Persistent ALT Elevation in HIV-HBV Coinfection May Signal Coexisting Fatty Liver Disease

fatty liver disease
Fatty liver, conceptual illustration. Fatty liver is commonly associated with alcohol or metabolic syndrome (diabetes, hypertension and obesity), but can also be due to any one of many causes. Fatty liver disease is a reversible condition wherein large vacuoles of fat (pale yellow circles) accumulate in liver cells.
Patients with persistent ALT elevation despite controlled HBV should undergo evaluation for metabolic risk and fatty liver disease.

Persistent alanine aminotransferase (ALT) elevation despite hepatitis B virus (HBV) control should prompt evaluation for metabolic risk and coexisting fatty liver disease in adults with HIV-HBV coinfection, according to study results published in Clinical Infectious Diseases.

Using data from a multicenter prospective cohort study of adults with HIV-HBV on antiretroviral therapy ( identifier: NCT01924455), researchers sought to determine the presence of coexisting fatty liver disease, its disease activity, and its clinical correlates, including cardiovascular disease (CVD) risk. In addition, they evaluated the effect of fatty liver disease on liver tests (ALT and aspartate aminotransferase [AST]) as a surrogate for liver disease activity over time.

Adults who were anti-HIV and hepatitis B surface antigen (HBsAg) positive for at least 6 months were recruited from 8 Hepatitis B Research Network sites in the United States and Canada. From April 28, 2014 to November 7, 2018, 114 participants underwent a liver biopsy and were followed for a median of 3 years. Steatohepatitis was based on presence of steatosis, ballooning, and perisinusoidal fibrosis. Fatty liver disease was defined as ≥5% steatosis and/or steatohepatitis.

The median age of the participants was 49 years, 93% were men, 51.3% were Black, 92.3% had HIV RNA <400 copies/mL, and 83% had HBV DNA <1000 IU/mL. Of the 114 participants, 11 (9.7%) had steatohepatitis, and an additional 23 participants (20.2%) had steatosis. A higher percentage of participants with at least twice normal ALT and abnormal AST had fatty liver disease. Half of the participants with steatohepatitis had at least twice normal ALT (vs 17.4% with steatosis and 7.8% with no fatty liver disease) and abnormal AST occurred in 60% with steatohepatitis compared with 30.4% in those with steatosis and 15.6% in those with no fatty liver disease. Fatty liver disease was more prevalent in those with higher grades of inflammation as measured by the Histology Activity Index, and in those with higher degrees of perisinusoidal fibrosis; however, there was no significant difference in the presence of fatty liver disease by Ishak fibrosis score.

Compared with participants with no fatty liver disease, participants with fatty liver disease had higher insulin (median, 19 vs 8.5 mμ/mL; P <.001), glucose (median, 94 vs 89 mg/dL; P =.12), and fatty acids levels (median, 0.49 vs 0.39 mg/dL; P =.21).

While traditional lipid profiles such as total cholesterol, low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were not significantly different among those with and without fatty liver disease, participants with fatty liver disease had significantly higher median triglyceride (171 vs 100.5 mg/dL, P <.001) and apolipoprotein B (95.5 vs 80.5 mg/dL, P =.028) levels compared with no fatty liver disease.  In addition, those with fatty liver disease had significantly higher LDL particle concentration, small dense LDL-C, small LDL particle concentration, and lower HDL subclass 2-C (P ≤.001 for all).

After adjusting for age, sex, and alcohol use, White and other vs Black race (adjusted odds ratio [aOR], 8.49 and 16.54, respectively; P =.0004), higher ALT (aOR, 3.13 per doubling of ALT; P =.003), hypertension (aOR, 10.93; P =.002), hyperlipidemia (aOR, 4.36; P =.04), and known family history of diabetes (aOR, 5.38; P =.02) were independently associated with higher odds of fatty liver disease.

After adjusting for HBV DNA level, age, and sex, in comparison with no fatty liver disease, having steatohepatitis was associated with 1.93 (95% CI, 1.37-2.72) times higher ALT across time, while having steatosis without steatohepatitis was associated with 1.34 (95% CI, 1.05-1.70) times higher ALT across time (P <.001).

Limitations of this study included the self-selection of participants willing to undergo liver biopsy, limiting the generalizability to the total HIV-HBV population. In addition, while ALT was higher with fatty liver disease cross sectionally, and this relationship persisted over time when accounting for HBV viral levels, researchers could not determine if ALT had increased with the initial development of fatty liver disease.

“Elevated ALT despite HBV control should prompt evaluation for metabolic risk and coexisting fatty liver disease,” noted the researchers. “While traditional metabolic abnormalities predicted fatty liver disease, triglyceride levels or lipid subfractions, rather than standard lipid measurements may be required to unmask CVD risk and target preventive management,” they concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Khalili M, King WC, Kleiner DE, et al; HIV-HBV Cohort Study of the Hepatitis B Research Network. Fatty liver disease in a prospective North American cohort of adults with HIV and hepatitis B coinfection [published online September 1, 2020]. Clin Infect Dis. doi: 10.1093/cid/ciaa1303