Vol. 15 Issue 4
On the cover: The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver
The burden of alcoholic liver disease continues to be a major public health problem worldwide. The spectrum of disease ranges from fatty liver to cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis (AH) is a type of acute-on-chronic liver failure and the most severe form of alcoholic liver disease. Severe AH carries a poor short-term prognosis and its management is still challenging, with scarce advances in the last decades. Corticosteroids are still the first line of therapy in severe cases. Unfortunately, many patients do not respond and novel targeted therapies are urgently needed. Liver transplantation has shown extraordinary results in non-responders to corticosteroids however; its applicability is very low. This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis.
Renal failure in cirrhotic patients is a very severe condition. Hepatorenal syndrome has the worst prognosis among all causes of kidney failure in such patients. Hepatorenal syndrome is diagnosed especially in cirrhotic patients with ascites who develop loss renal function, despite diuretic suspension and volume expansion with albumin and for whom other causes of kidney injury have been excluded. Patients with hepatorenal syndrome should be treated with a vasoconstrictor in combination with albumin as a bridge to receiving a liver transplant. The vasoconstrictor of choice is terlipressin or noradrenaline. In spite of higher drug-related costs associated to terlipressin, initial evidence demonstrates that, considering all direct medical costs involved, the treatment strategy using terlipressin is probably more economical than that using noradrenaline.
Introduction. Oxymatrine (OMTR) is widely used for the treatment of chronic hepatitis B (CHB) in China. Several recent reports revealed that OMTR together with interferon yielded a higher sustained virological response (SVR) than interferon alone. Aim. To elucidate this topic using meta-analysis of data from published randomized controlled trials (RCTs). Material and methods. The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, China National Knowledge Infrastructure, Wanfang Database and China Biomedical Database were searched to identify RCTs that evaluated SVR to interferón therapies and interferon plus OMTR therapies in CHB patients. Results. The literature search yielded 238 studies, and 11 RCTs comprising 968 patients matched the selection criteria. Overall, SVR was significantly higher in patients treated with interferon plus OMTR than in patients treated with interferon alone (SVR: 60.7 vs. 39.8%; relative risk: 1.56; 95% confidence interval: 1.37-1.77; p < 0.05). Combined therapy of interferon plus OMTR were also superior to interferon therapies alone in achieving the endof-treatment viral response, alaninetransaminase normalization, HBeAg loss, and HBeAg seroconversion. Conclusions. Combined therapy of interferon plus OMTR may yield a higher SVR than interferon therapies. The exact outcome needs to perform rigorously designed, multicenter, and large randomized controlled trials.
Background. Nutritional deficiencies may aggravate the course of chronic hepatitis C (CHC). Our aim has been to perform a comprehensive analysis of body composition and nutritional deficiencies in CHC patients in non-cirrhotic and compensated cirrhotic stages to correlate the detected deficiencies with the fibrosis stage. Material and methods. Body multifrequency bioimpedance analysis (BIA) and a wide and simultaneous analytical profile were prospectively performed in 74 CHC patients (36 male) with known METAVIR fibrosis stage established with liver biopsy or transient elastography. Results were analyzed to identify deviations from the normal range and variations according to the fibrosis stage. Results. Body fat compartment was greater in women. Body composition did not change among the 4 stages of liver fibrosis. Low levels (< 30 μg/L) of vitamin D were detected in 74.3% of patients irrespective of the fibrosis stage. Most analytical results remained into the normal range with the exceptions of thrombocytopenia and vitamin A deficiency, that were limited to the stage 4 of fibrosis, and low Zn and LDL-cholesterol values, that were frequently found in patients with advanced (F3 and F4) fibrosis stage. Conclusion. Body composition and most biochemical parameters, including cyanocobalamin, folic acid and vitamin E, are well preserved in compensated patients with CHC, with the exception of generalized vitamin D insufficiency and of deficiencies of vitamin A and zinc that are restricted to the more advanced, although still compensated, stages of the disease.
Introduction and aim. Studies suggest that entecavir and lamivudine are useful as prophylactics against hepatitis B virus (HBV) reactivation in patients undergoing chemotherapy or immunosuppressive therapy, but which drug is more effective is unclear. Here we meta-analyzed available evidence on relative efficacy of prophylactic entecavir or lamivudine therapy in patients with chronic or resolved hepatitis B infection who were undergoing chemotherapy or immunosuppressive therapy. Material and methods. Two reviewers searched PubMed, EMBASE and Google Scholar as well as reference lists in relevant articles to find studies published between January 2005 and May 2015 that met inclusion and exclusion criteria. Data on HBV reactivation, HBV-related hepatitis and all-cause mortality were extracted from the studies and meta-analyzed. Results. A total of eight studies involving 593 patients were included in the meta-analysis, which was performed using a fixed-effect model since no significant heterogeneity was found. Entecavir was associated with significantly lower risk of HBV reactivation than lamivudine (RR 0.29, 95% CI 0.17 to 0.52) as well as lower risk of HBV-related hepatitis (RR 0.11, 95% CI 0.03 to 0.40). The two drugs were associated with similar risk of all-cause mortality (RR 1.12, 95% CI 0.54 to 2.35). Eggers test suggested no significant publication bias in the meta-analysis. Conclusions. The available evidence suggests that entecavir is more effective than lamivudine for preventing HBV reactivation and HBVrelated hepatitis in patients with chronic or resolved HBV infection who are undergoing chemotherapy or immunosuppressive therapy.
Background and rationale. The REPLACE study (NCT01571583) investigated telaprevir-based triple therapy in patients who have recurrent genotype 1 hepatitis C virus (HCV) infection following liver transplantation and are on a stable immunosuppressant regimen of tacrolimus or cyclosporin A. Patients received telaprevir 750 mg 8-hourly with pegylated interferon 180 ?g weekly and ribavirin 600 mg daily, followed by a further 36 weeks of pegylated interferon and ribavirin alone and 24 weeks of follow-up. Efficacy (sustained virological response [SVR] 12 weeks after last planned study dose), safety and tolerability of telaprevir throughout the study were assessed. Pharmacokinetics of telaprevir, tacrolimus and cyclosporin A were also examined. Results. In total, 74 patients were recruited. Overall, 72% (53/74; 95% CI: 59.9 to 81.5) of patients achieved SVR at 12 weeks following completion of treatment. Anticipated increases in plasma concentrations of tacrolimus and cyclosporin A occurred during telaprevir treatment and were successfully managed through immunosuppressant dose reduction and, for tacrolimus, reduced dosing frequency. Safety and tolerability of telaprevir-based triple therapy were generally comparable with previous data in non-transplant patients, although rates of reported anemia (55% [41/74]) were higher. Elevated plasma creatinine (46% [34/74]) was observed during REPLACE consistent with the post-liver transplant population and the co-administered immunosuppressants. Conclusion. Telaprevir-based triple therapy in patients with recurrent genotype 1 HCV infection following liver transplantation produced high rates of SVR. Therapeutic concentrations of immunosuppressants were maintained successfully through dose modification during telaprevir treatment.
Background. Despite the introduction of direct antiviral agents, pegylated interferon remains the mainstay of treatment for chronic hepatitis C. However, pegylated interferon is associated with a high rate of severe adverse events and decreased quality of life. Specific interventions can improve adherence and effectiveness. We aimed to determine whether implementing a multidisciplinary approach improved outcomes in the treatment of chronic hepatitis C. Material and methods. We analyzed consecutive patients treated with pegylated interferon plus ribavirin between August 2001 and December 2011. We compared patients treated before and after the implementation of a multidisciplinary approach in 2007. We compared the baseline demographic and clinical characteristics and laboratory findings between groups, and used bivariate logistic regression models to detect factors involved in attaining a sustained virological response, calculating the odds ratios with their respective 95% confidence intervals. To evaluate the effect of the multidisciplinary team, we fitted a multivariate logistic regression model to compare the sustained virological response after adjusting for unbalanced variables and predictive factors. Results. We included 514 patients [228 (44.4%) in the pre-intervention cohort]. Age, viral genotype, previous treatment, aspartate transaminase, ferritin, and triglyceride were prognostic factors of sustained virological response. After adjusting for prognostic factors, sustained virological response was higher in the multidisciplinary cohort (58 vs. 48%, p = 0.038). Despite higher psychiatric comorbidity and age in the multidisciplinary cohort, we observed a trend toward a lower rate of treatment abandonment in this group (2.2 vs. 4.9%, p = 0.107). Conclusion. Multidisciplinary management of chronic hepatitis C improves outcomes.
Background and aim. Leukocyte antigen DQ (HLA-DQ) and interferon-λ4 (IFNL4) gene polymorphisms were associated with susceptibility to chronic hepatitis B and C virus infection. This study further confirmed that variants of these genes were associated with susceptibility and spontaneous clearance of HBV infection in a Chinese population. Material and methods. A total of 1,069 subjects were recruited and divided into three groups i.e. 397 with CLD (HBV-related chronic liver disease), 434 with SC (spontaneous clearance), and 238 HC (healthy controls). HLA-DQrs9275319 and IFNL4rs368234815, rs12971396, rs12979860, and rs8099917SNPs were genotyped using the Sequenom MassARRAY MALDI-TOF system. Results. HLA-DQ rs9275319 showed a significant association with HBV infection (allele model, OR, 0.514; 95% CI, 0.359-0.738, adjusted p = 0.0003) and with natural clearance (allele model, OR, 1.659; 95% CI, 1.197-2.300, adjusted. However, there was no association between IFNL4 polymorphism and HBV susceptibility or natural clearance (all p > 0.05). The multifactor dimensionality reduction (MDR) test with permutation correction showed that a three-way interaction between IFNL4 and HLA-DQ SNPs was identified for HBV susceptibility (permutation p = 0.009 for the best factor model) and clearance (permutation p = 0.014 for the best factor model). Conclusions. The data from the current study provided additional evidence for an SNP-SNP interaction between HLA-DQ and IFNL4 in regulation to HBV infection and natural clearance.
Background & aims. Hyperferritinemia (HF) is frequently present in patients with metabolic syndrome (MS). MS associated with HF is named dysmetabolic hyperferritinemia (DH). There are some publications that propose that DH is associated with a raised liver iron concentration (LIC). We studied the LIC in patients referred for HF to a secondary hospital to determine if there are differences between patients with or without MS. Material and methods. We conducted a prospective study of 132 consecutive patients with HF from January to December 2010. The MS was defined by the International Diabetes Federation criteria (2005). LIC was determined by Magnetic resonance imaging (MRI). Results. The number of patients for which there was enough data to determine MS was 97, out of which 54 had MS and 43 had no MS (NMS). In 54/97 patients, MRI for LIC determination was performed. From the MS group, 44 were men (27 underwent MRI) and 10 women (9 MRI). The mean LIC was 27.83 ± 20.90 ?mol/g for the MS group. In the NMS group, 36 were men (13 MRI), and 7 women (5 MRI). In 18 patients from the NMS group, LIC was determined by MRI. The mean LIC was 33.16 ± 19.61 ?mol/g in the NMS group. We compared the mean values of LIC from both groups (MS vs. NMS) and no significant differences were found (p = 0.067). Conclusion. Patients with DH present a mean LIC within normal values and their values do not differ from those of patients with HF but without MS.
Introduction. Men have higher risk for hepatocellular carcinoma (HCC) than women. Pre liver transplant (LT) alpha fetoprotein (AFP) levels strongly predict post LT HCC recurrence. Though women with HCC have higher AFP, the contribution of AFP level by gender to post LT HCC recurrence is unknown. Material and methods. In this UNOSbased, retrospective cohort study we investigate sex differences in HCC recurrence among LT recipients with MELD exception between 2006-2010. Covariates include race, disease etiology, co-morbidities, AFP at listing and LT, tumor burden, loco-regional therapy, and donor risk index. HCC recurrence was assessed by competing risks regression. Results. Of the eligible cohort (n = 5,002) included 3,872 men and 1,130 women. HCC recurred in 258 men (7%) and 66 women (6%). Median listing AFP was higher in women than men (14 vs. 11 ng/dL, p < 0.001). While no sex difference in overall HCC recurrence was detected (HR 0.9, 95% CI 0.7-1.2, p = 0.38), there was a strong interaction between gender and AFP on recurrence risk (p = 0.02). HCC recurrence was nearly three times higher in women (HR 4.2, 95% CI 2.2-8.2, p < 0.001) than men (HR 1.5, 95% CI 1.1-2.1, p = 0.02) with AFP at LT between 101-500 ng/dL. Conclusion. This study reveals novel sex differences in post LT HCC recurrence, which was nearly three times higher in women than men with high AFP at LT. Pre-LT AFP levels appear to carry a different prognosis in women than men, and a subset of female LT recipients may benefit from more intensive HCC surveillance after LT.
Background and aims. Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver in which the immunological mechanisms involved in tissue destruction and/or repair are still unclear. Different pro-inflammatory cytokines have been shown to play a determinant role in AIH pathogenesis. Here, we aim to compare the circulating levels of pro- and anti-inflammatory cytokines such as IL-6, TNF-alfa, IL-17A/F, IL-21, IL-22, IL-23, and IL-10 in patients with type 2 AIH compared to patients with type 1 AIH and healthy controls (HC). Fourty-six Mexican patients with AIH were recruited in our study. Patients were classified as type 1 or 2 AIH based on immune serological markers. Fourty-four serum samples from healthy individuals were included as controls. Serum cytokine levels were determined by ELISA technique. Results. Compared to healthy controls, serum levels of IL-17F, IL-21, IL-23, IL-10, IL-6, and TNF-alfa, but not IL-17A and IL-22, were significantly increased in AIH patients. When patients were grouped by aminotransferase activity, a biomarker of active disease, a positive correlation between serum IL-17F and alanine transaminase (rs: 0.4739; P = 0.0009) and aspartate transaminase (rs: 0.4984; P = 0.0004) levels was found. A cytokine signature profile associated with type 2 AIH was characterized by high serum IL-21 (type 1 AIH: 0.66 pg/mL; type 2 AIH: 331.1 pg/mL; P = 0.0042) and IL-22 (type 1 AIH: 0.1 pg/mL; type 2 AIH: 55.26 pg/mL; P = 0.0028) levels. Conclusions. We show for the first time, differential regulation of certain pro-inflammatory cytokines associated with disease progression and AIH type in Mexican patients.
Introduction and aim. Liver disease is associated with cognitive dysfunction also at early stages, and minimal hepatic encephalopathy, affecting 20-70% of patients, is frequently under-recognized. The main purpose of this work was to demonstrate that a substantial number of patients, enrolled due to an acute confusional state in absence of a diagnosis of liver disease, suffers of hepatic encephalopathy. Material and methods. Before a diagnosis of a well-compensated liver diseases was performed, 410 patients with an acute confusional state were enrolled in this study. Results. Even in the presence of minimal alterations of hepatic function, the psychometric tests applied demonstrated early signs of cerebral frontal alteration. The alteration was associated with the severity of liver disease, paralleling the progression of the patient to minimal hepatic failure or chronic liver disease. Conclusions. These psychometric tests are essential to detect early and subclinical frontal failure. Frontal dysfunction may be a useful tool in the follow-up of these patients.
Introduction and Aim. TGF-? signalling is involved in pathogenesis and progress of hepatocellular carcinoma (HCC). This bioinformatics study consequently aims to determine the underlying molecular mechanism of TGF- ? activation in HCC cells. Material and methods. Dataset GSE10393 was downloaded from Gene Expression Omnibus, including 2 Huh-7 (HCC cell line) samples treated by TGF- ? (100 pmol/L, 48 h) and 2 untreated samples. Differentially expressed genes (DEGs) were screened using Limma package (false discovery rate < 0.05 and |log2 fold change| > 1.5), and then enrichment analyses of function, pathway, and disease were performed. In addition, protein-protein interaction (PPI) network was constructed based on the PPI data from multiple databases including INACT, MINT, BioGRID, UniProt, BIND, BindingDB, and SPIKE databases. Transcription factor (TF)-DEG pairs (Bonferroni adjusted p-value < 0.01) from ChEA database and DEG-DEG pairs were used to construct TF-DEG regulatory network. Furthermore, TF-pathway-DEG complex network was constructed by integrating DEG-DEG pairs, TF-DEG pairs, and DEG-pathway pairs. Results. Totally, 209 DEGs and 30 TFs were identified. The DEGs were significantly enriched in adhesion-related functions. PPI network indicted hub genes such as CUL4B and NEDD4. According to the TF-DEG regulatory network, the two hub genes were targeted by SMAD2, SMAD3, and HNF4A. Besides, the 11 pathways in TF-pathway-DEG network were mainly enriched by UGT1A family and CYP3A7, which were predicted to be regulated by SMAD2, SMAD3, SOX2, TP63, and HNF4A. Conclusions. TGF- ? might influence biological processes of HCC cells via SMAD2/SMAD3-NEDD4, HNF4A-CUL4B/NEDD4, SOX2/TP63/HNF4A-CYP3A7, and SMAD2/SMAD3/SOX2/TP63/HNF4A-UGT1As regulatory pathways.
Introduction and aim. 5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic drug in the treatment of cholangiocarcinoma (CCA). Since development of drug resistance to 5-FU in CCA patients is the primary cause of treatment failure, a better understanding of the mechanism of drug resistance of this cancer is essential to improve the efficacy of 5-FU in CCA therapy. Material and methods. A 5-FU resistant CCA cell line (M214-5FUR) for a comparative chemo-resistance study was established. Real time RT-PCR was used to determine gene expression levels. Cell cytotoxicity was measured by the MTT assay. Protein expression levels were detected by the immunofluorescene method. Results. It was found that 5-FU resistance was associated with the overexpression of TB10 in CCA cell lines. 5-FU treatment at various concentrations induced the expressions of TB10 and ABC transporters (ABCB1, ABCG2 ABCA3) in two CCA cell lines, KKU-M055 and KKU-M214. M214-5FUR, a 5-FU-resistant cell line, exhibited a 5-FU resistant phenotype with a 16-fold extremely high expression of Tb10 and ABC transporters, as compared to the parental cells, KKU-M214. siRNA targeted to TB10 significantly reduced expression of ABC transporters tested in the M214-5FUR cells (P < 0.05). Conclusions. The present novel findings of TB10 connected with drug resistance as shown in this study provides a new insight for the therapeutic value of T?10 as a predictive biomarker of 5-FU chemoresistance. Inhibiting TB10 may be a valuable adjunct for suppression of ABC transporters and sensitizing chemotherapy treatment, especially 5-FU in CCA patients.
Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The close relationship between immune-mediated disorders makes it mandatory to perform serological screening periodically in order to avoid delayed diagnosis of additional autoimmune diseases. We studied a patient with type 1 diabetes (T1D) who later developed an autoimmune thyroid disease (ATD) and was referred to our hospital with a serious condition of his clinical status. The patient was suffering from an advance stage of celiac disease (CD), the delay in its diagnosis and in the establishment of a gluten-free dietled the patient to a severe proteincalorie malnutrition. Later, the patient developed an autoimmune hepatitis (AIH). We consider that clinical deterioration in patients with APS should alert physicians about the possible presence of other immune-mediated diseases. Periodic screening for autoantibodies would help to prevent delayed diagnosis and would improve patients quality of life.
Hepatic involvement in AL amyloidosis may present as acute liver failure. Historically, liver transplantation in these cases has achieved poor outcomes due to progress of amyloidosis and non-hepatic organ damage. In the era of bortezomib treatment, the prognosis of AL amyloidosis has been markedly improved and may also result in better post-transplant outcomes. We present a case of isolated acute liver failure caused by AL amyloidosis, bridged to transplantation with bortezomib and treated with sequential orthotopic liver transplantation (OLT) and autologous stem cell transplantation. The patient is in stable remission 3 years after OLT.
Hepatocellular adenomas (HCAs) are benign liver tumors recently characterized into 4 different types according to genetic, pathological and clinical features. The prognosis is not well established yet and malignant transformation has been recently associated with β-catenin activation. We aimed to describe a case of a pigmented HCA with β-catenin nuclear expression and inflammatory features and to review the cases of pigmented HCAs in the literature. We report a case of a young female patient without contraceptive use, with a liver tumor diagnosis. Liver biopsy revealed diffuse expression of β-catenin and a partial hepatic resection was performed. The histologic analysis revealed a hepatocellular tumor composed of uniform trabeculae of hepatocytes and solid areas, the later with a significant amount of black pigment highlighted by Masson-Fontana stain. Immunohistochemistry showed co-expression of C-reactive protein and serum amyloid A in the tumor. Literature review revealed that pigmented HCAs, previously reported as dark adenomas, are rare tumors. In HCAs, the presence of β-catenin activation should be searched for due to the higher risk of malignant transformation in hepatocarcinoma. We describe a pigmented HCA with β-catenin nuclear expression and inflammatory features being the fifth case reported so far.