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Clinical significance of elevated liver transaminases in HIV-infected patients: clinicians practicing HIV care should promptly approach the finding of elevated liver transaminases for its diagnostic and prognostic implications.
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Cai, Jiaa; Osikowicz, Mariab; Sebastiani, Giadab
AIDS: April 16 2019
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Conclusion
The proportion of deaths attributed to liver-related etiologies has undergone a 10-fold increase in the post-ART era[48, 125]. Elevated liver transaminases are now a common finding in HIV-infected patients. The main etiologic contributors to the burden of liver diseases in HIV-infected patients include viral hepatitis coinfection, NAFLD, alcohol abuse, ART related liver injury and infection-related factors. Chronic liver transaminase elevations are independently associated with hepatic steatosis and liver fibrosis in both HIV mono-infected and HIV/HCV coinfected patients. Several simple fibrosis biomarkers based on liver transaminases, including APRI, FIB-4 and NAFLD fibrosis score, can help guide the clinician in the management of the individual patient. Moreover, considering the clear association between elevated liver transaminases and related biomarkers with both liver related and all-cause mortality, these simple and inexpensive tests can help in risk stratification, resources utilization, and prioritization for specialist referral to hepatology.
Overall, clinicians practicing HIV care should promptly approach the finding of elevated liver transaminases for its diagnostic and prognostic implications.
ABSTRACT
Elevation of liver transaminases is common in patients infected with the Human Immunodeficiency Virus (HIV). Although this is usually an incidental finding during regular work-up, HIV-infected patients with transaminases elevations require additional visits for laboratory studies and clinical assessments, and often undergo interruptions and changes in antiretroviral therapy (ART).
Alanine aminotransferase (ALT) is present primarily in the liver, thus being a surrogate marker of hepatocellular injury.
Aspartate aminotransferase (AST) is present in the liver and other organs, namely cardiac and skeletal muscle, kidney and brain. Serum levels of both liver transaminases predict liver-related mortality.
Moreover, serum fibrosis biomarkers based on ALT and AST predict all-cause mortality. In a busy clinical setting, a diagnostic approach to elevated liver transaminases could be complicated given the frequency and non-specificity of this finding.
Indeed, HIV-infected individuals present multiple risk factors for liver damage and chronic elevation of transaminases, including co-infection with hepatitis B and C viruses, alcohol abuse, hepatotoxicity due to ART, HIV itself, and frequent metabolic comorbidities leading to nonalcoholic fatty liver disease. This review provides an update on epidemiology of elevated liver transaminases, summarizes the main etiologic contributors and discusses the prognostic significance and a pragmatic approach to this frequent finding in the clinical practice of HIV medicine.
With the aging of the HIV-infected population following the successful implementation of ART in Western countries, liver-related conditions are now a major comorbidity in this setting. As such, clinicians should be aware of the frequency, clinical significance and diagnostic approach to elevated liver transaminases.
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In studies of HIV mono-infection, the prevalence of elevated transaminases ranged from 6.4% to 32%[17, 30-33], with significant variation by study population and design. In most cases, the abnormalities were grade 1 or 2, although grade 3 elevations of ALT have been reported in 13.5% of HIV+ patients coinfected with HBV[34]. Longitudinal studies reported an incidence of ALT elevation ranging between 3.9 and 7.6 per 100 person-years[30, 33, 35]. In
HCV or HBV coinfected patients, the prevalence of elevated liver transaminases is higher, ranging from 13% to 51.8%[16, 36-41].
Interestingly, in the study by Shah and colleagues, reporting elevated ALT in 23.2% of HIV/HCV coinfected patients, 40% of women and 43% of men had ALT values <50 IU/L and <60 IU/L, respectively, while only 6% had ALT< 30 IU/l for men or <19 IU/l for women[36]. Similarly to HIV mono-infection, elevated transaminases were grade 1-2 in most studies, with only 1-4% having elevations in the grade
3-4 range[16].
The distribution of factors encompassed into the definition of metabolic syndrome, particularly obesity and
diabetes, in the study population may also account for those differences[16, 32]. Finally,
geographical variations in ART uptake and regimens may influence the prevalence of
elevated liver transaminases.
Causes of elevated transaminases in HIV-infected patients
Elevated transaminases are widely prevalent in HIV-infected patients, even without viral hepatitis coinfection. since the ART-era and resulting aging of the HIV-infected population, the spectrum of liver
disease has been significantly transformed by chronic infections with HCV and HBV, ART induced hepatotoxicity, alcoholic liver disease and NAFLD[27, 45-48] (Table 3). Another possible contributor to chronic liver injury is HIV infection itself or the associated immunodeficiency (Figure 1a)[18, 19].
ART-induced hepatotoxicity
Hepatotoxicity is one of the most common side effects associated with ART. The clinical manifestation can range from a mild and asymptomatic picture to liver failure (Figure 1b).
Hepatotoxicity may affect up to 23% of HIV-infected patients receiving ART[65]. The incidence of ART-related severe hepatotoxicity ranges between 2 and 18%[29, 30, 65]. All ART have a certain risk of hepatotoxicity, but some cause it more commonly than others (Table 3). Hepatic failure and fatalities have also been described, for example with abacavir, didanosine, stavudine, nevirapine and tipranavir[29]. Moreover, several factors may affect the
frequency and severity of drug-related liver injuries, such as viral hepatitis coinfection, older age, female sex, high body mass index (BMI), excessive alcohol consumption, low platelet count and high HIV viral load[29]. Acute or progressive ART-induced liver damages show different patterns: immune reconstitution syndrome, hypersensitivity reactions, mitochondrial toxicity, direct cell stress, liver steatosis. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs), abacavir, darunavir, fosamprenavir and maraviroc are the main drugs inducing hypersensitivity reactions.
Liver damage in association with use of protease inhibitors (PIs) has been observed in 2%-9% of HIV-infected patients[29]. Use of ritonavir-boosted PIs is particularly associated with elevations in
transaminases. Patients with baseline fibrosis and cirrhosis appear to have an increased risk of developing transaminases abnormalities when exposed to PIs, possibly through their association with metabolic complications, such as hypertriglyceridemia, insulin resistance and hepatic steatosis[42]. Some ART regimens, particularly older PIs and NRTIs still in use in low- and middle-income countries, may also contribute to elevated transaminases by inducing lipodystrophy. The term refers to metabolic complications resulting in the accumulation of visceral and central fat in the abdomen, with associated insulin resistance[67].
Elevation of liver transaminases have been observed in patients treated with integrase inhibitors.
NAFLD and hepatic steatosis
NAFLD is the most frequent cause of unexplained elevation of liver transaminases[70]. NAFLD is a spectrum of clinical and pathologic changes characterized by a fatty overload involving over 5% of the liver weight in the absence of other causes of liver disease. This can
evolve to non-alcoholic steatohepatitis (NASH), a progressive disease characterized by liver fibrosis leading to cirrhosis and related complications[71]. Importantly, NAFLD is a risk factor for all-cause mortality, due to excess cardiovascular disease and cancer[72]. NAFLD is the most common liver disease in Western countries, affecting 25% of the general population due largely to the epidemic of obesity and type 2 diabetes[71]. In HIV-infected people, this
prevalence is significantly higher. As a consequence, NAFLD is increasingly recognized as the most frequent liver disease in persons aging with HIV mono-infection[73, 74]. In studies conducted in diverse patient populations and employing different diagnostic methods, the
prevalence of NAFLD ranges from 13% to 65%[75]. NASH, the evolutive counterpart of NAFLD, has been reported in up to 65% of HIV mono-infected patients with chronically elevated ALT and in 10% of those attending a routine screening program[22, 23, 76]. Generally,
the elevation of transaminases caused by NAFLD is mild to moderate, with AST and ALT consistently <4 times ULN. Liver tests can be normal in up to 79% of patients with NAFLD[77]. When elevated, enzymes show hepatocellular pattern, often with an AST/ALT
ratio of less than 1 (Figure 1b). Therefore, liver tests are not useful to make a diagnosis of NAFLD. However, persistently chronic elevation of ALT in absence of other causes of liver disease strongly suggest NAFLD, particularly in patients with the classical metabolic
phenotype[11, 78].
Similarly to the general population, NAFLD is the most frequent finding in case of unexplained elevated liver transaminases in HIV-infected patients[22]. Overall, several studies reported that the levels of ALT or AST were significantly higher in HIV mono-infected
patients with NAFLD or NASH as compared to those without[20, 76, 79, 80]. Moreover, elevated transaminases were independently associated with NAFLD or NASH in HIV-infected patients[20, 76]. However, in other studies metabolic factors, particularly BMI and high
triglycerides, had the strongest association with NAFLD[20, 31, 79, 81]. Taken together, these findings suggest that, in HIV mono-infected patients, persistent elevation of transaminases should prompt investigation for NAFLD (Table 4). Consistently, recent guidelines from the European AIDS Clinical Society (EACS) recommend further assessment for liver disease severity and specialist referral in case of abnormal liver enzymes, with and without
NAFLD[82].
Introduction
In medicine, elevated transaminases refer to the elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Their function is to catabolize amino acids, permitting them to enter the citric acid cycle[1]. AST is found in the liver, cardiac and skeletal
muscle, pancreas, brain, kidneys, lungs, erythrocytes and leukocytes. ALT is found in liver, kidney, heart, and muscle. The concentration of ALT in the liver is significantly higher than in other tissues. Therefore, ALT levels are the most specific indicators of liver damage and
serum ALT is the most commonly used test to assess for liver diseases. Serum ALT and AST levels may also be affected by gender, age, alcohol consumption, strenuous exercise, nutrition, metabolic parameters, coinfections and medications[2]. The range of the upper limit of normal (ULN) for ALT or AST level spans between 30 and 50 International Units (IU)/L and it varies among laboratories and assays[3-10] (Table 1). Conventional normal range may have been set too high, because the reference people presumed to be healthy may have asymptomatic liver disease. Indeed, guidelines suggest that the optimal cutoff for ALT should be lower (33 IU/L for men and 25 IU/L for women) than the upper limit usually adopted by laboratories[11].
The prevalence of elevated liver transaminases depends on the definition and population but is likely to be between 10 and 20% of the adult general population[12-14]. In approximately 10% of the cases, no cause of chronic hypertransaminasemia is found and the prognosis of this finding is unknown[15]. Elevated liver transaminases are particularly common in HIV-infected
patients, occurring in 20%-93% of patients on antiretroviral therapy (ART), even in the absence of viral hepatitis coinfection[16, 17]. Causes of elevated transaminases in HIV-infected adults include coinfection with hepatitis viruses A, B, C, D, E, alcohol abuse, and ART toxicity. A possible contribution to chronic liver injury by HIV infection itself or the associated immunodeficiency has also been hypothesized[18, 19]. Furthermore, in HIV mono-
infected patients transaminases elevations may suggest the presence of an emerging and highly prevalent liver disease, namely nonalcoholic fatty liver disease (NAFLD), with
associated hepatic fibrosis and cirrhosis[20-23]. In the general population, elevated ALT is associated with liver-related mortality[12, 24]. Likewise, in HIV-infected patients elevated liver transaminases are independently associated with all-cause and liver-related mortality[25, 26]. Patients with transaminase elevations require additional visits for laboratory and clinical assessments and often undergo interruptions and changes in ART[27].
Serum ALT and AST are readily available, inexpensive and routine biochemical assay used in clinical practice. Considering their accessibility, especially in developing countries or limited-resource settings, it is important to understand the clinical significance of elevated liver transaminases in the diagnosis, follow-up, prognosis, and treatment of HIV-infected patients. The American College of Gastroenterology and the British Gastroenterology Association have recently endorsed two guidelines on management of abnormal liver tests[11, 28]. This article aims to review existing literature regarding epidemiology and etiology of elevated transaminases in the specific context of HIV infection. We also provide evidence for association of elevated ALT and AST with frequent liver conditions in HIV-infected patients, namely NAFLD and liver fibrosis/cirrhosis. Finally, a pragmatic stepwise algorithm providing clinical guidance into management of elevated transaminases in the context of HIV
infection is proposed.
Epidemiology of elevated transaminases in HIV-infected patients
The prevalence of elevated transaminases in HIV-infected patients varies by country, ethnicity, population characteristics and concomitant diseases (Table 2). According to the AIDS Clinical Trials Group Criteria, liver test abnormalities can be graded as follows: grade 1 (1.25 to 2.5 times ULN); grade 2 (2.6 to 5 times ULN); grade 3 (5.1 to 10 times ULN);
In studies of HIV mono-infection, the prevalence of elevated transaminases ranged from 6.4% to 32%[17, 30-33], with significant variation by study population and design. In most cases, the abnormalities were grade 1 or 2, although grade 3 elevations of ALT have been reported in 13.5% of HIV+ patients coinfected with HBV[34]. Longitudinal studies reported an incidence of ALT elevation ranging between 3.9 and 7.6 per 100 person-years[30, 33, 35]. In
HCV or HBV coinfected patients, the prevalence of elevated liver transaminases is higher, ranging from 13% to 51.8%[16, 36-41]. Interestingly, in the study by Shah and colleagues, reporting elevated ALT in 23.2% of HIV/HCV coinfected patients, 40% of women and 43% of men had ALT values <50 IU/L and <60 IU/L, respectively, while only 6% had ALT< 30 IU/l for men or <19 IU/l for women[36]. Similarly to HIV mono-infection, elevated transaminases were grade 1-2 in most studies, with only 1-4% having elevations in the grade 3-4 range[16].
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