Appearance
9.4 — The Liver
The liver performs over 500 known functions. It is the only internal organ that can regenerate — remove 70 percent of it and it grows back to full size within weeks. It is your largest internal organ at 1.5 kilograms, it receives about a quarter of your cardiac output, and it processes essentially everything you eat, drink or swallow before the rest of your body sees it.
It is also almost silent until it is badly damaged, which is why liver disease is so often diagnosed late.
Position and blood supply
In the right upper abdomen, under the diaphragm, protected by the lower ribs.
A normal liver is not palpable below the ribs. Feeling a liver edge means it is enlarged or pushed down, and it is one of the standard things checked in an abdominal examination.
Two blood supplies, which is unusual and important.
The hepatic artery brings oxygenated blood — about 25 percent of the flow but most of the oxygen.
The portal vein brings blood from the gut, spleen and pancreas — about 75 percent of the flow, low in oxygen but carrying everything absorbed from your last meal.
So the liver sees every absorbed substance before the rest of your body does. This is the first-pass effect, and it is why some drugs are almost useless taken by mouth (Chapter 7.5), and why the liver is the organ most exposed to anything toxic you swallow.
Both supplies mix in the sinusoids and drain into the hepatic veins and then the inferior vena cava.
The dual supply is also why the liver tolerates arterial occlusion reasonably well and why liver metastases, which are supplied almost entirely by the hepatic artery, can be treated by blocking that artery selectively while the normal liver survives on portal flow.
The microscopic arrangement
The functional unit is the lobule — a roughly hexagonal arrangement of hepatocytes in plates one or two cells thick, radiating out from a central vein.
At each corner sits a portal triad: a branch of the hepatic artery, a branch of the portal vein, and a bile duct.
Blood flows from the corners inward to the central vein. Bile flows the opposite way, from the centre outward to the ducts. Two fluids moving in opposite directions through the same tissue, in separate channels.
The sinusoids — the capillaries between the plates of cells — are lined by a discontinuous endothelium with large gaps. There is no basement membrane and no barrier. Plasma has direct contact with the hepatocyte surface, which is exactly what an organ processing the blood needs.
Kupffer cells are macrophages sitting in the sinusoids, clearing bacteria arriving from the gut. They form a large part of the body's total macrophage population, and they are the reason gut bacteria that enter the portal blood do not reach the general circulation.
Zonation matters clinically. Cells near the portal triads get the most oxygen; cells near the central vein get the least.
So the central zone is the first to die when oxygen delivery falls — in shock or heart failure, producing "centrilobular necrosis". And the central zone contains most of the drug-metabolising enzymes, which is exactly why paracetamol overdose damages that zone specifically.
What the liver does
Ten categories, and the reason to know them is that liver failure produces a symptom from almost every one.
1. Carbohydrate metabolism. Stores glucose as glycogen (about 100 g, Chapter 1.2), releases it between meals, and manufactures glucose from amino acids and glycerol when the store runs out.
This is why severe liver failure causes hypoglycaemia, and why it is checked urgently in anyone with liver failure who becomes confused.
2. Fat metabolism. Makes cholesterol and triglycerides, packages them into lipoproteins, produces ketone bodies during fasting, and makes bile.
3. Protein metabolism. Makes almost all plasma proteins — albumin, all the clotting factors except one, and the transport proteins.
Two clinical consequences follow immediately. Low albumin causes oedema and ascites (Chapter 7.1). And the liver's failure to make clotting factors causes bleeding — which is why the prothrombin time is one of the best measures of how well a liver is actually working. Albumin has a half-life of about 20 days, so it reflects chronic function; clotting factors have half-lives of hours to days, so they reflect acute function.
4. Nitrogen disposal. Amino acid breakdown produces ammonia, which is toxic to the brain. The liver converts it to urea for excretion by the kidney (Chapter 10.2).
When the liver fails, ammonia accumulates and causes hepatic encephalopathy — confusion progressing to coma, with a characteristic flapping tremor of the outstretched hands.
5. Detoxification. The cytochrome P450 system (Chapter 1.5) handles drugs, alcohol, hormones and toxins in two phases: chemical modification, then attachment of a water-soluble group so the kidney can excrete it.
6. Bilirubin processing. Takes up bilirubin from red cell breakdown, conjugates it to make it water-soluble, and excretes it in bile (Chapter 7.1).
7. Storage. Vitamins A, D, E, K and B12; iron; copper. The liver holds enough vitamin B12 for several years, which is why deficiency takes so long to appear.
8. Immune function. The Kupffer cells above.
9. Hormone clearance. Inactivates insulin, thyroid and steroid hormones.
This explains two signs of chronic liver disease that are otherwise puzzling. Failure to clear oestrogen produces breast enlargement and testicular atrophy in men, and spider naevi — small red vascular spots on the upper body — and palmar erythema, reddened palms.
10. Bile production — 600 to 1,000 ml a day.
Bile and the gallbladder
Bile contains bile salts, bilirubin, cholesterol, phospholipids and electrolytes.
Bile salts are made from cholesterol and are the detergents that emulsify fat (Chapter 9.3). This is also the body's main route for eliminating cholesterol.
The gallbladder stores and concentrates bile between meals, holding 30 to 50 ml and concentrating it five to tenfold by absorbing water.
When fat enters the duodenum, the hormone cholecystokinin is released, the gallbladder contracts, and the sphincter at the duct opening relaxes.
You can live without a gallbladder. Bile simply drips continuously into the duodenum instead of being delivered in a bolus. Most people notice nothing; some have looser stools or difficulty with very fatty meals, which usually settles over months.
Gallstones affect 10 to 15 percent of adults in Western countries, and about 80 percent are cholesterol stones, forming when bile contains more cholesterol than the bile salts can keep dissolved.
The classic risk factors are traditionally taught as the five Fs — female, forty, fertile, fat, fair — which is crude but broadly reflects the real associations: female sex, increasing age, pregnancy, obesity, and rapid weight loss.
Most gallstones cause no symptoms at all and need no treatment. This is worth emphasising, because incidental gallstones found on a scan frequently cause unnecessary alarm.
When they do cause trouble, where the stone lodges determines the illness:
Biliary colic — a stone temporarily blocking the outlet during gallbladder contraction. Severe pain in the right upper abdomen, often radiating to the right shoulder blade, coming on after a fatty meal, lasting minutes to hours and then settling. No fever.
Cholecystitis — the stone stays stuck and the gallbladder becomes inflamed and infected. Constant pain, fever, and marked tenderness. Treated with antibiotics and, usually, removal of the gallbladder.
Choledocholithiasis — a stone in the common bile duct. Bile cannot drain, so the person becomes jaundiced with pale stools and dark urine.
Ascending cholangitis — infection of the obstructed duct. Fever, jaundice and right upper abdominal pain together — Charcot's triad — is a medical emergency, because bacteria under pressure enter the bloodstream directly. It needs antibiotics and urgent drainage of the duct.
Gallstone pancreatitis — a stone lodging where the bile and pancreatic ducts join (Chapter 9.3).
Jaundice
Yellow discolouration of the skin and the whites of the eyes from raised bilirubin. Visible above about 40 to 50 µmol/L, roughly two to three times normal. The eyes yellow first, because the sclera binds bilirubin readily.
Three categories, and distinguishing them is done largely from the history and two simple observations.
Pre-hepatic — too much bilirubin being produced, from haemolysis. The liver is fine but overwhelmed. The bilirubin is unconjugated, so it cannot be excreted in urine — the urine stays normal in colour.
Hepatic — the liver cells are damaged and cannot process it. Hepatitis, cirrhosis, drugs.
Post-hepatic (obstructive) — the bile cannot get out. Gallstone, tumour, stricture.
And this one produces a recognisable triad: dark urine, pale stools, and itching.
Each has a mechanism worth knowing. The conjugated bilirubin is water-soluble, so when it cannot reach the gut it backs up into the blood and is excreted by the kidney — hence dark urine. None reaches the intestine, so the pigment that normally colours stool is absent — hence pale stools. And bile salts accumulate in the skin — hence the itching, which can be severe and is often the most distressing symptom.
Painless jaundice with weight loss in an older person is pancreatic cancer until proven otherwise, because a tumour in the head of the pancreas compresses the bile duct.
Neonatal jaundice is common and usually harmless. The newborn liver's conjugating enzyme is immature, and red cells are being broken down rapidly as fetal haemoglobin is replaced. Most cases resolve without treatment.
Phototherapy works by a genuinely elegant mechanism: blue light converts bilirubin in the skin into a water-soluble isomer that can be excreted without needing the liver enzyme at all. The liver problem is bypassed entirely.
The concern is kernicterus — bilirubin crossing into the brain and causing permanent damage — and it is what phototherapy and, rarely, exchange transfusion prevent. Jaundice appearing in the first 24 hours of life, or persisting beyond two weeks, needs assessment, whereas jaundice appearing on day 3 and settling is typical.
Liver disease
The liver has enormous reserve. Standard liver function tests can be normal with substantial disease, and symptoms often appear only when a large proportion of function is lost.
"Liver function tests" is partly a misnomer. ALT and AST are enzymes released by damaged cells — they measure injury, not function. Albumin, bilirubin and the prothrombin time measure actual function.
Cirrhosis — the end point of chronic injury from any cause. Repeated damage and repair replaces liver tissue with scar, and the architecture is destroyed.
Two consequences follow, and they explain every complication.
Loss of function — low albumin, clotting failure, jaundice, encephalopathy.
Portal hypertension — blood cannot flow through the scarred liver, so pressure rises in the portal vein. The blood then finds alternative routes back to the heart, and those routes become engorged.
Oesophageal varices — dilated veins at the lower oesophagus, which can bleed catastrophically. Ascites — fluid in the abdominal cavity, from high portal pressure plus low albumin. Splenomegaly — an enlarged spleen, which traps platelets and lowers the count. Caput medusae — visible dilated veins radiating from the navel.
Causes of cirrhosis: alcohol, chronic hepatitis B and C, non-alcoholic fatty liver disease, autoimmune disease, haemochromatosis (iron overload) and Wilson's disease (copper overload).
Non-alcoholic fatty liver disease is now the commonest liver disease in the developed world, affecting perhaps 25 percent of adults, driven by obesity and insulin resistance. Most cases never progress, but a minority develop inflammation and then fibrosis.
And it is largely reversible. Weight loss of 7 to 10 percent substantially improves and can resolve the inflammation, which makes it one of the more encouraging conditions in this chapter — a common serious disease with an effective non-drug treatment.
Hepatitis viruses are Chapter 17.10, and there the news is genuinely good: hepatitis C is now curable in over 95 percent of cases with 8 to 12 weeks of well-tolerated tablets, having been an incurable progressive disease a decade ago, and hepatitis B is preventable by vaccination.
Regeneration and transplant
The liver's regenerative capacity is unique among internal organs. Remove up to 70 percent and the remainder grows back to the original mass within 4 to 8 weeks.
Strictly it is compensatory growth rather than true regeneration — the remaining lobes enlarge rather than the removed ones regrowing — but the functional result is the same.
This makes living donor liver transplantation possible: a donor gives part of their liver, and both donor and recipient regrow to normal size.
And it is why paracetamol overdose is survivable if treated in time. The antidote, acetylcysteine, replenishes the liver's glutathione stores so the toxic metabolite is neutralised. Given within 8 hours it is close to completely effective; after 24 hours much less so. Chapter 23.6.
Cirrhosis is the limit. Once the architecture is destroyed by scar, regeneration produces nodules rather than functioning tissue, and it does not reverse.
Transplantation is the treatment for end-stage disease, with one-year survival around 90 percent and ten-year survival around 60 to 70 percent — figures that would have seemed impossible when the first liver transplant was performed in 1963.
What the next page fixes
The bile and pancreatic secretions have been described in passing throughout. Chapter 9.5 gives them their own treatment — how bile is made and recycled, what the exocrine pancreas produces and how it protects itself, and what happens when the shared duct system fails.