Yukihiko Tameda

Osteodystrophy in patients with chronic hepatitis and liver cirrhosis

Bone mineral density (BMD) of the lumber vertebrae and factors related to bone metabolism were determined in patients with chronic viral hepatitis and patients with liver cirrhosis to clarify correlations between hepatic dysfunction, considered to be one of the causes of hepatic osteodystrophy, and decrease in bone mass. BMD of the second to fourth lumbar vertebrae was determined with a Lunar (Madison, WI, USA) DPX, a dual-energy X-ray absorptiometry diagnostic system. BMD was significantly lowest in patients with liver cirrhosis, followed by patients with chronic hepatitis, and healthy subjects, in this order. There was a significantly positive but weak correlation between albumin and BMD. Levels of 25(OH)D and 1,25(OH)2D were significantly lower in patients with liver cirrhosis than in those with chronic hepatitis. BMD and vitamin D were decreased in all patients whose cholinesterase (ChE) was below 0.3ΔpH. Urinary pyridinoline(Upyr) was significantly higher in the patients with liver cirrhosis, in whom bone mass was decreased, than in the patients with chronic hepatitis, whereas serum osteocalcin levels were distributed in the upper normal range in patients with chronic hepatitis and those with liver cirrhosis. There was a positive correlation between 25(OH)D and serum osteocalcin levels in patients with liver cirrhosis. These results indicate that osteogenesis is decreased and suggest that the decrease in BMD which occurs in viral liver cirrhosis, probably related to decreased, bone formation and slight promotion of bone resorption, reflects deranged hepatic function. This is the first report of Upyr and urinary deoxypyridinoline (UDpyr) determination in patients with liver cirrhosis and patients with chronic hepatitis. The negative correlation of Upyr and UDpyr with ChE is a novel finding.

Infection with GB virus C (GBV-C) in patients with fulminant hepatitis

BACKGROUND/METHODS There appear to be hepatitis viruses other than hepatitis A, B, C, D and E. One of these has been proposed with a designation of GB virus C. Sera from 44 patients with fulminant hepatitis were tested for RNA of GB virus C by reverse-transcription polymerase chain reaction with nested primers deduced from the putative non-structural 3 (helicase) region. RESULTS RNA of GB virus C was detected in three (20%) of 15 patients with hepatitis B virus infection and three (12%) of 25 patients without markers of hepatitis A-E virus infection. Overall, GB virus C RNA was detected in six (14%) of the 44 patients with fulminant hepatitis, at a frequency significantly higher (p < 0.001) than that in three (0.9%) of 326 blood donors matched for age with the patients. CONCLUSIONS These results indicate a role of GB virus C in inducing fulminant hepatitis either by itself or in concert with the other hepatitis viruses.

Prognostic value of peritoneoscopic findings in cirrhosis of the liver

The prognostic value of peritoneoscopy was examined in 372 patients with liver cirrhosis according to the degree of development and size of regenerating nodules, the development of reddish markings, the development of small lymphatic vesicles, the presence or absence of patchy markings, the size of the right and left hepatic lobes, and the degree of splenomegaly. The cumulative survival rate was compared with these peritoneoscopic parameters. The usefulness of peritoneoscopic and histological findings in the prognosis of liver cirrhosis was evaluated using the proportional hazard model of Cox. Significant differences were observed in the cumulative survival rate with respect to the degree of development of regenerating nodules, the size of the right hepatic lobe, the formation of small lymphatic vesicles, and the degree of splenomegaly. Analysis using Coxs proportional hazard model indicated that peritoneoscopic findings are of greater clinical use than histological findings in determining the prognosis of liver cirrhosis.

Asymptomatic primary pulmonary hypertension associated with liver cirrhosis

We report a case of asymptomatic primary pulmonary hypertension associated with liver cirrhosis (type B) and portal hypertension found by chance during a preoperative Swan-Gantz catheterization study. Our experience suggests that the actual prevalence of primary pulmonary hypertension associated with liver cirrhosis may be greater than that previously reported. During the follow-up of liver cirrhosis with portal hypertension, we should consider primary pulmonary hypertension, even if the patient is free of symptoms, and a chest X-ray check may be necessary.

Fulminant hepatic failure caused by ecarazine hydrochloride (a hydralazine derivative)

The cause of fulminant hepatic failure is reported to be unknown in more than half the cases in Japan. We recently reviewed 23 cases of fulminant hepatic failure that had been treated at our hospital. The cause of disease had been regarded as unknown before this study. It was found that seven of these patients had been under ecarazine hydrochloride therapy when they developed fulminant hepatic failure. We examined the reasons why fulminant hepatic failure in these seven patients had not been previously attributed to ecarazine, and found that it could be explained by the following factors: (1) the time from the start of ecarazine therapy to the onset of hepatic failure was long; (2) in all cases, hepatic failure developed more than 10 days after the clinical recognition of hepatitis; and (3) characteristic signs of drug‐induced hepatic failure such as a skin rash and positive lymphocytes stimulation test with the drug were absent in all cases. Fulminant hepatic failure in these cases could be characterized by: (1) rapid decrease in serum alanine transaminase (ALT) level after discontinuation of ecarazine, (2) prolonged jaundice despite discontinuation of ecarazine, (3) high incidence of anti‐nuclear antibody (ANA) (57%), and (4) histological findings of extensive hepatocellular necrosis ranging from bridging necrosis to massive necrosis. Of the seven patients, four died of fulminant hepatic failure. These four patients had received high doses of ecarazine hydrochloride for prolonged periods. Our data suggest that there may be many cases in which the cause of fulminant hepatic failure or acute hepatitis was not previously determined that can be attributed to long‐ term drug therapy for chronic diseases.

Antithrombin III concentrate in the treatment of fulminant hepatic failure.

SummaryTwenty-six patients with fulminant hepatic failure were treated with daily infusions of antithrombin III concentrate until recovery of consciousness or death. Seven patients were alive (group A), 7 survived 17 to 47 days after treatment (group B), and 12 died within 9 days (group C). Decreased plasma antithrombin III levels increased on the day after treatment, irrespective of the pretreatment levels in all patients. Continuous or temporary normalization was seen in all patients in groups A and B, but in only 5 in group C patients whose bleeding was extensive (p<0.05). An abrupt drop in peripheral platelet counts occurred when plasma antithrombin III levels were below normal. General bleeding accompanied this drop. These results suggest that maintained normal plasma antithrombin III levels are beneficial for prolonged survival time in fulminant hepatic failure, probably through controlling intravascular coagulation, and that antithrombin III infusion may be useful for such treatment.

Long-term administration of natural interferon-α in patients with chronic hepatitis C: Relationship to serum RNA concentration, HCV-RNA genotypes, histological changes and hepatitis C virus

To virologically assess the efficacy of interferon therapy in chronic hepatitis C, either 5 or 10 MU/day natural interferon‐α (IFNα) was administered to 57 patients with chronic hepatitis C for 38 weeks. A complete and sustained response (CR‐SR), as evidenced by the absence of serum hepatitis C virus (HCV)‐RNA during the administration period and at 6 months after the final administration of IFNα and a normal GPT level at 6 months after final administration, occurred in 42.6% (23/54) of subjects. Liver tissue was histologically evaluated using the histological activity index (HAI) score before and after the administration period. In CR‐SR cases, significant improvements (P <0.01) occurred in periportal necrosis, intralobular necrosis, portal inflammation and total score. A comparison, by HCV genotypes, revealed that CR‐SR occurred in 60% (9/15) of subjects with type 2a and 30.3% (10/33) of subjects with type Ib. A comparison by virus concentration revealed that CR‐SR occurred in 71.4% (15/21) of those subjects having a virus concentration of < 105 copies/mL, but in only 24.2% (8/33) of those having a virus concentration of > 105 copies/mL. Analysis by a multiple logistic model revealed a strong correlation between the therapeutic effect of interferon therapy and the pre‐administration virus concentration (P=0.0061) and genotype (P=0.0015). These results suggest that the preadministration virus concentration and genotype are both key factors affecting the therapeutic effect of interferon therapy in chronic hepatitis C and that the therapeutic effect of interferon is satisfactorily high, irrespective of virus concentration, in subjects with type 2a HCV, but varies depending on virus concentration in subjects with type 1b.

CASE REPORT: Hepatocellular Carcinoma Associated with Adult-Type Citrullinemia

Hypercitrullinemia is a rare hereditary metabolic disorder caused by the deficiency in the activity of argininosuccinate synthetase. McMurrey et al first reported this disease in infants (1) and Saheki et al classified three types on the basis of qualitative and quantitative analysis of argininosuccinate synthetase (2). The classic neonatal and infantile forms were assigned to type I (abnormal kinetics of the enzyme) and III (undetectable or extremely low levels of the enzyme). Biochemically, the defect of the enzyme in the classical types is found in all tissues and/or cells where argininosuccinate synthetase is expressed (3). Analysis of the amplified cDNA from 14 neonatal/infantile type III citrullinemia patients identified mutations in the mRNA that are heterogeneous (4). Type II citrullinemia is an adult-onset type and is clinically characterized by a sudden onset of consciousness disturbance, a high serum citrulline concentration, and hyperammonemia. Most of this type of citrullinemia occurs in Japan unlike in the United States and Europe. Type II citrullinemia is characterized by a quantitative decrease of argininosuccinate synthetase only in the liver, while argininosuccinate synthetase levels in other tissues, such as kidney, brain, and fibroblasts, are normal. The hepatic content of the enzyme is about 10% of control value, but the translatable mRNA level for the enzyme is similar to the control value and there is no mutation in the argininosuccinate synthetase mRNA. Thus, it is confirmed that the liver contained the normal amount of mRNA coding for argininosuccinate synthetase, but there was increased degradation of the enzyme or inhibited translation (5–8). Although there are reports of the patients of type II citrullinemia complicated by hepatocellular carcinoma, the details were not well elucidated (7, 9). Here, we report on a patient with adult type citrullinemia who developed hepatocellular carcinoma after 29 years of follow-up, and we analyzed argininosuccinate synthetase in hepatocellular carcinoma tissues.

Hepatocyte regeneration in chronic hepatitis C and interferon treatment: Analysis of immunohistological identification of proliferating cell nuclear antigen (PCNA)

To evaluate the usefulness of proliferating cell nuclear antigen (PCNA) immunostaining in the assessment of the efficacy of interferon (IFN) therapy in chronic hepatitis C, we investigated the proliferative activity of hepatocytes in 67 patients with chronic hepatitis C, using this immunostaining method. The percentage of PCNA-positive hepatocytes was 2.4% in patients with chronic persistent hepatitis, 2.5% in those with chronic aggressive hepatitis 2A, and 3.9% in those with chronic aggressive hepatitis 2B. The PCNA count increased with the progression of the liver disease. Patients were classified as complete, partial, and non-responders to IFN; the percentage of PCNA-positive hepatocytes before IFN therapy was 1.6% in the complete responders, 3.9% in the partial responders, and 4.9% in the non-responders. There was a significant negative correlation between the percentage of PCNA-positive hepatocytes and the response to IFN treatment. Thirty-two of 53 cases (60.4%) in which the PCNA labeling index (LI) was less than 5.0 were complete responders compared with 13 of 14 cases (92.9%) in which the PCNA LI was higher than 5.0, representing partial responders or non-responders (P<0.001). Most complete responders had a low PCNA LI, irrespective of HCV genotype. Our findings indicate that PCNA immunostaining is a simple and reliable index of cell proliferation in liver regeneration, and may be a useful predictor of the response to IFN treatment in chronic hepatitis C.

A case of acute intermittent porphyria with acute pancreatitis

SummaryA case of acute pancreatitis in a 29-year-old female associated with an attack of acute intermittent porphyria (AIP) is reported. Following the attack of AIP, serum pancreatic amylase originating from the pancreas increased transiently, and mild swelling of the pancreas was detected by ultrasonography. On this basis acute pancreatitis was diagnosed. Additionally, this patient had mild hepatic dysfunction. Laparoscopy disclosed diffuse slightly dark bluish pigmentation on the irregular surface of the liver. Mild fibrous dilatation of the portal area with lymphocytic infiltration was seen histologically. Acute pancreatitis and hepatic damage with AIP is extremely rare, however it is possible that these findings are etiologically connected in this patient.