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Chronic pain, defined as pain existing for >4-6 weeks, affects >60% of patients with autosomal-dominant polycystic disease (ADPKD). It can have various causes, indirectly or directly related to the increase in kidney and liver volume in these patients. Chronic pain in ADPKD patients is often severe, impacting physical activity and social relationships, and frequently difficult to manage. This review provides an overview of pathophysiological mechanisms that can lead to pain and discusses the sensory innervation of the kidneys and the upper abdominal organs, including the liver. In addition, the results of a systematic literature search of ADPKD-specific treatment options are presented. Based on pathophysiological knowledge and evidence derived from the literature an argumentative stepwise approach for effective management of chronic pain in ADPKD is proposed.

BACKGROUND: Isolated polycystic liver disease (ADPLD) is an autosomal dominant Mendelian disorder. Heterozygous PRKCSH (where PRKCSH is protein kinase C substrate 80K‐H (80 kDa protein, heavy chain; MIM*177060) mutations are the most frequent cause. Routine molecular testing using Sanger sequencing identifies pathogenic variants in the PRKCSH (15%) and SEC63 (where SEC63 is Saccharomyces cerevisiae homolog 63 (MIM*608648); 6%) genes, but about approximately 80% of patients meeting the clinical ADPLD criteria carry no PRKCSH or SEC63 mutation. Cyst tissue often shows somatic deletions with loss of heterozygosity that was recently recognized as a general mechanism in ADPLD. We hypothesized that germline deletions in the PRKCSH gene may be responsible for hepatic cystogenesis in a significant number of mutation‐negative ADPLD patients. METHODS: In this study, we designed a multiplex ligation‐dependent probe amplification (MLPA) assay to screen for deletions of PRKCSH exons. Genomic DNA from 60 patients with an ADPLD phenotype was included. RESULTS: MLPA analysis detected no exon deletions in mutation‐negative ADPLD patients. CONCLUSION: Large copy number variations on germline level are not present in patients with a clinical diagnosis of ADPLD. MLPA analysis of the PRKCSH gene should not be considered as a diagnostic method to explain hepatic cystogenesis.

The frequency of certain medical procedures and their results vary strongly between countries, and also between regions within one country. These variations in clinical practice mean the quality of healthcare is suboptimal, result in unnecessary expense and patients are at risk of complications caused by unnecessary interventions. Patient Reported Outcome Measures (PROMs) are an instrument to clarify if a patient has benefited from a certain treatment. Systematic measurement of PROMs is necessary to show relevant differences in the effect of a therapy. If data of differences in results are combined with those of regional variations in clinical practice, it will become clear where too much or too less is treated. We expect that the systematic measurement of PROMs will make a valuable contribution to improving the quality of Dutch healthcare.

Background & Aims: Current treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse. Methods: A total of 131 patients (out of a cohort including 844 patients) from 7 academic and 14 regional centres in the Netherlands were identified in whom treatment was tapered after at least 2 years of clinical and biochemical remission. Relapse was defined as alanine-aminotransferase levels (ALT) three times above the upper limit of normal and loss of remission as a rising ALT necessitating the reinstitution of drug treatment. Results: During follow-up, 61 (47%) patients relapsed and 56 (42%) had a loss of remission. In these 117 patients, 60 patients had fully discontinued medication whereas 57 patients were still on a withdrawal scheme. One year after drug withdrawal, 59% of the patients required retreatment, increasing to 73% and 81% after 2 and 3 years, respectively. Previous combination therapy of corticosteroids and azathioprine, a concomitant autoimmune disease and younger age at time of drug withdrawal were associated with an increased risk of relapse. Subsequent attempts for discontinuation after initial failure in 32 patients inevitably resulted in a new relapse. Conclusions: This retrospective analysis indicates that loss of remission or relapse occurs in virtually all patients with AIH in long-term remission when immunosuppressive therapy is discontinued. These findings indicate a reluctant attitude towards discontinuation of immunosuppressive treatment in AIH patients. (C) 2012 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

Item does not contain fulltext BACKGROUND & AIMS: Clinical trials have shown that in patients with polycystic liver disease (PLD), short-term treatment with somatostatin analogues (SAs) reduces liver volumes by 4.5%-5.9%, compared with placebo. However, the effects of SA therapy vary among individuals. We collected data from individual patients with PLD to identify subgroups that benefit most from SA therapy. METHODS: We analyzed data from 107 patients with PLD from 3 randomized placebo-controlled trials (67 received SAs, 52 received placebo). We used multiple linear regression analysis to determine the effects of SAs based on patients' age, sex, baseline liver volume, and diagnosis (autosomal dominant polycystic liver or kidney disease). The primary outcome was change in liver volume after 6-12 months of treatment. RESULTS: The effects of SA therapy did not differ significantly among patients with different diagnoses or baseline liver volumes; the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001). Among subjects given placebo, young women (48 years old or younger) had the greatest increase in polycystic liver volume (4.8%; 95% confidence interval: 2.2%-7.4%), and mean liver volumes did not increase in older women and men. Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women (a reduction in liver volume of 4.1% compared with placebo; P = .022). CONCLUSIONS: Based on a pooled analysis of data from individual patients with PLD, treatment with somatostatin analogues is equally effective for patients with autosomal dominant polycystic kidney disease or polycystic liver disease; efficacy does not depend on size of the polycystic liver. Young female patients appear to have the greatest benefit from 6-12 months of SA therapy, which might avert the progressive course of the disease in this specific group.

Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.

Small fibre neuropathy is a neuropathy of the small non-myelinated C-fibres and myelinated Aδ-fibres. Clinically, an isolated small fibre neuropathy is distinguished by sensory and autonomic symptoms, with practically no abnormalities on neurological examination other than possible distorted pain and temperature sensation. Specific diagnostic tests for small fibre neuropathy are skin biopsy, including a count of the intra-epidermal small nerve fibres that cross the basal membrane, and quantitative sensory and autonomic testing. Diabetes mellitus is the most frequent underlying cause of small fibre neuropathy. Other causes can be classified into the following categories: toxic (e.g. alcohol), metabolic, immune-mediated, infectious and hereditary. Recently, in a substantial proportion (29%) of a group of patients with idiopathic small fibre neuropathy, a SCN9A gene mutation was demonstrated, which leads to hyperexcitability of the dorsal root ganglion neurons. Treatment of small fibre neuropathy consists of symptomatic pain relief and, if possible, treatment of the underlying cause of the condition.

To investigate the role of art and culture in the recreational activities of doctors, accountants and lawyers.Descriptive questionnaire study.In this study, doctors, accountants and lawyers were asked to respond to an online questionnaire. They were presented with 13 questions or statements concerning their recreational activities and their active or passive involvement with art and culture. To gain an impression in which respect doctors, accountants and lawyers could be distinguished from each other, predictive models based on logistic regression with possible results 'doctor', 'accountant' or 'lawyer' were generated. On the basis of these models, a miniquiz was created, which could distinguish the typical doctor, accountant or lawyer after answering of dichotomous questions.Among all respondents, museum and cinema visits were popular, sports or gardening were favourite activities, and apart from newspapers, the Internet was frequently consulted for news. It was remarkable that doctors and lawyers resembled each other in most of the areas investigated, whereas the accountants differed significantly. Doctors and lawyers particularly visited museums and dance, opera or theatre performances, and two-thirds themselves played music. The majority of these 2 groups also had an above average interest in art and culture, this being a significant part of the recreational activity. Therefore, we were able to differentiate between a doctor or lawyer and an accountant, but the difference between doctors and lawyers was less clear.Doctors and lawyers seemed to have comparable interests in art and culture, but accountants differed in important respects.

Patients with end-stage isolated polycystic liver disease (PCLD) suffer from incapacitating symptoms because of very large liver volumes. Liver transplantation (LT) is the only curative option. This study assesses the feasibility of LT in PCLD. We used the European Liver Transplant Registry (ELTR) database to extract demographics and outcomes of 58 PCLD patients. We used Kaplan-Meier survival analysis for survival rates. Severe abdominal pain (75%) was the most prominent symptom, while portal hypertension (35%) was the most common complication in PCLD. The explantation of the polycystic liver was extremely difficult in 38% of patients, because of presence of adhesions from prior therapy (17%). Karnofsky score following LT was 90%. The 1- and 5-year graft survival rate was 94.3% and 87.5%, while patient survival rate was 94.8% and 92.3%, respectively. Survival rates after LT for PCLD are good.

Background: The reported incidence of hepatocellular carcinoma (HCC) among patients with primary biliary cirrhosis (PBC) varies from 0.7-3.8%, whereas in cirrhotic patients the risk is considerably higher. Age, male sex, cirrhosis, and portal hypertension are reported risk factors. It has been suggested that ursodeoxycholic acid (UDCA) may protect against HCC. We aimed to define risk factors for the development of HCC at the time of PBC diagnosis and to identify, among patients treated with UDCA for a long term, a subgroup that could benefit from screening. Methods: Prospective multicenter cohort study of patients with established PBC treated with 13-15 mg/kg/day UDCA. Age, sex, antimitochondrial antibodies, bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, aspartate amino transferase, cirrhosis, portal hypertension, Mayo Risk Score, prognostic class (based on bilirubin and albumin levels), and response to UDCA (normalization of bilirubin and/or albumin levels) were analyzed as potential risk factors in Cox regression analysis. Results: Three hundred and seventy-five patients were included, median follow-up was 9.7 years. HCC occurred in nine patients, corresponding with an annual incidence of 0.2%. The factor significantly associated with the development of HCC was the response to UDCA (P

Contains fulltext : 89337.pdf (Publisher’s version ) (Closed access) 01 maart 2010

Contains fulltext : 88740.pdf (Publisher’s version ) (Closed access) 01 april 2010

To assess genetic, clinical and morphological characteristics of hereditary pancreatitis, a rare type of chronic pancreatitis with an early onset of symptoms, which is, among others, caused by mutations in the PRSS1 gene.Observational cohort study.The study population consisted of 496 patients (27,375 person-years) who were referred to Radboud University Nijmegen Medical Centre for molecular diagnosis of hereditary pancreatitis during period 2000 to 2007. 61 patients with a positive family history of hereditary pancreatitis were selected. Analysis for PRSS1 gene mutations was performed by complete sequence analysis of the exons. All patients received a structured questionnaire.From 25 families 61 patients were included (2,047 person-years). PRSS1 mutations were detected in 52 patients (85.2%): p.R122H (67.2%), p.N29I (14.8%), p.E79K (1.6%), p.N29T (1.6%). In the 40 patients whose clinical data were known the median age at diagnosis was 10.5 years (range: 0-42 years). Pain was reported in 28 (70% of 40 patients in whom all information was complete). 27 patients (67.5%) were admitted to the hospital once or more due to the attacks of pancreatitis. Exocrine and endocrine dysfunction was seen in 6 patients (15%). 24 patients (60%) had undergone a surgical intervention, 10 of whom had undergone a pancreaticojejunostomy. A family history of pancreatic carcinoma was found in 5 patients (12.5%).The percentage of PRSS1 mutation was high (85.2%) among this Dutch population that was selected on basis of a positive family history of hereditary pancreatitis. Most patients had no chronic pain.

Contains fulltext : 80007.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Therapy for polycystic liver is invasive, expensive, and has disappointing long-term results. Treatment with somatostatin analogues slowed kidney growth in patients with polycystic kidney disease (PKD) and reduced liver and kidney volume in a PKD rodent model. We evaluated the effects of lanreotide, a somatostatin analogue, in patients with polycystic liver because of autosomal-dominant (AD) PKD or autosomal-dominant polycystic liver disease (PCLD). METHODS: We performed a randomized, double-blind, placebo-controlled trial in 2 tertiary referral centers. Patients with polycystic liver (n = 54) were randomly assigned to groups given lanreotide (120 mg) or placebo, administered every 28 days for 24 weeks. The primary end point was the difference in total liver volume, measured by computerized tomography at weeks 0 and 24. Analyses were performed on an intention-to-treat basis. RESULTS: Baseline characteristics were comparable for both groups, except that more patients with ADPKD were assigned to the placebo group (P = .03). The mean liver volume decreased 2.9%, from 4606 mL (95% confidence interval (CI): 547-8665) to 4471 mL (95% CI: 542-8401 mL), in patients given lanreotide. In the placebo group, the mean liver volume increased 1.6%, from 4689 mL (95% CI: 613-8765 mL) to 4895 mL (95% CI: 739-9053 mL) (P < .01). Post hoc stratification for patients with ADPKD or PCLD revealed similar changes in liver volume, with statistically significant differences in patients given lanreotide (P < .01 for both diseases). CONCLUSIONS: In patients with polycystic liver, 6 months of treatment with lanreotide reduces liver volume.

Contains fulltext : 69533.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Patients with polycystic liver disease (PCLD) may develop symptoms due to increased liver volume. Laparoscopic fenestration is one of the options to reduce liver volume and to relieve symptoms. This study was performed to evaluate the safety and efficacy of laparoscopic liver cyst fenestration. PATIENTS AND METHODS: Twelve patients (all female, median age 45 years, range 35-58) with symptomatic PCLD were included between August 2005 and April 2007. Surgical data were recorded, liver volumes were measured on pre- and postoperative computed tomography (CT) scans, and patients completed a validated symptom-based questionnaire pre- and postoperatively. RESULTS: Median preoperative liver volume was 4,854 ml (range 1,606-8,201) and decreased to 4,153 ml postoperatively (range 1,556-8,232) resulting in median liver volume reduction of 12.5% (range +9.5 to -24.7%). Median procedural time was 123.5 min (range 50-318), and median hospitalization period was 3.5 days (range 1-8). Postoperative complications occurred in three patients including biliary leakage, obstruction of inferior vena cava and sepsis, all recovering with conservative management. Patients reported decreased symptoms of postprandial fullness and abdominal distension. CONCLUSION: Laparoscopic fenestration in PCLD patients results in volume reduction of 12.5% and decrease of symptoms.

Polycystic livers occur in the setting of two inherited conditions: (1) autosomal dominant polycystic kidney disease (ADPKD), also characterised by progressive development of renal cysts resulting in loss of renal function, and (2) polycystic liver disease (PCLD), with a polycystic liver as the sole manifestation. Symptoms, such as abdominal distension, result from hepatomegaly. Ascites is a rare complication and might be due to portal hypertension or caused by a ruptured cyst. Treatment strategies for polycystic livers are aimed at reducing liver volume. So far, only surgical options are available, but these are associated by considerable morbidity and mortality.1 Alternatively, ascites in the setting of polycystic livers might respond to endovascular stent placement in the narrowed caval vein,2 but medical options are conspicuously lacking so far. We wish to report two cases with severe polycystic liver …

The diagnosis of cholangiocarcinoma (CCA) is difficult, and due to the insidious course of the disease, most cases present at a relatively late stage. Positron emission tomography (PET), using [(18)F]fluoro-2-deoxyglucose ([(18)F]FDG) as a tracer is one the most powerful molecular imaging techniques available. We hypothesized that [(18)F]FDG accumulates at sites of early CCA development and that FDG-PET may be of value for the early diagnosis of CCA.We added 300 mg/L thioacetamide to the drinking water of rats who went on to develop CCA within 20 weeks. From eight weeks onwards, groups of three rats were injected with [(18)F]FDG, subsequently the liver was perfused, dissected and subjected to quantitative autoradiography using a phosphor imaging system. The liver sections were stained for histology, and glutathione S-transferase (GST) enzyme activity was determined. We correlated [(18)F]FDG uptake with pathological liver changes.The experiments demonstrate that thioacetamide causes atypical bile ducts and invasive CCA. Rat livers harvested early after the start of administration of thioacetamide contained only cirrhosis and/or atypical bile ducts, but CCA and FDG accumulation were absent. At 20 weeks, all rats had developed CCA and all, except two animals with a very small carcinoma, had strongly elevated focal FDG uptake. Quantitative autoradiography revealed tumor-to-normal-liver ratios as high as 5:4. In all rats with a carcinoma, there was a backdrop of cirrhosis, and interestingly cirrhotic areas did not show elevated FDG accumulation.[(18)F]FDG accumulates in CCA, is able to distinguish CCA from liver cirrhosis, but is probably unsuitable to detect very early CCA lesions.

Contains fulltext : 35130.pdf (Publisher’s version ) (Closed access) BACKGROUND: Antibodies directed against citrullinated proteins (eg anti-cyclic citrullinated peptide (CCP)) have excellent diagnostic and good prognostic potential for rheumatoid arthritis. Type 1 autoimmune hepatitis (AIH-1) is a chronic liver disease characterised by a variety of serum autoantibodies. Recently, in a large group of patients with AIH-1 without clear rheumatoid arthritis overlap, a relatively high percentage (9%) of anti-CCP2 positivity was scored. OBJECTIVES: To characterise the citrulline-dependence of the observed anti-CCP2 positivity in AIH-1 sera as well as in other groups of patients without rheumatoid arthritis (mainly rheumatic diseases). METHODS: Serum samples of 57 patients with AIH-1 and 66 patients without rheumatoid arthritis, most of them reported as anti-CCP positive, were tested for citrulline-specific reactivity with a second generation anti-CCP kit, with the citrullinated and the corresponding non-citrullinated (arginine-containing) antigen. A subset of AIH-1 sera was also tested with a CCP1 ELISA (and arginine control). RESULTS: The anti-CCP2 reactivity of most non-rheumatoid arthritis rheumatic diseases samples (87-93%) was citrulline-specific, whereas a relatively high percentage of AIH-1 samples (42-50%) turned out to be reactive in a citrulline-independent manner. The use of citrullinated and non-citrullinated CCP1 peptides confirmed a high occurrence of citrulline-independent reactivity in AIH-1 samples. CONCLUSIONS: In rheumatoid arthritis and most non-rheumatoid arthritis rheumatologic disease sera, anti-CCP positivity is citrulline-dependent. However in some patients, particularly patients with AIH-1, citrulline-independent reactivity in the anti-CCP2 test can occur. A positive CCP test in a non-rheumatic disease (eg liver disease) should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.

Item does not contain fulltext OBJECTIVE: To evaluate the risk factors for the development of acute renal failure (ARF) in severe rhabdomyolysis. DESIGN: Observational historical cohort study. SETTING: General intensive care unit of a university hospital. PATIENTS: Twenty-six patients with severe rhabdomyolysis, who were admitted between July 1996 and July 2001. MEASUREMENTS AND RESULTS: Clinical and laboratory data were reviewed and groups were stratified according to presence or absence of acute renal failure. The underlying cause of rhabdomyolysis was ischemia by vascular obstruction (50%), crush injury by trauma (23%), sepsis (11.5%), heatstroke/hyperthermia (11.5%) and hyponatremia in a single patient. Mean creatine kinase (CK) level was 38,351+/-35,354 U/l on admission and rose further in all patients (mean: 59,747+/-67,514 U/l). Renal failure developed in 17 patients (65%). Serum CK levels correlated with onset of ARF, as these patients had significantly higher admission and peak serum CK concentrations. Patients with ARF had a higher mortality (59% vs 22%). CONCLUSION: In our cohort of patients with severe rhabdomyolysis the level of serum CK predicted the development of ARF. Although our results suggest that series of CK determination might be beneficial for the evaluation of the effect of therapy, the value of CK determination as a prognostic tool is limited, given the wide range of CK levels.

Sir,—The results from the study by Srikanthan et al and its accompanying editorial regarding the use of fax machines in cardiology stimulated us to relate our own experience.1 2 In August 1987 we implemented a fax network to facilitate communication with residents out of office hours. At the same time we initiated a home thrombolysis programme using …

Liver cysts are common, affecting 5%-10% of the population. Most are asymptomatic, however 5% of patients develop symptoms, sometimes due to complications and will require intervention. There is no consensus on their management because complications are so uncommon. The aim of this study was to perform a collected review of how a series of complications were managed at our institutions. Six different patients presenting with rare complications of liver cysts were obtained from Hepatobiliary Units in the United Kingdom and The Netherlands. History and radiological imaging were obtained from case notes and computerised radiology. As a result, 1 patient admitted with inferior vena cava obstruction was managed by cyst aspiration and lanreotide; 1 patient with common bile duct obstruction was first managed by endoscopic retrograde cholangiopancreatography and stenting, followed by open fenestration; 1 patient with ruptured cysts and significant medical co-morbidities was managed by percutaneous drainage; 1 patient with portal vein occlusion and varices was managed by open liver resection; 1 patient with infected cysts was treated with intravenous antibiotics and is awaiting liver transplantation. The final patient with a simple liver cyst mimicking a hydatid was managed by open liver resection. In conclusion, complications of cystic liver disease are rare, and we have demonstrated in this series that both operative and non-operative strategies have defined roles in management. The mainstays of treatment are either aspiration/sclerotherapy or, alternatively laparoscopic fenestration. Medical management with somatostatin analogues is a potentially new and exciting treatment option but requires further study.

On the basis of clinical, laboratory, and histopathologic studies, the authors discern three distinct types of red, congested, and burning extremities that need to be distinguished for effective treatment according to their etiology: erythromelalgia in thrombocythemia, primary erythermalgia, and secondary erythermalgia. Each entry is discussed in turn.

EDITOR—Gershlick and More discuss the new therapeutic options for myocardial infarction and suggest that patients in whom thrombolysis fails should receive rescue angioplasty.1 We challenge this view and propose that rescue thrombolysis might be considered in cases in which primary thrombolysis has failed. Two trials have compared rescue angioplasty with conservative management, with equivocal results. 2 3 One trial randomised patients with an occluded artery three hours after the onset of symptoms; it detected a non-significant reduction in mortality in the angioplasty group …

EDITOR,—In their grand round on reactive systemic amyloidosis A R Allen and colleagues state that, while colchicine prevents the development of renal amyloidosis in familial Mediterranean fever, …

ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.