© Copyright Annals of Internal Medicine, 2011 Ann Int Med. 154 (9): ITC5-1. Terms of Use The In...

© Copyright Annals of Internal Medicine, 2011Ann Int Med. 154 (9): ITC5-1.

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in the clinic

Celiac Disease


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)


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


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


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



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



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



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



Sm subset of pts has severe manifestations at Dx

Physical Findings in Patients With Severe Celiac Disease


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


Dermatitis herpetiformisIntensely pruritic papulo-vesicular rash affecting extensor surfaces, such asshoulders (top), elbows, knees, back, and buttocks(bottom)


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


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


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


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


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.


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


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


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


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



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


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


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)


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


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


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)


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


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


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


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


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


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


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



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


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)


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

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