Age at infection with hepatitis B virus (HBV) is a known risk factor for chronic HBV infection. However, in addition, there is some evidence that early age at infection further increases the risk of primary liver cancer beyond its association with increased risk of chronic infection. This systematic review of observational studies assesses the association between age at initiation of chronic HBV infection and liver cirrhosis, hepatocellular carcinoma, and their predictors including indicators of ongoing viral replication and hepatic damage. The review includes birth order and maternal HBV serology as proxies for age at infection. Electronic searches in two English-language (Medline and Embase, until Jan 2012) and two Chinese-language (CNKI and SinoMed, until Sep 2012) databases without language restriction and manual search through reference lists identified 7,077 papers, of which 19 studies of 21 outcomes (8 primary liver cancer, 1 liver cirrhosis, 10 viral replication and 2 liver inflammation) are included. One study directly examined the age at infection in a longitudinal cohort, 12 assessed maternal sero-status and 6 investigated birth order. The direction of associations in all studies was in accordance with our hypothesis that earlier age at infection is associated with worse outcomes in addition to its effect of increasing the probability of chronic HBV infection. This has implications for the control of hepatitis B.
AIM: To evaluate the relationship between a positive family history of primary liver cancer and hepatocellular carcinoma (HCC) development in Korean HCC patients.
METHODS: We studied a total of 2242 patients diagnosed with HCC between January 1990 and July 2008, whose family history of primary liver cancer was clearly described in the medical records.
RESULTS: Of the 2242 patients, 165 (7.4%) had a positive family history of HCC and 2077 (92.6%) did not. The male to female ratio was 3.6:1, and the major causes of HCC were chronic hepatitis B virus (HBV) infection in 75.1%, chronic hepatitis C virus infection in 13.2% and alcohol in 3.1%. The median ages at diagnosis in the positive- and negative-history groups were 52 years (range: 29-79 years) and 57 years (range: 18-89 years), respectively (P < 0.0001). Furthermore, among 1713 HCC patients with HBV infection, the number of patients under 45 years of age out of 136 patients with positive family history was 26 (19.1%), whereas those out of 1577 patients with negative family history was 197 (12.5%), suggesting that a positive family history may be associated with earlier development of HCC in the Korean population (P = 0.0028).
CONCLUSION: More intensive surveillance maybe recommended to those with a positive family history of HCC for earlier diagnosis and proper management especially when HBV infection is present.
Liver cancer; Hepatocellular carcinoma; Family history; Epidemiology
The infection with hepatitis C virus (HCV) is one of the most important global chronic viral infections worldwide. It is estimated to affect around 3% of the world population, about 170-200 million people. Great part of the infections are asymptomatic, the patient can be a chronic carrier for decades without knowing it. The most severe consequences of the chronic infection are liver cirrhosis and hepatocellular carcinoma, which appears in 20%-40% of the patients, leading to hepatic failure and death. The HCV was discovered 25 years ago in 1989, is a RNA virus and classified by the World Health Organization as an oncogenic one. Hepatocellular carcinoma is one of the most important cancers, the fifth worldwide in terms of mortality. It has been increasing in the Ocidental world, mainly due to chronic hepatitis C. Hepatitis C is not only a liver disease and a cause of cirrhosis, but also a mental, psychological, familiar, and social disease. The stigma that the infected person sometimes carries is tremendous having multiple consequences. The main cause is lack of adequate information, even in the health professionals setting. But, besides the “drama” of being infected, health professionals, family, society and the infected patients, must be aware of the chance of real cure and total and definitive elimination of the virus. The treatment for hepatitis C has begun in the last 80´s with a percentage of cure of 6%. Step by step the efficacy of the therapy for hepatitis C is rapidly increasing and nowadays with the very new medications, the so called Direct Antiviral Agents-DAAs of new generation, is around 80%-90%.
Hepatitis C; Chronic; Therapy; Hepatocellular carcinoma; Hepatic cirrhosis; Interferon-alpha; Ribavirin; Social stigma; Depression
As part of a larger study designed to investigate the interaction of factors such as cirrhosis and hepatitis B virus infection as aetiological agents in the development of hepatocellular carcinoma, we investigated the status of hepatic HBV-DNA sequences in 156 cirrhotic patients. Forty-one were HBsAg seropositive and 18 (44%) of these had HBV-DNA sequences detectable in their livers. There are also 26 subjects who showed markers of a previous HBV infection (anti-HBs/anti-HBc), only one (4%) of whom had demonstrable hepatic HBV-DNA sequences. No sequences were found in any of the remaining 89 patients who were seronegative for all markers. Thus, liver HBV-DNA was only detected in the presence of a serum marker, usually HBsAg.
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and represents the third-leading cause of cancer-related death in the world. The incidence of HCC continues to increase worldwide, with a unique geographic, age, and sex distribution. The most important risk factor associated with HCC is liver cirrhosis, with the majority of cases caused by chronic infection with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse, although nonalcoholic fatty liver disease is emerging as an increasingly important cause. Primary prevention in the form of HBV vaccination has led to a significant decrease in HBV-related HCC, and initiation of antiviral therapy appears to reduce the incidence of HCC in patients with chronic HBV or HCV infection. Additionally, the use of ultrasonography enables the early detection of small liver tumors and forms the backbone of recommended surveillance programs for patients at high risk for the development of HCC. Cross-sectional imaging studies, including computed tomography and magnetic resonance imaging, represent further noninvasive techniques that are increasingly employed to diagnose HCC in patients with cirrhosis. The mainstay of potentially curative therapy includes surgery – either resection or liver transplantation. However, most patients are ineligible for surgery, because of either advanced disease or underlying liver dysfunction, and are managed with locoregional and/or systemic therapies. Randomized controlled trials have demonstrated a survival benefit with both local therapies, either ablation or embolization, and systemic therapy in the form of the multikinase inhibitor sorafenib. Despite this, median survival remains poor and recurrence rates significant. Further advances in our understanding of the molecular pathogenesis of HCC hold promise in improving the diagnosis and treatment of this highly lethal cancer.
hepatocellular carcinoma; viral hepatitis; liver transplantation; ablation; embolization; sorafenib
Hepatitis B virus (HBV) is a common cause of viral hepatitis with significant health complications including cirrhosis and hepatocellular carcinoma. Assays for hepatitis B surface antigen (HBsAg) are the most frequently used tests to detect HBV infection. Vaccination for HBV can produce transiently detectable levels of HBsAg in patients. However, the time course and duration of this effect is unclear. The objective of this retrospective study was to clarify the frequency and duration of transient HBsAg positivity following vaccination against HBV.
The electronic medical record at an academic tertiary care medical center was searched to identify all orders for HBsAg within a 17 month time period. Detailed chart review was performed to identify all patients who were administered HBV vaccine within 180 days prior to HBsAg testing and also to ascertain likely cause of weakly positive (grayzone) results.
During the 17 month study period, 11,719 HBsAg tests were ordered on 9,930 patients. There were 34 tests performed on 34 patients who received HBV vaccine 14 days or less prior to HBsAg testing. Of these 34 patients, 11 had grayzone results for HBsAg that could be attributed to recent vaccination. Ten of the 11 patients were renal dialysis patients who were receiving HBsAg testing as part of routine and ongoing monitoring. Beyond 14 days, there were no reactive or grayzone HBsAg tests that could be attributed to recent HBV vaccination. HBsAg results reached a peak COI two to three days following vaccination before decaying. Further analysis of all the grayzone results within the 17 month study period (43 results out of 11,719 tests) revealed that only 4 of 43 were the result of true HBV infection as verified by confirmatory testing.
Our study confirms that transient HBsAg positivity can occur in patients following HBV vaccination. The results suggest this positivity is unlikely to persist beyond 14 days post-vaccination. Our study also demonstrates that weakly positive HBsAg results often do not reflect actual HBV infection, underscoring the importance of confirmatory testing. This study also emphasizes that vaccination-induced HBsAg positives occur most commonly in hemodialysis patients.
False positive reactions; Hepatitis; Hepatitis B surface antigens; Public health; Renal dialysis; Vaccination
Primary liver cancer is an important cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 70%-85% of total liver cancer worldwide. Chronic hepatitis B virus (HBV) infection contributes to > 75% of HCC cases. High serum viral load is the most reliable indicator of viral replication in predicting development of HCC. HBV genotype C is closely associated with HCC in cirrhotic patients aged > 50 years, whereas genotype B is associated with development of HCC in non-cirrhotic young patients and postoperative relapse of HCC. Different HBV subgenotypes have distinct patterns of mutations, which are clearly associated with increased risk of HCC. Mutations accumulate during chronic HBV infection and predict occurrence of HCC. Chronic inflammation leads to increased frequency of viral mutation via cellular cytidine deaminase induction. Mutations are negatively selected by host immunity, whereas some immuno-escaped HBV mutants are active in hepatocarcinogenesis. Inflammatory pathways contribute to the inflammation-necrosis-regeneration process, ultimately HCC. Their hallmark molecules can predict malignancy in HBV-infected subjects. Continuing inflammation is involved in hepatocarcinogenesis and closely related to recurrence and metastasis. HBV load, genotype C, viral mutations and expression of inflammatory molecules in HBV-related HCC tissues are significantly associated with poor prognosis. Imbalance between intratumoral CD8+ T cells and regulatory T cells or Th1 and Th2 cytokines in peritumoral tissues can predict prognosis of HBV-related HCC. These factors are important for developing active prevention and surveillance of HBV-infected subjects who are more likely to develop HCC, or for tailoring suitable treatment to improve survival or postpone postoperative recurrence of HCC.
Hepatitis B virus; Hepatocellular carcinoma; Viral load; Genotype; Mutation; Immune cells; Signaling pathway; Cytokine; Prognosis
It has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet.
We conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed.
We found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively).
Our study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients.
Hepatitis B virus; Pancreatic cancer; Liver metastasis; Survival
Post-transplant malignancy is the major cause of later death of recipients after liver transplantation. Tumor recurrence after liver transplantation for patients with hepatocellular carcinoma in the end stage of cirrhosis has been frequently encountered. However, de novo hepatocellular carcinoma originating from the liver allograft has only rarely been reported. Here we reported a case of de novo hepatocellular carcinoma developed 2 years after living donor liver transplantation for hepatitis B-related liver cirrhosis with viral YMDD mutation. To the best of our knowledge, this is the first report of de novo hepatocellular carcinoma in a liver graft with recurrent hepatitis B virus infection after liver transplantation for hepatitis B-related liver cirrhosis with YMDD mutation. Moreover, the de novo cancer first presented as a lung mass with minimal liver involvement and was obscured by a pulmonary fungal infection.
De novo hepatocellular carcinoma; Liver transplantation; Living donor liver transplantation; Hepatitis B recurrence; YMDD mutation
Hepatitis D virus (HDV) superinfection in patients with chronic hepatitis B leads to accelerated liver injury, early cirrhosis, and decompensation. It may be speculated that hepatocellular carcinoma (HCC) may differ in these patients from hepatitis B virus (HBV) monoinfection. The aim of this study was to compare clinical aspects of hepatocellular carcinoma in patients of hepatitis D with HBV monoinfection.
Patients and Methods:
A total of 92 consecutive HCC cases seropositive for antibody against HDV antigen (HDV group) were compared with 92 HBsAg-positive and anti-HDV-negative cases (HBV group).
The features including sex, body mass index, presence of ascites, serum biochemistry, gross tumor appearance, child class, barcelona cancer liver clinic and okuda stages were not significantly different between the 2 groups. Decreased liver size was noticed more in cases of HDV compared with HBV group where the liver size was normal or increased (P=0.000). HDV patients had lower platelets (P=0.053) and larger varices on endoscopy (P=0.004). Multifocal tumors and elevated alpha-fetoprotein level >1000 IU/mL were more common in HBV group (P=0.040 and P= 0.061). TNM classification showed more stage III-IV disease in HBV group (P=0.000).
Decreased liver size and indirect evidence of more severe portal hypertension and earlier TNM stage compared with HBV monoinfection indicate that HDV infection causes HCC in a different way, possibly indirectly by inducing inflammation and cirrhosis.
Hepatocellular carcinoma; hepatitis D; hepatitis B
Hepatocellular carcinoma is the most common cause of primary liver neoplasms and is one of the main causes of death in patients with liver cirrhosis. High Alpha fetoprotein serum levels have been found in 60–70% of patients with Hepatocellular carcinoma; nevertheless, there are other causes that increase this protein. Alpha fetoprotein levels ≥200 and 400 ng/mL in patients with an identifiable liver mass by imaging techniques are diagnostic of hepatocellular carcinoma with high specificity.
We analysed the sensitivity and specificity of the progressive increase of the levels of alpha fetoprotein for the detection of hepatocellular carcinoma in patients with liver cirrhosis. Seventy-four patients with cirrhosis without hepatocellular carcinoma and 193 with hepatic lesions diagnosed by biopsy and shown by image scans were included. Sensitivity and specificity of transversal determination of alpha fetoprotein ≥ 200 and 400 ng/mL and monthly progressive elevation of alpha fetoprotein were analysed. Areas under the ROC curves were compared. Positive and negative predictive values adjusted to a 5 and 10% prevalence were calculated.
For an elevation of alpha fetoprotein ≥ 200 and 400 ng/mL the specificity is of 100% in both cases, with a sensitivity of 36.3 and 20.2%, respectively. For an alpha fetoprotein elevation rate ≥7 ng/mL/month, sensitivity was of 71.4% and specificity of 100%. The area under the ROC curve of the progressive elevation was significantly greater than that of the transversal determination of alpha fetoprotein. The positive and negative predictive values modified to a 10% prevalence are of: 98.8% and 96.92%, respectively; while for a prevalence of 5% they were of 97.4% and 98.52%, respectively.
The progressive elevation of alpha fetoprotein ≥7 ng/mL/month in patients with liver cirrhosis is useful for the diagnosis of hepatocellular carcinoma in patients that do not reach αFP levels ≥200 ng/mL. Prospective studies are required to confirm this observation.
Occult hepatitis B virus (HBV) infection (OBI) is frequently reported in patients with chronic hepatitis C virus (HCV) infection. An association between OBI and more liver damage, cirrhosis, hepatocellular carcinoma, and reduced response to interferon therapy in patients with HCV infection is suggested.
The aim of this study was to determine the prevalence of occult HBV, and evaluate its clinical influence on patients with chronic HCV.
Patients and Methods
A cohort study including50 patients with positive results for HCV, and negative results for HBsAg tests was performed. The patients were divided into two groups: one group had positive results for both HCV and occult HBV tests (n = 18), and the other had positive results for HCV, but negative findings for occult HBV (n = 32). All were treated with PEG-IFN alpha-2a and Ribavirin. Presence of HCV RNA was followed in these patients.
HBV-DNA was detected using nested-PCR in 20% of plasma and 32.6% of peripheral blood mononuclear cell (PBMC) compartments. No significant differences were observed between patients with and without occult HBV for sex, age, duration of HCV infection, histological markers, presence of anti-HBc, HCV viral load, and HCV genotype. The response rate was significantly higher in patients with positive results for HBV-DNA test compared to those with negative findings (100% vs. 71.9 %, P < 0.05).
In conclusion, occult HBV was found in 36% of patients with negative results for HBsAg, but positive results for HCV. Detection of HBV-DNA in both PBMCs and plasma together in comparison with plasma alone provided more true identification of OBI.The SVR rate was significantly higher in coinfected patients than mono-infected ones.
Hepatitis B; Hepatitis C Virus; Peripheral Blood Mononuclear Cell
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infection in other malignancies. This study aimed to determine whether HBV and HCV infections increase the risk for pancreatic cancer development.
Patients and Methods
At The University of Texas M. D. Anderson Cancer Center, Houston, TX, we recruited 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs).
Anti-HCV was positive in seven cases (1.5%) and nine controls (1%). Anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% CIs were as follows: anti-HCV–positive, 0.9 (95% CI, 0.3 to 2.8), anti-HBc–positive, 2.5 (95% CI, 1.5 to 4.2), anti-HBc–positive/anti-HBs–positive, 2.3 (95% CI, 1.2 to 4.2), and anti-HBc–positive/anti-HBs–negative, 4 (95% CI, 1.4 to 11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR, 7.1; 95% CI, 1.7 to 28.7).
Past exposure to HBV may be associated with pancreatic cancer development. Should such findings be confirmed by other studies, it may offer important insights into the etiology of pancreatic cancer and may suggest the need to consider prevention of HBV reactivation among patients with HBV-related pancreatic cancer during chemotherapy.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infection in other malignancies. This study aimed to determine whether HBV and HCV infection increase the risk for pancreatic cancer development.
Patients and Methods
At The University of Texas M.D. Anderson Cancer Center, Houston, we recruited 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs).
Anti-HCV was positive in 7 cases (1.5%) and 9 controls (1%). Anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% confidence intervals (CIs) were as follows: anti-HCV+, 0.9 (0.3–2.8), anti-HBc+, 2.5 (1.5–4.2), anti-HBc+/anti-HBs+, 2.3 (1.2–4.2), and anti-HBc+/anti-HBs-, 4 (1.4–11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR, 7.1; 95% CI, 1.7–28.7).
Past exposure to HBV may be associated with pancreatic cancer development. Should such findings be confirmed by other studies, it may offer important insights on the etiology of the pancreatic cancer and may suggest the need to consider prevention of HBV reactivation among HBV-related pancreatic cancer patients during chemotherapy treatment.
Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV (“preS2 mutant”) that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged—2-year-old—mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines—expressing either mutant or wildtype HBV—therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC.
To date, no attempt has been made to systematically determine the apportionment of the hepatocellular carcinoma burden in Europe or North America among established risk factors.
Using data collected from 1992 to 2006, which included 4 409 809 person-years in the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 125 case patients with hepatocellular carcinoma, of whom 115 were matched to 229 control subjects. We calculated odds ratios (ORs) for the association of documented risk factors for hepatocellular carcinoma with incidence of this disease and estimated their importance in this European cohort.
Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50 and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR = 2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98, 95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91, respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to 4.27) were associated with hepatocellular carcinoma. Smoking contributed to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2% and 20.9% were attributable to chronic HBV and HCV infection, respectively. Obesity and heavy alcohol intake contributed 16.1% and 10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to 79.3%) of hepatocellular carcinomas can be accounted for by exposure to at least one of these documented risk factors.
Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.
Hepatitis B virus (HBV) infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. HBV replicates through an RNA intermediate and can integrate into the host genome. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. Virological and serological assays have been developed for diagnosis of various forms of HBV-associated disease and for treatment of chronic hepatitis B infection. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. Most adults infected with the virus recover, but 5%–10% are unable to clear the virus and become chronically infected. Many chronically infected persons have mild liver disease with little or no long-term morbidity or mortality. Other individuals with chronic HBV infection develop active disease, which can progress to cirrhosis and liver cancer. These patients require careful monitoring and warrant therapeutic intervention. Extrahepatic manifestations of HBV infection are rare but can be difficult to diagnose and manage. The challenges in the area of HBV-associated disease are the lack of knowledge in predicting outcome and progression of HBV infection and an unmet need to understand the molecular, cellular, immunological, and genetic basis of various disease manifestations associated with HBV infection.
The clinical outcome of hepatitis B virus (HBV) infection is variable, ranging from spontaneous recovery to an inactive carrier state, chronic hepatitis, occult HBV infection, liver cirrhosis, or hepatocellular carcinoma.
This variable pattern and clinical outcomes of the infection were mainly determined by virological and host genetic factors. Since the most of host genetic factors associated with HBV infection have currently focused on human leukocyte antigen (HLA) associations and interleukin (IL)-10 gene polymorphisms, this review focuses on the recent progresses in these issues to provide prognostic markers for the outcome of HBV infection.
A study on serum levels of IL-10 in occult HBV infected patients reported that the higher level of IL-10 production may suppress function of the immune system against HBV in patients with occult HBV infection. IL-10 promoter polymorphism at position -592 is associated with susceptibility to occult HBV infection.
Findings of this study suggest that the host HLA polymorphism is an important factor in determining outcome of HBV infection but regarding IL-10 gene promoter polymorphisms, we are still have a long way to achieve a deﬁnite conclusion.
Hepatitis B Virus; Interleukin (IL)-10 gene; HLA Antigens
We compared the accuracy and usefulness of clinical diagnostic criteria for hepatocellular carcinoma in a hepatitis B virus (HBV)-endemic area.
We reviewed the medical records of 355 patients who had undergone liver resection or biopsy at our institution between January 2008 and December 2009. These patients were reevaluated using four noninvasive diagnostic criteria for hepatocellular carcinoma proposed by the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), the Korean Liver Cancer Study Group and the National Cancer Center (KLCSG/NCC), and National Comprehensive Cancer Network (NCCN) guidelines.
The overall sensitivity was highest using the KLCSG/NCC criteria (79.8%), followed by the AASLD (51.5%), EASL (38.4%), and NCCN (10.1%; P<0.001) criteria, whereas the specificity (84.5-98.3%) and positive predictive value (96.2-98.3%) were similar for all of the criteria. The KLCSG/NCC criteria had an acceptable false-positive rate and the highest sensitivity among all of the patients, including those positive for HBsAg, those without liver cancer, and those with a tumor of at least 2 cm.
The KLCSG/NCC and AASLD criteria exhibited the highest sensitivity, and all four guidelines had a high specificity among all of the patients. Based on the sensitivity and false-positive rate, the KLCSG/NCC criteria was the most useful in the majority of patients. Inclusion of HBV infection in the clinical diagnostic criteria for hepatocellular carcinoma would be reasonable and may lead to an improvement in the sensitivity, with acceptable false-positive rates, in HBV-endemic areas.
Comparison; Clinical diagnostic criteria; Hepatocellular carcinoma
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are global health problems affecting 600 million people worldwide. Indeed, HBV and HCV are hepatotropic viruses that can cause acute and chronic liver disease progressing to liver cirrhosis and even hepatocellular carcinoma. Furthermore, co-infections of HBV and HCV with HIV are emerging worldwide. These co-infections are even more likely to develop persistent infection and are difficult to treat. There is growing evidence that virus-specific CD4+ and CD8+ T-cell responses play a central role in the outcome and pathogenesis of HBV and HCV infection. While virus-specific T-cell responses are able to successfully clear the virus in a subpopulation of patients, failure of these T-cell responses is associated with the development of viral persistence. In this review article, we will discuss similarities and differences in HBV- and HCV-specific T-cell responses that are central in determining viral clearance, persistence and liver disease.
adaptive immunity; CD4+ and CD8+ T cells; hepatitis B virus; hepatitis C virus
Although occult hepatitis B virus (HBV) infections in individuals without detectable hepatitis B surface antigen (HBsAg) may occur and have been reported to be common in patients with chronic hepatitis C, the clinical relevance remains controversial. We searched for serum HBV DNA in 210 HBsAg-negative patients with hepatitis C virus (HCV)-related liver disease (110 patients with chronic hepatitis, 50 patients with cirrhosis, and 50 patients with hepatocellular carcinoma) by PCR. Most of the patients had detectable antibodies to HBsAg or HBV core antigen. All of the 110 chronic hepatitis C patients were treated with a combination therapy consisting of interferon plus ribavirin. In addition, 100 HBsAg-negative healthy adults served as controls. Thirty-one of the 210 patients (14.8%) had HBV DNA in their sera, as did 15 of the 100 healthy controls (15%). HBV DNA was not detected in the sera of those negative for serological markers of HBV infection. In patients with chronic HCV infection, the prevalence of occult HBV infection did not parallel the severity of liver disease (14.5% in patients with chronic hepatitis, 8% in patients with liver cirrhosis, and 22% in patients with hepatocellular carcinoma). In addition, the sustained response to combination therapy against hepatitis C was comparable between patients with and without occult HBV infection (38 versus 39%). In conclusion, these data suggest that occult HBV infection does not have clinical significance in chronic hepatitis C patients residing in areas where HBV infection is endemic.
Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer death in the United States. Although many risk factors for HCC, including hepatitis B (HBV), hepatitis C (HCV), and alcohol are well-defined, most series show that 5-30% of HCC patients lack a readily-identifiable risk factor for their cancer. The majority of “cryptogenic” HCC in the U.S. is attributed to non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome. Metabolic syndrome is a constellation of problems including insulin resistance, obesity, hypertension, and hyperlipidemia. Increasingly, components of the metabolic syndrome are being linked to various forms of cancer with respect to both increased risk of disease and worsened outcome. In this review, we focus on the relationship between metabolic syndrome and hepatocellular carcinoma. We discuss the increased risks of HCC in those with features of metabolic syndrome, potentially worsened cancer outcomes in these patients, possible pathogenic mechanisms to explain these relationships, and treatment options for those with NAFLD and its progressive counterpart, non-alcoholic steatohepatitis (NASH). Metabolic syndrome is predicted to lead to large increases in the incidence of HCC over the next decades. A better understanding of the relationship between these two diseases should ultimately lead to improved screening and treatment options for those with HCC.
Hepatocellular carcinoma; HCC; metabolic syndrome; NASH
As a proinflammatory cytokine, interleukin-17 (IL-17) contributes to the inflammation of many autoimmune diseases. We examined IL-17 levels in serum and tissues from patients with chronic hepatitis B virus infection (HBV), and especially evaluated the role of IL-17 in the pathogenesis and progression of liver fibrosis.
Materials and methods
Whole venous blood was obtained from four patient groups: chronic hepatitis B (CHB, n = 47), liver cirrhosis (LC, n = 49), primary hepatocellular carcinoma (PHC, n = 44), chronic liver failure (CLF, n = 33), and a normal control group (n = 20). HBsAg was positive in all patients. Liver biopsy samples were acquired from asymptomatic HBsAg carriers (ASC, n = 35), CHB (n = 57), and LC (n = 31) patients. We performed ELISA to measure IL-17 levels in serum samples, and used reverse RT-PCR to measure IL-17 mRNA levels in peripheral blood mononuclear cells (PBMC). IL-17 protein expression was detected in liver biopsy tissues by immunohistochemistry.
Compared to normal controls, serum IL-17 protein and mRNA levels were significantly higher in the four infection groups. LC patients exhibited the highest serum IL-17 and PBMC mRNA levels. No significant differences were found between the other three groups. High levels of IL-17 were also observed in tissues from CHB and LC patients, compared to ASC. IL-17 expression was mainly located in the portal area and was positively correlated with inflammation grade and fibrosis stage.
IL-17 expression was found to be increased with increasing degrees of liver fibrosis. This suggests that IL-17 may not only induce the inflammation, but also contribute to disease progression and chronicity.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5306959258322482
Asymptomatic; Hepatitis B surface antigen Carriers; Interleukin-17; Hepatitis B virus; Chronic hepatitis B; Liver cirrhosis; Primary hepatitis carcinoma; Chronic liver failure; Fibrosis
Hepatitis B virus (HBV) is one of leading causes of various hepatic diseases including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hundreds of million people worldwide are infected by HBV, chronically.
This study in conducted to investigate the inﬂuence of Hepatitis B virus (HBV) genotypes and type I IFN-αreceptor β subunit (IFNAR2) expression in liver on response to treatment with pegylated IFN-α-2a (Peg-IFN-α-2a) for chronic hepatitis B infection.
Patients and Methods
In this study, 65 eligible patients with chronic hepatitis B disease were enrolled. HBV genotypes of these patients were analyzed by using PCR-RFLP of the surface gene of HBV. The expression of IFNAR2 in the liver was immune histochemically investigated using anti-IFNAR2 antibody. All immune histochemical slides were read semi-quantitatively by image analysis. Chronic hepatitis B patients were treated with Peg-IFN-α2a therapy for a 48-week period and followed up for 24 weeks. Baseline characteristics and sustained viral response (SVR) to Peg-IFN-α-2a therapy were evaluated.
55 % of patients exhibited HBV genotype B and 31.7 % patients exhibited HBV genotypes C infections. After treatment with Peg-IFN-α-2a, SVR was achieved in 66.7 % of patients with HBV genotype B and in 26.3 % of patients with HBV genotype C (P = 0.009). Semiquantitative and the image analysis indicated by gray level values revealed a higher IFNAR2 expression in the group with severe inﬂammation (P < 0.001). Patients’ high IFNAR2 protein expression had a signiﬁcant impact on SVR to Peg-IFN-α-2a therapy (P = 0.028).
HBV genotype B and high expression of IFNAR2 in the liver of chronic hepatitis B patients are closely associated with better response to Peg-IFN-α-2a therapy in chronic hepatitis B disease.
Hepatitis B, Chronic; IFNAR2 Protein, Human; Peginterferon alfa-2a
Hepatocellular carcinoma (HCC) and cirrhosis are important causes of mortality worldwide. Persistent hepatitis B virus (HBV) infection is a major cause of these diseases. Double mutations in the basal core promoter (BCP) (A1762T and G1764A) and precore (pre-C) (G1896A) regions of the virus are associated with progression to HCC. The current study is aimed at developing a simple method for screening and detecting BCP and pre-C mutations in HBV carriers. We have developed and validated an oligonucleotide ligation assay (OLA) to detect point mutations in the HBV core gene. We have applied OLA methods to samples from HBV-infected carriers recruited from the Gambia Liver Cancer Study (GLCS) comprising asymptomatic HBsAg carriers, patients with cirrhosis, and patients with HCC. We observed an 89.3% and 95.8% concordance between the OLA and DNA sequencing for BCP and pre-C mutations, respectively. OLA detected the mutations in single-strain infections and in infections with mixtures of wild-type and mutant viruses under conditions where sequencing detected only the single dominant strains. BCP mutations were detected in 75.7% of patients with advanced liver disease (cirrhosis/HCC) compared to 47.6% of asymptomatic carriers, while pre-C mutations were detected in 34.5% of advanced liver disease patients and in 47.6% of asymptomatic HBsAg carriers. There was a significant association between the presence of BCP mutations and advanced liver disease. In conclusion, OLA is a simple, economical, and reliable assay for detection of pre-C and BCP mutations. Its application can lead to improvement in diagnosis and clinical care in regions where HBV is endemic.