From the Guidelines
Recurrent increased liver enzymes can be caused by various conditions, with non-alcoholic fatty liver disease (NAFLD) and alcohol-induced liver disease being the most common causes, as stated in the 2023 study 1. The causes of recurrent increased liver enzymes can be categorized into common and uncommon causes. Common causes include:
- Non-alcoholic fatty liver disease (NAFLD)
- Alcohol-induced liver disease
- Viral hepatitis (such as hepatitis B or C)
- Medication-induced liver injury
- Autoimmune hepatitis
- Metabolic disorders Certain medications like statins, antibiotics, and anti-seizure drugs can also lead to elevated liver enzymes. Obesity, diabetes, and metabolic syndrome are significant risk factors for NAFLD, which has become a leading cause of chronic liver enzyme elevation. The pattern of enzyme elevation (ALT, AST, ALP, GGT) can provide clues to the underlying cause. It is essential to undergo a comprehensive evaluation, including detailed medical history, physical examination, and appropriate laboratory and imaging studies, to identify the specific cause and implement appropriate treatment, as suggested by the study 1. Less common causes of recurrent increased liver enzymes include:
- Hemochromatosis (iron overload)
- Wilson's disease (copper accumulation)
- Alpha-1 antitrypsin deficiency
- Celiac disease
- Drug-induced liver injury, as mentioned in the 2024 study 1
- Methotrexate-induced liver injury, as discussed in the 2009 study 1 However, the most recent and highest quality study 1 provides the most relevant information for determining the cause of recurrent increased liver enzymes.
From the FDA Drug Label
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir [see Adverse Reactions (6. 1)] . Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including entecavir, alone or in combination with antiretrovirals. Increased transaminases.
Causes of recurrent increased liver enzymes may include:
- Severe acute exacerbations of hepatitis B after discontinuation of anti-hepatitis B therapy, including entecavir 2
- Lactic acidosis and severe hepatomegaly with steatosis associated with entecavir use, often in combination with other serious medical conditions or drug exposures 2
- Hepatotoxicity associated with entecavir use, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations 2
- Increased transaminases reported as an adverse reaction in postmarketing experience with entecavir 2
From the Research
Causes of Recurrent Increased Liver Enzymes
- Drug-induced liver injury (DILI) can be a cause of recurrent increased liver enzymes, as seen in patients who develop autoimmune features after exposure to certain medications 3, 4, 5.
- Specific drugs associated with DILI and autoimmune features include:
- Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac
- Antimicrobials like nitrofurantoin and minocycline
- Statins
- Anti-tumor necrosis factor alpha (TNF-α) agents
- Alpha-methyldopa
- Hydralazine
- The clinical features of DILI with autoimmune features can be indistinguishable from idiopathic autoimmune hepatitis (AIH), making diagnosis challenging 4, 5.
- A high degree of clinical suspicion is required for the diagnosis of DILI with autoimmune features, and a liver biopsy may be necessary to confirm the diagnosis 5.
- Complete recovery of liver injury is often seen with DILI, but cases of prolonged injury may occur and require treatment with immunosuppressive therapy 5.