Assessing nutrition status, sarcopenia, and frailty in adult transplant recipients.

The assessment of nutrition status, sarcopenia, and frailty holds significant relevance in the context of adult transplantation, as these factors are associated with an unfavorable prognosis; thus, transplant candidates must undergo a full nutrition assessment. Screening tools may be used to prioritize patients, this can be done using the Nutrition Risk Screening 2002 or Royal Free Hospital-Nutritional Prioritizing Tool. Subsequently, a thorough nutrition-focused physical examination should be conducted to evaluate clinical signs of nutrition deficiencies, fat and muscle loss, and fluid overload; dietary history and current intake must also be assessed. Apart from physical examination, specific testing for sarcopenia and frailty are recommended. For sarcopenia assessment, specifically for muscle quantification, the gold standard is the cross-sectional measurement of the muscle at L3 obtained from a computed tomography scan or magnetic resonance imaging; dual-energy x-ray absorptiometry is also a good tool especially when appendicular skeletal muscle index is calculated. Other more readily available options include phase angle from bioelectrical impedance or bioimpedance spectroscopy. In the sarcopenia assessment, muscle function evaluation is required, handgrip strength stands as the primary test for this purpose; this test is also part of the subjective global assessment and is included in some frailty scores. Finally, for frailty assessment, the Short Physical Performance Battery is useful for evaluating physical frailty, and for a multidimensional evaluation, the Fried frailty phenotype can be used. Specifically for liver transplant candidates, the use of Liver Frailty Index is recommended.

Effect of a monitored exercise protocol in cerebral and hepatic hemodynamics in patients with cirrhosis and portal hypertension.

BACKGROUND: Physical exercise (PE) has been proven to be beneficial in patients with cirrhosis; effects in cognitive function and cerebral hemodynamics, are yet to be explored. AIM: To evaluate the effects of a PE program (LFN-exercise protocol) in hepatic/cerebral hemodynamics. METHODS: Randomized open clinical trial in patients with cirrhosis; Control: Diet(n = 13),Intervention: Diet + exercise(n = 14) for 12 weeks. Patients received an educational session, mental exercises (printed book and sudoku), and high-protein diet. Exercise intervention consisted of walking 4 times/week with an intensity rated between 12 and 14 on the Borg scale, monitored through bracelet accelerometers. Patients received weekly text messages to encourage adherence and had monthly in-person visits. RESULTS: Patients were mainly Child-Pugh A(88.9 %), median MELD 8(8-10), mean age 53±8 years. In the exercise group the number of steps increased from 9667±3008 to 11,931±4463 (p = 0.002), vs 8004±3224 to 8903±3504 (p = 0.053) in controls. Exercise decreased HVPG from 11(8-14) to 8(6-11)mmHg (p = 0.032) vs no change in the control group from 14(12-16) to 15(11-17)mmHg (p = 0.959). Intervention group showed better cerebral hemodynamics, cognitive function, nutritional status and quality of life after the intervention. Adherence was >90 %, with no adverse events. CONCLUSION: The LFN-exercise protocol improves portal hypertension, cerebral hemodynamics and cognitive function, as well as nutritional status and quality of life. GOV NUMBER: NCT03932552.

Myostatin is associated with the presence and development of acute-on-chronic liver failure.

Background & Aims: Acute-on-chronic liver failure (ACLF) has been linked to different pathophysiological mechanisms, including systemic inflammation and mitochondrial dysfunction. Sarcopenia has also been proposed as a potential mechanism; myostatin is a key factor inducing sarcopenia. Therefore, this study aimed to evaluate the association of myostatin levels with the development of ACLF and mortality in patients with cirrhosis. Methods: We performed a prospective cohort study, including both outpatient and hospitalized patients with cirrhosis. Clinical, biochemical, and nutritional parameters were evaluated, and the development of acute decompensation (AD) or ACLF during follow-up was recorded. ACLF was defined according to the EASL-CLIF criteria. Receiver-operating characteristic, Kaplan-Meier and Cox regression analyses were performed. Results: A total of 186 patients with the whole spectrum of cirrhosis were included; mean age was 53.4 ± 14 years, mean Child-Pugh score was 8 ± 2.5 and mean MELD score was 15 ± 8. There was a stepwise decrease in myostatin levels from a compensated stage to AD and ACLF. Myostatin correlated positively with nutritional markers and negatively with severity scores. The prevalence of sarcopenia was 73.6%. During follow-up, 27.9% of patients developed AD and 25.8% developed ACLF. Most episodes were grade 2-3, mainly (62.5%) precipitated by infections. The most common organ failures observed were in the liver (63.3%) and the kidney (64.6%). Receiver-operating characteristic analysis yielded <1,280 pg/ml as the best serum myostatin cut-off for the prediction of ACLF. In Kaplan-Meier curves and multivariate analysis, myostatin levels remained independently associated with the incidence of ACLF and survival. Conclusions: There is a progressive decrease in myostatin levels as cirrhosis progresses, demonstrating an association of sarcopenia with the development of ACLF and increased mortality. Impact and implications: Myostatin is a muscle hormone, it is decreased in patients with muscle loss and is a marker of impaired muscle function. In this study we show that myostatin levels are decreased in patients with cirrhosis, with lower levels in patients with acute decompensation and acute-on chronic liver failure (ACLF). Low myostatin levels in cirrhosis predict the development of ACLF and mortality independently of liver disease severity and sex.

Novel therapeutic avenues for the study of chronic liver disease and regeneration: The foundation of the Iberoamerican Consortium for the study of liver Cirrhosis.

Unfortunately, there is a gap of understanding in the pathophysiology of chronic liver disease due to the lack of experimental models that exactly mimic the human disease. Additionally, the diagnosis of patients is very poor due to the lack of biomarkers than can detect the disease in early stages. Thus, it is of utmost interest the generation of a multidisciplinary consortium from different countries with a direct translation. The present reports the meeting of the 2021 Iberoamerican Consortium for the study of liver Cirrhosis, held online, in October 2021. The meeting, was focused on the recent advancements in the field of chronic liver disease and cirrhosis with a specific focus on cell pathobiology and liver regeneration, molecular and cellular targets involved in non-alcoholic hepatic steatohepatitis, alcoholic liver disease (ALD), both ALD and western diet, and end-stage liver cirrhosis and hepatocellular carcinoma. In addition, the meeting highlighted recent advances in targeted novel technology (-omics) and opening therapeutic avenues in this field of research.

Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

Abnormal Liver Function Test in Patients Infected with Coronavirus (SARS-CoV-2): A Retrospective Single-Center Study from Spain.

The outbreak of the novel coronavirus SARS-CoV-2 epidemic has rapidly spread and still poses a serious threat to healthcare systems worldwide. In the present study, electronic medical records containing clinical indicators related to liver injury in 799 COVID-19-confirmed patients admitted to a hospital in Madrid (Spain) were extracted and analyzed. Correlation between liver injury and disease outcome was also evaluated. Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyltransferase (GGT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and AST/ALT ratio were elevated above the Upper Limit of Normal (ULN) in 25.73%, 49.17%, 34.62%, 24.21%, 55.84% and 75% of patients, respectively. Interestingly, significant positive correlation between LDH levels and the AST/ALT ratio with disease outcome was found. Our data showed that SARS-CoV-2 virus infection leads to mild, but significant changes in serum markers of liver injury. The upregulated LDH levels as well as AST/ALT ratios upon admission may be used as additional diagnostic characteristic for COVID-19 patients.

Phase Angle From Bioelectrical Impedance for the Assessment of Sarcopenia in Cirrhosis With or Without Ascites.

BACKGROUND AND AIMS: Skeletal muscle index (SMI) from computed tomography (CT) reliably assesses sarcopenia, however, it is expensive and involves serial radiation exposure. Phase angle (PhA) from bioimpedance analysis (BIA) is a noninvasive, low cost, bedside nutritional tool used to monitor changes to nutritional interventions. We aimed to compare the performance of PhA with SMI to assess sarcopenia in cirrhosis. METHODS: Ambispective cohort study. Consecutive patients with cirrhosis and available images from abdominal CT scan were included. Monofrequency BIA was performed within 2 weeks CT. Spearman's correlation, ROC curve, and survival analysis with Kaplan-Meier, Cox and competing-risk regression were performed. RESULTS: 136 patients were included with a mean age of 54.5 years (60% female). Most had decompensated disease (66%) with ascites in 47%, and a mean MELD of 14 ± 6. We found positive correlations between SMI and PhA (r = 0.58 , P < .001), irrespective of the presence of ascites. The AUROC of PhA-sarcopenia in all patients was 0.702; (0.748 in males,0.677 in females). The best cutoffs of PhA for diagnosing sarcopenia were ≤5.6° in males and ≤5.4° in females. SMI and PhA were significantly associated with survival in Kaplan-Meier curves. In multivariable analyses, SMI was outperformed by age and MELD, whereas PhA remained independently associated with mortality. Considering transplantation as a competing risk, regression analysis showed both SMI and PhA to be independent predictors of mortality (sHR:0.95 [0.90-0.99] and sHR:0.61 [0.42-0.88]). CONCLUSION: PhA moderately correlates with SMI for the identification of sarcopenia in patients with cirrhosis. However, its prognostic accuracy is comparable to that of SMI, and it is not influenced by ascites.

Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan's nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.

Hepatic manifestations in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multi-organic autoimmune disease with a wide variety of clinical manifestations. However, hepatic dysfunction is not included in the diagnostic criteria for the disease and has not been recognized properly. The spectrum of hepatic involvement described in these patients ranges from abnormalities in liver function tests (LFTs) to fulminant hepatic failure. Usually, abnormalities in LFTs are only mild and transient, have a hepatocellular pattern and are not related to SLE but rather are mostly drug related. The most frequent finding on liver biopsy is steatosis (non-alcoholic fatty liver disease). Patients do not frequently progress to advanced chronic liver disease, and their outcome is favourable. Those who develop cirrhosis have traditional risk factors, such as other non-SLE-related conditions. In this work, we aim to review hepatic manifestations in patients with SLE, as well as the diagnostic and therapeutic approaches used for different liver diseases in these patients.

Clinical characteristics and treatment outcomes in patients with liver cirrhosis and lymphoma.

BACKGROUND: A significant number of patients with liver cirrhosis concomitantly develop some type of solid or hematological cancer, including lymphoma. Treatment of patients with lymphoma and cirrhosis is challenging for physicians due to the clinical characteristics related to cirrhosis, including biochemical and functional abnormalities, as well as portal hypertension and lack of scientific evidence, limiting the use of chemotherapy. Currently, experts recommend only offering oncological treatment to patients with compensated cirrhosis. AIM: To evaluate the clinical characteristics and treatment outcomes in patients with cirrhosis and lymphoma treated with chemotherapy. METHODS: This was a case-control study conducted at a tertiary care center in Mexico. Data was recorded from medical files and from 8658 possible candidates with cirrhosis and/or lymphoma (2000 to 2018). Only 23 cases had both diseases concomitantly; 10 patients with cirrhosis and lymphoma (cases) met the selection criteria and were included, and 20 patients with lymphoma (controls) were included and matched according to age, sex, and date of diagnosis, type and clinical stage of lymphoma. All patients received treatment with chemotherapy. For statistical analysis, descriptive statistics, Shapiro-Wilk test, Mann-Whitney U test, chi-square test and Fisher's exact test were used. Survival was evaluated using Kaplan-Meier curves and Log-rank test. RESULTS: There were differences in biochemical variables inherent to liver disease and portal hypertension in patients with cirrhosis. The most frequent etiology of cirrhosis was hepatitis C virus (50%); 80% were decompensated, the median Child-Turcotte-Pugh score was 7.5 (6.75-9.25), and mean Model for End-stage Liver Disease was 11.5 ± 4.50. Regarding lymphomas, non-Hodgkin's were the most common (90%), and diffuse large B cell subtype was the most frequent, with a higher International Prognostic Index in the cases (3 vs 2, P = 0.049). The chemotherapy regimens had to be adjusted more frequently in the case group (50% vs 5%, P = 0.009). The complications derived from chemotherapy were similar between both groups (80% vs 90%, P = 0.407); however, non-hematological toxicities were more common in the case group (30% vs 0%, P = 0.030). There was no difference in the response to treatment between groups. Survival was higher in the control group (56 wk vs 30 wk, P = 0.269), although it was not statistically significant. CONCLUSION: It may be possible to administer chemotherapy in selected cirrhotic patients, regardless of their severity, obtaining satisfactory clinical outcomes. Prospective clinical trials are needed to generate stronger recommendations.

Reclassifying Hepatic Cell Death during Liver Damage: Ferroptosis-A Novel Form of Non-Apoptotic Cell Death?

Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic.

Effect of non-alcoholic beer, diet and exercise on endothelial function, nutrition and quality of life in patients with cirrhosis.

BACKGROUND: The implementation of nutritional strategies targeting several variables at once could benefit patients with cirrhosis. Non-alcoholic beer has different compounds that exert antioxidant, anti-inflammatory and nutritional properties. AIM: To evaluate the effect of diet + exercise and non-alcoholic beer on nutritional status, endothelial function and quality of life in patients with cirrhosis. METHODS: In this randomized open clinical trial, patients with cirrhosis were randomized into two groups: The intervention (non-alcoholic beer + diet + exercise) and control (water + diet + exercise) group. Treatment consisted of 330 mL non-alcoholic beer/day or the same amount of water, plus an individualized dietary plan and an exercise program with a pedometer-based bracelet to reach at least 5000 steps/d and > 2500 above the baseline during 8 wk. Endothelial function (flow-mediated dilation, plethysmography), biochemical and nutritional variables and quality of life (CLDQ) were evaluated. RESULTS: Forty-three patients were included in the study, 21 in the control group and 22 in the intervention group. The mean age was 53.5 ± 7.8 years, 60% were women, the median MELD score was 8 (7-10) and most patients were Child-Pugh A (88%). Adherence to the interventions was > 90% in both groups, there were no adverse events and all biochemical parameters remained stable in both groups. Endothelial function improved in both groups. All measured nutritional parameters improved in the intervention group, compared to only 2 in the control group and quality of life improved in both groups; however, more domains improved in the intervention group. CONCLUSION: The intervention consisting of non-alcoholic beer, diet and exercise seems to be safe and well tolerated in patients with cirrhosis, and shows improvement in nutritional status, endothelial function, and quality of life. These results need to be further confirmed.

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 patient's 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.

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 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.

Clinical scenarios for the use of S100ß as a marker of hepatic encephalopathy.

AIM: To evaluate the association between serum concentrations of S100ß 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 Whitney's 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. S100ß 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 S100ß 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 S100ß 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 S100ß for the diagnosis of HE (sensitivity 83.3%, specificity 63.6%). CONCLUSION: Serum concentrations of S100ß 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 S100ß could help in the correct characterization of incipient stages of HE.

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. Student's 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.

Cerebral haemodynamics in cirrhotic patients with hepatic encephalopathy.

BACKGROUND & AIMS: 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. METHODS: We studied 90 subjects by TCD measuring PI and BHI in the middle cerebral artery: 30 with cirrhosis and no HE, 30 with cirrhosis and low-grade HE and 30 healthy subjects. Critical flicker frequency, psychometric hepatic encephalopathy score and West-Haven criteria were performed to assess MHE and HE respectively. RESULTS: Pulsatility index increased in decompensated cirrhotics (Child ≥ 7) when compared with compensated cirrhotics and healthy subjects [median (IQR) 1.07 (0.95-1.21) vs 0.90 (0.83-1.05) vs 0.87 (0.78-0.96); P < 0.001]. A reverse relationship was observed for BHI among the three groups [0.82 (0.45-1.11) vs 1.20 (0.82-1.52) vs 1.28 (1.06-1.68); P < 0.001]. Similar findings were observed in decompensation [model for end-stage liver disease (MELD) score ≥14]. Patients with HE showed higher PI and lower BHI [1.05 (1.00-1.16) and 0.89 (0.59-1.15)], when compared with patients without HE [0.96 (0.83-1.13) and 1.00 (0.60-1.53)] or controls [0.87 (0.78-0.96) and 1.28 (1.06-1.68)] (P < 0.001 for PI, and P = 0.007 for BHI). In multivariate regression models, only PI predicted HE, but it was outperformed by MELD-sodium and tumour necrosis factor-alpha. CONCLUSIONS: These results indicate that cerebral haemodynamics are altered in patients with cirrhosis, in relation to severity of disease and HE. Findings on impaired PI and BHI suggest that structural vascular damage and loss of vascular autoregulation are implicated in the pathophysiology of HE.