What are the considerations for initiating Pioglitazone (Thiazolidinedione) in a patient with undiagnosed liver dysfunction (abnormal liver function tests)?

From the Guidelines

Pioglitazone should not be initiated in patients with undiagnosed liver abnormalities until proper evaluation is completed. Before starting pioglitazone, baseline liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) should be obtained, and the medication should only be initiated if liver enzymes are normal or only mildly elevated (less than 2.5 times the upper limit of normal) 1. If liver abnormalities are detected, further investigation is necessary to determine the cause before considering pioglitazone therapy. According to the kasl clinical practice guidelines: management of nonalcoholic fatty liver disease, pioglitazone can be considered as a treatment option for NASH diagnosed by liver biopsy in patients with or without diabetes mellitus 1. However, weight gain is a common side effect of pioglitazone treatment, and other potential side effects of long-term pioglitazone should be considered.

Key Considerations

• Pioglitazone is contraindicated in patients with active liver disease or ALT levels greater than 2.5 times the upper limit of normal 1.
• The drug is metabolized by the liver, and impaired liver function can lead to increased drug levels and potential toxicity.
• Pioglitazone may worsen underlying liver conditions such as non-alcoholic fatty liver disease, which is common in patients with type 2 diabetes.
• The American Association for the Study of Liver Diseases recommends that pioglitazone improves liver histology in patients with and without T2DM with biopsy-proven NASH, and may be used to treat these patients, but risks and benefits should be discussed with each patient before starting therapy 1.

Monitoring and Evaluation

• Once treatment begins, liver function should be monitored periodically, especially during the first year.
• Imaging studies such as US abdomen, US duplex Doppler abdomen, CT abdomen and pelvis with IV contrast, and MRI abdomen without and with IV contrast may be necessary to evaluate liver abnormalities 1.
• The choice of imaging study depends on the patient's clinical presentation and the presence of hepatocellular predominance, cholestatic predominance, or hyperbilirubinemia.

From the FDA Drug Label

ACTOS therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, Hepatic Effects). Liver enzyme monitoring is recommended prior to initiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels)

Pioglitazone initiation with undiagnosed liver abnormality is not recommended if the patient has active liver disease or elevated serum transaminase levels.

• Liver enzyme monitoring is recommended before starting pioglitazone therapy in all patients.
• Patients with und diagnosed liver abnormality should have their liver function tested before starting pioglitazone. 2 2

From the Research

Pioglitazone Initiation with Undiagnosed Liver Abnormality

• The initiation of pioglitazone in patients with undiagnosed liver abnormality has been studied in several clinical trials 3, 4, 5.
• A 3-year, randomized, comparator-controlled study in the US found that pioglitazone had a similar hepatic safety profile to glibenclamide in patients with type 2 diabetes 3.
• The study found that the incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617) 3.
• Another study found that pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13% 4.
• A randomized controlled pilot study found that pioglitazone, metformin, and silymarin treatment had beneficial effects on non-alcoholic fatty liver disease (NAFLD) 5.
• The study found that all three treatments resulted in significant reductions in fasting blood sugar, lipid profiles, and liver enzymes, with pioglitazone showing the most reduction in fasting blood sugar and serum insulin level 5.

Evaluation of Abnormal Liver Tests

• Abnormal liver tests are common in adult asymptomatic patients, with up to 40% of patients having abnormal results 6.
• A systematic approach to evaluating abnormal liver tests is crucial, including detailed history gathering, alcohol use assessment, recognition of metabolic syndrome, and identifying patterns of liver test abnormalities 6, 7.
• The interpretation of liver test abnormalities can often identify the type and etiology of liver disease, allowing for a targeted investigation approach 7.
• Composite scores like the Model for End Stage Liver Disease can be used to assess the severity of liver injury, rather than relying on a single parameter 7.