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.

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.

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.

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.

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.

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

Endocrine changes are well documented in chronic liver disease and tend to be more common in alcoholic liver disease. Hypogonadism is common in patients with cirrhosis and in males results in testicular atrophy, female body hair distribution and gynaecomastia. This is thought, in part, to occur because the cirrhotic liver cannot metabolise oestrogen, leading to feminisation in males. Gynaecomastia is particularly found in alcoholics but is also seen in those taking spironolactone, when there is usually associated tenderness of the nipples. In women with chronic liver disease menstrual irregularity, amenorrhoea and reduced fertility are encountered in those of reproductive age, but few detectable physical

Investigations

All patients with liver disease must undergo a comprehensive and thorough assessment to ascertain the underlying aetiology. Although causes of acute and chronic liver disease may differ, a similar approach is used to investigate both patient groups to ensure no primary cause or co-factor is overlooked.

Biochemical tests

Biochemical liver function tests (LFTs) are simple, inexpensive and easy to perform but usually cannot be used in isolation to make a diagnosis. Biochemical parameters provide very useful information in monitoring disease progression or response to therapy. The liver enzymes usually measured are the aminotransferases which reflect hepatocellular pathology and the cholestatic liver enzymes, alkaline phosphatase and γ-glutamyl transpeptidase. Aspartate transaminase (AST) and alanine transaminase (ALT) are two intracellular enzymes present in hepatocytes which are released into the blood of patients as a consequence of hepatocyte damage. Extremely high values, where transaminases are recorded in the thousands, occur in acute liver disease, for example, viral hepatitis or paracetamol overdose. In chronic hepatitis, serum transaminases are rarely more than five to eight times the normal upper limit. Alkaline phosphatase is present in the canalicular and sinusoidal membranes of the liver but is also present in other sites, especially bone. Concomitant elevation of the enzyme γ-glutamyl transpeptidase confirms the hepatic origin of an elevated alkaline phosphatase. The serum alkaline phosphatase activity may be raised by up to four to six times the normal limit in intrahepatic or extra-hepatic cholestasis. It can also be raised in conditions associated with liver infiltration, such as metastases.

Bilirubin is commonly elevated in hepatocellular pathology and especially in acute hepatitis and end-stage chronic disease. An increase in bilirubin concentration results in jaundice and is usually clinically apparent when the serum bilirubin level exceeds 50 μmol/L. In acute liver disease, the serum bilirubin reflects severity of disease but is of little prognostic value. In chronic liver disease, a gradual increase for no apparent reason usually reflects serious disease progression. Hepatocellular damage, cholestasis and haemolysis can all cause elevations in the serum bilirubin concentration.

Synthetic function capacity is very important in assessing liver disease. Prothrombin time (PT), international normalised ratio (INR) and other coagulation studies are useful short-term markers of the synthetic function, especially in acute liver insults where they reflect the severity of the liver injury. PT or INR are also important indicators of chronic liver disease when combined with albumin levels. Albumin is synthesised in the liver and serum albumin levels reflect liver function over the preceeding months rather than days as with coagulation studies. Alternative causes of hypoalbuminaemia need to be considered, especially proteinuria.

Laboratory investigation of aetiology

All individuals presenting with derangement of liver function should be tested for hepatitis A, B, and C as part of a routine liver disease screen. Auto-antibodies and immunoglobulins to screen for autoimmune disease are also relevant to both acute and chronic liver disease. Serum ferritin, caeruloplasmin (in patients under 40 years), α₁-antitrypsin phenotype and lipid profile are standard investigations in patients with evidence of chronic liver disease.

Imaging techniques

Ultrasound is a non-invasive, low-risk procedure that is pivotal in the preliminary assessment of liver disease as it assesses the size, shape and texture of the liver and screens for dilatation of the biliary tract. In patients with chronic liver disease, it assesses patency of the portal vein and may detect signs of portal hypertension (increased spleen size, ascites). It is also routinely used to screen for hepatocellular carcinoma and other hepatobiliary malignancies. Computed tomography (CT) and magnetic resonance (MR) scans are regularly used for more precise definition of any abnormalities identified on ultrasound.

Liver biopsy

Liver biopsy is an invasive procedure with an associated morbidity and mortality, albeit extremely low. Nevertheless, it remains the gold standard in establishing a diagnosis and assessing the severity of chronic liver disease. Progress has been made in developing techniques to assess liver fibrosis non-invasively and a technique called Fibroscan appears to be effective in patients with HCV. In some instances, liver histology will contribute to the decision-making process with regard to therapy, for example, whether to initiate antiviral therapy for HBV or HCV. In acute hepatic dysfunction, a liver biopsy is usually unnecessary, especially if the condition is self-limiting.

Patient care

Pruritus

Pruritus is a prominent and sometimes distressing symptom of chronic liver disease and tends to be most debilitating in the context of cholestatic conditions. The pathogenesis of pruritus in liver disease is poorly understood but the deposition of bile salts within the skin is considered to be central to its development. However, the concentration of bile salts in the skin does not appear to correlate with the intensity of pruritus. Management of pruritus is variable. Relief of biliary obstruction by endoscopic, radiological or surgical means is indicated in patients with obstructed biliary systems. In other cases, pharmacological agents are used initially but in some cases plasmapheresis, molecular absorbants recirculating system (MARS) or even liver transplantation may be needed.

Anion exchange resins

Colestyramine and colestipol act by binding bile acids and preventing their reabsorption. These anion exchange resins are the first line of therapy in the treatment of pruritus. Colestyramine is usually initiated at a dosage of 4 g once or twice daily, and the dose is then titrated to optimise relief without causing side effects (predominantly gastro-intestinal). Such adverse effects are common and include constipation, diarrhoea, fat and vitamin malabsorption. Palatability is variable and consequently adherence is often a problem. In order to enhance compliance, patients should be advised that the benefits of therapy may take time to become apparent and often up to a week. Anion exchange resins can reduce the absorption of concomitant therapy and such drugs should be taken 1 h prior to or 4 h after colestyramine or colestipol ingestion. Drugs which are susceptible to this interaction include digoxin, thyroxine, ursodeoxycholic acid (UDCA), chlorothiazide, propranolol and the antibiotics tetracycline and penicillin.

Antihistamines

Although frequently used, antihistamines are usually ineffective in the management of the pruritus caused by cholestasis and should not be considered first-line therapy. A non-sedating antihistamine such as cetirizine (10 mg once daily) or loratidine (10 mg once daily) is preferred as these avoid precipitating or masking encephalopathy. Antihistamines such as chlorphenamine or hydroxyzine provide little more than sedative properties, although they may be useful at night if the severity of pruritus is sufficient to prevent a patient from sleeping.

Ursodeoxycholic acid

The bile acid UDCA (10 mg/kg daily in two divided doses) has been used frequently in cholestatic liver disease and long-term use has been shown to be effective in the treatment of pruritus. However, in about 5% of cases it worsens the pruritus.

Rifampicin

Rifampicin induces hepatic microsomal enzymes, which may benefit some patients, possibly by improving bile flow. Rifampicin, administered at a dose of 600 mg/day may be effective in the treatment of pruritus, albeit over a more prolonged period of time (1–3 weeks). It is most commonly used in patients with PBC. Its use is restricted by its potential hepatotoxicity and drug interactions with other agents.

Opioid antagonists

A growing spectrum of opioid antagonists have been used to treat pruritus because it is believed that endogenous opioids in the central nervous system are potent mediators of itch. As a consequence the centrally acting opioid antagonists naloxone, naltrexone and nalmefene are thought to reverse the actions of these endogenous opioids. The use of such agents is limited by their route of administration. Naloxone is given by subcutaneous injection, while naltrexone and nalmefene are reported to be more substantially bioavailable after oral administration. A summary of drugs used in the management of pruritus is shown in Table 16.2.

Table 16.2 Drugs commonly used in the management of pruritus

Topical preparations

Topical therapy may benefit some patients. Calamine lotion or menthol 2% in aqueous cream are standard preparations, but improvement of pruritus with such agents is variable.

The relationship of liver disease to clotting abnormalities is shown diagrammatically in Fig. 16.5. Haemostatic abnormalities develop in approximately 75% of patients with chronic liver disease and 100% of patients with ALF. The majority of clotting factors (with the exception of factor V) are dependent on vitamin K. Patients with liver disease who develop deranged blood clotting should receive intravenous doses of phytomenadione (vitamin K), usually 10 mg daily for 3 days. Administration of vitamin K to patients with significant liver disease does not usually improve the prothrombin time because the liver is unable to utilise the vitamin to synthesis clotting factors. Oral vitamin K is less effective than the parenteral form and so, has little or no place in the management of clotting abnormalities and bleeding secondary to liver disease.

Fig. 16.5 Mechanisms of deranged clotting in chronic liver disease.

Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants should be avoided in all patients with liver disease because of the risk of altering platelet function, causing gastric ulceration and bleeding. NSAIDs have also been implicated in precipitating renal dysfunction and variceal bleeding in patients with end-stage liver disease. Although COX-2 inhibitors may cause a lower incidence of bleeding complications, currently they are avoided in patients with liver disease as their use still poses a risk.

Ascites

The aim in the treatment of ascites is to mobilise the abnormal collection of third space fluid (intra-abdominal fluid) and this can be achieved by simple measures such as reduced sodium intake. A low-salt diet (60–90 mEq/day) may be enough to facilitate the elimination of ascites and delay reaccumulation of fluid. Salt reduction combined with fluid restriction (approximately 1–1.5 L/day) are practical measures taken to mobilise fluid and provide weight reduction and symptomatic relief.

Aggressive weight reduction in the absence of peripheral oedema should be avoided as it is likely to lead to intravascular fluid depletion and renal failure. Weight loss should not exceed 300–500 g/day in the absence of peripheral oedema and 800–1000 g/day in those with peripheral oedema to prevent renal failure. However, diuretics and/or paracentesis are the cornerstone in the management of moderate to large volume ascites. A sequential approach to the management of ascites is outlined in Box 16.1.

Box 16.1 The sequential approach to the management of cirrhotic ascites

Bedrest and sodium restriction (60–90 mEq/day, equivalent to 1500–2000 mg of salt/day)

Spironolactone (or other potassium-sparing diuretic)

Spironolactone and loop diuretic

Large-volume paracentesis and colloid replacement

Other measures

Transjugular intrahepatic portosystemic shunt (TIPS)

Peritonovenous shunt

Consider orthotopic liver transplantation

Diuretics

The aldosterone antagonist, spironolactone is usually used as a first-line agent in the treatment of ascites. In most instances, a negative sodium balance and loss of ascitic fluid can be achieved with low doses of diuretics. Spironolactone can be used alone or in combination with a more potent loop diuretic. The specific agents and dosages used are outlined in Table 16.3. Spironolactone acts by blocking sodium reabsorption in the collecting tubules of the kidney. It is usually commenced at 50–100 mg/day, but this varies, depending on the patient’s clinical status, electrolyte levels and concomitant drug therapies. It can take many days to have a therapeutic effect, so dose augmentation should be conducted with caution and strict observation of renal parameters. The addition of a loop diuretic, furosemide 40 mg/day enhances the natriuretic activity of spironolactone, and should be used when ascites is severe or when spironolactone alone fails to produce acceptable diuresis.

Table 16.3 Diuretics used in the management of ascites

The use of more potent diuretic combinations may result in excessive diuresis which can lead to renal failure of pre-renal origin. The initiation and augmentation of diuretic therapy should ideally be carried out in hospital. This allows strict urea and electrolyte monitoring to detect impending hyperkalaemia and/or hyponatraemia, which commonly occur with diuretic therapy. It also allows the baseline measurement of urinary sodium excretion, subsequent changes in the diuretic dose should be titrated against urinary sodium excretion. Aggressive and unchecked diuresis will precipitate the hepatorenal syndrome, which has a very poor prognosis. Generally, if the serum sodium level decreases to less than 130 mmol/L or if creatinine levels rise to greater than 130 μmol/L then dose escalation of diuretics should be stopped. Diuretic therapy can be complicated by encephalopathy, hypokalaemia, hyponatraemia and azotaemia. Gynaecomastia and muscle cramps are side effects of diuretic therapy.

Refractory ascites, which occurs in 5–10% of patients with ascites, is associated with a 1-year survival rate of 25–50%. Therapeutic strategies include repeated large volume paracentesis combined with the administration of plasma expanders or alternatively, TIPS. In some patients, liver transplantation may be indicated. Ascites is considered to be refractory or diuretic resistant if there is no response with once daily doses of 400 mg spironolactone and 160 mg furosemide. Again, urinary sodium excretion provides important information in terms of the response to or viability of dose augmentation with diuretic therapy. Patients on lower doses of diuretics are also considered to have refractory ascites if side effects are a problem, for example, hepatic encephalopathy, hyperkalaemia, hyponatraemia or azotemia.

Paracentesis

Repeated large volume paracentesis in combination with albumin administration is the most widely accepted therapy for refractory ascites. Patients generally require paracentesis every 2–4 weeks and the procedure is often performed in the outpatient setting. Paracentesis, however, does not affect the mechanism responsible for ascitic fluid accumulation and so early recurrence is common. Intravenous colloid replacement or plasma expanders are used to prevent adverse effects on the renal and systemic circulation. Colloid replacement in the form of 6–8 g albumin/L of ascites removed (equivalent to 100 mL of 20% human albumin solution [1 unit] for every 2.5 L of ascitic fluid removed) is a standard regimen.

Transjugular intrahepatic portosystemic shunting (TIPS)

TIPS is an invasive procedure, used to manage refractory ascites or control refractory variceal bleeding. It is carried out under radiological guidance. An expandable intrahepatic stent is placed between one hepatic vein and the portal vein by a transjugular approach (Fig. 16.6). In contrast to paracentesis, the use of TIPS is effective in preventing recurrence in patients with refractory ascites. It reduces the activity of sodium retaining mechanisms and improves the renal response to diuretics. However, a disadvantage of this procedure is the high rate of shunt stenosis (up to 30% after 6–12 months) which leads to recurrence of ascites. TIPS can also induce or exacerbate hepatic encephalopathy.

Fig. 16.6 Intrahepatic stent shunt links the hepatic vein with the intraheptic portal vein.

Spontaneous bacterial peritonitis (SBP)

Patients with ascites should be closely observed for SBP as it develops in 10–30% of patients and has a high mortality. Hepatorenal syndrome can complicate SBP in up to 30% of patients and also carries a high mortality. Conventional signs and symptoms of peritonitis are rarely present in such patients and if suspected, treatment with appropriate antibiotics should be started immediately after a diagnostic ascitic tap has been taken. A polymorphonuclear leucocyte count of greater than 250 cells/mm³ is diagnostic of this condition. The causative organism is of enteric origin in approximately three-quarters of infections, and originates from the skin in the remaining one-quarter. Cefotaxime (2 g, 8 hourly) is effective in 85% of patients with SBP and is commonly used as first-line antimicrobial therapy. Other antibiotic regimens have been used including co-amoxiclav, but third-generation cephalosporins are the treatment of choice. The quinolone, norfloxacin (400 mg/day), has a role in the prevention of recurrence of SBP, estimated as 70% at 1-year, and is recommended for long-term antibiotic prophylaxis. However, the emergence of quinolone-resistant bacteria is a growing problem in the management of SBP.

Hepatic encephalopathy

Hepatic encephalopathy is a reversible neuropsychiatric complication that occurs with significant liver dysfunction. The precise cause of encephalopathy remains unclear, but three factors are known to be implicated, namely portosystemic shunting, metabolic dysfunction and an alteration of the blood–brain barrier. It is thought that intestinally derived neuroactive and neurotoxic substances such as ammonia pass through the diseased liver or bypass the liver through shunts and go directly to the brain. This results in cerebral dysfunction. Ammonia is thought to increase the permeability of the blood–brain barrier, enabling other neurotoxins to enter the brain, and indirectly alter neurotransmission. Other substances implicated in causing hepatic encephalopathy include free fatty acids, γ-aminobutyric acid (GABA) and glutamate.

Clinical features of hepatic encephalopathy range from trivial lack of awareness, altered mental state to asterixis (liver flap) through to gross disorientation and coma. During low-grade encephalopathy, the altered mental state may present as impaired judgement, altered personality, euphoria or anxiety. Reversal of day/night sleep patterns is very typical of encephalopathy. Somnolence, semistupor, confusion and, finally, coma can ensue (Table 16.4).

Table 16.4 Grading of hepatic encephalopathy

Grade 0	Normal
Subclinical	Abnormal psychometric tests for encephalopathy (e.g. number correction test)
Grade 1	Mood disturbance, abnormal sleep pattern, impaired handwriting +/− asterixis
Grade 2	Drowsiness, grossly impaired calculation ability, asterixis
Grade 3	Confusion, disorientation, somnolent but arousable, asterixis
Grade 4	Stupor to deep coma, unresponsive to painful stimuli

Encephalopathy associated with cirrhosis and/or portal-systemic shunts may develop as a result of specific precipitating factors (Box 16.2) or spontaneously. Common precipitating factors include gastro-intestinal bleeding, SBP, constipation, dehydration, electrolyte abnormalities and certain drugs including narcotics and sedatives. Identification and removal of such precipitating factors is mandatory. Therapeutic management is then aimed at reducing the amount of ammonia or nitrogenous products in the circulatory system. Treatment with laxatives increases the throughput of bowel contents, by reducing transit time and also increases soluble nitrogen output in the faeces. Drug therapies for encephalopathy are summarised in Table 16.5.

Table 16.5 Drugs commonly used in the management of encephalopathy

Lactulose, a non-absorbable disaccharide, decreases ammonia production in the gut. It is widely used as it is broken down by gastro-intestinal bacteria to form lactic, acetic and formic acids. The effect of lactulose is to acidify the colonic contents which leads to the ionisation of nitrogenous products within the bowel, with a consequent reduction in their absorption from the gastro-intestinal tract. Lactulose is commenced in doses of 30–40 mL/day and titrated to result in two to three bowel motions each day. Patients unable to take oral medication or those with worsening encephalopathy are treated with phosphate enemas.

Antibiotics such as metronidazole or neomycin may also be used to reduce ammonia production from gastro-intestinal bacteria. Metronidazole has been the preferred option in the past, while the use of neomycin has largely been abandoned because of associated toxicity. Recent data has supported the use of the rifaximin, a minimally absorbed antibiotic, for the treatment of acute encephalopathy and the remission of chronic encephalopathy (Bass et al., 2010). Other therapies investigated for the treatment of encephalopathy include l-ornithine-l-aspartate (LOLA), sodium benzoate, l-dopa, bromocriptine and the benzodiazepine receptor antagonist, flumazenil.

Oesophageal varices

Variceal bleeding is the most feared complication of portal hypertension in patients with cirrhosis and there is a 30% lifetime risk of at least one bleeding episode among patients with cirrhosis and varices. Treatment of variceal bleeding includes endoscopic banding, or rarely sclerotherapy, of oesophageal varices in parallel with splanchnic vasoconsrictors and intensive medical care. Patients with variceal bleeding refractory to endoscopic intervention or patients bleeding from ectopic or uncontrolled gastric varices will need TIPS or surgical decompressive shunts. Refractory variceal bleeding should, therefore, be managed in centres with the appropriate expertise.

Initial treatment is aimed at stopping or reducing the immediate blood loss, treating hypovolaemic shock, if present, and subsequent prevention of recurrent bleeding. Immediate and prompt resuscitation is an essential part of treatment. Only when medical treatment has been initiated and optimised should endoscopy be performed. Endoscopy confirms the diagnosis and allows therapeutic intervention. Fluid replacement is invariably required, and should be in the form of colloid or packed red cells and administered centrally. Saline should generally be avoided in all patients with cirrhosis. Fluid replacement must be administered with caution, as over-zealous expansion of the circulating volume may precipitate further bleeding by raising portal pressure, thereby exacerbating the clinical situation. A flow chart for the management of bleeding oesophageal varices is shown in Fig. 16.7.

Fig. 16.7 Management of oesophageal variceal haemorrhage.

Endoscopic management

Variceal band ligation uses prestretched rubber bands applied to the base of a varix which has been sucked into the banding chamber attached to the front of an endoscope. Variceal band ligation (VBL) controls bleeding in approximately 90% of cases. It is at least as effective as sclerotherapy, which it has largely superceded, and is associated with fewer side effects. Balloon tamponade with a Sengstaken–Blakemore balloon or Linton balloon may be used to stabilise a patient with actively bleeding varices by directly compressing the bleeding varices, until more definitive therapy can be undertaken. Balloon tamponade can control bleeding in up to 90% of cases but 50% rebleed when the balloon is deflated. Gastric varices develop in approximately 20% of patients with portal hypertension. The risk of gastric variceal bleeding is lower than that of oesophageal variceal bleeding, but bleeding from fundal varices is more difficult to manage and is associated with a higher mortality. The most effective treatment strategy for fundal varices is now considered to be variceal obturation with tissue adhesives or ‘glue injection’. The use of cyanoacrylate injection in the treatment of fundal varices is associated with less rebleeding and is emerging as the treatment of choice in the hands of experienced endoscopists.

Drug treatment

Several pharmacological agents are available for the emergency control of variceal bleeding (Table 16.6). Most act by lowering portal venous pressure. They are generally used to control bleeding in addition to balloon tamponade and emergency endoscopic techniques. Vasopressin was the first vasoconstrictor used to reduce portal pressure in patients with actively bleeding varices. However, its associated systemic vasoconstrictive adverse effects limited its use. The synthetic vasopressin analogue, terlipressin, is highly effective in controlling bleeding and in reducing mortality. It can be administered in bolus doses every 4–6 h and has a longer biological activity and a more favourable side effect profile. Once a diagnosis of variceal bleeding has been established, a vasoactive drug infusion (usually terlipressin) should be started without further delay and continued for 2–5 days. Somatostatin and the somatostatin analogue, octreotide, are reported to cause selective splanchnic vasoconstriction and reduce portal pressure. Although they are reported to cause less adverse effects on the systemic circulation, terlipressin remains the agent of choice.

Table 16.6 Drugs used in the treatment of acute bleeding varices

Drug	Dosage and administration
Terlipressin	1–2 mg bolus 4–6 hourly for 48 h
Octreotide	50 μcg/h i.v. infusion for 48 h or longer if patient rebleeds

Transjugular intrahepatic portosystemic shunt (TIPS)

TIPS is now established as the preferred rescue therapy in cases where endoscopic intervention has failed to control bleeding (Fig. 16.7). Recent data suggests the use of early TIPS, within the first 48 h, may be life saving in patients with advanced liver failure.

Prevention of rebleeding

Endoscopic band ligation (EBL) is performed at regular intervals (1–2 weeks) as part of an eradication programme to obliterate the varices. Once varices have been eradicated, endoscopic follow-up can be performed less frequently (3 monthly) for the first year, then twice yearly thereafter. If varices reappear they should be banded regularly until eradicated again. Non-selective β-blockers, such as propranolol, are the medication of choice to prevent rebleeding and can also be used as primary prophlaxis against variceal bleeding in patients with known varices. The mechanism of action is complex, but they reduce portal hypertension by causing splanchnic vasoconstriction and reduced portal blood flow. At higher doses they can have a more marked negative effect on cardiac output and so must be titrated accordingly.

Acute liver failure

ALF occurs when there is a rapid deterioration in liver function in previously healthy individuals resulting in encephalopathy and a coagulopathy. ALF is a multisystem disorder with cerebral oedema and renal impairment being particularly important complications. In the past, viral hepatitis was a major consideration in the aetiology of ALF. However, the development of a commercial vaccine for hepatitis B has seen a dramatic decline in the contribution of HBV to ALF in Western countries. The most common cause of ALF in the UK and USA is paracetamol (acetaminophen) toxicity. Seronegative hepatitis is the other common aetiological group. Management of ALF is complicated, involving supporting the central nervous system, cardiovascular and renal systems. All patients with ALF are at risk of infection, and prophylactic administration of broad spectrum antibiotics and antifungal agents is standard practice. Coagulopathy and bleeding resulting from liver failure are well-recognised life-threatening complications which require specialised monitoring and early correction.

Liver transplantation

Liver transplantation is the established treatment for selected patients with ALF, decompensated chronic liver disease, inherited metabolic disorders and primary liver cancer. HCV and alcohol-induced end-stage liver disease are the commonest indications for liver transplantation in Europe and the USA. Typical 1 year survival rates are around 90% for elective transplants. Remarkably few transplants fail because of rejection and, nowadays, technical problems, infection and multisystem failure account for most deaths in the first year. Recurrence of the primary disease, malignancy and death with a functioning graft account for most late deaths.

An increasing number of immunosuppressive agents are now available and this has enabled clinicians to tailor immunosuppression to achieve a balance of good graft function and an acceptable side effect profile. The calcineurin inhibitors (CNIs), tacrolimus and ciclosporin remain the mainstay of immunosuppressive therapy. Corticosteroids are still commonly used, at least during the first 3 months after transplantation. The other drugs used regularly for long-term immunosuppression include azathioprine, mycophenolate, sirolimus and everolimus. Therapy is monitored closely and increasingly tailored to individual patients, with a particular emphasis on preserving renal function and reducing the risk of cardiovascular disease.

Disease specific therapies

Hepatitis B

The primary goal in the management of chronic HBV infection is to prevent cirrhosis, hepatic failure and hepatocellular carcinoma. The ideal outcome is eradication of HBV with HBsAg loss and the prevention of irreversible liver damage. However, the eradication of HBV is near impossible because of the presence of extra-hepatic reservoirs of HBV and the integration of HBV into the host genome and the presence of an intracellular conversion pathway which replenishes the pool of transcriptional templates in the hepatocyte nucleus without the need for reinfection. For this reason, the main treatment goal is continuous viral suppression and current therapies, specifically with oral antiviral agents, are judged by their ability to provide continuous viral suppression.

It is the persistence of covalently closed circular DNA (cccDNA) which is considered to preclude a ‘cure’ for HBV. Thus, therapies currently available for the treatment of chronic HBV are measured in terms of HBeAg seroconversion (in eAg positive disease), viral suppression, ALT normalisation and improvement in liver histopathology. More recently, there has been specific focus on HBsAg quantification, with loss of HBsAg considered a surrogate marker of cccDNA levels (Sung et al., 2005). Thus, all therapies in the treatment of HBV should be benchmarked against HBsAg loss, as a marker of drug utility and efficacy.

There is now concensus amongst the major liver disease authorities in terms of their clinical practice guidelines and the recommended agents available for the treatment of chronic HBV infection. Treatment strategies have broadened and include the potent oral antiviral agents tenofovir (Marcellin et al., 2008; National Institute for Health and Clinical Excellence, 2009) and entecavir (National Institute for Health and Clinical Excellence, 2008) as first-line monotherapies. While these two agents have emerged as the leading oral antivirals, the weaker and more outdated agents such as telbivudine, lamivudine and adefovir are still widely used. The use of lamivudine or adefovir as monotherapy is no longer recommended and should be avoided if at all possible, owing to the high rates of resistance reported with these drugs. Pegylated interferon (peginterferon) alfa-2a has re-emerged as a viable alternative to oral antiviral agents in the treatment of chronic HBV. This is due primarily to its potent immunomodulatory effects which gives it a clear advantage over oral antivirals. Significant rates of surface antigen (sAg) loss have been reported in both HBeAg positive and negative disease and the inclusion of surface antigen quantification has provided an objective tool to assess response to pegylated interferon. The advantages of interferon therapy, such as a finite treatment course, good rates of surface antigen loss in selected patients, must be weighed against the disadvantages associated with an injection-based therapy and the inherent side effect profile associated with interferons. Therefore, a careful and rational approach must be followed when considering treatment of chronic HBV. While reported rates of resistance is extremely low with entecavir, and none reported with tenofovir, the treatment landscape for chronic HBV has changed dramatically from the high rates of resistance previously seen with lamivudine and adefovir. However, when commencing oral antiviral agents, the patient must be aware they are potentially embarking on a lifelong course of treatment.

An issue which must be given further consideration is the potential side effect profile of these relatively new drugs, notwithstanding their potency and documented efficacy. The potential for unforeseen side effects must be considered unresolved, as safety data to date are limited by the relatively short period of time that these drugs have been used in clinical practice. Likewise, physicians will need to remain vigilant for the emergence of resistant virus, even with these potent agents with well-described high-genetic barriers to resistance.

Hepatitis C

The primary aim of treating patients with chronic HCV is viral clearance with sustained virologic response (SVR) defined as the absence of viraemia 6 months after antiviral therapy has been discontinued. Viral clearance improves the patient’s quality of life and reduces the risk of progression to cirrhosis and hepatocellular carcinoma.

Pegylated interferon and ribavirin combination therapy are now the standard care of chronic HCV (National Institute for Health and Clinical Excellence, 2010). The SVR for treatment of naïve patients is of the order of 55% for genotypes 1 and 4 (48 weeks of therapy) and 80–85% for genotypes 2 and 3 (24 weeks of therapy). The treatment duration, however, can be individualised based on the baseline viral load and the speed of virological response during treatment. Patients failing to achieve a significant reduction in viral load after 12 weeks will normally have therapy discontinued. The current standard of care combination therapy is limited by the side effect profile, complications of therapy and poor patient tolerability. Side effects of therapy include influenza-like symptoms, decrease in haematological parameters (haemoglobin, neutrophils, white blood cell count and platelets), gastro-intestinal complaints, psychiatric disturbances (anxiety and depression) and hypo- or hyperthyrodism. It is accepted that these side effects are a major obstacle preventing completion of therapy by hindering compliance or enforcing significant dose reductions. While growth factors (erythropoietin, GCSF) and antidepressants may alleviate some side effects, there remains a clear need for better treatment strategies in chronic HCV infection.

Significant progress has been made in the development of new HCV-specific inhibitors. Data from recent trials have shown a marked improvement in SVR when these new protease inhibitors, telaprevir and boceprevir are given in combination with current standard of care, increasing response rates to 61–75% in genotype 1 HCV infection. It is anticipated that these agents will be available for clinical practice from 2011. Several new HCV-specific inhibitors are currently in clinical evaluation including protease inhibitors, nucleoside and non-nucleoside polymerase inhibitors as well as non-HCV compounds with anti-HCV activity. It is envisaged, as a result of this evolution of HCV therapies, that the treatment options for HCV will become more robust.

Autoimmune hepatitis

Corticosteroids and/or azathioprine are the standard therapy for AIH. Prednisone or prednisolone are administered at doses of 40–60 mg/day alone or at lower doses when combined with azathioprine. The steroid dose is reduced over a 6-week to 3-month period to a target maintenance dose of 7.5 mg/day or lower. The disturbance in aminotransferases usually normalises within 6–12 weeks, but histological remission tends to lag by 6–12 months. Azathioprine at a dose of 1–1.5 mg/kg/day is used as an adjunct to corticosteroid therapy. Azathioprine, used alone, is ineffective in treating the acute phase of AIH. In patients intolerant of azathioprine, or in cases of proven treatment failure, other immunosuppressants have been used, for example, tacrolimus and mycophenolate. Newer corticosteroids such as budesonide, with fewer systemic side effects, have also been used effectively and may have a greater role in the future treatment of AIH.

Primary biliary cirrhosis

Several therapies have been associated with short-term symptomatic improvements in liver function tests. UDCA, the only medication widely used to treat PBC, reduces the retention of bile acids and increases their hepatic excretion. Therefore, it is effective in protecting against the cytotoxic effects of dihydroxy bile acids which accumulate in PBC. However, UDCA does not appear to prevent ongoing bile duct injury and disease progression. Therefore, liver transplantation remains the only effective option in patients with end-stage disease. Immunosuppressive agents such as ciclosporin, azathioprine and methotrexate have also been assessed for the treatment of PBC but clinically significant adverse events outweigh the potential benefits.

Primary sclerosing cholangitis

There is no effective treatment for this condition. UDCA can be used to manage associated cholestasis, and doses as high as 15 mg/kg/day have been advocated despite the limited evidence that it alters the natural history of the disease. Studies with various immunosuppressive agents have been disappointing and transplantation remains the only effective treatment option in patients with advanced disease.

Wilson’s disease

This rare autosomal recessive condition is usually managed with chelation therapy. Penicillamine is the agent of choice in Wilson’s disease as it promotes urinary copper excretion in affected patients and prevents copper accumulation in presymptomatic individuals.^.Initial treatment of 1.5–2 g/day is given in divided doses. Initially, neurological symptoms may worsen because of deposition of mobilised copper in the basal ganglia, but symptomatic patients tend to improve over a period of several weeks. Other therapy-related adverse effects include renal dysfunction, haematological abnormalities and disseminated lupus erythematosis. Therefore, regular monitoring of full blood count and electrolytes is required as well as small doses of pyridoxine (25 mg) to counteract the antipyridoxine effect of penicillamine and the associated neurological toxicity. Patients unable to tolerate penicillamine may respond to trientine. This chelating agent is less potent than penicillamine but has fewer adverse effects. Oral zinc is also used but it too is less potent than penicillamine.

Case studies

Case 16.1

A 56-year-old man is admitted to hospital following haematemesis and melaena. He has a known history of alcoholic liver disease (stopped drinking alcohol 1 year ago) with marked ascites. A provisional diagnosis of bleeding oesophageal varices is made.

A Sengstaken–Blakemore tube is inserted and the balloon inflated as a temporary measure to arrest bleeding. The patient is transferred 8 h later to a specialist regional centre for further management.

Laboratory data on admission are:

Na	124 (133–143 mmol/L)
K	3.0 (3.5–5.0 mmol/L)
Creatinine	131 (80–124 μmol/L)
Urea	14.3 (2.7–7.7 mmol/L)
Bilirubin	167 (3.15 μmol/L)
ALT	24 (0–35 IU/L)
PT	18.9 (13 s)
Albumin	24 (35–50 g/dL)
Hb	8.9 (13.5–18 g/dL)

Drugs on admission:

Spironolactone 200 mg one each morning.

Questions

1. What other action would you have recommended before the patient was transferred to the regional centre?

2. What options (drug and/or non-drug) are likely to be available at the regional centre for managing the patient’s bleeding varices?

3. What further long-term measures would you recommend for this patient?

Answers

1. Initial restoration of circulating blood volume with colloid, followed by cross-matched blood. Fluid replacement is necessary to protect renal perfusion. In view of the patient’s ascites, saline should be avoided. Dextrose 5% with added potassium (hypokalaemia present) would be a reasonable choice. A pharmacological agent to reduce portal pressure, such as terlipressin 1–2 mg every 4–6 h or octreotide 50 μcg/h, should be started. Current evidence supports terlipressin over octreotide. Broad spectrum antibiotics such as cefuroxime and metronidazole should be started intravenously if there is suspicion of abdominal infection or sepsis. There is no evidence that gastric acid suppression is beneficial, but if the bleeding is caused by a gastric mucosal lesion, a proton pump inhibitor such as lansoprazole or omeprazole, or a histamine type-2 receptor antagonist such as ranitidine can be administered.

Spironolactone is likely to be either causing or exacerbating the low sodium and should be discontinued.

Vitamin K, 10 mg intravenously once daily for 3 days, should be administered to try to correct the raised prothrombin time. As the patient has severe liver disease with varices and ascites there is a possibility he may develop encephalopathy. It would be advisable to start lactulose or, if the patient is unable to take medicines orally, administer an enema such as a phosphate enema.

2. Banding/ligation: this has a similar efficacy to sclerotherapy but fewer complications. It involves mechanical strangulation of variceal channels by small elastic plastic rings mounted on the tip of the endoscope.

Transjugular intrahepatic portosystemic shunt (TIPS): this can be used to reduce portal pressure, but there is a risk of precipitating encephalopathy.

Banding is the first-line option for managing bleeding oesophageal varices. Patients who continue to bleed after two endoscopic treatments should be considered for TIPS. Surgery involving portal-systemic shunts or devascularisation are possible options if the above alternatives repeatedly fail. Extra-hepatic portal-systemic shunts are situated outside the liver and divert portal blood flow into the systemic circulation bypassing the liver. Devascularisation involves obliteration of the collateral vessels supplying blood to the varices.

3. Banding/ligation can be performed at regular intervals of 1–2 weeks to obliterate the varices. Once varices have been eradicated, endoscopic follow-up should be undertaken every 3 months for the first year then every 6–12 months thereafter. If varices reappear they should be banded regularly until eradicated again. Non-selective β-blockers such as propranolol are used in the prophylaxis of further bleeds, with the dose adjusted until the heart rate is reduced by 25%, but to not less than 55 beats/min.

Case 16.2

A 68-year-old woman with a long-standing history of alcoholic liver disease is admitted to hospital with a 2-week history of vomiting, confusion, increased abdominal distension and worsening jaundice.

On admission laboratory data are as follows:

Na	116	(133–143 mmol/L)
K	3.8	(3.5–5 mmol/L)
Urea	8.5	(3.3–7.7 mmol/L)
Cr	119	(80–124 μmol/L)
Bilirubin	459	(3–17 μmol/L)
Albumin	23	(35–50 g/L)
ALT	23	(0–35 iu/L)
Alk P	524	(70–300 iu/L)
PT	18.6	(13 s)