The constitutional indocyanine green excretory defect--report of four cases.

Four cases revealed high retention of ICG test and normal retention of BSP test were reported. The results of liver function test of these cases showed within normal limit except ICG retention. ICG disappearance rate ranged from 0.017 to 0.025, whereas BSP disappearance rate ranged from 0.069 to 0.126. The transfer rate of ICG from plasma to liver markedly decreased by two compartmental analysis of the decay curve and slightly reduced transfer rate of BSP from plasma to liver was also observed. The step on both ICG and BSP disappearance curve was observed during 20 to 25 minutes after the injection in all cases and in repeated observations. The step formation is one of the characteristic changes in these cases. The ICG binding capacity of serum protein decreased in the first peak and increased in the third peak eluted by gel filtration of Sephadex G-200. Light microscopic findings of the liver showed normal histology. The electronmicroscopic findings showed the increase of lipofuscin-like lysosome, modification and paracrystalline like array of mitochondria and increase of reticulum fiber in Disse's space. Father of a case showed ICG retention without BSP retention. From these results it is suggested that these cases are a new type of dye excretory disorder of liver with heredity or constitution.     

Hepatic transport of serum bilirubin,bromsulfophthalein, and indocyanine green in patients with congenital non-hemolytic hyperbilirubinemia and patients with constitutional indocyanine green excretory defect

We carried out a retrospective study of 71 patients with congenital non-hemolytic hyperbilirubinemia who had been treated at our institution over the 25 years from 1965 to 1990. Twenty patients had Gilbert's syndrome, 1 had Crigler-Najjar syndrome, 1 had new type unconjugated hyperbilirubinemia, 21 had Dubin-Johnson syndrome, and 28 had Rotor's syndrome. We also reviewed 20 patients with constitutional indocyanine green (ICG) excretory defect. The study focused on the hepatic transport of serum bilirubin, bromsulfophthalein (BSP), and ICG. In Dubin-Johnson syndrome, a defect appeared in late-stage transport, while uptake and storage capacity were normal. In Rotor's syndrome, defects were found in the early stage, and storage capacity was reduced, while excretion into bile was slightly suppressed. A secondary rise in serum ICG was seen in 5 of the 10 patients with Dubin-Johnson syndrome. The transport defect in Gilbert's syndrome was unclear. It could not be considered to be homogeneous, but it may exist at multiple sites, from the conjugation with serum proteins to excretion into bile. Following phenobarbital administration, the ICG secondary rise in the 5 patients with Dubin-Johnson syndrome disappeared, and ICG was rapidly cleared from blood. However, in patients with Dubin-Johnson syndrome, BSP clearance in serum did not show any change before and after phenobarbital administration. ICG excretion in patients with constitutional ICG excretory defect was due only to the impairment o ICG transport, and the defect was suggested to be hepatic uptake. These results indicate that studies of the hepatic transport of bilirubin, BSP, and ICG are useful for determining the etiological factors involved in congenital hyperbilirubinemia and constitutional ICG excretory defect.     

Marked delay in indocyanine green plasma clearance with a near-normal bromosulphophthalein retention test: a constitutional abnormality?

Five patients showing a normal to near-normal BSP test and a marked delay in ICG plasma clearance, and two families with clustering of the same abnormality, are described. Two had Gilbert's syndrome, one was convalescing from acute hepatitis, and the other two had no detectable liver abnormality. Measured indices of ICG metabolism indicated a marked reduction in the hepatic uptake, storage capacity, biliary transport maximum, and an increased reflux into plasma. Biochemical studies on the binding of ICG by plasma proteins failed to demonstrate any difference from normal controls. Thus, the primary defect seems to be in the transport of ICG by the hepatocyte. Although the relationship of the defect in ICG metabolism to other constitutional hyperbilirubinaemias is not clear, it is possible that the defect in these patients is a constitutional one involving some steps in the hepatic disposal of organic anions.     

Dye Clearance Studies in Rotor''s Syndrome

Plasma clearances of sulfobromophthalein sodium (BSP), indocyanine green (ICG) and unconjugated bilirubin were studied in six patients with Rotor's syndrome. A marked retention of these three substances in the plasma was observed. At 60 minutes after injection, serum BSP consisted almost entirely of the unconjugated form. In three patients, BSP Tm and BSP S were significantly reduced. Clearance of unconjugated bilirubin was markedly impaired. This, together with the conjugated hyperbilirubinemia may be interpreted to reflect reduced storage. These results indicate that Rotor's syndrome is marked by reduced hepatic storage capacity and excretory function of BSP, ICG and bilirubin.     

Hepatectomy of cavernous hemangioma with constitutional indocyanine green excretory defect

The constitutional ICG excretory defect with marked ICG retention in spite of other normal hepatic functions has not been so rare in Japan. However, there is no previous report of hepatectomy in a patient with this disease. We describe a successful case of hepatectomy for cavernous hemangioma with this disease and use of technetium-99m diethylenetriaminepentaacetic acidgalactosyl-human serum albumin (99mTC-GSA) liver scintigraphy as the preoperative assessment of the liver functional reserve. In our case, ICGR15 was more than 55%, however, a modified receptor index obtained from 99mTC-GSA liver scintigraphy was normal. Left lateral segmentectomy of the liver was performed without any perioperative complications. Hepatectomy of patients with the constitutional ICG excretory defect is possible if modified receptor index value obtained from 99mTC-GSA scintigraphy is within the normal range.     

Hepatitis B core and surface antigen expression in HBeAg and HBV DNA positive chronic hepatitis B: correlation with clinical and histological parameters

The interrelationship between hepatitis B virus (HBV) infection, hepatic injury and clinical activity in chronic HBV infection is incompletely understood. We have scored histologic activity, the expression of hepatitis B core (HBcAg) and hepatitis B surface antigen (HBsAg) and assessed HBV replication to correlate HBV antigen expression with histologic disease. Forty-seven formalin-fixed, percutaneous liver biopsies from HBeAg carriers were studied. Twenty-nine were Black, 16 Caucasian and two Oriental. Fifty-nine percent had chronic active, 35% chronic persistent hepatitis and 14% cirrhosis. None were positive for antibodies to Human Immunodeficiency Virus (HIV). HBsAg and HBcAg in tissue were detected by immunochemical staining. Diffuse HBsAg staining was observed in 10/15 patients with CPH, but there was no correlation between histologic score and HBsAg expression. Intracytoplasmic HBcAg was observed in patients seroconverting to anti-HBe, but was also detected in patients with minimal hepatitis. An inverse correlation between histologic score and HBcAg expression was observed. HBcAg expression was more widespread in patients with CPH (mean 37%) than in CAH (mean 18%). A positive correlation was observed between serum aminotransferase concentrations and histologic score. Although no consistent pattern can be discerned, HBcAg expression and hepatic injury are frequently dissociated in patients with chronic HBV infection; complex host responses may determine the variable degree of disease activity and hepatic injury.     

Cholestasis in patients with amoebic liver abscess

Studies done on patients with amebic liver abscess have revealed a constant hepatic excretory defect for bromsulphthalein (BSP). This was evident from marked lowering of the transport maximum (Tm), with no significant alteration in storage capacity (S) and conjugation. It is inferred that a similar mechanism might contribute to the pathogenesis of jaundice in such patients.Supported in part by a grant from the Indian Council of Medical Research.The authors wish to thank Prof. B. K. Aikat for allowing access to autopsy material of 3 patients; Mr. Gupta for statistical analysis; and Mr. O. P. Nirankari for technical assistance.     

Simultaneous acute infections with hepatitis A and hepatitis B viruses in a chimpanzee.

The unexpected occurrence of a hepatitis B virus (HBV) infection in a chimpanzee experimentally inoculated with hepatitis A virus (HAV) provided an opportunity to examine the course of simultaneous acute infections with both agents. A chimpanzee inoculated intravenously with HAV developed elevated levels of aminotransferases in serum, detectable excretion of hepatitis A antigen in feces, and a marked antibody response to HAV. During the acute phase of this experimentally induced infection with HAV, the chimpanzee simultaneously developed an HBV infection. The latter was characterized by jaundice, a second increase in levels of aminotransferases in serum, and the appearance in serum of hepatitis B surface antigen (HBsAg), hepatitis B e antigen, antibody to hepatitis B core antigen, and, later, antibody to HBsAg. During the acute phase of both HAV and HBV infections, marked histopathologic inflammatory changes were observed in serial liver biopsy specimens. In this chimpanzee, the concurrent acute infection with both HAV and HBV occurred in association with marked liver damage.     

Effect of human immunodeficiency virus (HIV) infection on chronic hepatitis B hepatic viral antigen display

Immunofluorescent and immunoperoxidase monoclonal antibody-based techniques were used to demonstrate hepatitis B e antigen (HBeAg) and hepatitis B c antigen (HBcAg) display in the liver biopsy specimens of 45 chronic hepatitis B virus (HBV) carriers. Anti-human immunodeficiency virus (anti-HIV)-positive HBV carriers had many more HBe- and HBc-positive hepatocyte nuclei than anti-HIV-negative carriers (P less than 0.0003 and less than 0.02, respectively), and HBV-DNA levels were slightly, but not significantly, increased in the positive subjects. The number of HBe- and HBc-positive nuclei were positively correlated with serum HBV-DNA levels (P less than 0.05 comparing high serum HBV-DNA levels of greater than 2880 pg/ml and levels of 1-480 pg/ml), and were negatively correlated with disease activity (P less than 0.05 comparing those with severe chronic active hepatitis (CAH) and those with mild CAH and chronic persistent hepatitis (CPH]. These results indicate that male homosexual HBV carriers, positive for anti-HIV, may be immunosuppressed before there are clinical signs of immunodeficiency, and this allows an increased level of replication of at least one other virus (HBV).     

Chronic persistent hepatitis type B can be a progressive disease when associated with sustained virus replication

In 44 hepatitis B virus (HBV) carriers with chronic persistent hepatitis (CPH), serial liver biopsies were available. At presentation 38 patients had HBV-DNA in their serum including 31 HBeAg positive and seven anti-HBe positive cases. The remaining six patients were anti-HBe positive and HBV-DNA negative. During a mean histologic follow-up of 4.2 years, 12 (32%) of the 38 HBV-DNA positive patients progressed to chronic active hepatitis (six cases) or to active cirrhosis (six cases), while 26 patients showed either unchanged features of CPH (21 cases), or histologic improvement to normal liver (five cases). Persistence of HBV-DNA in serum, independently of HBeAg/anti-HBe events, was significantly (p less than 0.01) associated with deterioration of liver disease, while termination of HBV replication correlated significantly (p less than 0.05) with spontaneous biochemical remission and with unchanged or improved histology. None of the six anti-HBe positive patients without serologic markers of hepatitis B virus replication showed histologic deterioration. These findings indicate that continuing HBV replication is a marker which predicts unfavourable evolution of chronic persistent hepatitis and frequent transition to chronic active hepatitis or cirrhosis.     

乙型肝炎肝组织中Fas抗原表达的研究

目的；探讨乙型肝炎肝组织Ｆａｓ抗原表达民细胞凋亡和肝细胞损伤关系，方法：用免疫组织化学技术，对１０９例乙型肝炎肝组织Ｆａｓ抗原进行了检测。结果：Ｆａｓ抗原总检出率７６．１６％，急性重症肝炎（ＡＦＨ）慢性迁延型肝炎（ＣＰＨ）慢性活动肝炎（ＣＡＨ），活动性肝硬化（ＡＣ）Ｆａｓ抗原检出率分别为９０．９％，４３．４８％，７８．１２％，８５．７１％，急性重症肝炎Ｆａｓ抗原阳性细胞分布于大片坏死区域中残留肝细     

慢性肝病肝脏储备功能与肝纤维化的关系

目的:研究慢性乙型肝炎及乙肝肝硬化患者的肝脏储备功能及肝纤维化,进一步探讨肝脏储备功能与肝纤维化之间的关系.方法:60例慢性乙肝病毒感染患者,分为慢性乙型肝炎及乙肝肝硬化代偿期两组,利用脉冲式色素浓度图像分析仪(DDG)行吲哚氰绿(ICG)排泄试验,监测ICG血浆清除率(K)和15min滞留率(R15);同时利用Fib...     

B7-1在乙型肝炎肝组织的表达及其与病变的关系

目的阐明Ｂ７－１在乙型肝炎肝组织中的表达及其与病变发生、发展的关系。方法用免疫组织化学方法检测连续切片的乙型肝炎肝组织Ｂ７－１及表面抗原表达。结果正常对照２例均为阴性；１７例慢性迁延性肝炎（ＣＰＨ）中，胞浆Ｂ７－１阳性的有１６例，轻度阳性８例，中度５例，重度３例；１４例慢性活动性肝炎（ＣＡＨ）全部阳性，其中轻度阳性２例，中度３例，重度９例，经等级秩和检验，两者差异显著（Ｐ＜００１）。急性黄疸性肝炎、亚急性重型肝炎轻度阳性。在３４例乙型肝炎肝组织中，３３例ＨＢｓＡｇ阳性，轻度阳性３例，其余为中到重度阳性，且ＣＰＨ与ＣＡＨ两组之间无统计学差异。结论（１）乙型肝炎病毒感染可诱导Ｂ７－１在肝组织表达，且表达强弱与肝炎病变程度正相关；（２）乙型肝炎表面抗原在组织中表达强弱与Ｂ７－１表达无关。（３）Ｂ７－１在肝组织中的表达可能是肝细胞活化积极参与免疫反应的佐证。     

Pathogenesis of chronic liver disease in patients with chronic hepatitis B virus infection without serum HBeAg

Chronic hepatitis B in patients lacking hepatitis B e antigen has been attributed to a hepatitis B virus variant (G-to-A mutation at nucleotide 1896 in the precore region of the genome). We therefore assessed the frequency and significance of this variant among 43 United States patients (10 with chronic hepatitis B seropositive for e antigen, 19 seronegative for e antigen, and 14 healthy carriers). Sera were tested for HBV DNA by polymerase chain reaction and branched DNA assay. The A₁₈₉₆ variant was detected by direct sequencing and ligase chain reaction. Serum HBV DNA was more frequently found among patients with e antigenpositive than e antigen-negative chronic hepatitis B. Viral titers were generally higher in those with e antigen. None of the e antigen-positive and only 24% of e antigen-negative patients harbored the A₁₈₉₆ variant. Patients infected with the variant were more often Asian, had had hepatitis B for longer and had higher levels of viral DNA than HBeAg-negative patients with the wild-type virus. The A₁₈₉₆ variant was found exclusively in patients infected with HBV genotypes C and D. Thus, the A₁₈₉₆ variant is uncommon in the United States. The activity of liver disease appears to be more closely related to the level of HBV replication than the presence of mutations at nucleotide 1896 in the genome.     

Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis.

Using an oligonucleotide hybridization assay, we studied the clinical implication of wild-type hepatitis B virus (HBV) and a HBV mutant that is unable to secrete hepatitis B e antigen (HBeAg) because of a translational defect due to a stop codon in the pre-C region in 106 hepatitis B surface antigen-positive patients with chronic hepatitis B. Wild-type HBV was detected in 31 of 42 (73.8%) HBeAg-positive patients, whereas a mixed viral population was present in 10 (23.8%). Significant differences in the severity and outcome of liver disease were not observed in the two groups of patients. However, the emergence of HBeAg-minus HBV in wild-type HBV carriers was associated with an exacerbation of liver disease and was followed by the presence of antibodies against HBeAg (anti-HBe) in serum in 50% of the cases. In 61 of 64 (95.3%) anti-HBe-positive patients, HBeAg-minus HBV was the predominant virus: HBeAg-minus HBV was detected in 42 patients (65.6%), whereas both wild-type and HBeAg-minus HBV were present in 19 (29.7%). HBeAg-minus HBV was associated with a course of hepatitis characterized by flare-ups of liver cell necrosis interspersed with periods of asymptomatic HBV carriage (P less than 0.01). These data support the hypothesis that genetic heterogeneity of HBV significantly influences the course and outcome of chronic hepatitis B. Wild-type HBV secreting HBeAg induces immunologic tolerance and causes chronic infection. HBeAg-minus HBV might be unable to induce chronic infection without the helper function of wild-type HBV, but it appears to be more pathogenic. Once chronic infection is established, HBeAg-minus HBV variants may prevail and displace wild-type virus.     

Histomorphological characteristics of liver tissue in patients with chronic viral hepatitis

OBJECTIVE : Chronic viral hepatitis and cirrhosis caused by hepatitis B virus (HBV), hepatitis C virus (HBC) or both constitute the majority of cases of liver diseases in China. Pathologists often need to differentiate between the morphological features of HBV and HCV. The aim of this study was to explore the differences in inflammatory activity, fibrosis and morphological characteristics in various types of chronic viral hepatitis. METHODS : Inflammatory activity and degree of fibrosis in liver biopsies taken from 224 patients with chronic hepatitis were determined according to the Diagnostic Criteria of Chronic Hepatitis, China, 1995. Each of hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg) and the hepatitis C virus nuclear core protein (CP₁₀) were detected on paraffin sections of the biopsies by using immunohistochemical methods. Patients were divided into HBV, HCV and HBV + HCV infection groups and the differences among these groups were assessed on the basis of histopathological characteristics including inflammatory activity, fibrosis, steatosis, intrahepatic cholestasis, Councilman bodies and ground‐glass hepatocytes. RESULTS : The HCV infection group had more severe inflammatory activity, fibrosis and intrahepatic cholestasis than did the HBV infection group. The degree of inflammatory activity and fibrosis in the HBV + HCV infection group was moderate, but the degree of intrahepatic cholestasis was the most severe of the three study groups. Ground‐glass hepatocytes were only noted in HBV‐infected specimens. There was no difference in the occurrences of steatosis and Councilman bodies among the three study groups. CONCLUSIONS : The degree of inflammatory activity and fibrosis induced by HCV in hepatocytes is more severe than that induced by HBV. The histological changes observed in liver infected by both HBV and HCV are no more severe than those observed in liver infected with either HBV or HCV. Intrahepatic cholestasis may play an important role in aggravating damage to hepatocytes.     

Hepatectomy in a hepatocellular carcinoma case with Dubin–Johnson syndrome and indocyanine green excretory defect

A 77-year-old male patient with history of jaundice was referred to our hospital for treatment of hepatocellular carcinoma (HCC). He was found to have Dubin–Johnson syndrome (DJS), a clinical feature of constitutional jaundice with conjugated hyperbilirubinemia, and indocyanine green (ICG) excretory defect, both of which are rare conditions. Total bilirubin was 5.1 mg/dl and ICG retention at 15 min (ICGR15) (77.1 %). Converted ICGR15 from GSA scintigraphy was 15.9 %. Resection of the medial segment and ventral region of the anterior segment of the liver as well as cholecystectomy were performed. The background of the liver tissue was blackish yellow and consistent with DJS and chronic hepatitis. Although total bilirubin level increased to 8.2 mg/dl on the 2nd postoperative day, the patient ultimately recovered and he was discharged on the 14th day. His 1- and 2-year medical checkups indicated recurrence of HCC. He underwent transarterial chemoembolization and is presently doing well 39 months after surgery. We report here on evaluation and treatment of patients with such disorders.     

Fatal reactivation of hepatitis B virus following cytotoxic chemotherapy for acute myelogenous leukemia: fibrosing cholestatic hepatitis

Hepatitis B virus (HBV) is a well known pathogen that sometimes causes fulminant hepatitis in patients undergoing cytotoxic chemotherapy. Fibrosing cholestatic hepatitis (FCH) is a recently recognized unique variant of viral hepatitis, which has been occasionally reported in HBV-infected recipients of liver, renal, or bone marrow transplantation. We present here a 48-yr-old male in whom HBV was reactivated during post-remission chemotherapy for acute myelogenous leukemia, which resulted in rapidly fatal outcome. He manifested with deterioration of liver function in association with enormous replication of HBV. Liver biopsy showed marked ballooning of hepatocytes, cholestasis, and periportal fibrosis with minimum infiltrates. Immunostaining revealed that hepatocytes were strongly positive for hepatitis B surface antigen. Under the diagnosis of FCH, he was treated with lamivudine and interferon beta, which was not effective. Autopsy showed severe atrophy of the liver and marked degeneration of hepatocytes. Hematologists should be aware that FCH is a fatal complication that can develop under post-chemotherapy immunosuppressed conditions. Although there is no convincing evidence, prophylactic administration of lamivudine seems to be a reasonable strategy.     

Hepatitis B Virus Genotype D Prevails in Patients with Persistently Elevated or Normal ALT Levels in Turkey

Abstract.Background: The clinical relevance of hepatits B virus (HBV) genotypes are poorly understood and it is unclear if the prevalence of HBV genotypes differs with the various clinical features of HBV carriers. The aim of our study was to examine the prevalence of the HBV genotype in a group of patients with chronic hepatitis B, compared to a group with chronic inactive hepatits B surface antigen (HbsAg) carriers.Patients and Methods: HBV genotypes were determined in 32 patients with chronic hepatitis B and in 12 chronic inactive HBsAg carriers. 35 males and nine females with a mean age of 33.95 ± 13.04 were studied. Serum samples were examined for the presence of HBV DNA by polymerase chain reaction (PCR). Samples negative in first round PCR were further amplified with nested PCR. The PCR product was sequenced with the Cy5/5.5 dye primer kit on a Long Read Tower automated DNA sequencer.Results: HBV DNA was detectable in 29 (66%) and 44 (100%) patients by the PCR with universal primers and nested-PCR, respectively. All patients were found to be infected with HBV genotype D. Genotype D was the only detected type found in different clinical forms of chronic HBV infection, in all hepatitis B e antigen (HbeAg)-positive and negative patients, in all patients who had elevated or normal alanine transaminase (ALT) levels and in all ages.Conclusion: In the present study we could not find any association between genotype D and distinct clinical phenotypes. Genotype D is the predominant type among hepatitis B carriers residing in our region and is not associated with more severe liver diseases. This genotype did not influence clinical manifestations in carriers with chronic hepatitis B virus infection. However, additional large-scale longitudinal studies are needed to find the relationship of HBV genotypes to liver disease severity and clinical outcomes.     

Multicenter study of lamivudine therapy for hepatitis B after liver transplantation. Lamivudine Transplant Group

Hepatitis B after liver transplantation is often fatal, and no proven medical therapy exists for this condition. We chose to study the potential efficacy of lamivudine therapy for patients with chronic hepatitis B after liver transplantation. Fifty-two patients with chronic hepatitis B after liver transplantation were treated in an open label, multicenter study. Each had detectable hepatitis B virus (HBV) DNA in serum and 45 (87%) had detectable serum hepatitis B e antigen before treatment. Patients were treated for 52 weeks with lamivudine (100 mg daily). The primary endpoint was undetectability of HBV DNA; secondary endpoints included normalization of serum alanine transaminase (ALT) levels, disappearance of hepatitis B e antigen, and improvement in liver histology. After treatment, 60% of patients had undetectable HBV DNA by solution hybridization assay, 14 (31%) of the initially positive patients lost hepatitis B e antigen; hepatitis B surface antigen was undetectable in 3 (6%); and serum ALT levels normalized in 71%. Blinded histological assessments showed improvement in the histological activity index (P =.007 for periportal necrosis,.001 for lobular necrosis, and.013 for portal inflammation). YMDD variants of HBV, potentially associated with drug resistance, were detected in 14 (27%) of the patients. Repeat liver biopsies in 7 patients with the mutated virus were unchanged in 2, improved in 2, and worse in 3. We conclude that lamivudine is a potentially effective therapy for hepatitis B after liver transplantation.