Our study in over 1200 unselected HIV patients has several important findings and is the first attempt to quantify the prevalence and factors associated with elevated LFTs in HIV patients without HCV or HBV coinfection. First, in the absence of HCV or HBV, defined by the presence or absence of anti-HCV or HBV surface antigen, the prevalence of elevated liver enzymes was high (15–43%). Second, the majority of liver enzyme elevations were mild-moderate (1.25–5 x ULN). Third, increases in ALP were the most common abnormality seen in 43% and did not correlate with increased AST or ALT. And forth, PI use was independently associated with absence in elevations in both AST and ALT while features typical of hepatic steatosis (DM and increased BMI) were only associated with increased ALP.
Abnormal liver enzymes (AST, ALT, and ALP) can be classified as either hepatocellular (increases in AST and ALT), cholestatic (increases in ALP), or mixed (14
). Because patterns can have differing etiologies and pathogenic mechanisms, it is important to analyze them independently. Increased liver enzymes are frequently seen in those with HIV and may be due to a variety of factors including viral hepatitis coinfections, alcohol, opportunistic infections, steatohepatitis, and concomitant medications including HAART (15
). However, because most studies have focused on individuals that are coinfected with HBV or HCV or in those with severe (grade 3–4) elevations, factors associated with abnormal liver enzymes, particularly those with grade 1–2, in patients with HIV in the absence of viral hepatitis have not been explored.
In a recent report in a large cohort of 5957 HIV patients, the prevalence of abnormal ALT and AST (defined as greater than upper limit of normal) in those without HCV (n = 3997) was 55% and 76% respectively and lower than those with HCV coinfection (83% for ALT and 92% for AST) (9
). Importantly, 86% of these patients without HCV were also HBV surface antigen negative suggesting another etiology for increased liver enzymes. Of those without HCV, 53% were on HAART and another 30% were on an antiretroviral medication. Importantly, analyses for factors associated with increased liver enzymes were not performed. Conversely, in a study by Maida and colleagues cryptogenic liver disease, defined as increased liver enzymes in the absence of HCV and HBV coinfections, was identified in only 17 of 3200 (0.5%) HIV positive subjects (10
). However, they excluded patients with severe obesity, grade 3 to 4 dyslipidemias, hyperglycemia, insulin resistance, and/or ultrasonographic evidence of fatty liver, all established risk factors for elevated liver enzymes (16
). Interestingly, even in the absence of risk for hepatic steatosis, liver histology in 5 of the 17 patients who underwent biopsy demonstrated steatosis and inflammation. In their analysis, only longer ddI exposure was identified as an independent predictor of chronic liver enzyme elevations.
The high frequency of increased ALP in those without HCV or HBV coinfection has not previously been reported in those with HIV. In the study by Rockstroh (9
), no data on ALP was provided. In the study by Maida (10
), among those 17 with increased liver enzymes, ALP was elevated in 16. However, it is not clear if an isolated ALP met their criteria for cryptogenic liver disease. This high proportion of increased ALP compared to AST and ALT is different than reported from large drug induced liver registries of severe hepatitis in the general population which found hepatocellular pattern of injury more common (52–58%) than a cholestatic pattern (20–26%) (17
). In the current study, increased ALP was more common than AST or ALT and associated with a BMI > 30 and DM, both associated with hepatic steatosis. This finding was not surprising given that an isolated ALP has been observed in patients with nonalcoholic fatty liver disease (NAFLD) (19
). Although increased ALP was also associated with NRTI, NNRTI, and PI class use on univariate analysis, only NRTI use was identified on multivariate logistic regression. Independent predictors of increased AST and ALT in those without HCV or HBV coinfections were HTN while PI use was protective. While a HIV < 400 copies was not, a low CD4 < 200 and presence of the metabolic syndrome were also associated with increased ALT.
There are several potential mechanisms that are specific to HIV medications that can result in liver enzyme elevations. Because not all drugs within each class have similar effects on the liver, we also were able to look at individual drugs within each class and observed that only d4T was associated with increased AST while no specific agent was associated with increased ALT. Conversely, several agents were associated with increased ALP. Although the use of nevirapine has been associated with cholestatic liver enzyme elevations (20
), we found no association in increased ALP and nevirapine use in the absence of HCV coinfection.
Causes of increased liver enzymes in those with HIV can include direct cytopathic effects of HIV on either hepatocytes or biliary epithelia or specific drug toxicity of HAART. There are several potential mechanisms that are specific to HIV medications that can result in liver enzyme elevations. PIs have been associated with the development of insulin resistance (IR) and dyslipidemia, both risk factors for steatosis (21
). In addition, both ddI and d4T have been associated with steatosis in HCV coinfected patients (28
). Our findings of d4T support these prior observations. The inverse relationship of PI and increased liver enzymes may have several possible explanations. Several studies in HIV-HCV coinfected patients have shown that PI use is associated with lower fibrosis progression (31
). However, data were not provided on the impact of PI use on liver enzymes and their relationship to liver pathology in those without HCV is unknown. PI use has been reported to affect hepatocyte apoptosis which may impact on liver enzymes (33
). Therefore, the ability of HAART and other drugs to disrupt the normal production or elimination of reactive oxygen species in the liver may be an important factor relating to their potential cause of abnormal liver enzymes (15
). However, this area has not been well studied and requires further research.
Both IR and dyslipidemia are pathogenic mechanisms associated with NAFLD and non-alcoholic steatohepatitis (NASH) which often present as asymptomatic liver enzyme elevations and may explain elevations in liver enzymes in some of these individuals (19
). We observed that both HTN and DM, components of the metabolic syndrome, were independently associated with elevated liver enzymes, particularly, elevations in ALP. This was not unexpected given the association of isolated ALP elevations in those with steatohepatitis (16
). Therefore, in the absence of viral hepatitis, these enzyme elevations are most likely due to hepatic steatosis. Because NASH is now recognized as a significant cause of cirrhosis with associated morbidity and mortality, its recognition as a long term complication of HAART is important to the management of those living with HIV. Although we did not have histology, our findings that DM, BMI, and NRTI use are associated with elevated liver enzymes supports these previous observations.
The prevalence of steatosis in those with HIV is unknown in those without HCV coinfection. Several recent reports in HIV-HCV coinfected patients have found a high proportion (40–75%) with steatosis (29
) that is greater than expected (40
) from the general population and associated with increased weight or BMI (28
), hyperglycemia (28
), lipodystrophy (38
), d4T (28
), NRTI (29
) and PI use (28
). Conversely, in a cohort of 92 coinfected patients, Monto found a low (2%) prevalence of significant steatosis (>33%) compared to 9% in HCV controls which was unrelated to HIV therapy (37
). However, because hepatic steatosis is associated with increased fibrosis progression (28
), its presence is clinically significant.
There are several limitations of our analysis. First, we did not differentiate those with transient from those with persistent liver enzyme elevations and we defined abnormal liver enzymes as any elevation at any time. We also did not take into account renal function, alcohol use, concurrent medication use, coexisting liver diseases other than HCV or HBV that may also have caused increases in liver enzymes. Furthermore, confirmation of HCV infection by RNA, HBV DNA or E antigen status in those with HBV surface antigen may have resulted in misclassification of subjects. We did not directly measure IR nor take into account the normal fluctuations in liver enzymes and changes in HAART use over time. There also were missing data on HCV and HBV in a small proportion of patients which may have impacted our results. Furthermore, there are several additional causes of increased ALP, including primary biliary cirrhosis (PBC), biliary tract diseases (primary sclerosing cholangitis (PSC), sarcoidosis, gallstones, HIV cholangiopathy), and infiltrating tumors. In addition, elevations in ALP are not specific for liver disease and may also be elevated in bone diseases. Because ultrasound was not routinely performed in patients with elevated liver enzymes, that information was not included in our analysis. We also did not specifically look for PBC, sarcoidosis, biliary tract and bone diseases which are uncommon in our population and do not explain the observed high prevalence of increased ALP. Also, gamma glutamyl transferase (GGT) was not routinely obtained on all patients, especially those with isolated elevations in ALP. However, the majority of cases of increased ALP reported by Maida were associated with increased gamma glutamyl transferase (GGT) suggesting liver rather than bone origin (10
). The most important limitation of our findings was lack of histology in these patients. Therefore, the clinical significance of these mild liver enzyme elevations could not be assessed. Nevertheless, given these limitations, this study represents the first attempt to describe the prevalence and potential factors associated with abnormal liver enzymes in unselected HIV patients without HCV and HBV coinfections.
In conclusion, elevated liver enzymes are common in those with HIV, even in those without obvious HCV or HBV coinfections. In the absence of HCV or HBV, absence of PI use is independently associated with elevations in both AST and ALT while features typical of hepatic steatosis, DM and increased BMI, were associated with increased ALP. These observations need to be confirmed in prospective cohorts and ongoing studies with liver histology will determine the clinical significance of asymptomatic liver enzyme elevations. Until additional data are available, clinicians caring for those with HIV should monitor all their patients with mild to moderate liver enzyme elevations, regardless of the presence of HCV or HBV coinfections, and consider liver biopsy to assess the etiology and significance of this common clinical scenario.