Michele M. Tana

Race/ethnicity-specific disparities in cancer incidence, burden of disease, and overall survival among patients with hepatocellular carcinoma in the United States

Hepatocellular carcinoma (HCC) is one of the fastest rising causes of cancer‐related deaths in the United States, with disparities observed in cancer incidence and survival between ethnic groups. This report provides updated analyses on race‐specific disparities in US HCC trends.

Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis

BACKGROUND & AIMS: Predniso(lo)ne, alone or in combination with azathioprine, is the standard‐of‐care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second‐line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second‐line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second‐line therapy as a result of side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver‐related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log‐rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long‐term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis

OBJECTIVES In primary biliary cirrhosis (PBC), the antimitochondrial antibody is a cornerstone of diagnosis, but there have been conflicting reports about the correlation of autoantibodies with disease stage and prognosis. We studied whether autoantibody levels changed over time and sought correlations with clinical outcomes in a cohort of patients with PBC. METHODS We tested serial serum samples from patients with PBC at a research institution for several autoantibodies. Long-term clinical follow-up data were used to calculate the slopes (change over time) for autoantibodies, platelet count, Ishak fibrosis score, biopsy copper, and number of portal areas with bile ducts. An adverse clinical outcome was defined as hepatic decompensation, development of hepatocellular carcinoma, liver transplantation, or liver-related death. We performed linear or logistic regression or Fisher exact test as appropriate, adjusting for multiple comparisons. RESULTS Twenty-seven patients with PBC with 145 serum samples were studied. Of the cohort, 85% was white, 81% was female, and median follow-up time was 20 years. Of the autoantibodies tested, only sp100 changed significantly over time. The sp100 slope was inversely associated with the Ishak fibrosis slope (parameter estimate, -0.05; P = .0003). CONCLUSIONS While changes in most autoantibodies over time do not seem to correlate with clinical outcomes in PBC, a change in the sp100 autoantibody level may have prognostic utility with respect to the development of fibrosis on liver biopsy.

Factors associated with the platelet count in patients with chronic hepatitis C

BACKGROUND There are many potential causes of thrombocytopenia in patients with chronic hepatitis C (CHC). AIMS We sought to determine the association between thrombopoietin (TPO) level, immature platelet fraction (IPF), immunoglobulin G (IgG) level, spleen size, and the platelet count in CHC. METHODS We studied a consecutive sample of patients enrolled in an observational study at a referral-based research center, excluding subjects based on eligibility criteria. TPO, glycocalicin, and von Willebrand Factor (vWF) levels were determined using stored sera. Hepatic fibrosis was assessed via transient elastography (TE) when available, and clinical laboratory values and radiologic data were obtained from the medical record. We performed analyses of the relationships between independent variables and the platelet count. RESULTS On univariate analysis, the following variables were significantly associated with the platelet count: age, alanine aminotransferase (ALT), direct bilirubin, total bilirubin, IPF, international normalized ratio (INR), spleen size, vWF, glycocalicin, fibrosis stage on liver biopsy, and TE (P-values all <0.05). A multivariable model determined that imputed TE score, TPO, IPF, and spleen size were independently associated with the platelet count (P-values all<0.05). CONCLUSIONS The platelet count in CHC is significantly associated with fibrosis, TPO level, IPF, and spleen size. Our findings challenge the proposed mechanism of decreased TPO levels or decreased bone marrow production of platelets as a cause of thrombocytopenia in CHC. Future studies focusing on the effects of fibrosis and splenomegaly on platelets may shed more light on the pathophysiology of thrombocytopenia in patients with CHC.

Race/Ethnicity-specific Disparities in Hepatocellular Carcinoma Stage at Diagnosis and its Impact on Receipt of Curative Therapies.

Goals:To evaluate race/ethnicity-specific disparities in hepatocellular carcinoma (HCC) stage at diagnosis and how this impacts receiving curative therapies. Background:HCC is a leading cause of morbidity and mortality worldwide. The highest incidence of HCC is seen among ethnic minorities in the United States. Study:Using the 2003-2011 Surveillance, Epidemiology, and End Results database and United Network of Organ Sharing, population-based registries for cancer and liver transplantation (LT) in the United States, race/ethnicity-specific cancer stage at diagnosis and treatment received among adults with HCC were evaluated. Results:Compared with non-Hispanic whites, blacks had significantly more advanced HCC at diagnosis [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.10-1.30; P<0.001], whereas Asians were less likely to have advanced disease (OR, 0.87; CI, 0.80-0.94; P<0.001). Among patients with HCC meeting Milan criteria, Hispanics (OR, 0.64; 95% CI, 0.57-0.71; P<0.001) and blacks (OR, 0.67; 95% CI, 0.59-0.76; P<0.001) were significantly less likely to receive curative therapy (resection or LT), whereas Asians were more likely to receive curative therapy (OR, 1.22; 95% CI, 1.10-1.35; P<0.001) compared with non-Hispanic whites. However, Asians (OR, 0.49; 95% CI, 0.42-0.58; P<0.001) and Hispanics (OR, 0.51; 95% CI, 0.44-0.60; P<0.001) were less likely to receive LT. Conclusions:Among US adults with HCC, blacks consistently had more advanced stage at diagnosis and lower rates of receiving treatment. After correcting for cancer stage and evaluating the subset of patients eligible for curative therapies, blacks and Hispanics had significantly lower rates of curative HCC treatment.

Scar undone: long-term therapy of hepatitis B

In recent years, substantial progress has been made in the prevention and control of hepatitis B, a major cause of chronic liver disease, cirrhosis, and liver cancer worldwide. A safe and eff ective hepatitis B virus vaccine was developed in the early 1980s, and its subsequent widespread use resulted in notable decreases in rates of hepatitis B, at least in countries that adopted universal hepatitis B vaccination. Therapies for hepatitis B were developed more recently and are only now showing an eff ect on the burden of this disease. Interferon alfa was approved for this indication in the USA in 1991, but had low effi cacy and was not well tolerated. Oral antiviral agents with activity against hepatitis B were developed in the 1990s. The fi rst three agents approved in the USA (lamivudine in 1998, adefovir in 2002, and telbivudine in 2006) were very well tolerated, and yielded good viral suppression and clinical responses in 1–2 year studies. With more prolonged therapy, however, the effi cacy of these agents was limited by antiviral resistance. These shortcomings seem to be overcome by two newer, more potent antiviral agents—entecavir (approved in 2005) and tenofovir disoproxil fumarate (approved in 2008)— both of which have a high barrier to antiviral resistance. These antiviral agents suppress serum hepatitis B virus DNA to near or below detectable levels, and result in high rates of improvement in both biochemical and histological evidence of disease. Studies show that their long-term use (3–5 years) maintains viral suppression and biochemical improvements. In this issue of The Lancet, Patrick Marcellin and colleagues report that long-term therapy also leads to substantial histological improvements, including decreases in fi brosis and apparent regression of cirrhosis. Such eff ects of long-term antiviral therapy of hepatitis B (and C and D) have been reported previously, but no other report has been as large or convincing. In 489 patients with chronic hepatitis B treated with tenofovir for 4–5 years, 348 underwent repeat liver biopsy. Liver histology showed improvement in infl ammation and necrosis in almost all patients and a decrease in fi brosis in 51% (176 of 348 patients). An impressive fi nding was an apparent regression of cirrhosis in 74% of those with cirrhosis on initial biopsy (71 of 96 patients). Patients without resolution of cirrhosis were more likely to be overweight or obese. Regression of fi brosis, as shown by paired liver biopsies before and after 4 years of therapy, is a strong and convincing endpoint in support of treatment. Nevertheless, histological improvement is a surrogate endpoint for the clinical consequences of cirrhosis: clinical decompensation, death from end-stage liver disease, and hepatocellular carcinoma, the dreaded longterm complication of chronic hepatitis B. In the study from Marcellin and colleagues, these hard endpoints were apparently improved but less well documented than the histological changes. The rate of hepatocellular carcinoma was about 2% (12 cases). Importantly, in patients without hepatocellular carcinoma, none developed hepatic compensation or died of end-stage liver disease. The study did not include an untreated control group for obvious reasons, but historical controls would have predicted higher rates for both outcomes. This study and many others now support the recommendation that patients with chronic hepatitis B receive long-term treatment with a potent oral antiviral agent with a high barrier to resistance. If long-term treatment is recommended, how long should it be continued for, and what criteria should be used to decide when to stop therapy? In patients with HBeAg-positive hepatitis B, guidelines recommend discontinuation of antiviral therapy 6 months after loss of HBeAg. Furthermore, in patients with HBeAg-negative disease, fi ndings from case series have shown that Published Online December 10, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61721-8

Hepatitis B virus treatment: Management of antiviral drug resistance†‡

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A comparison of methods for evaluation of a case of suspected macro-aspartate aminotransferase

BACKGROUND Macro-aspartate aminotransferase (macroAST) is a high molecular weight form of AST that is usually formed through association with immunoglobulin (Ig) in the circulation. As a result of reduced inactivation, clearance or excretion, AST values are persistently increased. This can lead to problems interpreting these values and diagnosing the patient, especially if clinicians are not aware of this phenomenon. METHODS For a case of suspected macroAST, we compared three simple methods: polyethylene glycol precipitation, ultrafiltration, and Ig depletion using protein A and G. RESULTS All three methods were consistent with a diagnosis of macroAST. CONCLUSIONS The protein A and G method was straightforward and provided unambiguous results. However, given the affinity of protein A and protein G, it likely only detects AST-IgG macrocomplexes.

Autoantibodies in hepatitis C: red flag or bystander effect?

Autoantibody reactivity is a common occurrence in liver diseases. As in other liver diseases, chronic hepatitis C is associated with the presence of various autoimmune markers and autoimmune disease. This autoantibody reactivity in turn may be a reflection of immune system activation. Molecular mimicry of viral antigens by self antigens, chronic stimulation of B cells, and a bystander effect are some proposed mechanisms for the development of autoimmune phenomena in hepatitis C.1 The development of autoantibodies and autoimmune diseases is a recognized side effect of interferon therapy in adults.2 However, it is unclear whether interferon unmasks previously unrecognized autoimmune disease or causes de novo autoimmune disease. Interestingly, some studies report an association between baseline autoantibody levels and HCV treatment response in adults.3 In this issue of JPGN, Molleston and colleagues analyzed autoantibodies in stored serum from the PEDS-C trial.4 Autoantibodies were present in 19% of the children at baseline, with a non-significant upward trend in prevalence over the course of treatment. These autoantibodies were not predictive of treatment outcome, treatment side effects, or ALT elevations during treatment. Since the PEDS-C trial excluded children with evidence of preexisting autoimmune diseases, we cannot determine if interferon worsened pre-existing autoimmune disorders. However, the PEDS-C population was well suited for the assessment of de novo development of autoimmune disease. This occurred in 3 out of the 114 children, two of whom developed autoantibodies while on peginterferon. The scant data that is available suggests the presence of a positive ANA in approximately 6–15% of healthy controls.5 This is comparable to the ANA positivity rate in the PEDS-C cohort prior to treatment. The current study sheds light on an aspect of pediatric hepatitis C that has been largely unexplored until present. Molleston et al. were able to measure changes in autoantibodies over the course of HCV therapy in a well-characterized cohort of children. They determined that autoantibodies did not correlate with ALT, and probably are not mere markers of inflammation. They also did not find a relationship between autoantibodies and response to therapy, showing that the prognostic value reported in adults did not hold in this population. In addition, the authors determined the incidence of de novo autoimmune disease with HCV treatment. Furthermore, these findings are particularly timely. With the advent of new directly-acting antivirals, the end of the interferon era may be imminent, making it less feasible to study the effect of exogenous interferon on autoantibody reactivity. Thus, the present study adds to our understanding at an opportune moment in pediatric hepatology. For the practitioner, this article shows that if preexisting autoimmune disease has been excluded, one need not routinely check for autoantibodies during therapy in the absence of symptoms. The findings reported in this issue of JPGN are a major contribution, and the area of autoimmunity in pediatric HCV is in its nascent stages. Additional data from large cohorts, advances in immunology, and improved autoantibody tests will enhance our understanding of chronic hepatitis C and its myriad manifestations.

Hospitalizations for Autoimmune Hepatitis Disproportionately Affect Black and Latino Americans

Objectives:The healthcare burden of autoimmune hepatitis (AIH) in the United States has not been characterized. We previously showed that AIH disproportionately affects people of color in a single hospital system. The current study aimed to determine whether the same disparity occurs nationwide.Methods:We analyzed hospitalizations with a primary discharge diagnosis corresponding to the ICD-9 code for AIH in the National Inpatient Sample between 2008 and 2012. For each racial/ethnic group, we calculated the AIH hospitalization rate per 100,000 population and per 100,000 all-cause hospitalizations, then calculated a risk ratio compared to the reference rate among whites. We used multivariable logistic regression models to assess for racial disparities and to identify predictors of in-hospital mortality during AIH hospitalizations.Results:The national rate of AIH hospitalization was 0.73 hospitalizations per 100,000 population. Blacks and Latinos were hospitalized for AIH at a rate 69% (P<0.001) and 20% higher (P<0.001) than whites, respectively. After controlling for age, gender, payer, residence, zip code income, region, and cirrhosis, black race was a statistically significant predictor for mortality during AIH hospitalizations (odds ratio (OR) 2.81, 95% confidence interval (CI) 1.43, 5.47).Conclusions:Hospitalizations for AIH disproportionately affect black and Latino Americans. Black race is independently associated with higher odds of death during hospitalizations for AIH. This racial disparity may be related to biological, genetic, environmental, socioeconomic, and healthcare access and quality factors.