Amino Acids

avg pKa for -carboxylic acid groups is ~2 (1.8 2.4)

At pH values < pKa (i.e. at higher H+ ion [ ]s), all carboxylic acid groups
protonated (COOH). If pH = pKa, 50% of -carboxylic acid groups dissociated into
carboxylate anions & protons, & at pH 7.4, >99% of -carboxylic acid groups in
dissociated form (COO-) w/ve charge
avg pKa for -amino groups is ~9.5 (8.8 to 11.0)
At physiologic pH 7.4, (thats <pKa of -amino groups , most fully protonated & carry
+ve charge (NH3+). At pH equal to pKa, 50% of -amino groups dissociate into NH2 &
at pH>9.5, %age of -amino groups in NH2 form exceeds 50% towards
higher %age
- At physiologic pH 7.4, all AAs ionized, i.e., amino group has +ve charge & carboxylic
acid has -vely charge
- Organic acids w/carboxylic groups are weak acids (HA) that dissociates only to lmtd
extent in water
- reln btwn pH & pKa by Hendersen-Hasselbach eqn, pH = pKa + log [A-]/[HA];
most metabolic acids have pKa btw 2-5 (where acids w/pKa 2 are stronger acids than
those w/pKa of 5)
- isoelectric point (pI): pH when amino & carboxyl group ionized & sum of +ve charges
=s sum of -ve charges, & net charge is 0 & AA will be zwitter ion (electrically neutral)
Simplest AA: glycine, in bends, turns, or tightly packed chains of fibrous proteins; causes
least hindrance
Brd chain AAs: nonpolar aliphatic; valine, leucine & isoleucine
Sulfur containing AAs: methionine (not free here) & cysteine (has thiol group, sulfur free
here!) so 2 cysteines can undergo oxidative condensation to make cysteine (play imp role
in 3D folding of protein)
Imino acid: proline, so not as classic, NH2 in ring so rigid structure CANT be accommodation
in alpha helix b/c breaks helical structure, so helix breaker (doesnt break bonds,
PREVENTS further alpha helix formaton in chain)
Aromatic AAs: phenylalanine (nonpolar), tyrosine & tryptophan (both polar; has indole);
have aromatic benzene ring
Basic AAs: arginine (guanidinium; semi-essential b/c needed only during periods of +ve N
balance) & lysine w/extra NH2 so have net +ve charge
Weakly basic AA: Histidine (has imidazole), 50% protonated & 50% deprotonated at
physioal pH so both can accept/donate proteins depending on local pH, hence good
buffer
Acidic AAs: aspartate & glutamate w/extra COO so have ve charge under physioal pH
Neutral AAs: asparagine & Glutamine: look like derivatives of aspartate & glutamate
w/additional NH2 group at their side chain
Hydroxyl (OH) containing AAs: serine, threonine & tyrosine; all have OH group in side chain
(sites for certain post-translational modification) like phosphorylation (adding phosphate) or
glycosylation (adding carb)
Nonpolar hydrophobic AAs: found in hydrophobic core of globular proteins & memb
spanning region of transmemb proteins; glycine, alanine, proline, valine, isoleucine, leucine,
phenylalanine & methionine
Polar uncharged AAs (hydrophilic AAs): tyrosine, asparagine, glutamine, serine, threonine
& cysteine
Acidic & basic AAs (hydrophilic AAs): aspartate, glutamate, arginine, lysine & histidine;
charge on these enable ionic electrostatic bonds, ie. Interaxn of +ve w/-ve charge, H-bonds
& salt bridges (ie. Binding inorganic ion such Na+ btwn 2 partially or fully vely charged
groups)
Hydrophilic AAs found over surface of globular proteins & hydrophilic side of transmemb
proteins

hydropathy index: measure of hydrophobicity (water dispersing) of AA (higher #,

more hydrophobic)

Titration Curve for Histidine showing AA structure changes due to solns pH change
from <1 to 14 by addition of OH ions:
At low pH, all groups carry protons; amino groups w/+ve charge, & carboxylic groups w/0
charge. As pH increased by addition of alkali (OH-), proton dissociates from
carboxylic acid group, & its charge changes from 0 to -ve w/pKa of ~2, pH at
which 50% of protons have dissociated.
Histidine side chain is immidazole ring w/pKa of ~6 that changes from predominantly
protonated +vely charged ring to uncharged ring at this pH
Amino group on alpha-C titrates at much higher pH (btwn 9-10), & charge changes from +1
to 0 as pH rises.
isoelectric point (pI): pH when net charge on molecules in soln is 0; molecules WONT
migrate in electric field twd +ve pole (Anode) or -ve pole (Cathode) b/c # of -ve charges
on each = # of +ve charges
Albumin funcs as colloidal oncotic pressure - pulls water into vessels

Disassociation of side chains in AAs:

Acidic AAs lose proton from their carboxylic acid at pH of ~4 & are thus -vely
charged at pH 7.4
Cysteine & tyrosine gain protons at their pKa (~ 8.4 & 10.5), so their side chains uncharged
at physiologic pH
Histidine, lysine & arginine side chains change from +vely charged to neutral
when pH > their pKa
side chains of 2 basic AAs, arginine & lysine, have pKa values >10, so predominantly
protonated at physiologic pH
side chain some of histidine (pKa ~ 6) molecules undergo deprotonation at physiologic pH,
so some them lose their net +ve charge & remaining of them carry +ve charge
Vitamins
Fat soluble: Vit A, D, E, K
Vit A:

o Vit A overdose in pregnancy can cause craniofacial abnormalities, post fossa CNS dfx,
auditory dfx & abnormalities of great vessels (these dfx similar to those in DiGeorge
syndrome)

Polyol Pathway:

Aldose reductase: converts glucose to sorbitol in lens, retina, Schwann cells of peripheral
ns, liver, kidney, placenta, RBC, ovaries & seminal vesicles; when glucose accumulated
w/adequate NADPH excess sorbitol
Sorbitol DH: oxidizes sorbitol to fructose in liver, ovaries & seminal vesicles
Esp in tissues w/sorbitol DH low/absent: excess sorbitol trapped inside cell it cant
pass thru memb; aka in RETINA, LENS, KIDNEY & N cells; causes osmotic swelling due
to water retention cataract formation, peripheral neuropathy & micro vascular
problems (nephropathy & retinopathy) often in diabetes

Galactose Metabolism:
Galactokinase: phosphorylates galactose
GALT (galactose-1-phosphate uridyl tranferase): exchanges UDP & phosphate btwn
galactose-1-phosphate & UDP-glucose
4-epimerase: catalyzes epimerization of UDP-galactose to UDP-glucose
UDP-galactose in lactating mammary glands will make lactose on condensing w/glucose;
also used in making glycolipids, glycoproteins, glycosaminoglycans

Pentose Phosphate Pathway:

Oxidative: via G6PDH: rate limiting & regd step; inhibited by high NADPH, by insulin (FED)
to make ribose-5-phosphate
Nonoxidative:
Transketolase: only enzyme in RBCs that needs thiamine
Measurement of RBC Transketolase & its by thiamin pyrophosphate used to
asses thiamine nutritional status
Can make ribose-5-phosphate from glycolytic intermediary (backwards) if
lacking

Block 2 BIOCHEM diseases

MODY: maturity-onset diabetes of young (type 2); rare AD form due to mutated pancreatic
glucokinase; +ve fam hx; diff forms but all due to ineffective insulin production or release
from pancreatic-cells; 50% of 1st degree relatives inherit same mutation giving 95%
lifetime risk of MODY; onset in 20s-50s; 2 forms
1. Sig hyperglycemia & diabetic sx, polydipsia & polyuria
2. No signs/sx & dxd either by accident or when high glucose discovered during testing
for other reasons or screen of relatives of person w/diabetes; discovery of mild
hyperglycemia during routine glucose tolerance test for pregnancy is esp charac
Arsenic/arsenate poisoning: prevents net ATP & NADH production by glycolysis by
competing w/Pi (from inorganic phosphate pool, not ATP) for glyceraldehyde phosphate DH
forms complex to spontaneously hydrolyze & form 3-phosphoglycerate BYPASSING
synthesis of energy rich 1,3-bisphosphoglycerate (depriving energy N made here in
glycolysis)
o THUS, G3P directly converted to 3-phosphoglycerate, so no NADH+H & no ATPs made
(via phosphoglycerate kinase; exergonic rxn taken away), no substrate lvl
phosphorylation glycolysis still occurs but loses its main purpose
o >bisphosphoglycerate mutase in RBCs synthesize 2,3-BPG binds-chains of HbA
O2 affinity (R shift in O2 disassociation curve) T state O2 release from HbA in
peripheral tissues allowing 100% saturation in lungs
2,3-BPG also seen in high altitude adaptation for tissue oxygenation
O2 deprivation if sufficient energy in RBCs lose ATP when (1,3-BPG 2,3-BPG 3PG)
o Also inhibits Pi-H+ symporter by competing w/Pi for ATP synthase inhibiting ATP
generation
Arsenite: forms complex w/thiol (-SH) of lipoic acid, making lipoate compound unavailable
inhibiting all enzymes needing it as coenzyme (E2 of all 3 enzyme complexes needed by
B1) inefficient pyruvate conversion to acetyl CoA (cant do oxidation-reduction), pyruvate
accumulates so lactate accumulates
o Causes lactic acidosis & possibly metabolic acidosis! Doesnt happen in all cells (some
dont need it)
Pyruvate kinase def: when mutated/def ATP synthesis (0 ATP yield!) esp in RBCs
Na-K pump affected/memb permeability weakened osmosis RBC swells, bursts open =
HEMOLYSIS Hb leaked & lost in urine ANEMIA; seen w/2,3-BPG, mild-moderate
chronic hemolytic anemia, but NO Heinz bodies (seen in G6PDH def); MC glycolytic def BUT
2nd MC genetic def causing hemolytic anemia
o Accumulated phosphoenol pyruvate
o Causes R shift RBCs, Hb, those left go to lung & bring O2 (but less to peripheral
tissues hypoxia) compensates by 2,3-BPG, to unload O2 to peripheral tissues only

mild-moderate chronic hemolytic anemia due to this unloading capability via more
2,3BPG
Lactic acidosis: lactate in plasma, esp under circulatory collapse env (MI, pulm
embolism, shock) O2 supply ATP synthesis cells use anaerobic glycolysis to make
ATP lactic acid end product
Warburg effect: enhanced conversion/fermentation of glucose to lactate in tumor/cancer
cells (aerobic glycolysis of these via their metabolism), even in presence of normal O 2
PDH E1 def: rare X-linked dominant but MC biochemal cause of congenital lactic acidosis;
brain deprived of energy b/c acetyl CoA lacking so its sensitive to acidosis pyruvate to
lactate increased; seen w/neurodegeneration, m spasticity & early death
Leigh syndrome: subacute necrotizing encephalomyelopathy; are, progressive
neurological disorder due to dfx in mitochondrial ATP production b/c mutated PDH, ETC or
ATP synthase
Thiamine or Niacin def: serious CNS problems (Wernike-Korsakoff syndrome, dementia)
b/c PDH complex inactive brain unable to produce enough ATP
Uncouplers: proton gradient!
o Thermogenin: release heat, seen in BAT (brown adipose tissue) in newborns,
o 2,4-Dinitrophenol:
Inhibitors:
o Rotenone: binds to complex I
o Oligomycin: binds to ATP synthases F0 subunit & inhibits proton channel
o Dimercaprol/BAL (British anti-Lewisite): binds complex III
o Antimycin A: binds to complex III
o Cyanide
o Azide
o CO
o Doxorubicin
o Atractyloside: inhibits ANT (ATP-ADP antiporter) thus oxidative phosphorylation
CGD (chronic granulomatous dis): recurrent bouts of infection due to capacity of their
immune system to fight off dis-causing organisms; due to dfx in any essential subunit of
NADPH oxidase
G6PDH (Glucose-6-Phosphate Dehydrogenase) def: X-linked recessive mutated
G6PDH (afx African, Middle Easten & South Asians (Mediterranean) MEN; Fs w/1 affected X
heterozygous; asymptomatic UNLESS triggered by oxidant drug ingestion (antimalarials,
analgesics, fava beans) triggering ROS generation b/c G6PDH activity (PPP wont
work) def NADPH cant reduce glutathione to GSH in RBCs H2O2 & generate ROS
o antimalarial drugs (primaquine, pamaquine & chloroquine), sulfonamides (sulfanilamide,
sulfamethoxazole & mafenide), thiazolesulfone, methylene blue & naphthalene, certain
analgesics (aspirin, phenazopyridine & acetanilide) & few non-sulfa antibiotics (nalidixic
acid, nitrofurantoin, isoniazid, dapsone, & furazolidone)
o RBC lysis due to lipid peroxidation & memb damage chronic hemolytic anemia
(+bilirubin & jaundice), HEINZ BODIES (precipitated Hb) & bite cells (note: N 2,3-BPG)
o RBCs impaired ability to detoxify ROS gives protection against malaria so heterozygous
Fs have resistance malaria (heterozygote adv)
Essential fructosuria: def fructokinase
HFI (hereditary fructose intolerance): def aldolase B; lack Pi for ATP high AMP
degraded adenine uric acid hyperuricemia
Excess sorbitol: diabetic pt w/eye visual acuity issues; excess sorbitol trapped in cell as it
cant efficiently pass thru memb, this exacerbated in tissues where sorbitol DH -absent,
for ex. in retina, lens, kidney & n cells
o Accumuled sorbitol in these cells causes osmotic cell swelling (b/c water retention)
some complications of diabetes attributed, in pt, to this swelling ie.cataract

formation, peripheral neuropathy, & microvascular problems leading to

nephropathy & retinopathy
Classical galactosemia: GALT def
Nonclassical galactosemia (galactokinase def):
Glycogen Synthesis:

OR

GLYCOGEN DEGRADATION:

 Glycogen storages diseases orgd by type:

I.
Von Gierkes dis: glucose-6-phosphatase def glycogen accumulates fatty
cheeks, hypoglycemia, hepatorenomegaly*, hyperurecemia, ketone bodies, metabolic
acidosis, hyperventilation (respiratory alkalosis); no glycogen breakdown nor
gluconeogenesis
a. 1a: 80%, G6P mutated
b. 1b: 20% T1 (translocase) mutated; bleeding & risk infection from neutropenia &
neutrophil dysfunc, gout
II.
Pompes dis: acid maltase def (Lysosomal a14 glucosidase) glycogen
accumulated in lysosomes & enlarged & <3 failure, floppy baby, poor m tone, PAS+
III.
Limit dextrinosis/Forbes/Coris dis: def debring (4:4 transferase) enzyme;
glycogen w/SHORT outer brs, hepatomegaly, GR, m weakness & hypoglycemia
IV.
Amylopectinosis/Andersens dis: def bring (4:6 transferase) enzyme glycogen
w/LONG OUTER brs & few br pts failure to thrive, hypotonia, hepatosplenomegaly,
liver cirrhosis & failure
V.
Myophosphorylase def/McArdles syndrome: def m. glycogen phosphorylase
VI.
Hers dis: def liver glycogen phosphorylase
VII. Taruis dis: def phosphofructokinase in m & RBCs

 Pyruvate carboxylase def: gluconeogenic disorder; PC gene for pyruvate carboxylase

mutated; 5 signs lactic acidosis, hypoglycemia, MR, hyperammonemia & hypotonia
thus, lactate gluconeogenesis & transamination
Alcohol flush rxn (Asian flush syndrome): most Asians (Chinese, Korean) face or body
exps flushes/blotches due to acetaldehyde accumulation b/c of generation variation leading
to ADH activity but ALDH activity also causes N/V, distaste for alcohol & thus
protection against alcoholism
Ethanol metabolism efx/chronic alcohol abuse:
I-cell dis (inclusion cell): seen w/stunted growth, small orbits, proptotic eyes, full &
prominent mouth caused by gingival hypertrophy, short & broad hands; their fibroblasts
severely def in GlcNac phosphotransferase (N-acetylglucosamine phosphotransferase)
*most mutated (not phosphodiesterase)
Mucolipidosis Type I (sialidosis):
Structure of glycoprotein:
Glycoproteins: short brd carb chain (w/no repeating disaccharides) covalently linked to
protein; most proteins in body & blood; serve as hormones, enzymes, Abs, receptors,
transport molecules, structural pts of ECM like collagen; most secreted from cells, except
enzymes that func w/in cell
reason for large variety of sugars attached to proteins & lipids is that they have
relatively specific & diff funcs, like targeting protein twd memb; providing recognition
sites on cell surface for other cells, hormones, or viruses; or acting as lubricant or
molecular sieves
Synthesis includes:
protein portion synthesized on ER
initial glycosylation of protein occurs in lumen of ER & Golgi!
addition & mod of carb chains continues as protein moves from ER to Golgi complex
& in Golgi complex
All amino sugars in glycoproteins are derivatives of glucosamine-6phosphate*** (most imp to add monosaccharrides on glycoproteins, also
participates in nucleotide synthesis) amine portion donated from
glutamate!!!
*UDP-sugars: precursors for addition of 4 of 7 sugars in glycoproteins glucose,
galactose, N-acetylglucosamine & N-acetylgalactosamine
GDP-sugars: precursors for addition of mannose & L-fucose; GDP-mannose & GDPL-fucose
CMP-NANA: precursor of NANA (N-acetylneuraminic acid/sialic acid)
Highly brd oligosaccharide chain linked to protein by O- or N- type of glycosidic linkage
O-linked glycoproteins: made by sequential addition of nucleotide sugars on protein
by glycosyltransferases; H taken out & sugar added as UDP released; SEQUENTIAL
ADDITION of monosaccharrides
N-linked glycoproteins: made by dolichol phosphate that helps transfer brd sugar
chains to amide nitrogen of asparagine residues
Dolichol-P-P-GlcNAc (Dol-P-P-GlcNAc): key lipid acts as acceptor for other sugars in
assembly of Dol-P-P-oligosaccharide; comes from fernesyl pyrophosphate
Sequential addition of sugar nucleotides on dolichol by specific glycosyl transferases;
sugars added 1 over other
Oligosaccharide transferase: transfers oligosaccharide from dolichol to proteins
asparagine side group = glyco + protein; has strong preference for Dol-P-PGlcNAc2Man9Glc3 (synthesized in membs of ER)
PNH *paroxysmal nocturnal hemoglobinuria):
GAGs
Location
Func

Heparan
sulfate

EC, basement memb (esp

of kidney along w/type IV
collagen & laminin), &
ubiquitous pt of cell
surfaces

Receptor in PM, aids in mediating cell growth & cell-cell

comm, determining charge selectiveness of glomerular
filtration (in BM of kidney along w/type IV collagen &
laminin)
EC in basement memb & ubiquitous pt of cell surfaces
LPL anchored to capillary walls w/help of heparan
sulfate
*during metastasis
Hyaluronic High in embryonic tissues
Role in permitting cell migration during morphogenesis
acid
& cartilage!
& wound healing; compressibility in cartilage
SF of jts, vitreous humor of Lubricant/shock absorber
eye, umbilical cord, loose
Wound healing
CT & cartilage
*doesnt have sulfate
*during metastasis; *w/age
Heparin
IC pt of mast cells that line Anticoagulant binds w/factors IX & XI & esp* w/plasma
as, esp in liver, lungs &
ATIII
skin
Causes release of lipoprotein lipase from capillary walls
Keratan
Type II in Loose CT
Aids in transparency of cornea
sulfates I
proteoglycan aggregates
*exception b/c dont have acidic sugar (iduronic &
& II
w/chondroitin sulfate
glucoronic acid; has galactose)
Type I in cornea
*w/age
Dermatan Skin, blood vessels & <3
Aids in transparency of cornea & maintains overall
sulfate
valves, cornea
shape of eye
Has iduronic acid
*increased in atherosclerosis
Chondroiti Most abundant GAGs! High Compressibility in cartilage via binding collagen &
n 4-&-6
in cartilage! +tendons,
holding fibers in tight strong network
sulfates
ligaments & aorta
Forms proteoglycan aggregates noncovalently
At sites of calcification in
w/hyaluronic acid
endochondral bone &
Aid in forming bone, cartilage & cornea
cartilage
*w/age
*Age relating factors (chondroitin sulfate, keratin sulfate & hyaluronic acid) may contribute
to osteroarthritis
MPS (Mucopolysaccharidoses)/GAG/lysosomal storage diss: absence/def lysosomal
hydrolase leads to accumulation of under graded or partially degraded GAGs in lysosomes;
chronic, progressive multisystem disorders; dxd by partially degraded GAG in urine &
confirmed by specific enzyme assays in serum, leukocytes, skin fibroblasts tissue biopsy &
DNA tests;
3 classifications
Dysmorphic syndromes (bodily)
o *MPS I Hurler: progressive learning difficulties (MR not as common un Hunters!),
corneal clouding; CARDIOMYOPATHY (most common cause of early death) & deafness;
def -L-iduronidase accumulation of dermatan sulphate (DS) & heparan
sulphate (HS)
o *MPS II Hunter: cornea remains CLEAR, deafness, prominent Mongolian blue spots &
charac papular rash; no severe MR (maybe mild) but deafness also here; iduronate
sulfatase def accumulated HS & DS
o MPS IV (Maroteaux-Lamv)
w/LDs, behavioral disturbance & dementia
o MPS III Sanfilippo: more neurodegenerative; severe MR w/mild physical dfx;
accumulated heparin sulfate ONLY; 3 phases
1st: deval delay mainly affecting speech (b4 diagnosis)
2nd: 3-10 yrs; severe behaal disturbance, hyperactive challenging behavior & profound
sleep disturbance

3rd: after 1st dec, loss of skills & slow deterioration into vegetative state; death by early
3rd dec
Severe bone dysplasia
o MPS IV Mosquio
Type A:
Type B:

Naming
1.
2.
3.

FAs: Based on naming of FA from methyl end ( end), can be classified as:
9 series of FA: Oleic acid (18:1;9) or 189; 18 carbons, 1 db at 9th C
6 series of FA: Linoleic acid (18:2;9,12) or 189,12
3 series of FA: Linolenic acid (18:3;9,12,15) or 189,12,15

Lipid Metabolism summary:

1. Digesting lipids starts in stomach, catalyzed by lingual lipase & gastric lipase target
TAG w/short or medium chain FAs (in milk fat)
2. Emulsification via bile salts bind lipids globules (acting as detergents/forming
micelles) in small intestine adds surface area so intestinal m can use segmental
contraction breaking lipid into small lipid droplets (b/c allows digestive enzymes
from pancreas to attack lipids)
3. 4 Pancreatic enzymes released via cholecystokinin & secretin from pancreas
(lipase, colipase, cholesteryl esterase, phospholipase A2 & bicarbonate)
a. Pancreatic Lipase: hydrolyzes TAGs (FAs of all C lengths from pos 1 & 3 of glycerol)
w/colipase released in 1:1 ratio producing FFAs & 2-monoacylglycerol
b. Colipase: relieves bile salt (that inhibit pancreatic lipase) allowing TAG to enter lipase
active site; enhance pancreatic lipase
c. Cholesteryl esterase: removes FA in esterified cholesterol; bile salts enhance this
rxn
d. Phospholipase A2: digest phospholipids to release FAs & lysophospholipids
e. Bicarbonate: pH of small intestinal lumen (pH ~6) optimum for intestinal digestive
enzymes
4. Re-synthesis of TAG, cholesterol ester & phospholipids (3-4 pts)
a. Long chain FAs enter enterocytes & resynthesize into TAG, cholesterol ester &
phospholipids
b. Enterocytes take lipids to ER for complex lipid biosynthesis
c. Long chain FAs converted to active fatty acyl CoA by thiokinase (consuming 2 ATPs)
2 of them transfer to 2-MAG to form TAG via TAG synthase enzyme complex (acyl-CoA
MAG acyltransferase & acyl CoA DAG acyltransferase)

d. Cholesterol esterified to FA & lyso-phospholipids reacetylated to form phospholipids

e. Short & medium FAs carried in portal circulation by serum albumin to liver
f. New TAGs & cholesteryl esters packaged (b/c hydrophobic, to not aggregate) into lipid
droplets by phospholipids, unesterified cholesterol & Apo B-48 layer stabilizes &
solubility (prevent coalescing)
g. MTP (microsomal TAG transfer protein) assembles TAG-rich apolipoprotein B-containing
lipoprotein particles in ER
h. Basically only TAGs & cholesteryl esters enter CMs w/apolipoprotein B-48 &
phospholipids layer
5. Secretion of lipids from enterocytes
a. Vesicles fused w/PM undergo exocytosis, dumping CMs outside enterocytes
lymphatic vessel that penetrates into each villus
b. This CM lymph drains into systemic lymphatics bloodstream CMs digested &
used by peripheral tissues
Infant respiratory distress syndrome (IRDS)/neonatal RDS/hyaline memb dis: in
premature infants by deval insufficiency of surfactant production & structural immaturity in

lungs; due to def dipamitoyl lecithin/phosphotidylcholine in infants; incidence

w/advancing gestational age; shortly after birth w/ tachypnea, tachycardia, chest wall
retractions (recession), expiratory grunting, flaring nostrils & cyanosis during breathing
efforts (hypoxic)
Orlistat: anti-obesity drug inhibits gastric & pancreatic lipase to fat absorption = weight
loss!
Steatorrhoea: excess fat in feces/stools w/oily appearance, difficult to flush & foul
smelling; seen in pancreatitis, CF, Crohns dis, short bowel syndrome, pancreatic carcinoma,
tropical sprue, celiac dis, liver dis & diverticular dis; 3 biological causes Lack of bile acids
(due to liver damage, cholecystectomy or CBD blockage), Dfx/def pancreatic enzymes,
Defective mucosal cells
Ezetimibe: cholesterol absorption in intestine

Cholesterol & Bile Salts

TH hepatic de novo cholesterol synthesis by HMG-CoA reductase enhanced IC

[cholesterol] in hyperthyroidism & synthesis hypothyroidism [T3/T4 +vely
modulates HMG CoA reductase (thus, cholesterol synthesis)]
Cholesterol gallstones (cholelithiasis): when bile contains too much cholesterol & not
enough bile salts to solubilize them; 3 causes High cholesterol, How often & how well
gallbladder contracts, Proteins in bile that form nidus to initiates gallstone formation,
+pregnancy (high estrogen), aka FATTY FEMALE OVER 40
CoQ def: ETC ATP lethargy & pain in skeletal m (myositis); can be caused by statins
Statins: inhibit HMG CoA reductase, thus cant make FPP or do protein prenylation in
cholesterol synthesis
Farnesyltransferase inhibitors (FTIs)
Lipoprotein Metabolism/Hyperlipidemias (IN BLOOD VESSELS!)

CM remnant no C-2
5 major classes: CMs, VLDLs, IDLs, LDLs & HDLs (in order of size but density/protein)
o HDL has all apolipoproteins except apo-b48 & apo-b100
Has PON w/antioxidant properties & thiols on surface which donates & makes
disulfide bridge, LCAT & CETP
o Vit K is dependent on VLDL
Major Apolipoproteins: ApoB-48, ApoB-100 & ApoA-I
o ApoA-I: made in liver & intestine, in all HDL particles
o ApoB: major structural protein of CMs, VLDLs, IDLs & LDLs; apoB-48 (CM) or apoB-100
(VLDL, IDL or LDL) on each of these lipoproteins)
Liver synthesizes apoB-100

Intestine makes apoB-48

Minor lipoproteins: Apo(a) (little a)*, A-I, A-IV, C-I, C-II, C-III
o Apo C-II lipoprotein lipase
o Apo A-I lecithin:cholesterol acyltransferase (LCAT)
to + (anode) = slow pre beta, beta, alpha

Metabolism of CMs:
1. Intestinal mucosal cells secrete nascent TAG-rich CMs made from dietary (exogenous) lipids
2. Apo C-II & apo E transferred from HDL to nascent CM
3. EC-LPL, by apo C-II, degrades TAG in CM
4. Apo C-II returned to HDL
5. CE-rich CM remnants bind thru apo E to liver where theyre endocytosed; via Apo B100/LDL
receptor & Apo E receptor
Metabolism of VLDL:
1. Excess carbs + protein TAGs + CE + phospholipids + fat soluble vits loaded on
ApoB100 by MPT = mature VLDL
a. VLDLs: have high endogenous* TAGs (60%) & carry lipids from liver to peripheral
tissues
2. Secrete thru space of disse into lumen of blood sinusoids btwn hepatocytes
3. Apo C-II & apo E transferred from HDL to nascent VLDL becomes mature VLDL
4. EC LPL (lipoprotein lipase; by apo C-II) degrades TAG in VLDL into FA & glycerol
Mature CMs carry 5 things Apo-B48, ApoC II (for LPL axn, donated by HDL), Apo E (needed
to get back in liver, donated by HDL), exogenous TAGs from diet & fat soluble vits
Diff lipases:
- Pancreatic lipase & colipase: act on TAGs for any FA chain size
- Lingual & gastric lipases: act on TAGs specific for short & medium chain FAs
- Hepatic lipase: acts on TAGs present in IDLs
- LPL (Lipoprotein lipase):
- Hormone sensitive lipase: acts on TAGs in adipose tissue mediated by glucagon
3 enzymes present on surface of HDL:
1) CETP (cholesteryl ester transfer protein): transfers CE (from HDL) to VLDL, IDL & LDL
(these gives TAG in return)
2)
LDL-receptor structure divided into 5 domains
(1)*LDL binding site ligand binding domain; any mutation here (or in apo B100 ligand)
causes improper internalization of LDL from circulation (can lead to FH)*
(2)Homology w/EGF (epiderminal growth factor) precursor
(3)O-linked sugar domain (w/O-linked carb residues)
(4)Memb-spanning domain of hydrophobic residues
(5)*Cytoplasmic tail (w/50 AAs) imp in attaching clathrin & creating endocytosis
vesicles
Receptor mediated endocytosis of LDL:
1. LDL binds to clathrin coated LDL receptors so complex can be internalized
2. Vesicle fuse w/lysosomes to form endolysosome
3. pH of endolysosomes falls (proton pumping by endosomal ATPase) allowing its break
down while clathrin recycled to form LDL receptors
4. LDL hydrolyzed by acid hydrolases into its ind components l8r reutilized by cells

5. Once receptor releases LDL, LDL receptor recycles back to memb (used/recycled
every 5 mins; lifespan of 20 hrs); even in absence of bound LDL, internalization &
cycling still happens
Abetalipoproteinemia: AR; loss of func mutated MTP (N transfers lipids to nascent CMs &
VLDLs) cholesterol & TG plasma lvls, severe vit E def (+rest of fat soluble vits);
affected from intestine to liver; usually in early childhood w/diarrhea & failure to thrive due
to lipid malabsorption
o Vit E dependent on VLDL to go out liver to circulation b/c cant secrete
apoB-containing particles marked vit E def, mild-moderately def vit A & K
(not D b/c made in body)
o CMs, VLDLs, LDLs & apoB undetectable in plasma
o Spinocerebellar degeneration: loss deep tendon reflexes, distal lower extremity
vibratory & proprioceptive sense, dysmetria, ataxia & devt of spastic gait
o Progressive pigmented retinopathy: night & color vision followed by daytime
visual acuity near blindness
o Acanthocytosis: spiked cell membs of RBCs due to abnormal thorny projections
Type 1 Familial dyslipidemia/LPL def (Familial lipoprotein
lipase)/Hyperchylomicronemia: chylomicronemia syndrome abnormal LPL or apo C-II
def causing inactive LPL slow clearance & thus accumulated CMs*, VLDL & TAGs; in
childhood w/recurrent episodes of severe abdominal pain due to acute
pancreatitis, Fasting plasma lvls turbid (creamy supernatant), fasting TAGs (>1000
mg/dL)
o Lipemia retinalis (opalescent retinal blood vessels)
o Eruptive xanthomas (small yellowish-white papules, in clusters, buttocks & extensor
surfaces of arms & legs, painless skin lesions can become pruritic), hepatospenomegaly
(from uptake of circulating CMs by reticuloendothelial cells in liver & spleen)
3 fates of IDL hepatic uptake (via Lpr receptor), conversion to LDL via CETP or hepatic lipase
Atherosclerosis: excess LDL in blood
1. Superoxide, NO, H2O2 & other oxidants convert LDL to oxLDL
a. Vit E, ascorbic acid, beta-carotene & other antioxidants inhibit this!
2. Low affinity nonspecific & nonregd scavenger receptors take up modified LDL
(oxLDL) while high affinity receptors for LDL become down-regd when cell has sufficient
cholesterol
3. In resp to endothelial injury (caused at least in pt by oxidized LDL) monocytes adhere
to endothelial cells, move to subendothelium (initima), & are transformed into MOs
4. MOs consume excess modified (oxidized) lipoprotein, becoming foam cells
5. Foam cells, releasing GFs & cytokines that migration of SMCs from media to
intima; there proliferate, make collagen & take up lipid, potentially becoming
foam cells (collagenll calcify)
Sitosterolemia: rare AR; mutated ABC (ATP-binding cassette) transporter fam (ABCG5 &
ABCG8) plant sterols absorption in intestine (5) & sterol transport into bile by liver (8)
(biliary excretion) sitosterol (+other plant sterols) plasma & tissue lvls
o Impaired cholesterol trafficking so pts show LDL cholesterol (b/c not enough TAGs)
o develop tendon xanthomas & premature AS, may have hemolytic episodes due
to incorporation of plant sterols in RBC membs (how to differentiate from FH); usually
responsive to dietary cholesterol
o dx confirmed by gas chromatography

 Familial hypercholesterolemia (FH): heterozygous inheritance of 1 mutant LDL receptor

allele LDL-C plasma lvls & N lvls of TGs; often not detected until adulthood; +ve fam
hx for premature CAD on 1 side of fam or see symptomatic CAD; (senilis) corneal arcus &
tendon xanthomas (in dorsum of hands, elbows, knees & esp Achilles tendon)
o Geno dose efx w/homozygotes more severe LDL-C lvls >500 mg/dL, can exceed
1000, cutaneous xanthomas, accelerated AS (can result in disability & death in
childhood)
<2% N LDL receptor activity (receptor ve; sooner death)
& those w/225% N LDL receptor activity (receptor defective; not as severe)- Untxd,
receptorve pts w/homozygous FH rarely survive beyond 2nd DEC; pts w/receptordefective LDL receptor dfx have better prognosis but almost invariably develop
clinically apparent ASic vascular dis by age 30, & often much sooner. Carotid &
femoral dis develops later in life & not clinically sig
kids w/cutaneous xanthomas, accelerated AS resulting in disability & death
o Heterozygotes (less severe) LDL-C (200-400 mg/dL w/cholesterol & normal
TGs), corneal arcus, tendon xanthomas in 75% pts; born w/hypercholesterolemia
Early CHD in women but Late CAD in women
Corneal arcus, tendon xanthomas (in dorsum of hands, elbows, knees & esp Achilles
tendon) in 75%
fam hx frequently +ve for premature CAD (coronary AS dis) on 1 side of fam
not detected until adulthood
Tx: low-cholesterol & low-fat diet; use lipid lowering drug therapy, ie. Statins,
cholesterol absorption inhibitors, bile acid sequestrant (if none work = candidate for
LDL apheresis)
Tangier dis: ABCA1 def (mutated ABCA1 gene for generation & stabilization of mature
HDL) HDL rapidly cleared from circulation, so plasma HDL-C (<5 mg/dL) & extremely
circulating apoA-I lvls; cholesterol accumulates in reticuloendothelial system
hepatosplenomegaly & pathognomic enlarged, grayish yellow-orange tonsils, w/risk
premature ASic dis due to HDL-C plasma
o ABCA1: critical role in generating & stabilizing mature HDL particle; when absent, HDL
rapidly cleared from circulation; transporter that facilitates efflux of unesterified
cholesterol & phospholipids from cells to apoA-I
o obligate heterozygotes for ABCA1 mutations w/moderately HDL-C 15-30 mg/dL & also
@risk premature CHD
o Might see intermittent peripheral neuropathy (mononeuritis multiplex) or sphingomylia
like neurologic disorder
Familial LCAT (lecithin:cholesterol acyltransferase) def: AR mutated gene encoding
plasma LCAT sigly free cholesterol in circulating lipoproteins (25>70% total
plasma cholesterol), lack N cholesterol esterification impairing mature HDL particle
formation causes rapid catabolism of circulating apoA-I
o [CE & lysolecithin plasma], mature HDL (<10mg/dL) & apoA-I
o Abnormal LDL (lipoprotein X) & -VLDL found circulation
o Progressive corneal opacification due to deposited free cholesterol in lens, very
HDL-C plasma (<10 mg/dL) & variable hypertriglyceridemia
o LCAT: made in liver & secreted in plasma to circulate w/lipoproteins; mediates
esterification of cholesterol
o Partial def fish eye dis b/c corneal opacification
o Complete LCAT def: hemolytic anemia & progressive renal insufficiency
leading to ESRD

 Familial hypertriacylglycerolemia (FHTG): AD unknown etiology VLDL

production/impaired catabolism (& more CMs in rare case), associated w/intake of carbs,
obesity, insulin resistance, alcohol use, estrogen tx (all VLDL synthesis); dx made by triad
plasma TAG (250-1000 mg/dL), N-slightly cholesterol (<250 mg/dL) & HDL
Thyroid hormones do 5 things
1. LDL receptors (LDL receptor genes promoter has TRE (thyroid hormone responsive
element) to allow T3 to up regulate gene expression of LDL receptor)
2. CETP
3. LDL
4. HL
5. oxidation of LDL
Lipid abnormalities in Hypothyroidism: despite HMG-CoA reductase, SEE serum
total [cholesterol] b/c serum LDL cholesterol & IDL cholesterol
o LDL-receptors activity receptor-mediated catabolism of LDL & IDL is main cause of
hypercholesterolemia in hypothyroidism
o Hypertriglyceridemia: w/VLDL & sometimes fasting chylomicronemia (< common in
this pop); due to LPL that causes clearance of TG-rich lipoproteins (VLDL & CMs)
o VLDL & IDL particles here rich in cholesterol & apo-E, resembling -VLDL particles of
type III hyperlipoproteinemia; exhibit higher lvls of HDL cholesterol due to [HDL2
particles]
o CETP activity results in transfer of CEs from HDL to VLDL HDL cholesterol
o HL activity catabolism of HDL2 particles
o Lp(a) (Lipoprotein (a)) lvls (independent risk factor for cardiovascular events, also ^
hypothyroid pts)
o These abnormalities of lipid metabolism w/overt hypothyroidism predispose to devt of
AS CAD
o Substitution w/L-thyroxine sigly improves abnormalities of lipid metabolism & biliary
cholesterol excretion
Lipid abnormalities in Hyperthyroidism: despite HMG-CoA reductase, SEE total
cholesterol, LDL cholesterol & apolipoprotein B & Lp(a) due to bile excretion
of cholesterol & LDL receptor gene expression (causing enhanced LDL receptormediated catabolism of LDL particles); HDL cholesterol also b/c ^CETP mediated transfer
of CEs from HDL to VLDL & HL-mediated catabolism of HDL2
o Constitutes sig cause of acquired hypobetalipoproteinemia but also cause of
unexpected improvement of lipid profile of hyperlipidemic pts
o hepatic lipase enzyme & HDL2 particles
o CTEP & catabolism of HDL3
Ch.22 FA Oxidation & Ketone Body Metabolism
In oxidation of odd-chain length FAs:
Propionic acidemia: due to def/defected propionyl CoA carboxylase
Methylmalonic aciduria: def vit B12 cant make succinyl CoA accumulated
methylmalonyl CoA due to inefficient funcing methylmalonyl CoA mutase interferes
w/myelination process; methylmalonyl CoA converted to methylmalonic acid & excreted in
urine
note: CARTINITE synthesized from methionine & lysine
MCAD def (medium-fatty acyl CoA DH): AR; impairs medium chain (8-12Cs) FAs oxidation
these & their esters accumulate in tissues/blood toxicity as Spillover C8-12
acylcarnitines into blood! Lack ATPs gluconeogenesis profound hypoglycemia &
FA oxidation acetyl CoA so ketone body formation, +hyperammonemia; Tx: IV
glucose; Prevent w/frequent feeding, high carb & low fat diet

 Carnitine def (CPT I): impaired carnitine shuttle activity LCFA metabolism
accumulated long chain FAs in tissues & wasting of acyl-carnitine in urine produce
cardiomyopathy, skeletal m myopathy, encephalopathy & impaired liver func; inherited or
acquired
Inherited/genetic cause: AR mutated gene transport enzymes (CAT I or CAT II def;
m specific CPT II def more common)
Acquired cause: def dietary protein, impaired synthesis of carnitine in liver dis
or loss carnitine during hemodialysis process
o 6 Hallmarks:
1. M ache & mild-moderate m weakness
2. Rhabdomyolysis & myoglobinuria upon exercise
3. Severe if see hypoketotic hypoglycemia, hyperammonia & death
4. Provoked by prolonged exercise esp after fasting, cold or stress (E)
5. Exacerbated by high fat & low carb diet
6. m triacylglyceride detected as lipid droplets in cytoplasm
o Tx: IV glucose & cease m activity
Zellweger syndrome: AR mutated PEX genes encoding peroxins (for assembling
peroxisomes); accumulate VLCFAs & BRFAs in tissues (N degraded by peroxisomes
impairing N func of multiple organ systems)
o Broad list of abnormalities liver & kidney dysfunc w/hepatomegaly (b/c lack of bile
acids), copper & iron in blood, severe neurological dfx, hypomyelination, craniofacial &
skeletal malformations
o High incidence of perinatal mortality & rarely survive >1 yr
o biogenesis of plasmalogens (1 of memb phospholipids)
Refsum dis: AR def peroxisomal phytanic acid hydroxylase results in impaired -oxidation
of phytanic acid so this & derivatives build up in plasma & tissues; severe symptoms
reld to brain, eyes & ns (cerebellar ataxia, retinitis pigmentosa & chronic polyneuropathy)
o Tx: low-phytanic acid diet (restriction of diary products & avoid ruminant meat plant
phytol fermented to phytanic acid & stored in fat) results in marked improvement
Jamaican vomiting sickness: unripe Ackee fruit ingestion in Jamaica & West Africa has
hypoglycin A (which is metabolized to MCPA methylenecyclopropylacetic acid)
interferes w/transport of LCFAs into mitochondria & inhibits acyl-CoA DHs in -oxidation of
FAs causing ATP & hence gluconeogenesis ; w/sudden vomiting 2-6 hrs after
ingestion, then severe hypoglycemia convulsions, coma & death!
DKA (Diabetic ketoacidosis): often w/uncontrolled type 1 diabetes where
insulin/glucagon ratio, uncontrolled hyperglycemia & unopposed glucagon axn
exacerbates DKA)
o Dysfunc in fat metabolism due to insulin/glucagon ratio fat mobilization
from adipose tissue FAs flood liver IC acetyl CoA lvls by beta-oxidation
Produce academia & aciduria due to high [ketone bodies] acidic & lower pH
o Excess acetyl CoA/ -oxidation depletes liver NAD+; acetyl CoA (+NADH)
saturate/TCA cycle
o This shunts acetyl CoA twds ketone bodies where flux is twds utilization of NADH+H
o Acetoacetic acid & 3-hydroxybutyric acid (ketone bodies) blood pH metabolic
acidosis &+
o Lots of volatile acetone exhaled (fruit odor breath)
o Major sx N/V, dehydration, electrocyte imbalance, loss of concentrations & potentially
coma & death
Ch.23 Metabolism of Glycerophospholipids & Sphingophospholipids (Sphingolipidosis):
Sphingolipidoses: AR (except Fabry dis, X-linked) def enzymes cant degrade sphingolipids
accumulate (as complex lipids w/ceramide) esp in neurons, causing neurodegeneration &

shortening life span; N synthesis of storage lipids; defect in lysososomal degradation pathway
of sphingolipids; extent to which affected enzymes activity is similar all in tissues
GM1 gangliosidosis: accumulated gangliosides & keratin sulfate; neurologic deterioration,
hepatosplenomegaly, skeletal deformities & cherry red macula
Tay-Sachs dis: cherry red macula, deaf, blind & cant swallow
o Cherry red macula (13 diss have this!)
o 3 forms infantile (1st 6 mos; MC & fatal by early childhood), juvenile (2-10 yrs) &
adult (3rd & 4th dec)
Sandhoff dis: Hex B mutated so Hex A doesnt work either; sx same as Tay-Sachs except
GM2 & globoside accumulate!
Sandhoff activator dis: mutated (Sandhoff activator) protein needed for Hex A activity;
only accumulated GM2 ganglioside; same sx as Tay-Sachs & Sandhoff

**Fabry Dis: def alpha-galactosidase A accumulated glycolipid (ceramide

trihexoside/ globotriaosylceramide) in blood vessels, tissues & organs
o Kidney complications, renal insufficiency (MCCOD!) & renal failure can
worsen
o Cardiac complications when build in <3 cells (HTN (high BP) & cardiomyopathy)
o Fabry crises: episodes of intense, excruciating, burning pain felt initially in
hands & feet & radiating to other pts body; what brings pt in hospital
o Angiokeratomas: confirms dx after entering w/pain; tiny painless pinkish
papules on any region of body but predominant on thighs, around belly-button,
buttocks, lower abdomen & groin)

Gauchers Dis: def glucocerebrosidase (acid -glucosidase) esp in Ashkenazi Jews

glucocerebroside accumulates in WBCs, spleen, liver, lungs & brain & bone marrow
Niemann-Pick dis: def sphingomyelinase sphingomyelins accumulate; Foam cells!
MAINLY ONLY neurologic signs + cherry red macula; 4 Ds dysphagia, dystonia,
dysarrythria, dementia
Farber dis (lipogranulomatosis): def ceramidase thus ceramide accumulates in jts, CNS,
throat, liver &+; see subcutaneous nodules & tissue granulomas, jt pain, swollen jts,
contracture & arthritis; +hoarseness of voice & hoarse cry due to ceramide accumulation in
throat
Ch.24: Protein Digestion, Absorption & Fate of AAs, Urea cycle & its disorders:
o final digestion process occur at mucosal lining of upper jejunum where small intestinal
disaccharidases attached to memb in brush border of absorptive cells, ie. isomaltase,
maltase, lactase, sucrase, alpha-glucosidase break down isomaltose into 2 glucose,
maltose into 2 glucose, lactose into glucose & galactose, & sucrose into glucose &
fructose, oligosaccharides into glucose, respectively.
o Defect in specific disaccharidases in intestinal mucosa
Lactose intolerance: undigested carb (osmotically active) enters large intestine (^stool
osmolality, stool pH)
o Osmotically active material draws water from intestinal mucosa into lumen (osmotic
diarrhea)
o Bacterial fermentation of undigested carb ^CO2 & H2 gas (bloating, abdominal cramps,
flatulence). ^breath hydrogen content
o Lactose intolerance: 90% African & Asian descent lactase-def (less able to digest
lactose)
o Bloating, abdominal cramps, flatulence, diarrhea after consumption of milk & milk
products
o Tx: reduce consumption of milk & milk products, lactase pills, lactase txd products,
consumption of calcium rich foods

4 Clinical issues of protein digestion & absorption:

1. CF: defective chloride channel, dry & thickening exocrine pancreatic secretions, inability of
pancreatic enzymes to enter into intestinal lumen to digest dietary proteins, lipids & carbs
2. Hartnup dis: AR dfx in intestinal absorption & kidney reabsorption of neutral AAs including
tryptophan thus cant make Niacin (Niacin def & pellagra)
3. Cystinuria: dfx in transport of cystine & basic AAs (arginine, lysine, ornithine (nonstandard
basic AA) across both intestinal & renal epithelial cells; most serious problem is
insolubility of cystine, which can form kidney stone & its consequences (Nonstandard
= not pt of N polypeptide chain ie. Ornithine)
4. Acute necrotizing pancreatitis: inflammation & ischemia of pancreatic tissue lead to
acinar cell damage, abnormal activation of trypsin inside acinar cells. trypsin then other
proteolytic enzymes & starts self-sustaining cycle of digesting pancreatic tissues;
pancreatic autodigestion central event
Disorders of Urea cycle
N balance: normal when N amt incorporated into body each day = amt excreted
-ve N balance: N amt excreted >amt incorporated in body; exhibit protein malnutrition
(kwashiorkor), dietary def of even 1 essential AAs, starvation, uncontrolled diabetes &
infection
+ve N balance: amt N incorporated > amt excreted; during pregnancy, growth, recovery
phase from surgery/injury or ve N balance
CNS changes hyperammonemia: ammonemia & glutamine lvls, & -KG lvls in
circulation leads to TCA cycle & so ATP; accumulated urea-cycle intermediaries b4
block; neurotoxic efx
o Swelling of astrocytes
o glutamine, depleted -KG & glutamate
o -KG TCA (& thus ATP) & glutamate efx glutaminergic neurotransmission
Hereditary hyperammonemia due to any of 5 genetically def enzyme(s) in urea cycle:
1. Hyperammonemia type 1 (CPS I def)
2. Hyperammonemia type 2 (OTC def) *MC: ammonia & glutamine leads to neurotoxic
efx MR & orotic acid (carbamoyl phosphate + asparate via ATC); X-linked recessive;
[N in cytoplasm, carbamoyl phosphtaed made for pyrimidine synthesis by CPS II using
glutamine & bicarbonate]
3. Citrullinemia (Argininosuccinate synthetaste def)
4. Argininosuccinicaduria (argininosuccinate lyase def)
5. Hyperargininemia (arginase def)
Acquired hyperammonemia: often due to liver dis(s) in adults (ie. Acute viral hepatitis,
ischemia or hepatotoxins or chronic liver damage by alcoholism, hepatitis or biliary
obstruction); see urea cycle & accumulated ammonia
o Chronic cases may b/c of shunting portal blood directly into systemic circulation & no
access to liver
o Ammonia detox thus severely impaired circulatory ammonia
Ch.25 Select AAs Metabolism
Essential AAs (PVT TIM HALL: phenylalanine, valine, tryptophan, threonine, isoleucine,
methionine, histidine, arginine, leucine & lysine)
Non essential AAs: glycine, alanine, glutamate, glutamine, aspartate, asparagine, cysteine,
serine, tyrosine & proline
DEGRADATION OF PHENYLALANINE TO TYROSINE & Tyrosine catabolism disorders
1. Tyrosine undergo oxidative degradation to amphibolic intermediates
2. Tyrosine undergo transamination w/-KG to p-hydroxyphenylpyruvate

o Since ascorbate is reductant for conversion of p-hydroxyphenylpyruvate to

homogentisate, pts w/scurvy excrete incompletely oxidized products of tyrosine
catabolism
3. Subsequent rxns form MAA, FAA, &
4. fumarate, acetoacetate & ultimately acetyl-CoA
o 4 enzymes = 4 diss probable sites of metabolic dfx in 1.type II tyrosinemia (aculo
cutaneous tyrosinemia); 2. neonatal/transient tyrosinemia; 3. alkaptonuria***; & 4.
hepatorenal/type I tyrosinemia, or tyrosinosis
Classic Phenylketonuria (PKU): def PAH enzyme accumulate phenylalanine (& its
ketones phenylacetate, phenylpyruvate & phenylethanolamine; saturates LNAAT
delayed neuronal devt, albinism like& (excessively fair hair & skin, hypopigmentation &
eczema), must/mousy odor of babys sweat & urine; irreversible MR if not txd w/in 1 st
month; confirmed by phenylalanine counteracting afx of 2-thienylalanine & exhibiting
bacterial growth in Guthrie test; txd w/diet low in phenylalanine (meat, fish, eggs, nuts,
cheese, legumes, cow milk & soft drinks w/aspartame (has phe & Asc) & supplying tyrosine,
Lofenalac & PKU aid
o Maternal PKU must have low Phe diet be4 & during pregnancy failure babies
born w/congential <3 disease, GR, microcephaly & MR
Non-classic PKU: N PAH but works less b/c defective DHPR def BH4 coenzyme;
accumulated phe & phe pyruvate; txd w/low Phe diet but still get progressive neurological
manifestation & eventual death (1st 2 yrs life) due to other def NTs that also need BH4 (5HT & DA); malignant hyperphenylalaninemia
o Other case: when DHPR normal but defective in making BH4 from GTP
KUVAN (sapropterine dihydrochloride): FDA approved pharmaceutical formulaed BH4
interacts w/PAH like natural BH4 does; stimulates PAH in PKU pts whore BH4 responders to
metabolize Phe to tyrosine
***Hereditary tyrosinemia type 1/hepatorenal tyrosinemia/tyrosinosis: def FAA
hydrolase; most severe form; acute form w/liver failure, cabbage like body odor, renal
tubular dysfunc, rickets, polyneuropathy, accumulated FAA & MAA (both alkylating agents
DNA alkylation & tumorigenesis) death w/in 1st yr life
Alkaptonuria/alcaptonuria/black urine dis: AR def HGA (homogentisate) oxidase HGA
accumulates in body fluids & autooxidized to quinone derivative w/affinity twds
cartilaginous tissue so accumulates over cartilage; ochronosis & ochronotic arthritis; 50%
w/dark urine prior to other sx until middle life, foci of grey-brown scleral pigment
(+darkening ear after 30), low back pain @30-40, pigmented <3 valves, larynx, tympanic
memb, pigmented renal or prostatic calculi
o Ochronosis: oxidized pigments in bones, CT, sclera, skin
o Ochronotic arthritis: pain, stiffness, & some limitations of motion of hips, knees &
shoulders
o Bamboo spine: oxidized quinone accumulation over vertebral cartilage leading to charac
appearance spine in radiographic film
Albinism: commonly due to def/defective tyrosinase (or other enzymes converting tyrosine
to melanins); suffer from lack of pigment in skin, hair & eyes, & sensitive to sunlight
(photosensitivity/photophobia) & higher susceptibility for skin cancer
Cheese effect: during fermentation or decay process, tyrosine decarboxylated to tyramine

Carcinoid syndrome: ^ serotonin, tumors in midgut (foregut, serotonin, hindgut- n/a)

Disorders of Methionine Metabolism/ HOMOCYSTEINURIAS/ HYPERHOMOCYSTEINEMIAS

Cystathionuria: benign condition; due to def cystathionase cystathionine & in urine
Classic homocysteinemia: due to defected cystathionine-beta-synthase
homocysteine & methionine (b/c homocysteine can convert to this too)

 Non-classic homocysteinemia: due to defective/def methionine synthase, methyl

cobalamin or folate accumulated homocysteine & methionine
Ch.27 Purine salvage & degradation pathways
4 key enzymes regulate purine synthesis:
1. PRPP synthetase
2. PRPP Glutamine phosphoribosyl amidotransferase rate limiting enzyme of purine
synthesis; by PRPP
a. Major rate determinant of de novo purine nucleotide biosynthesis is PRPP
b. PRPP synthesis rate depends on availability of ribose-5-phosphate & PRPP synthase
activity (feedback inhibited by ADP & GDP); PRPP glutamine amidotransferase
3. Adenylosuccinate synthetase
4. IMP DH
GMP & AMP inhibit IMP DH & adenylosuccinate synthetase (feedback inhibit formation
of IMP) & HGPRT (hypoxantine-guanine phosphoribosyltransferase)
GDP & ADP inhibit glutamine PRPP phosphoribosyl amidotransferase & PRPP
synthetase
Cross-reg: serves to synthesis of 1 purine nucleotide when theres def of other nucleotide;
AMP & GMP
1) IMP adenylosuccinate requires GTP
2) XMP GMP requires ATP

Purine salvage pathway: dominant purine synthesis pathway; requires

1. APRT (adenine phosphoribosyl transferase): adenine AMP using PRPP ( PPi) by
adding ribose-5-phosphate from PRPP to free base generating nucleotide &
pyrophosphate
2. HGPRT (hypoxanthine-guanine phosphoribosyl transferase): hypoxanthine IMP &/or
guanine GMP
a. Def HGPRT Lesch Nyhan syndrome
Purines degraded to uric acid mainly in liver using salvage enzymes as well
1. ADA: adenosine inosine
2. Purine nucleoside phosphorylase: guanosine & inosine guanine & hypoxanthine
3. Xanthine oxidase: needs molybdenum, uses O2 & produces H2O2; guanine &
hypoxanthine xanthine uric acid
Cladribine: purine analog, synthetic anti-cancer agent suppresses immune system &
mimics nucleoside adenosine to inhibit ADA interfering w/cells ability to process DNA
Allopurinol: suicidally inhibits xanthine oxidase; prevents/eliminates signs due to hyperuricemia except behaal or neurological abnormalities (aka self-mutilation still there!); hence

uric acid formation & xanthine & hypoxanthine that get salvaged by HGPRT into IMP or
XMP (later to AMP or GMP thatll feedback inhibit glutamine phosphoribosyl amido transfer
& de novo purine synthesis); actual inhibition done by oxypurinol (binds after allopurinol
provides this opportunity)
Ribonucleotide reductase inhibitors: anti-cancer drugs interfere w/tumor growth by
blocking formation of deoxyribonucleotides; exs
o Motexafin gadolinium: inhibitor of thioredoxin reductase & RR; used to treat brain
tumor
o Hydroxyurea: RR inhibitor used in myoloproliferative disorders & in sickle cell anemia
as HbF
o Gemcitabine: nucleoside analogue irreversibly inhibit RR
Hyperuricemias: purine metabolism disorder; depends on whether pt under secretes or
over produces uric acid; commonly due to renal failure w/under excretion of uric acid
o Overproducing causes include (HYPERURICEMIAS)
Various genetic dfx in PRPP synthetase
Specific enzyme dfx ie. Hypoxanthine-guanine phosphoribosyl transferase, glucose-6phosphatase
Others 2ndary to diss ie. Cancer, psoriasis, cancer chemo or radiotherapy
(chemoradiation) that enhance tissue turnover
o Gout: purine catabolism disorder; when serum urate lvls exceed solubility limit, MSU
crystalizes in soft tissues & jts & causes inflammatory rxn, gouty arthritis; MSU crystal
accumulated in SF, show birefringence under polarized light; Tx for gout: acute;
Ibuprofen, diclofenac, colchicine (its inhibitory efx on neutrophil motility & activity); for
Chronic gout: Allopurinol
1st metatarsal phalangeal jt great toe = 1st place where acute Gout manifests (pain,
fever, redness)
o Diff genetic dfx in PRPP synthetase (elevated Vmax, affinity for ribose 5-phosphate, or
resistance to feedback inhibitionresults in overproduction & over excretion of purine
catabolites)
o *Lesch-Nyhan syndrome: X-linked; completely def HGPRT (converts

hypoxanthine to IMP & guanine to GMP; needs PRPP PPi) in purine

salvage pathway (main pathway of nucleotide synthesis); accompanying
rise IC PRPP results in purine overproduction by de novo (IMP & GMP no
inhibition on IMP DH & adenylosuccinate synthetase? (w/energy spent by
neurons to do this)
PRPP means adenine phosphoribosyl transferase & Hypoxanthineguanine phosphoribosyltransferase ACTIVE guanine & hypoxanthine
accumulates (due to HGPRT def 1st)
bizarre self-mutilation (change in neuronal network) ie. Bite my own
fingers, IQ, neurologic signs (choreoathetosis & spasticity),
hyperurecemia & frequent uric acid lithiasis episodes (stone form in kidney
or bladder OR *uric acid crystals in urine/orange sand), nephrolithiasis,
obstructive uropathy & gouty arthritis; orange sand in urine (small
crystals)
PRPP glutamyl amido transferase: rate limiting enzyme for purine
biosynthesis (end product IMP); +vely modulated by PRPP more purine
synthesis but de novo in this dis more degradation more uric acid

HERE lack ve effect of GDP & ADP

Tx: allopurinol (for hyperurecemia), brain stimulation for behavioral/self-mutilation
issues
o Kelley-Seegmiller syndrome: partially def HGPRT hyperuricemia but no CNS dfx
o Von Gierke Dis: Purine overproduction & hyperuricemia (G-6-P-ase def) 2ndary to
enhanced generation of PRPP precursor ribose 5-phosphate; lactic acidosis renal
threshold for urate, total body urates.
Hypouricemias: 3 possible causes
(1) ADA def: SCID (severe combined immunodef dis): AR mutated ADA def cause for
cases from purine salvage & degradation pathways; adenosine & deoxyadenosine
(cant convert to iosine)
AMP ( ADP ATP) & dAMP ( dADP dATP)
RR dGTP, dCTP, & TTP DNA & replication
other diff causes: IL-7 receptor alpha chain (IL7RA) gene mutated, RAG-1, RAG-2 genes
mutated
X-linked recessive cause defective gene encoding for chain of receptors for IL -2,-4,7,-9,-15
sx: SCID b/c ADA most in lymphocytes so immune resp compromised (b/c RR, cells
cant grow & differentiate in resp to cytokines so die) so B & T cells become sparse &
dysfuncal
(2) Purine nucleoside phosphorylase def
(3) Xanthine oxidase def: hypouricemia & hypoxanthine excretion & xanthine due to
genetic defect or severe liver damage; if severe enzyme def xanthinuria & xanthine
lithiasis
Pyrimidine biosynthesis:
- forming carbamoylaspartate is committed step (rate determining enzyme) BUT forming
cytosolic carbamoyl phosphate by CPSII is regd step
o CPS II: by PRPP & ATP but inhibited by UTP
- entire aspartate (donates 4 atoms in pyridimine ring, N1, C,4,5,6)* added to
carbamoyl phosphate in rxn catalyzed by carbamoyl phosphate transferase (aspartate
transcarbamoylase)- RATE DETERMINING ENZYME (COMMITTED STEP) for pyrimidine
biosynthesis
- glutamine donates amide N (N3)
- C2 from CO2

 Leflunomide: immunosuppressive drug for txing RA, inhibits dihydroorotate DH & hence
inhibits de novo pyrimidine nucleotide biosynthesis
Orotic aciduria: defective UMP synthase (either 1 or both enzymes in it); commonly
accompanies Reyes syndrome (damage to mitochondrial memb); orotic acid accumulates
in blood
o megaloblastic anemia that doesnt responds to admin of vit B12 or folic acid (b/c rmr
3 causes for Megaloblastic anemia: folate def, cobalamin & orotic aciduria)
o OTC def: seen orotic aciduria, citrulline increases, & carbamoyl phosphate accumulates
in mitochondria & leaves to condense w/(otherwise only source of carbamoyl
phosphate naturally is CPSII)
o Type 1: both orotate phosphoribosyltransferase & orotidylate decarboxylase def
o Type 2: only orotidylate decarboxylase def!
Methotrexate: anticancer drug inhibits DHFR (dihydrofolate reductase) thus inhibits
reduction of DHF to THF so cant make dUMP to TMP; indirectly inhibits thymidylate
synthase & RR so inhibit DNA synthesis
Ch.28 Heme Synthesis & Porphyrias & Other disorders
Hemin = Fe3+
Heme regulates synthesis of heme & globin in 5 ways:
1. inhibits activity of pre-existing -ALA synthase
2. diminishes -ALA synthase transport from cytoplasm to mitochondria (after being made
in cytoplasm)
3. represses -ALA synthase gene transcription & hence production
4. stimulates synthesis of globin at gene lvl
5.
Barbiturates: heme demand b/c metabolized by cyt-p450 so ALAS1 activity
Disorders of heme synthesis
o Acquired disorder: lead poisoning, vit B6 def
Lead poisoning: inhibits ferrochelatase & delta-ALA-dehydratase; protoporphyrin IX
binds w/zinc released from delta-ALA-dehydratase forming zinc-protoporphyrin (in
lead poisoning); microcytic hypochromic anemia (content, size & color of RBCs !)
Lead binds to any enzyme/protein w/sulfhydryl group (2 enzymes above)
Accumulated -ALA & zinc-protoporphyrin IX & thus Hb
Iron precipitates in ringed sideroblasts aka sideroblastic anemia from
lack of Hb
Energy production b/c lack of cyts for ETC
In vit B6 def slow heme production b/c 1st rxn requires PLP so less
heme made, causing microcytic hypochromic RBCs (small & pale)
w/iron stores
CH2

protoporphyrin IX

CH2

CH

CH3

CH

CH

H3C
NH
N

CH2

Fe

++

heme
CH3

CH

H3C

2H

Fe

HN

H3C

CH3

CH2

H 3C

Ferrochelatase

CH3

CH2

CH2

CH 2

CH2

CH2

CH2

CH 2

CH2

COO-

COO-

COO-

COO-

o Congenital disorder: porphyrias

X-linked sideroblastic anemia: loss of func mutated ALAS2 gene (expressed in erythroid
tissue & controlled by IC iron availability)

 Vit B6 def slow heme production by -ALA synthase needs PLP to combine succinyl CoA
+ glycine -ALA (rate limiting & committed step in heme synthesis) lack RBCs
small & pale & iron stores
Porphyrias: def enzymes in heme biosynthesis; accumulated heme precursors toxic at
high lvls! Attacks triggered by drugs, chemals, foods & sunlight (sunlightblisters); red
colored urine! All AD except
Congenital erythropoietic porphyria & delta-ALA dehydratase def
& delta-ALA synthase def is X-linked recessive

o porphyrinogen (colorless) porphyrin via UV light auto-oxidation

blisters & porphyrin has dbs giving rise to red colored urine!) (diff from
hemoglobinuria WHICH is also red but w/RBCs)
o Hepatic porphyrias: inherited enzyme defs in liver
AIP (Acute intermittent porphyria): 2nd MC porphyria, more in females even tho AD,
def PBGD (porphobilinogen deaminase) (HMB synthase, uroporphyrinogen I
synthase)
Case stem: female, neurological signs b/c delta-ALA in blood
Primarily afx NS:
o Intermittent (episodic) acute abdominal pain w/out any anatomical cause
(dont mistake for other problems pancreatitis, appendicitis clearned
upon ultrasound & tests)
o Acute neuropathy, m weakness & seizures
o Neuropsychiatric sx (hallucinations, depressed, anxiety & paranoia)
o Cardiac arrhythmias & tachycardia may develop as ANS affected
o Photosensitivity not seen
PCT (Porphyria cutanea tarda): most common porphyria;
No abdominal pain*
Blisters on sun exposed area
Red color urine
Hereditary coproporphyria:
Variegate porphyria:
o Erythropoeitic porphyrias: inherited enzyme defs in bone marrow
Congenital erythropoietic porphyria:
Erythropoietic protoporphyria:
o Tx: administer hemin (-ve feedback to inhibit further heme synthesis pathway precursor
production) & administer large glucose amts repressing heme synthesis enzymes &
prevent accumulated heme precursors
o IMP in class: glucose during starvation hepatic delta-ALA synthase (esp S1)
infusion of glucose is going to repress this enzyme so precursor of hemes great tx
for porphyrias b/c precursors give rise to signs/sx of dis
Ch.29 Heme Catabolism & Jaundice (Hyperbilirubenemia)
Bilirubin: metabolic end product of heme; daily make 250-300 mg 70-80% from
senescent RBCs/Hb, rest from heme containing proteins; made in following steps (ER of
reticuloendothelial cells esp in spleen & liver)
1. Heme oxygenase: in reticuloendothelial system & MOs, breaks open
porphyrin/tetrapyrrole heme ring & releases biliverdin, CO & Fe3+ (only source of
endogenous CO, thus CO amt exhaled = index of heme degraded; in hemolytic
anemia!)
a. Heme oxygenase system: substrate inducible = more heme (substrate) = more
heme oxygenase made to convert this heme
2. Biliverdin reductase: converts biliverdin (green) to bilirubin (yellow) (water insoluble,
lipid soluble)

Note* both heme oxygenase & biliverdin reductase need NADPH+H!

3. Unconjugated bilirubin binds w/plasma albumin & transported to liver (reversible & noncovalent interaxn); albumin w/2 binding sites
a. HIGH affinity sites bound when <25 mg UCB on albumin per 100 mL/blood
b. LOW affinity sites bound when excess >25 mg of UCB & diffuses into tissues (
Kernicterus)
4. Taken up by hepatocytes at sinusoidal surface via carrier mediated facilitated transport*
(bidirectional & saturable w/large capacity for bilirubin transport)
a. Once inside, binds to glutathione S-transferase to prevent its reverse/efflux into
circulation & binding to lipid proteins by keeping it solubilized prior conjugation
5. Conjugation to polar bilirubin by UGT1A1 in ER of hepatocytes
a. UGT1A1: glucoronosyltransferase: (UDPGT or UGT) solubilizes bilirubin into
both conjugated bilirubin w/glucoronic acid in ER; inducible enzyme & induced by
anticonvulsant drugs (phenobarbital); makes BMG then BDG (using 2 UDPglucoronates, releasing UDP each time)
6. Secretion of conjugated bilirubin into biliary canaliculi as bile via active transport
mechanism* (rate limiting mechanism) by MRP-2/MOAT
a. Rate limiting b/c then can take more bilirubin in; makes sure less in inside & more
outside via basal side of hepatocyte (connected to biliary caniculi) maintaining [ ]
gradient
b. Hepatic transport of conjugated bilirubin into bile inducible by
anticonvulsants ie. Phenolbarbitol; same drugs inducing conjugation of
bilirubin
7. CB drains into duodenum then in terminal ileum & colon, bacterial glucoronidases
unconjugated bilirubin & other gut bacterias oxidize it to UBG (urobilinogen)
8. 80-90% of UBG excreted in feces, unchanged or oxidized to urobilin (yellow-orange color)
9. 10-20% passively absorbed into portal venous blood & re-excreted by liver
(enterohepatic circulation)
10.
Small %age UBG (<3 mg/dL) escapes hepatic uptake, filters across renal
glomerulus & excreted in urine
Measurement of Bilirubin
- Van den Berg rxn: using diazotized sulfanilic acid, normal [total serum bilirubin] ~1.3 mg/dL,
upto 20% (0.26-0.3 mg) can be direct bilirubin
- Direct rxn: CB, water soluble, react w/sulfanilic acid to form dipyrrylmethene azopigment
(direct bilirubin!) which can absorb light at 540 nm (then color measured using photometer)
- Indirect rxn: above test done after addition of accelerator ethanol to test sample; ethanol
releases UCB (albumin bound) so both CB & UCB react w/sulfanilic acid (as total bilirubin)
- Total bilirubin direct bilirubin = indirect bilirubin (UCB)!
- Delta-bilirubin: direct reacting bilirubin (conjugated & covalently linked to albumin), in
cases of cholestasis (systemic retention of not only bilirubin but also other solutes N
eliminated in bile (esp bile salts & cholesterol) & hepatobiliary diss. Excess bilirubin
glucoronides binds to albumin. Tight binding w/albumin doesn't allow this type of bilirubin to
be eliminated by body until life albumin (12-14 days). So this causes presence of
hyperbilirubinemia when other liver func tests indicating resp to therapy & return to N state
after tx except for hyperbilirubinemia !!! ??
Hyperbilirubinemia: total serum bilirubin >1.3 mg/dL (N is 0.3-1.3 mg/dL); sign of either
liver dis or less often hemolytic disorder; not dis (sign!)
o Jaundice/icterus: sx; yellowish tissue discoloration due to deposited bilirubin; often in
eyes; >2.5-3 mg/dL
o Cause for unilateral icterus? Scleral icterus: sclera has high elastin content &
more affinity twds bilirubin indicating total serum bilirubin >3 mg/dL
o Causes of hyperbilirubinemia

1. Overproduction of bilirubin
2. Impaired uptake or conjugation
3. Impaired excretion of bilirubin
4. Regurgitation of UCB or CB bilirubin from damaged hepatocytes or bile ducts
*1&2 causes UCB
*3&4 causes CB
Hemolytic processes causing overproduction of (unconjugated) bilirubin:
1. Hemolytic disorders:
a. Inherited
i. Hereditary spherocytosis
ii. elliptocytosis
iii. G6PDH defiency
iv. Pyruvate kinase def
v. Sickle cell anemia
vi. Thalassemia
b. Acquired
i. Microangiopathic hemolytic anemia (hemolytic-uremic syndrome)
ii. PNH (paroxysmal nocturnal hemoglobinuria (PNH)
iii. Spur cell anemia
iv. ABO incompatibility (mismatched blood transfusion)
v. hemolytic dis of newborn (Rh incompatibility)
c. physioal jaundice of newborn (physioal hyperbilirubinemia)
2. Ineffective EPOsis: def cobalamin, folate & iron b/c inability bone marrow to make mature
RBCs
In these conditions, serum total bilirubin rarely >5mg/dL; higher lvls may be seen when
disorders associated w/accompanying hepatocellular dysfunc or if theres acute hemolytic
crisis (ie. Sickle cell crisis)
In pts w/chronic hemolysis, rmr theyll have higher incidence pigmented gallstones
(calcium bilirubinate) likelihood choledocholithiasis (gallstones in CBD) leading to
obstruction bile flow
In absence of hemolysis? Must be due to impaired hepatic uptake or conjugation of
bilirubin
In extravascular hemolysis:
1. Spherical RBCs degraded by MOs in spleen & liver
2. leads to MO production of UCB
3. & causes increase in serum UCB (++; CB% <20%).
4. also in uptake & conjugation of UCB to CB (++), & conversion of CB in bowel to UBG (+
+)
5. in UBG causes darkening of stool
6. greater %age of UBG recycled back to liver (wider arrow) & urine (wider arrow).
7. in urine UBG (++), darkens color of urine.
8. B/c RBCs contain aspartate aminotransferase (AST), hemolysis of RBCs causes in
serum AST
9. However, other liver func tests like ALT, ALP & GGT (-glutamyl transferase) lvls N

Impaired bilirubin conjugation occurs in 3 genetic conditions:

1. Crigler-Najjar syndrome type 1: in neonates, very rare but severe; complete absent
UDPGT1A1 via mutated 3 exon of UDPGT gene severe UCB hyperbilirubinemia (>20-25
mg/dL), @high risk kernicterus (>25 mg/dL); only tx is orthotopic liver transplantation
(remove native liver & replaced by donor organ in same anatomic location as original)
o Kernicterus interaxn of excess UCB (>25 mg/dL) w/lipid membs, esp neuronal
tissues (binding to low affinity sites of albumin for liver transport & diffusion into tissues)
2. Crigler-Najjar syndrome type 2: > common > type 1 but less severe; live into adulthood
w/serum UCB hyperbilirubinemia (6-25 mg/dL); UDPGT1A1 due to mutated UDPGT gene;
@risk kernicterus during stress of illness or surgery; Tx: UDPGT activity induced by
admining phenobarbital (serum UCB lvls)
3. Gilberts syndrome: very common, 3-7% pop, esp males!!!, impaired conjugation b/c
UDPGT via mutated TATA box of UDPGT gene promoter most often; mild UCB
hyperbilirubinemia; often jaundice only in fasting
Physioal jaundice of new born: everyone passes thru this, more severe in premature
infants, transient jaundice after 24 hrs & resolves in 1st 10 days due to insufficient UDPGT to
handle conjugation; UCB can reach >25 mg/dL in premature neonates, risk of kernicterus;
Tx: phototherapy UV-light (blue light = bili light, 420-470 nm), conversion to water soluble
photoisomers, exchange transfusion
o Jaundice w/in 1st 24 hrs of life or which takes >10 days to resolve usually
pathological!
Isolated conjugated hyperbilirubenemia seen in 2 rare inherited conditions:
a. Dubin-Johnson syndrome: asymptomatic jaundice in 2nd gen life; AR mutated gene
MRP-2 or MOAT & altered secretion of CB into biliary canaliculi; liver darkly pigmented on
gross & may be enlarged w/histopath centrilobular dark brown pigment granules
(polymers of E metabolites; pic), otherwise N
b. Rotors syndrome: defective hepatic storage of bilirubin where bilirubin values range
from 2-5 mg/dL, & other LFTs are N; liver is N (no pigmentation)
Hyperbilirubinemia w/Abnormal Other Liver Func tests; 2 types of patterns
1. Hepatocellular pattern: normal colored stool BUT DARK colored urine; combined
hyperbilirubinemia, CB btwn 20-50% of total bilirubin; AST & ALT ^ out of proportion to ALP;
liver dysfunc in uptake & conjugation of UCB, secretion of CB into bile ducts & recycling
UBG; hepatocellular conditions that cause jaundice
a. Viral hepatitis (hep A, B, C, D & E, Epsteine-Barr virus, cytomegalo virus, HSV) ALT
higher (+++) than AST (++) & slight ^ALP & GGT (+) if theres micro-obstruction;
only cytoplasmic enzyme affected

b. Alcoholic hepatitis AST>ALT, b/c alcohol damages mitochondria, since AST also in
mitochondria apt from cytoplasm, whereas ALT is > cytoplasmic than
mitochondrial***; AST released (vs. ALT); mitochondria & cytoplasmic enzyme
affected!!! IMP for path 2
c. Cirrhosis
d. Drug toxicity (acetaminophen, isoniazid)
e. Vinyl chloride toxicity
f. Mushroom poisoning (Amanita phalloides)
g. Wilsons disease
h. Autoimmune hepatitis
Prehepatocellular dark colored urine & dark stool
2. Cholestasis: obstructed flow of bile systemic retention of bilirubin, bile salts, bile acids &
cholesterol; increase in serum & urine CB (++) due to obstruction of intrahepatic
or extrahepatic bile flow (stone in CBD in this case) causes pressure in
intrahepatic bile ductules leading to rupture & regress of CB into sinusoidal blood; absence
UBG in stool (light-colored) & urine; CB% >50% & marked increase in serum ALP & GGT (++
+) & only slight in serum AST & ALT (+); 2 types
a. Intrahepatic cholestasis: blocked intrahepatic bile ductules, cant be surgically
txd; causes include
i. Drugs (oral contraceptive pills, anabolic steroids, chlorpromazine)
ii. Neonatal hepatitis, viral hepatitis (fibrosing cholestatic hepatitis hep B & C)
iii. Pregnancy induced cholestasis (estrogen)
iv. Biliary atresia, viral hepatitis, primary biliary cirrhosis, primary sclerosing
cholangitis, vanishing bile duct syndrome (sarcoidosis), progressive familial
intrahepatic cholestasis
b. Extrahepatic cholestasis: blocked common bile duct; possible to surgical tx; more
common than intrahepatic; causes include
i. Stone from gall bladder (choledocholithiasis MCC of extraheptic cholestasis),
Carcinoma of head of pancreas, 2nd MCC, Primary sclerosing pericholangitis, &
Extrahepatic biliary atresia
c. Clinical findings:
i. Jaundice w/pruritus due to bile salts deposited in skin; can be txd
w/cholestyramine
ii. Malabsorption of lipids& lipid soluble vits b/c bile salts dont enter small
intestine; def essential lipids & fat soluble vits in Hypercholesterolemia: from
backup of bile containing cholesterol
iii. Cholesterol deposits in skin xanthomas, xanthelasma
iv. Light colored stool due to lack of urobilin
v. Urine-dark orange color
d. Laboratory findings:
i. Marked of ALP & GGT, 5-nucleotidase (markers of obstruction)
ii. CB>50%
iii. Bilirubinuria
iv. Absent urine UBG
v. High serum cholesterol lvls
e. Green colored liver due to cholestasis enlarged green color, bile ducts distend w/bile
may rupture bile lakes & bile infarcts; & prolonged obstruction portal tract
fibrosis & eventually cirrhosis

f. Distended bile ducts & bile lakes

***Obstructive jaundice = clay colored stool b/c urobilinogen NOT PRESENT & tea colored
urine, ^ALP!
Urinary findings in types of jaundice
Urine bilirubin
Urine Urobilinogem
Normal
Absent
Trace
CB <20% (hemolytic jaundice)
Absent
Dark colored urine
CB 20 50% (hepatocellular

Dark colored urine

jaundice)
CB >50% (obstructive jaundice)
Tea colored urine
Absent
30. Integration of Metabolism Feed & Fast Cycle
31. Diabetes Mellitus Pathophysiology & Dx; group of metabolic disorders of
hyperglycemia; depending on etiology, factors contributing include insulin secretion,
glucose utilization & glucose production; classified on basis of pathogenic process leading
to hyperglycemia
1. Type 1 DM (beta cell destruction)
2. Type 2 DM (insulin resistance) overweight/obese peripheral resistance to insulin
3. Other specific types of diabetes ex. MODY & many other
4. Gestational diabetes mellitus (GDM)
o Criteria for dx of DM
FGP > 126 mg/dL (7.0 mmol/L) OR
2H PG > 200 mg/dL (11.1 mmol/L) during OGTT OR
A1C > 6.5%
OR
In pts w/classic sx hyperglycemia/hyperglycemic crises, & random PG>200 mg/dL
(11.1 mmol/L)
Fasting defined as no caloric intake for at least 8 hr
OGTT (oral glucose tolerance test): should be performed as described by WHO,
using glucose load containing equivalent of 75 g anhydrous glucose dissolved in
water
A1C test should be performed w/method certified by NGSP (National
Glycohemoglobin Standardization Program) & traceable to DCCT (Diabetes Control &
Complications Trial) reference assay
o Criteria for prediabetes (= relatively high risk for future devt of diabetes. IFG & IGT &
A1C 5.7-6.4% should not be viewed as clinical entities on own but rather risk factors for
diabetes & CVD (CVD). IFG & IGT associated w/obesity (esp abdominal or visceral
obesity), dyslipidemia w/TGs &/or HDL cholesterol & HTN)
FGP 100-125 mg/dL (5.6-6.9 mmol/L) & IFG (impaired fasting glucose) (70-99) OR

2-H PG in 75g OGTT 140-199 mg/dL (7.8-11.0 mmol/L) & IGT (impaired glucose
tolerance) (120-139) OR
A1C 5.7-6.4%
o Criteria for testing diabetes in asymptomatic adults:
1. Testing should be considered in all adults whore overweight (BMI > 25 kg/m2; but
American Diabetes Association recommendation to screen Asian Americans for type 2
diabetes starting at body mass index (BMI) of 23 kg/m2 instead of 25 kg/m2) & have
additional risk factors:
a. Physical inactivity
b. 1st degree relatives w/diabetes
c. high-risk race/ethnicity (African America, Latino, Native American, Asian
American & Pacific Islander)
d. women who delivered baby weighing >9 lb or were dxd w/GDM
e. hypertension (>140/90 mmHg or on therapy for HTN)
f. HDL cholesterol lvl <35 mg/dL (0.9 mmol/L) &/or TG lvl >250 mg/dL (2.82
mmol/L)
g. Women w/polycystic ovarian syndrome
h. A1C > 5.7%, IGT, or IFG on previous testing
i. Other conditions associated w/insulin resistance (ex. Severe obesity, acanthosis
nigricans)
j. History of CVD
2. In absence of above criteria, testing for diabetes should begin at age 45
3. If results N, testing should be repeated at least at 3 yr intervals, w/consideration of
more frequent testing depending on initial results (ex. Those w/prediabetes should be
tested yrly) & risk status
o GLP-1 (Glucagon-like peptide 1): most potent incretin, released from L cells in small
intestine & stimulates insulin secretion only when blood glucose above fasting lvl; afx
following tissues
o Brain: neuroprotection, appetite
o Stomach: gastric emptying
o Liver: glucose production
o Pancreas: insulin secretion, glucagon secretion, insulin biosynthesis, beta
cell proliferation, beta cell apoptosis
o Muscle: glucose uptake
o Heart: cardiac func & cardioprotection
o Vessel: vascular func