Showing papers in "Hepatology International in 2018"

Myosteatosis and sarcopenia are associated with hepatic encephalopathy in patients with cirrhosis

Abstract: Skeletal muscle is known to play a role in hepatic encephalopathy. Fatty infiltration of the muscle (myosteatosis) and muscle mass depletion (sarcopenia) are frequent complications of cirrhosis. The purposes of the study were to investigate if myosteatosis and sarcopenia are associated with overt hepatic encephalopathy in patients with cirrhosis and to evaluate their impact on mortality. A total of 675 cirrhotic patients were studied. Computed tomography scans were used to analyze the skeletal muscle. Hepatic encephalopathy was defined by either a hepatic encephalopathy-related hospitalization and/or taking ammonia-lowering treatment (i.e., lactulose, rifaximin). Myosteatosis was observed in 348 patients (52%), sarcopenia in 242 (36%), and hepatic encephalopathy in 128 (19%) patients. Both myosteatosis (70 vs. 45%, p < 0.001) and sarcopenia (53 vs. 32%, p < 0.001) were more frequent in patients with hepatic encephalopathy. By multivariable regression analysis, both myosteatosis and sarcopenia were associated with a higher risk of hepatic encephalopathy, independent of the MELD score (OR 2.25; 95% CI, 1.32–3.85, p = 0.003 and OR 2.42; 95% CI, 1.43–4.10, p = 0.001, respectively). In univariate Cox proportional hazards analysis, sarcopenia (csHR 2.02; 95% CI, 1.57–2.58, p < 0.001), myosteatosis (csHR 1.45; 95% CI, 1.16–2.91, p = 0.004), and hepatic encephalopathy (csHR 1.61; 95% CI, 1.20–2.18, p = 0.002) were associated with mortality, but only sarcopenia was significant in the multivariable analysis (csHR 2.15; 95% CI, 1.52–3.05, p < 0.001). Myosteatosis and sarcopenia are independently associated with overt hepatic encephalopathy in patients with cirrhosis. The association between hepatic encephalopathy and mortality may be explained at least partially by the presence of sarcopenia. These results identify the importance of muscle mass and suggest therapeutic strategies to attenuate muscle mass loss and improve muscle quality.

Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg.

Abstract: The term gut–liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized epithelial membrane which regulates transport across the mucosa. Due to dysbiosis, impairment of the intestinal barrier and altered immunity status, bacterial products can reach the liver through the portal vein, where they are recognized by specific receptors, activate the immune system and lead to a proinflammatory response. Gut microbiota and bacterial translocation play an important role in the pathogenesis of chronic liver diseases, including alcoholic and non-alcoholic fatty liver disease, cirrhosis, and its complications, such as portal hypertension, spontaneous bacterial peritonitis and hepatic encephalopaty. The gut microbiota also plays a critical role as a modulator of bile acid metabolism which can also influence intestinal permeability and portal hypertension through the farnesoid-X receptor. On the other hand, cirrhosis and portal hypertension affect the microbiota and increase translocation, leading to a “chicken and egg” situation, where translocation increases portal pressure, and vice versa. A myriad of therapies targeting gut microbiota have been evaluated specifically in patients with chronic liver disease. Further studies targeting intestinal microbiota and its possible hemodynamic and metabolic effects are needed. This review summarizes the current knowledge about the role of gut microbiota in the pathogenesis of chronic liver diseases and portal hypertension.

Hepatic encephalopathy: a critical current review

Abstract: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.

Budd–Chiari syndrome/hepatic venous outflow tract obstruction

Abstract: Budd–Chiari syndrome (BCS) is a rare disease characterized by hepatic venous outflow tract obstruction (HVOTO). Recent literature has been analyzed for this narrative review. Primary BCS/HVOTO is a result of thrombosis. The same patient often has multiple risk factors for venous thrombosis and most have at least one. Presentation and etiology may differ between Western and certain Eastern countries. Myeloproliferative neoplasms are present in 40% of patients and are usually associated with the V617F-JAK2 mutation in myeloid cells, in particular peripheral blood granulocytes. Presentation and symptoms vary, thus this diagnosis must be considered in any patient with acute or chronic liver disease. Doppler ultrasound, computed tomography, or magnetic resonance imaging of the hepatic veins and inferior vena cava usually successfully provide noninvasive identification of the obstruction or its consequences in the collaterals of hepatic veins or the inferior vena cava. The reported life expectancy in these patients is 3 years after the first symptoms. The therapeutic strategy includes first, anticoagulation, correction of risk factors, diuretics, and prophylaxis for portal hypertension, then angioplasty for short-length venous stenosis followed by transjugular intrahepatic portosystemic shunt (TIPS) and finally liver transplantation. The progression of treatment is based on the response to therapy at each step. This strategy results in a 5-year survival rate of nearly 85%. The medium-term prognosis depends upon the severity of liver disease, and the long-term outcome can be jeopardized by transformation of underlying conditions and hepatocellular carcinoma. BCS/HVOTO hepatic manifestations of BCS/HVOTO can be controlled in most patients with medical or radiological interventions. Underlying disease has become the major determinant of patient outcome.

The portal hypertension syndrome: etiology, classification, relevance, and animal models

Abstract: Portal hypertension is a key complication of portal hypertension, which is responsible for the development of varices, ascites, bleeding, and hepatic encephalopathy, which, in turn, cause a high mortality and requirement for liver transplantation. This review deals with the present day state-of-the-art preventative treatments of portal hypertension in cirrhosis according to disease stage. Two main disease stages are considered, compensated and decompensated cirrhosis, the first having good prognosis and being mostly asymptomatic, and the second being heralded by the appearance of bleeding or non-bleeding complications of portal hypertension. The aim of treatment in compensated cirrhosis is preventing clinical decompensation, the more frequent event being ascites, followed by variceal bleeding and hepatic encephalopathy. Complications are mainly driven by an increase of hepatic vein pressure gradient (HVPG) to values ≥10 mmHg (defining the presence of Clinically Significant Portal Hypertension, CSPH). Before CSPH, the treatment is limited to etiologic treatment of cirrhosis and healthy life style (abstain from alcohol, avoid/correct obesity…). When CSPH is present, association of a non-selective beta-blocker (NSBB), including carvedilol should be considered. NSBBs are mandatory if moderate/large varices are present. Patients should also enter a screening program for hepatocellular carcinoma. In decompensated patients, the goal is to prevent further bleeding if the only manifestation of decompensation was a bleeding episode, but to prevent liver transplantation and death in the common scenario where patients have manifested first non-bleeding complications. Treatment is based on the same principles (healthy life style..) associated with administration of NSBBs in combination if possible with endoscopic band ligation if there has been variceal bleeding, and complemented with simvastatin administration (20-40 mg per day in Child–Pugh A/B, 10–20 mg in Child C). Recurrence shall be treated with TIPS. TIPS might be indicated earlier in patients with: 1) Difficult/refractory ascites, who are not the best candidates for NSBBs, 2) patients having bleed under NSBBs or showing no HVPG response (decrease in HVPG of at least 20% of baseline or to values equal or below 12 mmHg). Decompensated patients shall all be considered as potential candidates for liver transplantation. Treatment of portal hypertension has markedly improved in recent years. The present day therapy is based on accurate risk stratification according to disease stage.

New concepts on the clinical course and stratification of compensated and decompensated cirrhosis.

Abstract: The clinical course of cirrhosis has been typically described by a compensated and a decompensated state based on the absence or, respectively, the presence of any of bleeding, ascites, encephalopathy or jaundice. More recently, it has been recognized that increasing portal hypertension and several major clinical events are followed by a marked worsening in prognosis, and disease states have been proposed accordingly in a multistate model. The development of multistate models implies the assessment of the probabilities of more than one possible outcome from each disease state. This requires the use of competing risks analysis which investigates the risk of several competing outcomes. In such a situation, the Kaplan–Meier risk estimates and the Cox regression may be not appropriate. Clinical states of cirrhosis presently considered as suitable for a comprehensive multistate model include: in compensated cirrhosis, early (mild) portal hypertension with hepatic venous pressure gradient (HVPG) >5 and <10 mmHg, clinically significant portal hypertension (HVPG ≥ 10 mmHg) without gastro-esophageal varices (GEV), and GEV; in decompensated cirrhosis, a first variceal bleeding without other decompensating events, any first non-bleeding decompensation and any second decompensating event; and in a late decompensation state, refractory ascites, sepsis, renal failure, recurrent encephalopathy, profound jaundice, acute on chronic liver failure, all predicting a very short survival. In this review, we illustrate how competing risks analysis and multistate models may be applied to cirrhosis.

Global HBV burden: guesstimates and facts

Abstract: Chronic hepatitis B virus infection (HBV) continues to pose a serious global health threat in many areas of the world, particularly in sub-Saharan Africa, the Western Pacific Region and areas of Eastern Europe. Endemicity is heterogeneous within and across regions owing to variable implementation of childhood and birth-dose vaccination programs, inconsistent screening of blood products, injection drug use, and poor education initiatives. This review aims to provide comprehensive up-to-date estimates of global seroprevalence of chronic HBV across six World Health Organization (WHO) regions, noting patterns of change over time and highlighting potential region-specific barriers to the diagnosis and elimination of HBV.

Management of ascites and hepatorenal syndrome.

Abstract: Ascites represents the most common decompensating event in patients with liver cirrhosis. The appearance of ascites is strongly related to portal hypertension, which leads to splanchnic arterial vasodilation, reduction of the effective circulating volume, activation of endogenous vasoconstrictor systems, and avid sodium and water retention in the kidneys. Bacterial translocation further worsens hemodynamic alterations of patients with cirrhosis and ascites. The first-line treatment of uncomplicated ascites is a moderate sodium-restricted diet combined with diuretic treatment. In patients who develop refractory ascites, paracentesis plus albumin represents the most feasible option. Transjugular intrahepatic portosystemic shunt placement is a good alternative for selected patients. Other treatments such as vasoconstrictors and automated low-flow pumps are two potential options still under investigations. Ascites is associated with a high risk of developing further complications of cirrhosis such as dilutional hyponatremia, spontaneous bacterial peritonitis and/or other bacterial infections and acute kidney injury (AKI). Hepatorenal syndrome (HRS) is the most life-threatening type of AKI in patients with cirrhosis. The most appropriate medical treatment in patients with AKI-HRS is the administration of vasoconstrictors plus albumin. Finally, ascites impairs both the quality of life and survival in patients with cirrhosis. Thus, all patients with ascites should be evaluated for the eligibility for liver transplantation. The aim of this article is to review the management of patients with cirrhosis, ascites and HRS.

Biology of portal hypertension

Abstract: Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.

Non-alcoholic hepatic steatosis attenuates hepatitis B virus replication in an HBV-immunocompetent mouse model.

Abstract: The relationship between chronic hepatitis B virus (HBV) infection and fatty liver in patients remains unclear. Although high-fat diets-induced hepatic steatosis was proved to reduce HBV replication in transgenic mice, the interplay between HBV and fatty liver in immunocompetent mouse model is yet to be elucidated. Here, we aimed to develop an effective animal model for intracellular HBV persistence combined with hepatic steatosis and to explore their interactions. FVB/N mice with HBV genotype B replicon DNA were established by hydrodynamic injection. Mice injected with HBV or control plasmid vectors were then randomized into NAFLD + HBV, HBV, NAFLD, and control groups and treated with a high-fat or standard diet for up to 14 weeks. The characteristics of NAFLD were evaluated by physical indices, liver function tests, glycolipid metabolism, and liver histopathological changes. Viral dynamics were also analyzed by HBV DNA and HBV-related antigens. HBV clone persistently replicated in the livers of FVB/N mice, and hepatic steatosis was induced by a high-fat diet. The NAFLD and NAFLD + HBV groups shared similar physical features, glycolipid metabolism, liver function, and hepatic steatosis. Serum hepatitis B e antigen (HBeAg), hepatic hepatitis B s antigen (HBsAg),hepatitis B c antigen (HBcAg), and HBV DNA were decreased in the NAFLD + HBV group compared with those in the HBV group at the end of 14 weeks. In an HBV-immunocompetent mouse model, non-alcoholic hepatic steatosis inhibited HBV replication, as indicated by the reduction of HBV DNA and HBV-related antigens. HBV replication did not alter lipid metabolism in mice.

Idiopathic portal hypertension and extrahepatic portal venous obstruction

Abstract: Idiopathic portal hypertension (IPH) and extrahepatic portal venous obstruction (EHPVO) are non-cirrhotic vascular causes of portal hypertension (PHT). Variceal bleed and splenomegaly are the commonest presentations. The present review is intended to provide the existing literature on etiopathogenesis, clinical profile, diagnosis, natural history and management of IPH and EHPVO. IPH and EHPVO are both characterized by normal hepatic venous pressure gradient, moderate to massive splenomegaly with preserved liver synthetic functions. While the level of block in IPH is presinusoidal, in EHPVO it is at prehepatic level. Infections, autoimmunity, drugs, immunodeficiency and prothrombotic states are possible etiological agents in IPH. Contrastingly in EHPVO, prothrombotic disorders and local factors around the portal vein are the incriminating factors. Diagnosis is often clinical, supported by simple radiological tools. Natural history is defined by episodes of variceal bleed and symptoms related to enlarged spleen. Growth failure, portal biliopathy and minimal hepatic encephalopathy are additional concerns in EHPVO. Long-term survival is reasonably good with endoscopic surveillance; however, parenchymal extinction leading to decompensation is seen in a minority of patients in both the disorders. Surgical shunts revert the complications secondary to PHT. Meso-Rex shunt has become the standard surgery in children with EHPVO. This review gives a detailed summary of these two vascular conditions of liver—IPH and EHPVO. Further research is needed to understand the pathogenesis and natural history of these disorders.

Pathogenesis of non-alcoholic fatty liver disease mediated by YAP

Abstract: This study aimed to investigate the mechanism of the interaction between Yes-associated protein (YAP) and transforming growth factor-β (TGF-β)/Smad signaling pathways in the development of non-alcoholic fatty liver disease (NAFLD). Serum samples of monkeys with biopsy-proven NAFLD and healthy normal monkeys were used to measure fasting plasma glucose (FPG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG) and albumin (ALB) with the BECKMAN CX5 PRO. Hematoxylin-eosin staining (HE the accumulation of YAP correlated with the severity of hepatocyte injury. Compared with normal monkeys, the expression of TGF-β, α-smooth muscle actin (α-SMA), Drosophila mothers against decapentaplegic protein 3 (Smad3) and connective tissue growth factor (CTGF) in the liver of simple steatosis monkeys significantly increased (p < 0.01). Compared with simple steatosis monkeys, the expression of TGF-β, α-SMA, Smad3 and CTGF in fibrosing NASH significantly increased (p < 0.01). However, the expression of Drosophila mothers against decapentaplegic protein 7 (Smad7) in the liver of fibrosing NASH monkeys significantly decreased (p < 0.01). With the severity of liver fibrosis, the expression of TGF-β, α-SMA, Smad3 and CTGF gradually increased, and the difference was statistically significant (p < 0.01). However, there was no significant difference in the expression of Smad3 between fibrosis stage 1a and 1c. Compared with normal monkeys, the expression of Smad7 in the liver of monkeys with fibrosis significantly decreased (p < 0.01), but was significantly higher at fibrosis stage 1c than at fibrosis stage 1a and 2. The YAP and TGF-β signaling pathways and the interaction between them promote the development and progression of NAFLD.

Small intestinal bacterial overgrowth in cirrhosis: systematic review and meta-analysis

Abstract: Small intestinal bacterial overgrowth (SIBO) was detected in cirrhosis in many studies. The aim is to perform a systematic review and meta-analysis on the prevalence of SIBO in cirrhosis and on the relationship of SIBO with features of cirrhosis. PUBMED search (until 14 January 2018) was performed. Specific search terms were: ‘(cirrhosis) AND (SIBO OR bacterial overgrowth)’. Studies not relating to cirrhosis or SIBO, animal studies, and non-original articles were excluded. A meta-analysis of all studies was performed using a random-effects model. 117 references were identified by the PUBMED search. 3 references were added after handsearching the reference lists of all the articles. 99 references were excluded. 21 studies (included in total 1264 cirrhotics and 306 controls) remained for qualitative analysis and quantitative synthesis. Prevalence of SIBO for cirrhosis was 40.8% (95% CI 34.8–47.1), while the prevalence of SIBO for controls was 10.7% (95% CI 5.7–19.0). OR 6.83 (95% CI 4.16–11.21; p < 0.001). Prevalence of SIBO for decompensated cirrhosis was higher than prevalence of SIBO for compensated cirrhosis (50.5% vs. 31.2%; p < 0.001). SIBO in cirrhosis was associated with ascites (p < 0.001), minimal hepatic encephalopathy (p = 0.001), bacterial translocation (p = 0.026), spontaneous bacterial peritonitis (p = 0.008), prolonged orocecal transit time (p < 0.001), and was not associated with hypocoagulation. Further studies are required to clarify the relationship of SIBO with hyperbilirubinemia, hypoalbuminemia, overt hepatic encephalopathy in past, esophageal varices and systemic inflammation. Small intestinal bacterial overgrowth is more often detected in cirrhosis than in healthy persons and is associated with some features of cirrhosis.

Immune checkpoint receptors: homeostatic regulators of immunity.

Abstract: Alcoholic liver disease (ALD) is an escalating global problem accounting for more than 3 million deaths annually. Bacterial infections are diagnosed in 25–47% of hospitalized patients with cirrhosis and represent the most important trigger for acute decompensation, multi-organ failure, septic shock and death. Current guidelines recommend intensive antibiotic therapy, but this has led to the emergence of multi-drug resistant bacteria, which are associated with increased morbidity and mortality rates. As such, there is a pressing need to explore new paradigms for anti-infective therapy and host-directed immunomodulatory therapies are a promising approach. Paradoxically, cirrhotic patients are characterised by heightened immune activity and exacerbated inflammatory processes but are unable to contend with bacterial infection, demonstrating that whilst immune effector cells are primed, their antibacterial effector functions are switched-off, reflecting a skewed homeostatic balance between anti-pathogen immunity and host-induced immunopathology. Preservation of this equilibrium physiologically is maintained by multiple immune-regulatory checkpoints and these feedback receptors serve as pivotal regulators of the host immunity. Checkpoint receptor blockade is proving to be effective at rescuing deranged/exhausted immunity in pre-clinical studies for chronic viral infection and sepsis. This approach has also obtained FDA approval for restoring anti-tumor immunity, with improved response rates and good safety profiles. To date, no clinical studies have investigated checkpoint blockade in ALD, highlighting an area for development of host-targeted immunotherapeutic strategies in ALD, for which there are no current specific treatment options. This review aims at framing current knowledge on immune checkpoints and the possibility of their therapeutic utility in ALD-associated immune dysfunctions.

Depression, fatigue and neurocognitive deficits in chronic hepatitis C

Abstract: Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.

Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype

Abstract: Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles.

Sofosbuvir–velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C who failed direct-acting antivirals

Abstract: In Japan, there is a growing population of patients with chronic hepatitis C virus (HCV) infection who failed a direct-acting antiviral (DAA)-based regimen. In this Phase 3 study, we evaluated sofosbuvir–velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 HCV infection who previously received DAAs. Patients were randomized 1:1 to receive sofosbuvir–velpatasvir plus ribavirin for 12 or 24 weeks. Randomization was stratified by HCV genotype and presence of cirrhosis. The primary endpoint was sustained virologic response 12-week post-treatment (SVR12). Of 117 participants, 81% had HCV genotype 1 infection, 33% had cirrhosis, and 95% had NS5A resistance-associated substitutions (RAS) at baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88–100%) with 24 weeks of treatment and 82% (47/57; 95% CI 70–91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. In both treatment groups, SVR12 rates in HCV genotype 1 patients were statistically superior to a historical control rate of 50% (p < 0.001). For patients with NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week group achieved SVR12. The most common adverse events were upper respiratory tract viral infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of adverse events. Sofosbuvir–velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen. Baseline NS5A RASs did not affect treatment outcomes.

Acute variceal bleeding: risk stratification and management (including TIPS)

Abstract: Acute variceal bleeding should be suspected in all patients with cirrhosis presenting with upper gastrointestinal bleeding. Vasoactive drugs and prophylactic antibiotics must be started as soon as possible, even before performing the diagnostic endoscopy. Once the patient is hemodynamically stable, upper gastrointestinal endoscopy should be performed in order to confirm the diagnosis and provide endoscopic therapy (preferably banding ligation). After this initial approach, the most appropriate therapy to prevent both early and late rebleeding must be instituted following a risk stratification strategy. The present chapter will focus on the initial management of patients with acute variceal bleeding, including general management and hemostatic therapies, as well as the available treatments in case of failure to control bleeding or development of rebleeding.

The growing burden of liver cirrhosis: implications for preventive measures

Abstract: Liver cirrhosis has become one of the major causes of morbidity and mortality. The Global Burden of Disease (GBD) reported that over one million people died due to cirrhosis in 2010 worldwide, compared with 676,000 deaths in 1980. Since the survival rate of cirrhosis is relatively low, data on the incidence of geographical variations are essential to prevent its related disability and mortality. However, the heavy burden of this medical condition might be even greater, as relevant data in 58/187 (31%) of countries were not available in the report [1]. Existing evidence showed that the burden of liver cirrhosis is growing in both the West and the East. The number of deaths caused by liver cirrhosis in the Caribbean, Latin America, Asia, Oceania, Africa and Europe had increased significantly from 1980 to 2010. Especially for the Caribbean, the mortality rate increased rapidly from 600,000 to 1 million. Egypt had the highest age-standardized mortality rate for cirrhosis, while Mexican had the greatest number of deaths in the Latin Americans. In Asia, the highest incidence of liver cirrhosis was observed in Thailand [2]. The growing prevalence of liver cirrhosis is due to the increasing burden of its risk factors. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the two major causes of liver cirrhosis. Globally, 257 million people were infected with chronic HBV in 2015. Asia and Africa were the two highest endemic continents, with an overall prevalence of over 8%. The rising prevalence of HCV is also an emerging issue for health in many regions. There were about 71 million people with HCV in 2015. The prevalence in highly endemic regions, for example, Central Asia and the Mediterranean, was over 3.5% [3]. Apart from hepatitis infection, alcohol is another important risk factor for liver cirrhosis. From 2005 to 2015, the global agestandardised prevalence of liver cirrhosis due to alcohol has increased by 16.1%, compared with HBV (11.9%), HCV (14.2%) and others (9.9%) [4]. Liver cirrhosis is the end-stage of different chronic liver diseases, and is often neglected until complications, such as variceal haemorrhage, spontaneous bacterial peritonitis, ascites, or hepatic encephalopathy occur. [5] More than half of all patients diagnosed with liver cancer have liver cirrhosis. In 2012, the prevalence of liver cancer ranked the fifth among all cancers, making up 9.1% of all cancer deaths worldwide. A significant number of years of life lost were induced by its aggressive history and low survival. The highest incidence mortality was observed in Eastern Asia, South-Eastern Asia and Northern Africa [6]. Cirrhosis was also found to be associated with other diseases, including non-alcoholic fatty liver disease (NAFLD), colorectal cancer, and metabolic syndrome [7, 8]. A recent review has highlighted the changing epidemiology of liver diseases in the Asia Pacific region [3]. In this issue of the Journal, Chung et al. [9] performed an eight-year, prospective cohort study using data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) database to compare the mortality between cirrhosis and five major cancers, including lung, colorectal, stomach, liver, and breast cancers. There occurred 2609 cases of liver cirrhosis and 4852 cases of the investigated cancers. The mortality was 46.9/1000 person-years for liver cirrhosis and 41.1/1000 person-years for the five cancers. At the end of eight-year follow-up, the survival probability was 69.5 and 73% for liver cirrhosis and cancers, respectively. From Cox Proportional hazards models, they found that the hazard ratio of cirrhosis for mortality was greater than the five major cancers by a magnitude of 13–87%. The fact that 16.7% of the liver cirrhosis patients had coexisting & Junjie Huang junjie_huang@link.cuhk.edu.hk

Endoscopic treatments for portal hypertension.

Abstract: Acute esophageal variceal hemorrhage is a dreaded complication of portal hypertension. Its management has evolved rapidly in recent years. Endoscopic therapy is often employed to arrest bleeding varices as well as to prevent early rebleeding. The combination of vasoconstrictor and endoscopic therapy is superior to vasoconstrictor or endoscopic therapy alone for control of acute esophageal variceal hemorrhage. After control of acute variceal bleeding, combination of banding ligation and beta-blockers is generally recommended to prevent variceal rebleeding. To prevent the catastrophic event of acute variceal bleeding, endoscopic banding ligation is an important tool in the prophylaxis of first bleeding. Endoscopic obturation with cyanoacrylate is usually utilized to arrest acute gastric variceal hemorrhage as well as to prevent rebleeding. It can be concluded that endoscopic therapies play a pivotal role in management of portal hypertensive bleeding.

Pharmacologic prevention of variceal bleeding and rebleeding.

Abstract: Variceal bleeding is a major complication of portal hypertension, which is associated with significant mortality. Moreover, patients surviving a variceal bleeding episode have very high risk of rebleeding, which is associated with mortality as high as that of the first bleed. Because of this, prevention of bleeding from gastroesophageal varices has been one of the main therapeutic goals since the advent of the first effective therapies for portal hypertension. This review deals with the present day state-of-the-art pharmacological prevention of variceal bleeding in primary and secondary prophylaxis. Pharmacological therapy aims to decrease portal pressure (PP) by acting on the pathophysiological mechanisms of portal hypertension such as increased hepatic vascular tone and splanchnic vasodilatation. Propranolol and nadolol block the beta-1 in the heart and the peripheral beta-2 adrenergic receptors. Beta-1 blockade of cardiac receptors reduces heart rate and cardiac output and subsequently decreases flow into splanchnic circulation. Beta-2 blockade leads to unopposed alpha-1 adrenergic activity that causes splanchnic vasoconstriction and reduction of portal inflow. Both effects contribute to reduction in PP. Carvedilol is more powerful in reducing hepatic venous pressure gradient (HVPG) than traditional nonselective beta-blockers (NSBBs) and achieves good hemodynamic response in nearly 75 % of cases. Simvastatin and atorvastatin improve endothelial dysfunction mainly by enhancing endothelial nitric oxide synthase (eNOS) expression and phosphorylation and NO production. In addition, statins deactivate hepatic stellate cells and ameliorate hepatic fibrogenesis. These effects cause a decrease in HVPG and improve liver microcirculation and hepatocyte perfusion in patients with cirrhosis. In addition, several promising drugs under development may change the management of portal hypertension in the coming years. This review provides a background on the most important aspects of the treatment of portal hypertension in patients with compensated and decompensated liver cirrhosis. However, despite the great improvement in the prevention of variceal bleeding over the last years, further therapeutic options are needed.

Management of acute-on-chronic liver failure: an algorithmic approach.

Abstract: Acute-on-chronic liver failure (ACLF) is a distinct syndrome of liver failure in a patient with chronic liver disease presenting with jaundice, coagulopathy and ascites and/or hepatic encephalopathy, developing following an acute hepatic insult and associated with high 28-day mortality. The definition though lacks global consensus, excludes patients with known distinct entities such as acute liver failure and those with end-stage liver disease. The initial Systemic Inflammatory Response Syndrome (SIRS) because of cytokine storm in relation to acute insult and/or subsequent development of sepsis due to immunoparalysis leads to extrahepatic organ failure. These cascades of events progress through a ‘Golden Window’ period of about 7 days, subsequent to which majority of the patients develop complications, such as sepsis and extrahepatic organ failure. Prevention of sepsis, support of organs and management of organ failure (commonly hepatic, renal, cerebral, coagulation) and early referral for transplant is crucial. The APASL ACLF research consortium (AARC) liver failure score is a dynamic prognostic model for management decisions and is superior to existing models. Aggressive multidisciplinary approach can lead to a transplant-free survival in nearly half of the cases. The present review provides an algorithmic approach to management of organ failure, sepsis prevention, use of dynamic prognostic models for management decision and is aimed to improve the skills for managing and improving the outcomes of such critically ill patients.

Invasive and non-invasive assessment of portal hypertension

Abstract: Portal hypertension is the central driver of complications in patients with chronic liver diseases and cirrhosis. The diagnosis of portal hypertension has important prognostic and clinical implications. In particular, screening for varices in patients with portal hypertension can effectively reduce the morbidity and mortality of variceal bleeding. In this article, we review the invasive and non-invasive methods to assess portal hypertension. Hepatic venous pressure gradient remains the gold standard to measure portal pressure but is invasive and seldom performed outside expert centers and research settings. In recent years, a number of non-invasive tests of fibrosis have shown good correlation with liver histology. They also show promise in identifying patients with portal hypertension and large varices. As a result, the latest Baveno VI consensus guidelines endorse the use of liver stiffness measurement by transient elastography and platelet count as initial assessment to select patients for varices screening. On the other hand, the performance of non-invasive tests in assessing the response to non-selective beta-blockers or transjugular intrahepatic portosystemic shunting is either suboptimal or unclear.

Efficacy and safety of sofosbuvir plus daclatasvir with or without ribavirin: large real-life results of patients with chronic hepatitis C genotype 4

Abstract: Clinical studies evaluating the efficacy of daclatasvir (DCV) for treatment of chronic hepatitis C virus (HCV) genotype 4 (GT4) infection are scarce. This study aims to evaluate the efficacy and safety of DCV plus sofosbuvir (SOF) with or without ribavirin (RBV) for treatment of Egyptian patients infected with HCV GT4. Between April 2016 and March of 2017, a large cohort of 946 patients with chronic HCV GT4 was enrolled for completing the treatment. Patients were classified into two groups: group 1 (easy to treat) was treated with a dual therapy of SOF/DCV daily for 12 weeks and group 2 (difficult to treat) was treated with a triple therapy of SOF/DCV/RBV daily for 12 weeks. Efficacy and safety of the treatments were estimated, and baseline characters associated with sustained virological response at 12 weeks post-treatment (SVR12) were investigated. Among the patient’s cohort, SVR12 was achieved by 94% (891/946) in the overall patients, by 95% (718/758) in the easy-to-treat group, and by 92% (173/188) in the difficult-to-treat group. The most common adverse events recorded were fatigue, headache, nausea, asthenia, and gastrointestinal troubles. No patient discontinued treatment due to severe adverse events. The findings from the present study suggested that SOF/DCV (with or without RBV) regimen exhibited high effectiveness, was well tolerated in the treatment of chronic HCV GT 4, and revealed itself as a better option for patients with advanced liver disease, making the eradication of HCV a more realistic target to achieve.

Prediction of the very early occurrence of HCC right after DAA therapy for HCV infection

Abstract: Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear. We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy. Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1 year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging “dysplastic nodule”. SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging “dysplastic nodule” was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of “dysplastic nodule” by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed.

Sofosbuvir plus Daclatasvir with or without ribavirin for treatment of chronic HCV genotype 4 patients: real-life experience.

Abstract: New regimens involving direct-acting antiviral agents have recently been approved for the treatment of HCV. Our aim was to assess the efficacy and safety of 12 or 24 weeks of Sofosbuvir 400 mg plus Daclatasvir 60 mg, with or without ribavirin (800–1000 mg) in treating chronic hepatitis C genotype 4 patients. This is an open-label observational study that describes the effect of 12 week or 24 weeks of daily oral Sofosbuvir (SOF) 400 mg plus Daclatasvir (DCV) 60 mg with or without ribavirin (RBV) with dose adjustment if indicated. It included the first 1168 patients that fulfilled the inclusion and exclusion criteria and treated in the Egyptian Liver Research Institute and Hospital, Mansoura, Egypt. Sustained viral response after 12 weeks of end of treatment (SVR12) was achieved in 96.6% (95% CI 95.1–98.2%) of the patients receiving 12 weeks of DCV + SOF treatment, in 95.7% (95% CI 93.6–97.8%) of the patients receiving 12 weeks of DCV + SOF + RBV, in 93.3% (95% CI 90.0–96.6%) of those receiving 24 weeks of DCV + SOF, and in 92.2% (95% CI 85.4–98.9%) of patients receiving 24 weeks of DCV + SOF + RBV treatment. SVR12 rate was significantly higher in patients with no cirrhosis receiving DCV + SOF only for 12 weeks or 24 weeks (97.4 and 97.4%, respectively) than in patients with cirrhosis (91.7 and 88.9%, respectively). The most common adverse events were fatigue, headache, insomnia, and anemia. No treatment-related serious adverse events or death were reported in the studied groups. Treatment with SOF (400 mg) plus DCV (60 mg), with or without RBV (800–1000 mg) for 12 or 24 weeks, was effective and well tolerated in chronic hepatitis C genotype 4 patients. SVR rates were higher for patients with no cirrhosis. Addition of RBV has benefit only in treatment-experienced group receiving 24 weeks.

Metabolic effects of reduced growth hormone action in fatty liver disease.

Abstract: Adult growth hormone (GH) deficiency is associated with fatty liver disease and shows several features of the metabolic syndrome Vice versa obesity is characterized as a state of low GH function Here, we aimed to define the role of hepatic GH signaling and its metabolic consequences in non-alcoholic fatty liver disease In humans, GHR and IGF-1 levels were determined in liver samples of 29 obese patients with non-alcoholic steatohepatitis (NASH) or simple steatosis Cellular effects of GH on insulin signaling were investigated in GH receptor (GHR) knockdown HepG2 cells Hepatic IGF-1 expression levels reflecting GH action were significantly lower and fasting glucose concentrations higher in patients with NASH than in patients with simple steatosis GHR knockdown in hepatocytes resulted in a scenario of high glucose output displayed by reduced glycogen content, increased gluconeogenesis and diminished insulin signaling Our data suggest that GH signaling in the liver is diminished in patients with NASH and associated with deteriorated hepatic insulin sensitivity and metabolic activity Reduced hepatic GH action might contribute to insulin resistance in obese patients with NASH

Linking the gut and liver: crosstalk between regulatory T cells and mucosa-associated invariant T cells

Abstract: The gut–liver axis is increasingly considered to play a vital part in the progression of chronic inflammatory gut and liver diseases. Hence, a detailed understanding of the local and systemic regulatory mechanisms is crucial to develop novel therapeutic approaches. In this review, we discuss in-depth the roles of regulatory T cells (Tregs) and mucosal-associated invariant T cells (MAITs) within the context of inflammatory bowel disease, primary sclerosing cholangitis, and non-alcoholic steatohepatitis. Tregs are crucial in maintaining peripheral tolerance and preventing autoimmunity. MAIT cells have a unique ability to rapidly recognize microbial metabolites and mount a local immune response and act as a ‘biliary firewall’ at the gut and biliary epithelial barrier. We also outline how current knowledge can be exploited to develop novel therapies to control the propagation of chronic gut- and liver-related inflammatory and autoimmune conditions. We specifically focus on the nature of the Tregs’ cell therapy product and outline an adjunctive role for low-dose IL-2. All in all, it is clear that translational immunology is at crucial crossroads. The success of ongoing clinical trials in cellular therapies for inflammatory gut and liver conditions could revolutionize the treatment of these conditions and the lives of our patients in the coming years.

Glecaprevir/pibrentasvir expands reach while reducing cost and duration of hepatitis C virus therapy.

Abstract: Hepatitis C virus (HCV) treatments have dramatically progressed from poorly tolerated, moderately successful interferon-based therapies to highly effective all-oral interferon-free regimens. While sustained virologic responses have significantly improved with fixed-dose combinations (FDC) of these direct-acting antivirals (DAA), cost remains high and certain populations of patients remain difficult to treat. Glecaprevir (GLE, an NS3/4A protease inhibitor) and pibrentasvir (PIB, NS5A inhibitor) were recently approved as a FDC therapy for HCV, and have expanded reach, reduced cost, and in certain populations, reduced HCV treatment duration. GLE/PIB is effective across all genotypes, and has been shown to be effective in HIV-infected patients, patients with chronic kidney disease, and Child–Pugh A-compensated cirrhosis. GLE/PIB is also effective for a shortened duration of 8 weeks in treatment-naive non-cirrhotic patients.

Liver cirrhosis and cancer: comparison of mortality

Abstract: Liver cirrhosis is known to have low survival rate, and its assessment in relation with other fatal diseases will help us design appropriate health interventions. This study compares the mortality of liver cirrhosis with that of five major cancers (lung, colorectal, stomach, liver, and breast cancers). We used the National Health Insurance Service–National Sample Cohort (NHIS–NSC) which provides data for 1,025,340 representative samples of the 46,605,433 people in Korea from 2002 to 2010. During the 8 years, 800 out of 2609 liver cirrhosis patients died and 1316 out of 4852 patients with the five major cancers died. When we estimated the mortality between liver cirrhosis and five major cancers, the relative mortality for liver cirrhosis was greater [hazard ratio 1.47 (95% CI 1.28–1.67) after age, gender, area of residence, type of insurance, insurance premium level (proxy for income level), and comorbidities were adjusted for]. When a sensitivity analysis was performed by excluding patients with both liver cirrhosis and one of the five cancers, the relative mortality was still greater for liver cirrhosis [hazard ratio 1.27 (95% CI 1.10–1.47)]. Furthermore, when we limited liver cirrhosis patients to those with decompensated liver cirrhosis, the relative mortality of decompensated liver cirrhosis was even greater than that of the five cancers [hazard ratio 1.82 (95% CI 1.51–2.20)]. The mortality of liver cirrhosis is greater than that of the five major cancers. This implies the need to prioritize appropriate health interventions for liver cirrhosis.