Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is characterized by fatty infiltration of the liver (hepatic steatosis involving > 5% of hepatocytes) either on liver histology or imaging.

To be diagnosed with NAFLD, a person must not have a history of heavy alcohol use or another condition that may be causing the liver condition (such as HCV).

It is often associated with components of the metabolic syndrome: overweight, type 2 diabetes, dyslipidemia and hypertension. However, NAFLD can occur in lean patients (BMI<25). NAFLD may affect 25% of lean people with HIV.

Experts proposed redefining NAFLD as metabolic-associated fatty liver disease (MAFLD) to provide a positive rather than exclusionary diagnosis. However, the role of contemporary ART on MAFLD (in particular regarding an association with weight gain) remains unknown.

There are two types of NAFLD:
1. Non-alcoholic fatty liver (NAFL), fatty infiltration but no inflammation
2. Non-alcoholic steatohepatitis (NASH), with fatty infiltration along with liver inflammation (hepatocyte injury with or without fibrosis)

The prevalence of NAFLD is higher in persons with HIV (30 - 40%) than in the general population. Nearly half of the persons with HIV who undergo evaluation for unexplained liver test abnormalities are found to have NAFLD.

Non-Alcoholic SteatoHepatitis (NASH)

  • Early NASH: no or mild (F0-F1) fibrosis
  • Fibrotic NASH: significant (≥ F2) or advanced (≥ F3, bridging) fibrosis
  • NASH-cirrhosis (F4)
  • HCC (can occur in the absence of cirrhosis and histological evidence of NASH)


  • Ultrasound is the preferred first-line diagnostic procedure for imaging of NAFLD
  • Whenever imaging tools are not available or feasible, serum biomarkers and scores are an acceptable alternative for the diagnosis
  • Where available and in experienced centres, transient elastography with controlled attenuation parameter could be used to diagnose HIV-associated NAFLD, although no optimal cut-off has been established yet. Few studies have validated CAP cut-off in HIV-associated NAFLD using different values (248 dB/m or 285 dB/m)
  • A quantitative estimation of liver fat can only be obtained by MR spectroscopy as well as MRI-PDFF. This technique is of value in clinical trials and experimental studies but is expensive and not recommended in the clinical setting
  • NASH has to be diagnosed by a liver biopsy showing steatosis, hepatocyte ballooning and lobular inflammation

Consideration of ARV drugs

  • Consider use of metabolic neutral ART regimens in individuals at risk of or with NAFLD (e.g. risk of weight gain induced by INSTI or TAF)

Treatment of NAFLD

  • Lifestyle modification and weight reduction is the cornerstone of treatment
  • Dietary restriction PLUS progressive increase in aerobic exercise/resistance training: Caloric restriction (500-1,000 /day) targeting 7-10% weight loss in persons with central obesity and/or overweight; 150-200 min/ week of moderate intensity aerobic physical activities in 3-5 sessions
  • A Mediterranean diet should be advised to improve steatosis and insulin sensitivity
  • Pharmacotherapy should be reserved for individuals with NASH, particularly for those with significant fibrosis ≥ F2 and individuals with less severe disease, but at high risk of faster disease progression (i.e. with diabetes, metabolic syndrome, persistently increased ALT, high necroinflammation)
  • Management of NASH should be discussed with hepatologists. Options with proven efficacy include pioglitazone, vitamin E and bariatric surgery. In the specific setting of HIV-associated NAFLD, tesamorelin and vitamin E have demonstrated efficacy, however larger studies are needed. Researchers advocate for inclusion of persons with HIV in ongoing global trials of new antifibrotic molecules for NASH
  • Statins may be safely used but have demonstrated no impact on NAFLD thus far. The same is true for n-3 polyunsaturated fatty acids


Diagnostic Flow-chart to Assess and Monitor Disease Severity in Case of Suspected NAFLD and Metabolic Risk Factors

Persons with HIV at risk of NAFLD
(any among NAFLD suggested by ultrasound, overweight, metabolic syndrome, persistent elevation of ALT, exposure to d-drugs)

Non-Alcoholic Fatty Liver Disease (NAFLD).png

These recommendations are largely inspired by the EASL–EASD–EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease: European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity

  1. NAFLD, Non-alcoholic fatty liver disease
  2. FIB-4 = Age ([years] x AST [U/L]) / ([platelet [109/L]) x ALT [U/L])
  3. NFS, Non-alcoholic fatty liver disease Fibrosis Score = -1.675 + 0.037 x age (years) + 0.094 x BMI (kg/m2) + 1.13 x impaired fasting glucose/diabetes mellitus(iv) (yes = 1/ no = 0) + 0.99 x AST/ALT ratio-0.013 x platelet (x109)-0.66 x albumin(g/dL)
  4. ELFTM test, Enhanced Liver Fibrosis Test is a blood test that provides an estimate of liver fibrosis severity by measuring Hyaluronic Acid (HA), Amino-terminal propeptide of type III procollagen (PIIINP), Tissue inhibitor of metalloproteinase 1 (TIMP-1)
  5. ARFI elastography, Acoustic Radiation Force Impulse