My name is Cyrus Rubin, and I have been on the University of Washington, School of Medicine
faculty for over 50 years. I am a teacher, clinical investigator, and gastroenterologist
whose early interest in celiac sprue and main research method was gastrointestinal pathology
revealed by endoscopic biopsy. I regret that the early details of our early research have not
been easily available, partly because we published our early findings in an obscure journal in
summary fashion. In the following presentation, I will try to remedy this and will also present
research of others that I think has historical value. I am doing this because I agree with the
philosopher George Santayana that “those who do not learn from history are doomed to repeat it”.
In the 1940’s and 1950’s, pioneering work was done on the treatment of celiac disease, by Dr.
Willem Dicke, a Dutch pediatrician, who proved the efficacy of the gluten free diet, and this
revolutionized the care and treatment of this disease. In the 1960’s, my talented trainees in
gastroenterology helped me study the acute small intestinal changes induced by wheat, barley and
rye in celiac disease, in real time, using a hydraulic biopsy tube. I will also present research
to bring us up to date on the present state of our knowledge about celiac sprue (CS) and related diseases.
I wish to acknowledge that I could never have done this research without the help of many other people.
I am thankful to all of them. First, I would like to acknowledge my medical school mentor, Dr. A. Stone
Freedberg. I never planned to become a teacher and clinical investigator until two other second year
Harvard medical students and I were introduced to internal medicine by Al’s kindly and inspired use of
Socratic teaching to analyze the patients we had worked up. It was a series of unforgettable experiences.
During the course, he devoted himself to teaching 10 to 12 hour days. He was also an outstanding internist
whom the faculty consulted for their own problems and those of their relatives and friends. I understand
he went on house calls well into his 90’s. Recently, I called him during his 100th birthday celebration,
and he sounded as sharp as he did in his late 30’s. I am dedicating the following teaching summary on celiac
sprue to him because he is my role model and the main influence on my career.
Secondly, I would like to acknowledge my collaborating graduate fellows in gastroenterology who were remarkably
talented and original. In my youth, I was a hard task master, but they tolerated me, albeit at times, with considerable
difficulty. I am most thankful to them for their forbearance. They were young, original and ambitious, and it made
all the difference. The work of our group was largely theirs. Most of them went on to teaching others and doing it
well. And finally, there were the patients who tolerated our discomforting studies, fully informed that our findings
would not necessarily help them personally, but who were happy to do anything that might help other patients with celiac
disease. We all ended up being good friends.
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a Deleterious Effect in a Case of Coeliac Disease.” Acta paediatrica. 1953 Vol.43: 34.
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Connection with Their Action on Patients with Coeliac Disease.” Acta Paediatrica. May 1953. Vol. 42:223-231.
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Lymphnode Biopsies.” British Medical Journal. 1953. 1318-1321.
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Congress of Gastroenterology. May 1958. Pp. 25-31.
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Gastroenterology. 1956. Vol. 49: 676-697.
Rubin CE. Brandborg LL. Phelps PC. Taylor Jr. AB. “Studies of Coeliac Disease I: The Apparent
Identical and Specific Nature of the Duodenal and Proximal Jejunal Lesion in Celiac Disease and Idiopathic Sprue.”
Gastroenterology. 1960. Vol. 38: 28-49.
Quinton WE. Flick AL. Rubin CE. “The Design of a Hydraulic Suction Tube for Peroral Biopsy
of the Lumina Gastrointestinal Tract.” Gastroenterology. 1960. Vol. 47: 281-283.
Flick AL. Quinton WE. Rubin CE. “A Peroral Hydraulic Biopsy Tube for the Multiple
Sampling at any Level of the Gastrointestinal Tract.” Gastroenterology. 1962. Vol. 40:120-126.
Rubin CE. Brandborg LL. Flick AL. Parmentier C. Van Niel S. “The Effect of Repeated
Wheat Instillation into the Proximal Ileum of Patients on a Gluten Free Diet.” Gastroenterology.
1962. Vol. 43: 621-641.
Rubin, CE. Brandborg LL. Flick AL. MacDonald WC. Parkins RA. Parmentier CM. Phelps P. Sribhibhadh
S. Trier JS. “Biopsy Studies on the Pathogenesis of Coeliac Sprue.” Ciba Foundation Study Group No. 14. Intestinal
Biopsy. Little Brown and Company. Boston. 1962. pp.65-81.
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Julkunen RJK. “A Comparison of Diets With and Without Oats in Adults with Celiac Disease.” New England Journal of
Medicine. 1995. Vol. 333: 1033-1037.
MacDonald WC. Brandborg LL. Flick AL. Trier JS. Rubin CE. “Studies of Celiac Sprue. VI. The Response
of the Whole Length of the Small Bowel to a Gluten-Free Diet.” Gastroenterology. 1964. Vol. 67: 573-589.
Perera DR. Weinstein WM. Rubin CE. “Small Intestinal Biopsy.”
Human Pathology. 1975. Vol. 6: 157-217.
Marsh M. “Gluten Major Compatibility Complex and the Small Intestine.” Gastroenterology.
1992. Vol. 102: 330-354.
MacDonald WC. Dobbins III WO. Rubin CE. “Studies of the Familial Nature of Celiac Sprue
Using Biopsy of the Small Intestine.” New England Journal of Medicine. 1965. Vol. 272: 448-456.
Bonamico M. Mariani P. Thanasi E. Ferri M. Nenna R. Tibert C. Mora B. Mazzilli MC. Magliocca FM.
“Patchy Villous Atrophy of the Duodenum in Childhood Celiac Disease.” Journal of Pediatric Gastroenterology and
Nutrition. 2004. Vol. 38: 204-207.
Dietrich W. Laag E. Schopper H. Volta U. Ferguson S. Gillet H. Riecken EO. Schuppan D.
“Autoantibodies to the Tissue Transglutaminase as Predictors of Celiac Disease.” Gastroenterology. 1988.
Vol. 115: 1317-1321.
Liu E. Li M. Bao F. Miao D. Rewers MJ. Eisenbarth GS. Hoffenberg EJ. “Need for Quantitative
Assessment of Transglutaminase Autoantibodies for Celiac Disease in Screening Identified Children.” Journal of
Pediatric Gastroenterology and Nutrition. 2005. Vol. 146: 494-499.
Hill I. Dirks M. Liptak G. Colletti R. Fasano A. Guandalini S. Hoffenberg E. Horvath K. Murray J.
Pivor M. Seidman E. “Guideline for the Diagnosis and Treatment of Celiac Disease in Children: Recommendations of
the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.” Journal of Pediatric
Gastroenterology and Nutrition. 2005. Vol. 40: 1-19.
Peracchi M. Trovato C. Longhi M. Gasparin M. Conte D. Tarantino C. Prati D. Bardella MT.
“Tissue Transglutaminase Antibodies in Patients with End Stage Heart Failure.” American Journal of Gastroenterology.
2002. Vol. 97: 2850-2854.
Bizzaro N. Villalta D. Tonutti E. Doria A. Tampoia M. Bassetti D. Tozzoli R. “IgA and IgG
Transglutiminase Antibody Prevalence and Clinical Significance in Connective Tissue Diseases, Inflammatory Bowel
Disease, and Primary Biliary Cirrhosis.” Digestive Diseases and Sciences. 2003. Vol. 48:2360-2365.
Di Tolla M. Barilla F. Trappolinni M. Palumbo HF. Gaudio C. Picarelli A. “Anti-tissue
Transglutaminase Antibodies in Acute Coronary Syndrome: An Alert signal of Myocardial Tissue Lesion?”
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Corrao G. Corazza GR. Bagnardi V. Brusco G. Ciacchi C. Cottone M. Guidetti CS. Usai P. Cesari P.
Pelli MA. Loperfido S. Volta U. Calabro A. Certo M. “Mortality in Patients with Coeliac Disease and Their Relatives:
A Cohort Study.” Lancet. 2001. Vol. 358:356-361.
Bagdi E. Diss TC. Munson P. Isaacson PG. “Mucosal Intra-epithelial Lymphocytes in Enteropathy
Associated T-Cell Lymphoma (EATL), Ulcerative Jejunitis, and Refractory Celiac Disease Constitute a Neoplastic
Population.” Blood. 1999. Vol. 94: 260-264.
Goddard CJR. Gillett HR. “Complications of Coeliac Disease: Are all Patients at Risk?”
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Marks J. Shuster S. Watson AJ. “Small Bowel Changes in Dermatitis Herpetiformis.”
Lancet. 1966. Vol. 2: 1280-1282.
Brow JR. Parker F. Weinstein WM. Rubin CE. “The small Intestinal Mucosa in Dermatitis
Herpetiformis— I. Severity and Distribution of the Small Intestinal Lesion and Associated Malabsorption.”
Gastroenterology. 1971. Vol. 60(3): 355-361.
Weinstein WM. Brow JR. Parker F. Rubin CE. The Small Intestinal Mucosa in Dermatitis Herpetiformis –
II. Relationship of the Small Intestinal Lesion to Gluten. Gastroenterology. 1971. Vol. 60(3): 362-369.
Fry L. Seah PP. Riches DJ. Hoffbrand AV. “Clearance of Skin Lesions in Dermatitis Herpetiformis
After Gluten Withdrawal.” Lancet. 1973; Feb. 10. Vol. 7798: 288-291.
Sárdy M. Kárpóti S. Merkl B. et. Al. “Epidermal Transglutinase is the Autoantigen of
Dermatitis Herpetiformis.” Journal Experimental Medicine. 2007. Vol. 195: 747-757.
Kagnoff, MF. “Overview and Pathogenesis of Celiac Disease.” Gastroenterology. 2005.
Vol. 128: S10-S18.
Hourigan, CS. “The Molecular Basis of Coeliac Disease.” Clinical Exp Med. 2006.
Vol. 6: 53-59.
Shan, Lu. Molberg, O. Parrot, I. Hausch, F. Filiz, F. Gray, G. Sollid, L. Kohsla, C.
“Structural Basis for Gluten Intolerance in Celiac Sprue.” Science. 2002. Vol. 297: 2275-2279.
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Malnutrition.” The American Journal of Clinical Nutrition. September 1968. Vol. 21(9): 976-983.
Mathan, VI. “Tropical Sprue.” Springer Semin Immunopathol. 1990. Vol. 12: 231-237.
Mathan, VI. “Tropical Sprue in Southern India.” Transactions of the Royal Society of Tropical
Medicine and Hygiene. 1988. Vol. 82: 10-14.
Swanson, VL. Thomassen, RW. “Pathology of the Jejunal Mucosa in Tropical Sprue.” The American
Journal of Pathology. April 1965. Vol. 46: 510-545.
Brunser, O. Eidelman, S. Klipstein, F. “Intestinal Morphology of the Rural Haitians.”
Gastroenterology. 1970. Vol. 58(5): 655-667.
Wheby, MS. Swanson, VL. Bayless, TM. “Comparison of Ileal and Jejunal Biopsies in
Tropical Sprue.” American Journal of Clinical Nutrition. 1971. Vol. 24: 117-123.
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“Intestinal Biopsy in Tropical Sprue.” Ciba Foundation Study Group No. 14. Intestinal Biopsy. Boston.
Little Brown. 1962. Pp. 85.
Rickles, FR. Klipstein, FA. Tomasini, J. Corcino, J. Maldonado N. “Long-Term Follow-Up
of Antibiotic Treated Tropical Sprue.” Annals of Internal Medicine. 1972. Vol. 76: 203-210.
Schuffler, M. Kaplan, LR. Johnson, L. “Small Intestinal Mucosa in Pseudo-obstruction
Syndromes.” Digestive Disease and Science. 1978. Vol. 23: 825-828.
Ament, ME. Rubin, CE. “Soy Protein—Another Cause of the Flat Intestinal Lesion.”
Gastroenterology. 1972. Vol. 62: 228-234.
Baker, AL. Rosenberg, IH. “Refractory Sprue: Recovery After Removal of Non-gluten
Dietry Proteins.” Annals of Internal Medicine. 1978. Vol. 89: 505-508.
Shimoda, SS. Saunders, DR. Rubin, CE. “The Zollinger-Ellison Syndrome with Steatorrhea.”
Gastroenterology. 1968. Vol. 55(6): 705-723.
Daum, S. Cellier, C. Mulder, C. “Refractory Coeliac Disease.” Elsevier: Best Practice
and Research Clinical Gastroenterology. 2005. Vol. 19: 413-424.
Bagdi, E. Diss TC. Munson, P. Isaacson, PG. “Mucosal Intra-epithelial Lymphocytes in
Enteropathy- Associated T- Cell Lymphoma (EATL) Ulcerative Jejunitis, and Refractory Celiac Disease Constitute
a Neoplastic Population.” Blood. 1999. Vol. 94: 260-264.
Daum, S. Weiss, D. Hummel, M. Ullrich, R. Heise, W. Stein, H. Riecken, EO. Foss, HD. “The
Intestinal Lymphoma Study Group. Frequency of Clonal Intraepithelial T Lymphocyte Proliferations in Enteropathy-
Type Intestinal T- Cell Lymphoma, Coeliac Disease, and Refractory Sprue.” Gut. 2001. Vol. 49: 804-812.
Al-toma, A. Visser, OJ. Van Roessel, HM. Von Blomberg, BME. Verbeek, WHM. Scholten, PET. Ossenkoppele,
GJ. Huijgens, PC. Mulder, CJJ. “Autologous Hematopoietic Stem Cell Transplantation in Refractory Celiac Disease with
Aberrant T-Cells.” Blood. 2007. Vol. 109: 2243-2249.
Al-toma, A. Verbeek, WHM. Mulder, CJJ. “Update in the Management of Refractory Coeliac Disease.”
Journal of Gastroenterology Liver Diseases. 2007. Vol. 16: 57-63.
Al- toma, A. Verbeek, WHM. Hadithi, M. Von Blomberg, BME. Mulder, CJJ. “Survival in Refractory
Coeliac Disease and Enteropathy- Associated T- Cell Lymphoma: Retrospective Evaluation of Single-Centre Experience.”
Gut. 2007. Vol. 56: 1373-1378.
Freeman, HJ. “Lymphoproliferative and Intestinal Malignancies in 214 Patients With Biopsy-
Defined Celiac Disease.” Journal of Clinical Gastroenterology. 2004. Vol. 38: 429-434.
Eidelman, S. Parkins, RA. Rubin, CE. “Abdominal Lymphoma Presenting as Malabsorption.”
Medicine. 1966. Vol.45: 111-137.
Salem, PA. Estephan, FF. “Immunoproliferative Small Intestinal Disease: Current Concepts.”
The Cancer Journal. 2005. Vol. 5: 374-382.
Selzer, G. Sacks, M. Sherman, G. Naggan, L. “Primary Malignant Lymphoma of the Small Intestine
in Israel. Changing Incidence With Time.” Israel Journal of Medical Science. 1979. Vol. 15: 390-396.
Ament, ME. Rubin, CE. “The relation of Giardiasis to Abnormal Intestinal Structure and Function in
Gastrointestinal Immunodeficiency Syndromes.” Gastroenterology. 1972. Vol. 62: 216-226.
Leinbach, GE. Rubin, CE. “Eosinophilic Gastroenteritis: A Simple Reaction to Food Allergens?”
Gastroenterology. 1970. Vol. 59: 874-889.
Trier, JS. Phelps, PC. Eidelman, S. Rubin, CE. “Whipple’s Disease: Light and Electron Microscope
Correlation of Jejunal Mucosal Histology With Antibiotic Treatment and Clinical Status.” Gastroenterology. 1965.
Vol. 48(8): 684-707.
Weinstein, WM. Saunders, DR. Tytgat, GN. Rubin, CE. “Collagenous Sprue—An Unrecognized Type of
Malabsorption.” New England Journal of Medicine. 1970. Vol. 83: 1297-1301.
Freeman, HJ. “Collagenous Sprue Associated with An Extensive T-Cell Lymphoma.” Journal of Clinical
Gastroenterology. 2003. Vol. 36: 144-146.
Medlicott, SAC. Beck, PL. Loken, S. Crabtree, T. “Synchronous Collagenous Sprue and Enteropathy –
Type T-Cell Lymphoma: Varients of the Same Disease.” Canadian Journal of Gastroenterology. 2004. Vol. 18 (5): 329-332.
Robert, ME. Ament, ME. Weinstein, WM. “The Histologic Spectrum and Clinical Outcome of Refractory
and Unclassified Sprue.” The American Journal of Surgical Pathology. 2000. Vol. 24:676-687.