Porto-sinusoidal vascular liver disorder with portal hypertension: Natural history and long-term outcome.

BACKGROUND & AIMS: Current knowledge of the natural history of patients with porto-sinusoidal vascular disorder (PSVD) is derived from small studies. The aim of the present study was to determine the natural history of PSVD and prognostic factors in a large multicenter cohort of patients. METHODS: We performed a retrospective study on patients with PSVD and signs of portal hypertension (PH) prospectively registered in 27 centers. RESULTS: A total of 587 patients were included, median age of 47 years and 38% were women. Four-hundred and one patients had an associated condition, which was graded as severe in 157. Median follow-up was 68 months. At diagnosis, 64% of patients were asymptomatic while 36% had a PH-related complication: PH-related bleeding in 112 patients, ascites in 117, and hepatic encephalopathy in 11. In those not presenting with bleeding, the incidence of first bleeding was 15% at 5 years, with a 5-year rebleeding rate of 18%. The 5-year cumulative incidence of new or worsening ascites was 18% and of developing PVT was 16%. Fifty (8.5%) patients received a liver transplantation and 109 (19%) died, including 55 non-liver-related deaths. Transplant-free survival was 97% and 83% at 1 and 5 years, respectively. Variables independently associated with transplant-free survival were age, ascites, serum bilirubin, albumin and creatinine levels at diagnosis and severe associated conditions. This allowed for the creation of a nomogram that accurately predicted prognosis. CONCLUSIONS: The prognosis of PSVD is strongly determined by the severity of the associated underlying conditions and parameters of liver and renal function. IMPACT AND IMPLICATIONS: Porto-sinusoidal vascular liver disorder (PSVD) is a rare entity that usually affects young people, frequently causes severe complications of portal hypertension, and may reduce life expectancy. To date, there is scarce information regarding its clinical manifestations, natural history and prognostic factors. The present study, including the largest number of patients with PSVD reported so far, shows that overall, when managed at centers of expertise, the prognosis of patients with PSVD is good, with LT-free survival rates of 83% and 72% at 5 and 10 years, respectively. Presence and severity of an underlying associated condition, presence of ascites, age and bilirubin, albumin and creatinine levels were associated with poor prognosis. These results are important to know for hepatologists. A final model combining these parameters enabled development of a nomogram that predicts prognosis with good discrimination and calibration capacity and can be easily applied in clinical practice.

Incidence and risk factors associated with hepatocellular carcinoma surveillance failure.

BACKGROUND AND AIM: Surveillance for hepatocellular carcinoma (HCC) intends to detect tumors at an early stage to improve survival. The study aims were to assess the frequency and risk factors associated with HCC surveillance failure. METHODS: The study analyzed data from 188 consecutive patients diagnosed with HCC within a surveillance program conducted among 1,242 cirrhotic patients and based on ultrasonography and alpha-fetoprotein (AFP) testing every 3 or 6 months. Program failure was defined as the detection of HCC exceeding the Milan criteria. Variables recorded at entry into the program, during follow-up and at HCC diagnosis, were analyzed. RESULTS: At diagnosis, 50 (26.6%) HCC tumors were beyond the Milan criteria. In univariate analysis, Child-Pugh B at entry (P = 0.03), development of complications of portal hypertension before tumor diagnosis (P = 0.03), and failure to complete the prior screening round (P = 0.02), Child-Pugh B/C (P = 0.001) and AFP ≥ 100 ng/mL (P = 0.03) at diagnosis, were associated with failure. In multivariate analysis, only Child-Pugh B/C (hazard ratio, 3.18; 95% confidence interval, 1.66-6.10, P < 0.001) and AFP ≥ 100 ng/mL, both at diagnosis (hazard ratio, 2.80; 95% confidence interval, 1.37-5.71, P = 0.005), were independently associated with failure. Survival was higher among patients with tumors within the Milan criteria than those with program failure (33.9 vs 7.6 months, P < 0.001). CONCLUSIONS: Approximately 25% of HCC cases diagnosed among patients included in a surveillance program were beyond the Milan criteria. Child-Pugh B/C and AFP ≥ 100 ng/mL at diagnosis were associated with program failure. However, Child-Pugh B at entry and development of liver-related complications during follow-up can be early predictors of failure.

Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection.

Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second-generation direct-acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4-infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin <3.5 g/dL (OMV/PTVr) and bilirubin >2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE-associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA-based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non-cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes.

Adherence to a Semiannual Surveillance Program for Hepatocellular Carcinoma in Patients With Liver Cirrhosis.

BACKGROUND: Patient adherence to screening for hepatocellular carcinoma (HCC) is not well known. Our aims were to analyze the adherence to a surveillance program in a prospective cohort of cirrhotic patients and to examine its association with HCC stage at diagnosis. MATERIALS AND METHODS: A total of 770 patients with cirrhosis were examined semiannually by ultrasound and alpha-fetoprotein at a tertiary center. We collected data on 17 variables at baseline. Suboptimal adherence was defined as failure to complete 2 consecutive screening rounds. RESULTS: Over a median follow-up period of 42.0 months (interquartile range: 60.0), 125 patients (16.2%) had suboptimal adherence. Active or previous intravenous drug use [hazard ratio (HR), 5.33; 95% confidence interval (CI), 3.07-9.23], active alcohol consumption (HR, 3.03; 95% CI, 2.03-4.51), absence of liver decompensation before the inclusion in the program (HR, 1.65; 95% CI, 1.07-2.55) and aspartate transaminase/alanine transaminase ratio ≥1.6 (HR, 1.82; 95% CI, 1.23-2.70) were independent predictors of suboptimal adherence. Compared with those with optimal adherence, patients with suboptimal adherence had a more advanced HCC stage at diagnosis (P=0.015), they were less frequently treated with curative intention (P=0.078) and survived less (median: 14.2 mo; IQR: 36.0 vs. 22.7 mo; IQR: 47.4; P=0.160), although these differences were not significant. CONCLUSIONS: The adherence to the process of HCC surveillance can be considered as adequate among cirrhotic patients. Active alcohol consumption and a history of intravenous drug use are the strongest predictors of suboptimal adherence. These patients have a more advanced HCC stage at diagnosis and tend to be less frequently treated with curative intention.

Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver. / Enfermedades vasculares del hígado. Guías Clínicas de la Sociedad Catalana de Digestología y de la Asociación Española para el Estudio del Hígado.

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy. This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide.

Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups.

BACKGROUND & AIMS: The incidence of hepatocellular carcinoma (HCC) and associated risk factors in patients with alcoholic cirrhosis are not well defined. Surveillance for HCC among patients with cirrhosis who do not have hepatitis B is cost effective only if the expected risk of HCC exceeds 1.5% per year. We performed a prospective study to determine the incidence of HCC among patients with alcoholic cirrhosis and to identify risk factors. METHODS: We analyzed data from a surveillance program of 450 patients, aged 40 to 75 years, with alcoholic cirrhosis of Child-Pugh class A or B; patients were enrolled at the liver unit of a tertiary center from September 1992 through March 2010. Data were collected on 20 demographic, clinical, and laboratory variables at the start of the study. Patients were examined every 3 to 6 months for 5 years to identify risk factors for HCC; incidence was determined from a median follow-up time of 42 months. RESULTS: Over the follow-up period, 62 patients developed HCC (43 in the first 5 y of follow-up evaluation), with an annual incidence of 2.6%. By using multivariate analysis, age 55 years and older (hazard ratio, 2.39; 95% confidence interval, 1.27-4.51) and platelet counts less than 125 × 10(3)/mm(3) (hazard ratio, 3.29; 95% confidence interval, 1.39-7.85) were associated independently with the development of HCC. These variables were used to define 3 risk groups. The annual incidence of HCC in the group without either of these factors was 0.3% (n = 93), the annual incidence with 1 factor was 2.6% (n = 228), and the annual incidence with both factors was 4.8% (n = 129) (P < .0001). CONCLUSIONS: The annual incidence of HCC among patients with alcoholic cirrhosis of Child-Pugh class A or B is around 2.5%. Age and platelet count can be used to classify the patients in 3 different risk groups for HCC development within the next 5 years.

Noninvasive Prediction of Outcomes in Autoimmune Hepatitis-Related Cirrhosis.

The value of noninvasive tools in the diagnosis of autoimmune hepatitis (AIH)-related cirrhosis and the prediction of clinical outcomes is largely unknown. We sought to evaluate (1) the utility of liver stiffness measurement (LSM) in the diagnosis of cirrhosis and (2) the performance of the Sixth Baveno Consensus on Portal Hypertension (Baveno VI), expanded Baveno VI, and the ANTICIPATE models in predicting the absence of varices needing treatment (VNT). A multicenter cohort of 132 patients with AIH-related cirrhosis was retrospectively analyzed. LSM and endoscopies performed at the time of cirrhosis diagnosis were recorded. Most of the patients were female (66%), with a median age of 54 years. Only 33%-49% of patients had a LSM above the cutoff points described for the diagnosis of AIH-related cirrhosis (12.5, 14, and 16 kPa). Patients with portal hypertension (PHT) had significantly higher LSM than those without PHT (15.7 vs. 11.7 kPa; P = 0.001), but 39%-52% of patients with PHT still had LSM below these limits. The time since AIH diagnosis negatively correlated with LSM, with longer time being significantly associated with a lower proportion of patients with LSM above these cutoffs. VNT was present in 12 endoscopies. The use of the Baveno VI, expanded Baveno VI criteria, and the ANTICIPATE model would have saved 46%-63% of endoscopies, but the latter underpredicted the risk of VNT. Conclusions: LSM cutoff points do not have a good discriminative capacity for the diagnosis of AIH-related cirrhosis, especially long-term after treatment initiation. Noninvasive tools are helpful to triage patients for endoscopy.

Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia.

BACKGROUND: Chronic hepatitis delta is a severe liver disease with rapid progression to cirrhosis. The impact of hepatitis delta virus (HDV)-RNA on disease progression and interferon treatment in a real-world cohort has been barely explored. AIM: To assess the development of clinical events in a cohort of chronic hepatitis delta patients according to the presence or absence of HDV-RNA METHODS: Multicentre study at four academic hospitals in Spain included anti-HDV-positive patients with compensated liver disease with a follow-up ≥12 months. RESULTS: Among 2888 HBsAg-positive subjects, 151 (5.2%) tested positive for anti-HDV, and 118 were included (58% men; median age, 49 years; 73% detectable HDV-RNA and 30% cirrhosis, most often in subjects with HDV-RNA). After a median follow-up of 8 years, subjects with initially detectable HDV-RNA were more prone to developing cirrhosis (31% vs 0%, P = .002) and/or liver decompensation (28% vs 3%, P = .019). Mortality rate was 0.44 per 1000 person-months. The probability of a clinical event was 6%, 25%, and 80% according to initial baseline-event-anticipation score. HDV-RNA became undetectable in 21 (24%) subjects either due to interferon or spontaneously (48% vs 52%, P = .29). Liver decompensation was reduced in interferon-treated patients (13% vs 38%, P = .026). CONCLUSIONS: Subjects with persistently positive HDV-RNA had a worse prognosis in terms of clinical events. Baseline-event-anticipation score is useful in predicting the risk of developing liver decompensation and hepatocellular carcinoma. Interferon was beneficial in reducing liver decompensation, even in the absence of virological response.

Genetic contribution of endoplasmic reticulum aminopeptidase 1 polymorphisms to liver fibrosis progression in patients with HCV infection.

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses, trimming peptides and loading onto HLA class I molecules. Coding single nucleotide polymorphisms within ERAP1 are associated with autoimmune diseases, viral infections, and cancer development. Our purpose was to analyze the influence of ERAP1 variants on fibrogenesis in hepatitis C virus (HCV)-infected patients. A range of ERAP1 polymorphisms were genotyped in 722 unrelated Caucasian patients diagnosed with chronic HCV from two Spanish cohorts. Patients were classified according to their fibrosis stage. Paraffin-embedded tissue microarrays were constructed to assess ERAP1 expression (HCV = 38; alcoholic = 20) by immunohistochemistry. A statistical algorithm was applied to derive a fibrogenesis prediction model. The ERAP1 variants rs30187/T (K528, pc < 0.001) and rs27044/G (Q730, pc < 0.001) were related with severe fibrosis. These results were validated in the two independent cohorts. Furthermore, patients with the rs30187/T allele had stronger ERAP1 protein expression than those with the rs30187/C (p < 0.05). The statistical model showed that patients with rs30187 C/T and T/T genotypes took 15.58 years (median) to develop advanced fibrosis, but this value was 32.08 years in patients carrying C/C genotype (p < 0.005). ERAP1 variants may influence the clinical course of fibrogenesis in HCV-infected patients. These polymorphisms could be exploited as constitutive new markers of fibrosis evolution. The results highlight the possibility of using modulators of ERAP1 to generate a protective immune response against chronic HCV infection. KEY MESSAGES: What is known Several ERAP1 polymorphisms are associated with autoimmune diseases and cancer. ERAP1 trims peptides to HLA class I presentation. What is new here ERAP1 polymorphisms are associated with fibrogenesis. The ERAP1 polymorphisms genotype could help us in clinical management of patients. Potential translational impact The use of modulators of ERAP1 could generate a protective response depending on SNPs.

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb-V and dialysis in Spanish clinical practice - Vie-KinD study.

BACKGROUND AND AIMS: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. MATERIAL AND METHODS: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. RESULTS: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision. CONCLUSIONS: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.

Prevalence and epidemiology of hepatitis D among patients with chronic hepatitis B virus infection: a report from Northern Spain.

BACKGROUND: The incidence of hepatitis delta virus (HDV) infection has decreased during the last decades. However, an increasing trend has been reported recently. PATIENTS AND METHODS: We carried out a case-control study to analyze changes in its prevalence in 1215 chronic hepatitis B virus (HBV) patients, diagnosed consecutively in a tertiary center, between 1983 and 2012. According to the year of diagnosis, patients were distributed into two groups: A [1983-1997 (n=786)] and B [1998-2012 (n=429)]. RESULTS: The prevalence of anti-HDV was 8.2% (9.4% in group A and 6.1% in group B) (P=0.04). Multivariate regression revealed that intravenous drug use [odds ratio (OR) 261.0; 95% confidence interval (CI), 28.7-2368.5; P<0.001], blood transfusion (OR 28.0; 95% CI, 2.7-295.9; P=0.03), anti-HIV(+) (OR 4.8; 95% CI, 1.6-14.5; P=0.004), and high alanine aminotransferase (OR 14.4; 95% CI, 3.4-60.6; P<0.001) were associated independently with the presence of anti-HDV in group A, whereas in group B, it was associated with immigration (OR 20.0; 95% CI, 4.7-84.9; P<0.001), intravenous drug use (OR 683.5; 95% CI, 52.7-8855.7; P<0.001), promiscuous sexual activity (OR 22.6; 95% CI, 2.2-228.5; P=0.008), and high alanine aminotransferase (OR 3.4; 95% CI, 1.1-10.0; P=0.02). CONCLUSION: Although a significant decrease in the prevalence of HDV infection has been observed, it is still above 5%. Immigration and sexual transmission have emerged as new risk factors for HDV infection.

Granulocytic sarcoma of the small bowel, greater omentum and peritoneum associated with a CBFß/MYH11 fusion and inv(16) (p13q22): a case report.

INTRODUCTION: Granulocytic sarcoma (GS) is an extramedullary disease which is composed of immature myeloid cells or myeloblasts and usually occurs in association with acute myeloid leukemia (AML), as an initial presentation or a relapse. GS has been associated with various cytogenetic abnormalities, particularly with the t(8;21) translocation and less frequently the inv(16) type. CASE PRESENTATION: We present a rare case of GS of the small bowel, greater omentum and peritoneum, which caused obstruction, in a patient with AML associated with a CBFß/MYH11 fusion gene and an inv(16) (p13q22). In this patient there was only mild myeloid hyperplasia in bone marrow aspiration but molecular analysis identified a CBFß-MYH11 fusion and inv(16) (p13;q22). CONCLUSION: Because of its nonspecific clinical and radiologic findings, this entity can be misdiagnosed and can mimic other solid neoplasms, making it a diagnostic challenge. In a GS with no or minimal morphological changes in bone marrow aspiration it is very important to perform a cytogenetic analysis to benefit from the diagnosis and therapeutic strategy.

Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis.

Better knowledge of the risk factors associated with the appearance of hepatocellular carcinoma (HCC) could improve the efficacy of surveillance programs. A total of 463 patients aged 40 to 65 years with liver cirrhosis in Child-Pugh class A or B were included in a program of early diagnosis. The predictive value of different risk factors was evaluated using the Kaplan-Meier method and Cox regression model. Thirty-eight patients developed HCC. In the multivariate analysis, 4 variables showed an independent predictive value for the development of HCC: age 55 years or older, antibody to hepatitis C virus (anti-HCV) positivity, prothrombin activity 75% or less, and platelet count less than 75 x 10(3)/mm(3). According to the contribution of each of these factors to the final model, a score ranging between 0 and 4.71 points was constructed to allow the division of patients into 2 different risk groups. The low-risk group included those with a score of 2.33 points or less (n = 270; 4 with HCC; cumulative incidence of HCC at 4 years, 2.3%), and the high-risk group included those with a score greater than 2.33 (n = 193; 34 with HCC; cumulative incidence of HCC at 4 years, 30.1%) (P =.0001). In conclusion, a simple score made up of 4 clinical and biological variables allowed us to distinguish 2 groups of cirrhotic patients at high and low risk for the development of HCC. We believe this score can be useful in establishing a subset of cirrhotic patients in whom a surveillance program for early detection of HCC could be unjustified.