13 Liver and biliary tract disease

The liver is the largest organ in the body and performs many important functions (Fig. 13.1). Cirrhosis caused more than 25 000 deaths in the USA in 2003. In the developed world, the most common cause of liver disease is alcohol abuse. In contrast, in the developing world, infections caused by hepatitis viruses and parasites are responsible for most chronic liver disease and hepatobiliary cancer.

PRESENTING PROBLEMS

‘ASYMPTOMATIC’ ABNORMAL LIVER FUNCTION TESTS (LFTs)

When LFTs are measured routinely prior to elective surgery, 3.5% of patients will have some elevation of transaminase concentrations. The majority of patients with persistently abnormal LFTs have significant liver disease. The most common abnormality is alcoholic or non-alcoholic fatty liver disease (pp. 506 and 507). Most hepatologists investigate patients with LFT results greater than twice the limit of normal. The investigations that make up a standard liver screen and additional or confirmatory tests are shown in Box 13.1. An algorithm for investigating abnormal LFTs is illustrated in Figure 13.2. The presence or absence of stigmata of chronic liver disease (p. 492) does not reliably identify patients with significant chronic liver disease. Also, normal LFTs do not exclude significant chronic liver disease, which might progress to cirrhosis, e.g. primary sclerosing cholangitis, haemochromatosis and chronic hepatitis C.

13.1 TESTS TO IDENTIFY THE CAUSE OF LFT ABNORMALITY

Fig. 13.2 Suggested management of abnormal LFTs in asymptomatic patients. (ERCP = endoscopic retrograde cholangiopancreatography; GGT = γ-glutamyl transferase; MRCP = magnetic resonance cholangiopancreatography)

CLINICAL EXAMINATION OF THE ABDOMEN FOR LIVER AND BILIARY DISEASE

JAUNDICE

Jaundice is the yellow appearance of the skin, sclerae and mucous membranes resulting from an increased bilirubin concentration in the body fluids. It is usually detectable clinically when the plasma bilirubin exceeds 50 μmol/l (∼3 mg/dl).

ASCITES

Ascites means the accumulation of free fluid in the peritoneal cavity and is usually due to malignant disease, cirrhosis or heart failure; however, primary disorders of the peritoneum and visceral organs can produce ascites, and these need to be considered, even in a patient with chronic liver disease (Box 13.2).

Pathogenesis of ascites in cirrhosis

Splanchnic vasodilatation, mediated mainly by nitric oxide, is thought to be the main factor leading to ascites in cirrhosis. Systemic arterial pressure falls due to splanchnic vasodilatation as cirrhosis advances, with activation of the renin–angiotensin system, secondary aldosteronism, increased sympathetic nervous activity, increased atrial natriuretic hormone secretion and altered activity of the kallikrein–kinin system (Fig. 13.4). These systems tend to normalise arterial pressure but produce salt and water retention. The combination of splanchnic arterial vasodilatation and portal hypertension alter intestinal capillary permeability, promoting fluid accumulation within the peritoneum.

Fig. 13.4 Pathogenesis of ascites.

Investigations

• USS is the best means of confirming ascites.

• Paracentesis may point to the underlying cause (Box 13.3).

• If the total protein concentration is <25 g/l and ascites albumen lower than serum albumin by 11 g/l or more, this indicates ascites due to transudation rather than exudation.

• Transudates strongly suggest portal hypertension and cirrhosis.

• Exudative ascites (total protein concentration >25 g/l or a serum–ascites albumin gradient <11 g/l) raises the possibility of infection (especially TB), malignancy, hepatic venous obstruction, pancreatic ascites or, rarely, hypothyroidism.

• Ascites amylase activity >1000 U/l identifies pancreatic ascites, and low ascites glucose suggests malignancy or TB.

• Cytology may reveal malignant cells (one-third of cirrhotic patients with a bloody tap have a hepatoma).

• Polymorphonuclear leucocyte counts >250 × 10⁶/l strongly suggest infection (spontaneous bacterial peritonitis, see below).

Management

Successful treatment of ascites relieves discomfort but does not prolong life, and if over-vigorous, can produce serious disorders of fluid and electrolyte balance and precipitate hepatic encephalopathy (p. 489).

Sodium restriction: Restriction to 100 mmol/day (‘no added salt diet’) is normally adequate. Avoid sodium-rich drugs (e.g. many antibiotics, antacids) and those promoting sodium retention (e.g. steroids, NSAIDs).

Diuretics: Most patients require diuretics in addition to sodium restriction. Spironolactone (100–400 mg/day) is the drug of choice for long-term therapy. Some patients will also require loop diuretics, e.g. furosemide.

Paracentesis: Large-volume paracentesis with i.v. albumin can be used as first-line treatment of refractory ascites or when other treatments fail.

Transjugular intrahepatic portosystemic stent shunts (TIPSS, p. 497): Can relieve resistant ascites but do not prolong life.

HEPATORENAL SYNDROME

Ten per cent of patients with advanced cirrhosis and ascites develop the hepatorenal syndrome, which is mediated by severe renal vasoconstriction due to extreme underfilling of the arterial circulation.

Type 1 hepatorenal syndrome: Characterised by progressive oliguria, a rapid rise of the serum creatinine and a very poor prognosis. There is usually no proteinuria, urine sodium excretion is <10 mmol/day and urine/plasma osmolarity ratio is >1.5. Treatment consists of albumin infusions in combination with terlipressin and is effective in about two-thirds of patients. Haemodialysis should not be used routinely because it does not improve the outcome.

Type 2 hepatorenal syndrome: Usually occurs in patients with refractory ascites, is characterised by a moderate and stable increase in serum creatinine, and has a better prognosis.

SPONTANEOUS BACTERIAL PERITONITIS (SBP)

Patients with cirrhosis are very susceptible to ascitic fluid infection.

• SBP usually presents suddenly with abdominal pain, rebound tenderness, absent bowel sounds and fever in a patient with obvious cirrhosis and ascites.

• Abdominal signs are mild or absent in about one-third of patients, in whom hepatic encephalopathy and fever dominate.

• The source of in-fection cannot usually be determined, but most organisms isolated from ascitic fluid or blood cultures are of enteric origin; Escherichia coli is the most frequently found.

• SBP needs to be differentiated from other intra-abdominal emergencies, and the finding of multiple organisms on culture should arouse suspicion of a perforated viscus.

Treatment should be started immediately with broad-spectrum antibiotics, such as cefotaxime. Recurrence of SBP is common and may be reduced by prophylactic quinolones such as norfloxacin (400 mg daily) or ciprofloxacin (250 mg daily).

HEPATIC (PORTOSYSTEMIC) ENCEPHALOPATHY

Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver disease which progresses from confusion to coma. Confusion needs to be differentiated from delirium tremens and Wernicke’s encephalopathy, and coma from subdural haematoma which can occur in alcoholics after a fall. Liver failure and portosystemic shunting of blood are two important factors underlying hepatic encephalopathy and the balance between these varies in different patients. The ‘neurotoxins’ causing the encephalopathy are thought to be mainly nitrogenous substances produced by bacterial action in the gut, which are normally metabolised by the healthy liver and therefore excluded from the systemic circulation. Ammonia has long been considered an important factor but much interest has centred recently on γ-aminobutyric acid.

Clinical assessment

The earliest features are very mild and easily overlooked but mental impairment increases as the condition becomes more severe (Box 13.4). Precipitating causes include trauma, drugs, infection, protein load (including GI bleeding) and constipation. Examination usually shows:

• A flapping tremor (asterixis).

• Inability to perform simple mental arithmetic.

• Inability to draw objects such as a star (constructional apraxia).

• Hyper-reflexia.

• Bilateral extensor plantar responses.

13.4 CLINICAL GRADING OF HEPATIC ENCEPHALOPATHY

Clinical grade	Clinical signs
Grade 1	Poor concentration, slurred speech, slow mentation, disordered sleep rhythm
Grade 2	Drowsy but easily rousable, occasional aggressive behaviour, lethargic
Grade 3	Marked confusion, drowsy, sleepy but responds to pain and voice, gross disorientation
Grade 4	Unresponsive to voice, may or may not respond to painful stimuli, unconscious

An EEG shows diffuse slowing of the normal alpha waves with eventual development of delta waves. Convulsions sometimes occur.

Management

Episodes of encephalopathy are common in cirrhosis and are usually readily reversible until the terminal stages are reached. The principles of management are to treat or remove precipitating causes and to suppress production of neurotoxins by bacteria in the bowel. Lactulose (15–30 ml 8-hourly) is a disaccharide which is taken orally and produces an osmotic laxative effect. It reduces the colonic pH, thereby limiting colonic ammonia absorption, and promotes the incorporation of nitrogen into bacteria. Neomycin (1–4 g 4–6-hourly) acts by reducing the bacterial content of the bowel. Dietary protein restriction is rarely needed and can lead to worsening nutritional state in already malnourished patients.

ACUTE LIVER FAILURE

Acute liver failure is an uncommon syndrome in which hepatic encephalopathy, characterised by mental changes progressing from confusion to stupor and coma, results from a sudden severe impairment of hepatic function (Box 13.5). Any cause of liver damage can produce acute liver failure, provided it is sufficiently severe.

13.5 CLASSIFICATION OF ACUTE LIVER FAILURE

Acute viral hepatitis is the most common cause world-wide. Paracetamol toxicity (p. 37) is the most frequent cause in the UK. Acute liver failure occurs occasionally with other drugs, or from Amanita phalloides (mushroom) poisoning, in pregnancy, in Wilson’s disease, or following shock (p. 22). The cause remains unknown in others; these patients are often labelled as having non-A–E viral hepatitis or cryptogenic acute liver failure.

Clinical assessment

• Cerebral disturbance (hepatic encephalopathy) is the cardinal manifestation of acute liver failure, but in the early stages this can be mild and episodic.

• The initial clinical features are described above.

• Cerebral oedema may occur and can produce increased intracranial pressure causing unequal or abnormally reacting pupils, fixed pupils, hypertensive episodes, bradycardia, hyperventilation, profuse sweating, local or general myoclonus, focal fits or decerebrate posturing.

• Papilloedema occurs rarely and is a late sign.

• More general symptoms include weakness, nausea and vomiting.

• Right hypochondrial discomfort is an occasional feature.

Examination shows:

• Jaundice, which develops rapidly and is usually deep in subsequently fatal cases. However, jaundice is not seen in Reye’s syndrome, and death in other causes of acute liver failure occasionally occurs before jaundice develops.

• Hepatomegaly is unusual and, in the presence of a sudden onset of ascites, suggests venous outflow obstruction (Budd–Chiari).

• Splenomegaly is uncommon and never prominent.

• Ascites and oedema are late developments and may be a consequence of fluid therapy.

Investigations

Investigations are used to determine the cause of the liver failure and the prognosis (Boxes 13.6 and 13.7).

• The prothrombin time rapidly becomes prolonged as coagulation factor synthesis fails; this is the laboratory test of greatest prognostic value and should be carried out at least twice daily.

• Plasma aminotransferase activity is particularly high after paracetamol overdose, reaching 100–500 times normal, but falls as liver damage progresses and is not helpful in determining prognosis.

13.7 ADVERSE PROGNOSTIC CRITERIA IN ACUTE LIVER FAILURE ^*

Paracetamol overdose

• H+ >50 nmol/l (pH <7.3) at or beyond 24 hrs following the overdose

• Serum creatinine >300 μmol/l + prothrombin time >100 secs + encephalopathy grade 3 or 4

^* Predict a mortality rate of ≥90%. Creatinine of 300 μmol/l = 3.39 mg/dl. Bilirubin of 300 μmol/l = 17.6 mg/dl.

Management

A patient with acute hepatic damage should be observed in a high-dependency or intensive care unit as soon as a progressive prolongation of the prothrombin time or hepatic encephalopathy is identified, so that prompt treatment of complications (hypoglycaemia, infections, renal failure, metabolic acidosis) can be initiated. Treatment is supportive in the hope that hepatic regeneration will occur. N-acetylcysteine therapy may improve outcome, particularly in patients with acute liver failure due to paracetamol poisoning. Liver transplantation is an increasingly important treatment option. Patients with a poor prognosis (Box 13.7) should, wherever possible, be transferred to a transplant centre early to allow time for assessment and to maximise the time for a donor liver to become available. Survival following liver transplantation for acute liver failure is improving and 1-yr survival rates of ∼60% can be expected.

CHRONIC LIVER FAILURE

Chronic liver failure develops when the functional capacity of the liver can no longer maintain normal physiological conditions and is characterised by the presence of encephalopathy and/or ascites. The term ‘hepatic decompensation’ or ‘decompensated liver disease’ is often used when chronic liver failure occurs. The most common cause is cirrhosis, which is usually the result of chronic liver injury occurring over many years. In addition to encephalopathy and/or ascites, patients may develop peripheral oedema, variceal bleeding, renal failure, jaundice, and hypoalbuminaemia and coagulation abnormalities due to defective protein synthesis.

CHRONIC LIVER DISEASE

CIRRHOSIS

Any condition leading to persistent or recurrent hepatocyte death may lead to hepatic cirrhosis (Box 13.8). World-wide, the most common causes are viral hepatitis and alcohol. Prolonged biliary damage or obstruction, as can occur in primary biliary cirrhosis, sclerosing cholangitis and post-surgical biliary strictures, will also result in cirrhosis.

Clinical features

Cirrhosis may be entirely asymptomatic; in life it may be found incidentally at surgery or may be associated with minimal features such as isolated hepatomegaly. Frequent symptoms include weakness, fatigue, muscle cramps, weight loss and non-specific digestive symptoms such as anorexia, nausea, vomiting and upper abdominal discomfort. Otherwise, clinical features are due mainly to hepatic insufficiency and portal hypertension.

• Hepatomegaly is common in alcoholic liver disease and haemochromatosis. In other causes of cirrhosis (e.g. viral hepatitis or autoimmune liver disease), progressive hepatocyte destruction and fibrosis gradually reduce liver size. The liver is often hard, irregular and painless.

• Jaundice is usually mild when it first appears and is due primarily to a failure to excrete bilirubin.

• Palmar erythema can be seen early in the disease but is of limited value as it occurs in many other conditions and in some normal people.

• One or two small spider telangiectasia are found in ∼2% of healthy people and can occur transiently in greater numbers in the third trimester of pregnancy, but otherwise they are a strong indicator of liver disease.

• Endocrine changes are noticed more readily in men, who show loss of male hair distribution and testicular atrophy. Gynaecomastia is common and can be due to drugs such as spironolactone.

• Easy bruising becomes more frequent as cirrhosis advances.

• Epistaxis is common and sometimes severe; it can mimic upper GI bleeding if the blood is swallowed.

• Splenomegaly and collateral vessel formation are features of portal hypertension, which occurs in more advanced disease.

• Ascites is due to a combination of liver failure and portal hypertension (p. 493) and signifies advanced disease.

• Evidence of hepatic encephalopathy also becomes increasingly common with advancing disease.

• Non-specific features include finger and toe clubbing.

• Dupuytren’s contracture is traditionally regarded as being associated with cirrhosis, especially that due to alcohol, but the evidence for this association is weak.

Management and prognosis

Management of cirrhosis is by treatment of the underlying cause and its complications, or by liver transplantation in selected cases of advanced cirrhosis. Prognosis is linked to severity (Box 13.9).

13.9 CHILD–PUGH CLASSIFICATION OF PROGNOSIS IN CIRRHOSIS

PORTAL HYPERTENSION

Portal hypertension is characterised by prolonged elevation of the portal venous pressure (normally 2–5 mmHg). Patients developing clinical features or complications of portal hypertension usually have portal venous pressures >12 mmHg.

Extrahepatic portal vein obstruction is the usual cause of portal hypertension in childhood and adolescence, while cirrhosis causes 90% or more of portal hypertension in adults in developed countries. Schistosomiasis is a common cause of portal hypertension world-wide but it is infrequent outside endemic areas. Other causes are shown in Box 13.10 and Figure 13.5. Increased portal vascular resistance leads to a gradual reduction in the flow of portal blood to the liver and simultaneously to the development of collateral vessels, allowing half or more of the portal blood to bypass the liver and enter the systemic circulation directly.

13.10 CAUSES OF PORTAL HYPERTENSION ACCORDING TO SITE OF ABNORMALITY

Extrahepatic post-sinusoidal 1

• Budd–Chiari syndrome

Intrahepatic post-sinusoidal 2

• Veno-occlusive disease

Sinusoidal 3

• Cirrhosis ^*

• Cystic liver disease

• Partial nodular transformation of the liver

• Metastatic malignant disease

Intrahepatic pre-sinusoidal 4

• Schistosomiasis ^*

• Sarcoidosis

• Congenital hepatic fibrosis

• Vinyl chloride

• Drugs

Extrahepatic pre-sinusoidal 5

• Portal vein thrombosis due to sepsis ^* (umbilical, portal pyaemia) or procoagulopathy (thrombotic diseases, oral contraceptives, pregnancy), or secondary to cirrhosis

• Abdominal trauma, including surgery

• Malignant disease of pancreas or liver

• Pancreatitis

• Congenital