02 02 10krish

2/8/2010
NEITHER THE PUBLISHER NOR

THE AUTHORS ASSUME ANY
LIABILITY FOR ANY INJURY AND
OR DAMAGE TO PERSONS OR
PROPERTY ARISING FROM THIS
WEBSITE AND ITS CONTENT.
2/8/2010
GuhaKrishnaswamy,M.D.
PatientInterview
ClinicalPresentation
BedsideToBench
2/8/2010
2/8/2010
Areasofnecroticulcerationofmouthand
tongueoverseveralyears
Thisisaccompaniedbysevereburningpain
andinabilitytosleeporeat
Nonspecificarthralgiaandphotosensitive
eruptionoverface?
Cycleslast3weeksormore
Severeepisodesoverthelastyear
2/8/2010
Myofascialpainsyndrome(Cymbalta)
Hypertension
Anemia:Requiringironinfusions
Headaches(Mixedfunctional/vascular)
VonWillebranddisease
OBGYN:Endometriosiswithcystinleftovary
OBGYN: Endometriosis with cyst in left ovary
Preeclampsia
Pre
S/physterectomyandleftoophorectomy
Recurrentinfections
Staphylococcalfaceinfections(hospitalized)
Recurrentsinusitisandbronchitis
5
2/8/2010
Thepatientsperipheralsmear
shownbelowdemonstrates:
Clusterofimmunoregulatorydisease
Eosinophilia
Megaloblast
Macropolycyte
4. Neutrophil
precursor
5. Megakaryocyte
1.
Aunt CVID
Aunt
2cousinswithIgAdeficiency
3cousinswithDiabetesmellitus
3 cousins with Diabetes mellitus
NephewwithleukemiaandIgAdeficiency
2.
3.
Digital image of patients

Peripheral smear obtained by
Dr Youngberg
2/8/2010
2/8/2010
2/8/2010
Test
Patient
Normal
Test
Patient
Normal
Sodium
136mmol/L
134145
WBC
6.8Thou/L
4.810.8
Potassium
3.6mmol/L
3.65.0
LY%
24.5%
20.551.1
AnionGap
716
MO%
4.4%
1.79.3
Glucose
126mg/dL
65110
GR%
71.1%
42.275.2
BUN
5mg/dL
717
RBC
3.91Mill/L
4.25.4
Creatinine
0.7mg/dL
0.71.2
HGB
13.7g/dL
12.016.0
3747
Calcium
9.1mg/dL
8.210.3
HCT
40%
Albumin
4.4g/dL
3.55.0
MCV
101.7fL
81.099.0
TSH
3.130IU/mL 0.44.0
MCH
35pg
2731
3337
ALT
7U/L
752
MCHC
35g/dL
AST
11U/L
1339
RDW
13.4%
11.514.5
Bilirubin
0.5mg/dL
0.21.3
Platelets
189Thou/L
130400
Protein
6.1g/dL
6.48.9
MPV
7.7fL
7.410.4
2/8/2010
1.
2.
3.
4.
Feature
Major
Minor
Frequency
10%
85%
5%
Size
>1.0cmlarge
<1.0cm
2mmshallow
ulcers
Location
Posterior oral
cavity
Nonkeratinized
N k ti i d
Anterior,
*keratinized
oropharynx
h
Keratinizedand
nonkeratinized
Pain
+++++
+++
++++
Healing
6weeks
10days
Days toweeks
HIV
+++
+/
2/8/2010
Minorapathousulcers
Herpetiformapthousulcers
Majorapthousulcers
Vincentsangina
10
^Herpetiform
1. Staphylococcalinfection
2. GlucagonomaSyndrome
3. AtrophicGlossitis
4. MigratoryGlossitis
5. Lemierressyndrome
*Keratinizedstratifiedsquamous:Dorsumtongue,hardpalateandgingiva
^Herpeticinfectionshaveusualprodromeandvesicleformation,absentinRAS
2/8/2010
11
2/8/2010
12
2/8/2010
1.
2.
3.
4.
5.
Psychologicalstress
Traumatic/iatrogenicinjury
Associatedsystemic
diseases/conditions/syndromes
PlummerVinsonSyndrome
Plummer
AtaxiaTelangiectasia
ImerslundGrasbecksyndrome
Imerslund
PFAPAsyndrome
FoodCobalaminmalabsorption
Food
syndrome
Crohn'sdisease/ulcerativecolitis
Behet'sdisease,SLE,Reiters
Behet'sdisease,SLE,Reiters
PFAPAsyndrome
Malabsorption/glutensensitive
Malabsorption/gluten
enteropathy
HIVdisease
Deficiency: B12,Folate,Fe
Sweet'ssyndrome(acute
neutrophilicdermatosis)
Chocolate
Tomatoes
Walnuts,hazelnuts,Brazilnuts
Foods
Menstrualcycle
2/8/2010
13
2/8/2010
14
Medianrhomboidglossitisalso
knownascentralpapillaryatrophy
andposteriormidlineatrophic
candidiasis
Rhomboidatrophyoffiliform
papillaeduetocandidalinfection
Itoccursinasmanyas1%ofadults
It occurs in as many as 1% of adults
andisoftenasymptomatic
Clinically,medianrhomboidglossitis
manifestsasawelldelineated
erythematousarealocatedalong
themidlineposteriordorsaltongue
justanteriortothevallatepapillae
1.GeographicTongue
1.
GeographicTongue
2.
2.Anthracyclineintoxication
2 Anthracyclineintoxication
A th
li i t i ti
3.Leadpoisoning
3.
Leadpoisoning
4.Medianrhomboidglossitis
4.
Medianrhomboidglossitis
5.TertiarySyphilis
5.
TertiarySyphilis
2/8/2010
15
2/8/2010
16
2/8/2010
Acutecandidiasis
Acutepseudomembranouscandidiasis(Thrush)
Acuteatrophic(erythematous)candidiasis
Smokers,HIVinfection
Chroniccandidiasis
Chronic
Chronichyperplasticcandidiasis
hyperplastic candidiasis
Candidalleukoplakia
CMCIFNgamma/CMIdefect
Candidalendocrinopathysyndrome
Dentureinducedcandidiasis
chronicatrophicerythematouscandidiasis
Medianrhomboidglossitis
Angularcheilitis(stomatitis)
1. MucocutaneousCandidiasis
2. Acutepseudomembraneous
candidiasis
3. Leukoplakia
4. Oralhairyleukoplakia
5. Migratoryglossitis
2/8/2010
17
2/8/2010
1.Atrophicglossitis
1.
Atrophicglossitis
2.HuntersGlossitis
2.HuntersGlossitis
3.Plummer
3.
PlummerVinsonSyndrome
4 LinguaVillosaNigra
4.LinguaVillosaNigra
4.
Lingua Villosa Nigra
5.MedianRhomboidGlossitis
5.
MedianRhomboidGlossitis
2/8/2010
19
18
1.OralHairyLeukoplakia
2.VincentsAngina
3.LemierresSyndrome
4.MigratoryGlossitis
4 Mi t
Gl iti
5.MalignantGlossitis
2/8/2010
20
2/8/2010
1.Glossopyrosis
2.Glossodynia
3.Uveitis
4.Parietalcellatrophy
5.Macroovalocytes
5 Macroovalocytes
2/8/2010
2/8/2010
21
23
2/8/2010
22
Test
Patient
Normal values
IgG
789
600
6001600mg/dL
IgA
<7/<5
68
68376mg/dL
IgM
54
45
45250mg/dL
IgE
<2
13.8
13.8128U/mL
Serumprotein
electrophoresis
l t h
i
Normal
Normal
IgG1
456
240
2401118mg/dL
IgG2
256
124
124549mg/dL
IgG3
64
21
21134mg/dL
IgG4
<1
789mg/dL
PneumococcalIgG response Robust14/14 serotypes
>1IU/mL
Tetanusantibody
3.7
>0.1IU/mL
Diphtheriaantibody
2.82
>0.1
>0.1
g/mL
CH50
74
50
50144CAEunits
24
2/8/2010
Test
Patient
Normalvalues
SerumB12
<150(L)
193
193982pg/mL
RBCfolate
339ng/mL
280
280903ng/mL
VitaminD(25OH)
24(L)
25
2580U/mL
VitaminB6
3.2(L)
530ng/mL
ANA/dsDNA
Neg
Neg
RF/CCP/SSA/SSB
Neg
Neg
Homocysteine
32(H)
<15mmol/L
MethylmalonicAcid
2385(H)
73
73376nmol/L
SerumGastrin
335
<100pg/mL
HPyloriantibody
Neg
Neg
AntibodytoIF
Neg
Neg
AntibodytoParietalcells
Neg
Neg
Celiacdiseasepanel
Neg
Neg
2/8/2010
25
2/8/2010
26
Healthy
Infection
SIgAD
Neoplasia
Allergy
NikhilHolla
VijayDamarla
Autoimmunity
PA
CTD
IBD
2/8/2010
Polyglandular
Autoimmune syndrome
Overlap autoimmunity
27
2/8/2010
28
2/8/2010
Prevalencerangesfrom5
Prevalencerangesfrom560%,averaging
1.
20%
2.
Framinghamestimatesprevalenceof12%
intheelderly
4.
Usingstringentcriteria,Frenchgroup
5.
estimatesoverallprevalenceof~5%
2/8/2010
3.
Deafness
Proteinuria
Mutationofcubilingene
Mutationofamnionlessgene
DefectiveilealreceptorforB12
intrinsicfactorcomplex
29
Perniciousanemia
Biermersdisease
2050%ofB12deficiency
AntiIFantibodysensitivity
50%,specificity>90%
Antiparietal cell antibody:
Antiparietalcellantibody:
sensitivity90%,specificity
50%
Hypergastrinemiahas
sensitivityof>80%and
specificity<50%
+veSchillingtestconfirms
dx(specificity>99%)
Hereditarydisorders
ImerslundGrasbecksyndrome
SelectiveB12malabsorption
Appearsinchildhood
Failuretothrive
Mildproteinuria
Appears at 4 months of age
Appearsat4monthsofage
MutationofCubilin(CUBN)on
chromosome10
Mutationofamnionless(AMN)on
chromosome14
DefectiveilealreceptorforB12IF
complexonileum
TCIIdeficiency
Appearsatbirth
2/8/2010
Elevationofhomocysteineonly
Elevationofbothhomocysteineand
methylmalonicacid
Lowplasmauricacidlevel
Mutationintetrahydrofolatereductase
Alloftheabove
1.
2.
3.
4.
5.
ElevatedMMAandhomocysteineareseeninB12deficiency;elevatedhomocyteine
canbeseeninfolatedeficiency;hyperhomocysteinemiacanleadtomyocardialinfarction
Andstroke.Theseconfirmdiagnosisofdeficiency
2/8/2010
1.
2.
3.
4.
5.
5
Personcanbeinfectedbyeatingraw,lightlycooked,under
Personcanbeinfectedbyeatingraw,lightlycooked,under
processedfreshwaterorcertainmigratoryspeciesofsalmon,
perch,pike,pickerel,andturbot
Thepopularityofeatingrawfishdishes,suchasJapanese
sushiandsashimi,helpstospreadthisdisease
Cookswhosampletheirfishdishesbeforetheyareproperly
cookedputthemselvesatriskofbeinginfected
Fishtapewormsarefoundwhereverhumans,bears,and
Fi h
f
d h
h
b
d
otherfisheatingmammalsdefecateinthesamelakesand
otherfish
streamsfromwhichthisfishareobtained
Nausea,diarrhea,abdominaldistension,weightlossand
B12/folatedeficiencymayresultthoughmanyare
asymptomatic
Guineaworminfection
DiphyllobotriumLatuminfection
SchiostosomiaHematobiuminfection
Trichinellspiralisinfection
AscarisLumbricoidesinfection
Ascaris Lumbricoides infection
Operculum
2/8/2010
34
Upto30feetlong
4000proglottids/segments
Colonicobstruction
Malnutrition
35
2/8/2010
36
2/8/2010
Serumcobalaminlevels<150pmol/l
MCV>100fL(usually>110)
Plusclinicalfeaturesand/orhematologicalanomalies
relatedtocobalamindeficiency
Serumcobalaminlevels<150pmol/l(<200pg/ml)on
twoseparateoccasions
p
Serumcobalaminlevels<150pmol/landtotalserum
homocysteinelevels>13mmol/lormethylmalonicacid
levels>0.4mmol/l
Intheabsenceofrenalfailureand/orseverefolateand
vitaminB6deficiencies
Lowserumholo
Lowserumholotranscobalaminlevels<35pmol/l
PBS:anisocytosis,macro
PBS:anisocytosis,macroovalocytes,
2/8/2010
1.
2.
3.
4.
hypersegmentedneutrophils,basophilic
stipling,nucleatedRBC,pancytopeniain
severecases
Bonemarrow:Markederythroid
hyperplasiawithmegaloblasticchanges
Schillingtest(NDnowdueto
reimbursementandIFrelatedsafetyissues)
reimbursementandIF
37
Bonemarrowdysfunction
Dimorphicanemia
Splenomegaly
Infection
1.
2.
3.
4.
5.
2/8/2010
Pancytopenia
Gastriccarcinoma
Psychosis
Diplopia
Sensoryataxia
39
10
2/8/2010
Lhermittessign
Poorjointsensation
Extensorplantarreflex
Briskanklejerk
Briskkneejerk
1.
2.
3.
4.
5.
1.
2.
3.
4.
5.
2/8/2010
Hematologic
Anemia weakness,
Anemia
palipitations,angina,
congestivefailure,systolic
flowmurmur
Hyperbilirubinemiadueto
higherythroidturnoverin
marrow
Purpura(rare)
P
(
)
GITract
Soresmoothbeefyred
tongue
Glossitis(Hunters) diffuse
Glossitis(Hunters)
erythemaandlingualatrophy
Glossodynia,dysgeusia,
xerostomia,cheilitis
Anorexia,weightloss,
diarrhea
Increasedfrequencyofgastric
neoplasms
41
Hypersplenism
Extravascularhemorrhagedueto
thrombocytopenia
Primarybiliarycirrhosis
Autoimmuneliverdisease
Ineffectiveerythropoiesis
2/8/2010
Neurological:peripheral
Neurological
:peripheral
nerves,posteriorandlateral
columnsandcerebrum
LinearGlossitis:
JournaloftheAmericanAcademyof
Dermatology Volume60,Issue3(March
2009)
Stages::
Stages
demyelination
axonaldegeneration
neuronaldeath
(irreversible)
Atrophicglossitis(baldtongue)
may be seen in patients with
maybeseeninpatientswith
perniciousanemia,irondeficiency
anemia,pellagra,andxerostomia
Moller
MollerHuntersyndrome:Itis
characterizedbyglossitis,
glossodynia,glossopyrosis,and
alteredsenseoftaste;B12
deficiency;associatedgastric
atrophypresent
JuliusOttoLudwigMller
WilliamHunter
Numbness,paresthesia(early)
Sphincterdisturbances
Ataxia
Diminishedreflexes,positionand
vibrationsenses
PositiveRombergandBabinskis
signs
Dementia,psychosis
CVS
Stroke,MI(homocysteine)
42
HuntersGlossitis
2/8/2010
Atrophicglossitis
44
11
2/8/2010
Estimateddaily
loss/requirement
Recommendeddailyallowance
Averagebodystoresof
cobalamin
Ratioofstorestodailylosses
Amount(percentage)
absorbedfromasingleoral
doseof:
1g
10g
50g
500g
1000g
Amount(percentage)retained
fromasingleinjectionof
fromasingleinjectionof::
10g
100g
1000g
2/8/2010
Normalabsorption
Malabsorptivedisease(eg,PA)
1g/day
2g/day*
2.4g/day
2500g
Supplementsarerequired
Dependsonstageofdepletion
2500:1
1200:1
0.56g(56%)
1.6g(16%)
1.5g(3%)
9.7g(2%)
13g(1.3%)
0.01g(1.2%)
0.1g(1.2%)
0.6g(1.2%)
7.0g(1.3%)
12g(1.2%)
9.7g(97%)
55g(55%)
150g(15%)
Sameasnormal
Sameasnormal
Sameasnormal
I.M.Cyanocobalamin1000g/day 1weekfollowed
I.M.Cyanocobalamin1000g/day
by1000g/week 1monthfollowedby1000g/monthforthe
by1000g/week
restofpatientslife(pernicious)
Briskreticulocytosisoccursin57days,hematologicalpicture
Briskreticulocytosisoccursin5
normalizesin2months;Femaydrop;Potassiummaydrop
OralCobalamin1000g/day
OralCobalamin1000g/day
1monthfollowedby125
Oral Cobalamin 1000g/day 1monthfollowedby125
1 month followed by 125
125
500g/dayforintakedeficiencyandfood
500g/dayforintakedeficiencyandfoodcobalamin
malabsorbptionor1000g/dayforperniciousanemia
Endoscopicsurveillanceevery3
Endoscopicsurveillanceevery35yearswithmultiplebiopsies
evenintheabsenceofmacroscopiclesionsisrecommended
forpatientswithperniciousanemiabecauseofincreased
frequencyofgastricneoplasms
Treatmentofunderlyingcause
45
1.
IgADeficiency
2.
3.
3
4.
5.
2/8/2010
Thereisahigherprevalenceofautoimmune
disease
Inseveredeficiency,anaphylaxistoblood
productsisaseriouscomplication
Onecauseistheuseofanticonvulsantssuch
One cause is the use of anticonvulsants such
asdilantin
Mostpatientsaresymptomaticwith
infections
PatientswithassociatedIgGsubclass
deficiencyareusuallymoresymptomatic
48
12
2/8/2010
STRUCTURE
2heavyand2lightchains
2antigenbindingsitesFab
1cellbindingsite/Fc
1cell
Cysteineresidues
Bindtoalpha
Bindtoalpha1antitrypsin,
fibronectinandlactoferrin
MonomericIgA(serum)
M
i I A(
)
SecretoryIgA:Dimericwith
secretorypiece(80kD)
Breastmilk
Mucosaltissue
Isunlikely
Isoftenduetocontaminationwithlatex
allergen
Presentsatypically
Isusuallyduetoanti
IsusuallyduetoantiIgAantibodies
Noneoftheabove
1.
2.
3.
4.
5.
Secondmostabundantimmunoglobulininserum
2subclasses:IgA1/2inserum,IgA2insecretions
Halflife3
Halflife36daysonly
IgA
IgAproducingBlymphocytesarefoundinGI,GenitourinaryandSinopulmonarytissue
2/8/2010
InabilitytoproduceantibodiesofIgA1
andIgA2subclasses
Mostcommonofprimaryantibody
deficiencies
Incidence:1/600
SelectiveIgAD:SerumIgAlevel<5mg/dL
PartialIgAD:SerumIgAleveldetectable
butdecreased2SDlessthangeneral
populationageadjustedmeans
populationage
49
2/8/2010
50
Familial(upto25%)
Mostcasesaresporadic
Drugs:Phenytoin,sulfasalazine,
penicillamine,valproicacid,
carbamazepine,thyroxine(reversible)
Infections:toxoplasmosis,rubella,
cytomegalovirus(reversible)
BonemarrowtransplantationfromIgAD
donor
Occupationalexposuretobenzene
13
2/8/2010
Exactdefectisunknown
Sometimesfamilial
Manytimessporadic
Bcelldifferentiation
defect?
RoleofantiIgAantibodyin
Roleofanti
mother?
RoleofTcell
Role of T cell
cellmediatedB
mediated B
cellsuppression
Normalantibodysynthesisandprimarydeficiencies
SIGAD,selectiveIgAdeficiency
2/8/2010
53
absenceofdisease
Connectivetissuedisease
LowlevelsofIgG2and4subclassesmaybeseen
Wehaveseenassociateddefectsincomplement
pathways(Mannosebindinglectin)
SomecasesofIgADmayremitspontaneously
S
f I AD
it
t
l
Somepatientsmayevolveincommonvariable
immunedeficiency(LowIgG,IgAandIgM)requiring
infusions
Anti
AntiIgAantibodiesmaybepresentandcause
anaphylaxistobloodproducts
Susceptibilitytorespiratoryinfection,autoimmunity
andGItractmalignancies
FunctionalEndoscopicSinusSurgery(FESS)
TympanostomytubesinCSOM
Pneumococcalandotherpolysaccharide
P
l d th
l
h id
RA,SLE,DM,Sjogrens
RA,SLE,DM,Sjogrenslike,Stillsdisease
Vasculitis HSP,cerebralvasculitis
Vasculitis
Hematologicaldisease
Hematological disease
Perniciousanemia,transfusionreactions,Coombs
positivehemolyticanemia,ITP
vaccinations
I.V.orS.C.IgGinpatientswithIgA+CVID
Precautionsshouldbetakenwhile
transfusingbloodproductstoavoid
anaphylaxis
Endocrinopathy
Addisonsdisease
Others
Vitiligo,Diabetesmellitus,PBC,IBD
NormallevelsofIgGandIgM(SIgAdeficiency)
Treatinfectionspromptlyandeffectively
Identifyandtreatcomorbidconditions
Multipleautoantibodiesmaybedetectedin
2/8/2010
IgA<5mg/dL
55
2/8/2010
56
14

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NEITHER THE PUBLISHER NOR

Digital image of patients

PneumococcalIgG response Robust14/14 serotypes

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