Liver
One organ does the body's protein synthesis, its drug metabolism, its ammonia disposal and its bilirubin excretion, and it does all of it on blood that has already passed through the gut — so when it scars you get bleeding, confusion, jaundice and ascites at once, and most of the drugs that treat it act somewhere other than the liver.
What it normally does
The liver makes the proteins that hold water inside blood vessels and stop bleeding. It makes about 10-15 g of albumin a day, which generates most of the oncotic pressure in plasma (half-life about 20 days). Hepatocytes make every clotting factor except von Willebrand factor (endothelium and platelets) and factor VIII, which comes mainly from liver sinusoidal endothelial cells rather than hepatocytes and so stays normal or high in liver disease. Factors II, VII, IX and X and the anticoagulant proteins C and S need vitamin K to be finished off (gamma-carboxylation), and factor VII has the shortest half-life of the lot — about 4-6 hours [hepatic synthetic function].
Explains why the INR is the first number to move in acute liver injury and is used to grade it, why albumin falls only in chronic disease, why cirrhotic patients leak fluid into the abdomen, why a normal or high factor VIII helps separate liver failure from DIC, and why warfarin works at all.
Everything absorbed from the gut meets the liver before it meets the rest of the body (first pass). Hepatocytes deal with drugs and toxins in two steps: phase I, mostly cytochrome P450 oxidation, which often produces a more reactive intermediate; then phase II conjugation — glucuronidation, sulfation, or attachment of glutathione — which makes it water-soluble enough to leave in bile or urine. Phase II pathways are saturable [hepatic drug metabolism].
Explains paracetamol poisoning, why the same dose of a drug hits harder in cirrhosis, and why enzyme inducers and inhibitors change the effect of a drug you did not touch.
Old red cells are broken down and their haem becomes bilirubin — about 300 mg (roughly 500 micromol) a day. It starts fat-soluble (unconjugated), travels stuck to albumin and cannot be filtered by the kidney. The liver conjugates it with glucuronic acid using the enzyme UGT1A1, which makes it water-soluble, then actively pumps it into bile (MRP2). That pumping step is the slowest step in the whole chain. In the gut, bacteria turn it into urobilinogen and then stercobilin, which is what makes stool brown [bilirubin conjugation and excretion].
Explains the three patterns of jaundice, why obstruction gives dark urine AND pale stools while haemolysis gives neither, and why Gilbert syndrome is harmless.
The liver sits in series between the gut and the rest of the body. About three-quarters of its blood arrives through the portal vein at low pressure (roughly 5-10 mmHg) and passes through leaky, low-resistance sinusoids. On the way through, the liver converts gut-derived ammonia into urea (the complete urea cycle runs essentially only in hepatocytes), metabolises oestrogen and aldosterone made elsewhere, and its resident macrophages (Kupffer cells) strip out bacteria and endotoxin coming from the bowel [portal circulation and hepatic clearance].
Explains why scarring raises portal pressure and opens collateral veins, why ammonia rises and confuses the brain, why cirrhotic men grow breasts and get spider naevi, and why circulating aldosterone stays high and fills the abdomen with fluid.
What goes wrong
- Cirrhosis and portal hypertension← from “The liver sits in series between the gut and t…”
Years of injury — alcohol, fat (metabolic dysfunction-associated steatotic liver disease, MASLD, formerly NAFLD), or chronic hepatitis B or C — activate stellate cells in the space of Disse to lay down collagen. The soft, leaky sinusoids become stiff scarred channels and the architecture is replaced by regenerative nodules. Two things follow. First, resistance to portal flow rises, so portal pressure climbs and blood finds collateral routes back to the systemic circulation: oesophageal and gastric varices, caput medusae, anorectal varices (which are distinct from ordinary haemorrhoids). Second, splanchnic arterioles dilate (nitric oxide) so the effective circulating volume the kidney senses falls; renin-angiotensin-aldosterone switches on, and the diseased liver can no longer clear the aldosterone the adrenal is now pouring out. Sodium and water are retained, and with a low albumin and a high portal pressure that fluid sits in the peritoneum as ascites.
Cirrhosis is two problems at once: a plumbing problem (high portal pressure, varices, ascites, splenomegaly) and a factory problem (low albumin, high INR, high bilirubin, encephalopathy). Every complication you can name belongs to one column or the other. Ascitic fluid with neutrophils above 250 x 10^6/L is spontaneous bacterial peritonitis and needs antibiotics, whatever the patient looks like.
You would find: Shifting dullness and a fluid thrill, spider naevi above the nipple line, palmar erythema, gynaecomastia and testicular atrophy, leuconychia from low albumin. Bloods: low albumin, high INR, low platelets (splenic sequestration plus low thrombopoietin — often the earliest hint), bilirubin rising late. Ultrasound with elastography or a FibroScan estimates stiffness without a biopsy. Severity is scored by Child-Pugh (bilirubin, albumin, INR, ascites, encephalopathy) or MELD (bilirubin, INR, creatinine, with sodium in MELD-Na), and both are built out of the physiology above. In Australia alcohol, MASLD and hepatitis C are the main drivers; chronic liver disease mortality and alcohol-related liver disease fall disproportionately on Aboriginal and Torres Strait Islander communities, alongside a chronic hepatitis B prevalence several times the national figure.
- Hepatic encephalopathy← from “The liver sits in series between the gut and t…”
Gut bacteria and protein digestion generate ammonia, which is normally trapped and converted to urea on its first pass through the liver. In cirrhosis two things defeat that: hepatocyte mass is reduced, and portal blood is shunted straight into the systemic circulation through collaterals, bypassing the liver entirely. Ammonia reaches the brain, where astrocytes mop it up by combining it with glutamate to make glutamine. Glutamine is osmotically active, so astrocytes swell and stop supporting neurotransmission — in acute liver failure that same swelling becomes frank cerebral oedema. Precipitants all work by increasing the ammonia load or reducing clearance: a gastrointestinal bleed (a large protein meal in the gut), constipation, infection, dehydration and hypokalaemia or alkalosis from over-diuresis, and sedatives the failing liver cannot clear.
Encephalopathy is almost never spontaneous. Find the trigger: bleed, sepsis, constipation, diuretics, sedation. Treating the trigger does more than treating the ammonia.
You would find: Reversed sleep-wake cycle and altered personality before anything dramatic. Asterixis (the flapping tremor of an outstretched hand), constructional apraxia, fetor hepaticus. Grade it clinically with West Haven. Plasma ammonia is useful in acute liver failure (very high values track cerebral oedema) but does not grade chronic encephalopathy — do not chase the number in a cirrhotic patient, look for the precipitant instead.
- Jaundice — sorting the three patterns← from “Old red cells are broken down and their haem b…”
Yellow skin means bilirubin has banked up, and where it banked up tells you which step failed. Before the liver (prehepatic): haemolysis or ineffective erythropoiesis floods the system with unconjugated bilirubin faster than UGT1A1 can conjugate it. Because unconjugated bilirubin is albumin-bound and fat-soluble, none of it appears in urine. In the liver (hepatocellular): hepatitis or cirrhosis damages the cells that both conjugate and excrete, giving a mixed picture. After the liver (posthepatic): a stone or a tumour blocks the duct, so conjugated bilirubin — already water-soluble — regurgitates into blood and is filtered into urine, while none reaches the gut. Gilbert syndrome is a reduced-activity UGT1A1 promoter variant present in roughly 5-10% of people: mild unconjugated jaundice that appears with fasting, illness or exercise and means nothing.
Bilirubin in the urine can only be conjugated bilirubin, so bilirubinuria excludes a purely prehepatic cause. And a coagulopathy that corrects after vitamin K is obstruction (no bile salts, so no absorption of fat-soluble vitamin K); one that does not correct is hepatocellular failure.
You would find: Sclerae yellow at a bilirubin around 50 micromol/L (normal below 20). Ask two questions: what colour is the urine and what colour is the stool. Dark urine plus pale stool plus itch equals obstruction — and the enzyme pattern follows, with ALP and GGT out of proportion to ALT. ALT and AST in the hundreds or thousands with normal-ish ALP means hepatocellular. Normal urine and normal stool with a raised unconjugated bilirubin and normal enzymes means haemolysis or Gilbert — check the reticulocytes and the haptoglobin. Painless obstructive jaundice with weight loss is pancreatic head cancer until disproved.
- Viral hepatitis B and C← from “The liver makes the proteins that hold water i…”
Neither virus is directly cytopathic in the usual case — the damage is done by cytotoxic T cells killing infected hepatocytes, which is why the transaminases rise. Acutely that releases ALT and AST and disturbs conjugation and excretion enough to cause jaundice. Hepatitis B becomes chronic in under 5% of infected adults but in around 90% of infants, because an immature immune system tolerates it: this is why perinatal transmission matters and why vaccination at birth matters more. Hepatitis C becomes chronic in about three-quarters. Decades of low-grade immune killing and repair drive the stellate cell fibrosis of pathology 0, and both viruses can cause hepatocellular carcinoma — hepatitis B can do it without cirrhosis, because it integrates into host DNA.
ALT measures injury; bilirubin and INR measure function. A patient with an ALT of 4000 and a normal INR is being hurt. A patient with a falling ALT and a rising INR is failing — the transaminases can drop simply because there are fewer hepatocytes left to leak.
You would find: ALT in the hundreds to thousands with a mixed jaundice and dark urine. Serology is the exam: HBsAg means the virus is present now; anti-HBs with no core antibody means vaccine-induced immunity; anti-HBc IgM means recent or acute infection; anti-HBc IgG with anti-HBs means past resolved infection — core antibody is what separates the vaccinated from the recovered, since natural clearance leaves both antibodies while the vaccine leaves only anti-HBs. For hepatitis C, anti-HCV says exposed, HCV RNA says currently infected. Australian context: universal infant hepatitis B vaccination since 2000, chronic hepatitis B concentrated in migrant and Aboriginal and Torres Strait Islander communities, and hepatitis C concentrated in people who inject or have injected drugs.
- Paracetamol hepatotoxicity and acute liver failure← from “Everything absorbed from the gut meets the liv…”
At normal doses about 90% of paracetamol is disposed of by phase II conjugation (glucuronidation and sulfation) and only a few per cent goes through CYP2E1 to the reactive intermediate NAPQI, which is immediately mopped up by glutathione. In overdose the conjugation pathways saturate, so far more paracetamol is pushed down the CYP2E1 route, and once glutathione stores drop below about 30% the unquenched NAPQI binds covalently to hepatocyte proteins and kills the cell. The damage is centrilobular (zone 3) because that is where CYP2E1 is densest and oxygen tension lowest. Chronic alcohol induces CYP2E1 and malnutrition depletes glutathione, so both shift the balance the wrong way.
Phase I makes the poison, phase II detoxifies it. Overdose is simply phase II running out. That single sentence gives you the mechanism, the antidote and the risk factors.
You would find: Nothing to see for the first 24 hours except nausea — the patient looks well while the injury is under way, which is exactly why the paracetamol level and the timing matter more than the examination. Day 2-4: right upper quadrant pain, ALT into the thousands, INR climbing, then jaundice, hypoglycaemia (no glycogen, no gluconeogenesis), lactic acidosis and encephalopathy. Acute liver failure is defined by encephalopathy plus coagulopathy in someone without pre-existing liver disease. Paracetamol overdose is the commonest single cause of acute liver failure in Australia; management uses a timed plasma level against the treatment nomogram, and the King's College criteria (pH, INR, creatinine, encephalopathy) flag who needs a transplant unit.
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
- No receptor. It is a cysteine donor: cysteine is the rate-limiting building block for glutathione synthesis.
- Which does
- Hepatocyte glutathione is regenerated, so NAPQI is conjugated and safely excreted instead of binding to cell proteins. At high concentrations acetylcysteine also directly conjugates NAPQI, supports the sulfation pathway, and improves mitochondrial oxygen use and microvascular flow — which is why it still helps once injury is established.
- So you see
- Started within 8 hours of ingestion it prevents hepatotoxicity almost completely. Started late it does not undo dead cells, but it reduces mortality in acute liver failure. Because the antidote is safe and the injury is silent, treatment is started on risk and stopped later if the level says it was unnecessary.
- And the same mechanism causes
- Anaphylactoid reactions — flushing, urticaria, wheeze — in a substantial minority, usually in the first hour. This is direct concentration-dependent histamine release from mast cells, not an IgE allergy, which is why it happens on first-ever exposure and why slowing the infusion usually fixes it. Calling it an allergy and withholding the antidote is the error to avoid.
- Handling
- The decision to treat rests on a timed plasma paracetamol level plotted against the treatment nomogram, or on the story alone when the timing is unknown or the ingestion staggered — a toxicology decision, taken from the current Australian and New Zealand poisoning guideline or the Poisons Information Centre, not from a page.
Catches people out: Vomiting is common in overdose and hides nothing; the well-looking patient at 12 hours is the dangerous one. Activated charcoal only helps very early.
- Binds
- No human enzyme can split lactulose, so it reaches the colon intact and becomes a substrate for colonic bacteria.
- Which does
- Bacterial fermentation produces lactic and acetic acid, dropping colonic pH. Ammonia (NH3, which diffuses across membranes) is protonated to ammonium (NH4+, which does not), so it is trapped in the lumen. The acid environment also shifts the flora away from urease-producing organisms, and the osmotic load speeds transit so there is less time to absorb what is made.
- So you see
- Ammonia load falls, the patient wakes up over a day or two. It is titrated against bowel actions — the endpoint is a couple of soft stools a day, not a blood test.
- And the same mechanism causes
- The same osmotic pull that traps ammonia pulls water into the gut. Overshoot and you get cramps, flatus and watery diarrhoea, and then hypovolaemia, hypernatraemia and hypokalaemia — every one of which precipitates the encephalopathy you were treating (low potassium in particular drives the kidney to make more ammonia). The commonest way to make hepatic encephalopathy worse is too much lactulose.
- Handling
- Underdosing is just as common: a constipated cirrhotic patient with confusion usually needs the bowels opened, not a sedative.
Catches people out: Rifaximin, a non-absorbed antibiotic that reduces ammonia-producing gut bacteria, is added for recurrent episodes — again acting in the bowel, not the liver.
- Binds
- The mineralocorticoid receptor, an intracellular steroid receptor in principal cells. Note that amiloride, often filed alongside these drugs as 'potassium-sparing', is not a receptor antagonist at all — it plugs the epithelial sodium channel directly, downstream of the receptor.
- Which does
- Aldosterone can no longer switch on transcription of epithelial sodium channels and Na/K-ATPase, so sodium reabsorption falls and, because sodium entry drives the electrical gradient for potassium secretion, potassium is retained instead of lost.
- So you see
- Sodium and water are excreted and ascites recedes. The response takes several days because the mechanism is transcriptional, not a channel block — do not expect the immediate diuresis a loop diuretic gives.
- And the same mechanism causes
- Two, both straight from the mechanism. Hyperkalaemia, because the drug's whole action is to stop potassium being secreted — dangerous with an ACE inhibitor, an ARB, or in kidney impairment. And gynaecomastia with breast tenderness in men and menstrual disturbance in women, because spironolactone is a steroid-shaped molecule that also blocks the androgen receptor; in cirrhosis this lands on top of the oestrogen excess the liver already fails to clear. Eplerenone is far more selective for the mineralocorticoid receptor and largely spares this.
- Handling
- Diuresis is limited by how fast ascitic fluid can move back into the circulation. Push harder than that and you empty the vascular compartment instead of the abdomen, and the result is acute kidney injury and hepatorenal syndrome.
Catches people out: Non-selective beta blockers (propranolol; carvedilol, which adds alpha-1 blockade) are the other cirrhosis drug that acts elsewhere: they lower portal pressure by reducing cardiac output and, through unopposed alpha constriction in the splanchnic bed once beta-2 is blocked, reducing portal inflow. Bronchospasm follows from the same beta-2 blockade, and in advanced ascites the loss of compensatory tachycardia can drop blood pressure and renal perfusion.
- Binds
- Non-structural viral proteins: NS5B, the RNA-dependent RNA polymerase (sofosbuvir is a nucleotide analogue that chain-terminates it); NS5A, a replication-complex assembly protein (the -asvir drugs); and NS3/4A protease (the -previr drugs).
- Which does
- Viral replication stops within days. Because these targets exist only in the virus, there is no equivalent human enzyme to hit — which is why these drugs are so well tolerated compared with the interferon they replaced.
- So you see
- Sustained virological response — undetectable HCV RNA 12 weeks after finishing — is a cure. The immune attack stops, transaminases normalise, and fibrosis can partially regress.
- And the same mechanism causes
- The predictable trouble is not the antiviral effect but the traffic jam in drug handling. Glecaprevir and pibrentasvir inhibit the OATP1B1 transporter and P-glycoprotein that carry statins into hepatocytes and limit their absorption, so statin concentrations rise steeply and myopathy follows. Sofosbuvir with amiodarone can cause severe symptomatic bradycardia. Every hepatitis C prescription is a drug interaction check.
- Handling
- Because these regimens are handled by the liver, the choice of combination changes in decompensated cirrhosis — protease inhibitors such as glecaprevir are contraindicated there.
Catches people out: Two traps. Curing hepatitis C in someone who already has cirrhosis does not end the risk of hepatocellular carcinoma, so six-monthly ultrasound surveillance continues. And in a patient who also carries hepatitis B, removing hepatitis C can allow hepatitis B to reactivate — screen for both before starting. Hepatitis B itself is not cured: entecavir and tenofovir suppress it by inhibiting the reverse transcriptase activity of its polymerase, usually long term.
ALT tells you hepatocytes are being injured; bilirubin and INR tell you whether the liver still works — a falling ALT with a rising INR means fewer cells left to leak, not improvement. Two derived rules: bilirubin in the urine must be conjugated, so bilirubinuria rules out a purely prehepatic jaundice; and a coagulopathy that corrects with vitamin K is biliary obstruction (no bile salts, no fat-soluble vitamin absorption), while one that does not correct is hepatocellular failure.
Now test whether it stuck
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