Exocrine Dysfunction Research Articles

Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic.

BackgroundHeterozygous mutations in the HNF1B gene are the most common monogenic cause of developmental kidney disease. Extrarenal phenotypes frequently occur, including diabetes mellitus and pancreatic hypoplasia; the latter is associated with subclinical exocrine dysfunction. We measured faecal elastase-1 in patients with HNF1B-associated disease regardless of diabetes status and assessed the degree of symptoms associated with pancreatic exocrine deficiency.MethodsFaecal elastase-1 was measured in 29 patients with a known HNF1B mutation. We defined a low faecal elastase-1 concentration based on the 2.5 percentile of 99 healthy control individuals (410 μg/g stool). Symptoms related to pancreatic exocrine dysfunction were assessed and a subset of the HNF1B cohort (n = 6) underwent pancreatic imaging.ResultsFaecal elastase-1 was below the 2.5 percentile of the control cohort in 18/29 (62%) patients with HNF1B-associated renal disease. A total of 8/29 (28%) had a measurement suggestive of exocrine pancreatic insufficiency at <200 μg/g stool; of these, 3 suffered with abdominal pain, loose stools and/or unintentional weight loss. All three experienced symptomatic improvement and weight gain after commencing pancreatic enzyme replacement therapy. Faecal elastase-1 was low in 7/15 (47%) HNF1B patients without diabetes compared with 11/14 (79%) of those with diabetes (P = 0.1).ConclusionsFaecal elastase-1 deficiency is a common feature of HNF1B-associated renal disease even when diabetes is not present and pancreatic exocrine deficiency may be more symptomatic than previously suggested. Faecal elastase-1 should be measured in all patients with known HNF1B-associated disease complaining of chronic abdominal pain, loose stools or unintentional weight loss. The discovery of a low faecal elastase-1 concentration in individuals with developmental kidney disease of uncertain cause should prompt referral for HNF1B genetic testing.

Clusterin is highly expressed in tubular complexes during spontaneous pancreatitis of spontaneous hypertensive rats.

Pancreatitis is an inflammatory disorder of pancreas which leads to varying degrees of pancreatic endocrine and exocrine dysfunction and manifests in either acute or chronic forms. Spontaneous pancreatitis in experimental animals has rarely been reported. Here, we found acute to chronic courses of spontaneous pancreatitis in spontaneously hypertensive rats (SHRs), showing the formation of tubular complexes (TCs) and enhanced islet regeneration. We investigated the expression pattern of clusterin in the pancreas of SHRs based on immunohistochemistry (IHC). IHC analysis revealed the strong expression of clusterin in dedifferentiated duct-like cells and regenerative islets of TCs. These results imply that clusterin might be involved in the formation of TCs and parenchymal regeneration during rat pancreatitis.

Exocrine Dysfunction Correlates with Endocrinal Impairment of Pancreas in Type 2 Diabetes Mellitus.

Background:Diabetes mellitus (DM) is a chronic abnormal metabolic condition, which manifests elevated blood sugar level over a prolonged period. The pancreatic endocrine system generally gets affected during diabetes, but often abnormal exocrine functions are also manifested due to its proximity to the endocrine system. Fecal elastase-1 (FE-1) is found to be an ideal biomarker to reflect the exocrine insufficiency of the pancreas.Aim:The aim of this study was conducted to assess exocrine dysfunction of the pancreas in patients with type-2 DM (T2DM) by measuring FE levels and to associate the level of hyperglycemia with exocrine pancreatic dysfunction.Methodology:A prospective, cross-sectional comparative study was conducted on both T2DM patients and healthy nondiabetic volunteers. FE-1 levels were measured using a commercial kit (Human Pancreatic Elastase ELISA BS 86-01 from Bioserv Diagnostics). Data analysis was performed based on the important statistical parameters such as mean, standard deviation, standard error, t-test-independent samples, and Chi-square test/cross tabulation using SPSS for Windows version 20.0.Results:Statistically nonsignificant (P = 0.5051) relationship between FE-1 deficiency and age was obtained, which implied age as a noncontributing factor toward exocrine pancreatic insufficiency among diabetic patients. Statistically significant correlation (P = 0.003) between glycated hemoglobin and FE-1 levels was also noted. The association between retinopathy (P = 0.001) and peripheral pulses (P = 0.001) with FE-1 levels were found to be statistically significant.Conclusion:This study validates the benefit of FE-1 estimation, as a surrogate marker of exocrine pancreatic insufficiency, which remains unmanifest and subclinical.

Is There Any Contribution of Pancreatic Exocrine Dysfunction to the Malnutrition in Chronic Kidney Disease and End Stage Renal Disease?

Amac: Kronik bobrek hastaligi (KBH) iliskili malnutrisyon ile pankreatik ekzokrin disfonksiyon arasindaki iliski henuz net olarak aciklanamamistir. Bobrek hastaliklarinda pankreatik ekzokrin disfonksiyona iliskin literatur yeterli degildir. Bu calismanin amaci boyle bir iliskinin olup olmadiginin arastirilmasidir. Materyal ve Metot: 40 SDBH, 40 KBH ve 42 saglikli gonullunun dahil edildigi calismada katilimcilarin beslenme durumlarinin belirlenmesi amaciyla “Kisa Nutrisyonel Degerlendirme (KND)” formu doldurulmus ve pankreasin ekzokrin islevlerinin belirlenmesi icin fekal elastaz 1 (FE1) duzeyleri olculmustur. Bulgular: Kontrol grubunda FE1 duzeyleri KBH ve SDBH ggruplarina gore anlamli derecede yuksek bulunmustur. FE1’in pankreas ekzokrin fonksiyonunu gostermedeki duyarliligi goz onune alindiginda, sonuclar bobrek hastalarinda kotu pankreatik ekzokrin fonksiyonunu isaret etmektedir. Sonuc: Bobrek hastaliginda malnutrisyonun cok farkli nedenleri olabilmesinin yani sira, pankreatik ekzokrin disfonksiyon bu nedenlerden biri olarak dusunulebilir. FE1 duzeyleri pankreasin ekzokrin fonksiyonunun belirlenmesinde kullanilabilir.

Evaluation of pancreatic exocrine functions in rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most common chronic inflammatory diseases. It mainly involves the joints and also affects directly or indirectly nearly all organ systems. The question whether RA causes exocrine pancreatic disfunction remains unclear. The purpose of this study is to evaluate whether or not RA contributes to pancreatic exocrine insufficiency. This was done by ruling out seconder Sjögren's syndrome (SjS) by using Schirmer's test. A total of 60 patients (20 RA, 20 RA + SjS and 20 SjS) and 20 healthy volunteers were included in the study. Patients with RA who had not undergonethe Schirmer's test in the last 6 months and all healthy volunteers included in the study underwent the Schirmer's test at an outpatient clinic. Random fecal samples were taken from all participants and fecal pancreatic elastase was measured to evaluate pancreatic exocrine functions. In the study, a statistically significant difference was found between the control group,SjS and RA+SjS groups. But there was no significant difference between the control group and RA group. In RA group, fecal elastase levels were statistically significantly higher compared to the SjS group. But there was no significant difference between RA+SjS and SjS groups. Fecal elastase significantly decreased in SjS compared to the normal population while pancreatic exocrine functions are considered to be impaired in SjS. There are also impaired pancreatic exocrine functions in the secondary SjS associated with RA. Consequently, pancreatic exocrine dysfunction, which can be seen in patients with RA, may be thought to be caused by secondary SjS associated with RA (Tab. 6, Fig. 1, Ref. 19).

Fecal pancreatic elastase-1 and erythrocyte magnesium levels in diabetes type 1 and type 2.

In the examinees, (56 with T1DM (F = 35 and M = 21), 62 with T2DM (F = 30 and M = 32), and 40 in the control group (F = 19 and M = 21)), we examined anthropometric parameters, and using standard biochemical methods, we measured the level of FE-1, magnesium concentration in blood and erythrocytes, and selected blood parameters. FE-1 concentration < 200μg/g was present in 14.2% of the examinees with T1DM, 20.9% with T2DM, and 2.5% in the control group. In all examinees with DM, there was a statistically significant correlation (P < 0.05) between the level of FE-1 and Mg concentration in the erythrocytes (R = 0.40). Prevalence of pancreatic exocrine insufficiency (PEI), according to the level of FE-1, is significantly higher in patients with DM than in the control group, while it is a bit higher in patients with T2DM than the ones with T1DM. In both types of DM, Mg concentration in erythrocytes is in a significant correlation with the level of FE-1.

Negotiating the complexities of exocrine and endocrine dysfunction in chronic pancreatitis.

Chronic pancreatitis is a chronic inflammatory disease of the pancreas characterised by irreversible morphological change and typically causing pain and/or permanent loss of function. This progressive, irreversible disease results in destruction of healthy pancreatic tissue and the development of fibrous scar tissue. Gradual loss of exocrine and endocrine function follows, along with clinical manifestations such as steatorrhoea, abdominal pain and diabetes. Nutrition in chronic pancreatitis has been described as a problem area and, until recently, there was little research on the topic. It is often asserted that >90 % of the pancreas must be damaged before exocrine insufficiency occurs; however, an exploration of the original studies from the 1970s found that the data do not support this assertion. The management of steatorrhoea with pancreatic enzyme replacement therapy is the mainstay of nutritional management, and early identification and treatment is a key. The presence of steatorrhoea, coupled with poor dietary intake (due to intractable abdominal pain, gastrointestinal side effects and often alcoholism) renders the chronic pancreatitis patients at considerable risk for undernutrition, muscle depletion and fat-soluble vitamin deficiency. Premature osteoporosis/osteopenia afflicts two-thirds of patients as a consequence of poor dietary intake of calcium and vitamin D, low physical activity, low sunlight exposure, heavy smoking, as well as chronic low-grade inflammation. Bone metabolism studies show increased bone formation as well as bone resorption in chronic pancreatitis, indicating that bone turnover is abnormally high. Loss of the pancreatic islet cells occurs later in the disease process as the endocrine cells are diffusely distributed throughout the pancreatic parenchyma. Patients may develop type 3c (pancreatogenic) diabetes, which is complicated by concurrent decreased glucagon secretion, and hence an increased risk of hypoglycaemia. Diabetes control is further complicated by poor diet, malabsorption and (for some) alcoholism, and therefore those with type 3c diabetes have clinical characteristics and therapeutic goals that are different from that of type 1 and type 2 diabetes patients. This review describes emerging research and clinical guidelines for nutrition in chronic pancreatitis.

PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease.

Maturity-Onset Diabetes of the Young (MODY) type 4 or PDX1 -MODY is a rare form of monogenic diabetes caused by heterozygous variants in PDX1 . Pancreatic developmental anomalies related to PDX1 are reported only in neonatal diabetes cases. Here, we describe dorsal pancreatic agenesis in 2 patients with PDX1 -MODY. The proband presented with diabetes since 14 years of age and maintained regular glycemic control with low doses of basal insulin and detectable C-peptide levels after 38 years with diabetes. A diagnosis of MODY was suspected. Targeted next-generation sequencing identified a heterozygous variant in PDX1 : c.188delC/p.Pro63Argfs*60. Computed tomography revealed caudal pancreatic agenesis. Low fecal elastase indicated exocrine insufficiency. His son had impaired glucose tolerance, presented similar pancreatic agenesis, and harbored the same allelic variant. The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1 -related diabetes diagnosed after the first year of life. This finding can improve the management of MODY4 patients, leading to precocious investigation of pancreatic dysgenesis and exocrine dysfunction.

Pancreatic exocrine dysfunction: common in type 3c diabetes, but don't forget types 1 and 2 diabetes mellitus

AbstractIt is well understood that the pancreas has two distinct roles: the endocrine and exocrine functions, that are functionally and anatomically closely related. As specialists in diabetes care, we are adept at managing pancreatic endocrine failure and its associated complications. However, there is frequent overlap and many patients with diabetes also suffer from exocrine insufficiency.Here we outline the different causes of exocrine failure, and in particular that associated with type 1 and type 2 diabetes and how this differs from diabetes that is caused by pancreatic exocrine disease: type 3c diabetes. Copyright © 2017 John Wiley &amp; Sons.

Long-term outcomes after pancreaticoduodenectomy using pair-watch suturing technique: Different roles of pancreatic duct dilatation and remnant pancreatic volume for the development of pancreatic endocrine and exocrine dysfunction

BackgroundWe evaluated long-term outcomes including endo- and exocrine functions after pancreaticoduodenectomy (PD) with standardized pancreaticojejunostomy, paying attention to postoperative pancreatic duct dilatation (PDD) and remnant pancreatic volume (RPV), and examined whether postoperative pancreatic fistula (POPF) influenced the configuration of remnant pancreas. MethodsWe analyzed the records of 187 patients with PD who could have RPV measured by CT volumetry at 1 month after operation and had been followed for more than 6 months. We assessed the risk factors of diabetes mellitus (DM) and PDD, and evaluated association between RPV and pancreatic endo- and exocrine functions assessed by several markers such as albumin, cholesterol, amylase and HbA1c. ResultsRegarding RPV, pancreatic exocrine functions were significantly impaired in the small-volume group (SVG: less than 10 ml) than in the large-volume group (LVG: 10 ml or more). The incidence of new-onset or exacerbation of DM did not differ between SVG and LVG. PDD and the primary disease (pancreatic ductal adenocarcinoma compared to bile duct cancer) were selected as the independent risk factors of new-onset or exacerbation of DM by multivariate analysis. Unexpectedly, there was no significant association between POPF and PDD. ConclusionsEarly occurrence of POPF after PD did not influence the development of PDD in late period, and long-term follow-up should be made by paying attention to PDD and RPV, because PDD was recognized as the most important risk factor of new-onset or exacerbation of DM and the patients with small RPV suffered from prolonged exocrine dysfunction rather than endocrine dysfunction.

Frey's procedure for chronic pancreatitis improves the nutritional status of these patients.

The aim of surgical intervention for chronic pancreatitis (CP) is to relieve symptoms and improve quality of life. However, the precise effect of surgery on the nutritional status of CP patients, which is often impaired by exocrine and endocrine pancreatic dysfunction, has not been elucidated. We conducted this study to evaluate whether Frey's procedure improves the nutritional status of CP patients. The nutritional status of 35 patients who underwent Frey's procedure for CP at our institute between April 2005 and December 2014, was assessed by the controlling nutritional status (CONUT) scoring before and 1year after the surgery, and compared with that of seven CP patients who underwent pancreatoduodenectomy. The occurrence of postoperative hepatic steatosis was also monitored. The nutritional status improved after Frey's procedure, but not after pancreatoduodenectomy. The median postoperative CONUT score after Frey's procedure was significantly lower than the preoperative score (1.0±0.5 vs. 4.0±2.5; p<0.001). Frey's procedure is superior to pancreatoduodenectomy for improving the nutritional status of CP patients.

Preoperative fecal elastase-1 is a useful prognostic marker following curative resection of pancreatic cancer

BackgroundThe clinical relevance of fibrosis with regard to tumor progression is supported by the correlation between fibrosis and poor outcomes. Fecal elastase-1 (FE-1) level has been used to assess exocrine dysfunction of the pancreas and to predict pancreas fibrosis. The aim of this study was to assess the impact of FE-1 on the survival of pancreatic cancer patients. MethodsBetween January 2006 and December 2014, 136 patients with pancreatic adenocarcinoma underwent R0 resection at Gangnam Severance Hospital, Korea. Preoperative FE-1 levels were available in 94 patients who were enrolled in the study. Patients were classified into two groups according to preoperative FE-1: “normal” (≥200 μg/g) or “reduced” (<200 μg/g). ResultsMedian preoperative FE-1 level was 130.1 μg/g (IQR 32.0; 238.3). 62 patients (66.0%) had reduced pancreatic function and 32 patients (34.0%) had normal pancreatic function. The two groups had significantly different disease-free survival (P < 0.001). On multivariate analysis, normal FE-1, no lymph node metastasis and completion of adjuvant chemotherapy were found to be independent prognostic factors for better DFS (P = 0.001, P = 0.017, P = 0.038, respectively). ConclusionFE-1 is a simple and non-invasive predictive clinical marker for prognosis of pancreatic cancer after attempted curative resection.

Endoscopic Therapies for Chronic Pancreatitis.

Chronic pancreatitis is a fibroinflammatory disease of the pancreas leading to varying degrees of endocrine and exocrine dysfunction. Treatment options are generally designed to control the pain of chronic pancreatitis, and endoscopic therapy is one of the main treatment modalities. Herein, we describe the endoscopic management of pancreatic duct calculi and strictures, entrapment of the intrapancreatic bile duct, celiac plexus interventions, and drainage of pancreatic pseudocysts.

Early pancreatic dysfunction after resection in trauma: An 18-year report from a Level I trauma center.

Early pancreatic dysfunction after resection in trauma has not been well characterized. The objective of this study was to examine the incidence and clinical impact of new-onset endocrine and exocrine dysfunction after pancreatic resection for trauma. All patients sustaining a pancreatic injury from 1996 to 2013 were identified. Patients with preinjury diabetes were excluded. Survivors were divided into three groups according to the extent of anatomic resection-distal, proximal, or total pancreatectomy. Clinical demographics and outcome data were abstracted. Blood glucose levels, hemoglobin A1c, and insulin requirements were used to assess endocrine pancreatic function. Reported steatorrhea, diarrhea, or supplemental pancreatic enzyme requirements were used to assess exocrine pancreatic function. During the study period, 331 pancreatic injuries were identified, of which 109 (33%) required resection and 84 survived to hospital discharge. Four were excluded. Of 80 cases analyzed, 73 (91%) underwent distal pancreatectomy, 7 (9%) proximal pancreatectomy, and none a total pancreatectomy. The distal resection group was predominantly male (88%), median age 24 years, and mean BMI 27 (kg/m). Thirty-eight (52%) required insulin postoperatively, with the greatest proportion (47%) requiring insulin for ≤1 day; no patients were discharged on insulin. The proximal resection group was predominantly male (86%), median age 31 years, and mean BMI 32 (kg/m). Six of seven required insulin postoperatively and two of seven were insulin dependent at time of hospital discharge. For both distal and proximal resections, none had evidence of exocrine dysfunction or received pancreatic enzyme supplementation at discharge. Exocrine dysfunction after distal or proximal pancreatectomy for trauma is rare. The incidence of early onset endocrine dysfunction after traumatic distal pancreatectomy is also rare; however, it can be seen after proximal resection. Therapeutic study, level IV.

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice

The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in β cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated β cell dysfunction and loss of proliferation capacity, two features of β cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in β cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in β cells prevented β cell dysfunction and loss in this model. Thus, we present a model of accelerated β cell aging that may be useful for studying the mechanisms underlying β cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining β cell identity in the context of SMAD7 failure.

Serum Trypsinogen Levels in Type 1 Diabetes.

OBJECTIVEThe pancreas in type 1 diabetes exhibits decreased size (weight/volume) and abnormal exocrine morphology. Serum trypsinogen levels are an established marker of pancreatic exocrine function. As such, we hypothesized that trypsinogen levels may be reduced in patients with pre–type 1 diabetes and type 1 diabetes compared with healthy control subjects.RESEARCH DESIGN AND METHODSSerum trypsinogen levels were determined in 100 persons with type 1 diabetes (72 new-onset, 28 established), 99 autoantibody-positive (AAb+) subjects at varying levels of risk for developing this disease, 87 AAb-negative (AAb−) control subjects, 91 AAb− relatives with type 1 diabetes, and 18 patients with type 2 diabetes.RESULTSTrypsinogen levels increased significantly with age in control subjects (r = 0.71; P < 0.0001) and were significantly lower in patients with new-onset (mean ± SD 14.5 ± 6.1 ng/mL; P < 0.0001) and established type 1 diabetes (16.7 ± 6.9 ng/mL; P < 0.05) versus AAb− control subjects (25.3 ± 11.2 ng/mL), AAb− relatives (29.3 ± 15.0 ng/mL), AAb+ subjects (26.5 ± 12.1 ng/mL), and patients with type 2 diabetes (31.5 ± 17.3 ng/mL). Multivariate analysis revealed reduced trypsinogen in multiple-AAb+ subjects (P < 0.05) and patients with type 1 diabetes (P < 0.0001) compared with AAb− subjects (control subjects and relatives combined) and single-AAb+ (P < 0.01) subjects when considering age and BMI.CONCLUSIONSThese findings further support the interplay between pancreatic endocrine and exocrine dysfunction. Longitudinal studies are warranted to validate trypsinogen as a predictive biomarker of type 1 diabetes progression.

Postprandial Symptoms Felt at the Lower Part of the Epigastrium and a Possible Association of Pancreatic Exocrine Dysfunction with the Pathogenesis of Functional Dyspepsia.

Objective In symptom-dependent diseases such as functional dyspepsia (FD), matching the pattern of epigastric symptoms, including severity, kind, and perception site, between patients and physicians is critical. Additionally, a comprehensive examination of the stomach, duodenum, and pancreas is important for evaluating the origin of such symptoms. Methods FD-specific symptoms (epigastric pain, epigastric burning, early satiety, and postprandial fullness) and other symptoms (regurgitation, nausea, belching, and abdominal bloating) as well as the perception site of the above symptoms were investigated in healthy subjects using a new questionnaire with an illustration of the human body. A total of 114 patients with treatment-resistant dyspeptic symptoms were evaluated for their pancreatic exocrine function using N-benzoyl-L-tyrosyl-p-aminobenzoic acid. Results A total of 323 subjects (men:women, 216:107; mean age, 52.1 years old) were initially enrolled. Most of the subjects felt the FD-specific symptoms at the epigastrium, while about 20% felt them at other abdominal sites. About 30% of expressed as epigastric symptoms were FD-nonspecific symptoms. At the epigastrium, epigastric pain and epigastric burning were mainly felt at the upper part, and postprandial fullness and early satiety were felt at the lower part. The prevalence of patients with pancreatic exocrine dysfunction was 71% in the postprandial fullness group, 68% in the epigastric pain group, and 82% in the diarrhea group. Conclusion We observed mismatch in the perception site and expression between the epigastric symptoms of healthy subjects and FD-specific symptoms. Postprandial symptoms were often felt at the lower part of the epigastrium, and pancreatic exocrine dysfunction may be involved in the FD symptoms, especially for treatment-resistant dyspepsia patients.

Germline and Somatic Genetic Characterization of Shwachman-Diamond Syndrome

The North American Shwachman-Diamond Syndrome Registry (SDSR) opened in 2008 to improve our understanding of the natural history of Shwachman-Diamond Syndrome (SDS), improve medical outcomes, and facilitate research. The diagnosis of SDS was defined by either biallelic SBDS gene mutations or by the clinical combination of exocrine pancreatic dysfunction with bone marrow failure. Median age of study subjects is 11.2 years (range, 0.6-52.8). SBDS genetic reports were available for 168 subjects. Eighty-one had biallelic SBDS mutations, while 48 individuals lacked SBDS mutations. Ongoing characterization of SBDS mutation-negative individuals has identified subgroups of SDS individuals meeting clinical diagnostic criteria as outlined above, as well as a more heterogenous subgroup with features of SDS but in whom a clinical diagnosis could not be confirmed by classic diagnostic criteria. Amongst those with biallelic SBDS mutations, cytopenias were noted in all but 1 subject. Intermittent neutropenia was noted in 97% (n=70/72) and was the most frequent hematologic abnormality. Anemia was noted in 53% (n=39/73) and thrombocytopenia in 64% (n=48/75). Congenital anomalies were seen in 50% (n=39/78).The mutational spectrum of SBDS was explored. In 80 of 81 patients harboring biallelic SBDS mutations, the c.258+2 T>C intron 2 splice donor mutation was found in at least one of the two mutant SBDS alleles. In these cases, the mutation spectrum of the second mutant SBDS allele included missense mutations, splice site mutations, and truncating mutations. The one patient lacking the intron 2 splice donor mutation had a c.183_184delTAinsCT mutation together with a c.523 C>T mutation in SBDS confirmed to be in trans. This results in the combination of a truncating p.Lys62X mutation with a p.R175W missense mutation at a conserved residue predicted to be deleterious. This patient presented with neonatal severe aplastic anemia requiring platelet and red cell transfusions with neutrophil counts of 0-200 unresponsive to G-CSF. The marrow showed irregular islands of cartilage surrounded by osteoid consistent with a disorder of bone formation. A low level of SBDS protein is expressed by the c.258+2T>C variant, so the absence of this hypomorphic allele may have contributed to this exceptionally severe phenotype.Bone marrow reports were available for 67 subjects with biallelic SBDSmutations. Marrow hypocellularity was noted in 79% (n=49/62). Mild morphologic marrow dysplasia was observed in 58% (n=35/60). Clonal abnormalities developed in 36%. The most common clonal abnormality was del20q in 16% (n=10/64). Isochromosome 7 was noted in 2% (n=1/64). Three individuals developed AML at ages 19.5, 38, and 39 years. Eleven (14%) have undergone hematopoietic stem cell transplantation (HSCT), 10 for MDS or AML and 1 for severe aplastic anemia.Given the frequency of del20q clones in SDS, we studied clinical features of the 10 SDSR subjects with del20q clones. Median age of this group was 17 years (range, 10.8-29.3). Congenital anomalies were noted in 80% (n=8/10). Frequency of cytopenias was similar to that of non-del20q subjects, with neutropenia, anemia and thrombocytopenia seen in 90%, 50%, and 80% respectively. Bone marrow pathology reports were available for 9 subjects. All were noted to have hypocellular marrows as well as mild marrow dysplasia. In many patients, the clone was persistent or grew over time, with longest duration of 14.6 years. Progression to MDS was reported in 3 subjects who initially had an isolated del20q clone. Two developed an additional loss of chromosome 7. Progressive marrow dysplasia and falling blood counts were seen in two subjects. All three were treated with HSCT at 5.4, 5.7 and 7 years. Deletion of 20q in SDS has been hypothesized to result in a milder hematologic phenotype due to compensatory deletion of eIF6. eIF6 binds to the nascent 60S ribosomal subunit and sterically inhibits joining of the 60S to the 40S ribosomal subunits. SBDS functions to facilitate release of eIF6 thus promoting assembly of the mature 80S ribosome. These data from the SDSR suggest that SDS patients with del20q clones remain at risk for clonal evolution. Higher patient numbers are needed to quantitate risk of MDS in SDS patients with del20q.The SDSR continues to expand and mature as a resource for biological and clinical studies in this rare disorder advancing our understanding of marrow failure and clonal evolution. DisclosuresDavies:Novartis: Honoraria. Dale:Amgen: Consultancy, Honoraria, Research Funding.

Hepcidin knockout mice spontaneously develop chronic pancreatitis owing to cytoplasmic iron overload in acinar cells.

Iron is both an essential and a potentially toxic element, and its systemic homeostasis is controlled by the iron hormone hepcidin. Hepcidin binds to the cellular iron exporter ferroportin, causes its degradation, and thereby diminishes iron uptake from the intestine and the release of iron from macrophages. Given that hepcidin-resistant ferroportin mutant mice show exocrine pancreas dysfunction, we analysed pancreata of aging hepcidin knockout (KO) mice. Hepcidin and Hfe KO mice were compared with wild-type (WT) mice kept on standard or iron-rich diets. Twelve-month-old hepcidin KO mice were subjected to daily minihepcidin PR73 treatment for 1 week. Six-month-old hepcidin KO mice showed cytoplasmic acinar iron overload and mild pancreatitis, together with elevated expression of the iron uptake mediators DMT1 and Zip14. Acinar atrophy, massive macrophage infiltration, fatty changes and pancreas fibrosis were noted in 1-year-old hepcidin KO mice. As an underlying mechanism, 6-month-old hepcidin KO mice showed increased pancreatic oxidative stress, with elevated DNA damage, apoptosis and activated nuclear factor-κB (NF-κB) signalling. Neither iron overload nor pancreatic damage was observed in WT mice fed iron-rich diet or in Hfe KO mice. Minihepcidin application to hepcidin KO mice led to an improvement in general health status and to iron redistribution from acinar cells to macrophages. It also resulted in decreased NF-κB activation and reduced DNA damage. In conclusion, loss of hepcidin signalling in mice leads to iron overload-induced chronic pancreatitis that is not seen in situations with less severe iron accumulation. The observed tissue injury can be reversed by hepcidin supplementation. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Enucleation: A treatment alternative for branch duct intraductal papillary mucinous neoplasms

Small, asymptomatic, branch-duct intraductal papillary mucinous neoplasms of the pancreas are often kept under surveillance despite their malignant potential. The management of branch-duct intraductal papillary mucinous neoplasm is controversial with regard to indications and extent of any operative intervention. The present study aimed to evaluate enucleation as an alternative operative approach for branch-duct intraductal papillary mucinous neoplasms to exclude and prevent malignancy. For branch-duct intraductal papillary mucinous neoplasms of <30mm in diameter and an acceptable distance from the main pancreatic duct, enucleation was considered as the operative approach of choice. All patients scheduled for enucleation of branch-duct intraductal papillary mucinous neoplasm on the basis of these features between January 2004 and September 2014 were analyzed. Among these, patients with successful enucleation were compared with those who were scheduled for enucleation but converted intraoperatively to pancreatic resection (intention-to-treat analysis). End points were hospital morbidity and mortality as well as histopathology and functional outcome at a mean follow-up of 32months. In the study, 115 patients with presumed branch-duct intraductal papillary mucinous neoplasm and the intention to perform pancreatic enucleation were included; 87 enucleations were performed in 74 patients. In 41 patients, enucleation was converted to a pancreatic resection (procedure-specific success rate 64%); indications for conversion included location or size (46%), presence of multicystic lesions (39%), or involvement of the main pancreatic duct (15%). Of the 74 patients with enucleation, 64 branch-duct intraductal papillary mucinous neoplasms revealed low- (85%), 11% moderate dysplasia-, and 4% high-grade dysplasia on histology. Among converted resections, 6 intraductal papillary mucinous neoplasms revealed high-grade dysplasia or invasive carcinoma (15%). Intention-to-treat analysis with patients converted to pancreatic resection showed that enucleations resulted in less blood loss (100 vs 400mL) and a shorter operation time (146 vs 255minutes; P<.001 each). Postoperative morbidity including postoperative pancreatic fistula was similar in both groups. No mortality occurred after enucleation; after formal resection, 1 patient died due to multiorgan failure. Both hospital stay (10 vs 14days) and rates of postoperative endocrine and exocrine dysfunction rates were less after enucleation (P<.02 each). Intraductal papillary mucinous neoplasm-specific recurrence rates (3% vs 6%) were similar in both groups. Enucleation is a safe procedure that can be performed successfully in a high proportion of branch-duct intraductal papillary mucinous neoplasms and should be considered instead of standard resections as an important function-preserving alternative. Limitations may occur due to malignancy, size, localization, multilocularity, or main-duct involvement requiring conversion to a formal, anatomic resection. Beside the advantages in the short-term course, functional outcome seems to be superior after enucleation, and intraductal papillary mucinous neoplasm-specific recurrence rates are not increased compared with standard resections, at least at a mean follow-up of 32months.