|NOTES: Celiac disease (celiac sprue) is one of the protein related autoimmune enteropathies. When the protein related problem is associated with increased intra-epithelial villus tip lymphocytes (VTLs), it is a protein related autoimmune disease. Increased duodenal and/or small bowel villus tip lymphocytes (sort of like the IFA test for ANA on HEp-2 cells) represents a global marker for small bowel impacting autoimmune disease. In the case of gluten, the disease is additionally associated with certain detectable serum autoantibodies. A protein "intolerance" is a gut problem related to dietary intake of a protein but without (1) presence of fixed-tissue increased villus tip lymphocytes or (2) presence of the required specifically diagnostic circulating serum autoantibody. An example would be non-celiac gluten sensitivity (NCGS14)...nonceliac gluten intolerance (NCGI15)...where the clinical abnormal symptoms are related to dietary intake of gluten containing products but there (1) is not an increase in VTLs, and (2) the serum antibody test is negative.
- celiac disease 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.
- 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 (IELs) [with IHC stain
for CD3] in search of increased VTL IELs to estimate the villus tip score (VTS).
- Morphologically diagnostic of PSE: Presence of abnormal biopsy (increased VTL IELs as seen by CD3-amplified histology) when
patient on ordinary diet, and improvement in histologic features
when on a gluten-free diet.
- Clinically diagnostic: a 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 residual comorbidities such as lactase deficiency, pancreatic
insufficiency, IBS, IBD, bacterial overgrowth, collagenous or lymphocytic
colitis, etc...whereas a still abnormal biopsy might be PSE/GSE or T-cell lymphoma6.
- 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.
- Is celiac disease "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 autoimmune GSE 3:
- iron-deficiency anemia (about
3% of cases9...10-15%11)
- osteoporosis (4.5% of cases)8
- diarrhea (45-85% of cases)11
- fatigue (75-80% of cases)11
- borborygmus (rumbling inside abdomin (35-72% of cases)11
- weight loss (45% of cases)11
- bloating/abdominal distension (33% of cases)11
- flatulence (28% of cases)11
- 10% have elevated SGPT (ALT)
- lactose intolerance
- pregnant women have a 9-fold
increased rate of spontaneous abortion4
- failure to thrive (and IUGR4)
- abdominal distension
- less common:
- short stature
- delayed puberty
- neurologic dysfunction (such as cerebellar ataxia11)
- nausea and/or vomiting
- recurrent mouth ulcers (aphthous
- recurrent abdominal pain
- abnormal serum liver function
- folate-deficiency anemia
- vitamin K deficiency (PT prolonged)
- thrombocytosis (hyposplenism)
- arthralgia, arthropathy [L10-10530]
- unexplained delayed puberty
- peripheral neuropathy
- dental enamel defects
- dermatitis herpetiformis
- 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.
- 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:
- Villous length vs. crypt depth: Normal
is > 3:1 & GSE has lower ratios later in the disease.
- Apoptotic cells
- Reactive nuclei
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
- Loss of brush boarder
- Cytoplasmic vacuolization
- Goblet cells increased in number
- Crypt hyperplasia later in the disease
- Increased mitoses
- Endocrine cell hyperplasia (chromogranin
- Pyloric metaplasia later in the disease (or is THAT due to hyperacidity?)
- 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
- 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:
- infectious gastroenteritis
- tropical sprue
- tuna, cow milk, soy bean, and other protein intolerance
- common variable hypogammaglobulinemia
- AIDS enteropathy
- Crohn’s disease
- eosinophilic gastroenteritis
- dermatitis herpetiformis
- viral enteritis
- auto-immune enteritis
- drug effects (?)......................[back
to enteritides (more detail)]
- Fenoglio-Preiser textbook
(primary ref. source)
- NEJM 17 Jan. 2002 346:180-187.
- Loftus CG, Murray JA, (Division of Gastroenterology & Hepatology,
Mayo Clinic, Rochester) Celiac Disease: Diagnosis and Management,
JCOM 9(6):341-349 June 2002.
- Goldstein, NS and Underhill, J, Morphologic Features Suggestive
of Gluten Sensitivity in Architecturally Normal Duodenal Biopsy
Specimens, AJCP 116(1):63-71, July 2001.
- Schade RR, Prof. & Chief GI @ MCG, Augusta, Ga., Letter
to Ed., Medical Crossfire 5(3):19, April 2003.
- 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).
- Settakorn J, et. al., "Imunohistologic Parameters...",
Applied Immunohistochemistry & Molecular Morphology, 12(3):198-204,
- Barclay L, online Medscape Medical News, 2/28/05, All Patients
With Celiac Disease May Benefit From Screening for Celiac Disease.
- South Med J. 2004;97:30-34...noted
in online Medscape Medical News, 2/12/04.
- Carter JB, NewsPath, March 2008 (celiac serology review).
- Presutti RJ, et. al., "Celiac Disease", American Family Physician 76(12):1795-1802, 15 Dec. 2007.
- see how primary care doc may be working a case up at Family Practice Notebook.
- our lab update memo of 8/31/2009 HERE.
- National Foundation for Celiac Awareness, HERE.
- Volta U, et. al., "Serological Tests in Gluten Sensitivity (Nonceliac Gluten Intolerance), J. Clin. Gastroenterol. 46(8):680-685, Sept. 2012, HERE (their ref. #15).
2/9/02; latest modification 23 May 2015)