As noted by Dr Brandman, NAFLD is a disorder that is reaching epidemic proportions in the United States. Histologically, the spectrum of NAFLD includes fat deposition within the liver, evolution to a chronic inflammatory state that may progress to fibrosis, and, ultimately, cirrhosis and its sequelae, including end-stage liver disease and hepatocellular carcinoma. It is still unclear why some patients with NAFLD progress to nonalcoholic steatohepatitis (NASH) and more severe forms of the disease while others do not. NAFLD is far more common in the setting of obesity and diabetes than in the general population. Rheumatologic patients are fairly representative of the general population, although NAFLD is overexpressed in psoriatic arthritis, which is often comorbid with obesity.

An important concern for rheumatologists relates to the risks of antirheumatic drugs in patients with rheumatoid arthritis (RA) and NAFLD. In fact, in those with NAFLD, there is evidence of increased vulnerability to hepatotoxicity from certain types of antirheumatic agents. The 2 drugs that are of greatest relevance to the rheumatologist are prednisone and methotrexate (MTX). Prednisone is associated with an increased incidence and severity of NAFLD, owing to its association with metabolic syndrome, insulin resistance, central obesity, and fatty deposition within the liver. MTX has been associated with alanine aminotransferase elevations, hepatic injury, and cirrhosis. However, over the last 10 to 20 years, we have learned how to use MTX wisely. End-stage liver disease as a sequela of MTX therapy is exceedingly uncommon with modern dosing and appropriate monitoring. One challenge that is encountered with some regularity is a modest elevation of hepatic enzymes in patients starting MTX who had normal levels at baseline. Having persistently elevated hepatic enzymes is a risk factor for MTX-induced liver injury, as is obesity and diabetes. In cases of NAFLD and suspected MTX toxicity, liver biopsy may show an admixture of liver injury and fat deposition, and NASH is one of the more common histopathologic pictures that is documented. The clinical importance of all of this is that people who are vulnerable to NAFLD (and thus are vulnerable to NASH) are at high risk of MTX hepatotoxicity, which, today, looks like an admixture of classical liver injury with fibrosis and underlying fatty liver disease. Dr Brandman noted in this session that, when it has been determined that a patient on MTX should no longer be on MTX, the choice of an alternative  disease-modifying antirheumatic drug (DMARD) should be guided by the patient’s RA, and I agree with that principle.

The question of what to do when the patient with RA has elevated hepatic enzymes at baseline is an evolving one. In the past, when there were fewer treatment options, management included baseline liver biopsy followed by careful monitoring during MTX therapy. Today, a variety of strategies are used. If one initiates a hepatic workup in advance, it might be determined that the patient has NAFLD. In this case, one might proceed cautiously with MTX or one might deem that patient to be a poor candidate for MTX and monotherapy with a biologic DMARD or a targeted synthetic DMARD would be considered. In patients who are at high risk from the hepatology perspective, an assessment of fibrosis is recommended, in concert with a hepatology consultation. 

Finally, the role of rheumatologists in the treatment of patients with NAFLD is an evolving one. Dr Brandman noted that the treatments we have for NAFLD are, at present, quite poor. She also noted that weight loss has the potential to counter some of the pathology of NAFLD, which was a very important point. Weight loss, prudent diet, exercise, and stress reduction all contribute to an improvement in the wellness quotient, and I think that counseling patients on wellness behaviors can be just as important in rheumatology as it is in primary care.