Masaaki Hiura

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.

Early decrease in serum IV-7S levels during IFN treatment predicts anti-fibrogenic effect in nonresponders with chronic hepatitis C

BackgroundWe evaluated whether early changes in serum levels of fibrogenic markers during interferon (IFN) treatment can predict long-term anti-fibrogenic effects in patients with chronic hepatitis C (CHC).MethodsWe retrospectively examined the serum levels of N-terminal peptide of type III procollagen (P-III-NP) and 7S domain of type IV collagen (IV-7S) in 56 patients with CHC who were revealed to be IFN-nonresponders. We measured these markers before (T0) and 1 month (T1) after the commencement of IFN therapy, at the end of 24 weeks’ IFN therapy (T24), and 1 year (T24-1) and more than 2 years (T24-2) after the cessation of IFN therapy. We also measured these markers twice, at intervals of more than 2 years, in 43 IFN-untreated patients with CHC as controls.ResultsIn nonresponders, both P-III-NP and IV-7S levels at T24-2 were significantly decreased compared with those at T0. P-III-NP levels at T1 were significantly decreased compared with those at T0, and remained at significantly low levels until the end of the observation period. IV-7S levels at T1 were not significantly different from those at T0. In patients whose IV-7S levels at T24-2 were decreased compared with those at T0, IV-7S levels at T1 were significantly lower than those at T0. In patients whose IV-7S levels at T24-2 were elevated or unchanged compared with those at T0, IV-7S levels at T1 were significantly higher than those at T0. In unteated patients, both P-III-NP and IV-7S levels at more than 2 years after the initial time were significantly increased compared with those at the initial time.ConclusionsAn early decrease in IV-7S levels after IFN treatment is a useful indicator of anti-fibrogenic effects in nonresponders.

Methotrexate-related Primary Hepatic Lymphoma in a Patient with Rheumatoid Arthritis

A 56-year-old woman with rheumatoid arthritis treated with methotrexate (MTX) was admitted to our hospital due to multiple liver tumors. Contrast-enhanced computed tomography (CT) revealed multiple hypovascular masses, and 18F-fluorodeoxyglucose positron emission tomography CT showed diffuse abnormal accumulation in the liver only. We therefore made a diagnosis of MTX-related primary hepatic lymphoma (MTX-PHL) exhibiting features of diffuse large B-cell lymphoma. Although MTX has been reported to increase the risk of lymphoproliferative disorders, MTX-PHL has not been reported previously. The present case is the first case in which MTX appears to have been involved in the development of PHL.

Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis

A 71‐year‐old male patient was diagnosed with rheumatoid arthritis (RA) in 2000. Various disease‐modifying anti‐rheumatic drugs (DMARDs) and an anti‐tumor necrosis factor biologic etanercept were administrated, but were unable to control the disease activity of RA. He was then diagnosed with rheumatoid vasculitis and received a total of 3 courses of an anti‐interleukin‐6 receptor antibody, tocilizumab. After the 3 courses of tocilizumab therapy, ascites and renal dysfunction gradually appeared and he was admitted to our hospital. Biochemical data suggested that he had developed decompensated liver cirrhosis. His renal function deteriorated rapidly, and he died 9 days after the admission. Serum aminotransferase levels had been relatively low during the treatment with tocilizumab, however, autopsy showed marked atrophy of the liver. Immunohistochemical analysis revealed that the hepatocytes had fallen into apoptosis and that hepatic regeneration had been extremely suppressed. Although molecular target drugs such as tocilizumab are being widely used and are important emerging treatment options in adult patients with moderate to severe RA, these drugs could induce liver failure by inhibiting liver regeneration as in this case. Physicians need to stay alert to the impact of these drugs on liver regeneration and should follow up with ultrasonography or computed tomography.

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.

Activation of hepatic macrophage contributes to hepatic necrosis after post-ischemic reperfusion in alcoholic fatty liver

Fatty livers are vulnerable to ischemia/reperfusion (I/R) injury. We investigated the role of hepatic macrophages in the I/R injury in the fatty liver. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm ischemia for 30 min. A bolus of gadolinium chloride (GdCl(3)) was injected intravenously twice before I/R to block hepatic macrophage activity. Alcoholic fatty liver developed more extensive hepatic necrosis with neutrophil infiltration in association with a higher production of cytokine-induced neutrophil chemoattractant (CINC)-1, a potent neutrophil chemokine in rat, after I/R than the nonalcoholic fatty liver or control liver without steatosis. Hepatic apoptosis after I/R increased to a similar degree (3-fold) in each of the two fatty liver models, compared with the control liver. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-kappa B (NF-kappaB) binding activity. The GdCl(3) pretreatment significantly reduced NF-kappaB binding activity, CINC-1 level and necrosis in alcoholic fatty liver, despite no significant decrease in the extent of apoptosis. Our results suggest that the activation of hepatic macrophages in alcoholic fatty liver may contribute to hepatic necrosis after I/R, and that the apoptosis might be less dependent on the macrophage activity.

Alleviation mechanisms against hepatocyte oxidative stress in patients with chronic hepatic disorders.

Autophagy induction and Mallory–Denk body (MDB) formation have been considered to have cytoprotective effects from cellular stress in liver diseases. We investigated the relations among oxidative stress, autophagy and MDB formation in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC) and non‐alcoholic fatty liver disease (NAFLD) to clarify the alleviation mechanisms against oxidative stress of hepatocytes.

Bullous Pemphigoid Associated with the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin in a Patient with Liver Cirrhosis Complicated with Rapidly Progressive Hepatocellular Carcinoma

A 78-year-old man presented with cutaneous blisters of the limbs and abdominal distension. He had been treated for various diseases, including liver cirrhosis. He had begun receiving sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for diabetes mellitus three years before the hospitalization. A skin biopsy demonstrated bullous pemphigoid. Ultrasonography (US) revealed multiple liver tumors, although he had been receiving regular US studies. We stopped sitagliptin and started insulin and corticosteroids. However, his renal dysfunction progressed, and he died 14 days after the hospitalization. We should therefore be careful of various complications, including bullous pemphigoid and progression of tumors, when using DPP-4 inhibitors.

Hepatic peribiliary cysts with rapidly progressive refractory obstructive jaundice and esophageal varices.

A 54-year-old man with decompensated alcoholic liver cirrhosis presented with acute cholangitis. Although no localized lesions were detected in the liver on contrast-enhanced computed tomography and no risky varices were noted on endoscopy, hepatic peribiliary cysts (HPBCs) developed along the intrahepatic portal vein in the course of only 40 days. Moreover, esophageal varices with the red color sign grew rapidly during the same period, and the patient ultimately died due to rupture. HPBC formation is a rare complication of liver disease, including cirrhosis. Although HPBCs are generally harmless, on rare occasions they may induce the rapid progression of esophageal varices.

Churg–Strauss syndrome manifesting as cholestasis and diagnosed by liver biopsy

A 56‐year‐old woman was referred to our hospital due to fever and cholestatic liver dysfunction. Her eosinophil count was normal and she had no abdominal pain or neurological manifestations. We performed a liver biopsy and found fibrinoid necrosis of the hepatic artery with granulomatous reaction and eosinophilic infiltration in the portal area in the liver. Later, sensory abnormalities of the arms and legs appeared and the eosinophil count increased. Serum immunoglobulin E and immunoglobulin G4 were elevated and rheumatoid factor was strongly positive. Endoscopic retrograde cholangiopancreatography revealed no abnormality of the bile duct and pancreatic duct. We made a diagnosis of Churg–Strauss syndrome and began corticosteroid treatment. Fever and liver function immediately improved. In the present patient, Churg–Strauss syndrome manifested first in the liver, before hypereosinophilia and neural manifestations. We believe that Churg–Strauss syndrome is an autoimmune liver disease, and it is important to recognize that the liver may be involved in Churg–Strauss syndrome.