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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: Acetaminophen

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC
    • Los Angeles, California, United States, 91105
      • USC HCC II (Fatty Liver Clinic)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

NAFLD patients:

Inclusion criteria:

1. "Presence of NAFLD": This will be defined by the presence of at least two of the following criteria: (a) suggestion of liver fat by an imaging study (ultrasound, CT scan, MRI or MR spectroscopy) performed in the 6 months prior to enrollment; (b) elevated aminotransferase levels (ALT > 31 U/L for men or > 19 U/L for women, or AST > 30 U/L) on at least two occasions in the 6 months preceding enrollment; and (c) presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria. Biopsies are not required; however, previous biopsy done within the 6 months prior to the initiation of the study will be considered diagnostic if typical findings of NAFLD are described and other causes of liver disease are ruled out;
2. Individuals who are 18-70 years old;
3. Written informed consent.

Exclusion criteria:

1. Serum ALT > 3 times ULN at baseline.
2. Evidence of another form of liver disease including viral hepatitis, autoimmune hepatitis, cholestatic liver disease, Wilson's disease, Alpha-1-antitrypsin deficiency, hemochromatosis or DILI.
3. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year.
4. Evidence of liver cirrhosis on labs or imaging.
5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis in the previous 6 months.
6. Significant systemic or major illnesses other than liver disease.
7. Positive test for anti-HIV.
8. Active substance abuse.
9. Pregnancy or inability to practice adequate contraception in women of childbearing potential
10. Evidence of hepatocellular carcinoma.
11. Any other condition which, in the opinion of the investigators, would impede competence or compliance.
12. Serum creatinine >1.5 mg/dl.
13. Starting medications that have been shown to cause drug induced liver injury (eg, augmentin, statins.) within one month prior to enrollment. Medications that have been known to cause DILI but have taken for more than one month prior to enrollment (such as statins) should not be an exclusion.

Healthy Controls:

Inclusion criteria:

1. Individuals who are 18-70 years old
2. Normal Liver enzymes
3. Negative hepatitis B surface antigen, and hepatitis C antibody
4. BMI (18.5 - 24.9) kg/m2
5. Written informed consent.

Exclusion criteria:

1. Presence of the metabolic syndrome, defined according to the modified AHA/NCEP criteria
2. Taking concomitant medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: NAFLD patients; Twenty patients with NAFLD will take 3g of APAP daily for 14 days. Serum liver chemistries and trough acetaminophen (APAP) concentrations will be measured on treatment days 0, 2, 4, 7, 9, 11, 14 and on follow up day 17	Drug: Acetaminophen; acetaminophen will be given for patient for both arms for 14 days; Other Names: APAP
Active Comparator: Healthy controls; Twenty healthy controls will take 3g of APAP daily for 14 days. Serum liver chemistries and trough acetaminophen (APAP) concentrations will be measured on treatment days 0, 2, 4, 7, 9, 11, 14 and on follow up day 17	Drug: Acetaminophen; acetaminophen will be given for patient for both arms for 14 days; Other Names: APAP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploring possible mechanism of acetaminophen liver injury in NAFLD patients	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).	14 days

Collaborators and Investigators

• Sponsor: University of Southern California
• Investigators: Principal Investigator: Mazen Noureddin, University of Southern California

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): March 19, 2015
• Study Completion (Actual): March 19, 2015

Study Registration Dates

• First Submitted: June 7, 2014
• First Submitted That Met QC Criteria: July 16, 2014
• First Posted (Estimate): July 18, 2014

Study Record Updates

• Last Update Posted (Actual): March 30, 2017
• Last Update Submitted That Met QC Criteria: March 28, 2017
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Acetaminophen, Non-alcoholic Fatty Liver Disease (NAFLD)
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: HS-13-00771