Nutrient handling: where absorption happens

What it normally does

• Carbohydrate and protein are finished off and absorbed at the surface of the small bowel. The lining is folded, then villous, then carpeted in microvilli (brush border), giving roughly 30 m² of working surface. Enzymes sit on that brush border — lactase, sucrase-isomaltase, maltase-glucoamylase, peptidases — and hand the products straight to transporters beside them: glucose and galactose on a sodium-coupled carrier (SGLT1), fructose on a facilitated one (GLUT5), amino acids and di- and tripeptides on their own carriers (including PepT1). Most of this is done by mid-jejunum, so the distal small bowel is spare capacity (reserve length).

  Explains why oral rehydration fluid must contain glucose AND sodium — SGLT1 moves the two together and water follows the osmotic gradient, so glucose-free salt solution rehydrates poorly; why damage to the proximal lining takes out lactase first, because it is the most vulnerable of the brush border enzymes, producing bloating and osmotic diarrhoea after dairy; and why losing distal small bowel is tolerated far better than losing proximal.

• Fat will not dissolve in water, so it needs two things made outside the bowel wall. Pancreatic lipase (with colipase) splits triglyceride into fatty acids and monoglyceride; bile salts from the liver wrap those into tiny water-soluble parcels (micelles) that ferry them to the duodenal and jejunal brush border. Vitamins A, D, E and K ride in those same parcels. Absorbed long-chain fat is repackaged into chylomicrons and leaves in lymph, not portal blood — medium-chain fatty acids are the exception and go straight into portal blood without needing micelles. The bile salts themselves are reclaimed further down, in the terminal ileum, and recycled through the liver several times a day (enterohepatic circulation).

  Explains why greasy stool with low A, D, E and K points first at the pancreas or the bile supply — and why the discriminator is the company it keeps: severe mucosal disease (untreated coeliac, giardiasis, bacterial overgrowth, short bowel) also causes steatorrhoea, but it drags iron, folate or B12 down with it, whereas a pure lipase or bile problem leaves them alone. Also explains why removing the terminal ileum can starve the bile salt pool and cause fat malabsorption from a completely normal jejunum, and why medium-chain triglyceride is the fat that still gets absorbed when bile is missing.

• Iron is absorbed in one short stretch — the duodenum and the very top of the jejunum — and essentially nowhere else. Only the ferrous form (Fe2+) crosses on the apical carrier DMT1, and dietary ferric iron needs stomach acid and a brush border reductase (duodenal cytochrome b) to get there; haem iron from meat crosses by a separate route, still not fully worked out, and is absorbed several times more efficiently. The body has no regulated way of excreting iron — it leaks only through shed cells and bleeding — so absorption is the only control point. The liver hormone hepcidin binds and closes ferroportin, the exit door on the far side of the enterocyte, trapping iron in a cell that is shed into the stool a few days later. Inflammation drives hepcidin up.

  Explains iron deficiency after gastrectomy or bariatric surgery, on long-term acid suppression, and in coeliac disease; explains the anaemia of inflammation and why oral iron cannot fix it; and explains why iron overload happens when hepcidin signalling fails (haemochromatosis).

• Vitamin B12 needs a four-step relay. Acid and pepsin free it from food protein in the stomach; it binds haptocorrin, a carrier from saliva and gastric juice that protects it in an acid environment; pancreatic proteases strip that carrier off in the duodenum; it then binds intrinsic factor made by the gastric parietal cells, and the intrinsic factor–B12 complex is taken up by one specific receptor (cubam, cubilin plus amnionless) in roughly the last 60 cm of ileum, and nowhere else. The liver holds two to five years of stores. Folate is quite different: absorbed proximally in the jejunum, with stores that last only weeks to months.

  Explains how four completely different lesions — no acid, no parietal cells, no pancreatic enzymes, no terminal ileum — all end in the same macrocytic anaemia; why B12 deficiency appears years after a gastrectomy while folate deficiency appears within months of a poor diet, pregnancy or heavy alcohol use.

What goes wrong

• Coeliac disease← from “Carbohydrate and protein are finished off and …”

  In people carrying HLA-DQ2 or DQ8, gluten peptides deamidated by tissue transglutaminase are presented to T cells, and the resulting immune attack damages the proximal small bowel lining. Villi flatten (villous atrophy), crypts lengthen, and lymphocytes infiltrate the surface layer. Absorptive area and brush border enzymes are lost from the top down — exactly where iron, folate and calcium are handled — while the ileum is spared, so B12 usually stays normal and calorie absorption is often maintained. Severe extensive disease can still cause steatorrhoea, but it does so alongside a low iron and folate, not instead of them.

  Proximal villous atrophy: iron, folate and calcium go first because that is the duodenum and jejunum; B12 is normal because that is the ileum. tTG IgA plus total IgA, on gluten. There is no drug — the treatment is lifelong gluten avoidance.

  You would find: About 1 in 70 Australians, most still undiagnosed. Iron deficiency anaemia that does not respond to oral iron is a classic presentation, with bloating, loose stool, low ferritin and folate, early bone loss, and sometimes an intensely itchy blistering rash on elbows, knees and buttocks (dermatitis herpetiformis). Test tissue transglutaminase IgA together with a total IgA, while the person is still eating gluten — selective IgA deficiency is over-represented in coeliac and gives a false negative. Duodenal biopsy on a gluten-containing diet confirms, with multiple samples including the duodenal bulb. Screen in type 1 diabetes and autoimmune thyroid disease. Many patients are a normal weight or overweight, so body habitus does not exclude it.

• Exocrine pancreatic insufficiency← from “Fat will not dissolve in water, so it needs tw…”

  The gland is destroyed or its duct blocked — chronic pancreatitis from alcohol, cystic fibrosis, pancreatic head cancer, or pancreatectomy. Reserve is enormous, so symptoms appear only once about 90% of enzyme output is gone. Fat malabsorption dominates, and for two reasons: pancreatic lipase is acid-labile and is inactivated in a duodenum that the failing pancreas can no longer alkalinise, and the only back-up, gastric lipase, handles a modest share of dietary fat and cannot make up the shortfall, whereas starch also meets salivary amylase and protein also meets gastric and brush border proteases. So carbohydrate and protein absorption limp on while undigested triglyceride passes into the colon, and the vitamins that travel in micelles never get delivered.

  Fat malabsorption with a normal iron, folate and B12 means lipase or bile, not mucosa. Low faecal elastase makes the diagnosis. A raised INR that corrects with vitamin K is vitamin loss, not liver failure.

  You would find: Pale, oily, foul-smelling stool that floats and is hard to flush, weight loss despite a good appetite, and the fat-soluble vitamin picture — night blindness (A), bone pain and low vitamin D, easy bruising with a prolonged INR that corrects with vitamin K. Faecal elastase-1 is low. Cystic fibrosis is the usual cause in children; alcohol-related chronic pancreatitis in adults.

• Terminal ileal disease or resection (Crohn disease)← from “Vitamin B12 needs a four-step relay. Acid and …”

  Crohn disease has a strong preference for the terminal ileum, and surgery for it removes the same segment. That one segment does two jobs, so both fail together: the cubam receptors that take up intrinsic factor–B12, and the recovery of bile salts. Lose a short length (under roughly 100 cm) and bile salts spill into the colon, where they drive the mucosa to secrete water and speed transit — watery diarrhoea, but the liver replaces the loss and fat absorption holds. Lose more and synthesis cannot keep up: the bile salt pool shrinks, the diarrhoea turns fatty, and A, D, E and K fall. Unabsorbed fat also grabs calcium in the lumen, leaving oxalate free to be absorbed by a colon that bile salts have made more permeable to it, and deposited in the kidney. B12 falls last, once the liver store finally runs down.

  The terminal ileum does two things — B12 and bile salts — and both go together. Short segment lost: watery bile-salt diarrhoea. Long segment lost: steatorrhoea, low A, D, E and K, and oxalate kidney stones.

  You would find: A young adult with right iliac fossa pain, diarrhoea, weight loss, mouth ulcers and perianal disease. Later: macrocytic anaemia with a low B12 and a perfectly normal stomach. Watery diarrhoea after ileal resection that settles within days on a bile acid sequestrant. Renal colic from calcium oxalate stones — note this needs an intact colon, so it does not happen after colectomy with an ileostomy.

• Pernicious anaemia and the loss of intrinsic factor← from “Vitamin B12 needs a four-step relay. Acid and …”

  Autoimmune atrophic gastritis destroys the parietal cells of the gastric body, with antibodies against the cells themselves and against intrinsic factor. No intrinsic factor means B12 cannot be picked up in the ileum however healthy that ileum is. Surgery reproduces it: total gastrectomy removes the intrinsic factor source outright, while partial gastrectomy, sleeve gastrectomy and Roux-en-Y bypass cut parietal cell mass and acid enough to produce the same deficiency more slowly. Long-standing atrophic gastritis, Helicobacter pylori and prolonged acid suppression cause a milder version by blocking only the first step, freeing B12 from food, so synthetic B12 in supplements is still absorbed. Without B12, methionine synthase stalls and DNA synthesis in the marrow fails (megaloblastic change); methylmalonyl-CoA mutase also stalls, and the accumulating methylmalonate — together with the loss of methylation downstream of methionine synthase — is the usual explanation for the damage to myelin in the cord, though the exact step is not settled. Loss of acid also blocks the reduction of dietary iron, so iron deficiency often rides along.

  No intrinsic factor: the ileum is healthy but useless. Megaloblastic anaemia plus dorsal column signs, and the neurology can come first. Always check B12 before giving folate.

  You would find: Pallor with a lemon tinge of jaundice from red cells dying in the marrow (raised LDH, low haptoglobin, low reticulocytes), a sore smooth tongue, macrocytosis and hypersegmented neutrophils on the film. Then the neurology: numb feet, lost vibration and joint position sense, unsteady with eyes closed (subacute combined degeneration of the dorsal columns and corticospinal tracts). The neurology can arrive before the anaemia, and can occur with a normal MCV. Intrinsic factor antibody is specific but misses about half of cases, so a negative result does not exclude pernicious anaemia; parietal cell antibody is the reverse — sensitive but not specific. Achlorhydria drives gastrin up, and the condition carries a raised long-term risk of gastric adenocarcinoma and type 1 gastric carcinoid.

• Iron deficiency anaemia — reading it back to the duodenum← from “Iron is absorbed in one short stretch — the du…”

  Either the duodenum cannot absorb, or losses outrun what it can take up — around 1 to 2 mg a day ordinarily, and only a few mg at most even when stores are empty. Absorption fails in coeliac disease, after gastrectomy or bariatric surgery, and with the loss of acid from chronic acid suppression or Helicobacter pylori. Losses are usually blood: menstrual, or from the gut. Separately, inflammation raises hepcidin, which shuts ferroportin — so iron taken up by the enterocyte is never exported, and iron recovered by macrophages from old red cells is locked in the same way. The body has iron but cannot move it to the marrow.

  Iron crosses only at the duodenum. Low ferritin means deficient; a ferritin that is normal or high with a low transferrin saturation and a high CRP means hepcidin, not iron in the diet. Unexplained iron deficiency in an adult means scope the gut.

  You would find: Low MCV and MCH, low ferritin. A ferritin under 30 µg/L confirms deficiency. Ferritin is also an acute phase reactant, so with a raised CRP a ferritin up to about 100 does not exclude deficiency — a transferrin saturation under 20% supports it, though saturation is also low in anaemia of inflammation, which is why the CRP has to be read alongside. Fatigue, pica, spoon nails, cracked mouth corners. In an adult male or postmenopausal woman, unexplained iron deficiency is gastrointestinal blood loss until proven otherwise, and that means endoscopy at both ends. Iron deficiency and anaemia fall disproportionately on Aboriginal and Torres Strait Islander children, particularly in remote communities, where measured rates in the under-fives run far above the national figure; the drivers are the cost and availability of fresh food, recurrent infection pushing hepcidin up, and, in northern and central regions, intestinal parasites — Strongyloides remains endemic, and hookworm, though much less common than it once was, still occurs.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.