Astrid Ruiz-Margáin

Malnutrition assessed through phase angle and its relation to prognosis in patients with compensated liver cirrhosis: A prospective cohort study

BACKGROUND Malnutrition is a frequent complication of cirrhosis and it has been associated to more severe disease and development of complications. Phase angle is a bedside reliable tool for nutritional assessment based on conductivity properties of body tissues. AIM To evaluate the association between malnutrition assessed through phase angle and mortality in patients with liver cirrhosis. METHODS We performed a prospective cohort study in a tertiary care centre; 249 patients were enrolled with 48 months of follow-up. Clinical, nutritional (malnutrition = phase angle ≤ 4.9°) and biochemical evaluations were performed. Students t-test and χ(2) method were used as appropriate. Kaplan-Meier curves and multivariate Cox regression were used to evaluate mortality. RESULTS Mean follow-up was 33.5 months. Survival analysis showed higher mortality in the malnourished group compared to the well-nourished group (p = 0.076), Kaplan-Meier curves were further stratified according to compensated and decompensated status showing higher mortality in compensated patients according to Child-Pugh (p = 0.002) and Model for End-Stage Liver Disease score (p = 0.008) when malnutrition was present. Multivariate analysis showed that malnutrition was independently associated with mortality (HR = 2.15, 1.18-3.92). CONCLUSIONS In our cohort, malnutrition was independently associated with mortality. This is the first study showing higher mortality in malnourished compensated cirrhotic patients.

Exercise and physical activity for patients with end‐stage liver disease: Improving functional status and sarcopenia while on the transplant waiting list

Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end‐stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic inflammation, altered macronutrient and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patients functional status and presents in approximately 1 in 5 patients on the liver transplantation waiting list. Sarcopenia, poor physical fitness/cardiopulmonary endurance (CPE), and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, CPE, health‐related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well‐being, and possibly less complications from portal hypertension. In conclusion, although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home‐based physical activity interventions may be able to effectively reach a larger number of patients. Liver Transplantation 24 122–139 2018 AASLD.

Changes in Hepatic Venous Pressure Gradient Induced by Physical Exercise in Cirrhosis: Results of a Pilot Randomized Open Clinical Trial.

OBJECTIVES:Exercise has been scarcely studied in patients with cirrhosis, and prior evidence showed hepatic venous pressure gradient (HVPG) to be increased in response to exercise. The aim of this study was to investigate the effects of a supervised physical exercise program (PEP) in patients with cirrhosis.METHODS:In an open-label, pilot clinical trial, patients with cirrhosis were randomized to PEP (cycloergometry/kinesiotherapy plus nutritional therapy, n=14) or control (nutritional therapy, n=15); for 14 weeks. Primary outcomes were: the effect of PEP in HVPG, and quality of life (chronic liver disease questionnaire, CLDQ). As secondary outcomes we investigated changes in physical fitness (cardiopulmonary exercise testing), nutritional status (phase angle—bioelectrical impedance), ammonia levels, and safety.RESULTS:Twenty-two patients completed the study (11 each). HVPG decreased in subjects allocated to PEP (−2.5 mm Hg (interquartile range: −5.25 to 2); P=0.05), and increased in controls (4 mm Hg (0–5); P=0.039), with a significant between-groups difference (P=0.009). No major changes were noted in CLDQ in both groups. There was significant improvement in ventilatory efficiency (VE/VCO2) in PEP group (−1.9 (−3.12 to −0.1); P=0.033), but not in controls (−0.4 (−5.7 to 1.4); P=0.467). Phase angle improvement and a less-pronounced exercise-induced hyperammonemia were noted only in PEP group. No episodes of variceal bleeding or hepatic encephalopathy were observed.CONCLUSIONS:A supervised PEP in patients with cirrhosis decreases the HVPG and improves nutritional status with no changes in quality of life. Further studies evaluating physical training in cirrhosis are eagerly awaited in order to better define the benefits of sustained exercise. ClinicalTrials.gov:NCT00517738.

Exercise and physical activity for patients with ESLD: Improving functional status and sarcopenia while on the transplant waitlist

Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end‐stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic inflammation, altered macronutrient and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patients functional status and presents in approximately 1 in 5 patients on the liver transplantation waiting list. Sarcopenia, poor physical fitness/cardiopulmonary endurance (CPE), and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, CPE, health‐related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well‐being, and possibly less complications from portal hypertension. In conclusion, although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home‐based physical activity interventions may be able to effectively reach a larger number of patients. Liver Transplantation 24 122–139 2018 AASLD.

Cerebral haemodynamics in cirrhotic patients with hepatic encephalopathy

Factors other than elevated levels of ammonia may be implicated in hepatic encephalopathy (HE) pathophysiology, including abnormal cerebral haemodynamics. Transcranial Doppler ultrasonography (TCD) evaluates cerebrovascular structural integrity and reactivity, through pulsatility index (PI) and breath‐holding index (BHI) respectively. The aim of this study was to evaluate cerebral haemodynamics by TCD in patients with compensated and decompensated cirrhosis, and patients with and without HE.

Low phase angle is associated with the development of hepatic encephalopathy in patients with cirrhosis

AIM Evaluate the association between phase angle and the development of hepatic encephalopathy in the long-term follow-up of cirrhotic patients. METHODS This was a prospective cohort study. Clinical, nutritional and biochemical evaluations were performed. Mann-Whitney’s U and χ2 tests were used as appropriate. Kaplan-Meier curves and Cox proportional Hazards analysis were used to evaluate the prediction and incidence of hepatic encephalopathy. RESULTS Two hundred and twenty were included; the most frequent etiology of cirrhosis was hepatitis C infection, 52% of the patients developed hepatic encephalopathy (18.6% covert and 33.3% overt); the main precipitating factors were infections and variceal bleeding. Kaplan-Meier curves showed a higher proportion of HE in the group with low phase angle (39%) compared to the normal phase angle group (13%) (P = 0.012). Furthermore, creatinine and phase angle remained independently associated to hepatic encephalopathy in the Cox regression multivariate analysis [hazard ratio = 1.80 (1.07-3.03)]. CONCLUSION In our cohort of patients low phase angle was associated with an increased incidence of hepatic encephalopathy. Phase angle is a useful nutritional marker that evaluates cachexia and could be used as a part of the integral assessment in patients with cirrhosis.

Clinical scenarios for the use of S100β as a marker of hepatic encephalopathy

AIM To evaluate the association between serum concentrations of S100β in patients with cirrhosis and the presence of low grade hepatic encephalopathy (HE). METHODS This was a cross-sectional study. The population was categorized into four groups healthy subjects, cirrhosis without HE, cirrhosis with covert hepatic encephalopathy (CHE) and cirrhosis with overt HE. Kruskal-Wallis, Mann Whitneys U with Bonferroni adjustment Spearman correlations and area under the ROC were used as appropriate. RESULTS A total of 61 subjects were included, 46 cirrhotic patients and 15 healthy volunteers. S100β values were different among all groups, and differences remained significant between groups 1 and 2 (P < 0.001), and also between groups 2 and 3 (P = 0.016), but not between groups 3 and 4. In cirrhotic patients with HE S100β was higher than in patients without HE [0.18 (0.14-0.28) ng/mL vs 0.11 (0.06-0.14) ng/mL, P < 0.001]. There was a close correlation between serum concentrations of S100β and psychometric hepatic encephalopathy score in patients with cirrhosis without HE compared to the patients with cirrhosis with CHE (r = -0.413, P = 0.019). ROC curve analysis yielded > 0.13 ng/mL as the best cutoff value of S100β for the diagnosis of HE (sensitivity 83.3%, specificity 63.6%). CONCLUSION Serum concentrations of S100β are higher in patients with cirrhosis than in healthy volunteers, and are further increased in the presence of hepatic encephalopathy. The results suggest that serum biomarkers such as S100β could help in the correct characterization of incipient stages of HE.

Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis

Acute‐on‐chronic liver failure (ACLF) develops in acute decompensation (AD) of cirrhosis and shows high mortality. In critically ill patients, early diagnosis of ACLF could be important for therapeutic decisions (eg, renal replacement, artificial liver support, liver transplantation). This study evaluated fibroblast growth factor 21 (FGF21) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals (112 critically patients and 42 healthy controls) divided into a training and a validation cohort. In the training cohort of 42 healthy controls and 34 critically ill patients (of whom 24 were patients with cirrhosis), levels of FGF21, interleukin (IL) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow‐up and underwent daily clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, especially in patients with cirrhosis admitted to the intensive care unit (ICU). Moreover, FGF21 as well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the severity of ACLF. Interestingly, in the validation cohort, FGF21 was also elevated in the patients who developed ACLF in the next 7 days. In these patients, FGF21 levels were an independent predictor of ACLF presence and development in multivariate analysis together with Child‐Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this study demonstrates that FGF21 levels are of specific diagnostic value regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. Further studies are warranted to address pathophysiological and possible therapeutic implications. Liver Transplantation 24 595–605 2018 AASLD.

Risk factors associated with complications in cirrhotic patients undergoing endoscopic retrograde cholangio-pancreatography

Objective Endoscopic retrograde cholangio-pancreatography (ERCP) is useful for the management of biliary tract diseases; in patients with cirrhosis, portal hypertension may increase the risk for complications from ERCP. We evaluated the outcome and risk factors related to ERCP in patients with cirrhosis and portal hypertension. Patients and methods In this case–control study, 37 patients (71 procedures) with cirrhosis and portal hypertension (group 1) and 37 controls (group 2) undergoing ERCP were included. Logistic regression and receiver operating characteristic curve analysis were used to predict the risk factors. Results Mean Child–Pugh and model for end-stage liver disease (MELD) score were 9±2.1 and 17.8±6, respectively. Ascites was present in 46% of the patients, esophageal varices in 63% (large esophageal varices 43.7%), and hepatic encephalopathy in 16%. The main indication for ERCP in both groups was choledocholithiasis. Successful cannulation rate was 97% in both groups. Biliary sphincterotomy was performed more frequently in group 2 than in group 1 (60 vs. 35%, P=0.036); there was no difference in the frequency of complications related to ERCP between cirrhotics and noncirrhotics (10 vs. 8%, P=0.677). Complications in patients with cirrhosis were related to lower alkaline phosphatase and sphincterotomy rate; in the multivariable analysis only sphincterotomy was independently associated with complications [odds ratio 9.8 (1.7–56.3)]. Receiver operating characteristic curve analysis yielded a MELD score of more than 16 to best predict complications after ERCP in cirrhosis. Conclusion Outcomes after ERCP in patients with cirrhosis are similar to those of noncirrhotics despite the alteration in coagulation parameters and the presence of disease-specific complications; however, a more cautious approach in patients with cirrhosis undergoing sphincterotomy and MELD of more than 16 is needed.

Changes in cerebral hemodynamics in cirrhotic patients after liver transplantation

Improvement in cognitive function after orthotopic liver transplantation (LT) has been demonstrated in the acute setting immediately after LT and in acute liver failure. However, the longterm changes in cerebral hemodynamics after LT remain unexplored. Therefore, we aimed to evaluate the longterm changes in cerebral hemodynamics of patients with cirrhosis after LT. In this prospective cohort study, we performed transcranial Doppler ultrasonography (TCD) measuring the pulsatility index (PI), resistance index (RI), and breath‐holding index (BHI) to evaluate cerebrovascular structural integrity and reactivity, respectively, in both middle cerebral arteries before and after LT. Neuropsychometric tests and West‐Haven criteria were used for hepatic encephalopathy (HE) characterization. Interleukin 6 and tumor necrosis factor α plasma levels were measured. Descriptive statistics and Wilcoxon’s test were used. There were 27 patients who were included. Median follow‐up after LT was 6 months, mean age before LT was 46.3 ± 10.3 years, the main etiology was hepatitis C virus (59%), and most of the patients were Child‐Pugh B (15/27). Model for End‐Stage Liver Disease (MELD) score was 16 ± 7.5, MELD‐Na was 19.3 ± 7.1, Psychometric Hepatic Encephalopathy Score was –3.48 ± 3.66, and critical flicker fusion (CFF) was 40.28 ± 5.70 Hz. Before LT, 17/27 patients had HE and 11/27 ascites. A decrease of 20.8% and 13.5% in PI and RI was observed after LT (P < 0.001, both), together with an increase in BHI (32.4%, P = 0.122). These changes in cerebral hemodynamics paralleled those in systemic inflammation. Clinical improvement in cognition was observed in all patients with overt HE after LT. In conclusion, these results show a significant improvement in cerebral hemodynamics after LT, obtained through TCD, indicating less arterial cerebral vasoconstriction together with a decrease in systemic inflammation. Changes in cerebral vasoconstriction can be the basis for the improvement in cognitive function after LT in the long term.