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The taming of the sprue

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I presented this as a grand rounds case when I was fellow. It was a patient who had collagenous sprue that responded with a gluten free diet.

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The taming of the sprue

  1. 1. The Taming ofThe Taming of the Spruethe Sprue Edwin McDonald 1st year GI Fellow Rush University GI Clinical Grand Rounds
  2. 2. Case:Case: • 62 y.o. female • History of celiac disease o diagnosed 18 mo ago at OSH (bx, unknown TTG) o responsive to a gluten-free diet • 1 year ago, recurrent watery diarrhea • 6 mo ago nausea/vomiting with diarrhea • Lost 97 lbs in past 6 months • Admitted for diarrhea, dehydration and severe malnutrition
  3. 3. Case Continued…Case Continued… • Past Medical History o Celiac Disease o Polymyalgia Rheumatica o Anemia o Hyperthyroidism o Hypertension • Medications o Amlodipine 5mg o Benicar 40mg o Prednisone 40mg o Lunesta prn o Zofran 4mg prn
  4. 4. Case Continued…Case Continued… • Family History: o Irish Descent o No history celiac disease or lymphoma o Father-prostate cancer o Brother- diabetes and rectal CA • Social Hx: o Retired secretary, married, 2 children o No tobacco o Occasional ETOH
  5. 5. Physical Examination - Cachectic appearing with temporal, deltoid, quadriceps muscle wasting - Poor strength - Ht 5’6”, Wt 44.2 kg/97 lbs, T 97, HR 76, BP 100/60 - Sclera white - Neck: no adenopathy or palpable thyroid - Lungs: clear to auscultation - Heart: normal S1, S2, without gallop, murmur - Abdomen: soft, nontender to palp - Extremities: no edema
  6. 6. Laboratory StudiesLaboratory Studies WBC 5.5 Hgb 11.8 Plt 309 MCV 92.6 CBC Iron 47 TIBC 136 (L) Ferritin 540 (H) Iron Studies Na 135 K+ 4.3 Cl 98 HCO3 29 BUN 17 Cr 0.6 Chemistry TP 4.2 (L) Alb 2.5 (L) T bil 0.2 ALKP 68 AST 75 (H) ALT 100 (H) LFTs CRP 3 Prealb 11 (L) Vitamin B12 1203 (H) Vitamin A 30.2 (L) Vitamin E 11.2 Zinc 0.44 (L) Folate 15.6 Vitamin D 23 (L) EMA: Negative TTG IgA: Negative IgA level: normal TSH 1.13
  7. 7. Stool Studies • Culture Negative • O & P: negative • C Difficile Negative
  8. 8. Differential DiagnosisDifferential Diagnosis Non -adherence to Gluten-free Diet Refractory Celiac disease Collagenous Sprue T-Cell Lymphoma Autoimmune Enteropathy Microscopic Colitis Small Intestinal Bacterial Overgrowth Ulcerative Jejuno-ileitis
  9. 9. 50 mg gluten Nonresponse: Got Gluten?Nonresponse: Got Gluten? Catassi, C. Am J Clin Nutr. 2007 Jan;85(1):160-6
  10. 10. 0 5 10 15 20 25 30 35 40 glutencontamination IBS RCD lactoseintolerance SBBO microscopiccolitis other Celiac Disease and Gluten Non-respondersCeliac Disease and Gluten Non-responders Leffler et al. CLIN GASTRO AND HEP 2007;5:445–450
  11. 11. Refractory Celiac Disease:Refractory Celiac Disease: A point of clarificationA point of clarification Type 1 Refractory CD •IEL CD3/ CD8 + •Polyclonal TCR Type 2 Refractory CD •Most IELs aberrant CD3(+/-)/CD8- •Monoclonal TCR EAT-Lymphoma •Infiltration of large pleomorphic lymphoid cells •CD30 and CD3+,CD 8- •Monoclonal TCR Ho-Yen et al. Histopathology 2009, 54, 783–795.
  12. 12. RCD vs. Celiac DiseaseRCD vs. Celiac Disease Comparison of Clinical DataComparison of Clinical Data • 4.0 % RCD • 14.7% (5/34) RCD II • 2 deaths EAT-L Leffler, et al. Am J Gastroenterol. 2011
  13. 13. Back to the Patient…Back to the Patient… Further Work Up?Further Work Up?
  14. 14. MR EnterographyMR Enterography 1. No bowel wall thickening 2. No lymphadenopathy. 3. Normal spleen
  15. 15. EGDEGD 1. 2. 3. 4.3 • EGD: atrophic stomach, duodenum scalloped • Impression: - Atrophic gastritis. - Enteropathy
  16. 16. ColonoscopyColonoscopy 2.1. 3. 4. 1 + 2. Cecum 3. Terminal Ileum All normal appearing 1 + 2. Cecum 3. Terminal Ileum All normal appearing
  17. 17. Genetic TestingGenetic Testing Kagnoff, M. J Clin Invest. 2007. 2; 117(1): 41–49
  18. 18. Let’s Be BluntLet’s Be Blunt Causes of Villous Atrophy Other Than Celiac Disease Giardiasis HIV enteropathy Common Variable Immunodeficiency Tuberculosis Autoimmune Enteropathy Intestinal Lymphoma Radiation Enteritis Zollinger Ellison Syndrome Whipple’s Disease Crohn’s Disease Tropical Sprue Other Food Intolerances Eosinophilic Gastroenteritis Collagenous Sprue Nutrient Deficiencies GVHD
  19. 19. Biopsies ColonDuodenum CD8 Duodenum Duodenum
  20. 20. Biopsies/PathologicBiopsies/Pathologic FindingsFindings • Marked villous blunting with increased subepithelial collagen layer • No increased intraepithelial lymphocytes • T-cell markers:(+)CD3, CD4, CD5, CD7, CD8 • collagenous sprue, polyclonal lymphocyte population • no lymphoma or Type II RCD • Colon- normal mucosa in TI, L/R colon • No collagenous/lymphocytic colitis
  21. 21. DIAGNOSIS: Collagenous Sprue
  22. 22. Collagenous Sprue: Background • Distinct from collagenous colitis • Villous atrophy and thickened sub-epithelial collagen band in small bowel • “Collagenous Sprue” 1st used 1971 in NEJM • Etiology not well understood • Unclear relationship with Collagenous Colitis • Only 60 cases reported up to Dec. 2009 • Incidence/prevalence not well established Zhao. Arch Pathol Lab Med. 2011;135:803–809)
  23. 23. Collagenous Sprue:Collagenous Sprue: 2 Largest Studies2 Largest Studies
  24. 24. Collagenous Sprue:Collagenous Sprue: CharacteristicsCharacteristics Age at Dx 72.5 (53-91) Female 21 (70%) Diarrhea 30 (100%) Wt Loss 29 (97%) Vomiting 23 (33%) Abd Pain 6 (20%) Hgb 12.5 (7.8-16.4) Albumin 3.2 (1.7-4.3) • Murray et al, retrospective cohort study 30 pts at Mayo in 2010 Previous Dx CD 11 (37%) TTG/EMA positive 3 (10%) HLA DQ2/DQ8 17 /22 (77%) Collagenous Colitis 11 Lymphocytic Colitis 4 Autoimmune Enteropathy 3 •Murray et al. Clin Gastro and Hep 8 (2010)
  25. 25. Murray et al: Pathologic FindingsMurray et al: Pathologic Findings Median collagen band thickness 29 μm Min/Max 18 and 95 μm Total Villous Atrophy 20 (67%) IEL 21 (70%) Aberrant Clonal IELs (57%) •Murray. Clin Gastro and Hep 8 (2010)
  26. 26. Murray Et al: Treatment • All patients recommended GFD • 80% clinical response, 2 deaths (stroke/sepsis) • 15 pts re-biopsied, 9 improved (5 complete resolution, 4 reversal of fibrosis) • Median follow of 18 mos, 6 weaned off steroids (median 22 mos), 5 unable to wean off steroids. Budesonide (9mg) 12 patients Prednisone/ Budesonide 9 patients Prednisone 3 patients Prednisone +Aza 2 patients Octreotide 1 patient TPN + GFD 2 patients
  27. 27. Green et al: CharacteristicsGreen et al: Characteristics Green et al. Modern Path (2009). Mean Age (y) 57 (22-80 ) Gender 15 women, 4 men Celiac disease 17/19 (89%) (+) Celiac serologies 14/17 Refractory Celiac Disease 9/17 HLA DQ 2 6/6 Autoimmune disorders 12/19 (63%) Microscopic Colitis 9 (7 collagenous)
  28. 28. •Defined increased collagen band as >5 μm •10 patients had 10-20μm Green et al: PathologicGreen et al: Pathologic FindingsFindings
  29. 29. • Histological improvement occurred in 7 of 11 re-biopsed(64%) • 8/19 (42%) responded to gluten-free diet • 3 patients on TPN • 10 responded to immuno-modulatory therapy (prednisone, budesonide, azathioprine, cyclosporine) • 1 patient died (refractory CD II, malnutrition) Green et al: OutcomesGreen et al: Outcomes
  30. 30. All with Collagenous SprueAll with Collagenous Sprue had Marsh III lesionshad Marsh III lesions
  31. 31. PathophysiologyPathophysiology • 2x increase procollagen I mRNA • No difference in matrix metalloproteinases • Increased TIMP-1 • Role of zinc deficiency? Daum, S. Clin Gastro Hep. 2006. Abuzakouk, Dig Dis Sci. 2006
  32. 32. Collagenous Sprue Collagenous Sprue:Collagenous Sprue: SummarySummary Refractory Celiac Disease Celiac Disease • Diarrhea • Sub-epithelial collagen band thickening >5 μm • Heterogenous disease • Pathophysiology is poorly understood
  33. 33. Collagenous Sprue SummaryCollagenous Sprue Summary How to Tame the SprueHow to Tame the Sprue •Verify Diagnosis of Celiac Disease- Biopsies, HLA, Serologies •If Celiac Disease- Gluten Free Diet and Steroids (open capsule if budesonide) •No Celiac Disease- Steroids and unclear benefit of Gluten Free Diet
  34. 34. ReferencesReferences • Bakht, Roshan, Daniel Leffler, and Shailaja Jamma. "The Incidence and Clinical Spectrum of Refractory Celiac Disease in a North American Referral Center." American Journal of Gastroenterology 106 (2011): 923-28. Print. • Freeman, Hugh J. "Refractory Celiac Disease and Sprue-like Intestinal Ilness." World J Gastroenterol 14.6 (2008): 828-30. Print. • Freeman, Hugh James. "Update on Collagenous Sprue." World Journal of Gastroenterology 16.3 (2010): 296. Print. • Ho-Yen, C., F. Chang, J. Van Der Walt, T. Mitchell, and P. Ciclitira. "Recent Advances in Refractory Coeliac Disease: a Review." Histopathology 54.7 (2009): 783-95. Print. • Leffler, Daniel A., Melinda Dennis, Brian Hyett, Eoin Kelly, Detlef Schuppan, and Ciaran P. Kelly. "Etiologies and Predictors of Diagnosis in Nonresponsive Celiac Disease." Clinical Gastroenterology and Hepatology 5.4 (2007): 445-50. Print. • Rubio-Tapia, A., and J. A. Murray. "Classification and Management of Refractory Coeliac Disease." Gut 59.4 (2010): 547-57. Print. • Rubio-Tapia, Alberto, and Joseph A. Murray. "Gluten Free Diet and Steroid Treatment Are Effective Therapy for Most Patients with Collagenous Sprue." Clinical Gastroenterology and Hepatology 8 (2010): 344+. Print. • Tjon, Jennifer May-Ling, Jeroen Bergen, and Frits Koning. "Celiac Disease: How Complicated Can It Get?" Immunogenetics 62.10 (2010): 641-51. Print. • Vakiani, Efsevia, Carolina Arguelles-Grande, Mahesh M. Mansukhani, Suzanne K. Lewis, Heidrun Rotterdam, Peter H. Green, and Govind Bhagat. "Collagenous Sprue Is Not Always Associated with Dismal Outcomes: a Clinicopathological Study of 19 Patients." Modern Pathology (2009). Print. • Zhao, Xiangrong. "Collagenous Sprue A Rare, Severe Small-Bowel Malabsorptive Disorder." American Pathol Lab Med 135 (2011). Print.

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