Patients have liver function tests checked for a variety of reasons both in the community and in hospital settings. Liver tests can be acutely or chronically deranged and can be abnormal for a number of reasons. A ‘liver screen’ is commonly requested to investigate abnormal liver functions tests. The screen can be modified depending on the age of the patient and whether acute or chronic liver disease is suspected.
A careful history is vital. Salient points in the history should be:
A thorough examination should include
The following tests should be included in a non-invasive liver screen:
In patients <40 years old – caeruloplasmin should be checked
If an acute hepatitis is suspected then Hepatitis A IgM, Hepatitis E IgM, CMV IgM, EBV IgM and HSV IgM should also be checked. If the patient is immunosuppressed then Hepatitis E PCR should be checked rather than the IgM.
Hepatitis B is a DNA virus that is blood borne, spread through contact with infected blood and/or bodily fluids. A vaccine is available to protect against infection. The risk of Hepatitis B infection progressing to chronic Hepatitis B depends on when the infection was acquired. Infections acquired at birth or in childhood are far more likely to progress to chronic hepatitis B. The majority of infections acquired in adulthood will be cleared by the patient’s immune system and will not require treatment.
Hepatitis B surface antigen (HBsAg) – this suggests active infection which could be acute or chronic infection.
Hepatitis B surface antibody (HbsAb) – this will be positive in isolation (other tests will be negative) in someone who has been vaccinated against Hepatitis B. When HbsAb is positive in combination with the core antibody, then this would suggest immunity from previous exposure to the virus.
Hepatitis B core antibody (HbcAb) - this appears during acute infection and persists for life. If positive in isolation it usually suggests resolved past infection. This not usually clinically relevant unless the patient is on immunosuppressive medications or chemotherapy as Hepatitis B can reactivate in this setting. This group of patients do not require referral but should be informed of diagnosis and to be aware if they are offered immunosuppressive medications or chemotherapy.
Acute or chronic? Acute Hepatitis B infection is characterised by the presence of HBsAg and immunoglobulin M (IgM) to the antibody to the core antigen (HBcAg). Chronic Hepatitis B infection is characterised by the persistence of HBsAg for at least 6 months.
Treatment is not required for all patients with Hepatitis B. The decision to treat is based on Hepatitis B DNA levels, ALT levels and the severity of liver disease. Treatment aims to suppress viral replication and is usually required long-term. The goal of treatment is to prevent progression of liver disease and reduce the risk of the complications of cirrhosis such as liver cancer.
Patients with evidence of Hepatitis B (Hepatitis B surface antigen positive) should be referred for assessment, monitoring and consideration of treatment.
Hepatitis B core antibody positive (in isolation) patients do not need referred but need to be told about the diagnosis of past Hepatitis B infection as they need to be aware of the risk of reactivation with immunosuppressive medication. They may require prophylactic treatment if being offered immunosuppressive medication or chemotherapy.
First degree relatives and sexual partners of patients with Hepatitis B should be tested for Hepatitis B and vaccinated if they are negative.
Hepatitis C is an RNA virus which predominantly affects the liver. Not everyone who is infected will develop chronic infection. Approximately 20% of those infected with Hepatitis C will clear the virus spontaneously. The remaining 80% will develop chronic infection and are at risk of liver damage from inflammation, fibrosis, cirrhosis and the development of complications including liver cancer. Treatment aims to clear the virus and therefore prevent progression of liver disease, reduce the complications of cirrhosis including liver cancer and also to prevent onward transmission of Hepatitis C.
Hepatitis C antibody test determines if there has been any previous exposure to the virus but does not test for active infection. It can take a few months for antibodies to develop so the test may need to be repeated if exposure or potential exposure is recent.
Hepatitis C core antigen is a marker of viral replication and will be positive in patients with acute or chronic hepatitis C infection and can be particularly useful when RNA levels are not available.
Hepatitis C RNA tests for virus circulating in the blood stream and if positive indicates active infection.
Treatment is not always required because if the infection is diagnosed acutely, then it may still be cleared by the patient’s own immune system. Treatment is nearly always required for chronic infection and there is highly effective anti-viral treatment for Hepatitis C. Treatment will cure infection in approximately 95% of patients. Treatment is an 8 or 12 week course of tablets. The treatments are very well tolerated by patients with few side effects.
If Hepatitis C antibody is positive but RNA levels are negative then this indicates that the patient has been exposed to the virus but has either previously been successfully treated or has cleared the virus. This group of patients do not need referred for treatment as they do not have active infection.
A positive Hepatitis C antibody test with either a positive core antigen or detectable RNA (i.e. PCR positive) should be referred for assessment and consideration of treatment.
It is important to remember that reinfection can occurs both in individuals who have spontaneously cleared the virus and in those who have been treated and achieved sustained virological response (SVR). This is particularly relevant if risk behaviours continue.
The three main types of autoimmune liver disease are Primary Biliary Cholangitis (PBC), Autoimmune Hepatitis (AIH) and Primary Sclerosing Cholangitis (PSC). Serum autoantibodies and immunoglobulins are frequently checked as part of the liver screen but are not particularly sensitive or specific. Hypergammaglobulinaemia is frequently observed in patients with chronic liver disease of any cause.
Anti-mitochondrial antibody (AMA) - this is raised in >95% of patients with Primary Biliary Cholangitis. Can also be found in up to 20% patients with AIH.
Anti-nuclear antibody (ANA) can be raised in a number of autoimmune conditions and is not sensitive or specific to liver disease. It is raised in patients with type 1 autoimmune hepatitis. It can however be present in other forms of autoimmune liver disease (PBC and PSC) and other forms of chronic liver disease.
Anti-smooth muscle antibody (ASMA) is raised in type 1 autoimmune hepatitis but can also be raised in other forms of chronic liver disease.
Soluble liver antigen / liver pancreas antigen is positive in 10-30% patients with AIH
Liver kidney microsome-1 antibody (LKM) is associated with type 2 autoimmune hepatitis
IgG - is raised in approximately 85% patients with AIH and is used to guide response to treatment
IgA – this can be raised in both alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD)
IgM - this is raised in Primary Biliary Cirrhosis
Patients with abnormal liver function tests and positive autoantibodies or immunoglobulins who are suspected of having autoimmune liver disease should be referred to a gastroenterologist or hepatologist for further assessment.
There are a number of causes of raised serum ferritin which are covered in the haematology module - see this for more.
This section covers hyperferritaemia in the context of liver disease.
Secondary iron overload is seen in a variety of conditions including chronic liver disease of all causes. If ferritin is raised it should prompt checking of transferrin saturations. This will help differentiate between hereditary haemochromatosis and the secondary iron overload seen in chronic liver disease.
Genetic Haemochromatosis (GH) is an autosomal recessive genetic condition characterised by excessive intestinal absorption of iron resulting in iron overload. In Northern Europe, 95% of patients with GH will have mutations in the HFE gene.
The most common mutation associated with GH is the C282Y variant of the HFE gene and clinical signs of iron overload may be seen when two copies of the mutation are present (C282Y homozygotes). A second mutation of the HFE gene is H63D. This is not usually associated with iron accumulation. When a single copy of the H63D mutation is inherited along with a single copy of C282Y this is called a compound heterozygote. In Northern Europe, 10% of people are carriers of one of the two significant mutations: C282Y and H63D, with 1 in 200 being homozygous for the C282Y mutation.
C282Y homozygotes are most at risk of iron overload and account for >90% of GH clinical cases. However not everyone who is C282Y homozygous will develop iron overload or the clinical syndrome of iron overload. Compound heterozygotes (C282Y/H63D) rarely develop clinically significant iron overload. Indeed, in compound heterozygotes, additional factors such as alcohol excess or the metabolic syndrome likely contribute to any hyperferritinaemia more than the molecular abnormality itself.
If ferritin is raised (>300mcg/l in men & postmenopausal women, or >200mcg/l in premenopausal women) then transferrin saturations should be checked. Ferritin is an acute phase protein so can be raised with intercurrent illness.
If fasting transferrin saturation is >50% in men or postmenopausal women or >40% in premenopausal men then an HFE genotype should be requested.
If the HFE gene confirms C282Y homozygosity, they should be referred to a Haemochromatosis specialist. In C282Y homozygotes, with serum ferritin >1000, there is an increased risk of hepatic fibrosis and they should be referred to gastro/liver specialist to undertake fibrosis assessment.
However, there are many causes for an isolated raised serum ferritin. These include intercurrent illness, a wide range of inflammatory conditions, alcohol excess, metabolic syndrome and malignancy. Therefore a raised serum ferritin on its own is not diagnostic of genetic haemochromatosis.
Patients >18 years old with a first degree relative with genetic haemochromatosis should be screened for haemochromatosis with ferritin, transferrin saturations and HFE genotype.
Caeruloplasmin is a copper binding protein. It is requested as part of a liver disease to screen for Wilson’s disease.
Levels can be reduced in:
Levels can be raised in:
Wilson’s disease is an autosomal recessive disorder. It is caused by various mutations in a gene (ATP7B) on chromosome 13. In Wilson’s disease there is a defect in hepatic copper metabolism which causes decreased hepatocellular excretion of copper into bile. This results in accumulation of copper within the liver which is toxic to hepatocytes. Copper is then released into the bloodstream and is deposited in the kidneys, brain and cornea.
Wilson’s disease usually present in childhood or early adulthood. Most patients present with acute or chronic liver disease, neurological or psychiatric symptoms.
Diagnostic features are:
Wilson’s disease can be very challenging to diagnose and patients with suspected Wilson’s disease should be discussed with and or referred to a hepatologist.
Alpha-1 antitrypsin is an enzyme inhibitor which is produced by hepatocytes and transported to the lungs. It protects the lungs against the proteases released by inflammatory cells, particularly neutrophils.
Alpha-1 antitrypsin deficiency is an inherited disorder which increases the risk of chronic obstructive pulmonary disorder (COPD) and chronic liver disease. It is characterised by low levels of alpha-1 antitrypsin. If low levels are detected then phenotyping studies should be done. There are a number of different phenotypes which are coded by the allele which has been inherited. The different phenotypes confer different risks of patients having lung or liver disease. Patients with liver disease are at risk of cirrhosis and hepatocellular carcinoma.
Patients with suspected or confirmed alpha-1 antitrypsin deficiency should be discussed and or referred to a hepatologist for assessment.