Pablo Ruiz

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

BACKGROUND & AIMS There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after SVR in recurrent hepatitis C.

Sustained virological response (SVR) improves survival in post‐liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post‐SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after‐SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus–infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post‐SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty‐seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%‐85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post‐SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post‐SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). Conclusion: In conclusion, SVR post‐LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683‐1694).

Early non‐invasive selection of patients at high risk of severe hepatitis C recurrence after liver transplantation

The early identification of patients at high risk of severe post liver transplant hepatitis C recurrence is relevant, as these patients may be treated using interferon (IFN)‐free regimens.

Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation

Liver stiffness measurement (LSM) is a useful method to estimate liver fibrosis and portal hypertension. The inflammatory process that takes place in post–liver transplant acute cellular rejection (ACR) may also increase liver stiffness. We aimed to explore the association between liver stiffness and the severity of ACR, as well as to assess the relationship between liver stiffness and response to rejection treatment in a prospective study that included 27 liver recipients with biopsy‐proven ACR, 30 stable recipients with normal liver tests, and 30 hepatitis C virus (HCV)–infected LT recipients with histologically diagnosed HCV recurrence. Patients with rejection were stratified into 2 groups (mild and moderate/severe) according to the severity of rejection evaluated with the Banff score. Routine biomarkers and LSM with FibroScan were performed at the time of liver biopsy (baseline) and at 7, 30, and 90 days in patients with rejection and at baseline in control patients. Median baseline liver stiffness was 5.9 kPa in the mild rejection group, 11 kPa in the moderate/severe group (P = 0.001), 4.2 kPa in stable recipients (P = 0.02 versus mild rejection), and 13.6 kPa in patients with recurrent HCV (P = 0.17 versus moderate/severe rejection). The area under the receiver operator characteristic curve of LSM to discriminate mild versus moderate/severe ACR was 0.924, and a LSM value of 8.5 kPa yielded a positive predictive value of 100% to diagnose moderate/severe rejection. Liver stiffness improved in 7%, 21%, and 64% of patients with moderate/severe rejection at 7, 30, and 90 days. In conclusion, according to the results of this exploratory study, LSM is associated with the severity of ACR in liver transplantation and thus may be of help in its assessment. Liver Transpl 22:298–304, 2016.

Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis

BACKGROUND & AIMS Research on vasopressin (AVP) in cirrhosis and its role in the assessment of prognosis has been hindered by the difficulty of measuring AVP levels accurately. Copeptin, a 39-aminoacid glycopeptide, is released from the neurohypophysis together with AVP. Copeptin could have a role as biomarker of prognosis in cirrhosis as it may reflect circulatory dysfunction. The aim of this study is to investigate the role of copeptin as biomarker of disease progression and prognosis in cirrhosis. METHODS This prospective study is divided in 2 study protocols including 321 consecutive patients. Plasma copeptin levels were measured in all patients at study inclusion. Protocol 1: to investigate the relationship of copeptin with kidney and circulatory function (56 patients). Protocol 2: to investigate the relationship between copeptin and prognosis, as assessed by the development of complications of cirrhosis or mortality at 3months (265 patients admitted to hospital for complications of cirrhosis). RESULTS Patients with decompensated cirrhosis showed significantly higher plasma copeptin levels compared to those of patients with compensated cirrhosis. Copeptin levels had a significant positive correlation with model for end-satge liver disease (MELD) score, AVP, endogenous vasoconstrictor systems, and kidney function parameters. Patients developing complications of cirrhosis or mortality had significantly higher plasma copeptin levels compared to those of the remaining patients. Plasma copeptin levels were an independent predictive factor of both the development of complications and mortality at 3months. This was confirmed in a validation series of 120 patients. CONCLUSIONS Copeptin is a novel biomarker of disease progression and prognosis in cirrhosis. LAY SUMMARY Copeptin is a fragment of the vasopressin precursor, a hormone that is known to be increased in patients with cirrhosis and that plays a role in the development of complications of the disease. Vasopressin is difficult to measure, but copeptin is a more stable molecule and is easier to measure in blood. Solà and Kerbert and colleagues have shown in a series of 361 patients that copeptin is markedly increased in patients with cirrhosis who develop complications during the following 3months, compared to those patients who do not develop complications. Moreover, copeptin correlates with prognosis.

Mannose-Binding Lectin–Deficient Donors Increase the Risk of Bacterial Infection and Bacterial Infection–Related Mortality After Liver Transplantation

Mannose‐binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL‐deficient or MBL‐sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated‐event analysis for infection episodes (negative binomial regression, Andersen–Gill model) was performed in 240 LTs. Four hundred twenty‐eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]‐related, and 38 viral non–CMV‐related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL‐deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04–2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33–4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92–16.4], p = 0.002) compared with recipients of MBL‐deficient livers. The 1‐year bacterial infection–related mortality was higher in recipients of MBL‐deficient versus MBL‐sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL‐deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1‐year bacterial infection–related mortality after LT.

Increased risk of portal vein thrombosis in patients with autoimmune hepatitis on the liver transplantation waiting list

Liver transplantation (LT) is indicated in autoimmune hepatitis (AIH) for both acute presentation with liver failure and end‐stage chronic liver disease. Few studies have suggested an association between AIH and coagulation disorders and a higher incidence of portal vein thrombosis (PVT) in patients with AIH listed for LT. The aim of this study was to determine the incidence of thrombotic complications, particularly PVT, in a cohort of 37 patients undergoing LT because of AIH. PVT was present before transplantation in 30% (n=11) of these patients compared to 11% in the whole population transplanted in our center (P=.002). On comparing only patients with cirrhosis, PVT was present in 55% of the AIH group, being 12% in the whole cohort (P<.001). Among patients with PVT before LT, no patient receiving anticoagulation therapy early after LT developed recurrence of PVT, whereas two patients (33%) without anticoagulation therapy did. The increased incidence of PVT in the pretransplant period and the possibility of thrombosis recurrence after LT suggest that patients with AIH and PVT could benefit from anticoagulation therapy after transplantation. However, further studies are needed to recommend anticoagulation in these patients in clinical practice.

Primary adrenal insufficiency due to hereditary apolipoprotein AI amyloidosis: endocrine involvement beyond hypogonadism

Abstract Several mutations in the gene encoding apolipoprotein AI (apoAI) have been described as a cause of familial amyloidosis. Individuals with apoAI-derived (AApoAI) amyloidosis frequently manifest with liver, kidney, laryngeal, skin and myocardial involvement. Although primary hypogonadism (PH) is considered almost pathognomonic of this disease, until now, primary adrenal insufficiency (PAI) has not been described as a common clinical feature. Here, we report the first kindred with AApoAI amyloidosis in which PAI is well-documented. All family members with the Leu60_Phe71delins60Val_61Thr heterozygous mutation who were regularly followed-up at our centre were considered. Nineteen individuals had the confirmed APOA1 deletion/insertion mutation, with detailed medical records available in 11 cases. Of these, 6 had PAI and 3 (all males) had PH. Among them, one 47-year-old man, not previously diagnosed with PAI, developed adrenal crisis after liver transplantation, precipitated by an opportunistic infection. Transplantation due to organ failure, which necessitates use of immunosuppressive medication such as corticosteroids, is frequently required during the course of hereditary amyloidosis. Consequently, PAI can remain masked, being discovered only when an adrenal crisis develops. Therefore, according to the present evidence, patients with AApoAI amyloidosis should be submitted to regular testing of corticotrophin and cortisol levels in order to avoid delaying corticosteroid replacement.