Digestion and absorption

Surface area and sites

Circular folds (of Kerckring), villi and microvilli (the brush border) enlarge the small intestinal surface to roughly 200 m². Villous atrophy therefore causes widespread malabsorption, and the site of disease predicts the deficiency.

• Coeliac disease damages the proximal small bowel most, so iron and folate deficiency are common while B12 (terminal ileum) is usually normal. Recurrent iron deficiency in a young adult should prompt IgA anti-tissue transglutaminase testing while the patient still eats gluten (check total IgA); a gluten-free diet beforehand gives false negatives.
• Terminal ileal resection or Crohn disease causes B12 deficiency and bile salt loss.

Carbohydrates

• Starch is split by salivary and pancreatic amylase to maltose, maltotriose and α-limit dextrins; brush-border lactase, sucrase-isomaltase and maltase produce monosaccharides.
• Glucose and galactose enter by SGLT1 (secondary active transport with Na⁺) and leave by GLUT2. Fructose uses GLUT5 (facilitated diffusion), then GLUT2.
• Oral rehydration solution works because Na⁺–glucose cotransport stays intact in cholera; water follows the absorbed solute.
• Lactase deficiency: undigested lactose is fermented in the colon, giving bloating, flatus and acidic osmotic diarrhoea; hydrogen breath test is positive. Secondary lactase loss follows any injury that flattens the brush border, such as gastroenteritis or coeliac disease in a toddler.

Proteins

• Pepsin starts digestion in the stomach; pancreatic trypsin, chymotrypsin, elastase and carboxypeptidases continue; brush-border aminopeptidases and dipeptidases finish.
• Absorbed as amino acids (several Na⁺-coupled carriers) and, faster, as di- and tripeptides via the H⁺-coupled PepT1; peptides are hydrolysed inside the enterocyte.
• Hartnup disease: defective neutral amino acid (tryptophan) transport, pellagra-like rash. Cystinuria: defective transport of cystine, ornithine, lysine and arginine.

Fats and lipoproteins

• Bile salts emulsify fat; pancreatic lipase with colipase splits triglyceride into 2-monoglyceride and fatty acids.
• Products travel in bile salt micelles to the brush border and diffuse in.
• Enterocytes re-form triglyceride and package it with apolipoprotein B-48 into chylomicrons using microsomal triglyceride transfer protein; chylomicrons enter lacteals and reach blood through the thoracic duct. Blood taken after a fatty meal looks milky because of chylomicrons.
• Short- and medium-chain fatty acids pass directly into portal blood, so medium-chain triglyceride feeds help in fat malabsorption.
• Lipoprotein lipase on capillary endothelium (activated by apoC-II) clears chylomicron triglyceride. Its deficiency causes massive chylomicronaemia: milky fasting plasma, triglycerides above 1,000 mg/dL (11 mmol/L), eruptive xanthomas and recurrent pancreatitis.
• Abetalipoproteinaemia (failure to make apoB-containing lipoproteins): no chylomicrons, VLDL or LDL; fat malabsorption, acanthocytes, and vitamin E deficiency causing ataxia and retinitis pigmentosa.

• Fat-soluble vitamins A, D, E and K are malabsorbed too, giving a prolonged prothrombin time, osteomalacia and night blindness.
• Bile acid diarrhoea: after cholecystectomy or ileal disease, excess bile acids reach the colon and stimulate water and chloride secretion. Colestyramine binds them; give other drugs at a different time because it binds them too.

Iron

• Dietary non-haem iron is mostly ferric (Fe³⁺). Duodenal cytochrome b reduces it to ferrous (Fe²⁺), helped by gastric acid and vitamin C (taking iron with orange juice improves absorption); DMT1 carries it into the enterocyte. Haem iron enters by a separate, more efficient route.
• Inside the cell, iron is either stored as ferritin (lost when the cell is shed) or exported by ferroportin; hephaestin oxidises it to Fe³⁺ for transferrin.
• Hepcidin from the liver binds and degrades ferroportin, blocking export. It rises in inflammation (anaemia of chronic disease) and iron overload, and falls in iron deficiency and hypoxia.
• Hereditary haemochromatosis (HFE C282Y): the liver fails to sense iron stores and makes inappropriately low hepcidin, so absorption continues despite overload. Transferrin saturation rises before ferritin and is the best screening test.
• Phytates, tannins (tea), calcium, antacids, PPIs and gastrectomy reduce absorption. There is no regulated excretion of iron; balance is set at absorption.
• Copper shares this pathway (needed for hephaestin and ceruloplasmin). Copper deficiency (long-term parenteral nutrition, bariatric surgery, zinc excess) causes anaemia, neutropenia and a myelopathy mimicking B12 deficiency with a normal B12.

Vitamin B12

• Liver stores last 3–5 years, so deficiency develops slowly.
• Causes: pernicious anaemia, gastrectomy, ileal resection or Crohn disease, bacterial overgrowth, fish tapeworm, pancreatic insufficiency, strict vegan or vegetarian diet, metformin, long-term PPIs.
• Biochemistry: B12 is a cofactor for methionine synthase (homocysteine to methionine, using methyl-tetrahydrofolate) and methylmalonyl-CoA mutase (methylmalonyl-CoA to succinyl-CoA; odd-chain fatty acids give propionyl-CoA, which needs biotin then B12 to reach succinyl-CoA). Deficiency raises both homocysteine and methylmalonic acid; folate deficiency raises homocysteine alone. A low B12 with raised MMA confirms deficiency.
• Methyl-folate trap: without B12, folate is locked as methyl-tetrahydrofolate and cannot be recycled for DNA synthesis, so B12 deficiency causes functional folate deficiency and megaloblastic anaemia. Folic acid alone bypasses the trap and corrects the anaemia, but the neuropathy (subacute combined degeneration, linked to MMA accumulation and myelin damage) progresses.

Exam trap Never give folic acid alone when B12 deficiency is possible: the blood improves while the cord worsens.

Folate

Absorbed in the jejunum; body stores last only about 3–4 months. Deficiency follows poor diet, alcohol, coeliac disease, pregnancy, haemolysis and drugs (methotrexate and trimethoprim inhibit dihydrofolate reductase; phenytoin impairs absorption). Bacterial overgrowth can raise serum folate because bacteria synthesise it.

Calcium

• Active absorption in the duodenum: apical TRPV6 channels, intracellular calbindin and basolateral Ca²⁺-ATPase, all induced by 1,25-dihydroxyvitamin D (calcitriol). Passive paracellular absorption occurs throughout the bowel. PTH increases absorption indirectly by stimulating renal calcitriol synthesis.
• Absorption rises in growth, pregnancy and lactation; falls with phytates, oxalates and fat malabsorption (calcium soaps).
• Calcium carbonate needs acid to dissolve, so it is poorly absorbed in patients on PPIs or with achlorhydria unless taken with food; calcium citrate dissolves without acid and is preferred.

Water and electrolytes

• About 9 L enters the small bowel daily; water follows solutes, mainly Na⁺. Most is absorbed in the jejunum.
• Crypt cells secrete Cl⁻ through CFTR; villus cells absorb. Cholera toxin ADP-ribosylates Gs, keeping adenylyl cyclase on; cAMP opens CFTR and causes profuse secretory diarrhoea that continues during fasting.
• The colon absorbs Na⁺ through aldosterone-sensitive ENaC and secretes K⁺, so diarrhoea causes hypokalaemia.

Remember Iron and calcium in the duodenum, folate in the jejunum, B12 and bile salts in the terminal ileum.

How FCPS asks about this

• Site of maximal iron absorption: duodenum, as Fe²⁺ via DMT1; vitamin C helps.
• Step of B12 absorption needing pancreatic proteases: release from haptocorrin.
• Confirming B12 deficiency in a vegetarian: low B12 with raised methylmalonic acid.
• Iron and folate deficiency with normal B12 in coeliac disease: proximal bowel bears the damage.
• Continued iron absorption in haemochromatosis: inappropriately low hepcidin.
• Calcium absorption: active in the duodenum under calcitriol; use calcium citrate with PPIs.
• Absent chylomicrons, acanthocytes, ataxia: abetalipoproteinaemia; milky fasting plasma with pancreatitis: lipoprotein lipase deficiency.