© copyright annals of internal medicine, 2011 ann int med. 154 (9): itc5-1. terms of use the in...
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© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
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© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
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© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
in the clinic
Celiac Disease
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Which patients should be screened?Patients with…
10 family or other close relative w/ Bx-confirmed celiac disease
Inherited HLA-DQ2 or HLA-DQ8 genes necessary but not sufficient for disease development
Absence HLA-DQ2/DQ8 = high negative predictive value
Autoimmune disease sharing HLA susceptibility genes celiac disease (type 1 diabetes; autoimmune thyroid; hepatobiliary disorders)
Conditions associate w/ celiac disease (e.g., Down and Turner syndromes)
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How should screening be done?
In older children, adults screen for IgA antibodies
Increased serum IgA antibodies to tissue transglu-taminase (tTG) in most active celiac disease cases
tTg is a ubiquitous enzyme also called transglutaminase 2 (TG2)
Exception: Screen pts w/ IgA deficiency w/ IgG test
In genetically at-risk children test tTG IgA after age 2
And after ≥1y wheat-containing diet or suggestive signs/symptoms
Test tTG IgA every 3y If children w/ family Hx positive for HLA DQ2/DQ8
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How should screening be done? In relatives of pts w/ celiac disease use PCR test for
HLA DQ2/DQ8 If positive HLA DQ/DQ8 use serum tTG IgA screening Prevents needless tTG IgA testing if virtually no risk
HLA DQ2 and HLA DQ8 Testing
How to test: PCR of RNA from cells in cheek swab/ blood sample
Whom to test: Close relatives of pts w/ confirmed celiac disease who want to know if they are at risk Pts on gluten-free diet who are candidates to undergo gluten challenge to confirm possible celiac disease; only genetically susceptible pts at risk for celiac disease should be challenged Equivocal histologic and serologic findings in which negative test result would make celiac disease highly unlikely
How often to test: Once in a lifetime
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How should screening be done?
Celiac disease can develop at any time Avg age Dx: 5th decade of life
In pts w/ autoimmune disorder at increased risk
Consider duodenal Bx when endoscopy done for another reason
e.g., 1° biliary cirrhosis, type 1 diabetes, autoimmune hepatitis, thyroid disease
Do not screen for antibodies to gliadin
No longer recom’d in adults
Low sensitivity & specificity of both antibodies to gliadin IgA and IgG
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What symptoms and conditions should prompt consideration of celiac disease?
10 and 20 relatives w/ CD
GI symptoms: heartburn, dyspepsia, IBS-like, diarrhea, altered bowel habits, bloating, lactose intolerance
Extraintestinal : Dermatitis herpetiformis, iron or folate deficiency, osteopenic bone disease, chronic fatigue, neuropsych manifestations, short stature, recurrent fetal loss, low birthweight, infertility
Autoimmune endocrine disorders: adrenal disease, autoimmune thyroid, type 1 diabetes
Autoimmune connective tissue disorders: Sjögren syndrome, rheumatoid arthritis, SLE
Hepatobiliary condition: 1° biliary cirrhosis, autoimmune cholangitis, 1° sclerosing cholangitis, transaminase
Other inflammatory luminal GI disorders: IBD, lymphocytic gastritis, microscopic colitis
Misc conditions: IgA deficiency, IgA nephropathy, Down or Turner syndrome
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What symptoms and conditions should prompt consideration of celiac disease?
Diarrhea common presenting symptom of more “classical” form of celiac disease
Occurs in ≈50% of celiac patients
“Atypical” forms now more commonly encountered
Steatorrhea relatively uncommon
Lactose intolerance at presentation
Maldigestion of sugars may cause postprandial bloating, flatulence, diarrhea
Conduct serologic testing for celiac disease in pts w/ diarrhea-predominant IBS or mixed-type IBS
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What symptoms and conditions should prompt consideration of celiac disease?
Iron deficiency (esp resistant to oral iron supplement)
Refer pts ≥50 y for GI testing, including upper endoscopy & duodenal Bx
Vitamin D and calcium malabsorption
Assess pts w/ unexplained metabolic bone disease or severe osteoporosis, even in absence of GI symptoms Unexplained infertility (men and women) or recurrent
spontaneous abortion
Axonal neuropathy and cerebellar ataxia
Consider serologic assessment for celiac disease in idiopathic peripheral neuropathy or cerebellar ataxia
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What symptoms and conditions should prompt consideration of celiac disease?
Sm subset of pts has severe manifestations at Dx
Physical Findings in Patients With Severe Celiac Disease
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the significance of dermatitis herpetiformis in patients with suspected celiac disease?
Uncommon but characteristic papulovesicular rash affecting extensor surfaces of elbows, knees, and trunk
Immunologic response to intestinal gluten sensitivity but relationship often unrecognized
Typical symptoms of malabsorption often absent when skin disease present
However intestinal Bx similar regardless of rash
Treating only dermatologic problem leaves underlying cause of rash / GI pathology unaddressed
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Dermatitis herpetiformisIntensely pruritic papulo-vesicular rash affecting extensor surfaces, such asshoulders (top), elbows, knees, back, and buttocks(bottom)
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the significance of dermatitis herpetiformis in patients with suspected celiac disease? Consult dermatologist for skin Bx of perilesional areas
for histologic, immunofluorescence staining
Granular IgA deposits at dermal-epidermal junction of affected skin characteristic
When skin Bx confirms Dx, intestinal Bx not needed
Only ingested gluten will cause problems
Despite info instructing pts w/ celiac disease and dermatitis herpetiforms to avoid topical products w/ gluten
Lifelong gluten-free diet recommended
Dapsone/sulfapyridine resolves dermatitis, but does not ameliorate intestinal mucosal injury
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What other diagnoses should clinicians consider?
Some of these conditions can coexist w/ or complicate celiac disease
Conditions or Disorders to Consider in Dx of Celiac Disease Irritable bowel syndrome
Inflammatory bowel diseases
Microscopic colitis
Lactose intolerance
Other carbohydrate intolerances
Eosinophilic gastroenteritis
Food protein-induced enteropathies
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What blood tests should be sent to evaluate a patient with suspected celiac disease?
Measure serum anti-tTG IgA
To assess clinically suspected celiac disease
To determine which pts should have intestinal Bx
Obtain intestinal Bx
If anti-tTG, endomysial antibody, or anti-deamidated gliadin peptide antibody tests positive
If results negative when clinical suspicion high
Other blood testing
For disease complications (vitamin & mineral deficiencies, anemia, electrolyte imbalances, elevated transaminases, coagulopathies)
Don’t use wheat allergy skin testing to Dx celiac disease Celiac disease not IgE-mediated allergic condition
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What blood tests should be used to evaluate for suspected celiac disease?
Anti-tTG IgA testing unhelpful in pts w/ IgA deficiency
Selective IgA deficiency ≈2%-5% of celiac pts (vs. 1/500 to 1/700 of general population)
May cause false-negative results on serologic testing
Obtain IgG-based serologic test, and measure total IgA level if tTG IgA values in low-normal range or negative
tTG IgG antibodies usually positive in IgA-deficient pts w/ celiac disease
If IgA/IgG test positive, perform endoscopy w/ Bx
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the role of endoscopy in the evaluation of patients with possible celiac disease?
Primarily: confirm Dx by obtaining Bx of proximal small intestine
In pts w/ positive serologic test results
High clinical suspicion of celiac disease in absence positive serologic test results
Have pathologist w/ expertise in GI diseases examine Bx slides (esp if Dx uncertain)
Scalloping or notching of folds, fissuring or cracking of flat intervening mucosa between folds also seen. Features help target Bx sites; absence does not r/o Dx.
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the role of endoscopy in the evaluation of patients with possible celiac disease?
Characteristic: Inflammation + varying degrees villous atrophy. Inflam-mation comprises lymphocytes, plasma cells, macrophages, other chronic inflammatory cells in lamina propria; intraepithelial lymphocytes (prominent toward tips of villi).
Bx w/ varying degrees villous blunting + lymphocytic & plasma cell infiltrates highly predictive of response to gluten-free diet
Help differentiate celiac from other conditions
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How can a patient already on a gluten-free diet be diagnosed?
1st visit: Obtain serologic studies even if diet gluten-free If tTG IgA elevated, order intest’l Bx If not (and not IgA deficient) defer
testing until gluten reintroduced long enough to reproduce serologic abnormalities + intestinal changes
If ≤2 months partly gluten-free diet: unlikely to affect intestinal Bx or sensitive tTG assay in pts w/ severe malabsorption
Histologic abnormalities: months to yrs to normalize on gluten-free diet
Prolonged gluten-free diet may take several years to relapse after gluten reintroduced
If genetically susceptible to celiac disease perform gluten challenge 3-4 wks: enough gluten
to produce symptoms (≈3-4 slices bread/day)
If symptoms don’t recur, use development of antibodies to guide Bx timing
If no clinical symptoms and no development of antibodies, continue ≥3-6 month, obtain Bx
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How can a patient already on a gluten-free diet be diagnosed? Mgmt unclear for
Pts who improve on gluten-free diet but not genetically susceptible to celiac disease
Pts w/ HLA susceptibility genes but no antibodies or intestinal lesions after gluten challenge
Do not start empirical trial of gluten-free diet w/o establishing Dx of celiac disease (Bx)
Gluten-free diet relieves symptoms of other disorders (functional GI disorders)
Essential to differentiate b/w celiac and other disorders impacts long-term mgmt & risk assessment
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How can a patient already on a gluten-free diet be diagnosed?
Growing “gluten-sensitive” population: improve on gluten-free diet
Persons w/ celiac disease (diagnosed and undiagnosed) and unknown # w/ “gluten-sensitivity” w/o celiac disease
Extent to which gluten-sensitive persons w/o celiac disease should adhere to gluten-free diet: unknown
Often recommended: Gluten-sensitive HLA-neg adults: gluten-free diet if controls sxs, maintains good health & acceptable restrictions
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
When should patients be hospitalized?
Acutely ill needing rehydration and/or parenteral nutrition
Presence of tetany, frank dehydration, severe electrolyte disorders, or severe malnutrition
Weight loss >10% of body weight in short period
Refractory disease transitioning from parenteral nutrition to enteral tube-feeding w/ concern for relapse and severe diarrhea and malabsorption
Hospitalization rarely required
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the importance of diet?
Gluten-free diet: cornerstone of Tx
Nearly always reverses disease manifestations
There is no alternative treatment
American Gastroenterological Association: Lifelong adherence to gluten-free diet treatment of choice for
celiac disease
Complex diet strict adherence needed to avoid complications (e.g., bone loss, cancer risk)
Lack of noted symptoms when eating gluten-containing food doesn’t mean can eat w/o harm
Immunologic intolerance to gluten doesn’t go away
Even 50 mg/d gluten may cause small bowel histologic changes w/o overt clinical symptoms
Symptoms can resolve w/in days or wks, but damage will recur if gluten reintroduced in diet
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What specific dietary recommendations should be made?
Nutritional Advice for Patients With Celiac Disease Maintain a gluten-free diet for life Optimize nutritional content of meals and snacks Choose naturally gluten-free foods Minimize processed or packaged foods Focus on what can be eaten rather than what cannot Avoid lactose-containing dairy products (milk, cream, ice cream, fresh cheeses) for 1st few weeks after starting gluten-free diet until intestinal lactase levels restored Eat naturally low-lactose dairy products (yogurt, older cheeses, kefir) Choose foods rich in bioavailable iron, esp dark meat, poultry, fish (plant sources or oral supplements less bioavail)
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Are vitamin supplements required?
Vitamin D & calcium
Monitor vitamin D and supplement if low (sun exposure may not be adequate)
Assess bone density and encourage calcium supplementation
Lactose intolerance should resolve w/ intestinal recovery resulting from gluten-free diet
If lactase insufficient low-lactose dairy products and lactase supplements required long-term
Don’t avoid all dairy products—many naturally low in lactose
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Are vitamin supplements required?
Vitamins D, E, A, and K, folic acid, and iron
Celiac disease can lead to their malabsorption (preferentially absorbed thru proximal small intestine)
Thiamin, B6, B12
Deficiencies may occur (less common)
Magnesium, copper, zinc, selenium, other minerals
Can be low based on disease severity + diet
Vitamin and mineral replacement typically recommended (in addition to gluten-free diet) until intestinal healing and previously low levels replete
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
How should patients be monitored?
Follow-up w/in few weeks of Dx
Discuss intestinal Bx results and other tests
Confirm Dx by objective response to gluten-free diet and assess dietary compliance
Discuss Dx and answer pt questions
Assess potential complications (e.g., nutritional deficiencies, osteoporosis)
Visit expert dietitian on same day or soon after
Life-long follow-up recommended
Evaluate pts at regular intervals (frequency based on needs of pt & family)
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Are repeated endoscopies and biopsies required for follow-up? Follow pts based on: (1) Symptoms (2) Improved lab
abnormalities, (3) Declining levels celiac disease serology
Measure antibodies every 3-6 mos until in normal range
Higher antibody titers longer to return to normal
Consider repeat endoscopy w/ Bx if antibodies remain elevated or become positive after 6-12 mos treatment
Intestinal healing lags serologic response histology may remain abnormal for yrs
Possible causes: low-level gluten contamination, persistent immune response independent of gluten, other unknown mechanisms
Limited rationale for repeated Bxs Clinical consequence of low-grade inflammation unknown
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What are the reasons for failure to respond to a gluten-free diet?≈5% w/ celiac disease do not respond to gluten-free diet
Continued gluten ingestion Primary cause of failure
Unintentional or intentional
W/ expert dietitian, carefully review dietary Hx w/ pt
Lactose, other carbohydrate intolerance
Pancreatic insufficiency
Microscopic colitis
Sm intestinal bacterial overgrowth, w/ or w/o IgA deficiency
Gastroparesis, IBS, other forms functional GI disorders, may be postinflammatory in nature
Rarely, pts have both celiac disease and IBD
False-positive serologic results, (e.g., antigliadin IgG antibodies
Intestinal specimens falsely interpreted
Complicating or coexisting conditions
Incorrect Dx of celiac disease
Refractory celiac disease
Persistent recurrent symptoms + villous atrophy despite strict gluten-free diet for 6-12 mos
Absence other causes nonresponsiveness/ presence overt cancer
Complications: ulcerative jejunitis, collagenous sprue, T-cell lymphoma due to intraepithelial lymphocytes
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
When is immunosuppressive therapy required?
Refractory celiac disease
Requires treatment beyond (or other than) gluten-free diet
Refer to gastroenterologist for evaluation and treatment
Corticosteroids improve symptoms but should be avoided as many pts already have poor bone density
Immunomodulators (thiopurines, cyclosporin, other immunosuppressive agents)
No RCTs of immunosuppressive agents for treatment of refractory disease
Limited observational studies inconsistent benefit
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Which patients are at risk for lymphoma?
Pts w/ refractory celiac disease greatest risk
Pts w/ new or recurrent malabsorption, abdominal pain, fever, and weight loss (despite compliance with gluten-free diet)
Evaluate for potential small intestinal cancer
Barium X-rays, CT scan, capsule endoscopy
Perform endoscopic exam (obtain multiple Bx from duodenum and more distal small intestine)
Immunohistochemical and molecular studies to assess abnormal lymphoid cells
Molecular genetics to categorize refractory celiac disease: type I w/o rearrangement of T-cell genes; type II w/ rearrangement of of T-cell genes)
If lymphoma or prelymphoma suspected
Order bone marrow Bx
May need full-thickness surgical Bx of small intestine
Consult hematologist /oncologist
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
Is it ever safe to discontinue the gluten-free diet?
Unclear when, if ever, to relax or discontinue
One study: some pts start tolerating gluten over time, but this isn’t endorsed by other studies/ experts
Retrospective U.S. study: mortality of untreated celiac disease increased 4- to 5-fold versus control
Recent review: mortality in celiac disease may increase if gluten intake high both before & after Dx
Elderly w/ unrecognized, untreated celiac disease: don’t appear to have worse overall outcomes than peers w/o celiac disease
Pts w/ terminal illness may discontinue diet If gluten causes no troubling symptoms/improves QOL
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
When should a nutritionist be consulted?
Refer pts to registered dietitian w/ expertise in celiac disease and the gluten-free diets
Gluten-free diet is challenging to teach & learn
Few doctors have knowledge of food ingredients, training, or time to effectively instruct pts
Important topics for dietary counseling Hidden sources of gluten Ensuring adequate nutrition while eliminating gluten Focusing on what can be eaten vs. cannot Increased costs of prepared gluten-free foods Importance of lifelong adherence to gluten-free diet Counseling for concomitant issues (diabetes mellitus, obesity, hyperlipidemia, vegetarianism, food allergies)
Note: “gluten-free diets” often not entirely gluten-free long-term health effect unknown
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
When should a gastroenterologist be consulted? Confirm Dx by EGD w/ intestinal Bx (pts w/ suggestive
serology)
Unexplained iron deficiency anemia, chronic diarrhea, malabsorption, weight loss, other problems suggesting celiac disease despite negative serology tests
Might include unexplained osteoporosis or infertility
Unresponsiveness to gluten-free diet or relapse despite continuation of gluten-free diet (in pts w/ Bx-proven celiac disease)
Symptoms suggesting cancer
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the role of patient education?
Patients should understand… Dietary noncompliance ≈5%-70%, depending on assessment method, pt age, definition
Noncompliance w/ gluten-free diet may be associated w/increased risk for certain cancer s and death
Absence of symptoms (or ability to tolerate symptoms) resulting from nonadherence to diet doesn’t reduce health risks
Dietitian w/ expertise in celiac disease management should help provide education
Causes of celiac disease
Medical complications of insufficiently controlled disease
Risk for family members to develop celiac disease
Importance of a strictly gluten-free diet for life
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What is the role of patient education? Living gluten-free not
simple compliance difficult
Specific challenges:
Meal planning
Eating out
Traveling
Consuming adequate calories
Maintain growth & development needs in children, teens
Many foods contain wheat, rye, or barley derivatives that may damage intestine
Some pts have specific nutritionally related needs + celiac disease
Obesity
Multiple nutritional deficiencies
Diabetes
Low bone mass
Other dietary restrictions (religious/ personal beliefs)
© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.
What resources are available? Many books, Web sites, pt support groups
Not all info evidence-based (beware incorrect information at some otherwise-helpful Web sites, books)
Physicians w/ expertise in celiac disease: recommend appropriate local or national support to pts and colleagues
Support group involvement = pts generally more compliant w/ gluten-free diet
National Institutes of Health Celiac Disease Awareness Campaign (http://celiac.nih.gov)
Includes helpful educational materials, resources Lists professional & voluntary groups devoted to celiac disease awareness Provides examples of gluten-free diet