Clinical Trial: The Effect of Acetaminophen on Non-alcoholic Fatty Liver Disease Patients

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional

Official Title: The Effect of Daily Acetaminophen on Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Compared to Healthy Controls

Brief Summary:

In this first pilot study, we will examine the effects of acetaminophen dosing in adult patients with NAFLD in comparison to the effects in a healthy control group. Both groups will receive 3 grams (g) of acetaminophen, the maximum recommended daily dose, daily for 14 days. We hypothesize that NAFLD patients are more prone to APAP toxicity than normal controls.Treatment will be stopped after two weeks or in the following conditions:

Treatment with APAP will be stopped in healthy volunteers if ALT and/or AST reached three times the ULN. In patients with NAFLD, treatment will be stopped if: ALT or AST reach ≥ three times the upper limit of entry value or ≥ 5 times the ULN; or if there is ALT or AST >3 times ULN and TBili >2xULN or INR >1.5; or if there is ALT or AST >3 times ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). We follow a conservative approach derived from the FDA guidelines for stopping medications expected to cause drug induced liver injury (DILI). Indeed, the FDA allows continuation of the medication until ALT or AST are >8x ULN in the absence of elevated Tbili or INR. Patients who have hepatotoxicity will have close monitoring of their liver enzymes until they normalize. Taking acetaminophen up to 3g daily has been shown to be safe and acceptable. We have followed very strict criteria for monitoring and stopping rules however in the usually cases of toxicity the patient will be admitted for monitoring.


Detailed Summary:
Sponsor: University of Southern California

Current Primary Outcome: This pilot study will seek to answer the question of whether or not NAFLD patients are more prone to APAP toxicity and whether or not lower doses should be recommended. [ Time Frame: 14 days ]

Liver injury in controls will be defined as an increase in the alanine aminotransferase (ALT) level and/or Aspartae aminotransferase (AST) ≥ three times the upper limit of normal (ULN). Liver Injury in NAFLD patients will be defined as rise of ALT and/or AST ≥3 times baseline levels (which are likely to be elevated) and reaching 5 times ULN. Acetaminophen will be immediately discontinued once the ALT and/or AST reache the defined liver injury level and patients will continue to be monitored. Comparison between the two groups will assess whether or not NAFLD patients are more prone to liver injury than controls.


Original Primary Outcome: Same as current

Current Secondary Outcome: Exploring possible mechanism of acetaminophen liver injury in NAFLD patients [ Time Frame: 14 days ]

We plan to measure the serum and urine levels of APAP metabolites including serum levels of acetaminophen-glucuronide (APAP-G) and acetaminophen-sulfate (APAP-S) and the urine levels of cysteine and mercapturic acid conjugates (APAP-C and APAP-M). We also plan to measure APAP protein adducts which are biomarkers of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite NAPQI. We will measure the serum glutathione level and serum markers of mitochondrial injury, including glutamate dehydrogenase (GLDH) and acylcarnitine, as well as markers of necrosis such as miR-122, high-mobility group box-1 protein (HMGB1), full-length keratin 18 and apoptosis marker keratin 18 fragments. The activity of UGT will be estimated by the plasma ratio of APAP-G to APAP at 4 hours (when the first sample is drawn). Expression of CYP2E1 in the peripheral lymphocytes will be assessed using reverse transcription polymerase chain reaction (RT-PCR).


Original Secondary Outcome: Same as current

Information By: University of Southern California

Dates:
Date Received: June 7, 2014
Date Started: June 2014
Date Completion:
Last Updated: March 28, 2017
Last Verified: June 2014