Non-alcoholic fatty liver disease common in people living with HIV – metabolic disorders are key risk factors

Over a third of people with HIV have non-alcoholic fatty liver disease (NAFLD) in the absence of hepatitis B or C, according to the results of a meta-analysis and systematic review published in AIDS. Metabolic disorders including high body mass index (BMI), diabetes and elevated lipids were key risk factors. The study also revealed high prevalences of non-alcoholic steatohepatitis (NASH) and liver fibrosis, possible outcomes of NAFLD, with metabolic disorders once again shown as the most important factors.

“NAFLD is common in HIV-monoinfected patients. Metabolic disorders are key risk factors for NAFLD independent of HIV parameters and predict its complications,” comment the authors. “Our systematic review underlines the need for additional data on NAFLD in HIV infection as well as a better standardised assessment and management of the disease.”

Liver disease is now a leading cause of serious illness and death in people with HIV. Until now, much of the liver disease occurring in people living with HIV has been associated with co-infection with hepatitis B or C, but NAFLD is emerging as a new concern in the management of individuals with HIV infection who do not have hepatitis B or C co-infection.

Glossary

non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a very common disorder and refers to a group of conditions where there is accumulation of excess fat in the liver of people who drink little or no alcohol. The most common form of NAFLD is a non-serious condition called fatty liver, by which fat accumulates in the liver cells. A small group of people with NAFLD may have a more serious condition named non-alcoholic steatohepatitis (NASH).

non-alcoholic steatohepatitis (NASH)

In NASH, fat accumulation is associated with liver cell inflammation and different degrees of scarring. NASH is a potentially serious condition that may lead to severe liver scarring and cirrhosis. It sometimes affects older people living with HIV.

fibrosis

Scarring of the liver – the development of hard, fibrous tissue. See also ‘cirrhosis’, which is more severe scarring.

metabolism

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

The condition is defined by the accumulation of fat in the liver and the presence of triglycerides in liver cells in the absence of a cause such as excess alcohol consumption. NAFLD may progress to NASH, in which the liver becomes inflamed and liver cells are damaged, and possibly to fibrosis (death of liver tissue and scarring) or to liver cancer. There is some evidence that NAFLD also increases the risk of developing cardiovascular disease.

Numerous pharmaceutical treatments for NASH are being investigated in clinical trials but it is far from clear which types of drugs are likely to prove effective, and if treatment of NASH will have any long-term impact on mortality and serious illness due to liver disease or cardiovascular disease.

In HIV-negative individuals, NAFLD is usually associated with metabolic syndrome including obesity, insulin resistance and elevated lipids. Global prevalence of NAFLD is estimated at 25%, with prevalence higher in people with type 2 diabetes.

It is important that NAFLD is diagnosed promptly in people with HIV so that appropriate lifestyle changes and therapies can be initiated. A team of UK investigators therefore performed a systematic review and meta-analysis of research to identify the prevalence and risk factors of NAFLD, NASH and fibrosis in people with HIV mono-infection.

Studies were eligible for inclusion if they compared adult patients with HIV mono-infection with and without NAFLD, diagnosed using imaging or histology. Exclusion criteria included co-infection with hepatitis B and/or hepatitis C or excess alcohol consumption. Prospective and retrospective observational studies and randomised trials were all eligible for inclusion.

Ten studies met the inclusion criteria. Four were carried out in the United States, two in France and one each in Canada, Japan and Italy. Study populations ranged in size from 14 to 435 participants. One study excluded people with diabetes, with the others having a prevalence of type 2 diabetes of between 5 and 49%. Almost all (over 90%) of the participants were male. BMI ranged from 22.8 kg/m2 (the study in Japan) to 29.9 kg/m2 (a US study). Liver biopsy was used to diagnose NAFLD in five studies. All the studies were single-centre and cross-sectional in their design, and three were case-controlled. Overall, their quality was rated as poor to moderate.

The investigators restricted their analysis of the prevalence of NAFLD to the five studies that used imaging to diagnose this disorder. They found an overall prevalence of 35% with significant heterogeneity between studies.

As regards NASH, six studies with 208 cases confirmed by liver biopsy (histological confirmation) were analysed, showing an overall prevalence of 42%. Six studies also provided data on 208 histologically confirmed cases of fibrosis, with an overall prevalence of 22%.

Six studies provided sufficient data to determine risk factors for NAFLD. These included BMI (p < 0.00001), waist circumference (p < 0.00001), type 2 diabetes (p = 0.02), hypertension (p = 0.00006), high triglycerides (p = 0.001), high total cholesterol (p = 0.001), low HDL cholesterol (p = 0.003), high LDL cholesterol (p = 0.003), high fasting glucose (p = 0.0007), high ALT and AST (both p < 0.0001).

Three studies provided data for meta-analysis of individuals with histological diagnosis of NASH. The studies were small in size (a total of 141 people) and no significant factors were detected.

Four studies provided data on risk factors for fibrosis. These included BMI (p = 0.04), fasting glucose (p < 0.000001) and AST level (p = 0.003).

“The current study provides the first systematic review of the literature with meta-analysis examining the prevalence and risk factors of NAFLD, NASH and fibrosis in HIV-monoinfected patients,” write the investigators, who believe their research has three important take-home messages:

  • NAFLD is common in people with HIV, but longitudinal studies with good-quality histological data are needed to give a clearer idea of its prevalence.
  • People with features of metabolic syndrome should be thoroughly investigated for NAFLD.
  • Lifestyle changes are the mainstay of treatment for NAFLD, but few people manage to achieve the changes needed to remedy the disorder. People with HIV should, therefore, be allowed to participate in clinical studies investigating experimental drug therapies for the condition.

The author of an accompanying editorial believes the study’s findings are “remarkable” for three reasons:

  • The high prevalences of NAFLD, NASH and fibrosis which by far exceed the rates seen in the general population.
  • The importance of metabolic risk factors.
  • The lack of research into the condition.

“Perhaps the most important take-home message is that persistently elevated aminotransferase levels in HIV-infected patients should not be ignored or attributed to minor ART-related toxicities,” concludes the author. “They may be the first clue to significant liver disorders that can have major clinical implications.”

References

Maurice JB et al. Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection. AIDS 31: 1621-32, 2017.

Morse CG. Fatty liver disease in HIV: common, underappreciated, and understudied. AIDS 31: 1633-35, 2017.