Dr. M.A. SOFI MD; FRCP(London); FRCPEdin; FRCSEdin

Failure to fully absorb nutrients from the gastrointestinal tract. There are many causes including abnormalities of the gut wall, failure to produce digestive enzymes and abnormalities of gut flora. Clinical features Malabsorption, from whatever cause, may be accompanied by: Changes in weight and growth:  Inadequate absorption of calories will lead to loss of weight in adults or stunting of growth in children.  Adults will complain of unintended weight loss and perhaps tiredness, lethargy and fatigue.  Children may have similar symptoms accompanied by failure to thrive with growth failure (falling through the centile charts for height and weight). Malabsorption Syndrome :

Diarrhea: Diarrhea frequently is watery, reflecting the osmotic load received by the intestine.  Bacterial action producing hydroxy fatty acids from undigested fat further worsening the diarrhea. Steatorrhea: is the result of fat malabsorption.  The hallmark of steatorrhea is the passage of pale, bulky, and malodorous stools.  Such stools often float on top of the toilet water and are difficult to flush. Also, patients find floating oil droplets in the toilet following defecation. Malabsorption Syndrome:

Weight loss and fatigue:  Weight loss is common and may be pronounced.  Weight loss increases in diseases involving the intestine, such as celiac disease and Whipple disease. Flatulence and abdominal distention  Bacterial fermentation of unabsorbed food releases gaseous products, such as hydrogen and methane, causing flatulence.  Flatulence often causes uncomfortable abdominal distention and cramps. Malabsorption

Edema  Hypoalbuminemia from chronic protein malabsorption or from loss of protein into the intestinal lumen causes peripheral edema.  Extensive obstruction of the lymphatics, can cause protein loss.  Severe protein depletion, ascites may develop. Anemia  Anemia can be either microcytic or macrocytic  Iron deficiency anemia often is a manifestation of celiac disease.  Ileal involvement in Crohn disease or ileal resection can cause megaloblastic anemia due to vitamin B-12 deficiency. Malabsorption

Bleeding disorders:  Bleeding usually is a consequence of vitamin K malabsorption and subsequent hypoprothrombinemia.  Ecchymosis usually manifests, although, occasionally, melena and hematuria occur. Metabolic defects of bones:  Vitamin D deficiency can cause bone disorders, such as osteopenia or osteomalacia.  Bone pain and pathologic fractures may be observed.  Malabsorption of calcium can lead to secondary hyperparathyroidism. Malabsorption

Neurologic manifestations:  Hypocalcemia & hypomagnesemia, can lead to tetany, manifesting as the Trousseau sign and the Chvostek sign. Vitamin malabsorption can cause:  Generalized motor weakness (pantothenic acid, vitamin D)  Peripheral neuropathy (thiamine)  Loss for vibration and position (cobalamin),  Night blindness (vitamin A)  Seizures (biotin). Malabsorption

Clinical features Laboratory findings CaloriesWeight loss with normal appetite Fat Pale and voluminous stool, diarrhea without flatulence, steatorrhea Stool fat >6 g/day Protein Edema, muscle atrophy, amenorrhea Hypoalbuminemia, hypoproteinemia Carbohydrates Watery diarrhea, flatulence, acidic stool pH, milk intolerance, stool osmotic gap Increased breath hydrogen Vitamin B12 Anemia, subacute combined degeneration of the spinal cord (early symptoms are paresthesias and ataxia associated with loss of vibration and position sense) Macrocytic anemia, vitamin B12 decreased, abnormal Schilling test, serum methylmalonic acid and homocysteine increased Folic acidAnemia Macrocytic anemia, serum and RBC folate decreased, serum homocysteine increased Signs and symptoms of malabsorption

MalabsorptionClinical features Laboratory findings Folic acidAnemia Macrocytic anemia, serum and RBC folate decreased, serum homocysteine increased Vitamin B, general Cheilosis, painless glossitis, acrodermatitis, angular stomatitis Iron Microcytic anemia, glossitis, pagophagia Serum iron and ferritin decreased, total iron binding capacity increased Calcium and vitamin D Paresthesia, tetany, pathologic fractures due to osteomalacia, positive Chvostek and Trousseau signs Hypocalcemia, serum alkaline phosphatase increased, abnormal bone densitometry Vitamin A Follicular hyperkeratosis, night blindness Serum retinol decreased Vitamin KHematoma, bleeding disorders Prolonged prothrombin time, vitamin K-dependent coagulation factors decreased Signs and symptoms of malabsorption

Acrodermatitis enteropathica Cheilosis Glossitis Follicular Keratosis

General physical examination  Patients may have orthostatic hypotension.  Patients may complain of fatigue.  Signs of weight loss, muscle wasting, or both may be present.  Patients may have signs of loss of subcutaneous fat. Abdominal examination  The abdomen may be distended, and bowel sounds may be hyperactive.  Ascites may be present in severe hypoproteinemia. Physical signs

Dermatologic manifestations  Pale skin may reveal anemia.  Ecchymoses due to vitamin K deficiency may be present.  Dermatitis herpetiformis, erythema nodosum, and pyoderma gangrenosum may be present.  Pellagra, alopecia, or seborrheic dermatitis may be present. Neurologic examination  Motor weakness, peripheral neuropathy, or ataxia may be present.  The Chvostek sign or the Trousseau sign may be evident  Cheilosis, glossitis, or aphthous ulcers of the mouth Physical signs

Luminal phase Impaired nutrient hydrolysis  The most common cause for impaired nutrient hydrolysis is pancreatic insufficiency. The resultant deficiencies in lipase and proteases lead to lipid and protein malabsorption, respectively.  Inactivation of pancreatic enzymes by gastric hypersecretion, as seen in Z- Ellison syndrome, is another cause.  Inadequate mixing of nutrients, bile, and pancreatic enzymes, as seen in rapid intestinal transit, gastrojejunostomy also causes impaired hydrolysis.  Rarely, a failure to convert a proenzyme to active form, such as enterokinase and trypsinogen deficiencies, also can cause protein maldigestion and malabsorption. Causes: The best way to classify the numerous causes of malabsorption is to consider the 3 phases of digestion and absorption.

Impaired micelle formation : Inadequate fat solubilization and subsequent fat malabsorption. This impairment is due to  Decreased bile salt synthesis from severe parenchymal liver disease  Impaired bile secretion from biliary obstruction or cholestatic jaundice  Impaired enterohepatic bile circulation, as seen in small bowel resection or regional enteritis  Stasis of intestinal content caused by:  Motor abnormality (e.g., scleroderma)  Diabetic neuropathy  Intestinal obstruction  Anatomic abnormality (e.g., small bowel diverticula, stricture, ischemia, blind loops)  Small bowel contamination from enterocolonic fistulas can cause bacterial overgrowth. Causes:.

Luminal availability and processing  Luminal bacterial overgrowth can cause a decrease in the availability of substrates, including carbohydrates, proteins, and vitamins (eg, vitamin B-12, folate).  Vitamin B-12 deficiency due to pernicious anemia is caused by a lack of intrinsic factor and by pancreatic enzyme deficiency. Mucosal phase: Impaired brush-border hydrolase activity  Disaccharidase deficiency can lead to disaccharide malabsorption.  Lactase deficiency, either primary or secondary, is the most common form of disaccharidase deficiency.  Immunoglobulin A (IgA) deficiency is due to decreased or absent serum & intestinal IgA, which clinically appears similar to celiac disease and is unresponsive to a gluten-free diet. Causes:.

Mucosal phase: (Continued)  Acrodermatitis enteropathica is an autosomal recessive disease with selective inability to absorb zinc, leading to villous atrophy and acral dermatitis.  Autoimmune enteropathy primarily diagnosed in children presenting with intractable secretory diarrhea and villous atrophy. Autoimmune enteropathy is due to antibodies directed against intestinal epithelial and goblet cells. Impaired nutrient absorption Nutrient malabsorption is due to inherited or acquired defects.  Inherited defects include glucose-galactose malabsorption, abetalipoproteinemia, cystinuria, and Hartnup disease.  Other carbohydrase deficiencies, such as sucrase- isomaltase deficiency, may be the cause. Causes:

Impaired nutrient absorption Acquired disorders are far more common and are caused by the following: 1. Intestinal resection of intestinal bypass; 2. Damaged absorbing surface, as seen in celiac sprue, tropical sprue, Crohn's disease 3. Infiltrating disease of the intestinal wall, such as lymphoma and amyloidosis; and infections, including bacterial overgrowth, giardiasis, Whipple's disease, cryptosporidiosis, and microsporidiosis. Postabsorptive phase:  Obstruction of the lymphatic system, both congenital (e.g., intestinal lymphangiectasia, Milroy disease) and acquired (e.g., Whipple disease, neoplasm [including lymphoma], tuberculosis), impairs the absorption of chylomicrons and lipoproteins and may cause fat malabsorption or a protein-losing enteropathy. Causes:

Whipple’s Disease Cryptosporidiosis

Malabsorption: Examples of conditions causing malabsorption, categorized by the phase of absorption that is impaired Phase and nature of malabsorptive defect Example Luminal phase A. Substrate hydrolysis 1. Digestive enzyme deficiencyChronic pancreatitis 2. Digestive enzyme inactivationZollinger-Ellison syndrome 3. Dysynchrony of enzyme release, inadequate mixingPost Billroth II procedure B. Fat Solubilization 1. Diminished bile salt synthesisCirrhosis 2. Impaired bile secretionChronic cholestasis 3. Bile salt de-conjugationBacterial overgrowth 4. Increased bile salt lossIleal disease or resection C. Luminal availability of specific nutrients 1. Diminished gastric acidAtrophic gastritis - vitamin B12 2. Diminished intrinsic factorPernicious anemia - vitamin B12 3. Bacterial consumption of nutrients Bacterial overgrowth - vitamin B12

Malabsorption: Examples of conditions causing malabsorption, categorized by the phase of absorption that is impaired Phase and nature of malabsorptive defect Example Mucosal (absorptive) phase A. Brush border hydrolysis* 1. Congenital disaccharidase defectSucrase-isomaltase deficiency 2. Acquired disaccharidase defectLactase deficiency B. Epithelial transport 1. Nutrient-specific defects in transportHartnup's disease 2. Global defects in transportCeliac sprue Postabsorptive, processing phase A. Enterocyte processingAbetalipoproteinemia B. LymphaticIntestinal lymphangiectasia * This process is sometimes considered as part of the luminal phase.

Mucosal causes  Coeliac disease usually presents in childhood but can present later. It is due to allergy to gluten in the diet that results in subtotal villous atrophy.  Cows' milk intolerance.  Soya milk intolerance.  Fructose intolerance and malabsorption: simultaneous consumption of glucose reduces fructose malabsorption. Malabsorption syndrome: Causes

Infection:  Giardiasis  Whipple's disease  Intestinal tuberculosis  Tropical sprue  Traveller's diarrhoea  Diphyllobothriasis (tapeworm can cause vitamin B12 malabsorption)  Ancylostomiasis (hookworm)  Strongyloidiasis (nematode)  In patients with an inflammatory bowel disorder and malabsorption, an immune deficiency, including HIV enteropathy, should be considered.  Intestinal lymphangiectasia and other causes of lymphatic obstruction include lymphoma, tuberculosis and cardiac disease. Malabsorption syndrome: Causes

Intraluminal causes  Pancreatic insufficiency:  Cystic fibrosis  Chronic pancreatitis  Carcinoma of pancreas  Zollinger-Ellison syndrome  Defective secretions of bile salts, due to cholestatic jaundice or disease of the terminal ileum.  Drugs. Structural causes  Intestinal hurry:  Post-gastrectomy  Post-vagotomy  Gastrojejunostomy  The blind loop syndrome involves disturbance of normal gut flora with malabsorption.  Fistulae.  Diverticulae and strictures.  Crohn's disease.  Amyloidosis.  Short bowel syndrome.  Eosinophilic gastroenteropathy.  Mesenteric arterial insufficiency.  Radiation enteritis. Malabsorption syndrome: Causes

 Acrodermatitis Enteropathica  Cystic Fibrosis  Hartnup Disease  Intestinal Lymphangiectasia  Whipple Disease  Zollinger-Ellison Syndrome  Laboratory studies: Hematologic tests:  A CBC count may reveal microcytic anemia due to iron deficiency or macrocytic anemia due to vitamin B-12 or folate malabsorption.  Serum iron, vitamin B-12, and folate concentrations may help establish a diagnosis.  Prothrombin time may be prolonged because of malabsorption of vitamin K, a fat-soluble vitamin. Differential diagnosis:

Electrolytes and chemistries: Malabsorption can involve electrolyte imbalances, such as hypokalemia, hypocalcemia, hypomagnesemia, and metabolic acidosis.  Protein malabsorption may cause hypoproteinemia and hypoalbuminemia.  Fat malabsorption can lead to low serum levels of triglycerides, cholesterol, and alpha- and beta- carotene.  Westergren sedimentation rate is elevated in Crohn disease and Whipple disease. Serology:  No serologic tests are specific for malabsorption.  Serum antigliadin and antiendomysial antibodies can be used to help diagnose celiac sprue.  Serum IgA can be used to rule out IgA deficiency.  Determination of fecal elastase and chymotrypsin (2 proteases produced by the pancreas) can be used to try to distinguish between pancreatic causes and intestinal causes of malabsorption. Laboratory Studies:

Imaging Studies: Small bowel barium studies  An abnormal small bowel pattern from barium studies may reveal the nature of malabsorption.  The mucosa pattern associated with celiac disease often becomes obliterated or coarsened.  Flocculation of the barium occurs in the gut lumen.  Small bowel dilatation and diverticulosis are frequently identified in scleroderma.  Regional enteritis of the small intestine can lead to stricture, ulceration, and fistula formation.  Other anatomic abnormalities, such as surgical changes or enterocolonic fistula, also can be detected on x-ray films. Imaging Studies:  CT scan of the abdomen: Performing this study may help detect evidence of chronic pancreatitis, such as pancreatic calcification or atrophy. Enlarged lymph nodes are seen in Whipple disease and lymphoma.  Endoscopic retrograde cholangiopancreatogram (ERCP): This study helps document malabsorption due to pancreatic or biliary-related disorders. Laboratory Studies:

 Plain abdominal x-ray film: Pancreatic calcifications are indicative of chronic pancreatitis. Other Tests Tests of fat malabsorption  This usually is the first test because many disease processes result in fat malabsorption.  Quantitative measurement of fat absorption, a 72-hour fecal fat collection is often performed and is considered the criterion standard.  Qualitative tests include the acid steatocrit test and Sudan III stain of stool, but these tests are less reliable.  Serum retinyl palmitate to identify severe cases of fat malabsorption may be useful relative to the 72-hour fecal fat test.  Instruct patients to consume a normal amount ( g/d) of fat before and during the collection. Based on this intake, fecal fat excretion in healthy individuals should be less than 7 g/d. Imaging Studies

D-xylose test  If the 72-hour fecal fat collection results demonstrate fat malabsorption, the D-xylose test is used to document the integrity of the intestinal mucosa.  Facilitated diffusion in the proximal intestine primarily absorbs D-xylose.  Approximately half of the absorbed D-xylose is excreted in urine, unmetabolized.  If the absorption of D-xylose is impaired due to either a luminal factor (e.g., bacterial overgrowth) or a reduced or damaged mucosal surface area (e.g., surgical resection, celiac disease), urinary excretion is lower than normal.  Cases of pancreatic insufficiency usually result in normal urinary excretion because the absorption of D- xylose is still intact. Laboratory Studies

Tests of carbohydrate absorption: A simple sensitive test for carbohydrate malabsorption is the hydrogen breath test, in which patients are given an oral solution of lactose.  In cases of lactase deficiency, colonic flora digest the unabsorbed lactose, resulting in an elevated hydrogen content in the expired air.  Bacterial overgrowth or rapid transit also can cause an early rise in breath hydrogen, necessitating the use of glucose instead of lactose to make a diagnosis. However, 18% of patients are hydrogen nonexcretors, causing a false- negative test result. Other tests:

Test of bile salt absorption: Bile salt breath test can determine the integrity of bile salt metabolism.  The patient is given oral conjugated bile salt, such as glycine cholic acid with the glycine radiolabeled in the carbon position.  The bile salt is deconjugated and subsequently metabolized by bacteria, leading to a radioactively labeled elevated breath carbon dioxide level if interrupted enterohepatic circulation, such as bacterial overgrowth, ileal resection, or disease, is present. Other tests:

Wireless capsule endoscopy :  Wireless capsule endoscopy allows for visualization of the entire small bowel and allows for much more detailed evaluation of small bowel mucosal disease than barium studies. Thus, it may have a role in evaluating suspected small bowel disease (such as Crohn's disease) associated with malabsorption.  Because of the risk of retention, wireless capsule endoscopy should generally be avoided in patients with known or suspected small bowel strictures Other tests:

Upper endoscopy with small bowel mucosal biopsy  Establishing a definitive diagnosis of malabsorption of the mucosal phase often can be achieved by histologic examination of biopsied mucosal specimens obtained during routine upper endoscopy  Examples of conditions that can be diagnosed this way include celiac sprue, giardiasis, Crohn disease, Whipple disease, amyloidosis, abetalipoproteinemia, and lymphoma. Other tests:

 There are three major principles underlying the management of patients with malabsorption and maldigestion, and appropriate care of such patients in the majority of cases necessitates that each of these three are addressed: 1. Identification and treatment of the underlying disease 2. Treatment of the diarrhea that often accompanies these disorders 3. Identification and correction of nutritional deficits. Principles of management:

Summary and recommendations:  Malabsorption depend upon the cause and severity of the disease  The etiology can often be obtained from a detailed patient history, which can also exclude other causes of symptoms.  Deficiencies of specific nutrients and vitamins may also identify the underlying cause and its duration  Because symptoms may be absent or mimic other diseases, a routine battery of blood tests is often helpful as an initial step  Several invasive and noninvasive tests are available to establish the cause of malabsorption. Further testing may not be necessary in patients who have gross steatorrhea. Principles of management: