The possible impact of sortilin in reducing HBsAg expression in chronic hepatitis B.

Hepatitis B virus (HBV) infection is a major global health problem. Chronically infected people are at risk for progressive hepatic fibrosis and consequent cirrhosis. Hepatitis B surface antigen (HBsAg) level in serum is a complementary marker for intrahepatic HBV DNA and covalently closed circular DNA (cccDNA). Sortilin-1 (SORT1) has been reported to be involved in the post-Golgi vesicle trafficking of Apo lipoproteins degradation pathways. This study was designed to evaluate the hepatic and serum expression of HBsAg and its association with hepatic SORT1 gene expression in patients with chronic HBV. Thirty chronic hepatitis B patients with histological examination results were enrolled in this study. Liver biopsies were analyzed for hepatic HBsAg and SORT1 gene expression by immunohistochemistry and quantitative real time PCR (qRT-PCR), respectively. Twenty seven out of 30 (90%) liver biopsies had positive staining for HBsAg and showed a significant inverse association with hepatic SORT1 fold change gene expression (ß = -0.5, P = 0.042). There was significant association between HBV DNA levels and HBsAg expression in hepatocyte or serum titer of HBsAg (r = 0.39, P = 0.029; r = 0.39, P = 0.032 respectively). Serum ALT was also correlated with hepatic activity index (HAI) score (ß = 0.6, P = 0.001). Inverse association between hepatic SORT1 gene expression and hepatic HBsAg expression indicates the possible role of sortilin in HBsAg particle formation.

Chronic hepatitis B infection is not associated with increased risk of vascular mortality while having an association with metabolic syndrome.

This study aimed to assess the association of chronic hepatitis B (CHB) with vascular mortality and metabolic syndrome (MS) using data from a large population-based cohort study in Iran. A total of 12,781 participants (2249 treatment-naïve CHB and 10,532 without CHB) were studied. Logistic regression model was used to assess the association between MS and CHB with adjustment for age, ALT, PLT, alcohol intake, smoking, exercise, and socioeconomic status. MS was defined according to the ATPIII guidelines. Cox proportional hazards model was used to assess the hazard ratios for overall and vascular related mortality. There was a significant association between CHB infection and overall mortality (hazard ratio (95%CI) of 1.44 (1.16-1.79), P < 0.001) after adjusting for other confounders. However, we found no association between CHB infection and mortality from vascular events (hazard ratio (95%CI) of 1.31 (0.93-1.84), P = 0.124) even after subgroup analysis by ALT. Furthermore, increased risk of overall mortality in CHB infected individuals was not related to MS and vice versa (P for interaction = 0.06). We noted a significant direct association between CHB infection and MS in women (OR (95%CI); 1.23 (1.07-1.42), P < 0.004). However, CHB was inversely associated with MS in men (OR (95%CI), 0.85 (0.79-0.99). This gender dependent association was related to high BP levels in women. In this study no association between CHB infection and mortality from vascular events was found. Further longitudinal studies should be done to investigate the exact impact of HBV infection on metabolic parameters and vascular pathology.

A histologic scoring system for prognosis of patients with alcoholic hepatitis.

BACKGROUND & AIMS: There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS: We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS: The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS: We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.

OBJECTIVE: Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive. DESIGN: Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against KRT19 and submitted to invasion and cytotoxicity assays. RESULTS: In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p<0.01), decreased tumour differentiation (p<0.001), metastasis (p<0.05) and microvascular invasion (p<0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, VASP, TACSTD2, LAMB1, LAMC2, PDGFRA), biliary/HPC markers (eg, CD133, GSTP1, NOTCH2, JAG1) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/KRT19 knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib. CONCLUSIONS: Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.

Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives.

When there is a massive loss of hepatocytes and/or an inhibition in the proliferative capacity of the mature hepatocytes, activation of a dormant cell population of resident hepatic progenitor cells (HPCs) occurs. Depending on the type of liver damage HPCs generate new hepatocytes and biliary cells to repopulate the liver placing them as potential candidates for cell therapy in human liver failure. Liver injury specific mechanisms through which HPCs differentiate towards mature epithelial cell types are recently become understood. Such new insights will enable us not only to direct HPCs behaviour for therapeutic purposes, but also to develop clinically feasible methods for in vivo differentiation of other stem cell types towards functional hepatocytes. This review aimed to provide the current improved knowledge of the role of HPCs niche and its signals in directing the behaviour and fate of HPCs and to translate this basic knowledge of HPCs activation/differentiation into its clinical applications.

Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study.

BACKGROUND: 'Acute-on-chronic liver failure' (ACLF) is characterised in a more advanced stage by liver failure associated with multiple other end-organ failure. The global clinical characteristics of this entity remain, however, ill-defined. OBJECTIVE: To characterise and evaluate the clinicopathological features of patients with ACLF compared with patients with chronic decompensated cirrhosis (CHD) in a prospective, homogeneous cohort of patients with histologically proven alcoholic cirrhosis from 2002 to 2007. RESULTS: In total 250 patients were screened (ACLF (n=70, 28%) and CHD (n=180, 72%)). Alcoholic liver disease was observed in respectively 61/70 (87%) of patients with ACLF and 72/180 (40%) of patients with CHD. After exclusion of 31 patients, 102 patients were studied: 54 with ACLF (median age 51 years; Child-Pugh 12±2; in-hospital mortality 46% (25/54)) and 48 patients with CHD (median age 53 years; Child-Pugh 10±2; in-hospital mortality 10% (5/48)). In the patients with ACLF who survived the hospital stay, the difference in transplant-free survival compared with patients with CHD tended to attenuate with time. At admission the apparent infection of patient groups was comparable but during hospitalisation infection occurred more frequently in patients with ACLF (31/53 (58%)) than in those with CHD (12/47=26%) (p=0.007). Early signs of infection, positive systemic inflammatory response syndrome (SIRS) criteria at admission and ductular bilirubinostasis (p=0.04), were early features that predicted outcome in ACLF. CONCLUSION: Patients with ACLF have a high short-term mortality but those who survived the acute exacerbation show a long-term outcome comparable to that of patients with CHD. Infection is the most common cause of mortality in these patients. Positive SIRS criteria and ductular bilirubinostasis are early markers of ACLF and might allow more rapid identification of high-risk patients.

Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin.

BACKGROUND: Hepatocellular carcinoma (HCC) responds poorly to chemotherapy owing to multidrug resistance (MDR). Recent studies showed that part of HCC could be of progenitor cell origin. Because some MDR-conferring transporters [multidrug resistance-associated protein 1 (MRP1), MDR1, MRP3 and breast cancer resistance protein (BCRP)] are expressed in hepatic progenitor cells (HPCs), expression in HCC might reflect a progenitor cell origin and provide the tumour cells with a MDR phenotype. METHODS: The transcriptional profile of transporter genes was assessed in 139 HCCs earlier subjected to global gene expression analysis. In addition, we performed real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry for MRP1, MRP3, MDR1, BCRP and biliary/HPC markers keratin 7 and/or keratin 19 (K7/K19) on an independent set of 23 HCCs and surrounding liver. RESULTS: Micro-array analysis showed that MRP1 was the only transporter with increased mRNA levels in HCC compared with the surrounding tissue. MRP1 mRNA levels were significantly higher in HCCs with poor survival and the 'hepatoblast subtype' of HCC, thought to be derived from HPCs. In 11 of 23 HCCs of the independent set, we found a diffuse protein expression of MRP1 compared with negative hepatocytic expression observed in normal (surrounding) hepatocytes. MRP1 was expressed in K19(+) non-neoplastic HPCs and K19(+) tumour cells. In addition, MRP3 and BCRP were expressed in K7/K19(+) tumour cells. MRP1 expression was high in poorly differentiated HCCs, large tumours (>7 cm) and microvascular invasive tumours. CONCLUSIONS: MRP1 correlated with K19 mRNA and protein expression in two independent series of HCC. In addition, MRP1 was, together with MRP3 and BCRP, colocalized with K7/K19 in the tumour. Therefore, MRP1 expression could be a reflection of the HPC origin of this subgroup of HCCs and may result in an aggressive tumour phenotype.

Intra-familial Transmission of Chronic Hepatitis B Infection: A Large Population-Based Cohort Study in Northern Iran.

AIM: The aim of this study was to investigate the intra-familial transmission of chronic hepatitis B (CHB) in Golestan province, that has the highest prevalence of CHB in Iran. METHODS: The Golestan Cohort Study (GCS) is a population-based prospective study of 50045 individuals, 40 years or older, initially set-up to study upper GI cancers in Northern Iran. In 2008, a baseline measurement of hepatitis B surface antigen (HBsAg) on the stored serum of all GCS participants identified 3505 HBsAg+ individuals. In 2011, we assessed HBV serological markers in 2590 initially HBsAg+ individuals and their first-degree relatives including spouses (1454) and children (3934). RESULTS: The median (IQR) age of spouses and children were 52 (12) and 25 (12) years respectively. Out of 5388 family members, 2393 (44.5%) had no HBV markers, indicating susceptibility to infection. Of these, 378 (15.8%) were fully-vaccinated children with no apparent response to primary immunization. HBsAg was positive in 2.2% (n = 33) of spouses and 8.2% (n = 325) of children (overall rate of 6.6%). HBcAb was positive in 761 (52.3%) and 914 (23%) spouses and children, respectively. The rate of spontaneous loss of HBsAg (HBsAg-, HBsAb+ and HbcAb+) was 41.3% and 13.9% in spouses and children, respectively. A higher rate of HBsAg+ children (10.2%) was found in families in which the mother was positive for HBsAg compared with families where the father was positive for HBsAg (6.3%) (P < 0.001). When both parents were positive for HBsAg, the rate of HBsAg positivity was high (23.5%, P < 0.001). Despite high virus exposure rates between spouses (52.6 %), the prevalence of HBsAg positivity among them was very low (2.3 %). CONCLUSION: Sexual and parent-to-child transmission are important routes of CHB spread in this population from northern Iran despite the fact that 24 years have passed since the beginning of hepatitis B vaccination in infants. Low percentage of HBsAg positivity in spouses is related to high HBsAg clearance rate among them.

Breast cancer resistance protein (BCRP/ABCG2) is expressed by progenitor cells/reactive ductules and hepatocytes and its expression pattern is influenced by disease etiology and species type: possible functional consequences.

Breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette transport protein that is expressed in several organs including the liver. Previous studies have shown that ABC transport proteins play an important pathophysiological role in several liver diseases. However, to date, expression pattern and possible role of BCRP in human liver diseases and animal models have not been studied in detail. Here we investigated the expression pattern of BCRP in normal liver, chronic parenchymal and biliary human liver diseases, and parallel in different rat models of liver diseases. Expression was studied by immunohistochemistry and additionally by RT-PCR analysis in Thy-1-positive rat oval cells. Bile ducts, hepatic progenitor cells, reactive bile ductules, and blood vessel endothelium were immunoreactive for BCRP in normal liver and all types of human liver diseases and in rat models. BCRP was expressed by the canalicular membrane of hepatocytes in normal and diseased human liver, but never in rat liver. Remarkably, there was also expression of BCRP at the basolateral pole of human hepatocytes, and this was most pronounced in chronic biliary diseases. In conclusion, BCRP positivity in the progenitor cells/reactive ductules could contribute to the resistance of these cells to cytotoxic agents and xenotoxins. Basolateral hepatocytic expression in chronic biliary diseases may be an adaptive mechanism to pump bile constituents back into the sinusoidal blood. Strong differences between human and rat liver must be taken into account in future studies with animal models.

Immune-Regulatory Events in the Clearance of HBsAg in Chronic Hepatitis B: Focuses on HLA-DP.

Successful clearance of hepatitis B virus (HBV) is a promising event in which host's immune system will attempt to get rid of the virus. The immunological events of HBsAg seroclearance have attracted great attention in both natural history investigations and therapeutic trials. Recent genome-wide association studies (GWAS) has confirmed polymorphisms in the human leukocyte antigen (HLA)-DP locus associated with spontaneous HBV clearance. In this review the impact of host immune response in declining HBsAg during the natural history of the infection has been discussed.

Physicians' Knowledge and Attitude Towards Fecal Microbiota Transplant in Iran.

BACKGROUND Fecal microbiota transplant (FMT) is employed to replace the 'unhealthy' microbiota of the patient with the 'healthy' microbiota of a pre-screened healthy donor. Given the growing importance of gut microbiota dysbiosis in the pathogenesis of intestinal or extraintestinal diseases; it is conceivable that FMT becomes integrated in the routine clinical practice. Our objective was to assess the knowledge and attitude of the Iranian physicians towards FMT. METHODS We surveyed the participants of Iranian gastroenterology and hepatology 2014 conference. RESULTS Overall, 146 (68.5%) were familiar with FMT; of whom 132 (94.28%) were willing to accept FMT if scientifically and ethically approved and 115 (88.46%) were willing to refer their patients for FMT if indicated. In total, 42 (30.7%) had identified stool preparation as the most unappealing aspect of FMT, while 17 (11.6%) reported the therapeutic use of fecal material as the most unappealing and 39 (28.5%) indicated that both are equally unappealing. The doctors who had an overall positive opinion toward FMT reported less negative feelings towards FMT. CONCLUSION Iranian physicians are willing to accept FMT as a therapeutic option if it is scientifically justified and ethically approved. Nevertheless, physicians prefer to skip the stool preparation phase; as they are more in favour of synthetic microbiota as opposed to fecal microbiota.

Association of Mutations in the Basal Core Promoter and Pre-core Regions of the Hepatitis B Viral Genome and Longitudinal Changes in HBV Level in HBeAg Negative Individuals: Results From a Cohort Study in Northern Iran.

BACKGROUND: Although certain HBV mutations are known to affect the expression of Hepatitis e antigen, their association with HBV viral level or clinical outcomes is less clear. OBJECTIVES: We evaluated associations between different mutations in the Basal Core promoter (BCP) and Pre-core (PC) regions of HBV genome and subsequent changes in HBV viral DNA level over seven years in a population of untreated HBeAg negative chronic hepatitis B (CHB) participants in Northeast of Iran. MATERIALS AND METHODS: Participants in the current study were drawn from the Golestan Hepatitis B Cohort Study (GHBCS), a cohort of approximately 2590 HBsAg positive subjects (living in Gonbad city) embedded in the Golestan Cohort Study (GCS). At baseline, HBsAg was measured in all participants and revealed 2590 HBsAg positive cases. We randomly selected 304 participants who their blood sample were taken at both baseline and seven years later in follow-up and had not been treated for HBV during this time. HBV viral load were assessed at baseline and at year 7. The BCP and PC regions of the HBV DNA, at baseline, were amplified via hemi-nested PCR and sequenced by cycle sequencing. At year 7, liver stiffness was assessed by fibroscan; also, other parameters of liver disease were assessed following standard clinical protocols. Associations were assessed via tabulation, chi-square, t-tests and logistic regression. P values < 0.05 were considered statistically significant and all tests were two-sided. RESULTS: Among 304 HBsAg positive participants, 99 had detectable HBV DNA at study baseline. Of these, 61.6% had PC mutations (48.5% A1896 and 25.2% G1899). In contrast to other mutations, A1896 was associated with a higher proportion of detectable HBV DNA at year 7 (39.6%) compared to patients with the wild type (13.7%) (OR: 4.36, CI95% = 1.63-11.70; P Value = 0.002). Although participants with the A1896 mutation had higher year-7 HBV viral load than participants with G1896 (2.30 ± 1.66 IU/mL vs. 1.76 ± 1 IU/mL among patients with detectable HBV; P value = 0.052), no association was observed with either serum level ALT or liver stiffness. Interestingly, mutations in the basal core promoter (BCP) region had no significant effect on virus DNA detection. CONCLUSIONS: In this population with chronic HBeAg negative hepatitis B, an association was observed between the G1896A mutation in the Pre-core region of HBV and subsequent level of HBV DNA seven years later, which indicated that mutations in this region of HBV genome may contribute to disease progression in these patients and play an important role in HBV natural course of disease.

Nonalcoholic Fatty Liver: The Association with Metabolic Abnormalities, Body Mass Index and Central Obesity--A Population-Based Study.

BACKGROUND: To assess the prevalence of nonalcoholic fatty liver (NAFL) in Iran and to evaluate correlates of NAFL in categories of body mass index (BMI). METHODS: Using a cluster random sampling approach, 7723 subjects over 18 years of age underwent abdominal ultrasonography, laboratory evaluations, blood pressure, and anthropometric measurements and were interviewed to obtain baseline characteristics. Prevalence of NAFL according to BMI and waist to hip ratio and its association with metabolic abnormalities in categories of BMI were assessed in multivariate analysis. RESULTS: The overall prevalence of NAFL was 35.2% [95% confidence interval (CI) 34.1-36.3]. A significant number of subjects with BMI < 30 had NAFL [22.1% (CI 21.0-23.2)]. Waist to hip ratio for 38.2% (CI 35.6-40.8) of the subjects with NAFL, and BMI < 30 was higher than normal values. The odds ratio for association of NAFL and dyslipidemias were higher in subjects with BMI < 30 versus those with BMI ≥ 30: (1) hypertriglyceridemia: 2.21 vs. 1.57, P = 0.006; (2) lower high-density lipoprotein: 1.29 versus 0.98, P = 0.046. Higher low-density lipoprotein also revealed greater association with NAFL in subjects with BMI < 25 than those with BMI ≥ 25 (odds ratio 1.84 vs. 1.1, P = 0.015). CONCLUSIONS: NAFL shows stronger association with central obesity compared to high BMI. NAFL has stronger association with dyslipidemias in subjects with low compared with high BMI.

Adult Hepatic Progenitor Cell Niche: How it affects the Progenitor Cell Fate.

The hepatic progenitor cell (HPC) niche is a special microenvironment composed of different cell types, extracellular matrix (ECM) components, growth factors and cytokines released by the niche cells that help to maintain the characteristics of HPCs and the balance between their activation, proliferation and differentiation. Composition of this special microenvironment, created in response to specific liver damage, together with critical interactions between different partners of the HPC niche can determine the fate decision and differentiation pathways of HPCs. A number of recent studies have shed light on factors and signals from the HPC niche that determines the choice of HPCs differentiation towards a specific cell type depending on the nature of the liver injury and resultant microenvironment created by this injury. This paper seeks to provide an in-depth review, through a literature review and the authors' experiences, of the most recent findings on the role of the HPC niche in fate choice option of HPCs toward either hepatocytes or bile duct epithelial cells and its clinical relevance.

Potential mutations associated with occult hepatitis B virus status.

CONTEXT: Occult hepatitis B virus (HBV) status (OHBS) is simply defined as the presence of HBV DNA in the liver (with or without detectable HBV DNA in the serum), in the absence of serum HBV surface antigen (HBsAg). Importance of OHBS is mostly clinical, related to its possible role in spreading through blood transfusion and liver transplantation; causing classic forms of HBV. Mechanisms underlying this entity are poorly defined. Several possibilities have been suggested, with major classification into two groups: defective host immune response and viral replication activity through mutations of HBV DNA sequence. Mutations are extensively investigated in all four overlapping open reading frames (ORFs) of HBV genome, to define their possible role in the pathogenesis of OHBS. Some of these mutations like S-escape mutants could not be detected by the routine available assays, making them difficult to diagnosis. Therefore, trying to detect this covert condition could be more helpful for defining better preventive and therapeutic strategies. EVIDENCE ACQUISITION: In the present study we provided an in-depth review of the most important new data available on different mutations in HBV genome of patients with OHBS, which may play a role in the pathogenesis of OHBS. The data were collected through reviewing the full-text articles, identified by the PubMed search, using the following keywords and their different combinations: occult hepatitis B, HBV genome, "a" determinant, HBV open reading frames, S mutations, X mutations, P mutations and C mutations. RESULTS: Variants within the major hydrophilic region (MHR) of the HBsAg, deletions in the pre-S1region, codon stop in the S open reading frames (ORF), sporadic non common mutations, some mutations affecting the posttranslational production of HBV proteins in the S ORF like deletion mutations, mutations in start codon and nucleotide changes in the X ORF, deletion and point mutations in P ORF and sometimes, nucleotide substitution in the C ORF are among the assumed mutations detected to have a role in OHBS appearance. CONCLUSIONS: Studies mostly lacked a control group and the whole-length HBV sequencing was scant with conflicting results, suggesting that OHBS is often a result of multiple mechanisms. Additional studies on full-length HBV genomes from occult and non-occult HBV cases may shed more light on the interplay between different mechanisms involved in the pathogenesis of OHBS.

Clinical feature of intrahepatic B-lymphocytes in chronic hepatitis B.

Humoral immunity constitutes major defense mechanism against viral infections. However, the association of hepatic injury and B-cells population in chronic hepatitis B virus (HBV) carriers has not been studied well. In this study, fifty seven hepatitis B surface antigen (HBsAg) positive and HBeAg negative patients were studied to determine the expression of CD20, a cell surface marker expressed on B-cells, in liver biopsy sections using immunohistochemistry. The patients' clinical data at the time of liver biopsy were acquired from their medical records. There was a significant association between log HBV DNA and both ALT (r = 0.36, P = 0.006) and histologic activity index (HAI) total score (r = 0.3, P = 0.02), respectively. The CD20 was expressed in all 57 liver biopsy samples with a submembranous and membranous staining pattern and its expression was significantly associated with HAI total score (r = 0.32, P = 0.01) and stage of fibrosis (r = 0.31, P = 0.02). The susceptible B lymphocytes to hepatitis B virus might be implicated in the development of immune mediated inflammation of HBV-induced hepatic injury. The present data also support that the liver is potentially one of the secondary lymphoid organs.

Cohort profile: golestan hepatitis B cohort study- a prospective long term study in northern iran ​.

Hepatitis B virus (HBV) infection is the most common cause of end stage liver disease in Iran and in Golestan province. Large-scale population-based prospective cohort studies with long term follow-up are the method of choice to accurately understand the natural course of HBV infection. To date, several studies of HBV epidemiology, natural history, progression to cirrhosis and association with HCC have been reported from other countries. However, few of these are prospective and fewer still are population-based. Moreover, the underlying molecular mechanisms and immunogenetic determinants of the outcome of HBV infection especially in low and middle income countries remains largely unknown. Therefore, the hepatitis B cohort study (HBCS), nested as part of the Golestan Cohort Study (GCS), Golestan, Iran was established in 2008 with the objective to prospectively investigate the natural course of chronic hepatitis B with reference to its epidemiology, viral/host genetic interactions, clinical features and outcome in the Middle East where genotype D HBV accounts for >90% of infections. In 2008, a baseline measurement of HBV surface antigen (HBsAg) was performed on stored serum samples of all GCS participants. A sub-cohort of 3,505 individuals were found to be HBsAg positive and were enrolled in the Golestan HBCS. In 2011, all first degree relatives of HBsAg positive subjects including their children and spouses were invited for HBV serology screening and those who were positive for HBsAg were also included in the Golestan HBCS.

Hepatic progenitor cells: an update.

Liver progenitor cells are activated in most human liver diseases. The dynamics, and therefore subpopulations, of progenitor cells are, however, different in acute versus chronic hepatocytic diseases and in biliary diseases. The role of Wnt and Notch signaling pathways in activation and differentiation of human hepatic progenitor cells holds great promise because they can be manipulated by drugs. Hepatocytic differentiation requires inhibition of Notch (numb switched on), whereas cholangiocytic differentiation requires Notch activation. In this way, the patients' own regenerative response could be supported, which could eventually even avoid the need for transplantation in several patients.

MELD score to predict outcome in adult patients with non-acetaminophen-induced acute liver failure.

AIMS/BACKGROUND: A model for end stage liver disease (MELD) score >30 was proposed as an excellent predictor of mortality in patients with non-acetaminophen-induced acute liver failure (ALF). We analyzed the prognostic value of MELD score in our patients with ALF who were prospectively registered in our database since 1990. METHODS: Overall, 106 patients met the criteria of ALF. Excluding seven patients with acetaminophen etiology, 99 patients (42+/-15 years, 40M/59F) were studied. RESULTS: Causes were cryptogenic (n=38), viral (n=29), drugs (n=20) and miscellaneous (n=12). Of these, 37% (n=37) survived with medical management alone (group I), 16% (n=16) died (group II) and 46% (n=46) underwent liver transplantation (group III). The strongest predictors of poor outcome were advanced encephalopathy, cryptogenic/drug-induced/hepatitis B etiology and a high MELD score. At the time of diagnosis, King's College Hospital criteria and MELD score >30 had similar high negative predictive value (92% and 91%, respectively) and low positive predictive value (52% and 56%, respectively). The predictive values improved only slightly during follow-up. The best cut-off point for MELD score to discriminate between survivors and nonsurvivors was >35, with a sensitivity and specificity of 86% and 75%, respectively. CONCLUSIONS: MELD score, which mostly takes into consideration the degree of liver impairment, has a similar prognostic value as King's College Hospital criteria to predict outcome in adult patients with nonacetaminophen-induced ALF. Overall, all current scores miss accuracy and therefore there is a clear need for factors that can better predict the regeneration of the liver in this setting.

Liver regeneration in acute severe liver impairment: a clinicopathological correlation study.

BACKGROUND: Although normally quiescent, the adult mammalian liver possesses a great capacity to regenerate after different types of injury. Major players in the regeneration process are mature residual cells, including hepatocytes, cholangiocytes and stromal cells. However, if the regenerative capacity of mature cells is impaired, hepatic progenitor cells (HPCs) are activated and expand into the liver parenchyma. Upon transit amplification, the progenitor cells generate new hepatocytes and biliary cells to restore liver homeostasis. AIMS/METHODS: To study the relationship between different histopathological parameters as well as their correlations with clinical parameters and outcome, we examined liver specimens from 74 patients with acute or subacute severe liver impairment by immunohistochemistry for CK7/CK19 (evaluation of HPCs activation/differentiation), Mib1(Ki 67)/P21 (evaluation of proliferative activity/proliferation arrest of hepatocytes) and hematoxylin and eosin (evaluation of hepatocyte loss). RESULTS: Of the 74 patients, 32% survived without transplantation, 14% died without transplantation and 54% were transplanted. Our results show that a threshold of 50% loss of hepatocytes, associated with significant decrease in the proliferative activity of remaining mature hepatocytes, is needed for extensive hepatic progenitor cell activation. Such activation is a sign of disease severity and occurs early (within 1 week) in the disease course. However, development of intermediate hepatocytes, suggesting HPCs differentiation towards mature hepatocytes, takes at least 1 week's time. We found a positive correlation between histopathological parameters (percentage hepatocyte loss, number of proliferating hepatocytes and number of HPCs) and clinical parameters of liver impairment such as model for end stage liver diseases (MELD). Surviving patients compared with those who either died or were transplanted had significantly less hepatocyte loss, less HPCs activation and more mature hepatocyte proliferative activity. Hepatocyte proliferative activity and degree of hepatocyte loss were the most important independent histopathological parameters in predicting outcome. CONCLUSION: Liver biopsy can provide important additional information in a patient with severe acute liver impairment.