Chronic Liver Disease

Introduction Ultrasound (US) has a major role in the diagnosis and manage- ment of chronic liver diseases by providing diagnostic and prognostic information as well as detecting complications such as HCC and portal hypertension. While conventional ultrasound is valuable in the assessment of liver parenchyma and detection of liver lesions, a range of other US techniques has been devel- oped that increases its potential value. Noninvasive methods of measurements in chronic liver disease are rapidly changing in performance capabilities and availability. These include labora- tory tests and imaging studies. An area of intense recent interest has been elastography because of its ability to provide noninva- sive information about the stage of liver fibrosis.

years after bariatric surgery (that is right after the weight loss has reached its peak) the association between the 148M variant and higher transaminases is abolished. Conversely, it is still present in obese subjects whose body weight remained unchanged. We also show that the start of at-risk drinking at an older age increases by two-fold the risk of alcoholic cirrhosis conferred by PNPLA3 148M variant in younger subjects. These first two parts of the thesis show that both environmental (e.g., obesity and alcohol) and genetic (e.g., PNPLA3) factors are risk factors for the onset of chronic liver disease. However, the individual susceptibility to chronic liver disease depends on the interaction between environmental and genetic factors. Since we can more easily modify environmental factors, we should try to reduce or abolish them (e.g., by long- term weigh loss in obese subjects) or to identify, among exposed subjects, those who are at higher risk and should be more followed-up or should benefit more from a specific treatment.

If not corrected, muscle and body fat loss can result in a variety of health complications. A high protein diet is important for people with chronic liver disease as the protein is used to maintain muscles and body tissues (including the liver) and to the keep the body working normally.

MANAGEMENT OF RENAL FAILURE IN CHRONIC LIVER DISEASE: General measures: Cirrhotic patients with acute onset renal dysfunction should be treated aggressively as early interventions can significantly lower the mortality. Precipitating factors like sepsis and blood loss from variceal bleeding due to portal hypertension should be identified and taken care of at the earliest. Third generation cephalosporins are the preferred drugs for the treatment of sepsis in patients with cirrhosis with ascites.

6 INTRODUCTION Chronic liver disease is a pathologically defined entity which is associated with a spectrum of characteristic clinical manifestations. The cardinal pathologic features reflect irreversible chronic injury to the hepatic parenchyma and include extensive fibrosis in association with formation of regenerative nodules. These features result from hepatocyte necrosis, collapse of the supporting reticular network with subsequent connective tissue deposition, distortion of the vascular bed, and nodular regeneration of remaining liver parenchyma most common causes of chronic liver disease in general order of frequency are chronic hepatitis C, alcoholic liver disease, non alcoholic steatohepatitis. Chronic hepatitis B, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis and Wilson‟sdisease. These chronic liver disease ultimately develop cirrhosis.

Orthotopic liver transplantation OLT off ers the best long-term outcome for patients with advanced liver disease. Th e method for allocating liver grafts to patients with advanced liver disease relies on scoring systems, like MELD, which helps to predict survival without transplantation. Th e MELD score incorporates serum creatinine and this carries a high integer weighting which may have a signifi cant impact on the composite score. Consequently, there are two signifi cant problems associated with MELD. First, the prognostication of chronic liver disease itself is somewhat blurred by the emphasis apportioned to kidney dysfunction. Second, the reliance on serum creatinine potentially underestimates prognosis with respect to renal outcomes and overestimates true prognosis with respect to liver outcomes. To address this imbalance, MELD should perhaps incorporate a measure of GFR, either by using a gold standard measure of GFR or cystatin C, to more accurately represent residual kidney function. In recognition of these problems, MELD has been adapted to form the UKELD score, which incorporates the serum sodium concentration, with downward adjustment of the integer weighting for serum creatinine [51]. Consequently, in the UK population, UKELD is a better predictor of survival following listing for liver transplantation [50].

Abstract The development of cirrhosis and portal hypertension in the natural history of chronic liver disease is associ- ated with many complications. A transjugular intrahe- patic portosystemic stent shunt (TIPS) is a metal pros- thesis that has been shown to be very effective in low- ering sinusoidal portal pressure, and therefore is effective in the management of complications of cir- rhosis, especially those related to portal hypertensive bleeding and sodium and water retention. In patients with acute variceal bleeding not responding to phar- macologic and endoscopic treatments, a reduction of the hepatic venous pressure gradient to < 12 mmHg or by > 20% with TIPS has been shown to be effective in controlling the acute bleed and in preventing rebleed- ing. For stable patients whose acute variceal bleed is controlled, TIPS is equal to combined beta-blocker and band ligation in the prevention of recurrent va- riceal bleed. TIPS is also more effective than large vol- ume paracentesis in the control of refractory ascites, and may confer a survival advantage over repeated large volume paracentesis. TIPS has also been used in the management of other complications related to por- tal hypertension including ectopic varices, hepatic hy- drothorax, and hepatorenal syndrome with some suc- cess, but experience is still rather limited. Miscellaneous uses include treatment of Budd Chiari Syndrome, por- tal hypertensive gastropathy and hepatopulmonary syndrome. Careful patient selection is vital to a suc- cessful outcome, as patients with severe liver dysfunc- tion tend to die post-TIPS despite a functioning shunt.

Fax +1 718 547 4773 Email ssigal@montefiore.org Abstract: Thrombocytopenia is the most common hematological abnormality encountered in patients with chronic liver disease (CLD). In addition to being an indicator of advanced disease and poor prognosis, it frequently prevents crucial interventions. Historically, thrombocytopenia has been attributed to hypersplenism, which is the increased pooling of platelets in a spleen enlarged by congestive splenomegaly secondary to portal hypertension. Over the past decade, however, there have been significant advances in the understanding of thrombopoiesis, which, in turn, has led to an improved understanding of thrombocytopenia in cirrhosis. Multiple factors contribute to the development of thrombocytopenia and these can broadly be divided into those that cause decreased production, splenic sequestration, and increased destruction. Depressed thrombopoietin levels in CLD, together with direct bone marrow suppression, result in a reduced rate of platelet production. Thrombopoietin regulates both platelet production and maturation and is impaired in CLD. Bone marrow suppression can be caused by viruses, alcohol, iron overload, and medications. Splenic sequestration results from hypersplenism. The increased rate of platelet destruction in cirrhosis also occurs through a number of pathways: increased shear stress, increased fibrinolysis, bacterial translocation, and infection result in an increased rate of platelet aggregation, while autoimmune disease and raised titers of antiplatelet immunoglobulin result in the immunologic destruction of platelets. An in-depth understanding of the complex pathophysiology of the thrombocytopenia of CLD is crucial when considering treatment strat- egies. This review outlines the recent advances in our understanding of thrombocytopenia in cirrhosis and CLD.

Abstract: It is becoming increasingly clear that quality of life (QOL) is impaired in those with chronic liver disease (CLD). One of the most important contributors to impaired QOL is the symptomatic burden which can range from slight to debilitating. Autonomic dysfunction accounts for a significant proportion of these symptoms, which can be common, non-specific and challenging to treat. Investigating the autonomic nervous system can be straight forward and can assist the clinician to diagnose and treat specific symptoms. Evidence-based treatment options for autonomic symptoms, specifically in CLD, can be lacking and must be extrapolated from other studies and expert opinion. For those with severely impaired quality of life, liver transplantation may offer an improvement; however, more research is needed to confirm this.

diagnose patients with a congenital de ficiency of procoagu- lants, but not to diagnose patients with a congenital de ficien- cy of anticoagulants. The PT is within normal limits in patients with a congenital de ficiency of naturally occurring antico- agulants —antithrombin, protein C, or protein S—a condition where the PT should be shortened because these patients generate greater amounts of thrombin than normal subjects. Prothrombin time displays different sensitivity toward pro- and anticoagulants because upon triggering coagulation in vitro, procoagulants act quickly and limit thrombin genera- tion and fibrin formation (i.e., the PT endpoint), whereas anticoagulants act at a much slower rate. 6 For example, protein C, one of the most powerful anticoagulants, circulates in plasma as a zymogen and is activated in vivo by thrombin in complex with its endothelial receptor thrombomodulin. 7 Neither the reagent nor plasma used to measure the PT contains suf ficient amounts of thrombomodulin. Therefore, protein C that is markedly decreased in chronic liver disease (CLD) cannot be optimally activated within the relatively short time needed for PT execution (few seconds) and cannot exert its full anticoagulant activity as it occurs in vivo.

It acts as a storage depot for Iron, Folic acid & Vitamin B12, secretes clotting factors and inhibitors. Hence it’s not surprising to see a wide range of hematological abnormalities in liver diseases. In chronic liver disease the presence of jaundice, liver cell failure, portal hypertension and hypersplenism, reduced red cell half- life all influence peripheral blood picture 2 . Both Liver cell failure & cholestasis can derange the coagulation system. Dietary deficiencies, bleeding, alcoholism and abnormalities in hepatic synthesis of proteins used for blood formation or coagulation add to the problem liver disease 3 .

Liver dysfunction is frequently accompanied by a hemostatic defect.Bleeding is usually due to an anatomic lesion that is exacerbated by a hemostatic defect. Most patients with chronic liver disease bleed from complications of portal hypertension,esophageal varices, or gastritis and peptic ulcer disease.Portal hypertension also causes splenomegaly, with splenic sequestration of platelets and thrombocytopenia, which contributes to the hemostatic defect. Other causes of bleeding are variceal rupture,coagulation disorders due to multiple causes : decreased synthesis of clotting and inhibitor factors ; decreased clearance of activated factors , quantitative and qualitative platelet defects , hyperfibrinolysis and accelerated intravascular coagulation.

Course Introduction c o u r s e o v e r v i e w This CME conference will review new medications and therapies that are now available, or will soon be available, and discuss their comparative values. The results of trials using new drugs to treat chronic viral hepatitis B and C, non-alcoholic fatty liver diseases, primary biliary cirrhosis, pri- mary sclerosing cholangitis, hepatocellular carcinoma and complications of end-stage liver disease will be reviewed in detail. New Treatments in Chronic Liver Disease is a comprehensive yet concise program for updat- ing physicians on these and other commonly encountered problems in the treatment of liver diseases.

Published online: December 27, 2014 Abstract Vitamin D is an important secosteroid hormone with known effect on calcium homeostasis, but recently there is increasing recognition that vitamin D also is involved in cell proliferation and differentiation, has immunomod- ulatory and anti-inflammatory properties. Vitamin D de- ficiency has been frequently reported in many causes of chronic liver disease and has been associated with the development and evolution of non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) virus infection. The role of vitamin D in the pathogenesis of NAFLD and CHC is not completely known, but it seems that the involvement of vitamin D in the activation and regulation of both innate and adaptive immune systems and its antiproliferative effect may explain its impor- tance in these liver diseases. Published studies provide evidence for routine screening for hypovitaminosis D in patients with liver disease. Further prospectives studies demonstrating the impact of vitamin D replacement in NAFLD and CHC are required.

org/standards. Course Overview This conference will review the latest medica- tions and therapies in liver treatment and trans- plantation. The results of trials and real world data using oral drugs to treat chronic viral hepatitis B and C, non-alcoholic fatty liver diseases, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular carcinoma and complications of end-stage liver disease including thrombocyto- penia will be reviewed in detail. New Treatments in Chronic Liver Disease is a comprehensive yet concise program for updating physicians on these and other commonly encountered prob- lems in the treatment of liver diseases.

INTRODUCTION Chronic liver disease (CLD) and its sequelae form a major part of gastroenterological workload in any large hospital. As well known, it is a disease with very high degree of morbidity and mortality. In the past, CLD was broadly divided into alcoholic and post hepatitis varieties. Over the years, with the advent of newer techniques for identification of viruses, biochemical markers, and newer histopathological methods, it is now possible to enlarge the classification and attach more informative labels to such cases. Even among virus related CLD, a large group so far labeled as Non A, Non B, identification of Hepatitis C has become an established practice. Transfusion associated NANB hepatitis has a new perspective now. Despite these transformations, a small proportion of patients fail to demonstrate any known viral marker raising further questions.

12 This is due to deterioration in inotropic and chronotropic function which takes place in parallel with a diastolic dysfunction and cardiac hypertrophy. In majority of cases of chronic liver disease, cardiovascular complications develop as a subclinical condition which manifests only during stressful situations like TIPS and liver transplantations, which have a poor outcome. 13 As many as 50% of cirrhotic patients undergoing liver transplantation show signs of cardiac dysfunction, and 7% to 21% of deaths after orthotopic liver transplantation result from overt heart failure. 14 Hence early detection of cirrhotic cardiomyopathy by Echocardiography (ECG) and 2D-ECHO studies in all the patients of chronic liver disease help in reducing the morbidity and mortality. 15 METHODS

Results: MTAP was downregulated in hepatocytes in murine fibrosis models and in patients with chronic liver disease, leading to a concomitant increase in MTA levels. In contrast, activated hepatic stellate cells (HSCs) showed strong MTAP expression in cirrhotic livers. However, also MTA levels in activated HSCs were significantly higher than in hepatocytes, and there was a significant correlation between MTA levels and collagen expression in diseased human liver tissue indicating that activated HSCs significantly contribute to elevated MTA in diseased livers. MTAP suppression by siRNA resulted in increased MTA levels, NFκB activation and apoptosis resistance, while overexpression of MTAP caused the opposite effects in HSCs. The anti-apoptotic effect of low MTAP expression and high MTA levels, respectively, was mediated by induced expression of survivin, while inhibition of survivin abolished the anti-apoptotic effect of MTA on HSCs. Treatment with a DNA demethylating agent induced MTAP and reduced survivin expression, while oxidative stress reduced MTAP levels but enhanced survivin expression in HSCs.

belonged to low socioeconomic class, which obviously reflects the overall majority in our general population. In addition this group is also likely to be more exposed to risk factors for acquiring chronic hepatitis B and C infections which is the leading cause of chronic liver disease in our population. Similarly 42% patients were illiterate and their illiteracy coupled with poverty may become an important factor contributing towards increased exposure to un-necessary parenteral injections. A large number of patients (47.6%) had some co-existing disease like diabetes mellitus, hypertension and ischaemic heart disease which otherwise are prevalent in this age group. Anorexia and pain abdomen were major presenting symptoms seen in >80% cases.

4. Drug Properties and Choice Drug properties like the extrarenally excreted fraction, plasma protein binding and metabolism pathways in the liver and kidneys also affect how much viable liver tissue is needed to properly metabolize and excrete a specific drug. To this day, there exists no exo- or endogenous substance to estimate the hepatic clearance of drugs comparable to creatinine clearance in renal failure although many substances have been evaluated(21). Another issue is direct liver toxicity of certain drugs. Methods to guide clinicians in drug choice and dose adjustments in chronic liver disease are badly needed. There is a wide array of literature on dose adjustment with respect to general principles of hepatic drug clearance and single drug dose adjustments in patients with cirrhosis (21, 38). However, many issues regarding liver drug metabolism in CLD remain.