Decompensated Liver Function Research Articles

Morphometric parameters of hepatocytes in experimental complete extrahepatic bile duct obstruction

Liver changes observed in complete extrahepatic bile duct obstruction (CEBDO) with consideration to its morphometric parameters, may reflect the upcoming decompensation of liver function and may serve as objective criteria for the disease prognosis. The aim. To study the morphological changes of hepatocytes in experimental CEBDO using macro- and micromorphometry. Materials and methods . In 41 rats, the CEBDO was done by ligation and transection of the common bile duct. The time points were on postoperative Day 1, 3, 7, 14, 21, 28 and 35. Control group included 10 non-operated rats. The total blood bilirubin (TB), liver volume (LV), the area of hepatocytes (AH), the hepatocyte nuclear-cytoplasmic ratio (HNCR), the hepatocyte bulk density (HBD) were investigated. The LV and HBD parameters were used to calculate the total volume of hepatocytes (TVH). Results. The highest mortality was recorded on Day 22-35 of the experiment (7 out of 11 animals). Bilirubin level was significantly higher than in the control group with its maximum on Day 1 (295±100 vs. 8±6, μmol/l, p 0.05), with its lowest level (5.0±0.9cm³) on Day 35 (p<0.05 compared with max value on Day 3). The HNCR index, which reflects proliferative activity of hepatocytes, had its maximum on Day 14 (0.53±0.01 vs. 0.21±0.05 in Control group, p<0.001). Conclusions. In experimental CEBDO, reduction of the HBD index less than 60 % and reduction of TVH less than the value of a normal liver are accompanied by highest mortality, i.e., are a sign of hepatic decompensation. That was preceded by the maximum proliferative activity of hepatocytes, the criterion of which is the HNCR index

Optimization of long-term prognosis of patients with alcoholic liver disease

Aim: to prove the effectiveness of combined physical and psychological assessment in improving the long-term outcome of patients with alcoholic liver disease (ALD).Materials and methods: the active outpatient follow-up (AOF) group included 29 patients with ALD consisted of active liver function and motivation assessment, motivational interviewing, liver panel lab tests with the rate once at 3 months. The AOF program consisted of dynamic monitoring of liver function at least 1 time in 3 months and psychological support provided by the hepatologist using brief interventional approach. The control of abstinence was provided by using self-reports and indirect biomarkers of alcohol consumption. The control group included 36 patients with ALD and history of two-years follow-up after first alcoholinduced liver injury who received comprehensive therapy and a simple advice to avoid alcohol.Results: the adherence to abstinence were significantly higher in AOF group compared with control group. The proportion of patients with decompensated cirrhosis was significantly lower in AOF group compared with control group at 12 and 24 months after enrollment. The long-term survival in AOF-group was significantly higher than in control group. The only parameter independently associated with long-term survival was the presence of AOF program.Conclusion: the combined physical and psychological assessment of patients with ALD, provided by internists improves adherence to abstinence, reduces the risk of decompensation of liver function, severity of ALD and improves patients survival in the long term period.

Prediction of acute-on-chronic liver failure and integrated traditional Chinese and Western medicine therapy

Acute-on-chronic liver failure(ACLF) is a reversible and complex clinical syndrome caused by various factors in patients with pre-existing chronic liver diseases,with the clinical features of acute liver function decompensation and high short-term mortality rate.ACLF has a complex pathogenesis,rapid progression,and a dangerous prognosis,and early and accurate prediction of prognosis is of vital importance. At present,there is still no ideal therapy for ACLF,and in recent years,integrated traditional Chinese and Western medicine therapy has achieved a certain effect in the treatment of this disease. This article reviews the advances in prognostic evaluation and integrated traditional Chinese and Western medicine therapy for ACLF,in order to provide guidance to prognostic evaluation of ACLF and selection of the regimens of integrated traditional Chinese and Western medicine therapy.

Impaired circulating CD56dim NK cells are associated with decompensation of HBV-related cirrhosis

NK cells play an important role in immune regulation and defense of infection, but their characteristics in patients with decompensated cirrhosis and their relationship with liver function remain unclear. We studied the functional properties of NK cells (including CD56dim NK and CD56bright NK cells) in patients with HBV-related decompensated liver cirrhosis (HBV-DLC) and analyzed their relationship with decompensation of liver function. Thirty patients with HBV-DLC and 25 patients with HBV-related compensated liver cirrhosis (HBV-CLC) were recruited in this study. Twenty five age- and sex-matched healthy individuals were recruited as healthy controls (HCs). The phenotypical and functional characteristics of NK cell subsets were detected by flow cytometry, and the correlation between NK cells and decompensation of liver function was analyzed. The frequency of circulating CD56bright NK cells was significantly increased while circulating CD56dim NK cells was significantly decreased in HBV-DLC patients as compared with HCs and HBV-CLC patients. Peripheral activated-CD56bright NK cells from HBV-DLC patients might express lower levels of inhibitory receptor CD158b1/2 and higher levels of activating receptor NKG2D and their expression of perforin and granzyme A/B also increased significantly compared with HCs, suggesting a high immune activation status of peripheral CD56bright NK cells in HBV-DLC patients. In HBV-DLC patients, the expression of CD107a and perforin in circulating CD56dim NK cells was positively correlated with cytolytic capacity while CD107a and perforin expression in circulating CD56dim NK cells were significantly decreased, suggesting an impaired cytolytic capacity of circulating CD56dim NK cells. Besides, we found that the perforin expression of circulating CD56dim NK cells correlated negatively with child-pugh classification in HBV-DLC patients. The functional properties of circulating NK cell subsets in HBV-DLC patients have changed significantly, especially of CD56dim NK cells which closely related to decompensation of liver function. These findings may help provide new perspectives and theoretical basis for the treatment of patients with HBV-DLC.

SOFOSBUVIR: TREATMENT OF CHRONIC HEPATITIS C AND THE MAIN TRENDS IN PATENT PROTECTION

The purpose of the study was to analyze and systematize the literature data on the benefit/risk ratio of sofosbuvir administration in the treatment of patients with chronic hepatitis C and the main trends in its patent protection. Studies were conducted using databases on the Internet: Ukrainian patent office, the European patent office, the US patent office, the Food and drug administration, European Medicines Agency (EMEA), State enterprise “The State Expert Center” of the Ministry of Health of Ukraine. It has used retrospective, logical, systematic and analytical methods. Data from clinical studies abroad and meta-analyses indicate that sofosbuvir is one of the most promising drugs for the treatment of chronic HCV infection. Its indisputable advantages are that this drug can be used with different genotypes of the virus, decompensated liver function, it is well tolerated. Sofosbuvir has an improved safety profile and a low probability of viral resistance. The high cost of sofosbuvir is due to the powerful patent protection. As mechanisms for working with patent barriers, it is recommended to use the flexible mechanisms of the TRIPS Agreement: the grant of compulsory licenses, the implementation of parallel imports, the tightening of the criteria for patentability (prohibition of patenting new forms that do not improve therapeutic efficacy).

Hepatocellular carcinoma with portal vein tumor thrombosis: deficiencies in the currently available classifications

There are two international classifications for hepatocellular carcinoma with portal vein tumour thrombosis (HCC with PVTT): the Cheng′s Classification and the Liver Cancer Study Group of Japan. These two classifications are quite similar. Personally I prefer the Cheng′s Classification for 2 reasons: (1) it is not easy to differentiate Vp1 and Vp2 in the Japanese Classification; and (2) the Japanese Classification does not have a stage for PVTT that extends to the superior mesenteric vein, i. e. the Cheng′s Type IV. The main defect of these two classifications is that both classifications consider only the extent of PVTT without considering other factors which impact on treatment and prognosis. I apply some important prognostic factors used in the Barcelona Clinic Liver Cancer (BCLC) Classi-fication for liver cancer onto the Cheng′s Classification of HCC with PVTT, to come up with a new Lau-Cheng Classification. These factors include: (1) the general condition of the patient, the liver functional status and whether there is any serious associated medical diseases; (2) extrahepatic metastasis; (3) main PVTT; (4) resectability of the primary liver cancer; (5) combination with microvascular invasion (MVI). This new classification divides HCC with PVTT into the very early stage (MVI only), early stage (resectable HCC with PVTT), intermediate stage (not resectable), late stage (with extrahepatic metastases), and terminal stage (poor general condition, decompensated liver function, or associated with serious medical diseases). The early, intermediate and late stages can further be divided into A and B according to whether the main portal vein is not involved or is involved by PVTT. All these different stages of HCC with PVTT have their own recommended treatment and prognosis. This new classification needs to be supported by clinical data before it can be used. Key words: Hepatic neoplasms; Portal vein tumor thrombosis; Classifications; Therapy; Prognosis

Liver-enriched transcription factor expression relates to chronic hepatic failure in humans.

The mechanisms by which the liver fails in end‐stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver‐enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer‐binding protein (CEBP)α, and CEBPβ. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho‐ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p‐ERM], phospho‐myosin light chain [p‐MLC], low‐density lipoprotein receptor‐related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child‐Pugh classification, Model for End‐Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4α expression was down‐regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4α expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho‐associated protein kinase pathways, which have been implicated in the regulation of HNF4α, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4α and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582‐594)

Abstract No. 655 Treatment of peristomal hemorrhage: a review of outcomes and comparison of two minimally invasive techniques

Development of peristomal variceal bleeding in patients who undergo ostomy formation and have or develop portal hypertension is common. While many different minimally invasive techniques have been described the data is sparse and no direct comparison between techniques has been made. This article aims to review and compare outcomes between percutaneous sclerotherapy and transjugular intrahepatic portosystemic shunt (TIPS) treatments. After IRB approval 5 patients who underwent 9 sclerotherapy treatments and 7 patients who underwent TIPS placement for peristomal variceal bleeding were retrospectively reviewed. Data pertaining to the technical aspects of the procedure, demographics, and information regarding the underlying cause of ostomy and portal hypertension were collected. Treatment was considered a primary success if no further hemorrhage occurred. Sclerotherapy patients trended toward having a poorer nutritional status (albumin mean 2.04 and 2.95 g/dL in sclerotherapy and TIPS groups respectively p = 0.04) and worse liver function (total bilirubin 4.9 and 1.6 mg/dL in the sclerotherapy and TIPS group respectively p = 0.07). Primary success was statistically better in the TIPS cohort (100%) versus the sclerotherapy cohort (40%) (p = 0.04). One patient died of recurrent massive peristomal hemorrhage 6 months after initial sclerotherapy, and one patient required admission for hepatic encephalopathy following TIPS. There was no statistically significant difference in complications following TIPS and sclerotherapy (p = 1). TIPS appears to be more effective than sclerotherapy in treating peristomal variceal bleeding. However, sclerotherapy may be an effective bridging technique for patients who have acute decompensation of liver function.

Efficacy of sequential therapy with telbivudine in treatment of HBeAg-positive chronic hepatitis B patients with partial response to pegylated interferon-α therapy

Objective: To investigate the efficacy of sequential therapy with telbivudine in the treatment of HBeAg-positive chronic hepatitis B (CHB) patients with partial response after a standard course of interferon therapy. Methods: A retrospective cohort study was performed for 58 HBeAg-positive CHB patients with partial response at the end of interferon therapy (48-60 weeks) from January 2009 to December 2013. According to whether telbivudine was used sequentially or withdrawn at the end of the course of treatment, the patients were divided into telbivudine sequential therapy group and withdrawal group, and the two groups were compared with in terms of biochemical, virological, and serological response rates. The chi-square test, the t-test, and the non-parametric test were used based on data type. Results: A total of 58 patients were enrolled in this study, with 31 in the telbivudine sequential therapy group and 27 in the withdrawal group. At 12 and 24 weeks after interferon therapy ended, the telbivudine sequential therapy group had a significantly higher HBeAg clearance rate than the withdrawal group (22.6%/29.0% vs 0%/3.7%, P < 0.05). At week 48 of follow-up, the telbivudine sequential therapy group had a significantly higher combined response rate than the withdrawal group (22.6% vs 0%, P = 0.015). Among the 31 patients in the telbivudine sequential therapy group, 11 had an increase in creatine kinase during the administration of telbivudine. No patient in either group experienced serious adverse reactions during follow-up, such as muscular soreness, myositis, peripheral neuropathy, renal dysfunction, and liver function decompensation. Conclusion: In HBeAg-positive CHB patients with partial response to interferon therapy, sequential therapy with telbivudine can increase serological HBeAg clearance rate and combined response rate at week 48, and it is safe in HBeAg-positive CHB patients achieving partial response at the end of interferon therapy.

ROLE OF SERUM INTERLEUKIN – 10 AND INTERLEUKIN -28B GENE POLYMORPHISMS IN PREDICTING TREATMENT RESPONSE OF HEPATITIS C PATIENTS

Background: Hepatitis C virus infection (HCV) is a global health problem which develops chronic hepatic diseases including liver cirrhosis and hepatocellular carcinoma. IL28B polymorphisms rs12979860 CC genotype and low serum level of interleukin10 were associated to protect the patients of HCV infection and rapid virological response (RVR) in HCV patients treated for four weeks with pegIFNα/ribavirin (IFNα/RIB). Subjects and methods: The study was carried out on 49 Egyptian HCV patients, Patients with other types of viral hepatitis, unfavourable haematological picture & decompensated liver function including cirrhosis and Autoimmune hepatitis were excluded. Patients who responsing to IFNα/RIB after four weeks were classified as RVR (n = 18) and Non-RVR (n = 31). IL28B polymorphisms at rs12979860, the resulting genotypes are CC, CT or TT, and Serum IL10 was measured by standard sandwich enzyme-linked immune-sorbent assay technology for both groups. Results: Il28B CC genotype was 67.4 % in responder group (RVR) 38.7% in non-responder group (non RVR) (p= 0.01), CC genotype with serum IL10 80 pg/mL (p= 0.00). Conclusion: the relationship of genotype CC of IL28B at rs12979869 and the effect of IFNα/RIB to maintain the serum level of IL10 decrease and to achieve better chances to cure the HCV patients from the virus.

Asymptomatic Hepatitis C in Patient with Oral Lichen Planus: A Case Report

Lichen planus (LP) is a chronic inflammatory condition that affects the oral mucous membrane/skin with a variety of clinical presentations. Oral Lichen Planus (OLP) is considered to be associated with numerous systemic conditions one of which includes hepatitis C virus (HCV) infection. The geographic variation of the hepatitis C prevalence proved to be an important factor influencing the statistical results of the studies analyzing the association of the oral plan lichen with the hepatitis C virus. LP patients have about a fivefold higher risk than the controls of being HCV seropositive, with geographic variability, being most prevalent in the region of Japan, Mediterranean countries and the USA. Treatment outcomes in patients with oral lichen planus associated with chronic hepatitis C virus are often unsatisfactory compared to patients suffering from idiopathic oral lichen planus. Also, the evolution of oral lesions is often fluctuating, with repeated periods of relapse according to the degree of liver function decompensation. Herewith, a case of oral lichen planus in a female patient is reported, which on investigation revealed hepatitis C antibodies.

The Association between Expression of NK Cells and Prognosis of Patients with HBV Acute-on-Chronic Liver Failure in Advanced Phase

Acute-on-chronic liver failure (Acute-on-chronic liver failure, ACLF) is acute liver function decompensation on the basis of chronic liver disease. The progression of ACLF develops from advanced phase, plateau phase to remission phase. The pathophysiological basis of ACLF in different phases is various. In advanced phase, immune imbalance and systemic inflammatory reaction plays key roles. In this study, we try to assess the association between expression of NK cells and its receptors and prognosis of patients with ACLF in advanced phase. A total of 35 inpatients with HBV acute-on-chronic liver failure in advanced phase were recruited. They were divided into case group (n = 18) and control group (n = 17) according to whether the patients was dead in the 12 weeks. PBMC were detected for the frequency and expression of NK cell receptors by flow cytometric analysis. Our results demonstrated that patients who died had lower expression of NK cells and inhibitory receptor KIR3DL1, higher levels of FASL. During 12-week follow-up in those case alive, we found that NK cells increased, while expression of FASL decreased. High short-term mortality of ALCF was associated with NK cell, especially related to KIR3DL1 and FASL (PNK = 0.036, PKIR3DL1 = 0.0265, PFasL = 0.0008).

Non-cirrhotic portal fibrosis at a tertiary care centre in South India.

Non-cirrhotic portal fibrosis (NCPF) is one of the important causes of upper gastrointestinal haemorrhage in patients in tropical countries. The aim of this study was to describe the clinical and laboratory profile of 68 patients with NCPF. NCPF is defined as liver disease with: (1) evidence of portal hypertension; (2) a liver biopsy showing no cirrhosis or a Tc-labelled sulphur colloid scan showing a pattern suggestive of NCPF; and (3) a patent splenoportal axis. The clinical, laboratory and demographic features of 68 patients with such criteria were studied and analysed. NCPF was common in women (73.5%) in the fourth decade of life. The median duration of illness was 24 months (range, 1 month-28 years). Patients presented to hospital with the sensation of a mass in the abdomen (50%) or with haematemesis (26.5%). They had splenomegaly (95.6%) and thrombocytopenia (88.2%). The majority of patients had normal liver function tests. Abdominal ultrasonography showed increased periportal and peri gallbladder echoes (72%), spontaneous collaterals (41.2%) and ascites (19.1%). Liver biopsy revealed portal venous sclerosis (76.3%) and periportal fibrosis (55.3%). Tc-labelled sulphur colloid scan was suggestive of NCPF in the remaining 30 cases. NCPF is common in South India. Transient ascites occurs due to decompensation of liver function after variceal bleeding and in long standing cases of NCPF. Our study used Tc-sulphur scan for diagnosing NCPF in patients where liver biopsy was contraindicated in view of severe thrombocytopenia; however, the diagnostic utility of Tc-sulphur nuclear scan to diagnose NCPF in patients with severe hypersplenism needs to be further evaluated in future studies.

Sofosbuvir in therapy of chronic HCV-infection

Objective of review: to present new approaches to therapy of patients with chronic NCV-infection based on the clinical use of the direct antiviral action drug Sofosbuvir. Major provisions: until recently a standard approach to therapy of HCV-infection included prescription of schemes on the basis of the pegylated interferons (PEG-IFN) in combination with Ribavirin. Drugs of focused action at functional proteins of the virus – direct anti￾viral drugs – have become drugs of choice, which significantly increases effectiveness and safety of treatment. Drugs of direct antiviral action are classified by the type of viral proteins that serve as the target of their action: protease inhibitors (names of the drugs end with - previr), polymerase inhibitors (names of the drugs end with –buvir), NS5A inhibitors (names of the drugs end with – asvir). Sofosbuvir is an analogue of the uridine nucleotide, a powerful NS5B inhibitor, a key enzyme of HCV-RNA replication, it is widely used in various scheme of antiviral therapy. Conclusion: Sofosbuvir is one of the most promising drugs for therapy of chronic NCV-infection. Its indisputable advantages: it can be used at various viral genotypes, decompensated liver function. Sofosbuvir stands out for its good tolerability and low possibility of development of viral resistance.

Covering the Cover

Covering the Cover

간부전을 동반한 간세포암종 환자에서 경간동맥 Deferoxamine 투여 후 종양표지자 수치의 호전을 보인 1예

간부전을 동반한 간세포암종 환자에서 경간동맥 Deferoxamine 투여 후 종양표지자 수치의 호전을 보인 1예

Acute liver function decompensation in a patient with sickle cell disease managed with exchange transfusion and endoscopic retrograde cholangiography.

Sickle cell intrahepatic cholestasis is a relatively uncommon complication of homozygous sickle cell anemia, which may lead to acute hepatic failure and death. Treatment is mainly supportive, but exchange transfusion is used as salvage therapy in life threatening situations. We describe a case of a 16-year-old female with homozygous sickle cell anemia who presented to the emergency room with fatigue, malaise, dark urine, lower back pain, scleral icterus and jaundice. She was found to have marked hyperbilirubinemia, which persisted after exchange transfusion. Because of the concomitant presence of gallstones and choledocholithiasis, the patient underwent endoscopic ultrasound and laparoscopic cholecystectomy followed by endoscopic retrograde cholangiography and sphincterotomy.

Non-hepatic gastrointestinal surgery in patients with cirrhosis

Gastrointestinal surgery is feasible in patients with Child A cirrhosis, but is associated with higher morbidity and mortality. Hernia repair, biliary and colonic surgery are the most frequently performed interventions in this context. Esophageal and pancreatic surgery are more controversial and less frequently performed. For patients with decompensated liver function (Child B or C patients), the indications for surgery should be discussed by a multi-specialty team including the hepatologist, anesthesiologist, surgeon; liver function should be optimized if possible. During emergency surgery, histologic diagnosis of cirrhosis should be confirmed by liver biopsy because the histologic diagnosis has therapeutic and prognostic implications. The management of patients with Child A cirrhosis without portal hypertension is little different from the management of patients without cirrhosis. However, the management of patients with Child B or C cirrhosis or with portal hypertension is more complex and requires an accurate assessment of the balance of benefit vs. risk for surgical intervention on a case-by-case basis.

Role of BMSCs in liver regeneration and metastasis after hepatectomy

Hepatocellular carcinoma (HCC), which develops from liver cirrhosis, is highly prevalent worldwide and is a malignancy that leads to liver failure and systemic metastasis. While surgery is the preferred treatment for HCC, intervention and liver transplantation are also treatment options for end-stage liver disease. However, the success of partial hepatectomy and intervention is hindered by the decompensation of liver function. Conversely, liver transplantation is difficult to carry out due to its high cost and the lack of donor organs. Fortunately, research into bone-marrow stromal cells (BMSCs) has opened a new door in this field. BMSCs are a type of stem cell with powerful proliferative and differential potential that represent an attractive tool for the establishment of successful stem cell-based therapy for liver diseases. A number of different stromal cells contribute to the therapeutic effects exerted by BMSCs because BMSCs can differentiate into functional hepatic cells and can produce a series of growth factors and cytokines capable of suppressing inflammatory responses, reducing hepatocyte apoptosis, reversing liver fibrosis and enhancing hepatocyte functionality. Additionally, it has been shown that BMSCs can increase the apoptosis rate of cancer cells and inhibit tumor metastasis in some microenvironments. This review focuses on BMSCs and their possible applications in liver regeneration and metastasis after hepatectomy.

Correlation between standard remnant liver volume and liver function decompensation in patients after surgery for hepatocellular carcinoma

Correlation between standard remnant liver volume and liver function decompensation in patients after surgery for hepatocellular carcinoma