Natural History Of Liver Disease Research Articles

Hepatitis co-infection in paediatric HIV: progressing treatment and prevention.

To analyse the main evidence and recommendations for the management of hepatitis co-infection in children living with HIV. We analysed available data pertaining to the natural history of liver disease and treatment of co-infected children. Viral hepatitis co-infection in people living with HIV (PLHIV) is a global problem owing to the shared routes of transmission, particularly in areas of high endemicity for the three viruses. Viral hepatitis co-infection can accelerate liver disease progression and increase morbidity and mortality, even in patients on suppressive antiretroviral treatment (ART). Viral hepatitis should be routinely screened in PLHIV and, once diagnosed with viral hepatitis, PLHIV should be closely monitored for liver disease progression and complications. Children living with HIV-HBV co-infection should be treated with ART containing agents which are active against both viruses. Children living with HIV-HCV co-infection should receive directly acting antivirals (DAA) to eradicate HCV infection. Prevention measures to reduce vertical and horizontal transmission of HBV and HCV (anti-HBV vaccination and immunoglobulins, anti-HBV treatment in pregnancy, anti-HCV DAAs in people of childbearing age, avoiding blood contact, sexual barrier precautions) should be adopted and encouraged, particularly in high endemicity countries.

The Liver and Lysosomal Storage Diseases: From Pathophysiology to Clinical Presentation, Diagnostics, and Treatment.

The liver, given its role as the central metabolic organ, is involved in many inherited metabolic disorders, including lysosomal storage diseases (LSDs). The aim of this manuscript was to provide a comprehensive overview on liver involvement in LSDs, focusing on clinical manifestation and its pathomechanisms. Gaucher disease, acid sphingomyelinase deficiency, and lysosomal acid lipase deficiency were thoroughly reviewed, with hepatic manifestation being a dominant clinical phenotype. The natural history of liver disease in the above-mentioned lysosomal disorders was delineated. The importance of Niemann-Pick type C disease as a cause of cholestatic jaundice, preceding neurological manifestation, was also highlighted. Diagnostic methods and current therapeutic management of LSDs were also discussed in the context of liver involvement.

Microbiota and Gut-Liver Axis: An Unbreakable Bond?

The gut microbiota, amounting to approximately 100 trillion (1014) microbes represents a genetic repertoire that is bigger than the human genome itself. Evidence on bidirectional interplay between human and microbial genes is mounting. Microbiota probably play vital roles in diverse aspects of normal human metabolism, such as digestion, immune modulation, and gut endocrine function, as well as in the genesis and progression of many human diseases. Indeed, the gut microbiota has been most closely linked to various chronic ailments affecting the liver, although concrete scientific data are sparse. In this narrative review, we initially discuss the basic epidemiology of gut microbiota and the factors influencing their initial formation in the gut. Subsequently, we delve into the gut-liver axis and the evidence regarding the link between gut microbiota and the genesis or progression of various liver diseases. Finally, we summarise the recent research on plausible ways to modulate the gut microbiota to alter the natural history of liver disease.

Reply.

We thank Drs Singh and Mondia for their interest in our work and their comments regarding our article titled “Natural history of liver disease in a large international Cohort of children with Alagille syndrome: results from The GALA Study.” We acknowledge the absence of detailed analyses of extrahepatic manifestations in our paper. Since Alagille syndrome (ALGS) is dominated by cholestatic liver disease, the focus of our first manuscript was to describe the natural history of liver disease in the largest real-world cohort of ALGS. Additional analyses into other organ systems were simply beyond the scope of this paper. However, we absolutely agree that as Hepatologists/Gastroenterologists, we must think beyond the liver, and through the rich and robust Global Alagille Alliance (GALA) data set, these analyses are finally possible. The suggested analyses are currently planned or in progress and will allow us to coordinate subspecialist care and provide evidenced-based holistic care. We look forward to sharing these results in upcoming publications. CONFLICT OF INTEREST Binita M. Kamath consults for and received grants from Mirum and Albireo. She consults for Audentes. Shannon M. Vandriel has no conflicts to report.

Rising incidence, progression and changing patterns of liver disease in Wales 1999-2019.

Liver disease incidence and hence demand on hepatology services is increasing. To describe trends in incidence and natural history of liver diseases in Wales to inform effective provision of hepatology services. The registry is populated by International Classification of Diseases-10 (ICD-10) code diagnoses for residents derived from mortality data and inpatient/day case activity between 1999-2019. Pseudo-anonymised linkage of: (1) Causative diagnoses; (2) Cirrhosis; (3) Portal hypertension; (4) Decompensation; and (5) Liver cancer diagnoses enabled tracking liver disease progression. The population of Wales in 2019 was 3.1 million. Between 1999 and 2019 73054 individuals were diagnosed with a hepatic disorder, including 18633 diagnosed with cirrhosis, 10965 with liver decompensation and 2316 with hepatocellular carcinoma (HCC). Over 21 years the incidence of liver diseases increased 3.6 fold, predominantly driven by a 10 fold increase in non-alcoholic fatty liver disease (NAFLD); the leading cause of liver disease from 2014. The incidence of cirrhosis, decompensation, HCC, and all-cause mortality tripled. Liver-related mortality doubled. Alcohol-related liver disease (ArLD), autoimmune liver disease and congestive hepatopathy were associated with the highest rates of decompensation and all-cause mortality. A 10 fold increase in NAFLD incidence is driving a 3.6 fold increase in liver disease in Wales over 21 years. Liver-related morbidity and mortality rose more slowly reflecting the lower progression rate in NAFLD. Incidence of ArLD remained stable but was associated with the highest rates of liver-related and all-cause mortality.

Busting the myth of methotrexate chronic hepatotoxicity.

Methotrexate is a key component of the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis. Hepatotoxicity has long been a concern for prescribers envisaging long-term treatment with methotrexate for their patients. However, the putative liver toxicity of methotrexate should be evaluated in the context of advances in our knowledge of the pathogenesis and natural history of liver disease, especially non-alcoholic fatty liver disease (NAFLD). Notably, patients with NAFLD are at increased risk for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD. Understanding the mechanisms of acute hepatotoxicity can facilitate the interpretation of elevated concentrations of liver enzymes in this context. Liver fibrosis and the mechanisms of fibrogenesis also need to be considered in relation to chronic exposure to methotrexate. A number of non-invasive tests for liver fibrosis are available for use in patients with rheumatic disease, in addition to liver biopsy, which can be appropriate for particular individuals. On the basis of the available evidence, practical suggestions for pretreatment screening and long-term monitoring of methotrexate therapy can be made for patients who have (or are at risk for) chronic liver disease.

Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE)

Background & aims The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were: 1) to describe a large cohort of patients with cirrhosis in terms of neuropsychological/neurophysiological HE indices, and 2) to test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. Method 461 patients with cirrhosis (59±10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow up information on mortality/HE-related hospitalization in 134/127, respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow up in 124. Results Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Amongst patients without a history of overt HE, those with worse PHES had higher HE risk. Amongst patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. Conclusions In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.

Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE).

The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. Four hundred and sixty-one patients with cirrhosis (59±10years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow-up in 124. Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.

Long-term natural history of liver disease in patients with chronic hepatitis B virus infection: an analysis using the Markov chain model.

The relationship between the hepatitis B e antigen (HBeAg) seroconversion and the long-term natural history of liver disease has not been sufficiently investigated. A total of 408 [4352 person-year (PY) units] patients with chronic hepatitis B virus (HBV) without antiviral therapy were enrolled. The study patients were divided into three groups, as follows: Group A (2666 PY units), seroconverted of HBeAg at age < 40; Group B (413 PY units), seroconverted of HBeAg at age ≥ 40; Group C (1273 PY units), persistently HBeAg positive. Yearly transition probabilities from each liver state [chronic HBV infection, chronic hepatitis B, cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) negativity] were calculated using the Markov chain model. In the analysis of 1year liver disease state transition probabilities, the liver states remained almost the same in Group A. In Groups B and C, each liver state tended to progress to a worse state. Assuming a chronic hepatitis B state at age 40 as the starting condition for simulation over the next 40years, the chronic hepatitis B state accounted for approximately 60% of males aged ≥ 50 and approximately 40% of females aged ≥ 60 in Group A, and the HBsAg-negative state accounted for approximately 30-40% of males and females aged ≥ 60. In Groups B and C, the probabilities of patients with cirrhosis and HCC gradually increased with age. Not only patients with persistent HBeAg positive, but also patients with delayed HBeAg seroconversion showed poor prognosis of liver-related natural history.

Systematic review: the natural history of alpha-1 antitrypsin deficiency, and associated liver disease.

Alpha-1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD. To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review. A comprehensive search was conducted across multiple databases. Two independent authors selected the articles and assessed bias using the Newcastle-Ottawa Scale. Data were pooled for analysis, where comparable outcomes were reported. Thirty-five studies were identified related to disease progression and 12 for the treatment of AATD. Seven per cent of children were reported to develop liver cirrhosis, with 16.5% of individuals presenting in childhood requiring liver transplantation. Of those surviving to adulthood, 10.5% had liver cirrhosis and 14.7% required transplantation. Liver transplantation was the only effective treatment reported and outcomes compare favourably to other indications, with 5-year survival reported as over 90% in children and over 80% in adults. The clinical course of liver disease in individuals with AATD remains poorly understood, but affects about 10% of those with AATD. More research is required to identify those patients at risk of developing liver disease at an early stage, and to provide alternative treatments to liver transplantation.

IN CHILDREN WITH FONTAN PHYSIOLOGY, LIVER STIFFNESS IS CORRELATED WITH AGE, TIME SINCE FONTAN COMPLETION AND BIOCHEMICAL MARKERS OF LIVER DISEASE

Liver disease is of growing concern in children and young adults with Fontan physiology. The natural history of liver disease is this patient population is not presently well defined, largely because a definitive diagnosis is reliant on invasive liver biopsy. Non-invasive investigations to detect liver pathology in Fontan patients have not yet been validated. Transient elastography (TE), to assess liver stiffness, is a validated measurement of liver fibrosis in patients a number of chronic liver diseases. This modality may represent a non-invasive method to assess liver fibrosis in pediatric Fontan patients. We hypothesized that TE values would be associated with age and biochemical markers of liver disease in children with Fontan physiology. We prospectively enrolled 60 patients with Fontan physiology at British Columbia Children’s Hospital. All patients underwent comprehensive liver evaluation including liver enzymes (ALT, AST, GGT, ALP), albumin, bilirubin, INR, CBC, abdominal ultrasound, and TE measurement. The AST to platelet ratio index (APRI) was calculated from the laboratory results. Trained personnel obtained TE measurements of liver stiffness using age-specific probes. A total of 86 TE measurements were performed on 60 unique patients with a median age of 11.3 years (interquartile range 7.7-14.7 years, 55% male). There was a significant correlation between liver stiffness and both the time since Fontan completion (rho=0.45, p < 0.001) and age at the time of TE measurement (rho=0.48, p < 0.001). In addition, there was a significant correlation between liver stiffness and laboratory measures of liver health including APRI (rho=0.39, p=0.01), AST (rho=-0.50, p < 0.01), and INR (rho=0.3128, p=0.05). Findings on ultrasound imaging of the liver and spleen did not correlate with liver stiffness. This represents the largest reported cohort of pediatric Fontan patients to undergo TE as part of a comprehensive liver assessment. While liver stiffness is elevated in the early post Fontan period, we found that TE measurements of liver stiffness increased with both age and time from Fontan completion. Furthermore, the rise in liver stiffness over time was also associated with worsening biochemical markers of liver disease. Our results support the notion that liver disease begins in childhood in this population, and that TE measurement of liver stiffness may be a non-invasive method to identify and monitor the progress of liver disease in pediatric Fontan patients.

Non-pharmacological interventions in non-alcoholic fatty liver disease patients.

Patients with non-alcoholic fatty liver disease have unhealthy diets, sedentary behaviour and not enough physical activity. This lifestyle triggers liver disease and probably favours its progression. It also has significant deleterious effects on health and longevity and should therefore be corrected by first-line therapy at all stages of the disease. However, important questions remain: is weight loss alone beneficial or do particular diets have beneficial effects beyond weight loss? Which specific micro- or macronutrients are clearly harmful? Does exercise without weight loss improve hepatic histology and what type of exercise is optimal? Does moderate or only vigorous exercise have metabolic and hepatic benefits? What is the efficacy of lifestyle measures outside of clinical trials? And most importantly, what is the turning point in the natural history of liver disease when non-pharmacological measures should be combined with drug therapy?

Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is a frequent complication of morbid obesity, but its severity varies greatly and thus there is a strong need to better define its natural history...

Seroprevalence of hepatitis C virus among people living with HIV/AIDS in Latin America and the Caribbean: a systematic review.

BackgroundStudies have shown that the immunosuppression induced by the human immunodeficiency virus (HIV) accelerates the natural history of liver disease associated with hepatitis C virus (HCV), with 3- to 5-fold higher odds of coinfected individuals developing cirrhosis. However, estimates of the seroprevalence of hepatitis C among people living with HIV/acquired immune deficiency syndrome (AIDS) (PLHA) in Latin America and the Caribbean (LAC) are widely variable.MethodsWe performed a systematic review to estimate the seroprevalence of HCV among PLHA. We searched studies on HIV and HCV infections in LAC included in the PubMed, LILACS and Embase databases in December of 2014 with no time or language restrictions. The following combinations of search terms were used in the PubMed and Embase databases: (HIV OR Acquired Immunodeficiency Syndrome Virus OR AIDS OR HTLV OR Human Immunodeficiency Virus OR Human T Cell) AND (HCV OR HEPATITIS C OR HEPATITIS C VIRUS OR HEPACIVIRUS) AND (name of an individual country or territory in LAC). The following search terms were used in the LILACS database: (HIV OR AIDS OR Virus da Imunodeficiencia Humana) AND (HCV OR Hepatite C OR Hepacivirus). An additional 11 studies were identified through manual searches. A total of 2,380 publications were located, including 617 duplicates; the remaining articles were reviewed to select studies for inclusion in this study.ResultsA total of 37 studies were selected for systematic review, including 23 from Brazil, 5 from Argentina, 3 from Cuba, 1 from Puerto Rico, 1 from Chile, 1 from Colombia, 1 from Mexico, 1 from Peru and 1 from Venezuela. The estimated seroprevalence of HCV infection varied from 0.8 to 58.5 % (mean 17.37; median 10.91), with the highest in Argentina and Brazil and the lowest in Venezuela and Colombia.ConclusionsInvestigation of HCV infection among PLHA and of HIV infection among people living with HCV is highly recommended because it allows for better follow up, counseling and treatment of HIV/HCV-coinfected patients. Future studies with larger sample sizes are needed in both South and Central America to understand and address the risk factors associated with the acquisition of infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1988-y) contains supplementary material, which is available to authorized users.

Alcoholic Liver Disease and Hepatitis C Chronic Infection.

Alcoholic and virus C hepatitis currently represent the main causes of chronic liver disease worldwide. Every year many people die and are subjected to complex hospitalization and medical assistance due to these pathologies. Alcoholic liver disease and hepatitis C virus chronic infection are often present in the same patient. These two pathologies sinergically act in determining the onset and progression of liver damage that, from the chronic hepatitis staging, may rapidly progress to fibrosis, cirrhosis and hepatocellular carcinoma. In this review we analysed physiopathological aspects and biomolecular interactions that relate ethanol and hepatitis C virus in determining liver damage; moreover we took into account the effect on the natural history of liver disease deriving from the co-presence of these pathologies. Therefore we paid particular attention to the ability of ethanol and hepatitis C virus to in inducing oxidative stress or lipid accumulation, and analyzed the basic mechanisms of fibrogenesis that both diseases have got, amplified by their co-presence in the same patient. Finally we paid attention to the oncogenetic mechanisms inducing hepatocellular carcinoma and variability of response to antiviral therapy that derives from alcohol abuse in a subject affected by C hepatitis.

Natural history of liver disease and effect of hepatitis C virus on HIV disease progression.

Due to high prevalence rates, the hepatitis C virus (HCV) and the HIV cause two viral infections of global importance. Shared routes of transmission lead to a high number of dually infected individuals especially in specific populations such as intravenous drug users or people from highly endemic regions for both viruses. Treatment progress made in the field of HIV in the past three decades diminished the number of HIV patients who die from opportunistic infections and enabled a rise of HCV-associated liver disease in the HIV-HCV-coinfected population. An HIV-HCV coinfection is mainly characterized by a faster progression to liver cirrhosis that may lead to hepatic decompensation or the development of hepatocellular carcinoma (HCC). The treatment of HIV with highly active antiretroviral therapy (HAART) may only partly reverse this effect by the restoration of the immune system. Although no clear deleterious effect of HCV on the course of HIV infection is described, an increased HIV-associated and non-HIV-associated mortality has been described in patients not cured from their HCV infection. In this article, we review the latest knowledge on the natural course of HCV in the HIV-infected population, the role of HIV treatment, and the possible effects of HCV on HIV disease progression.

Review article: the management of cirrhosis in women.

There are differences in the predisposition, natural history of liver disease, complications and treatment response between men and women. To review clinical differences in cirrhosis between men and women and to address unique management issues of fertility, pregnancy and contraception in this patient population. PubMed and MEDLINE were searched using the terms 'cirrhosis' and 'chronic liver disease', each cross-referenced with specific liver diseases, as well as terms such as 'cancer', 'hepatocellular carcinoma', 'smoking', 'liver transplantation', 'metabolic bone disease', 'fertility',' pregnancy' and 'contraception'. Pre-menopausal status is protective in viral hepatitis C and non-alcoholic steatohepatitis. However, smoking, especially in combination with alcohol, is a stronger risk factor for cirrhosis and malignancies in women with chronic liver disease compared to men, although they are less likely than men to develop hepatocellular carcinoma. Women with cirrhosis have more osteopenic bone disease than men and require active management. Successful pregnancy is possible in well-compensated cirrhosis or with mild portal hypertension, although the maternal and foetal mortality and morbidity are higher than in the general population. The maternal risk correlates with liver disease severity and derives mostly from variceal bleeding. The choices for contraception in compensated cirrhosis are generally the same as for the general population. Women with cirrhosis are disadvantaged by the current MELD system of organ allocation, at least in part due to body size. The management of women with chronic liver disease is unique in regards to counselling, screening for complications, fertility and pregnancy.

Difference in serum complement component C4a levels between hepatitis C virus carriers with persistently normal alanine aminotransferase levels or chronic hepatitis C

Certain hepatitis C virus (HCV) carriers exhibit persistently normal alanine aminotransferase (ALT) levels (PNALT) (≤30 IU/l) accompanied by normal platelet counts (≥15×104/μl); these individuals show milder disease activity and slower progression to cirrhosis. This study aimed to elucidate the characteristics of HCV carriers with PNALT using serum proteomics. The first group of subjects, who underwent clinical evaluation in the hospital, consisted of 19 HCV carriers with PNALT (PNALT-1) and 20 chronic hepatitis C (CHC-1) patients. The second group of subjects was part of a cohort study on the natural history of liver disease, and included 37 PNALT (PNALT-2) and 30 CHC (CHC-2) patients. Affinity bead-purified serum protein was subjected to matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis. Serum proteomics showed that 6 protein peaks with mass-to-charge ratios ranging from 1,000 to 3,000 differed significantly between the PNALT-1 and CHC-1 groups. Among these peaks, a 1738-m/z peak protein was identified as a fragment of complement component 4 (C4) and correlated significantly with serum C4a concentrations as determined by enzyme immunoassay. Serum C4a levels were also significantly higher in the PNALT-2 group compared to the CHC-2 group and healthy volunteers. Furthermore, in the PNALT-2 group, serum C4a levels negatively correlated with transaminase levels, but not with other biochemical tests, HCV core antigen levels, peripheral blood cell counts or serum hepatic fibrosis markers. This study indicates that host factors such as C4a not only differ between HCV carriers with PNALT and CHC, but that proteomic approaches could also contribute to the elucidation of factors in PNALT as more differences are discovered.

Calcineurin Inhibitors in Liver Transplantation: To Be or Not to Be

Orthotopic liver transplantation is currently the procedure of choice for patients with end-stage liver disease, with survival rates greater than 90% and 80% at 1 and 5 years, respectively. These excellent results are largely due to knowledge of the natural history of liver diseases, improved surgical techniques and postoperative management of recipients, and availability of active antibacterial, antiviral, and antifungal drugs, as well as the development and application of potent immunosuppressive drugs. The introduction of calcineurin inhibitors (CNI)—cyclosporine and tacrolimus—has been one of the most important advances in solid-organ transplantation. Nevertheless, the survivals have been impaired by an increasing prevalence and long-term consequences of drug-related cardiovascular diseases, de novo neoplasias, recurrence of both viral and tumor diseases, and posttransplant renal dysfunction. Strategies for immunosuppression include the design of individualized protocols with the objective to increase immunologic efficacy with a reduced number and severity of secondary effects, according to the clinical status and the posttransplant complications: renal failure, de novo neoplasia, recurrent hepatocellular carcinoma. In this setting, new immnunosuppressive protocols have been investigated to include reduction in or withdrawal of CNI.

Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON) second interim analysis in more than 1,500 patients: Clinical findings in patients with liver dysfunction.

4001 Background: GIDEON is an ongoing, global, prospective, noninterventional study of hepatocellular carcinoma (HCC) patients (pts) suitable for systemic therapy and receiving sorafenib (Sor) in real-life practice. Its aim is to evaluate Sor safety and efficacy in diverse settings and pt subgroups where data are limited such as pts with liver dysfunction ie Child-Pugh B (CP-B). Methods: Demographics, medical/disease/treatment history are recorded. At follow-up visits Sor dose, concomitant treatment, liver function, adverse events (AEs) and efficacy are recorded. From Jan 2009 to Dec 2010, 2,770 pts were enrolled in 37 countries. Per protocol, the 2nd interim analysis (IA) was planned when ~1,500 treated pts were followed ≥4 mos. Results: 1,586 pts comprise the safety population; CP-A, 965 (61%); CP- B, 368 (23%). Sor median daily dose was higher in the CP-B group, but median duration of therapy was shorter (Table). Treatment-emergent drug-related AE rates were similar in both groups, but a greater percentage of CP-B pts discontinued Sor due to AEs. Deaths during treatment up to 30 days of last Sor dose were greater in the CP-B group (34%) than in the CP-A group (15%). In the ITT population (1614 pts), preliminary median overall survival (OS) was 10.5 mos in the CP-A pts (n=982) and 5 mos in the CP-B pts (n=373). Conclusions: These preliminary second IA results indicate that the Sor safety profile is generally similar in the CP-B and CP-A pts. The shorter median OS in the CP-B pts most likely reflects the poorer prognosis and natural history of liver disease in this patient population. N = 1,586 CP-A n = 965 (61%) CP-B n = 368 (23%) 800 mg starting dose (n [%]) 738 (76) 261 (71) Daily dose (median, mg)* 684.5 721.0 No. dose reductions (n [%]) 353 (37) 99 (27) Treatment duration (median, wks)* 13.7 8.5 Treatment-emergent AEs (n [%]) All Drug-related All Drug-related All grades 768 (80) 632 (66) 322 (88) 227 (62) Grade 3 241 (25) 211 (22) 94 (26) 67 (18) Grade 4 37 (4) 16 (2) 20 (5) 9 (2) Serious, all grades (n (%)) 273 (28) 75 (8) 198 (54) 53 (14) Sor discontinued due to AEs (n [%]) 217 (23) 139 (38) * Missing data not tabulated.