Hepatology International

Hyponatremia (Na+ <135 mmol/l) is the most common electrolyte disorder. Cirrhosis represents a rather frequent cause of hyponatremia mainly due to systemic and splanchnic vasodilation resulting in decreased effective arterial blood volume, which leads to excessive non-osmotic secretion of antidiuretic hormone. However, hyponatremia of multifactorial origin may be seen in patients with liver diseases. The review focuses on the factors and pathogenetic mechanisms of decreased sodium levels other than the hemodynamic compromise of cirrhosis in patients with liver diseases. The mechanisms and causal or contributing role of pseudohyponatremia, hyperglycemia, infections, drugs and toxins as well as of endocrine disorders, renal failure and cardiac disease in patients with liver disease are meticulously discussed. Hyponatremia of multifactorial origin is frequently observed in patients with liver diseases, and special efforts should be made to delineate the underlying causative and precipitating factors as well as the risk factors of the osmotic demyelination syndrome in order to properly manage this serious electrolyte disorder and avoid treatment pitfalls.

Strong impact of hepatitis C virus (HCV) on normal regulation of cellular processes has been reported that could have significant implications for HCV pathogenesis. We aimed to determine the altered cellular processes during HCV infection with particular reference to advanced disease stages. Liver biopsy specimens of chronic hepatitis C patients classified on histological basis as early (fibrosis stage 1–2) or advanced (fibrosis stage 3–4) HCV disease were studied using microarray technology (Affymetrix GeneChip™ System). For comparison, liver specimens from patients with non-viral hepatitis (NV-hepatitis) were also analyzed by microarray. Expression data generated were analyzed using software Genespring GX and Ingenuity Pathway analysis to find the association with biological functions. We further validated the microarray results using quantitative reverse transcriptase-polymerase chain reaction. Data analysis through Genespring software revealed that in advanced HCV (A-HCV) a total of 792 genes are differentially expressed when compared to early HCV (E-HCV) and 417 genes are differentially expressed when compared to NV-hepatitis. Most of these genes are involved in cancer, cellular growth and proliferation, and tissue morphology. Real time (RT) PCR analysis confirmed the differential expression of six of these genes. The results of this study reflect the changes taking place during the transition from early to advanced liver fibrosis, when the liver function becomes impaired and extracellular matrix deposition increases. In addition, it showed altered expression of genes with functions in cancer development, cell growth, proliferation, and cell death that might indicate high risk of cell transformation and hepatocellular carcinoma (HCC) in A-HCV disease patients.

To obtain the biomechanical and morphological remodelling of hepatic arteries in swine with portal hypertension. A number of 20 white pigs was used, of which 14 were subjected to liver cirrhosis and portal hypertension (PHT) induced by carbon tetrachloride and pentobarbital; the rest were used as the control group. The biomechanical remodelling of the hepatic arteries was measured, namely, the incremental elastic modulus (E inc), pressure–strain elastic modulus (E p), volume elastic modulus (E v), the incremental compliance (C), the opening angle and the stained microstructural components of the vessels. The percentages for the microstructural components and the histologic data significantly changed in the experimental group, three incremental elastic moduli (E inc, E p, and E v) of the experimental group were significantly larger than those of the control group (P < 0.05); the compliance of hepatic arteries decreased greatly (P < 0.05) too. The opening angle (OA) was considerably larger than that of control group (P < 0.05). The study suggests that the morphological and biomechanical properties of swine hepatic arteries have changed significantly during the process of portal hypertension and that from biomechanical aspects, the hepatic arteries have also suffered from extensive remodelling, which in turn deteriorates the existing portal hypertension.

While HCC is an inflammation-associated cancer, CRLM develops on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated. 40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4+CD25+ Tregs, M/PMN-MDSC and PB-derived CD4+CD25− T-effector cells (Teffs) were isolated and characterized. Tregs’ function was also evaluated in the presence of the CXCR4 inhibitor, peptide-R29, AMD3100 or anti-PD1. RNA was extracted from PB/PT/TT tissues and tested for FOXP3, CXCL12, CXCR4, CCL5, IL-15, CXCL5, Arg-1, N-cad, Vim, CXCL8, TGFβ and VEGF-A expression. In HCC/CRLM-PB, higher number of functional Tregs, CD4+CD25hiFOXP3+ was detected, although PB-HCC Tregs exert a more suppressive function as compared to CRLM Tregs. In HCC/CRLM-TT, Tregs were highly represented with activated/ENTPD-1+Tregs prevalent in HCC. As compared to CRLM, HCC overexpressed CXCR4 and N-cadherin/vimentin in a contest rich in arginase and CCL5. Monocytic MDSCs were highly represented in HCC/CRLM, while high polymorphonuclear MDSCs were detected only in HCC. Interestingly, the function of CXCR4-PB-Tregs was impaired in HCC/CRLM by the CXCR4 inhibitor R29. In HCC and CRLM, peripheral blood, peritumoral and tumoral tissues Tregs are highly represented and functional. Nevertheless, HCC displays a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hit therapy in liver cancer patients.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related disease worldwide. Although HCC is mainly associated with viral hepatitis and alcoholic cirrhosis, numerous physiological and biochemical events are associated with HCC progression. The transcription factor Twist, which plays a key role in epithelial to mesenchymal transition, is reported to be associated with HCC. Overexpression of Twist causes various biochemical changes, such as increase of cell proliferation, reduction of apoptosis, cell cycle deregulation, generation of hepatic cancer stem cells, and in some cases, drug resistance. These changes result in various physiological changes, such as angiogenesis, cellular migration and invasion, and vasculogenic mimicry, which ultimately causes hepatocellular metastasis. Interestingly, targeting Twist via different strategies, especially small RNA technology, has shown promising therapeutic potential for future HCC treatment.

The number of amino acid (AA) mutations in the interferon sensitivity determining region (ISDR) of NS5A is reported to affect the response to interferon (IFN) therapy in patients with chronic hepatitis C (CHC). The aim of this study was to clarify whether host immunity is influenced by the number of AA mutations in the ISDR. Subjects included 44 patients with CHC infected with genotype 1b and high viral load. The number of AA mutations in the ISDR was retrospectively determined using stored serum samples taken immediately before starting therapy. All patients received IFN-alpha 2b or pegylated-IFN (PEG-IFN)-alpha 2b and ribavirin. When serum hepatitis C virus-ribonucleic acid (HCV-RNA) was negative at 4 or 12 weeks after starting therapy, the patient was defined as having rapid viral response (RVR) or early viral response (EVR), respectively. CD4+ T cell (Th1 or Th2) in peripheral blood (PB) before and until day 56 of treatment was analyzed. Rates of RVR and EVR were 0 (0/21) and 14% (3/21), respectively, in patients with one or fewer AA mutations in the ISDR (ISDR0-1), and 30 (7/23), and 74% (17/23), respectively, with two or more AA mutations in the ISDR (ISDR > 2). Although the percentage of PB Th1 cells did not differ between the two groups during the study period, the percentage of PB Th2 cells was significantly lower in the ISDR0-1 group than in the ISDR > 2 group at baseline and on days 3, 7, 14, and 28 of treatment. The number of AA mutations in the ISDR influenced PB Th2 cells before and until day 28, and was associated with higher RVR and EVR rates.

Occult hepatitis B virus infection (OBI) poses a challenge to the safety of blood donation. The prevalence of OBI is not well documented in Indonesia, although this information in such an endemic country is needed. This study was aimed to evaluate the prevalence of occult hepatitis B in blood donors from two cities of Indonesia, and to study the genetic variation and its effect on the predicted antigenicity of HBsAg. Serum samples of 309 regular blood donors negative for HBsAg were tested for anti-HBs and anti-HBc. Hepatitis B virus (HBV) DNA isolated from anti-HBc-positive samples were analyzed by polymerase chain reaction, cloned and sequenced. Antigenic properties of identified HBsAg mutants were predicted by calculation of the antigenic index. Of the 309 HBsAg-negative samples, anti-HBc was positive in 134 (43.4%) and HBV DNA was detected in 25 (8.1%). Seven of the viremic samples had nucleotide substitutions (A521G, A551T, C582T, and A562G) in the S gene, causing amino acid mutations (T123A, M133L, and T143M) in the ‘a’ determinant of HBsAg that resulted in changes in the predicted antigenicity. OBI was detected in blood donors’ samples in Indonesia. Anti-HBc was shown to be a better screening parameter than HBsAg, however, it might result in the loss of donors particularly in endemic countries. HBsAg detection failure in this study might be due to mutations altering the protein antigenicity and/or the low-level carriage of HBV.

To investigate the etiological characteristics of patients with liver failure in the past 10 years. Clinical and investigational data in hospitalized patients with liver failure admitted from 2002 to 2011 were retrospectively analyzed. Standard definitions and criteria were used to assess disease etiology. Of these 3,916 patients, 3,429 (87.6 %) had acute-on-chronic liver failure (ACLF), 114 (2.9 %) acute liver failure (ALF), and 373 (9.5 %) subacute liver failure. Viral infection was the most common cause of liver failure in the 3,295 patients (84.1 %). Hepatitis of unknown etiology was deemed responsible for 371 cases of liver failure (9.5 %). Drug-induced liver injury, alcoholic hepatitis, and autoimmune hepatitis led to 120 cases (3.1 %), 109 cases (2.8 %), and 19 cases (0.5 %), respectively. The most common cause of ACLF was HBV infection (87.3 %), while the main causes of acute and subacute liver failure were hepatitis of unknown etiology (39.4 %), viral infection (36.6 %), and drug-induced liver injury (19.3 %). Our data showed that the incidence of liver failure caused by HBV gradually decreased from 86.5 % in 2002 to 69.2 % in 2011. However, the incidence of hepatitis of unknown etiology, drug-induced liver injury, and alcoholic hepatitis was increased. HBV infection is the main cause of liver failure in China. However, the incidence of HBV-related liver failure has gradually decreased in the past 10 years. Hepatitis of unknown etiology has replaced HBV infection as the most common apparent cause of acute liver failure.