Liver disease

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16 Liver disease

P. Kennedy, J.G. O’Grady

Key points

• The liver is a complex organ central to the maintenance of homeostasis.
• The liver is notable for its capacity to regenerate unless cirrhosis has developed. There are now some data to suggest that cirrhosis is reversible in selected cases, for example treated hepatitis B virus.
• The spectrum of liver disease extends from mild, self-limiting conditions to serious illnesses which may carry significant morbidity and mortality.
• Liver disease is defined as acute or chronic on the basis of whether the history of disease is less than or greater than 6 months, respectively.
• Viral infections and paracetamol overdose are the leading causes of acute liver disease, but a significant number of patients have no defined aetiology (seronegative hepatitis).
• Alcohol abuse and chronic viral hepatitis (B and C) are the major causes of chronic liver disease.
• Cirrhosis may be asymptomatic for considerable periods of time.
• Ascites, encephalopathy, varices and hepatorenal failure are the main serious complications of cirrhosis.
• A careful assessment is required prior to the use of any drug in a patient with liver disease due to unpredictable effects on drug handling.

The liver weighs up to 1500 g in adults and as such is one of the largest organs in the body. The main functions of the liver include protein synthesis, storage and metabolism of fats and carbohydrates, detoxification of drugs and other toxins, excretion of bilirubin and metabolism of hormones, as summarised in Fig. 16.1. The liver has considerable reserve capacity reflected in its ability to function normally despite surgical removal of 70–80% of the organ or the presence of significant disease. It is noted for its capacity to regenerate rapidly. However, once it has been critically damaged multiple complications develop involving many body systems. The distinction between acute and chronic liver disease is conventionally based on whether the history is less or greater than 6 months, respectively.

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Fig. 16.1 Normal physiological functions of the liver, with examples of each.

The hepatocyte is the functioning unit of the liver. Heptocytes are arranged in lobules and within a lobule hepatocytes perform different functions depending on how close they are to the portal tract. The portal tract is the ‘service network’ of the liver and contains an artery and a portal vein delivering blood to the liver and bile duct which forms part of the biliary drainage system (Fig. 16.2). The blood supply to the liver is 30% arterial and the remainder is from the portal system which drains most of the abdominal viscera. Blood passes from the portal tract through sinusoids that facilitate exposure to the hepatocytes before the blood is drained away by the hepatic venules and veins. There are a number of other cell populations in the liver, but two of the most important are Kuppfer cells, fixed monocytes that phagocytose bacteria and particulate matter, and stellate cells responsible for the fibrotic reaction that ultimately leads to cirrhosis.

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Fig. 16.2 Illustration of the relationship between the three structures that comprise the portal tract, with blood from both the hepatic artery and portal vein perfusing the hepatocytes before draining away towards the hepatic veins (central veins). Each hepatocyte is also able to secrete bile via the network of bile ducts.

(Reproduced with permission of McGraw-Hill from Vander, 1980.)

Acute liver disease

Acute liver disease is a self-limiting episode of hepatocyte damage which in most cases resolves spontaneously without clinical sequelae. This is a rare condition in which there is a rapid deterioration in liver function with associated encephalopathy (altered mentation) and coagulopathy. Acute liver failure (ALF) carries a significant morbidity and mortality and may require emergency liver transplantation.

Chronic liver disease

Chronic liver disease occurs when permanent structural changes within the liver develop secondary to long-standing cell damage, with the consequent loss of normal liver architecture. In many cases, this progresses to cirrhosis, where fibrous scars divide the liver cells into areas of regenerative tissue called nodules (Fig. 16.3). Conventional wisdom is that this process is irreversible, but therapeutic intervention in hepatitis B and haemochromatosis has now repeatedly documented cases of reversal of cirrhosis. Once chronic liver disease progresses, patients are at risk of developing liver failure, portal hypertension or hepatocellular carcinoma. Cirrhosis is a sequel of chronic liver disease of any aetiology and it develops over very variable time periods from 5 to 20 or more years.

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Fig. 16.3 The gross post-mortem appearance of (A) a normal and (B) a cirrhotic liver demonstrating scarring and nodule formation in part B.

Causes of liver disease

Viral infections

Viruses commonly affect the liver, resulting in a transient and innocuous hepatitis. Viruses which target the liver are primarily described as hepatotropic viruses, and each of these can lead to clinically significant hepatitis and in some cases to the development of chronic viral hepatitis with viral persistence. Five human viruses have been well described to date, including hepatitis A (HAV), B (HBV), C (HCV), D (HDV) and E (HEV). Each type of viral hepatitis causes a similar pathology with acute inflammation of the liver. Types A and E are classically associated with an acute and sometimes severe hepatitis which is invariably self-limited, but occasionally fatal. Hepatitis B causes acute hepatitis in adults and 5% of patients become chronic carriers, while 95% of patients infected in the neonatal period are chronically infected. Hepatitis C rarely causes an acute hepatitis but up to 85% of patients become chronic carriers. Both viruses cause chronic liver inflammation or hepatitis, cirrhosis and hepatocellular carcinoma.

Hepatitis A

Hepatitis A virus (HAV) is a non-enveloped RNA virus and a major cause of acute hepatitis worldwide, accounting for up to 25% of clinical hepatitis in the developed world. HAV is an enteric virus and the faecal oral route is the main mechanism of transmission. The virus is particularly contagious and constitutes a public health problem throughout the world. The virus may go unnoticed by the patient in the absence of an icteric episode, particularly in children. However, HAV can cause ALF in less than 1% of patients who are typically older adults. The virus is particularly prevalent in areas of poor sanitation, and often associated with water- and food-borne epidemics. Hepatitis A has a relatively short incubation period (2–7 weeks), during which time the virus replicates and abnormalities in liver function tests can be detected.

Hepatitis B

Up to 500 million people worldwide are chronically infected with the hepatitis B virus (HBV). Chronic HBV is defined as the presence of hepatitis B surface antigens (HBsAg) for a period of more than 6 months. In endemic areas of Africa and the Far East, up to 15–20% of the population are chronic carriers of HBV and exposure to HBV at birth (vertical transmission) is the single most important risk factor for the development of chronic HBV infection. Acquisition of HBV in adulthood is often via sexual transmission and is usually associated with a discrete episode of hepatitis. HBV can also be transmitted parenterally, by the transfusion of blood or blood products from contaminated stocks and by intravenous drug use or needle sharing.

There are many factors that determine the outcome of HBV infection, ranging from age and genetic factors of the host to virus characteristics. Acute HBV infection has a peculiarly long incubation period of 3–6 months, which is generally self-limiting and does not require antiviral therapy. Most patients recover within 1–2 months of the onset of jaundice. The protracted incubation period and the ability of the virus to escape the host immune response contribute to the development of chronic HBV. Chronic HBV is associated with varying levels of viraemia and hepatic inflammation. The level of viraemia, and thus infectivity, was conventionally determined by the presence of the hepatitis Be antigen (HBeAg); and HBeAg loss resulted in a reduction in HBV viraemia and a more favourable outcome. However, HBeAg negative chronic hepatitis with significantly elevated levels of HBV DNA is now recognised as a growing health care problem and is associated with a poorer prognosis. HBeAg negative chronic HBV results as a consequence of the emergence of escape mutants from the core promoter or pre-core regions of the virus. It is estimated that 15–40% of HBV carriers will develop serious sequelae during their lifetime, namely liver cirrhosis and/or hepatocellular carcinoma, which can develop in chronic HBV in the absence of cirrhosis. Childhood infection is associated with a different disease outcome with a higher percentage of patients developing chronic HBV infection, and owing to the protracted exposure to the virus a higher proportion develop cirrhosis and hepatocellular carcinoma.

Hepatitis C

Over 170 million people worldwide are chronically infected with hepatitis C virus (HCV). HCV is a hepatotropic, non-cytopathic, predominantly blood borne virus with greater infectivity than the human immunodeficiency virus (HIV). It is estimated that more than 2.7 million people in the USA are chronically infected with HCV, where it is the leading cause of death from liver disease. The equivalent estimate for the UK is between 200,000 and 500,000, although a considerable proportion of these have not yet been diagnosed. HCV is transmitted parenterally, most commonly through intravenous drug use and the sharing of contaminated needles. Prior to its identification in 1990, HCV (previously known as Non-A, Non-B viral hepatitis) was also contracted through contaminated blood and blood products. The introduction of widespread screening of blood donors and pooled blood products has largely consigned blood transfusion as a mode of transmission to history. There remains a small risk of HCV infection associated with tattooing, electrolysis, ear piercing, acupuncture and sexual contact. The vertical transmission rate from HCV infected mother to child is less than 3%.

Hepatitis D

Hepatitis D virus (HDV) is an incomplete virus that can establish infection only in patients simultaneously infected by HBV. It is estimated that 5% of HBV carriers worldwide are infected with HDV. It is endemic in the Mediterranean basin and is transmitted permucosally, percutaneously or sexually. In other geographical areas, it is confined to intravenous drug users.

HCV infection is associated with the development of a recognised episode of acute hepatitis in only a small percentage of individuals. The majority of patients remain asymptomatic and so are often unaware of the infection or the timing of when they contracted the virus. Symptoms associated with HCV infection tend to be mild constitutional upset with malaise, weakness and anorexia being most commonly reported. Up to 85% of subjects exposed to HCV develop chronic disease, which can lead to progressive liver damage, cirrhosis and hepatocellular carcinoma. Unlike HBV, the risk of developing hepatocellular carcinoma is almost totally linked to the presence of cirrhosis. Approximately 20–30% of patients with chronic HCV infection progress to end-stage liver disease within 20–30 years and alcohol consumption is a recognised co-factor that accelerates disease progression. HCV infection is now the leading worldwide indication for liver transplantation.

Hepatitis E

Hepatitis E virus (HEV) is endemic in India, Asia, the Middle East and parts of Latin America. It is an RNA virus which is transmitted enterically and leads to acute hepatitis. The symptoms of HEV are no different from other causes of viral hepatitis, with an average incubation period of 42 days. It was previously thought that the risk of death was increased in pregnancy, especially in the final trimester, but more recent data do not support this belief.

Alcohol

Alcohol is the single most significant cause of liver disease throughout the Western world accounting for between 40% and 60% of cases of cirrhosis in different countries. In general, deaths from alcoholic liver disease in each country correlate with the consumption of alcohol per head of population, although additional factors can influence this trend. Liver disease related to recent alcohol consumption presents a broad spectrum, ranging from the relatively benign fatty liver disease to the development of alcoholic hepatitis, a condition with an immediate mortality of between 30% and 60%. An estimated 20% of alcohol abusers develop progressive liver fibrosis, which can eventually lead to alcoholic cirrhosis, typically after a period of 10–20 years of heavy indulgence.

The central event in the development of hepatic fibrosis is the transformation of hepatic stellate cells into matrix secreting cells producing pericellular fibrosis. This network of collagen fibres develops around the liver cells and gradually leads to hepatocyte cell death. The extent of fibrosis progresses and micronodular fibrotic bands develop characterising alcoholic cirrhosis. The anatomical changes within the liver increase resistance to blood flow from the portal system, causing an increase in pressure within this system resulting in portal hypertension. As the number of normally functioning liver cells reduces further, because of continued liver cell failure and death, the clinical condition deteriorates progressively with the development of liver failure. The rate of disease progression, and indeed regression, is very strongly linked to whether or not patients continue to consume alcohol.

Non-alcohol related fatty liver disease

Liver pathology that is very similar to alcohol-induced disease is now well recognised in a number of settings including obesity, diabetes mellitus and the metabolic syndrome. As a result, the entities of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been introduced. It has been suggested that up to 25% of the U.S. population have NAFLD. The majority of cases of cryptogenic cirrhosis probably reflect the end stage of the NAFLD/NASH disease process even though by that stage the characteristic fatty infiltrate has disappeared.

Immune disorders

Autoimmune disease can affect the hepatocyte or bile duct and is characterised by the presence of auto-antibodies and raised immunoglobulin levels.

Autoimmune hepatitis (AIH)

AIH is an unresolving inflammation of the liver characterised by the presence of auto-antibodies (anti-smooth muscle [type 1] or anti-kidney, liver microsomal [type 2]), hypergammaglobulinemia and an interface hepatitis on liver histology. It is usually a chronic, progressive disease which can occasionally present acutely with a severe hepatitis. AIH typically occurs in young women, between 20 and 40 years, and often with a history or family history of autoimmune disorders.

Primary biliary cirrhosis (PBC)

PBC is an autoimmune disease of the liver which predominantly affects middle aged women (95% of cases are female). It is characterised by the presence of antimitochondrial antibodies and a granulomatous destruction of the interlobular bile ducts leading to progressive ductopenia, fibrosis and cirrhosis. The disease is progressive, albeit over a period of 20 years or longer if diagnosed at an early stage, and liver transplantation is the only effective treatment.

Primary sclerosing cholangitis (PSC)

PSC is an idiopathic chronic inflammatory disease resulting in intra- and extra-hepatic biliary strictures, cholestasis and eventually cirrhosis. There is a strong association with inflammatory bowel disease, particularly ulcerative colitis; 75% of PSC patients have ulcerative colitis and 5–8% of patients with ulcerative colitis develop PSC. It has a predeliction for young Caucasian males (mean age at presentation 39 years), but it can occur in infancy or childhood and can affect any race. Cholangiocarcinoma develops in up to 10% of patients with PSC.

Vascular abnormalities

The Budd–Chiari syndrome (BCS) is a rare, heterogeneous and potentially fatal condition related to the obstruction of the hepatic venous outflow tract. The prevalence of underlying thrombophilia is markedly increased in patients with BCS. Affected patients are commonly women with an average age at presentation of 35. Early recognition and immediate use of anticoagulation has vastly improved outcome. More advanced disease can be treated in a number of ways including venoplasty, transjugular intrahepatic portosystemic shunt (TIPS), surgical shunts or liver transplantation.

Metabolic and genetic disorders

There are various inherited metabolic disorders that can affect the functioning of the liver.

Haemochromatosis

Hereditary haemachromatosis (HH) is the most commonly identified genetic disorder in the Caucasian population. It is associated with increased absorption of dietary iron resulting in deposition within the liver, heart, pancreas, joints, pituitary gland and other organs. This can lead to cirrhosis and hepatocellular carcinoma.

Wilson’s disease

Wilson’s disease is an autosomal recessive disorder of copper metabolism. The disorder leads to excessive absorption and deposition of dietary copper within the liver, brain, kidneys and other tissues. Presentation can vary widely from chronic hepatitis, asymptomatic cirrhosis, ALF to neuropsychiatric symptoms with cognitive impairment.

α1-Antitrypsin deficiency

This is an autosomal recessively inherited disease and is the most common genetic metabolic liver disease. The disease results in a reduction in α1-antitrypsin which is protective against a variety of proteases including trypsin, chymotrypsin, elastase and proteases present in neutrophils. The homozygous form of the disease (ZZ phenotype) is associated with the development of liver disease and cirrhosis in 15–30% of both adult and paediatric patients.

Glycogen storage disease

Glycogen storage disease is a rare disease occurring in 1 in 100,000 births. Enzymatic deficiencies at specific steps in the pathway of glycogen metabolism cause impaired glucose production and accumulation of abnormal glycogen in the liver.

Gilbert’s syndrome

Gilbert’s syndrome is characterised by persistent mild unconjugated hyperbilirubinaemia. It is most frequently recognised in adolescents and young adults with an incidence of between 2% and 7% in the general population. Serum bilirubin levels fluctuate but can increase to 80–100 μmol/L during periods of stress, sleep deprivation, prolonged fasting, menstruation and intercurrent infections. Gilbert’s syndrome is an asymptomatic condition requiring no therapy, although patients may inappropriately associate being jaundiced with the symptoms of the condition that triggered the increase in the bilirubin levels.

Drugs

Drugs are an important cause of abnormal liver function tests and acute liver injury, including ALF (DILI drug-induced liver injury). Drugs can also be relevant to a number of chronic liver diseases including steatosis, fibrosis/cirrhosis, autoimmune and vascular disease. In most situations, the drug is implicated because of an appropriate temporal relationship between the disease and drug exposure.

Clinical manifestations

Symptoms of liver disease

In patients who have liver disease, weakness, increased fatigue and general malaise are common but non-specific symptoms. Weight loss and anorexia are more commonly seen in chronic liver disease and loss of muscle bulk is a characteristic of very advanced disease. Abdominal discomfort may be described by patients with an enlarged liver or spleen while distension with ascites is usually the cause in more advanced disease. Abdominal pain is common in hepatobiliary disease, frequently localised to the right upper quadrant. This is often a feature of rapid or gross enlargement of the liver when the pain is thought to be a consequence of capsular stretching. Tenderness over the liver is a symptom of acute hepatitis, hepatic abscess or hepatic malignancy.

Jaundice is the most striking symptom of liver disease and can present with or without pain, depending on the underlying aetiology of disease. Pruritus can be a distressing symptom in cholestatic liver disease and patients usually complain that it is worse at night. Patients with acute and chronic liver disease can develop bleeding complications because of defective hepatic synthesis of coagulation factors and low platelet counts

Signs of liver disease

Cutaneous signs

Hyperpigmentation is common in chronic liver disease and results from increased deposition of melanin. It is particularly associated with PBC and haemachromatosis. Scratch marks on the skin suggest pruritus which is a common feature of cholestatic liver disease. Vascular ‘spiders’ referred to as spider naevi are small vascular malformations in the skin and are found in the drainage area of the superior vena cava, commonly seen on the face, neck, hands and arms. Examination of the limbs can reveal several signs, none of which are specific to liver disease. Palmar erythema, a mottled reddening of the palms of the hands, can be associated with both acute and chronic liver disease. Dupuytren’s contracture, thickening and shortening of the palmar fascia of the hands causing flexion deformities of the fingers, was traditionally associated with alcoholic cirrhosis. It is now considered to be multifactorial in origin and not to reflect primary liver disease. Nail changes, highly polished nails or white nails (leukonychia) can be seen in up to 80% of patients with chronic liver disease. Leukonychia is a consequence of low serum albumin. Finger clubbing is most commonly seen in hypoxaemia related to hepato-pulmonary syndrome, but is also a feature of chronic liver disease (Table 16.1)

Table 16.1 Physical signs of chronic liver disease

Common findings End-stage findings
Jaundice Ascites
Gynaecomastia & loss of body hair Dilated abdominal blood vessels
Hand changes: Fetor hepaticus
Palmar erythema Hepatic flap
Clubbing Neurological changes:
Dupuytren’s contracture Hepatic encephalopathy
Leuconychia Disorientation
Liver mass reduced or increased Changes in consciousness
Parotid enlargement Peripheral oedema
Scratch marks on skin Pigmented skin
Purpura Muscle wasting
Spider naevi  
Splenomegaly  
Testicular atrophy  
Xanthelasma  
Hair loss  

Abdominal signs

Abdominal distension, notably of the flanks, is suggestive of ascites which can develop in both acute (less commonly) and chronic liver disease. An enlarged liver (hepatomegaly) is a common finding in acute liver disease. In cirrhotic patients the liver may be large, but alternatively it may be small and shrunken reflecting end-stage chronic disease. An enlarged spleen (splenomegaly) in the presence of chronic liver disease is the most important sign of portal hypertension. Dilated abdominal wall veins are a notable finding in chronic liver disease with the detection of umbilical and para-umbilical veins, a feature of portal hypertension.

Jaundice

Jaundice is the physical sign regarded as synonymous with liver disease and is most easily detected in the sclerae. It reflects impaired liver cell function (hepatocellular pathology) or it can be cholestatic (biliary) in origin. Hepatocellular jaundice is commonly seen in acute liver disease, but may be absent in chronic disease until the terminal stages of cirrhosis are reached. The causes of jaundice are shown in Fig. 16.4.

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Fig. 16.4 Common causes of jaundice. Obstructive: due to blockage of the bile ducts; Hepatocellular: due to drugs, hepatitis, chronic liver disease or tumour formation; Prehepatic: due to increased blood breakdown such as occurs in haemolysis.

Portal hypertension

The increased pressure in the portal venous system leads to collateral vein formation and shunting of blood to the systemic circulation. Portal hypertension is an important contributory factor to the formation of ascites and the development of encephalopathy due to bypassing of blood from the liver to the systemic circulation. The major, potentially life-threatening complication of portal hypertension is torrential venous haemorrhage (variceal bleed) from the thin walled veins in the oesophagus and upper stomach. Patients with portal hypertension are often asymptomatic, while others may present with bleeding varices, ascites and/or encephalopathy.

Ascites

Ascites is the accumulation of fluid within the abdominal cavity. The precise mechanism by which ascites develops in chronic liver disease is unclear, but the following are all thought to contribute:

• Activation of the renin–angiotensin–aldosterone axis as a consequence of central hypovolaemia, leading to a reduction in sodium excretion by the kidney and fluid retention. Reduced aldosterone metabolism due to reduced liver function may also contribute to increased fluid retention.
• A reduction in serum albumin and reduced oncotic pressure is thought to contribute to the collection of fluid in the third space. Peripheral oedema (swollen lower limbs) occurs through this mechanism in a manner similar to the development of ascites.
• Portal hypertension and splanchnic arterial vasodilation alters intestinal capillary pressure and permeability and so facilitates the accumulation of retained fluid in the abdominal cavity.

Sexual characteristics

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