Rochester, MN, United States
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Sah R.P.,Fiterman Center for Digestive Diseases | Chari S.T.,Fiterman Center for Digestive Diseases | Chari S.T.,Miles and Shirley Fiterman Center for Digestive Diseases
Current Gastroenterology Reports | Year: 2012

Autoimmune Pancreatitis (AIP) is a recently recognized chronic fibro-inflammatory disease of the pancreas. Although rare, its recognition continues to increase worldwide. Patients often present with painless obstructive jaundice mimicking pancreatic cancer. Two subtypes of AIP are known-type 1 is a multi-organ disease associated with IgG4; type 2 appears to be a pancreas-specific disorder. Dramatic response to steroid treatment is characteristic of both forms. A non-invasive diagnosis of type 1 AIP may be possible using diagnostic criteria (in ~70% cases) while diagnosis of type 2 requires histology. These subtypes differ in natural history- type 1 often relapses while initial reports suggest that type 2 does not. Long term complications include endocrine and exocrine insufficiency and in case of type 1, disease relapses and complications from extra-pancreatic involvement. Neither form affects long term survival. The treatment and follow-up guidelines continue to evolve with our increasing experience in AIP. © Springer Science+Business Media, LLC 2012.


Treeprasertsuk S.,Fiterman Center for Digestive Diseases | Treeprasertsuk S.,Chulalongkorn University | Lopez-Jimenez F.,Mayo Medical School | Lindor K.D.,Fiterman Center for Digestive Diseases
Digestive Diseases and Sciences | Year: 2011

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and is recognized as part of the metabolic syndrome (MetS). Patients with NAFLD have a lower life expectancy compared to the general population, with coronary artery disease (CAD) as the leading cause of death. Aims: We aim to address the epidemiological data of CAD, the possible pathogenesis or linkage mechanisms of NAFLD and atherosclerosis and the strategies to reduce the CAD risk in NAFLD patients. Methods: We reviewed data from a Medline and PubMed search which was performed to identify relevant literature using search terms "NAFLD," "metabolic syndrome" and "coronary artery disease." Results: Patients with steatohepatitis, a part of the spectrum of NAFLD, have more cardiovascular events than patients without steatohepatitis. However, the association between liver histological progression and the risk of CAD events is not linear. A multidisciplinary approach to NAFLD patients based on controlling related risk factors and monitoring for CAD risks and liver complications is necessary. The combination of lifestyle modification with pharmacological treatment tailored to each individual's risk factors needs to be considered. There is a need for more research on primary prevention for CAD in NAFLD patients and interventional studies for determining the nature of the relationship between NAFLD and CAD. Conclusions: NAFLD is recognized as part of the MetS and increases cardiovascular risks. Therefore, a multidisciplinary approach to these patients of controlling the related risk factors and monitoring for cardiovascular and liver complications must be done. © 2010 Springer Science+Business Media, LLC.


Huang S.,Fiterman Center for Digestive Diseases | Sinicrope F.A.,Fiterman Center for Digestive Diseases
Autophagy | Year: 2010

Apoptosis and autophagy have been shown to be negatively regulated by prosurvival Bcl-2 proteins. We determined whether the anticancer agent celecoxib, alone or combined with a small molecule Bcl-2/Bcl-xL antagonist (ABT-737), can induce autophagy in colon cancer cells. Furthermore, we determined whether inhibition of autophagy can drive colon cancer cells into apoptosis. Celecoxib was shown to induce apoptosis that was attenuated by ectopic Bcl-2 or Bax knockout. ABT-737 synergistically enhanced celecoxib-induced cytotoxicity that was primarily due to apoptosis as shown by caspase cleavage and Annexin V labeling that was attenuated by a pan caspase inhibitor (z-VAD-fmk). Celecoxib triggered conversion of the autophagosome-associated protein light chain 3 (LC3) from a cytosolic (LC3I) to a membrane-bound (LC3II) form, as shown by immunoblotting and a punctate fluorescence pattern of an ectopic GFP-LC3 protein. celecoxib-induced conversion of LC3 was due to autophagy induction, as supported using the lysosome inhibitor, bafilomycin A1, which produced an accumulation of LC3II. ABT-737 enhanced celecoxib-induced LC3 conversion and p62/ SQSTM1 degradation. Inhibition of autophagy was then studied in an effort to drive cells into apoptosis. 3-methyladenine (3-MA) blocked LC3 conversion, and 3-MA and wortmannin significantly enhanced apoptotic signaling in cells treated with celecoxib plus ABT-737. Furthermore, knockdown of Atg8/LC3B or Vps34 using siRNA attenuated p62 degradation and enhanced apoptotic signaling; Vps34 siRNA potentiated annexin V+, PI- labeled cells induced by celecoxib + ABT-737. In conclusion, celecoxib induces apoptosis and autophagy that can both be potentiated by ABT-737. Inhibition of autophagy was shown to enhance apoptosis, suggesting a novel therapeutic strategy against colon cancer. © 2010 Landes Bioscience.


Sah R.P.,Fiterman Center for Digestive Diseases | Chari S.T.,Fiterman Center for Digestive Diseases | Pannala R.,Fiterman Center for Digestive Diseases | Sugumar A.,Fiterman Center for Digestive Diseases | And 9 more authors.
Gastroenterology | Year: 2010

Background & Aims: Autoimmune pancreatitis (AIP) has been divided into subtypes 1 (lymphoplasmacytic sclerosing pancreatitis) and 2 (idiopathic duct centric pancreatitis). We compared clinical profiles and long-term outcomes of types 1 and 2 AIP. Methods: We compared clinical presentation, relapse, and vital status of 78 patients with type 1 AIP who met the original HISORt criteria and 19 patients with histologically confirmed type 2 AIP. Results: At presentation, patients with type 1 AIP were older than those with type 2 AIP (62 ± 14 vs 48 ± 19 years; P < .0001) and had a greater prevalence of increased serum levels of immunoglobulin G4 (47/59 [80%] vs 1/6 [17%]; P = .004). Patients with type 1 were more likely than those with type 2 to have proximal biliary, retroperitoneal, renal, or salivary disease (60% vs 0; P < .0001). Inflammatory bowel disease was associated with types 1 and 2 (6% vs 16%; P = .37). During median clinical follow-up periods of 42 and 29 months, respectively, 47% of patients with type 1 and none of those with type 2 experienced a relapse. In type 1 AIP, proximal biliary involvement (hazard ratio [HR], 2.12; P = .038) and diffuse pancreatic swelling (HR, 2.00; P = .049) were predictive of relapse, whereas pancreaticoduodenectomy reduced the relapse rate (vs the corticosteroid-treated group; HR, 0.15; P = .0001). After median follow-up periods of 58 and 89 months (types 1 and 2, respectively), the 5-year survival rates for both groups were similar to those of the age- and sex-matched US population. Conclusions: Types 1 and 2 AIP have distinct clinical profiles. Patients with type 1 AIP have a high relapse rate, but patients with type 2 AIP do not experience relapse. AIP does not affect long-term survival. © 2010 AGA Institute.


Sinicrope F.,Mayo Medical School | Sinicrope F.,Fiterman Center for Digestive Diseases | Foster N.R.,Mayo Medical School | Sargent D.J.,Mayo Medical School | And 3 more authors.
Cancer | Year: 2010

BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil-based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n=982) from 6 5-fluorouracil-based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n=326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic=0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n=326), a model including proximal site, TILs (>2/ high-power field), and female sex showed even better discrimination (c statistic=0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions. © 2010 American Cancer Society.


Sah R.P.,Fiterman Center for Digestive Diseases | Chari S.T.,Fiterman Center for Digestive Diseases
Current Opinion in Rheumatology | Year: 2011

Purpose of review: IgG4-related systemic disease (ISD) is a recently recognized syndrome affecting multiple organs. Autoimmune pancreatitis (AIP) is the pancreatic manifestation of ISD and mimics pancreatic cancer. Current data show frequent association with serum IgG4 elevation and other serologic abnormalities. Here we explore the diagnostic and possible prognostic utility and pathogenetic implications of serologic abnormalities in ISD. Recent findings: Serum IgG4 elevations (>140 mg/dl) are seen in 70-80% of AIP patients and also in 5% of normal population and 10% of pancreatic cancer making it an unsuitable single marker for diagnosis. However, when combined with other features of AIP, it can be of great diagnostic value though its utility in monitoring of therapy or as a marker or predictor of relapse is limited. Several other antibodies have been identified in AIP against pancreas-specific antigens like trypsinogens I and II, pancreatic secretory trypsin inhibitor (PSTI) and plasminogen binding protein (PBP) and other nonpancreas-specific antigens. Anti-PBP antibodies appear to have potential diagnostic utility but require further validation. Summary: No single serologic marker is diagnostic of ISD. Serum IgG4 elevation has convincing diagnostic utility when combined with other disease features although its value in disease monitoring may be limited. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Sah R.P.,Fiterman Center for Digestive Diseases | Pannala R.,Fiterman Center for Digestive Diseases | Chari S.T.,Fiterman Center for Digestive Diseases | Sugumar A.,Fiterman Center for Digestive Diseases | And 8 more authors.
Clinical Gastroenterology and Hepatology | Year: 2010

Background & Aims: Little is known about how many patients with features of acute pancreatitis (AP) or chronic pancreatitis (CP) have autoimmune pancreatitis (AIP); most information comes from case reports. We explored the clinical profiles and relationship between these diseases. Methods: We evaluated 178 patients presenting to our Pancreas Clinic between January 2005 and June 2006 for evaluation of the etiology of their suspected pancreatitis; AIP was diagnosed when patients met HISORt (Histology, Imaging features, Serology, Other organ involvement and Response to steroid treatment) criteria. In a separate cohort of patients with AIP from our database, we identified patients who presented with features of AP (≥2 of abdominal pain, increased pancreatic enzymes, pancreatic inflammation determined by imaging analyses) or CP (≥1 of pancreatic calcification, irregular main pancreatic duct dilation, or marked atrophy) and determined their clinical profile. Results: Only 7/178 (3.9%) patients evaluated for etiology of suspected pancreatitis had AIP. Among 63 AIP patients in our database, 22 (34.9%) had features of AP (n = 15) or CP (n = 7) at presentation (average age 53.4 ± 19.0 years, all males). Patients with AIP and pancreatitis were characterized by presence of obstructive jaundice (59.1%), increased levels of liver enzymes (81.8%), increased levels of serum immunoglobulin G4 (80.9%), and other organ involvement (69.1%). All 19 patients presenting with pancreatitis who were treated with steroids responded to treatment. Conclusions: While AIP is an uncommon etiology for acute or chronic pancreatitis, >33% of AIP have features of acute or chronic pancreatitis at presentation. © 2010 AGA Institute.


PubMed | Fiterman Center for Digestive Diseases
Type: Comparative Study | Journal: Gastroenterology | Year: 2010

Autoimmune pancreatitis (AIP) has been divided into subtypes 1 (lymphoplasmacytic sclerosing pancreatitis) and 2 (idiopathic duct centric pancreatitis). We compared clinical profiles and long-term outcomes of types 1 and 2 AIP.We compared clinical presentation, relapse, and vital status of 78 patients with type 1 AIP who met the original HISORt criteria and 19 patients with histologically confirmed type 2 AIP.At presentation, patients with type 1 AIP were older than those with type 2 AIP (62 +/- 14 vs 48 +/- 19 years; P < .0001) and had a greater prevalence of increased serum levels of immunoglobulin G4 (47/59 [80%] vs 1/6 [17%]; P = .004). Patients with type 1 were more likely than those with type 2 to have proximal biliary, retroperitoneal, renal, or salivary disease (60% vs 0; P < .0001). Inflammatory bowel disease was associated with types 1 and 2 (6% vs 16%; P = .37). During median clinical follow-up periods of 42 and 29 months, respectively, 47% of patients with type 1 and none of those with type 2 experienced a relapse. In type 1 AIP, proximal biliary involvement (hazard ratio [HR], 2.12; P = .038) and diffuse pancreatic swelling (HR, 2.00; P = .049) were predictive of relapse, whereas pancreaticoduodenectomy reduced the relapse rate (vs the corticosteroid-treated group; HR, 0.15; P = .0001). After median follow-up periods of 58 and 89 months (types 1 and 2, respectively), the 5-year survival rates for both groups were similar to those of the age- and sex-matched US population.Types 1 and 2 AIP have distinct clinical profiles. Patients with type 1 AIP have a high relapse rate, but patients with type 2 AIP do not experience relapse. AIP does not affect long-term survival.


PubMed | Fiterman Center for Digestive Diseases
Type: Journal Article | Journal: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | Year: 2010

Little is known about how many patients with features of acute pancreatitis (AP) or chronic pancreatitis (CP) have autoimmune pancreatitis (AIP); most information comes from case reports. We explored the clinical profiles and relationship between these diseases.We evaluated 178 patients presenting to our Pancreas Clinic between January 2005 and June 2006 for evaluation of the etiology of their suspected pancreatitis; AIP was diagnosed when patients met HISORt (Histology, Imaging features, Serology, Other organ involvement and Response to steroid treatment) criteria. In a separate cohort of patients with AIP from our database, we identified patients who presented with features of AP (>/=2 of abdominal pain, increased pancreatic enzymes, pancreatic inflammation determined by imaging analyses) or CP (>/=1 of pancreatic calcification, irregular main pancreatic duct dilation, or marked atrophy) and determined their clinical profile.Only 7/178 (3.9%) patients evaluated for etiology of suspected pancreatitis had AIP. Among 63 AIP patients in our database, 22 (34.9%) had features of AP (n = 15) or CP (n = 7) at presentation (average age 53.4 +/- 19.0 years, all males). Patients with AIP and pancreatitis were characterized by presence of obstructive jaundice (59.1%), increased levels of liver enzymes (81.8%), increased levels of serum immunoglobulin G4 (80.9%), and other organ involvement (69.1%). All 19 patients presenting with pancreatitis who were treated with steroids responded to treatment.While AIP is an uncommon etiology for acute or chronic pancreatitis, >33% of AIP have features of acute or chronic pancreatitis at presentation.

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