An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis.

BACKGROUND: Drug-induced liver injury (DILI) sometimes resembles autoimmune hepatitis (AIH) in its hepatic histology. However, there is lacking data of a comparison of the characteristics between such DILI and DILI without histological findings like AIH. METHODS: We enrolled 62 patients with DILI who were diagnosed using the Roussel Uclaf Causality Assessment Method, and performed a liver biopsy. These patients were classified into two groups: DILI with histology like AIH (group A, n = 23) and DILI without such histology (group B, n = 39). Sixteen patients of group A could be further classified into two groups: patients with relapse of the liver injury (group C, n = 8) and without relapse (group D, n = 8), after the recovery of the DILI. We compared the clinical and histological findings between group A and B, and group C versus D. RESULTS: Group A was characterized by an older age (p = 0.043), higher immunoglobulin G level (p = 0.017), positive antinuclear antibody status (p = 0.044), and a higher frequency of complementary alternative medicines and Chinese herbal medicines as the causative drug (p = 0.008). There were no significant differences between group C and D regarding the clinical data and liver histological findings. CONCLUSIONS: The clinical characteristics of DILI, which showed histological findings similar to AIH, were revealed. In such patients, a liver biopsy is recommended in order to determine the appropriate treatment strategy. In DILI with histology like AIH patients, long-term follow-up is needed to perceive the relapse.

Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis.

Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.

The importance of a prior psychiatric examination in pegylated interferon and ribavirin combination treatment for chronic hepatitis C.

UNLABELLED: Some patients receiving pegylated interferon and ribavirin treatment for chronic hepatitis C are forced to discontinue the treatment due to psychiatric disorders. We performed a retrospective study to evaluate whether pre-treatment psychiatric examinations could increase successful completion rates for this treatment. METHODS: A total of 535 patients who started pegylated interferon-α-2b and ribavirin treatment at 6 hospitals affiliated with our hospital were included in this study. The patients were divided into two groups. Those who had visited a psychiatric clinic before treatment were Group A (N=223), and those who did not visit a psychiatric clinic before treatment were Group B (N=312). We analyzed the rate of discontinuation due to psychiatric disorders in the two groups. RESULTS: The rate of discontinuation due to psychiatric disorders in Group A was found to be significantly lower than that of Group B (1.8% (4/223) vs. 6.1% (19/312), P=0.035). In Group A, 6.1% (4/65) discontinued the treatment due to psychiatric disorders, while the comparable rate in Group B was 27% (19/68) (P=0.0004). Among patients who presented with psychiatric symptoms during treatment, the rate of treatment completion was significantly higher in Group A than in Group B (69.2% (18/26) vs. 5.0% (1/20), P=0.0067). In patients with a history of psychiatric symptoms, no discontinuation due to psychiatric disorder was observed in Group A. CONCLUSIONS: A psychiatric examination before pegylated interferon and ribavirin treatment was found to positively contribute to the successful completion of the treatment.

Do the national survey results reflect the state of drug-induced liver injury in a single local city in which there is no hospital having Members of the Board of Councilors of the Japan Society of Hepatology? Results of a questionnaire survey conducted in a local city.

AIM: This survey aims at clarifying if there are common features of drug-induced liver injury (DILI) in local areas and in the national surveys, and the degree of dissemination of the new diagnostic criteria (JDDW scale) proposed during the Japan Digestive Disease Week (JDDW) in 2004 and Manual for Serious Side-Effects of DILI (Manual) published in April 2008. METHODS: An anonymous questionnaire for DILI was conducted for 6 weeks starting on 20 October 2008. The participants were 179 medical doctors. One hundred and fifty-seven of them belonged to the Medical Association of Nakatsu City (population: 86 000 persons), which is located in northern Kyushu, and 22 physicians working in a core hospital, Nakatsu Municipal Hospital. RESULTS: Seventy-four percent of the responding doctors with 13 various specialties had experienced DILI cases. The three most frequent causative drugs were antibiotics, folk medicines and drugs for the circulatory system. DILI associated with folk medicines was encountered mostly after 2000. The doctors' recognition of the JDDW scale and Manual were as low as 17% and 29%, respectively. CONCLUSION: This survey revealed that the results of the national investigations conducted by the Japan Society of Hepatology (JSH) reflect the current state of DILI in local areas in which there is no hospital with Members of the Board of Councilors of the JSH. Widespread utilization of the Manual and JDDW scale by local doctors must be facilitated for early diagnosis of DILI and the prevention of severe conditions.

Predictive factors associated with the progression to hepatic failure caused by lamivudine-resistant HBV.

The aims of this study were to select the patients with a potential for progression to hepatic failure due to lamivudine-resistant HBV and to standardize the treatment for patients with lamivudine-resistant HBV. Patients (n = 47) with reactivated hepatitis due to lamivudine-resistant HBV were classified into two groups, with and without potential for progression to hepatic failure, according to the criteria using the data of serum bilirubin level and prothrombin activity after the reactivated hepatitis. Multivariate analysis showed that prothrombin activity at the initiation of lamivudine therapy was related to the deterioration of the liver function after the emergence of lamivudine-resistant HBV (P = 0.0025, 95%CI 0.8269-0.9601). We assume that earlier additional or substitutive treatment with other antiviral agent, such as adefovir dipivoxil, should be recommended when the lamivudine-resistant HBV is detected in patients with the history of decompensated liver disease before the administration of lamivudine, even when hepatitis has not been reactivated yet.

A mutational shift from domain III to II in the internal ribosome entry site of hepatitis C virus after interferon-ribavirin therapy.

We focused on the relationship between variation in the IRES of hepatitis C virus (HCV) genotype 1b and clinical outcome, since the internal ribosome entry site (IRES) has a comparatively low heterogeneity and it might be easy to find unique substitutions. Patients infected with HCV were selected using strict criteria, and unique mutations in the IRES were extracted by the subtraction of common mutations. We found that most mutations accumulated in domain III (dIII) of IRES in sustained virological responders (SVRs) and non-SVRs before therapy. However, these mutations were exclusively observed in domain II (dII) in non-SVR at 2 weeks after the start of therapy.

Treatment of minimal hepatic encephalopathy.

Several reports, conducted as a placebo-controlled, double-blind study, presented a favorable result in treating MHE. They included branched chain aminoacid, fluzazenil-a benzodiazepin receptor antagonist, lactulose, lactitol, and L-ornithin-L-aspartate. Lactulose and lactitol have been shown to be effective in MHE. It improved psychomotor tests and lowered ammonia levels as well as quality of life. Branched chain amino acids (BCAAs) were reported to improve nitrogen metabolism, blood ammonia level, and psychomotor tests. Flumazenil, an antagonist of benzodiazepine receptor, has not been associated with established consensus on the effectiveness in MHE. L-ornithine-L-aspartate (OA) exerts its ammonia-lowering action in the kidney, skeletal muscles, brain, as well as in the liver. OA administered per orally improved number connection test, ammonia levels, and mental state. OA may be a promising therapy for patients with MHE. A shunt-closure manipulation with balloon occluded retrograde transvenous obliteration (BRTO) has been shown to be effective for hepatic encephalopathy and its efficacy in MHE has not been elucidated. Synbiotic modulation of gut flora. was shown to increase fecal content of non-urease-producing Lactobacillus species and this change was associated with a reversal of MHE. In conclusion, there are no definitive conclusion on the treatment of MHE because of difficulties in diagnosis and evaluation. Therapeutic strategy should be planned specifically for each patient depending on the etiological factors.

[A periappendiceal abscess during combination interferon and ribavirin treatment for chronic hepatitis C].

A 57-year old woman received interferon alfa-2b and ribavirin combination treatment for chronic hepatitis C. High fever and lower abdominal pain developed 10 months after the start of treatment. Antibiotic drugs were not effective. After two weeks, colonoscopic findings revealed a periappendiceal abscess. After colonoscopy study, fever decreased. We have to suspect abscess formation too as appearing a high fever during interferon and ribavirin combination treatment.

Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model.

BACKGROUND & AIMS: We investigated whether endothelial progenitor cell (EPC) transplantation could reduce established liver fibrosis and promote hepatic regeneration by isolating rat EPCs from bone marrow cells. METHODS: Recipient rats were injected intraperitoneally with carbon tetrachloride (CCl(4)) twice weekly for 6 weeks before initial administration of EPCs. CCl(4) was then readministered twice weekly for 4 more weeks, and EPC transplantation was carried out for these same 4 weeks. RESULTS: At 7 days in culture, the cells expressed Thy-1, CD31, CD133, Flt-1, Flk-1, and Tie-2, suggesting an immature endothelial lineage. Immunohistochemical analyses showed fluorescent-labeled, transplantation EPCs were incorporated into the portal tracts and fibrous septa. Single and multiple EPC transplantation rats had reduced liver fibrosis, with decreased alpha2-(I)-procollagen, fibronectin, transforming growth factor-beta, and alpha-smooth muscle actin-positive cells. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area, in accordance with EPC location. Real-time polymerase chain reaction analysis of multiple EPC-transplantation livers showed significantly increased messenger RNA levels of matrix metalloproteinase (MMP)-2, -9 and -13, whereas tissue inhibitor of metalloproteinase-1 expression was significantly reduced. Expression of hepatocyte growth factor, transforming growth factor-alpha, epidermal growth factor, and vascular endothelial growth factor was increased in multiple EPC-transplantation livers, while hepatocyte proliferation increased. Transaminase, total bilirubin, total protein, and albumin levels were maintained in EPC-transplantation rats, significantly improving survival rates. CONCLUSIONS: We conclude that single or repeated EPC transplantation halts established liver fibrosis in rats by suppressing activated hepatic stellate cells, increasing matrix metalloproteinase activity, and regulating hepatocyte proliferation.

Lamivudine treatment-related morphological changes of esophageal varices in patients with liver cirrhosis.

AIM: Many studies have reported the therapeutic effects of lamivudine on cirrhotic patients with hepatitis B; however, no study has investigated the morphological changes of esophageal varices after lamivudine treatment. METHOD: The morphological changes of esophageal varices in patients with cirrhosis were retrospectively compared between 12 patients treated with lamivudine and six historical untreated patients. RESULTS: In the treated group, the HBV DNA and hyaluronic acid (HA) levels in the serum were significantly lower than those in the untreated group (P = 0.013 and P = 0.009, respectively) at the end of follow-up, with a significant improvement in the Child-Pugh-Turcotte score (P = 0.022). In the treated group, the disappearance or reduction of esophageal varices was observed in six (50%) of the 12 patients. In three (25%) of the 12 patients, esophageal varices worsened. In the remaining three patients (25%), there were no changes in esophageal varices. In the untreated group, all patients showed the worsening of esophageal varices during the follow-up period, with a significant difference between this group and the treated group (P = 0.009). The serum HA level decreased in the nine treated patients without worsening of esophageal varices. However, in the three patients with worsening, the HA level significantly increased. CONCLUSION: Lamivudine treatment for patients with cirrhosis improves not only liver function but also esophageal varices.

Surveillance program for early detection of hepatocellular carcinoma in Japan: results of specialized department of liver disease.

OBJECTIVE: Surveillance of cirrhotic patients enables early detection of hepatocellular carcinoma (HCC) and possibly prolongs survival. The aim of this study was to explore whether early-stage HCC can be detected earlier at a specialized department of liver disease than in other institutions. METHODS: The study subjects were 574 patients with HCC. Patients were subdivided into 3 groups according to the manner of HCC detection: group A, HCC was detected in 91 patients during periodic examination at Kurume University School of Medicine; group B, HCC was detected in 301 patients during periodic examination at other institutions; group C, HCC was detected incidentally or because of symptoms in 182 patients. RESULTS: The HCC detected in group A was significantly of smaller size (20.4 mm) compared with groups B (27.1 mm, P<0.0001) and C (57.8 mm, P<0.0001). The frequency of receiving treatment (surgery or local ablation therapy) was significantly higher in group A (73%) than in groups B (52%, P=0.002) and C (26%, P<0.0001). The 5-year survival rates were 52% for group A, 40% for group B, and 23% for group C, respectively. The survival of group A was significantly better than that of groups B (P=0.0157) and C (P<0.0001). CONCLUSIONS: Surveillance for HCC at specialized Department of Liver Disease can detect early-stage HCC, resulting in a higher chance of receiving promising treatment.

Granulocytapheresis (GCAP) for severe alcoholic hepatitis-A preliminary report.

AIM: To evaluate the efficacy of granulocytapheresis therapy in alcoholic hepatitis. METHODS: We attempted to trap leukocytes in the peripheral circulation using the granulocytapheresis (GCAP) technique in patients with severe alcoholic hepatitis who showed a marked elevation of peripheral leukocytes. Corticosteroids were co-administered. RESULTS: The Maddrey's indices for these patients varied between 42 and 117 and MELD scores for alcoholic hepatitis (Mayo) ranged from 20 to 44. Survival rate was 50% (3/6), which is better than the results reported recently for similar patients in a national survey (29%). The effect of GCAP was reflected in decreases in interleukin-6 and interleukin-8 levels as well as in serum concentrations of soluble intercellular adhesion molecule. White blood cell counts were not affected. In the surviving patients, the Maddrey's indices and MELD scores for alcoholic hepatitis varied between 49 and 67, and 20 and 22, respectively, showing that GCAP is effective in patients with disease of moderate severity. Hemolytic anemia occurred in one patient after GCAP therapy. Other events such as pancreatitis, pneumonia, and cerebral hemorrhage were considered to be related to the alcoholic hepatitis itself. CONCLUSION: GCAP therapy deserves further evaluation as a new therapeutic modality for a moderately severe alcoholic hepatitis.

Value of fusing PET plus CT images in hepatocellular carcinoma and combined hepatocellular and cholangiocarcinoma patients with extrahepatic metastases: preliminary findings.

BACKGROUND/AIMS: This study aimed to evaluate the usefulness of (18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) and PET plus computed tomography (CT) fusion images for the detection of extrahepatic metastases of hepatocellular carcinoma (HCC) and combined hepatocellular and cholangiocarcinoma (combined HCC/CC). METHODS: Twenty-one patients with HCC and combined HCC/CC were enrolled in the study from December 2004 to February 2005. In all patients, PET and CT of the chest to pelvis region were performed. The sensitivity of PET plus CT fusion images was compared with the sensitivity of PET, CT, and bone scintigraphy. RESULTS: In 14 patients, a total of 58 extrahepatic metastases were diagnosed. The detection rate of PET plus CT fusion images, PET, CT, and bone scintigraphy was 98.2% (57 of 58 metastases), 89.6% (52 of 58 metastases), 91.2% (52 of 57 metastases), and 68.7% (11 of 16 bone metastases), respectively. No extrahepatic metastases were detected in the other seven patients. The detection rate of PET was 10/18 (55.6%) for intrahepatic lesions of HCC and combined HCC/CC. CONCLUSIONS: The fusion of PET plus CT images is useful in detecting extrahepatic metastases in HCC and combined HCC/CC patients.

Gene transfer of kringle 1-5 suppresses tumor development and improves prognosis of mice with hepatocellular carcinoma.

BACKGROUND & AIMS: Recent studies indicate that kringle 1-5 has a potent and specific antiangiogenic activity. Here, we investigated the antitumor effect of kringle 1-5 gene transfer on hepatocellular carcinoma in mice. METHODS: The inhibitory effect of kringle 1-5 protein on proliferation of bovine capillary endothelial cells was evaluated by a tetrazolium-based assay. To study tumor growth, intrahepatic metastasis, and survival, liposome/kringle 1-5 complementary DNA complexes were injected intravenously in nude mice preimplanted with 1 of 3 hepatoma cell lines into the liver. Production of kringle 1-5 was tested by immunohistochemistry and Western blotting. Intratumoral vessel density was quantified. Expression of vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in tumors was examined by Western blotting. Serum alanine aminotransferase and alpha-fetoprotein levels and body weights were measured. RESULTS: Proliferation of bovine capillary endothelial cells was inhibited by purified kringle 1-5 in a dose-dependent manner. Gene transfer of kringle 1-5 caused a significant reduction in vessel density with suppression of tumor growth of the 3 hepatoma cell lines and serum alpha-fetoprotein levels, prolonged the survival period, and reduced the number of intrahepatic metastases. Among the analyzed angiogenic factors, kringle 1-5 reduced angiopoietin-2 expression levels. Expression of kringle 1-5 protein was detected on hepatoma cells and hepatocytes in the liver. However, it did not alter serum alanine aminotransferase levels and body weights, suggesting kringle 1-5 lacks severe side effects. CONCLUSIONS: Antiangiogenic gene therapy with kringle 1-5 complementary DNA is a promising safe and effective strategy for suppression of growth of hepatocellular carcinoma.

A decrease in AFP level related to administration of interferon in patients with chronic hepatitis C and a high level of AFP.

It is known that there is a very high incidence of hepatocellular carcinoma (HCC) among patients with type C chronic hepatitis and cirrhosis, and alpha -fetoprotein (AFP) has been widely used as a diagnostic marker for HCC. However, there are some patients showing continuous high AFP values but no evidence of HCC, and some studies have defined such patients as a high-risk group for HCC. In vitro study has shown that interferon (IFN) inhibits cell proliferation and enhances apoptosis as well as specific cytotoxic T lymphocytes against HCC, resulting in direct anticancer actions. In this study, we investigated the effect of IFN on AFP changes in chronic hepatitis C patients. Of 40 patients with chronic hepatitis C in whom diagnostic imaging confirmed the absence of HCC, 24 patients showed high pretreatment AFP values (high AFP group: AFP level > 10 ng/dl; mean +/- SD, 46.3 +/- 41.5 ng/dl) and 16 showed low pretreatment AFP values (low AFP group: pretreatment AFP level < or = 10 ng/dl; mean +/- SD, 5.3 +/- 2.2 ng/dl). Pretreatment clinical parameters were statistically evaluated in relation to the AFP value. In the high AFP group, the platelet count, albumin level, and prothrombin (%) were significantly lower (P = 0.047, P = 0.0002, and P = 0.044, respectively), suggesting that AFP value increases with advancing liver disease. Subsequently 27 patients were administered IFN (IFN group), and the remaining 13 patients were administered Stronger Neo-minophagen C (SNMC), a glycyrrhizin preparation (SNMC group), as a control group receiving liver-protective therapy. Alanine aminotransferase was reduced in both the IFN and the SNMC group (mean, 132.56 to 60.07 mg/ml [P < 0001] and 147.85 to 56.23 mg/ml [P = 0.0240], respectively). AFP was significantly reduced in the IFN group (mean, 30.03 to 12.65 ng/ml; P = 0.0034), but there was no significant change in AFP in the SNMC group (mean, 29.70 to 39.17 ng/ml). AFP is useful for diagnosing HCC; however, some patients show a persistently high AFP level in the absence of HCC, and these patients have been described as a high-risk group for HCC. In this study, we found that IFN therapy but not SNMC universally reduced the AFP baseline. Since AFP is a significant predictor for HCC, therapeutic strategies for hepatitis C, e.g., long-term low-dose IFN treatment, may reduce hepatocarcinogenesis.

Antibody to hepatitis B core antigen is associated with the development of hepatocellular carcinoma in hepatitis C virus-infected persons: a 12-year prospective study.

Several studies have reported that antibody to hepatitis B core antigen (anti-HBc) positivity may influence the development of hepatocellular carcinoma (HCC) in chronic hepatitis C patients, but the evidence is still not conclusive. In this study, we examined whether the presence of anti-HBc positive was associated with the development of HCC in hepatitis C virus (HCV)-infected subjects among the residents in an HCV hyperepidemic area who were followed up for 12 years. In an HCV hyperendemic area (positive rate of anti-HCV: 23.4%), 509 residents were examined by health screening in 1990. After 12 years of follow-up, we evaluated the risk factors for HCC. The incidence of HCC was compared between anti-HBc positive and anti-HBc negative subjects after 12 years of prospective observation. Univariate and multivariate analyses were conducted to determine risk factors for the development of HCC. The incidence of HCC was significantly higher in the anti-HBc positive group (13 subjects) than in the anti-HBc negative group (0 subjects) (P=0.012). Multivariate analysis identified positivity for anti-HBc and HCV RNA, history of icterus, and female gender as independent determinants of the development of HCC. Our findings provide clear evidence in a prospective study that presence of anti-HBc, that is, past hepatitis B virus (HBV) infection, is a risk factor for the development of HCC in HCV-infected people.