Vol. 17 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
Occult hepatitis B infection (OBI) is the presence of hepatitis B virus (HBV) DNA in the liver and/or serum (< 200 IU/mL) in HBsAgnegative patients with or without serologic markers of previous viral exposure. The clinical significance of OBI is of concern in posttransfusional hepatitis B infection, hepatitis B reactivation, chronic liver disease and hepatocellular carcinoma (HCC). The diagnosis of OBI relays on the use of highly sensitive and specific laboratory techniques. Herein, comments derived from a study analyzing the frequency and characteristics of OBI in HCC Japanese patients are stated. While OBI and other causes of HCC have been highly studied in Asia and Europe, research in Latin America in these topics is limited. Several findings such as population risk groups with high prevalence of overt and OBI infection, HBV genotype F in Argentinean HCC patients, and the clinical impact of the foreign A-D genotypes suggest the need of further investigation. Additionally, alcoholism, obesity, NASH and type 2 diabetes may override the presence of OBI. Therefore, OBI diagnosis is essential. It is known that anti-HBc alone is a predictive signal of potential OBI and given the fluctuations of the HBV infection markers, testing for HBsAg and anti-HBc at baseline and follow-up is recommended. In conclusion, OBI and other causes involved in the epidemiology of HCC in Latin America are unexplored risk factors. Genome-based research is required to decipher the role of gene-environmental interactions associated with chronic liver disease. Novel algorithms to detect OBI supported by basic/applied/clinical research are also needed.
Based on high seroprevalence, null surveillance, and lack of diagnostics, Mexico is a high-risk region for hepatitis E Virus (HEV) infection. However, few local news on infection are available. Clinicians and general population are in need of increasing awareness, and preventive measures should be emphasized.
Decompensated liver cirrhosis has a dismal prognosis, with an overall survival of 2-4 years, which is worse than for many oncological diseases. Albumin is an important tool in the management of patients with cirrhosis, since it decreases for less than half the risk for post-paracentesis cardiocirculatory dysfunction and mortality associated with spontaneous bacterial infection, as well as, it triplicates the response to terlipressin in patients with hepatorenal syndrome. Recently, research on albumin has been a hot topic, with important new insights such as the characterization of the pleiotropic effects of albumin (which surpass its oncotic properties) and the concept of effective albumin concentration. In fact, patients with liver cirrhosis present posttranslational modifications on albumin that compromises its function. Those modified albumin forms were proved to have prognostic value and its knowledge may change the paradigm of albumin treatment. In this review, we critically summarize the latest evidence on the potential benefits of albumin in patients with end-stage liver disease.
Introduction and aim. HAVCR1 protein is the cellular receptor for hepatitis A virus (HAV). Genetic polymorphism in this gene may alter the outcome of HAV infection. In a previous study, a 6-amino acid insertion (157insMTTTVP) in HAVCR1 gene was associated with more severe disease. We decided to investigate this association further. Material and methods. We sequenced exon 4 of the HAVCR1 gene in patients with clinical hepatitis A attending our institution, and a group of healthy controls in a disease-endemic setting in India. Frequencies of different haplotypes of a genomic region with two overlapping insertion-deletion polymorphisms (indels; rs141023871 and rs139041445) were compared between patients and controls, as well as between patients with and without a severe form of disease (liver failure). Results. The gene had three haplotypes in the region of interest - a short form, an intermediate-form with a 5-amino acid 157insMTTVP insertion and a long-form with a 6-amino acid 157insMTTTVP insertion. The allele frequency (29/150 [19%] vs. 43/146 [29%]; p = ns) and haplotype frequency (29/75 [39%] vs. 39/73 [53%]; p = ns) of the 157insMTTTVP variant were similar in hepatitis A patients and healthy controls (30%). Further, the allele frequency (12/58 [21%] vs. 17/92 [18%]; p = ns) and haplotype frequency (12/29 [41%] vs.17/46 [37%]; p = ns) of the longest variant were also similar in patients with severe and mild disease. Discussion. In the study population, the 157insMTTTVP variant of HAVCR1 gene was not associated with more severe outcome of HAV infection. Further studies in other populations around the world are needed to assess the relation of this genetic variation with disease outcome.
Introduction and aim. The correlation between interleukin-28B (IL-28B) polymorphisms and chronic hepatitis C (CHC) progression is debatable. Here, we aimed to evaluate the relation between IL-28B C/T genotypes and the development of cirrhotic liver. Extracellular matrix (ECM) proteins, FibroScan and model for end-stage liver disease (MELD) were used to substantiate the severity of liver disease. Material and methods. IL-28B rs12979860, liver stiffness and ECM proteins were assessed in 272 CHC patients. Results. Cirrhosis percentage increased to 10%, 52% and 96% with the increasing number of T alleles (CC, CT and TT, respectively). Also, elevated ECM proteins levels were correlated with the increasing number of T alleles. Interestingly, among cirrhotic patients, liver stiffness, MELD and ECM proteins were significantly (P < 0.0001) higher in patients with TT more than CT genotype. FibroScan, hyaluronic acid, Laminin, Collagen IV and the N-terminal pro-peptide of collagen type III have high accuracy to differentiate liver status in CC from TT genotype. Area under receiver-operating characteristic curve (95% CI) were 1.0 (1.0-1.0), 0.97 (0.96- 1.0), 0.93 (0.85-1.0), 0.98 (0.97-1.0) and 0.93 (0.91-0.97), respectively. Conclusion. This study suggests that IL-28B T allele affects the natural course of CHC type 4 and also suggests that carriage of the IL-28B C allele protects from unfavorable clinical outcomes in CHC as coexistence of C allele with T allele reduced cirrhosis severity.
Introduction and aim. Nonalcoholic fatty liver disease (NAFLD) is closely associated with overweight and obesity, becoming one of the most prevalent hepatic diseases nowadays. Circulating hemoglobin (Hb) concentration is significantly higher in people with NAFLD, compared to healthy patients. While liver biopsy remains the gold standard for NAFLD diagnosis, it is not the best technique due to adverse events that may occur. Therefore it is important to find less invasive and more sensitive markers. This study aimed to determine the association of serum Hb levels in patients with steatosis and fibrosis as a noninvasive marker. Material and methods. A 1,186 patient cross-sectional study nested in a randomized clinical trial (NCT01874249) was conducted. Patients were diagnosed by ultrasound for hepatic steatosis and fibroscan for fibrosis; blood test and anthropometric measurements were also assessed. Results. Serum Hb increased proportionally related to the steatosis level, being significantly higher in patients with severe steatosis than in patients with moderate and mild steatosis. Conclusion. Patients with non-alcoholic fatty liver disease showed elevated levels of circulating Hb, evidence that suggests that Hb exerts a protective role, as it may act as an antioxidant and may counteract the adverse effects of this disease.
Introduction and aim. The prevalence of obesity, type 2 diabetes mellitus and non-alcoholic fatty liver disease are increasing. Type 2 diabetes mellitus may aggravate non-alcoholic fatty liver disease, increasing the risk of developing cirrhosis and hepatocellular carcinoma. This study aims to determine the effect of type 2 diabetes mellitus and insulin therapy on non-alcoholic fatty liver disease in the patients with morbid obesity. Material and methods. Clinical, anthropometric and laboratory data were analyzed together with intraoperative liver biopsies from morbidly obese patients undergoing bariatric surgery. Results. 219 patients with morbid obesity were evaluated. Systemic arterial hypertension (55.9% vs. 33.8%, p = 0.004) and dyslipidemia (67.1% vs. 39.0%, p < 0.001) were more prevalent in patients with diabetes when compared to patients without diabetes. In multivariate analysis, type 2 diabetes mellitus was an independent risk factor for severe steatosis (RR = 2.04, p = 0.023) and severe fibrosis (RR = 4.57, p = 0.013). Insulin therapy was significantly associated with non-alcoholic steatohepatitis (RR = 1.89, p = 0.001) and fibrosis (RR = 1.75, p = 0.050) when all patients were analysed, but when only patients with diabetes were analysed, insulin therapy was not associated with non-alcoholic steatohepatitis or fibrosis. Conclusion. Type 2 diabetes mellitus plays an important role in the progression of non-alcoholic fatty liver disease as an independent risk factor for severe fibrosis.
Introduction and aim. Neonatal cholestasis constitutes for 19 to 33% of all chronic liver disease in India. Cholestasis leads to fibrosis of liver and ultimately cirrhosis. There are various methods of diagnosis of fibrosis of liver like fibroscan, APRI index, FIB-4, fibro index, forns index, heap score, magnetic elastography. Here we are comparing APRI index with METAVIR index in patients with neonatal cholestasis without biliary atresia and determining whether APRI index can be used as a tool to determine fibrosis in these patients. Material and methods. Patients with neonatal cholestasis without biliary atresia were included in the study. This retrospective analysis was done between 2009 and 2015. All patients underwent a liver biopsy and METAVIR index was calculated. APRI at the time of liver biopsy was determined. Results. Forty-eight patients were included in this study with mean age of 3.5 ± 2.8 months with a male: female ratio of 35:13. Metavir Index F0 was seen in was 32 (66.67%) patients, F1 in 6(12.5%), F2 in 4(8.33%), F3 in 0 and F4 in 6(12.5%) patients respectively. Mean APRI for F0-F3 was 1.38 and for F4 was 3.74 respectively. With an APRI of 1.38, the sensitivity and specificity to detect fibrosis/cirrhosis was 100% and 21.43% respectively. Conclusion. APRI is not an effective tool to measure fibrosis or cirrhosis in patients with non-BA neonatal cholestasis in Indian children.
Introduction and aim. Occult hepatitis B virus (HBV) infection (OBI) represents a state without detectable hepatitis B surface antigen, but positive for HBV DNA. The correlation between OBI and hepatocellular carcinoma (HCC) carcinogenesis is controversial. We studied the frequency and characteristics of OBI among HCC patients and metastatic liver cancer patients. Material and methods. DNA was obtained from tumor and non-tumor tissues from 75 HCC patients (15 chronic hepatitis B (CHB), 39 chronic hepatitis C (CHC), 21 cryptogenic) and 15 metastatic liver cancer patients who underwent liver resection. HBV DNA and covalentlyclosed circular (ccc) DNA were detected using real-time polymerase chain reaction (PCR), and four HBV DNA regions were detected by nested PCR. Clinicopathological factors were compared between patients with and without OBI. Results. HBV DNA was detected in 14 (93.3%) CHB, five (22.7%) cryptogenic and four (10.3%) CHC patients. cccDNA was detected in 12 (80.0%) CHB, three (14.3%) cryptogenic and two (5.1%) CHC patients. All CHB, eight (38.1%) cryptogenic and ten (25.6%) CHC patients tested positive with nested PCR. No metastatic liver cancer patients were positive for any HBV DNA regions. OBI patients had shorter prothrombin times (P = 0.0055), and lower inflammation activity score in non-tumor liver (P = 0.0274). There were no differences in anti-HBV antibodies. Conclusions. OBI was detected in 38% of cryptogenic and 25.6% of CHC patients. There was no correlation between OBI and anti-HBV antibodies, but fewer patients with OBI had high inflammatory activity, suggesting that factors other than inflammation may be involved in HCC carcinogenesis in patients with OBI.
Introduction and aim. Despite reports of increased incidence of intrahepatic cholangiocarcinoma (iCCA) in the United States, the impact of age or influences of race and ethnicity are not clear. Disparities in iCCA outcomes across various population subgroups also are not readily recognized due to the rarity of this cancer. We examined ethnic, race, age, and gender variations in iCCA incidence and survival using data from the Surveillance, Epidemiology, and End Results Program (1995-2014). Material and methods. We assessed age-adjusted incidence rates, average annual percentage change in incidence, and hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause and iCCA-specific mortality. Results. Overall, 11,127 cases of iCCA were identified, with an age-adjusted incidence rate of 0.92 per 100,000. The incidence rate increased twofold, from 0.49 per 100,000 in 1995 to 1.49 per 100,000 in 2014, with an average annual rate of increase of 5.49%. The iCCA incidence rate was higher among persons age 45 years or older than those younger than 45 years (1.71 vs. 0.07 per 100,000), among males than females (0.97 vs. 0.88 per 100,000) and among Hispanics than non-Hispanics (1.18 vs. 0.89 per 100,000). Compared to non-Hispanics, Hispanics had poorer 5-year allcause mortality (HR = 1.11, 95%CI: 1.05-1.19) and poorer iCCA-specific mortality (HR = 1.15, 95%CI: 1.07-1.24). Survival rates were poor also for individuals age 45 years or older, men, and Blacks and American Indians/Alaska Natives. Conclusion. The results demonstrate ethnic, race, age and gender disparities in iCCA incidence and survival, and confirm continued increase in iCCA incidence in the United States.
Introduction and aim. Sarcopenia is an independent predictor of mortality in cirrhosis. Hypogonadism is common in cirrhosis and has been associated with sarcopenia in non-cirrhotic chronic liver disease populations. The aim of this study is to investigate if sarcopenia is associated with low testosterone levels in patients with cirrhosis. Material and methods. This is a retrospective analysis of prospectively collected data of 211 cirrhotic patients undergoing evaluation for liver transplantation. Sarcopenia was defined by computed tomography (CT) scan using specific cutoffs of the 3rd lumbar vertebra skeletal muscle index (L3 SMI). Morning testosterone levels were obtained in all patients. Results. Of the 211 patients, sarcopenia was noted in 94 (45%). Testosterone levels were lower in sarcopenic patients (10.7 ± 1.1 vs. 13.7 ± 1.4 nmol/L, p = 0.03) and hypotestosteronemia was more frequent in them too (34 vs. 16%, p = 0.004). In males, those with sarcopenia had lower testosterone levels (14.6 ± 1.4 vs. 21.9 ± 1.8, p = 0.002), and the corresponding frequency of hypotestosteronemia (42 vs. 19%, p = 0.006) was also higher. There were no significant differences in female patients. There was a weak correlation between L3 SMI and testosterone levels (r 0.37, p < 0.001). On multivariable regression analysis including sex, body mass index (BMI), hypotestosteronemia, MELD and etiology of cirrhosis, only hypotestosteronemia (RR 2.76, p = 0.005) and BMI (RR 0.88, p < 0.001) were independently associated with sarcopenia. Conclusion. Low testosterone levels are associated with sarcopenia in male cirrhotic patients. The potential therapeutic effect of testosterone to reverse sarcopenia in these patients warrants evaluation in future trials.
Introduction and aim. It is well known that development of acute kidney injury (AKI) increases mortality in hospitalized cirrhotic patients; therefore many novel markers have been studied for early detection, differential diagnosis and prognosis in cirrhotic patients with AKI. The aim of the current work is to evaluate urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) as a diagnostic biomarker for different causes of acute kidney injury in liver cirrhosis and to assess it as a prognostic marker. Material and methods. Out of 83 cirrhotic patients with AKI admitted between October 2015 and June 2016; 70 patients were included in this prospective study. Routine laboratory tests, uNGAL and fractional excretion of Na were obtained on admission. End points were death or improvement of kidney function and discharge. Results. The patients included in our study were 41 males and 29 females with mean age 54.27 ± 6.08 years. HCV was the etiology of cirrhosis in 69 cases while one had combined HBV and HCV infection. More than 50% of patients were classified as Child C. Causes of kidney injury were prerenal, hepatorenal syndrome (HRS) and intrinsic tubular injury (iAKI) in 39 patients (55.7%), 17 patients (24.3%) and 14 patients (20%) respectively. mean value of uNGAL in prerenal, HRS and iAKI was 21.70 ± 7.31, 115.53 ± 68.19 and 240.83 ± 116.94 ng/mg creatinine respectively. MELD above 20 and uNGL above 32 were predictors of mortality. Conclusion. A single baseline measurement of uNGAL level has the ability to determine type of kidney dysfunction in cirrhotic patients, perhaps accelerating management decisions and improving outcomes.
Introduction and aim. Procalcitonin is widely used as a biomarker to distinguish bacterial infections from other etiologies of systemic inflammation. Little is known about its value in acute liver injury resulting from intoxication with paracetamol. Material and methods. We performed a single-center retrospective analysis of the procalcitonin level, liver synthesis, liver cell damage and renal function of patients admitted with paracetamol-induced liver injury to a tertiary care children's hospital. Children with acute liver failure due to other reasons without a bacterial or fungal infection served as the control group. Twelve patients with acute paracetamol intoxication and acute liver injury were compared with 29 patients with acute liver failure. Results. The procalcitonin levels were higher in children with paracetamol intoxication than in patients with acute liver failure without paracetamol intoxication (median 24.8 (0.01-55.57) ng/mL vs. 1.36 (0.1-44.18) ng/mL; p < 0.005), although their liver and kidney functions were better and the liver cell injury was similar in both groups. Outcome analysis showed a trend towards better survival without transplantation in patients with paracetamol intoxication (10/12 vs. 15/29). Within each group, procalcitonin was significantly correlated with alanine aminotransferase and aspartate aminotransferase but was not correlated with the International Normalized Ratio or paracetamol blood levels in the paracetamol group. In conclusion, paracetamol intoxication leads to a marked increase in procalcitonin serum levels, which are significantly higher than those seen in acute liver failure. Conclusion. The underlying mechanism is neither caused by infection nor fully explained by liver cell death alone and remains to be determined.
Introduction and aim. Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction. This work aims to analyze the pattern of vascular involvement in Egyptian patients with BCS, demonstrates its relation to etiology and shows its impact on clinical presentation. Material and methods. The current retrospective study was conducted at The Tropical Medicine Department, Ain Shams University on one hundred Egyptian patients with confirmed diagnosis of primary BCS who were presented to the Budd-Chiari Study Group (BCSG) from April 2014 to May 2016 by collecting clinical, laboratory and radiological data from their medical records. Results. Isolated hepatic vein occlusion (HVO) was the most common pattern of vascular involvement (43%), followed by combined HVO and inferior vena cava (IVC) compression by enlarged caudate lobe (32%), then combined HVO and IVC stenosis/webs (21%), and lastly isolated IVC occlusion (4%). Ascites was more significantly encountered in BCS patients with HVO than in those with isolated inferior vena cava (IVC) occlusion and patent HVs (P = 0.005). Abdominal pain was significantly encountered in patients with occluded three major HVs (P = 0.044). Behcet's disease was significantly detected in isolated IVC occlusion. Protein C deficiency was significantly detected in patients with combined HVO and IVC compression. Conclusion. Isolated HVs occlusion was the most common pattern of vascular involvement in Egyptian patients with primary BCS. Vascular pattern of involvement affected the clinical presentation and was related to the underlying thrombophilia in those patients.
Introduction and aim. To investigate the effect of mTOR inhibitor Rapamycin combined with transcatheter arterial embolization (TAE) on the growth, metastasis, and prognosis of hepatocellular carcinoma (HCC) in rat model. Material and method. McARH7777 cells were used to construct rat models of HCC, which were randomly divided into Model, Rapamycin, TAE, and Rapamycin + TAE groups. Quantitative reverse transcription-PCR (qRT-PCR) and Western Blot were used to detect the expression of Epithelial-Mesenchymal Transition (EMT)-related molecules, and immunohistochemical staining to determine the expression of EMTrelated proteins, angiogenic factors as well as microvessel density (MVD)-CD34. Results. The hepatic tumor volume of rats in the other three groups were all significantly smaller than the Model group on the 7th, 14th, and 21st day after treatment and the combination treatment was apparently more effective than either treatment alone. Besides, both the number and the size of metastatic nodules of HCC rats after combination treatment were remarkably reduced. In addition, compared with rats in the Rapamycin + TAE group, N-cadherin, Vimentin, HIF-1α, VEGF, and MVD-CD34 were obviously enhanced, while E-cadherin was lowered in those TAE group, which were the complete opposite to the Rapamycin group. Besides, the median survival time of rats in the Rapamycin + TAE group was evidently longer than the resting groups. Conclusion. Rapamycin combined with TAE may effectively suppress the EMT formation and angiogenesis, thereby inhibiting the growth and lung metastasis of HCC rats, which provides a new idea for countering the recurrence and metastasis of HCC.
A 76-year-old woman was referred to our hospital due to massive gingival bleeding following teeth extraction. Laboratory findings suggested disseminated intravascular coagulopathy (DIC). Enhanced computed tomography and magnetic resonance imaging disclosed multiple hypervascular liver masses of 2-6 cm in diameter, the largest of which displaying an irregular enhancement pattern. We considered that her DIC was caused by the multiple liver masses and commenced repeated erythrocyte/fresh frozen plasma infusion and gabexate mesilate administration. However, the DIC proved uncontrollable and trans-arterial embolization could not be attempted. The patient eventually died 4 months after admission due to spontaneous hepatic tumor rupture and hepatic failure. Post-mortem hepatic tumor biopsy led to a final diagnosis of hepatic angiosarcoma with Kasabach-Merritt phenomenon (KMP). Among the 7 cases of hepatic angiosarcoma representing KMP found in the literature, mortality occurred within 4 months of the appearance of bleeding tendency primarily due to abdominal bleeding and hepatic failure. The possibility of hepatic angiosarcoma should be considered in patients with DIC and hypervascular liver tumors. Since treatment is uncertain and prognosis is poor, novel diagnostic and therapeutic advances are needed for angiosarcoma.
Directly-acting antivirals (DAA) have changed the chronic hepatitis C virus (HCV) infection therapeutic scenario allowing virus eradication in more than 95% of patients, independently from the genotype, with 12 to 24-week treatment regimens. We describe a 51-year-old Pakistani man with a chronic HCV-genotype 3 (GT3a) infection with moderate liver fibrosis, who achieved sustained virological response (SVR) 24 after a tripled dose of Daclatasvir (DCV) taken erroneously associated to Sofosbuvir (SOF). The patient had a concomitant intestinal TB infection whose treatment had been delayed in order to firstly eradicate HCV to reduce the liver toxicity of anti-mycobacterial drugs. Thanks to the cultural mediator support, we explained to the patient the correct posology of each drug to take during the day consisting of 12 week SOF (400 mg daily) plus DCV (60 mg daily) regimen. He returned 13 days after for a programmed visit and we were surprised to learn that he had taken 3 pills of DCV (180 mg/daily) instead of one, thus ending DCV assumption after only 9 days while SOF was taken correctly. He complained no symptoms. We immediately performed blood test that showed alteration of lactate dehydrogenase, creatine phosphokinase, and creatin kinase MB activity. At day 15 we stopped SOF closely monitoring the patient. Blood test alterations returned normal after one week of treatment suspension, HCV viremia remained suppressed after 4, 12 and 24 weeks proving HCV eradication. If confirmed, these data could suggest that higher doses of DCV, if tolerated, might be employed in short-time HCV-GT3 treatment.