Annalisa Berzigotti

The management of portal hypertension: Rational basis, available treatments and future options ☆

Variceal bleeding is the last step in a chain of events initiated by an increase in portal pressure, followed by the development and progressive dilation of varices until these finally rupture and bleed. This sequence of events might be prevented - and reversed - by achieving a sufficient decrease in portal pressure. A different approach is the use of local endoscopic treatments at the varices. This article reviews the rationale for the management of patients with cirrhosis and portal hypertension, the current recommendations for the prevention and treatment of variceal bleeding, and outlines the unsolved issues and the perspectives for the future opened by new research developments.

Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.

BACKGROUND & AIMS Noninvasive methods are needed to identify clinically significant portal hypertension (CSPH) and esophageal varices (EVs) in patients with compensated cirrhosis. We looked for markers of the presence of CSPH and EVs in patients with cirrhosis. METHODS We performed a cross-sectional study that included a training set of 117 patients with compensated cirrhosis, confirmed by histology, from a tertiary referral center. Spleen diameter was measured by ultrasound, and liver stiffness (LS) was measured by transient elastography; endoscopy was used as the standard for detection of EVs, and measurements of hepatic venous pressure gradient were used as the standard for identifying CSPH. We assessed the ability of platelet count, spleen diameter, LS, and combinations of these factors (ie, ratio of platelet count to spleen size, and LS × spleen size/platelet count [LSPS]) to identify patients with CSPH and EV. The analysis included 2 new statistical models: the PH risk score and the varices risk score. Results were validated using an independent series of 56 patients with compensated patients from another center. RESULTS LS was the best single noninvasive variable for identifying patients with CSPH (area under the receiver operating characteristic, 0.883; 95% confidence interval [CI], 0.824-0.943; P < .0001). The area under the receiver operating characteristic value increased when LS was combined with platelet count and spleen size, either as LSPS (0.918; 95% CI, 0.872-0.965; P < .0001) or PH risk score (0.935; 95% CI, 0.893-0.977; P < .0001). More than 80% of patients were accurately classified using LSPS and PH risk score. Analyses of the varices risk score and LSPS were superior to all other noninvasive tests for identifying patients with EVs (area under the receiver operating characteristic, 0.909; 95% CI, 0.841-0.954 and 0.882; 95% CI, 0.810-0.935, respectively); they correctly classified 85% of patients in the training set and 75% in the validation set. CONCLUSIONS Combined data on LS, spleen diameter, and platelet count can be used to identify patients with compensated cirrhosis most likely to have CSPH and EV.

Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.

This guidance provides a data-supported approach to risk stratification, diagnosis, and management of patients with cirrhosis and portal hypertension (PH). A guidance document is different from a guideline. Guidelines are developed by a multidisciplinary panel of experts who rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This guidance focuses on PH, varices, and variceal hemorrhage (VH), and statements are based on the following: (1) review of the recent literature using PubMed, giving more weight to large, well-designed, prospective trials and well-performed meta-analyses; (2) several consensus conferences among experts; and (3) the authors’ years of experience caring for patients with cirrhosis and varices. Management of ascites and encephalopathy is addressed in other documents.

Portal hypertension and gastrointestinal bleeding.

Variceal bleeding is one of the most serious complications of portal hypertension. The driving force for the development of varices is an increase in portal pressure. As portal hypertension progresses, varices dilate until they finally rupture and bleed. This sequence of events might be prevented by achieving a sufficient decrease in portal pressure or by acting locally at the varices with endoscopic treatments. This article reviews the rationale for the management of portal hypertension and the current recommendations for the prevention and treatment of variceal bleeding.

Noninvasive Prediction of Clinically Significant Portal Hypertension and Esophageal Varices in Patients With Compensated Liver Cirrhosis

OBJECTIVES:We aimed to develop a model based on noninvasive variables for the prediction of clinically significant portal hypertension (CSPH) and of esophageal varices (EV) in patients with compensated liver disease.METHODS:Sixty patients with compensated liver cirrhosis diagnosed by histology were included in the training set. All patients had physical examination, laboratory tests, abdominal color-Doppler ultrasound, upper digestive tract endoscopy, and measurement of hepatic venous pressure gradient. Predictive models for the presence of CSPH and of EV were calculated. The models were validated in an independent series of 74 patients with compensated liver disease.RESULTS:Clinical and laboratory variables were selected in the final models, while ultrasonography did not add statistical power for the prediction of CSPH and EV. The model for prediction of CSPH included albumin, INR, and ALT. The best cutoff had 93% sensitivity and 61% specificity in the training set, and correctly classified 77% of patients in the validation set. Spider angiomas, ALT, and albumin predicted EV. The best cutoff of the model in the training set had a sensitivity of 93% and a specificity of 37% and correctly classified 72% of cases in the validation set.CONCLUSIONS:Noninvasive prediction of EV in well-compensated cirrhotic patients is not accurate. However, a model obtained by combining simple laboratory variables has a high sensitivity to predict CSPH in this population and may be useful to select the subset of patients requiring screening endoscopy. By this method, endoscopic screening could be obviated in about 40% of patients.

Assessing portal hypertension in liver diseases

Portal hypertension is a common complication of chronic liver diseases and is responsible for most clinical consequences of cirrhosis, which represent the more frequent causes of death and liver transplantation in these patients. This review is aimed at clarifying the state-of-the art assessment of portal hypertension and at discussing recent developments in this field. Particular attention is paid to new noninvasive techniques that will be soon available for potential routine use.

Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: A systematic review and meta‐analysis

Whether preoperative clinically significant portal hypertension (CSPH) has or not an impact on the outcome of surgery for hepatocellular carcinoma (HCC) in patients with compensated cirrhosis is debated. This systematic review assesses the impact of CSPH on the outcome of HCC in patients with compensated cirrhosis treated with surgery. We performed a systematic search of the MEDLINE database (articles published in full in English language from 1996 to October 2013) and related bibliography for studies reporting on the postoperative outcomes (3‐ and 5‐year mortality and/or early clinical decompensation) of patients with HCC and compensated cirrhosis treated with surgery according to the presence or absence of CSPH. Independent extraction of articles by two authors using predefined data fields, including study quality indicators, was used; pooled analyses were based on random‐effects models. Eleven studies in total met our inclusion criteria (eight studies for 3‐ and 5‐year postoperative mortality and eight for postoperative clinical decompensation). Moderate heterogeneity among studies for both outcomes was observed, which disappeared after pooling studies using similar methods to assess CSPH. The presence of CSPH increased the risk of 3‐ and 5‐year mortality versus absence of CSPH (pooled odds ratio [OR] for 3‐year mortality: 2.09; 95% confidence interval [CI]: 1.52‐2.88; for 5‐year mortality: 2.07; 95% CI: 1.51‐2.84). CSPH also increased the risk of postoperative clinical decompensation (pooled OR: 3.04; 95% CI: 2.02‐4.59). Conclusions: CSPH (evaluated by any method) significantly increases the risk of 3‐ and 5‐year mortality and of clinical decompensation after surgery for HCC. (Hepatology 2015;61:526‐536)

Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis

Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta‐blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow‐up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P = 0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P = 0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01‐1.12), P = 0.02] was an independent predictor of decompensation, together with HVPG and albumin. Conclusion: Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population. (HEPATOLOGY 2011;)

Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension

BACKGROUND/AIMS Cirrhotic patients chronically treated with beta-blockers who achieve a decrease of hepatic venous pressure gradient (HVPG) > or =20% from baseline or to < or =12 mmHg have a marked reduction of first bleeding or re-bleeding. However, two HVPG measurements are needed to evaluate response. This study was aimed at investigating the predictive role of acute HVPG response to i.v. propranolol for bleeding and survival. METHODS We retrospectively studied 166 cirrhotic patients with varices with HVPG response to i.v. propranolol (0.15 mg/kg). All patients subsequently received non-selective beta-blockers to prevent first bleeding (n=78) or re-bleeding (n=88). RESULTS Thirty-seven patients developed a portal hypertension-related bleeding over 2 years of follow-up. Decrease (12%) in HVPG was the best cut-off for bleeding risk discrimination. This parameter was used to classify patients in responders (n=95) and non-responders (n=71). In primary prophylaxis (54 responders vs. 24 non-responders) the actuarial probability of bleeding was half in responders than in non-responders (12% vs. 23% at 2 years; ns). In secondary prophylaxis (41 responders vs. 47 non-responders) a good hemodynamic response was also significantly and independently associated with a 50% decrease in the probability of re-bleeding (23% at 2 years vs. 46% in non-responders; p=0.032) and a better survival (95% vs. 65%; p=0.003). CONCLUSION The evaluation of acute HVPG response to i.v. propranolol before initiating secondary prophylaxis for variceal bleeding is a useful tool in predicting the efficacy of non-selective beta-blockers. If adequately validated, this might be a more cost-effective strategy than the chronic evaluation of HVPG response and might be useful to guide therapeutic decisions in these patients.

A MELD-Based Model to Determine Risk of Mortality Among Patients With Acute Variceal Bleeding

BACKGROUND & AIMS Patients with cirrhosis with acute variceal bleeding (AVB) have high mortality rates (15%-20%). Previously described models are seldom used to determine prognoses of these patients, partially because they have not been validated externally and because they include subjective variables, such as bleeding during endoscopy and Child-Pugh score, which are evaluated inconsistently. We aimed to improve determination of risk for patients with AVB. METHODS We analyzed data collected from 178 patients with cirrhosis (Child-Pugh scores of A, B, and C: 15%, 57%, and 28%, respectively) and esophageal AVB who received standard therapy from 2007 through 2010. We tested the performance (discrimination and calibration) of previously described models, including the model for end-stage liver disease (MELD), and developed a new MELD calibration to predict the mortality of patients within 6 weeks of presentation with AVB. MELD-based predictions were validated in cohorts of patients from Canada (n = 240) and Spain (n = 221). RESULTS Among study subjects, the 6-week mortality rate was 16%. MELD was the best model in terms of discrimination; it was recalibrated to predict the 6-week mortality rate with logistic regression (logit, -5.312 + 0.207 • MELD; bootstrapped R(2), 0.3295). MELD values of 19 or greater predicted 20% or greater mortality, whereas MELD scores less than 11 predicted less than 5% mortality. The model performed well for patients from Canada at all risk levels. In the Spanish validation set, in which all patients were treated with banding ligation, MELD predictions were accurate up to the 20% risk threshold. CONCLUSIONS We developed a MELD-based model that accurately predicts mortality among patients with AVB, based on objective variables available at admission. This model could be useful to evaluate the efficacy of new therapies and stratify patients in randomized trials.