Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 prevents CCl-induced liver cirrhosis by protecting the intestinal barrier in rats.
Shi Ding,Lv Longxian,Fang Daiqiong,Wu Wenrui,Hu Chenxia,Xu Lichen,Chen Yanfei,Guo Jing,Hu Xinjun,Li Ang,Guo Feifei,Ye Jianzhong,Li Yating,Andayani Dewi,Li Lanjuan
Alterations in the gut microbiome have been reported in liver cirrhosis, and probiotic interventions are considered a potential treatment strategy. This study aimed to evaluate the effects and mechanisms of Lactobacillus salivarius LI01, Pediococcus pentosaceus LI05, Lactobacillus rhamnosus GG, Clostridium butyricum MIYAIRI and Bacillus licheniformis Zhengchangsheng on CCl-induced cirrhotic rats. Only administration of LI01 or LI05 prevented liver fibrosis and down-regulated the hepatic expression of profibrogenic genes. Serum endotoxins, bacterial translocations (BTs), and destruction of intestinal mucosal ultrastructure were reduced in rats treated with LI01 or LI05, indicating maintenance of the gut barrier as a mechanism; this was further confirmed by the reduction of not only hepatic inflammatory cytokines, such as TNF-α, IL-6, and IL-17A, but also hepatic TLR2, TLR4, TLR5 and TLR9. Metagenomic sequencing of 16S rRNA gene showed an increase in potential beneficial bacteria, such as Elusimicrobium and Prevotella, and a decrease in pathogenic bacteria, such as Escherichia. These alterations in gut microbiome were correlated with profibrogenic genes, gut barrier markers and inflammatory cytokines. In conclusion, L. salivarius LI01 and P. pentosaceus LI05 attenuated liver fibrosis by protecting the intestinal barrier and promoting microbiome health. These results suggest novel strategies for the prevention of liver cirrhosis.
Propranolol prevents liver cirrhosis by inhibiting hepatic stellate cell activation mediated by the PDGFR/Akt pathway.
Ding Qian,Li Zhen,Liu Bin,Ling Liping,Tian Xiangguo,Zhang Chunqing
Propranolol is known to reduce portal pressure by decreasing blood flow to the splanchnic circulation and the liver. However, it is unknown if propranolol improves fibrogenesis and sinusoidal remodeling in the cirrhotic liver. The aim of this study was to investigate the therapeutic effects of propranolol on carbon tetrachloride (CCl)-induced liver fibrosis in a mouse model and the intrinsic mechanisms underlying those effects. In this study, a hepatic cirrhosis mouse model was induced by CCl administration for 6 weeks. Propranolol was simultaneously administered orally in the experimental group. Liver tissue and blood samples were collected for histological and molecular analyses. LX-2 cells induced by platelet-derived growth factor-BB (PDGF-BB) were used to evaluate the anti-fibrogenic effect of propranolol in vitro. The results showed that treatment of mice with CCl induced hepatic fibrosis, as evidenced by inflammatory cell infiltration, collagen deposition and abnormal vascular formation in the liver tissue. All these changes were significantly attenuated by propranolol treatment. Furthermore, we also found that propranolol inhibited PDGF-BB-induced hepatic stellate cell migration, fibrogenesis, and PDGFR/Akt phosphorylation. Taken together, propranolol might prevent CCl-induced liver injury and fibrosis at least partially through inhibiting the PDGF-BB-induced PDGFR/Akt pathway. The anti-fibrogenic effect of propranolol may support its status as a first-line treatment in patients with chronic liver disease.
The antifibrogenic effect of etanercept on development of liver cirrhosis induced by thioacetamide in rats.
Abdul-Hamid Manal,Ahmed Rasha R,Moustafa Nadia,Nady Rehab
Liver cirrhosis is an elevating cause of morbidity and mortality worldwide. TNF-α/TNF-R1 signal is implicated in progression of many liver diseases. This study provides histological and ultrastructural view that clarifies the effect of etanercept, a TNF-α inhibitor, on development of thioacetamide (TAA)-induced liver cirrhosis and the accompanied hemosiderosis in rats, highlighting the implication and distribution pattern of hepatic TNF-R1. Sixty male albino rats (Rattus norvegicus) were equally randomized into three groups. Group I served as the control. Liver cirrhosis was triggered in the other two groups by intraperitoneal injection of TAA twice a week for five months. Group II received TAA only, while group III subcutaneously injected with etanercept one hour before TAA, along five months. At the end of the experiment, blood was collected for biochemical analysis and livers were excised for histological, immunohistochemical, and electron microscopical preparations. Rats treated with TAA only developed hepatic cirrhosis accompanied by massive deposition of hemosiderin; strong and widespread expression of hepatic TNF-R1 in sinusoidal endothelial cells (SECs), Kupffer cells (KCs), and many hepatocytes; and frequent appearance of fibrogenic, plasma, and mast cells, at the ultrastructural level. By contrast, administration of etanercept diminished the expression of TNF-R1, attenuated the accumulation of collagen and hemosiderin, and preserved the hepatic histoarchitecture. In conclusion, TNF-α signal via TNF-R1 may be implicated in the mechanism of fibrogenesis and the associated hemosiderosis. Etanercept may provide a promising therapeutic approach not only for attenuating the progression of fibrogenesis, but also for hepatic iron overload-associated disorders.
Hepatitis C-related liver cirrhosis - strategies for the prevention of hepatic decompensation, hepatocarcinogenesis, and mortality.
Toshikuni Nobuyuki,Arisawa Tomiyasu,Tsutsumi Mikihiro
World journal of gastroenterology
Liver cirrhosis (LC) is a critical stage of chronic liver disease, including that caused by hepatitis C virus (HCV). In the absence of antiviral therapy, 67%-91% of patients with HCV-related LC patients die of liver-related causes, including hepatocellular carcinoma (HCC) and liver failure. Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin, which induces a sustained virological response (SVR) in 25% of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3. SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation, HCC, and mortality. More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy, with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50% of patients with HCV genotype 1 LC. Branched-chain amino acid supplementation, improvement of insulin resistance, and the use of β-blockers for portal hypertension may also reduce liver-related complications. Here, we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.
CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis.
Ehling Josef,Bartneck Matthias,Wei Xiao,Gremse Felix,Fech Viktor,Möckel Diana,Baeck Christer,Hittatiya Kanishka,Eulberg Dirk,Luedde Tom,Kiessling Fabian,Trautwein Christian,Lammers Twan,Tacke Frank
OBJECTIVES:In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesised that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis. DESIGN:Angiogenesis in livers of c57BL/6 mice upon carbon tetrachloride- or bile duct ligation-induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro computed tomography (µCT) and ex vivo anatomical µCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36. RESULTS:Contrast-enhanced in vivo µCT imaging allowed non-invasive monitoring of the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, colocalised with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including upregulated VEGF and MMP9. Functional in vivo and anatomical ex vivo µCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis. CONCLUSIONS:Inflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo µCT methodology can accurately monitor angiogenesis and antiangiogenic therapy effects in experimental liver fibrosis.
[Acting mechanism of Cordyceps mycelia extract for antagonizing hepatic sinusoidal capillarization in rats with dimethylnitrosamine induced liver cirrhosis].
Wang Xian-Bo,Liu Ping,Tang Zhi-Peng
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine
OBJECTIVE:To study the acting mechanism of Cordyceps mycelia extract (CME) for antagonizing hepatic sinusoidal capillarization (HSC) in rats with dimethylnitrosamine (DMN) induced liver cirrhosis. METHODS:Rat liver cirrhosis model was established by peritoneal injection of DMN 10 mg/kg 3 times a week for 4 weeks. To rats in the CME-prevented group CME were administrated at a dose of 10 mL/kg, once a day, for 4 weeks. The observation time points were scheduled on the 3rd day (d3), and at the end of the 2nd (W2) and 4th week (W4) after modeling, and the following items were observed: hepatic ultrastructure was observed under electron microscope; expressions of CD44, von Willebrand factor (vWF) and type IV collagen (Col lV) in the liver sinusoidal walls by immunohistochemistry; matrix metalloproteinase-2 and-9 (MMP-2, MMP-9) activity under zymogram method; and serum hyaluronic acid (HA) content by radioimmunoassay. RESULTS:Observation at d3 showed MMP-2 and MMP-9 activity significantly increased, Col IV deposition and CD44 positive staining decreased, vWF positive staining increased in the liver sinusoidal walls, the fenestrae in the sinusoidal endothelial cells (SECs) decreased, and serum HA content increased (P<0.05); at W4, SECs defenestration and sub-SECs basal membrane formation were shown. In the CME-prevented group MMP-2 and MMP-9 activity significantly decreased (P<0.05); defenestration and basal membrane formation alleviated in the early stage (d3, W4); and at W2 and W4 decreases of HA content and vWF positive staining were shown, with increase of CD44 positive staining (P<0.05), more SECs fenestrae, and alleviated basal membrane formation. CONCLUSIONS:The elevation of MMP-2 and MMP-9 activity in the early stage, which degrades the Col IV normally distributed under the sinusoidal endothelium, is an important factor for HSC formation. CME could inhibit the initiation of HSC by decreasing MMP-2 and MMP-9 activity in the early stage, and prevent its formation by decreasing SECs injury and phenotypic changes.
Proline supplementation mitigates the early stage of liver injury in bile duct ligated rats.
Heidari Reza,Mohammadi Hamidreza,Ghanbarinejad Vahid,Ahmadi Asrin,Ommati Mohammad Mehdi,Niknahad Hossein,Jamshidzadeh Akram,Azarpira Negar,Abdoli Narges
Journal of basic and clinical physiology and pharmacology
Background Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences.
Prevention of hepatocellular carcinoma in nonviral-related liver diseases.
Fan Jian-Gao,Farrell Geoffrey C,
Journal of gastroenterology and hepatology
Although chronic infection with hepatitis B virus and/or hepatitis C virus are the most important risk factors for hepatocellular carcinoma (HCC) worldwide, other causes of cirrhosis can also lead to HCC. Given the high prevalence of alcoholism and the worldwide obesity epidemic, the relevant importance of nonviral liver disease-related HCC is expected to increase in the future. Some evidence supports mechanistic interactions between host or environmental factors and chronic viral hepatitis in the development of HCC. For example, food- and water-borne carcinogens have contributed to unusually high rates of HCC in parts of China and sub-Saharan Africa. With some of these conditions, appropriate public health measures to reduce the population's exposure to known etiologic agents, or early therapeutic intervention for 'at-risk' individuals before development of cirrhosis (e.g. hereditary hemochromatosis) can prevent HCC. Community-based programs to discourage and deal with excessive alcohol intake, to promote tobacco smoking awareness, to avoid exposure to aflatoxin and other food toxins, and measures to reduce the pandemic of obesity and diabetes are vital for effective interruption of the rising tide of HCC from nonviral liver disease.
Prevention of Liver Cancer Through the Early Detection of Risk-related Behavior Among Hepatitis B or C Carriers.
Fan Jun-Yu,Huang Tung-Jung,Jane Sui-Whi,Chen Mei-Yen
BACKGROUND:Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the leading causes of liver cirrhosis and hepatocellular carcinoma. Little is known about the relationship between health-related behaviors and health status among HBV or HCV carriers. OBJECTIVE:The purpose of this study was to explore the relationship between health status (eg, specific biomarkers) and health-related behaviors (eg, alcohol consumption) in individuals with or without HBV or HCV infection. METHODS:A cross-sectional descriptive design was used, and a community-based health screening survey was conducted between August 2011 and July 2012 in Taiwan. RESULTS:In total, 6 805 community residents 20 years or older participated in the study. The HBV and HCV infection rate was 18.7% and 20.8%, respectively, and HBV/HCV infections were significantly associated with current alcohol use, smoking, and self-medication. Multivariate analysis indicated that HBV/HCV infection, overweight status, higher fasting blood sugar level, higher systolic blood pressure, and 3 unhealthy habits were independent risk factors for abnormal liver function. CONCLUSION:Our findings suggest that both HBV and HCV carriers are more likely to have unhealthy habits and a poor health status. In addition to some factors that cannot be modified, being overweight, drinking alcohol, betel nut chewing, smoking, and self-medication are all risk factors for poor liver health among both hepatitis carriers. IMPLICATIONS FOR PRACTICE:For clinicians, the results could be applied by providing more education to help the community better understand the relationships between specific risk factors and liver health, encouraging hepatitis carriers in rural areas to undergo annual physical check-ups.
Chinese guidelines on management of hepatic encephalopathy in cirrhosis.
Xu Xiao-Yuan,Ding Hui-Guo,Li Wen-Gang,Jia Ji-Dong,Wei Lai,Duan Zhong-Ping,Liu Yu-Lan,Ling-Hu En-Qiang,Zhuang Hui,Hepatology Chinese Society Of,Association Chinese Medical
World journal of gastroenterology
The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy (HE) including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.
Cancer prevention and control: hepatocellular carcinoma.
Hainaut Pierre,Amadou Amina,Gormally Emmanuelle
Liver cancer (mostly hepatocellular carcinoma, HCC) is both common and highly lethal throughout Africa, in particular in western and middle Africa where HCC is the first cause of cancer death in men and the third in women. In these high-incidence areas, HCC develops mostly early (<50 years), with an aggressive clinical course and frequently without prior diagnosis of liver cirrhosis. The dynamics of African populations predict that the burden of liver cancers will be multiplied by three to four in the next decades unless effective prevention and therapy is achieved. This article outlines a path for significantly curbing the mortality of liver cancer in Africa by combining primary prevention, improved early detection and introduction of innovative and appropriate management strategies.
Risk factors and outcome of bacterial infections in cirrhosis.
Bruns Tony,Zimmermann Henning W,Stallmach Andreas
World journal of gastroenterology
Viable and non-viable pathological bacterial translocation promote a self-perpetuating circle of dysfunctional immune activation and systemic inflammation facilitating infections and organ failure in advanced cirrhosis. Bacterial infections and sepsis are now recognized as a distinct stage in the natural progression of chronic liver disease as they accelerate organ failure and contribute to the high mortality observed in decompensated cirrhosis. The increasing knowledge of structural, immunological and hemodynamic pathophysiology in advanced cirrhosis has not yet translated into significantly improved outcomes of bacterial infections over the last decades. Therefore, early identification of patients at the highest risk for developing infections and infection-related complications is required to tailor the currently available measures of surveillance, prophylaxis and therapy to the patients in need in order to improve the detrimental outcome of bacterial infections in cirrhosis.
Interferon reduces the risk of hepatocellular carcinoma in hepatitis C virus-related chronic hepatitis/liver cirrhosis.
Masuzaki Ryota,Yoshida Haruhiko,Omata Masao
The efficacy of interferon therapy against hepatitis C virus (HCV) has much improved, showing a sustained virologic response rate of 40-50% even in the genotype 1b with a high viral load. Several cohort studies conducted in Japan in the 1990s unanimously concluded that the risk of hepatocellular carcinoma (HCC) development was reduced in patients who achieved a sustained virologic response or persistent normalization of alanine aminotransferase as compared to untreated patients. Recently, a large-scale randomized controlled trial, called the HALT-C study, showed no significant difference in the incidence of HCC between patients on maintenance interferon therapy and those without. The reason for the discrepant results in Japanese and USA studies needs further clarification, together with analysis of the difference in incidence rates of HCC among cirrhotic patients. There has also been progress in the treatment of HCC, and together with advances in diagnostics facilitating HCC detection at an early stage, tumor nodules can often be completely removed either by medical ablation or surgical resection. Nevertheless, recurrence of HCC after apparently curative treatment is extraordinarily frequent, since the remaining liver is still at a high risk of HCC. The prevention of the recurrence of HCC, or tertiary prevention, is currently one of the most challenging tasks in hepatology.
The Role of the Nurse Practitioner in the Management of Nonalcoholic Fatty Liver Disease.
Hearn Chelsea,Ellington Betty J,Jones Roberta
Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates
The incidence of nonalcoholic fatty liver disease (NAFLD) has increased over the past few decades because of the obesity epidemic and is also strongly associated with diabetes Type 2. Patients often present asymptomatically until the liver disease becomes advanced. Alternatively, persons with NAFLD can present with various stages of inflammation, hepatosis, or fibrosis, which can eventually result in cirrhosis and lead to hepatocellular carcinoma. Lifestyle modifications are the most important aspects of cirrhosis prevention. These changes are crucial because cirrhosis is a known cause of long-term liver disease. Nurse practitioners play an important role in the early detection of NAFLD and prevention of its potentially life-threatening complications.
[Current problems in the prevention and treatment of infections in patients with cirrhosis].
Bellot Pablo,Jara Pérez López Neftalí,Martínez Moreno Belén,Such José
Gastroenterologia y hepatologia
Infections in patients with cirrhosis are a common complication causing substantial morbidity and mortality. Bacterial translocation plays an important role in the pathogenesis of many infections in cirrhosis. In turn, infections are involved in the pathogenesis of many episodes of decompensated cirrhosis, such as esophageal variceal bleeding, renal insufficiency, the hemodynamic alterations of cirrhosis, and hepatic encephalopathy. Spontaneous bacterial peritonitis is currently the most frequent infection in cirrhosis. Mortality from this entity has recently decreased due to early diagnosis, the use of appropriate antibiotic therapy, and albumin administration. However, infections due to multiresistant microorganisms have recently increased, leading to greater mortality. Primary prophylaxis with quinolones is effective in preventing infections and is associated with lower mortality in a selected population of patients with liver cirrhosis.
Reasons to consider early treatment in chronic hepatitis B patients.
Koffas Apostolos,Petersen Jörg,Kennedy Patrick T
In spite of a decrease in the prevalence and incidence seen in recent years, chronic hepatitis B (CHB) still remains a major healthcare challenge, prevalent mostly in developing but also in developed regions. CHB is associated with significant morbidity and mortality, secondary to the complications of disease progression; cirrhosis and hepatocellular carcinoma (HCC). Historically, antiviral treatment has been restricted to patients with active hepatitis, established liver disease, fibrosis or cirrhosis and/or the risk of HCC development. As a result, patients with hepatitis B 'e' antigen (HBeAg) -positive chronic infection, formerly referred to as the 'immune tolerant' disease phase, have been excluded from treatment, since immune tolerant CHB had been considered 'benign' with no ostensible progressive liver disease. However, recent advances in 'decoding' the immunopathogenesis of CHB challenged the accuracy of this classical perception: it is now well-recognised that HBeAg-positive chronic infection is not characterized by immunological tolerance and that events associated with tumourigenesis are already present during this early disease phase. These findings have led to a paradigm shift: in 2017, the European Association for the Study of the Liver (EASL) recommended a change in the nomenclature and clinical categorisation of CHB and proposed lowering the threshold for antiviral treatment to include patients with HBeAg-positive chronic infection. It is anticipated that this could delay or even prevent disease progression and the development of HCC, alongside the potential to achieve functional cure (hepatitis B 'surface' antigen loss with or without development of hepatitis B 'surface' antibody). The current article reviews relevant literature and discusses the reasons for considering early treatment in CHB.
Quality of Care Provided by Hepatologists to Patients with Cirrhosis at Three Parallel Health Systems.
Sclair Seth N,Carrasquillo Olveen,Czul Frank,Trivella Juan P,Li Hua,Jeffers Lennox,Martin Paul
Digestive diseases and sciences
BACKGROUND:Evidence-based guidelines and quality indicators for cirrhosis care have been established. Whether there are variations in adherence to these cirrhosis standards at different specialty settings has not been investigated. AIMS:To evaluate the quality of cirrhosis care delivered at diverse hepatology care sites. METHODS:We conducted a retrospective study comparing the quality of care at three hepatology specialty clinics: a Faculty Practice, safety-net hospital, and Veterans Affairs (VA) Medical Center. Consecutive patients with cirrhosis (85 Faculty Practice, 81 safety-net, and 76 VA) between 2010 and 2011 were included. Median follow-up was 2.3 years. Outcome measures were the adherence to six cirrhosis-specific quality-of-care indicators. RESULTS:Adherence to hepatitis A and B vaccinations was highest at the safety-net hospital, 81 and 74 %, compared to 46 and 30 % at the Faculty Practice (P < .001). Adherence to yearly hepatocellular carcinoma surveillance was highest at the safety-net site (79 %) versus the VA (50 %) and Faculty Practice (42 %), P = .001. In contrast, screening rates for esophageal varices were 75 % at the Faculty Practice and only 58 and 43 % at the VA and safety-net sites, respectively (P < .001). Liver transplant discussions were documented most consistently at the Faculty Practice (82 %) compared to the safety-net site (53 %) and VA (54 %), P < .001. CONCLUSIONS:Disparities in cirrhosis quality measures existed by site. Strategies to overcome these disparities need to be developed to improve the delivery of quality cirrhosis care as we face a rise in cirrhosis-related complications over the next two decades.
Sepsis in Patients With Cirrhosis Awaiting Liver Transplantation: New Trends and Management.
Martin Mateos Rosa,Albillos Agustín
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
Bacterial infections are more frequent and severe in patients with advanced liver disease and, therefore, in liver transplant candidates. The increased risk of infection in these patients parallels the severity of the immune dysfunction associated with cirrhosis, which is related to systemic inflammation and progressive immunodeficiency. Other factors contribute to this risk, such as genetic polymorphisms, proton pump inhibitor overuse, the numerous invasive procedures and hospitalizations these patients go through, or the immunosuppressive effects of malnutrition or alcohol abuse. Bacterial infections have a great impact on disease progression and significantly increase mortality rates before and after liver transplantation. Mechanisms leading to organ failure in sepsis are associated not only with the hemodynamic derangement but also with an excessive inflammatory response triggered by infection. Furthermore, prophylactic and empirical antibiotic treatment strategies in patients with cirrhosis are being modified according to the growing prevalence of multidrug-resistant bacteria in the past decade. Also, new criteria have been introduced for the diagnosis of sepsis and septic shock. These new definitions have been validated in patients with cirrhosis and show a better accuracy to predict in-hospital mortality than previous criteria based on systemic inflammatory response syndrome. Accurate prophylaxis and early identification and treatment of bacterial infections are key to reducing the burden of sepsis in patients with cirrhosis awaiting liver transplantation.
Current and future pharmacological therapies for managing cirrhosis and its complications.
Kockerling David,Nathwani Rooshi,Forlano Roberta,Manousou Pinelopi,Mullish Benjamin H,Dhar Ameet
World journal of gastroenterology
Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis, and may impede hepatic fibrogenesis and decompensation. Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management, nutritional optimisation and patient education.
Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis.
Ma Wen-Lung,Lai Hsueh-Chou,Yeh Shuyuan,Cai Xiujun,Chang Chawnshang
Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of noncancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or hepatitis B virus-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC.
The etiology, diagnosis and prevention of liver cirrhosis: part 1 of a series on liver cirrhosis.
Wiegand Johannes,Berg Thomas
Deutsches Arzteblatt international
BACKGROUND:Cirrhosis of the liver is the end stage of chronic liver disease. Among the many liver disorders that can lead to cirrhosis, some progress rapidly (years) and others more slowly (decades). In Germany, cirrhosis is often a consequence of fatty liver disease due to alcoholism or other causes, but can also be caused by hepatitis B and hepatitis C. Cirrhosis is more common in overweight persons and smokers. The underlying causes of cirrhosis determine its rate of progression and are the focus of preventive efforts and treatment. The prevalence of cirrhosis in Germany is rising; it now ranks among the top 20 causes of death in the country. METHODS:This article is based on a selective review of pertinent literature, including reviews and current guidelines. RESULTS:Strictly speaking, cirrhosis is a pathological diagnosis; it is, nevertheless, usually diagnosed clinically, by history, physical examination (e.g., cutaneous signs of liver disease), ancillary testing (e.g., ultrasonography, transient elastography) and laboratory analyses (e,g., APRI, which is the quotient of the GOT concentration and the platelet count). There are no laboratory cutoff values for the diagnosis of cirrhosis. Early detection of chronic liver disease, followed by individually tailored, risk-adapted treatment, is the best way to prevent it. Esophagogastroduodenoscopy can be performed early on to assess the risk of variceal bleeding. In most patients, the progression of fibrosis can be averted by early detection and appropriate treatment. CONCLUSION:Screening for chronic liver disease should include history and physical examination, serum transaminase measurement, upper abdominal ultrasonography, and, in some cases, transient elastography.
[Risk factors for the development of liver cancer in patients with hepatitis B-related liver cirrhosis treated with long-term nucleos(t)ide analogues].
Zang W W,Su M H,Ling X Z,Wang R M,Cao B C,Wu Y L,Deng D L,Wei H L,Liang X S,Jiang J N
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
To retrospectively analyze the risk factors for the development of liver cancer in patients with hepatitis B-related liver cirrhosis (LC) treated and fully managed with long-term nucleos(t)ide analogues (NAs). The study subjects were derived from the follow-up cohort of chronic hepatitis B and liver cirrhosis who received antiviral therapy in the Department of Infectious Diseases of the First Affiliated Hospital of Guangxi Medical University from February 2004 to September 2019. LC patients who met the inclusion criteria were enrolled. The life-table method was used to calculate the incidence of liver cancer. Multivariable Cox regression model was used to analyze the risk factors that may affect the development of liver cancer in patients with LC. A subgroup analysis was conducted in liver cirrhotic patients who developed liver cancer to evaluate the effectiveness of antiviral treatment compliance. The (2) test was used for rate comparison. The median follow-up time of 198 LC cases treated with NAs was 6.0 years (1.0-15.3 years). By the end of the visit: (1) 16.2% (32/198) of LC patients had developed liver cancer, and the cumulative incidence of liver cancer in 1, 3, 5, 7, and 9 years were 0, 8.9%, 14.3%, 18.6%, and 23.4%, respectively, with an average annual incidence of 3.1%. Among the 32 cases with liver cancer, 68.7% had developed small liver cancer (22/32). (2) Univariate Cox model analysis showed that the development of liver cancer was related to four factors, i.e., the presence or absence of LC nodules, whether the baseline was first-line medication, the family history of liver cancer, and patient compliance. The results of multivariate Cox model analysis showed that poor patient compliance and baseline non-first-line medication were risk factors for liver cancer. (3) The results of log-rank test subgroup analysis showed that the 5-year cumulative incidence of liver cancer in patients with hardened nodules was significantly higher than that of patients without hardened nodules (21.7% vs. 11.5%, = 0.029). The 5-year cumulative incidence of liver cancer in patients with non-first-line drugs was significantly higher than that of patients with first-line drugs (22.0% vs.8.2%, = 0.003). The 5-year cumulative incidence of liver cancer in patients with poor compliance was significantly higher than that of patients with good compliance (21.3% vs. 12.7%, = 0.014). The 5-year cumulative incidence of liver cancer in patients with a family history of liver cancer was significantly higher than that of patients without a family history of liver cancer (22.3% vs. 8.1%, = 0.006). (4) Compared with patients with poor compliance, patients with good compliance had higher HBV DNA negative serconversion rate (98.7% vs. 87.8%, = 0.005), and a lower virological breakthrough rate (12.1% vs. 29.3%, = 0.007). The long-term NAs antiviral therapy can reduce the risk of liver cancer, but it cannot completely prevent the development of liver cancer, especially in patients with a family history of liver cancer and baseline hardened nodules (high risk of liver cancer). Furthermore, the complete management can improve patient compliance, ensure the efficacy of antiviral therapy, and reduce the risk of liver cancer development, so to achieve secondary prevention of liver cancer, i.e., early detection, diagnosis and treatment.
[Management of compensated liver cirrhosis 2018 - Evidence based prophylactic measures].
Karkmann Kathrin,Piecha Felix,Rünzi Anna Caterina,Schulz Lisa,von Wulffen Moritz,Benten Daniel,Kluwe Johannes,Wege Henning
Zeitschrift fur Gastroenterologie
In 2015, more than 13 000 people died due to the consequences of liver cirrhosis in Germany. Frequently, relevant liver fibrosis is diagnosed by non-invasive methods (e. g., ultrasound-based measurement of liver stiffness) already in the compensated stage. Following diagnosis of liver fibrosis, a thorough investigation of the underlying chronic liver disease and effective treatment are important to prevent progression to decompensated cirrhosis. Since morbidity and mortality dramatically increase in the decompensated stage (patients may present with jaundice, ascites, hepatic encephalopathy, gastrointestinal bleeding) with an upsurge in 1-year-mortality from 1 - 3.4 % to 20 - 57 %, prophylactic measures to prevent decompensation are indicated. Based on a risk stratification, these measures include propranolol or carvedilol as non-selective betablockers, as well as endoscopic band ligations as primary prophylaxis to prevent variceal bleeding. Because of the high risk for malignant transformation (2 - 8 % per year depending on the underlying etiology), surveillance by liver ultrasound every six months is essential to detect liver cancer in an early stage and to facilitate curative therapy. Currently under debate is the administration of antibiotics to prevent bacterial infections, which commonly trigger acute decompensation. To this regard, studies are not convincing and the risk to induce drug resistance has to be observed. However, health care providers should check the vaccination status and recommend missing vaccinations. The management of compensated liver cirrhosis also includes counseling and potentially also a drug therapy to prevent osteoporosis and muscle wasting. In this review, we will discuss specific prophylactic measures in the management of compensated liver cirrhosis based on the pathophysiological background and central clinical studies. If a patient decompensates despite these prophylactic measures (approximately 15 % of patients with liver cirrhosis per year), liver transplantation has to be discussed as definitive therapy (especially in patients with MELD > 15).
[Clinical effect of low-molecular-weight heparin in prevention and treatment of liver cirrhosis and portal vein thrombosis after splenectomy: a systematic review and meta-analysis].
Zhang W,Zhou D M,Li Y
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
To investigate the clinical effect of low-molecular-weight heparin (LMWH) in the treatment of liver cirrhosis and portal vein thrombosis and the value of early application of LMWH in the prevention of portal vein thrombosis after splenectomy. The databases of PubMed, Google Scholar, CNKI, Wanfang Data, and VIP were searched, and manual searching and internet searching were used to retrieve grey literature. The articles which met the inclusion criteria were included, and a systematic review and meta-analysis was performed. A total of 12 randomized controlled trials were included, with 1397 patients enrolled, among whom 723 were enrolled in the LMWH group and 674 were enrolled in the control group. A meta-analysis was performed for the trials above, and the results showed that the patients with early application of LMWH had a lower rate of thrombosis compared with those in the control group ( = 0.37, 95% 0.28-0.48, < 0.001). The results of three randomized trials with the application of LMWH in the treatment of portal vein embolism showed that the patients treated with LMWH had a higher rate of recanalization of thrombus than those in the control group ( = 5.08, 95% 1.74-14.84, < 0.001). Early application of LMWH can reduce the rate of portal vein thrombosis after splenectomy, and LMWH for the treatment of portal vein embolism can increase the rate of recanalization of thrombus.
Treatment of Oesophageal Varices in Liver Cirrhosis.
Sauerbruch Tilman,Wong Florence
BACKGROUND:The development of cirrhosis with resultant portal hypertension can lead to oesophageal varices at a rate of 7% per annum. Bleeding from varices happens when the portal pressure is ≥12 mm Hg and can threaten life. SUMMARY:Eliminating the aetiology of cirrhosis is a pivotal step to prevent the formation of varices. In patients with established varices, primary prophylaxis with non-selective beta blockers (NSBB) may slow down the progression of varices and prevent the first variceal bleed. NSBB, similar to other agents such as renin/angiotensin blockers, statins, and rifaximin, may have the additional advantage of blunting inflammatory stimuli, which can contribute to the progression of varices. Variceal band ligation is an alternative for primary bleeding prophylaxis with excellent results. Any acute variceal bleed should be managed with band ligation after careful resuscitation. Early pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) in decompensated cirrhotic patients is very effective in controlling the bleeding and improves survival. Secondary prophylaxis against further variceal bleeding using NSBB and band ligation is recommended in most other patients. TIPS may be considered in appropriate patients as a secondary prophylaxis against recurrent variceal bleed. Future research should be directed towards the prevention of varices and targeting inflammation to reduce cirrhotic complications. Key Messages: Treatment strategies depend on the stage the patient is at along the natural history of varices: NSBB or band ligation for primary prophylaxis; band ligation or early TIPS for acute bleed; and a combination of NSBB + band ligation or TIPS for secondary prophylaxis (Fig. <xref ref-type="fig" rid="f01">1</xref>).
[Current status and perspectives of diagnosis and treatment of complications related to liver cirrhosis].
Nan Y M
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
Liver cirrhosis is the severe period of chronic liver diseases, especially decompensated liver cirrhosis and its complications, such as ascites, esophagogastric variceal bleeding, hepatic encephalopathy, acute kidney injury, and hepatocellular carcinoma, which greatly affect patients' quality of life and even threaten their lives. Early prevention and treatment of the causes of development and progression and pathogenic mechanism may slow down or reverse liver cirrhosis and its severe complications. Once the disease progresses to portal hypertension and related complications, it is very important to select preventive measures for acute exacerbation of different complications, as well as the methods and timing for treatment in acute stage, which may help to save patients' lives and improve their prognosis.
Protective role of melatonin in early-stage and end-stage liver cirrhosis.
Hu Chenxia,Zhao Lingfei,Tao Jingjing,Li Lanjuan
Journal of cellular and molecular medicine
The liver is composed of hepatocytes, cholangiocytes, Kupffer cells, sinusoidal endothelial cells, hepatic stellate cells (HSCs) and dendritic cells; all these functional and interstitial cells contribute to the synthesis and secretion functions of liver tissue. However, various hepatotoxic factors including infection, chemicals, high-fat diet consumption, surgical procedures and genetic mutations, as well as biliary tract diseases such as sclerosing cholangitis and bile duct ligation, ultimately progress into liver cirrhosis after activation of fibrogenesis. Melatonin (MT), a special hormone isolated from the pineal gland, participates in regulating multiple physiological functions including sleep promotion, circadian rhythms and neuroendocrine processes. Current evidence shows that MT protects against liver injury by inhibiting oxidation, inflammation, HSC proliferation and hepatocyte apoptosis, thereby inhibiting the progression of liver cirrhosis. In this review, we summarize the circadian rhythm of liver cirrhosis and its potential mechanisms as well as the therapeutic effects of MT on liver cirrhosis and earlier-stage liver diseases including liver steatosis, nonalcoholic fatty liver disease and liver fibrosis. Given that MT is an antioxidative and anti-inflammatory agent that is effective in eliminating liver injury, it is a potential agent with which to reverse liver cirrhosis in its early stage.
[Research progress and prospect of liver cirrhosis].
Xu J H,Yu Y Y,Xu X Y
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
Liver cirrhosis is the final stage of many chronic liver diseases, and is still a heavy disease burden. The proportion of liver cirrhosis caused by the hepatitis B virus is declining, while that caused by the non-alcoholic fatty liver disease (metabolic-associated fatty liver disease) is rising. Several predictive models and techniques such as transient elastography have been used for the early non-invasive evaluation of liver cirrhosis. Effective etiological treatment and complication management are the possible key to reverse and recompense liver function during liver cirrhosis treatment. In recent years, the effectiveness and availability of anti-hepatitis B and C virus drugs have been significantly improved, which provides the basis for effective etiological treatment of liver cirrhosis. However, there is still a lack of etiological treatment measures for non-alcoholic fatty liver disease. Therefore, in addition to focusing on common complications, we should also manage "rare" complications. This article reviews the changes in epidemiological characteristics, the update of the natural history concepts, diagnostic evaluation methods, and the treatment measures for liver cirrhosis.