Portal circulation
Every drop of blood from gut and spleen goes through the liver before it goes anywhere else. Scar the liver and that blood forces open old back-doors — so the patient bleeds, swells and becomes confused.
What it normally does
All blood leaving stomach, intestine, pancreas and spleen goes to the liver first, not straight to the heart. The superior mesenteric and splenic veins join behind the neck of the pancreas to form the portal vein, carrying roughly 1000-1200 mL/min and about 75% of the liver's blood supply (but only about half its oxygen). Ammonia is fed into the urea cycle, gut bacteria are taken up by Kupffer cells, and absorbed drugs are metabolised here before anything reaches the systemic circulation (first-pass metabolism).
Explains hepatic encephalopathy and spontaneous bacterial peritonitis — when this blood bypasses the liver, gut ammonia and gut bacteria arrive in the circulation undetoxified.
The normal liver is a low-resistance sponge. Portal pressure is 5-10 mmHg and the pressure difference across the liver (hepatic venous pressure gradient, HVPG) is under 5 mmHg. That small gradient is the only thing driving flow, and the portal system has no valves anywhere.
Explains portal hypertension — anything that stiffens the sinusoids raises the gradient, and with no valves the blood can simply reverse and flow away from the liver (hepatofugal flow).
At four sites, portal tributaries touch systemic veins (portosystemic anastomoses): the lower oesophagus (left gastric to azygos), around the umbilicus (paraumbilical to superficial epigastric veins), the anorectum (superior rectal to middle and inferior rectal), and the bare area and retroperitoneum. In health these channels carry almost nothing.
Explains varices and caput medusae — these are pre-existing doors, not new vessels. Raised portal pressure just forces them open.
Liver sinusoids are leaky (fenestrated, no basement membrane), so the liver is the body's single largest source of lymph — around 1 L a day, a quarter to a half of everything in the thoracic duct. The liver also makes all of the body's albumin, and its Kupffer cells strip out the bacteria and bacterial products (endotoxin) that translocate from the gut into portal blood.
Explains ascites — raised sinusoidal pressure pushes lymph production past what the thoracic duct can carry, while unfiltered gut bacterial products drive splanchnic vasodilation and switch the kidney into salt-retention mode.
What goes wrong
- Portal hypertension (usually from cirrhosis)← from “The normal liver is a low-resistance sponge. P…”
Fibrous bands and regenerative nodules distort the sinusoids, and activated stellate cells contract around them, so resistance rises — worsened by a relative shortage of nitric oxide inside the sinusoids, where the endothelium is dysfunctional. Then the second hit, out in the splanchnic bed: bacterial products translocating from a leaky gut are no longer cleared by the liver, and together with increased shear stress they upregulate endothelial nitric oxide synthase in the mesenteric vessels. The nitric oxide is therefore made locally rather than escaping past the liver — it survives only seconds, so it never travels as a circulating hormone. The mesenteric arterioles dilate and push more blood into a system that already cannot drain. Resistance up, flow up, pressure up.
Two mechanisms, not one: scarring raises resistance and splanchnic vasodilation raises flow. That is why treatment attacks both ends. Note the nitric oxide paradox — too little inside the liver, too much in the splanchnic bed. HVPG at or above 10 mmHg is clinically significant portal hypertension, the threshold for varices and decompensation; bleeding essentially requires 12 mmHg or more.
You would find: A big spleen with a low platelet count is often the first hint — the congested spleen pools platelets, so platelets under 150 x 10^9/L with splenomegaly should make you think portal pressure. Then ascites, dilated abdominal wall veins, and a measured HVPG above 10 mmHg. In Australia the causes are alcohol, metabolic dysfunction-associated fatty liver disease (MASLD) and hepatitis B and C; chronic hepatitis B and alcohol-related liver disease fall disproportionately on Aboriginal and Torres Strait Islander communities, where chronic hepatitis B prevalence runs around three times the national rate.
- Oesophageal varices and variceal haemorrhage← from “At four sites, portal tributaries touch system…”
Blood in the left gastric vein cannot get through the liver, so it reverses into the submucosal veins of the lower oesophagus and escapes into the azygos vein. Those veins sit directly under thin mucosa with little supporting tissue. Wall tension rises with both radius and pressure and falls with wall thickness (Laplace), so the more they dilate the closer they get to rupture.
Left gastric vein to azygos vein — that single anastomosis is the one that kills people. Screening gastroscopy at diagnosis for anyone with cirrhosis, with one modern exception: compensated patients whose liver stiffness is under 20 kPa and platelets above 150 x 10^9/L are unlikely enough to have varices needing treatment that endoscopy can be deferred (Baveno criteria). Note that anorectal varices are portal, but ordinary haemorrhoids are not.
You would find: Sudden, painless vomiting of large volumes of blood and black tarry stool in someone with the stigmata of chronic liver disease. Bleeding is often torrential; even with modern care roughly 15-20% die within six weeks of an episode.
Sinusoidal pressure rises, lymph production outstrips what the thoracic duct can carry, and fluid weeps off the liver surface into the peritoneum. At the same time splanchnic vasodilation drops the effective arterial blood volume; the kidney reads this as hypovolaemia and switches on renin-angiotensin-aldosterone, sympathetic outflow and ADH. Sodium and water are retained and go straight into the abdomen. Low albumin from a failing liver makes it worse but is not the main driver.
Cirrhotic ascites is a sodium-retention problem, not simply a low-protein problem. That is why the mainstay is salt restriction plus an aldosterone blocker, not albumin infusions (albumin has its own narrow uses — after large-volume paracentesis, in spontaneous bacterial peritonitis and in hepatorenal syndrome).
You would find: Distension, shifting dullness, steady weight gain. Tap it: a serum-ascites albumin gradient (SAAG) of 11 g/L or more indicates portal hypertension as the cause with about 97% accuracy, while less than 11 g/L points elsewhere — peritoneal tuberculosis or malignancy.
- Hepatic encephalopathy← from “All blood leaving stomach, intestine, pancreas…”
Colonic bacteria generate ammonia from protein and urea. Normally the portal vein delivers it straight to hepatocytes and the urea cycle disposes of it. With shunting past the liver and failing hepatocytes it reaches the brain, where astrocytes mop it up by converting glutamate to glutamine. Glutamine is osmotically active, the astrocytes swell, and neurotransmission falters — with inflammation and sedative-like endogenous compounds adding to it.
It is a clinical diagnosis. A blood ammonia level does not grade severity and should not be used to follow treatment; a normal level in an untreated patient should instead make you doubt the diagnosis and look harder for another cause of the confusion. Find the trigger and fix that.
You would find: Reversed sleep-wake cycle and personality change early; a flapping tremor of the outstretched hands (asterixis) and inability to copy a five-pointed star later. Always hunt the precipitant — a GI bleed (a large protein load sitting in the gut), infection, constipation, dehydration or electrolyte disturbance from over-diuresis, or sedatives.
- Spontaneous bacterial peritonitis← from “All blood leaving stomach, intestine, pancreas…”
Gut bacteria cross a leaky bowel wall into mesenteric lymph nodes and portal blood. Kupffer cells lining the sinusoids normally strip them out; with shunting and a cirrhotic liver they are not cleared, and ascitic fluid — poor in complement and opsonins — makes an excellent culture medium.
No perforation and no surgical source: the organism walked through the bowel wall and was never filtered. Tap before antibiotics, then treat immediately — a third-generation cephalosporin such as ceftriaxone or cefotaxime is the usual empirical choice, checked against local guidelines and resistance patterns, with intravenous albumin to reduce the risk of hepatorenal syndrome.
You would find: Often silent. Any patient with cirrhosis and ascites who deteriorates in any way — fever, abdominal pain, new confusion, worsening kidney function — gets a diagnostic tap. An ascitic neutrophil count of 0.25 x 10^9/L (250/mm3) or more makes the diagnosis, culture or no culture.
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
- Beta-1 and beta-2 adrenoceptors, blocked together (both G-protein coupled). Carvedilol additionally blocks alpha-1 adrenoceptors.
- Which does
- Beta-1 blockade at the SA node and myocardium slows the heart and drops cardiac output, so less blood arrives at the gut. Beta-2 blockade on splanchnic arterioles removes the dilating signal and leaves alpha-1 constriction unopposed, narrowing the vessels that fill the portal vein. Carvedilol's alpha-1 blockade adds a third action inside the liver, relaxing the contractile elements that raise sinusoidal resistance.
- So you see
- Portal inflow falls, the pressure gradient across the liver falls, and fewer patients bleed. A cardioselective drug like metoprolol does not work here — the splanchnic half of the effect is the beta-2 half, and that is exactly what selectivity removes.
- And the same mechanism causes
- The same beta-2 receptors sit on bronchial smooth muscle, so blocking them narrows airways — dangerous in asthma. Carvedilol's alpha-1 blockade adds systemic vasodilation, so hypotension is its dose-limiting effect.
- Handling
- In advanced disease with tense ascites the blood pressure is being held up by cardiac output and systemic vasoconstriction; beta-1 blockade plus alpha-1 blockade can then drop perfusion pressure and starve the kidney, so titrate to blood pressure rather than to a fixed dose. Beta blockade also flattens the tachycardia that would otherwise tell you a patient is bleeding.
Catches people out: Asthma and other reversible airways disease. In decompensated disease, systolic blood pressure under about 90 mmHg, sodium under 130 mmol/L, or acute kidney injury are reasons to reduce or withhold — refractory ascites is a reason for low doses and close review rather than an automatic ban, which is a change from older teaching.
- Binds
- V1 vasopressin receptors on vascular smooth muscle. Terlipressin is a prodrug, cleaved slowly to lysine-vasopressin, which is why it can be given as intermittent injections rather than an infusion.
- Which does
- V1 is Gq-coupled: phospholipase C, then IP3, then calcium release, then calcium-calmodulin activation of myosin light chain kinase. The arteriole constricts.
- So you see
- Mesenteric inflow drops within minutes, portal pressure falls with it, and the variceal bleeding slows enough to get the patient safely to endoscopy.
- And the same mechanism causes
- V1 receptors are not confined to the gut, so the same constriction hits coronary, digital and mesenteric vessels — angina, cold dusky fingers, and at worst ischaemic bowel.
- Handling
- There is enough V2 cross-activation to retain free water, so sodium falls; check it, because a fast drop can cause seizures.
Catches people out: Ischaemic heart disease and peripheral vascular disease.
- Binds
- The mineralocorticoid receptor inside principal cells of the late distal tubule and collecting duct — an intracellular steroid receptor, not one on the surface.
- Which does
- Aldosterone normally binds this receptor and drives transcription of epithelial sodium channels and the sodium-potassium pump. Spironolactone sits in the receptor and blocks that transcription, so fewer sodium channels reach the luminal membrane. Note that amiloride, often grouped with it as 'potassium-sparing', plugs the sodium channel directly and never touches the receptor.
- So you see
- Sodium is lost in the urine and water follows it. Ascites and peripheral oedema shrink and weight falls — daily weight is the measure that matters, not the tape measure.
- And the same mechanism causes
- The mineralocorticoid receptor is one of a family of steroid receptors and spironolactone is not fussy: it also antagonises the androgen receptor, so men get tender gynaecomastia and loss of libido. Eplerenone binds the mineralocorticoid receptor far more selectively and causes much less of this, though not none.
- Handling
- Less sodium reabsorbed means a smaller lumen-negative gradient to drive potassium into the urine, so potassium rises — check it. Diuresing faster than the ascites can refill the circulation empties the intravascular space and precipitates kidney injury or encephalopathy, so aim for gradual weight loss and watch renal function and sodium.
Catches people out: Existing hyperkalaemia, or combination with ACE inhibitors, angiotensin receptor blockers and potassium supplements.
- Binds
- No human receptor at all. Lactulose is a synthetic galactose-fructose disaccharide and no human intestinal enzyme can split it, so it arrives in the colon intact and is fermented by the resident bacteria.
- Which does
- Fermentation produces lactic and acetic acid. The falling luminal pH converts ammonia (NH3, which crosses membranes freely) into ammonium (NH4+, which does not), trapping nitrogen in the stool. The undigested sugar also holds water osmotically and speeds transit, leaving less time for absorption and shifting the flora away from urease-producing organisms.
- So you see
- Two or three soft stools a day, and confusion and asterixis clear over hours to days.
- And the same mechanism causes
- Bacterial fermentation makes gas, so the patient gets bloating, cramps and flatulence — the process that works is the process that hurts.
- Handling
- Overshoot gives watery diarrhoea, a dropping circulating volume and a rising sodium (free water is lost faster than salt), and that alone will precipitate encephalopathy again. Titrate to stool frequency, not to a number on a chart.
Catches people out: Suspected bowel obstruction. Galactosaemia.
Almost nothing in the portal hypertension cabinet treats the diseased liver itself. Propranolol works on the heart and splanchnic arterioles, terlipressin on the mesenteric arteriole, spironolactone on the distal nephron, lactulose in the colon — they manage the consequences of a pressure gradient they largely cannot reach. The partial exception is carvedilol, whose alpha-1 blockade does lower intrahepatic resistance as well. The things that change the gradient itself are removing the cause (alcohol abstinence, treating hepatitis B or C, weight loss in MASLD), which can genuinely regress fibrosis, bypassing the liver with a TIPS shunt, or transplantation. TIPS lowers portal pressure but causes new or worse encephalopathy in roughly a quarter to a third of patients, because it does deliberately what the varices were doing by accident.
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