Malabsorption Syndromes

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Malabsorption Syndromes:

Malabsorption Syndromes By Dr Shashidhar Patil Postgraduate in Medicine Basappa Memorial Hospital Mysore


Malabsorption Malabsorption is a clinical term that encompasses defects occurring during the digestion and absorption of food nutrients by and infections of the gastrointestinal tract Impairment can be of single or multiple nutrients depending on the abnormality.

Classification of Malabsorption Syndrome:

Classification of Malabsorption Syndrome Inadequate digestion: 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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Inadequate absorptive surface: Resection Diseased intestine Lymphatic obstruction. e.g Lymphoma D. Primary mucosal defects. Crohn ’ s disease Coeliac disease Tropical Sprue Disaccharide Deficiency Lymphoma TB


causes Exocrine pancreatic insufficiency ch. Pancreatitis pancreatic CA cystic fibrosis Inactivation of pancreatic lipase – Gastrinoma (ZES) drugs ( orlistat ) bile acid (impaired micelle formation) parenchymal liver D. cholestatic liver D. Bacterial overgrowth Anatomic stasis (blind loop,stricture,fistula ) Functional stasis (DM, scleroderma) Interrupted interohepatic circulation of bile acid ( ileal resection, crohn’s D.) Drugs(bind or precipitate bile salt) neomycin, chlestyramine Impaired mucosal absorbtion / mucosal loss or defect intestinal resection or bypass inflammation/infiltration/infect. (celiac sprue , tropical sprue , whippl’s disease, lymphoma, mastocytosis , eosinophilic e., scleroderma, crohn’s D., …) Impaired nutrient transport lymphatic obstruction (lymphoma, lymphangectasia ) CHF Genetic disorders disacharidase defficiency Agamaglobulinemia Abetalipoprotinemia Endocrine/Metabolic disorders DM Hyperthyroidism adrenal insufficiency carcinoid syndrome

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Malabsorptive disorders can be categorized into 1-Generalized mucosal abnormalities resulting in multiple nutrient malabsorption 2-Specific nutrient malabsorption disorder ( carbohydrate, fat, protein, vitamin and mineral malabsorption )

Malabsorptive disorders with generalized mucosal defects:

Malabsorptive disorders with generalized mucosal defects Celiac disease Cow’s milk allergy Microvillous inclusion disease Tufting enteropathy Lymphangiectasia Short bowel syndrome Chronic malnutrition Congenital immunodeficiency disorders HIV Parasitic infections Tropical sprue Bacterial overgrowth

Specific nutrient malabsorptive disorder:

Specific nutrient malabsorptive disorder Carbohydrate malabsorption - lactase deficiency (congenital, secondary) Congenital sucrase-isomaltase deficiency Glucose- galactose malabsorption Protein malabsorption - Enterokinase deficiency - Amino acid transport defect ( eg;Hartnup disease ) Fat malabsorption - Pancreatic exocrine insufficiency (cystic fibrosis, shwachman diamond syndrome, chronic pancreatitis) - liver and biliary disorders - abetalipoproteinemia

Specific nutrient malabsorptive disorder:

Specific nutrient malabsorptive disorder Mineral and vitamin malabsorption - Congenital chloride diarrhea -Congenital sodium absorption defect - Acrodermatitis enteropathica - Menke disease -Vitamin D dependent rickets -Vitamin B 12 malabsorption


M echanisms 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 of nutrients Mucosal phase Epithelial transport defect – inflammations infections Brush border hydrolysis defect congenital/acquired disacharidase deficiency Post-absorptive phase Enterocyte processing – Abetalipoproteinemia Lymphocytic obstruction – intestinal lymphangectasia


CLINICAL MANIFESTATIONS History: Diarrhea/ steatorrhoea , Weight loss Symptoms of anaemia Diarrhoea – bulky, floating, malodorous stool – difficult to flush. Weight loss – may be profound, usually associated with anorexia. Anaemia – B12, iron, folate malabsorption . Patient may complain of dizziness, dyspnoea and fatigue

Important part of history: :

Important part of history: Recent travel - giardiasis Drug abuse/multiple blood transfusions or ethanol abuse  surgical resection - small bowel - gastric Malabsorption + chronic lung disease = cystic fibrosis Fever + weight loss = TB, lymphoma

Clinical features Depend on the cause and severity:

Clinical features Depend on the cause and severity Global Diffuse mucosal involvement Impaired absorption of all nutrients Classic manifestation Diarrhea( steatorrhea ) weight loss Majority – sub clinical E.g.. Celiac disease Partial (isolated) 2 ° to diseases that interfere with absorption of specific nutrients E.g.Pernicious Anemia Lactase deficiency

Signs and Symptoms Suggestive of Malabsorption:

Signs and Symptoms Suggestive of Malabsorption Sign or Symptom Wasting, edema Weight loss, oily-bulky stool Parasthesias, tetany, bone pain Ecchymosis, petechiae, purpura Anemia - macrocytic - microcytic Initial Lab Finding Serum albumin Stool fat Serum carotene Serum ca, alk.phos. Mineralization of bone Prothrombin time Serum folate or vit B 12 Serum iron

Signs & symptoms:

Signs & symptoms Calori Weight loss with normal appetite Fat Pale,voluminous,greasy offensive diarrhea Protein Edema, muscle atrophy, amenorrhea carbohydrate Abdominal bloating, flatus, w. diarrhea B12 Macrocytic anemia Subacut 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

Clinical Evaluation:

Clinical Evaluation In 75-80% of cases Dx by expert Hx & P/E + focused lab tests 25% - need extensive study/ Hospitalization History: - Diarrhea- duration, consistency, frequency stool characteristics, Volume time of occurrence, association with diet etc…. Bloating,borborigmi , flatus Abdominal pain Sxs of extra intestinal manifestation (joint pain, mouth ulcer..) Previous abd . Surgery medication Alcohol intake Recurrent PUD DM , CLD Falmily Hx – celiac disease, crohn’s D.) Risk factors – HIV infection

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P/E – thorough examination Look for  signs of specific nutrient Malabsorption  extraintestinal signs Lab. CBC, PT, serum protein, ALP Checks for depletion of iron,folate , B 12 , Vit D, Vit K) RFT,electrolytes Stool exam Additional tests: Serum carotene, cholesterol, albumin, iron, folate cobalamine


Endoscopy Gross morphology – gives diagnostic clue Reduced duodenal folds and scallopng of duodenal mucosa – celiac disease Use of vital dyes to identify villous atrophy Biopsy – to establish Dx For p’ts with documented steatorrhea or ch. Diarrhea Lesions seen – classifid in to three Diffuse,specific e.g. whippl’s Disease Patchy, specific – crohn’s D., lymphoma infectious causes Diffuse,non -specific – celiac sprue , Tropical sprue autoimmune enteropathy Suspected distal pathology - push enteroscopy wireless capsule endoscopy

Barium studies:

Barium studies Important information about the gross anatomy and morphology of SB Upper GI series with SB follow through Enteroclysis double contrast study by passing a tube into proximal SB and injecting barium+ methylcellulose Normal study doesn’t exclude SB disease

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A. Normal individual. B. Celiac sprue . C. Jejunal diverticulosis. D. Crohn's disease.

Tests for steatorrhea:

Tests for steatorrhea Quantitative test 72hr stool fat collection – gold standard > 6gm/day – pathologic P’ts with steatorrhea - >20gm/day Modest elevation in diarrheal disease (may not necessarily indicate Malabsorption ) Qualitative tests Sudan lll stain Detect clinically significant steatorrhea in >90% of cases Acid steatocrit – a gravimetric assay Sensitivity – 100%, specificity – 95% , PPV – 90% NIRA (near infra reflectance analysis) Equally accurate with 72hr stool fat test Allows simultaneous measurement of fecal fat, nitrogen, CHO

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Tests for pancreatic function: 1) Bentiromide test: Chymotrypsin PABA + pepside PABA  absorbed and conjugated in liver  urine excretion 2) Schilling test

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3) Pancreatic stimulation test Secretin stimulation – 4) Radiographic techniques: - Plain abdominal X-ray - U/S abdomen - ERCP - CT abdomen

Schilling test:

Schilling test To determine the cause of cobalamine (B 12 ) malabsorbtion Helps to asses the integrity of gastric, pancreatic and ileal functions. Abnormal cobalamine absorbtion in: pernicious anemia, ch. Pancreatitis, Achlorohydria , Bacterial overgrowth, ileal dysfunction The test Administering 58Co-labeled cobalamine p.o. Cobalamine 1mg i.m . 1hr after ingestion to saturate hepatic binding sites Collecting urine for 24 hr ( dependant on normal renal & bladder function) Abnormal - <10% excretion in 24 hrs

Schilling test cont….:

Schilling test cont…. 58Co-Cbl With Intrinsic factor With pancreatic enzyme 5 Days Of Ab Pernicious Anemia  N   Chronic Pancreatitis   N  Bacterial overgrowth    N Ileal disease    

D-xylose test :

D-xylose test D-xylose A Pentose monosacharide absorbed exclusively at the proximal SB Used to asses proximal SB mucosal function The test After overnight fast, 25gm D-xylose p.o. Urine collected for next 5 hrs Abnormal test - <4.5 gm excretion show duodenal / jejunal mucosal D. False + ve results: Renal dysfunction Inadequate urine sample Impaired gastric empyting , Ascitis Drugs( ASA,indometacin,Neomycin )

D-Xylose Test Helpful in Distinguishing Maldigestion from Malabsorption:

D-Xylose Test Helpful in Distinguishing Maldigestion from Malabsorption MALDIGESTION (pancreatic insufficiency) MALABSORPTION (celiac sprue ) Fecal Fat D-Xylose Excretion Normal Jejunal Biopsy Normal Abnormal “flat”

PowerPoint Presentation:

Othe tests for carbohydrate malabsorbtion Lactose tolerance test P.o. 50gm lactose Bloood glucose at 0,60,120 min. BG <20mg/l + dev’t of Sxs – diagnostic Breath tests (hydrogen,4Co 2, 13Co 2 ) Test for bacterial overgrowth Quantitative bacterial count from aspirated SB. Normal count: < 10 /ml (jejunum) > 10/ml (ileum) Tests for pancreatic insufficiency Stimulation of pancreas through adm. Of a meal or hormonal secretagogues , then analysis of duodenal fluid Indirect tests – schilling test Tests for protein malabsorption Enteral protein loss  measuring alpha-1 antitirypsin clearance

PowerPoint Presentation:

Selection of tests in evaluation malabsorption Quantitaive fecal fat Normal Abnormal D-xylose test Normal Abnormal Abd. Radiograph 14 C-D-xylose test Bentiromide test CT-abd. Normal Small intestinal Bx Abnormal Jej culture Tetracyclin Then repeat breath test

Small Bowel Biopsy and Malabsorption:

Small Bowel Biopsy and Malabsorption Diseases with Continuous Involvement Normal Biospy Excludes Diagnosis Celiac Disease Tropical Sprue Whipple’s Disease Agammaglobulinemia Other Diseases with Diagnostic Biopsies Intestinal Lymphoma Parasites (Giardia, Crytosporidia ) Viral (CMV, Herpes) Amyloidosis Eosinophilic Gastroenteritis

Disorders in Which Biopsy is Diagnostic:

Disorders in Which Biopsy is Diagnostic Whipple’s Disease Agammaglobulinemia Abetalipoprotienemia

Disorders in Which Biopsy May Be Diagnostic:

Disorders in Which Biopsy May Be Diagnostic Lymphoma Lymphangiectasia MAI Crytosporidiosis Coccidiosis Giardiasis Collagenous sprue etc .

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Whipple’s Disease


Epidemiology a rare infectious disorder caused by Tropheryma whipplei . first described in1907 , only 696 cases reported between 1907 and 1987, annual incidence of approximately 30 cases per year since 1980. chronic, systemic infection affecting mostly middle-aged males underlying genetic predisposition that leads to colonization of T. whipplei throughout the intestinal tract, lymphoreticular system, and central nervous system

Whipple's Disease: History:

1907: First described by George Hoyt Whipple. 1949: Black-Schaffer describe PAS stain. 1961: Electron microscopy demonstrates "bacillary bodies." 1992: PCR amplification of 16S ribosomal RNA: New genus: Tropheryma whippelii trophe: "Nourishment" eryma: "Barrier" Phylogenetically, an actinomycete. 1997: 1 st report of successful culture of organism in PBMs. Whipple's Disease: History

Whipple's Disease: Epidemiology:

Rare: Only 696 cases reported between 1907- 1987 Annual incidence ~ 30 cases per year since 1980. Predilection for males of European ancestry. 8:1 Men:Women . Mean age 50 years. Majority have occupational exposure to soil or animals. Whipple's Disease: Epidemiology Lancet 361 : 239 (2003) Clin Microbiol Rev 14 : 561 (2001)

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Tropheryma whippelli I solated in a cell culture from a patient with endocarditis aerobic , rod-shaped, gram-positive, non- acid fast , periodic acid-Schiff (PAS) positive bacillus member of the Actinomycetes ( placed between the genus Cellulomonas and the Actinomycetes clade ) It is found both intracellularly and extracellularly grow slowly in acidic vacuoles of cells

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Pathogenesis /Immunology H ost immune deficiency and possibly secondary immune down regulation are responsible S ource of transmission is unknown - likely per oral The bacteria most commonly invades the intestinal lamina propria and the vacuoles of "foamy" macrophages T issue macrophages are unable to kill and clear T.whipplei .  CD11b on macrophages mediates intracellular degradation of ingested bacteria This deficiency in killing then causes Whipple’s disease

Clinical Manifestations :

Clinical Manifestations There are four cardinal clinical manifestations of Whipple's disease Arthralgias Weight loss Diarrhea Abdominal pain

PowerPoint Presentation:

Less common symptoms include fever and skin hyperpigmentation symptoms or signs related to cardiac disease (dyspnea, pericarditis, culture-negative endocarditis), pleuropulmonary (pleural effusion), mucocutaneous disease; nonthrombocytopenic purpura can also occur

GI Features:

GI Features Weight loss: usually 20-30 lbs. May present years before diagnosis. Early GI symptoms are nondescript, often diagnosed as IBD. Diarrhea: steatorrhea , but may be watery. Abdominal pain tends to be epigastric and exacerbated following meals.

CNS Features:

CNS Features 21–43% of cases of Whipple's disease have neurologic symptoms 43% - 100% have central nervous colonization Characteristic triad: Dementia External opthalmoplegia Facial myoclonus Oculomasticatory myorhythmia (OMM) is diagnostic. CNS colonization may serve as a repository for bacteria and a mechanism for CNS relapse

CNS Features:

CNS Features Imaging: generalized cerebral atrophy, scattered small chalky nodules in cortical and subependymal gray matter (true granulomas that contain PAS-positive foamy macrophages) Areas of intense demylination resembling MS Micro-infarcts


Endocarditis Whipple endocarditis has been described in a small number of patients. Affected patients may have no clinical or histologic evidence of gastrointestinal disease or arthralgias . Endocarditis caused by T. whipplei may not be associated with the classical clinical presentation of Whipple's disease.

Common clinical syndromes that suggest the possible diagnosis of Whipple's disease include :

Common clinical syndromes that suggest the possible diagnosis of Whipple's disease include F ever of unknown origin, chronic serositis , progressive central nervous system disease with myoclonus or ophthalmoplegia , migratory polyarthropathy , and generalized lymphadenopathy. Vitamin or iron deficiency anemia, hypoalbuminemia , and relative lymphopenia should increase the level of suspicion.

PowerPoint Presentation:

Among the disorders which should be excluded prior to making a diagnosis of Whipple's disease are: Hyperthyroidism Connective tissue disease Inflammatory bowel disease with migratory polyarthropathy AIDS

Diagnosis :

Diagnosis Periodic acid schiff : PAS-positive, diastase-resistant inclusions on light microscopy Confirmed by characteristic trilaminar cell wall Polymerase Chain reaction: PCR-sequenced bacterial 16sRNA PCR can be applied to duodenal tissue, lymph node, pleural-fluid cells, and peripheral blood Abnormal Labs: ESR, CRP anaemia of chronic disease hypoalbuminaemia

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The hallmark of Whipple’s disease is the histopathological finding of macrophages containing diastase-resistant p- aminosalicylic acid (PAS)-positive material, which are T. whipplei bacteria or partly digested remnants there of .

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Bacilli with a characteristic trilamellar wall is specific for Whipple's disease.

List of organisms that stain positively with the periodic acid Schiff reagent:

List of organisms that stain positively with the periodic acid Schiff reagent Actinomycetes Atypical mycobacteria Mycobacterium avium intracellulare 55 Mycobacterium genavense Bacillus cereus 56 Corynebacterium spp Fungi Histoplasma Rhodococcus equi 57 ( Corynebacterium equi )

PowerPoint Presentation:

Diagnostic methods for Whipple's disease. Strausbaugh L J et al. Clin Infect Dis. 2001;32:457-463 © 2001 by the Infectious Diseases Society of America

Treatment :

Treatment Tetracycline became the mainstay of therapy for many years. high relapse rate of 35 percent among patients treated primarily with tetracycline. Even more alarming was a high rate of CNS relapse, and a dismal response (five percent) to retreatment of CNS relapse with tetracycline.

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A combination of streptomycin (1g) and benzylpenicillin (penicillin G; 1.2 million units) for 14 days and there after Oral cotrimoxazole (trimethoprim- sulfamethoxazole ; 160 mg/800 mg twice daily) for 1 year With this treatment regimen, however, relapses have been reported after cessation of antibiotic therapy, may be because trimethoprim- sulfamethoxazole is only bacteriostatic despite the high intracellular concentrations

PowerPoint Presentation:

Recommended therapy for Whipple's disease. Strausbaugh L J et al. Clin Infect Dis. 2001;32:457-463 © 2001 by the Infectious Diseases Society of America

PowerPoint Presentation:

Pen G 6- 24M U IV OD+ Streptomycin 1g IM OD Ceftrixone 2g IV OD Co- Trimoxazole 160/ 800 PO BID Doxycycline (or tetracycline) 100 mg PO BID - induction (first 10- 14 days) - induction (first 10- 14 days) -long- term therapy; first line drug; good CNS penet but prone to relapse -used for many years

Celiac disease:

Celiac disease Syn : Gluten-sensitive enteropathy , celiac sprue , non-tropical sprue Definition : A common autoimmune disorder characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy , and crypt hyperplasia in the small intestine .


Prevalence Now thought to be one of most common inherited diseases: 1:266 people worldwide ; 1:133 Americans (~ 2 million), more in North Europeans. However, as few as 1 out of 10 people diagnosed. Slightly more prevalent in female. There is strong HLA-linked genetic predisposition It has been reported in Indians, Arabs, Hispanics, Israeli Jews, Sudanese, and people of Cantonese extraction Punjabis and Gujaratis from India who lived in England developed celiac 2.7 times as often as Europeans when on a gluten-rich diet

History of Celiac Disease:

History of Celiac Disease

History of Celiac:

History of Celiac Cereal grains were first domesticated from wild grasses in the Fertile Crescent about 10,000 years ago Simopoulos AP (ed): Evolutionary Aspects of Nutrition and Health. Diet, Exercise, Genetics and Chronic Disease. World Rev Nutr Diet. Basel, Karger, 1999, vol 84, pp 19–73

History of Celiac:

History of Celiac Aretaeus from Cappadochia (now Turkey) in the 2nd century AD described a chronic malabsorptive condition He named this disorder "koiliakos ” which is Greek for "suffering in the bowels.” Booth, CC. History of celiac disease. BMJ 1989; 298:527.

History of Celiac:

History of Celiac The second classical description was in 1888 in a report entitled "On the Coeliac Affection“ by Samuel Gee S. Gee: “ On the coeliac affection” Saint Bartholomew’s Hospital Reports, London, 1888, 24: 17-20 "to regulate the food is the main part of treatment ... The allowance of farinaceous foods must be small ... but if the patient can be cured at all, it must be by means of diet."

History of Celiac:

History of Celiac During World War II, celiac children improved during the food shortages when bread was unavailable. After the war, symptoms reoccurred when bread and cereals were reintroduced. Dutch pediatrician Willem K Dicke recognized and confirmed this association between cereal grains and malabsorption . Dicke, WK. Simple dietary treatment for the syndrome of GheeHerter. Ned Tijdschr Geneeskd 1941; 85:1715. DICKE, WK, WEIJERS, HA, VAN DE, KAMER JH. Coeliac disease. II. The presence in wheat of a factor having a deleterious effect in cases of coeliac disease. Acta Paediatr 1953; 42:34.

History of Celiac:

History of Celiac The celiac lesion in the proximal small intestine was first described by Paulley in 1954. It was learned that celiac disease and adult non-tropical sprue share many of the same features These classic findings are: mucosal inflammation crypt hyperplasia villous atrophy PAULLEY, JW. Observation on the aetiology of idiopathic steatorrhoea; jejunal and lymph-node biopsies. Br Med J 1954; 4900:1318 RUBIN, CE, BRANDBORG, LL, PHELPS, PC, TAYLOR, HC Jr. Studies of celiac disease. I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue. Gastroenterology 1960; 38:28

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease Celiac disease as an immune disorder that is triggered by an environmental agent (the gliadin component of gluten) in genetically predisposed individuals Kagnoff, MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am 1992; 21:405. Schuppan, D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119:234.

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease Grain protein exists in four general storage forms which are categorized by their solubility characteristics: Prolamins (soluble in ethanol) Glutenins (partially soluble in dilute acid or alkali solutions) Globulins (soluble in 10 percent NaCl ) Minor albumins (soluble in water) Glutens specifically are the prolamins and the glutenins Bernardin, JE, Saunders, RH, Kasarda, DD. Absence of carbohydrate in coeliac toxic A-gliadin. Cereal Chem 1976; 53:612. Freedman, AR, Galfre, G, Gal, E, et al. Western immunoblotting of cereal proteins with monoclonal antibodies to wheat gliadin to investigate coeliac disease. Int Arch Allergy Appl Immunol 1988; 85:346. Troncone, R, Auricchio, S, De Vincenzi, M, et al. An analysis of cereals that react with serum antibodies in patients with coeliac disease. J Pediatr Gastroenterol Nutr 1987; 6:346. Vader, LW, Stepniak, DT, Bunnik, EM, et al. Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology 2003; 125:1105

Taxonomy of Grains:

Taxonomy of Grains KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18 Gliadins Secalins Hordeins Avenins Zeins

Celiac Disease:

Slide 75 Celiac Disease

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease The pathophysiology of gliadin toxicity in celiac patients is poorly understood One hypothesis is that similarities between gliadin proteins and certain enteral pathogens may result in the immunologic response to antigens in gluten. Kagnoff, MF, Paterson, NY, Kumar, PJ, et al. Evidence for the role of a human intestinal adenovirus in the pathogenesis of coeliac disease. Gut 1987; 28:995

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease The current hypotheses: Gliadin -sensitive T cells in genetically predisposed individuals recognize gluten-derived peptide epitopes and develop an inflammatory response which produces mucosal damage Nilsen, EM, Lundin, KE, Krajci, P, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 1995; 37:766

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease Genetic factors play an important role- there is significantly increased risk of celiac among family members A close association with the HLA-DQ2 and/or DQ8 gene locus has been recognized HLA-DQ2 is found in 98 percent of celiac patients from Northern Europe . However, ~25% of “normal” individuals in this population will also demonstrate HLA-DQ2 Kagnoff, MF. Celiac disease. A gastrointestinal disease with environmental, genetic, and immunologic components. Gastroenterol Clin North Am 1992; 21:4 Schuppan, D. Current concepts of celiac disease pathogenesis. Gastroenterology 2000; 119:234. Petronzelli, F, Bonamico, M, Ferrante, P, et al. Genetic contribution of the HLA region to the familial clustering of coeliac disease. Ann Hum Genet 1997; 61:307 Houlston, RS, Ford, D. Genetics of coeliac disease. QJM 1996; 89:737. Houlston, RS, Tomlinson, IP, Ford, D, et al. Linkage analysis of candidate regions for coeliac disease genes. Hum Mol Genet 1997; 6:1335

Current Model for Pathogenesis of Celiac Disease:

Current Model for Pathogenesis of Celiac Disease KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

Pathophysiology of Celiac Disease:

Pathophysiology of Celiac Disease HLA class II molecules are expressed on the surface of antigen-presenting cells They can bind to and subsequently present “foreign” peptides to populations of CD4 T cells that recognize the DQ2- or DQ8-peptide complex KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

Role of Tissue Transglutaminase:

Role of Tissue Transglutaminase Tissue transglutaminase can deamidate glutamine, converting glutamine to negatively charged glutamic acid This renders these peptides better binders to the disease relevant DQ2 or DQ8 molecules Once bound to DQ2 or DQ8, the DQ-“gluten” peptide complexes activate DQ2 or DQ8 restricted T cells KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

Celiac Disease: Clinical Manifestations:

Celiac Disease: Clinical Manifestations

Celiac Disease: Clinical Manifestations in Children:

Celiac Disease: Clinical Manifestations in Children The classical presentation is in children after weaning and introduction of cereals into the diet: Failure to thrive Apathy Pallor Anorexia Muscle wasting with generalized hypotonia Abdominal bloating and distention Soft, bulky, clay-colored, offensive stools

Celiac Disease: Clinical Manifestations in Children:

Celiac Disease: Clinical Manifestations in Children Catassi, C, et al Acta Paediatr 1996; 412(suppl):29. Symptoms and signs at presentation Overall prevalence (%) Iron deficiency with anemia 29 Iron deficiency without anemia 27 Recurrent Abdominal Pain 24 Mood Changes 17 Recurrent Aphthous Stomatitis 11 Poor appetite 10 Recurrent diarrhea 9 Short stature 7 Abdominal distension 5 Constipation 2 Pubertal delay 2 Hypoalbuminemia 2

Celiac Disease: Clinical Manifestations in Adults:

Celiac Disease: Clinical Manifestations in Adults In a study of 1138 people with biopsy–proven celiac disease: Majority of individuals were diagnosed in their 4th to 6th decades. Women predominated (2.9:1)- the female predominance was less marked in the elderly. Diarrhea was the main presenting symptom occurring in 85%. 36% had a previous diagnosis of irritable bowel syndrome. Symptoms were present a mean of 11 years before diagnosis. Green PHR, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 2001;96:126–131.

Spectrum of Celiac Disease:

Spectrum of Celiac Disease Few if any GI symptoms Marked GI symptoms Fatigue Depression, irritability Menstrual irregularity Weakness Infertility Growth Disturbance Neurologic Complaints Diarrhea Bulky, Pale, Foul stools Abdominal Distension, Bloating Abdominal cramps Weight loss Loss of or increased appetite KAGNOFF, MF. “Overview and Pathogenesis of Celiac Disease” GASTROENTEROLOGY 2005;128:S10–S18

Classification of Celiac Disease:

Classification of Celiac Disease Classical celiac disease Celiac disease with atypical symptoms Silent celiac disease Latent celiac disease NATIONAL INSTITUTES OF HEALTH, CONSENSUS DEVELOPMENT CONFERENCE STATEMENT: Celiac Disease. June 28–30, 2004

Celiac Disease: Associated Disorders:

Celiac Disease: Associated Disorders

Celiac Disease: Associated Disorders:

Celiac Disease: Associated Disorders Dermatitis Herpetiformis Iron deficiency anemia Osteoporosis, Osteomalacia and Vitamin D deficiency Malignancies Type 1 diabetes Other autoimmune endocrine disorders Neuropsychologic Features Others (Downs syndrome, IgA deficiency, rheumatologic disorders)

Celiac Disease: Dermatitis Herpetiformis:

Celiac Disease: Dermatitis Herpetiformis Symmetric vesicles, crusts and erosions distributed over the extensor areas of the elbows, knees, buttocks, shoulders and scalp, with a tendency to grouping of individual lesions. PRUESSNER, HT. Detecting Celiac Disease in Your Patients. 1998 by the American Academy of Family Physicians University of Texas Medical School at Houston

Celiac Disease: Dermatitis Herpetiformis:

Celiac Disease: Dermatitis Herpetiformis It has been reported that up to 10 percent of individuals with celiac will also have dermatitis herpetiformis American Gastroenterological Association, Ciclitra , PJ, Gastroenterology 2001; 120: 1526. Guidetti , CS, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders,Gut 2001;49:502–505

Celiac Disease: Other Skin Disorders:

Celiac Disease: Other Skin Disorders Acquired icthyosis Cutaneous amyloid Cutaneous vasculitis Eczema Epidermal necrolysis Nodular prurigo Pityriasis rubra pilara Pustular dermatitis American Gastroenterological Association, Ciclitra , PJ, Gastroenterology 2001; 120: 1526 .

PowerPoint Presentation:

Malignancy Overall Relative Risk All cancers 2 to 3 Enteropathy -associated T-cell lymphomas 30 to 40 (w/o gluten free diet) Small intestinal adenocarcinoma 83 Mouth, pharynx, esophagus cancer 23 (w/o gluten free diet) Celiac Disease: Malignancies American Gastroenterological Association, Ciclitra , PJ, Gastroenterology 2001; 120: 1526 .

Celiac Disease: Type 1 Diabetes:

Celiac Disease: Type 1 Diabetes An association between CD and type 1 diabetes mellitus (T1DM) has been recognized for decades Several studies in children and adults, have shown that there is a 1.5% to 7% prevalence of CD in type 1 diabetes A community-based study of type 1 diabetics of all ages in Olmsted County, MN, revealed that 6.5% had celiac disease. Talal AH, et al . Celiac disease in an adult population with insulin-dependent diabetes mellitus: use of endomysial antibody testing. Am J Gastroenterol 1997;92:1280. Fraser-Reynolds KA, et al. Use of immunoglobulin A- antiendomysial antibody to screen for celiac disease in North American children with type 1 diabetes. Diabetes Care 1985;1009:21. Koletzko S, et al . Prevalence of coeliac disease in diabetic children and adolescents: a multicentre study. Eur J Pediatr 1998;148:113. Sigurs N, et al . Prevalence of coeliac disease in diabetic children and adolescents in Sweden. Acta Paediatrica 1993;82:748. Collin P, et al. High frequency of coeliac disease in adult patients with type-I diabetes. Scand J Gastroenterol 1989;24:81.

Celiac Disease: Type 1 Diabetes:

Celiac Disease: Type 1 Diabetes Untreated celiac disease may increase risk of developing type 1 diabetes Autoantibodies directed against islet cells are frequently present in untreated CD but disappear with the gluten-free diet Patients in whom CD was identified and treated in early childhood had a lower rate of developing diabetes than children in whom CD was diagnosed later in childhood or as adults Ventura AMG, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999;117:297. Ventura A, Neri E, Ughi C, Leopaldi A, Citta A, Not T. Glutendependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease. J Pediatr 2000;137:263.

Celiac Disease: Autoimmune Thyroid Disease :

In one study of 83 patients with autoimmune thyroid disease found a frequency of celiac disease of 4.8 percent An epidemiologic study of 335 patients diagnosed with celiac disease between 1980 and 1990 determined that 5.4 percent of the patients with celiac disease also had autoimmune thyroid disease Celiac Disease: Autoimmune Thyroid Disease Collin P, Reunala T, Pukkala E, Laippala P, Keyrilainen O, Pasternack A. Coeliac disease--associated disorders and survival. Gut 1994;35:1215-8. Collin P, Salmi J, Hallstrom O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol 1994;130:137-40

Celiac Disease: Other Autoimmune Endocrine Disorders :

Celiac Disease: Other Autoimmune Endocrine Disorders Guidetti , CS, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders,Gut 2001;49:502–505 In study of 605 controls and 422 patients (aged 16–84 years): 30% of adult patients with CD had at least one AI disease with an overall 2–3-fold higher frequency than controls.

Celiac Disease: Neuropsychologic Features :

Celiac Disease: Neuropsychologic Features Depression- 10.6% Epilepsy- 3.5% Migraine headaches- 3.2% Anxiety- 2.6% Suicidal tendency- 2.1% Carpal tunnel- 1.8% Myopathy- 1.5% Holmes, JKT, Acta Paediatr 1996; 412 ( Suppl ): 68

Celiac Disease: Other Associated Disorders:

Celiac Disease: Other Associated Disorders Aphthous stomatitis- unexplained oral ulcers have been reported as the sole presenting feature Glossitis, angular stomatitis, and cheilosis have also been associated

New paradigm: multi-organ autoimmune disease:

New paradigm: multi-organ autoimmune disease Celiac disease villous athrophy malnutrition malignancies Bone osteoporosis, fractures arthritis dental anomalies Hepatitis Cholangitis Skin & mucosa dermatitis herpetiformis aphtous stomatitis hair loss Reproductive miscarriage, infertility delayed puberty Central nervous system ataxia, seizures depression Carditis, cardiomyopathy Anemia

Diagnosis of Celiac Disease:

Diagnosis of Celiac Disease

Celiac disease:

Celiac disease Diagnosis : All tests must be done during normal intake of gluten. 1. Serologic : antibody tests (Many false negatives): • IgA endomysial (EMA): very specific to celiac disease • IgA tissue transglutaminase (tTG): very specific to celiac disease • Antigliadin IgA or IgG Anibody tests are 80-95% sensitive, are valuable in screening and atypical casees and become negative after treatment. 2. Histolopathology : The only definitive test is small intestinal biopsy taken endoscopically (the proximal duodenum is maximally affected) or by Crosby capsule. It shows subtotal or total villous atrophy with intense inflammatory infiltration. 3. Genetic Testing : HLA‐DQ2 and HLA‐DQ8 markers in >90% CD patients

Diagnosis of Celiac Disease:

Diagnosis of Celiac Disease Clinical Findings Small Intestines Mucosal Biopsy Gluten Re-challenge Serologic testing

Diagnosis: Small Bowel Endoscopy:

Diagnosis: Small Bowel Endoscopy Normal Celiac

Diagnosis: Small Bowel Endoscopy:

Diagnosis: Small Bowel Endoscopy

Diagnosis: Small Bowel Endoscopy:

Diagnosis: Small Bowel Endoscopy

Histologic Findings of Celiac :

Histologic Findings of Celiac Normal Jejunum Celiac

Histologic Findings of Celiac:

Histologic Findings of Celiac Normal Flattened Villi in Celiac

Histologic Findings of Celiac:

Histologic Findings of Celiac The lamina propria shows a marked increase in the number of plasma cells and lymphocytes and transepithelial migration of lymphocytes across the surface epithelium (arrow) is common. Virginia Commonwealth Univ, Richmond, Virginia Celiac Disease (Gluten-Induced Enteropathy) 65000-45800-F2923

Intestinal Lesions of Celiac Disease:

Intestinal Lesions of Celiac Disease Marsh, MN, Gastroenterology 1992; 102:330.

Other Causes of Villous Atrophy:

Other Causes of Villous Atrophy Bacterial Overgrowth Crohn’s disease Cow’s milk protein intolerance (children) Eosinophilic gastroenteritis Giardiasis Lymphoma Peptic duodenitis Post gastroenteritis Tropical sprue Zollinger Ellison syndrome American Gastroenterological Association, Ciclitra, PJ, Gastroenterology 2001; 120: 1526.

Diagnosis of Celiac: Gluten Rechallenge:

Diagnosis of Celiac: Gluten Rechallenge Gluten Rechallenge - improvement in symptoms and histology with gluten avoidance with a documented return of these features upon gluten reintroduction. May be performed by consuming 10 g of gluten per day (an amount contained in four slices of regular bread) for four to six weeks. One hazard of rechallenge is development of fulminant diarrhea, with dehydration, acidosis, and other metabolic disturbances (" gliadin shock"). KRAINICK, HG, DEBATIN, F, GAUTIER, E, et al. [Additional research on the injurious effect of wheat flour in celiac disease.I. Acute gliadin reaction (gliadin shock).]. Helv Paediatr Acta 1958; 13:432

Diagnosis of Celiac: Serologic Testing:

Diagnosis of Celiac: Serologic Testing Some of the serologic tests used to diagnose celiac: IgA and IgG antigliadin antibodies IgA endomysial antibodies IgA and IgG tissue transglutaminase antibodies Anti reticulin antibodies (no longer used)

Diagnosis of Celiac: Antigliadin Antibodies:

IgA and IgG antigliadin antibody tests are considered less accurate, less sensitive and less specific than other serologic tests . Frequent false positive results (15 to 20 %) often leads to unnecessary endoscopy with biopsy Therefore , antigliadin antibody is no longer recommended for initial diagnostic evaluation or screening Diagnosis of Celiac: Antigliadin Antibodies

Diagnosis of Celiac: IgA Endomysial Antibodies:

Endomysial antibodies bind to connective tissue surrounding smooth muscle cells IgA endomysial antibodies bind to the endomysium , producing a characteristic staining pattern, which is visualized by indirect immunofluorescence . IgA endomysial antibody testing is moderately sensitive and highly specific for untreated celiac disease Diagnosis of Celiac: IgA Endomysial Antibodies National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at Walker-Smith, JA, Guandalini, S, Schmitz, J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909.

Diagnosis of Celiac: Anti-tissue Transglutaminase Antibodies :

The antigen against which antiendomysial antibodies are directed is a tissue transglutaminase ( tTG ) IgA anti- tTG antibodies testing by ELISA are considered easier to perform and less costly than the immunofluorescence assay used to detect IgA endomysial antibodies. Anti- tTG antibodies are both highly sensitive and specific Diagnosis of Celiac: Anti-tissue Transglutaminase Antibodies National Institutes of Health Consensus Development Conference Statement. Celiac Disease 2004. Available at Walker-Smith, JA, Guandalini , S, Schmitz, J, et al. Revised criteria for diagnosis of coeliac disease. Arch Dis Child 1990; 65:909.

Diagnosis of Celiac Disease:

Diagnosis of Celiac Disease Positive Negative Probability < 2 to 5 percent Obtain IgA endomysial or tTG Ab and serum IgA level Small bowel biopsy Diagnosis excluded

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Probability > 2 to 5 percent IgA endomysial or tTG Ab + IgA AND Small bowel biopsy Family history Unexplained iron deficiency anemia Steatorrhea or other GI symptoms Failure to thrive Type 1 diabetes mellitus or other associated disorders Other symptoms { Both positive Histology - Serology + Histology + Serology - Both negative Review and/or repeat biopsy Diagnosis excluded Rule out other causes of villous atrophy - + + TREAT -

Management of Celiac Disease:

Management of Celiac Disease

Management of Celiac Disease:

Management of Celiac Disease Gluten avoidance is the mainstay of treatment Prior to the introduction of a strict gluten-free diet, prognosis was very poor Mortality was 12 percent in one retrospective study of 544 children

Management of Celiac Disease:

Management of Celiac Disease In general, the following advice can be given to all patients: Foods containing wheat, rye, and barley should be avoided. Soybean or tapioca flours, rice, corn, buckwheat, and potatoes are safe. Read labels on prepared foods and condiments carefully (many stabilizers or emulsifiers contain gluten) Dairy products may need to be avoided initially- many patients have secondary lactose intolerance.

Foods That May Contain Gluten:

Foods That May Contain Gluten Bouillon Cubes Canned soups Catsup Cheese spreads Chips and dips mixes Hot chocolate mixes or cocoa Ice cream Luncheon meats Meat sauces (soy, Worcestershire, etc ) Mustard Non-dairy creamer Peanut butter Processed canned meats and poultry Salad dressing Soup mixes Tomato sauces Wieners and other sausages products Yogurt with fruit Trier, JS. Celiac Sprue and refractory sprue. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 6 th Ed, Feldman, M, Scharscmidt, BF, Sleisenger, MH (Eds), Saunders, Philadelphia 1998. p. 1568

Management of Celiac Disease:

Management of Celiac Disease Serum IgA antigliadin titers at diagnosis and after 12 – 16 months of dietary therapy N=20 N=10

Monitoring Adherence by Serologic Testing:

A pretreatment antibody level should be determined at the time of diagnosis. Serologic testing is of no use if antibody levels are not elevated prior to therapy. Exclusion of gluten from the diet results in a gradual decline in serum IgA antigliadin and IgA tTG levels. A normal baseline value is typically reached within three to six months. If the levels do not fall as anticipated, the patient may be continuing to ingest gluten either intentionally or inadvertently Monitoring Adherence by Serologic Testing Kelly, CP. Coeliac disease: Non-invasive tests to screen for gluten sensitive enteropathy and to monitor response to dietary therapy. Dublin University, Trinity College, Dublin 1995.

Celiac disease:

Celiac disease Treatment : Life-long gluten-free diet . Rice, potato and maize are satisfactory sources of complex carbohydrates. Celiac societies publish booklets and guidelines for gluten-free diets which are available in many countries. Failure of treatment is due to non-compliance or unrecognized presence of gluten in diet. Correct vitamin and mineral deficiencies . Rarely corticosteroids are required in refractory cases. Regular follow up of compliance, response and complications especially small intestinal carcinoma or T-cell lymphoma

Tropical sprue:

Tropical sprue Tropical sprue : is a malabsorption disease commonly found in the tropical regions, marked with abnormal flattening of the villi and inflammation of the small intestinal mucosa. Unrelated to gluten ingestion


Causes No specific causal agent has been clearly associated with tropical sprue , but bacterial overgrowth by enterotoxigenic organisms ( e.g., E.coli and hemophilus ) has been implicated.


Morphology Intestinal changes range from near normal to severe diffuse enteritis . Unlike celiac sprue , injury is seen at all levels of the small intestine . Patients frequently have folate and vitamin B12 deficiency, leading to enlargement of the nuclei of epithelial cells , reminiscent of the changes seen in pernicious anemia


Symptoms The symptoms of tropical sprue are: - Diarrhea. - Indigestion. - Cramps. - Weight loss and malnutrition. - Fatigue.


Signs - Abnormal flattening of villi and inflammation of the lining of the small intestine, observed during an endoscopic procedure. Presence of inflammatory cell in the biopsy of small intestine tissue . Low levels of vitamins A, B12, E, D, and K, as well as albumin, calcium, and folate , revealed by a blood test. Excess fat in feces

PowerPoint Presentation:

The biopsy in tropical sprue will have less villous architectural alteration and more mononuclear cell infiltrate in the lamina propria. In contrast to celiac disease, the histologic features of tropical sprue are present with a similar degree of severity throughout the small intestine, and a gluten-free diet does not result in either clinical or histologic improvement in tropical sprue .


Management Prevention :- Preventions of tropical sprue include avoiding travel to the affected regions. If you have to travel, remember to use only bottled water for drinking, brushing teeth, and washing food . -Nutritional deficiencies must also be corrected.


Treatment:- Treatment is usually 3 to 6 months of antibiotics (tetracycline) and folic acid supplements . People with vitamin B12 deficiency will receive vitamin supplements as well.

Malabsorption due to bacteral over growth of small bowel:

Malabsorption due to bacteral over growth of small bowel Normal small intestine is bacterial sterile due to : Acid Int. peristalsis (major) Immunoglobulin Cause of bacterial growth. e.g. Small intestinal diverticuli Blind loop Strictures DM/ Scleroderma


Pathophysiology Bacterial over growth: Metabolize bile salt resulting in deconjugation of bile salt   Bile Salt  Impaired intraluminal micelle formation Malabsorption of fat. Intestinal mucosa is damaged by  Bacterial invasion  Toxin  Metabolic products  Damage villi  may cause total villous atrophy.

Pathogenesis of Bacterial Overgrowth Syndromes:

Pathogenesis of Bacterial Overgrowth Syndromes Small Bowel Lesions Intestinal Stasis Vit B 12 Malabsorption Steatorrhea

PowerPoint Presentation:

Clinically:  Steatorrhea  Anaemia  B12 def . Reversed of symptom after antibiotic treatment . Diagnosis:  Breath test  xylose test  Culture of aspiration (definitive) Treatment: Antibiotic  Tetracyclin  Ciproflexacin  Metronidazole  Amoxil

Protein-Losing Enteropathy:

Protein-Losing Enteropathy Characterized by excessive loss of serum proteins into the gut Hypoproteinemia , hypoalbuminemia , edema, muscle atrophy May occur as isolated phenomenon or part of global malabsorption Need to r/o malnutrition, nephrosis , liver disease

Conditions Associated with Protein-Losing Enteropathy:

Conditions Associated with Protein-Losing Enteropathy Mucosal disease IBD, Celiac, Whipple’s, Tropical sprue , Menetrier’s , GI malignancy, chemotherapy, eosinophilic dz , SIBO Lymphatic obstruction Lymphangiectasia , lymphoma, constrictive pericarditis, Crohn’s , radiation, Fontan procedure

Tests of Protein Malabsorption:

Tests of Protein Malabsorption Nutrient balance studies with fecal nitrogen measurement Radioisotopic methods 51 Cr-labeled albumin 99 mTc-labeled transferrin 125 I-labeled albumin Indirect methods Fecal - 1 antitrypsin clearance (> 25 mg/d)

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PowerPoint Presentation:

Common problem Europe and U.S.A; 7-20% - Caucasians (lowest in north Europe) , 80-95% Native American , 65-75% Africans and African Americans , 50% Hispanics Eastern Asia, Jewish descent > 90%

Lactose intake:

Lactose intake Varies with age Infants – 35-55% of daily calories ingested Lactose intake falls as weaning foods are introduced Average adult ingests 300 gram of carbohydrates per day (52% starch , 37% sucrose , 5% lactose (mainly in milk), 3% fructose )

Lactose digestion and colonic salvage of nonabsorbed lactose:

Lactose digestion and colonic salvage of nonabsorbed lactose

Etiology of lactose malabsorption:

Etiology of lactose malabsorption Primary lactose malabsorption Racial or ethnic lactose malabsorption Developmental lactase deficiency Congenital lactase deficiency Secondary lactose malabsorption Bacterial overgrowth/stasis Mucosal injury of GIT that causes villus flattening

Racial or ethnic lactose malabsorption:

Racial or ethnic lactose malabsorption Genetically determined reduction of lactase activity Most common form of lactose malabsorption The great majority of the world’s population develop low intestinal lactase during mid-childhood (approximately at age 5 yrs ) This finding is most prominent in Asian and African populations; rare in Caucasians of Scandinavian background Molecular basis remains unknown

Developmental lactase deficiency:

Developmental lactase deficiency Low lactase levels as a consequence of prematurity Lactase activity in the fetus increases late in gestation Premature infants born at 28-32 weeks of gestation have a reduced lactase activity

Congenital lactase deficiency:

Congenital lactase deficiency Rare autosomal recessive disorder (Finnish population) Characterized by the absence of lactase activity in the small intestine, with normal histologic findings A gene located on the same chromosome of the lactase gene, is responsible for CLD Affected infants have diarrhea from birth, hypercalcemia and nephrocalcinosis

Secondary lactose malabsorption:

Secondary lactose malabsorption Bacterial overgrowth or stasis syndromes Increased fermentation of dietary lactose in the small bowel, leading to symptoms of lactose intolerance Suspected from clinical history and from a very early peak of breath hydrogen during lactose challenge

Secondary lactose malabsorption - 2:

Secondary lactose malabsorption - 2 Mucosal injury Villus flattening or damage to the intestinal epithelium Celiac disease Crohn’s disease Radiation enteritis, chemotherapy HIV enteropathy Whipple’s disease

Secondary lactose malabsorption -3:

Secondary lactose malabsorption -3 Lactase usually first affected disaccharidase in these disorders, because of its distal location on the villus Treatment of the primary disorder can lead to restoration of lactase activity Restoration of lactase activity lags behind the return of normal intestinal morphology

Clinical manifestations:

Clinical manifestations Abdominal pain – crampy , localized to periumbilical area, or lower quadrant Bloating Flatulence Diarrhea Vomiting Stools are usually bulky, frothy and watery

Clinical manifestations - 2:

Clinical manifestations - 2 Meals with higher osmolality and fat content slow gastric emptying and reduce the severity of symptoms Rapid intestinal motility  rapid movement of sugar are more symptomatic Individuals have variable sensitivity to the abdominal distention produced when undigested lactose stimulates an influx of water into the lumen or to gas production

Differential diagnosis:

Differential diagnosis Irritable bowel disease Inflammatory bowel disease Cystic fibrosis Diverticulitis Celiac sprue Acute gastroenteritis Giardiasis


Diagnosis Test absorption ( lactose absorption test ) or malabsorption ( lactose breath hydrogen test ) Lactose tolerance test Oral administration of 50 gram lactose Blood glucose levels 0, 60 and 120 min Increase of blood glucose by less than 20mg/dl + symptoms – diagnostic False negative – diabetes, bacterial overgrowth, delayed gastric emptying Sensitivity of 75%, specificity of 96%

Diagnosis - 2:

Diagnosis - 2 Lactose breath hydrogen test Oral lactose (2g/kg) Breath hydrogen sampled at baseline and at 30 min intervals for three hours Breath hydrogen value of 10ppm – normal, 10-20ppm – indeterminate unless symptomatic, >20ppm – diagnostic False positive – recent smoking, false negative – recent use of antibiotics, lung disorders, 1% non-hydrogen producers

Diagnosis -3:

Diagnosis -3 Under the age of 5 years – abnormal test reflects an abnormal intestinal mucosa or bacterial overgrowth, both of which require further evaluation by appropriate diagnostic tests Normal breath hydrogen test – psychologic factors, intolerance to other factors in milk


Treatment In the absence of a correctable underlying disease, the treatment includes four general principles: Reduced dietary lactose intake Substitution of alternative nutrient sources to maintain energy and protein intake Administration of a commercially available enzyme substitute Maintenance of calcium intake

Dietary lactose restriction:

Dietary lactose restriction Highest concentration in milk and ice-cream, much lower quantities in cheese Complete restriction of lactose-containing foods should be necessary for a limited period to ascertain the specificity of the diagnosis Since patients can tolerate graded increases in lactose intake, small quantities of lactose may subsequently be reintroduced into the diet, with careful attention to development of symptoms

Enzyme replacement:

Enzyme replacement Commercially available “lactase” preparations (bacterial or yeast beta galactosidases) Lactaid, Lactrase, LactAce, DairyEase and Lactrol Start with two Lactaid tablets with lactose ingestion, and adjust both the Lactaid dose and the lactose load to tolerance

Calcium intake:

Calcium intake Avoidance of milk and other dairy products can lead to reduced calcium intake, and increase in risk of osteoporosis and fracture Calcium carbonate Tums – popular and effective Infants and young children – liquid calcium gluconate Yogurt containing lactose is well tolerated by the patients. The yogurt contains live cultures of bacteria that produce lactase

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