Stomach
The only organ that deliberately makes a strong acid and then has to survive it — so almost everything on this page is one of two stories: acid winning against a barrier that has been undermined, or decades of inflammation turning the lining into a cancer.
What it normally does
Parietal cells, packed into the glands of the upper two-thirds of the stomach (body and fundus), pump hydrogen ions into the lumen against a millionfold gradient using the H+/K+-ATPase — the proton pump — sitting in the membrane of a deep infolding called the secretory canaliculus. Three signals switch it on: acetylcholine from the vagus (M3 receptors), gastrin from the antrum (CCK2 receptors), and histamine from neighbouring enterochromaffin-like (ECL) cells (H2 receptors). Their wiring is not the same: gastrin's effect on acid is largely indirect, acting mainly on ECL cells to release histamine, which is why histamine is the amplifier of the system; acetylcholine acts directly on M3 receptors on the parietal cell itself (as well as on ECL cells), and vagal fibres also release gastrin-releasing peptide onto antral G cells. Whatever the signal, the pump is the last step. The same cell also makes intrinsic factor, the only carrier that gets vitamin B12 absorbed in the terminal ileum.
Explains why a drug aimed at the pump itself beats any drug aimed at one receptor, why blocking histamine alone still cuts acid substantially (it removes the amplifier the gastrin arm runs through) yet never completely (the direct vagal input survives), and why losing parietal cells costs you B12 as well as acid.
Acid at pH 1-2 with pepsin would digest the stomach itself. What stops it is a stack of defences: a sticky mucus layer holding bicarbonate against the surface so the epithelial cell membrane sits near pH 7, tight junctions between cells, an epithelium that patches damage within minutes to hours, and generous mucosal blood flow to wash away any acid that gets through. Prostaglandins, made locally by cyclo-oxygenase-1 (COX-1), maintain nearly all of it — mucus, bicarbonate, blood flow, repair — and restrain the parietal cell as well.
Explains why an ulcer is usually a defence failure rather than an acid excess, why anti-inflammatories ulcerate the stomach, why shocked and ventilated patients bleed from it, and how misoprostol works.
The stomach is really two organs. The body makes acid; the antrum makes gastrin. G cells in the antral lining release gastrin into the blood when peptides and amino acids arrive and when the vagus fires; gastrin drives ECL and parietal cells and also keeps the acid-secreting mucosa growing (a trophic effect). The off switch is acid itself: once luminal pH drops below about 3, antral D cells release somatostatin, which silences the G cell beside them. Acid turns off its own signal — a negative feedback loop.
Explains why anything that removes acid drives gastrin up, why H pylori sitting in the antrum ends up making too much acid, and what happens when a gastrin-secreting tumour ignores the feedback.
The stomach lining is a wound that never finishes healing. Stem cells in the isthmus and neck of each gland renew the entire surface epithelium every three to five days. That copes with intermittent injury. Sustained inflammation over decades wears the specialised glands away (atrophy) and the stomach replaces them with cells that look like intestine (intestinal metaplasia) — a lining that no longer makes acid and is one step from dysplasia.
Explains how an infection acquired at five becomes a cancer at seventy, and why an atrophic stomach is hypochlorhydric and hypergastrinaemic at the same time.
What goes wrong
- Peptic ulcer disease← from “Parietal cells, packed into the glands of the …”
A break that goes through the muscularis mucosae, where acid and pepsin have beaten the defences. Two causes account for almost all of it: H pylori and NSAIDs. Duodenal ulcers generally sit on too much acid; gastric ulcers generally sit on normal or low acid with a broken barrier. Depth decides the complication — erode into an artery and it bleeds, go through the full thickness and it perforates, scar beside the pylorus and it obstructs.
Two causes: H pylori and NSAIDs. Duodenal wakes them at night and eats to feel better; gastric hurts when they eat, so they lose weight. Posterior bleeds, anterior perforates. Every gastric ulcer gets biopsied and re-scoped, because cancer looks exactly like an ulcer.
You would find: Gnawing epigastric pain. Duodenal: hunger pain that wakes them at 2 am and settles with food or an antacid. Gastric: pain that arrives with eating, so they stop eating and lose weight. Bleeding shows as haematemesis or black tarry melaena with a urea raised out of proportion to creatinine. A posterior duodenal ulcer erodes the gastroduodenal artery and bleeds hard; an anterior one perforates, giving sudden rigid abdomen and free gas under the diaphragm on an erect chest X-ray. Vomiting old food with a succussion splash means gastric outlet obstruction. Alarm features — weight loss, dysphagia, anaemia, persistent vomiting, new dyspepsia over 50 — mean endoscopy, not a trial of tablets.
- Helicobacter pylori infection← from “The stomach is really two organs. The body mak…”
A spiral, flagellated bacterium that lives in the mucus layer rather than inside cells. Its urease splits urea into ammonia and carbon dioxide, buffering its immediate surroundings so it survives an acid nobody else tolerates; the ammonia and the inflammation it provokes damage the lining. It then goes one of two ways. Antral-predominant infection reduces antral D cells and somatostatin, the brake on gastrin is released, acid output rises, and the acid load delivered into the duodenum drives gastric metaplasia in the duodenal bulb, which H pylori then colonises — duodenitis, and duodenal ulcer. Body-predominant infection inflames the acid-secreting glands themselves, so acid falls and atrophy sets in — the road to gastric cancer.
Urease is the whole story: survival in acid, the breath test, and the ammonia that injures the mucosa. Antral disease means more acid and a duodenal ulcer; body disease means less acid, atrophy and cancer.
You would find: Usually nothing: most infected people never get an ulcer. Diagnose with a urea breath test or faecal antigen — the breath test works by feeding the patient labelled urea and catching the organism's own urease at work in the exhaled labelled CO2. Serology only says they met it once. Both active tests go falsely negative on acid suppression, so stop a PPI for two weeks and antibiotics (and bismuth) for four weeks before testing. Australian adult prevalence is roughly one in five, concentrated in older people and those born overseas, and it is far higher in Aboriginal and Torres Strait Islander communities — over half of adults in some remote settings — which is much of why gastric cancer falls on them harder and younger.
- NSAID and aspirin ulceration← from “Acid at pH 1-2 with pepsin would digest the st…”
NSAIDs block COX-1 and remove the prostaglandins that were maintaining mucus, bicarbonate, blood flow and epithelial repair. The dominant damage is delivered through the bloodstream, not the lumen, so enteric-coated tablets, suppositories and intravenous doses all cause it. Aspirin blocks COX irreversibly and low doses are enough. Being weak acids, these drugs also cross the mucus layer un-ionised in the acid lumen and then ionise and become trapped inside the near-neutral epithelial cell, adding a direct local injury on top.
Enteric coating protects the tablet, not the stomach — the injury arrives through the blood. No pain does not mean no ulcer. The definitive treatment is stopping the drug.
You would find: Classically silent until it bleeds, because the same drug blunts the pain. The typical patient is older, on low-dose aspirin or a regular anti-inflammatory for arthritis, presenting with melaena or a haemoglobin of 70 g/L and no ulcer history at all. The ulcers are usually gastric and in the antrum. Risk multiplies with age over 65, previous ulcer, co-existing H pylori, corticosteroids, anticoagulants, SSRIs, or a second NSAID stacked on the first.
- Gastric adenocarcinoma← from “The stomach lining is a wound that never finis…”
Decades of H pylori gastritis run a stepwise sequence: chronic inflammation, then atrophy, then intestinal metaplasia, then dysplasia, then carcinoma. Smoking, high salt and preserved or smoked foods push it along. That is the intestinal type, which forms a mass or a malignant ulcer. A separate diffuse type, more often in younger patients and linked to loss of the adhesion protein E-cadherin (CDH1), forms no mass at all: single signet-ring cells infiltrate the wall and stiffen the whole stomach (linitis plastica).
Iron deficiency anaemia in a man or a postmenopausal woman is an endoscopy, not an iron script. New dyspepsia over 50, or a gastric ulcer that has not healed on repeat scope, is cancer until biopsy says otherwise.
You would find: Nothing early, which is why it presents late — weight loss, early satiety, epigastric pain that only partly answers a PPI, or iron deficiency anaemia from slow oozing. Feel for a hard left supraclavicular node (Virchow), an umbilical nodule (Sister Mary Joseph), a craggy liver edge. Diagnosis is endoscopy with biopsy; a linitis plastica stomach can look near-normal but fails to distend when the endoscopist insufflates. Around 2,500 Australians are diagnosed each year and five-year survival is around a third. Incidence and mortality are roughly double in Aboriginal and Torres Strait Islander people, who also present younger.
- Autoimmune atrophic gastritis and pernicious anaemia← from “Parietal cells, packed into the glands of the …”
Autoantibodies (and T cells) directed at the parietal cell H+/K+-ATPase destroy the body and fundal glands, and anti-intrinsic-factor antibodies block what intrinsic factor remains, so two things are lost together. Without intrinsic factor, B12 cannot be absorbed in the terminal ileum, and after three to five years hepatic stores run dry. Without acid, antral D cells never get the signal to release somatostatin, so gastrin climbs unopposed; its trophic drive expands ECL cells into small type 1 gastric neuroendocrine tumours, and the atrophic body mucosa carries a raised risk of adenocarcinoma. Acid is also needed to free iron from food and reduce it to the absorbable ferrous form, so iron deficiency arrives as well.
No parietal cells means no intrinsic factor and no acid: B12 deficiency plus a sky-high gastrin. Replace B12 before folate, or you can unmask the cord signs.
You would find: Macrocytic anaemia with hypersegmented neutrophils and a low B12, often mixed with iron deficiency so the MCV comes back deceptively normal. Sore, smooth, beefy tongue. The neurology is the part that may not reverse: symmetrical numbness and tingling, lost vibration and proprioception, and the classic mixed picture of absent ankle jerks with an upgoing plantar (knee jerks may be brisk or absent) — subacute combined degeneration of the cord. Anti-intrinsic-factor antibody is specific, parietal cell antibody sensitive but not specific; gastrin is high and pepsinogen I low. Look for the company it keeps — Hashimoto thyroiditis, type 1 diabetes, vitiligo.
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.
- Binds
- The H+/K+-ATPase on the canalicular membrane of the parietal cell. The drug is a prodrug: absorbed in the small intestine, it circulates as an inactive weak base and is trapped and converted to a reactive sulfenamide only in a strongly acidic space — which in the body means the canaliculus of a parietal cell that is actively secreting.
- Which does
- The activated drug forms a covalent bond with cysteine residues on the pump. That pump is finished for good; acid secretion returns only as the cell manufactures new pumps over the following day or two.
- So you see
- Gastric pH sits above 4 for most of the day. Ulcers heal over four to eight weeks, and a clot on a bleeding ulcer holds, because platelet aggregation fails below about pH 6 and pepsin digests a fresh clot at lower pH still — which is why the target is a pH held above 6.
- And the same mechanism causes
- Most of the problems follow from a stomach with no acid. Acid is the first barrier to swallowed organisms, so enteric infections become more likely, and Clostridioides difficile rates rise (its spores are acid-resistant, so here the shift in flora matters as much as the pH itself). Acid is needed to release B12 from food protein, to reduce iron to its absorbable ferrous form and to dissolve poorly soluble calcium salts — hence B12 and iron deficiency and a modest fracture signal with long use. Hypomagnesaemia is a real and occasionally severe PPI effect, but do not reason it from pH: it comes from impaired active magnesium uptake in the intestine, not from lack of acid. And no acid means no somatostatin brake, so gastrin rises and the parietal cell mass grows under its trophic drive; stop a long-term PPI abruptly and that expanded mass gives rebound acid hypersecretion with symptoms that can be worse than the original complaint, which is much of why patients struggle to get off them and why it is tapered.
- Handling
- Plasma half-life is about an hour but the effect lasts more than a day, because the pump is destroyed rather than occupied — blood levels tell you nothing about effect. It can only reach pumps that are switched on, so it is taken 30-60 minutes before a meal; given to a fasting patient it does far less. Full effect takes three to five days as the pump population turns over.
Catches people out: A PPI settles the symptoms of a gastric cancer just as neatly as those of an ulcer. New dyspepsia over 50, or any alarm feature, means endoscopy first. And stop it two weeks before a urea breath test or faecal antigen or you will call an infected patient clear.
- Binds
- The G protein-coupled histamine H2 receptor on the parietal cell, bound competitively and reversibly.
- Which does
- Less Gs-coupled adenylyl cyclase activity, so less cAMP and less protein kinase A signalling; fewer proton pumps are trafficked into the canalicular membrane and those already there work less hard.
- So you see
- Acid output falls, most obviously the histamine-driven basal secretion that runs overnight, and symptoms ease within an hour. Within days the response fades as the receptor upregulates — genuine tolerance, and a real difference at the bedside.
- And the same mechanism causes
- H2 receptors are not confined to the stomach. The ones in the brain explain confusion and delirium in frail older patients, especially when the drug accumulates in renal impairment. Cimetidine's gynaecomastia, galactorrhoea and impotence are not H2 effects at all — it separately blocks androgen receptors and inhibits cytochrome P450, which is why it was superseded.
- Handling
- Famotidine is largely renally cleared, so the dose comes down in kidney impairment — which is precisely the patient in whom it accumulates.
Catches people out: Fast relief, but tolerance develops within days and the acid suppression never matches a PPI. Ranitidine was withdrawn in Australia in 2020 over nitrosamine (NDMA) contamination, and nizatidine and cimetidine are no longer marketed here — famotidine is effectively the only H2 antagonist in current Australian practice.
- Binds
- Amoxicillin binds bacterial penicillin-binding proteins; clarithromycin binds the 50S ribosomal subunit; metronidazole is reduced inside the organism to a nitro radical. The PPI's target is the host's own proton pump, used here to make the niche survivable for the antibiotics.
- Which does
- Peptidoglycan cross-linking fails, bacterial protein synthesis stops, and bacterial DNA is fragmented — the organism is killed where it lives, under the mucus.
- So you see
- Around 85-90% cure when the organism is susceptible and the patient completes the course, and lower than that where clarithromycin resistance is common. Duodenal ulcer recurrence falls from most patients within a year to a few per cent.
- And the same mechanism causes
- Wiping out commensal gut flora alongside the target gives the nausea, diarrhoea and thrush most patients report, and occasionally C difficile colitis. Metronidazole is held to inhibit aldehyde dehydrogenase — the mechanism is debated, but the product advice to avoid alcohol during and just after the course stands, as flushing, vomiting and headache are reported — and it leaves a metallic taste. Clarithromycin inhibits CYP3A4, pushing up statin, colchicine and warfarin levels, and prolongs the QT interval.
- Handling
- Given as a combination pack for 7 to 14 days. Adherence is the single biggest determinant of success, and the packs are deliberately blister-packed by day for that reason.
Catches people out: Clarithromycin resistance is climbing in Australia and is the commonest reason a course fails — never re-use it after a failed attempt. Always confirm cure with a urea breath test at least four weeks after finishing and two weeks off the PPI, rather than assuming it worked.
- Binds
- EP3 receptors on the parietal cell, plus EP4 and EP2 receptors on surface mucous cells and mucosal blood vessels.
- Which does
- On the parietal cell, Gi coupling lowers cAMP so fewer pumps operate. On surface cells, prostaglandin signalling raises mucus and bicarbonate output, opens up mucosal blood flow and speeds epithelial repair.
- So you see
- The barrier is rebuilt at the same time as acid falls, so NSAID ulcers are prevented in patients who have to keep taking the NSAID.
- And the same mechanism causes
- The same EP receptors sit on intestinal and uterine smooth muscle. In the gut they drive secretion and motility, giving dose-related cramping and diarrhoea in roughly a quarter of patients. In the uterus they cause contraction and cervical ripening: misoprostol is abortifacient, and is contraindicated in pregnancy for precisely the reason obstetrics uses it — medical termination, induction of labour, and postpartum haemorrhage.
- Handling
- Short-acting, so it must be taken with each NSAID dose — several times a day — which is another reason adherence is poor.
Catches people out: Never give it to a woman who could be pregnant without a negative test and reliable contraception. Its obstetric uses are the same mechanism, not a surprise.
Two questions answer most stomach vignettes. First: H pylori or NSAID? Between them they cause nearly every peptic ulcer, and the treatment is to remove the cause, not just the acid. Second: ulcer or cancer? Iron deficiency anaemia in a man or a postmenopausal woman, new dyspepsia over 50, or any alarm feature goes to endoscopy before it goes on a PPI — and every gastric ulcer is biopsied and re-scoped. Then remember the test trap everybody falls into: a urea breath test or faecal antigen taken while the patient is on a PPI is falsely negative, so stop it two weeks first.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.