Cirrhosis is a diffuse process and the damage is usually irreversible. The scarring disrupts and impairs blood flow through the liver, elevating the portal venous pressure (portal hypertension). As a consequence, blood flow increasingly bypasses the liver and flows through lower resistance vessels that communicate between the portal and systemic circulations. These anastomoses arise at four main sites:

There are two serious consequences of this vascular shunting:

Portal hypertension also causes splenomegaly and contributes to the development of ascites. Portal hypertension can be caused by other lesions that obstruct hepatic blood flow in the absence of cirrhosis, such as portal vein thrombosis and Budd–Chiari syndrome (see Section 18.3).

Cirrhosis is associated with development of hepatocellular carcinoma, although the degree of risk varies with the underlying disease.

Liver failure can be acute or chronic, and results when hepatic functional impairment is extreme. Mortality exceeds 70%. It is often precipitated by an event such as gastrointestinal haemorrhage or infection in a patient with chronic liver disease. Acute liver failure is uncommon, but may follow viral infection, drug exposure (e.g. paracetamol overdose, halothane), toxin damage (carbon tetrachloride), acute fatty liver of pregnancy and Reye’s syndrome (Section 18.3). In acute liver failure without pre-existing hepatic disease, there is extensive liver necrosis with shrinkage of the organ, and clinical features of hepatic failure – clotting deficiencies, jaundice, hepatic encephalopathy – developing over 2–3weeks. Massive liver destruction may prove fatal without transplantation, or cause irregular scarring in survivors.

Viral infection of the liver has various clinical manifestations, according to the specific agent involved:

Hepatitis B infection occurs worldwide, but is extremely common in southeast Asia, where the disease is frequently transmitted from mother to fetus. Exposure early in life creates a permanent carrier state in over 90% of patients. Infection in the UK is usually acquired in adult life, through sexual contact, infected needles (drug misusers and healthcare workers) or an unknown source. Needlestick injury from a hepatitis B carrier confers a 30% risk of infection. The virus is present in blood and body fluids during incubation (which can be up to 6months from inoculation) and during periods of acute liver inflammation. The viral antigens and host antibodies detected in the serum reflect the stage of disease and infectivity of the patient. Core antigen (HbcAg) and the related HBe antigen are infective. The presence of IgM anti-HBc indicates recent infection. As the time period from infection increases, the antibody class switches to IgG. Surface antigen (HbsAg) positivity indicates acute infection or carrier state. HbsAb appears late and indicates immunity.

Hepatitis C prevalence is uncertain, but estimated at between 0.1% and 1% of the UK population. There is an estimated 3% risk of transmission from an infected needlestick injury. Acute infection is asymptomatic in the majority. HCV antibodies are found in many patients with previously unexplained cirrhosis and hepatocellular carcinoma. Liver function tests characteristically fluctuate throughout the course of the disease, and HCV RNA is detectable despite anti-HCV antibodies (the latter do not appear to confer immunity). Liver damage in part appears immunologically mediated. Patients may benefit from immune modulation therapy with interferon. Selection for such treatment is based on histological assessment of the degree of active inflammatory damage and the extent of fibrosis in a liver biopsy specimen.

Other causes of infectious hepatitis include:

Hydatid disease is a systemic infection due to the canine tapeworm Echinococcus. Although uncommon in the UK, hydatid disease occurs worldwide and incidence is increased in sheep- and cattle-farming areas. The liver is frequently involved with formation of single or multiple infected cysts, causing mass effects. There is a risk of disease dissemination or fatal anaphylactic shock if the cyst contents are liberated and care must be taken during surgical removal.

Liver abscess is uncommon in the UK and is usually due to bacterial infection. Organisms reach the liver via the bloodstream, biliary system or direct spread. Abscesses can be single or multiple. Surgical drainage is usually necessary. Parasitic and protozoal abscesses are more common in the developing world.

Autoimmune liver disease typically occurs in young and middle-aged adult females. Patients have a chronic hepatitis, which clinically and histologically resembles viral hepatitis, but serological tests show raised serum IgG and specific autoantibodies. The latter include antinuclear antibodies (ANA), antimitochondrial antibodies (AMA), antismooth-muscle and antimicrosomal antibodies. There is often associated extrahepatic autoimmune disease such as thyroiditis or rheumatoid arthritis.

Fatty change is the accumulation of fat droplets within the cytoplasm of hepatocytes, usually as a single large vacuole (macrovesicular steatosis). The change occurs throughout the liver, and may develop in chronic alcohol misuse or following ‘binge’ drinking in non-habituated individuals. Fatty change is reversible over several days of abstinence, but with repeated attacks, fibrosis can develop.

In alcoholic hepatitis (steatohepatitis) fatty change is accompanied by acute inflammation, with neutrophil polymorph infiltration around degenerate and necrotic hepatocytes. Abnormal liver cells may contain condensed intracytoplasmic proteins, known as Mallory bodies. Alcoholic hepatitis is associated with developing liver fibrosis, which characteristically starts around centrilobular veins. Whereas simple fatty change usually produces no clinical symptoms, patients with alcoholic hepatitis present with right upper quadrant pain and jaundice. Either condition may cause hepatomegaly.

With or without recurrent attacks of alcoholic hepatitis, individuals who maintain a high regular alcohol intake over several years are at risk of progressive fibrosis, cirrhosis and liver failure. Women appear to be at greater risk with a relatively lower alcohol intake. Coexistent liver disease, particularly haemochromatosis and hepatitis C infection, can be important contributory factors in progression to cirrhosis. Current recommendations are for women to drink no more than 14 units of alcohol per week, and men fewer than 21 units. Moderate regular intake seems less harmful than erratic, heavy, binge drinking. Indeed, regular, low ethanol intake seems to have a protective influence in coronary heart disease.

Acute alcohol intoxication causes injury and death through accidents, hypoglycaemia, epilepsy and direct cerebral toxicity. Chronic alcohol misuse can result in pancreatitis, cardiomyopathy, physical dependence, malnutrition and neurological disease (Wernicke–Korsakoff syndrome – confusion, ataxia and ocular disturbances due to thiamine deficiency; if untreated, severe, irreversible amnesia often results).

Hepatic fat accumulation is most frequently seen in association with ethanol but other causes include:

Drugs can cause many morphological changes in the liver; more common examples are shown in Table 31. As the histological features often mimic endogenous liver disease a thorough clinical history is essential. Mechanisms of drug damage are:

Drug damage may be predictable, occurring in any individual who ingests a large enough dose, or idiosyncratic (host dependent).

Haemochromatosis is an autosomal recessive disease with excessive iron storage predominantly in the liver, pancreas, myocardium and synovial joints. The gene involved is on chromosome 6. The heterozygote rate is approximately 10% in the white UK population and the homozygote disease state is relatively common (0.5%). Gene testing can confirm suspected clinical cases of haemochromatosis and can be used to screen other family members for the disease. Men are affected more often than women, possibly due to the ameliorating effect of menstruation in reducing total body iron. Presentation is most frequent in middle-aged adults.

The typical clinical triad consists of cirrhosis, diabetes and skin pigmentation (‘bronze diabetes’). Depending on the stage of disease, liver biopsy in homozygotes shows fibrosis or cirrhosis with excess iron in hepatocytes and Kupffer cells (liver macrophages). Iron is present in the form of haemosiderin pigment and appears yellow-brown on histological examination. A special stain, known as Perl’s stain, gives a bright blue colour to iron deposits and this allows the degree of iron overload to be graded microscopically. Heterozygotes for the abnormal haemochromatosis gene also show increased hepatic iron storage but not sufficient to cause significant tissue damage. The liver shows little inflammation. Cirrhosis occurring in haemochromatosis carries a very high risk of hepatocellular carcinoma, which is the leading cause of death in these patients. Complications of diabetes or of cardiac involvement (arrhythmias, cardiomyopathy) may also prove fatal. Treatment with iron chelators and regular venesection in the precirrhotic phase is successful.

Secondary causes of hepatic iron overload include severe anaemia, repeated blood transfusions and excessive dietary intake linked to use of iron cooking utensils.

α₁-Antitrypsin deficiency is a rare autosomal recessive disease which causes emphysema (see Ch. 15) and hepatic cirrhosis. Liver biopsy shows variably sized, round intracytoplasmic globules of α₁-antitrypsin within hepatocytes, demonstrated by diastase periodic acid–Schiff (PAS) staining (see Box 27). Depending on the exact nature of the allele mutation, α₁-antitrypsin can present in neonates, children or adult life. In severe disease, liver transplantation is curative.

Wilson’s disease is a rare autosomal recessive disorder of copper metabolism, which affects the liver, eye and brain. The incidence is approximately 1 : 200 000. There is a decrease in the serum copper-containing protein caeruloplasmin. Histological examination shows increased hepatic copper, often with quite marked chronic inflammation, fibrosis and fatty change. Presentation can be at any age but is often in adolescents or young adults. Extrahepatic manifestations include a parkinsonian movement disorder, psychiatric symptoms and iris abnormalities (Kayser–Fleischer rings; green-brown copper deposits). If diagnosed early enough, copper chelating drugs are effective. If cirrhosis intervenes, liver transplantation may be considered.

Ascending cholangitis is infection of the biliary tree, usually by Gram-negative gut bacteria. There is often a biliary stone or stricture causing obstruction and stasis, which predispose to infection.

Primary biliary cirrhosis (PBC) is characterised by granulomatous inflammation and destruction of intrahepatic bile ducts. It is an autoimmune condition with female predominance, which peaks in middle age. Symptoms include itching, jaundice and xanthomas (the latter due to cholesterol retention). LFTs show a marked increase in alkaline phosphatase, and autoantibodies to mitochondria. PBC is associated with other autoimmune diseases including Sjögren’s syndrome, thyroiditis and rheumatoid arthritis. Some cases will progress to cirrhosis.

Primary sclerosis cholangitis (PSC) describes chronic inflammation with obliterative fibrosis and segmental dilatation of intra- and extrahepatic bile ducts. As with other causes of bile duct damage, serum alkaline phosphatase is increased. Males are most frequently affected and 70% have coexistent ulcerative colitis. The aetiology of PSC is uncertain. Progressive bile duct obstruction leads to secondary biliary cirrhosis.

Secondary biliary cirrhosis follows prolonged extrahepatic biliary obstruction, most commonly due to gallstone impaction in the common bile duct.

Bile duct damage can also occur in viral hepatitis, drug injury and liver transplant rejection.

Gallstones occur in 20% of the adult population, but most do not cause symptoms. Female gender, increasing age, obesity, high-fat diet, pregnancy and oral contraceptive use are risk factors for the commonest type of stone (cholesterol rich). Stone formation requires supersaturation of cholesterol in bile. Biliary stasis – due to prolonged fasting, pregnancy, rapid weight loss or parenteral nutrition – is a promoting factor. Gallstones rich in pigment material develop in individuals with haemolytic anaemia. Biliary tract infection induces deconjugation of bilirubin, and the concentration of deconjugated bilirubin can exceed the low solubility. Clinical consequences of gallstones include biliary colic, obstructive jaundice and cholecystitis (Figure 50). Gallstones are a major cause of acute pancreatitis.

Acute cholecystitis is usually caused by impaction of a stone in the neck of the gall bladder or the cystic duct. Bile outflow obstruction leads to chemical irritation of the gall bladder mucosa. With increasing distension and intraluminal pressure, blood flow to the gall bladder becomes compromised and ischaemia develops. The microscopic changes are typical of acute inflammation, with oedema and neutrophil polymorph infiltration. Complications of acute cholecystitis include:

• secondary bacterial infection

• gall bladder perforation and abscess formation

• rupture with peritonitis and fistula formation between gall bladder and bowel

• gall bladder infarction.

Recurrent attacks of acute cholecystitis can progress to chronic cholecystitis with fibrosis and mucosal outpouchings into the muscle layer (Rokitansky–Aschoff sinuses). Acute cholecystitis can also occur in the absence of calculi; precipitating factors include dehydration, gall bladder stasis, bile concentration (‘biliary sludge’) and bacterial infection. Such patients are often post operative or have suffered severe trauma, burns, sepsis and multiple organ failure.

Extrahepatic biliary atresia occurs 1 in 100 000 live births. Bile flow is completely obstructed due to destruction or absence of extrahepatic bile ducts in the neonatal period. The aetiology is uncertain – viral infection, genetic inheritance and anomalous embryological development have been suggested. Untreated, cirrhosis will develop within 6months. Surgical correction is not often possible as intra-hepatic ducts are also involved, and transplantation may offer the only chance of survival.

Cholangiocarcinoma is a malignant tumour of either the intrahepatic or extrahepatic bile ducts. Associated factors include:

Cholangiocarcinoma is usually a well-differentiated adenocarcinoma, which induces a large amount of fibrous stroma (desmoplasia), imparting a very hard consistency to the tumour. Prognosis is poor due to local invasion and irresectability.

Carcinoma of the gall bladder is rare; it occurs in the elderly, usually associated with gallstones. Extensive local invasion is common at presentation and these unresectable tumours have a very poor prognosis. The vast majority are adenocarcinomas.