Abstract
With an increase in prevalence of alcohol abuse and obesity, cirrhosis is on the rise. To prevent progression to end-stage liver disease and liver failure, abnormalities must be picked up early. This article provides an overview of liver failure and how to approach investigation and management of patients at risk.
The GP curriculum and liver failure
Disorders of the liver are not featured prominently in the GP curriculum. However,
Symptoms: haematemesis and malaena and jaundice Investigations: liver function tests, abdominal ultrasound and knowledge of secondary care investigations including liver biopsy
Manifestation of alcohol problems: liver damage Aetiology, presenting symptoms, treatment and prevention of hepatitis B and C
The liver is one of the most complex organs in the body. Its functions include
glycogen storage processing fat and proteins production of clotting factors metabolism of drugs removal of alcohol, poisons and toxins production of bile for transport to the gut to aid digestion of fat
Therefore, when the liver is diseased, the consequences are far-reaching. Liver failure occurs when the liver loses the ability to regenerate or repair. It can be acute or chronic. Acute liver failure occurs in patients with a previously normal liver, while chronic liver failure occurs in people with underlying chronic liver disease in whom decompensation has occurred.
Acute liver failure
Acute liver failure is an uncommon condition with a multitude of causes. The most common cause is paracetamol overdose, although you might also see it in patients with hepatitis A and B, or idiosyncratic drug reactions (e.g. isoniazid/rifampicin combination treatment or non-steroidal anti-inflammatory drugs [NSAIDs]). See Box 1 for a list of causes. The symptoms in the early stages include jaundice and right upper quadrant pain. However, as the condition worsens, encephalopathy can develop. This occurs when the liver fails to metabolize toxins — including ammonia. The resulting brain and nervous system damage lead to changes in mental state, ranging from mild confusion to coma in severe cases. Encephalopathy is graded from 1 to 4:
Grade 1 — altered mood or behaviour Grade 2 — increasing drowsiness, confusion and slurred speech Grade 3 — stupor, incoherence, restlessness and significant confusion Grade 4 — coma
Causes of acute liver failure
Infection — hepatitis A, B, C and E; cytomegalovirus; Epstein Barr virus and varicella Drugs — paracetamol, isoniazid, monoamine oxidase inhibitors, NSAIDs, ecstasy, phenytoin and herbal medicines Metabolic — Wilson's disease and Reye's syndrome Vascular — Budd—Chiari syndrome and ischaemic hepatitis Other — acute fatty liver of pregnancy and lymphoma
It may be necessary to have a collateral history due to the alteration in mental state. Ask about the onset of jaundice and encephalopathy and try to identify a potential cause. This should include taking a thorough drug history, including over-the-counter, alternative and recreational drugs.
It is essential to refer to a hospital urgently so that appropriate treatment can be started as soon as possible. Treatment will depend on the cause (such as N-acetylcysteine for paracetamol ingestion) but patients also require intensive monitoring for complications. Patients with grade 3 or 4 encephalopathy usually require ventilation. Sepsis, renal failure and haemorrhage may develop. In some cases, supportive treatment is enough and the liver can regenerate completely. However, if the liver damage is so severe that this cannot occur, then the only definitive treatment is liver transplantation.
Chronic liver disease and cirrhosis
With small insults, the liver can potentially recover with no long-term effects. Chronic liver disease is the process by which there is gradual destruction of the liver over time. This leads to fibrosis and eventually cirrhosis. Cirrhosis is the pathological end stage of any chronic liver disease. Cirrhosis implies irreversible liver damage and can lead to end-stage liver disease (chronic liver failure). However, in the early stages of disease, there are often no symptoms and minimal derangement in liver function tests, if any, and so cases are often severe when they are picked up.
Aetiology
The most common causes of cirrhosis are alcoholic liver disease, chronic hepatitis B or C infection and non-alcoholic liver disease. These are discussed in more detail later. See Box 2 for more causes.
Causes of cirrhosis
Chronic alcohol abuse Chronic hepatitis B or C infection Non-alcoholic fatty liver disease (NAFLD)
Autoimmune disease — primary biliary cirrhosis, autoimmune hepatitis and primary sclerosing cholangitis Genetic disorders — alpha-1-antitrypsin deficiency, Wilson's disease and haemachromatosis Drugs — amiodarone and methotrexate Vascular causes — Budd-Chiari syndrome
The cause remains unknown in 15% of cases.
Classification
Cirrhosis can be classified into compensated and decompensated cirrhosis. In compensated cirrhosis, the liver is still able to perform the majority of its functions and complications such as portal hypertension have not yet developed. Therefore, patients may be completely asymptomatic or have vague symptoms such as fatigue, malaise, anorexia, nausea and weight loss.
As cirrhosis progresses, more hepatocytes die and portal hypertension develops, so the liver can no longer function properly. This is decompensated cirrhosis. See Box 3 for a summary of the main features of decompensated cirrhosis.
Signs of decompensated cirrhosis
Encephalopathy Jaundice Haemorrhage from varices leading to haematemesis/malaena Ascites
In decompensated cirrhosis, the liver cannot make proteins such as albumin as effectively. There is reduced production of clotting factors and reduced clearance of waste products such as bilirubin.
What causes portal hypertension? As cirrhosis progresses, the scar tissue restricts blood flow within the liver. This leads to ‘back pressure’ within the portal vein — or portal hypertension. Because the portal vein delivers blood from the gut to the liver, portal hypertension can also cause increased pressure in the oesophageal and gastric vessels, causing varices. These can bleed easily, resulting in haematemesis and malaena.
Another feature of decompensation is ascites. The main factors causing this in cirrhosis are portal hypertension and sodium retention. Portal hypertension forces more fluid into the peritoneal cavity due to the increased hydrostatic pressure. Sodium retention occurs due to systemic vasodilation that leads to a reduction in effective blood volume. The resulting decrease in renal blood flow causes activation of the renal angiotensin system and retention of sodium and water, which contributes to ascites and peripheral oedema. Low albumin levels have little effect on ascites formation.
As with acute liver failure, impaired liver function leads to less ammonia being metabolized. In addition, cirrhosis causes shunting of blood from the portal to the systemic circulation, reducing ammonia clearance further. This causes encephalopathy.
Assessment
In assessing a patient with suspected chronic liver disease or cirrhosis, it is essential to take a comprehensive history. Ask about constitutional symptoms, such as fatigue, nausea and weight loss, and symptoms of decompensation that are
abdominal distension (due to ascites) haematemesis and/or malaena episodes of altered mental state jaundice and pruritus
A thorough past medical history should include any history of metabolic syndromes (such as diabetes, obesity, dyslipidaemia and hypertension), which might suggest Non-alcoholic fatty liver disease (NAFLD). A past history of autoimmune conditions might suggest autoimmune hepatitis as a potential cause. It is important to elicit an accurate alcohol and drug history, including prescription, over-the-counter, alternative and recreational drugs. Ask about family history of autoimmune or liver diseases. Enquire sensitively about risk factors for hepatitis infection, including unprotected sexual intercourse and intravenous drug use.
Possible features to be elicited on examination are listed in Box 4.
Possible examination findings in cirrhosis
Asterixis — ‘liver flap’ — take the patient's hand and gently hyperextend the wrist and fingers. Hold their hand in that position and if you feel a slow clonic flexion movement of the patient's fingers against your hand, then asterixis is present Jaundice Spider naevi, dupuytren's contracture, gynaecomastia and palmar erythema Abdominal distension and shifting dullness Hepato-and/or splenomegaly Muscle wasting Bruising Hair loss Oedema
Investigations
Investigations determine the severity of the cirrhosis and aim to identify an underlying cause. The initial battery of tests should include
liver function tests albumin alpha fetoprotein full blood count coagulation screen urea and electrolytes viral hepatitis screen
There are many biochemical changes associated with chronic liver disease. Within the liver function tests, aspartate aminotransferase (AST) and alanine transaminase (ALT) are increased with hepatocellular damage, although it is important to note that normal values do not exclude cirrhosis. An AST : ALT ratio of greater than 1 is a strong predictor of cirrhosis.
Bilirubin is often normal in uncomplicated cirrhosis and increases as cirrhosis progresses. Gamma glutamyl transferase is increased in enzyme activation by alcohol and some drugs. Albumin is produced by the liver, so is a marker of its synthetic function and is reduced in decompensated cirrhosis.
Hyponatraemia is a common finding in cirrhosis with ascites and worsens as cirrhosis progresses. Alpha fetoprotein is important, in combination with ultrasound, to check for the presence of hepatocellular carcinoma.
Among the haematology tests, the full blood count may show anaemia and thrombocytopenia (as portal hypertension causes hypersplenism and sequestration of platelets) and there can be a macrocytosis with alcohol abuse. The coagulation screen is an important test of liver function due to the liver's role in the production of clotting factors. Prolonged prothrombin time (and therefore international normalized ratio [INR]) is a marker of hepatic synthetic dysfunction.
Tests aimed at finding a cause for the liver disease include a viral hepatitis screen. For hepatitis C, this involves an antibody test. A positive antibody test should prompt a test for hepatitis C RNA to check for chronic infection. A positive hepatitis B surface antigen (HBsAg) test with evidence of active viral replication by hepatitis B virus DNA indicates chronic hepatitis B infection.
Other blood tests to consider include:
autoantibodies — anti-nuclear and anti-smooth muscle for autoimmune hepatitis and anti-mitochondrial for primary biliary cirrhosis alpha-1-antitrypsin levels caeruloplasmin and urinary copper — to exclude Wilson's disease transferrin saturation to exclude haemochromatosis fasting glucose, insulin, triglycerides and uric acid if considering NAFLD
Imaging is also important. Liver ultrasound, computerized tomography and magnetic resonance imaging show a small, nodular liver and allow detection of complications of cirrhosis, such as splenomegaly, ascites and hepatocellular carcinoma. Liver biopsy is the most specific and sensitive test for cirrhosis. As well as confirming the diagnosis, it can also give a clue to the underlying cause.
Oesophagogastroduodenoscopy is recommended for all patients with cirrhosis to screen for varices and portal hypertensive gastropathy secondary to portal hypertension. This allows patients to be started on prophylaxis — either through medical (with beta blockers) or through a prophylactic banding programme.
Classification of severity
The Child—Pugh—Turcotte system is used to classify the severity of cirrhosis and is based on the presence of ascites, encephalopathy and the serum bilirubin, albumin and clotting (See Box 5). Cirrhosis is classified as
A — well compensated B — significant functional compromise and C — decompensated.
Management of cirrhosis
There is no treatment that can reverse the scarring that has already occurred in cirrhosis. However, treating the underlying cause can slow the progression of cirrhosis and therefore prevent the patient advancing to a higher Child—Pugh—Turcotte score. In addition, it is important to prevent any superimposed injury. This is done through
avoiding alcohol and hepatotoxic drugs (e.g. NSAIDs or paracetamol at doses greater than 2 g/day) vaccinating against hepatitis A and B weight loss for those with a high body mass index and adequate nutrition
Ascites is treated with fluid restriction, a low-salt diet and diuretics. Spironolactone is the best initial choice and works by increasing sodium excretion. Transjugular intrahepatic portosystemic shunt can be an option to treat ascites by reducing portal hypertension. Patients with varices can be treated medically, usually with beta blockers. In addition, endoscopic screening allows for banding or ligation of varices if required.
Child-Pugh (Child—Pugh—Turcotte) classification
A score of 5–6 is class A (life expectancy, 15–20 years), a score of 7–9 is class B (life expectancy, 4–14 years) and a score of 10–15 is class C (life expectancy, 1–3 years). This aligns with a perioperative mortality (for abdominal surgery) of 10, 30 and 80%, respectively.
Cirrhosis is a major risk factor for hepatocellular carcinoma. The degree of risk varies according to the cause of the cirrhosis, with hepatitis C being most commonly associated. Regular liver ultrasound scans and alpha fetoprotein measurements are used to screen for this.
The only definitive treatment for cirrhosis is liver transplantation and this should be considered early in the disease. Crucially, if patients with cirrhosis have an increase in their Child—Pugh—Turcotte score, for example if they present with new-onset ascites or jaundice, they should be referred back to the gastroenterologist for consideration of transplantation.
Referring to secondary care
As a GP, it can be difficult to know when to refer patients and if so how urgently. It is imperative that all patients with chronic liver disease or cirrhosis are referred to a liver or gastro-intestinal specialist. They should also be monitored for complications. Patients with rapid worsening of jaundice, signs of infection, bleeding or increasing ascites should be considered for immediate referral. Any patient showing signs of encephalopathy should be immediately referred.
Common causes of cirrhosis
Alcoholic liver disease
As the liver metabolizes 90% of the alcohol that is consumed, prolonged excessive alcohol use has a major effect on the liver. The breakdown of alcohol produces fat, which is stored in the liver, causing ‘fatty liver’. Continuing to drink alcohol can lead to alcoholic hepatitis. This ranges from mild (which can be asymptomatic and cause only mild derangement of liver function tests) to severe, where jaundice and eventual liver failure can quickly occur, leading to death in some cases. Just as with all causes of liver disease, the repeated damage over time leads to fibrosis and cirrhosis. Stopping drinking, even at this late stage, is beneficial as it can prevent progression of the cirrhosis.
Non-alcoholic fatty liver disease
NAFLD is now the most common cause of chronic liver disease in affluent countries and will continue to rise in incidence due to the high prevalence of obesity. It is a spectrum of conditions, from steatosis (fatty liver) to steatohepatitis [fat associated with inflammation and known as non alcoholic steatohepatitis (NASH)] through to cirrhosis.
Previously, fatty liver was thought to be a benign condition. However, it has emerged that alcoholic liver disease and non-alcoholic liver disease share the same stages: steatosis followed by steatohepatitis and progressing to cirrhosis. The only difference is that alcoholic liver disease is caused by drinking too much alcohol whereas the non-alcoholic form does not have alcohol as a causative factor. The major risk factors for NAFLD are
obesity insulin resistance (type 2 and not type 1 diabetes is associated) hypertension hyperlipidaemia
NAFLD is thought to be the liver's manifestation of the metabolic syndrome. It is usually picked up on blood tests that show raised liver transaminases (although these can be normal even in NASH). The diagnosis is one of exclusion. There should be no history of excessive alcohol use and a blood screen should not have revealed an alternative cause. In these patients, it is reasonable to have a 4-month trial of lifestyle modification, with a controlled weight loss programme. Too rapid loss of weight has been associated with accelerated progression of NASH in some patients. If this does not cause an improvement in liver function, then the patient should be referred to a hepatologist for further assessment and management.
Viral hepatitis
Chronic viral hepatitis is most commonly due to infection with hepatitis B or C. About a fifth of patients with chronic viral hepatitis go on to develop cirrhosis. This can take months or years to develop, so it is important to test people who may be at risk for infection as treatment can prevent progression of the disease — see Box 6.
Blood test findings in hepatitis B and C
HBsAg positive and hepatitis B virus DNA positive
Hepatitis C antibody positive and hepatitis C virus DNA positive
Both hepatitis B and C are transmitted by the parenteral route, for example through intravenous drug use or sexual contact. If a patient is found to test positive for either virus, then refer to a hepatologist for consideration of antiviral therapy to reduce the rate of progression of disease. Cirrhosis secondary to hepatitis C has a 15% chance of progressing to hepatocellular carcinoma.
Key points
Acute liver failure occurs in patients with a previously healthy liver and must be referred immediately Chronic liver disease has many different causes but can progress to cirrhosis if untreated. High-risk patients must be investigated and treated early Abnormal liver function tests with raised transaminases are not a benign result and must be acted upon