Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression.

Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection.

Hepatic peroxisome proliferator-activated receptor γ and α-mRNA expression in HCV-infected adults is decreased by HIV co-infection and is also affected by ethnicity

OBJECTIVE: To determine peroxisome proliferator activated receptor α and γ mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor α and γ mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor α and γ mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor γ mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor α mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients.

Hepatic peroxisome proliferator-activated receptor γ and α-mRNA expression in HCV-infected adults is decreased by HIV co-infection and is also affected by ethnicity.

OBJECTIVE: To determine peroxisome proliferator activated receptor α and γ mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor α and γ mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor α and γ mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor γ mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor α mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients.

Cutaneous Metastases from Primary Hepatobiliary Tumors as the First Sign of Tumor Recurrence following Liver Transplantation.

Cutaneous metastasis from hepatobiliary tumors is a rare event, especially following liver transplantation. We report our experience with two cases of cutaneous metastases from both hepatocellular carcinoma and mixed hepatocellular/cholangiocarcinoma following liver transplantation, along with a review of the literature.

Leptospirosis with acute liver injury.

A 61-year-old man with no significant medical history presented with fever, muscle pain, and weakness. He was found to be in multiorgan failure due to leptospirosis, a condition known as Weil's disease. A timely workup, combined with early initiation of antibiotics, led to effective treatment for this patient.

Epidemiology of metastatic hepatocellular carcinoma, a nationwide perspective.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. AIMS: The aim of this study was to describe the prevalence, trends, and predictors of metastatic HCC on a national scale. METHODS: We used two nationwide datasets for our study: the University Health Consortium (UHC) and the Nationwide Inpatient Sample (NIS) databases. We included adults with a primary diagnosis of HCC from 2000 to 2011. We collected information regarding demographics, insurance, HCC risk factors, liver decompensation, and the sites and frequencies of metastases. Multivariable regression analysis was used to examine predictors of metastatic HCC. Trend analysis was performed to examine the change in metastatic HCC prevalence over time. RESULTS: We included 25,671 and 26,054 HCC patients from UHC and NIS, respectively. Prevalence of metastatic HCC was 18 % with lung being the most frequent site (31 %). Compared with Caucasian, African American ethnicity was an independent predictor of metastasis in both the NIS [OR 1.13 (1.02-1.25)] and UHC [OR 1.4 (1.3-1.6)] databases. Lack of long-term insurance was associated with significantly higher prevalence of metastasis in both the NIS [OR 1.6 (1.4-1.9)] and UHC [OR 1.9 (1.6-2.2)] databases. There has been an increased prevalence of metastatic HCC over the last decade with an annual percentage change of +1.25 and +1.60 % (p = 0.03 and p = 0.08) for the NIS and UHC databases, respectively. CONCLUSIONS: Metastasis is not rare among HCC patients and is rising in prevalence over the last decade. Lungs were the most common metastatic site. Ethnicity and insurance status are independent predictors of metastasis.

Mixed large cell neuroendocrine carcinoma and adenocarcinoma with spindle cell and clear cell features in the extrahepatic bile duct.

Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP) were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6 cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9-postive) surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC). Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patient's poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas.

HCV infection selectively impairs type I but not type III IFN signaling.

A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-α (IFN-α), IFN-λ, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-α+RBV combination treatment, whereas IFN-λ treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-α receptor-1 chain of type I, but not type II (IFN-γ) or type III (IFN-λ) IFN receptors. Down-regulation of IFN-α receptor-1 resulted in defective JAK-STAT signaling, impaired STAT phosphorylation, and impaired nuclear translocation of STAT. Furthermore, HCV replication impaired RBV uptake, because of reduced expression of the nucleoside transporters ENT1 and CNT1. Silencing ER stress and the autophagy response using chemical inhibitors or siRNA additively inhibited HCV replication and induced viral clearance by the IFN-α+RBV combination treatment. These results indicate that HCV induces ER stress and that the autophagy response selectively impairs type I (but not type III) IFN signaling, which explains why IFN-λ (but not IFN-α) produced a sustained antiviral response against HCV. The results also indicate that inhibition of ER stress and of the autophagy response overcomes IFN-α+RBV resistance mechanisms associated with HCV infection.

Thyroid storm complicated by fulminant hepatic failure: case report and literature review.

OBJECTIVES: Thyroid storm is a presentation of severe thyrotoxicosis that has a mortality rate of up to 20% to 30%. Fulminant hepatic failure (FHF) entails encephalopathy with severe coagulopathy in the setting of liver disease. It carries a high mortality rate, with an approximately 60% rate of overall survival for patients who undergo orthotopic liver transplantation (OLT). Fulminant hepatic failure is a rare but serious complication of thyroid storm. There have been only 6 previously reported cases of FHF with thyroid storm. METHODS: We present a patient from our institution with thyroid storm and FHF. A literature review was performed to analyze the outcomes of the 6 additional cases of concomitant thyroid storm and FHF. RESULTS: Our patient underwent thyroidectomy followed by OLT. Her serum levels of thyroid-stimulating hormone, triiodothyronine, thyroxine, and transaminase normalized, and she was ready for discharge within 10 days of surgery. She has survived without complication. There is a 40% mortality rate for the reported patients treated medically with these conditions. Of the 7 total cases of reported FHF and thyroid storm, 2 patients died. Only 2 of the 7 patients underwent thyroidectomy and OLT--both at our institution. Both patients survived without complications. CONCLUSIONS: Thyroid storm and FHF each independently carry high mortality rates, and managing patients with both conditions simultaneously is an extraordinary challenge. These cases should compel clinicians to investigate liver function in hyperthyroid patients and to be wary of its rapid decline in patients who present in thyroid storm with symptoms of liver dysfunction. Patients with rapidly progressing thyroid storm and FHF should be considered for total thyroidectomy and OLT.

United States women receive more curative treatment for hepatocellular carcinoma than men.

BACKGROUND: Previous database studies have found gender disparities favoring men in rates of liver transplantation, which resolve in cohorts examining only patients with hepatocellular carcinoma (HCC). AIMS: Our study aims to use two large, multicenter United States (US) databases to assess for gender disparity in HCC treatment regardless of transplant listing status. METHODS: We performed a retrospective database analysis of inpatient admission data from the University Health Consortium (UHC) and the Nationwide Inpatient Sample (NIS), over a 9- and 10-year period, respectively. Adults with a primary discharge diagnosis of HCC, identified using the International Classification of Diseases 9th Edition (ICD-9) code, were included. Series of univariate and multivariate analyses were performed to examine gender disparities in metastasis, liver decompensation, treatment type, and inpatient mortality after controlling for other possible predictors. RESULTS: We included 26,054 discharges from the NIS database and 25,671 patients from the UHC database in the analysis. Women with HCC appear to present less often with decompensated liver disease (OR = 0.79, p < 0.001). Furthermore they are more likely to receive invasive HCC treatment, with significantly higher rates of resection across race and diagnoses (OR = 1.34 and 1.44, p < 0.001). Univariate analyses show that US women have lower unadjusted rates of transplant; however, the disparity resolves after controlling for other clinical and demographic factors. CONCLUSIONS: US women more often receive invasive treatment for HCC (especially resection) than US men with no observed disparity in transplantation rates when adjusted for pre-treatment variables.

Donor Risk Index for African American liver transplant recipients with hepatitis C virus.

UNLABELLED: African American (AA) liver transplant (LT) recipients with hepatitis C virus (HCV) have higher rates of graft loss than other racial/ethnic groups. The Donor Risk Index (DRI) predicts graft loss but is neither race- nor disease-specific and may not be optimal for assessing donor risk for AA HCV-positive LT recipients. We developed a DRI for AA with HCV with the goal of enhancing graft loss predictions. All U.S. HCV-positive adult AA first deceased donor LTs surviving ≥30 days from March 2002 to December 2009 were included. A total of 1,766 AA LT recipients were followed for median 2.8 (interquartile range [IQR] 1.3-4.9) years. Independent predictors of graft loss were donor age (40-49 years: hazard ratio [HR] 1.54; 50-59 years: HR 1.80; 60+ years: HR 2.34, P < 0.001), non-AA donor (HR 1.66, P < 0.001), and cold ischemia time (CIT) (HR 1.03 per hour >8 hours, P = 0.03). Importantly, the negative effect of increasing donor age on graft and patient survival among AAs was attenuated by receipt of an AA donor. A new donor risk model for AA (AADRI-C) consisting of donor age, race, and CIT yielded 1-year, 3-year, and 5-year predicted graft survival rates of 91%, 77%, and 68% for AADRI <1.60; 86%, 67%, and 55% for AADRI 1.60-2.44; and 78%, 53%, and 39% for AADRI >2.44. In the validation dataset, AADRI-C correctly reclassified 27% of patients (net reclassification improvement P = 0.04) compared to the original DRI. CONCLUSION: AADRI-C identifies grafts at higher risk of failure and this information is useful for risk-benefit discussions with recipients. Use of AA donors allows consideration of older donors.

Mastabol induced acute cholestasis: A case report.

A 26-year-old male presented with three weeks of jaundice after the self-initiation of the injectable anabolic steroid, Mastabol [Dromastanolone Di-Propionate (17 beta-Hydroxy-2alpha-methyl-5alpha-androstan-3-one propionate)]. He reported dark urine, light stools, and pruritus. He denied abdominal pain, intravenous drug use, intranasal cocaine, blood transfusions, newly placed tattoos, or sexually transmitted diseases. He used alcohol sparingly. Physical exam revealed jaundice with deep scleral icterus. The liver was palpable 2 cm below the right costal margin with no ascites. The peak bilirubin was 23.6 mg/dL, alkaline phosphatase was 441 units/L, and aspartate aminotransferase/alanine aminotransferase were 70 units/L and 117 units/L respectively. A working diagnosis of acute intrahepatic cholestasis was made. Liver biopsy revealed a centrilobular insult with neutrophilic infiltrates and Ito cell hyperplasia consistent with acute drug induced cholestasis. The patient's clinical symptoms resolved and his liver enzymes, bilirubin, and alkaline phosphatase normalized. Anabolic steroids with 17 alpha carbon substitutions have been associated with a bland variety of cholestatic injury with little hepatocellular injury. Cholestasis, under these circumstances, may be secondary to the binding of drugs to canalicular membrane transporters, accumulation of toxic bile acids from canalicular pump failure, or genetic defects in canalicular transport proteins. Mastabol is an injectable, 17 beta hydroxyl compound with no alpha alkyl groups at the 17 carbon position. As such, it has been reported to have little potential toxic effects on the liver. This is the first known reported case of Mastabol-induced cholestatic liver injury. It highlights the need for physicians to consider such widely available substances when faced with hepatic injury of unclear etiology.

An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.

Racial disparity and their impact on hepatocellular cancer outcomes in inner-city New Orleans.

BACKGROUND: The role of socioeconomic factors that affect survival, particularly for hepatocellular cancer (HCC), has yet to be fully analyzed. This study attempts to elucidate those racial and socioeconomic factors that affect differences in survival for patients with HCC. METHODS: In a retrospective cohort study of 206 patients with HCC diagnosed in an inner-city urban center from 2003 to 2011, outcomes by race (African Americans versus white) were analyzed. Additional attention was paid to socioeconomic factors. Continuous variables were compared with the Student t-test, and categorical variables were compared with the χ(2) or Fisher exact test. Multivariate analysis was conducted using a logistic regression model. Patient death and survival data were analyzed with Kaplan-Meier and Cox proportional hazards. RESULTS: Comparison of 138 white and 68 African-American patients revealed that African-American patients were more likely to present with larger tumor size at the time of diagnosis (4.7 vs 3.7 cm; P < .05). African-American patients were also more likely to be intravenous drug users (25.4% vs 11.6%; P < .05) and have cirrhosis from hepatitis C (81% vs 60%; P < .01). African-American patients were less likely to have private insurance compared with white patients (68% vs 92%; P < .01). Despite these findings in our inner-city practice, there was no difference in liver transplantation rates or survival rates between the 2 groups. CONCLUSION: Despite presentation with less-favorable tumor characteristics, African-American patients are able to achieve survival that is comparable with their white counterparts when treated in a program that is attuned to the challenges faced by their specific population.

Kidney transplantation alone in ESRD patients with hepatitis C cirrhosis.

BACKGROUND: Kidney transplantation (KTx) alone in patients with cirrhosis and renal failure (end-stage renal disease [ESRD]) infected with hepatitis C virus (HCV) is controversial. The aim of this study was to compare outcomes of HCV+ patients with ESRD and cirrhosis (C group) versus HCV+ patients with ESRD but with no cirrhosis (NC group) listed for KTx. METHODS: Ninety HCV+ patients with ESRD were evaluated for KTx between 2003 and 2010. Listed patients underwent transjugular liver biopsy with hepatic portal venous gradient (HPVG) measurements. Only patients with HPVG less than 10 mm Hg were considered for KTx alone. We analyzed patient demographics, waitlist/liver disease characteristics, and posttransplant outcomes between groups. RESULTS: Sixty-four patients listed for KTx alone were studied. Twelve patients (18.75%) showed biopsy-proven cirrhosis. Thirty-seven patients underwent KTx alone (9 from C and 28 from NC). No patients developed decompensation of their liver disease, although one patient for NC group developed metastatic hepatocellular carcinoma 16 months after transplantation. One- and three-year graft survival rates were 75% and 75% versus 92.1% and 75.1% for groups C and NC, respectively (P=0.72). One- and three-year patient survival rates were 88.9% and 88.9% versus 96.3% and 77.9% for groups C and NC, respectively (P=0.76). Only increasing recipient age and decreasing albumin levels were significantly associated with worse graft and patient survival. CONCLUSIONS: Our study suggests that KTx alone may be safe in patients with compensated HCV, cirrhosis, and ESRD with HPVG less than 10 mm Hg. A simultaneous liver-kidney transplantation may be an unnecessary use of a liver allograft in these patients.

Non-contrasted computed tomography for the accurate measurement of liver steatosis in obese patients.

BACKGROUND: Hepatic macrosteatosis (HMS) is prevalent among high BMI patients, but a lack of validation of non-invasive measures of liver fat hampers non-alcoholic liver disease (NAFLD) investigation in general. Recent work suggests BMI adjusted, non-contrasted computed tomography (nc-CT) attenuation data (Hounsfield units) reflects liver fat accumulation in a normal weight population. However, this and other CT-based HMS studies have only approximated macrosteatosis (%) histologically, but have not validated findings with chemical liver triglyceride (TG) concentrations (mg/gram protein). Also, all previous CT based steatosis studies excluded high BMI subjects, whose habitus may affect properties of the scan. We hypothesized that in high BMI patients nc-CT attenuation measurements expressed in Hounsfield units (HU) accurately estimate liver triglyceride concentrations as well as histological macrosteatosis. METHODS: With informed consent, 15 patients underwent nc-CT scan of the abdomen prior to weight loss surgery with intraoperative wedge and core needle liver biopsy. Mean left lobe nc-CT Hounsfield units (CT(L)), liver TG (mg/g Pr), HMS (%), BMI (kg/m(2)), liver-spleen index (CT(L/S) = hepatic HU/splenic HU), and liver-spleen difference (CT(L-S) = hepatic HU - splenic HU) were a priori outcomes. RESULTS: In 15 patients (11 female) with a BMI of 44.4 ± 1.1 (mean ± SEM), CT(L/S), CT(L-S), and CT(L) measures were significantly associated with liver TG concentrations (r = -0.80, P < 0.001; r = -0.80, P < 0.001; and r = -0.71, P < 0.01, respectively; Table 1). Macrosteatosis (%) and liver triglyceride concentration were positively associated (r = 0.83; P < 0.0001). BMI did not correlate strongly to liver triglyceride (r = 0.44, P = NS). CONCLUSION: Estimates of liver fat obtained by nc- CT scans (esp. CT(L/S), CT(L-S)) correlate to chemical measurement of liver triglyceride concentrations, suggesting non-contrasted CT may be a suitable non-invasive "gold standard" for hepatic steatosis quantification in these patients.

Virological rather than host factors are associated with transaminase levels among HIV/HCV-coinfected patients.

Alanine aminotransferase (ALT) is a routine parameter in the assessment and monitoring of chronic hepatitis C viral (HCV) infection. Hepatitis C virus-infected African Americans (AAs) have been reported to have lower ALT levels. In this retrospective, cross-sectional, multicenter study, host and virological factors possibly associated with ALT levels were analyzed by multivariate regression analyses among HIV/HCV-coinfected patients. Of the 289 patients included, 142 were African Americans and 144 Caucasians. In multivariate analysis, only HCV genotype 3 (B 0.2 [95% CI 13.39-52.33]; P = .001) and HCV RNA >500 000 IU/mL (B 3.1 [95% CI 7.67-34.75]; P = .002) were independent predictors of higher ALT levels. Per the American Association for the Study of Liver Disease (AASLD) definition, 18.2% had ALT levels within normal limits. Male sex and HCV RNA <500 000 IU/mL predicted ALT within normal limits. Hepatitis C viral factors rather than race were associated with ALT levels in this HIV/HCV-coinfected population. ALT were within normal limits in 18% of patients, who more often were male and had lower Hepatitis C viral load.