R Zenouzi

Low Risk of Hepatocellular Carcinoma in Patients With Primary Sclerosing Cholangitis With Cirrhosis

BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary malignancies. However, little is known about the incidence of hepatocellular carcinoma (HCC) among patients with PSC; current recommendations on screening these patients for HCC are conflicting. We investigated the risk of HCC in patients with PSC with cirrhosis. METHODS We performed a retrospective study of patients with well-defined PSC from 2 large-volume tertiary care centers in Germany; data were collected from periods of up to 33 years. Liver cirrhosis was based on histology results or the presence of ascites, esophageal varices, or transient elastography values greater than 14 kPa. Statistical analysis was performed using the Kaplan-Meier method and the Cox proportional hazard model. Data from 509 patients (67% male), with a total of 4202 patients-years, were included in the final analysis. RESULTS We identified 119 patients with cirrhosis. During 292 patient-years, none of these patients developed HCC. Most HCCs were identified incidentally at the time of liver transplantation. We therefore reviewed data on liver explants from 140 patients who underwent transplantation; none were found to contain HCC. In contrast to the low numbers of HCCs among patients with PSC, 35 patients developed cholangiocarcinoma, 3 patients developed gallbladder cancer, and 9 patients developed colorectal cancer. CONCLUSIONS Based on a retrospective analysis of more than 500 patients with PSC, we confirm their high risk for hepatobiliary malignancies. However, the risk of HCC, even among patients with cirrhosis, seems to be low--regular HCC surveillance may not be warranted.

Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis.

BACKGROUND & AIMS There is an unmet need for the non-invasive monitoring of fibrosis progression in patients with autoimmune hepatitis (AIH). The aim of this study was to assess the diagnostic performance of transient elastography in patients with AIH and to investigate the impact of disease activity on its diagnostic accuracy. METHODS Optimal cut-offs were defined in a prospective pilot study (n=34) and the diagnostic performance of transient elastography validated in an independent second cohort (n=60). To explore the impact of disease activity on liver stiffness, patients were stratified according to biochemical response and the time interval between start of immunosuppression and transient elastography. RESULTS Liver stiffness strongly correlated with histological fibrosis stage (pilot study: ρ=0.611, p<0.001; validation cohort: ρ=0.777, p<0.0001). ROC curves defined an area under the receiver operating curve of 0.95 for diagnosing cirrhosis at the optimal cut-off of 16kPa. The performance of transient elastography was impaired when patients were analysed in whom transient elastography was performed within 3months from start of treatment. In this setting, liver stiffness correlated with histological grading (ρ=0.558, p=0.001), but not with staging. In contrast, using the cut-off of 16kPa, the accuracy for diagnosing cirrhosis was excellent in patients treated for 6months or longer (area under the receiver operating curve 1.0). CONCLUSIONS Liver inflammation has a major impact on liver stiffness in the first months of AIH treatment. However, transient elastography has an excellent diagnostic accuracy for separating severe from non-severe fibrosis after 6months of immunosuppressive treatment. LAY SUMMARY Transient elastography is a special ultrasound scan, which assesses liver stiffness as a surrogate marker for liver fibrosis/scarring. Transient elastography has been shown to be a reliable non-invasive method to assess liver fibrosis in various chronic liver diseases, it takes less than 5min and has a high patient acceptance. The current study validated for the first time this technique in a large cohort of patients with autoimmune hepatitis (AIH) and demonstrates that it is a reliable tool to detect liver fibrosis in treated AIH. For the monitoring of potential disease progression under treatment, the validation of liver stiffness as non-invasive marker of liver fibrosis will greatly improve patient care in autoimmune hepatitis.

Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis

Dear Sir, Primary sclerosing cholangitis (PSC) is a progressive disease of unknown aetiology. The presumed involvement of the gut–liver axis in disease pathogenesis1 has prompted investigations into mucosal2 and faecal intestinal microbiota composition, as has been reported by Kummen et al 3 in this journal. Microbiota as diagnostic biomarkers of disease are of interest from the clinician’s point of view and Kummen et al 3 have suggested a panel of taxa and even a single genus ( Veillonella ) with a reasonable diagnostic accuracy differentiating PSC and healthy controls (HCs). We here report on a cohort study from northern Germany, using stool samples of 98 HC subjects, 73 patients with well-characterised PSC and 88 subjects with UC for 16S rDNA sequencing of the V1-V2 variable region. The PSC subgroup included 38 subjects with concomitant UC (PSC-UC). The data were subjected to quality control and operational taxonomic units (OTU) picking according to the methods described.3 Of the 12 taxa proposed to be differentially abundant in …

Efficacy and Limitations of Budesonide as a Second-Line Treatment for Patients With Autoimmune Hepatitis

BACKGROUND & AIMS: Many patients with autoimmune hepatitis (AIH) develop steroid‐specific side effects or require doses of steroids that are unacceptable for long‐term treatment. We investigated the efficacy of budesonide as an alternative steroid for patients previously treated with prednisolone who developed side effects or were unable to reduce their dose of prednisolone below acceptable levels. We also report the effects of more than 12 months of budesonide treatment in a large cohort of patients with AIH. METHODS: We performed a retrospective analysis of data from 60 patients (51 female) with AIH who were treated initially with prednisolone (mean time, 47 mo) but then switched to budesonide, managed at a single center in Germany from 2001 through June 2016. Patients were evaluated after 6 months, 12 months, 24 months, 36 months, and at the last follow‐up evaluation; response to treatment with budesonide was assessed based on normal serum levels of aminotransferases and IgG (biochemical response). RESULTS: Thirty patients were switched to budesonide therapy because of prednisolone‐induced side effects and 30 patients switched because of prednisolone dependency. Overall, a biochemical response was detected in 55% of patients after 6 months of budesonide treatment, in 70% after 12 months, and in 67% after 24 months. At the last follow‐up evaluation (mean time, 63 mo) 23 patients (38%) still were receiving budesonide treatment. Fifteen patients (25%) had switched back to prednisolone therapy because of insufficient response to budesonide or its side effects. Fifteen patients with osteopenia at the beginning of budesonide treatment were followed up and evaluated by dual‐energy X‐ray absorptiometry. After a median of 24 months of budesonide treatment, bone mineral density had improved in 6 patients, remained stable in 8 patients, and worsened in 1 patient. CONCLUSIONS: We performed a retrospective analysis of patients with AIH that confirmed the therapeutic value of budesonide beyond 12 months of treatment in patients who are intolerant to or dependent on prednisolone. Although budesonide‐induced side effects appear to be mild in real life, effectiveness was limited in a considerable proportion of patients; close monitoring is advised.

Long-term outcome in PSC/AIH "overlap syndrome": does immunosuppression also treat the PSC component?

To the Editor: Features of both primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) in the same patient were first described about 2 decades ago, including a small first case series published in the Journal of Hepatology in 1996 by Gohlke et al. [1,2]. Most notably, at first diagnosis all three patients from this early report fulfilled the criteria for a definite (patient 1 and 2) or probable (patient 3) AIH, according to the scoring system of the International Autoimmune Hepatitis Group (IAIHG) from 1993 [3], but responded insufficiently to immunosuppression, particularly with respect to cholestatic biochemical parameters. Therefore in all patients a retrograde endoscopic cholangiography was performed, showing a peripheral bile duct rarefication and multiple strictures and dilatations of the intra(patients 1–3) and extrahepatic (patient 3) bile ducts. Additionally, early follow-up liver biopsy in two patients detected portal fibrosis with fibrous obliterative cholangitis and a reduction of bile ducts (patient 1) and a progression to liver cirrhosis with rarefication of bile ducts and partly onion-like periductular fibrosis (patient 3), respectively The findings strongly suggested that from the beginning these patients were affected not only by AIH but also by cholangiopathy. Under the assumption of an ‘‘overlap syndrome’’ between PSC and AIH ursodeoxycholic acid (UDCA) was therefore added to the immunosuppressive regime and cholestatic biochemical parameters decreased. Since this early report, there has been an increasing awareness for patients with features of both conditions, often called ‘‘PSC/AIH overlap’’, and nowadays overlapping features are widely accepted to constitute a variant of the primary disorder mostly PSC, rather than a separate disease entity. This, indeed is a renunciation from the original term of the ‘‘overlap syndrome’’ and a consequence of a lack of specific diagnostic tests evidence based treatment strategies and implications for prognosis [4]. In fact, despite some larger cohorts published on this issue in the last years [5–8], data on PSC/AIH overlap patients are scarce and the long-term outcome is not well characterized underlining that follow-up data focussing on this special patient cohort are required. Therefore, we here report the long-term follow-up of the three cases originally published by Gohlke et al. in 1996 [1]. The most important message is, that all patients (patients 1–3) are still alive 22, 27, and 25 years after first presentation – yet disease has been progressive in all three cases despite a combined regime of immunosuppression and UDCA (Table 1) In patient 1, the further clinical course was characterized by progressive bile duct destruction recently treated by balloon dilatation with partial success. The therapeutic regime with azathioprine and UDCA has been continued until today. Still 20 years after the first presentation, follow-up liver biopsy demonstrated an incomplete biliary cirrhosis, while at the same time oesophageal varices were first diagnosed in this patient Due to these findings and a progressive weight loss, the patient has now been listed for liver transplantation. In patient 2, bile duct interventions due to dominant strictures were required in the first years after diagnosis. While the patient’s condition is

Validation of Transient Elastography and Comparison with Spleen Length Measurement for Staging of Fibrosis and Clinical Prognosis in Primary Sclerosing Cholangitis

Background Patients with primary sclerosing cholangitis (PSC) develop progressive liver fibrosis and end-stage liver disease. Non-invasive and widely available parameters are urgently needed to assess disease stage and the risk of clinical progression. Transient elastography (TE) has been reported to predict fibrosis stage and disease progression. However, these results have not been confirmed in an independent cohort and comparison of TE measurement to other non-invasive means is missing. Methods In a retrospective study we collected data from consecutive PSC patients receiving TE measurements from 2006 to 2014 (n = 139). Data from 62 patients who also underwent a liver biopsy were used to assess the performance of TE and spleen length (SL) measurement for the staging of liver fibrosis. Follow-up data from this cohort (n = 130, Hamburg) and another independent cohort (n = 80, Paris) was used to compare TE and SL as predictors of clinical outcome applying Harrel’s C calculations. Results TE measurement had a very good performance for the diagnosis and exclusion of higher fibrosis stages (≥F3: AUROC 0.95) and an excellent performance for the diagnosis and exclusion of cirrhosis (F4 vs. < F4: AUROC 0.98). Single-point TE measurement had very similar predictive power for patient outcome as previously published. In a combined cohort of PSC patients (n = 210), SL measurements had a similar performance as TE for the prediction of patient outcome (5 x cross-validated Harrel’s C 0.76 and 0.72 for SL and TE, respectively). Conclusions Baseline TE measurement has an excellent performance to diagnose higher fibrosis stages in PSC. Baseline measurements of SL and TE have similar usefulness as predictive markers for disease progression in patients with PSC.

Criteria used in clinical practice to guide immunosuppressive treatment in patients with primary sclerosing cholangitis

Background & Aims Current guidelines recommend immunosuppressive treatment (IT) in patients with primary sclerosing cholangitis (PSC) and elevated aminotransferase levels more than five times the upper limit of normal and elevated serum IgG-levels above twice the upper limit of normal. Since there is no evidence to support this recommendation, we aimed to assess the criteria that guided clinicians in clinical practice to initiate IT in patients with previously diagnosed PSC. Methods This is a retrospective analysis of 196 PSC patients from seven German hepatology centers, of whom 36 patients had received IT solely for their liver disease during the course of PSC. Analyses were carried out using methods for competing risks. Results A simplified autoimmune hepatitis (AIH) score >5 (HR of 36, p<0.0001) and a modified histological activity index (mHAI) greater than 3/18 points (HR 3.6, p = 0.0274) were associated with the initiation of IT during the course of PSC. Of note, PSC patients who subsequently received IT differed already at the time of PSC diagnosis from those patients, who did not receive IT during follow-up: they presented with increased levels of IgG (p = 0.004) and more frequently had clinical signs of cirrhosis (p = 0.0002). Conclusions This is the first study which investigates the parameters associated with IT in patients with PSC in clinical practice. A simplified AIH score >5 and a mHAI score >3, suggesting concomitant features of AIH, influenced the decision to introduce IT during the course of PSC. In German clinical practice, the cutoffs used to guide IT may be lower than recommended by current guidelines.

Risk of cholangiocarcinoma in patients with primary sclerosing cholangitis: diagnosis and surveillance

Purpose of review Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary and extrahepatic malignancy. Particularly the risk of cholangiocarcinoma (CCA) is greatly increased. To provide potentially curative treatments for affected patients an early diagnosis of CCA is crucial. We here review the current advances with respect to CCA diagnosis and surveillance and discuss a rational approach on how to perform surveillance of CCA in PSC patients. Recent findings Given the shortcomings of the current modalities for the surveillance and diagnosis of CCA in PSC, recent studies have focused on novel biomarkers for CCA. These include serum biomarkers (e.g., circulating angiopoeitin-2, cytokeratin-19 fragments, and antiglycoprotein 2 IgA autoantibodies, microRNA) as well as proteomics obtained from urine and/or bile. Novel approaches that may enhance the diagnostic value of brush cytology in future include the optimization of fluorescence in situ hybridization probes and the assessment of genetic aberrations. In addition, studies on advanced techniques (e.g., single-operator cholangioscopy and probe-based confocal laser endomicroscopy) have shown promising results with respect to CCA detection. Summary Despite recent advances in the diagnosis of CCA in PSC, the detection of early-stage CCA remains difficult. A better understanding of CCA pathogenesis and large prospective studies on novel biomarkers and techniques are required to timely diagnose CCA in the future.

Is fatigue in primary biliary cirrhosis cured by transplantation

The name primary biliary cirrhosis (PBC) was coined when the disease was mostly diagnosed in its late cirrhotic stage [1]. Today, PBC must be considered a historic misnomer, as the disease nowadays presents usually many years or decades prior to the development of cirrhosis, and with timely diagnosis and adequate treatment, the majority of patients never reach the stage of cirrhosis [2–4]. It is considered an autoimmune disease characterized by non-suppurative destructive cholangitis, and it is thus considered a disease of the small intra-hepatic bile ducts. However, there may be a second reason why PBC is a misnomer: probably the disease is not only confined to the liver, but may have extra-hepatic manifestations. In addition to the immune-mediated inflammation in the liver, patients may suffer from a number of extra-hepatic manifestations as varied as Siccasyndrome, arthralgias and, most of all, fatigue. Fatigue is a complex symptom characterized by the feeling of exhaustion, lethargy, and discomfort. Fatigue affects 40–80% of PBC patients [5,6]. Fatigue is not only common, for most patients it also constitutes the primary clinical problem, as about 50% of the patients affected describe fatigue as the most bothersome symptom of their disease [7]. In addition to this enormous impact on quality of life, new data suggest an influence on survival in PBC, as well [8]. In order to meet this highly challenging problem in PBC, effective therapeutic strategies for patients affected by fatigue would be highly desirable. However, to date there is no specific treatment for fatigue in PBC [9]. Even though different drugs have been tested in clinical trials, favorable effects have only been shown for Modafinil, such as decreased somnolence and night sleep as well as increased energy levels [10,11], and for methotrexate [12], albeit only described in small case series without adequate placebo controls. In addition to the limited effectiveness, side-effects will limit therapeutic options frustrating both patients and their treating physicians.

Association of gadolinium-enhanced magnetic resonance imaging with hepatic fibrosis and inflammation in primary sclerosing cholangitis

Objective To evaluate magnetic resonance imaging (MRI) parameters T2 signal, contrast enhancement (CE), and relative liver enhancement (RLE) of extracellular gadolinium-based contrast agent (GBCA)-enhanced MRI as a marker for hepatic fibrosis and inflammation in patients with primary sclerosing cholangitis (PSC). Methods 3.0-Tesla MRI scans and liver biopsies of 40 patients (41.2 ± 17.1 years) were retrospectively reviewed. Biopsies were obtained within a mean time of 54 ± 55 days to MRI scans and specimens were categorized according to Ishak modified hepatic activity index (mHAI) and Scheuer staging of fibrosis. T2 signal (N = 40), CE alterations (N = 29), and RLE (N = 29) were assessed by two raters. Mixed-effects regression models were applied to estimate the association between histopathology and MRI parameters. Results No significant association was observed between T2 signal or CE alterations with stages of fibrosis or mHAI grading. Regression models revealed significant positive associations of portal venous phase RLE with mHAI grade ≥ 7 points [β = 25.5; 95% CI (2.53; 48.62); p = 0.04] and delayed phase RLE with stages of fibrosis [stage 2: β = 35.13; 95% CI (11.35; 58.87); p = 0.007; stage 3/4: β = 69.24; 95% CI (45.77; 92.75); p < 0.001]. The optimal cut-off value of 66.6% delayed phase RLE distinguished fibrosis stages 0–2 from 3–4 with a sensitivity of 0.833 and specificity of 0.972. Inter-rater reliability (IRR) for quantification of RLE was ‘excellent’ (r = 0.90–0.98). IRR was ‘substantial’ for detection of T2 signal in the right liver lobe (RL) (Kappa = 0.77) and ‘almost perfect’ for T2 signal of the left liver lobe (LL) and CE of both lobes (Kappa = 0.87–1.0). Conclusion The simple and reproducible method of RLE quantification on standard extracellular GBCA-enhanced MRI may provide a correlate measure of advanced stages of hepatic fibrosis and potentially also inflammation in PSC patients, if validated in larger cohorts.