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Assessing a Patient with an Abnormal Liver Function Test Result

Essentials

  • When investigating hepatocyte injury, cholestasis etc., the main laboratory tests are ALT, ALP and GT. AST may be useful in the diagnoses of alcoholic liver disease and fatty liver, for example.
  • If the liver enzyme values of a patient are found to be slightly elevated, it is recommended that the values are monitored and the patient is provided, as necessary, with lifestyle guidance (on weight reduction, alcohol, etc.)
    • Further investigations are performed within primary health care if the values remain increased for more than 6 months.
    • The patient is referred to additional investigations within specialized health care if the liver enzyme values are significantly and permanently elevated or if any sign suggesting a chronic liver disease or malignancy is found.
  • If, in addition to elevated liver test values, the patient has jaundice, signs of liver failure or clinically acute symptomatic hepatitis (notably high ALT) or is in pain, urgent or emergency investigations are indicated.

Differentiating investigations

  • See tables T1 and T2.

Laboratory diagnosis of liver injury

Test targetInvestigations
Hepatocellular injuryALT, (AST)
Cholestasis and biliary duct injuryALP, GT, bilirubin (total and conjugated)
Liver functionAlb, Prealb, TT (INR)

The main causes of liver disease and investigations depending on the suspected aetiology

Cause of liver injuryLaboratory tests
Alcoholic liver disease, NAFLD/NASH Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH)ALT, AST, GT, CDT, MCV, lipids, GHb-A1C, glucose tolerance, IgA, (blood PEth, plasma ethanol)
Autoimmune liver diseases: AIH Autoimmune Hepatitis, PBC Primary Biliary Cholangitis, PSC Primary Sclerosing CholangitisIgG, IgA, IgM, antinuclear antibodies, smooth muscle antibodies, mitochondrial antibodies
Viral liver diseases Viral HepatitisHBsAg, HCV antibodies, HAV-IgM antibodies, HEV antibodies, CMV nucleic acid, EBV nucleic acid
Other rare diseases causing increased liver values, such as coeliac disease Coeliac Disease, haemochromatosis Haemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiencyAnti-transglutaminase antibodies, ferritin, transferrin saturation, U-Cu, ceruloplasmin, alpha-1-antitrypsin

Increased ALT levels

  • Upper reference limits: men 50 U/l, women 35 U/l. In some places, higher upper reference limits may still be in use.
  • A sensitive and quite specific indicator of hepatocellular injury
  • Diseases causing increased ALT levels
  • Sources of error
    • Moderately increased ALT levels in the absence of liver injury may be seen in patients with sepsis, pulmonary infarction, muscular dystrophy, after heavy muscular exertion, heart or kidney failure.
    • Haemolytic samples give increased ALT values.
  • ALT slightly increased (< 3 × upper reference limit)
    • Assess the potential role of alcohol or obesity based on the patient's history (AUDIT Audit), clinical findings (BMI Bmi) and any complementing laboratory tests.
    • In otherwise asymptomatic patients, lifestyle guidance and follow-up for 4-12 weeks
    • Alcohol-induced liver damage is suggested by
      • daily alcohol consumption of > 20 g in women, > 40 g in men
      • increased MCV, GT, CDT; AST/ALT ratio > 1.5; serum ethanol +; increased IgA level, blood PEth > 0.30 (heavy alcoholic intake within the last 2 weeks)
      • normalization of ALT after 2 weeks of abstinence from alcohol (MCV and GT return to normal more slowly).
    • Fatty liver Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) is suggested by
      • marked obesity (BMI > 30)
      • type 2 diabetes.
    • If the levels do not return to normal or, at least, become lower during follow-up, the following further investigations are indicated:
      • upper abdominal ultrasonography
      • laboratory tests depending on the suspected aetiology (table T2).
  • ALT markedly increased (> 3 × upper reference limit)
    • Make sure that the patient has no alarming symptoms, such as marked fatigue or itching, jaundice, pain, anorexia or any palpable mass in the stomach. If the patient has even one of these, referral to hospital is indicated.
    • If there are no symptoms, the patient should be re-examined after 1-2 weeks already and further investigations carried out if the condition is not resolving.
    • Even if the condition is resolving, aetiological alternatives such as acute viral hepatitis or resolved cholestasis should be kept in mind and the required further investigations carried out.

Increased AST levels

  • AST occurs primarily in the myocardium, liver and skeletal muscles but in moderate amounts also in many other tissues (the kidneys, erythrocytes).
  • In special cases, determination of the AST/ALT ratio may be indicated.
    • In patients with viral, drug-induced or autoimmune hepatitis, AST is usually at a lower level than ALT, giving an AST/ALT ratio below 1.
    • In extensive liver tissue damage, the AST/ALT ratio often exceeds 1.
    • Highest AST/ALT ratios (possibly exceeding 2) are seen in patients with alcoholic hepatitis.
  • An AST test is also needed for non-invasive calculation of the risk of NASH by fibrosis scoring http://www.nafldscore.com/index.php.

Increased ALP levels

  • In adults, the upper reference limit is 105 U/l. In pregnant women (placental) and growing children (below the age of 18 years; bone-specific), the reference values are higher (check the reference values applied by your laboratory).
  • Alkaline phosphatase is produced by many types of tissue.
    • Liver, bile ducts and the intestine
    • Bones
    • Placenta
  • The factors most commonly increasing ALT levels (alcohol, obesity) do not affect ALP levels significantly.
  • Diseases increasing ALP levels
  • Slightly elevated bone-specific alkaline phosphatase levels are also seen in patients with hyperparathyroidism, healing fractures or sarcoidosis.
  • ALP is rarely elevated in association with intestinal diseases.
  • Investigations for elevated ALP levels
    • In patients with liver disease, GT behaves similarly to ALP but increases more easily. If GT levels are normal and ALP is elevated, the ALP is usually not hepatic in origin.
    • Elevated ALP and GT levels usually suggest intra- or extrahepatic cholestasis.
    • If the origin of elevated ALP levels is unclear (bone or liver), an ALP isoenzyme test can be performed to detect the origin of the enzyme.
    • Drugs rarely cause elevated ALP levels. Here, too, GT is more sensitive (as is ALT).
    • For further investigation of bone diseases, Ca, Pi, PTH and 25-OH vitamin D levels (if vitamin D deficiency is suspected) can be measured.
    • The primary further radiological investigation is ultrasonography to detect any biliary tract obstruction, gallstones, tumours, biliary tract diseases (PSC, PBC) or cirrhosis of the liver. MRI can be used for more specific diagnosis related to the biliary ducts or if cirrhosis is suspected.

Increased GT levels

  • Higher upper reference limits: for men and women below 40 years 80 U/l and 45 U/l, respectively; for men and women over 40 years 115 U/l and 75 U/l, respectively. Lower upper reference limits have been adopted in some places: for men and women over 17 years 60 U/l and 40 U/l, respectively.
  • GT is a more sensitive indicator of both extra- and intrahepatic cholestasis than alkaline phosphatase but factors such as drugs, alcohol and certain dietary factors can also elevate GT levels.
  • As GT levels are not increased by bone disease or in growing children, the test is more specific than the alkaline phosphatase test.
  • Slightly increased GT levels without increase in other liver values are usually not associated with any significant liver disease, and further investigations and follow-up are often unnecessary.
    • Alcohol consumption and the use of drugs etc. should be investigated.
  • Regular heavy alcohol consumption increases GT levels. In such cases, increased GT activity may be induced by the alcohol and not necessarily signify liver damage. When alcohol is withdrawn, GT activity will become normal in 2-3 weeks.
    • Increased MCV and CDT levels support alcohol as the aetiological factor.
    • In patients with alcohol-induced liver damage, GT levels are moderately or clearly increased.
  • Some drugs, such as antiepileptic drugs and tricyclic antidepressants, increase GT levels.
  • Other causes of increased GT levels include, for instance,
  • Sources of error
    • GT may be increased due to obesity and in patients with acute pancreatitis, myocardial or pulmonary infarction, pneumonia, heart failure, ulcerative colitis or bronchial carcinoma, for example.
  • Investigation of increased GT levels
    • In outpatient care, the most important thing to investigate is the history of alcohol consumption; complete abstinence and check-up in 3-4 weeks.
    • If alcohol does not appear to be an underlying factor but GT levels are clearly increased and other liver values may also be increased, investigations for liver disease should be carried out as outlined above.

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