Liver, biliary system and exocrine pancreas

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Part 1: Liver178

18.1 Inflammation, fibrosis, cirrhosis and liver failure178
18.2 Alcohol- and drug-related liver disease181
18.3 Genetic, metabolic and vascular liver disease182
18.4 Liver tumours183
Part 2: Biliary disease184

18.5 Inflammatory and other non-neoplastic biliary disease184
18.6 Bile duct and gall bladder neoplasia185

Part 3: Exocrine pancreas186

18.7 Inflammatory disease of the pancreas186
18.8 Neoplastic disease of the exocrine pancreas186

Self-assessment: questions187
Self-assessment: answers189

Chapter overview
The liver performs many varied and vital functions. These include: the metabolism of protein, carbohydrate and fat; synthesis of proteins (including albumin, α1-antitrypsin, transferrin and coagulation factors); detoxification of waste products and ingested chemicals; and participation in the reticuloendothelial system. Chronic liver disease, the causes and consequences of which are discussed in this chapter, most frequently results from viral or alcohol-induced injury. Genetic, autoimmune and vascular diseases also affect the liver. Primary hepatocellular carcinoma is uncommon in the UK but is very common in countries with high rates of hepatitis B infection. The liver is a very common site for metastatic malignancy.
The biliary system functions include digestion of dietary fat and excretion of certain metabolites via the bile. While gall bladder stones and inflammation are very common in the Western world, congenital biliary atresia and malignant disease are unusual but clinically important conditions.
The exocrine pancreas produces digestive enzymes, including lipases, amylases and trypsin. These enzymes have a role in pancreatitis, a disease that is usually precipitated by alcohol ingestion or gallstones. Pancreatic adenocarcinoma is a major cause of cancer mortality.

Part 1: Liver

Learning objectives
You should:

• understand the definition, causes and clinical consequences of cirrhosis
• know the natural history of hepatitis B and C infections
• know the pathological effects of alcohol on the liver
• understand how therapeutic drugs can cause liver disease
• understand the range of viral, genetic and autoimmune diseases that can cause chronic hepatitis
• know the epidemiology and pathology of hepatocellular carcinoma.

18.1. Inflammation, fibrosis, cirrhosis and liver failure

The clinical effects of cellular injury in the liver depend on the extent of cell death and the duration of the insult. For example, infection with hepatitis A virus may cause minimal asymptomatic disease, clinically apparent acute hepatitis with jaundice or, very rarely, acute liver failure (Box 25). In virtually every case, liver mass and architecture will be restored once the transient infection is cleared, and there is no residual hepatic damage. However, chronic inflammation in the liver can result in extensive fibrous tissue formation. Scarring may link portal tracts and central veins. Bands of fibrous tissue entrap regenerating nodules of hepatocytes, causing liver cirrhosis (Figure 49). Cirrhosis is the end stage of chronic inflammatory liver disease from numerous causes, including:

• alcohol
• chronic viral hepatitis (B and C)
• biliary disease (primary and secondary biliary cirrhosis)
• haemochromatosis
• idiopathic.
Box 25

Hepatic failure


• drowsiness, confusion, coma
• coarse hand tremor (‘liver flap’)
• fetor hepaticus
Hepatorenal syndrome (renal impairment secondary to liver failure)

Chronic liver disease

Testicular atrophy
Palmar erythema
Dupuytren’s contracture (alcoholic cirrhosis)
Xanthomas (primary biliary cirrhosis)
Spider angiomas (spider naevi)
Raised liver enzymes, coagulopathy, hyponatraemia
Raised serum ammonia in liver failure


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:

• gastro-oesophageal junction (oesophageal varices)
• rectum
• retroperitoneum
• anterior abdominal wall (caput medusae).
There are two serious consequences of this vascular shunting:

• life-threatening haemorrhage from rupture of oesophageal varices
• impaired detoxification of noxious chemicals (e.g. ammonia), contributing to hepatic encephalopathy, coma and death.
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

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.

Infectious hepatitis

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

• asymptomatic subclinical infection with complete resolution
• acute hepatitis
• chronic hepatitis
• asymptomatic carrier state
• hepatic failure (acute or chronic)
• cirrhosis
• hepatocellular carcinoma.

Acute hepatitis

In acute viral hepatitis (Box 26) there may be isolated liver cell necrosis or more severe bridging necrosis between portal tracts and central veins. Portal tracts are inflamed and there are increased numbers of Kupffer cells (sinusoidal macrophages). Swelling, necrosis and regeneration of hepatocytes produces architectural distortion called lobular disarray. All of these changes can revert to normal if infection is cleared.
Box 26

• Symptoms can include fever, fatigue, nausea, anorexia and right upper quadrant pain.
• Mild hepatomegaly may be detected on examination.
• Liver function tests (LFTs) are abnormal, with raised serum liver enzymes.
• If there is conjugated hyperbilirubinaemia, jaundice develops.
• Increased urinary bilirubin excretion produces dark urine, whereas decreased biliary excretion results in pale stools.
• Bile salt retention in the skin causes itching.

Chronic hepatitis

Chronic hepatitis is defined as abnormal LFTs and/or clinical evidence of continuing hepatic inflammation for >6months. The severity of inflammation varies within and between individual cases over time. Bile duct injury, fatty change, portal tract lymphoid aggregates and lobular inflammation are typical features of hepatitis C. Hepatocytes infected with hepatitis B may show ‘ground glass’ pink (eosinophilic) cytoplasm. The fibrosis and hepatocyte regeneration associated with chronic inflammatory damage may develop into cirrhosis.
Chronic hepatitis is not only due to viral infection – drugs, autoimmune disease and certain genetic disorders (see later) can cause very similar histological changes. Reaching the correct diagnosis requires consideration of all the clinical, serological, biochemical and pathological findings.

Carrier state

Disease carriers harbour persistent asymptomatic infection; they may be entirely healthy or have covert subclinical chronic liver disease. A carrier can pass infective virus on to non-immune contacts. Hepatitis B, C and D infections can produce a carrier state.

Hepatic failure, cirrhosis and hepatocellular carcinoma

These have been discussed above. Within the family of specific hepatitis viruses (Table 30), hepatitis B and C are the clinically most important causes.
Table 30 Hepatitis viruses
Hepatic virus Nature of virus Mode of spread Clinical disease
A Single-stranded RNA virus Faecal–oral spread from contaminated food and water, especially seafood Usually self-limiting acute infection
Acute liver failure occurs in <1%
No chronic disease
No carrier state
B Double-stranded DNA virus Vertical (mother to fetus), sexual contact, blood transfusion, intravenous drug misuse Very high rate of carrier state if infected in early life, with frequent chronic hepatitis, cirrhosis and hepatocellular carcinoma
Risk of chronic disease and malignancy is less if infection is acquired in adult life
C Single-stranded RNA virus Blood transfusion (patients with haemophilia) and inoculation (intravenous drug misuse) Up to 85% develop chronic hepatitis; up to 50% of these progress to cirrhosis ± hepatocellular carcinoma ± hepatic failure
D Defective RNA virus only infective in association with HBV Parenteral Can co-infect with HBV (usually recover normally, but risk of severe acute hepatitis is increased) or super-infect a HBV chronic carrier, with greatly increased risk of chronic hepatitis and cirrhosis
E Single-stranded RNA virus Faecal–oral spread from contaminated water Usually self-limiting but 20% mortality rate in pregnant women

Hepatitis B

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

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:

• bacterial – tuberculosis, leptospirosis
• viral – cytomegalovirus (CMV), infectious mononucleosis (EBV)
• parasitic – malaria, amoebiasis.

Liver abscesses

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 hepatitis

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.

18.2. Alcohol- and drug-related liver disease

Alcohol misuse is the major cause of chronic liver disease in the UK. Excessive alcohol intake can cause:

• fatty change (steatosis)
• alcoholic hepatitis
• cirrhosis, ± hepatocellular carcinoma.

Fatty change

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.

Alcoholic hepatitis

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

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:

• non-alcoholic steatohepatitis (diabetes mellitus, obesity, drugs)
• hepatitis C infection
• drugs
• Reye’s syndrome
• acute fatty liver of pregnancy.

Drugs and the liver

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:

• direct toxicity
• conversion of drug to active toxin by liver
• immune-mediated (e.g. drug causes autoantibody production).
Table 31 Drugs and the liver
Liver lesion Examples of drugs responsible
Fatty change Methotrexate, tetracycline
Hepatocyte necrosis Paracetamol, halothane, isoniazid
Hepatitis and fibrosis Methotrexate, amiodarone
Granulomatous inflammation Sulphonamide antibiotics
Cholestasis Chlorpromazine, contraceptive pill
Veno-occlusive disease Cytotoxic drugs
Venous thrombosis Cytotoxic drugs, contraceptive pill
Hepatocellular adenoma Contraceptive pill
Drug damage may be predictable

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