MALABSORPTION DISEASE

A broad spectrum of conditions with multiple etiologies and varied clinical manifestations They are associated with diminished intestinal absorption of one or more dietary nutrients ….. malabsorption syndrome This term is a pathophysiologic state, does not provide an etiologic explanation for the underlying problem, and should not be considered an adequate final diagnosis.

Hemochromatosis and Wilson’s disease … absorption of iron and copper are elevated Most malabsorption syndromes are associated with steatorrhea … stool fat excretion to >6% of dietary fat intake Some are not associated with steatorrhea: primary lactase deficiency and pernicious anemia

ENTEROHEPATIC CIRCULATION OF BILE ACIDS Bile acids did not present in the diet but synthesized in the liver by …. cholesterol catabolism(7a hydroxylase , rate limiting enzyme) … interruption of the enterohepatic circulation of bile acids …. reduce serum cholesterol levels by 10% Bile acids are either primary or secondary Primary B.A(colic acid, chenodeoxy colic acid) synthesized in the liver from cholesterol and secondary(deoxycholic acid and lithocholic acid) synthesized from primary in the intestine by colonic bacterial enzymes … the two most secondary

The liver synthesizes ~500 mg of bile acids daily … conjugated to either taurine or glycine (to form tauroconjugated and glycoconjugated bile acids) and are secreted into the duodenum in bile The functions of bile acids (1) to promote bile flow (2) to solubilize cholesterol and phospholipid by mixed micelle formation (3) to enhance dietary lipid digestion and absorption by forming mixed micelles in the proximal small intestine

the capacity to increase bile acid synthesis is limited to ~2- to 2 the capacity to increase bile acid synthesis is limited to ~2- to 2.5-fold The enterohepatic circulation(pool circulated) about twice during each meal, or six to eight times during a 24-h period Defects in any of steps in enterohepatic circulation … decrease in the duodenal concentration of conjugated bile acids …. Steatorrhea

Thus steatorrhea can be caused by abnormalities in bile acid synthesis , Excretion and reabsorption Chronic liver disease, but steatorrhea often is not a major component of illness in these patients

Secretion biliary obstruction(cholestasis), steatorrhea is rare a significant problem Primary biliary cirrhosis : defect in canalicular excretion of organic anions(bile acids) .. steatorrhea and its consequences (e.g., chronic bone disease … osteopenia/osteomalacia ) steatorrhea & cholestasis in cholestatic syndrome … leads to calcium and vitamin D malabsorption

Maintenance of Conjugated Bile Acids Bacterial overgrowth syndromes … diarrhea, steatorrhea, and macrocytic anemia Colonic type of bacterial flora is increased in the SI. … deconjugation B.A … impairment of micelle formation (1) Unconjugated bile acids are rapidly absorbed in the jejunum by nonionic diffusion, and the result is a reduced concentration of duodenal bile acids (2) The critical micellar concentration (CMC) of unconjugated is higher than of conjugated bile acids …. unconjugated are less effective than conjugated bile acids in micelle formation

Reabsorption(Ileum impairment) Crohn’s disease , surgical resection … Ileal dysfunction …. decrease in bile acid reabsorption in ileum … increase delivery of bile acids to large intestine … diarrhea with or without steatorrhea(degree of ileal dysfunction and response enterohepatic circulation to bile acid losses)

Limited ileal disease or resection … diarrhea but not steatorrhea The diarrhea … result of stimulation of active Cl secretion by bile acids in the colon … called bile acid diarrhea or choleretic enteropathy and responds to cholestyramine(anion-binding resin) patients with greater degrees of ileal disease and/or resection … diarrhea and steatorrhea that do not respond to cholestyramine

ileal disease is associated with increased volumes of bile acids entering the colon …. hepatic synthesis can no longer increase sufficiently to maintain the bile-acid pool size The intraduodenal concentration reduced to less than the CMC … impaired micelle formation and steatorrhea … fatty acid diarrhea Cholestyramine not be effective

LIPIDS Steatorrhea … one or more defects in the digestion and absorption of dietary fat Three types of fatty acids compose fats long-chain fatty acids (LCFAs , 16 or 18 carbon) ,medium- chain fatty acids (MCFAs , 12), and short-chain fatty acids (SCFAs ,8) Dietary fat composed of long-chain triglycerides (LCTs) : glycerol that is bound via ester linkages to three LCFAs

Assimilation of dietary lipid requires three processes: (1) an intraluminal, or digestive, phase (lipolysis and micelle formation) (2) a mucosal, or absorptive, phase (3) a delivery, or post absorptive, phase

CARBOHYDRATES Diet carbohydrates in the form of starch, disaccharides (sucrose and lactose), and glucose, are absorbed only in the small intestine and only in the form of monosaccharides Starch and disaccharides digested by pancreatic amylase and intestinal brush border disaccharidases to monosaccharides … absorption occurs by a Na-dependent process mediated by the brush border transport protein SGLT1. Lactose malabsorption …. only clinically important disorder of carbohydrate absorption

Lactose, the disaccharide present in milk, requires digestion by brush border lactase ….. glucose and galactose Lactase is present in almost all species in the postnatal period but then disappears throughout the animal kingdom, except in humans Lactase activity persists in many individuals throughout life Two different types of lactase deficiency exist—primary and secondary

In primary lactase deficiency decrease or absence of lactase while all other aspects of both intestinal absorption and brush border enzymes are normal common in adulthood of nonwhite groups Most individuals with primary lactase deficiency do not have symptoms.

Secondary lactase deficiency association with small-intestinal mucosal disease, with abnormalities in both structure and function of other brush border enzymes and transport processes is often seen in celiac disease. Symptoms includes diarrhea, abdominal pain, cramps, and/or flatus, Individuals with persistant symptoms …. R/O IBS

The development of symptoms of lactose intolerance is related to several factors 1.Amount of lactose in the diet 2. Rate of gastric emptying 3. Small-intestinal transit time 4. Colonic compensation by production of SCFAs from nonabsorbed lactose

PROTEINS Protein in food almost exclusively as polypeptides and requires extensive hydrolysis to di- and tripeptides and amino acids Proteolysis occurs in stomach and the small intestine …mediated by pepsin(which is secreted as pepsinogen by gastric chief cells) and by trypsinogen and other peptidases The proenzymes pepsinogen and trypsinogen must be activated to pepsin (at a pH <5) and to trypsin (by the intestinal brush border enzyme enterokinase and subsequently by trypsin) Proteins are absorbed by separate transport systems for di- and tripeptides

PROTEINS Three rare genetic disorders involve protein digestion/absorption: (1) Enterokinase deficiency ….. absence of the brush border enzyme …… diarrhea, growth retardation, and hypoproteinemia (2) Hartnup’s syndrome, a defect in neutral amino acid transport …. pellagra-like rash and neuropsychiatric symptoms (3) Cystinuria, a defect in dibasic amino acid transport ….. renal calculi and chronic pancreatitis.

APPROACH TO THE PATIENT The history, symptoms, and initial preliminary observations For example, patient with malabsorption and who has recently undergone extensive small-intestinal resection for mesenteric ischemia …. short-bowel syndrome Steatorrhea with long-standing alcohol abuse …. chronic pancreatitis Diarrhea can be caused by changes in fluid and electrolyte movement in either the small or the large intestine, dietary nutrients are absorbed almost exclusively in the small intestine

Dietary nutrient absorption may be segmental or diffuse along the small intestine and is site specific, calcium, iron, and folic acid are exclusively absorbed by active-transport processes in the proximal small intestine, especially the duodenum; in contrast, the active- transport mechanisms for both cobalamin and bile acids are operative only in the ileum Glucose, amino acids, and lipids—are absorbed throughout the small intestine, absorption rate is greater in the proximal than in the distal segments

However, after segmental resection of the small intestine, the remaining segments undergo both morphologic and functional “adaptation” to enhance absorption Adaptation is critical for the survival of individuals who have undergone massive resection of the small intestine and/or colon.

Establishing the diagnosis of steatorrhea and identifying its specific cause are often quite difficult, the “gold standard” test …. timed, quantitative stool-fat determination Because stool collections are invariably difficult and often incomplete, qualitative test—Sudan III staining—has long been available , it is rapid and inexpensive but, as a qualitative test, does not establish the degree of fat malabsorption and is best used as a preliminary screening study

Routine laboratory studies … Routine laboratory studies ….. CBC, PT, serum protein, ALKp, iron, folate, cobalamin, and vitamins D and K, serum carotene, cholesterol, albumin, and cobalamin levels The serum carotene level can be reduced in poor leafy vegetables intake

If steatorrhea ….. history, clinical observations, and laboratory testing ….. fat-soluble vitamin (A, D, E, or K) Vitamin D malabsorption ….. elevated alkaline phosphatase and/or reduced serum calcium levels Vitamin K deficiency ….. elevated prothrombin time without liver disease Macrocytic anemia… possible cobalamin or folic acid malabsorption IDA in the absence of occult bleeding ….. in either a male or a nonmenstruating female patients …iron malabsorption and the exclusion of celiac disease

A timed (72-h) quantitative stool collection(on a defined diet)…determine stool fat content….diagnosis of steatorrhea Schilling test , Urinary D-xylose test, duodenal mucosal biopsy, small- intestinal radiologic examination, and tests of pancreatic exocrine function

RADIOLOGIC EXAMINATION Barium contrast (small-bowel series or study)….. useful for anatomic abnormalities, such as strictures and fistulas (as in Crohn’s disease) or blind loop syndrome (e.g., multiple jejunal diverticula) and to define the extent of a previous surgical resection Enteroclysis study … ( flocculation, segmentation) A normal barium contrast study does not exclude the possibility of small- intestinal disease

CT enterography and magnetic resonance enterography(integrity of small- intestinal morphology ) Capsule endoscopy and double-balloon enteroscopy

BIOPSY OF SMALL-INTESTINAL MUCOSA A small-intestinal mucosal biopsy is essential in documention steatorrhea or chronic diarrhea (i.e., that lasting >3 weeks) , primary indications (1) either with documented or suspected steatorrhea or with chronic diarrhea (2) with diffuse or focal abnormalities of the small intestine defined on a small-intestinal series Lesions seen on small-bowel biopsy can be classified into three categories

Diffuse, specific lesions Whipple’s disease Abetalipoproteinemia Immune globulin deficiency 2. Patchy, specific lesions: Crohn’s disease Lymphangiectasia Aamyloidosis

3. Diffuse, nonspecific lesions: Celiac disease Tropical sprue Many of these infections occur in immunocompromised patients with diarrhea …… Cryptosporidium, Isospora belli, microsporidia, Cyclospora, Toxoplasma, cytomegalovirus, adenovirus, Mycobacterium aviumintracellulare, and G. lamblia

In immunocompromised patients, when Candida, Aspergillus, Cryptococcus, or Histoplasma organisms are seen on duodenal biopsy …. reflects systemic infection Patients with steatorrhea require assessment of pancreatic exocrine function The secretin test that collects pancreatic secretions by duodenal intubation following intravenous administration of secretin is the only test that directly measures pancreatic exocrine function

NORMAL

CELIAC DISEASE

JEJUNAL DIVERTICULOSIS

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