Browsing by Author "Alkaade, Samer"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Chronic pancreatitis: Pediatric and adult cohorts show similarities in disease progress despite different risk factors
    (Lippincott, Williams & Wilkins, 2020-04) Schwarzenberg, Sarah J.; Uc, Aliye; Zimmerman, Bridget; Wilschanski, Michael; Wilcox, C. Mel; Whitcomb, David C.; Werlin, Steven L.; Troendle, David; Tang, Gong; Slivka, Adam; Singh, Vikesh K.; Sherman, Stuart; Shah, Uzma; Sandhu, Bimaljit S.; Romagnuolo, Joseph; Rhee, Sue; Pohl, John F.; Perito, Emily R.; Ooi, Chee Y.; Nathan, Jaimie D.; Muniraj, Thiruvengadam; Morinville, Veronique D.; McFerron, Brian; Mascarenhas, Maria; Maqbool, Asim; Liu, Quin; Lin, Tom K.; Lewis, Michele; Husain, Sohail Z.; Himes, Ryan; Heyman, Melvin B.; Guda, Nalini; Gonska, Tanja; Giefer, Matthew J.; Gelrud, Andres; Gariepy, Cheryl E.; Gardner, Timothy B.; Freedman, Steven D.; Forsmark, Christopher E.; Fishman, Douglas S.; Cote, Gregory A.; Conwell, Darwin; Brand, Randall E.; Bellin, Melena; Barth, Bradley; Banks, Peter A.; Anderson, Michelle A.; Amann, Stephen T.; Alkaade, Samer; Abu-El-Haija, Maisam; Abberbock, Judah N.; Lowe, Mark E.; Yadav, Dhiraj; Medicine, School of Medicine
    Objectives: To investigate the natural history of chronic pancreatitis (CP), patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. Methods: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1,063 adults were compared using appropriate statistical tests for categorical and continuous variables. Results: Alcohol was a risk in 53% of adults and 1% of children (p<0.0001); tobacco in 50% of adults and 7% of children (p<0.0001). Obstructive factors were more common in children (29% vs 19% in adults, p=0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, p=0.107). Diabetes was more common in adults than children (36% vs 4% respectively, p<0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared to INSPPIRE subjects. These two cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, p=0.011). Conclusions: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.
  • Thumbnail Image
    Item
    Constant-Severe Pain in Chronic Pancreatitis is Associated with Genetic Loci for Major Depression in the NAPS2 Cohort
    (Springer, 2020) Dunbar, Ellyn; Greer, Phil J.; Melhem, Nadine; Alkaade, Samer; Amann, Stephen T.; Brand, Randall; Coté, Gregory A.; Forsmark, Christopher E.; Gardner, Timothy B.; Gelrud, Andres; Guda, Nalini M.; LaRusch, Jessica; Lewis, Michele D.; Machicado, Jorge D.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Romagnuolo, Joseph; Sandhu, Bimaljit S.; Sherman, Stuart; Wilcox, Charles M.; Singh, Vikesh K.; Yadav, Dhiraj; Whitcomb, David C.; NAPS2 study group; Medicine, School of Medicine
    Background: Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients. Study: A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested. Results: Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p < 2.2 × 10- 16). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes including ROBO2, CTNND2, SGCZ, CNTN5 and BAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2, and CTNND2). Conclusion: Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted.
  • Thumbnail Image
    Item
    Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early- vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort
    (Elsevier, 2020) Lewis, Michele D.; Talluri, Jyothsna; Wilcox, C. Mel; Abberbock, Judah N.; Tang, Gong; Conwell, Darwin L.; Banks, Peter A.; Cote, Gregory A.; Sherman, Stuart; Alkaade, Samer; Gardner, Timothy B.; Anderson, Michelle A.; Sandhu, Bimaljit S.; Muniraj, Thiruvengadam; Forsmark, Chris E.; Guda, Nalini; Gelrud, Andres; Romagnuolo, Joseph; Brand, Randall; LaRusch, Jessica; Amann, Stephen T.; Slivka, Adam; Whitcomb, David C.; Yadav, Dhiraj; Medicine, School of Medicine
    Background & Aims Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early-onset ICP (EO-ICP; median age, 19.2 years) and late-onset ICP (LO-ICP; median age, 56.2 years). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, or ACP. Methods We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2 studies, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants. Results Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P=.04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P=.001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P=.001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. Conclusions We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared to about one-quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.
  • Thumbnail Image
    Item
    Formation of Pancreatoduodenal Fistula in Intraductal Papillary Mucinous Neoplasm of the Pancreas Decreased the Frequency of Recurrent Pancreatitis
    (Elmer Press, 2019-02) Khneizer, Gebran; Reddy, Kavya M.; Hammami, Muhammad B.; Alkaade, Samer; Department of Medicine, Indiana University School of Medicine
    Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are characterized by proliferation of mucin-secreting cells in the main pancreatic duct (PD) or its branches. The secreted thick mucin usually leads to PD obstruction and dilation. A common complication of IPMN is recurrent acute pancreatitis secondary to poor pancreatic fluid drainage, and rarely, pancreatobiliary and pancreatointestinal fistulae. We describe a unique case of IPMN in a 57-year-old male who was referred to our institution for evaluation of recurrent acute pancreatitis. After extensive evaluation, he was diagnosed with main duct IPMN. Intraductal PD biopsy revealed intestinal type IPMN with intermediate grade dysplasia. Patient was managed clinically by large caliber (10 French) PD stenting which eliminated his recurrent acute pancreatitis. The patient was initially referred for pancreatic resection; however, surgery was aborted and evaluated to be high risk with high morbidity secondary to the extensive adhesions between the pancreas and surrounding structures. Patient remained clinically stable for a few years except for an episode of acute pancreatitis that happened after a trial of stent removal. Subsequently, the patient did well after the PD stent was replaced. Recently, repeat abdominal imaging revealed a large pancreatoduodenal fistula which was confirmed on repeat endoscopic retrograde cholangiopancreatography. We were able to perform pancreatoscopy by advancing a regular upper scope through the fistula and into the PD. Interestingly, the fistula relieved the symptoms of obstruction and subsequently decreased the frequency of recurrent pancreatitis episodes with no further episodes at 6 months follow-up. This case highlights the importance of providing adequate PD drainage to reduce the frequency of recurrent acute pancreatitis in the setting of main duct IPMN, especially if the patient is not a surgical candidate. Also, physicians need to monitor for complications such as fistula formation between the pancreas and surrounding structures in the setting of chronic inflammation due to recurrent episodes of pancreatitis. Early identification of a fistula is important for surgical planning. Furthermore, since recent studies suggested a higher incidence of additional primary malignancies in patients with IPMN of the pancreas compared to the general population, patients may be considered for screening for other primary malignancies.
  • Thumbnail Image
    Item
    Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis
    (Public Library of Science, 2014-07-17) LaRusch, Jessica; Jung, Jinsei; General, Ignacio J.; Lewis, Michele D.; Park, Hyun Woo; Brand, Randall E.; Gelrud, Andres; Anderson, Michelle A.; Banks, Peter A.; Conwell, Darwin; Lawrence, Christopher; Romagnuolo, Joseph; Baillie, John; Alkaade, Samer; Cote, Gregory; Gardner, Timothy B.; Amann, Stephen T.; Slivka, Adam; Sandhu, Bimaljit; Aloe, Amy; Kienholz, Michelle L.; Yadav, Dhiraj; Barmada, M. Michael; Bahar, Ivet; Lee, Min Goo; Whitcomb, David C.; North American Pancreatitis Study Group; Medicine, School of Medicine
    CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.
  • Thumbnail Image
    Item
    Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain
    (Wolters Kluwer, 2021) Dunbar, Ellyn K.; Greer, Phil J.; Amann, Stephen T.; Alkaade, Samer; Banks, Peter; Brand, Randall; Conwell, Darwin L.; Forsmark, Christopher E.; Gardner, Timothy B.; Guda, Nalini M.; Lewis, Michele D.; Machicado, Jorge D.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Romagnuolo, Joseph; Sandhu, Bimaljit S.; Sherman, Stuart; Slivka, Adam; Wilcox, C. Mel; Yadav, Dhiraj; Whitcomb, David C.; NAPS2 Consortium; Medicine, School of Medicine
    Introduction: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. Methods: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. Results: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). Discussion: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.