Liver cirrhosis Tsochatzis, Emmanuel A, PhD; Bosch, Jaime, Prof; Burroughs, Andrew K, Prof
The Lancet (British edition),
05/2014, Letnik:
383, Številka:
9930
Journal Article
Recenzirano
Summary Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, ...cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.
Background & Aims Standard RECIST criteria may not be the optimal method to assess response to loco-regional therapy for hepatocellular cancer (HCC). EASL and mRECIST, which measure changes in ...arterialized tumor, have been proposed. Here we compare the three criteria and their associations with survival. Methods Response was determined using RECIST 1.1, EASL, and mRECIST criteria in 83 consecutive patients with HCC undergoing palliative therapy with transarterial (chemo) embolization. Results were compared at the first assessment after therapy. Cox regression and Kaplan–Meier survival analyses were used to explore differences in overall survival between the responders and non-responders defined by each method. Results There was a good correlation between EASL and mRECIST with overall response rates; 58% and 57%, and target lesion responses; 74% and 73%, respectively. There was a poor correlation with RECIST 1.1 with overall and target response rates of 7%. Overall and target lesion progression rates were similar for all three assessments; 27% and 2% for both EASL and mRECIST and 28% and 6% for RECIST 1.1. There was a significant association between survival and overall EASL and mRECIST responses, which was retained in multivariate analysis. EASL response was associated with a 44% risk reduction and mRECIST with a 42% reduction. There was no significant association between survival for RECIST 1.1 responses or target EASL and mRECIST responses. Conclusions When measured at a single, early time point post-therapy, EASL and mRECIST overall response rates are associated with survival and should be used in preference to RECIST 1.1 or target responses.
Summary
Splanchnic vein thrombosis (SVT) is one of the most important complications of myeloproliferative neoplasms (MPN). Although MPN are common causes of SVT, the pathophysiological mechanisms ...underlying this predisposition, their epidemiology and natural history are not fully understood. Studies have concentrated on the generalized prothrombotic environment generated by MPN and their relationship with abnormal blood counts, thereby furthering our knowledge of arterial and venous thrombosis in this population. In contrast, there are few studies that have specifically addressed SVT in the context of MPN. Recent research has demonstrated in patients with MPN the existence of factors increasing the risk of SVT such as the presence of the JAK2 V617F mutation and its 46/1 haplotype. Features unique to the circulating blood cells, splanchnic vasculature and surrounding micro‐environment in patients with MPN have been described. There are also abnormalities in local haemodynamics, haemostatic molecules, the spleen, and splanchnic endothelial and endothelial progenitor cells. This review considers these important advances and discusses the contribution of individual anomalies that lead to the development of SVT in both the pre‐neoplastic and overt stage of MPN. Clinical issues relating to epidemiology, recurrence and survival in these patients have also been reviewed and their results discussed.
Background & Aims Although hepatitis B virus (HBV) transmission after liver transplantation of grafts from HBsAg-negative, anti-HBc positive donors is well established, the growing organ shortage ...favours the use of such marginal grafts. We systematically evaluated the risk of HBV infection after liver transplantation with such grafts and the effect of anti-HBV prophylaxis. Methods We performed a literature review over the last 15 years identifying 39 studies including 903 recipients of anti-HBc positive liver grafts. Results Recurrent HBV infection developed in 11% of HBsAg-positive liver transplant recipients of anti-HBc positive grafts, while survival was similar (67–100%) to HBsAg-positive recipients of anti-HBc negative grafts. De novo HBV infection developed in 19% of HBsAg-negative recipients being less frequent in anti-HBc/anti-HBs positive than HBV naive cases without prophylaxis (15% vs 48%, p < 0.001). Anti-HBV prophylaxis reduced de novo infection rates in both anti-HBc/anti-HBs positive (3%) and HBV naive recipients (12%). De novo infection rates were 19%, 2.6% and 2.8% in HBsAg-negative recipients under hepatitis B immunoglobulin, lamivudine and their combination, respectively. Conclusions Liver grafts from anti-HBc positive donors can be safely used, preferentially in HBsAg-positive or anti-HBc/anti-HBs positive recipients. HBsAg-negative recipients should receive prophylaxis with lamivudine, while both anti-HBc and anti-HBs positive recipients may need no prophylaxis at all.
Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk ...factors for HCC development in patients with PBC.
Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates.
Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001).
This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.
Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these ...patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy‐refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6‐C13, MELD Model of Endstage Liver Disease 5‐28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short‐term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (P < 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE‐free over a mean follow‐up period of 697 ± 157 days (P < 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three‐quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure‐related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites. Conclusion: This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve. (HEPATOLOGY 2013;57:2448–2457)
Background & Aims One-year survival in cirrhosis ranges from 1 to 57% depending on the clinical stage. Accurate sub-classification has important prognostic implications but there is no stage beyond ...cirrhosis using current qualitative histological systems. We compared the performance of all histological semi-quantitative and quantitative methods specifically developed for sub-classifying cirrhosis that have been described to date, with collagen proportionate area (CPA), to evaluate how well they distinguish patients with and without hepatic clinical decompensation at presentation, and in predicting future decompensating events. Methods We included consecutive patients with a histological diagnosis of cirrhosis that had a suitable liver biopsy between 2003 and 2007. We used semi-quantitative histological scoring systems proposed by Laennec, Kumar, and Nagula. We also measured quantitatively nodule size, septal width and fibrous tissue expressed in CPA. Results Sixty-nine patients, mean age 52.3 ± 11 years, mean MELD 11.8 ± 5.8, median follow-up 56 months. Main aetiologies were alcohol (38%) and hepatitis C (27.5%). Twenty-four patients (34.8%) had had a previous episode of clinical decompensation. Amongst the 45 patients who were compensated, 11 (24%) decompensated on follow-up. In Cox regression, amongst all histological parameters, CPA was the only variable independently associated with clinical decompensation up to the time of biopsy, with an odds ratio that ranged from 1.245 to 1.292. Furthermore, only CPA was significantly associated with future decompensation (OR: 1.117, 95% CI 1.020–1.223; p = 0.017). Conclusions Cirrhosis can be accurately sub-classified using quantification of fibrosis with CPA, and furthermore CPA is the only independent predictor of clinical decompensation amongst all other histological sub-classification systems described to date.
Background
Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented.
Methods
The associations of nutritional ...status and sarcopenia with post‐transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital‐Global Assessment (RFH‐GA) tool and the L3‐psoas muscle index (L3‐PMI) on CT, respectively.
Results
A wide range of RFH‐SGA and L3‐PMI were observed within similar Model for End‐stage Liver Disease (MELD) sub‐categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post‐transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002–1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99–21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036–1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48–48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056–5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004–1.106), MELD (OR = 1.137, 95%CI = 1.057–1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57–35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004–4.419) and L3‐PMI (OR = 0.996, 95%CI = 0.994–0.999); 1 year mortality with L3‐PMI (OR = 0.996, 95%CI = 0.992–0.999). Patients at the lowest L3‐PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections.
Conclusions
Malnutrition and sarcopenia are associated with early post‐liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals.
Summary Background Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of ...end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. Methods We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov , NCT00299260. Findings 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients. Interpretation Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. Funding National Institute of Allergy and Infectious Diseases , Grant R01AI051355 and Wellcome Trust , Grant 078332 . Sponsor: University College London (UCL).
Primary biliary cirrhosis (PBC) has a complex clinical phenotype, with debate about the extent and specificity of frequently described systemic symptoms such as fatigue. The aim of this study was to ...use a national patient cohort of 2,353 patients recruited from all clinical centers in the UK to explore the impact of disease on perceived life quality. Clinical data regarding diagnosis, therapy, and biochemical status were collected and have been reported previously. Detailed symptom phenotyping using recognized and validated symptom assessment tools including the PBC‐40 was also undertaken and is reported here. Perception of poor quality of life and impaired health status was common in PBC patients (35% and 46%, respectively) and more common than in an age‐matched and sex‐matched community control group (6% and 15%, P < 0.0001 for both). Fatigue and symptoms of social dysfunction were associated with impaired perceived quality of life using multivariate analysis. Fatigue was the symptom with the greatest impact. Depression was a significant factor, but appeared to be a manifestation of complex symptom burden rather than a primary event. Fatigue had its greatest impact on perceived quality of life when accompanied by symptoms of social dysfunction, suggesting that maintenance of social networks is critical for minimizing the impact of fatigue. Conclusion: The symptom burden in PBC, which is unrelated to disease severity or ursodeoxycholic acid response, is significant and complex and results in significant quality of life deficit. The complexity of symptom burden, and its lack of relation to disease severity and treatment response, suggest that specific approaches to symptom management are warranted that address both symptom biology and social impact. (Hepatology 2013;58:‐)
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