An expert consensus for the management of chronic hepatitis B in Asian Americans.

BACKGROUND: Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM: To generate recommendations for the management of Asian Americans infected with HBV. METHODS: These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS: Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS: Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.

Treatment rates in patients with chronic hepatitis C after liver biopsy.

Hepatitis C virus (HCV) infection is a major health problem in the United States. Only about 30% of patients infected with HCV are being treated despite the development of increasingly effective therapies. The aims of this study were to determine the rate of treatment for patients with HCV after undergoing liver biopsy, to assess any change in their treatment rates over recent years and to delineate the reasons for nontreatment. We retrospectively reviewed the charts of all HCV patients who had liver biopsies at Beth Israel Medical Center, New York between 1998 and 2002. The data gathered included patient demographics, stage of liver fibrosis, insurance information, treatment history and reasons for nontreatment. There were 433 liver biopsies done for chronic hepatitis C between 1998 and 2002. Of those, 267 (61%) were men. The mean age was 47 years (range, 18-72). Only 159 (37%) patients were treated after liver biopsy. Overall there were no significant differences in the treatment rates from 1999 to 2002. The common reasons for nontreatment included minimal/mild disease (stage 0-1 fibrosis, 38%), lost to follow-up or noncompliance (31%) and patient refusal (22%). Older patients more frequently had co-morbid conditions (P = 0.009). Younger age and female gender correlated with minimal disease on biopsy (P = 0.004 and 0.01, respectively). Men were lost to follow-up more frequently than women (37%vs 22%, P = 0.01). Multivariate analysis showed that age and gender were both independent predictors of minimal disease. Patients having Medicaid with or without Medicare were significantly more likely to be treated than patients with private or commercial insurance or patients with Medicare alone. A minority of HCV infected patients were treated even after having undergone liver biopsy. The proportion of HCV patients being treated after liver biopsy has been relatively stable despite advances in therapeutic success. Liver histology frequently identified patients with mild disease in whom antiviral therapy was deemed not urgent.

The rate of treatment of chronic hepatitis C in patients co-infected with HIV in an urban medical centre.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is common. HIV co-infection results in a higher rate of histologic progression and shorter interval to HCV-related cirrhosis. Successful treatment of HCV with interferon-based therapy reduces the morbidity and mortality of patients. Significant factors may limit the availability of treatment in co-infected patients. The rate of treatment of HCV and limiting factors to treatment in a co-infected population in an urban setting were determined. A retrospective review of co-infected patients was conducted at our liver and gastrointestinal (GI) clinics for treatment of HCV from July 2001 to June 2002. Treatment of HCV and reasons for nontreatment were recorded. A total of 104 HCV/HIV co-infected patients were identified. Seventy-two per cent were males. Mean age was 47.2 years (32-72). Seventy-four of the 82 (90%) with identifiable risk factors for HCV infection had a history of intravenous drug use (IVDU). Twenty per cent (21/104) of the total underwent a liver biopsy. Sixty-seven per cent who had a liver biopsy were treated. Overall, sixteen patients were treated. Eighty-eight (85%) patients were not treated for the following reasons: 13 refused treatment, and 75 were ineligible. Of the ineligible patients, 40% were noncompliant with visits, 15% were active substance abusers, 13% had decompensated cirrhosis, 8% had significant active psychiatric conditions and 24% had significant co-morbid disease. A majority of patients co-infected with HCV/HIV had a IVDU history. Most co-infected patients were not eligible for HCV treatment. A majority of noncandidates had potentially modifiable psychosocial factors leading to nontreatment.

Prospects for cell-based therapies for liver disease.

Liver parenchymal maintenance and regeneration after injury are physiologically supported by 3 cell compartments: mature liver cells, intra-organ stem cells such as cells of the proximal biliary tree and periductal cells, and extra-organ stem cells from the circulation and the bone marrow. In the latter case, hepatocyte derivation from circulating cells (plasticity) can arise via direct transdifferentiation (site specific, receptor/ligand dependent) or by fusion of circulating cells with pre-existing hepatocytes. Other non-physiologic stem cells, such as mesenchymal stem cells from the bone marrow and embryonic stem cells, may be potentially used in treatment of inherited and acquired liver diseases. This review updates our current understanding of these various cell populations and of possible approaches to their future therapeutic uses in cell transplantation, bioartificial liver devices, cytokine/chemokines manipulation of physiological repair pathways, and gene therapy.

Efficacy of high-dose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone.

OBJECTIVE: Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial. METHODS: We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon alpha-2b and ribavirin (1000-1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon monotherapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period. RESULTS: The mean age of the subjects was 47 yr (range 28-68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21 (14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon alpha-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17). CONCLUSIONS: Sustained virological response to combined interferon alpha-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable.

Hepatology at Mount Sinai: the present and the future.

The Division of Liver Disease at Mount Sinai, now into its fifth decade, has evolved through two remarkable periods in its development and is on the cusp of a third exciting era. The first, extending from the division's creation in 1957 to the retirement in 1988 of its first division chief, Fenton Schaffner, was characterized by brilliant clinical and pathophysiologic insights derived from the unique collaboration of Schaffner, a master clinician, with Hans Popper, a world renowned pathologist widely acknowledged as the father of the modern discipline of hepatology. The second, extending from the appointment in 1988 of Paul D. Berk as Schaffner's successor to the present day, has witnessed enormous growth in the clinical and scientific activities of the division, together with the emergence of a world-class liver transplant program at Mount Sinai. During this recent period, an extensive program of formal clinical research was established; the basic research program then expanded into the areas of hepatic transport, molecular virology, and the cellular and molecular pathogenesis of hepatic fibrosis; and both the clinical and research productivity of the division increased dramatically. A major undertaking, now in its second year, has been the creation of the Center for the Study of Primary Biliary Cirrhosis; Mount Sinai has contributed important advances toward the understanding of this disease. Funding for the Center, from the Artzt Family Foundation Trust, supports a series of interrelated basic studies on the immunology and pathobiology of the disease, as well as creation of a unique clinical database, a serum and tissue bank, and a program of clinical studies. This integration of basic and clinical research in pursuit of new methods of diagnosis and treatment serves as a model for the division's continued leadership role.

Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation.

OBJECTIVE: Recognition of hepatocellular carcinoma (HCC) is important in the management of patients awaiting liver transplantation. HCCs >5 cm in diameter are at high risk to recur after transplant. The goal of this study was to assess the sensitivity of the diagnostic tests employed in a pretransplant screening program. METHODS: The study is a retrospective analysis of charts of 106 consecutive adults transplanted over a 1-yr period. All patients had ultrasonography (US), computerized tomography (CT), and serum alpha fetoprotein (AFP) testing within 6 months of transplantation. Radiographic reports were subdivided into low-risk and high-risk groups, based upon level of suspicion for HCC. The results were compared to explant pathology. RESULTS: Pathological analysis of 106 explants revealed HCC in 19 patients. High-risk US exams had a positive predictive value (PPV) of 0.69 and a negative predictive value (NPV) of 0.91 in the diagnosis of HCC. High-risk CT exams had a PPV of 0.67 and an NPV of 0.90. When patients had either a high-risk US or a high-risk CT, there was a PPV of 0.59 and an NPV of 0.83. Of the 19 patients with HCC, three had high-risk US and low-risk CT; two had high-risk CT and low-risk US. Four patients, all with HCC <4 cm, had low-risk US, CT, and serum AFP. CONCLUSIONS: US, CT, and serum AFP, as single tests, are insensitive for detection of HCC in the cirrhotic liver. However, they are highly specific. Sensitivity and specificity for US are comparable to those for CT. Given its lower cost, US is preferable to CT for routine screening of HCC in patients with end-stage liver disease undergoing liver transplantation.

Primary hepatic marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type in a patient with primary biliary cirrhosis.

Primary lymphoma of the liver is rare. Recently, marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type have been described in the liver. Most of these cases occurred without known underlying liver disease, while others were seen in patients with chronic hepatitis. A case of primary hepatic MALT lymphoma in a patient with primary biliary cirrhosis was reported recently. Some authors have proposed that chronic persistent immunogenic stimulation causes development of acquired MALT and subsequently MALT lymphoma, based on the observation of MALT lymphoma in association with infectious agents, such as Helicobacter pylori and hepatitis C virus, and autoimmune diseases, such as Hashimoto thyroiditis and Sjögren syndrome. Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease characterized by destruction of intrahepatic small to medium-sized bile ducts; this disease is mediated by a cytotoxic T-cell reaction. The prolonged immune activation in primary biliary cirrhosis may play a role in the lymphomagenesis of hepatic MALT lymphoma. We describe another case of primary hepatic MALT lymphoma, which was found incidentally in a patient with end-stage primary biliary cirrhosis. This case further supports the role of immunogenic stimulation in the pathogenesis of this particular low-grade B-cell lymphoma.

Accuracy and significance of computed tomographic scan assessment of hepatic volume in patients undergoing liver transplantation.

BACKGROUND: A small liver volume is considered to be a poor prognostic factor in cirrhosis, often indicative of advanced liver disease. Radiologic assessment of liver volume before liver transplant is routinely performed in many transplant centers. We sought to assess the accuracy and significance of computed tomographic (CT) scanning in hepatic volumetric analysis by correlating CT-derived estimation of liver volume with that of corresponding liver explants. METHODS: A chart review of all patients aged 17 years or older undergoing liver transplant at Mount Sinai Medical Center between 1989 and 1995 was performed. Each patient underwent conventional CT scanning with measurement of liver volume (CTLV). Recipient liver volume (RLV) was defined as weight of liver explant after all attached ligaments, portal structures, and gallbladder were dissected free. Expected liver volume was calculated pretransplant based on age, gender, height, and weight. Patients were categorized into three groups based on etiology of liver disease: (1) hepatocellular (e.g., viral hepatitis, alcohol-related), (2) cholestatic (e.g., primary biliary cirrhosis), and (3) cryptogenic. The ratio of CTLV to RLV was used as a measure of the accuracy of CT volumetric analysis. RESULTS: A total of 579 patients was studied (group 1=376, group 2=139, group 3=64). All three groups were statistically similar with regard to age, prothrombin time and total bilirubin. Median CT liver volume was 1308 ml (range: 338-3847), 1651 ml (range: 641-3861), and 1210 ml (range: 348-2575) in groups 1-3, respectively; median ratio of CTLV to RLV was 1.02 (range: 0.50-2.31), 1.05 (range: 0.52-2.22), and 1.05 (range: 0.50-1.56) for groups 1-3, respectively. When RLV was small, it tended to be overestimated by CTLV. In contrast, when RLV was large, it was often underestimated. Clinical features such as history of esophageal variceal bleed, encephalopathy or ascites, and laboratory data did not influence accuracy of CT volumetric analysis. CONCLUSIONS: CT-derived estimation of liver volume appears to correlate closely with actual weight of liver explant regardless of the etiology of chronic liver disease. With extremes in CT volumetric analysis, actual liver volume tends to be under- or overestimated. For patients with end-stage liver disease, both CT-derived and actual liver volume are greater in cholestatic than in hepatocellular disorders.

Outcome of hepatitis C patients with and without hepatocellular carcinoma undergoing liver transplant.

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with development of hepatocellular carcinoma (HCC). The aim of this study was to examine clinical characteristics and outcome of patients with HCV with or without HCC undergoing liver transplant. METHODS: We reviewed the charts of all 55 patients transplanted between November 1990 and December 1996 for HCV cirrhosis with HCC and compared them with a control group of HCV patients without HCC. Patients with a history of alcohol abuse or HBsAg positivity were excluded. There were 37 men and 18 women, with a mean age of 57.6 yr (range, 19-70 yr) in the HCC group. RESULTS: There was no significant difference between the HCC and nonHCC groups regarding Child's class or United Network for Organ Sharing (UNOS) status at the time of transplant. Twenty-six (45%) patients were diagnosed or suspected of having HCC before transplant. Twenty-five patients (45.5%) had a single focus of HCC. Fourteen percent (seven of 50) of the patients with HCC had been treated with interferon, whereas 12% (six of 52) of patients in the nonHCC group had received interferon. Duration of interferon therapy ranged from 1 to 9 months. All interferon treatment occurred within 5 yr of transplant. A history of intravenous drug use or transfusion was identified in 37 (67%) of HCC patients. Thirty-two patients (58%) without HCC had a parenteral exposure. There was no significant difference in patient or graft survival rates between the patients with and without HCC. CONCLUSION: Approximately one-half of HCC was not detected before liver transplant. There was no significant difference in the mode of transmission, clinical status at the time of transplant, or outcome between the HCV patients with and without HCC.

Adult presentation of Caroli's syndrome treated with orthotopic liver transplantation.

When Caroli's disease, defined as a congenital dilation and ectasia of segmental intrahepatic bile ducts in the absence of other histological abnormalities, is associated with periportal fibrosis, it is termed Caroli's syndrome. We describe the case of a 35-yr-old woman with Caroli's syndrome without clinical manifestation of portal hypertension despite diffuse involvement of the liver who was successfully treated with orthotopic liver transplantation after recurrent nearly fatal episodes of cholangitis.

Reassessing the role of medical therapy in the management of hepatic vein thrombosis.

Hepatic venous outflow obstruction caused by hepatic vein thrombosis (HVT) is a manifestation of a hypercoagulable state, most commonly a myeloproliferative disorder (MPD). In the past, HVT was thought to have a poor prognosis unless treated surgically with portosystemic shunt or orthotopic liver transplantation (OLT). The aim of this study was to assess whether early diagnosis of the underlying hematologic disorder and institution of appropriate medical therapy have altered outcome. We reviewed the charts of 22 patients with HVT evaluated at our center from January 1986 to January 1995. The median age was 32 years (range, 14 to 59 years). Underlying etiologies were MPD, 13 (polycythemia vera, 8; essential thrombocythemia, 4; undefined, 1); dysfibrinogenemia, 1; anticardiolipin antibody, 1; oral contraceptive use, 3; and idiopathic, 4. All patients had ascites, hepatomegaly, and/or abdominal pain. Two underwent mesocaval shunting, and 1 had a peritoneal-venous shunt. Seven patients, including 1 with a mesocaval shunt, underwent OLT. The median duration of symptoms before transplantation was 6 months (range, 1.5 to 11 months). Six transplant patients are alive on long-term anticoagulation therapy at a mean post-OLT follow-up of 42 months (range, 2 to 77 months), without recurrence. Of 13 patients treated medically, 10 (77%) are alive at a median follow-up of 40 months (range, 17 months to 14 years 8 months), 1 has died, and 2 have been lost to follow-up. In a majority of patients, symptoms improve with prompt treatment of the underlying hematologic disorder, with a favorable long-term prognosis. Patients with decompensated liver disease can successfully undergo OLT with a low risk of recurrence on long-term oral anticoagulation.

Fatal fungemia resulting from an infected transjugular intrahepatic portosystemic shunt stent.

Placement of a transjugular intrahepatic portosystemic shunt is a well accepted treatment in the management of gastroesophageal variceal bleeding. Although morbidity and mortality associated with the use of transjugular intrahepatic portosystemic shunts have dramatically decreased, complications still occur. We report a case of fatal fungemia resulting from an infected transjugular intrahepatic portosystemic shunt stent.

Malignant schwannoma of the liver in a patient without neurofibromatosis: a case report and review of the literature.

Primary schwannomas of the liver are extremely rare. We report a case of malignant schwannoma of the liver occurring in a 49-year-old man, who did not have neurofibromatosis, and review the literature. The clinical and histologic findings of benign and malignant schwannomas of the liver are compared.

Autoimmune hepatitis in a patient with sickle cell disease.

In this report, we describe the case of a 28-yr-old woman with sickle cell anemia who presented with acute hepatic failure manifested by anorexia, malaise, painless jaundice, elevated aminotransferase activities, and severe coagulopathy. Liver biopsy revealed changes consistent with autoimmune hepatitis. Treatment with corticosteroids and azathioprine was followed by improvement in biochemical liver test results. The literature on sickle cell-associated liver diseases is reviewed.

Organic anion transport in HepG2 cells: absence of the high-affinity, chloride-dependent transporter.

In previous studies, we identified a 55 kD organic anion-binding protein in liver cell sinusoidal plasma membrane subfractions. Other investigators identified another 55 kD bromosulfophthalein/bilirubin binding protein on the surface of rat hepatocytes and HepG2 cells and suggested that this protein served as a transporter for these ligands. In this study, transport of 35S-sulfobromophthalein by the human hepatoma cell line, HepG2, was quantified in the presence and absence of bovine serum albumin to further clarify the possible function of these plasma membrane binding proteins. In contrast to results in normal rat hepatocytes, virtually no uptake of 35S-sulfobromophthalein by HepG2 cells in the presence of bovine serum albumin was found. In the absence of albumin, HepG2 cells expressed temperature-dependent uptake of 35S-sulfobromophthalein. However, the high-affinity Cl(-)-dependent sulfobromophthalein transport that characterizes normal rat hepatocytes was absent, as indicated by an approximately 95-fold lower affinity and 170-fold higher capacity of HepG2 cells for sulfobromophthalein compared with previous results with rat hepatocytes. These results suggest that 55 kD sulfobromophthalein/bilirubin-binding protein on the liver cell surface differs from organic anion-binding protein and is not responsible for sulfobromophthalein extraction in the presence of albumin, although it may play some role in lower affinity transport by cells. Immunoblot analysis and metabolic labeling of HepG2 cells demonstrated synthesis of organic anion-binding protein. However, light microscopic immunocytochemistry and immunoprecipitation of surface iodinated rat hepatocytes and HepG2 cells with antibody to a recombinant organic anion-binding protein fusion protein indicated absence of organic anion-binding protein on the surface of HepG2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of chloride and intracellular pH on the activity of the rat hepatocyte organic anion transporter.

Previous studies in cultured rat hepatocytes revealed that initial uptake of sulfobromophthalein (BSP) was markedly reduced upon removal of Cl- from the medium. In the present study, unidirectional Cl- gradients were established in short-term cultured rat hepatocytes and their effect on BSP uptake was determined. These investigations revealed that BSP uptake requires external Cl- and is not stimulated by unidirectional Cl- gradients, suggesting that BSP transport is not coupled to Cl- transport. In contrast, BSP transport is stimulated by an inside-to-outside OH- gradient, consistent with OH- exchange or H+ cotransport. As the presence of Cl- is essential for but not directly coupled to BSP transport, binding of 35S-BSP to hepatocytes was determined at 4 degrees C. This revealed an approximately 10-fold higher affinity of cells for BSP in the presence as compared to the absence of Cl- (Ka = 3.2 +/- 0.8 vs. 0.42 +/- 0.09 microM-1; P less than 0.02). Affinity of BSP for albumin was Cl(-)-independent, and was approximately 10% of its affinity for cells in the presence of Cl-. These results indicate that extracellular Cl- modulates the affinity of BSP for its hepatocyte transporter.