Background/Purpose: Non-alcoholic fatty liver disease (NAFLD), the most common form of liver disease, refers to a spectrum of conditions which includes non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and fibrosis.  Progression of NAFL to cirrhosis via inflammatory pathways has been associated with low levels of adiponectin.   Hydroxychloroquine (HCQ) is concentrated in the liver, has been shown do increase adiponectin levels, and, per one animal study, shown to improve hepatic steatosis.  The role of HCQ in the prevention of NAFLD has not been explored.

Methods: A retrospective review of adult patients with RA (ICD 10 M05 and M06) seen at a tertiary academic rheumatology practice from 12/1/2014 to 5/30/2017 was constructed.  Electronic health records (EHR) of patients with any history of liver disease were manually reviewed to confirm eligibility.  The primary outcome was incident NAFLD during the observation period.  RA diagnoses were confirmed using a previously validated algorithm with greater than 90% accuracy.  The diagnosis of NAFLD, according to the American Association for the Study of Liver Disease (AASLD) criteria, was validated by reviewing right upper quadrant ultrasound, abdominal CT imaging, and/or liver biopsy results.  History of prior NAFLD, alcohol abuse, alcoholic cirrhosis, infectious hepatitis, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, acetaminophen toxicity were exclusion criteria.  Multivariate regression analysis was performed to determine the association between HCQ use and the development of incident NAFLD, after adjusting for relevant confounders, including demographics (age, sex, body mass index (BMI)), medications (dose and duration of HCQ use, concomitant MTX, and statin use), comorbidities (diabetes, metabolic syndrome, dyslipidemia, hypertension, alcohol use), and laboratory values (AST, ALT).

Results: Our study included 5617 patients with RA, including 1285 HCQ users. 95 patients were found to have history of liver disease in our database (20 in HCQ users and 75 in non-users) and underwent EHR review to screen for incident NAFLD.  During the observation period, 5 incident NAFLD events were found in the HCQ users (0.39%) and 19 in the non-users (0.43%).  The unadjusted odds ratio (OR) for incident NAFLD was calculated at 0.89 (95% CI 0.33-2.38, p=0.81).  When adjusted for age, sex, and race, the OR for incident NAFLD is 0.76 [0.22, 2.6], p= 0.24. Metabolic syndrome, diabetes, hypertension, and MTX use were more prevalent in the HCQ user group. Hypertension and statin use were significantly different between the HCQ group and non- HCQ group.

Conclusion: In this exploratory study, HCQ use was associated with a 24% decrease in incident NAFLD.  The higher prevalence of metabolic syndrome and related risk factors in our HCQ user group is unexpected, given the favorable relationship that others and we have described previously. This is the first study to examine the association of HCQ with NAFLD. Given the observational design and small number of events, our findings warrant confirmation in larger studies.

Table 1: Risk of NAFLD According to HCQ Use

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-hydroxychloroquine-use-with-development-of-non-alcoholic-fatty-liver-disease-in-rheumatoid-arthritis/