitis (inflam m atory and dystropic pathology o f the pancreas) digestion gel
disordered.
T here are acquired and genetic varieties o f protein balance disorder.
A m ino acids are absorbed on the microvilli o f the intestinal m ucosa with ih>
aid o f proteolytic enzym es and then en ter the portal vein system. A lack o f the.
enzym es is m ore often o f genetic origin. D isorder o f am ino acid absorption ma
appear due to pathological changes o f the intestinal wall, for exam ple, in its inflam
m ation, dystrophy and edem a.
Deficit o f even one essential amino acid hampers the process o f protein bio
synthesis and creates a relative surplus o f other am ino acids with accumulation о
intermediate products o f the metabolism o f these amino acids.
The genetic deficit o f intestinal proteolytic eii/.ynics can lead to the situation
when proteins can be absorbed into the blood without preliminary proteolysis aiu
sensitize the organism (lactase deficit is connct led with milk intolerance).
C h a p te r l(>. Pathology o f P ro te in M etabolism
Amino acids, absorbed into the blood, are used by tissues for synthesis o f
i "«ly's own proteins as well as for other organs and blood.
As to etiology, protein synthesis disorder may be acquired and hereditary (ge
helically determined).
Acquired Disorders o f Protein Synthesis
Protein synthesis may be disordered under the influence o f various external and
internal harmful factors.
Protein synthesis disorder may be connected with a lack o f amino acids, which
hie protein precursors (tyrosine for thyroxin, tryptophan for oxidizing enzymes).
Protein synthesis may be stopped by the absence in a cell o f even one essential
imino acid. The need for essential amino acids is connected with their participa
Hun in the synthesis o f hormones, mediators and BAS. Essential amino acids are
11 \ ptophan (its deficit leads to decreased plasma protein concentration), arginine
11 uls to spermatogenesis suppression), histidine (decreased hemoglobin concentra
n u n ) , methionine (fatty liver degeneration as a result o f a deficit o f labile methyl
rumps necessary for lecitin synthesis), valine (growth retardation, body weight loss,
ki-iutoses development), lysine, leucine.
I)isorder o f 7-globulin synthesis is o f especial importance. It leads to a decrease
I immunoglobulin (antibody) synthesis and immunological reactivity disorder.
Blocking o f protein catabolism enzym es leads to protein synthesis disorder.
Since the organism has no protein reserves, starvation (exogenous and endo
ye nous) causes alimentary protein deficiency.
Disorder o f the ratio o f anabolic and catabolic factors, which regulate protein
metabolism, leads to protein synthesis disorder. Hormonal derangements, namely,
imbalance between hormones with anabolic (insulin, somatotropic and sex hor
nioncs) and catabolic (thyroxin, adrenaline, hydrocortisone) mechanisms, signifi
■ mtly influence protein metabolism. A lack o f somatotropin leads to a decrease
•I protein synthesis. A lack o f insulin has the same effect and leads to metabolism
"m utation at increased glucose production (glyconeogenesis).
A lack o f microelements can also impair protein synthesis (thyroxin needs
Iodine).
Hepatic insufficiency and disorder o f its protein synthesis function arc also a
и ison for decreased protein synthesis or production o f anomalous proteins (para
piolcins).
I ach protein is encoded by a gene, and any code (gene) can hr disrupted
(Quantitative changes o f normal proteins or synthesis o f anomalous ones wit Ii a
I'ilrt 1 (•(‘lU-riil PulliopliVNioloK)
P R O T E IN CA TA BO LISM D IS O R D E R
Proteolysis Disorder
Arrest o f the synthesis o f the enzymes, which regulate protein and amino acid
iuinform ation, leads to a disorder o f intermediate amino acid metabolism due to
lunsamination, deamination and decarboxylation (scheme 14).
IWarboxylation Disorder
Tyrosine Disbolism
D ihydroxyphenyl- D ihydroxyphenyl-
alan in e (D O P A ) a la n in e (D O P A )i
------------ 1---------
r
D opam ine D opaquinonc
5r
N oradrenaline I >o|>.n.hrumc I
r
A drcnalinc
~ T
IIhtnhm
C h a p te r 16. PalholoKV o f P ru li'in M etabolism
I'limylalanine Disbolism
I he disease m entioned above presents one o f the m ost dram atic exam ples ol
mil i relationship betw een m utations o f one gene, absence o f one enzym e, dism c
lnholism o f one am ino acid, severity o f clinical m anifestations, phenotype depen
i nre on the environm ent, and effective prophylaxis by rather sim ple m easures as
• >ln ion o f som e sim ple products in a diet.
index o f a disorder o f their form ation and elim ination is the level and com position
o f the so-called residual (non-protein) nitrogen in the blood. Its norm al level о
14.3—21.4 mmol/1. As to com position, it consists o f 50 % urea. 25 % am ino acid*,
and nitrogen products.
A final product o f the m etabolism o f purine bases (adenine and guanine, win» It
belong to th e structure o f nucleic acids), is uric acid. D isorder o f its synthesis .mil
excretion leads to hyperuricem ia, which is a rather widespread syndrom e (in мин*
populations up to IX %). An exam ple o f im paired synthesis and excretion o f nil»
acid is gout.
C h a p te r U>. I ’utholoK) <>l 1’iotc'iii M rliilm lism
Л 15-year-old boy suffers from alkaptonuria. His urine becom es black aftei
settling. M etabolism o f w hat substance is genetically disturbed?
A. U ric acid.
B. Cysteine.
C. Alanine.
D. Urea.
E. Tyrosine.
In som e m onths after birth a child has a C N S lesion. T he skin and hair bright
encd. A ddition o f a solution o f trichloracetic iron to fresh urine leads to the
appearance o f olive-green coloring. W hat kind o f hereditary disbolism took
place?
A. Tyrosinosis.
B. A lkaptonuria.
C. Fructosuria.
D. Phenylketonuria.
E. Albinism.
Since the m ajority o f interm ediates (products o f interm ediate m etabolism ) arc
acids, pH regulation is provided continually. M any m echanism s (in the liquid me
dia, blood and cells) are constantly participating in acid-base balance regulation.
1. Buffer systems neutralize surplus o f acids and alkalis, transferring them into
a form convenient for further secretion by the lungs and kidneys.
• H ydrocarbonate buffer system H 2C 0 j /N a H C 0 3 = 1/20 m aintains pH in
the blood plasm a and interstitial fluid. This buffer has a volatile form о
acid ( C 0 2), which can be easily excreted by the lungs.
• Phosphate buffer system N aH jP O y N ajH P C ), = 1/4 participates in acid
base regulation in the kidneys.
• Hem oglobin buffer functions in erythrocytes.
• Protein buffer regulates intracellular pH .
2. Lungs role consists in constant discharge o f carbon acid in the form o f cai
bon dioxide C O r 1
3. kidneys role consists in acid-base regulation through three m ech an ism .
(schem es 16, 17, 18):
• Acidofienesis is secretion o f H* ions into the renal tubules.
• Ammoniogenesis is form ation and secretion o f am m onia ion (N11,) into the
renal tubules. T hen, N11, reacts with H* to form N ll4'. Afterwards il is
accom panied by anion Cl . N eutral am m onium salt N11,(1 is form ed and
excreted in the urine.
• Rcuhsorplion of hicurhonutc ( N a l K ' ( ), ) ill llic ren al tu b u le s.
Chapter 17. Га|||и||>к> of Acid-Base Balance
Consequently, urine examination reflects the acid-base state. Two urine indices
.ire of practical use. They are:
• urinary acidity tested by titration;
• ammonium salt content.
4. Aldosterone (hormone of the adrenal cortex) supports acidogenesis in the
kidneys, participates in H +and Na+exchange (H +ion secretion and N a+ion
reabsorption).
ETIOLOGY
Glutamin
-NH,
( ilulamin
Glutaininic acid
+Cl N IM I
-NH,
-> N II, + H ‘- •N11,
a-ketoglularic acid
Part I Gmeral I'lilluiphysioloKy
• poisoning that manifests itself through vomiting (loss of acid) and din
rhea (loss of alkalis);
• starvation;
• infection that results in pulmonary or renal insufficiency and in dison
of the main physiological mechanisms of acid-base balance regulation
Endogenous causes are the following:
• disorders in metabolism regulation and accumulation of acid intermed
ates (D M );
• pathology of the organs that participate in acid-base balance regulaii
(inflammation, vascular disorders leading to malfunctioning of the lui
kidneys, and adrenal glands);
• various diseases that manifest themselves through vomiting, diarrhea,
excessive salivation.
PATHOGENESIS
и ""i" nsaling possibilities of the organism with any form of acid-base dysfunction.
(It I" 1 ‘>i hypoproduction of aldosterone may also provoke decompensation.
I '( compensation is manifested by a change in blood pH. This state is incom
toiii'l' with life and is called acidic coma. The patient dies without urgent medical
M l'
CLASSIFICATION
l iking into account all the aspects, the following four forms of acid-base dis
pel- i are distinguished (table 6 gives additional characteristics).
Non-Respiratory Acidosis
given oil with each breath. Thus, in order to exhale a particular amount of COr hy
perventilation must be maintained until the plasma 1 1 ( 0 , concentration is again
normal, either through raised renal excretion of acid or through the breakdown of
organic acids. Increased urinary acidity and ammonium salt content are the signs
ol kidney participation in compensation.
In extracellular acidosis cells lose K +. Hyperkalemia develops. Due to Na+up
lake cells arc swelling. Intracellular acidosis inhibits K +channels and has a negative
t*licet 0 1 1 the cardiac muscle. Prolonged intracellular acidosis inhibits cell division
and favors apoptotic cell death.
lixcrelory non-respiratory acidosis is illustrated by the following clinical ex
amples.
• I )iarrhea, when alkaline intestinal juice loss takes place.
• Renal dysfunction, when acidogenesis, ammoniogenesis and bicarbonate reab
sorption are depressed.
• Adrenal gland disease accompanied with aldosterone deficiency.
Compensation and disorders are the same as mentioned above. Hyperventila
lion plays the main role.
Respiratory Acidosis
Non-Respiratory Alkalosis
more Ca2+ is bound to plasma proteins; there is a fall in the concentration of C a"
in the plasma. Chronic non-gaseous alkalosis influences carbohydrate metabolism
Ii inhibits p-cells, activates а -cells, causes hyperglycemia and decreases tolerance
in glucose.
This disorder may be illustrated by the following clinical examples.
• Abuse of alkaline mineral water (exogenous type of disorder).
• Uncontrollable vomiting and loss of acidic gastric content.
• Different disorders of the adrenal cortex, when excessive aldosterone formation
lakes place (tumor).
hihle 6
Characteristics of Acid-Base Conditions
1 )isorders
of Acid- Clinical
PH н со,
и
О
Etiological Factors
Manifestations
N
Base
Balance
Acute re- Acute respiratory insuf Tachycardia, tac I T Un
\|>iratory ficiency, cardiopul hypnea, sweating, changed
acidosis monary insufficiency, headache, cyanosis,
trauma of the breast arrhythmia, arterial
bone, asphyxia, CNS hypotension
trauma/tumor, dam
age of the respiratory
muscles
( hronic Chronic obstructive Dyspnea or tac I T Т
nspiratory disease of the lungs hypnea, coma
Hinipen-
Mited aci
dosis
Г.н I I ( ■ciirrul l*Mlh<i|)hv4ioli>K>
/<//>/<•ft conliniuul
I )isorders
of Acid- Clinical
Etiological Factors PH CO, H CO ,
Base Manifestations
Balance
Metabolic DM, starvation (com Kussmaul’s respira
acidosis plete), shock, heart tion (hyperpnea),
block, respiratory fail hypotension,
ure sweating, cold skin,
coma, arrhythmia
Non- Chronic renal insuf Weakness 4-less
rcspiratory ficiency than in
excretory the acute
acidosis form
Respira Hyperventilation, CNS Dizziness, par Un
tory alka damage esthesia changed
losis
Non- Wasting HC1 under Muscle weakness,
rcspiratory vomiting, hyperadre- arrhythmia apathy,
excretory nocorticism (Cushing’s confusion, stupor
alkalosis syndrome), aldostero-
nism
Л. Respiratory alkalosis.
Ii. Metabolic alkalosis.
C. Non-respiratory alkalosis.
D. Respiratory acidosis.
E. Excretory acidosis.
I lie water balance is regulated by many mechanisms. Some o f them act locally
mi tissues; some are systemic for the whole organism
Chapter IX. Pathology of Water anil Kleetrolyle llalauee
total Mechanisms
I ocal (tissue) mechanisms regulate the water balance between the blood and
ii nos through the capillary walls.
I Starling and other scientists (Vidal, Fisher) studied the factors, which de-
i nnine liquid passing from the blood stream into the intercellular space (llllui
11 <hi) and its return into the vessels. This balance is regulated by physicochemical
tiK'chanisms:
Hydrodynamic pressure difference between the blood and extracellular fluid. I hc
blood moves in the capillaries at a definite speed and under a definite pressure,
л liich results in the formation of hydrodynamic force, which makes water go out
ol the capillaries into the interstitial space. The higher blood pressure and ihc
less tissue fluid pressure, the higher effect of hydrodynamic force. Hydrodynamic
blood pressure in the arterial section of the capillaries is 35—40 mmHg, and in ihc
venous section — 10—15 mmHg (Starling, fig. 26).
• Oncotic pressure (of proteins) difference between the blood and interstitial liquid
An increase of vascular permeability for proteins occurs in a number of pallm
logic processes and essentially influences this parameter (Starling, fig. 26).
• Osmotic pressure difference between the blood and interstitial liquid (Vidal).
Interstitial tissue pH. The hydrophilic nature of colloids depends on H ' con
ccntration and rises in acid media. Then colloids swell and detain more walct
i Fisher).
I he resultant force is called filtration pressure.
Hie ratio of these forces determines the passage of liquid into tissues from the
.nioiial part of the capillaries and its return to the blood in the venous part.
Systemic Mechanisms
Systemic mechanisms regulate the water balance between the organism and
Ihc environment. One should understand that all the organism water cannot be
и ulated by the physicochemical laws mentioned above. It is regulated by biologi
■il (neurohumoral) mechanisms with the participation of such a high-level organ
is ihc hypothalamus.
These mechanisms are the following.
• Participation of the volumoreceptors ol the vasiulai wall and the left atrium «»!
the heart, which control the circulating blood volume.
• Participation of osmoreceptors o f the vascular wall (arches of aorta and carotid
sinus), which control blood osmotic pressure.
• Participation of aldosterone of the adrenal cortex, which regulates (increases)
Na reabsorption from the primary urine into the blood (antinatriuretic mechu
nism).
• Participation of the hypothalamus, which reacts both to decreased bloo<l
volume and increased blood osmolarity in response to volumo- and osmoreccptot
iriials. It releases vasopressin (antidiuretic hormone, A D H ) by the supraoptii .il
and paraventricular hypothalamic nuclei. The point of vasopressin action is th«
renal tubule epithelium. Vasopressin increases water reabsorption from the primals
urine and thus regulates diuresis (the primary urine quantity is 180 1/day; the final
urine quantity — 1 —2 1 ).
• Participation of the kidneys with their receptors and renin. Stimulation of tin
adducting renal arteriole volumoreceptors and of the osmoreceptors of the macula
densa of the juxtaglomerular complex intensifies renin synthesis and release. Ли
giotensin II, which is formed under renin influence, increases aldosterone secretion
and stimulates the thirst center located in the lateral part of the hypothalamus.
• Retention of water and Na+ in the organism is opposed by two mechanism-,
of natriurcsis:
• renomcdullar prostaglandins;
• atrial natriuretic factor (A N F, atriopeptide of 28 amino acids).
Antidiuretic and antinatriuretic mechanisms oppose the diuretic and natriurcin
ones Renomcdullar prostaglandins and A N F increase diuresis and natriuresis, re
lax the vessel smooth muscles and decrease arterial blood pressure. The amount ol
AN I in the atrium and its secretion into the blood increases after excessive water oi
i omnion salt intake, blood pressure rise as well as stimulation of p-adrenoreceptor,
oi vasopressin receptors.
All these mechanisms are constantly functioning and provide water-electrolvh
homeostasis restoration in case of blood loss and dehydration, water retention In
tin organism as well as osmotic concentration changes.
H Y PER H Y D R A T IO N
EDEMA
Local lilcimt
Systemic Edema
Systcmic edema may take such forms - cardiac, nephritic, hepatic, endocrine
iih I i ichexial (fasting).
t anlin с Edema
One more mechanism of systemic watei icleution hi the organism joins the
mentioned ones. It is described below.
Disorder of renal blood supply caused by cardiac insufficiency —>renin pro
duction and angiotensin formation -» aldosterone secretion -> stimulation «>1
Na' reabsorption from the primary urine into the blood -» increase of blood
osmotic pressure -» reaction of vascular osmoreceptors -» transmission ol
impulses to the hypothalamus -» vasopressin (A D H ) liberation - »stimulation
of water reabsorption from the primary urine into the blood - » limitation ol
diuresis -+ retention of water in the blood -» hypervolemia -» redistribution
of water into the intercellular space (according to Starling’s law).
This is cardiac edema pathogenesis.
I lie given sequence of events is physiological (it is compensation in case ol
circulating blood volume reduction, for example in blood loss). In case of heart in
sullicicncy this chain of events can be named «an error of adaptation» and becomes
the main pathogenetic factor of systemic edema development.
I Itus, all pathogenic factors participate in cardiac edema and it is their combi
nation and mutual reinforcing effect that provide its pathogenesis.
The understanding of this pathogenesis allows a physician to treat effectively
a patient with cardiac edema. The therapy is directed at heart disease treatment
However, this therapy requires time while quick removal of excessive water is nee
essary, since hypervolemia overloads the sick heart. Therapy is guided not by the
fact of venous congestion, but by the mechanisms, which are responsible for sys
temic water retention. It becomes clear that neither the hypothalamus nor vasculai
receptors are proper targets for the drugs. The effect of contemporary diuretics is
directed a) against angiotensin or aldosterone formation and b) inhibition of then
activity. Salt-free diet must be recommended to the patient.
Nephritic Edema
Causes
Hypohydration develops when water loss exceeds its intake by the organism
It may develop in water intake limitation (water starvation, dysphagia, esophagc
atresia, comatose state, etc.). An increased water loss (diarrhea, vomiting, blood
loss, loss of fluid with exudate in bum, etc.) has the same effect. A combination о
these conditions may take place.
In dehydration the extracellular fluid and sodium ions are lost first. In the end
cells may lose potassium and the intracellular fluid.
Types
Consequences
IihIIih millions, and coma. The functions of the nervous centers and respiratory
tliMlmi become disturbed. Body temperature rises.
A marked decrease of arterial pressure may be accompanied by impairment of
liliiiiiion in the nephrons, oliguria (decreased diuresis), hyperazotemia and non
Iv-pn itory acidosis.
I hsorders of microcirculation, hemoconcentration, blood viscosity increase
m i l i.i m s result in the tissue form of hypoxia. Hypoxia combined with tissue dchy
ELERCTOLYTE IMBALANCE
pun >il ihe Ca2+channels so that the intracellular Ca2+concentration again falls and
||h muscle relaxes.
\n increase of Na+concentration in the blood causes predisposition to edema
M.i i niry into myocytes increases their tone (aldosterone easily provides it). Thus,
■мы. i llular retention of N a+ predisposes to arterial blood pressure increase. I lu*
h i m . . llular position of K + relaxes myocytes, ensures their rest, decreases their ex
Kji.iinlily threshold and prevents blood pressure increase. It is not easy to provide
Ии мши entry into a cell (due to heavy density gradient). The vagus nerve, atn.il
E Ittlmelic factor and renal prostaglandins promote it. Potassium loss from myocytes
ih. blood (hyiH'ikalemia) leads to disorders of myocardial excitability (cardiac
I ’a i l I (it-m-ral Pathophysiology
lahlc 7
Electrolyte Imbalance
/w/'/с 7continued
I). Hypokalemia.
E. Hypoglycemia.
2. Л girl is 6 years old. After eating an orange she suffered from edemas of the
eyelids, lips and tongue mucosa. Earlier after eating oranges rash and itch ap
peered. What pathogenetic mechanism is the main one in girl edematization?
Л. Decreased oncotic blood pressure.
H. Disorder of lymph drainage.
C. Increased oncotic blood pressure.
I). Increased permeability of the capillaries.
I Increased hydrostatic blood pressure in the capillaries.
4. Л person who was stung by bees suffers from edema of the upper extremities
and face. What is the basic pathogenetic mechanism of edema development?
A. Increased permeability of the vessel walls.
B. Increased hydrostatic pressure in the capillaries.
C. Decreased hydrostatic blood pressure.
I). Increased oncotic tissue pressure.
I Decreased oncotic blood pressure.
<i Л patient is ill with pneumosclerosis. Pulmonary hypertension and right veil
tricular heart failure with ascites and edemas have developed. What is the basic
pathogenetic mechanism of edema development?
Л. Increased hydrostatic vein pressure.
B. Increased oncotic tissue pressure.
C. Decreased oncotic blood pressure.
I). Decreased osmotic blood pressure
I Increased permeability of vessels
Chapter IS. radiology of Water and Klectrolytc Italanee
Chapter 19
BLOOD VOLUME DISORDERS. HEMORRHAGE
I'he normal state of the blood may be disordered prim arily (due to pathologi
i ill influence on the blood or bone marrow) and secondarily (due to pathological
changes in different organs and systems, which regulate blood functions and sustain
Us morphological, protein, electrolyte and gas homeostasis, e.g. in the lungs, liver,
kidneys, nervous and endocrine systems).
All typical pathological processes can develop in the blood system — inflam
mation and neoplasia of the bone marrow, allergy, hypoxia, dystrophy, typical
sysicmic disorders of metabolism.
Pathologic changes can develop in any part of the blood system — in the he
mopoietic organs (color fig. 28 represents the scheme of normal hemopoiesis), in
tin- blood circulation or deposition in the vessels, and in the organs and tissues, in
which (he blood is destroyed. These parts are tightly interconnected. As a result, a
pathologic process is not, as a rule, strictly isolated. The entire blood system reads
to the pathologic process as a whole.
As to pathophysiological and clinical inanilestalions, they are different depend
iiik on the part of the blood system, which gets primarily disordered. They may In*
localized in the systems of blood production, >In ulillion and destruction as well as
in the whole organism (systemic).
Chapter 19. ItliNNl Volume Disorders. I l<-inorrha|(<‘
Systemic Disorders
TO TAL BLO O D V O L U M E D IS O R D E R S
I IMM.OGY
i<>pi;in tube rupture in extrauterine pregnancy, etc.). Platelet deficiency and a lack
.•I any clotting factor may cause hemorrhage. Endocrine disturbance may cause
in morrhage as it is in metrorrhagia (uterine bleeding).
Important conditions, which determine the course of hemorrhage, arc:
• size of the damaged vessel;
• volume of blood loss;
• rate of blood escape (speed of bleeding);
• ability of the organism to stop bleeding by thrombosis (coagulative system,
quantity of platelets, etc.);
• localization of hemorrhage;
•whether hemorrhage is external (hemoglobin is lost) or internal (hemoglobin
is reutilized).
The localization of hemorrhage is of critical significance. Even a relatively
small hemorrhage in the brain or pericardial sac may cause death. If the blood
• >apes into the serous cavity, it is called hemothorax, hemopericardium or lictп о р т
i maim. Small hemorrhage into the skin is known as petechia, purpura or ecchymo
tlx Microscopic hemorrhage may be produced by marked blood congestion ihc
phenomenon is called red cell diapedesis (arterial hypertension is worthy of spci ial
mention in this context).
In this chapter hemorrhage is mentioned as blood loss ( bleeding) in connection
with blood volume decrease (hypovolemia).
IV IIIO G EN ESIS
radiological Changes
Pathological changes in bleeding concern not only the blood system but the
whole organism - the cardiovascular and respiratory systems, metabolism, pigment
balance, etc. Pathological changes are:
• decrease of the circulating blood volume (hypovolemia);
• decrease of erythrocyte and hemoglobin content;
• disorder of hemodynamics — decrease of arterial blood pressure, decrease ol
the venous blood entering the heart, decrease of systolic output;
• disorder of microcirculation in tissues;
• deficiency of tissue oxidation and respiratory function of the blood due to
the development of circulatory, hemic and tissue hypoxia;
• disorders of the functions of the vitally important organs (the nervous system
and heart as a result of hypoxia);
• disorders of tissue metabolism;
• acid-base imbalance (non-respiratory metabolic acidosis).
Secondarily blood loss may cause or aggravate arrhythmia, insufficiency of
югопагу blood supply and external respiration, as well as disorders of hemostasis
and renal filtration.
I’utl 2 S |n ‘<'mI (Systemic) I’iilliopliysioloKy
External bleeding causes vital iron loss In <.ts< ol bleeding into a body tis
sue or cavity hemoglobin and iron are reutili/ed In ihe course of this hemoglobin
resorption, an increased amount of bilirubin is formed and may causc transient
laundicc.
( onipensatory Reactions
Renin
( кич liolainines
I
Vasopressin Angiolcnsin II
Angiotensin
+ | Constriction of nrtcriolcii
► Opening of'nrtcrio vcnoir. Ik-«I
► Venous c o n s tiu iio n
Chapter 19. Blood Volume Disorders. Непинiliu^e
Acute Hemorrhage
Acute hemorrhage occurs after an injury of a large vessel. In this case the cel
hiliii elements and liquid part of the blood are lost proportionally (simple hypo
vnlcmia).
Acute loss of up to 10 % of blood volume and slow loss of even greater amount
itmy have no grave manifestations. Sudden loss of 25-40 % of the blood is very
iliingcrous. 60 % blood loss is lethal.
I he state of the hemostasis system plays an important role; thus, in its disorder
I... age of even a small vessel may lead to acute blood loss.
In clinical manifestations such changes play a critical role:
• acute disorder of the systemic blood circulation;
• critical decrease of arterial blood pressure;
• decrease of heart filling and systolic output, cardiac insufficiency (decrease
of coronary blood supply);
• development of acute circulatory hypoxia;
• acute renal insufficiency;
• acute posthemorrhagic anemia development;
• hemorrhagic shock may occur if compensation fails and is characterized hy
extreme impairment of all vital functions, loss of consciousness and death il
not treated.
Immediate compensatory reactions mentioned above may save the patient’s
hi- All the reactions are reflex. Hormones (vasopressin, adrenaline) and renin (an
yii iiensin) play an important role.
I ’.нt 2 S p e c i a l ( N v s lc n iic ) r u tl io p liy s io liiK y
II a patient survives, the cell, protein and electrolyte content in the blood is
restored, but up to complete restoration acute anemia lasts with oligocythemia
normovolemia.
Hemorrhage shock develops in sudden and massive blood loss, when potential
compensatory ability is insufficient for homeostasis normalization. Overstraining’
ol all physiological systems develops, and their activation becomes extreme. It is .1
potentially fatal situation if not properly treated.
In young people 20-40 % (1—2 1) blood loss leads to the development of mod
11 ate shock, loss of more than 40 % (more than 2 1) of the blood — grave shock
Not only the amount but also the rate, intensity and term of blood loss transform
hemorrhage into hemorrhage shock. The initial state of the organism and conconn
taut factors (starvation, overcooling, etc.) play a negative role.
Primary disorders in hemorrhage shock pathogenesis are a decrease of effective
blood volume, arterial pressure, heart filling and systolic output. It causes acute
circulatory hypoxia.
I II hemorrhage shock (as in any other form of shock) compensatory reactions
I.nl to be synchronic, balanced and properly regulated. Then these very reaction.
become additional mechanisms of damage and aggravate the situation. Numeron
vicious circles develop, the process becomes irreversible. The range of defense reac
lions narrows. The specificity of adaptive reactions to causative factors is lost.
I lie suppressed nervous system becomes insensitive to afferent influences from
v, it (receptors. The limbic system avoids regulation and leads to extreme activation
Chronic Hemorrhage
BLOOD TRANSFUSION
A healthy driver had acute massive bleeding as a result of a car crash. In hall
an hour he was hospitalized in the state of posthemorrhagic shock. What is the
slate of his blood volume?
A. Oligocythemic normovolemia.
B. Oligocythemic hypovolemia.
C. Simple hypovolemia.
D. Polycythemic hypovolemia.
E. Oligocythemic hypervolemia
A healthy driver had acute massive bleeding as a result of a car crash but was
hospitalized only in a day. What is the state of his blood volume?
A. Oligocythemic normovolemia.
B. Oligocythemic hypovolemia.
C. Simple hypovolemia.
D. Polycythemic hypovolemia.
E. Oligocythemic hypervolemia.
Го master the material of this chapter one should know the physiological
histological and biochemical aspects of the structure and function of erythrocytes
and bone marrow, types of erythropoiesis (adult normoblastic (erythroblastic) and
embryonal megaloblastic), hemopoietic factors (the role of renal erythropoietin,
iron, vitamin B l2and folic acid), normal indices of the blood.
Pathological changes of erythrocytes may be quantitative and qualitative.
ANEMIA
CLASSIFICATION
POSTHEMORRHAGIC ANEM IA
/.!/»/«• S
Classification of Anemia
Principles of Classification Classifications
I linlogy (causes) Traumatic (mechanical destruction of erythro
cytes), toxic, immune
I'.iiticipation of genetic mechanisms Acquired and hereditary
г iihogenesis Posthemorrhagic, hemolytic, dyserythropoietic
I vpc of hemopoiesis Normoblastic (erythroblastic) and megaloblas
tic
M'llity of the bone marrow to regenerate Regenerative, hyporegenerative (hypoplastic),
1 iIns ability is estimated by the quantity
aregenerative (aplastic), hyperregeneralivc
o! n-generative erythrocyte forms)
<olor index Normochromic (0.85—1.15), hypochromic
(< 0.85), hyperchromic (> 1.15)
Si/e of erythrocytes Normocytic (7-8 ц), microcytic (< 7 ц),
macrocytic (> 8 ц), megalocytic ( 1 0 - 1 2 and
more)
1 linical course Acute and chronic
Acute posthemorrhagic anemia occurs after acute blood loss in case of Iran
in.is of large blood vessels or inability of the organism to stop bleeding because of
hnnostasis disorder.
Immediately after blood loss and during the first hours the quantitative indices
I (lie peripheral blood are delusively normal because erythrocytes, hemoglobin and
i i i wna are equally reduced (simple hypovolemia, p. 268).
Immediate compensatory reactions directed at the restoration of the total blood
■ilume and arterial blood pressure develop (peripheral blood vessel spasms, resloni
... . of Ihe circulating blood volume due to the reserved blood, decrease of diuresis,
i г p. 270). Then, erythrocyte release from the depots (the liver and spleen) partly
n stores the cellular blood composition.
Alter restoration of the total blood volume (in some hours) a reduction ol
niuhrocyte and hemoglobin concentration is recorded. Delayed mechanisms ol
....ipensation are observed later as increased hemopoiesis. On the 4,h—5"' day alici
i' nic blood loss, proliferation of the erythrocytic stem cells of the bone marrow
т .iv be observed (it is provided by erythropoietin). In this period a microscopic
Mitmination of the cellular composition of the blood shows signs of regeneration
Ilu regenerative forms of erythrocytes (reticulocytes, polychromatophils) appeal
hi the peripheral blood (regenerative anem ia). Their content rellccts the capability
P . i l l 2 S | x i ia l ( S y s lt- i iiit'> l >u lh o |ih > s io lo K v
Itlood Picture
h« the blood, it does not pass through the renal filter, but transforms into indirect
1'ilirubin in spleen macrophages causing jaundice. In case of massive hemolysis and
i hi oat amount of free hemoglobin in the blood, the latter passes through the renal
hltcr and appears in the urine (hemoglobinuria), which becomes dark.
In case of massive acute hemolysis, body temperature rises (because of II I
pi eduction by activated macrophages). D IC syndrome (p. 332) development is pos
nblc in case of massive production of thromboplastin.
i lussification
I Oology
products of nitrous metabolism may have the same result. Splenomegaly may Inul
to excessive erythrocyte destruction.
rhe causes of acquired hemolysis may be of genetic origin — somatic mutation
of crythroblasts under the influence of viruses, microorganisms, medicinal prepani
lions with formation of pathologic populations of erythrocytes.
Pathogenesis
In cases when antibodies against erythrocytes are found in a patient and the
"inplement content gets lowered, participation of immune reactions in a disease
i beyond doubt. It is an allergy of cytotoxic type (p. 94) or autoimmune aggression
Ip % ). It means that treatment needs to use immunodepressants.
Autoantibodies are formed against body’s own erythrocytes when their antigen
ptopcrties are changed under the influence of microorganisms, viruses, drugs, or
I t result of somatic mutation of immunocytes, when forbidden clones of lym
phocytes appear producing antibodies against normal erythrocytes (in leukemia,
v.temic lupus erythematosus, etc.).
Antibodies against erythrocytes belong to IgG and IgM type. They get con
tm ted with the erythrocyte membrane, and then two mechanisms develop:
I rythrocytes with IgG and IgM on their membrane are phagocytized by mac
tophages of the spleen, liver and bone marrow, which have receptors to these
Immunoglobulins.
IgG and IgM join the complement to the erythrocyte membrane, the formet
causing lysis after its activation (complement-dependent hemolysis).
Cold sometimes causes hemolysis and immune mechanisms participate in tc
ih/ation of this damage. It is connected with the presence of cryoglobulins (im
nmitoglobulins, which change their form under the effect of temperature and react
with body’s own erythrocytes).
Anemia of newborn may result from an immune conflict (rhesus incompati
hlllty) of the mother’s and fetal erythrocyte proteins. Antirhesus agglutinins, which
и1 formed in the organism of a rhesus-negative mother, cause hemolysis of rhesus
pn Hive erythrocytes of the fetus or newborn.
Hole of Drugs
I lie role of drugs in blood cell damage (not only erythrocytes) is a problem. In
pharmacological prescriptions one can see such indications.
Some drugs (quinine, antituberculous medicines, ftivazide) act as oxidizers
пт! directly damage the erythrocyte membrane (this is often underlain by genetic
pn disposition to hemolysis).
I lie role of drugs in the realization of immune mechanisms of hemolysis is
piovtded by the following mechanisms:
• I lie antigen structure of erythrocytes may change under the effect of medicines
uul subsequently antibodies form against erythrocytes.
• Medicines can act as haptens. Binding of medicines with erythrocyte antigens
Ь ids to the formation of the antigen complex, which initiates formation of anti
bodies, which act against body’s own erythrocytes.
blood Picture
Etiology
Etiological factors are mutagens, which damage the genes responsible for crylh
rocyte protein synthesis. If a patient inherits a pathological gene, other physii .il
chemical and biological factors play the role of risk factors, which realize pathologl
cal predisposition.
Pathogenesis
Hemoglobinopathy
I n:\nwpathy
1 vie destruction.
I 11 hereditary G-6 -PDGase-deficiency anemia erythrocytes have a reduced
t iniient of restored glutathione (antioxidant). A deficit of the enzyme glutathione
petoxidase, which contains iron, leads to SH-group oxidation, decreased cry thro
. \t. plasticity and membrane damage.
Such erythrocytes are sensitive to oxidizers. These diseases are drug-dcpcndcnt
(medicines with an oxidizing action play a special role). The usage of such medi
Plirt 2 Spccuil (Systemic) Ги1 ||(1 ||||\ч1 о|<>к\
cines as primachin, sulfanilamides, aspirin, phenaluin play ihc role of risk fact oh
and may cause acute intravascular erythrocyte hemolysis
Лlemhrurwpathy
Itlood Picture
К Oology
poisons, including drug abuse, damage the bone marrow and cause anemia. Any
*m’ic pathology in the organism (kidney insufficiency, hepatitis, uremic or hcpatic
•on.i, etc.) is accompanied with formation of toxic products of endogenous origin,
*Inch lead to anemia development. Severe infections and immune causes may be
■Unlogical factors as well. All these situations are accompanied with dyserythropoi
*in anemia as hematologic syndrome.
As to participation of genetic factors, this anemia may be acquired and heredi
birv.
I'xlhogenesis
Etiology
Etiological factors, which cause iron deficiency anemia, are those, which lead
to impaired entering of iron into the organism or disorders of its utilization.
Etiological factors may be exogenous or endogenous, which cause prim ary and
secondary iron deficiency in the organism.
The causes are the following:
• Iron loss in bleeding is the most often cause. It may be a repeated or massive
single blood loss in the uterus, gastrointestinal, renal, pulmonary diseases.
• Impaired entering of iron into the organism occurs in:
• starvation;
• iron deficit in food (if children are fed with cow or goat milk only).
• Impaired iron absorption in digestive tract pathology (hypoacid gastritis,
chronic enteritis) or resection.
• Impaired iron transport (hypotransferrinemia in liver disturbances, genet н
atransferrinemia).
• Disorders of iron utilization from reserves (in infection, intoxication, helmin
thie invasion).
• Disorders of iron deposition (in hepatitis, hepatic cirrhosis).
• Increased needs of the organism for iron and its increased consumption dm
ing:
• pregnancy;
• growth;
• lactation.
Pathogenesis
Illood Picture
I Oology
Exogenous vitamin deficit is possible only in t hlldieii arlilicially ted with goal
milk or dry milk mixtures. In adults this anennn develops lor endogenous reason ч
m stomach diseases when gastromucoprotein is not formed.
Deficit of internal Castle’s factor (gastromucoprotein) may be acquired and
inherited. Acquired deficit may result from gastric mucosa damage in case of:
• chronic atrophic gastritis;
• tumor of the stomach;
• destruction of internal Castle’s factor by antibodies against the parietal stom
ach cells or gastromucoprotein;
• autoimmune aggression with antibodies of stimulating type against gastim
receptors of the accessory stomach cells (discussed on p. 91);
• resection of the stomach.
Hereditary defects of internal Castle’s factor formation result from mutations
ol Ihe genes responsible for this protein synthesis by the gastric gland cells. Ii is
inherited as an autosomal recessive trait.
Impaired cyanocobalamin deposition in the liver (vitamin depot) in case «>1 и
diffuse lesion (cirrhosis, hepatitis) as well as increased need for the vitamin (dm me
pregnancy) are also reasons for vitamin deficit.
1'athogencsis
Development of this form of anemia is connected with ineffective erythropoi
esis.
In deficiency of cyanocobalamin (of its coenzyme — methylcobalamin), then*
is no transformation of folic acid into its coenzyme form (tetrahydrofolic acid),
which is necessary for the synthesis of thymidine monophosphate (one of DNA
components). Disorders of D N A synthesis cause disorders of hemopoietic tissm
cell division. Giant cells appear as a result of atypical mitosis. Normal hemopoicsli
(erythroblastic) is replaced by the embryonic one (megaloblastic).
I he final products of this form of hemopoiesis are giant erythrocytes (megalu
cytes). Their lifetime is very short (10-14 days) because of hemolysis.
Regenerative processes in the bone marrow are intensified, but regeneration
t ells are pathological - megaloblasts are produced in a large quantity and appear
in the peripheral hlood.
I eukopoiesis and thrombocytopoiesis are suppressed.
Mitosis disorders are also observed in the cells of the digestive mucosa. Giant
mucous cells appear. Inflammatory and atrophic changes in the digestive mucosa
(Ihe oral cavity, stomach, intestine) are observed as glossitis, stomatitis, esophagi
lis. enteritis. Hydrochloric acid is absent in the stomach (ach ylia). Digestion is
impaired.
As a result of cyanocobalamin lack, methymalonic acid, which is toxic for i Im
nervous cells, is accumulated in the organism. Myclination is disturbed, impulse
conduction is disordered. Signs of nervous tissue degeneration arc present Defi ne
ration ol Ihe posterior and lateral columns ol the spinal cortl develops (lunitulai
myelosis) Ihe cranial and peripheral nerves are allectcd developing multiple nett
rologicul symptoms
Chapter 20. l’ath»l»Kv of Erythrocytes. Anemia
Without treatment the disease results in death. Therefore this anemia is called
ivnticious (malignant).
Illood Picture
I liissidcation
I Oology
Pathogenesis
The scleras and skin of a 20-year-old patient periodically become yellow; the
patient feels sick. Diagnosis: Minkowski—Chauffard disease. What is typical ol
blood investigation in this case?
A. Agranulocytosis.
B. Anulocytosis.
C. Microspherocytosis.
D. Macrocytosis.
E. Thrombocytosis.
A patient who has arrived from Tunis has a-thalassemia willi erythrocylc
hemolysis and jaundice. Presence of what cells in the blood is typical of this
illness?
A. Target cells.
B. Spheroidal erythrocytes.
C. I’olychromatophilic erythrocytes.
1'inl 2 Sp rcia l (System ic) Ги11ю||||>лК)1оку
I). Normocytes.
E. Reticulocytes.
(> A patient is ill with iron deficiency anemia. As a consequence there may devc
lop atrophic and dystrophic processes in the digestive tube (glossitis, gingivitis,
caries, esophagitis). What is the cause of such changes associated with this type
of anemia?
A. Decreased activity of glycolysis.
B. Increasing activity of transaminase.
C. Increasing activity of proteases.
I). Decreased activity of iron-containing enzymes.
E. Increasing activity of catalase.
') A patient with chronic diffuse glomerulonephritis suffers from anemia. W lut r.
the pathogenesis of this anemia?
A. Presence of antibodies against peripheral hlood cells.
H. Iron deficiency.
C. Deficiency of internal Castle’s liictoi
D Hemolysis of erythrocytes.
I Dei teased erythropoietin production
Chapter 20. P;ithol<»K> <>Г Krylhrocyles. Липши
11. The erythrocytes of a patient with hypochromic anemia contain 45 % HbS and
55 % HbA,. What form of anemia is it?
A. Microspherocytic.
B. a-Thalassemia.
C. Addison—Biermer’s disease.
D. GIucose-6 -phosphate dehydrogenase deficiency.
E. Sickle-cell.
I.’ A 36-year-old patient is ill with a respiratory viral infection. He was treated
with sulphanilamide drugs. Later hyporegenerative normochromic anemia, leu
kopenia, thrombocytopenia were found. In the bone marrow the amount ol
megakaryocytes is decreased. What anemia is it?
A. Posthemorrhagic.
B. Hemolytic.
C. Hypoplastic.
D. Vitamin B 12 and folate deficiency.
E. Iron deficiency.
18. A 7-year-old boy has spontaneous hemorrhages. The hemoglobin blood cod
tent is 80 g/1. A diagnosis of chronic posthemorrhagic anemia was put con
nected with hemophilia (biochemical blood investigation showed antihemo
philic globulin deficit). A physician is deciding whether anemia is regeneral m
or not. Blood smear investigation showed a deficit of the regenerative forms n(
erythrocytes and a lot of degenerative ones.
Degenerative forms o f erythrocytes are:
1. Polychromatophils.
2. Poikilocytes.
3. Ovalocytes.
4. Target cells.
5. Macrocytes.
6 . Sickle-like cells.
Regenerative forms are:
7. Hypochromic erythrocytes.
8. Hyperchromic erythrocytes.
9. Reticulocytes
10. Sphcrocytcs.
11. Microcytes.
12. Anisocytosis.
1.3. Mcgalocytcs.
( hup te r 21
PATHOLOGY OF LEUKOCYTES. LEUKOCYTOSIS AND
11 UKOPENIA
Etiology
Pathogenesis
Q U A N TITA TIV E D IS O R D E R S O F LE U K O C Y T E S
Leukoformula Analysis
lii this connection, absolute and relative changes in I lie i|iiantity of leukocyte»
are distinguished.
I'he correlation between mature and immature forms of leukocytes also miit.i
be analyzed in the leukoformula.
In the Shilling leukocyte formula, all types of cells are located horizontal
depending on their maturity. Immature forms of neutrophils (myelocytes, metamy
elocytes, band neutrophilic granulocytes) are placed in the left part of the formula,
and mature forms (segmented neutrophilic granulocytes) — in the right part. Ли
increase of young neutrophil amount in the peripheral blood is called the left-sul#
nuclear shift o f neutrophils. The prevalence of mature forms (with many nucle.n
segments - 5-6 and more) associated with the absence of young cells is called the
right-side nuclear shift o f neutrophils.
An increase of young leukocyte content in the leukoformula associated with ait
increased amount of leukocytes reflexes leukopoiesis activation caused by reactive
01 tumorous hyperplasia.
Absence of young forms of leukocytes in the leukoformula with a decrease <»l
the total amount of leukocytes (leukopenia) reflexes leukopoiesis inhibition.
Regenerative
Ilyperregenerative
H.11 •iterative-Degenerative
tKuvnerative
Q U A LIT A T IV E C H A N G ES IN I I I K« К Y I KS
LEU K O C Y T O SIS
I llolugy
I'alhogenesis
I he substances, which arc formed in non Inlet tlous Inllammation, also Minm
late neutrophil production. They arc:
• products of tissue dccay and necrosis (myocardial infarction, malignant in
mor decay, products of decay in chronic myeloleukemia), tissue destnu .....
by physical factors (cold, heat);
• products of crythrocyte hemolysis;
• toxic metabolites in uremia and hepatic coma.
/ osinophilic Leukocytosis
Allergy is the most frequent reason for eosinophilic leukocytosis. Activation "i
cosinophilopoiesis and release of eosinophilic granulocytes from the bone maim*
into the blood are observed in allergic diseases connected with an increased ( I
synthesis by lymphocytes after antigenic stimulation. Mast cells produce the eosum
phil chemotactic factor. It is also connected with increased permeability of the ......
marrow to eosinophils under the influence of histamine and other BAS released tin.
to antigen-antibody reaction.
To understand the importance of eosinophilia one must take into account i
function of eosinophils in allergy. Eosinophils contain histaminase and arylsull.ii .i •
in their granules and neutralize BA S in allergy (leukoformula in allergy is герм
se nled 011 p. 93; increased quota of eosinophils in leukoformula is a diagnostic m»hi
ol allergic component in patient’s disease). The amount of eosinophils is elev.iieil
in helminthic invasion (eosinophils release a protein, which damages the membiim.
of helminths).
Eosinophilia is observed in chronic myeloleukemia.
Hasophilic Leukocytosis
l ymphocytic Leukocytosis
Monocytosis
8
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2
Jx>
о
ЯOil
a
8
00 • 2
с
f 1 •a
2, 1
00 10 о
О
4> о
li 1
oo
■i-jc
\:.r r-
.—I
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8
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Ш ь
w II о b
J= f*
1 §
& s*
Ф
_ I О о о у
z l/
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G
On
Fig 33. Degenerative changes of leukocytes:
1 - toxic granulosity; 2 - vacuolization of the
nucleus and cytoplasm; 3 - Kniazkov’s bodies;
4 - hypcrsegmcntation of the nucleus; 5 - ani
socytosis
14ikemoid Reaction
IUoihI Picture
HlKiilfleance
LE U K O P E N IA
Types
Ktiology
Pathogenesis
о
о
T
T
С1
Norm, %
1
51-67 20-40
40
OO
Ч O
Norm 06-0 06-0 40- 2040- 800- 160—
•rj 1 о
00 £
^
in 1 mkl 540 6030 3600 720
Pneumonia
Acute tonsillitis
.Appendicitis
Bronchial asthma
Rheumatism
Tuberculosis
| Lues
1
/)
<
Leukemoid reac
tion
Regenerative
nuclear left shift
Hypenegene-
rathe nuclear left
shift
‘2
i l
* a
v "Si
Chapter 21. I’alholoKy of leukocytcs. leukocytosis anil Lrukopcnla
I ’rnt ) S|M'« litl (S y s ln iilt ) Гя11|ор||уч1о||>кУ
< Л 32-year-old man fell ill with pneumonia Wli.ii elian^es of the blood are lypi< al
of this disease?
Л. Regenerative nuclear shift to the lelt
B. Ilyperregenerative nuclear shift to the left.
C. Degenerative nuclear shift to the left.
E. Nuclear shift to the right.
•I Л 7-year-old child fell ill with acute tonsillitis. There is a significant incie.i •
of leukocyte count in the peripheral blood; young forms of leukocytes have ,ц>
peared (the Ilyperregenerative nuclear shift to the left). It is possible to susp.«t
leukemia. But a doctor decided it was leukemoid reaction. Give the charai t<1
isiics of leukemoid reaction.
1. Leukemoid reaction is an acute increase of immature forms of Icukn
cytes in the peripheral blood.
2. It is observed in patients with instable hemopoiesis in response to ami.
infection.
3. Blood picture resembles leukemia.
4. It differs from leukemia in etiology but not pathogenesis.
5. The cause is often known (it is always infection) contrary to leukemia
6. It is hyperreactive hyperplasia of the leukopoietic tissue.
7. There are two types of leukemoid reaction - myeloid and lymphoid
depending on the type of cells, which underwent proliferation.
8. Leukemoid reaction is temporary and irreversible.
9. It is neoplastic hyperplasia of the leukopoietic tissue.
10. Leukemoid reaction usually turns into leukemia.
C LA SSIFIC A TIO N
КЛОНИЛ'
I tiological factors, which cause leukemia, arc the same as those of neoplasia
All ol them are mutagens (cancerogens). They are divided into physical (ionizing
tadiation), chem ical (cancerogens), biological (DNA- and RNA-containing viruses
and genetic anomalies).
Ionizing Radiation
( hemieal Cancerogens
I he same chemical cancerogens, which cause malignant tumors (p. 144), cause
leukemia as well.
С hemieal cancerogens may cause leukemia in people subjected to occupational
contact with certain substances (benzol, pesticides) or treatment with medicines
having a mutagenic effect (cytostatics, immunodepressants, butadiene, chlorani
phcnicol, cyclophosphamide). Derivatives of tryptophane, tyrosine, and indole in
ducc leukemia under experimental conditions.
Oncogenic Viruses
PATHOGENESIS
«plastic Transformation
Neoplastic Promotion
Neoplastic Progression
и .nit in the appearance of new tumor clones. The leukemic tissue becomes geneti
•nils and phenotypically heterogeneous.
It is the so-called polyclonal stage of leukemia.
Selection of the most malignant cells takes place. They avoid immune system
.... .. Among the cells, which are subjected to treatment with cytostatics (chcmi
■il hormonal and radioactive), some are destroyed (more mature), but the most
Hiiihgnant cells are resistant to these effects. Only they continue to multiply as a
'Milt of such selection. Therefore, treatment for leukemia with cytostatics, ionizing
i filiation and radioactive substances becomes ineffective at the polyclonal stage.
t ransition of the monoclonal stage into the polyclonal one is an indicator ol
.... plastic progression.
I.eukemic cells may spread throughout the blood system and beyond il (me
•i uses) forming leukemic infiltrates in the lymph nodes, spleen, liver and ollici
HtjIIIIIS.
Accumulation of mature leukocytes in the blood (in chronic lympholcukcmta)
t •\plained not only by their intensive formation but also by apoptosis impairment
when mature cells do not die for a long time.
MANIFESTATIONS
I lie manifestations of leukemia are local (changes in the malignant cells of the
•«••с marrow and peripheral blood) and systemic (in the whole organism).
Clinical Manifestations
Clinical manifestations are identical in all types of leukemia. They are fatigue,
weakness, fever, night sweats, decrease in weight, exhaustion of the organism. Seve
ral pathophysiological syndromes determine the manifestations. They are anemic,
hemorrhage and D IC syndromes, immunological insufficiency, some extramcdul
lary syndromes together with hematological syndrome, which is different in various
types of leukemia.
Acute leukemia leads to death of the patient in several weeks. Cancerous ca
chcxia and secondary infection are the reasons for death.
Anemic Syndrome
Hemorrhage Syndrome
/>/( ’ Syndrome
present 111 п. I tie intermediate forms between Must «ill', iiiul mature neutroplulu
granulocytes (promyelocytes, myelocytes, uiclaniyclocvtcs, band cells) are absent
(color lig. 34). This phenomenon is called hiatus Iruknnicus
Hiatus leukemicus reflects a deep disorder ol leukopoiesis in the hemopoietic
organs neoplastic cells lose the ability to differentiate. Neutrophils do not matiue
in the bone marrow. Only myeloblasts multiply and get into the peripheral blood
Maiure neutrophils, which are found in the peripheral blood, are the ones which
were formed earlier, before the beginning of t