How is transaminitis treated?

Treatment of Transaminitis

The treatment of transaminitis is fundamentally determined by its severity grade and underlying etiology, with immediate discontinuation of hepatotoxic agents for Grade 2 or higher elevations, corticosteroid therapy for immune-mediated causes, and targeted management of the specific underlying condition. 1

Severity-Based Treatment Algorithm

Grade 1 Transaminitis (AST/ALT >ULN to 3.0× ULN)

• Close monitoring without specific treatment is recommended, with laboratory monitoring 1-2 times weekly 2, 1
• Continue current medications unless clear hepatotoxic culprit is identified 1
• Repeat liver enzymes in 2-4 weeks to assess for spontaneous resolution or progression 1

Grade 2 Transaminitis (AST/ALT >3.0 to 5.0× ULN)

• Discontinue all potentially hepatotoxic medications immediately if medically feasible, including antiarrhythmics, anticonvulsants, NSAIDs, methotrexate, tamoxifen, and glucocorticoids 1
• Increase monitoring frequency to every 3 days 1
• Consider prednisone 0.5-1 mg/kg/day if no improvement after 3-5 days of medication discontinuation 1
• For tuberculosis treatment-related transaminitis, if AST/ALT is under 2 times normal, repeat at two weeks; if above 2 times normal, monitor weekly for two weeks then biweekly until normal 2

Grade 3 Transaminitis (AST/ALT >5.0 to 20× ULN)

• Urgent hepatology consultation is mandatory 1
• Discontinue all hepatotoxic medications immediately 1
• Start methylprednisolone 1-2 mg/kg/day or equivalent 1
• Consider liver biopsy if steroid-refractory or diagnostic uncertainty exists 1
• For tuberculosis medications, if AST/ALT rises to five times normal or bilirubin rises, stop rifampicin, isoniazid, and pyrazinamide immediately 2

Grade 4 Transaminitis (AST/ALT >20× ULN)

• Immediate hospitalization, preferably at a liver center 1
• Permanently discontinue causative agents 1
• Administer methylprednisolone 2 mg/kg/day with planned 4-6 week taper 1
• Add second-line immunosuppression if transaminases don't decrease by 50% within 3 days 1

Etiology-Specific Treatment

Drug-Induced Liver Injury (DILI)

• Identify and discontinue the offending agent immediately 1
• Discontinuing hepatotoxic medications leads to enzyme normalization in 83% of cases 1
• For tuberculosis medication rechallenge after resolution: wait for complete normalization, then reintroduce sequentially starting with isoniazid at 50 mg/day, increasing to 300 mg/day over 2-3 days, then add rifampicin at 75 mg/day increasing to full dose, finally pyrazinamide at 250 mg/day increasing to full dose 2
• If patient is unwell or sputum smear positive, use streptomycin and ethambutol until liver function normalizes 2

Autoimmune Hepatitis

• Initiate prednisolone 0.5-1 mg/kg/day (typically starting at 60 mg/day for a 60 kg patient) 2, 1
• Add azathioprine after 2 weeks at 50 mg/day, increasing to 100 mg/day (1-2 mg/kg) as steroid-sparing agent 2
• Taper prednisolone gradually: reduce to 50 mg at week 2,40 mg at week 3,30 mg at week 4,25 mg at week 5,20 mg at week 6,15 mg at weeks 7-8,12.5 mg at weeks 8-9, then 10 mg from week 10 onward 2
• Further reduce to 7.5 mg/day once aminotransferases normalize, then to 5 mg/day after three months 2
• Continue treatment for at least 3 years and for at least 2 years after complete normalization of transaminases and IgG 1
• Treatment goal is complete normalization of transaminases and IgG levels 2
• For acute severe autoimmune hepatitis, use high doses of intravenous corticosteroids (≥1 mg/kg) 2

Immune Checkpoint Inhibitor-Related Hepatitis

• For Grade 2 or higher: hold immune checkpoint inhibitor and monitor, or permanently discontinue and start steroids 1
• Follow the severity-based corticosteroid algorithm outlined above 1

Post-Liver Transplant Rejection with Transaminitis

• For chronic antibody-mediated rejection with raised transaminases and moderate inflammatory infiltrates: intensify conventional immunosuppression regimens (e.g., higher tacrolimus levels and/or addition of corticosteroids or MMF/everolimus/azathioprine) 2
• For combined acute T cell-mediated rejection and antibody-mediated rejection: treat T cell component first with steroid boluses 2
• For persistent antibody-mediated rejection: consider plasmapheresis +/- intravenous immunoglobulin 2
• Second-line options for refractory cases: rituximab or eculizumab 2

Non-Alcoholic Fatty Liver Disease (NAFLD)

• Primary management focuses on lifestyle modifications including weight loss, dietary changes (Mediterranean diet with calorie restriction), and increased physical activity 1
• Address metabolic syndrome components: obesity, diabetes, hypertension, and hyperlipidemia 1

Critical Monitoring Parameters

Frequency of Monitoring

• Grade 1: Monitor liver function tests every 1-2 weeks 2, 1
• Grade 2: Monitor every 3 days 1
• Grade 3-4: Daily monitoring during acute phase 1
• For patients with chronic liver disease on hepatotoxic medications: weekly for two weeks, then biweekly for first two months 2

Red Flags Requiring Immediate Action

• Any elevation with bilirubin ≥2× ULN or INR >1.5 suggests potential acute liver injury requiring immediate evaluation 1
• Liver-related symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) with Grade 2 or higher elevation require urgent evaluation 1

Common Pitfalls to Avoid

• Do not assume normal ultrasound excludes NAFLD - ultrasound misses mild steatosis (<20-30% hepatocyte involvement) and cannot assess for NASH or fibrosis 1
• Do not rely solely on normal immunoglobulins to exclude autoimmune hepatitis - autoantibodies are more sensitive and specific 1
• Do not dismiss low-normal ceruloplasmin - this warrants 24-hour urine copper collection to exclude Wilson disease 1
• Statin-induced transaminitis (>3× ULN) is infrequent and often resolves with dose reduction - statins are not contraindicated in chronic stable liver disease like NAFLD 1
• In patients with pre-existing liver disease (cirrhosis, cancer), baseline abnormal liver function tests make it challenging to determine the cause of worsening transaminases 3
• Budesonide should not be used in cirrhotic patients due to loss of first-pass metabolism and high risk of systemic side effects 2

Special Populations

Patients with Advanced Liver Disease

• Azathioprine hepatotoxicity frequency is increased in patients with advanced liver disease 2
• Consider delaying azathioprine introduction by 2 weeks when starting treatment to avoid diagnostic confusion between drug toxicity and primary non-response 2

Pregnant Patients

• Exercise caution with azathioprine use - conduct individual risk-benefit analysis 2
• Prednisolone remains the preferred agent when immunosuppression is necessary 2