against the grain: an overview of celiac disease

PRACTICE

Against the grain: An overview of celiac diseaseSuzanne Martin, RN, FNP-C (Clinical Instructor)

College of Nursing and Student Health Center, University of Utah, Salt Lake City, Utah

Keywords

Celiac disease; diarrhea; malabsorption

syndrome; gluten-free diet.

Correspondence

Suzanne Martin, RN, FNP-C, College of Nursing

and Student Health Center, University of Utah,

555 Foothills Boulevard, Salt Lake City,

UT 84112.

Tel: 801-581-6546; Fax: 801-585-5294;

E-mail: [email protected]

Received: December 2006;

accepted: July 2007

doi:10.1111/j.1745-7599.2008.00314.x

Abstract

Purpose: To review the epidemiology, pathophysiology, clinical presentation,

diagnosis, and management of celiac disease (CD).

Data sources: Review of literature using Pub Med and Access Medicine. The

following search terms were used: celiac disease, malabsorption syndromes,

diarrhea, and gluten-free diet (GFD). There was no limitation placed on pub-

lication year. Only articles written in English were included.

Conclusions: CD is a chronic systemic autoimmune disorder triggered in

genetically susceptible individuals by the ingestion of gluten proteins (wheat,

barley, and rye). CDoften presents atypically, and diagnosis delays are common.

Currently, the only effective treatment for CD is strict adherence to aGFD. This is

a difficult diet to comprehend and follow. Adherence to a GFD requires ongoing

education and support from a multidisciplinary healthcare team, support

groups, family, and friends.

Implications for practice: Once considered a rare disease of childhood, CD is

now recognized as a common disorder that can occur at any age. Clinicians need

to be cognizant of risk factors, clinical manifestations, conditions, and compli-

cations associated with CD in order to make a timely diagnosis, ameliorate

symptoms, and minimize disease complications.

Introduction

Celiac disease (CD) is a chronic systemic autoimmune

disorder triggered in genetically susceptible individuals

by gluten proteins (wheat, barley, and rye). It can affect

the gut, skin, joints, uterus, brain, heart, and other organs

(Rewers, 2005). The emergence of new serologic tests has

enabled large-scale screening studies across the globe.

Fasano et al. (2003) conducted a large multicenter study

to determine the prevalence ofCD in ‘‘at-risk’’ and ‘‘not-at-

risk’’ populations in the United States between 1996 and

2001. Among the at-risk populations, they found the

prevalence of CD to be 4.5% (1/22) in first-degree rela-

tives, 3.3% (1/30) in second-degree relatives, and 1.8%

(1/56) in symptomatic individuals. Among the not-at-risk

populations, they found a prevalence of 0.95% (1/105) in

adults and 0.31% (1/320) in children. The increase of

prevalence in not-at-risk adults compared to not-at-risk

children suggests the development of an immune response

to gluten over time. The overall prevalence in the not-at-

risk population was 0.75% (1/133).

Many cases of CD go undiagnosed because the con-

dition presents in a variety of ways and can even be

clinically silent, as depicted in Figure 1. Green et al.

(2001) found that the average time between the onset

of symptoms and the diagnosis of CD in adults is 11 years.

Primary care clinicians (PCPs) need to have a working

understanding of CD in order to make a timely diagnosis,

lessen symptoms, and reduce the risk of disease-related

complications.

Pathogenesis

CD is characterized by chronic inflammationof the small

intestinal mucosa, which may result in atrophy of intes-

tinal villi, malabsorption, and a variety of clinical mani-

festations (National Institutes of Health, 2004). A biopsy of

the luminal surface of the normal small intestinal mucosa

Journal of the American Academy of Nurse Practitioners 20 (2008) 243–250 ª 2008 The Author(s)Journal compilation ª 2008 American Academy of Nurse Practitioners

243

will show abundant villi, a smattering of intraepithelial

lymphocytes, and a normal complement of lymphocytes

and plasma cells in the lamina propria consistent with

normal physiologic inflammation. In contrast, a biopsy of

the luminal surface of the small intestinal mucosa in

patients with CD will show loss of villi, a flat mucosal

surface marked by ridges and numerous crypt openings

onto the laminal surface, increased intraepithelial lym-

phocytes, chronic lymphocyte and plasma cell infiltration

of the lamina propria, and marked crypt hyperplasia (see

Figure 2). The severity of these changes varies among CD

patients (Kagnoff, 2005).

The pathogenesis of CD is only partly understood but

involves a clear interaction between environmental,

genetic, and immunologic factors. The environmental

factors are disease-activating proteins collectively re-

ferred to as ‘‘gluten’’ found in wheat, barley, and rye.

Gluten contains two protein fractions, glutamine and

proline, that are particularly resistant to proteolytic

digestion and play a key role in the pathogenesis of

CD. Genetics also play a critical role in the pathogenesis

of CD. Ninety to ninety-five percent of CD patients

exhibit the HLA-DQ2 genotype, while the remaining

5%–10% of CD patients exhibit the HLA-DQ8 genotype

(Kagnoff, 2005). Autoantibodies specific to tissue trans-

glutaminase develop in patients with CD. These auto-

antibodies facilitate the binding of proline-rich peptides

to DQ2 and DQ8 molecules. The DQ–gluten peptide

complex then activates CD4 T cells in the lamina propria

of the intestinal mucosa. These CD4 T cells trigger the

production of cytokines that contribute to the chronic

inflammation seen in CD. Finally, the increased intra-

epithelial lymphocyte count seen in CD has been recog-

nized for many years. The role of this increase is still

unclear, but it may play a role in epithelial cell damage,

refractory CD, and CD-associated T-cell lymphoma

(Kagnoff).

Risk factors, associated conditions, andcomplications

Risk factors associated with CD include a positive family

history of CD and white race (Fasano et al., 2003). CD is

associated with dermatitis herpetiformis (DH), an

intensely pruritic papulovesicular rash over buttocks,

scalp, face, elbows, and knees (Wolff, Johnson, &

Suurmond, 2005). CD is also associated with other

autoimmune disorders (e.g., type 1 diabetes, thyroiditis,

hepatitis, and cardiomyopathy), selective IgA deficiency,

and genetic disorders (e.g., Down, Williams, and Turner

syndromes).

The most concerning complication of CD is cancer.

Adults with CD have a threefold increased risk of non-

Hodgkin lymphoma. They also have an increased risk

of other gastrointestinal cancers, including small bowel

Figure 2 Normal versus CD small bowel biopsy. Top: Normal small bowel

biopsy with finger-like villi. Bottom: CD small bowel biopsy with villous

atrophy and hypertrophy of crypt.

Note. Reprinted with permission from Endocrine Reviews [Collin, P.,

Kamkinen, K., & Valimaki, M. (2002). Endocrinological disorder and celiac

disease. Endocrine Reviews, 23(4), 464–483].

Figure 1 The celiac iceberg.

Note. Reproduced with permission from The Children’s Digestive Health

and Nutrition Foundation, September 2006 (http://www.celiachealth.org).

An overview of CD S. Martin

244

adenocarcinoma, esophageal and pharyngeal carcinoma,

and primary liver cancer. Early intervention and strict

adherence to a gluten-free diet (GFD) have been shown

to reduce the risk of these rare but aggressive cancers

(Catassi, Bearzi, & Holmes, 2005). Interestingly, two

studies have demonstrated a significantly reduced risk of

pre- and postmenopausal breast cancer. This may be

because of lower body weights and smoking rates associ-

ated with CD (Card, West, & Holmes, 2004; Swinson,

Slavin, Coles, & Booth, 1983).

Another complication of CD is iron deficiency anemia

because ofmalabsorption.More than 10%of patientswith

iron deficiency anemia not because of gastrointestinal

blood loss may have CD (McPhee, Papadakis, & Tierney,

2007). More extensive CD will result in a megaloblastic

anemia because of deficient folate or vitamin B12 defi-

ciency. Decreased serum calcium and elevated serum

alkaline phosphatase reflect reduced calcium and vitamin

D absorption and osteomalacia or osteopenia. Elevation of

prothrombin time reflects malabsorption of fat-soluble

vitamins, including vitamins A and K. Reduced serum

albumin suggests small intestine protein loss or poor

nutrition (McPhee et al.). Additional complications of

CD include lactose intolerance, amenorrhea, infertility,

repeated miscarriage, peripheral neuropathy, ataxia,

depression–anxiety, and elevated liver enzymes (Green,

2005).

Patient presentation/patient history

The onset of CD can occur at any age. Infants and

toddlers begin to express classic CD symptoms when glu-

ten is introduced to their diet between 6 and 24 months.

Classic symptoms include diarrhea, abdominal distention,

impaired growth, muscle wasting, decreased appetite,

weight loss, lethargy, and irritability. Atypical presenta-

tions are less likely to occur in this population (Fasano,

2005).

Older children between the ages of 5 and 7 years tend

to present with unusual intestinal symptoms, including

recurrent abdominal pain, abdominal bloating, nausea,

vomiting, and constipation. They may also present with

atypical extraintestinal symptoms, such as short stature,

delayed puberty, dental enamel defects, liver function

abnormalities, and/or iron-deficient anemia (Fasano,

2005).

Themajority of adults will presentwith atypical or silent

CD. The term silent is a misnomer as many patients in this

category have mild or nonspecific symptoms, such as

fatigue or depression. Adults frequently present with

complications of CD, such as lactose intolerance, unex-

plained iron deficiency anemia, or decreased bonemineral

density. Atypical CD may be diagnosed in patients under-

going endoscopy for symptomsnot usually associatedwith

CD, such as gastroesophageal reflux or dyspepsia. Finally,

silent CD may be truly asymptomatic when diagnosed

through screening of family members and other high-risk

patients. Adults who present with classic symptoms will

report diarrhea, steatorrhea, flatulence, abdominal pain,

abdominal distention, vomiting, anorexia, andweight loss

(Green, 2005).

Physical examination

The physical exam in pediatric patients may reveal

failure to thrive, weight loss, dental enamel defects,

abdominal distention, muscle wasting, and lethargy. The

physical exam in adults may be normal or may demon-

strate pallor, aphthous ulcers, hypotension, edema, bruis-

ing, diminished sensation, diminished deep tendon

reflexes, ataxia, muscle spasm, bone pain, and rash con-

sistent with DH.

Laboratory workup and diagnosis

All tests for CDmust be performed on a gluten-contain-

ing diet. Either the IgA endomysium (IgA EMA) or IgA

tissue tranglutaminase (IgA tTG) is recommended to

screen for CD (Hill, 2005). The sensitivity and specificity

of these tests exceed 90% and 95%, respectively, in

research settings in patients with more extensive disease.

In this setting, a negative test dependably excludes the

diagnosis of CD (McPhee et al., 2007). The sensitivity and

specificity of these testsmay not be as high in patientswith

less extensive disease. Therefore, negative serology results

should not preclude small bowel biopsy in patients with

symptoms that are suggestive of CD (Dewar, 2005).When

selective IgAdeficiency is present, itmaybe best to proceed

directly to small bowel biopsy (Hill).

Patients with positive serologic tests require small bowel

biopsy to confirm or refute CD (Dewar, 2005). Patients

with biopsy-proven DH, a dermatologic manifestation of

CD, do not need small bowel biopsy as they are presumed

to have CD and a GFDwill often relieve symptoms of both

DH and CD (Zone, 2005). Small bowel biopsy must reveal

some degree of inflammation and villous atrophy to sup-

port the diagnosis of CD. The Marsh and Oberhuber

classifications are designed to describe the progression of

abnormalities seen in CD as shown in Table 1 (Chand &

Mihas, 2006). If the biopsy is normal in the setting of

positive serology, the diagnosis of latent CD is appropriate.

The natural history of latent CD is largely unknown, but

anecdotal reports suggest that some individualswith latent

CD eventually develop clinical CD. If the biopsy is sugges-

tive of CD, a presumptive diagnosis of CD is appropriate

(Dewar).

S. Martin An overview of CD

245

Treatment/management

Currently, the only known treatment for CD is strict

adherence to the GFD. The GFD eliminates all foods that

contain wheat, rye, and barley as depicted in Table 2. A

subset of CD patients who have concurrent lactose intol-

erancewill also have to restrict lactose-containing foods, at

least until the intestine recovers (Murray, 1999). This diet

is extremely complicated and demanding; therefore, all

patients diagnosed with CD require prompt referral to

a qualified registered dietician (RD) for comprehensive

patient and family education. Periodic follow-up visits are

often needed to support long-term adherence to the GFD.

The GFD can become monotonous and nutrient deficient

unless care is taken to diversify food choices. A qualified

RDcanhelp patientsmeet their nutrient needs and expand

meal options despite dietary constraints. Dietary supple-

ments such as iron, vitamins A, D, and B, calcium, zinc,

and magnesium are commonly used to prevent and/or

correct nutrient deficiencies (Kupper, 2005). Local and

national CD support groups also play a critical role for

patients and families byproviding emotional support along

with practical resources, such as gluten-free friendly

supermarkets, manufacturers, literature, and restaurants

(Case, 2005).

There is controversy overwhat constitutes an acceptable

GFD. These issues often lead to inconsistent recommen-

dations, consumer confusion, and unnecessary dietary

restrictions (Thomas, 2000). For example, the inclusion

of oats in the GFD is not widely recommended in the

United States because of concerns over cross-contamina-

tion of commercial oats (Kupper, 2005). However, results

of several studies suggest that most adults with CD can

safely consume a moderate amount (approximately one-

half cup of dry whole-grain rolled oats per day) of uncon-

taminated oats. To avoid contaminated oats, patients

should purchase oats that are milled and processed in

oat-dedicated facilities (Thomson, 2003).

Adherence rates to aGFD range from17%to83%(Case,

2005). Adhering to a strict GFD is a daunting task because

of the ubiquitous presence of wheat and wheat-based

products in the North American diet, along with the

hidden sources of gluten found in many products, such

as food additives, lipstick, envelope glue, andmedications.

Even small amounts of gluten can trigger symptoms in

some patients, so vigilant label reading is critical. Hectic

U.S. households may have difficulty finding affordable

gluten-free convenience/packaged foods (Case). More-

over, the GFD can easily become a social liability by

restricting food choices when visiting friends, dining

out, and traveling (Case). Symptomatic patients are more

likely to adhere to a GFD than asymptomatic patients,

despite findings that asymptomatic patients report ahigher

quality of life after initiating a GFD (Pietzak, 2005). Young

adults diagnosed with CD prior to age 4 were much more

likely to adhere to the GFD than young adults diagnosed

after age 4, suggesting that an earlier diagnosismay predict

greater adherence to the GFD (Hogberg, Grodzinsky, &

Stenhammar, 2003).

Patient education

PCPs will often be the first source of patient education

and must approach the patient and his or her family in

a positive and reassuring manner. Patients need to have

a basic understanding of the pathogenesis of CD. They also

need to be aware of the typical and atypical symptoms,

associated conditions, andpossible complications ofCD.As

mentioned above, all patients with CD need prompt refer-

ral to a qualified RD and local support groups in order to

Table 1 Pathologic classification of celiac disease

Marsh classification

Type 0 (preinfiltrative) No detectable changes in inflammation

No detectable changes in crypt/villous height ratio

Type 1 (infiltrative) Increase in the number of intraepithelial lymphocytes (IELs)

Type 2 (hyperplastic) Inflammation, villous blunting, and increase crypt/villous height ratio

Type 2 (destructive) Severe inflammation, flat villi, and hyperplastic crypts

Oberhuber classification

Type 0 Normal mucosa with <40 IEL/EC

Type 1 Increased IEL/EC, normal villous architecture, and normal height of crypts

Type 2 Normal villous architecture, increased IEL, and crypt hyperplasia

Type 3 Destructive type with varying degrees of villous atrophy; in all subtypes, there is increased crypt

height and influx of inflammatory cells

Type 3a Partial villous atrophy; villi blunt/shortened with villous/crypt ratio <1:1

Type 3b Subtotal villous atrophy; villi atrophic but still separate and recognizable

Type 3c Total villous atrophy; villi rudimentary or absent; mucosa resembles colonic mucosa

Type 4 Atrophic hypoplastic lesion; flat mucosa with normal crypt height and no significant inflammation

with normal IEL counts

Note. Adapted with permission from Chand and Mihas (2006). EC, epithelial cell.


246

Table 2 GFD guidelines

Food

Milk products Recommended

Milk, cream, buttermilk, plain yogurt, cheese, cream cheese, processed cheese and processed cheese

foods, and cottage cheese

Question

Milk drinks, flavored yogurt, frozen yogurt, and sour cream

Not allowed

Malted milk

Breads Recommended

Products made from corn, rice, soy, arrowroot, pea flour, corn, starch, potato starch, potato flour, whole-bean

flour, tapioca, sago, rice bran, cornmeal, buckwheat, millet, flax, teff, sorghum, quinoa, and amaranth

Not allowed

Products containing wheat, rye, triticale, barley, oats, wheat germ, wheat bran, graham flour, gluten flour, durum

flour, wheat starch, oat bran, bulgur, farina, wheat-based semolina, spelt, kamut, and imported foods labeled

‘‘gluten free’’ (may contain wheat starch)

Cereals Recommended

Hot—cream of rice, soy cereal, hominy, hominy grits, brown/white rice, buckwheat groats, millet, cornmeal, and

quinoa flakes

Cold—puffed corn, puffed rice, puffed millet, and rice flakes

Question

Rice and soy pablum

Not allowed

Products make from wheat, rye, triticale, barley, and oats; products with added malt extract and malt flavoring

Pastas Recommended

Products from rice, corn, soy, quinoa, beans, potato, pea, or other allowed flours

Not allowed

Products from wheat, wheat starch, and other ingredients not allowed

Miscellaneous Recommended

Corn tacos and corn tortillas

Question

Rice crackers, rice cakes, and popped corn cake

Not allowed

Wheat tacos and wheat tortillas

Meat/meat alternatives Recommended

Fresh, frozen, canned, salted, and smoked

Question

Prepared/preserved meats, for example, luncheon meat, ham, bacon, meat and sandwich spreads, meat loaf,

frozen meat patties, sausages, pate, wieners, bologna, salami, imitation meats or fish products, and meat

product extenders

Not allowed

Fish canned in vegetable broth containing hydrolyzed vegetable protein (HVP) or hydrolyzed plant protein

(HPP) from ingredients not allowed; turkey basted or injected with HVP/HPP

Eggs Recommended

Eggs

Question

Egg substitutes, dried eggs, and egg whites

Other Recommended

Lentils, chickpeas, peas, beans, nuts, seeds, and tofu

Question

Baked beans, dry roasted nuts, and peanut butter

Fruits/vegetables Recommended

Fruits—fresh, frozen, and canned fruit juices

Vegetables—fresh, frozen, and canned

Question

Fruits—pie filling and dried fruits

Vegetables—fried potatoes (especially in restaurants)


247

Table 2 Continued

Not allowed

Fruits—scalloped potatoes (containing wheat flour)

Vegetables—battered dipped vegetables

Soups Recommended

Homemade broth, gluten-free bouillon cubes, cream soups, and broths made from ingredients allowed

Question

Canned soups, dried soup mixes, soup bases, and bouillon cubes

Not allowed

Products containing ingredients not allowed and HVP/HPP

Fats Recommended

Butter, margarine, lard, vegetable oil, cream, shortening, homemade salad dressing with allowed ingredients

Question

Salad dressings and some mayonnaise

Not allowed

Packaged suet

Desserts Recommended

Ice cream, sherbet, water, ice, whipped toppings, egg custards, gelatin desserts, cakes, cookies, pastries

made with allowed ingredients

Question

Milk puddings, custard powder, and pudding mixes

Not allowed

Ice cream, cakes, cookies, muffins, pies with ingredients not allowed; ice cream cones, wafers, and waffles

Beverages Recommended

Tea, instant and ground coffee (regular/decaffeinated), cocoa, soft drinks, cider, distilled alcoholic beverages

such as rum, gin, whiskey, and vodka; wines and pure liqueurs

Question

Instant tea, coffee substitutes, fruit-flavored drinks, chocolate drinks, chocolate mixes, and flavored and

herbal teas

Not allowed

Beer, ale, and lager; cereal and malted beverages

Snack foods Recommended

Plain popcorn and nuts

Question

Dry roasted nuts, flavored potato chips, and tortilla chips

Not allowed

Pizza, unless made with ingredients allowed

Condiments Recommended

Plain pickles, relish, olives, ketchup, mustard, tomato paste, pure herbs/spices, pure black pepper,

all vinegars, and gluten-free soy sauce

Question

Worcestershire sauce and mixed spices/seasoning (e.g., chili or curry powders)

Not allowed

Soy sauce (made from wheat), mustard pickles (made from wheat), and imitation pepper (small packets

found in some restaurants and airline meals)

Other Recommended

Sauces/gravies made with ingredients allowed, pure cocoa, pure baking chocolate, chocolate chips,

carob chips and powder, monosodium glutamate, cream of tartar, baking soda, yeast, brewer’s yeast,

coconut, and aspartame

Question

Baking powder

Not allowed

Sauces/gravies made from ingredients not allowed, for example, HVP/HPP if source is from wheat protein

or plant source is unknown, oat gum, and communion wafers

Note. Adapted with permission from American Dietetic Association and Dieticians of Canada (2000).


248

Figure 3 An approach in the management of a patient with CD.

Note. Reprinted from Pietzak (2005) with permission from the American Gastroenterological Association.


249

acquire detailed information about the GFD along with

practical suggestions and ongoing emotional support.

After initiating the GFD, symptoms typically decrease

over the course of severalweeks. Serologic tests and biopsy

changes may require several months to return to normal.

Negative serology is oftenmore suggestive of adherence to

the GFD and does not guarantee intestinal mucosal recov-

ery. Serology test results may not return to normal in

patients with concurrent autoimmune disorders and,

therefore, may not be useful in this group. The American

Gastroenterological Association recommends a small

bowel biopsy 4–6months after initiating the GFD to assess

improvement (Pietzak, 2005).

The main goals of follow-up in CD are monitoring for

adherence to therapy and screening for recognized com-

plications of CD. Newly diagnosed patients should be

checked for nutritional deficiencies such as iron-deficiency

anemia and fat-soluble vitamin deficiencies. In addition,

they need to be screened for osteoporosis, neurological

symptoms, and autoimmune thyroid and liver disease.

Children need to be monitored for growth problems and

delayed puberty. First- and second-degree relatives should

be screened for CD.

After 3–6 months of gluten restriction, patients should

follow up with either the PCP or the gastroenterologist to

discuss symptoms and to reinforce the importance of

adhering to therapy. If adherence to the treatment regi-

men is acceptable and no complications are detected, the

patient may follow up with either the PCP or the gastro-

enterologist annually. Annual visits should include

a detailed review of dietary adherence, follow-up IgA

EMA or IgA tTG, and screening for nutrient deficiencies

and complications (see Figure 3; Pietzak, 2005).

Conclusion

CD is an important diagnosis to understand and consider

when seeing patients with risk factors, symptoms, associ-

ated conditions, or complications of CD. Advances in

serologic tests have allowed more accurate screening in

these patients. The only treatment available at this time is

the GFD. Adherence to the GFD will require a motivated

and educated patient who has the support of family,

friends, and a multidisciplinary healthcare team.

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