Oral Manifestations of Systemic Disease

D. V. Watkins, D.D.S
CAPT DC USN
Oral Manifestations of:
Nutritional disorders
Hematologic disorders
Metabolic disorders
Endocrine disorders
Other internal diseases
Nutritional Disorers
Vitamin A (Retinol) deficiency
Vitamin B2 (Riboflain) deficiency
Vitamin B! (Niacin) deficiency
Vitamin B" (#yrido$ine) deficiency
Vitamin % deficiency
&olic acid deficiency
'inc deficiency
!ematolo"ic isorers
Anemia
(ron deficiency
Vitamin B)2 deficiency
*eu+emia
Acute leu+emia
%hronic leu+emia
*ym,homa
Non Hodg+in-s lym,homa
Multi,le myeloma
Bur+itt-s lym,homa
Meta#olic isorers
Amyloidosis
*i,oid ,roteinosis
&abry-s disease
$nocrine isorers
.iabetes mellitus
Hy,othyroidism
Addison-s disease
Hy,er,arathyroidism
Ot%er internal iseases
%rohn-s disease
/lceratie colitis
/remic stomatitis
)
Nutritional Disorers
Vitamin A (Retinol) deficiency
Vitamin B2 (Riboflain) deficiency
Vitamin B! (Niacin) deficiency
Vitamin B" (#yrido$ine) deficiency
Vitamin % deficiency
&olic acid deficiency
'inc deficiency
Vitamin deficiencies are not common in the /nited 0tates1 #atients 2ith
malabsor,tion syndromes3 eating disorders3 ,ersons 2ho follo2 fad diets and alcoholics
are the grou,s most commonly affected1
Vitamin A Deficiency
Retinol is essential for the maintenance of ision1 Vitamin A can be obtained
directly from meats or mil+ or the body can synthesi4e it from beta carotene3 2hich is
found in red and yello2 egetables1
A seere deficiency of Vitamin A during infancy may lead to blindness1 *ac+ of
itamin A in later life leads to night blindness1 5ith seere3 ,rolonged deficiency dryness
of the s+in and con6unctia deelo, and ocular changes lead to corneal ulceration and
blindness1 7he oral mucosa is similarly affected3 2ith dryness3 atro,hy and3 eentually
the a,,earance of leu+o,la+ia1 0imilary changes are seen in other mucosal surfaces
throughout the body1 7he li,s are often described as 8retreating93 since the mucosal
surface contracts bac+ into the mouth1 Angular cheilitis is also common1
E$cessie doses of Vitamin A ,roduce similar effects as deficiency states1
7herefore ,atients ta+ing isotretinoin (Accutane) may hae similar clinical
manifestations1
Vitamin &' Deficiency
Riboflain functions as the ,recursor for flain mononucleotide (&MN) and flain
adenine dinucleotide (&A.)1 &MN and &A. act as hydrogen carrier to ,roduce A7#
through metabolism of carbohydrates and fats1 Ribflain is found in mil+3 green
egetables3 meat (lier)3 fish and eggs1
Riboflain deficiency can deelo, in ,atients 2ith seer lier disease3 diabetes
mellitus3 and achlorhydria1 7he oral mucosa is a faored site for manifestations of
riboflain shortage1 Angular cheilitis is a classic sign but this ,resentation is not s,ecific
and may be initially misleading1 (nitially the tongue is s2ollen3 but after a ,eriod of time
it becomes dar+ red and atro,hic1 0ore throat and s2elling 2ith erythema of the oral
mucosa may also be ,resent1
A normocytic3 normochromic anemia may be ,resent and seborrheic dermatitis
may affect the s+in (nasolabial fold and ears)1 7he nails may e$hibit a s,oon sha,e
2
a,,earance (+oilonychia)1 Other sym,toms include reduced ision at dus+1 (ron
deficiency is the main differential diagnosis1
Vitamin &( )Niacin* eficiency
Niacin is a ,recursor to Nicotinamide Adenine .inucleotide (NA.) and
Nicotinamide Adenine .inucleotide #hos,hate (NA.#)1 NA. and NA.# sere as
coen4ymes for glycolysis3 amino acid and ,rotein metabolism3 and the ,roduction of high
energy ,hos,hate bonds1 Niacin is found in lean meat and lier3 ,eanuts3 yeast3 and
cereal bran1
.eficiency of niacin is +no2n as ,ellagra ((talian ernacular for 8rough s+in9)
and is characteri4ed by the 8: .-s9; ermatitis, iarr%ea, ementia, an eat%1 7he
classic research on ,ellagra 2as done among ,oor farmers in the 0outheast /101 at the
beginning of the 2<
th
century1 A limited diet of beans and cornmeal contributed to niacin
deficiency and many ,eo,le 2ere ,laced in mental institutions3 2here3 2ith ,ro,er
nutrition3 their condition im,roed1 7oday ,ellagra is a ,roblem among alcoholics3
,atients 2ith malabsor,tion and rare indiiduals 2ith abnormalities of try,to,han
metabolism1
Oral manifestations of niacin deficiency hae been described as stomatitis and
glossitis1 7he tongue a,,ears red3 smooth3 and ra21 At first it is s2ollen but later
becomes dar+er red and atro,hic1 #atients may com,lain of burning mouth or burning
tongue1 Erosions and a,hthous=li+e ulcers may a,,ear on the tongue and gingia 1
#atients 2ith early ,ellagra may e$hibit increased saliary flo23 resulting in drooling and
more mar+ed angular cheilitis1 *ater saliary flo2 decreases and there may be chronic
saliary gland s2elling1
Vitamin &+ eficiency
#yrido$ine is an essential cofactor in transamination3 decarbo$ylation3 hydrolysis
of glycogen and synthesis ,ath2ays1 #yrido$ine is found in many animal and egetable
food sources1
.eficiency of ,yrido$ine is unusual because of its 2ides,read occurrence in a
ariety of foods1 A ariety of drugs such as isonia4id3 and3 less often3 cyclos,orine or
,enicillin3 act as ,yrido$ine antagonists1 #yrido$ine deficiency causes blood3 s+in and
nere changes1 Both ,yrido$ine deficiency and e$cess can cause ,eri,heral neuro,athy1
#atients may e$hibit 2ea+ness3 di44iness or sei4ure disorders1
Oral manifestations of ,yrido$ine deficiency include cheilitis and glossitis
(similar to ,ellagra)1
!
Vitamin C eficiency
Vitamin % is an essential cofactor in collagen synthesis1 (t is found in many
egetables and fruits3 although it is most abundant in citrus fruits1
(n the /101 the deficiency is limited to those 2ho lac+ fruits and egetables in
their diet1 (nner city infants and edentulous elderly men are most li+ely to e$hibit effects
from 8scury91 7he classic cutaneous findings in scury are seen on the legs
(,erifollicular hemorrhages associated 2ith 8cor+scre2 hairs9)1 5ea+ened essels are
res,onsible for ,etechial hemorrhage3 ecchymosis3 delayed 2ound healing and
sub,eriosteal hemorrhage in children1 &olic acid is not absorbed ,ro,erly3 leading to
anemia1
Oral findings include generali4ed gingial s2elling 2ith s,ontaneous
hemorrhage3 ulceration3 tooth mobility and increased seerity of ,eriodontal infection and
,eriodontal bone loss (scorbutic gingiitis)1 7he teeth may e$foliate1 #alatal hemorrhage
is seen3 but the tongue is not usually inoled in scury1 (n children deelo,ment of
bones and teeth is affected since osteoid and dentin are de,endent on itamin %1 (n
adults3 bleeding into the dental ,ul, along 2ith degeneration of odontoblasts and
resor,tion of dentin may be seen1
,olic aci eficiency
&olic acid deficiency is seen in ,atients ta+ing methotre$ate (cancer thera,y and
,soriasis thera,y) and related folic acid inhibitors1 (t is also seen in ,atients 2ith s,rue
and chronic lier disease1 7he main sym,tom of folic acid deficiency is a megaloblastic
anemia1 &olic acid and itamin B)2 metabolism are intricately associated1
Oral findings include cheilitis3 angular cheilitis3 ulcers3 and glossitis1
-inc eficiency
'inc deficiency can arise from an inherited inability to absorb the mineral
(acrodermatitis entero,athica) or from a nutritional deficiency1 Acrodermatitis
entero,athica is an autosomal recessie disorder1 #atients deelo, sym,toms 2hen
breast=feeding is discontinued1 7hey deelo, a ,eriorofacial and acral erythematous rash
that a,,ears ,soriasiform 2ith scales and ,ustules1 (t is often misdiagnosed as a yeast
infection (thrush)1 7here may also be alo,ecia and loss of nails1 Oral features include
crusting3 scaling rash of the li,s as 2ell as ulcers3 erosions and fissures1
An ac>uired form of 4inc deficiency is most common in ,atients 2ith %rohn-s
disease1 7hese ,atients deelo, an im,aired sense of smell1 Other ,atients 2ith
malabsor,tion may deelo, 4inc deficiency1 &or a number of years3 4inc 2as not added
to hy,eralimentation formulas 2ith the result that ,atients on long=term ,arenteral
nourishment deelo,ed 4inc deficiency (ac>uired acrodermatitis entero,athica)1
:

!ematolo"ic isorers
Anemia
(ron deficiency
Vitamin B)2 deficiency
*eu+emia
Acute leu+emia
%hronic leu+emia
*ym,homa
Non Hodg+in-s lym,homa
Multi,le myeloma
Bur+itt-s lym,homa
AN$M.A
.ron eficiency
(ron deficiency anemia is the most common cause of anemia in the /101 and
2orld2ide1 7his ty,e of anemia deelo,s under four conditions;
)1 e$cessie blood loss
21 increased demands for red blood cells
!1 decreased inta+e of iron
:1 decreased absor,tion of iron
(t is estimated that 2<? of 2omen of childbearing age are iron=deficient due to
chronic blood loss from e$cessie menstrual flo21 (t is also estimated that 2? of adult
men are iron deficient due to chronic blood loss from @( disease such as ,e,tic ulcer3
dierticulosis3 hiatal hernia or malignancy1 (ncreased demands for iron occur during
gro2th s,urts and decreased inta+e occurs due to ,oor diet in infancy and in elderly
,atients 2ith dental conditions that ,rohibit eating ,ro,er foods and inability to afford
iron rich foods (meats and egetables)1 .ecreased absor,tion can be seen in ,atients 2ith
celiac s,rue (gluten sensitiity 2ith diarrhea)1
#atients may com,lain of fatigue3 ,al,itations3 lightheadedness and lac+ of
energy1 Oral manifestations include angular cheilitis and atro,hic glossitis or generali4ed
mucosal atro,hy1 7he glossitis may be characteri4ed as diffuse or ,atchy atro,hy of the
dorsal tongue ,a,illae 2ith tenderness or burning sensation1 0ome inestigators ,ro,ose
that iron deficiency ,redis,oses ,atients to %andidiasis1
7he diagnosis is made by a %B% 2ith RB% indices because hy,othyroidism3
other anemias or clinical de,ression may elicit similar clinical com,laints1 *ab findings
sho2 hy,ochromic microcytic RB%-s 2ith reduced numbers of RB%-s1 7hera,y consists
of daily iron su,,lementation1
A
Vitamin &/' eficiency
#ernicious anemia is an uncommon condition that historically is seen most often
in elderly ,atients of northern Euro,ean heritage1 Recent studies hae also identified the
disease in blac+ and His,anic ,o,ulations as 2ell1 7he disease is a megaloblastic anemia
caused by ,oor absor,tion of itamin B)2 (e$trinsic factor3 cobalamin)1 (ntrinsic factor3
,roduced by the ,arietal cells lining the stomach is re>uired for absor,tion of the B)2=
intrinsic factor in the duodenum1 (n ,ernicious anemia most ,atients lac+ intrinsic factor
due to autoimmune destruction of ,arietal cells1 #ernicious anemia can also deelo, after
gastric by,ass surgery due to loss of ,arietal cells1 0trict egetarians may also deelo,
,ernicious anemia since itamin B)2 is mostly deried from animal sources1
#atients com,lain of fatigue3 2ea+ness3 shortness of breath3 headache3 and feeling
faint1 7hese features are seen in most ty,es of anemias and are most li+ely due to the
reduced o$ygen carrying ca,acity of the blood1 #atients also re,ort ,aresthesia3 tingling
or numbness of the e$tremities1
Oral sym,toms include burning sensations inoling the tongue3 li,s3 buccal
mucosa and other oral mucosal sites1 %linically the oral mucosa may sho2 ,atchy areas
of erythema and atro,hy1 7he tongue is inoled in A< to "<? of ,atients and changes of
the dorsal surface may be easier to a,,reciate1 Microsco,ically there is e,ithelial
atro,hy3 loss of rete ridges and increase nuclear to cyto,lasmic ratio1 7hese features may
be mista+en for e,ithelial dys,lasia1
*ab findings sho2 a macrocytic anemia 2ith reduced serum cobalamin leels1
0hilling test uses radiolabeled cobalamin to determine etiology of the deficiency by
com,aring absor,tion and e$cretion rates1 7hera,y consists of monthly (M in6ections of
cobalamin1 High dose oral cobalamin has also been utili4ed and is cost effectie and
aoids ,ainful in6ections1
0$U1$M.A
*eu+emia re,resents seeral ty,es of malignancies of hemato,oietic stem cell deriation1
One ty,e of stem cell ,roliferates in the bone marro2 and eentually oerflo2s into the
,eri,heral blood1 7he disease manifests itself 2hen the leu+emic cells cro2d out normal
immune cell and RB% ,recursors1 *eu+emias are classified according to their
histogenesis and clinical behaior and are described as acute or c%ronic and myeloi or
lym2%ocytic 3 lym2%o#lastic1 Acute leu+emias are aggressie and result in death 2ithin
a fe2 months if untreated1 %hronic leu+emias follo2 a long term indolent course but
eentually cause death1 *eu+emias are ,robably caused by a combination of genetic and
enironmental factors1 %ertain syndromes (.o2n3 Bloom3 &anconi-s anemia) are
associated 2ith an increased ris+ and some ty,es of leu+emia sho2 s,ecific chromosomal
abnormalities (%M* B translocation of long arms of chromosomes C B 22)1
Enironmental agents (,esticides3 ben4ene and ben4ene deriaties)3 ioni4ing radiation
(%M* in Da,anese atomic bomb blast suriors) and iruses (H7*V ) ty,e leu+emia) are
also im,licated in the etiology of leu+emia1
"
7he myeloid leu+emias generally affect an adult ,o,ulation1 AM* (acute myeloid
leu+emia) affects a broader age range that includes children1 %M* (chronic myeloid
leu+emia) has a ,ea+ incidence in the !
rd
and :
th
decades1 A** (acute lym,hoblastic
leu+emia) almost al2ays affects children and is one of the more common childhood
malignancies1 %**(chronic lym,hocytic leu+emia)3 the most common ty,e of leu+emia3
mostly affects elderly adults1
Many of the clinical signs and sym,toms of leu+emia are related to the mar+ed
reduction in the numbers of normal 2hite and red blood cells that results from the
cro2ding out of normal hemato,oietic stem cells by the malignant cells1 #atients
com,lain of fatigue and dys,nea on mild e$ertion1 Malignant cells infiltrate other organs
and cause s,lenomegaly3 he,atomegaly and lym,hadeno,athy1 #atients com,lain of easy
bruising and bleeding cause by decrease in ,latelets due to mega+aryocytes being
cro2ded out in the marro21
Oral findings include ,etechial hemorrhages of the ,osterior hard ,alate and the
soft ,alate along 2ith s,ontaneous gingial hemorrhage1 /lceration of oral mucosa is
,resent as a result of im,aired host immune ca,ability to combat normal flora1 @ingia is
usually the most affected due to the ,resence of abundant bacteria around the teeth1
/lcers are dee,3 ,unched out lesions 2ith a gray=2hite necrotic base1 Oral candidiasis
may be ,resent and her,etic infections may inole any area of mucosa rather than 6ust
the +eratini4ed mucosa as seen in immunocom,etent indiiduals1 Boggy s2ellings may
be ,resent and re,resent infiltrates of leu+emic cells1 7his is seen in myelomonocytic
leu+emia and may cause diffuse gingial enlargement1
04MP!OMA
Non !o"kin5s lym2%oma
Non Hodg+in-s lym,homa re,resents a dierse and com,le$ grou, of
malignancies of lym,horeticular histogenesis1 7hey usually arise in lym,h nodes and
gro2 as solid masses1 0ome lym,homas (MA*7 lym,homas) arise in e$tranodal tissue
such as ,arotid gland tissue and gastrointestinal tissue1 Most non Hodg+in-s lym,homa
arise from B cells and a,,ro$imately EA? of Euro,ean and American lym,homas arise
from B cells1 (n the far east (Da,an B Forea) A<? of non Hodg+in-s lym,homas are
e$tranodal1 7 cell lym,homas are less common and true histiocytic lym,homas are ery
rare1
Non Hodg+in-s lym,homas 2ere originally classified by their HBE a,,earance
but are no2 classified based on immunohistochemical ((H%) and genetic studies1
.ifferent classifications hae been attem,ted and the 82or+ing formulation9 and more
recent 8Reised Euro,ean and American lym,homa9 (REA*) classification hae been
the most accurate method to classify this dierse grou, of malignancies1 7he 2or+ing
formulation is based on gro2th ,attern (diffuse s follicular) and grade (lo23
intermediate3 high) based on cell ty,e (small non=cleaed3 small cleaed3 mi$ed3 large)1
7he 2or+ing formulation is limited in its usefulness since it does not include recently
G
defined ty,es1 7he REA* classification utili4es histo,athologic features3 immunologic
cell surface mar+ers and gene rearrangement studies1
*ym,homas usually ,resent as nodal disease 2ith the ,atient a2are of a
nontender mass that has been enlarging for months1 7he ,rocess usually inoles a
regional node collection (cerical3 a$illary3 inguinal) 2ith the nodes being moable1
Eentually the inoled nodes become more numerous and fi$ed to ad6acent structures
2ith other regional node grou,s inoled1
(n the oral caity3 lym,homa usually a,,ears as e$tranodal disease1 7he lesion
may deelo, in the soft tissues or 2ithin bone1 0oft tissue lesions a,,ear as nontender3
boggy masses usually inoling the buccal estibule3 ,osterior hard ,alate3 or gingia1
7he lesions may a,,ear erythematous or ,ur,lish and may or may not be ulcerated1
.enture 2earers may com,lain that their denture no longer fits1 *ym,homa of bone may
cause ague ,ain or discomfort and may be mista+en for a toothache1 Radiogra,hs sho2
an ill=defined radiolucency and3 if untreated3 2ill eentually cause e$,ansion of bone
usually causing ,erforation and inolement of soft tissue1
7reatment usually consists of radiation thera,y andHor chemothera,y1 *o2 grade
lym,homas either tend to not res,ond to thera,y or recur follo2ing thera,y1 Median
surial for these older adult ,atients is E to )< years (2ithout treatment) and clinicians
may o,t to 82atch and 2ait9 before initiating thera,y1 7reatment for intermediate and
high grade lym,homas de,ends on both grade and stage of the malignancy1 Multiagent
chemothera,y andHor radiation thera,y are used1 Res,onse rate is good but intermediate
grade tumors recur in !< to A<? of cases and high grade tumor mortality rate is "<? at A
years1
Multi2le myeloma
Multi,le myeloma is a relatiely uncommon malignancy of ,lasma cells that
a,,ears to hae a multi=centric origin in bone1 Multi,le myeloma ma+es u, )? of all
malignancies3 )<=)A? of hematologic malignancies and (e$cluding metastatic disease)
nearly A<? of all malignancies inoling bone1 7he abnormal ,lasma cells are
monoclonal and ,robably arise from a single malignant ,recursor cell1 7hese monoclonal
cells ,roduce the same immunoglobulin that is nonfunctional and tend to accumulate as
amyloid1
Multi,le myeloma is a disease of adults and median age at diagnosis is bet2een
"< and G< years1 Blac+s are affected t2ice as often as 2hites and men slightly more than
2omen1 Bone ,ain is the most common ,resenting sym,tom1 #athologic fracture may
occur due to bone destruction1 Anemia and ,etechial hemorrhages may also be seen1
Radiogra,hically the ,rocess ,resents as multi,le 8,unched out9 2ell=defined or
ragged radiolucencies1 7hese may be es,ecially eident on s+ull films1 7he 6a2s hae
been re,orted to be inoled in !<? of cases1 Renal failure may be the ,resenting sign as
tumor ,roduced immunoglobulin accumulates in the +idneys1 *ight chains (Bence Dones
E
,rotein) may be found in the urine in !< to A<? of ,atients1 Amyloid may be de,osited
in soft tissues of the tongue1 7he tongue may sho2 diffuse enlargement and firmness or
a,,ear nodular1 #eriorbital s+in may also sho2 signs of amyloid de,osits and a,,ear as
2a$y3 firm3 and ,la>ueli+e1
7he lesions are com,osed of monotonous sheets of cro2ded aty,ical ,lasma cells1
Amyloid de,osits may be seen and are confirmed by %ongo red3 7hioflain 73 or crystal
iolet stains1 (n addition to bio,sy3 screening electro,horesis of urine or serum should be
,erformed to ealuate for the ,resence of myeloma ,rotein1 7he ,resence of an 8M
s,i+e9 indicates massie oer,roduction of one abnormal immunoglobulin by the
neo,lastic ,lasma cells1
7reatment consists of chemothera,y 2ith ,rednisone and I"<? of ,atients 2ill initially
res,ond1 Radiation thera,y is useful for ,alliation only1 #rognosis is ,oor but younger
,atients do better than older ones1 Median surial of !< to !" months after onset of
sym,toms can be e$,ected1 7he surial rate remains at )<? after A years1 Een 2ith
aggressie chemothera,y and bone marro2 trans,lant the surial rate is only marginally
im,roed1
&urkitt5s lym2%oma
Bur+itt-s lym,homa is a B cell deried malignancy that re,resents an
undifferentiated lym,homa1 &irst described by .r1 .enis Bur+itt3 the tumor has been
termed African Bur+itt-s lym,homa3 or more recently3 endemic Bur+itt-s lym,homa since
the disease is also seen in areas other than sub=0aharan Africa such as northeastern
Bra4il1 7he lesion is related ,athogenetically to E,stein=Barr irus (EBV) since more
than C<? of tumor cells sho2 e$,ression of EBV nuclear antigen and ,atients hae
eleated antibody titers to EBV1 H(V ,ositie ,atients also may deelo, an aggressie
Bur+itt-s lym,homa1
As many as A< to G<? of African Bur+itt-s lym,homa cases ,resent in the 6a2s1
7he tumor usually affects children (,ea+ ,realence J G years of age) 2ith males more
often affected1 #osterior segments of the 6a2s are inoled and the ma$illa is more
commonly inoled than the mandible (2;))1 0ometimes all four >uadrants are inoled1
Kounger ,atients hae more 6a2 inolement than older ,atients1 African Bur+itt-s
lym,homa sho2s a ,redilection for the abdominal iscera (+idneys3 oaries and adrenal)1
American Bur+itt-s lym,homa ty,ically affects a greater age range than African Bur+itt-s
and the abdominal region is more often inoled1
7he tumor may cause facial s2elling and ,ro,tosis1 #ain3 tenderness3 and
,aresthesia are usually minimal1 Mar+ed tooth mobility may be ,resent due to bone
destruction1 #remature e$foliation of deciduous teeth may be seen1 7he bony lesions
a,,ear radiolucent 2ith ragged3 ill=defined margins1
C
7umor cells are undifferentiated3 small3 noncleaed B=cells1 7he tumor
histologically ,resents as sheets of these cells e$hibiting bris+ mitotic actiity 2ith
a,o,totic cells and benign macro,hages (starry s+y ,attern)1
Bur+itt-s lym,homa is aggressie and can cause death 2ithin : to " months if untreated1
(ntensie chemothera,y causes remission (cureL) in oer C<? of ,atients1 Multiagent
chemothera,y results in an EA to CA? surial rate ! to A years after treatment for
,atients 2ith stage ( or (( disease and GA to EA? surial rate in ,atients 2ith stage ((( or
(V disease1
Meta#olic isorers
Amyloidosis
*i,oid ,roteinosis
&abry-s disease
Amyloiosis
Amyloidosis is a heterogeneous grou, of conditions that is characteri4ed by the
de,osition of an e$tracellular ,roteinaceous substance1 Vircho2 coined the term in the
)C
th
century because he belieed it to be a starchli+e material1 Amyloidosis may be due
to a number of different conditions but the material is al2ays arranged in a beta=,leated
sheet molecular configuration1 7he substance can be identified by %ongo Red stain3
crystal iolet stain or thioflain 7 immunofluorescent stain1 .e,ending on the clinical
,resentation3 amyloidosis may hae no to minimal effect on ,atient health or may result
in death 2ithin a fe2 years due to cardiac or renal failureM1
Or"an limite amyloiosis
Organ limited amyloidosis is rare in the oral caity1 An e$am,le is the 8amyloid
nodule9 that a,,ears as a solitary submucosal de,osit1 Most forms of organ=limited
amyloidosis are caused by de,osition of immunoglobulin light chains unassociated 2ith
any systemic disease1
Systemic amyloiosis
0ystemic amyloidosis occurs in seeral different forms illustrated belo2;
#rimary H Myeloma associated amyloidosis
0econdary amyloidosis
Hemodialysis associated amyloidosis
Heredofamilial amyloidosis
#rimary and myeloma associated amyloidosis occurs in older ,atients ("A years)
2ith a slight male ,redilection1 (nitial signsHsym,toms are ague and may delay
diagnosis1 &atigue3 2eight loss3 ,aresthesia3 hoarseness3 edema3 and orthostatic
hy,otension are among the first indications follo2ed by car,el tunnel syndrome3
)<
mucocutaneous lesions3 he,atomegaly and macroglossia due to de,osition of amyloid
,rotein1 0+in lesions are smooth=surfaced3 firm3 2a$y ,a,ules most commonly affecting
the eyelid region3 retroauricular region3 nec+ and li,s1 Macroglossia is re,orted in )< N
:<? of ,atients and a,,ears as diffuse3 nodular enlargement1 Amyloid also infiltrates
lacrimal and saliary glands causing dry eyes and dry mouth1
0econdary amyloidosis results as a result of a long=standing infection such as
osteomyelitis3 tuberculosis3 or sarcoidosis1 Abundant immunoglobulin is ,roduced and
de,osited in arious organs1 *ier3 +idney3 s,leen and adrenal inolement is seen1 7his
form of amyloidosis is rare due to aailability of antibiotic treatment1
Hemodialysis associated amyloidosis occurs in ,atients on long=term
hemodialysis1 B=2 microglobulin is not filtered by hemodialysis and accumulates in the
,lasma and eentually is de,osited in bone and 6oints causing car,el tunnel syndrome3
cerical s,ine ,ain and tongue inolement1
Heredofamilial amyloidosis is uncommon but significant3 occurring in 02edish3
#ortuguese3 and Da,anese ,o,ulations mostly as an autosomal dominant trait1 &amilial
Mediterranean feer3 autosomal recessie3 has also been described1 Most conditions
,resent as ,olyneuro,athies3 but cardiomyo,athies and arrhythmias3 congestie heart
failure and renal failure eentually occur1
Once the diagnosis of amyloidosis is made3 the ,atient must be ealuated to
determine the etiology1 0erum electro,horesis to rule out a monoclonal gammo,athy is
done1
No effectie thera,y is aailable for most forms of amyloidosis1 0urgical
debul+ing of the tongue is done 2ith limited success1 Effectie treatment 2ith antibiotics
and anti=inflammatory agents 2ill aid in control of secondary amyloidosis1 Renal
trans,lantation may sto, the ,rogress of hemodialysis=associated amyloidosis but it 2ill
not reerse de,osits in bones and 6oints1 &amilial Mediterranean feer may res,ond to
systemic colchicines thera,y1 7reatment of ,rimary and myeloma associated amyloidosis
2ith colchicines3 ,rednisone and mel,halan may im,roe the ,rognosis in ,atients
2ithout renal or cardiac inolement1
0i2oi 2roteinosis )%yalinosis cutis et mucosae6 Ur#ac%7Wiet%e synrome*
*i,oid ,roteinosis is an autosomal recessie genetic disease characteri4ed by the
de,osition of a 2a$y material in the dermis and submucosal connectie tissue1 7he e$act
nature of the disease is essentially un+no2n1
7he laryngeal mucosa and ocal cords are usually first affected 2ith the infant
unable to cry or a hoarse cry and deelo,ment of a hoarse oice during early childhood1
7he ocal cords become thic+ened due to de,osition of an amor,hous material that may
re,resent basement membrane material1 Eentually the ,rocess inoles other mucosal
and cutaneous sites1 0+in lesions a,,ear as thic+ened3 yello2ish3 2a$y areas on the li,s
))
and eyelids1 7he oral mucosal lesions become a,,arent in the second decade1 7he
tongue3 labial mucosa3 and buccal mucosa become nodular3 enlarged3 and thic+ened1 7he
dorsal tongue ,a,illae are destroyed and the tongue deelo,s a smooth or nodular
surface1 7he accumulation of the amor,hous material may result in the tongue being
bound to the floor of the mouth1
7here is no effectie treatment other than genetic counseling1 (n those ,atients
2ho e$,erience difficulty in breathing3 debul+ing of the lesions may be necessary1 Most
,atients hae a normal life s,an but the >uality of life is most li+ely affected by ocal
hoarseness and s+in a,,earance1
,a#ry5s isease )an"iokeratoma cor2oris iffusum*
&abry-s disease is a rare O=lin+ed recessie disease characteri4ed by the lac+ of
the en4yme lysosomal a=galactosidase A1 7he lac+ of this en4yme leads to the
accumulation of s,hingoli,ids1 7he s,hingoli,ids are de,osited in many different cells
but endothelial cells and smooth muscle cells are most affected1 Males are affected 2hile
females are carriers and may e$hibit some signs of the disease1 0igns and sym,toms
begin in late childhood or adolescence1 By age 2<=2C3 most affected males e$,erience
the full effects of the disease1
7he disease is characteri4ed by cloudiness of the cornea3 burning sensations in the
hands and feet3 and small raised red=,ur,le lesions on the s+in (angio+eratomas)1 As the
disease ,rogresses heat intolerance is e$,erienced along 2ith angina3 myocardial
infarction3 mitral ale ,rola,se3 and congestie heart failure1 %N0 sym,toms include
,aresis3 sei4ures3 hemi,legia3 a,hasia and loss of consciousness1 Angio+eratomas are
seen on the oral mucosa and the li,s are the most common site1 Hereditary hemorrhagic
telangiectasia should be considered in the differential diagnosis1
7reatment at ,resent is limited to dealing 2ith the affects of the disease and
include %O2 laser to remoe angio+eratomas on the s+in3 hemodialysis to deal 2ith renal
insufficiency3 renal trans,lantation 2hich may su,,ly a source of the missing en4yme3
and antisei4ure medications1 Research is directed at en4yme re,lacement and eentual
gene thera,y1
$nocrine isorers
.iabetes mellitus
Hy,othyroidism
Addison-s disease
Hy,er,arathyroidism
Dia#etes mellitus
.iabetes mellitus is a common disorder of carbohydrate metabolism caused by
decreased and eentual lac+ of ,roduction of insulin (ty,e () or tissue resistance to the
)2
effects of insulin (ty,e (()1 7y,e ( diabetes mellitus is usually diagnosed during
childhood and ,atients re>uire insulin in6ections to surie1 7he etiology of ty,e (
diabetes is un+no2n but may be triggered by a iral infection that leads to an
autoimmune res,onse that destroys ,ancreatic islet cells1 7y,e (( diabetes is usually seen
in obese adults3 and3 increasingly in younger obese ,atients3 and insulin ,roduction is
normal or increased1 7he etiology of ty,e (( diabetes is also un+no2n but may be related
to decreased number of cell membrane rece,tors that inhibits insulin u,ta+e in cells1
7y,e (( diabetes also has a genetic ,redis,osition1 (f one ,arent has ty,e (( diabetes there
is a :<? chance that a child may hae the disease1 (f one identical t2in has ty,e ((
diabetes3 the other t2in has a C<? chance of deelo,ing the disease1
= diabetes mellitus affects "? of the /101 ,o,ulation (I)" million ,eo,le)
= IE<<3<<< ne2 cases each year in the /1 01 (C<=CA? are ty,e (()
= A<3<<< am,utation ,erformed each year due to diabetes
= )23<<< ,eo,le in the /101 lose their site each year due to diabetes
One of the main ,roblems seen in diabetes mellitus is ,eri,heral ascular disease
that results in +idney failure3 ischemia and gangrene of e$tremities1 Retinal inolement
also leads to blindness 2hile ascular occlusion may affect the coronary arteries
increasing the ris+ of myocardial infarction1 Neutro,hil chemota$is is also im,aired1
Oral findings are usually limited to ty,e ( diabetes ,atients1 #roblems include ,eriodontal
disease that occurs more fre>uently and ra,idly than in other2ise healthy ,atients1
Enlargement of the ,arotid glands may be seen (diabetic sialadenosis)1 Enlargement and
erythema of attached gingial has been described in uncontrolled diabetics1
Erythematous candidiasis occurring as central ,a,illary atro,hy of the dorsal tongue is
also seen1 'ygomycosis (mucormycosis) may also occur and is a deastating3 ,otentially
fatal deelo,ment1
7reatment for ty,e (( disease usually inoles diet modification in order to achiee
2eight loss1 Oral hy,oglycemic agents (tolbutamide3 chlor,ro,amide3 tola4amide3
glyburide) may be re>uired1 (n adanced ty,e (( ,atients3 insulin re,lacement may be
necessary1 7y,e ( diabetics re>uire insulin in6ections and arious ty,es of insulin are
,roduced offering different degrees of duration and times of ,ea+ actiity1
!y2ot%yroiism )cretinism, my8eema*
Hy,othyroidism may occur at different times during life1 (f it occurs during
infancy (cretinism) it tends to be irreersible and may be caused by a,lasia3 hy,o,lasia or
dys,lasia of the thyroid gland1 Hy,othyroid infants are at ris+ of seere mental
retardation if not ,rom,tly treated 2ith thyroid re,lacement1 0creening is carried out at
birth and the ,realence in North America is a,,ro$imately ) in :<<< births1 (f
hy,othyroidism occurs during adult life de,osition of a glycosaminoglycan in
subcutaneous tissues may occur resulting in a non=,itting edema termed my$edema1
Hy,othyroidism may be due to abnormalities in the thyroid gland (,rimary
hy,othyroidism) or the thyroid gland may be normal but the ,ituitary gland does not
,roduce ade>uate thyroid=stimulating hormone (70H)1 0econdary hy,othyroidism
)!
occurs follo2ing radiation thera,y for brain tumors1 Most cases of hy,othyroidism are
the ,rimary ty,e1
7he most common signs of hy,othyroidism include lethargy3 dry coarse s+in and
s2elling of the face and e$tremities1 Hus+iness of the oice occurs along 2ith 2ea+ness
and fatigue1 7he li,s may a,,ear thic+ened due to the accumulation of
glycosaminoglycans1 .iffuse enlargement of the tongue occurs for the same reason1 (f
the condition occurs during childhood3 teeth may fail to eru,t1
7he diagnosis is made by assaying the free thyro$ine (7:) leels1 (f 7: leels are
lo23 70H leels are measured to determine the site of the ,roblem1 5ith ,rimary
hy,othyroidism 70H leels are eleated1 5ith secondary hy,othyroidism 70H leels are
normal or borderline1 7hyroid re,lacement thera,y is indicated for confirmed cases of
hy,othyroidism1 (f thera,y is not started early in infants3 mental retardation 2ill occur1
(f started early in childhood3 results can be >uic+ and dramatic1 7reatment for adult
hy,othyroidism is usually satisfactory1
Aison5s isease )%y2oarenocorticism*
Addison-s disease (,rimary hy,oadrenocorticism) occurs do to insufficient
,roduction of adrenal corticosteroid hormones due to destruction of the adrenal corte$1
7he incidence in the 2estern hemis,here is :< to A< ne2 cases ,er million ,o,ulation ,er
year1 7he causes are dierse and include autoimmune destruction3 infections (7B and
dee, fungal diseases=es,ecially in H(V ,ositie indiiduals) and metastatic tumors1
0econdary hy,oadrenocorticism occurs secondary to decreased ,roduction of A%7H by
the ,ituitary gland1
%linical features do not a,,ear until at least C<? of the gland is destroyed1
#atients ,resent 2ith fatigue3 irritability3 de,ression3 2ea+ness and hy,otension1
@enerali4ed ,igmentation of the s+in occurs (bron4ing)1 #atients com,lain of anore$ia3
nausea3 omiting diarrhea3 2eight loss and a craing for salt1 Oral signs include diffuse
or ,atchy bro2n macular ,igmentation of the oral mucosa caused by e$cess melanin
,roduction1 Oral signs often ,recede s+in hy,er,igmentation1
.iagnosis is confirmed by ra,id A%7H stimulation test and ,lasma A%7H leels1
(n ,rimary hy,oadrenocorticism ,lasma A%7H leels are high1 (n secondary
hy,oadrenocorticism the leels are lo21 Addison-s disease is managed 2ith
corticosteroid re,lacement thera,y1 #hysiologic dose is considered to be Amg of
,rednisone ,er day3 usually gien in diided doses1 0tress increases the corticosteroid
dose re>uirement and ad6ustment may be necessary for ,ro,osed dental and oral surgical
,rocedures1
!y2er2arat%yroiism
Hy,er,arathyroidism results from the oer,roduction of ,arathyroid hormone
(#7H)1 Primary %y2er2arat%yroiism is most often caused by ,arathyroid adenoma
):
(E< to C<? of cases)3 ,arathyroid hy,er,lasia ()< to )A?) or rarely by ,arathyroid
carcinoma (P 2?)1 0econdary hy,er,arathyroidism occurs as a result of continuous #7H
,roduction in res,onse to lo2 serum calcium leels3 usually due to chronic renal disease1
7he +idney ,rocesses itamin .3 2hich is re>uired for calcium absor,tion in the gut1 (n
chronic renal disease itamin . is not ,roduced and less calcium is absorbed3 resulting in
lo2er serum calcium leels1
Most ,atients 2ith ,rimary hy,er,arathyroidism are older than "< years of age
and 2omen are affected 2 to : times as often as men1 #atients ,resent 2ith the triad of
8stones, #ones, an a#ominal "roans91 Fidney stones deelo, due to eleated serum
calcium leels1 Metastatic calcifications may also be ,resent in blood essel 2alls3
subcutaneous tissues3 the sclera3 the dura3 and regions around 6oints1 7he bones undergo
changes such as sub,eriosteal resor,tion of the ,halanges of the inde$ and middle
fingers1 @enerali4ed loss of the lamina dura surrounding the roots of teeth is also an
early sign of the disease1 Alterations in trabecular ,attern occur and often a 8"roun
"lass9 a,,earance results1 As the disease ,rogresses other bony lesions occur3 such as
#ro9n tumor of %y2er2arat%yroiism so named due to the bro2n color that results due
to hemorrhage and hemosiderin de,osition 2ithin the tumor1 Radiogra,hically the tumor
a,,ears as a unilocular or multilocular radiolucency1 Bro2n tumors commonly affect the
mandible and may also deelo, in claicle3 ribs3 and ,elis1 Bro2n tumors are
histologically identical to central giant cell granuloma1 Osteitis fibrosa cystica deelo,s
in long=standing bro2n tumors and is the result of central degeneration and fibrosis of the
tumor1 #atients 2ith secondary hy,er,arathyroidism from end=stage renal disease (renal
osteodystro,hy) are ,rone to deelo, enlargement of the 6a2s and a ground=glass
radiogra,hic ,attern1 Abdominal groans refers to the tendency for these ,atients to
deelo, duodenal ulcers1 &inally changes in mental status often deelo, and range from
lethargy and 2ea+ness to dementia1
#rimary hy,er,arathyroidism is treated by remoing the underlying ,arathyroid
etiology (adenoma3 hy,er,lasia3 carcinoma)1 7he ideal treatment for secondary
hy,er,arathyroidism is renal trans,lant3 since this ,rocedure usually restores normal
,rocessing of itamin . as 2ell as ,hos,horous and calcium reabsor,tion and e$cretion1
(f renal trans,lant is not done then restriction of dietary ,hos,hate3 use of ,hos,hate=
binding agents and treatment 2ith actie itamin . metabolite (calcitriol) may +ee, the
disease ,rocess under control1
Ot%er internal iseases
%rohn-s disease
/lceratie colitis
/remic stomatitis
Cro%n5s isease )re"ional ileitis, re"ional enteritis*
%rohn-s disease is an inflammatory and ,robably immunologically mediated
condition of un+no2n etiology1 7he disease ,rimarily affects the distal ,ortion of the
)A
small bo2el and ,ro$imal colon3 but the disease may be seen any2here in the
gastrointestinal tract from the oral caity to the anus1 7he disease may also inole the
s+in3 eyes and 6oints1 Oral lesions are significant because they may ,recede the
gastrointestinal lesions in as may as !<? of cases haing bone oral and @( inolement1
&or un+no2n reasons %rohn-s disease a,,ears to be increasing in incidence1
%rohn-s disease usually first becomes eident during adolescence1 @( signs and
sym,toms include abdominal cram,ing3 ,ain3 nausea3 and diarrhea3 occasionally 2ith
feer1 5eight loss and malnutrition may deelo, leading to anemia3 decreased gro2th
and short stature1 7here are many re,orted oral manifestations of %rohn-s disease3
ho2eer3 many are nons,ecific and may be associated 2ith other conditions that cause
orofacial granulomatosis1 7he more s,ecific findings include diffuse or nodular s2elling
of the oral and ,erioral tissues 2ith a cobblestone a,,earance of the mucosa and dee,3
granulomatous=a,,earing ulcers1 7he ulcers often are linear and occur in the buccal
estibule1 0oft tissue s2ellings that resemble denture=related fibrous hy,er,lasia may
also occur een if the ,atient is not edentulous in the area1 A,hthous ulcers hae also
been re,orted3 but the significance of this finding is uncertain1 0tudies sho2 that
a,hthous ulcers do not occur more fre>uently in %rohn-s ,atients than in the general
,o,ulation1 Microsco,ically3 the lesional tissue consists of non=necroti4ing
granulomatous inflammation1 0,ecial stains for microorganisms are negatie1
Most ,atients 2ith %rohn-s disease are treated 2ith a sulfa ty,e of drug
(sulfasala4ine)1 0ystemic ,rednisone may be combined 2ith a4athio,rine
(immunosu,,ressant drug) in ,atients 2ith moderate to seere inolement1 (n some
cases surgical thera,y of the inoled bo2el is re>uired1 (n those ,atients 2ho hae had
a significant ,ortion of the terminal ileum remoed3 ,eriodic itamin B)2 in6ections may
be re>uired to ,reent megaloblastic anemia1 Magnesium3 iron3 fat=soluble itamins and
folate may also be re>uired to malabsor,tion ,roblems1 Oral lesions tend to clear 2ith
treatment of the @( lesions1 Oral lesions that ,ersist may re>uire treatment 2ith to,ical or
intralesional steroids1
Ulcerati:e colitis
/lceratie colitis is a form of inflammatory bo2el disease of un+no2n etiology
that ,rimarily inoles the colon and rectum1 @( lesions consist of broad areas of
hemorrhagic ulceration and abscesses1 *esions are su,erficial and inole the mucosa
and submucosa1 /lceratie colitis may afflict any age but there is a bimodal distribution
2ith a ma6or ,ea+ at ages )A to !< and a smaller ,ea+ at ages A< to G<1
Oral lesions include ma6or or minor a,hthae1 7hese lesions affect : to 2<? of
,atients and the onset is sudden and may coincide 2ith e$acerbations of the @(
sym,toms1 /lcers similar to ,yoderma gangrenosum of the s+in may also be seen and
hae been re,orted to occur on the tongue1 7hese lesions e$hibit ,rogressie necrosis
2ith dee, ulceration1
)"
7reatment of ulceratie colitis inoles sulfasala4ine andHor systemic steroids1 (n
some cases surgical resection of inoled areas may be necessary1 #atients 2ith long
term generali4ed ulceratie colitis are at ris+ of deelo,ing colon cancer (!2 $ general
,o,ulation)1 Oral com,lications of management of ulceratie colitis are similar to those
seen in %rohn-s disease and include nutritional deficiencies and anemia (iron deficiency
,ossibly due to blood loss from lesions)1 %andidal infections may also occur1 7reatment
of oral lesions is un,redictable1 7o,ical andHor systemic corticosteroids are used1
Pyostomatits :e"etans
#yostomatitis egetans is a relatiely rare condition that may be associated 2ith
inflammatory bo2el disease (ulceratie colitis B %rohn-s disease)1 7he ,athogenesis is
,oorly understood1 #atients deelo, yello23 slightly eleated3 linear3 ser,entine ,ustules
on erythematous mucosa1 *esions are usually affect the buccal and labial mucosa3 soft
,alate and entral tongue1 7hese lesions hae been termed 8snail trac+9 ulcerations
although most of the lesions are not ulceratie1 #ain is usually minimal1 7he oral lesions
may either occur concomitantly 2ith bo2el sym,toms or may ,recede intestinal lesions1
Microsco,ically the lesions a,,ear acantholytic 2ith an accumulation of
numerous eosino,hils 2ithin the s,inous layer forming intrae,ithelial abscesses1 7he
underlying connectie tissue is remar+able for a dense infiltrate of eosino,hils3
neutro,hils and lym,hocytes1
7reatment of the gastrointestinal lesions 2ith sulfasala4ine or systemic
corticosteroids also clears the oral lesions1
Uremic stomatitis
#atients 2ith acute or chronic renal failure e$hibit mar+edly eleated leels of
urea and other nitrogenous 2aste ,roducts in the blood stream1 Rarely ,atients may
deelo, oral lesions secondary to renal failure1 7he lesions are ,ainful and although the
etiology is unclear some inestigators suggest that urease3 an en4yme ,roduced by oral
microflora3 may degrade urea secreted in the salia1 7he end ,roduct is free ammonia3
2hich is thought to damage the oral mucosa
Most cases hae been re,orted in ,atients 2ith acute renal failure1 7he onset is
sudden3 2ith 2hite ,la>ues distributed on the buccal mucosa3 tongue3 and floor of mouth1
#atients may com,lain of un,leasant taste3 ,ain or a burning sensation and the clinician
may detect an odor of ammonia or urine on the ,atient-s breath1 %lincally the lesions
may resemble oral hairy leu+o,la+ia1
Renal dialysis usually clears the oral lesions but the ,rocess may ta+e 2 to !
2ee+s1 7reatment 2ith diluted hydrogen ,ero$ide may hel, to clear the lesions and
iscous lidocaine may be used to tem,orarily reliee ,ain1
)G
References
Bor+ F3 et al1 .iseases of the Oral Mucosa and the *i,s1 #hiladel,hia; 51B1 0aunders3
)CC!
%otran3 R1 01 et al1 Robbins #athologic Basis of .isease1 "
th
edition1 51B1 0aunders;
#hiladel,hia3 )CCC1
Mar$3 R1 E13 0tern .1 Oral and Ma$illofacial #athology1 %hicago; Quintessence3 2<<!1
Neille3 B1 51 et al1 Oral and Ma$illofacial #athology1 2
nd
edition1 #hiladel,hia; 51B1
0aunders3 2<<2
Rege4i3 D1 A1 et al1 Oral #athology %linical #athologic %orrelations1 :
th
edition1 0t1 *ouis;
0aunders3 2<<!1

)E