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Clinical, biochemical and histological differences between
HIV-associated NAFLD and primary NAFLD: a case-control study
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"HIV-associated NAFLD
cases had significantly higher prevalence of NASH
compared to primary NAFLD controls."
"We performed a cross-sectional, case-control study comparing patients with HIV-associated NAFLD vs. patients with primary NAFLD. All HIV-infected patients were identified from a database of consecutive liver biopsies performed at the University of California, San Diego, between 1 December, 1999 and 9 May 2012.
.....HIV-associated NAFLD patients have significantly higher rates of NASH and increased severity of liver disease than age-sex-matched patients with primary NAFLD. This is the first study to provide a detailed clinical, biochemical and histopathological description of HIV-associated NAFLD. The age-sex-matched case-control design allows the clinicians to appreciate the differences between HIV-associated NAFLD and primary NAFLD using a standardised and validated histological scoring system. As new therapies emerge for HIV-associated NAFLD, improvement in liver histology will be an important treatment end-point. Therefore, detailed characterisation and understanding of the histopathology of HIV-associated NAFLD is a key step for initiating prospective studies to better characterise the natural history of HIV-associated NAFLD, and to develop histological end-points to assess treatment response."
Clinical, biochemical and histological differences between HIV-associated NAFLD and primary NAFLD: a case-control study
APT 2014 - I. Vodkin*, M. A. Valasek, R. Bettencourt, E. Cachay & R. Loomba
Summary
Background
There are limited data regarding the clinical, biochemical and liver histological characteristics of patients with HIV-associated nonalcoholic fatty liver disease (NAFLD), and whether this entity differs in presentation and severity from primary NAFLD
Aim
To examine the clinical and histological differences between HIV-associated NAFLD and primary NAFLD.
Methods
This is a cross-sectional, case-control study comparing patients with HIV-associated NAFLD vs. patients with primary NAFLD. HIV-infected patients were identified from a database of consecutive liver biopsies performed at the University of California at San Diego, over a 13-year period. HIV-infected patients with biopsy-proven NAFLD were selected as cases, after exclusion of other causes of liver disease and hepatic steatosis. Age-sex-matched controls with biopsy-proven primary NAFLD were randomly identified from the same pathology database. All biopsies underwent a standardised, detailed, histological research evaluation by a liver pathologist who was blinded to clinical and case-control status.
Results
Compared to age-sex-matched patients with primary NAFLD (n = 33), patients with HIV-associated NAFLD (n = 33) had significantly higher mean aspartate aminotransferase (P < 0.001), alanine aminotransferase (P < 0.001), alkaline phosphatase (P = 0.003) and serum triglycerides (P = 0.024). Similarly, compared to age-sex-matched primary NAFLD, patients with HIV-associated NAFLD had significantly higher rates of definite steatohepatitis (37% vs. 63%, P = 0.04), and more features of liver injury, including lobular inflammation (<0.001) and acidophil bodies (<0.001).
Conclusion
Compared to age-sex-matched primary NAFLD, HIV-associated NAFLD has increased severity of liver disease and a higher prevalence of NASH.
Introduction
Non-alcoholic fatty liver disease (NAFLD) has become one of the most common causes of chronic liver disease in Europe and the United States (US).[1-4] NAFLD is defined as the presence of hepatic steatosis in the absence of other causes of liver disease in individuals who consume little or no alcohol. The American Association for the Study of Liver Diseases practice guidelines divide NAFLD into primary and secondary NAFLD.[5] The primary form of NAFLD is associated with metabolic risk factors such as obesity, insulin resistance and the metabolic syndrome.[6-8] Other aetiological factors, such as hepatitis C virus, acquired or genetic metabolic diseases and certain medications (including steroids, methotrexate, amiodarone and some antiretroviral agents), can result in a similar pattern of steatosis and liver injury, which is termed secondary NAFLD.[5, 9] HIV-associated NAFLD is an important cause of secondary NAFLD, which is likely multifactorial, and is linked to HIV-associated lipodystrophy,[10] direct medication effects and metabolic risk factors.
Non-alcoholic fatty liver disease is a spectrum of liver disease that ranges from non-alcoholic fatty liver, which is considered to be nonprogressive form of NAFLD, to non-alcoholic steatohepatitis (NASH), which is considered to be the progressive form of NAFLD. NASH can lead to adverse liver-related outcomes such as cirrhosis, hepatocellular carcinoma and increased risk of death from liver disease in a subset of patients.[11-15]
HIV is a major global health issue, with 35.3 million people living with the disease worldwide, with 2-3 million in the United States and Western and Central Europe.[16] In the era of effective combination antiretroviral therapy (cART), major reductions in acquired immunodeficiency syndrome (AIDS)-related mortality have resulted in a shift towards HIV becoming a chronic illness. Accordingly, liver disease has become the second leading cause of non-AIDS-related deaths, accounting for nearly 7-14% of all deaths in patients with HIV.[17-19] Although viral hepatitis is still the leading cause of liver-related morbidity and mortality in this population, nearly half of the HIV-infected patients that undergo evaluation for unexplained liver test abnormalities are found to have NAFLD.[20] The prevalence of NAFLD is higher in individuals with HIV infection (30-40%) than in the general population.[21, 22] As HIV-infected patients are ageing, there has been a rise in the prevalence of obesity (8-14%)[23, 24] and the metabolic syndrome (14-18%),[25, 26] which will likely further increase the risk of NAFLD in this population.
Despite the high prevalence of NAFLD in the HIV-infected population, limited data exist regarding the clinical, biochemical and histopathological characteristics of HIV-associated NAFLD, and whether this entity differs in clinical presentation and histological severity from primary NAFLD. Therefore, we aimed to examine the differences between HIV-associated NAFLD and primary NAFLD. Our hypothesis is that HIV-associated NAFLD leads to more severe liver disease and higher rates of NASH than primary NAFLD.
Discussion
Main findings
The aim of this study was to provide an in-depth clinical, biochemical and histopathological characterisation of HIV-associated NAFLD, and systematically examine differences between HIV-associated NAFLD and primary NAFLD. Our study demonstrated a significantly higher proportion of NASH as well as other laboratory and histological features of more severe liver injury in HIV-associated NAFLD, despite similar metabolic characteristics in the two groups. This highlights the fact that HIV-infected subjects are a particularly high-risk group for advanced liver disease, even without the presence of viral hepatitis.
In context with the published literature
Previous studies have shown that the prevalence of NAFLD (based upon imaging-based assessment) may be higher in HIV-infected subjects than the general population. Crum-Cianflone et al. conducted a cross-sectional study of 216 HIV-infected patients and showed that the prevalence of hepatic steatosis was 31% using an ultrasound-based evaluation. Among the patients who underwent a liver biopsy evaluation in this study, 36% were found to have evidence of NAFLD.[22] Another study using computer tomography showed steatosis in 37% of 225 patients.[21] The prevalence of HIV-associated NAFLD in our study population was 38%. Therefore, the findings are consistent with prior reports. Patients with HIV-associated NAFLD in our study had higher rates of NASH compared to patients with age-sex-matched primary NAFLD and compared to the general population.[1, 3, 31] Although there were more Hispanic patients in the HIV group, our findings remained statistically significant when adjusted for ethnicity.[32, 33] There is a paucity of data on this topic in the existing literature, with small pathological studies reporting rates of NASH between 20% and 89%. Crum-Cianflone et al. showed NASH in 20% of 20 patients with biopsy-proven NAFLD.[22] Higher prevalence was seen in studies by Mohammed et al. and Ingiliz et al. who found NASH in 54.8% of 26 patients and 89% of 18 patients with NAFLD respectively.[34, 35] However, detailed description of clinical, biochemical and histological characteristics of HIV-associated NAFLD has not been previously reported.
Through detailed histological assessment, we identified additional features of advanced disease as well as ongoing liver injury in HIV-associated NAFLD compared to primary NAFLD. The HIV-associated NAFLD group had significantly higher NAS scores and more lobular inflammation and acidophil bodies. These are novel findings in this population. Laboratory evaluation supported our pathological findings, with more significant transaminitis and higher APRI and FIB-4 scores in HIV-associated NAFLD. These makers were selected because they are readily available and have been evaluated in HIV-infected patients.[29]
We found similar BMI and metabolic risk factors, with the exception of higher triglyceride levels, in HIV-associated NAFLD compared to age and sex matched controls. Indeed, our findings are consistent with recent studies showing increasing obesity in the HIV population, and especially in HIV-infected women.[23, 24] The increase in triglycerides levels is also consistent with recent studies [22, 34] and is likely multifactorial, due to direct effect of certain antiretrovirals, indirect association with lipodystrophy or the reflection of metabolic syndrome in the context of increased BMI. Lipodystrophy, a syndrome associated with cART, is characterised by an increase in visceral adiposity, insulin resistance, hypertriglyceridaemia and low HDL.[25, 26, 36, 37] Acquired and genetic lipodystrophy is known to be associated with secondary NAFLD.[10]
The only HIV-specific factor correlating with advanced pathology in our study was duration of HIV infection. Longer duration was associated with NASH, even when adjusted for age. We speculate that either HIV infection itself or longer duration of ART use could explain this finding. Although hepatic steatosis has been linked to NRTI use,[38] and multiple metabolic abnormalities have been linked to PIs,[39] we saw no differences in disease severity based on cART regimen. In the existing literature, findings are mixed. Exposure to NRTIs was identified as a risk factor for hepatic steatosis in two studies,[21, 40] but not in others.[22, 41]
Strengths and limitations
The following are the key strengths of our study. We conducted a standardised, detailed, histological research evaluation of all biopsies by a liver pathologist who was blinded to clinical as well as case-control status. In contrast to prior studies, liver biopsies were scored using the well-validated NASH CRN Histologic Scoring System[30] and were used as the gold standard for the diagnosis of both NAFLD and NASH. Clinical and biochemical data were also collected through a systematic chart review by a single trained investigator. Cases and controls were identified from the same pathology database and matching was randomised. No significant differences were seen in the indication for liver biopsy, history of transaminitis or presence of fatty liver on imaging when comparing cases and controls (Table S2). To date, this is the first systematic assessment and detailed pathological description of HIV-associated NAFLD. With the emergence of novel therapies for the treatment of HIV-associated NAFLD,[37] a detailed description of liver histology of HIV-associated NAFLD is the quintessential next step in the eventual development of histological end-points to assess treatment response in HIV-associated NAFLD and NASH. However, we would like to acknowledge several limitations of our study. The main weaknesses of this study include its' retrospective design and cross-sectional nature. The relatively small sample size did not allow us to examine whether HIV-associated NAFLD is more likely to be associated with a higher fibrosis stage than primary NAFLD. It was, however, associated with significantly higher APRI and FIB-4 scores (non-invasive biomarkers for advanced fibrosis) than primary NAFLD. Larger studies are needed to examine the association between HIV-associated NAFLD and the stage of fibrosis. This is also a single centre study in a tertiary referral setting so there is a possibility of a referral bias. We do not think that referral bias was different between the two groups because there were no significant differences in the indications for liver biopsy between the HIV-associated NAFLD and primary NAFLD. An additional limitation was that biopsies were reviewed by a single pathologist, so inter-rater agreement could not be assessed.
Conclusion
HIV-associated NAFLD patients have significantly higher rates of NASH and increased severity of liver disease than age-sex-matched patients with primary NAFLD. This is the first study to provide a detailed clinical, biochemical and histopathological description of HIV-associated NAFLD. The age-sex-matched case-control design allows the clinicians to appreciate the differences between HIV-associated NAFLD and primary NAFLD using a standardised and validated histological scoring system. As new therapies emerge for HIV-associated NAFLD, improvement in liver histology will be an important treatment end-point. Therefore, detailed characterisation and understanding of the histopathology of HIV-associated NAFLD is a key step for initiating prospective studies to better characterise the natural history of HIV-associated NAFLD, and to develop histological end-points to assess treatment response.
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