My study notes in this post focus on Celiac Disease. See my post, Food Intolerance, for my notes on the diagnosis of that problem [Coming Soon]. And please be sure and review the 7 Additional Resources after this post – all are relevant to Celiac Disease and Food Intolerance.
Episode #95: Food allergy, food intolerance and celiac disease
[MAY 14, 2018 By MATTHEW WATTO, MD from The Curbsiders ] is another awesome episode. The show notes are perfect so just go to the above web page and review them after you have listened to the podcast [which I have embedded below for convenience].
I’ve listened to this post a number of times. The notes can’t be excerpted because every part of them are pearls.
Here are some additional resources (below) that I found helpful.
What follows are excerpts from Resource (1) below, Optimizing the Diagnosis of Celiac Disease. The article lists 86 references on Celiac disease available on the article side bar. Here are the excerpts [These are, as always, basically my study notes. If you have a patient in whom you are concerned about the possibility of celiac disease you need to read the whole article]:
Key Points
- Regarding the biopsy-free approach based on serology and HLA testing in asymptomatic children with TTG more than 10 times the ULN, it is important to locally validate TTG cutoff values for biopsy requirement in order to avoid variation errors because of the marked divergence of results with different TTG assays across different laboratories.
- A 3 g gluten/day challenge for 2 weeks was shown to be sufficient to induce Marsh 3 villous atrophy in 68% of celiac disease patients.
- Single bite biopsy technique and an additional duodenal bulb biopsy sampling have been shown to significantly increase the diagnostic yield of celiac disease.
- Evidence suggest that ultrashort celiac disease patients and symptomatic potential celiac disease patients derive clinical, serological and histological (for ultrashort celiac disease) benefits from a GFD.
- Seronegative celiac disease was found to be associated with older patients and more severe villous atrophy, suggesting that it lies in the longer standing, more severe disease spectrum (excluding other causes for seronegativity, e.g. IgA deficiency, immunosuppression and so on).
Summary Recent work has demonstrated the clinical significance of the celiac disease subtypes, emphasizing the importance of careful diagnosis and recognition. There is a move toward a less invasive and perhaps more cost-effective diagnostic approach in celiac disease, but duodenal biopsy remains the gold standard at present for all adults and the majority of pediatric patients
Introduction
Celiac disease is a common yet underdiagnosed immune-mediated small intestinal enteropathy triggered by gluten in genetically susceptible individuals, with an approximately 1% prevalence in the United States and beyond.[1–3] . . . This review provides a critical summary of recent and clinically relevant developments in the diagnosis of celiac disease.
Who to Test?
Celiac disease manifests itself in a wide array of signs and symptoms which can be nonspecific. The 2015 National Institute of Clinical Excellence (NICE) guidance has highlighted that unexplained neuropathies such as ataxia are now indications for which serological testing is recommended.[11] Gluten ataxia accounts for 40% of all sporadic ataxias, and is characterized by positive IgA/IgG antigliadin antibodies and triggered by gluten in genetically susceptible people, with a mean age of onset of 53 years. Up to 40% of patients with gluten ataxia have evidence of enteropathy, yet interestingly, they often have no gastrointestinal symptoms. A gluten-free diet (GFD) can improve or halt the progression of neurological symptoms in most patients.[12]
Table 1. 2015 National Institute of Clinical Excellence guidelines on screening indications for celiac disease Celiac screening recommended Celiac screening should be considered Persistent unexplained abdominal or gastrointestinal symptoms Metabolic bone disorders (reduced bone mineral density or osteomalacia) Faltering growth Unexplained neurological symptoms (particularly peripheral neuropathy or ataxia) Prolonged fatigue Unexplained subfertility or recurrent miscarriage Unexpected weight loss Persistently raised liver enzymes with unknown cause Severe or persistent mouth ulcers Dental enamel defects Unexplained iron, vitamin B12 or folate deficiency Down’s syndrome Type 1 diabetes Turner syndrome Autoimmune thyroid disease Irritable bowel syndrome First-degree relatives of people with celiac disease The NICE guidelines recommend screening with IgA-tissue transglutaminase antibodies (TTG) as the first-line test alongside IgA levels, and those who are positive require duodenal biopsies for histological confirmation. IgA-endomysial antibodies (EMAs) should be performed in cases of weak-positive TTG. In IgA deficiency, IgG-EMA and IgG-deamidated gliadin peptide or IgG-TTG should be performed.[11]
The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines for celiac disease were updated in 2012, incorporating contemporary diagnostic approaches.[15] ESPGHAN newly defined celiac disease as an immune-mediated systemic disorder rather than sole enteropathy triggered by gluten, with both intestinal and extra-intestinal manifestations.
For asymptomatic children who are at risk of celiac disease (e.g. autoimmunity, family history, Down’s syndrome and so on), HLA genotyping is recommended by ESPGHAN as the initial test, where a negative HLA genotype obviates further investigations. Duodenal biopsy is then mandatory in cases of positive serology following a positive HLA genotype, given the fact that the individual is asymptomatic.[15] The risk of celiac disease increases considerably to one in 10 for first-degree relatives. A recent 10-year follow-up study revealed that initial screening detected celiac disease in 19 of 450 (4.2%) first-degree relatives of patients with celiac disease, and a further eight of 205 (3.9%) seroconverted after a decade (five with biopsy-proven celiac disease), corresponding to an annual seroconversion incidence of 0.141 (95% confidence interval: 0.7–1.0).[21] Nevertheless, there are currently no recommendations for interval screening for first-degree relatives.
Diagnostic Challenges
HLA Genotyping
HLA genotyping can be valuable in equivocal diagnoses, usually in patients with seronegative villous atrophy, those already on a GFD who are unwilling or unable to undergo a gluten challenge, and those who refuse a gastroscopy. HLA genotyping was shown to provide the highest diagnostic yield (60%) in patients with raised intraepithelial lymphocytes (IELs) and normal TTG, whereas the yield was lowest in those with villous atrophy (16.4%) or positive TTG (14.3%).[22] The absence of HLA DQ2 and DQ8 virtually excludes celiac disease, with an NPV of more than 99%. However, for patients with a high clinical suspicion of celiac disease, certain HLA DQ2.5 alleles, either in cis or trans configuration, should be checked as these can be seen in celiac disease although rare.
Seronegative Celiac Disease
Seronegative celiac disease (SNCD) occurs in 1.7–15% of the celiac population.[23–25] SNCD can result from impaired immunoregulation such as IgA deficiency, common variable immunodeficiency, and those who are on immunosuppressants. It can also occur early in celiac disease,[26] late in the disease[27] or in patients who have placed themselves on a GFD prior to testing. Recent work by Volta et al.[25] compared the clinical characteristics between seropositive and seronegative celiac disease (total n = 810), and found that SNCD patients were older at diagnosis (49 vs. 36 years, P < 0.005) and had significantly more frequent typical symptoms such as diarrhea (100 vs. 34%, P < 0.001). SNCD was also associated with more severe villous atrophy (67 vs. 36%) and coexisting autoimmune diseases.
SNCD requires careful diagnosis with the support of HLA DQ2/DQ8 presence and a response to a GFD after excluding other causes of seronegative villous atrophy (SNVA). A large retrospective analysis of 200 cases of SNVA revealed that 31% were due to celiac disease, 27% of infective cause and 18% of idiopathic cases where 72% spontaneously resolved without any intervention. Intriguingly, nonwhite ethnicity was significantly associated with SNVA (OR 10.8, P = 0.003), and 66% of nonwhite patients with SNVA had an infective cause.[28]
Potential Celiac Disease
There is a paucity of data pertaining to the natural history and long-term outcomes of potential celiac disease (PCD), defined by positive serology and HLA genotype without villous atrophy. The latest prospective follow-up study demonstrated a 10.5% prevalence of PCD (77 of 735) within their celiac disease cohort.[30] Their diagnosis of PCD was defined as positive EMA* and TTG, HLA DQ2 and/or DQ8 and Marsh 0–1 duodenal histology. This study reinforces the fact that most adult PCD patients are symptomatic (79%), and the majority present atypically with anemia, osteoporosis and irritable bowel, mirroring other study findings.[31,32] Over a median of a 3-year follow-up period, all symptomatic patients on a GFD had symptomatic, clinical and serological improvement. For the 16 asymptomatic PCD patients who stayed on a gluten containing diet, biannual serological titers fluctuated in five patients and one developed villous atrophy. These findings suggest that there is a beneficial role for a GFD in symptomatic PCD patients. For asymptomatic PCD, a gluten-containing diet with regular follow-up may be the appropriate management. Further studies with longer follow-up periods are required to validate these results.
The anti-endomysial antibody test (EMAIgA), EMA-IgA, is very specific for celiac disease. It’s estimated that a person with an elevated titer of EMA is almost assured of having celiac disease. However, the EMA test isn’t as sensitive as the tTG-IgA test; about 5-10% of celiacs do not have a positive EMA test. May, 2013
Resources:
(1) #95: Food allergy, food intolerance and celiac disease
MAY 14, 2018 By MATTHEW WATTO, MD from The Curbsiders
(2) Optimizing the Diagnosis of Celiac Disease [PubMed Abstract] [Link To Full Text Article provided courtesy of Medscape]. Michelle Shui Yee Lau; David S. Sanders. Curr Opin Gastroenterol. 2017;33(1):173-180.
(4) Severe Spruelike Enteropathy Associated With Olmesartan [PubMed Abstract] [Full Text HTML] [Full Text PDF]. Mayo Clin Proc. 2012 Aug;87(8):732-8. doi: 10.1016/j.mayocp.2012.06.003. Epub 2012 Jun 22.
(5) Diagnosis and management of food allergies: new and emerging options: a systematic review [PubMed Abstract] [Full Text HTML] [Full Text PDF]. J Asthma Allergy. 2014 Oct 24;7:141-64. doi: 10.2147/JAA.S49277. eCollection 2014.
(6) The differential diagnosis of food intolerance [PubMed Abstract] [Full Text HTML] [Full Text PDF]. Dtsch Arztebl Int. 2009 May;106(21):359-69; quiz 369-70; 4 p following 370. doi: 10.3238/arztebl.2009.0359. Epub 2009 May 22.
(7) Correspondence (letter to the editor): Bacteriological stool examinations [PubMed Abstract] [Full Text HTML] [Full Text PDF]. Dtsch Arztebl Int. 2010 Jan;107(3):40; author reply 40-1. doi: 10.3238/arztebl.2010.0040a. Epub 2010 Jan 15.
