Asymptomatic Raised Transaminases (ALT & AST)

Introduction

1. Always test for and consider the liver function as measured by synthetic liver function (prothrombin times – half life is days and albumin – half life of about 1 month) and excretory liver function (bilirubin).
2. Transaminases do not reflect liver function which is most relevant in the management of patients.
3. Transaminases can be normal in advanced liver disease, cirrhosis, liver impairment and liver failure. Always test for both AST and ALT since a high AST/ALT ratio (and in combination with a low platelet count – calculated as Fib-4 score) indicates advanced fibrosis / cirrhosis. Also, always consider whether the liver disease is acute or chronic. Scotland has double the mortality from liver disease compared to England and Wales. Of those dying from liver disease 80% is alcohol related but often people have several risk factors.
4. To de-stigmatise liver disease we should think in terms of:
   • acute or chronic (or acute on chronic) liver disease
   • the severity of disease in terms of function (synthetic: albumin and PT, bilirubin: excretory)
   • the amount of inflammation (transaminases for hepatocyte inflammation)
   • the progression in terms of fibrosis / cirrhosis
   • the risk factors (alcohol, metabolic syndrome, genetic factors including iron overload, alpha1-antitrypsin phenotype and other unknown factors,…)

How High?

1. If mildly elevated (<100iu/l) in an asymptomatic patient without risk clinical signs of liver disease, repeat in 3 months.  An isolated raised AST or ALT is can be transient due to an intercurrent illness such as a viral infection or an intervention (results should normalise after a few weeks if this is the case). If there is a likely cause such as sepsis / hospitalisation, nothing else needs to be done.
2. If AST or ALT >100iu/l, repeat to confirm, make sure both AST and ALT as well as Alk Phos, albumin and prothrombin time are tested.
3. If AST or ALT >1000iu/l likely causes acute viral hepatitis (hepatitis B, rarely E or A), ischaemic liver injury (shock liver) or sepsis and toxin induced liver injury eg. paracetamol. Rarer causes are autoimmune hepatitis and drug induced liver injury (DILI). If DILI suspected consult LiverTox

Alcohol Related Liver Disease

1. 80 % of liver disease in Scotland are due to alcohol, 60 % of alcohol related deaths are due to liver disease.
2. History is best to determine the alcohol risk. Often the gamma GT is high (enzyme induction and not a marker of liver cell damage) MCV >100 (direct bone marrow toxicity from alcohol).
3. Is never the sole cause of liver disease if transaminases are over 400 and is unlikely if > 300.

Metbolic Syndrome Associated Fatty Liver Disease (MAFLD)

1. Common cause of ↑ transaminases, usually with ALT > AST if non cirrhotic. Calculate Fib-4 score: https://www.hepatitisc.uw.edu/page/clinical-calculators/fib-4.
2. Unlikely if transaminases > 4 x normal.
3. Ultrasound does not distinguish between fat and other parenchymal damage such as cirrhosis (but complications of cirrhosis can be seen).
4. Other causes of liver disease need to be excluded and this a risk factor for more pronounced elevation in transaminases.
5. Check for all risk factors of the metabolic syndrome: BP, lipid profile, glucose and BMI (central obesity) as well as renal function

Viral Hepatitis

1. HCV – in most cases chronic presentation / pre-existing: HCV antibody is sign of previous contact but not protection. HCV-RNA by PCR positivity indicates active infection (HCV-AB will be positive as well). In Scotland most commonly seen in iv drug users.
2. HBV – request HBV surface antigen (indicates viral presence, replication and infectivity). Test for HBV-DNA if positive. But if acute infection suspected and liver impairment and failure as consequence this requires urgent life-saving antiviral treatment – don’t wait for DNA to start treatment. Horizontal transmission is most common in Scotland (e.g. sexual contact with people from endemic areas (South East Asia) or iv drug use).
3. HEV – Request HEV antibody in patients with negative HBV and negative HCV in whom no other cause of abnormal LFT apparent (but is often found and not causing the liver disease).  HEV hepatitis found in patients who eat undercooked pork, work in abbatoirs.
4. Other viral causes of raised transaminases include EBV, CMV

Auto-Immune Hepatitis

1. Can affect people of all ages but more common in female.
2. Early symptoms are non-specific and include tiredness, malaise, joint and muscle pain.
3. Can present very acutely with high transaminases or chronically with very low transaminases and cirrhosis
4. Raised ANA, SMA and serum IgG strongly suggest diagnosis which must be confirmed by liver biopsy.

Haemochromatosis

1. Ferritin is a useful screening test but ferritin is also an acute phase reactant.
2. If ferritin elevated, request iron studies to detect iron overload – suggested if transferrin saturation (iron/TIBC) >45% in women or >50% in men, often >70%.
3. Genetic testing will identify mutation(s) in HFE gene that causes over 90 % cases.

Drugs

1. A wide variety of drugs are associated with liver disease, and a requirement for the monitoring of liver functions on drug initiation may be necessary.
2. Review the drugs most commonly implicated included (antibiotics and antiepileptic / psychoactive drugs): carbamazepine, methyldopa, minocycline, macrolide antibiotics, nitrofurantoin, statins, sulfonamides, terbinafine, chlorpromazine and methotrexate. Always consult LiverTox to compare the patient’s presentation with the signature biochemistry of the drug in question.
3. Methotrexate treatment requires special care, to prevent dose-dependent liver fibrosis, and non-invasive markers of fibrosis should be monitored.
4. Although statins can lead to drug-induced liver injury, this is very rare, with studies demonstrating they are safe in patients with pre-existing abnormal liver enzymes.
5. On occasions it can be difficult to establish the relative contribution of a drug or drugs alongside possible concomitant liver disease. In this situation clinical judgement and use Livertox to determine what is the major contributor and the need to discontinue medication. This will be influenced by the pattern of liver blood tests; the timing of medication use with respect to the liver blood abnormality developing and the clinical setting.

Other Causes

1. Alpha1-antitryptin deficiency (test for A1AT levels)
2. Wilson’s disease  (test for coeruloplasmin in people under the age of 50), can present very acutely with liver failure and haemolysis)
3. Muscle disorders
4. Thyroid disease
5. Coeliac disease
6. Primary and secondary malignancy

Links

• Abnormal Liver Function Tests Information from patient.co.uk
• Krier M, Ahmed A.  The asymptomatic patient with abnormal LFTs. Clinics in Liver Disease. 2009; 13: 167-177

Content by Dr Mathis Heydtmann & Dr Moawad Mahgoub