ion Syndrome

8/4/2019 ion Syndrome

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MALABSORPTION SYNDROMEby

DURRIYA RAZA

House officer

Medicine unit IV, CHK

Death sits in the bowels . . . Baddigestion is the root of all evil.

Hippocrates, 400 B.C.


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Case 37-year-old man

32-year history of type 1 diabetes. presented with nausea, vomiting,

abdominal pain, and watery diarrhea forlast 1 week.

His wife and two young children hadsimilar symptoms that had lasted 45 daysand resolved.

Two weeks earlier, he had been treatedwith azithromycin (Zithromax) for sinusitis.

No fevers, chills, hematochezia, andmelana..


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Bowel sounds were present.

soft, flat abdomen with mild diffusetenderness but no rebound orguarding.

Stools for fecal leukocytes, ova andparasites, and c-difficile were allnegative.

He was treated symptomatically withImodium and promethazine withgradual resolution of his symptoms


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Over the subsequent year and a half,the patient had seven similarepisodes.

During these episodes, he wasafebrile but had vomiting and liquid

bowel movements with mucus. The episodes generally lasted for 2

weeks and resolved. Between

episodes, he generally had oneformed bowel movement per day buthad alternating periods ofconstipation and diarrhea.


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Differentials? This patient's history of spouse and young

children with similar symptoms certainly

raises the possibility of viralgastroenteritis and bacterial and parasiticenteric pathogens.

In addition, his previous treatment with abroad-spectrum antibiotic for sinusitisraises the possibility ofpseudomembranous colitis. Appropriatetesting ruled out these possibilities andthe recurrence of symptoms made these

diagnoses less likely. Nausea and vomiting in a patient with

long-standing type 1 diabetes mayrepresent gastroparesis, a manifestation ofdiabetic autonomic neuropathy.


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Medication-induced diarrhea,

enteric pathogens, pseudomembranous colitis,

primary intestinal diseases, such as

inflammatory bowel disease andceliac disease, and pancreaticexocrine insufficiency.


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a s a a sorp on The integrated processes of digestion

and absorption have 3 phases:

Luminal phase

Mucosal phase

Transport phase

Disturbances of these processes lead tomalabsorption


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Mechanism1. Luminal phase (processing defect)

Digestive enzyme deficiency /inactivation

bile salt synthesis; Excretion;loss;bile salt de-conjugation

gastric acid; intrinsic factor (p.anemia)

Bacterial consumption ofnutrients


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Postgastrectomy steatorrhea.

Exocrine Pancreatic insufficiency. Reduced bile salt concentration in

intestine:

I.) Liver Disease

II.) Cholestasis

III.) Bacterial over growth

IV.) Interruption of enterohepatic

circulation of bile salt.


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Mucosal phase

Epithelial transport defectinflammations

infections Brush border hydrolysis defect

congenital/acquireddisacharidase deficiency


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Crohns disease

Coeliac disease Tropical Sprue

Disaccharide Deficiency Lymphoma

TB


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Post-absorptive phase(transport

phase) Enterocyte processing

Abetalipoproteinemia

Lymphocytic obstructionintestinal

lymphangectasia


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gns symp omsCalori Weight loss with normal appetite

Fat Pale,voluminous,greasy offensive diarrhea

Protein Edema, muscle atrophy, amenorrhea

carbohydrate Abdominal bloating, flatus, w. diarrhea

B12 Macrocytic anemiaSubacut combined degeneration of sp.cord

Folic acid Macrocytic anemia

Vit B (general) Cheliosis, glossitis,A.stomatitis, Acrodermatitis

Iron Microcytic anemia

Ca & Vit D Osteomalacea (bone pain,pathologic#), Tetany

Vit A Follicular hyperkeratosis, Night blindness

VIt K Bleeding diathesis, Hematoma


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Malabsorption of fatsDigestive Less time to

mix- gastric

resection,autonomicneuropathy,amyloidosis

Dec micelleformation-

Decreased bile acidsynthesis/secretion-Cirrhosis, Biliaryobstruction, CCKdeficiency, Smallintestinal bacterialovergrowth,

DecreasedLipolysis- Chronic

pancreatitis, Cysticfibrosis,Pancreatic/ampullary tumors, Lowluminal pH,Excessive calciumingestion,Lipase/co-lipasedeficiency (rare)

Absorptive Decreased Chylomicron Formation and/or Mucosal

Absorption Celiac Disease, Abetalipoproteinemia (AR),Hypobetalipoproteinemia (incomplete AD), ChylomicronRetention Disease

Postabsorptive

Defective Lymphatic Transport-Primary IntestinalLymphangiectasia,Lymphoma, Whipple Disease, Trauma,Retroperitoneal Fibrosis


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Malabsorption of carbohydrates

Digestive Severe pancreatic insufficiency (amylase

deficiency)

absorptive Primary or Acquired Lactase Deficiency

Post-infectious Lactase Deficiency Celiac Disease Crohn Disease Sucrase-isomaltase deficiency Trehalase deficiency


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Malabsorption of proteinsDigestive Ppartial or total gastrectomy (poor mixing)

Eexocrine pancreatic insufficiency

Ttrypsinogen deficiency

Ccongenital deficiency of intestinal enterokinase

absorptive Celiac Disease and Tropical Sprue

Methionine Malabsorption Syndrome and BlueDiaper Syndrome (tryptophan)

Short Bowel Syndrome

Jejunoileal bypass

Defects in neutral AA transporters (Hartsnup

Disease)

Cystinuria I-III (Cystine and bibasic amino acids)

Oculocerebral Syndrome of Lowe(Lysine/arginine)


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Malabsorption of vitamins

Vitamin B12

(Cobalamin)

Atrophic gastritis (impaired peptin/acid secretion)

Deficiency of gastric intrinsic factor (pernicious anemia /antrectomy )Pancreatic insufficiency/Z-E Syndrome (reduced release ofB12 from R-binding protein)Helminth Infection/SI BOIleal Crohn Disease/Resection

Folic acid Caused by diseases affecting the proximal small bowel

Celiac disease/Whipple/Tropical SprueAlcoholism

Fat SolubleVitamins

(ADEK)

Anything that disrupts fat absorption will result in one/moredeficiency


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Malabsorption of minerals

Calcium #Selective deficiency can occur.

Renal disease/hypoparathyroidism Inborn defect in the vitamin D receptor or 1,25-dihydroxyvitamin D formation#Diseases that reduce intestinal surface area and/or causeformation of insoluble calcium soaps with long-chain fattyacids.

Celiac Disease Bile acid deficiency

Magnesium Usually caused by loss of mucosal surface area and/orluminal binding by malabsorbed fatty acids.

Iron Caused by reduced mucosal surface area, but most often

caused by GI bleeding.

Zinc: Acrodermatitis enteropathica (defect in the Zinc transportprotein hZIP4)

Copper Menkes Disease (kinky hair disease) is caused by an

inherited disorder of cellular copper transport.


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Approach to diagnosis-history

Steatorrhea

Chronic

pancreatitis

Cystic

fibrosis

Surgery

Cholecystect

my, resectio

Bloody

diarrhea Large

volume

Arsenic, drugs,

bowel resection,

crohns,

carcinoid,

gastrinoma

Radiation

IBD,

eosinophilicgastroenteritis,

immunodef

+ pain,

fever

Lactase

def

Osmotic

+ low pH

Chronicdiarrhea

Crohns


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1)anemia,

dermatitis

herpetiformis,edema

ulcerative

colitis

dermatitis

herpetiformis

IBD

2)abdominal

mass or

tenderness

erythemanodosum

Flushing

Carcinoid

celiac

disease

4)mucocutane

ous

manifestations

Edema

ptn losing enteropathy

3)Flatus

undigested CHO

6)amenorrhea

, infertility,

and

impotence

due to malnutrition

Clinical examination

5)Manifestations of

vitamin and mineral

deficiencies

Xeropthalmia, glossitis,

purpura, tetany, peripheral

neuropathy etc


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Investigations:

General: - CBC

- Blood film

- Ca. - B12, folate

- Iron study

- LFT, PT, APTT


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SpecificTests of fat absorption:

Quantitative fecal fat Patient should be on daily diet containing

80-100 grams of fat. Fecal fat estimated on 72 H collection. 6 grams or more of fat/day is abnormal. May be due to: - Pancreatic

- Small intestinal

- Hepatobiliary disease


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Tests for pancreatic function:

1) Bentiromide test: A test ofpancreatic exocrine function in whichorally administered bentiromide is

cleaved by chymotrypsin within thelumen of the small intestine, releasing p-aminobenzoic acid. Diminished urinaryexcretion of p-aminobenzoic acid may

indicate pancreatic insufficiency.

2) Schilling test


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The Schilling Test-

determine the cause for cobalamin

malabsorption. Since cobalamin absorption requires

multiple steps, including gastric, pancreatic,and ileal processes, the Schilling test can

also be used to assess the integrity of theseother organs

Achlorhydria, Bacterial overgrowthsyndromes

administering 58Co-labeled cobalamin orallyand collecting urine for 24 h. Urinaryexcretion of cobalamin will reflect

cobalamin absorption


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3) Pancreatic stimulation test

Secretin stimulation

4) Radiographic techniques:

- Plain abdominal X-ray- U/S abdomen

- ERCP

- CT abdomen


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Carbohydrate absorption test

1) Hydrogen breath test

the patient takes a base reading of hydrogenlevels in his/her breath. The patient is thengiven a small amount of fructose, and thenrequired to take readings every 15, 30 or 60minutes for two to three hours. If the level ofhydrogen rises above 20 ppm (parts permillion) over the lowest preceding valuewithin the test period, the patient is typicallydiagnosed as a fructose malabsorber.

Hydrogen excretion in bacterialovergrowth

small intestinal malabsorption
http://en.wikipedia.org/wiki/Fructosehttp://en.wikipedia.org/wiki/Fructose


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2) D-xylose test

5-carbon sugar excreted unchanged in urine 25 grams given Urine collected for 5 hours Normally 25% is excreted In patients with fat malabsorption, this test

differentiates pancreatic from small intestinalmalabsorpton.

D-xylose is normal in pancreatic disease Serum level of D-xylose at 1-2 hours after

ingestion can be measured.

An abnormal test (


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1) Radiography of small intestine:

Barium swallow and follow-through to see

- Blind loop

- Stricture- J. diverticular


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2) Intestinal mucosal biopsy:

- using crossby capsule- endoscopy

Coeliac disease:- Villous atrophy

Tropical spure:

- short villi and increased lymphocyte


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Coeliac Disease(gluten-free diet results in eventual restoration)

Normal mucosa

Villi( V) ,

Small crypts (C)

Coeliac diseaseInflammatory cells (L)Loss of villiElongated crypts (C)

Coeliac disease (dissecting microscope)


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Coeliac disease (dissecting microscope)

Normal jejunal mucosa

series of ridges and

finger-like projections

Coeliac diseasesurface becomesfiattened, developinga mosaic-like pattem

Selection of tests in evaluation malabsorption


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Selection of tests in evaluation malabsorption

Quantitaive fecal fat

Normal Abnormal

D-xylose test

Normal Abnormal

Abd. Radiograph14 C-D-xylose test

Bentiromide test

CT-abd. Normal

Small intestinalBx

Abnormal

Jej culture

Tetracyclin

Then repeat breath test


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Endoscopy Gross morphology gives diagnostic clue

Cobblestone appearance crohn's D.

Reduced duodenal folds and scalloping

of duodenal mucosa celiac disease Use of vital dyes to identify villous atrophy

Biopsy to establish Dx For pts with documented steatorrhea

or ch. Diarrhea

Lesions seen classifid in to three Diffuse,specific e.g. whippls Disease

Patchy, specificcrohns D., lymphomainfectious causes

Diffuse,non-specific celiac sprue, Tropical sprueautoimmune enteropathy

Suspected distal pathology - push enteroscopywireless capsule

endoscopy

opsy o ma - n es na ucosa


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opsy o ma n es na ucosaDiffuse, specific

Whipples disease Macrophages containing PAS+ material

Agammaglobulinemia No plasma cells, no villi

Patchy, specific

Intestinal lymphoma Malignant cells in lamina propria

Intestinal lymphangiectasia Dilated lymphatics

Eosinophilic gastroenteritis Eosinophil infiltration

Amyloidosis Amyloid deposits

Crohns disease Noncaseating granulomas

Mastocytosis Mast cell infiltration

Diffuse, nonspecific

Celiac and tropical sprue Short or absent villi; mononuclear infiltrate;

Bacterial overgrowth Patchy damage to villi;

Folate, B12 deficiency, Radiation Short villi

Zollinger-Ellison syndrome Mucosal ulceration

Protein-calorie malnutrition Villous atrophy

RESULTS OF DIAGNOSTIC STUDIES IN


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RESULTS OF DIAGNOSTIC STUDIES IN

DIFFERENT CAUSES OF

STEATORRHEA

Second line tests


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Second line tests

Sigmoidoscopy, colonoscopy, ERCP

Esophagogastroduodenoscopy with smallintestinal biopsies

Abdominal ultrasound

Capsule endoscopy

immunoglobulins, human immunodeficiencyvirus antibodies, antinuclear antibodies,ferritin, food allergen-specific IgE,adrenocorticotropic hormone, cortisol,chromogranin A, gastrin, urinary 5-HIAA

Quantitative fecal fat


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Third line tests MRI Abdominal angiogram

PET Somatostatin (octreotide) scan Endoscopic ultrasound

Enteroscopy, including biopsies Spiral CT of the pancreas for tumor Tests for bile acid malabsorption Glucagon, somatostatin in

serum/plasma


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Back to our case CBC, electrolytes, blood urine nitrogen,

creatinine, liver function studies, and

thyroid-stimulating hormone were allwithin normal limits. Treatment with metaclopramide (Reglan)

and domperidone did not prevent theepisodes, nor did treatment withtetracycline 250 mg 3 times per day for 14days.

A hydrogen breath test was negative. Colonoscopy was normal.

Upper GI endoscopy revealed a normalesophagus, stomach, pylorus, andduodenum.


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Multiple biopsy specimens wereobtained from the post-bulbar

duodenum and sweep. Biopsies from the small intestine

revealed blunting of the villaeconsistent with celiac disease.

In addition, IgA anti-endomysialantibodies were performed. Thesewere positive in a titer of 1 to 640.

The patient began a gluten-free dietwith complete resolution of hissymptoms and a 10-lb weight gainwithin 2 months.


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Celiac disease and type 1 diabetes areautoimmune diseases with a common

genetic predisposition. Both celiac diseaseand type 1 diabetes are associated with ahigh frequency of HLA-DR3 genotypes. Asa result, celiac disease is more frequent in

type 1 diabetes than in type 2 diabetes orin the general population. Studies thathave screened patients with type 1diabetes for celiac disease have found

rates of celiac disease between 1% and8%. These rates are 411 times higher thanrates of celiac disease in the generalpopulation.


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CELIAC

DISEASE


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Celiac disease (CD) is an immune-mediated disorder that develops in

genetically susceptible persons whengluten, a major protein found in wheat,barley, and rye is ingested in the diet.Also called nontropical sprue, celiac

sprue, or gluten-sensitive enteropathy,CD is primarily an enteropathycharacterized by inflammation of the

small bowel mucosa and atrophy of thevilli, resulting in nutrient malabsorption,wasting, and diarrhea.


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Any organ system may be involved inCD, and patients can developextraintestinal manifestationsalsocalled atypical manifestationssuch as

anemia, bone disease, infertility,unfavorable outcomes of pregnancy,lymphoma, and liver disease.


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Prevalence and epidemiology

Women are affected more commonly

than men, but there is no agepredilection.


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Patients Who Are at Risk for CeliacDisease and Should Be Tested Patients with gastrointestinal and

classic symptoms: diarrhea, weightloss, abdominal distention, failure tothrive

Patients with autoimmune diseases,type 1 diabetes, thyroid disorders,Sjgren's syndrome, microscopiccolitis, inflammatory bowel disease

First-degree relatives

Patients with elevated liver enzymes


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Patients with Down syndrome

Patients with iron deficiency anemia Patients with osteoporosis

Patients with delayed puberty

Infertile patients Patients with irritable bowel

syndrome


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Pathophysiology Celiac disease is a multifactorial and

a multisystem disorder involving agenetic predisposition,environmental exposure of the small

bowel mucosa to gluten, and animmunologic response to gluten.


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Genetic susceptibility definespersons who possess the gene pairencoding the majorhistocompatibility complex class IIHLA DQ2 or DQ8. These genes are

virtually required for CD to occur, andlack of these genes makes CD veryunlikely.

The majority ( 90%) of persons with CD


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The majority (>90%) of persons with CDpossess the HLA DQ2 haplotype, and 5% to10% possess the DQ8 haplotype, conferring a

negative predictive value greater than 98%.These haplotypes are encoded within the HLAclass II region of the major histocompatibilitycomplex on chromosome 6p.

However, about 40% of the general population

carry these haplotypes without having thedisease, which makes their presencenecessary but not sufficient for itsdevelopment.

Intestinal antigen-presenting cells in peopleexpressing HLA-DQ2, or HLA-DQ8, bind withdietary gluten peptides in their antigen-binding grooves activate specific mucosalT lymphocytes cytokines mucosaldamage.


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Clinical manifestations Celiac disease exhibits a spectrum of

clinical and pathologic manifestations. Symptoms can manifest in infancy and as

early as cereals are introduced in the diet. Crampy abdominal pain, steatorrhea,

failure to thrive, apathy and irritability,muscle wasting, and hypotonia aredescribed.

Any of these symptoms should trigger adiagnostic workup.

Catch-up growth is well documented oncea gluten free-diet is introduced.


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In adults, the clinical symptoms arevariable and not specific.

The classic symptoms of malabsorptionare less encountered.

On the other hand, atypical presentationsare increasingly recognized and becomingmore common.


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Patients with CD can exhibit weakness,fatigue, and dyspnea as a result ofvitamin B12, folate, and iron deficiency;

bone fractures, muscular atrophy, andtetany as a result of osteoporosis andosteopenia due to vitamin D and calciumdeficiencies;

peripheral neuropathy and ataxia as aresult of cerebellar and posterior columninflammatory damage;

and secondary hyperparathyroidism,edema, petechiae, and dermatitis

herpetiformis. Infertility is observed inmen and women. Amenorrhea,intrauterine growth retardation, andunfavorable outcomes of pregnancy have

been reported.


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Essentials of diagnosis Weight loss

Distention, flatulence, greasy stools Increased fecal fat (>7g/24h)

Abnormal small bowel biopsy

Clinical improvement on gluten-freediet


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Diagnosis Once the clinical suspicion in patients at risk

factors is raised, the initial step toward a

diagnosis is to obtain celiac serology antibodytesting. This should be followed by a small bowelbiopsy. The patient should be tested whilefollowing a gluten-containing diet.

The most sensitive and specific serologic tests

are endomysial antibody IgA EMA and tissuetransglutaminase antibody IgA tTG. Sensitivitiesand specificities are higher than 85% and 97%,respectively, for EMA and 90% and 97%,respectively, for tTG. Gliadin antibodies have

lower sensitivities and specificities and are notrecommended for screening; however, gliadinantibodies may have a role in monitoringadherence to a gluten-free diet.


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Pathologic changes on small-bowel biopsyare characterized by a spectrum of

abnormalities described by Marsh andknown as the Marsh criteria. The hallmarkof CD is Marsh 3 or villous atrophy;however, this may be patchy or present inother disorders as inhypogammaglobulinemia, acute infectiousgastroenteritis, or milk intolerance.

Additionally, there is growing evidencethat CD may be diagnosed when changesof earlier phase on biopsy such as Marsh 1or Marsh 2 are seen.

Establishing Diagnosis in the


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Absence of Typical Symptoms The wide range of clinical

manifestations of the diseasecoupled with less than Marsh 3 onbiopsy makes the diagnosis of CD

challenging for the clinician. Inthese situations, genetic testing orgluten challenge may be necessary

for a definite diagnosis. A fewscenarios may be encountered in aclinical setting and their proposeddiagnostic workups include:


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Positive serology and villousatrophy: Diagnosis established.Patient should be treated.

Positive serology and normal smallbowel mucosa biopsy: Disease isconsidered latent and biopsy shouldbe repeated after a gluten challengeor a few months later on a normal

diet.


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Positive serology and increasedintraepithelial lymphocytes: Potential

celiac disease; repeat biopsy after a glutenchallenge or in a few months on a normaldiet, or obtain HLA typing. If any ispositive, start a gluten-free diet.

Normal serology and normal biopsy: Lookfor other causes of the patient'ssymptoms.

Normal serology and villous atrophy:Exclude other causes of villous atrophy,immunodeficiency, IgA deficiency.

TREATMENT


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Treatment consists of withdrawinggluten from the diet for life. It entailseliminating wheat, barley, and rye.This allows healing of the smallbowel mucosa and restitution of

nutritional status.


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Deficiencies of vitamins D and B12,folic acid, calcium, and iron andnutritional deficiencies should bereplaced as necessary.

Prevention of bone loss andpneumococcal vaccination due tohyposplenism are necessary.


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Response to the gluten-free diet isassessed by clinical and serologicimprovement. There is no clearconsensus on whether a repeat smallbowel biopsy is necessary. However,

repeat biopsy may be indicated incases where adherence to diet isproved but response to diet is

equivocal or lacking.

Foods That Are Safe in Celiac


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Disease

Plain meat (no bread or bread

crumbs)

Poultry

Fish

Shellfish Milk

Vegetables

Fruit Fats and oils

Butter

References


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Harrisons internal medicine

Current diagnosis and treatment ingastroenterology

Pubmed.com

Emedicine.com


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THANK YOU

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