Mindie H. Nguyen

α-Fetoprotein, Des-γ Carboxyprothrombin, and Lectin-Bound α-Fetoprotein in Early Hepatocellular Carcinoma

BACKGROUND & AIMS Alpha-fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with cirrhosis. Des-gamma carboxy-prothrombin (DCP) and lectin-bound AFP (AFP-L3%) are potential surveillance tests for HCC. The aims of this study were to determine performance of DCP and AFP-L3% for the diagnosis of early HCC; whether they complement AFP; and what factors affect DCP, AFP-L3%, or AFP levels. METHODS We conducted a large phase 2 biomarker case-control study in 7 academic medical centers in the United States. Controls were patients with compensated cirrhosis and cases were patients with HCC. AFP, DCP, and AFP-L3% levels were measured blinded to clinical data in a central reference laboratory. RESULTS A total of 836 patients were enrolled: 417 (50%) were cirrhosis controls and 419 (50%) were HCC cases, of which 208 (49.6%) had early stage HCC (n = 77 very early, n = 131 early). AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77-0.84), followed by DCP (0.72, 95% CI: 0.68-0.77) and AFP-L3% (0.66, 95% CI: 0.62-0.70) for early stage HCC. The optimal AFP cutoff value was 10.9 ng/mL leading to a sensitivity of 66%. When only those with very early HCC were evaluated, the area under the receiver operating characteristic curve for AFP was 0.78 (95% CI: 0.72-0.85) leading to a sensitivity of 65% at the same cutoff. CONCLUSIONS AFP was more sensitive than DCP and AFP-L3% for the diagnosis of early and very early stage HCC at a new cutoff of 10.9 ng/mL.

Prevalence and Treatment of Hepatitis C Virus Genotypes 4, 5, and 6

Infection with hepatitis C virus (HCV) genotypes 4-6 (with the previously named genotypes 7-9 included as subtypes of genotype 6) is distributed and studied less widely than genotypes 1-3. However, genotypes 4-6 are very common in geographic areas where chronic hepatitis C is highly prevalent. In fact, the majority (87%) of the 169.7 million HCV-infected individuals worldwide are from western Pacific countries (62.2 million), southeast Asia (32.3 million), Africa (31.9 million), and eastern Mediterranean countries (21.3 million). It is among this large population outside of the Americas and Europe that these less well known genotypes are found: genotype 4 in Egypt and Africa, genotype 5 in South Africa, and genotype 6 in southeast Asia. The existing literature, although limited, suggests that patients with chronic hepatitis C genotypes 4-6 may exhibit different clinical courses and treatment outcomes. Ethnicity-related factors may contribute to the presence of more advanced disease in patients with genotype 4, who also tend to have a poor response to interferon-based therapy. HCV genotype 5 appears to be an easy-to-treat virus with response rates similar to those of genotypes 2 and 3 after a 48-week course of therapy. Response to treatment in patients with HCV genotype 6 may be at an intermediate level between that seen with genotype 1 and genotype 2 or 3. The optimal duration of treatment (24 vs 48 wk) for HCV genotype 6 is unclear and currently is under investigation.

Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil

Renal dysfunction has been reported in patients treated with adefovir dipivoxil (ADV); however, its incidence and clinical importance may be underappreciated given the lack of long‐term follow‐up and data outside of a clinical trial setting. Our goal was to examine the severity and incidence of renal dysfunction in a real‐life setting for patients treated with ADV and whose baseline estimated glomerular filtration rate (eGFR) was >50 mL/minute. We performed a cohort study of 290 chronic hepatitis B patients: 145 patients treated with 10 mg ADV and 145 patients unexposed to ADV at two community clinics, who were matched for age (±10 years), sex, and baseline eGFR. The exposed and unexposed populations were well‐matched with a similar mean age (46–47 years), proportion of male patients (76.5%), baseline serum creatinine (0.97–0.99 mg/dL), and baseline creatinine clearance (85.0–85.4 mL/minute). The incidence density for renal dysfunction defined by treatment termination and/or development of eGFR ≤50 mL/minute was five cases per 100 patient‐years in the exposed group compared with 1.36 cases per 100 patient‐years in the unexposed group (P = 0.02). The relative risk of exposed to unexposed was 3.68 (95% confidence interval 1.1–19.3). On Cox proportional hazard analysis also inclusive of sex, ADV was a significant predictor of significant renal dysfunction (hazard ratio [HR] 3.94, P = 0.03). There were also significant trends for age >50 years (HR 3.49, P = 0.087), mild renal impairment at baseline (HR 4.49, P = 0.073), and hypertension and/or diabetes mellitus (HR 2.36, P = 0.074). Conclusion: ADV is an independent predictor for significant deterioration of renal function. Patients on ADV should be monitored, especially patients who are older, have baseline renal insufficiency, or have hypertension and/or diabetes mellitus. (HEPATOLOGY 2009.)

Transarterial Chemoinfusion for Hepatocellular Carcinoma as Downstaging Therapy and a Bridge toward Liver Transplantation

Favorable outcomes after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) are well described for patients who fall within defined tumor criteria. The effectiveness of tumor therapies to maintain tumor characteristics within these criteria or to downstage more advanced tumors to fall within these criteria is not well understood. The aim of this study was to examine the response to transcatheter arterial chemoinfusion (TACI) in HCC patients awaiting LT and its efficacy for downstaging or bridging to transplantation. We performed a retrospective study of 248 consecutive TACI cases in 122 HCC patients at a single U.S. medical center. Patients were divided into two groups: those who met the Milan criteria on initial HCC diagnosis (n = 95) and those with more advanced disease (n = 27). With TACI treatment, 87% of the Milan criteria group remained within the Milan criteria and 63% of patients with more advanced disease were successfully downstaged to fall within the Milan criteria. In conclusion, TACI appears to be an effective treatment as a bridge to LT for nearly 90% patients presenting within the Milan criteria and an effective downstaging modality for over half of those whose tumor burden was initially beyond the Milan criteria.

Screening for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is common throughout the world and most often develops as a late complication of chronic viral hepatitis or cirrhosis of any cause. As a result of the high prevalence rate of chronic hepatitis C, the incidence of HCC is rising in the United States, as well as in European and Asian countries. The overall survival rate of HCC is poor, and surgical resection and liver transplantation are the only curative treatment options. Screening for HCC offers the best hope for early detection, eligibility for treatment, and improved survival. Most physicians routinely screen at-risk patients with chronic viral hepatitis and cirrhosis for HCC, despite the lack of official guidelines. The current consensus recommendations are to screen healthy hepatitis B virus carriers with annual or semiannual serum alpha-fetoprotein; carriers with chronic hepatitis or cirrhosis and patients with cirrhosis of any etiology are surveyed with twice yearly serum alpha-fetoprotein and liver ultrasound. This article will review the current recommendations for HCC screening, the rationale that led to these recommendations, and the challenges of cost–effectiveness research in this area.

Systematic review: Asian patients with chronic hepatitis C infection.

Chronic hepatitis C (CHC) infection is a risk factor for both the development of end‐stage liver disease and hepatocellular carcinoma (HCC). Globally, approximately 170 million people are chronically infected with the hepatitis C virus (HCV), and the majority of these individuals come from the western Pacific and Southeast Asia regions (94.6 million persons combined). CHC is an understudied and underappreciated health problem in many Asian countries and in the US, where Asians represent one of the fastest growing groups of new Americans.

Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis.

BACKGROUND AND AIMS In the United States, hepatocellular carcinoma (HCC) is more common among Asians and African Americans than Caucasians, with chronic hepatitis C virus (HCV) infection accounting for up to half of the patients. Our study examined ethnicity as a potential risk factor for HCC among patients with chronic hepatitis C. METHODS We conducted a case-control study of 464 patients with chronic hepatitis C and cirrhosis (207 cancer patients and 257 controls) using medical records and pathology records at 4 medical centers. We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period on sex and age groups (< or =45, 46-55, 56-65, >65 yr). To control for potential confounding caused by severity of cirrhosis and residual confounding caused by age, we also included Child-Turcotte-Pugh (CTP) scores and age (continuous variable) in all regression analyses. RESULTS Compared with Caucasians, the cancer risk was increased significantly among Asians (adjusted odds ratio, 4.3; 95% confidence interval, 2.1-9.0 for men, and 4.6; 1.2-18.5 for women) and somewhat increased among African-American men (adjusted odds ratio, 2.4; 95% confidence interval, 0.9-6.3). CONCLUSIONS This study suggests that, among patients with chronic hepatitis C and cirrhosis, liver cancer risk is increased 4-fold in Asians and may be doubled in African-American men, compared with Caucasians. These results need confirmation in larger studies from racially diverse populations, but, if confirmed, these results point to high-risk populations that should be targeted for screening and preventive efforts.

Treating hepatitis C in lower-income countries.

With costs that may exceed

Significant Prevalence of Histologic Disease in Patients With Chronic Hepatitis B and Mildly Elevated Serum Alanine Aminotransferase Levels

90,000 per course, effective new hepatitis C treatments seem beyond the reach of low- and middle-income countries. But the global rollout of HIV treatment teaches us that its possible to make these agents broadly available and affordable.

Clinical course of hepatitis B virus infection during pregnancy.

BACKGROUND & AIMS Serum ALT remains the most accessible test available to clinicians for monitoring chronic hepatitis B virus infection, but appropriate action when ALT levels are only mildly elevated is ambiguous in standard guidelines. METHODS A retrospective study was conducted to investigate the prevalence of significant histology in a patient population with mildly elevated serum ALT levels. A total of 193 consecutive patients were selected and divided into 2 groups according to HBeAg status. Patients were further divided into cohorts on the basis of their highest ALT elevation during follow-up and whether it was 1-1.5 times the upper limit of normal (ULN), 1.5-2 times the ULN, or greater than twice the ULN. The ULN that was used is 30 U/L for men and 19 U/L for women. RESULTS In all cohorts there was a substantial fraction of patients with histologic disease as evaluated by liver biopsy. HBeAg-negative patients were older, had lower viral load, and had a higher prevalence of disease. After adjustments for age, HBeAg status and HBV DNA viral load were not predictors of significant histology. Age >35 years, male gender, and increasing ALT levels were predictors for significant histology on multivariate analysis. CONCLUSIONS A substantial proportion of patients with mildly elevated ALT levels have significant histologic disease. The prevalence increased with the higher ALT levels and age.