Evaluating abnormal liver tests

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CHAPTER 30 EVALUATING ABNORMAL LIVER TESTS

• Liver enzyme abnormalities may be physiological or pathological.

• Any persistent elevation of liver function tests must be investigated.

• A detailed history and physical examination is mandatory.

• The degree and pattern of elevation of liver tests may provide clues to its aetiology.

• Upper abdominal ultrasonography is a useful non-invasive imaging procedure.

APPROACH TO THE PATIENT WITH ABNORMAL LFTs

The presence of any persistent abnormality of liver tests warrants further assessment. The initial step in evaluating a patient with raised liver enzymes is to undertake a thorough history and physical examination, with particular emphasis on risk factors for liver disease.

A detailed drug history is important including:

• prescribed medications in particular, antibiotics during the preceding 3 months

• alcohol intake

• ingestion of allopathic and traditional medications including vitamins and herbal preparations (CAM: complementary and alternatives medicines)

• recreational drugs.

Liver injury may manifest several weeks after drug cessation.

Risk factors for viral hepatitis must be elicited such as injecting drug use.

Sudden, marked elevations in transaminase levels necessitates exclusion of viral, drug-induced and ischaemic hepatitis.

INTERPRETING PATTERNS OF LIVER TEST ABNORMALITIES

The degree and pattern of liver tests’ elevation may provide clues as to aetiology (Figure 30.1). A practically useful classification is provided below.

FIGURE 30.1 Evaluating liver function test abnormalities.

Liver test abnormalities are designated as:

1. ‘Hepatocellular’ when there is an ALT increase of over twice the upper limit of normal or R ≥5, where R is the ratio of serum ALT/serum ALP in multiples of the upper limit of the normal range

2. ‘Cholestatic’ if serum ALP is increased above twice the upper limit of the normal range or R ≤2

3. ‘Mixed’ in pattern when both ALT and ALP are raised, and 2 ≤R ≤5. The ratio R may vary during the course of liver injury.

In the vast majority of patients with liver disease, the serum ALT exceeds the AST. Exceptions include those with alcoholic liver disease and those with cirrhosis from any aetiology.

The presence of liver test abnormalities in association with a low serum albumin or a prolonged prothrombin time infers significantly impaired hepatic synthetic function, while an elevated bilirubin reflects hepatic excretory dysfunction.

Disorders associated principally with elevations in aminotransferase levels

Aminotransferase levels are sensitive indicators of hepatic injury; ALT and AST are present normally in serum at low levels, usually less than 30–40 U/L.

AST is found in:

• cardiac muscle

• skeletal muscle

• leucocytes and erythrocytes.

Because the highest levels of ALT are in the liver, an elevation of ALT is a more specific indicator of liver injury than the AST.

Common causes of liver enzyme abnormalities according to the pattern of enzyme elevation are presented in Table 30.1.

TABLE 30.1 Causes of elevated liver enzyme levels

Hepatocellular	Cholestatic
• Excessive alcohol consumption	• Drug-induced liver injury
• Drug-induced liver disease	• Choledocholithiasis
– Chronic hepatitis B and C	• Primary biliary cirrhosis
– Non-alcoholic fatty liver disease	• Primary sclerosing cholangitis
– Haemochromatosis	• Pancreatic carcinoma
• Autoimmune hepatitis	• Neoplastic infiltration
• Wilson’s disease	• Sarcoidosis
• Alpha₁-antitrypsin deficiency

Additional laboratory tests useful in identifying specific disorders are listed in Table 30.2.

TABLE 30.2 Laboratory tests to clarify the cause of liver test abnormalities

Laboratory test	Diagnosis
• Hepatitis C antibody	• Positive test suggests chronic hepatitis C infection
• Hepatitis B surface antigen	• Positive test suggests chronic hepatitis B infection
• Hepatitis B e antigen	• Positive test suggests active viral replication
• Serum ferritin, transferrin saturation	• Iron overload suggests haemochromatosis
• Antimitochondrial antibodies	• Detected in primary biliary cirrhosis
• Antinuclear antibodies, anti-smooth muscle antibodies	• Detected in autoimmune hepatitis
• Serum caeruloplasmin	• Reduced in Wilson’s disease
• Serum alpha₁-antitrypsin	• Decreased in alpha₁-antitrypsin deficiency

Causes of elevated aminotransferase levels

Alcohol-related liver disease (ALD)

• The diagnosis of alcohol-related liver disease is supported by the finding of a ratio of AST to ALT of at least 2:1.

• The degree of elevation of aminotransferase levels may provide further evidence for a diagnosis of ALD. It is rare for AST levels to be greater than 8 times the normal value in patients with alcohol abuse, and even less common for ALT levels to exceed 5 times the normal value. ALT levels may be normal in patients with severe ALD.

• ALT levels >300 U/L in those with significant alcohol intake usually indicates the presence of another cause for the liver test elevation (e.g. coincident drug toxicity or viral hepatitis).

• A GGT level that is twice normal in patients with an AST:ALT ratio of at least 2:1 strongly implicates alcohol as the likely cause for the liver enzyme abnormalities. However, the lack of specificity of GGT precludes its use as a single test to diagnose alcohol abuse.

Laboratory features suggestive of alcohol abuse are:

– ALT <300 U/L

– Elevated GGT

– Raised MCV (mean corpuscular volume)

– Thrombocytopenia which corrects following abstinence from alcohol.

Drug-induced liver disease

• Almost any medication, herbal preparation or illicit substance can cause abnormal liver tests. Meticulous history taking is critical. Changes in liver tests may persist long after cessation of the offending agent. Prevention and treatment of drug-induced liver disease is predicated on awareness and early cessation of the suspected offending agent. Commonly implicated drugs are listed in Table 30.3.

TABLE 30.3 Commonly prescribed medications causing abnormal liver tests

Class of medication	Examples
• Antibiotics	• Flucloxacillin, minocycline
• Antiepileptics	• Carbamazepine, phenytoin
• Antipsychotics	• Chlorpromazine
• Antituberculotics	• Isoniazid, rifampicin
• Lipid-lowering medications	• HMG-CoA reductase inhibitors (statins)
• Non-steroidal antiinflammatory drugs	• Ketoprofen, naproxen
• Oestrogens	• Oral contraceptive pill

Chronic viral hepatitis

Chronic hepatitis C

Afflicts up to 1% of Australians, with 85% of incident cases related to injecting drug use. All patients with chronic HCV infection should be considered for antiviral therapy, which demonstrates excellent cost effectiveness.

• Risk factors for acquiring hepatitis C infection include:

– Having received blood transfusions prior to February 1990

– Injecting drug use

– Exposure to non-sterile instruments including acupuncture needles, needle stick injury, tattooing, body piercing

– Snorting cocaine

– Country of birth (South East Asia, Mediterranean region, Middle East, Africa, South America): probably relates to use of non-sterile medical equipment

– Infants born to hepatitis C virus (HCV)-infected mothers.

• In a patient with risk factors, a diagnosis of chronic hepatitis C infection is suggested by the presence of a positive hepatitis C antibody test with or without a raised ALT.

• Up to 30% of patients with a positive antibody result have no ongoing HCV viraemia, particularly if the ALT is persistently normal. The positive antibody result in this instance reflects prior exposure to the virus.

• Confirmation of hepatitis C infection can be sought by the detection of hepatitis C virus RNA in serum (polymerase chain reaction [PCR] test).

• A liver biopsy should be considered to assess the severity of liver damage in any viraemic patient with chronic hepatitis C and an elevated ALT.

• Individuals who are viraemic with persistently normal ALTs are currently not eligible for treatment but should be monitored.

Chronic hepatitis B

Results when immune elimination does not occur following acute infection and the hepatitis B virus (HBV) continues to replicate (see Chapter 36).

• At risk populations include:

– those from countries with high hepatitis B endemicity (e.g. South East Asia)

– indigenous Australians

– individuals with a history of injecting drug use.

• Serologic testing for hepatitis B infection includes tests for hepatitis B surface antigen, hepatitis B surface antibody and core antibody. A positive test for hepatitis B surface antibody and core antibody indicates the presence of immunity to hepatitis B.

• A positive hepatitis B surface antigen is indicative of hepatitis B infection. Viral replication can be assessed by determining hepatitis B e antigen status:

– Patients who are hepatitis B e antigen positive have high levels of replicating virus.

– When hepatitis B e antigen is negative but ALT levels are paradoxically raised, individuals may be infected with a mutant form of hepatitis B virus or have another cause for liver injury.

• The presence of mutant HBV can be confirmed by determining serum HBV DNA levels. Those infected with mutant HBV often run a more aggressive course.

• Patients with chronic hepatitis B have an approximately 30% lifetime risk of developing hepatitis B-related complications including hepatocellular carcinoma and liver failure.

• Any patient who is surface antigen and e antigen positive with an elevated ALT (especially if >100 U/L) or with precore mutant hepatitis B and elevated ALT should be considered for specialist assessment, liver biopsy and treatment with potent antiviral drugs, such as lamivudine.

Non-alcoholic fatty liver disease (NAFLD)

• Non-alcoholic fatty liver disease is the most common cause for liver test abnormalities in Western countries, affecting 20% of obese and 3% of lean individuals (see Chapter 39).

• Hepatic steatosis and non-alcoholic steatohepatitis (NASH) can manifest as mild elevations in serum aminotransferase levels (<4 × normal value). Patients with NASH usually have an AST:ALT ratio less than 1:1, unless cirrhosis intervenes which can reverse this ratio.

• Hepatic steatosis and NASH are found in association with disorders of insulin resistance:

– Type 2 diabetes

– Obesity (central)

– Hyperlipidaemia (hypertriglyceridaemia, low HDL).

• Ultrasonography is useful in the assessment of a patient with suspected NASH. Fatty involvement of the liver appears on ultrasonography as a hyperechoic liver but such an appearance is non-specific, and indistinguishable from that due to hepatic iron deposition or fibrosis.

• Steatosis and NASH can be distinguished on liver biopsy, with the former showing bland fatty infiltration (steatosis), while NASH is characterised by steatosis as well as inflammation and variable fibrosis.

• Steatosis is a benign, non-progressive or slowly progressive condition. In contrast, a proportion of patients with NASH can progress to cirrhosis and liver failure. Serious consideration has to be made in implementing lifestyle modifications early in this group of patients including regular exercise, a low-fat weight-reduction diet, as well as careful monitoring and control of underlying disorders of insulin resistance.

Haemochromatosis

• Hereditary haemochromatosis is a common genetic disorder (1 in 200) that can present with abnormal liver tests (see Chapters 37 and 42).

• A transferrin saturation value (serum iron divided by total iron binding capacity) >45% is suggestive of haemochromatosis.

• Serum ferritin provides less specific information as it is an acute phase reactant and is often raised in conditions such as alcoholic liver disease and NAFLD.

• Genetic testing can now be performed to identify the mutations (C282Y and H63D) in the haemochromatosis (HFE) gene.

• A liver biopsy is necessary to assess the degree of fibrosis if:

– iron overload is present on iron studies but no HFE mutation is found on genetic testing, or

– a patient with the HFE mutation is older than 40 years of age, has a serum ferritin >1000 μg/L, abuses alcohol or has hepatomegaly or an abnormal AST.

• If the individual has an elevated transferrin saturation and is a C282Y homozygote, or a compound heterozygote C282Y/H63D, then a liver biopsy can be avoided if the patient is under the age of 40 years and the serum aminotransferase levels are normal.

• Family screening is mandatory in all first-degree relatives of patients with hereditary haemochromatosis.

Autoimmune hepatitis

• Typically, this condition affects young women who present with a hepatocellular pattern of elevation of liver enzymes and raised serum globulins (predominantly IgG) (see Chapter 38).

• Autoimmune markers for this condition include antinuclear antibodies and antibodies against smooth muscle and liver-kidney microsomes. A liver biopsy is essential in confirming the diagnosis.

• Untreated, autoimmune hepatitis can rapidly progress to cirrhosis and liver failure. Patients must be referred early for assessment and immunosuppressive therapy.

Wilson’s disease

• Wilson’s disease is a rare genetic disorder in which copper accumulates in the liver and brain in excess of normal metabolic needs. The underlying defect in copper homeostasis is a reduction in the biliary excretion of copper (see Chapter 42).

• All young patients (<40 years) with new onset liver test abnormalities should be screened for Wilson’s disease by way of a serum caeruloplasmin level. Serum caeruloplasmin levels are reduced in 85% of affected individuals. Ophthalmological assessment looking for Kayser-Fleischer rings is recommended.

• A 24-hour urine collection to quantify copper excretion may be useful, particularly if a clinician is strongly suspicious of the diagnosis of Wilson’s disease in a patient with absent Kayser-Fleischer rings and a normal serum caeruloplasmin level.

• Liver biopsy is recommended to measure hepatic copper levels and ascertain the degree of hepatic fibrosis.

Alpha₁-antitrypsin deficiency

• This is an uncommon cause for abnormal liver tests in adults. Decreased levels of alpha₁-antitrypsin can be detected by direct measurement of serum levels. The diagnosis is established by determination of the genotype of the affected individual.

Other liver test abnormalities

Hyperbilirubinaemia

• Hyperbilirubinaemia may be present in association with both hepatocellular (e.g. viral hepatitis) and cholestatic (e.g. bile duct obstruction) patterns of liver test abnormalities.

• Familial abnormalities of bilirubin metabolism should be entertained once haemolytic or overt liver diseases have been excluded.

• The most common abnormality is Gilbert’s syndrome, which is a benign, mild, unconjugated hyperbilirubinaemia (not due to haemolysis), in the setting of normal synthetic liver function and histology. It affects up to 5% of the population and is inherited as an autosomal dominant condition. Jaundice is mild and intermittent, with exacerbations following infection or fasting and may be associated with malaise, nausea and right upper quadrant discomfort. Gilbert’s syndrome has an excellent prognosis, with normal lifetime expectancy (see Chapter 42).

Assessment of a patient with ‘cholestatic’ liver tests

• In the assessment of cholestatic liver tests not considered to be drug related, ultrasonography is recommended to assess the hepatic parenchyma and bile ducts.

• If biliary dilatation or choledocholithiasis is found, then diagnostic and therapeutic endoscopic retrograde cholangiopancreatography should be undertaken.

• If no obstructive lesion is identified on ultrasonography then the patient will require referral to exclude rare conditions such as primary biliary cirrhosis, primary sclerosing cholangitis or granulomatous hepatitis. Serologic testing for antimitochondrial antibodies is used to screen for primary biliary cirrhosis. If a patient tests positive, the diagnosis is confirmed by liver biopsy.

SUMMARY

Liver enzyme abnormalities may be physiological or pathological. Persistent elevation of liver tests must be investigated. Eliciting a detailed history and performing a thorough physical examination is mandatory (Figure 30.1).

Assess the degree and pattern of elevation of liver tests. Serologic testing for common causes of liver dysfunction should be undertaken. Upper abdominal ultrasonography is a useful non-invasive imaging procedure. Liver biopsy should be considered in consultation with a gastroenterologist.

FURTHER READING

Dunn W, Angulo P, Sanderson S, et al. Utility of a new model to diagnose an alcohol basis for steatohepatitis. Gastroenterology. 2006;131:1057-1063.

Keegan A. Abnormal liver function test results. In: Talley NJ, Martin CJ, editors. Clinical gastroenterology: a practical problem-based approach. 2nd edn. Sydney: Elsevier; 2006:373-423.

Sherlock S, Dooley J. Diseases of the liver and biliary system, 11th edn. Oxford: Blackwell Science; 2002.

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