OVERVIEW: What every practitioner needs to know
Are you sure your patient has Celiac Disease? What are the typical findings for this disease?
Celiac disease will typically present with diarrhea, abdominal pain, failure to thrive or faltering growth. The most common symptoms include chronic or intermittent diarrhea, abdominal pain, cramping, distension, failure to thrive/growth failure, unexpected weight loss and loss of appetite. Other symptoms include constipation, nausea and vomiting, prolonged fatigue, and unexplained iron deficiency anemia.
Classic celiac disease can be diagnosed when the above GI symptoms are present and confirmed with a small bowel histology with presence of positive serologic tests (IgA anti-tTG and/or EMA).
Atypical Celiac Disease
Atypical celiac disease presents commonly as short stature, pubertal delay, dental enamel hypoplasia of permanent teeth, persistent unexplained abnormal liver transaminases, and osteopenia/osteoporosis.
Consider serologic testing for celiac disease with any of following: Addisons disease, amenorrhea, apthous stomatitis, autoimmune myocarditis, chronic thrombocytopenic purpura, neuropsychiatric disease, epilepsy, low trauma fracture, lymphoma, metabolic bone disease (rickets, osteomalacia), recurrent miscarriage, sarcoidosis, sjogrens syndrome, and unexplained alopecia, unexplained subfertility, autoimmune hepatitis. Atypical celiac disease is diagnosed when the above symptoms are present and with confirmed small bowel histology with presence of positive serological tests (IgA anti tTG and/or EMA).
Silent Celiac Disease
Conditions that increase risk of developing Silent celiac disease include dermatitis herpetiformis, type 1 diabetes mellitus, autoimmune thyroiditis, autoimmune liver disease, first degree relatives with celiac disease, Turner syndrome, Down Syndrome, Williams syndrome, and selective IGA deficiency. Silent celiac disease presents symptom free with confirmed small bowel histology with presence of positive serological tests (IgA anti tTG and/or EMA).
Latent Celiac Disease
Latent celiac disease can be confirmed by positive celiac serologies (ie; positive IGA anti tTG and/or EMA) with normal duodenal biopsy. A positive response to a gluten free diet is controversial and yearly follow up for detection of celiac disease is warranted.
Refractory Celiac Disease
Refractory celiac disease (RCD) is defined as lack of clinical and histological response to a gluten free diet. 50% develop enteropathy associated T-cell lymphoma. RCD subdivides into two categories, RCD I and RCD II. In RCD I intraepithelial cells are polyclonal with normal phenotype. Liu et al. showed 80% progressed to aberrant IEL immunophenotype and 45% to monoclonality during follow up biopsies. RCD II is characterized by clonal expansion of an aberrant intraepithelial population. Surveillance follow-up is important in RCD II.
What other disease/condition shares some of these symptoms?
Diseases or conditions that share the same symptoms of celiac disease include parasites (eg;Giardia), allergic enteropathy, irritable bowel syndrome, Crohns Disease, small bowel bacterial overgrowth, tropical sprue, autoimmune enteropathy, Hirschsprungs disease, gastroesophageal reflux disease, lymphangiectasia, malrotation, post infectious enteropathy, primary or secondary immunodeficiencies (eg HIV), Peptic Disease.
What caused this disease to develop at this time?
Development of celiac disease is multigenic. About 40% of the heritability of celiac disease includes human leukocyte antigen HLA DQ2 and HLA DQ8 heterodimers. The remaining 60% is thought to be shared between unknown number non HLA genes.
HLA DQ2 and HLA DQ8 molecules are necessary to develop celiac disease but are not alone sufficient for expression of celiac disease phenotype. 90-95% of patients with celiac disease have HLA DQ2 heterodimer formed by a B chain encoded by the allele HLA DQB1*02 and an alpha chain encoded by the allele HLA DQA1*05. Remainder 5-10% of patients with celiac disease have HLA DQ8 heterodimer formed by a B chain encoded by the allele HLA DQB1*0302 and alpha chain encoded by the allele HLA DQA1*03.
Homozygosity for HLA DQ2 alleles may be associated with early onset disease and confer higher likelihood of developing celiac disease phenotype. Although HLA DQ2 genes confer genetic susceptibility to celiac disease, approximately 30% of general population in North America is DQ2 positive. HLA DQ2 and DQ8 probes have low positive predictive value but very high negative predictive value for celiac disease. Ingestion of gluten is required for development of the disease. The trigger for disease development at this time is unknown.
Pathogenesis of Celiac Disease
Susceptibility to celiac disease is determined partly by HLA association with major histocompatibility complex class II antigens HLA-DQA1 *05 and DQB1*02 (DQ2) and HLA-DQA1*03 and DQB1*0302 (DQ8).
Wheat, barley and rye contain disease activating peptides (gliadin and glutenin in wheat, hordein in barley, and secalin in rye ) widely termed “gluten peptides”. The “gluten peptides” are characterized by a high content of glutamine and proline amino acids. The high proline content renders the peptides resistant to proteolytic digestion by human gastro-intestinal digestive enzyme. Consequently, the relatively large peptide fragments accumulate in the small intestine and cross over the brush border membrane of the small bowel enterocytes. The “gluten peptides’ are then modified by Tissue Transglutaminase enzyme resulting in peptides which contain deamidated acidic glutamine (glutamic acid) residues.
These modified “gluten peptides” have an increased affinity to bind well to HLA DQ2/DQ8 molecules on the antigen presenting cell stimulating a TH type 1 dependent inflammatory reaction. “Gluten peptides” bound to HLA DQ2/DQ8 are then recognized by CD4 T cells in lamina propria of celiac disease patients stimulating expansion of cytotoxic intrepithelial lymphocytes (IELS) and expression of activated NK (natural killer) cells which mediate epithelial cell destruction.
In susceptible patients, gliadin may interact with the intestine to trigger Zonulin release leading to disassembly of interenterocyte tight junctions and increased intestinal permeability. The increased intestinal permeability may occur prior to onset of clinical expression of celiac disease.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
The first choice in testing is the IgA tissue transglutaminase (tTGA) test. If the IgA anti-tTGA result is equivocal, then check IgA anti endomysial antibody (EMA). Check serum IgA level to ensure that the patient is not IgA deficient (which can result in a negative IgA anti-tTGA test and negative IgA-EMA test).
Positive serologies should be confirmed with small bowel biopsy showing at least Marsh 2 lesion to confirm a diagnosis of celiac disease. Small intestinal biopsies should be obtained by grasp biopsy forceps during Esophagogastroduodenoscopy. Given the patchy nature of mucosal changes in children with celiac disease, multiple endoscopic duodenal biopsies (6 to 8 biopsies in total) should be obtained from distal segments duodenum and from duodenal bulb.
In a case where celiac disease is suspected in a patient with confirmed IgA deficiency: If IgA anti tTG is negative, then one can assess IgA/IgG anti DGP (anti- deamidated gliadin peptide) and IgG tTG and IgG EMA.
If serologies are negative but there is still a high clinical suspicion of celiac disease: refer to GI for small bowel biopsies. Do not use serological testing for celiac disease in infants before gluten is introduced into the diet. Prior to checking celiac serologies and small bowel biopsies, individual should be on gluten containing diet daily for at least 6 weeks before testing (Timing of gluten exposure not fully known) .
Genetic Testing for HLA DQ2- HLA DQ8
HLA DQ2 and HLA DQ8 testing is a polymerase chain reaction of RNA extracted from blood sample or cells from a cheek swab. Testing occurs one time and is not related to gluten exposure. Testing of asymptomatic children in ” genetically at risk” group include children and siblings of first degree family member with biopsy proven celiac disease.
HLA DQ2 and DQ8 probes have low positive predictive value but very high negative predictive value for celiac disease. HLA DQ2/DQ8 heterodimer is necessary but not sufficient for development of celiac disease. If HLA DQ2 and or DQ8 hetrodimer is positive, then one can begin screening first degree asymptomatic family member with serum tTG IGA after age 2 years provided they have been on gluten containing diet for at least 1 year.
Follow up screening should be every few years or sooner if symptoms occur. Optimal frequency of follow up screening is not known (see laboratory studies section).
HLA DQ2 and HLA DQ8 testing can be helpful in patients already on a gluten free diet for alternative reasons. Only genetically susceptible patients would then benefit from a gluten challenge to determine if they have biopsy proven celiac disease.
Certain individuals with autoimmune diseases(eg: Type I Diabetes mellitus, autoimmune thyroid disease and autoimmune liver disease) and chromosomal disorders (eg: Down Syndrome and Turners Syndrome) may similarly share HLA DQ2 and/ or DQ8 hetrodimer genes.
IgA anti Endomysial ab (EMA): Sensitivity in children: 0.88-1.00. Specificity in children: 0.91-1.00.
IgA Tissue Transglutaminase antibody using human TTG protein (tTG IgA): Sensitivity in children and adults: 0.92-1.00. Specificity 0.91-1.00.
Composite IgA/IgG ant DGP sensitivity 0.75-0.99 and specificity 0.87-1.00.
IgG ant tTG sensitivity 0.45-0.95 and specificity 0.94-1.00.
Histopathology of Celiac Disease
There are revised criteria for diagnosis of celiac disease in children. For those 2 years or older, children with symptoms suggestive of celiac disease can obtain a definitive diagnosis confirmed with histologic findings on small bowel biopsy (> or equal to Marsh 2) (see below) and clinical resolution on gluten free diet. Positive serologic tests that revert to negative on a GFD is supportive evidence.
For children under the age of two with symptoms suggestive of celiac disease, a small bowel biopsies with Marsh I lesions with positive IgA anti EMA or tTG can prove definitive. Celiac disease is highly likely and a gluten free diet should be strongly considered.
Marsh Criteria for Celiac Disease
Type 0: normal
Type 1: Infiltrative lesion: Increased intraepithelial lymphocytes
Type 2: Hyperplastic Lesion: Type 1 plus hyperplastic crypts
Type 3: Destructive lesion: Type 2 plus variable degree villous atrophy
Type 3a: Partial villous atrophy
Type 3b: Subtotal villous atrophy
Type 3c: Total villous atrophy
Type 4: Hypoplastic lesion: Total villous atrophy with crypt hypoplasia
Endoscopic findings in Celiac Disease
In patients with celiac disease, the mucosal changes can be patchy. Endoscopic visual finding can include absence of mucosal folds, scalloped mucosal folds, visible submucosal blood vessels, and mosaic pattern of mucosa between folds (may only be seen with marsh 3b and 3c histology).
Screening Recommendations for Celiac Disease
Screen symptomatic patients, asymptomatic individuals with increased risk of developing celiac disease, and consider screening asymptomatic individuals with potentially HLA shared autoimmune diseases (eg; type 1 Diabetes mellitus, autoimmune thyroid and heptobiliary disorders) or certain chromosomal disorders (eg; Down or Turner Syndrome).
The value of screening asymptomatic individuals is to prevent the potential morbidity that can be associated with individuals with diagnostic small bowel injury confirming celiac disease (eg; possible impact on growth in developing child, possible risk of malignancy on gluten containing diet, possible development of osteoporosis).
The optimal timing of screening/ treatment of celiac disease in children with Type I Diabetes Mellitus remains controversial.
Confirming the diagnosis
Please refer to Figure 1.
If you are able to confirm that the patient has Celiac Disease, what treatment should be initiated?
Appropriate treatments include life-long adherence to a strict gluten free diet. Currently less than 20 ppm in each food substance is considered gluten free. However, no solid scientific data confirms the amount at which no harm occurs.
Lactase supplementation for secondary lactose intolerance may be helpful temporarily while the bowel is healing. Gluten free multivitamin, calcium, and Vitamin D are helpful supplements to take to ensure age appropriate vitamin ingestion.
A gluten free diet is one where all wheat, barley, and rye grains are removed from consumption. In addition, variants of these grains should also be avoided and include the following: triticale, kamut, spelt, farro, semolina, farina, einkorn, bulger, and couscous, and malt.
While oats are permittable, contamination of oats with gluten can occur during the harvesting and milling process. If purity of oats is guaranteed, they can be safely ingested by most patients. Oats have been found to activate intestinal T cells derived from some CD patients. Oats should not be eaten immediately after diagnosis and should only be considered when resolution of symptoms and healing of duodenum on biopsy. If patient elects to eat pure oats, close clinical follow up is needed.
What are the adverse effects associated with each treatment option?
Removing these several forms of grains from the diet can significantly reduce ingestion of micronutrients. Therefore, patients should moderate their diet to insure a balanced diet with adequate micronutrients. Regular monitoring for potential nutritional deficiencies is indicated.
If there are questions of unbalanced diet or ongoing non-compliance, consider monitoring the following labs: cbc, iron, folate, Vitamin D 25 OH, fat soluble vitamins A, E and K. Less commonly, deficiencies can occur with vitamin B12 , B6 and thiamin, or minerals magnesium, zinc, copper, and selenium.
Children with CD diagnosed and treated before puberty should attain normal bone mineral density on GFD.
What are the risks/benefits of the available treatment options?
For symptomatic celiac disease, gluten free diet results in resolution of gastrointestinal symptoms, normalization of nutritional measures, improved growth in height and weight with normalization of stature and hematological and biochemical parameters. Bone mineralization will fully normalize in children treated before puberty.
A gluten free diet can decrease the risk of intestinal cancers. Adhering to a gluten free diet before permanent teeth may decrease one’s risk of dental enamel disorders.
The evidence that early treatment of celiac disease prevents the onset of other autoimmune disease is weak.
Patients diagnosed with Refractory celiac disease may experience continued signs of ongoing small bowel injury despite a gluten free diet.
What are the possible outcomes of Celiac Disease?
If left untreated, celiac disease can result in continued symptoms, pubertal delay, and nutritional deficiency. It can also lead to risk of osteopenia and osteoporosis, increased fracture risk, T cell non hodgkins lymphoma, small bowel adenocarcinoma. Some possible negative outcomes include unfavourable pregnancy outcomes and dental enamel hypoplasia of permanent teeth in children diagnosed under the age of seven.
What causes this disease and how frequent is it?
The prevalence of celiac disease in children by biopsy is 0.5 to 1.0% and by serology 0.3-1.9% (NIH report AHRQ 2004 report). Among first degree relatives of individuals with celiac disease, the majority of studies report a prevalence of 4.5 to 12%. HLA identical siblings and dizygotic twins have concordance rates of 30 to 40% and 10% respectively with concordance rates for monozygotic twins of 75%.
There is an increased prevalence of celiac disease in individuals with autoimmune thyroid disease (up to 7%), irritable bowel syndrome (up to 7%), type 1 Diabetes (2-10%).
There is some evidence of increased prevalence of celiac disease in people with autoimmune myocarditis, chronic thromboycytopeniac purpura, depression/bipolar disorder, Down syndrome, Williams Syndrome, epilepsy, liver conditions, lymphoid malignancy, polyneuropathy, sjogrens syndrome, sarcoidosis, Turner syndrome, and unexplained subfertility.
No seasonal variation known.
There is preliminary evidence to suggest that a high frequency of rotavirus infections may also increase the risk of celiac disease autoimmunity in children and genetically predisposed individuals.
Gluten exposure is necessary for the disease to present.
Other clinical manifestations that might help with diagnosis and management
Celiac serologies may be unreliable in children under the age of two due to breast milk consumption, lower IgA levels, and immature immunity. For these patients, consider IgA anti-gliadin abs (IgA AGA) and small bowel biopsy. Also consider repeat biopsies while the patient is on a gluten free diet and with re-exposure to gluten. This test will confirm diagnosis of celiac disease as distinct from self limited milk protein allergy, a common cause for abnormal small bowel biopsies, and transient seropositivity which can occur in young children and may not be predictive of celiac disease.
Selective IgA deficiency may coexist with celiac disease with approximately 2% of cases occurring in celiac disease versus 0.2% in non-celiac disease. IgA deficiency is often defined as serum IgA <5 mg/dl.
Children at risk for asymptomatic celiac disease include those with first degree relatives with celiac disease and autoimmune/nonautoimmune condtions associated with the disease. Consider HLA DQ2/DQ8 heterodimer testing. If negative, no further workup is needed. If positive then TTG IgA after 2 years old on adequate gluten containing diet for at least 1 year before testing. If negative then repeat testing at unspecified intervals or if symptoms develop.
There is apparent disconnection in some patients between severity of symptoms with celiac disease and severity of histological abnormalities (defined in proximal small bowel). This may reflect the variable extent of histological involvement in the more distal small bowel.
What complications might you expect from the disease or treatment of the disease?
Monitoring Gluten free diet in Celiac Disease
Periodic visits (consider yearly after first year of diagnosis if doing well) for assessment of symptoms, growth, adherence to the gluten free diet, and other manifestations of autoimmunity are necessary once diagnosis are confirmed.
Consider screening for the following conditions every 3 to 6 months for the first year after diagnosis: autoimmune thyroid disease, immunogenicity response to Hepatitis B vaccine, measurement of tissue transglutaminase IgA (in individuals with normal serum IgA level) and dietary review to insure adherence to gluten free diet. One can expect a decline in IgA anti tTG by 6 months with symptom resolution. However, follow up practice recommendations are based on expert opinion and are not based on rigorous scientific studies.
Individuals with persistent or recurrent symptoms will have a rise in IgA anti tTG. This suggests dietary non-adherence, an ubiquitous and unrecognized gluten source, an initially incorrect diagnosis, or infrequently Refractory celiac disease. Recommend dietary review and reinforcement of need for dietary compliance.
If symptoms cannot be explained, consider repeat intestinal biopsies to determine if still compatible with celiac disease. However, IGA anti tTG is not very sensitive or a very specific marker to small intakes of gluten in patients. Therefore continue to require expert nutritional assessment. Studies suggest normalization of serologies does not always predict normalization of intestinal histology. The clinical significance of possible low grade histologic inflammation in asymptomatic individuals is not known.
Are additional laboratory studies available; even some that are not widely available?
If serum IgA is low but detectable, the accuracy of the IgA based serologies is not thought to be significantly compromised. If IgA anti tTG is negative and the patient is IgA deficient, assess IgA/IgG anti DGP (anti- deamidated gliadin peptide) and IgG tTG and IgG EMA.
For asymptomatic individuals belonging to groups at risk for celiac disease, a negative test for HLA DQ2/DQ8 renders celiac disease highly unlikely and there is no need for subsequent serologic testing.
Although DQ2 genes confer genetic susceptibility to celiac disease, approximately 30% of general population in North America is DQ2 positive. HLA DQ2 and DQ8 probes have low positive predictive value but very high negative predictive value.
How can Celiac Disease be prevented?
Some evidence that introducing gluten between 4- 7 months while continuing breast feeding until 9 months may decrease risk of developing celiac disease but research is ongoing.
What is the evidence?
Abadie, V. “Integration of genetic and immunological insights into a model of celiac disease pathogenesis”. Annu Rev Immunol. vol. 29. 2011. pp. 493-526. (Excellent review of current knowledge of celiac disease pathogenesis.)
Crowe, SE. “Celiac Disease”. Ann Intern Med. vol. 154. 2011;May 3.
Freeman, HJ. “Recent advances in Celiac Disease”. World Journal of Gastroenterology. vol. 17. 2011;May 14. pp. 2259-2272.
Green, PH, Cellier, C. “Celiac Disease”. NEJM. vol. 357. 2007. pp. 1731-1743. (Excellent clinical review of celiac disease.)
Hill. “Guideline for the diagnosis and treatment of celiac disease in children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition”. JPGN. vol. 40. 2005. pp. 1-19. (Official recommendations of NASPGHN on diagnosis and treatment of celiac disease in children.)
Moore, J. “Advances in celiac disease”. Curr opin gastroenterol. vol. 27. 2011. pp. 1-7. (Review of developments in celiac disease over past year.)
“NIH Consensus Development Conference on Celiac Disease: National Institutes of Health Consensus Development Conference Statement”. June 28–30, 2004.
Walker, Smith. “Revised Criteria for diagnosis of celiac disease”. Arch Dis Child. vol. 65. 1990. pp. 909-11. (Report of Working Group of European Society of Pediatric Gastroenterology and Nutrition.)
Leffler, DA, Schuppan, D. “Update on serologic testing in Celiac disease”. Am J Gastroenterol. vol. 105. 2010. pp. 2520-2524. (Review of serologic tests for celiac disease and recommended use in different settings.)
Lewis, NR, Scott, BB. “Metaanalysis of deamidated gliadin peptide antibodies and tissue transglutaminase antibody compared as screening tests for celiac disease”. Aliment Pharmacol Ther. vol. 31. 2009. pp. 73-81. (Meta-analysis that TTG antibody outperfomed IgG DGP test.)
Marsh, MN. “Gluten, major histocompatability complex and the small intestine; a molecular and immunobiologic approach to the spectrum of gluten senstitivity”. Gastroenterology. vol. 102. 1992. pp. 330-54. (A review of Marsh classification.)
Van der Windt, D. “Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review”. JAMA. vol. 303. 2010. pp. 1738-1746. (A review of performance of diagnostic tests for CD in primary care.)
Vivas, S. “Duodenal biopsy may be avoided when high transglutaminase antibody titres are present”. World J Gastroenterology. vol. 15. 2009. pp. 4775-4780.
Ertem, D. “The response to hepatitis B vaccine: does it differ in celiac disease?”. Eur J Gastroenterol Hepatol. vol. 22. 2010;Jul. pp. 787-93.
Liu, H. “Continual monitoring of intraepithelial lymphocyte immunophenotype and clonality is more important than snapshot analysis in the surveillance of refractory celiac disease”. Gut. vol. 59. 2010. pp. 452-460.
Mora, S. “Celiac Disease in children: impact on bone health”. Rev Endocr Metab Disord. vol. 9. 2008;June. pp. 123-30. (Excellent review of celiac disease and bone health in children.)
Mukherjee, R, Kelly, CP, Leffler, DA. “Gastrointestinal Cancer in Celiac Disease: "The first days are the hardest, dont you worry anymore?"”. Clin Gastroenterol Hepatol. 2011. Oct 5.
Rashid, M. “Oral manifestations of celiac disease pathogenesis: A clinical guide to dentists”. J Can Dent Assoc. vol. 77. 2011. pp. b39
Sattar, N. “Celiac disease in children, adolescents and young adults with autoimmune thyroid disease”. J Pediatr. vol. 158. 2011 Feb. pp. 272-5.
Garcia-Manzanares, A, Lucendo, AJ. “Nutritional and dietary aspects of celiac disease”. Nutr Clin Prac. vol. 26. 2011. Apr. pp. 163-73.
Hogen, EC. “The prevent CD study design: towards new strategies for the prevention of celiac disease”. Eur J Gastroenterol Hepatol. vol. 12. 2010. Dec 22. pp. 1424-30.
Moore, J. “Advances in celiac disease”. Curr opin gastroenterol. vol. 27. 2011. pp. 1-7. (Review of developments in celiac disease over past year.)
Stene, LC. “Rotavirus infection frequency and risk of Celiac Disease autoimmunity in early childhood: a longitudinal study”. Am J Gastroenterol. vol. 101. 2006 October. pp. 2333-40.
Ongoing controversies regarding etiology, diagnosis, treatment
Currently less than 20 ppm in each food item is considered gluten free (based on expert opinion) but there is no solid scientific data for the threshold of gluten consumption below which no harm occurs.
There is no widely accepted consensus on routine screening asymptomatic increased risk individuals (ie;IDDM, Down syndrome, Williams syndrome, Turner syndrome, autoimmune thyroid or liver disease) nor guidelines for optimal age of initial screening or interval screening in these asymptomatic individuals.
There is no widely accepted consensus on optimal age of initial screening or interval screening in asymptomatic first degree relatives of patients with celiac disease. Some adult evidence to suggest that despite following a strict gluten free diet and normalization of anti tTG, in some patients, intestinal histology may still exhibit persistent inflammation. Clinical significance in healthy appearing asymptomatic individuals is unknown.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has Celiac Disease? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Confirming the diagnosis
- If you are able to confirm that the patient has Celiac Disease, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of Celiac Disease?
- What causes this disease and how frequent is it?
- Other clinical manifestations that might help with diagnosis and management
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can Celiac Disease be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment