Yasuji Komorizono

Characteristics of Patients With Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma

BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC. METHODS In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed. RESULTS Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008). CONCLUSIONS Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients.

Inhibition by arsenic trioxide of human hepatoma cell growth

Arsenic trioxide (As(2)O(3)) has been shown to be effective for treatment of patients with refractory or relapsed acute promyelocytic leukemia and a variety of other malignant hematopoetic disorders. We studied the effect of this agent on proliferation of human hepatoma-derived cell lines (SK-Hep-1, HepG2, and HuH7). In HuH7 cells, As(2)O(3) reduced proliferation time- and dose-dependently at 1 and 2 microM, while in SK-Hep-1 and HepG2 cells, As(2)O(3) inhibited proliferation at 2 and 4 microM respectively. Cell cycle analysis by flow cytometry showed that As(2)O(3) induced apoptosis in these hepatoma-derived cells as confirmed by appearance of sub-G(1) cells. Sensitivity of hepatoma-derived cells to As(2)O(3) was inversely related to their intracellular glutathione (GSH) and intensity of GSH synthesis. Arsenic sensitivity was restored to relatively resistant cell lines when GSH was depleted by L-buthionine sulfoximine (BSO). These results indicate that As(2)O(3) may have therapeutic potential for treatment of hepatocellular carcinoma.

Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma

Aim:  Non‐alcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to examine the clinical and pathological course of how NASH progresses to HCC.

Systemic combined chemotherapy with low dose of 5-fluorouracil, cisplatin, and interferon-alpha for advanced hepatocellular carcinoma: a pilot study.

The purpose of this pilot study was to evaluate the efficacy and adverse events of systemic combined chemotherapy with low dose of 5-fluorouracil (250 mg/m2, 5 days), cisplatin (10 mg/m2, 5 days), and interferon-α (2.5 million units, three times weekly) for advanced hepatocellular carcinoma (HCC) underlying liver cirrhosis. Six patients who had advanced HCC with tumor thrombi in the main portal trunk were enrolled in this study. Partial response was achieved in 2, stable disease in 1, and disease progressed in 3. Objective responses were achieved in 2 (33%), however, marked decreases of α-fetoprotein protein and protein-induced vitamin K antagonist or absence (PIVKAII) levels were also seen in one patient (stable disease). Four patients showed hematologic or renal toxicity, which were well tolerated and managed. Our systemic combined chemotherapy resulted in favorable response and was well tolerated in those with advanced HCC underlying liver cirrhosis, complicated by leukocytopenia and thromobocytopenia.

Data mining reveals complex interactions of risk factors and clinical feature profiling associated with the staging of non-hepatitis B virus/non-hepatitis C virus-related hepatocellular carcinoma

Aim:  Non‐hepatitis B virus/non‐hepatitis C virus‐related hepatocellular carcinoma (NBNC‐HCC) is often detected at an advanced stage, and the pathology associated with the staging of NBNC‐HCC remains unclear. Data mining is a set of statistical techniques which uncovers interactions and meaningful patterns of factors from a large data collection. The aims of this study were to reveal complex interactions of the risk factors and clinical feature profiling associated with the staging of NBNC‐HCC using data mining techniques.

The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased in Kyushu area

Summary Background The incidence of hepatocellular carcinoma (HCC) in Japan has still been increasing. The aim of the present study was to analyze the epidemiological trend of HCC in the western area of Japan, Kyushu. Material/Methods A total of 10,010 patients with HCC diagnosed between 1996 and 2008 in the Liver Cancer study group of Kyushu (LCSK), were recruited for this study. Cohorts of patients with HCC were categorized into five year intervals. The etiology of HCC was categorized to four groups as follows; B: HBsAg positive, HCV-RNA negative, C: HCV-RNA positive, HBsAg negative, B+C: both of HBsAg and HCV-RNA positive, nonBC: both of HBsAg and HCV-RNA negative. Results B was 14.8% (1,485 of 10,010), whereas 68.1% (6,819 of 10,010) had C, and 1.4% (140 of 10,010) had HCC associated with both viruses. The remaining 1,566 patients (15.6%) did not associate with both viruses. Cohorts of patients with HCC were divided into six-year intervals (1996–2001 and 2002–2007). The ratio of C cases decreased from 73.1% in 1996–2001 to 64.9% in 2002–2007. On the other hand, B and -nonBC cases increased significantly from 13.9% and 11.3% in 1996–2001 to 16.2% and 17.6% in 2002–2007, respectively. Conclusions The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased after 2001 in Kyushu area. This change was due to the increase in the number and proportion of the HCC not only nonBC patients but also B patients.

Adult T-Cell Leukemia in a Liver Transplant Recipient That Did Not Progress after Onset of Graft Rejection

A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T- cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.

Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67–2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25–1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23–1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84–4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63–0.67)]. Conclusions: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

CASE REPORT: Successful Balloon-Occluded Retrograde Transvenous Obliteration for Ruptured Gastric Fundal Varices in a Patient with Child–Pugh C Cirrhosis: Case Report and Literature Review

The rupture of gastroesophageal varices is one of the leading causes of death in cirrhotic patients. Once gastric fundal varices bleed, the mortality rate is particular very high. Surgical procedures such as Hassab’s devascularization and transection have a limitation in urgent treatment of ruptured gastric varices because of poor underlying hepatic reserves. Endoscopic sclerotherapy, transjugular intrahepatic portsystemic shunt, and percutaneous transhepatic obliteration for ruptured gastric fundal varices can achieve temporary hemostasis but have unsatisfactory results and many complications. Child–Pugh C patients with bleeding from gastric fundal varices, in particular, have a higher mortality rate compared with Child A or B patients. Balloon-occluded retrograde obliteration with ethanolamine oleate–iopamidol is a promising treatment for ruptured gastric fundal varices. A case of successful balloon-occluded retrograde transvenous obliteration and the follow-up management for ruptured gastric fundal varices in a patient with Child–Pugh C cirrhosis is reported, and the literature reviewed.

Natural Beta Interferon as an Initial Treatment for the Elderly with Chronic Hepatitis C

antiviral therapy during the acute course of the illness to avoid the progression toward chronic hepatitis. Many studies of therapy for acute hepatitis C have used interferon monotherapy, with sustained loss of hepatitis C virus (HCV)-RNA in 62% of interferon-treated patients, compared with only 12% in untreated subjects (4). There have been no studies of interferon–ribavirin combination therapy nor of the newly developed peginterferons. We report a case of a 20-yr-old woman without risk factors for acute HCV infection. She had been well until 2 months earlier, when asthenia developed. Physical examination was normal. Laboratory tests were performed: ASAT 883 U/L, ALAT 2289 U/L, alkaline phosphatase 332 U/L, -glutamyl transpeptidase 240 U/L. A test for antibodies to HIV, hepatitis B virus, cytomegalovirus, and Epstein-Barr virus were negative. A test for antibodies to HCV and HCV-RNA were positive. HCV genotype was 1b, and viral load was 22,500 copies of HCV-RNA 10 /ml. We excluded other liver diseases. The diagnosis of acute hepatitis C was established, and 8 wk after diagnosis the patient received peginterferon -2b 80 g/wk and ribavirin 800 mg/day for 24 wk. Serum levels of ALAT normalized within 4 wk after the initiation of treatment, and serum levels of HCV-RNA became undetectable at 12 wk. Therapy was well tolerated. At the end of both therapy and follow-up (24 wk after the end of therapy), the patient had undetectable levels of HCV-RNA in serum and normal serum ALAT levels. Interferon monotherapy is an effective treatment for acute hepatitis C (5–8), but data are insufficient to draw firm conclusions as to who should be treated, when therapy should be started (immediate vs delayed therapy to avoid treatment of patients who spontaneously recover), and what regimen of therapy should be used. In chronic hepatitis C, therapy with interferon–ribavirin combination or the newly developed peginterferons is considerably more effective than standard interferon monotherapy. For this reason, we thought that the peginterferon–ribavirin combination should be more effective than interferon monotherapy, and we used this regimen. In our patient, peginterferon and ribavirin for 24 wk was effective for acute hepatitis C. In the future, more prospective studies with larger numbers of patients should focus on the efficacy and tolerability of combined peginterferon–ribavirin therapy.