Investigating abnormal liver function tests

Contributed by Dr Stephen Ryder, consultant hepatologist at Queens Medical Centre, Nottingham University Hospitals NHS Trust.

Section 1 Types of liver function test
Biochemical tests of liver function are now routine in the investigation of a wide range of symptoms and during health checks.

The usual LFTs ordered include two separate tests. Serum albumin and bilirubin provide a true measure of hepatic function, although both can be abnormal for a number of non-hepatic causes.

Other tests conducted are liver enzyme levels, usually alanine aminotransferase (ALT) or aspartate transaminase (AST) in combination with gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP).

ALT or AST are sensitive markers of hepatocyte injury but are also found in decreasing concentration in cardiac muscle, skeletal muscle, the kidney, brain, pancreas, lung and blood cells. As transaminases are present in highest concentrations in liver, significant elevation is usually due to hepatocyte injury.

GGT is found in both hepatocytes and in biliary epithelial cells. Its main utility as a marker is in the diagnosis of biliary tract disease, in combination with ALP. It is widely and incorrectly regarded as a sensitive and specific marker of alcohol misuse.

Transaminases
Most laboratories produce a normal range for transaminases based on local population values, with a cut off for abnormality two standard deviations from the mean. This should imply that some patients will have abnormal tests but no liver pathology.

In reality, the situation is more complex than this, because the value of ALT varies with age (increases) and there is compelling evidence from diseases such as hepatitis C and haemochromatosis that significant liver injury may be present with normal transaminase levels.

There is no doubt that abnormal transaminases are a marker for increased risk of morbidity and mortality, partly from liver disease, but there is also an increased risk of death from non-hepatic causes, probably as a result of the association of non-alcoholic fatty liver disease (NAFLD) with the metabolic syndrome.

AST and ALT are transiently raised in a variety of acute illnesses, including acute hepatitis when a patient may or may not be symptomatic. AST and ALT may be chronically raised in asymptomatic patients in a variety of chronic liver diseases.

Very high levels of amino-transferases have a smaller differential diagnosis. In hospital populations, levels greater than 1,000IU/l are most likely due to hepatic ischaemia or cholangitis due to bile duct stones.1

In primary care, viral hepatitis is probably more common as a cause of elevated ALT levels.

Other tests
LFTs contain no information about the process most important in determining the outcome of any cause of chronic liver disease, hepatic fibrosis. While markers of fibrosis are available (hyaluronic acid, procollagen III) these have a relatively low sensitivity and specificity for hepatic fibrosis and have not yet gained wide acceptance.

Non-serological methods of assessing fibrosis are available, for example measurements of liver stiffness using ultrasound, but these are also subject to considerable inter- and intra-observer variability and are not widely used. Biopsy remains the only commonly available method to assess liver fibrosis.

Section 2 Investigating abnormal transaminases
Clinically, by far the commonest scenario is abnormal transaminases in asymptomatic patients. Patients with jaundice or a low albumin are easily recognised as having serious disease.

An asymptomatic patient found to have abnormal liver enzymes should have a history taken for specific factors that may predispose to liver disease, including alcohol consumption, prior medical interventions such as surgery or transfusion, and IV drug use or tattooing, plus a detailed drug history.

Ultrasound of a fatty liver: variants account for a significant proportion of elevated liver enzyme cases

The history and examination should also aim to exclude non-hepatic causes of liver enzyme elevation. The commonest are right-sided heart failure or constrictive pericarditis, which can produce significant hepato-megaly and abnormal LFTs with relatively modest symptoms, and endocrine disorders, diabetes and thyroid dysfunction.

BMI and ideally waist circumference should also be recorded, as the fatty liver variants now account for a significant proportion of elevated liver enzymes.

Physical examination aims to detect stigmata of chronic liver disease: spider naevi, clubbing, hepatomegaly or splenomegaly. These signs are rarely present in the absence of hepatic cirrhosis.

Liver disease
Abnormal LFTs may be the only indication of chronic liver disease, and a proportion of patients with chronic liver disease will progress to cirrhosis. There is now some evidence that increasing LFT levels (AST and ALT) are directly associated with increased liver-related mortality rates.2 When thorough investigation is performed, the majority of patients are found to have significant disease warranting treatment or follow up.3

There is no evidence that the level of abnormality of transaminases affects the rate of positive findings on investigation or the severity of any liver disease found on biopsy.

GGT
There is some evidence that the yield from investigating an isolated elevated GGT may be different than for ALT/AST. The myth that a raised GGT is sensitive and specific for alcohol excess persists despite considerable evidence to the contrary.

In asymptomatic patients with a raised GGT alone, who do not drink excessively, hepatic fibrosis is present in only 11 per cent of patients.4 In contrast, patients drinking excess alcohol who have an isolated raised GGT rarely had significant liver damage.

AST:ALT ratio
The ratio of AST to ALT can give a clue as to the aetiology of the liver disorder. In most chronic liver diseases, ALT levels are higher than AST, except when cirrhosis has developed. However, an AST:ALT ratio greater than two is suggestive of alcoholic liver disease.

Section 3 Timing
There are no data on the best time to investigate abnormal LFTs in asymptomatic patients. When liver biopsy has been used to investigate such patients, with or without a prior liver screen, all studies have used a minimum of six months' duration of abnormality.

It has been suggested that LFTs should either be investigated after three months or that there should be a staged approach to investigation over 0 to six months.

Likely causes
Some expert reviews suggest treating the most likely cause of the abnormal LFTs - alcohol (by abstinence), hepatotoxic drugs (by drug cessation) and non-alcoholic fatty liver disease (by weight reduction and diabetes control) - prior to more detailed investigation.

There is very compelling evidence that obesity and diabetes, acting via fatty liver, cause abnormal liver enzymes and increase the risk of death.5 In these groups there is no evidence that abnormal liver enzymes have lesser significance.

Serological screening
The purpose of initial serological screening is to establish a cause for liver enzyme elevation wherever possible. The serology is cheap and effective at producing a diagnosis.

The route of investigation (ultrasound or blood tests) is generally directed by the pattern of enzyme abnormality. Elevated ALP and GGT should primarily be investigated by ultrasound followed by serology, whereas the opposite is the case for transaminitis.

An appropriate panel of initial investigations is shown in the box on the right.

INVESTIGATION OF ASYMPTOMATIC PATIENTS WITH ELEVATED LIVER ENZYME LEVELS
TestAbnormalityInterpretation
FBC
  • Macrocytosis
  • Thrombocytopenia
  • Specific alcohol for excess only if GGT elevated
  • Suggest hypersplenism (portal hypertension)
Autoantibodies and immunoglobulins
  • AMA positive, IgM - Diagnostic of primary
  • ASM/ANA positive, biliary cirrhosis IgG
  • Strongly suggestive of autoimmune hepatitis
FerritinElevatedSuggests haemochromatosis - HFE mutations can confirm in 90%
Hepatitis B surgace antigenPositive
Implies chronic infection

Hepatitis C
surgace antigen
Positive Implies chronic infectioImplies chronic infection
Anti-endomysial antibodiesPositiveAnti-endomysial Positive Suggests coeliac disease
antibodies
Alpha-1- antitrypsin level LowSuggests deficiency.
Phenotype required. (PiZZ
or PiM implicated)
Ultrasound liverMass/dilated ductsTumour/stones
AMA: antimitochondrial antibodies
ASM: anti-smooth muscle; ANA: anti-nuclear antibodies

SECTION 4 FURTHER INVESTIGATION
For the majority of patients with abnormal liver enzyme levels, the pattern is non-specific, commonly raised ALT and GGT. The only investigation likely to produce a diagnosis in the absence of diagnostic serology is liver biopsy. The effects of alcohol, drugs and the non-alcoholic fatty liver variants can only be diagnosed on liver biopsy.

Biopsy
Percutaneous liver biopsy does, however, involve a finite risk, primarily of haemorrhage, and hence the decision to offer liver biopsy has to be a balance of potential benefits of a diagnosis in the prevention of progressive hepatic fibrosis versus the risk.

In a study using a cut off for transaminase levels of twice normal in 354 patients, a histologically normal liver was found on biopsy in only 6 per cent of patients,4 suggesting there is usually a diagnosis to be made.

The commonest diagnosis made on liver biopsy in this setting is fatty liver or non-alcoholic steatohepatitis (NASH), (see box). This diagnostic group accounts for two-thirds of unexplained elevation of liver enzymes. Other important diagnoses were conditions such as antimitochondrial antibody negative primary biliary cirrhosis and autoimmune hepatitis.

The balance between the risk and benefits of liver biopsy is important to consider. This benefit is clear in conditions such as autoimmune hepatitis, but less so in conditions such as alcoholic liver injury.

Conditions with a specific treatment that can change the natural history of the liver injury are found in 7-18 per cent of patients undergoing biopsy.

Steatosis
NASH accounts for two-thirds of the patients undergoing liver biopsy for abnormal LFTs. Simple steatosis is benign but those with significant inflammation, particularly with fibrosis on index biopsy, can and do progress to cirrhosis, with between 10 and 30 per cent having developed cirrhosis within 10 years.6

There is as yet no specific medical therapy for NASH, but weight loss has been proposed as a strategy to normalise liver enzyme levels and may improve prognosis. No data is currently available to confirm this. This would seem a sensible strategy provided weight loss is not too rapid, because starvation can also cause fatty liver.

Risk factors

At present, in patients with suspected NASH, risk factors such as hypertriglycerideaemia and diabetes should be addressed and a programme of exercise and weight reduction tried before liver biopsy is offered.

If these manoeuvres are unsuccessful, biopsy will confirm the diagnosis and allow identification of those at significant future risk for clinical trials of new therapy.

Early reports of the use of drugs that reduce insulin resistance, such as metformin and pioglitazone, show promise for the future.

Conclusion
ALT and GGT are commonly elevated and there is evidence that significant pathology is found if these elevations are further investigated. There is also evidence that our current normal ranges for these investigations are inappropriate and the population group being screened should be taken into account.

There is no evidence to suggest that the level of enzyme abnormality in asymptomatic patients has any influence on this risk of finding significant abnormalities on further investigation.

Biopsy findings
Findings on liver biopsy for unexplained abnormal liver enzyme elevation in 354 patients4
Final diagnosisNumber (%)
Non-alcoholic steatohepatitis120 (34)
Fatty liver115 (32)
Cryptogenic hepatitis32 (9)
Drug-related damage27 (7.6)
Normal liver21 (5.9)
Alcohol10 (2.8)
Autoimmune hepatitis7 (1.9)
Granuloma/sarcoid6 (1.7)
Primary biliary cirrhosis5 (1.4)
Primary sclerosing cholangitis4 (1.1)
Haemochromatosis3 (0.9)
Secondary biliary cirrhosis2 (0.6)
Amyloid1 (0.3)
Glycogen storage disease1 (0.3)

 

References

1. Whitehead M, Hawkes N, Hainsworth I, Kingham J. A prospective study of the causes of notably raised aspartate aminotransferase of liver origin. Gut 1999; 45(1): 129-33.

2. Kim C, Nam M, Jee S, Han H, Oh K, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ 2004; 328: 983-6.

3. Sherwood P, Lyburn I, Brown S, Ryder S. How are abnormal results for liver function tests dealt with in primary care? BMJ 2001; 322: 276-8.

4. Skelly M, James P, Ryder S. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol 2001; 35: 195-9.

5. de Marco R, Locatelli F, Zoppini G, et al. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999; 22: 756-61.

6. Teli M, James O, Burt A, Bennett M, Day C. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 1995; 22: 1,714-9.

  • For an archive of all GP clinical reviews, visit www.healthcarerepublic.com/clinical/GP

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