Ke-Qin Hu

OCCULT HEPATITIS B VIRUS INFECTION AND ITS CLINICAL IMPLICATIONS

Occult hepatitis B virus (HBV) infection is characterized by presence of HBV infection with undetectable hepatitis B surface antigen (HBsAg). Serum HBV level is usually less than 104 copies/mL in these patients. Diagnosis of occult HBV infection requires sensitive HBV‐DNA PCR assay. Several possibilities have been hypothesized as the mechanisms of occult HBV infection. These include: (i) mutations of HBV‐DNA sequence; (ii) integration of HBV‐DNA into hosts chromosomes; (iii) infection of peripheral blood mononuclear cells by HBV; (iv) formation of HBV‐containing immune complex; (v) altered host immune response; and (vi) interference of HBV by other viruses. The precise prevalence of occult HBV infection remains to be defined. The clinical implications of occult HBV infection involve different clinical aspects. First of all, occult HBV infection harbours potential risk of HBV transmission through blood transfusion, haemodialysis, and organ transplantation. Second, it may serve as the cause of cryptogenic liver disease, contribute to acute exacerbation of chronic hepatitis B, or even fulminant hepatitis. Third, it is associated with development of hepatocellular carcinoma. Fourth, it may affect disease progression and treatment response of chronic hepatitis C. Most of the previous studies utilized retrospective observation without control groups, and lacked direct association of occult HBV infection with specific pathological changes and disease progression. Highly sensitive, quantitative, and functional molecular analyses of HBV, combined with a well‐designed prospective clinical assessment will provide the best approach for the future study of occult HBV infection.

Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection

BACKGROUND:Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.METHODS:We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.RESULTS:Overall, 32.2% (95% CI, 30.8–33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2–42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24–25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85–13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70–13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42–16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0–78.3%) agreed to be treated and multivariable analysis showed that persons ≥50 yr of age (OR = 1.37; 95% CI, 1.07–1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08–1.93) were more likely to decline treatment.CONCLUSIONS:The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.

Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis

Nephrogenic fibrosing dermopathy (NFD) is a recently described cutaneous fibrosing disorder associated with renal dysfunction. It appears similar to scleromyxedema but with some notable exceptions, including the lack of involvement of the face and absence of plasma cells on histology, systemic involvement, and paraproteinemia. Patients can present with thickened or edematous skin with indurated papules and plaques involving the extremities and the trunk. We report the first three cases of NFD after liver transplantation successfully treated with plasmapheresis. Two patients underwent liver transplantation for hepatitis C virus–induced cirrhosis and one for hepatitis B virus–induced cirrhosis. All the patients had encephalopathy, refractory ascites, and malnutrition prior to transplantation. Like those patients with NFD, all three of our patients had renal dysfunction and required hemodialysis before and after transplantation. Two were not dependent on dialysis at the time of diagnosis, however. These patients had excellent liver allograft function, but the other patient had allograft failure secondary to recurrent hepatitis C. Immunosuppression therapy consisted of basiliximab, mycophenolate mofetil, calcineurin inhibitor, and prednisone. The patients developed “woody” skin induration of the distal extremities, erythematous papules, and contractures at 1, 2, and 120 months after transplantation. Skin biopsies resembled NFD. No paraproteinemia was evident. One to three 5-day courses of plasmapheresis resulted in moderate to marked clinical improvement. The improvement of the kidney function in two of our patients did not appear to correlate with that of the skin disorder, because the kidney function was improving at the time the diagnosis of NFD was made. In conclusion, we report the first three cases of NFD after liver transplantation. Plasmapheresis was moderately successful in resolving the skin-indurated papules, severe skin induration, and associated joint contractures. Preliminary studies (unpublished data) show that decreasing plasma levels of transforming growth factor-&bgr;1 after plasmapheresis appear to correlate with the amelioration of this clinical condition.

Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States

BACKGROUND Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined. AIMS The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients. METHODS This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center. RESULTS The frequency of hepatic steatosis was 66.0%. We demonstrated that not only being obese, but also overweight (i.e. body mass index > or =25 kg/m(2)) was independently associated with hepatic steatosis. In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis. Grade II/III steatosis, was significantly associated with a higher histology activity index as well. Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. CONCLUSIONS Being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.

Octreotide/Midodrine Therapy Significantly Improves Renal Function and 30-Day Survival in Patients with Type 1 Hepatorenal Syndrome

Type 1 hepatorenal syndrome (HRS) can be a rapidly fatal consequence of liver failure. Recent studies have utilized vasoconstrictor therapies to combat splanchnic vasodilatation. We aimed to evaluate the efficacy of a promising treatment for type 1 HRS. We compared the survival of HRS patients who received octreotide and midodrine treatment at Rancho Los Amigos Medical Center with a concurrent untreated control group of HRS patients who did not receive this treatment. Of the 81 patients, 60 were treated with octreotide/midodrine and 21 were controls. Mortality was significantly lower in the treatment group (43%) than in the controls (71%; P < 0.05). Furthermore, 24 study patients (40%) had a sustained reduction of serum creatinine compared with only 2 controls (10%; P < 0.05). This large retrospective study suggests that octreotide/midodrine treatment appears to improve 30-day survival. A randomized, controlled trial is the next important step toward evaluating this treatment modality.

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

Elevated low‐density lipoprotein (LDL) levels and statin use have been associated with higher sustained virological response (SVR) rates in patients receiving chronic hepatitis C therapy. However, these relationships have not been well characterized in randomized controlled trials. Furthermore, little is known about the relationship between high‐density lipoprotein (HDL) and virological response. To determine whether baseline LDL or HDL levels and statin use affect SVR rates, we retrospectively evaluated the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, in which 3070 treatment‐naive, hepatitis C virus (HCV) genotype 1–infected patients were treated for up to 48 weeks in one of the following arms: (1) peginterferon (PEG‐IFN) alfa‐2b at 1.5 μg/kg/week with ribavirin (RBV) at 800 to 1400 mg/day, (2) PEG‐IFN alfa‐2b at 1.0 μg/kg/week with RBV at 800 to 1400 mg/day, or (3) PEG‐IFN alfa‐2a at 180 μg/week with RBV at 1000 to 1200 mg/day. Virological responses were assessed by pretreatment statin use and baseline elevated LDL levels (≥130 mg/dL) or low HDL levels (<40 mg/dL for men and <50 mg/dL for women). In 1464 patients with baseline elevated LDL levels or low HDL levels, the SVR rate was significantly higher than that in patients with normal levels (44.9% versus 34.0%, P < 0.001). In 66 patients receiving a statin pretreatment, the SVR rate was higher than the rate of those not receiving it (53.0% versus 39.3%, P = 0.02). In a multivariate logistic regression analysis using the stepwise selection method with baseline characteristics, a high LDL level [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4‐1.8, P < 0.001], a low HDL level (OR = 0.5, 95% CI = 0.3‐0.8, P = 0.004), and statin use (OR = 2.0, 95% CI = 1.1‐3.7, P = 0.02) were independently associated with SVR. Conclusion: Baseline elevated LDL levels or low HDL levels and preemptive statin usage were associated with higher SVR rates. Prospective studies may be considered to explore the biological impact of these factors on HCV RNA replication and treatment response. (HEPATOLOGY 2010;)

Clinical Significance of Elevated Alpha-Fetoprotein (AFP) in Patients with Chronic Hepatitis C, but not Hepatocellular Carcinoma

BACKGROUND:Although elevated serum alpha-fetoprotein (AFP) is often seen in patients with chronic hepatitis C (CHC), its prevalence, risk factors, and clinical significance remain to be determined.AIMS:The present study assessed the frequency of, the risk factors for, and the clinical significance of elevated AFP in patients with CHC, but not hepatocellular carcinoma.METHODS:This retrospective study utilized systematic chart review and statistical analyses to investigate 357 U.S. patients with CHC from a university medical center and a regional veteran administration medical center.RESULTS:The prevalence of elevated serum AFP (i.e., ≥10.0 μg/L) was 23.0%, including 15.3% (28/183), 24.5% (25/102), and 42.0% (29/69) in patients with chronic hepatitis C and stage 0–II, III, and IV hepatic fibrosis, respectively. After adjusting for age, HCV load, and hepatic steatosis, stage III/IV fibrosis, elevated aspartate aminotransferase (AST), and prolonged prothrombin time as measured by international normalized ratio (INR) remained independently associated with elevated serum AFP in these patients. A serum AFP level of 15.0 μg/L was 22.8% sensitive and 94.5% specific for stage III/IV fibrosis.CONCLUSIONS:In patients with chronic hepatitis C, 23.0% had elevated serum AFP that is independently associated with stage III/IV hepatic fibrosis, elevated level of AST, and prolonged INR.

Transcriptional factor C/EBP binds to and transactivates the enhancer element II of the hepatitis B virus

The human hepatitis B Virus genome (HBV) contains a liver-specific enhancer upstream of the X ORF which has been studied in detail by several investigators. A second liver-specific enhancer element, designated here as enhancer II, has been relatively recently described in the HBV genome, which is located within the core/pregenomic promoter. We have studied the interactions of transcriptional factors with this element and show here that the nuclear factor CCAAT/enhancer binding protein (C/EBP) binds at a unique site within these sequences. Further, using the transient cotransfection scheme of expression with C/EBP encoding vectors and an enhancer II-reporter gene construct, we demonstrate that the enhancer element II responds to increasing amounts of C/EBP by displaying transactivation. Evidence for the functional role of the enhancer element II in transcriptional regulation of the HBV gene expression is presented. A major influence of the enhancer II appears to be on the surface antigen expression.

Severe Intraoperative Hyperglycemia Is Independently Associated With Surgical Site Infection After Liver Transplantation

Background. Surgical site infection (SSI) is a common postoperative complication associated with increased morbidity and mortality in patients undergoing liver transplantation (LT). Although intraoperative hyperglycemia has been shown to be associated with adverse postoperative outcomes including overall infection rate in LT patients, a relationship between intraoperative hyperglycemia and SSI in LT has not been established. We sought to determine if intraoperative hyperglycemia was associated with SSI after LT. Methods. Patients undergoing LT at our medical center between January 2004 and November 2007 were included in the study. Recipient, donor, and intraoperative variables including a variety of glucose indices were retrospectively analyzed. Independent risk factors of SSI were identified using a multivariate logistic regression model. Results. Of 680 patients, 76 (11.2%) experienced postoperative SSIs. Among all intraoperative glucose indices analyzed, severe hyperglycemia (≥200 mg/dL) was independently associated with postoperative SSI (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.26–4.03, P=0.006). Other independent risk factors include repeat surgery (OR 6.58, 95% CI 3.41–12.69, P<0.001), intraoperative administration of vasopressor (OR 3.14, 95% CI 1.65–5.95, P<0.001), preoperative mechanical ventilation (OR 3.01, 95% CI 1.70–5.33, P<0.001), and combined liver and kidney transplantation (OR 2.95, 95% CI 3.41–12.69, P<0.001). Conclusions. Severe, but not mild or moderate, intraoperative hyperglycemia is independently associated with postoperative SSI and should be avoided during LT surgery.

Hyperfibrinolytic activity in hospitalized cirrhotic patients in a referral liver unit

ObjectiveIncreased frequency of hyperfibrinolytic activity was reported in patients with cirrhosis. However, the incidence, clinical presentation, and the parameters related to hyperfibrinolysis remain largely unknown in these patients. By utilizing euglobulin lysis time (ELT) and other clinical coagulation tests, the present study investigated the incidence of and clinical parameters related to hyperfibrinolytic activity, and assessed predicting factors to ɛ-aminocaproic acid (EACA) treatment in cirrhotic patients with hyperfibrinolysis in a liver unit.METHODS:The study included 86 consecutive patients who were referred and admitted to a referral liver unit for various liver diseases. The mean age was 50.0 yr, with a male:female ratio of 60:26. Sixty-six patients (76.7%) were Hispanic and 75 (87.2%) were cirrhotic. The etiologies of liver diseases included alcoholic liver disease (n = 68, 79.1%), hepatitis B (n = 2, 2.3%), hepatitis C (n = 6, 7.0%), autoimmune hepatitis (n = 3, 3.5%), cryptogenic liver disease (n = 4, 4.7%), and hepatocellular carcinoma (n = 3, 3.5%). Coagulation studies included ELT, PT, PTT, fibrinogen, D-dimer, and fibrin degradation product levels.RESULTS:Hyperfibrinolytic activity as reflected by shortened ELT was present in 27/75 cirrhotic (31.3%) but 0/11 noncirrhotic patients, which was significantly correlated with higher Child-Pugh (C-P) class, abnormal levels of PT, PTT, fibrinogen, platelet count, and total bilirubin. Shortened ELT was more frequently seen in patients with hepatic decompensation and mucocutaneous bleeding, although these relationships were not statistically significant. In 27 patients with hyperfibrinolysis, five (18.5%) required EACA treatment for progressive mucocutaneous bleeding and/or hematoma. EACA treatment was significantly associated with higher C-P scores; greatly shortened ELT (≤50% of normal value); and abnormal levels of fibrinogen, total bilirubin, and PT, indicating that these factors may serve as predictors for EACA treatment.CONCLUSION:Hyperfibrinolytic activity was seen in 31.3% of patients with cirrhosis, which is correlated with higher C-P scores; abnormal PT, PTT, fibrinogen level, and platelet count; and hyperbilirubinemia. Patients who received EACA treatment usually have a more severe hyperfibrinolytic activity as indicated by shortened ELT and low level of fibrinogen, and more severe liver disease as indicated by higher C-P scores and hyperbilirubinemia.