Non-alcoholic fatty liver disease: a growing health problem in people with HIV

Non-alcoholic fatty liver disease (NAFLD) is a major emerging health challenge for people living with HIV, according to a review of evidence by doctors from the University Medical Center, Utrecht, published in the journal Infectious Disease Therapies.

NAFLD occurs when fat accumulates in liver cells, in people with low alcohol consumption. In some people fat accumulation will cause no symptoms but in a minority of people with NAFLD, fat accumulation leads to more serious liver damage in the form of non-alcoholic steatohepatitis (NASH) and cirrhosis. Around 10% of people with NAFLD develop NASH, and approximately one-third of people with NASH will go on to develop fibrosis or cirrhosis, resulting in declining liver function.

Immune activation caused by HIV and a history of treatment with the first generation of antiretroviral drugs, as well as the classic risk factors of obesity and metabolic syndrome, may place people living with HIV at higher risk of developing NAFLD and NASH.


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.


A hormone produced by the pancreas that helps regulate the amount of sugar (glucose) in the blood.

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.


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.

A systematic review and meta-analysis published in 2017 found a prevalence of NAFLD in people living with HIV (PLHIV) of 35%, compared to a general population prevalence of 25%. The prevalence of NAFLD is much higher in PLHIV with persistent liver enzyme elevations; studies found prevalence ranged from 57 to 72%.

However, studies that have matched PLHIV with HIV-negative controls do not consistently find a higher prevalence in PLHIV and show that classic risk factors for NAFLD were more important than HIV-related factors.

Risk factors for NAFLD and NASH

Possible causes of NAFLD and NASH in HIV infection include:

  • Insulin resistance induced by HIV infection and by use of older protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) (especially stavudine) leads to triglyceride accumulation in the liver.
  • Mitochondrial toxicity caused by older NRTIs (stavudine, zidovudine) prevents liver cells from processing triglycerides, promoting accumulation.
  • Boosted protease inhibitors promote higher lipid levels.
  • Insulin resistance and raised glucose levels encourages production of lipids in the liver.

Traditional risk factors are insulin resistance and type 2 diabetes, high body mass index and high waist circumference, hypertension and high triglycerides.

NAFLD is thought to predispose the liver to further injury from other sources such as antiretroviral drugs that cause mitochondrial toxicity, changes in the activity of adipose tissue due to metabolic syndrome or antiretroviral drugs, and inflammation caused by chronic HIV infection. But experts are still uncertain why NASH develops in some people with NAFLD.

As people with HIV age, the authors say, it is likely that traditional risk factors for NAFLD will become more important than HIV-related factors in determining the burden of NAFLD in PLHIV. One study found almost two-thirds of a cohort of PLHIV was either overweight or obese and therefore at risk of developing NAFLD.

Diagnosis and treatment

Diagnosis of NAFLD and NASH, especially in epidemiological studies, remain problematic. Liver biopsy is the gold standard but cannot be used for screening owing to the potential risks of bleeding and pain. MRI scanning cannot be used for screening studies owing to its cost but a new addition to the Fibroscan non-invasive tool for measurement of liver stiffness called Controlled Attenuation Parameter (CAP) can be used to assess the extent of steatosis with a high degree of sensitivity at all stages.

European AIDS Clinical Society guidelines recommend ultrasound screening for NAFLD in all PLHIV with metabolic syndrome (defined as any three of impaired fasting glucose or type 2 diabetes, elevated triglycerides, low HDL cholesterol, high blood pressure, and increased waist circumference).

Potential treatment options for NASH include the following:

  • NASH can be improved by weight loss of 10% or more.
  • Alcohol consumption should be confined to the recommended limits; high alcohol consumption raises the risk of liver cancer in people with NASH. The European Association for the Study of the Liver (EASL) recommends complete abstinence for anyone diagnosed with NASH.
  • Pioglitazone has shown some efficacy against NASH but is associated with weight gain. EASL recommends an insulin sensitiser such as pioglitazone in people with type 2 diabetes whereas the American Association for the Study of Liver Diseases (AASLD) recommends an insulin sensitiser for anyone with NASH.
  • Vitamin E can be considered for anyone without type 2 diabetes and without cirrhosis, EASL and AASLD recommend.
  • Antiretroviral regimens associated with metabolic complications should be replaced with more benign regimens containing newer non-nucleoside reverse trancriptase inhibitors such as rilpivirine or doravirine and integrase inhibitors.

Van Welzen BJ et al. A review of non-alcoholic fatty liver disease in HIV-infected patients: the next big thing? Infect Dis Ther, advance online publication, 3 January 2019.