Low sphingolipid levels predict poor survival in patients with alcohol-related liver disease.

Background & Aims: Alcohol-related hepatitis (AH) and alcohol-related cirrhosis are grave conditions with poor prognoses. Altered hepatic lipid metabolism can impact disease development and varies between different alcohol-related liver diseases. Therefore, we aimed to investigate lipidomics and metabolomics at various stages of alcohol-related liver diseases and their correlation with survival. Methods: Patients with newly diagnosed alcohol-related cirrhosis, who currently used alcohol (ALC-A), stable outpatients with decompensated alcohol-related cirrhosis with at least 8 weeks of alcohol abstinence (ALC), and patients with AH, were compared with each other and with healthy controls (HC). Circulating lipids and metabolites were analysed using HPLC and mass spectrometry. Results: Forty patients with ALC, 95 with ALC-A, 30 with AH, and 42 HC provided plasma. Lipid levels changed according to disease severity, with generally lower levels in AH and cirrhosis than in the HC group; this was most pronounced for AH, followed by ALC-A. Nine out of 10 free fatty acids differed between cirrhosis groups by relative increases of 0.12-0.66 in ALC compared with the ALC-A group (p <0.0005). For metabolomics, total bile acids increased by 19.7, 31.3, and 80.4 in the ALC, ALC-A, and AH groups, respectively, compared with HC (all p <0.0001). Low sphingolipid ([d42:1] and [d41:1]) levels could not predict 180-day mortality (AUC = 0.73, p = 0.95 and AUC = 0.73, p = 0.95) more accurately than the model for end-stage liver disease score (AUC = 0.71), but did predict 90-day mortality (AUC d42:1 = 0.922, AUC d41:1 = 0.893; pd42:1 = 0.005, pd41:1 = 0.007) more accurately than the MELD score AUCMELD = 0.70, pMELD = 0.19). Conclusions: Alcohol-related severe liver disease is characterised by low lipid levels progressing with severity of liver disease, especially low sphingomyelins, which also associate to poor prognoses. Impact and implications: Lipidomics has the potential to diagnose and risk stratify patients with liver diseases. Lipidomics differed between patients with alcohol-related hepatitis and alcohol-related cirrhosis with and without recent alcohol use. Furthermore, lipidomics could predict short-term mortality and might be suitable as a prognostic tool in the future. Clinical Trials Registration: Scientific Ethics Committee of the Capital Region of Denmark, journal no. H-21013476.

The impact of rifaximin on inflammation and metabolism in alcoholic hepatitis: A randomized clinical trial.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism. METHODS: The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function. RESULTS: Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days. CONCLUSION: Rifaximin does not alter inflammation or metabolism in patients with AH.

Cholesteryl ester storage disease of clinical and genetic characterisation: A case report and review of literature.

BACKGROUND: Cholesteryl ester storage disease (CESD) is a rare genetic disease. Its symptoms and severity are highly variable. CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver, as well as gastrointestinal and cardiovascular disease. The majority of patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved based on a randomized trial. Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation, as well as their first-degree family members. CASE SUMMARY: The siblings were compound heterozygous for the missense variant in LIPA exon 8, c.894G>A, (p.Gln298Gln) and a single base pair deletion, c.482del (p.Asn161Ilefs*19). Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients. Clinically, both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD. Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value. One of these carriers, a seven-year-old boy, was found to have severe dyslipidemia and was subsequently treated with statins. CONCLUSION: Our study underlines that CESD is a multi-organ disease, the progression of which may occur post-liver transplantation. Our findings underline the need for monitoring of complications and assessment of possible further treatment.

[New name and new treatments for primary biliary cholangitits].

The name of chronic liver disease: primary biliary cirrhosis, has been changed to: primary biliary cholangitis, primarily because of the stigma associated with the word "cirrhosis", as only a minority of the patients develop cirrhosis. In this review we present data on epidemiology and discuss the current treatments with focus on ursodeoxycholic acid and the newly described effects of the farnesoid receptor agonist obeticholic acid.

Predictors of heavy drinking after liver transplantation for alcoholic liver disease in Denmark (1990-2013): a nationwide study with competing risks analyses.

OBJECTIVE: Heavy drinking following liver transplantation decreases survival. Little is known of predictors of heavy drinking, which should guide clinicians identifying patients at high risk of return to heavy drinking after transplantation. MATERIAL AND METHODS: We calculated the cumulative incidence of heavy drinking among patients transplanted for alcoholic liver disease in Denmark 1990-2013. We then analyzed pre-transplant demographic and psychiatric characteristics as predictors of post-transplant heavy drinking. Information was obtained from medical records, from nationwide registries and by interview. RESULTS: Among 156 liver-transplanted patients, the cumulative incidence of heavy drinking was 18%, 24% and 27% after 5, 10 and 15 years post-transplant. In univariate analyses of pre-transplant predictors of heavy drinking after transplantation, younger age (p < 0.001), being retired (p = 0.007), anxiety (p = 0.04), personality disorder (p = 0.05) and no lifetime diagnosis of alcohol dependence (p = 0.03) were associated with heavy drinking after transplantation. Smoking (p = 0.06) tended to be associated, whereas depression (p = 0.7) or being married was not (p = 0.7). In the multivariate analysis, only younger age (p = 0.03), being retired (p = 0.007) and no lifetime diagnosis of alcohol dependence (p = 0.003) remained significant predictors. Heavy drinking after transplantation decreased survival beyond 5 years post-transplant (p = 0.004). CONCLUSIONS: There is a high incidence of heavy drinking after liver transplantation for alcoholic cirrhosis in Denmark. Younger age, being retired and no lifetime diagnosis of alcohol dependence were predictors of heavy drinking after transplantation.

Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis.

BACKGROUND & AIMS: Patients with cirrhosis and alcoholic hepatitis are often malnourished and have a superimposed stress metabolism, which increases nutritional demands. We performed a systematic review on the effects of nutritional therapy vs. no intervention for patients with cirrhosis or alcoholic hepatitis. METHODS: We included trials on nutritional therapy designed to fulfil at least 75% of daily nutritional demand. Authors extracted data in an independent manner. Random-effects and fixed-effect meta-analyses were performed and the results expressed as risk ratios (RR) with 95% confidence intervals (CI). Sequential analyses were performed to evaluate the risk of spurious findings because of random and systematic errors. Subgroup and sensitivity analyses were performed to evaluate the risk of bias and sources of between trial heterogeneity. RESULTS: Thirteen randomized controlled trials with 329 allocated to enteral (nine trials) or intravenous (four trials) nutrition and 334 controls. All trials were classed as having a high risk of bias. Random-effects meta-analysis showed that nutritional therapy reduced mortality 0.80 (95% CI, 0.64 to 0.99). The result was not confirmed in sequential analysis. Fixed-effect analysis suggested that nutrition prevented overt hepatic encephalopathy (0.73; 95% CI, 0.55 to 0.96) and infection (0.66; 95% CI, 0.45 to 0.98, respectively), but the results were not confirmed in random-effects analyses. CONCLUSION: Our review suggests that nutritional therapy may have beneficial effects on clinical outcomes in cirrhosis and alcoholic hepatitis. High-quality trials are needed to verify our findings.

Predictors of health-related quality of life in outpatients with cirrhosis: results from a prospective cohort.

Background. Cirrhosis may lead to a poor health-related quality of life (HRQOL), which should be taken into consideration when addressing the cirrhotic outpatient. Methods. Prospective cohort study evaluating predictors of HRQOL in outpatients with cirrhosis. Patients with overt hepatic encephalopathy at baseline were excluded. HRQOL was evaluated at baseline using the six point Chronic Liver Disease Questionnaire. Predictors of low quality of life scores (<4 points) and mortality were analyzed using multivariable logistic regression. Results. In total, 92 patients were included (mean age 61 years, 59% male). Nineteen patients died (mean duration of follow-up 20 months). The mean Child-Pugh score was 6.9. Twenty percent had a poor HRQOL judged by the Chronic Liver Disease Questionnaire score and 45% had covert hepatic encephalopathy. The only predictors of poor HRQOL were the Child-Pugh score (ß=0.45;P = 0.013), nonalcoholic etiology of cirrhosis (ß=-2.34;P = 0.009), and body mass index (ß=-0.20;P = 0.023). The body mass index predicted poor HRQOL independently of the presence of ascites and albumin level. Conclusions. The body mass index was associated with a low HRQOL. This suggests that malnutrition may be an important target in the management of patients with cirrhosis.

A Doppler waveform index to characterize hepatic vein velocity pattern and evaluate hepatic fibrosis.

PURPOSE: To describe a Doppler waveform index representing the hepatic vein flow velocity pattern and to examine its relationship to the degree of hepatic fibrosis. METHODS: Doppler waveforms were obtained in 66 patients scheduled for percutaneous liver needle biopsy and categorized as normal (with a retrograde flow phase) or abnormal (without retrograde flow). Waveforms were also characterized using a hepatic vein waveform index (HVWI): (maximum - minimum velocity)/(maximum velocity). Biopsy specimens were graded for fibrosis. RESULTS: There was a highly significant decrease in HVWI with increasing fibrosis score in the biopsy (p < 0.001, Jonckheere trend test). The biopsy showed cirrhosis in 14 of 29 patients (48%) with absent retrograde flow and 5 of 37 patients (14%) with a normal flow pattern. Using HVWI as the criterion, cirrhosis was present in 13 of 21 (62%) patients with HVWI < 0.75, in 6 of 31 (19%) patients with 0.75 < HVWI < 1.50, and in none of 14 (0%) patients with HVWI > 1.50. CONCLUSIONS: HVWI is inversely correlated to the degree of liver fibrosis and may be more efficient than the presence or absence of retrograde flow in diagnosing and grading hepatic fibrosis.

Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials.

BACKGROUND & AIMS: A system for screening of nutritional risk is described. It is based on the concept that nutritional support is indicated in patients who are severely ill with increased nutritional requirements, or who are severely undernourished, or who have certain degrees of severity of disease in combination with certain degrees of undernutrition. Degrees of severity of disease and undernutrition were defined as absent, mild, moderate or severe from data sets in a selected number of randomized controlled trials (RCTs) and converted to a numeric score. After completion, the screening system was validated against all published RCTs known to us of nutritional support vs spontaneous intake to investigate whether the screening system could distinguish between trials with a positive outcome and trials with no effect on outcome. METHODS: The total number of randomized trials identified was 128. In each trial, the group of patients was classified with respect to nutritional status and severity of disease, and it was determined whether the effect of nutritional intervention on clinical outcome was positive or absent. RESULTS: Among 75 studies of patients classified as being nutritionally at-risk, 43 showed a positive effect of nutritional support on clinical outcome. Among 53 studies of patients not considered to be nutritionally at-risk, 14 showed a positive effect (P=0.0006). This corresponded to a likelihood ratio (true positive/false positive) of 1.7 (95% CI: 2.3-1.2). For 71 studies of parenteral nutrition, the likelihood ratio was 1.4 (1.9-1.0), and for 56 studies of enteral or oral nutrition the likelihood ratio was 2.9 (5.9-1.4). CONCLUSION: The screening system appears to be able to distinguish between trials with a positive effect vs no effect, and it can therefore probably also identify patients who are likely to benefit from nutritional support.