Vol. 14 Issue 6
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
About 80% of patients with liver cirrhosis may have glucose metabolism disorders, 30% show overt diabetes mellitus (DM). Prospective studies have demonstrated that DM is associated with an increased risk of hepatic complications and death in patients with liver cirrhosis. DM might contribute to liver damage by promoting inflammation and fibrosis through an increase in mitochondrial oxidative stress mediated by adipokines. Based on the above mentioned the effective control of hyperglycemia may have a favorable impact on the evolution of these patients. However, only few therapeutic studies have evaluated the effectiveness and safety of antidiabetic drugs and the impact of the treatment of DM on morbidity and mortality in patients with liver cirrhosis. In addition, oral hypoglycemic agents and insulin may produce hypoglycemia and lactic acidosis, as most of these agents are metabolized by the liver. This review discusses the clinical implications of DM in patients with chronic liver disease. In addition the effectiveness and safety of old, but particularly the new antidiabetic drugs will be described based on pharmacokinetic studies and chronic administration to patients. Recent reports regarding the use of the SGLT2 inhibitors as well as the new incretin-based therapies such as injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral inhibitors of dipeptidylpeptidase- 4 (DPP-4) will be discussed. The establishment of clear guidelines for the management of diabetes in patients with CLD is strongly required.
Over the past decades, many drugs have been identified, that can potentially induce steatohepatitis in the predisposed individual. Classically this has been incriminated to amiodarone, perhexiline, and 4,4-diethylaminoethoxyhexestrol (DH), all of which have been found to independently induce the histologic picture of non-alcoholic steatohepatitis (NASH). Pathogenetic mechanisms of hepatotoxicity although still evolving, demonstrate that mitochondrial dysfunction, deranged ATP production and fatty acid catabolism likely play an important role. Drugs like steroid hormones can exacerbate the pathogenetic mechanisms that lead to NASH, and other drugs like tamoxifen, cisplatin and irenotecan have been shown to precipitate latent fatty liver as well. Further research aiming to elucidate the pathogenesis of drug-induced steatosis and steatohepatitis is needed in order to better design therapeutic targets.
Hepatitis C infection is a worldwide problem. The global prevalence of the hepatitis C virus (HCV) averages 3%. Moreover, its prevalence among patients undergoing haemodialysis (HD) varies worldwide, ranging from as low as 1% to up to 70%. There are few data on its prevalence in developing countries, and even less information is available on HD patients. A literature review revealed that the prevalence of HCV infection among patients undergoing HD in Latin America ranges from 4.2 to 83.9%, with most data stemming from Argentina, Brazil, Mexico, Peru, Chile, Venezuela and Cuba. The most common genotype was genotype 1, and subtype 1b was the most frequent. The risk factors associated with this condition were the duration of the HD treatment and blood transfusion before hepatitis C screening. In addition, HCV RNA detection by polymerase chain reaction is crucial for the diagnosis of HCV infection in HD patients. Trials using combinations of new oral antiviral drugs, such as sofosbuvir and combo (ombitasvir, paritaprevir, ritonavir and dasabuvir), should be the next step in the improvement of care among HD patients with HCV, because these therapeutic agents apparently do not require dose adjustment according to renal function. Finally, information on this subgroup of patients remains unavailable in some countries; therefore, additional studies are needed to determine the prevalence trend of HCV infection in these populations.
Background and rationale. Epidemics of hepatitis B and C are a public health burden, and their prevalence in Brazil varies among regions. We determined the prevalence of hepatitis markers in an urban university population in order to support the development of a comprehensive program for HBV immunization and HBV/HCV diagnosis. Students, employees, and visitors (n = 2,936, 31 years IQR 24.5-50, female = 69.0% and 81.1% with at least 12 years of education) were enrolled from May to November 2013. Antibodies against hepatitis B surface antigen (anti-HBs), against hepatitis B core antigen (anti-HBc), and hepatitis B surface antigen (HBsAg) were detected with enzyme immunoassays and anti-hepatitis C virus (anti-HCV) antibodies with a chemiluminescence immunoassay. The results were confirmed with polymerase chain reaction for HCV and nucleic acid amplification test for hepatitis B virus (HBV). Results. The overall prevalence of markers among the participants was 0.136% (95% confidence interval [CI]: 0.003-0.270) for HBsAg, 6.44% (95% CI: 5.55-7.33%) for anti-HBc, 50.8% (95% CI: 48.9-52.7%) for anti-HBs > 10 mIU/mL, and 0.44% (95% CI: 0.20-0.68) for anti-HCV. Almost 30.4% had anti-HBs titers > 100 mIU/mL. Participants with a detectable HCV viral load (n = 9) were infected with genotype 1a. Conclusions. In an urban university population, in which 80% of participants had > 11 years of education, prevalence increased with age, and self-declared ethnicity for anti-HBc and with age, marital status and professional activity for anti-HCV antibodies. A periodical offer of HCV rapid testing should be implemented, and HBsAg rapid testing should be offered to individuals above 20 years of age.
Background & aims. A novel controlled attenuation parameter (CAP) using the signals acquired by the FibroScan ® has been developed as a method for evaluating steatosis. The aim of this study is to assess the performance of the CAP for the detection and quantification of steatosis in patients with chronic hepatitis B (CHB). Material and methods. 136 subjects with CHB underwent liver biopsy and FibroScan® within 60 days. CAP was evaluated retrospectively using raw FibroScan® data. Steatosis was graded as follows: S0 (steatosis < 10% of hepatocytes), S1 (10 to < 30%), S2 (30 to < 60%) or S3 (≥ 60%). Performance was evaluated by area under the receiver operating characteristic (AUROC) curve. Results. Proportions of each steatosis grade (S0-S3) were 78, 10, 9 and 3%, respectively. Using univariate analysis, liver stiffness measurement (LMS) significantly correlated with fibrosis (τ = 0.43; P < 10-10), sex, necro-inflammatory activity, steatosis, age, NASH, and perisinusoidal fibrosis, and with liver fibrosis (P < 10-8) and perisinusoidal fibrosis (P = 0.008) using multivariate analysis. CAP correlated with steatosis (τ = 0.38, P < 10-7), body mass index, NASH, fibrosis and perisinusoidal fibrosis using univariate analysis, but only steatosis (P < 10-10) and perisinusoidal fibrosis (P = 0.002) using multivariate analysis. AUROCs for LSM were: 0.77 (0.69-0.85), 0.87 (0.80-0.95), and 0.93 (0.83-1.00), respectively, for fibrosis stages F ≥ 2, F ≥ 3 and F = 4. AUROCs for CAP were: 0.82 (0.73-0.92), 0.82 (0.69-0.95), and 0.97 (0.84-1.00) for ≥ S1, ≥ S2 and S3 steatosis, respectively. Conclusions. In conclusion CAP is a novel, accurate non-invasive tool and may be suitable for detecting and quantifying steatosis in CHB patients.
Background. Diagnosis of non-alcoholic fatty liver disease (NAFLD) is limited by the need for liver biopsies. Serum cytokeratin 18 (CK-18) levels have been investigated as potential biomarkers for the presence of NAFLD and non-alcoholic steatohepatitis (NASH). Herein, we assessed the correlation between CK-18 levels and NAFLD progression. Material and methods. Serum CK-18 levels were estimated using the M30 antibody enzyme-linked immunosorbent assay in 147 patients diagnosed with NAFLD. In 72 patients, disease progression was evaluated by repeated liver biopsy, which was conducted after 4.3 ± 2.6 years. The relationship between the CK-18 levels and liver histological findings was assessed. Results. The CK-18 levels were useful for identifying NAFLD patients with NAFLD activity scores (NAS) ≥ 5 (NAS ≥ 5 vs. ≤ 4: 675.1 U/L vs. 348.7 U/L; p < 0.0001). A cut-off value of 375 U/L was calculated using the receiver operating characteristic curve approach, with a specificity and sensitivity of 81.5 and 65%, respectively, for the diagnosis of NASH. Among the 72 patients who underwent repeated liver biopsy, 11 patients with a progressed NAS also had significantly increased serum CK-18 levels (p < 0.01); in 30 patients with an improved NAS, there was a significant improvement in the mean CK-18 levels (p < 0.0001). The 31 patients with static NAS had static CK-18 levels. Conclusions. In conclusion, serum CK-18 levels can predict NAS ≥ 5 in NAFLD patients. In NAFLD patients, serum CK-18 levels reflect NAS values and correlate with histological changes, and they appear to be useful indicators of progression and improvement.
Background & rationale. Limited information related to Liver Transplantation (LT) costs in South America exists. Additionally, costs analysis from developed countries may not provide comparable models for those in emerging economies. We sought to evaluate a predictive model of Early Discharge from Hospital after LT (ERDALT = length of hospital stay ≤ 8 days). A predictive model was assessed based on the odds ratios (OR) from a multivariate regression analysis in a cohort of consecutively transplanted adult patients in a single center from Argentina and internally validated with bootstrapping technique. Results. ERDALT was applicable in 34 of 289 patients (11.8%). Variables independently associated with ERDALT were MELD exception points OR 1.9 (P = 0.04), surgery time < 4 h OR 3.8 (P = 0.013), < 5 units of blood products consumption (BPC) OR 3.5 (P = 0.001) and early weaning from mechanical intubation OR 6.3 (P = 0.006). Points in the predictive scoring model were allocated as follows: MELD exception points (absence = 0 points, presence = 1 point), surgery time < 4 h (0-2 points), < 5 units of BPC (0-2 points), and early weaning (0-3 points). Final scores ranged from 0 to 8 points with a c-statistic of 0.83 (95% CI 0.77-0.90; P < 0.0001). Transplant costs were significantly lower in patients with ERDALT (median $23,078 vs. $28,986; P < 0.0001). Neither lower patient and graft survival, nor higher rates of short-term re-hospitalization and acute rejection events after discharge were observed in patients with ERDALT. In conclusion, the ERDALT score identifies patients suitable for early discharge with excellent outcomes after transplantation. This score may provide applicable models particularly for emerging economies.
Aim. To evaluate the value of D-dimer and P-selectin in cirrhotic portal hypertension (PHT) patients for prediction of portal vein thrombosis (PVT) after devascularization. Material and methods. 137 patients with cirrhotic PHT who undergone devascularization from January 2012 to April 2014 were retrospectively reviewed, all of them were divided into two groups (PVT group and non-PVT group) by Doppler ultrasonography (DU) examination. The level of D-dimer and P-selectin was tested during the peri-operative period. Results. 38 patients (27.7%) were found PVT by DU examination post-operatively. In contrast to the non-PVT group, the level of D-dimer and P-selectin in the PVT group was much higher significantly at 1, 3 and 7 days after devascularization (P < 0.05). However, in the 15 days after surgery, the difference of P-selectin between the two groups was not significant (P = 0.260). It was shown that the higher sensitivity of the two markers for PVT was D-dimer, the higher specificity belonged to P-selectin. The area under receiver operating characteristic (ROC) curve of P-selectin was the bigger of the two markers. When the two markers were combined to be used to diagnose PVT, the sensitivity was increased to 0.911, with a slight drop of specificity to 0.715, the area under ROC curve was 0.919. Conclusion. The level of D-dimer and P-selectin might be good candidate predictive markers for PVT in patients with cirrhotic PHT after devascularization. The combined test of the two markers can increase the value of prediction.
Background and rationale. Cirrhosis is responsible for significant health-care costs and morbidity. This study aims to evaluate the burden of illness associated with cirrhosis, its impact on the universal coverage public health care system in Thailand. Material and methods. We used data from the 2010 Nationwide Hospital Admission Data, the National Health Security Office (NHSO), Thailand. Their baseline characteristics, hospital costs, and outcomes were analyzed according to national health insurance categories including medical welfare scheme (MWFS), social security scheme (SSS) and civil servant medical benefit scheme (CSMBS). Results. 92,301 admissions were eligible for analysis. The mean age was 55 ± 12.8 years, and 63.3% of patients were above 50 years old. The majority of patients (79%) belonged to the MWFS group. The MWFS group incurred the lowest medical expense and had the shortest hospital stay compared to the SSS and CSMBS groups. Overall in-hospital mortality was 10.7%. Cirrhosis complications include bleeding esophageal varices, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma. These complications significantly increased mortality rates compared to patients without complications (26 vs. 8.9%, p < 0.001). In-hospital mortality of patients with cirrhosis complications did not differ among the three national health insurance groups. Respiratory failure and septicemia were associated with the highest risk of death (HR 5.4; 95% CI: 4.8-5.9 and HR 5.2; 95% CI: 4.9-5.6 respectively; P < 0.001). Conclusions. Illness associated with cirrhosis is a significant public health problem in Thailand. Outcomes of cirrhosis complications did not differ between universal public health care coverage systems in Thailand.
Background and rationale for the study. Continuing search for suitable tumor-markers is of clinical value in managing patients with various malignancies. These markers may be presented as intracellular substances in tissues or may be released into the circulation and appear in serum. Therefore, this work is concerned with identification and quantitative determination of epithelial membrane antigen (EMA) and fibronectin and estimating their performances as surrogate markers for identifying hepatocellular carcinoma (HCC). Results. A total of 627 individuals constituted this study [fibrosis (F1-F3) = 217; cirrhosis = 191; HCC = 219]. Western blot was used for identifying EMA and fibronectin in sera. As a result, a single immunoreactive band was shown at 130-kDa and 90-kDa corresponding to EMA and fibronectin, respectively. They were quantified using ELISA providing values in HCC higher than fibrosis or cirrhosis with a significant difference (P < 0.0001). For identifying HCC, EMA showed 0.82 area under receiver-operating characteristic curve (AUC) with sensitivity = 70% and specificity = 78% while fibronectin yielded AUC = 0.70 with sensitivity = 67% and specificity = 82%. FEBA-Test comprising fibronectin and EMA together with total-bilirubin and AFP was constructed yielding AUC = 0.92 for identifying HCC from cirrhosis with sensitivity = 89% and specificity = 85%. FEBA-Test was then tested for differentiating HCC from fibrosis showing AUC = 0.97 with sensitivity = 90% and specificity = 89%. FEBA-Test enabled the correct identification of HCC patients with CLIP 0-1 and size ≤ 3 cm with AUC = 0.80 and AUC = 0.84, respectively, indicating its ability in identifying early HCC. Conclusions. A four-marker index may improve the early detection of HCC with a high degree of accuracy.
The objective of this study was to establish modified cutoff values of serum alpha-fetoprotein (AFP) according to hepatitis status. While AFP is used as a serum marker in the diagnosis or monitoring of hepatocellular carcinoma (HCC), its use as a screening method to the general population is controversial. We evaluated its screening performance in a hepatitis prevalent East Asian population, and suggest different cutoff values according to the individuals hepatitis status. We evaluated the performance of AFP as a screening test in 48,123 consecutive Koreans during the period from March, 2012 to August, 2013 who underwent routine health checks at a single institution. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with fixed cutoff and with modified cutoffs according the individuals hepatitis status. A total of 24 out of 48,123 subject (0.05%) were newly diagnosed with HCC after screening. Among the 1,874 subject with positive hepatitis B virus surface antigen (HBsAg), 17 (0.91%) developed HCC, compared with two out of 393 (0.51%) individuals with hepatitis C virus antibody (anti-HCV). Five out of 45,855 (0.01%) subject with neither HBsAg nor anti-HCV developed HCC. Compared to the performance of a fixed cutoff, specificity, PPV, and NPV improved without sacrificing sensitivity when applying modified cutoff. In conclusion, our findings suggest that AFP with modified cutoffs according to the individuals hepatitis status might be a useful screening marker for HCC in hepatitis prevalent areas.
Background. The evaluation of liver disease in HIV patients is cumbersome because may result from a number of different causes. The aim of this retrospective study was to estimate the incidence of severe drug induced liver injury (DILI) in a group of HIV inpatients and investigate potential risk factors. Material and methods. We performed a retrospective analysis of data from HIV-infected patients hospitalized between August 2010 and August 2011 in a tertiary hospital in São Paulo, Brazil. Severe hepatotoxicity was defined as grade 3 (5.1 to 10 x ULN) or 4 (> 10 x ULN) of ALT and AST levels. Factors analyzed included demographics, infection with hepatitis viruses, alcohol history and use of hepatotoxic drugs prior to or during hospital admission. Results. A total of 149 patients with HIV were hospitalized during the study period. The majority were male over 42 years of age and 82 (55%) were taking HAART initiated prior to admission. Mean CD4 counts were 164 cells/mm3. Thirty three patients (22.1%) developed severe DILI during hospital stay, which had a mean duration of 26 days. Factors associated with severe DILI in the multivariate analysis were abnormal baseline ALT levels [OR 2.02 (95%CI 1.13-3.59); p = 0.017] and tuberculosis therapy [OR 2.31 (95% CI 1.27-4.19); p = 0.006]. In conclusion, in this group of HIV patients admitted to a tertiary hospital in Brazil, we found a high incidence (22.1%) of severe DILI. The use of anti-tuberculosis drugs and baseline liver injury were independent factors associated with severe DILI during hospital stay.
Background. The nephrotoxic potential of intravenous iodinated contrast (IC) is controversial. Cirrhotic patients are often submitted to imaging procedures involving IC and small changes in renal function may have detrimental effects. Material and methods. Retrospective analysis of hospitalized patients with elective imaging by either contrast-enhanced CT or MRI. Contrast induced acute kidney injury (CI-AKI) was diagnosed if there was either an increase of SCr by 25% or by 44 μmol/L or a decrease of estimated glomerular filtration rate by 25% by day 3. Results. Between 2004 and 2012 152 patients (female: 30.3%, age: 60 ± 10.8 years, MELD 13 ± 6) were included in this study of which 84 (55.3%) had received IC and 68 (44,7%), who served as controls, MRI with gadolinium based contrast (non-IC). Baseline paremeters were well matched except for age (61.7 vs. 56.9) years in the IC vs. non-IC groups, p = 0.005). 15 patients (17.9%) receiving IC and 4 patients (5.9%) not receiving IC (p = 0.026) reached the composite end-point for CI-AKI. In multivariable regression analysis INR [B = 0.252 (95% CI: 0.108-0.397), p = 0.001]; IC [B = 0.136 (95% CI: 0.023-0.248), p = 0.019] and serum sodium [B = 0.011 (95% CI: 0.001-0.023); p = 0.080] were independently associated with changes of SCr. In conclusion IC may cause renal dysfunction in cirrhotic patients. Patients subjected to imaging using IC should be closely monitored.
Background and rationale for the study. The aim of the study was to determine the prognostic value of histopathological findings with special care to the severity of liver fibrosis at the moment of hepatoportoenterostomy (HPE) in children with biliary atresia (BA). We performed analysis of 142 wedge liver biopsies taken at the time of HPE. All patients were operated by the same surgical team between 1995 and 2007. According to the outcome 6 months after HPE patients were divided into prognostic groups: group 1-bilirubin level < 2 mg% (n = 65), group 2-bilirubin level > 2 mg% (n = 77). Liver biopsies were re-evaluated according to the extended histopathological protocol and then were compared between the prognostic groups. Survival with native liver (SNL) estimates were performed in regard to severity of liver fibrosis. Results. Survival with native liver estimates after 2, 5 and 10 years in patients after successful operation were 96%, 91%, 75% vs. 30%, 11%, and 5% if operation failed (p < 0.001). There was no difference between groups in the following variables: fibrosis (p = 0.69), portal inflammation (p = 0.99), lobular inflammation (p = 0.95), cholangiolitis (p = 0.23), accumulation of bile pigments (zone 1:p = 0.49; zone 2:p = 0.51; zone 3:p = 0.48), bile plugs in canaliculi (p = 0.12), bile plugs in ducts (p = 0.32), bilirubinostasis in hepatocytes (p = 0.45), bile ductular proliferation (p = 0.59), ductal plate malformation (p = 0.12), focal necrosis (p = 0.44), giant cell transformation (p = 0.45), haematopoesis (p = 0.52), ductopenia (p = 0.46), microabscesses (p = 0.49), ballooning of hepatocytes (p = 0.08). The actuarial 5/10-year SNL was not dependent on severity of liver fibrosis (log-rank test p = 0.84). The severity of fibrosis corresponded neither with the age at HPE nor with the laboratory findings before operation but increased the risk of portal hypertension. Conclusion. Liver histology at the time of HPE is of limited value in prognosis making in BA.
Background and rationale for the study. We designed to test whether there is interaction of maternal separation (MS) on the ethanol-preferring rats liver structure. The UCh rat pups were separated daily from their mothers during the stress hyporesponsive period (SHRP), between four and 14 days-old, always at the same time for four hours in a cage containing eight subdivisions, one for each pup. Subsequently, rats that presented the highest (UChB) and the lowest (UChA) ethanol (EtOH) consumption were selected to the study. Both UChB and UChA rats received 10% (v/v) EtOH and distilled water ad libitum until the end of the experiment (120 days-old). The liver was collected to histological routine for morphometric and stereological analyses, and immunohistochemistry. Results. There was an interaction of MS and EtOH on the liver: increased liver mass, peritubular vessels, stellate cell numbers, steatosis and cell death, decreased necrosis, sinusoidal capillary diameters and cell proliferation. While there was a decrease in FSH, testosterone and 5α-di-hidrotestosterone, and increasing corticosterone and cholesterol. Conclusions. There is interaction of MS and EtOH on the liver structure, dependent on the amount of EtOH intake. Furthermore, the interaction of stress and drugs can increase or decrease their effects on the liver or indirectly via hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes.
Lipoprotein X (LpX) is an abnormal lipoprotein associated with cholestasis. It is a significant cause of severe hypercholesterolemia and should always be considered in patients with cholestatic liver disease. This case highlights the significance of LpX as a cause of severe hypercholesterolemia in a patient with cholestasis secondary to a granulomatous hepatitis attributed to tuberculosis. Lipoprotein agarose gel electrophoresis and gradient gel electrophoresis were performed for the detection of LpX. The liver function tests, electrolytes, lipid profile and bile acids were also determined. Anti-tuberculous therapy was initiated and the liver functions improved with normalisation of the lipid profile.
Pulmonary hypertension is a common finding in patients with advanced liver disease. Similarly, among patients with advanced pulmonary arterial hypertension, right heart failure leads to congestive hepatopathy. Diuretic resistant fluid overload in both advanced pulmonary hypertension and chronic liver disease is a demanding challenge for physicians. Venous congestion and ascites-induced increased intra-abdominal pressure are essential regarding recurrent hospitalization, morbidity and mortality. Due to impaired rightventricular function, many patients cannot tolerate extracorporeal ultrafiltration. Peritoneal dialysis, a well-established, hemodynamically tolerated treatment for outpatients may be a good alternative to control fluid status. We present a patient with pulmonary arterial hypertension and congestive hepatopathy hospitalized for over 3 months due to ascites induced refractory volume overload treated with peritoneal ultrafiltration. We report the treatment benefits on fluid balance, cardiorenal and pulmonary function, as well as its safety. In conclusion, we report a case in which peritoneal ultrafiltration was an efficient treatment option for refractory ascites in patients with congestive hepatopathy.
Today the knowledge of genotype-phenotype correlation in cystic fibrosis is enriched by the growing discoveries of new mutations of the CFTR gene. Although the combination of two severe mutations usually leads to the classic disease (pulmonary and pancreatic insufficiency, sterility, nasal polyposis), the presence of a complex genotype characterized by severe and milder mutations or polymorphism can cause a hidden disease, which is often asymptomatic at early ages. We report on a case of a 15 years old boy, in whom the only clinical signs of CF were chronic hypertransaminasemia and hyperbilirubinemia, and in whom it was demonstrated the presence of the mutations F508del associated with TG11-9T-470M in one allele and TG12-5T-470V in the other allele. Although a clear genotype-phenotype correlation for liver disease is still missing for CF patients, it is possible to state that this isolated clinical presentation could represent an unusual phenotype of CF, related to a complex genotype characterized by a severe mutation and one (or more) polymorphism.