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High liver enzymes signal serious disease in HIV-positives without viral hepatitis.

Three quarters of HIV-positive adults with high liver enzymes and without viral hepatitis had undetected liver disease, (1) including more than half with nonalcoholic steatohepatitis (NASH *) (2) and fibrosis *, which can lead to permanent liver disease. Insulin resistance *, obesity, and two gene changes raised the risk of NASH and fibrosis, but length of antiretroviral therapy * did not.

Aminotransferase (liver enzyme) levels climb abnormally high in as many as 60% of everyone taking antiretroviral therapy, even people without hepatitis caused by hepatitis B virus (HBV) or hepatitis C virus (HCV). Antiretrovirals may raise liver enzyme levels. Other possible causes besides HBV and HCV are alcohol abuse, illegal drug use, nonalcoholic fatty liver disease (NAFLD, which includes NASH), and HIV infection itself.

Despite the frequency of high liver enzymes in people without HBV or HCV while taking antiretrovirals, research has not pinned down the cause of high enzymes or determined their impact on the health of people with HIV. There are no guidelines for stopping or changing antiretroviral therapy because of high liver enzymes. HIV clinicians usually check patients regularly when their liver enzymes are high and make sure they do not have HBV, HCV, or another treatable cause. But high liver enzymes alone are not a reason to stop antiretroviral therapy.

To get a better understanding of how above-normal liver enzymes may affect the health of HIV-positive people without HBV or HCV, and to help define possible causes, researchers at the National Institutes of Health conducted this study.

* How the study worked. HIV-positive adults taking antiretroviral therapy for at least 1 year entered the study from 2007 to 2013. Everyone had levels of a key liver enzyme--aspartate aminotransferase (AST) or alanine aminotransferase (ALT)--above the upper limit of normal three or more times over at least 6 months. No one had HBV or HCV infection or other liver diseases, and no one drank too much alcohol. All study participants completed a questionnaire and interview about their health and HIV infection. From medical records, researchers collected information on current and past antiretroviral use, CD4 count, viral load, previous liver test results, and other health data.

When people entered the study, researchers measured a wide array of liver-related values (including AST and ALT), CD4 count, and viral load. They also used three methods to see if people had fibrosis (nonfunctioning scar tissue in the liver). The researchers also measured glucose (blood sugar), insulin *, insulin resistance, cholesterol, and triglycerides.

Study participants had CT scans to check for an unhealthy, enlarged liver. Everyone also had liver biopsy, a procedure in which a needle removes a small liver sample to test for fibrosis and steatosis (fat build-ups). The investigators also looked for two gene changes that prior research linked to NASH and fibrosis.

The researchers used a standard statistical test to identify predictors of NASH and advanced fibrosis in study participants. This type of analysis singles out factors that predict NASH and fibrosis regardless of whatever other risk factors a person has.

* What the study found. The study involved 62 people, 58 of them (94%) men. Forty study participants (65%) were white, 18 (29%) Hispanic, and 5 (8%) black. Half of the study group had HIV infection for 17.5 years or longer, and half had taken antiretroviral therapy for 13 years or more. Everyone had a low or undetectable viral load. Years spent with high liver enzymes ranged from 1.1 to 11.4. Almost half of the study group (48%) was overweight and 31% were obese (see note 3). Forty-nine study participants (82%) had insulin resistance, which can lead to diabetes *.

Liver biopsy detected nonalcoholic fatty liver disease (NAFLD) in 45 people (73%) (Figure 1). Forty people (65%) had serious liver disease, including 34 (55%) with NASH and 11 (18%) with advanced fibrosis. ** Ten of the 11 people with advanced fibrosis also had NASH. Both NASH and advanced fibrosis pose a high risk of more serious liver disease, including liver cancer or cirrhosis. Twenty-two people had milder liver problems, such as mild steatosis and mild inflammation *.

Three standard markers of liver changes were higher in people with NASH than without NASH--the liver enzymes AST and ALT, and APRI, which is AST divided by the number of platelets (cells that help blood to clot). (4) Other measures higher in people with than without NASH included body mass index, waist width, waist-tohip ratio, insulin, and insulin resistance.

Median * body mass index stood at 29.1 (near the top of the overweight range) in people with NASH versus 25.4 (close to normal) in people without NASH. Median insulin resistance values (measured by the HOMA-IR method) were 6 versus 3.4 in people with and without NASH and 7.1 versus 3.9 in people with and without advanced fibrosis.

Factors that did not differ between people with and without NASH or with and without significant fibrosis included length of HIV infection, length of antiretroviral therapy, use of specific antiretrovirals, current CD4 count, and lowest-ever CD4 count.

Statistical analysis identified four factors linked to NASH or advanced fibrosis--obesity (see note 3), insulin resistance, and either of two gene changes tied to high liver enzyme levels in prior research. (5)

* What the results mean for you. This study of antiretroviral-treated people with high liver enzymes but without hepatitis virus infection found that many had serious liver problems called NASH (55%) and advanced fibrosis (18%). (1) These NASH and fibrosis rates are higher than those reported earlier in people who had high liver enzymes but did not have HIV or viral hepatitis. The National Institutes of Health researchers who conducted this study believe their findings suggest that NASH and fibrosis may be overlooked in people with HIV and high liver enzyme levels.

Liver-related symptoms, lab values, and CT imaging results were similar in people with NASH or advanced fibrosis and in those with milder liver changes. Thus the researchers suggest clinicians should get a liver biopsy if they cannot explain persistently high liver enzymes in HIV-positive people without hepatitis virus infection. They add, however, that an ultrasound (sound wave) test not requiring a liver sample collected with a large needle--Fibroscan--may be useful for detecting fibrosis in people like those studied here. The research team observed that early detection and management of fatty liver disease in HIV-positive adults may help prevent or delay more serious complications of this condition. Fatty liver disease, especially NASH, can lead to liver failure and liver cancer.

The high rate of insulin resistance in study participants with NASH and advanced fibrosis led the authors of this study to recommend insulin resistance testing with an oral glucose tolerance test for HIV-positive people with unexplained high liver enzymes. Early detection of insulin resistance could allow clinicians to recommend lifestyle changes (such as diet and exercise) or to treat people with antidiabetes drugs called glitazones.

In addition to insulin resistance, the study identified another important risk factor for NASH or fibrosis--obesity. Almost one quarter of HIV-positive adults in a nationwide US study were obese, and obesity rates were higher in women with HIV than without HIV (40% versus 36%). (6) Being overweight or obese can lead to diabetes and heart disease, and, as this study shows, obesity also poses a risk of liver disease. If you are overweight or obese, your HIV provider has probably talked to you about losing weight. You should cooperate with your provider to find a weight-loss strategy that works for you. Losing weight is not easy. But many people do shed pounds--and keep them off--through diet, exercise, and other strategies.

Another important finding of this study is that longer time with HIV infection and longer time taking antiretrovirals did not affect chances of NASH or advanced fibrosis. People in this study had taken antiretrovirals from 1.7 to 22.8 years. Antiretrovirals can have longterm side effects, but NASH and fibrosis are not among those side effects in people with high liver enzymes but without hepatitis virus infection.

In an article discussing findings of this study and interpreting their meaning, an HIV-liver expert predicted that nonalcoholic fatty liver disease and NASH "will likely become the dominant liver disease among HIV-infected persons" because treatment of HCV infection has improved dramatically in recent years. (7) HBV infection can also be treated, and it can be prevented with a vaccine. US experts recently released guidelines on caring for nonalcoholic fatty liver disease. (8)


(1.) Morse CG, McLaughlin M, Matthews L, et al. Nonalcoholic steatohepatitis and hepatic fibrosis in HIV-1-monoinfected adults with elevated aminotransferase levels on antiretroviral therapy. Clin Infect Dis. 2015;60:1569-1578.

(2.) National Institute of Diabetes and Digestive and Kidney Diseases. Nonalcoholic steatohepatitis. Last updated May 28, 2014.

(3.) Overweight means a body mass index between 25 and 29.9 kg/m2. Obese means a body mass index of 30 kg/m2 or greater. To calculate your body mass index, go to

(4.) Hepatitis C Online. AST to platelet ratio index (APRI) calculator.

(5.) The gene changes are called rs738409 and rs2281135. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ, Nash CRN. The association of genetic variability in patatin-like phospholipase domain containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology. 2010;52:894-903; Yuan X, Waterworth D, Perry JR, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008;83:520-528.

(6.) Thompson-Paul AM, Wei SC, Mattson CL, et al. Obesity among HIV-infected adults receiving medical care in the United States: data from the cross-sectional Medical Monitoring Project and National Health and Nutrition Examination Survey. Medicine (Baltimore). 2015;94:e1081.

(7.) Crum-Cianflone NF. Elevated aminotransferase levels among HIV-infected persons: what's lurking under the surface? Clin Infect Dis. 2015;60:1579-1581.

(8.) Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592-1609.

* Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts.

** Bridging fibrosis, which can lead to cirrhosis.
Figure 1. Among 62 people with HIV and
persistently high liver enzymes--but without
hepatitis virus infection--73% had
nonalcoholic fatty liver disease (NAFLD), 55%
had nonalcoholic steatohepatitis (NASH), and
18% had advanced fibrosis. Almost everyone
with advanced fibrosis also had NASH.

Rates of fatty liver disease and fibrosis with
HIV and high liver enzymes

NAFLD      73%
NASH       55%
Fibrosis   18%

Note: Table made from bar graph.
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Title Annotation:Article 9
Publication:HIV Treatment: ALERTS!
Date:Sep 1, 2015
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