Ewa Wunsch

Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis.

Ursodeoxycholic acid (UDCA) is no longer recommended for management of adult patients with primary sclerosing cholangitis (PSC). We undertook a prospective evaluation of UDCA withdrawal in a group of consecutive patients with PSC. Twenty six patients, all treated with UDCA (dose range: 10‐15 mg/kg/day) were included. Paired blood samples for liver biochemistry, bile acids, and fibroblast growth factor 19 (FGF19) were collected before UDCA withdrawal and 3 months later. Liquid chromatography/tandem mass spectrometry was used for quantification of 29 plasma bile acid metabolites. Pruritus and health‐related quality of life (HRQoL) were assessed with a 10‐point numeric rating scale, the Medical Outcomes Study Short Form‐36 (SF‐36), and PBC‐40 questionnaires. UDCA withdrawal resulted in a significant deterioration in liver biochemistry (increase of alkaline phosphatase of 75.6%; P < 0.0001; gamma‐glutamyl transpeptidase of 117.9%, P < 0.0001; bilirubin of 50.0%, P < 0.001; alanine aminotransferase of 63.9%, P < 0.005; and aspartate aminotransferase of 45.0%, P < 0.005) and increase of Mayo Risk Score for PSC (change from baseline of +0.5 point; P < 0.003). Bile acid analysis revealed a significant decrease in lithocholic acid and its derivatives after UDCA withdrawal, but no effect on concentrations of primary bile acids aside from an increased accumulation of their taurine conjugates. After UDCA removal cholestatic parameters, taurine species of cholic acid and chenodeoxycholic acid correlated with serum FGF19 levels. No significant effect on HRQoL after UDCA withdrawal was observed; however, 42% of patients reported a deterioration in their pruritus. Conclusion: At 3 months, discontinuation of UDCA in patients with PSC causes significant deterioration in liver biochemistry and influences concentrations of bile acid metabolites. A proportion of patients report increased pruritus, but other short‐term markers of quality of life are unaffected. (Hepatology 2014;60:931–940)

Expression of hepatic Fibroblast Growth Factor 19 is enhanced in Primary Biliary Cirrhosis and correlates with severity of the disease

Cholestasis induces adaptive mechanisms protecting the liver against bile acids (BA) toxicity including modulation of BA synthesis. Whether fibroblast growth factor 19 (FGF19) or farnesoid X receptor (FXR) dependent signaling are involved in the regulation of BA homeostasis in primary biliary cirrhosis (PBC) remains unknown. Here we analyzed hepatic expression of FGF19 and other genes relevant to the adaptive response to cholestasis in tissues from non-cirrhotic (n = 24) and cirrhotic (n = 21) patients along with control tissues (n = 21). Moreover we searched for relationships between serum FGF19 and laboratory/clinical findings in 51 patients. Hepatic FGF19 mRNA expression was increased in non-cirrhotic and cirrhotic tissues (9-fold,p = 0.01; 69-fold,p < 0.0001, respectively). Protein levels of FGF19, FGF receptor 4, FXR and short heterodimer partner were increased in cirrhotic livers (9-fold, p < 0.001; 3.5-fold,p = 0.007; 2.4-fold,p < 0.0001; 2.8-fold,p < 0.0001 vs controls, respectively) which was accompanied by down-regulation of CYP7A1 (50% reduction, p = 0.006). Serum and liver levels of FGF19 correlated with worse liver biochemistry, BAs, quality of life and Mayo Risk Score. Serum FGF19 was elevated in UDCA non-responders. We conclude that PBC induces characteristic changes in liver expression of BAs synthesis regulatory molecules. FGF19 correlates with severity of liver disease and can potentially serve as an indicator of chronic cholestatic liver injury.

Minimal hepatic encephalopathy does not impair health-related quality of life in patients with cirrhosis: a prospective study.

Background: Minimal hepatic encephalopathy (HE) is a serious complication of cirrhosis; however, the impact of minimal HE on health‐related quality of life (HRQoL) remains controversial. The Psychometric Hepatic Encephalopathy Score (PHES) remains a ‘gold standard’ for the assessment of minimal HE, but its results clearly differ between studied populations.

Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases

Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1–60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease-specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4-fold higher risk of death/liver transplantation in patients with PBC and a 2.6-fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival.

Prospective evaluation of PBC-specific health-related quality of life questionnaires in patients with primary sclerosing cholangitis.

Primary biliary cirrhosis and Primary sclerosing cholangitis are autoimmune cholestatic liver diseases sharing a lot in common, including a significant impairment of patients’ health‐related quality of life HRQoL HRQoL in PBC is assessed with disease‐specific PBC‐40 and PBC‐27 questionnaires. A PSC‐specific questionnaire has not been developed. Neither PBC‐40 nor PBC‐27s applicability for PSC has been evaluated. We applied these three questionnaires for HRQoL assessment in a large homogenous cohort of PSC patients.

Plasmapheresis exerts a long‐lasting antipruritic effect in severe cholestatic itch

The amelioration of refractory cholestatic pruritus after plasmapheresis has been reported in single patients. Here, we analyse the efficacy of plasmapheresis in a cohort of patients with primary biliary cholangitis (PBC).

Enhanced liver fibrosis test predicts transplant‐free survival in primary sclerosing cholangitis, a multi‐centre study

Biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC) have not been firmly established. Enhanced liver fibrosis (ELF) test was previously reported to predict outcome in PSC. We aimed to validate the prognostic utility of ELF test in an independent, multi‐centre, retrospective PSC study population.

Normalization of the psychometric hepatic encephalopathy score in Polish population. A prospective, quantified electroencephalography study

The psychometric hepatic encephalopathy score (PHES) is recommended as a gold standard in evaluation of minimal hepatic encephalopathy (HE). Normative databases have been collected in few countries, clearly showing differences among studied groups. Thus, the standardization of PHES for selected populations remains necessary.

Mini-Mental State Examination in patients with hepatic encephalopathy and liver cirrhosis: a prospective, quantified electroencephalography study

BackgroundMini-Mental State Examination (MMSE) is one of the most commonly used methods in the assessment of cognitive mental status. MMSE has been used in hepatology but its usefulness in the evaluation of hepatic encephalopathy (HE) has never been properly assessed. The aim of the study was to investigate the value of MMSE in detection of HE in patients with cirrhosis.MethodsOne hundred and one consecutive patients with liver cirrhosis underwent neurological examination, MMSE and electroencephalography (EEG). Spectral analysis of EEG was done with calculation of mean dominant frequency (MDF) and relative power of delta, theta, alpha and beta rhythms. Minimal HE was diagnosed in patients with normal neurological status and alterations in spectral EEG. Statistical analysis included Fisher’s exact and Anova analysis. Categorical data were compared using Levene’s test for equality of variances. Correlation-coefficient analysis was performed by the Pearson’s r or Z-test, as needed. Tests performance was assessed by the calculating the area under the ROC curve (AUC) and evaluating its difference from reference area (AUC=0.5). A p value <0.05 was considered statistically significant.ResultsOvert HE was identified in 49 (48.5%) and minimal HE in 22 (21.8%) patients. Although there were significant correlations between both severity of liver disease (Child-Pugh classification), overt HE (West-Haven criteria) and various MMSE items, MDF showed no correlation with any of MMSE items as well as MMSE summary score. MMSE (score and items) did not discriminate patients without HE and minimal HE. The only significant differences between patients without HE and with overt HE were seen in respect of MMSE score (p<0.02), orientation to place (p<0.003), repetition (p<0.01) and complex commands-understanding (p<0.02). Test performance analysis has shown that MMSE has no value as a prediction method in determining minimal HE and in respect of overt HE has a sensitivity of 63% and specificity of 52% by a cut-off level at 27.5 points to diagnose overt HE.ConclusionsIn conclusion, although MMSE score and single items are altered in patients with overt HE, MMSE has no value in the assessment of minimal HE. Because MMSE could be impaired in several cognitive dysfunctions, more specific test should be used for measuring HE.

Esophageal duplication cysts: Endosonographic findings in asymptomatic patients

Esophageal duplication cysts are rare inherited lesions usually diagnosed in early childhood. Most of them are found in the mediastinum and manifest themselves as separate masses along or in continuity with the native esophagus. Their prevalence remains unknown and they are treated either surgically or endoscopically. In this report we describe a series of four adult patients in whom esophageal duplication cysts were localised intramurally as masses pressing on the esophageal lumen and who were diagnosed with endoscopic ultrasonography. All patients were initially referred to other centres for upper gastroduodenoscopy due to non-specific dyspeptic symptoms. After finding suspicious lesions in the esophagus their endoscopists referred them for endoscopic ultrasound examination at our centre. In two of the cases lesions mimicked esophageal varices and the other two submucosal tumours. In all four patients endoscopic ultrasonography has shown esophageal duplication cysts. Patients had no symptoms suggesting disease of the esophagus and required no treatment. As the true prevalence of esophageal cysts is unknown, it is very likely that in many patients, like in these four described by us, they may cause no symptoms, remain undetected and require no intervention. Increasing availability of new diagnostic modalities such as endoscopic ultrasonography may change the current view regarding the prevalence of esophageal duplication cysts and prove that they may, in fact, not be such rare findings.