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. The Taming ofThe Taming of the Spruethe Sprue Edwin McDonald 1st year GI Fellow Rush University GI Clinical Grand Rounds
- 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. 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. 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. 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. 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. Stool Studies • Culture Negative • O & P: negative • C Difficile Negative
- 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. 50 mg gluten Nonresponse: Got Gluten?Nonresponse: Got Gluten? Catassi, C. Am J Clin Nutr. 2007 Jan;85(1):160-6
- 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. 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. 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. Back to the Patient…Back to the Patient… Further Work Up?Further Work Up?
- 14. MR EnterographyMR Enterography 1. No bowel wall thickening 2. No lymphadenopathy. 3. Normal spleen
- 15. EGDEGD 1. 2. 3. 4.3 • EGD: atrophic stomach, duodenum scalloped • Impression: - Atrophic gastritis. - Enteropathy
- 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. Genetic TestingGenetic Testing Kagnoff, M. J Clin Invest. 2007. 2; 117(1): 41–49
- 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
- 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
- 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. Collagenous Sprue:Collagenous Sprue: 2 Largest Studies2 Largest Studies
- 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. 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. 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. 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. •Defined increased collagen band as >5 μm •10 patients had 10-20μm Green et al: PathologicGreen et al: Pathologic FindingsFindings
- 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. All with Collagenous SprueAll with Collagenous Sprue had Marsh III lesionshad Marsh III lesions
- 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. 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. 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. 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.
Hinweis der Redaktion
- Some of these associated conditions include the following
- Before we go on with the case, I want to make a couple of brief points about nonresponsives to GFD The most obvious diagnosis is occult gluten ingestion and it doesn’t take that much gluten. IN 2007, catassi et al demonstrated that 50mg of gluten can elicit significant hisologic changes with a double randomnized placebo controlled where the randomized 49 biopsy proven celiac patient gfd to 0 , 10, 50mg for 90day and assesed histologic changes. Villous height/crypt depth were significantly different in the 50mg group. The little ditzle just how small 50mg of gluten is.
- In 2007, leffler et al demonstrated that the etiology of non response to a gluten free diet includes possibilities beyond gluten ingestion/contamination They reviewed the biopsy proven Celiac cases at Beth-Israel for non-responders 113 of 603 patients (19%) defined as non-responsive Celiac Disease Non-responders defined as: looked at etiologies of nonresponsives referral to a CD specialist for gluten non response failure of clinical symptoms/lab abnormalities to improve in 6 mos on GFD recurrence of symptoms and/or laboratory abnormalities on GFD No significant difference in gender, age, ttg, psychiatric, associated autoimmune condition 35% Gluten, 22% IBS, 6% MC, 10% Refractory sprue, 8% lacose def, 4% eating disored, 6% SIBO, 8% miscellaneos (gastroparesis, crohns, PUD, folod allergy, CVID, duodenal adeno
- Refractory cd and non-responsive cd are not interchangble terms. Refractory cd is defined persistent malabsorptive symptoms w/ villous atrophy despite GFD for 6-12 mos in the absence of other causes of nonresponsive celiac disease. There are two types: I and II, each are characterized by type of IEL and T cell receptor mon Leffler 34/844 (4.0%)
- HLA-DQB1*0302 and HLA-DQA1*03= DQ* A heterodimer on APC that binds Which are the genes the encode heterodimers HLA DQ2 wheich are the heterodimers on APCs that binds gluten and presents it to CD 4 Tcells
- Final Pathologic DiagnosisMarked villous blunting with an increased subepithelial collagen layer,consistent with collagenous sprue and no morphologic or immunophenotypicevidence of either a T- or B-cell lymphoma, "second and third portion of theduodenum", biopsies-see microscopic descriptionjdJerome Dickstein, M.D., Ph.DInterpretation performed by the Attending Pathologist.Electronically Signed Out by Jerome Dickstein, M.D., Ph.DClinical HistoryThe patient is a 62-year-old female who undergoes biopsy of second and thirdportion of duodenum for a history of refractory celiac sprue, rule outenteropathy associated T-cell lymphoma- request for gene rearrangement.Microscopic DescriptionThe "second and third portion of the duodenum" show marked villous blunting, anincreased subepithelial collagen layer, consistent with collagenous sprue. Thereis a mild lymphoid infiltrate with a background of numerous plasma cells in thelamina propria. The lymphocytes are small to intermediate in size with slightlyirregular contours and a high N/C ratio. No significant increase inintraepithelial lymphocytes is seen. In order to further investigate for apossible lymphoproliferative disorder, immunohistochemical studies are conductedwith appropriately reacting controls. By far, T-cells comprise the majority ofthe lymphocyte population. T-cells are positive for CD3, CD4, CD5, CD7 and to alesser extent for CD8 immunostains. CD56 shows non-specific background staining,but lymphoid cells are clearly negative for this antibody stain. CD43 highlightsT-cells in a similar number and distribution as does the anti-CD3 antibodyimmunostain. CD20 immunostain outlines small numbers of singly scattered and asmall cluster of B-cells. The B-cell cluster is negative for CD43. In situhybridization for kappa and lambda mRNA demonstrates that the plasma cells arepolyclonal.Overall, the findings observed in this case are marke
- FINAL PATHOLOGIC DIAGNOSISUpper GI endoscopic biopsies,Body:- Fundic mucosa without diagnostic abnormality.Antrum:- Antral mucosa without diagnostic abnormality.Duodenal bulb:- Duodenal mucosa with severe villous blunting and increasedsubepithelialcollagen layer, consistent with collagenous sprue.Duodenum:- Duodenal mucosa with severe villous blunting and increasedsubepithelialcollagen layer, consistent with collagenous sprue.
- Looked at 10 normal patients biopsies
- 13 with total villous atrophy No phenotypically aberrant intraepithelial lymphocytes PCR showed 1 pt. with dominant T-cell clone
- All lesions are Marsh type III in collagenous sprue. Grade III above atrophy, abc only differ in degree of atrophy.
- 2 CS/ 10pts untreated Celeiac Disease, in situ hybridization. Excess collagen production, decreased collagen breakdown.