Malabsorption Syndrome - Harrison's Principles of Internal Medicine 22E (2025)

Definition and Overview

1. Luminal phase - initiated by lingual/gastric lipase, gastric pepsin, and continued in the small bowel by pancreatic enzymes and bile salts
2. Mucosal phase - mediated by enterocyte brush border enzymes (disaccharidases, enterokinases, peptidases), transporters, and micelle-mediated lipid uptake
3. Postmucosal phase - nutrients transported into lymphatics (long-chain triglycerides as chylomicrons) or the portal circulation

Steatorrhea

• Stool volume/weight is normally <200 mL or <200 g in 24 hours
• Gold standard: 72-hour stool collection for weight and fecal fat determination
• Stools are large, bulky, and malodorous
• Malabsorptive diarrhea is precipitated by eating and resolves or significantly decreases at night - this distinguishes it from secretory diarrheas (e.g., toxigenic E. coli) which continue even during fasting

Classification of Causes (Table 336-1)

I. Inadequate Digestion (Luminal Phase Disorders)

• Roux-en-Y gastric bypass or Billroth II anastomosis cause rapid gastric emptying into the jejunum - inadequate mixing with bile and pancreatic secretions

• Exocrine pancreatic insufficiency
• Chronic pancreatitis
• Pancreatic carcinoma
• Cystic fibrosis
• Gastrinoma (acid inactivation of lipase)
• Drugs (orlistat)

• Parenchymal liver disease
• Cholestatic disease (primary sclerosing cholangitis, primary biliary cholangitis)
• Ileal resection or disease (Crohn's disease)
• Small bowel bacterial overgrowth

II. Impaired Mucosal Digestion and Absorption (Mucosal Phase Disorders)

• Celiac disease
• Whipple's disease
• Abetalipoproteinemia
• Lymphoma
• Radiation enteritis
• Eosinophilic enteritis
• Mastocytosis
• Tropical sprue
• Graft-versus-host disease
• Folate and vitamin B12 deficiency
• Infections - giardiasis
• Genetic disorders: disaccharidase deficiency, agammaglobulinemia, abetalipoproteinemia, Hartnup's disease, cystinuria

III. Impaired Nutrient Delivery to/from Intestine (Postmucosal Disorders)

• Lymphoma
• Lymphangiectasia

• Congestive heart failure
• Constrictive pericarditis
• Mesenteric artery atherosclerosis
• Vasculitis

• Diabetes mellitus
• Hypoparathyroidism
• Adrenal insufficiency
• Hyperthyroidism
• Carcinoid syndrome

Specific Nutrients

Lipid Absorption

1. Pancreatic enzymes and bile salts for hydrolysis and physicochemical dispersion
2. Absorption of lipids dispersed in bile salt-mixed micelles across intestinal epithelium
3. Re-esterification to triglycerides in enterocytes and packaging into chylomicrons
4. Secretion into lymphatics (too large for capillaries)

Carbohydrate Absorption

• Digestion by salivary amylase, pancreatic amylase, and brush border disaccharidases (lactase, sucrase-isomaltase)
• Products absorbed via specific transporters

Protein Absorption

• Digested by gastric pepsin and pancreatic proteases (trypsin, chymotrypsin)
• Brush border peptidases produce dipeptides, tripeptides, and amino acids absorbed via specific transporters

Disorders That Affect the Luminal Phase

Gastric Resection

Disordered Intestinal Motility

• Hyperthyroidism: increased intestinal motility - inadequate mixing with pancreatic/biliary secretions
• Diabetes mellitus: enteric neuropathy causes either increased motility/diarrhea or reduced motility/constipation
• Scleroderma: affects intestinal smooth muscle profoundly

Pancreatic Disorders

• Steatorrhea (voluminous, bulky, malodorous stools)
• Deficiency of fat-soluble vitamins: A, E, D (most commonly), and K
• Weight loss

Bile Salt Deficiency

• Hepatobiliary disease: decreased bile acid synthesis (hepatocyte dysfunction) or reduced secretion (bile duct disease)
• Ileal resection/disease:
  • <100 cm resection: bile acid spillage into colon → secretory diarrhea; responds to cholestyramine

  • 100 cm resection: loss exceeds liver synthetic capacity → fat malabsorption dominates (>20 g steatorrhea); responds to low-fat diet

Small Bowel Bacterial Overgrowth (SIBO)

Mucosal Phase Disorders

Lactase Deficiency

• Primary (adult-type hypolactasia): autosomal recessive; absence of LCT-13910 "persistence" allele
• Secondary: viral, bacterial, or parasitic infections; intestinal mucosal diseases
• Mechanism: undigested lactose acts as osmotic substance drawing fluid into the lumen; colonic bacteria ferment lactose producing H₂, CO₂, methane, causing bloating and pain
• Symptoms: diarrhea, abdominal pain, gassiness, bloating after dairy ingestion

Celiac Disease (Celiac Sprue / Gluten-Sensitive Enteropathy)

• Diarrhea, weight loss, growth failure in children
• Isolated iron-deficiency anemia (duodenal disease)
• Bloating, irregular bowel habits, migraine headaches, ataxia
• Osteoporosis, abnormal liver enzymes
• Proximal small intestine primarily affected

1. Screening: TTG-IgA (test of choice) + serum IgA level (to detect false negatives from IgA deficiency)
2. If IgA deficient: TTG-IgG or anti-deamidated gliadin peptide (DGP-IgG)
3. Confirmation: Endoscopy with small-intestinal biopsy showing villus blunting, crypt hyperplasia

Postmucosal Phase Disorders

Intestinal Lymphangiectasia

• Primary: congenital or acquired; intrinsic lymphatic dysfunction
• Secondary: retroperitoneal fibrosis, fibrosing mesenteritis, lymphoma, Fontan physiology, constrictive pericarditis, congestive heart failure
• Result: malabsorption + protein-losing enteropathy

Protein-Losing Enteropathy

1. Mucosal ulceration (exudation across damaged mucosa): ulcerative colitis, GI carcinomas
2. Non-ulcerated mucosa with altered permeability: celiac disease, Ménétrier's disease
3. Lymphatic dysfunction: primary lymphatic disease or secondary obstruction (enlarged nodes, cardiac disease)

Clinical Manifestations of Malabsorption (Table 336-5)

Evaluation of the Patient with Suspected Malabsorption

History

• Abdominal pain, diarrhea, weight loss, bloating
• Signs of selective nutrient deficiency: iron-deficiency anemia, bone fractures/osteoporosis (vitamin D/calcium), peripheral neuropathy (B12), hair loss (protein deficiency)
• Predisposing disorders: chronic pancreatitis, liver/biliary disease (primary biliary cholangitis, primary sclerosing cholangitis)
• History of small-bowel resection (Crohn's disease, trauma, ischemia)
• Travel history (tropical sprue, giardiasis)

Physical Examination

• Bitemporal wasting and reduced arm circumference - significant weight loss
• Nail spooning - iron deficiency
• Peripheral neuropathy (sensory reduction, tingling, numbness) - vitamin B12 deficiency

Diagnostic Tests

• 72-hour stool collection for fecal fat: gold standard for steatorrhea
• Serum TTG-IgA for celiac disease screening
• Serum IgA level
• Alpha-1 antitrypsin clearance for protein-losing enteropathy
• Serum albumin, globulins
• CBC (anemia, lymphopenia)
• Serum B12, folate, iron studies, vitamins D, A, E, K (PT/INR)