Koujirou Takase

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.

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.

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.

Survivin promotes cell proliferation in human hepatocellular carcinoma

Survivin is a recently described inhibitor of apoptosis. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression and function of survivin in human hepatocellular carcinomas (HCCs). We have shown that 4 HCC cell lines and 7 out of 8 human HCC tissues expressed survivin messenger RNA (mRNA), whereas expression of survivin mRNA was not detected in normal liver and nontumor areas of these tissues using the reverse transcription polymerase chain reaction. Survivin was detected primarily in the nucleus by immunofluorescence staining of HCC cells. In addition, 14 of 20 (70%) HCC tissues showed positive nuclear staining for survivin, whereas nontumor tissues showed little detectable staining by immunohistochemistry. Survivin expression strongly correlated with the proliferation index but not significantly with the apoptosis index in HCC tissues. Therefore, we performed cell cycle analysis after survivin transfection and showed that overexpression of survivin resulted in a decrease in the G(0)/G(1) phase and an increase in the S phase in all 4 HCC cell lines. Furthermore, we have found that survivin interacted with cyclin-dependent kinase 4 (Cdk4) and overexpression of survivin released p21(WAF1/Cip1) (p21) from Cdk4. From these results, we conclude that survivin promotes cell proliferation by interacting with Cdk4 and releasing p21 from Cdk4. This may play an important role in carcinogenesis and progression of human HCCs.

Late onset hepatic failure due to hepatitis B virus with mutations in the pre-core region

A 60-year-old man complained of severe general fatigue on October 11, 1992. Pertinent laboratory findings were: aspantate aminotransferase (AST) 1920 IU, alanine aminotransferase (ALT) 2050 IU, and total bilirubin (T.Bil) 124 micromol/l (normal range, 0–17 micromol/l). Virological assay revealed that hepatitis B surface antigen (HBsAg), anti-hepatitis B e (HBe), anti-HBc, and immunoglobulin M (IgM) anti-HBc were positive, and anti-HBs, HBeAg, and anti-delta antibody were negative. A diagnosis of acute hepatitis due to hepatitis B virus was made. Despite a decrease in transaminase, jaundice worsened and prothrombin time was prolonged. On the 60th day of hospitalization, massive ascites developed, but the patients consciousness was not impaired. Although albumin and diuretics were given, the ascites further increased. Paracentesis of 2000ml of ascitic fluid was performed twice a week. On the 120th day of hospitalization, the patient passed black stools and he exhibited renal failure 3 weeks later. Although severe jaundice persisted, he was still alert. On the 150th day of hospitalization, massive gastrointestinal bleeding occurred, due to hemorrhagic gastritis. Despite receiving intensive care, the patient died. Determination of the HBV DNA sequence revealed two point mutations in the pre-core region; these have not been reported elswwhere.

Second‑line triple therapy in failures with vonoprazan‑based triple therapy for eradication of Helicobacter pylori

Gastric acid inhibition during treatment is important for the eradication of Helicobacter pylori (H. pylori) infection. A novel potassium-competitive acid blocker, vonoprazan (VPZ), has been demonstrated to achieve high eradication rates; however, the efficacy of second-line treatment in failures of VPZ-based triple therapy has not been well studied. The aim of the current study was to determine the efficacy of VPZ in a first-line regimen for H. pylori eradication, and the efficacy of a second-line regimen using metronidazole (MTZ) in failures with the first-line regimen. Of 580 subjects enrolled in the study, 524 patients completed first-line treatment (275 patients who received VPZ and 249 patients who received LPZ). First-line regimens consisted of a combination of clarithromycin (CAM) 200 or 400 mg twice a day, amoxicillin (AMPC) 750 mg twice a day, and either LPZ 30 mg or VPZ 20 mg twice a day, administered orally for 7 days. CAM and VPZ/LPZ were replaced with metronidazole (MTZ) 250 mg and rabeprazole 10 mg in the second-line regimens. The eradication of H. pylori was assessed by the H. pylori stool antigen test. The overall first-line eradication rate with VPZ was significantly higher than that with LPZ [91.0% (250/275) vs. 84.7% (211/249), respectively, P=0.030]. The dose of CAM (400 vs. 800 mg) did not affect the eradication rate in either the VPZ or LPZ regimens. The overall eradication rates of the second-line regimens with MTZ did not differ significantly between the VPZ-failure and LPZ-failure groups [87.0% (20/23) vs. 87.9% (29/33), respectively, P=0.700]. Therefore, VPZ was significantly more effective than LPZ for first-line treatment. In patients with failure of first-line eradication therapy, successful results of second-line eradication therapy did not differ between the VPZ- and LPZ-failure groups. In conclusion, VPZ-based triple therapy should be recommended for eradication of H. pylori.

Retroperitoneal perforation of a pancreatic cyst during endoscopic retrograde pancreatography

A 70‐year‐old man was admitted to Ueno Municipal Hospital, Ueno, Japan, for evaluation of abdominal distension. Computed tomography showed a 1 × 1 cm cyst at the pancreas tail. Endoscopic retrograde pancreatography (ERP) showed a normal pancreatic duct after the first gentle injection and an enhanced cyst at the pancreas tail. Extravasation of the contrast medium occurred from the pancreatic duct to the superior‐dorsal extrapancreas at the same time of the next low‐pressure manual injection. Computed tomography showed extravasation of the contrast medium from the pancreas cyst to the retroperitoneal space after ERP. It was considered that the cyst wall weakness, in addition to slight elevated pancreatic duct pressure, caused the disruption of the cyst wall.

Pneumatosis intestinalis and necrotizing enterocolitis associated with liver cirrhosis

We report a 58-year-old woman with pneumatosis intestinalis and necrotizing enterocolitis associated with liver cirrhosis. She was receiving treatment for liver cirrhosis and hepatic failure when sudden severe right upper abdominal pain and fever developed. Abdominal radiograph disclosed pneumatosis intestinalis, involving the ascending colon, and small collections of free air along the right hemidiaphragm. The pneumatosis intestinalis appeared in both cystic and linear form. Autopsy revealed necrosis and multiple gas-filled mural cysts in the ascending colon. To our knowledge, this is the first case to be reported of pneumatosis intestinalis and necrotizing enterocolitis associated with liver cirrhosis.