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Hepatitis C virus (HCV) infection has recently been suggested to be a risk factor for the development of diabetes mellitus. The aim of our study was to investigate whether the prevalence of diabetes is increased among liver transplant recipients infected with HCV. We compared the prevalence of diabetes among 278 liver transplant recipients whose original cause of liver failure was HCV infection (110 patients), hepatitis B virus infection (HBV; 53 patients), and cholestatic liver disease (CLD; 115 patients). The pretransplantation prevalence of diabetes was higher in the HCV group (29%) compared with the HBV (6%) and CLD (4%) groups (P <.001). The prevalence of diabetes remained higher in the HCV group 1 year after transplantation: 37%, 10%, and 5% in the HCV, HBV, and CLD groups, respectively (P <.001). The cumulative steroid dose during the first year of transplantation was significantly lower in the HCV group compared with the CLD group. Multivariate analysis revealed that HCV-related liver failure (P =.002), pretransplantation diabetes (P <.0001), and male sex (P =.019) were independent predictors of the presence of diabetes 1 year after transplantation. The high prevalence of diabetes persisted in the HCV group, with 41% diabetic at 5 years. The majority of patients with diabetes mellitus (89%) required insulin therapy after transplantation. Patient and graft survival rates were similar among patients with and without diabetes. In conclusion, our study shows that there is a high prevalence of diabetes among liver transplant recipients infected with HCV both before and after transplantation.
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PMID:Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation. 1086 93

Hepatitis C is a heterogeneous disease whose natural history is controversial and perplexing. However, it can be a pernicious disease and is responsible for considerable mortality and morbidity. More than 80% individuals infected with the hepatitis C virus (HCV) develop chronic infection; the remaining 10-20% develop spontaneous clearance with natural immunity. The majority of patients who develop chronic HCV infection are asymptomatic; but 60-80% develop chronic hepatitis as indicated by elevated ALT; around 30% maintain normal ALT. One-third of chronically infected patients develop progressive liver injury, fibrosis and cirrhosis over a period of 20-30 years, and 15% develop hepatocellular carcinoma. Acquiring infection after the age of 40 years, male sex, excessive alcohol-consumption, HBV or HIV co-infection and the immunosuppressive state have been identified as factors associated with progression of fibrosis and development of cirrhosis. The relationship between virus load, HCV genotype I and quasispecies variability and progression of live disease is controversial. In the present study on 141 patients with chronic HCV infection and established chronic liver disease, the median time to develop cirrhosis was 20 years. Progression to cirrhosis was faster (16 vs 20 years) in those who acquired infection after the age of 35 years, and in immunosuppressed patients (8 vs 21 years), whereas diabetes, sex and HBV co-infection were not associated with faster progression.
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PMID:Natural history of hepatitis C virus infection. 1092 91

Liver transplant recipients have an increased risk for cardiovascular disease because of a high incidence of obesity, arterial hypertension, diabetes mellitus, and hyperlipidemia. Hyperhomocysteinemia has been found to be an important risk factor for cardiovascular disease in large studies. Fasting serum levels of homocysteine were measured in 105 liver transplant recipients, and hyperhomocysteinemia was defined as a fasting serum homocysteine level greater than 13 micromol/L. Patients with versus without hyperhomocysteinemia were compared. The possible association of hyperhomocysteinemia with age, sex, cause of liver disease, time elapsed since liver transplantation, immunosuppressive therapy, folic acid level, liver function test results, renal function, and other cardiovascular risk factors was investigated. Patients with serum homocysteine levels greater than 15 micromol/L were treated with folic acid, 10 mg/d, and serum homocysteine levels were measured again 1 to 3 months later in 10 patients. Hyperhomocysteinemia was detected in 28 patients (27%). In univariate analysis, it was associated with hepatitis C virus infection, treatment with mycophenolate mofetil, and greater serum levels of alkaline phosphatase, gamma-glutamyl transpeptidase, urea, and creatinine. In multivariate analysis, only greater serum levels of creatinine (P =.006) were associated with hyperhomocysteinemia. Treatment with folic acid resulted in a decrease in fasting serum homocysteine levels in 9 of the 10 patients tested (P =.01). Hyperhomocystinemia, associated with renal dysfunction, is a frequent finding in liver transplant recipients. Treatment with folic acid may reduce fasting homocysteine levels.
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PMID:Hyperhomocysteinemia in liver transplant recipients: prevalence and multivariate analysis of predisposing factors. 1098 61

Liver transplantation is the treatment of choice for end-stage liver disease. During the past 8 years we performed 102 liver transplants in 84 adults and 16 children. In the adults, 9 were combined transplants: 1 a liver-pancreas transplant for type I diabetes, and 8 liver-kidney transplants. In the children, transplants included 5 whole-livers, 5 left-lateral liver segments from living-related donors, 4 reduced-grafts of right or left lobes, and 2 split left-lateral segments. At a mean follow-up of 31 months (range 1-96) 70 were alive, 3 had died during surgery and 15 during the first postoperative months. Mortality was due to primary graft non-function (7), sepsis (10), intracranial hemorrhage (1), tumors (4), recurrent hepatitis B (2), biliary strictures (2) and chronic rejection (1). The 1- and 4-year survival rates were 79.5% and 69.6%, respectively. After transplantation, 10 developed biliary stricture (5 corrected by balloon dilatation) and 8 anastomotic stricture (7 corrected by surgery), and there were 2 multiple intrahepatic strictures. There was hepatic artery thrombosis in 5, including 4 children. In 3, grafts were salvaged by thrombectomy and 2 others underwent re-transplantation. In those who survived transplantation by more than 1-month, recurrent hepatitis B was seen in 6 of 17 (35%) and recurrent hepatitis C in 12 of 19 (63%). Thus, results of our first 100 liver transplants are similar to those reported by larger centers, showing that in an appropriate setting good results can be achieved by small transplant programs.
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PMID:[Experience with 100 liver transplant recipients at the Rabin Medical Center and the Schneider Children's Medical Center]. 1106 44

The purpose of this study was to identify the significance and clinical correlation of steatosis in donor and posttransplantation liver biopsies. One hundred twenty-six liver biopsies with fatty change from 86 liver transplant patients were reviewed. Micro- and macro-steatosis were graded semiquantitatively and correlated with clinical and other pathologic parameters. Fifty-one donor biopsy specimens, from 50 patients, had combinations of micro- (predominantly) and macro-steatosis. One of 2 patients with high-grade micro- and macro-steatosis required a retransplantation on the third day. Three early deaths were not related to graft dysfunction. In 36 patients, steatosis developed after transplantation. In 13 of 36, steatosis was seen in the early postoperative period with a background of severe ischemic injury, 6 of whom died within 45 days posttransplantation. Other causes of steatosis developing after liver transplantation included hepatitis C (n = 12), alcoholic steatohepatitis (n = 3), diabetes mellitus or obesity (n = 7) and poor nutrition (n = 2). The presence of steatosis in 1 patient's donor and all posttransplantation biopsy specimens remained unexplained. In conclusion, (1) microsteatosis in donor liver biopsy specimens has no effect on graft function; (2) ischemic injury with development of steatosis in the early posttransplantation period may be associated with poor clinical outcome; and (3) steatosis in the posttransplantation period is uncommon and usually related to recurrent or acquired hepatitis C.
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PMID:Steatosis in donor and transplant liver biopsies. 1107 Jan 13

A 75-year-old man developed subacute progressive muscle weakness and painful paresthesia of the left upper and right lower limbs. The patient had no history of diabetes mellitus. On physical examination, there was no evidence of icterus or hepatosplenomegaly. Palmar erythema without rash was noted. Neurologic examination revealed muscle atrophy and weakness in the left upper limb and mild muscle weakness in the right proximal lower limb. Dysesthesia, severe hypesthesia, and hypalgesia were found in the left upper limb. The tendon reflexes were decreased in the left upper limb and absent in the lower limbs. The cranial nerves were preserved on the day of admission, followed by the involvement of the right oculomotor nerve. Serological examination revealed a mixed IgG/IgM cryoglobulinemia and hepatitis C virus (HCV) infection with evidence of HCV virus replication by PCR for HCV RNA. The patient was diagnosed as having a mixed cryoglobulinemic neuropathy associated with HCV infection. Interferon-alpha therapy with 3 million units subcutaneously was initiated three times per week; however, there was no clinical improvement, although cryoglobulins became undetectable and the level of serum HCV RNA decreased remarkably. Intravenous immunoglobulin therapy 20 g per day for 5 days was also ineffective. The patient developed right facial nerve palsy, followed by right abducens nerve palsy. Treatment with prednisolone 40 mg per day improved and stabilized neurologic symptoms. Although interferon-alpha is considered to be a promising therapy for neurologic complications of HCV infection with mixed cryoglobulinemia, the optimal treatment remains unestablished.
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PMID:[Peripheral neuropathy involving cranial nerves in a patient with hepatitis C virus infection and mixed cryoglobulinemia]. 1108 99

An increased prevalence of hepatitis C virus (HCV) infection in patients with diabetes and a higher prevalence of diabetes in HCV-infected patients have been reported. However, the relationship between these two conditions remains controversial. In addition, although the effect of interferon treatment on thyroid autoimmunity has been extensively reported, its influence on beta-cell autoantibodies has not been investigated. The aims of the study were (1) to evaluate whether autoimmune beta-cell damage could be involved in the development of diabetes mellitus in HCV-infected patients and (2) to determine whether interferon treatment influences the appearance of beta-cell and thyroid autoantibodies. The prevalence of islet cell autoantibodies (glutamic acid decarboxylase antibodies [GADAs], tyrosine phosphatase antibodies [IA-2s], islet cell antibodies [ICAs]) was assessed in 303 non-selected HCV-infected patients (277 non-diabetic and 26 type 2 diabetic patients) and in 273 sex- and age-matched control subjects. ICAs and thyroid autoantibodies were also determined before and 6 and 12 months after treatment with interferon for 24 weeks in a subgroup of 46 HCV-infected patients. GADAs were detected in 4 of 277 (1.4%) HCV-infected non-diabetic patients, 1 of 273 (0.3%) control subjects, and 0 of 26 (0%) HCV-infected patients with diabetes. Anti-IA2s and ICAs were negative in all subjects. Both GADAs and anti-IA2s were negative in all HCV-infected patients treated with interferon. After therapy, only thyroid antibodies became positive in 5 of 46 (10.9%) treated patients, disappearing in all but 1 of these at the 12-month follow-up. Our results suggest that beta-cell autoimmunity is not associated with HCV infection, thus making it unlikely that the increased diabetes mellitus prevalence among HCV-infected patients could be mediated by autoimmune mechanisms. In addition, interferon treatment induces a transient increase in thyroid autoantibodies but does not influence the appearance of beta-cell autoantibodies.
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PMID:Islet cell and thyroid antibody prevalence in patients with hepatitis C virus infection: effect of treatment with interferon. 1115 22

Organ transplantation and subsequent therapeutic agents may induce or worsen preexisting diabetes mellitus. We report the case of a diabetic patient whose insulin needs disappeared after liver transplantation. Non insulin-dependent diabetes mellitus was diagnosed when she was 47, and was treated by hypoglycemic drugs and then insulin. Chronic post-hepatitis C cirrhosis was diagnosed at the age of 55 and required liver transplantation 2 years later. During the postoperative course, the insulin doses required to maintain normal glucose levels progressively decreased, and insulin became completely unnecessary by the 29(th) postoperative day. After insulin was stopped, glucose levels remained within normal ranges for the 5-year-long follow-up, despite the worsening of a preexisting diabetic nephropathy and the occurrence of a diabetic retinopathy. This case highlights the fact that liver transplantation may eliminate insulin needs in a diabetic patient but also shows that degenerative complications may occur despite apparent remission of diabetes.
Diabetes Metab 2000 Dec
PMID:Liver transplantation eliminates insulin needs of a diabetic patient. 1117 21

One third of the world population has been infected with Mycobacterium tuberculosis, and the number of tuberculosis will increase worldwide without more effective programs of tuberculosis control. Despite of the presence of very potent anti-tuberculosis drugs the global tuberculosis situation is still very serious, and such gloomy feature are caused, at least partly, by the failures in the treatment of tuberculosis. The most important factor for the failure in chemotherapy is incompliance of the patients to the regimens. History of the chemotherapy of tuberculosis can be said as the history of the efforts to reduce such defaulters. Modern chemotherapy of tuberculosis has started from the discovery of streptomycin. Streptomycin monotherapy could improve temporally symptoms and bacteriological status, but could not cure the patients with moderately advanced pulmonary tuberculosis because of the emerge of drug-resistant tuberculosis. This problem was overcome by combining use of para-aminosalicylate and/or isoniazid developed later on. About 97% of patients with pulmonary tuberculosis became bacteriologically quiescent by the 12 months of streptomycin, para-aminosalicylate and isoniazid. Since 1950s through 1970s three drug combination of streptomycin, para-aminosalicylate and isoniazid had been the standard regimen for the treatment of tuberculosis. By the introduction of rifampicin, the duration of chemotherapy could be shortened to 9 months. Subsequent to the successful animal experiments carried out by Grosset which demonstrated that the addition of pyrazinamide for initial 2 months to the standard two-drug combination (isoniazid and rifampicin) could remarkably shorten the duration of chemotherapy, many clinical trials have been done all over the world to compare the efficacy and safety of pyrazinamide-containing intensified short-course regimen with those of standard regimen without pyrazinamide. Sputum negative conversion rates after 2 months of treatment with PZA-regimen was 70-95%, and the relapse rates after the completion of the treatment course were less than 4%. The incidence of adverse events was less than 4%. The pyrazinamide-containing 6 months short-course regimens has been established as a new standard regimen for the initial treatment of pulmonary tuberculosis worldwide. But, in Japan, this regimen had not been adapted as the standard until April 1996 because of undue fear for high incidence of liver toxicity induced by pyrazinamide. However, in many clinical trials carried out in various parts of the world did not show any causative relationship between the higher incidence of liver toxicity and pyrazinamide. According to our own experience in Fukujuji Hospital, Japan Anti-tuberculosis Association, the frequency of drug induced hepatitis among 632 patients with normal liver function at the onset of chemotherapy was 7.9 percent (50/632) when treated with pyrazinamide-containing regimens, and was similar to that among 412 patients treated with other regimens without pyrazinamide (7.3 percent 30/412). These figures were higher than those reported in the literatures. The risk factors of drug-induced hepatitis so far reported included elderly, positive hepatitis C virus antibody, low serum albumin and so on. Such known risk factors could not wholly explain the higher rate of liver dysfunction observed among our Japanese patients. We have examined additional factors affecting the frequency of drug-induced hepatitis in our hospital, and noticed that the past history of gastrectomy and over-dosing of isoniazid (> or = 7.5 mg/kg) and/or pyrazinamide (> or = 30 mg) were relating to the higher incidence of drug-induced hepatitis. Another important finding is that the relapse rate among patients complicated with diabetes mellitus is significantly higher than that of the patients without diabetes mellitus (6.31/100 person-years vs 0.90/100 person-years, P < 0.001). Further research will need whether the patients complicated with diabetes mellitus have any immunological deficient to kill Mycobacterium tuberculosis. WHO, CDC and ATS recommended that 4-drug regimen including pyrazinamide for the initial treatment of all cases of tuberculosis. Considering that the incidence of initial resistance to isoniazid is 4.4% in Japan, we should start to treat all cases of newly diagnosed tuberculosis with pyrazinamide-containing regimen (isoniazid, rifampicin, pyrazinamide, plus streptomycin or ethambutol). To do this, further studies on the risk factors of drug-induced hepatitis are urgently needed.
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PMID:[Effectiveness and problems of PZA-containing 6-month regimen for the treatment of new pulmonary tuberculosis patients]. 1121 81

A 77-year-old man was referred to our hospital because a periodic examination for hepatitis C cirrhosis and diabetes mellitus at a nearby clinic had revealed an elevated AFP level. Abdominal ultrasound and CT scan revealed a giant tumor in the right hepatic lobe, and a diagnosis of hepatocellular carcinoma was made with a biopsy. A pulmonary CT scan also revealed a diffuse granular shadow in the right lung field, leading to a diagnosis of multiple pulmonary metastases from the hepatocellular carcinoma. Arterial infusion chemotherapy was performed, but was ineffective. Thus, the administration of 600 mg/day of UFT was initiated. Both the AFP and PIVKA-2 levels, which had been increasing, returned to normal 3 months later. Ultrasound and CT scan showed that the hepatocellular carcinoma and lung metastatic foci had disappeared completely. The administration of UFT therefore appears promising for the treatment of hepatocelluar carcinoma and can be used safely, even with patients in poor general condition.
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PMID:[Complete response of a massive hepatocellular carcinoma with lung metastasis to UFT (DPD inhibitory fluoroprymidines: DIF)]. 1124 56


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