1. affects 1 in every 120-300 North Americans²...1 in 100-200 in USA¹¹! Yet about a third of the population is constitutionally genetically positioned to have it.
2. serological & genetic screening tests: But, serology only has a chance to detect gluten sensitive enteropathy (GSE...celiac disease [CD])...a type of protein sensitive enteropathy (PSE)...protein intolerance enteropathy (PIE)...and will not detect other types of PIEs or PSEs (soy, tuna, chicken, etc.). And 3% of celiac cases are IgA deficient¹¹. Serology plus biopsy: therefore, our gastroenterologists tend to work up possible PIE (especially looking for CD) with serology plus EGD with distal duodenal biopsy (and we carefully analyze biopsy morphology and the presence and character of intra-epithelial T lymphocytes [with IHC stain for CD3] in search of increased IELs).
3. Morphologically diagnostic: Presence of abnormal biopsy (increased IELs as seen by CD3-amplified histology) when patient on ordinary diet, and improvement in histologic features when on a gluten-free diet. 
4. Clinically diagnostic: usually steadily consistent⁵ set of symptoms of chronic disease (whereas IBS tends to be intermittent) which improves on a strict gluten free diet. Refractory sprue most commonly is due to diet never getting completely gluten free; and, since proximal mucosa is the last to become normal after gluten elimination, refractoriness with a normal biopsy suggests comorbidities such as lactase deficiency, pancreatic insufficiency, IBD, bacterial overgrowth, collagenous or lymphocytic colitis, etc...still abnormal biopsy might be GSE or T-cell lymphoma⁶.
5. Biopsy location affects histology & EGD biopsies preferred:
   • Proximal has most prominent findings; terminal ileum has minimal change (therefore, biopsy distal duodenum endoscopically).
   • Crest of mucosal fold has greater change than intervening troughs.
6. Is celiac "ruled out"? Maybe it is a GSE family member, & the screening serology was negative & they are currently medically normal. If correctly performed genetic testing [check here] is negative for the constitutional genotype making GSE possible, then GSE is probably ruled out in that patient. And, on the other hand, constitutional lack of the proper genetic setting probably rules it out in people with GSE "disease-compatible" signs & symptoms. [August 2009 memo to one of our FPs].

• Clinical Presentations of GSE ³:
  1. common:
     • adults:
       1. iron-deficiency anemia (about 3% of cases⁹...10-15%¹¹)
       2. osteoporosis (4.5% of cases)⁸
       3. diarrhea (45-85% of cases)¹¹
       4. fatigue (75-80% of cases)¹¹
       5. borborygmus (35-72% of cases)¹¹
       6. weight loss (45% of cases)¹¹
       7. steatorrhea
       8. bloating/abdominal distension (33% of cases)¹¹
       9. flatulence (28% of cases)¹¹
       10. 10% have elevated SGPT (ALT)
       11. lactose intolerance
       12. pregnant women have a 9-fold increased rate of spontaneous abortion⁴
     • children:
       1. diarrhea
       2. failure to thrive (and IUGR⁴)
       3. abdominal distension
  2. less common:
     • general:
       1. short stature
       2. delayed puberty
       3. neurologic dysfunction (such as cerebellar ataxia¹¹)
       4. nausea and/or vomiting
       5. constipation
     • gastrointestinal:
       1. recurrent mouth ulcers (aphthous stomatitis)
       2. recurrent abdominal pain
       3. abnormal serum liver function tests
       4. vomiting
       5. constipation
     • other:
       1. asymptomatic¹¹
       2. folate-deficiency anemia
       3. vitamin K deficiency (PT prolonged)
       4. thrombocytosis (hyposplenism)
       5. arthralgia, arthropathy
       6. unexplained delayed puberty
       7. infertility
       8. peripheral neuropathy
       9. dental enamel defects
       10. dermatitis herpetiformis
  3. associated clinical conditions: relatives with celiac disease, irritable bowel syndrome (IBS), Sjogren's syndrome, autoimmune hepatitis, primary biliary cirrhosis, premature onset of osteoporosis, autoimmune thyroid disorders; Down syndrome; Turner syndrome; type I diabetes mellitus¹¹.
  4. potential complications or presenting complications: small bowel lymphoma...non-Hodgkin lymphoma is 3-6x more common in celiac cases and oropharyngeal, esophageal, and small intestinal carcinomas are more prevelant in celiac cases¹¹.
• Histologic Features:
  1. Villous length vs. crypt depth: Normal is > 3:1 & GSE has lower ratios later in the disease.
  2. Epithelium:
  • Apoptotic cells
  • Reactive nuclei
  • Increased IELs (intra-epithelial lymphs...> 1 lymph/ 5 epithelials...lymphs are T-cells...by H&E [we found that IHC amplification will find apparently normal...not GSE...IELs by VTS within a range of 1-8 per 20 villus tip epithelials...I report about 8-11 as borderline and higher as abnormal).
  • Loss of nuclear polarity...pseudo-stratified appearance
  • Loss of brush boarder
  • Cytoplasmic vacuolization
  • Goblet cells increased in number
  3. Crypts:
     • Crypt hyperplasia later in the disease
     • Increased mitoses
     • Endocrine cell hyperplasia (chromogranin pos.) later
     • Pyloric metaplasia later in the disease (or is THAT due to hyperacidity?)
  4. Lamina Propria:
  • Increased B-lymphs & plasma cells
  • May have increased eos & mast cells
  • Adipose metaplasia
  • Plasma cells go from IgA to IgG & M
  • Increased nerve fibers
  5. Two Forms:
  • Flat mucosa with villous blunting
  • Relatively normal architecture, with increased IELs. This change is said to be present in 33% of relatives of patients with GSE.

• Conditions which may mimic GSE histologically:
  1. infectious gastroenteritis
  2. malnutrition
  3. tropical sprue
  4. kwashiorkor
  5. tuna, cow milk, soy bean, and other protein  intolerance enteropathies (PIEs).
  6. GVHD
  7. common variable hypogammaglobulinemia
  8. giardia
  9. AIDS enteropathy
  10. Crohn’s disease
  11. eosinophilic gastroenteritis
  12. dermatitis herpetiformis
  13. lymphoma
  14. viral enteritis
  15. auto-immune enteritis
  16. drug effects (?)......................[back to enteritides (more detail)]

References:

1. Fenoglio-Preiser  textbook (primary ref. source)
2. NEJM 17 Jan. 2002 346:180-187.
3. Loftus CG, Murray JA, (Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester) Celiac Disease: Diagnosis and Management, JCOM 9(6):341-349 June 2002.
4. Goldstein, NS and Underhill, J, Morphologic Features Suggestive of Gluten Sensitivity in Architecturally Normal Duodenal Biopsy Specimens,  AJCP 116(1):63-71, July 2001.
5. Schade RR, Prof. & Chief GI @ MCG, Augusta, Ga., Letter to Ed., Medical Crossfire 5(3):19, April 2003.
6. Petras RE, A Practical Approach to Gastrointestinal pathology: Small Bowel Biopsy Interpretation and Specimen Handling, US & Canadian Academy of Pathology, March 2002 (91st annual meeting) short course handout, 10 pages (online @ USCAP website).
7. Settakorn J, et. al., "Imunohistologic Parameters...", Applied Immunohistochemistry & Molecular Morphology, 12(3):198-204, Sept. 2004.
8. Barclay L, online Medscape Medical News, 2/28/05, All Patients With Celiac Disease May Benefit From Screening for Celiac Disease.
9. South Med J. 2004;97:30-34...noted in online Medscape Medical News, 2/12/04.
10. Carter JB, NewsPath, March 2008 (celiac serology review).
11. Presutti RJ, et. al., "Celiac Disease", American Family Physician 76(12):1795-1802, 15 Dec. 2007.
12. see how primary care doc may be working a case up at Family Practice Notebook.
13. our lab update memo of 8/31/2009 HERE.

   (posted 2/9/02; latest addition 2 January 2013)