Malabsorption (malabsorption syndrome)

Malabsorption (malabsorption syndrome, malabsorption syndrome, chronic diarrhea syndrome, sprue) is inadequate absorption of nutrients due to impaired digestion, absorption or transport processes.

Malabsorption affects macronutrients (eg, proteins, carbohydrates, fats) or micronutrients (eg, vitamins, minerals), causing large stool losses, nutritional deficiencies, and gastrointestinal symptoms.

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What causes malabsorption?

Malabsorption has many causes. Some malabsorption changes (eg, celiac disease) interfere with the absorption of most nutrients, vitamins, and trace elements (general malabsorption); others (eg, pernicious anemia) are more selective.

Pancreatic insufficiency causes malabsorption when more than 90% of pancreatic function is impaired. Hyperacidity (e.g., Zollinger-Ellison syndrome) inhibits lipase and fat digestion. Liver cirrhosis and cholestasis reduce liver bile synthesis and the flow of bile salts into the duodenum, causing malabsorption.

Causes of Malabsorption

Mechanism	Cause
Insufficient mixing in the stomach and/or rapid passage out of the stomach	Gastric resection according to Billroth II Gastrocolic fistula Gastroenterostomy
Lack of digestive factors	Biliary obstruction Chronic liver failure Chronic pancreatitis Cholestyramine-induced bile salt deficiency Cystic fibrosis of the pancreas Small intestinal lactase deficiency Pancreatic cancer Pancreatic resection Small intestinal sucrase-isomaltase deficiency
Changing the environment	Secondary motility disorders in diabetes, scleroderma, hyperthyroidism Excessive growth of microflora - blind intestinal loop (deconjugation of bile salts) Diverticula Zollinger-Ellison syndrome (low pH in the duodenum)
Acute intestinal epithelial injury	Acute intestinal infections Alcohol Neomycin
Chronic intestinal epithelial damage	Amyloidosis Diseases of the abdominal organs Crohn's disease Ischemia Radiation enteritis Tropical malabsorption Whipple's disease
Short intestine	Ileojejunal anastomosis in obesity Bowel resection (eg, for Crohn's disease, volvulus, intussusception, or gangrene)
Violation of transport	Acanthocytosis Addison's disease Lymphatic drainage disorder - lymphoma, tuberculosis, lymphangiectasia

Pathophysiology of malabsorption

Digestion and absorption occur in three phases:

1. inside the intestinal lumen, hydrolysis of fats, proteins and carbohydrates occurs under the action of enzymes; bile salts increase the solubilization of fat in this phase;
2. digestion of cellular microvilli by enzymes and absorption of end products;
3. lymphatic transport of nutrients.

Malabsorption develops if any of these phases is disrupted.

Fats

Pancreatic enzymes break down long-chain triglycerides into fatty acids and monoglycerides, which combine with bile acids and phospholipids to form micelles that pass through the enterocytes of the jejunum. Absorbed fatty acids are resynthesized and combined with protein, cholesterol, and phospholipid to form chylomicrons, which are transported by the lymphatic system. Medium-chain triglycerides can be absorbed directly.

Unabsorbed fats trap fat-soluble vitamins (A, D, E, K) and possibly some minerals, causing their deficiency. Excessive microflora development leads to deconjugation and dehydroxylation of bile salts, limiting their absorption. Unabsorbed bile salts irritate the colon, causing diarrhea.

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Carbohydrates

Enzymes on the microvilli break down carbohydrates and disaccharides into their component monosaccharides. Microflora in the large intestine ferment unabsorbed carbohydrates into CO2 _, methane, H2, and short-chain fatty acids (butyrate, propionate, acetate, and lactate). These fatty acids cause diarrhea. Gases cause bloating and flatulence.

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Squirrels

Enterokinase, an enzyme in the microvilli of enterocytes, activates trypsinogen to trypsin, which converts many pancreatic proteases to their active forms. Active pancreatic enzymes hydrolyze proteins into oligopeptides, which are directly absorbed or hydrolyzed into amino acids.

Diseases associated with malabsorption syndrome

• Exocrine pancreatic insufficiency.
• Malformations of the pancreas (ectopia, anular and bifurcated gland, hypoplasia).
• Shwachman-Diamond syndrome.
• Cystic fibrosis.
• Trypsinogen deficiency.
• Lipase deficiency.
• Pancreatitis.
• Cholestasis syndrome of any etiology.
• Primary bowel diseases.
• Primary disorders of digestion and absorption of proteins and carbohydrates:
  • deficiency of enterokinase, duodenase, trypsinogen;
  • lactase deficiency (transient, primary adult type, secondary);
  • sucrase-isomaltase deficiency;
  • congenital malabsorption of monosaccharides (glucose-galactose, fructose).
• Primary disorders of absorption of fat-soluble substances:
  • abetalipoproteinemia;
  • impaired absorption of bile salts.
• Electrolyte malabsorption:
  • chloride diarrhea,
  • sodium diarrhea.
• Micronutrient malabsorption:
  • vitamins: folates, vitamin B ₁₂;
  • amino acids: cystine, lysine, methionine; Hartnup disease, isolated tryptophan absorption disorder, Lowe syndrome;
  • minerals: enteropathic acrodermatitis, primary hypomagnesemia, familial hypophosphatemia; idiopathic primary hemochromatosis, Menkes disease (copper malabsorption).
• Congenital disorders of enterocyte structure:
  • congenital microvillous atrophy (microvillous inclusion syndrome);
  • intestinal epithelial dysplasia (tuffting enteropathy);
  • syndromic diarrhea.
• Inflammatory bowel disease.
• Intestinal infections.
• Crohn's disease.
• Allergic intestinal diseases.
• Infectious and inflammatory bowel diseases in congenital immunodeficiencies:
  • Bruton's disease;
  • IgA deficiency;
  • combined immunodeficiency;
  • neutropenia;
  • acquired immunodeficiency.
• Autoimmune enteropathy.
• Celiac disease.
• Reduction of absorption surface.
• Short bowel syndrome.
• Blind loop syndrome.
• Protein-energy malnutrition.
• Pathology of blood and lymphatic vessels (intestinal lymphangiectasia).
• Endocrinopathies and hormone-producing tumors (vipoma, gastrinoma, somatostatinoma, carcinoid, etc.).
• Parasitic lesions of the gastrointestinal tract.

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Symptoms of malabsorption

Impaired absorption of substances causes diarrhea, steatorrhea, bloating, and gas. Other symptoms of malabsorption result from nutritional deficiencies. Patients often lose weight despite adequate nutrition.

Chronic diarrhea is the main symptom. Steatorrhea is fatty stool, a sign of malabsorption, develops if more than 6 g/day of fat is excreted in the stool. Steatorrhea is characterized by foul-smelling, light-colored, abundant and fatty stool.

Marked vitamin and mineral deficiencies develop as malabsorption progresses; symptoms of malabsorption are related to specific nutritional deficiencies. Vitamin B12 deficiency _may be caused by blind pouch syndrome or after extensive resection of the distal ileum or stomach.

Symptoms of malabsorption

Symptoms	Malabsorption agent
Anemia (hypochromic, microcytic)	Iron
Anemia (macrocytic)	Vitamin B12, folate
Bleeding, hemorrhage, petechiae	Vitamins K and C
Muscle cramps and pain	Sa, Md
Edema	Protein
Glossitis	Vitamins B2 and B12, folate, niacin, iron
Night blindness	Vitamin A
Pain in the limbs, bones, pathological fractures	K, Md, Ca, vitamin D
Peripheral neuropathy	Vitamins B1, B6

Amenorrhea may result from malnutrition and is an important symptom of celiac disease in young women.

Diagnosis of malabsorption

Malabsorption is suspected in patients with chronic diarrhea, weight loss, and anaemia. The etiology is sometimes obvious. Chronic pancreatitis may be preceded by episodes of acute pancreatitis. Patients with celiac disease typically have prolonged diarrhea that is exacerbated by gluten-rich foods and may have features of dermatitis herpetiformis. Liver cirrhosis and pancreatic cancer commonly cause jaundice. Abdominal distension, excessive flatus, and watery diarrhea 30 to 90 minutes after a carbohydrate meal suggest a deficiency of a disaccharidase enzyme, usually lactase. Previous abdominal surgery suggests short bowel syndrome.

If the history suggests a specific cause, investigations should be directed toward its diagnosis. If no cause is obvious, laboratory blood tests (eg, complete blood count, red cell indices, ferritin, Ca, Mg, albumin, cholesterol, PT) may aid in diagnosis.
If macrocytic anemia is diagnosed, serum folate and B12 levels should be measured. Folate deficiency is characteristic of proximal small bowel mucosal disorders (eg, celiac disease, tropical sprue, Whipple's disease). Low B12 levels _may occur in pernicious anemia, chronic pancreatitis, bacterial overgrowth syndrome, and terminal ileitis. The combination of low B12 _and high folate levels may suggest bacterial overgrowth syndrome because intestinal bacteria use vitamin B12 and synthesize folate.

Microcytic anemia suggests iron deficiency, which may be seen in celiac disease. Albumin is a major indicator of nutritional status. Decreased albumin may result from decreased intake, decreased synthesis, or protein loss. Low serum carotene (a precursor of vitamin A) suggests malabsorption if dietary intake is adequate.

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Confirmation of malabsorption

Tests to confirm malabsorption are useful when symptoms are vague and the etiology is unknown. Most malabsorption tests evaluate fat malabsorption because it is easy to measure. Confirmation of carbohydrate malabsorption is of little use if steatorrhea is first detected. Tests for protein malabsorption are rarely used because fecal nitrogen measurements are sufficient.

Direct measurement of stool fat over 72 hours is the standard for establishing steatorrhea, but the test is unnecessary if steatorrhea is obvious and the cause is identifiable. Stool is collected over a 3-day period during which the patient consumes more than 100 g of fat per day. The total fat content of the stool is measured. Stool fat greater than 6 g/day is considered abnormal. Although severe fat malabsorption (stool fat greater than 40 g/day) suggests pancreatic insufficiency or small intestinal mucosal disease, this test cannot diagnose a specific cause of malabsorption. Because the test is unpleasant and labor-intensive, it should not be performed in most patients.

Stool smear staining with Sudan III is a simple and direct method, but not quantitative, for demonstrating the fat content of stool. Steatocrit is a gravimetric test performed as a primary stool test; sensitivity is reported to be 100% and specificity 95% (using 72-hour stools is standard). Using infrared reflectance analysis, stool can be tested simultaneously for fat, nitrogen, and carbohydrates and may become the leading test.

A D-xylose absorption test should also be performed if the etiology is unclear. This is the best noninvasive test to assess the integrity of the intestinal mucosa and differentiate mucosal lesions from pancreatic disease. This test has a specificity of up to 98% and a sensitivity of 91% for small intestinal malabsorption.

D-xylose is absorbed by passive diffusion and does not require pancreatic enzymes for digestion. Normal D-xylose test results in the presence of moderate to severe steatorrhea indicate exocrine pancreatic insufficiency rather than small intestinal mucosal pathology. Bacterial overgrowth syndrome may cause abnormal D-xylose test results due to the metabolism of pentose sugars by enteric bacteria, which reduces the conditions for D-xylose absorption.

On an empty stomach, the patient drinks 25 g of D-xylose in 200-300 ml of water. Urine is collected over 5 hours, and a venous blood sample is collected after 1 hour. D-xylose levels in serum less than 20 mg/dL or less than 4 g in urine indicate impaired absorption. Falsely low levels may be seen in renal disease, portal hypertension, ascites, or delayed gastric emptying.

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Diagnosis of the causes of malabsorption

Endoscopy with biopsy of the small intestinal mucosa is performed if a small intestinal disease is suspected or if changes in the D-xylose test are detected in massive steatorrhea. The small intestinal biopsy should be sent for bacterial culture and colony count to determine the presence of bacterial overgrowth syndrome. Histologic features in the small intestinal mucosa biopsy may establish a specific disease of the mucosa.

Small bowel radiography may reveal anatomic changes that predispose to bacterial overgrowth. These include jejunal diverticula, fistulas, blind intestinal loops and anastomoses following surgical procedures, ulcerations, and stenosis. Abdominal radiography may reveal pancreatic calcifications characteristic of chronic pancreatitis. Barium studies of the small bowel (small bowel follow-through or enteroclysm) are not diagnostic, but the findings may provide some information about mucosal disease (eg, dilated small bowel loops, thinned or thickened mucosal folds, coarse fragmentation of barium columns).

Tests for pancreatic insufficiency (eg, stimulated secretin test, bentiromide test, pancreolauril test, serum trypsinogen, stool elastase, stool chymotrypsin) are performed if the history suggests disease, but the tests are insensitive in mild to moderate pancreatic disease.

The Xylose breath test helps diagnose bacterial overgrowth. Xylose is taken orally and the concentration in exhaled air is measured. Xylose catabolism by bacterial overgrowth causes it to appear in exhaled air. The hydrogen breath test measures hydrogen in exhaled air, formed by the degradation of carbohydrates by the microflora. In patients with disaccharidase deficiency, intestinal bacteria break down unabsorbed carbohydrates in the colon, increasing the hydrogen content in exhaled air. The lactose hydrogen breath test only confirms lactase deficiency and is not used as a primary diagnostic test in malabsorption workup.

The Schilling test evaluates vitamin B12 malabsorption. It has four steps to determine whether deficiency is due to pernicious anemia, pancreatic exocrine insufficiency, bacterial overgrowth, or ileal disease. The patient takes 1 mcg of radiolabeled cyanocobalamin orally, with 1000 mcg of unlabeled cobalamin injected intramuscularly to saturate the hepatic binding sites. Urine collected over 24 hours is analyzed for radioactivity; urinary recovery of less than 8% of the oral dose indicates cobalamin malabsorption (step 1). If abnormalities are detected in this step, the test is repeated with the addition of intrinsic factor (step 2). Pernicious anemia is diagnosed if this addition normalizes absorption. Step 3 is performed after the addition of pancreatic enzymes; Normalization of the index at this stage indicates secondary malabsorption of cobalamin due to pancreatic insufficiency. Stage 4 is performed after antibacterial therapy, including against anaerobes; normalization of the index after antibiotic therapy suggests excessive growth of microflora. Cobalamin deficiency as a result of ileal disease or after its resection leads to changes at all stages.

Investigations for rarer causes of malabsorption include serum gastrin (Zollinger-Ellison syndrome), intrinsic factor and parietal cell antibodies (pernicious anemia), sweat chloride (cystic fibrosis), lipoprotein electrophoresis (abetalipoproteinemia), and plasma cortisol (Addison's disease).

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