What is the cause of elevated transaminases (Alanine Transaminase (ALT) and Aspartate Transaminase (AST))?

From the Guidelines

Elevated transaminases, specifically Alanine Transaminase (ALT) and Aspartate Transaminase (AST), are primarily caused by hepatocellular injury, which can result from various factors including fatty liver disease, viral hepatitis, alcohol consumption, medications, and autoimmune conditions, as indicated by the most recent study 1. The most common causes of elevated transaminases are nonalcoholic fatty liver disease (NAFLD) and alcohol-induced liver disease, with NAFLD being the most prevalent liver disease in first-world countries, affecting 20-30% of the general population, and up to 90% of individuals with diabetes mellitus 1. Key factors to consider when evaluating elevated transaminases include:

• The pattern and ratio of ALT and AST elevation, which can help differentiate between hepatocellular and non-hepatocellular causes 1
• The severity of aminotransferase elevation, classified as mild, moderate, or severe, which can guide further investigation and management 1
• The presence of other liver function test abnormalities, such as alkaline phosphatase (ALP) elevation, which can indicate cholestatic liver disease 1 The initial step in managing elevated transaminases is to identify and address the underlying cause, rather than treating the enzyme elevation itself, as emphasized in the most recent guidelines 1. This may involve discontinuing hepatotoxic medications, limiting alcohol intake, treating viral infections, and implementing lifestyle modifications, such as weight loss and dietary changes, for fatty liver disease 1. In cases of mild, asymptomatic elevations, monitoring with repeat testing in 2-4 weeks may be appropriate, while more significant elevations or persistent abnormalities warrant further investigation with additional blood tests, imaging studies, or possibly liver biopsy 1.

From the FDA Drug Label

When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury. In a placebo controlled study in which naltrexone hydrochloride was administered to obese subjects at a dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day), 19% (5/26) of naltrexone hydrochloride recipients and 0% (0/24) of placebo-treated patients developed elevations of serum transaminases

The cause of elevated transaminases (Alanine Transaminase (ALT) and Aspartate Transaminase (AST)) in patients taking naltrexone is multifactorial. Possible causes include:

• Pre-existing liver disease, such as alcoholic liver disease
• Hepatitis B and/or C infection
• Concomitant use of other hepatotoxic drugs
• Abrupt opioid withdrawal, which may lead to systemic sequelae, including acute liver injury
• Naltrexone hydrochloride itself, as evidenced by elevations of serum transaminases in some clinical trials, particularly at high doses 2, 2

From the Research

Causes of Elevated Transaminases

The causes of elevated transaminases, including Alanine Transaminase (ALT) and Aspartate Transaminase (AST), can be categorized into common, uncommon, and rare causes.

• Common causes:
  • Nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) 3, 4
  • Alcoholic liver disease 3, 4
• Uncommon causes:
  • Drug-induced liver injury 3, 4, 5
  • Hepatitis B and C 3, 4, 5
  • Hereditary hemochromatosis 3, 4
• Rare causes:
  • Alpha1-antitrypsin deficiency 3, 4
  • Autoimmune hepatitis 3, 4
  • Wilson disease 3, 4
• Extrahepatic causes:
  • Thyroid disorders 3
  • Celiac sprue 3
  • Hemolysis 3
  • Muscle disorders 3
  • Celiac disease 4
  • Hyperthyroidism 4
  • Rhabdomyolysis 4
  • Pregnancy-associated liver disease 4

Evaluation and Diagnosis

The evaluation of elevated transaminases should include an assessment for metabolic syndrome and insulin resistance, a complete blood count with platelets, measurement of serum albumin, iron, total iron-binding capacity, and ferritin, and hepatitis C antibody and hepatitis B surface antigen testing 3, 4.

• The nonalcoholic fatty liver disease fibrosis score and the alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in the evaluation of mildly elevated transaminase levels 3.
• If testing for common causes is consistent with nonalcoholic fatty liver disease and is otherwise unremarkable, a trial of lifestyle modification is appropriate 3.
• If the elevation persists, hepatic ultrasonography and further testing for uncommon causes should be considered 3.
• A needle liver biopsy may be justified in cases where a diagnosis cannot be reached with non-invasive methods 6.

Marked Transaminase Elevation

Marked transaminase elevation (>1000 IU/L) can be caused by various factors, including:

• Ischemic hepatitis 5
• Viral hepatitis 5
• Toxins or drug-induced liver injury (DILI) 5
• Pancreaticobiliary-related injury 5 Mortality is significantly higher in ischemic hepatitis compared to other causes of marked transaminase elevation 5.

Association with Other Conditions

Non-alcoholic steatohepatitis (NASH)-like pattern in liver biopsy has been found in rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment, suggesting a strong association between NAFLD/NASH and liver injury during low-dose methotrexate treatment for rheumatoid arthritis 7.