Identification and characterization of a prevalent hepatitis B virus X protein mutant in Taiwanese patients with hepatocellular carcinoma.

The aim of this study was to investigate whether there was a particular hepatitis B virus (HBV) X protein (HBx) mutant associated with Taiwanese patients with hepatocellular carcinoma (HCC). Initially, the entire coding region of HBx gene from the serum samples of 14 Taiwanese patients were sequenced. A novel mutant, HBx-A31, was preferentially found in patients with HCC. Sera from 67 patients with HCC and 100 patients with chronic hepatitis B were thus subjected for codon 31 analysis using a dual amplification created restriction site method. HBx-A31 was detected more frequently in patients with HCC (52% versus 12%; P<0.001) and in patients with liver cirrhosis (44% versus 6%; P<0.001). Site directed mutagenesis experiment revealed that HBx-A31 was less effective in transactivating HBV enhancer I-X promoter complex, less efficient in supporting HBV replication, and less potent in enhancing TNF-alpha induced increment of CPP32/caspase 3 activities in HepG2 cells. In conclusion, a prevalent HBx mutant was identified in Taiwanese patients with hepatocellular carcinoma. Development of this mutant might represent a strategy of the virus to escape immune surveillance and thus contribute to the process of multiple-step hepatocarcinogenesis.

Hepatobiliary imaging of functional and morphological changes following hepatic arterial embolization in hepatocellular carcinoma.

UNLABELLED: Hepatic arterial embolization (HAE) is the treatment of choice for inoperable hepatocellular carcinoma. There are functional changes following HAE in the tumor and in the adjoining normal liver and biliary structures. We sought to determine if a 99mTc-HIDA hepatobiliary scan could evaluate the morphological and functional changes of the liver and biliary systems in patients with hepatocellular carcinoma undergoing HAE. METHODS: Patients with hepatoma were evaluated by 99mTc-HIDA hepatobiliary scans before and after HAE. RESULTS: Ten patients with histologically proven hepatomas had 44 99mTc-HIDA scans over a 319-mo period. Liver uptake was good in all patients, none developed hepatic failure. Liver tumors were detected in five of the eight studies done before the first HAE. The HIDA scan failed to locate the tumor throughout the whole study period in only one patient. Two patients showed evidence of tumor uptake of the HIDA agent. In one of these two patients the hot uptake disappeared after the HAE but reappeared after tumor recurrence. Gallbladder filling time and contractility worsened in all eight patients the day after embolization. On the HIDA scans, the gallbladder was not visualized in three of four patients who survived longer than 40 mo after HAE. Bile stasis in the left intrahepatic duct was found in six of the eight patients who survived longer than 8 mo after HAE. CONCLUSIONS: Biliary complications were common in patients who received HAE, and HIDA scans may be useful for evaluating the biliary system and hot uptake in hepatocellular carcinoma in candidates for HAE.

Replication of hepatitis B virus in first-degree relatives of patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) may occur in family clusters. No genetic mechanism has been identified as responsible for this familial tendency. We suspected that a longer hepatitis B virus (HBV) replication phase might be the reason for a higher risk of HCC in families with this disease. We performed liver biochemical tests, test for viral hepatitis markers and hepatitis B e antigen (HBeAg), and liver ultrasonography in relatives of patients with HCC. A total of 1,885 first-degree relatives from 688 families participated in this study. Seven hundred fifty-two relatives were found to be carriers of hepatitis B surface antigen (HBsAg) and 675 of them were tested for HBeAg. The prevalence of HBeAg was 27.4% in relatives of those with HCC and 20% in asymptomatic HBsAg carriers. The HBeAg prevalence rate was higher in relatives of those with HCC > or = 40 years old than in asymptomatic HBsAg carriers. Moreover, HBeAg was more likely to persist in men than in women > or = 40 years old. We conclude that families with HCC showed a prolonged HBV replication phase that may be one of the cofactors for a familial tendency for HCC.

Liver biochemical tests and dengue fever.

The impact of dengue on liver function was studied by biochemical tests on 125 male and 145 female patients diagnosed with this disease during an outbreak that extended from November 1987 to December 1988. Abnormal levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase (G-GT) were observed in 93.3%, 82.2%, 7.2%, 16.3% and 83.0% of the patients, respectively. The elevation of transaminases was mild to moderate in most cases, but was 10-fold greater than the normal upper limit for AST and ALT in 11.1% and 7.4% of the patients, respectively. Initially, the level of AST was greater than that of ALT, increasing to maximum levels nine days after the onset of symptoms, then decreasing to normal levels within two weeks. Results of the biochemical tests did not differ significantly between the cases with and without hepatitis B or hepatitis C virus infection, but significantly higher elevations of AST, ALT, and G-GT were observed in patients with episodes of bleeding. Liver biopsies of two patients showed features of lobular hepatitis. Of the five fatal cases, three died of hepatic failure. It is concluded that dengue fever may cause hepatic injury and transaminase elevation similar to that in patients with conventional viral hepatitis. In epidemic or endemic areas, dengue fever infection should be considered in the differential diagnosis of hepatitis.

Sequential invasions of pancreatic pseudocysts in pancreatic tail, hepatic left lobe, caudate lobe, and spleen.

A 66-year-old male patient without a history of risk factors for pancreatitis suffered from pancreatitis and developed pseudocyst. During the course of treatment and follow-up, the pseudocyst was found to have migrated through the pancreatic tail, left hepatic lobe, caudate lobe, and spleen on abdominal sonography and computed tomography scan. Finally, emergent laparotomy was done for splenic abscess and removal of infected pseudocyst in the spleen and lesser sac of the abdomen. The patient made a full recovery after operation.

Prognostic factors for pyogenic abscess of the liver.

BACKGROUND: Percutaneous drainage and antibiotics for pyogenic abscess are well established therapeutic modalities. However, the mortality rate for hepatic abscess of liver remains high. STUDY DESIGN: Three hundred fifty-two cases of pyogenic hepatic abscesses were studied to evaluate prognostic factors. RESULTS: Using univariate analysis, the following factors were associated with a high mortality rate: patient age, gas-forming abscess, rupture of abscess, bilobe involvement, clinical sepsis, bilirubin (more than 2 mg per dL), blood urea nitrogen (more than 20 mg per dL), serum creatinine (more than 2 mg per dL), aspartate aminotransferase (more than 100 U per L), and albumin (less than 2.5 gm per dL). Using multivariate analysis, the following were independent significant factors in predicting mortality: patient age (more than 60 years), blood urea nitrogen (greater than 20 mg per dL), serum creatinine (greater than 2 mg per dL), total bilirubin (greater than 2 mg per dL), and albumin (less than 2.5 gm per dL). CONCLUSIONS: Systemic effects of hepatic abscess with sepsis and multiple organ failure were significant factors in predicting mortality. Local findings, such as rupture of the abscesses, multiple abscesses, and gas-forming abscesses, were not independent factors. Percutaneous drainage is always considered if the condition of the patient can not be improved with antibiotic therapy. Operative treatment is indicated if the patient is unresponsive to medical treatment and percutaneous drainage or if the patient has complications of biliary tract stone or rupture of the abscess.

Reappearance of HBsAg with compartmentalized different HBV strains in allograft versus PBMC of the recipient.

A woman who was positive for anti-hepatitis B surface antigen (anti-HBs) and anti-hepatitis B core antigen (anti-HBc) received an orthotopic liver transplantation from an anti-HBc-seropositive donor in November 1985. Reappearance of hepatitis B surface antigen (HBsAg) was noted 5 months after the transplantation, but it was not associated with significant liver inflammation. Ten years after the transplantation, results of serum hepatitis B virus (HBV) DNA study, by nested polymerase chain reaction, were negative. However, HBV DNA was detected in the transplanted liver tissues and peripheral blood mononuclear cells. Different strains were identified in these two organs. An adw strain was found in the transplanted liver, whereas an adr strain with long segment deletions in the core gene was found in the peripheral blood mononuclear cells. Covalently closed circular HBV DNA was not detected in any of the tissues examined. Occult HBV infection in the donor as well as the recipient is common in HBV endemic areas. The recipient in this case had reappearance of hepatitis B surface antigen (HBsAg) in the serum after transplantation. Nevertheless, 10 years later, two different strains of HBV were identified in different organs, without cross infection. The present case demonstrates that HBsAg reappearance was not associated with reactivation of the virus and liver inflammation. This type of HBsAg reappearance did not appear to produce a significant hazard to the transplanted liver.

Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis.

Two hundred and twenty-five patients diagnosed as having non-malignant acute cholangitis were studied to evaluate the incidence and prognostic significance of pre-drainage acute renal failure. Thirty-seven patients (16.4%) were found to have serum creatinine greater than, or equal to, 1.5 mg/dl before the drainage procedure. The risk factors for impaired renal function evaluated by multivariate analysis were advanced age, low albumin, low globulin, and clinical presentation of Charcot's triad or Reynold's pentad. The mortality rate in the abnormal pre-drainage serum creatinine group was 21.6%, which was much higher than the mortality (3.7%) seen in the normal serum creatinine group (p less than 0.0001). The other risk factors of mortality evaluated by multivariate analysis were the bilirubin level, combined common bile duct stones and intrahepatic duct stones, and bile duct stricture. We conclude that abnormal pre-drainage serum creatinine is not an uncommon finding in acute cholangitis. It is of prognostic significance, and should be considered as important as the clinical findings of Reynold's pentad.

Brain abscess following endoscopic injection sclerotherapy: report of a case.

A 33-year-old male patient with hepatitis B surface antigen positive cirrhosis, received 2 courses of endoscopic injection sclerotherapy for bleeding esophageal varices. A Streptococcus viridans brain abscess developed 2 weeks after the first sclerotherapy (or 1 week after the second sclerotherapy). In cirrhotic patients, an increase in pulmonary vasodilatation and pulmonary arteriovenous shunting has been well recognized. Sclerosant as well as bacteria may pass through a pulmonary arteriovenous shunt and reach the brain, directly after an infection of esophageal varices. Brain ischemia and a bacterial infection may occur at the same time, this can accelerate the development of a pyogenic brain abscess. Careful observation for the early detection and treatment of infection following endoscopic sclerotherapy is essential.

Tc-99m HIDA hepatobiliary agent in the diagnosis of pulmonary metastasis from hepatocellular carcinoma.

Twelve patients with hepatocellular carcinoma and multiple metastatic pulmonary nodules were studied with Tc-99m HIDA imaging. Lung scanning was performed 1, 2, 3, 4, and 5 hours after administration of 6 mCi of Tc-99m HIDA with a preset count format of 400 K. In two patients, pulmonary uptake was clearly seen at 1 hour; in the other two patients, uptake could not be detected until 3 hours later. The overall detection rate of 33% suggests that Tc-99m HIDA has limited usefulness as a routine diagnostic tool in the detection of hepatoma metastases. The uptake may include both specific and nonspecific mechanisms.

Apoptosis in viral hepatitis B and C.

Tumor necrosis factor (TNF) and TNF receptors (TNFR) are members of the growing TNF ligand and receptor families known to be involved in apoptosis, viral pathogenesis and immune regulation. The present report will focus on the role of apoptosis in the pathogenesis of viral hepatitis B and C. Although TNF was reported years ago to modulate viral infections, recent findings on the molecular pathways involved in TNFR signaling have allowed a better understanding of the molecular interactions between cellular and viral factors within the infected cell. The interactions of viral proteins with intracellular components downstream of the TNFR have highlighted at the molecular level that viruses can manipulate the cellular machinery to escape the immune surveillance and to favor spread infection. We will review here the mechanism of apoptosis and the role of viral proteins that regulate apoptosis in viral hepatitis B and C.

Hepatitis delta virus infection in southern Taiwan.

To determine the prevalence of hepatitis delta virus (HDV) infection in Southern Taiwan in comparison to that of Northern Taiwan, a consecutive series of 389 HBsAg-positive patients were tested for serum antibody to HDV (anti-HD) by radioimmunoassay. The anti-HD was positive in 2/122 (1.6%) asymptomatic "healthy" carriers, 1/61 (1.6%) blood donors, 1/24 (4.2%) patients with acute type B hepatitis, 4/25 (16%) carriers with superimposed acute hepatitis, 5/53 (9.4%) patients with chronic hepatitis, 3/42 (7.1%) patients with liver cirrhosis and 1/62 (1.6%) patients with hepatocellular carcinoma. Our findings confirm that the prevalence of HDV infection is low in asymptomatic carriers, acute type B hepatitis and hepatocellular carcinoma, but significantly higher in patients with chronic active liver disease. No significant difference in the prevalence of HDV infection between Southern and Northern Taiwan was observed.

Portal vein velocity by duplex Doppler ultrasound as an indication of the clinical severity of portal hypertension.

The portal vein (PV) velocity was measured by duplex Doppler ultrasound to predict the severity of portal hypertension. A total of 143 patients with liver cirrhosis were studied from January 1991 to June 1992. There were 104 males and 39 females with a mean age of 52 years old (range 23-76). The maximal PV velocity was significantly lower in patients with moderate and severe varices, cardiac varices, red-color signs on varix, esophagitis and congestive gastropathy. The patients with bleeding esophageal varices or upper gastrointestinal tract were found to have a significantly maximal PV velocity. Comparing patients without ascites or victims with controllable ascites. The maximal PV velocity in Child's C or mortality cases was also significantly lower than that in Child's A, Child's B and surviving cases. If we set the cut off value of PV velocity at 15 cm/sec, we could get the accuracy of 67.8%, 62.2%, 67.8% and 73.5% in the prediction of massive ascites, varices severity, Child C class and mortality respectively. In conclusion, PV velocity may reflect the severity of clinical portal hypertension in cirrhotic patients; it could be a prognostic factor in cirrhotic patients.

Gallbladder volume in patients with common hepatic duct dilatation. An evaluation of Courvoisier's sign using ultrasonography.

To evaluate the usefulness of Courvoisier's sign in ultrasonography, gallbladder size in patients with common hepatic duct dilatation was measured using the ellipsoid method during ultrasonographic examination. During a 6-month period 24 patients with malignant obstructions (6 with carcinoma of the ampulla of Vater, 9 with pancreatic head tumors, 5 with carcinoma of the bile duct, and 4 with malignant lymphadenopathy), 50 patients with calculous obstructions, and a group of 50 normal control patients were examined in this study. Gallbladder volumes were larger in patients with biliary tract dilatation (88.8 +/- 6.8 ml) than in the control group (34.3 +/- 2.8 ml) (p < 0.01). Although the duration and total serum bilirubin level were higher in patients with malignant obstructions, the gallbladder volumes were the same in these two groups (93.0 +/- 11.3 ml versus 86.7 +/- 8.5 ml). A linear relationship was found between gallbladder volume and total serum bilirubin in patients with malignant biliary obstructions (r = 0.6, p < 0.001) and in patients with calculous biliary obstructions without gallbladder stones (r = 0.68, p < 0.001). We hypothesized that the gallbladder volume is irrelevant in differentiating the nature of the biliary tract dilatation and that the gallbladder size is dependent on the degree of biliary obstruction when the gallbladder is not afflicted by fibrosis.

Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis.

To examine hepatic decompensation associated with acute exacerbation preceding hepatitis B e antigen clearance in chronic type B hepatitis, 376 patients with chronic hepatitis who were hepatitis B e antigen-positive were prospectively studied for up to 7 yr (mean 25 mo). Among the 165 patients who underwent hepatitis B e antigen clearance, 4 patients experienced hepatic decompensation and one of them eventually developed hepatic encephalopathy and died. The incidence of hepatic decompensation associated with hepatitis B e antigen clearance was 2.4%. We suggest that such an event in previously unrecognized chronic hepatitis B carriers could have been erroneously interpreted as acute or subacute hepatic failure, and that it might have been the result of a stronger enhancement of the host immune response.

Vascular ectasia of the duodenum detected by duodenoscopy.

A 65-yr-old Chinese woman suffered from repeated episodes of upper gastrointestinal bleeding for 5 yr. Despite repeated panendoscopic and angiographic studies, the bleeder was not found until a duodenoscopic examination was performed. A small bleeder was found near the papilla vater area. The lesion was excised and proved to be a vascular ectasia of duodenum.

Hepatic tuberculosis; a rare case of bleeding gastric varices.

A laparotomy was performed on a 68-year-old female who, in spite of medical treatment, suffered from uncontrolled upper gastrointestinal bleeding due to ruptured gastric varices. Histological examination of the liver tissue taken during operation revealed tuberculosis. Hepatic tuberculosis, although rare, should be kept in mind as one of the differential diagnosis when there is unexplained, noncirrhotic bleeding gastric varices.

The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.

The incidence and contributing factors of cirrhosis developing in patients with chronic type B hepatitis were assessed prospectively in 684 clinicopathologically verified patients, of which 509 were HBeAg positive and 175 were anti-HBe positive at entry into the study. During an average follow-up period of 35.3 months, cirrhosis occurred 6 to 64 months after entry in 35 HBeAg-positive and 7 anti-HBe positive patients with a calculated annual incidence of 2.4 and 1.3%, respectively (p greater than 0.05). The incidence increased significantly with the increasing age at entry. Patients who had experienced (a) hepatic decompensation, (b) repeated episodes of severe acute exacerbation (with alpha-fetoprotein greater than 100 ng per ml and/or bridging hepatic necrosis), (c) severe acute exacerbation not accompanied by subsequent HBeAg seroconversion and (d) hepatitis B virus reactivation (particularly those with HBeAg reappearance) were found to develop cirrhosis much more frequently (p less than 0.001). Contrary to general belief, patients who had hepatitis delta virus superinfection and patients with chronic active hepatitis were not particularly prone to develop cirrhosis. We conclude that in addition to age factor, the extent, severity, duration, frequency and etiology of the hepatic lobular alterations are important factors for the development of cirrhosis in patients with chronic type B hepatitis.