Ryoichi Narita

Efficacy of Short-Term Interferon Therapy for Patients Infected with Hepatitis C Virus Genotype 2a

BACKGROUND AND AIMS:The efficacy of interferon (IFN)-based antiviral therapy for chronic hepatitis C (CHC) varies depending on predictive factors such as hepatitis C virus (HCV) genotype and viral load. For patients with good predictive factors, a low dose and short course of IFN-based therapy may be adequate. However, there is no evidence about the optimal duration of IFN-based therapy for these patients. The aim of this study was to clarify whether the duration of IFN therapy could be shortened to less than the conventional treatment period for patients with good predictive factors.METHODS:A total of 25 treatment-naive CHC patients with genotype 2a were randomized to receive either IFN monotherapy for 24 wks (group A: long-term IFN therapy, n = 13) or for 6 wks (group B: short-term IFN therapy, n = 12). Patients were monitored for HCV RNA and routine liver function tests during and following treatment, and data were examined according to intention-to-treat analysis.RESULTS:Eleven of 13 patients in group A and all patients in group B completed IFN therapy according to the original planned schedule. At the end of the treatment, viral clearance occurred in all patients. However, 4 patients in group A and 5 in group B relapsed within 6 months of follow-up. There was no significant difference of sustained response rate between group A (53.8%) and group B (58.3%). Among patients who had HCV viral load of <100 kIU/ml, the sustained response rate was 83.3% (5/6) in group A and 100% (5/5) in group B.CONCLUSIONS:In this study, our results suggest that the duration of IFN therapy can be shortened to less than 24 wks in patients with good predictive factors. Further studies, however, should examine the optimal regimen of IFN therapy based on the backgrounds of patients.

Biliary obstruction caused by intrabiliary transplantation from hepatocellular carcinoma

A rare autopsy case of hepatocellular carcinoma (HCC) presenting as extrahepatic bile duct obstruction is reported. A 54-year-old man who had been treated at another hospital for obstructive jaundice was referred to our hospital and admitted on March 1, 1998, because of progressive jaundice. On hospital day 94, he died of bleeding esophageal varices. At autopsy, a bile duct tumor, measuring 3.0 x 3.5 cm and adhering to the wall of the left hepatic duct, occluded the common hepatic duct at the hilus. A tumor measuring 2.0 x 2.0 cm was found in the parenchyma of the left liver lobe. The parenchymal tumor was not continuous with the extrahepatic bile duct tumor. Histologically, the bile duct tumor and the parenchymal tumor of the left lobe were diagnosed as HCC. The bile duct tumor was attached to the mucosa of the bile duct with a thin stalk. No invasive growth into the submucosa was observed. The tumor may have been an intrabiliary transplantation from the HCC in the left lobe via the bile duct.

Impact of Steatosis on Insulin Secretion in Chronic Hepatitis C Patients

OBJECTIVES:Liver steatosis is frequently observed in patients with chronic hepatitis C (CHC) and is an identified risk factor for progression of liver fibrosis. This study aimed to evaluate the relationship between steatosis and host/viral factors, and the correlation between steatosis and insulin secretion in CHC patients with normal glucose tolerance (NGT).METHODS:A total of 212 CHC patients were enrolled in this study. Insulin resistance and insulin secretion were determined in response to oral loading of 75 g glucose. Liver fibrosis and steatosis were quantified by the image analysis.RESULTS:Of the 212 CHC patients, 165 (78%) had steatosis, mostly of a mild degree. Multiple ordinal regression analysis revealed body mass index (BMI) (P = 0.011) as the main factor associated with severe steatosis. Of the 212 CHC patients, 148 (61%) showed NGT, and the serum insulin response to oral glucose loading in these NGT patients with steatosis was significantly different from that in patients with NGT but no steatosis. The peak insulin response occurred at 60 min in cases of mild steatosis, and at 90 min in patients with moderate or severe steatosis. The insulin level at 120 min in patients with severe steatosis was higher than that in those without steatosis. The total area under the response curve of insulin during OGTT in the patients with steatosis is higher than that in those without steatosis.CONCLUSION:Exaggerated insulin secretion was observed even in CHC patients with mild steatosis and NGT, suggesting the presence of insulin resistance. Exaggerated insulin secretion may accelerate the progression of liver fibrosis in CHC patients.

Late diagnosed Wilson disease with hepatic and neurological manifestations.

A 50‐year‐old woman was referred to our hospital due to liver dysfunction and progressive neurological symptoms. She had previously been diagnosed with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) had effectively normalized her serum aminotransferase levels, however, she presented with loss of balance, dysarthria and difficulty in handwriting. Autoantibodies and hepatitis virus markers were negative. Serum ceruloplasmin and copper levels were noted to be 9 mg/dL and 32 µg/dL, respectively. The 24‐h urinary copper excretion was 331.8 µg/day. Kayser‐Fleischer ring was demonstrated. Histological examination of the liver revealed inflammatory infiltrate and fibrosis, and the hepatic copper concentration was 444.4 µg/g dry weight. We diagnosed her as having Wilson disease and started treatment with trientine. Immuohistochemistry for keratin 8 and p62 demonstrated Mallory‐Denk bodies. Many of the p62‐expressing cells were positive for 4‐Hydroxy‐2‐nonenal (HNE). Few Ki‐67‐positive hepatocytes were present in the liver. Wilson disease is one of the causes of NASH and UDCA may be a supportive therapeutic agent for Wilson disease. Cell proliferation is suppressed under copper‐loaded conditions and this phenomenon may be associated with the clinical course of Wilson disease.

Sepsis presenting with severe jaundice.

TO THE EDITOR: Hyperbilirubinemia is frequently observed in patients with sepsis (1). In this condition, the elevated bilirubin level in plasma consists predominantly of conjugated bilirubin, suggesting that hyperbilirubinemia is mainly caused by impaired canalicular secretion (1). Both endotoxins and endotoxin-induced mediators could be responsible for the impaired hepatobiliary transport during sepsis (2). We describe here a patient with diabetes mellitus who developed marked conjugated hyperbilirubinemia during bacteremia caused by Escherichia coli. Endotoxin and serum bilirubin returned to normal levels after treatment with antibiotics and endotoxin adsorption. The patient was a 37-yr-old man who had been under treatment in another hospital for jaundice after presentation with a 7-day history of difficulty and increased frequency of micturition. He was referred to our hospital and admitted on January 10, 2000 for progressive jaundice accompanied by disseminated intravascular coagulation and adult respiratory distress syndrome. His medical history was not significant, with no history suggestive of diabetes. On admission to our hospital he was deeply jaundiced and had a spike fever. The body temperature was 38.4°C; pulse rate, 140/min; respiratory rate, 40 breaths/min; and arterial blood pressure, 56/40 mm Hg. Abnormal laboratory findings were as follows: white blood cell count, 15,900/ l (normal range 3,100– 9,700); platelets, 14,000/ l (normal range 147,000–365,000); total bilirubin, 24.6 mg/dl (normal range 0.3–1.5); direct bilirubin, 17.2 mg/dl (normal range 0.1–0.4); AST, 83 IU/L (normal range 13–33); ALT, 72 IU/L (normal range 8–42); ALP, 602 IU/L (normal range 115–359); albumin, 2.3 g/dl (normal range 4.0–5.0), C-reactive protein, 20.5 mg/dl (normal range 0.0–0.6); glycosylated Hb, 9.4% (normal range 4.1–5.4); and endotoxin, 17.4 pg/ml (normal range 10.0). Urinalysis demonstrated 10–15 white blood cells per high power field, 1 glucosuria, and 2 bilirubinuria. Blood cultures grew E. coli. A urine culture obtained after the patient had been started on antibiotics was sterile. On admission, ultrasonography revealed no significant hepatobiliary abnormalities, and abdominal CT confirmed the presence of an abnormal mass in the right kidney. The final diagnosis was urinary tract infection, septic shock, and diabetes mellitus. The conjugated hyperbilirubinemia in the presence of disproportionately mild increase in ALP suggested that an isolated defect of excretion of conjugated bilirubin was the cause of jaundice. This biochemical pattern was consistent with that of jaundice caused by severe infection. After all other possible causes of clinical jaundice were excluded, the cause of jaundice was considered to be urinary tract infection and sepsis. The patient responded to systemic antibiotic therapy (2 g of sulbactam plus cefoperazon for 2 days, 1 g of imipenem plus cilastatin for 5 days, and 0.4 g of isepacin for 10 days), methylprednisolone (0.5 g for 2 days), immunoglobulin (2.5 g for 2 days), and endotoxin adsorption; the blood endotoxin level decreased significantly together with the disappearance of jaundice (Fig. 1). Liver biopsy was performed on hospital day 36. There was a mild portal inflammation, but the bile duct appeared normal and there was no cholangitis. Although it is generally accepted that jaundice may complicate many systemic infections, there are few detailed reports of its nature in adults (3, 4). Severe jaundice may be misdiagnosed as a sign of primary hepatic or biliary tract disease and thus divert attention from the underlying infection and lead to inappropriate treatment (5). Diagnostic errors of this kind are especially likely if the jaundice is

Effect of combination therapy with ribavirin and high-dose interferon-α2b for 24 weeks in chronic hepatitis C

Background and Aim:  The aim of the present study was to determine whether a 24‐week course of combination therapy with ribavirin and high‐dose interferon‐α2b (IFN‐α2b) could provide an acceptable treatment efficacy in chronic hepatitis C (CHC).

Biclonal multiple myeloma in liver cirrhosis due to hepatitis C virus infection.

Hepatitis C virus (HCV) infection is implicated in a number of extrahepatic manifestations.1 Several reports have suggested that HCV infection is one of the causes of lymphoproliferative diseases such as malignant lymphoma2,3 and multiple myeloma (MM).4–6 A recent case-control study demonstrated greater risks in HCV infection not only for liver cancer but also for B-cell non-Hodgkin’s lymphoma (NHL) and MM.7 Several studies from Japan have also found a positive association between HCV infection and NHL8–10 or MM.8,9 Here, we report that MM was found in a patient with liver cirrhosis (LC) due to HCV infection. Moreover, immunoelectrophoresis revealed biclonal gammopathy. A 67-year-old Japanese man was referred to the University Hospital of Occupational and Environmental Health because of massive ascites due to LC. He had been diagnosed as having LC due to HCV (serotype 1) infection at the age of 63 years, and had had ascites since age 66. His ascites was refractory to medication, and was treated by occasional paracentesis. Biochemical examination had been performed several times before the present admission, and had revealed elevated serum levels of aminotransferase, as well as γ-globulin without M-component. On admission, electrophoresis of the patient’s serum protein on a cellulose acetate membrane showed one M-component in the γ-globulin zone (3.9 g/dl; 48.8% of total protein) (Fig. 1a). Immunoelectrophoresis of serum identified two monoclonal proteins, IgG (λ) and IgA (k) (Fig. 1b). Serum concentrations of IgG and IgA were 3.623g/dl and 0.309 g/dl, respectively. Immunoelectrophoresis of urine also demonstrated a slow monoclonal protein, IgG (λ)-type Mcomponent. However, Bence-Jones protein was not detected. Bone marrow aspiration study revealed 27.5% of atypical plasma cells. Although the patient had multiple pathological fractures of bilateral ribs shown on admission, no punched-out lesion in the skull was shown by X-ray. He died of liver failure on the eightieth hospital day. Autopsy revealed severe liver fibrosis with anasarca and jaundice. IgG (λ)-type protein was highly increased in bone marrow, determined by immunohistochemistry. HCV infection can cause chronic liver disease, subsequently resulting in LC in which serum γ-globulin levels rise due to increased production. Increased numbers of plasma cells in the bone marrow, and even in the liver itself, may be the source of γ-globulin.11 Most γ-globulin on electrophoresis shows a peak with a wide base, suggesting a polyclonal-γ response. Monoclonal gammopathy in LC is rare, but it has been found.11 In addition to an association between HCV infection and MM, a possible association between MM and alcoholic LC has also been reported.12,13 While monoclonal gammopathy characterizes a group of B-cell disorders which result in the production of a specific and unique M-component, biclonal gammopathy is characterized by the simultaneous appearance of two different M-components.14,15 Although biclonal gammopathy is relatively rare in M-proteinemia, the clinical features seem to be similar to those of monoclonal gammopathy. It is suggested that biclonal gammopathy results from either one monoclonal cell clone in monoclonal gammopathy or two different monoclonal cell clones. In our patient, only an IgG (λ)-type protein was found in urine by immunoelectrophoresis and in the bone marrow, (obtained from an autopsy specimen), by immunohistochemistry. The serum concentration of IgA was only 0.309 g/dl. However, immunoelectrophoresis of serum revealed IgG (λ)and IgA (k)-types of biclonal gammopathy. Although little is known about the underlying mechanisms of the development of MM in HCV infection or in LC, MM may be associated with HCV infection or LC in some cases. Therefore, electrophoresis of serum protein is needed in patients with HCV infection with an increased concentration of serum γglobulin. Fig. 1. a Electrophoresis of the patient’s serum protein on cellulose acetate membrane, performed on admission. Alb, albumin. b Immunoelectrophoresis of normal human serum (NS), the patient’s serum (PS), and the patient’s urine (PU). Anti-total S, anti-whole normal human serum. Arrows indicate IgG (λ)-type M-component on a slow-γ level and IgA (k)-type M-component on a slowlevel monoclonal protein in serum, and IgG (λ)-type M-component on a slow-γ level monoclonal protein in urine a

Increased soluble IL-2 receptor levels during interferon and ribavirin treatment are associated with a good response in genotype 2a/2b patients with chronic hepatitis C.

Objectives Serum levels of soluble interleukin-2 receptor (sIL-2R) are known to serve as a marker for the activation of T lymphocytes. We measured serum levels of sIL-2R in patients with chronic hepatitis C (CHC) during interferon (IFN)-based treatment to determine the correlation between those levels and therapeutic efficacy, and to clarify whether there is a difference in the activation of T lymphocytes among HCV genotypes after the treatment. Methods Forty-four patients received IFN-&agr;2b monotherapy (group IFN-M), whereas 82 patients received the combination therapy with IFN-&agr;2b and ribavirin (group IFN+R). We measured serum sIL-2R levels in these patients before (T0) and 2 weeks (T2) after the treatment. Results The sustained virologic response rates in genotype 2a/2b patients were significantly higher than those in genotype 1b patients in both groups (P<0.005). In sustained virologic responders, sIL-2R levels at T2 were significantly higher than those at T0 in both groups (P<0.001). In nonresponders, sIL-2R levels at T2 were not different from those at T0 in group IFN-M, but were significantly higher than those at T0 in group IFN+R (P=0.0072). In genotype 1b patients, sIL-2R levels at T2 were not different from those at T0 in group IFN-M, but were significantly higher than those at T0 in group IFN+R (P=0.0064). In genotype 2a/2b patients, sIL-2R levels at T2 were significantly higher than those at T0 in both groups (P<0.0005). Conclusion These findings suggest that the activation of T lymphocytes after IFN-based treatment contributes to a high-sustained virologic response rate, especially in genotype 2a/2b patients.

Idiopathic thrombocytopenic purpura with acute hepatitis c viral infection

To the Editor , Idiopathic thrombocytopenic purpura (ITP) is characterized by increased platelet destruction as a result of the presence of platelet autoantibodies. 1 The resulting thrombocytopenia may expose patients to life-threatening hemorrhagic complications. 1 Although ITP generally occurs in otherwise healthy subjects, various viral infections have been suspected of triggering acute and chronic forms of ITP. 1 Idiopathic thrombocytopenic purpura is associated with the production of plateletassociated immunoglobulin G (PAIgG) that binds to platelet-specific antigens. 1 Chronic hepatitis C virus (HCV) infections can be associated with various serum antitissue antibodies and immunological diseases, including ITP. 2–4 We report a patient with acute HCV infection who developed ITP. A 22-year-old female nurse was admitted to our hospital for evaluative investigation of purupura on the legs, hypermenorrhea and thrombocytopenia in March 2001. She had been under treatment in our hospital for chronic hepatitis C (genotype 2b). In September 1998, a liver biopsy specimen obtained before interferon (IFN) therapy revealed active hepatitis with moderate fibrosis. Ten million units of recombinant IFNa 2b (Intron; Schering-Plough, Osaka, Japan) was administered intramusculary as a single dose. This dose was repeated daily for 2 weeks followed by administration three times weekly for 22 weeks. Serum alanine aminotransferase (ALT) activity had normalized and HCV RNA had been negative from serum for about 2 years after the end of the IFN treatment. She sustained several injuries with needles contaminated by blood from patients, prior to the admission. On admission to our hospital she had multiple petechiae over the extensor surfaces of the lower extremities. Laboratory findings were as follows: white blood cell count, 9400/ m L (normal range (NR), 3100–9700); hemoglobin, 13.8 g/dL (NR, 10.5–15.3); red blood cell count, 4.67 ¥ 10 6 / m L (NR, 3.68–4.92); hematocrit, 41.1% (NR, 32.5–44.7); platelet count, 28 000/ m L (NR, 147 000–365 000); total bilirubin, 0.5 mg/dL (NR, 0.3–1.5); aspartate aminotransferase (AST), 63 IU/L (NR, 13–31); ALT, 125 IU/L (NR, 8–42). The patient was HCV RNApositive. The HCV genotype was found to be 2a and HCV RNA concentration was 17 KIU/mL. Although she had suffered from chronic hepatitis because of HCV infection in 1998, the HCV genotype was identified to be 2b. As the genotype at this time was 2a, she was diagnosed as having acute hepatitis as a result of HCV infection. The PAIgG was 80.8 ng/10 7 cells (NR, < 25.0). A bone marrow aspiration revealed mild hypercellularity of all cell lines with normal maturation of myeloid and erythroid precursors. Megakaryocytes were increased in number with normal morphology. Based on these laboratory findings, she was diagnosized as having ITP. A test for antinuclear antibody and rheumatoid factor was negative. Serological analyses were negative for varicella zoster virus, rubella, hepatitis A and B virus, human immunodeficiency type 1 virus, Epstein–Barr virus and cytomegalovirus. The cause of ITP was considered to be acute HCV infection. Her platelet count increased up to 39 000/ m L on the fifth hospital day and she was discharged on the seventh hospital day. After 6 months of follow-up, the PAIgG returned to the NR and she remained with stable platelet count without any therapy. However, levels of ALT and HCV RNA were persistently elevated. A liver biopsy specimen obtained on 10 August 2001 showed chronic active hepatitis, and second-term IFN treatment was initiated (Fig. 1). This report shows that there is no protective immunity against HCV genotype 2a after infection by HCV genotype 2b strain. Hepatitis C virus infection can be associated with several autoimmune manifestations. 3,4

Therapeutic experience of hyperbaric oxygenation in entero-Behcet syndrome

TO THE EDITOR: This is the first report that confirms the efficacy of hyperbaric oxygen (HBO) therapy for an ileocecal ulcer in a patient with entero-Behcet syndrome who was unresponsive to steroid therapy.