Hepatocellular Dysfunction Research Articles

Alcohol-associated capillarization of sinusoids: A critique since the discovery by Schaffner and Popper in 1963.

This article reviews the literature on capillarization of hepatic sinusoids since its discovery in 1963. Liver sinusoidal endothelial cells are uniquely fenestrated and lack an underlying basement membrane. In chronic liver disease, the sinusoids capillarize and transform into systemic capillaries, a process termed capillarization of sinusoids. The histopathology is marked by defenestration, basement membrane formation, and space of Disse fibrogenesis. Capillarized sinusoids compromise the bidirectional exchange of materials between sinusoids and hepatocytes, leading to hepatocellular dysfunction. Sinusoidal capillarization was first described in active cirrhosis of alcoholics in 1963. Since then, it has been found in early and progressive stages of alcoholic hepatic fibrosis before the onset of cirrhosis. The sinusoidal structure is not altered in alcoholic steatosis without fibrosis. Defenestration impairs the ability of the endothelium to filter chylomicron remnants from sinusoids into the Disse's space, contributing to alcohol-induced postprandial hyperlipidemia and possibly atherosclerosis. Ethanol also modulates the fenestration dynamics in animals. In baboons, chronic alcohol consumption diminishes endothelial porosity in concomitance with hepatic fibrogenesis and in rats defenestrates the endothelium in the absence of fibrosis, and sometimes capillarizes the sinusoids. Acute ethanol ingestion enlarges fenestrations in rats and contracts fenestrations in rabbits. In sinusoidal endothelial cell culture, ethanol elicits fenestration dilation, which is likely related to its interaction with fenestration-associated cytoskeleton. Ethanol potentiates sinusoidal injury caused by cocaine, acetaminophen or lipopolysaccharide in mice and rats. Understanding ethanol's mechanisms on pathogenesis of sinusoidal capillarization and fenestration dynamics will lead to development of methods to prevent risks for atherosclerosis in alcoholism.

A CASE REPORT REGARDING MANAGEMENT OF KAMALA THROUGH AYURVEDA

Ayurveda is traditionally skilful in treating liver diseases for centuries. Although named Jaundice as a liver disorder was not mentioned in Ayurveda literature but based on common characteristics and Pathology, Kamala can be correlated with jaundice. Jaundice is a clinical manifestation of disorders of underlying bilirubin metabolism, hepa- tocellular dysfunction, or biliary obstruction. Jaundice occurs in settings of cholestasis or inability to effectively secrete bile as well as disorders of bilirubin metabolism and hepatocellular dysfunction. Today's lifestyle with un- hygienic and poor dietary habits and alcoholic habits, etc are responsible factors to promote hepatic damage which is clinically reflected as Kamala. This paper discusses a patient seen in the OPD of Kayachikitsa Quadra Institute of Ayurveda Roorkee Haridwar. Her chief complaints Udara shool (pain in the abdomen), Kshudha Mandhya (loss of appetite), Daurbalya (weakness), Hrullas (Nausea), Mutrapitata (yellow discolouration of urine, Vibhandha (constipation) for 15 days. This patient was effectively treated by the combination of Kutaki Churna, Triphala, Trivrita Churna, Bhunimba Churna, Arogya Vardhini Vati, Phalatrikadi Kashaya, Punarnava Mandoor and Liv 52. All the symptoms showed highly significant results. Hence it can be concluded that these medicines are very effective in patients with jaundice. Keywords: Udara shool, Kshudha mandhya, Daurbalya, Hrullas, Mutrapitata, Vibhandha.

Gene Expression Characteristics of Liver Tissue Reveal the Underlying Pathogenesis of Hepatocellular Carcinoma.

Background Hepatocellular carcinoma (HCC) is high-mortality primary liver cancer and the most common malignant tumor in the world. This study is based on a hepatocellular carcinoma-related dysfunction module designed to explore the dysregulation of genes in liver cancer tissue. Methods By downloading the relevant data on the GEO database, we performed a differential analysis of healthy liver tissue and liver cancer tissues as well as healthy liver tissue and hepatocellular carcinoma tissue and then obtained two sets of differential genes and combined them. We performed a cointerpretation analysis of these differential genes and constructed related functional disorder modules. A hypergeometric test was performed to calculate the potential regulatory effects of multiple factors on the module, and a series of ncRNA and TF regulators were identified. We obtained a total of 4479 differentially expressed genes in hepatocellular carcinoma, and these genes were clustered into ten hepatocellular carcinoma-related functional interpretation disorder modules. Results Enrichment analysis revealed that these modular genes are mainly involved in signal transduction including cell cycle, TGF-beta signal transduction, and p53 signal transduction. Depending on the predictive analysis of multidimensional regulators, 323 ncRNAs and 52 TF-mediated hepatocellular carcinoma-related dysregulation modules were found to regulate disease progression. Conclusions Based on a series of investigations, it was found that miR-30b-5p may participate in the peroxisome signal transduction by downregulating ABCD3-mediated module 1, thereby promoting the development and progression of hepatocellular carcinoma. Our research results not only provide a theoretical basis for biologists to study hepatocellular carcinoma further but also offer new methods and new ideas for the personalized care and treatment of hepatocellular carcinoma.

552 NON-ALCOHOLIC FATTY LIVER DISEASE AND THE HEPATIC RESPONSE TO SURGERY AMONG PATIENTS WITH ESOPHAGEAL ADENOCARCINOMA

Abstract Visceral obesity, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) represent risk factors for esophageal adenocarcinoma (EAC). The prevalence of NAFLD, and its impact on the hepatic response to esophageal cancer surgery, has never been systematically evaluated, and was the focus of this study. Methods Consecutive patients (n = 547) treated with curative intent for esophageal cancer from 2007–2017 were studied. In an unselected subgroup (n = 138), liver biopsies were collected intraoperatively and assessed for NAFLD, defined as ≥5% macrovesicular steatosis. Postoperative complications were recorded prospectively, including Clavien-Dindo grade (CD) and comprehensive complications index (CCI). Liver function tests were monitored in the first postoperative week, with hepatocellular dysfunction defined as a transaminase rise ≥3-times the upper limit of normal. Multivariable logistic and Cox proportional hazards regression were utilised to determine independent predictors of operative and oncologic outcome. The study was registered on clinicaltrials.gov (NCT04152044). Results NAFLD was evident in 62 patients (47.7%) who had biopsies, with a mean (SD) score of 10.1(9.3)%. NAFLD was associated with metabolic syndrome (41.9 vs 25%, P = 0.04), obesity (44.1 vs 11.9%, P < 0.001) and visceral adiposity (172.8 vs 136.5 cm2, P = 0.008), but not clinical or pathologic disease stage. Postoperative hepatocellular dysfunction was observed in 287 (54.8%) patients, associated with NAFLD (P = 0.006), but not visceral obesity (P = 0.396), and normalized in a median (range) of 9 (1–76) days. NAFLD did not impact oncologic outcome, but postoperative hepatocellular dysfunction was independently associated with reduced overall survival (HR 1.87 (1.16–2.29), P = 0.002) on multivariable analysis. Conclusion A marker of metabolic dysregulation in obesity-associated carcinogenesis, NAFLD is prevalent among patients with esophageal cancer. Liver dysfunction post esophagectomy is common, and although temporary, is associated with worse oncologic outcomes. Baseline NAFLD did not incur an adverse long-term oncologic outcome.

Parasitaemia estimation and prediction of hepatocellular dysfunction among Ghanaian children with acute malaria using haemoglobin levels

Malaria is an important global health disease which puts individuals, particularly children, at a greater risk of mortality. Plasmodium falciparum is distinguished from the rest of the Plasmodia by its high level of parasitaemia. They infect liver cells (hepatocytes), and multiply into merozoites and rupture liver cells in the process, prior to infection of red blood cells. This study sought to estimate the extent to which P. falciparum parasitaemia correlates with hepatocellular dysfunction among Ghanaian children suffering from acute malaria in three malaria endemic districts in Ashanti Region and to predict liver dysfunction from the estimation of haemoglobin (HB) levels. A prospective uncontrolled before- and after study was conducted among under five years children with acute malaria (n = 300) and a control group (n = 20) within the same age brackets. The serum activities of liver enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) were measured in patients and control subjects. The study observed an inverse relationship between mean HB and parasitaemia (mean HB level of 10.34 ± 0.14 versus parasitaemia <10,000 parasites/μL as against 8.06 ± 0.16 versus parasitaemia ≥10,000 parasites/μL). The mean levels of AST, ALT, ALP and GGT were higher (p < 0.0001) in the serum of the infected children before treatment compared with post treatment. Moreover, the receiver operating characteristics (ROC) curve was applied to establish that HB level at 10.9 g/dL predicted liver dysfunction with the area under the curve (AUC) being 0.75 ± 0.03 (P < 0.0001). The parasitaemia estimation and prediction of hepatocellular dysfunction in Ghanaian children with acute malaria could be done via HB levels.

Design and Usability Evaluations of a 3D-Printed Implantable Drug Delivery Device for Acute Liver Failure in Preclinical Settings.

Acute liver failure (ALF) requiring liver transplantation is a disease that occurs due to rapid hepatocellular dysfunction. As liver transplantation has various limitations, including donor scarcity, high cost, and immuno-incompatibility, continuous local delivery of biopharmaceuticals to the liver tissue can be a promising ALF treatment option. Here, the in vivo safety and usability of a 3D-printed implantable drug delivery device for effective ALF treatment is evaluated. The implantable reservoir consists of a 3D-printed container and a semipermeable membrane for repeated administrations of drugs, specifically to the liver tissue. The physical stability and function of the 3D-printed reservoir are confirmed by the mechanical properties and in vitro drug release test, respectively. In mice implanted with the reservoir system, mortality, weight changes, clinical signs, hematological and serum biochemical changes, and organ weight changes are not observed, suggesting no foreign body reaction. The usability of the reservoir system is further evaluated using an ALF model of 70% hepatectomized mice treated with N-acetylcysteine through the system, showing cell-specific regeneration and significant liver injury alleviation. Overall, the 3D-printed reservoir system is safe for studying the therapeutic potential of ALF treatment, and it can be used for the delivery of various active pharmaceutical ingredients.

Clinical and capillaroscopic findings in patients with liver disease and proximal apparent leukonychia (Terry nails and its variants).

Terry nails and Lindsay nails are similar forms of proximal apparent leukonychia (PAL). A change in nail bed vascularity is thought to be responsible for PAL. The study was aimed at investigating the frequency of PAL in patients attending a liver disease clinic, the factors associated with its presence, its value for detecting cirrhosis, its prognostic value for mortality, and associated capillaroscopic findings.A total of 521 patients were included (age range, 18–94 years; 69% men). Systematic nail photographs were evaluated by 2 independent investigators. Disease-related data were obtained from the medical records. Mortality was evaluated after 7 years of follow-up. Nailfold capillaroscopy was performed on a subset of 80 patients.PAL was present in 228 patients (43.8%; Terry nails in 205, Lindsay nails in 20, and both in 3). The kappa-coefficient of interobserver agreement was 0.82. The presence of PAL was associated with cirrhosis and, accordingly, with portal hypertension and hepatocellular dysfunction. The positive likelihood ratio of PAL for the diagnosis of cirrhosis was 1.6 (95% CI 1.3–1.92). PAL was independently associated with chronic alcohol abuse and was not a significant predictor of mortality. Venous loop dilatation and prominence of the venous plexus were observed on capillaroscopy in patients with cirrhosis but were not significantly associated with PAL.In summary, PAL is a common finding in patients from a liver clinic; it is associated with liver cirrhosis and with alcohol abuse. PAL is not associated with specific capillaroscopic findings. We propose the generic term proximal apparent leukonychia instead of classic eponymous titles to avoid confusion in the literature.

Camel (Camelus Dromedarius) Milk Antibodies Ameliorated Diethylnitrosamine-Induced Hepatocellular Carcinoma in Wistar Rats

Hepatocellular carcinoma (HCC) is an extremely aggressive solid tumor and relates to numerous cases of cancer-associated deaths globally. Current studies reveal that natural compounds retain various therapeutic effects. This study was aimed to investigate the beneficial antitumor effects of camel (Camelus dromedarius) milk antibodies (CM-IgG) on diethylnitrosamine (DENA)-induced hepatocellular carcinoma in male Wistar rats. Hepatocarcinoma was induced in rats using DENA (50 mg/kg, twice/week) for 2 weeks followed by CCl4 (1 ml/kg, trice/week) for 6 weeks. At week 17th, HCC-bearing rats were orally administrated CM-IgG (100 mg/kg, orally) daily for 4 weeks. Liver enzyme activities and levels of alpha-fetoprotein (AFP) were measured in serum. Lipid peroxidation, nitric oxide, reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity were determined in liver homogenate. Histological analysis using hematoxylin and eosin stain was examined in liver tissues. Hepatic mRNA gene expression of placental glutathione-s-transferase (GST-P) was determined by qRT-PCR. Treatment HCC-bearing rats with CM-IgG significantly reduced liver injury biomarkers and attenuated oxidative stress as well as enhanced antioxidant status. Moreover, CM-IgG significantly alleviated hepatocellular morphology alterations and down-regulated GST-P gene expression levels in liver. Our results revealed the potential role of total immunoglobulin IgG purified from camel milk in amelioration of DENA-induced hepatocellular dysfunction and oxidative stress in hepatocarcinoma-bearing rats.

Evaluation of conventional and non-conventional biomarkers of liver toxicity in greenhouse workers occupationally exposed to pesticides

The liver plays a prominent role in maintenance of homeostasis and is the major organ for xenobiotic metabolism, including pesticides. Conventional liver function tests are widely used to assess hepatocellular and biliary system dysfunction by measuring serum levels of aminotransferases (ALT, AST) and cholestasis enzymes (alkaline phosphatase –ALP– and γ-glutamyl transferase –GGT–), respectively. Although these tests are not entirely specific for liver damage, their specificity increases when measured concurrently, but still have limited usefulness to predict early liver dysfunction. Hence, non-conventional biomarkers may have a better performance for the early detection of biochemical hepatotoxicity with a greater specificity and sensitivity. A cross-sectional study with a follow-up component was conducted on 175 greenhouse workers regularly exposed to pesticides under integrated production system, and 91 controls living in the same geographical area. All individuals were evaluated for conventional (ALT, AST, ALP, GGT) and non-conventional biomarkers of hepatotoxicity (ornithine transcarbamylase (–OTC–), Arginase-1 –ARG1– and glutathione S-transferase alpha –GSTα–) over two periods of the same crop season, one of high pesticide exposure and other of low exposure. A slight increase in AST was observed in greenhouse workers relative to controls, suggestive of subtle hepatocellular toxicity. Although ALP, ARG1 and GST-α levels were decreased in greenhouse workers, this might be related to a potential homeostatic mechanism that regulates their expression. Altogether, these findings do not represent unambiguous evidence of liver dysfunction (e.g., hepatocellular or biliary system impairment) but may be the result of the low-toxicity pesticides used by greenhouse workers.

Oxidative stress and hepatocellular mitochondrial dysfunction attenuated by asiatic acid in streptozotocin-induced diabetic rats

Oxidative stress produced by mitochondria is one of the main causes for diabetes associated complications. This study was planned to assess the efficacy of asiatic acid (AA) on oxidative stress mediated hepatocellular mitochondrial dysfunction in streptozotocin (STZ)-induced type-2 diabetic rats. Diabetic rats were generated by intraperitoneal injection of STZ administered as single dose at 40 mg/kg body weight (b. wt.). Then the rats were treated with 20 mg of AA or 600 μg of glibenclamide (Glib)/kg b. wt, once in a day for 45 days. The results of this study illustrated that diabetic rat liver mitochondrial malondialdehyde (MDA), reactive oxygen species (ROS) and protein carbonyl (PCO) levels were significantly increased at the same time antioxidant enzymes and non-enzymes status was markedly diminished when compared with the liver mitochondria of normal control rats. A marked reduction in ROS, MDA, PCO and significant amelioration in non-enzymatic and enzymatic antioxidants were observed in diabetic rats treated with AA or Glib as compared with untreated diabetic control rats. Tricarboxylic acid (TCA) cycle enzymes like isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and electron transport chain (ETC) complexes activities were significantly diminished in diabetic rats. Besides, mitochondrial uncoupling protein-2 (UCP2) expression was significantly upregulated at the same time adenosine triphosphate (ATP) level and mitochondrial membrane potential (MMP) was markedly lowered in the mitochondria of diabetic rats. AA or Glib treatment with diabetic rats restored the TCA cycle enzymes activities, ETC complexes, UCP2, MMP and ATP level to near normal control rats as compared with untreated diabetic control rats. Hence, the results of the current study indicated that AA ameliorated mitochondrial function by attenuating oxidative stress in STZ-induced type-2 diabetic rats.

Thyroid profile in patients of liver cirrhosis and correlation with severity and etiology of liver disease

INTRODUCTION: Thyroid disease has been observed to be associated with liver injuries or deranged liver function. This study was conducted to study thyroid dysfunction in patients of liver cirrhosis and any association between severity of liver cirrhosis and thyroid profile. MATERIALS AND METHODS: In this case-control study, liver cirrhosis patients aged &gt;18 years with evidence of hepatocellular dysfunction with portal hypertension compared with apparently healthy age-gender matched. Data were collected on a semistructural questionnaire with general physical and systemic examinations, including thyroid examination. The etiology of disease was ascertained on the basis of clinical examination and investigation. RESULTS: The study included 72 case (70.8% male and 29.2% female) and equal number of control participants. Controls as compared to cases had free triiodothyronine (fT3) (2.45 ± 0.40 vs. 1.60 ± 0.50 pg/ml) and free tetraiodothyronine (fT4) (1.26 ± 0.21 vs. 1.15 ± 0.48 ng/ml). Thyroid-stimulating hormone (TSH) value of cases were 3.61 ± 0.95 μIU/ml and controls were 3.01 ± 0.66 μIU/ml. CONCLUSIONS: Liver disease cases as compared to controls had significantly lower fT3 levels and significantly higher TSH levels. Mortality rate of liver disease cases with thyroid dysfunction was also found to be significantly higher.

Hepatobiliary Scintigraphy to Evaluate Biliary Complications of Pediatric Liver Transplantation: An Account of an Experience

Hepatobiliary scintigraphy (HS) is a noninvasive imaging technique whose use in the follow-up of liver transplantation has not been duly documented. The main objective of this study is to describe the experience of using this technique to detect biliary complications in pediatric patients following liver transplantation. A retrospective, observational, and descriptive study involving 86 pediatric patients who had undergone liver transplantation between 2013 and 2018. Of the 86, 31 had undergone at least one HS during their postoperative period. A total of 45 studies were performed on 31 patients (36% of the patients undergoing transplantation during that time period). Patient ages ranged from 5 to 204 months (mean = 50 months). A total of 22 transplants (71%) were from living donors and 9 (29%) were from cadaveric donors. Of the 45 studies, 22 were positive for biliary complications, and all of them had an impact on clinical decision-making. The remaining 23 studies were negative. Of these 23, 19 continued under medical treatment and the other four underwent an additional intervention with positive surgical outcomes in all cases. All scintigraphy studies revealed hepatocellular dysfunction and cholestasis. The HS is a useful, noninvasive, and diagnostic procedure for the early diagnosis of biliary complications that may impact the evolution of disease in liver transplant patients. It allows the treating physician to make a more informed decision regarding expectant management, surgical management, or a less invasive course of action for transplantation complications.

Circulating Glycosaminoglycan Anticoagulants Associated With Suramin Treatment

A complex coagulopathy appeared in three women receiving suramin as treatment for metastatic adrenocortical carcinoma. Although hepatocellular dysfunction accounted for some of the abnormality, a unique feature of the coagulopathy was the presence of an inhibitor of the thrombin clotting time. The potency of this circulating anticoagulant increased markedly during exacerbations of hepatic injury. The anticoagulant was removed from plasma samples from two of the patients by passage over a column of diethylaminoethyl (DEAE)-Sephacel. It eluted from the DEAE at salt concentrations that removed "high-charge" glycosaminoglycans. Elimination of the purified anticoagulant activity in vitro required a combination of heparitinase and chondroitinase ABC, suggesting that the activity was mediated by both heparan sulfate and dermatan sulfate. Suramin is hypothesized to inhibit enzymes that normally degrade glycosaminoglycans, resulting in accumulation of these substances, which are released from the liver into the circulation during periods of hepatic injury.

S2543 Polycystic Liver Disease, Portal Hypertension, and Refractory Ascites: Is PLD the Cause?

INTRODUCTION: Polycystic liver disease (PLD) is a rare genetic disorder typically characterized by the presence of more than twenty hepatic cysts. The prevalence of autosomal dominant polycystic kidney disease (ADPKD) associated PLD is 0.2%. We present an unusual case of PLD associated with refractory ascites in the absence of liver fibrosis or hepatic venous outflow obstruction. CASE DESCRIPTION/METHODS: This is a 54-year-old female with a history of ADPKD status post kidney transplant without evidence of cirrhosis or any decompensating events pre-transplant. Her post-transplant course was complicated by cecal and mesenteric volvulus status post right hemicolectomy. Roughly five weeks later, she developed severe ascites. Initial lab evaluation revealed no hepatocellular dysfunction. Diagnostic paracentesis indicated a SAAG of 1.4, ascitic total protein 2.1 and no evidence of SBP. Portal package showed abnormally tortuous venous vasculature. Right hepatic vein was difficult to wedge but measured 70-80 mm Hg; free right hepatic vein pressure was 5 mm Hg, IVC pressure was 4 mm Hg and a right atrial pressure was 5 mm Hg; overall, findings were consistent with portal hypertension. Liver biopsy showed no significant fibrosis or evidence of congenital hepatic fibrosis, but did show mild sinusoidal dilatation, potentially indicative of a vascular outflow abnormality. An abdominal CT was without evidence of extrinsic compression of the large hepatic veins. Due to anatomic difficulties, TIPS was not technically feasible, so she had a Denver shunt placed for refractory ascites with good control thereafter. DISCUSSION: Portal hypertension and ascites in the presence of PLD typically arises from three etiologies: liver cirrhosis, congenital hepatic fibrosis and hepatic venous outflow obstruction. This patient had no imaging to support large hepatic venous outflow obstruction, but given her histologic findings it is possible that her presentation is due to cystic compression of small venules, which cannot be visualized on cross sectional imaging. However, there is not any literature to support hepatic venule compression leading to portal hypertension. Due to chronic injury from elevated outflow pressures, these patients can develop fibrotic replacement of the hepatic parenchyma and may ultimately develop cirrhosis. Recognition and surveillance of these patients is necessary, as liver transplant may need to be considered if progressive cirrhosis complications become apparent.

S1019 Indirect Bilirubin Predominates in Hyperbilirubinemia Due to Cirrhosis: Comparison With Alcoholic Hepatitis

INTRODUCTION: Research done in the 1950’s and 60’s described the occurrence of extravascular hemolysis in a subset of patients with alcoholic cirrhosis. Subsequent studies suggested that hemolysis in this setting is the result of acquired red blood cell abnormalities in the setting of hypersplenism. In the decades since, this phenomenon and its potential clinical significance have received little attention. The objective of this study was to examine levels of indirect hyperbilirubinemia in patients with different forms of advanced liver disease. METHODS: Clinical and laboratory data were compared among 3 groups of patients admitted to the University of Iowa Hospital between January 2010 and January 2018. Fifty subjects each with alcoholic hepatitis (AH), decompensated alcoholic cirrhosis (AC) and decompensated cirrhosis due to causes other than alcohol (N-AC) in whom fractionated bilirubin had been obtained at admission were selected for study. Statistical analysis was done using Excel. RESULTS: As would be expected, total bilirubin was significantly higher in AH versus AC and N-AC. Absolute levels of direct bilirubin were also highest in AH but the indirect bilirubin comprised only about a quarter of the total in this group. Conversely, the indirect bilirubin comprised nearly half of the total bilirubin in AC and about 60% in N-AC. Hemoglobin levels were similar among the groups, but RBC counts were slightly lower in AH versus N-AC. MCV, MCH, and MCHC were highest in AH, perhaps reflecting the effects of recent heavy alcohol ingestion. Spleen sizes were similar among the groups. CONCLUSION: Our data show that, in contrast to AH, hyperbilirubinemia in decompensated cirrhosis is characterized by a large indirect fraction. Indirect bilirubin in cirrhotic patients seems unlikely to be a direct consequence of the severity of the underlying liver disease, given that direct bilirubin predominates in severe AH, which indicates that the ability to conjugate bilirubin is preserved even in conditions of severe hepatocellular dysfunction. Extravascular hemolysis due to acquired red cell membrane abnormalities and/or hypersplenism may contribute to elevations in indirect bilirubin. Hemolysis markers (LDH, haptoglobin) were not routinely obtained in the patients in this study, limiting our ability to evaluate this possibility. Further study is needed to determine the cause and clinical significance of indirect hyperbilirubinemia in cirrhosis.Table 1.: Comparison of variables with features of advanced liver disease among three study groups; 1. alcoholic hepatitis (AH) 2. decompensated alcoholic cirrhosis (AC) and 3. decompensated non-alcoholic cirrhosis (N-AC)Table 2.: Comparison of clinical and laboratory data among the three study groups i.e. 1. alcoholic hepatitis (AH) 2. decompensated alcoholic cirrhosis (AC) and 3. decompensated non-alcoholic cirrhosis (N-AC)Figure 1.: Comparing the proportion of indirect bilirubin between three study groups.

MiR-451a ameliorates alcoholic hepatitis via repressing HDAC8-mediated proinflammatory response.

Alcoholic hepatitis (AH) is identified as an inflammatory syndrome with high morbidity and mortality as a result of severe hepatocellular dysfunction and liver injury. Accumulated studies indicated that miRNAs are involved in AH. The potential effect of miR-451a in AH mice was examined in the current study. A mice AH model was established and the miR-451a expression in AH mice compared with the sham group was tested by real-time polymerase chain reaction (qRT-PCR). AH mice were injected with pre-miR-451a lentivirus for miR-451a overexpression and histone deacetylase (HDAC8) lentivirus for HDAC8 overexpression in AH mice. The underlying mechanisms were explored by searching the potential target genes of miR-451a in miRanda database and then we confirmed this. We found that miR-451a expression was significantly decreased in AH mice compared with the sham group. Moreover, miR-451a overexpression alleviated alcohol-induced liver inflammation and injuries of AH mice. Additionally, further mechanism exploration disclosed that HDAC8 was a target of miR-451a. The protective effect of miR-451a on AH in AH mice was abolished by HDAC8 overexpression. In summary, miR-451a ameliorates AH via repressing HDAC8-mediated proinflammatory response.

C-peptide corrects hepatocellular dysfunction in a rat model of type 1 diabetes.

C-peptide is gaining much interest recently due to its well-documented beneficial effects on multiple organ dysfunction induced by diabetes. Our study was designed to investigate the effect of C-peptide on hepatocellular dysfunction in diabetic rats. Wistar male rats were separated into four groups: control, diabetic, diabetic + insulin, and diabetic + C-peptide. Serum levels of glucose, insulin, and liver biomarkers were assessed. Liver sections were collected for histopathological examination and immuno-histochemical assessment of tumor necrosis factor alpha (TNF-α). Oxidative stress markers and gene expression of inducible nitric oxide synthase (iNOS), transforming growth factor beta 1 (TGF-β1), and glucose-6-phosphatase (G6Pase) were also measured in liver tissues. C-peptide administration prevented hepatic dysfunction induced by diabetes to a similar extent as that of insulin which was confirmed microscopically. We concluded that C-peptide could be used as an alternative therapy to insulin to correct hepatocellular dysfunction associated with type 1 diabetes mellitus (T1DM).

Pathogenetic Association of Digestive System Lesions with Systemic Lupus Erythematosus: Characteristics and Prevalence

Introduction The prevalence rate of the digestive system lesions in patients with systemic lupus erythematosus (SLE) ranges from 8.0 to 50.0%. The symptoms caused by systemic lupus erythematosus (immunocomplex inflammation, vasculitis, etc.) have not been clearly distinguished yet from those that are associated with co-occurring diseases or adverse effects of medications used to treat patients with SLE. Objective To characterize and clarify the prevalence of the digestive system lesions that are pathogenetically associated with systemic lupus erythematosus. Materials and methods 370 patients (331 women and 39 men), stratified by age, duration, and activity of SLE, were included in the study and subjected to comprehensive examinations. The results were processed in Microsoft Excel using descriptive statistics, χ2 test, z-test for comparisons between two proportions; the relationship was considered to be statistically significant when p &lt; 0.05. Results The digestive system lesions were detected in 225 (60.81%) patients with systemic lupus erythematosus. The prevalence of steatohepatitis, autoimmune hepatitis, and chronic pancreatitis rose with the progression of the underlying disease, so we concluded that they may be considered to be pathogenetically associated with systemic lupus erythematosus as syntropic comorbid lesions. Other digestive system lesions – chronic pharyngitis, cardiochalasia, gastroesophageal reflux disease, esophagitis, chronic gastritis, peptic ulcer, chronic duodenitis, duodenogastric reflux, duodenal ulcer, chronic viral hepatitis B, chronic viral hepatitis C, toxic hepatitis, liver cirrhosis, acalculous cholecystitis, chronic cholecystitis (asymptomatic gallstones, chronic calculous cholecystitis, gallbladder polyps), irritable bowel syndrome, chronic colitis, hemorrhoids, dolichosigma, peritoneal adhesions – are only comorbidities, ie. co-occurring digestive system lesions, since there was no relationship between their prevalence and the progression of the underlying disease. The mesenchymal inflammatory syndrome was detected in most patients with systemic lupus erythematosus and pathogenetically associated syntropic comorbid steatohepatitis. Hepatocellular dysfunction syndrome was detected in the three-fourths of patients with SLE and steatohepatitis. The mesenchymal inflammatory syndrome was also detected in all patients with SLE and pathogenetically associated syntropic comorbid autoimmune hepatitis. More than half of the patients with SLE and autoimmune hepatitis were also diagnosed with hepatocellular dysfunction and hepatic cytolysis syndromes. The asthenic-neurotic clinical syndrome occurred in the three-fourths of patients with SLE and pathogenetically associated syntropic comorbid chronic pancreatitis. Almost every second patient with SLE and chronic pancreatitis had a dyspeptic syndrome. Steatohepatitis was detected predominantly in patients aged 25 to 59 (young age subgroup II and middle age group). It was not detected in patients with the SLE duration of less than one year. Autoimmune hepatitis was detected predominantly in elderly patients and patients with the SLE duration of more than ten years. Chronic pancreatitis was significantly less prevalent in women and more prevalent in elderly patients – it occurred in almost half of them. It was absent in patients with the SLE duration of less than one year. Patients with the SLE duration of 6-10 years had the highest prevalence of chronic pancreatitis.

HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats.

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.

Hepatitis C virus in Iran; transmission routes, growth in 3a genotype distribution, and lack of liver marker relation with genotypes.

Background:The hepatitis C virus (HCV) outbreak in Iran is increasing. This study investigated the dissemination and transmission routes of HCV genotypes in different regions of Iran. The relationship between serum biochemical markers and viral genotypes was also assessed to find whether liver enzymes level can be considered as the markers for HCV genotypes.Materials and Methods:HCV-infected patients from different provinces of Iran (from August 2017 to March 2019) were enrolled. Nested reverse transcriptase polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR were used to discover the genotypes. The infection transmission routes in the study population were investigated and recorded. Serum samples with equal viral loud from the patients without other liver disorders were recruited to explore the association between the genotypes and the liver biochemical markers.Results:One thousand serum samples positive for the HCV genome were recruited. Genotype 3a was the most prevalent in the north, while genotype 1a was dominant at the center. In total, genotype 3a was the dominant genotype closely followed by 1a. Needle sharing by addicts was the most common transmission way of infection in Iran. This way was also the most for genotype 3a dissemination, and genotype 1a was transmitted mostly between family members. No significant association (P > 0.05) was observed between biochemical marker titers and HCV genotypes.Conclusion:A shift in the distribution profile of HCV genotypes, related to the transmission routes, has happened over time. Public awareness of the main routes of HCV transmission can break the cycle of transmission. Liver enzyme values in HCV-infected patients showed no relation with genotypes and only represented hepatocellular dysfunction.