Liver Function Monitoring in Therapy

Introduction to Liver Function Monitoring

• Baseline liver function tests are recommended before starting therapy, and regular monitoring schedules should be established for patients taking hepatotoxic medications, as recommended by the American College of Gastroenterology (ACG) and the American Thoracic Society 1, 2
• Patients with pre-existing liver disease, alcohol consumption, obesity, diabetes, advanced age, or concomitant use of multiple hepatotoxic drugs are at higher risk of medication-induced liver injury, as stated by the American Association for the Study of Liver Diseases 3

Baseline Testing and Monitoring Schedule

• The American Thoracic Society recommends baseline liver function tests before starting therapy, and for patients with normal baseline liver function, no regular monitoring is required, but testing should be done if symptoms develop 2
• For patients with chronic liver disease, the American Thoracic Society suggests weekly testing for the first 2 weeks, then biweekly for the first 2 months 2
• The European Association for the Study of the Liver classifies the pattern of liver injury according to R value (ALT × ULN/ALP × ULN), with hepatocellular injury having an R ≥5, cholestatic injury having an R <2, and mixed injury having an R between 2 and 5 4, 5

Medications Associated with Hepatotoxicity

• Certain medications, including Lapatinib, Pazopanib, Imatinib, Dasatinib, Erlotinib, Gefitinib, Nilotinib, Sorafenib, and Sunitinib, undergo bioactivation to form reactive intermediates that can cause idiosyncratic liver reactions 6
• Sulindac, most NSAIDs, Remdesivir, Lopinavir/Ritonavir, Infliximab, and Acitretin are associated with a higher risk of hepatotoxicity or liver enzyme elevations 7, 8, 9, 10
• The following medications have a likelihood score of liver injury according to NIH LiverTox:

8, 11, 12, 13

• Statins can cause transaminase elevations in approximately 1% of patients, according to the American College of Cardiology 14
• Anti-tuberculosis drugs, including Isoniazid, Rifampin/Rifabutin, and Ethambutol, can cause hepatitis and require periodic monitoring of liver enzymes, as recommended by the American Thoracic Society 15
• Immune checkpoint inhibitors can cause immune-mediated hepatitis, and the American Society of Clinical Oncology recommends holding treatment and considering steroids for Grade 2 hepatitis (AST/ALT >3.0 to ≤5.0× ULN) and permanently discontinuing treatment and starting steroids for Grade 3-4 hepatitis (AST/ALT >5.0× ULN) 16

Stopping Medication

• The European Respiratory Society guidelines indicate that medication should be stopped if liver enzymes rise to five times normal or if bilirubin levels increase, with a strength of evidence based on clinical expertise 2
• The European Respiratory Society also recommends stopping medication if clinical symptoms such as fever, malaise, vomiting, jaundice, or weight loss develop, based on moderate-strength evidence 17
• For elevations >5× ULN, discontinue medication and consider hepatology consultation, as recommended by the American Academy of Dermatology 13

Reintroduction Protocol

• After liver function normalizes, the American Thoracic Society suggests that drugs can be reintroduced sequentially, starting with isoniazid, then rifampin, and finally pyrazinamide if needed, using gradual dose escalation with close monitoring, with a strength of evidence based on clinical experience 2
• Isoniazid causes transaminitis in approximately 10-20% of patients, with age-related risk (highest in those >50 years old at 2.3%) 18
• Ethambutol is associated with a lower risk of hepatotoxicity compared to other TB medications, but still contributes to transaminitis 19

Patient Education and Monitoring

• Patients should be advised against alcohol consumption while taking hepatotoxic medications and educated about avoiding over-the-counter medications containing acetaminophen, as recommended by the American Liver Foundation 3
• Patients should be instructed to report symptoms like fatigue, nausea, right upper abdominal discomfort, dark urine, or jaundice, as recommended by the American Liver Foundation 3
• The following guidelines are recommended for liver enzyme elevations:
• N-acetylcysteine should be administered as early as possible for acetaminophen overdose, as recommended by the American College of Clinical Pharmacology 20
• Concomitant use of multiple hepatotoxic drugs increases the risk of liver injury, and patients should be closely monitored, as recommended by the American Association for the Study of Liver Diseases 21, 11