Hepatitis viruses and hepatocellular carcinoma

Of the hepatitis viruses that have been identified and their pathological consequences characterised, three - hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) - have been implicated as risk factors for hepatocellular carcinoma (HCC) in humans. Sufficient evidence is now available to justify the conclusions that chronic infection with HBV and HCV, but not HDV, are causes of HCC. Hepatocellular carcinogenesis is a complex step-wise process that evolves over many years, and the precise way(s) in which these two viruses induce malignant transformation remain uncertain. The observation that HBV DNA is integrated into cellular DNA in the great majority of, and perhaps all, HBV-related HCCs, whereas replicative intermediates of HCV do not insert into host DNA in HCVrelated HCC, makes it very likely that different pathogenic mechanisms operate in HBV- and HCV-induced HCC. Indeed, evidence is mounting that both direct and indirect mechanisms, and often the two together, are involved in the genesis of HBV-related HCC, but that HCV appears only to induce HCC indirectly by causing chronic necroinflammatory hepatic disease which in turn is responsible for tumour formation. There is some evidence that the two viruses may interact in the development of HCC, but this remains to be proven. Animal models - other members of the hepadnavirus family (to which HBV belongs) that also cause HCC in their respective animal hosts, and transgenic mice into which sequences of HBV DNA have been inserted - are proving useful in elucidating putative mechanisms of HBV-related hepatocellular carcinogenesis, but no models for studying HCV-induced HCC are yet available. Whatever the pathogenesis of HBV-induced and HCV-induced HCC, the viruses do not act alone but in conjunction with other environmental carcinogens and a number of host factors

Thyroxine-binding globulin, hyperthyroxinemia and hepatocellular carcinoma

To determine serum thyroxine-binding globulin (TBG) levels, we used radioimmunoassay, and compared the results obtained with other tests in 231 patients with chronic hepatitis B virus infection to evaluate its clinical implications. All of these patients were hepatitis B surface antigen (HBsAg)-positive. Among them, 38 patients had hepatocellular carcinoma (HCC), 18 had chronic persistent hepatitis, 70 had chronic lobular or active hepatitis (grouped as CAH), 31 had active cirrhosis (AC), 25 had inactive cirrhosis, 20 had decompensated cirrhosis, and 29 were “healthy” HBsAg carriers. Twenty-seven patients with acute hepatitis, 12 with cancer metastasis to the liver, and 81 normal adults served as disease or normal controls. The results showed that serum TBG level increased significantly in patients with CAH, AC, or HCC. Serum TBG did not correlate with albumin or bilirubin level, but correlated with alanine aminotransferase (ALT) positively in patients with CAH ( p < 0.001) and negatively in patients with HCC ( p < 0.01) (slope difference p < 0.05). Serial determination of serum TBG and ALT also showed parallel changes in 15 patients with CAH, but not in nine patients with HCC. In contrast, the fall and rise of serum TBG levels in patients with HCC coincided with tumor resection and recurrence. The data suggest that serum TBG elevation in patients with hepatitis activity is the result of hepatocellular damage, whereas that in patients with HCC is due to increased synthesis. Whether serum TBG elevation without concomitant rise of ALT could be used as a marker of HCC awaits further study.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38358/1/1840130434_ftp.pd

HBV and proteinuria in relatives and contacts of children with hepatitis B virus-associated membranous nephropathy

HBV and proteinuria in relatives and contacts of children with hepatitis B virus-associated membranous nephropathy.BackgroundHepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) is an important cause of childhood nephrotic syndrome in regions endemic for the virus, but little is understood of the biosocial context in which the disease develops. We evaluated HBV status and proteinuria in family members and household contacts of index children with HBVMN to test the hypothesis that HBV carriage and asymptomatic proteinuria are closely linked and may be causally associated.MethodsThirty-one black children with biopsy-proven HBVMN were the index cases. One hundred and fifty-two family members and 43 black household contacts were the subjects of the study. We assessed HBV carrier status by testing for HBV antigens and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA by using slot-blot hybridization and the polymerase chain reaction. Sequencing of the precore region of HBV was done in a subset of both index cases and subjects. Proteinuria was assessed by measuring the urinary protein/creatinine ratio.ResultsSeventy-two (37%) of the 195 family members and household contacts were HBV carriers, and 53 (27%) had a protein/creatinine ratio greater than the physiological limit. The frequency of abnormal proteinuria was not significantly different in those with [22 out of 72 (30.5%)] or without [33 out of 104 (32%)] HBV carriage. This lack of association remained when carriers were classified into those who were HBsAg positive only and those with active viral replication (HBsAg and/or HBeAg and/or HBV DNA; P = 0.01). Family members were more predisposed to HBV carriage than household contacts, but abnormal proteinuria was present with equal frequency (P = 0.48). Age had a significant impact on proteinuria, with children less than five years being more likely to have abnormal proteinuria (P = 0.008). The prevalence of abnormal proteinuria in family members and household contacts of the index cases was more than that in community-based controls. The 10 index HBVMN cases and the 14 family members and household contacts who were tested all had HBV of genotype A.ConclusionThese results suggest that the family members and household contacts of children with HBVMN are at very high risk of HBV carriage; they also have asymptomatic proteinuria at a significantly higher rate than community-based controls. The HBV carrier status was not associated with proteinuria, a finding supported by peak prevalences of proteinuria in those under five years but no corresponding peak for HBV carriage. Proteinuria may indicate glomerular basement membrane dysfunction. Environmental and social factors may underpin development of these two covert disorders, but are insufficient to account for the index cases of HBVMN. The emergence of children with HBVMN from such households additionally depends on unidentified and possibly genetic factors

Effects of Exogenous Antioxidants on Dietary Iron Overload

In dietary iron overload, excess hepatic iron promotes liver damage. The aim was to attenuate free radical-induced liver damage using vitamins. Four groups of 60 Wistar rats were studied: group 1 (control) was fed normal diet, group 2 (Fe) 2.5% pentacarbonyl iron (CI) followed by 0.5% Ferrocene, group 3 (Fe + V gp) CI, Ferrocene, plus vitamins A and E (42× and 10× RDA, respectively), group 4 (Fe – V gp) CI, Ferrocene diet, minus vitamins A and E. At 20 months, glutathione peroxidase (GPx), superoxide dismutase (SOD), Oxygen Radical Absorbance Capacity (ORAC), Ames mutagenicity test, AST, ALT and 4-hydroxynonenal (4-HNE) immunohistochemistry were measured. 8OHdG levels of the Fe + V and Fe – V groups were 346 ± 117 and 455 ± 151, ng/g w.wt, respectively. Fe + V and Fe – V differences were significant (p<0.005). A positive correlation between DNA damage and mutagenesis existed (p<0.005) within the iron-fed gps. AST levels for Fe + V and Fe – V groups were 134.6 ± 48.6 IU and 202.2 ± 50.5 IU, respectively. Similarly, ALT levels were 234.6 ± 48.3 IU and 329.0 ± 48.6 IU, respectively. However, Fe – V and Fe + V groups transaminases were statistically insignificant. 4-HNE was detected in Fe + V and Fe – V gp livers. Vitamins A and E could not prevent hepatic damage

The appropriateness of ceftriaxone and metronidazole as empirical therapy in managing complicated intra-abdominal infection—experience from Western Health, Australia

Purpose This study aims to assess the microbiological profile, antimicrobial susceptibility and adequacy of intravenous ceftriaxone and metronidazole as empirical therapy for surgical patients presenting with complicated intra-abdominal infection. Methods This retrospective audit reviews the microbiological profile and sensitivity of intra-abdominal cultures from adult patients with complicated intra-abdominal infection who presented to the emergency department at Western Health (Melbourne, Australia) between November 2013 and June 2017. Using the hospital’s database, an audit was completed using diagnosis related group (DRG) coded data. Ethics approval has been granted by the Western Health Human Research Ethics Committee. Results are stratified according to surgical conditions (appendicitis, cholecystitis, sigmoid diverticulitis and bowel perforation). The antimicrobial coverage of ceftriaxone and metronidazole is evaluated against these microbial profiles. Results A total of 1,412 patients were identified using DRG codes for intra-abdominal infection. All patients with microscopy and sensitivity results were included in the study. Patients without these results were excluded. 162 patients were evaluable. 180 microbiological cultures were performed through surgical intervention or radiologically guided aspiration of the intra-abdominal infection. Single or multiple pathogens were identified in 137 cultures. The most commonly identified pathogens were mixed anaerobes (12.6%), Escherichia coli (E. coli) (12.1%), mixed coliforms (11.6%) and Pseudomonas aeruginosa (7%). Other common pathogens (6% each) included Enterococcus faecalis, Streptococcus anginosus, Vancomycin-resistant Enterococci (VRE) and Extended Spectrum Beta-Lactamases (ESBL) producing E. coli. Organisms isolated in our study are consistent with existing literature. However, a significant proportion of antibiotic resistant organisms was identified in cases of perforated bowel and sigmoid diverticulitis. Broader spectrum antimicrobial therapy should therefore be considered in lieu of ceftriaxone and metronidazole in these cases. Ceftriaxone and metronidazole remain as appropriate empirical therapy for patients who presented with perforated appendicitis and cholecystitis. Discussion The empirical regime of ceftriaxone and metronidazole remains appropriate for intra-abdominal infection secondary to appendicitis and cholecystitis. In cases involving perforated small and large bowel, including complicated sigmoid diverticulitis, the judicious use of ceftriaxone and metronidazole is recommended

A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D

There are two subtypes of hepatitis B virus genotype A (HBV/A) and they are provisionally designated Aa (a standing for Africa/Asia) and Ae (e for Europe). In a case-control study, 78 HBV/Aa, 78HBV/Ae, and 78HBV/D carriers from several countries were compared. The prevalence of HBe antigen (HBeAg) in serum was significantly lower in carriers of HBV/Aa than in carriers of HBV/Ae (31% vs. 49%; P = .033), with a difference more obvious in the carriers aged 30 years or younger (34% vs. 67%; P = .029). HBV DNA levels in the carriers of HBV/Aa (median, 3.46 log copies/mL; 95% CI, 2.93-3.95) were significantly lower than those of carriers of HBV/Ae (6.09 log copies/mL; 95% CI, 4.24-7.64) or of carriers of HBV/D (5.48 log copies/mL; 95% CI, 4.06-7.02), regardless of the HBeAg status (P &lt; .001). The most specific and frequent substitutions in 54 HBV/Aa isolates were double substitutions for T1809 (100%) and T1812 (96%) immediately upstream of the precore initiation codon, which would interfere with the translation of HBeAg in HBV/Aa infections. They were not detected in 57 HBV/Ae or 61 HBV/D isolates examined. The double mutation in the core promoter (T1762/A1764) was more frequent in both HBV/Aa (50%) and HBV/Ae (44%) than in HBV/D isolates (25%; P &lt; .01), whereas the precore mutation (A1896) occurred in HBV/D isolates only (48%; P &lt; .0001). In conclusion, the clearance of HBeAg from serum may occur by different mechanisms in HBV/Aa, HBV/Ae, and HBV/D infections, which may influence clinical manifestations in the Western countries where both genotypes A and D are prevalent