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Professor of Medicine
Medical Director, Viral Hepatitis Center
Chief, Infectious Disease
Johns Hopkins Bayview Medical Center
Johns Hopkins University School of Medicine
Mark S. Sulkowski, MD, has disclosed that he has received consulting fees from AbbVie, Assembly Bio, Antios, Gilead Sciences, Virion, and ViiV and has received funds for research support from AbbVie, Assembly Bio, Gilead Sciences, and Janssen.
When I started my infectious diseases training, our patients with HIV suffered devasting and often fatal illnesses related to acquired immunodeficiency. In the early days of highly active antiretroviral therapy (ART), our patients frequently had abnormal liver enzyme levels due to many threats to their livers: drug-induced liver injury due to medications used to treat HIV and its complications, chronic hepatitis B and hepatitis C, and alcohol-related liver injury.
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) were rarely on the differential diagnosis in the late 1990s and 2000s. As I think about our patients with HIV today, my first thought is: Wow! We have made remarkable progress with safe, tolerable (nonliver toxic) ART, which can also treat hepatitis B, and Nobel Prize–winning advances in hepatitis C treatment. Yet, our patients frequently still have abnormal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Why? With control of HIV, our patients have gained weight like many Americans (possibly due to ART) and developed metabolic diseases, such as cardiovascular disease.
Although we still need to consider the potential contribution of reported/unreported alcohol consumption when we evaluate our patients with elevated liver enzymes, in the absence of alcohol, NAFLD/NASH is near the top of my differential diagnosis, particularly in persons with elevated BMI, diabetes, hyperlipidemia, or other metabolic diseases. I educate and counsel my patients on healthy eating and physical activity and how these conditions can affect the liver. I also order tests to detect the presence of steatosis (liver fat) and, if detected, to quantify the amount of fat.
I typically start with liver ultrasound and, when possible, transient liver elastography to quantify liver stiffness (a correlate of fibrosis) and steatosis (using the controlled attenuation parameter, or CAP). I also like to determine the FIB-4 in all my patients. It’s based on readily available tests (AST, ALT, and platelet count) and easy to calculate using online calculators, and of importance, the score predicts mortality in people with HIV monoinfection. I also consider liver biopsy for some patients, especially those for whom the cause of the liver abnormalities is uncertain.
Why do I workup these patients? If unrecognized, our patients with undiagnosed NASH are at risk for liver complications, including cirrhosis, liver failure, hepatocellular carcinoma, and even death. Because liver disease can progress over time, I also talk to my patients about the need to continue to monitor their liver with blood tests and ultrasound.
If we recognize NASH in our patients, we can focus on evidence-based interventions for healthy eating, better glucose control, and when available, disease-directed therapies.
Although weight loss is challenging, multiple studies demonstrate clinically significant improvements in NASH and clinical outcomes in patients who lose approximately 5% to 10% of their body weight. Both the American Association for the Study of Liver Diseases and the European AIDS Conference Society (EACS) guidelines recommend lifestyle modification as the foundation of NASH treatment in patients with HIV. Therefore, I refer patients to expert healthcare professionals who have established a multidisciplinary approach to managing patients with an obesity-related medical condition.
Based on the results of published trials, professional society guidelines discuss the potential role of pioglitazone in people with biopsy proven NASH and vitamin E 800 mg/day in persons without diabetes. In a small study of 61 people with HIV and NAFLD, the growth hormone-releasing hormone analog tesamorelin, taken for 12 months, reduced liver fat (compared with placebo), and the EACS guidelines mention this option with the caveat that larger studies are needed. In patients with obesity, medications for weight loss and bariatric surgery are also important considerations. If my patient has both type 2 diabetes and NAFLD, I talk with the endocrinologist or primary care provider about the possibility of treatment with a glucagon-like peptide-1 receptor agonist like semaglutide, which has evidence for diabetes management, weight loss and some emerging evidence in NASH.
My patients also need to know about the clinical research underway to identify novel NASH treatments, but I stress that we need to take action today to improve their liver and overall health. An abnormal ALT is never “normal,” and our patients with abnormal liver enzymes need our attention and consideration of NASH.
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