Functional Nutrition for Celiac Disease

What is celiac disease?

Celiac disease (CD) is an autoimmune disease in which certain gluten-related proteins in the diet cause the immune system to attack the lining of the small intestine and degrade the brush border.

According to a 2013 consensus paper, the agreed-upon definition of celiac disease is: “a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals” (1).

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How common is celiac disease?

In the United States, the incidence of celiac disease has increased 5x since 1974, possibly due, in part, to better screening and diagnosis methods (2).

The general prevalence worldwide is 0.5 – 1%. It is also 2 to 3 times more common in women than in men (3).

Celiac disease is most likely to be diagnosed in the first two years of life (after weaning and exposure to gluten) or between the ages of 10 and 30 years old (3).

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What are the symptoms of celiac disease?

There are two main categories of symptoms that can occur with celiac disease: intestinal and extraintestinal. They can occur together or in isolation (3).

Intestinal symptoms of celiac disease include:

• Abdominal pain
• Bloating
• Constipation
• Diarrhea
• Loss of appetite
• Nausea & vomiting

Extraintestinal symptoms of celiac disease include:

• Arthritis (4)
• Ataxia (5, 6)
• Canker sores (occur in 20% of people with celiac disease) (7)
• Dementia (8)
• Depression (9)
• Dermatitis herpetiformis (10)
• Early menopause (11)
• Elevated alkaline phosphatase (due to calcium malabsorption) (12)
• Elevated liver enzymes (occurs in 40 to 50% of untreated patients due to increased gut permeability and more antigens reaching the liver) (13)
• Exocrine pancreatic insufficiency (14)
• Failure to thrive, short stature in children (15)
• Fatigue (16)
• Headaches (17)
• Hyposplenism, as detected by abnormal red blood cells and high platelet count (18, 19)
• Indigestion (20)
• Infertility (21, 22)
• Iron deficiency anemia (microcytic) w. low ferritin (occurs in up to 40% of people with celiac disease, due to malabsorption and/or chronic inflammation or bleeding) (23)
• Lactose intolerance (24)
• Late or missing periods (11)
• Low albumin (25)
• Macrocytic anemia due to folate or B12 malabsorption or co-occurring autoimmune atrophic gastritis (less common) (26)
• Nutrient deficiencies (vitamin A, vitamin B6, vitamin D, vitamin K, folate, vitamin B12, calcium, copper, iron, phosphorus, selenium, zinc) (27, 28, 29, 30)
• Osteopenia or osteoporosis (occurs in 70% of people at the time of diagnosis, related to calcium and/or vitamin D3 deficiencies) (31, 32)
• Pancreatitis (33)
• Peripheral neuropathy (34)
• Recurring miscarriages (11)
• Reduced sperm count or motility (35)
• Tooth decay and/or enamel defects (5)
• Weight loss (36)

Sometimes people with celiac disease experience low levels of these symptoms and don’t even realize how poorly they felt until they begin a gluten-free diet and start to feel better. This most commonly occurs when someone is diagnosed through routine screening (due to family history or other health conditions) (3).

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How is celiac disease diagnosed?

It is very important to diagnose as early as possible to reduce damage. People with a family history of celiac disease or other autoimmune disorders should be screened by a physician as a precaution.

Step 1: Antibody Testing

The first step is screening with blood tests. The following are often tested (37):

• Anti-endomysium (EMA) IgA
• Anti-tissue transglutaminase (tTG) IgA
• Anti-deamidated gliadin peptide (DPG) IgG

Total IgA levels are also measured because if you don’t produce enough IgA, tTG and EMA IgA tests won’t be reliable (false negatives). In cases of IgA-deficiency, DPG IgG antibodies can still be measured (38).

Tests can be ordered through the following companies:

• Lab Corp Celiac Antibodies Profile (serology only)
• Prometheus Labs Celiac Plus Panel (serology + genetics)
• Vibrant America Wheat Zoomer (serology only)

Over the last decade, point-of-care tests (finger-prick tests for anti-tTG IgA antibodies) have been used across Europe as low-cost screening tools for celiac disease. A review of the data found they are considered reliable for that purpose (39).

Some physicians start by just ordering tTG-IgA and total IgA.

If that is positive, they’ll move on to step 2 (biopsy) for confirmation.

If the tTG is negative, then they will order an EMA and/or DGP test for more information. If those are positive, they will move on to biopsy.

It is important to note that someone must still be ACTIVELY eating gluten in order for the antibodies to show up. If someone is already on a gluten-free diet, these tests will not be accurate.

If someone is already on a GF diet, the first step should be genetic testing (see below). If they do not have the genes for celiac disease, then at least it can be ruled out and no further testing is needed (40).

Step 2: Intestinal Biopsy

If blood tests are positive, the next step is for a physician to order a small intestinal (duodenum) biopsy to look for damage. (Done by sticking an endoscope down the throat and into the small intestine.)

Current recommendations are to take 4 samples in the second portion of the duodenum and 2 samples at the bulb (40).

Doctors are looking for several things:

Crypt hyperplasia = the crypts in the small intestine get larger in response to injury/threat.

Intra-epithelial lymphocytes (IELs)  = white blood cells (lymphocytes) leave the crypts and hang out at the tips of the villi. If there are more than 25 IELs per 100 enterocytes then that is suggestive of celiac disease. Sometimes stains are used on the biopsied tissue to make the lymphocytes easier to see and count (41).

Villus atrophy = a flattening of the villi within the small intestine

The severity of each of these findings can be used to classify the type of damage according to various classification protocols (42).

These things indicate damage to the small intestine but are not necessarily always due to gluten-related damage/celiac disease.

Other possible factors that can cause villous atrophy or IELs include (3):

• Autoimmune enteropathy
• Bacterial or parasitic infections like Giardia or H.pylori
• Collagenous sprue
• Common variable immunodeficiency
• Eosinophilic gastroenteritis
• Food allergies
• HIV
• IBD (Crohn’s and ulcerative colitis)
• Intestinal lymphoma
• Medications, including NSAIDs
• SIBO
• Whipple disease

Because of this, a positive biopsy with negative antibodies and negative genetics is NOT enough to diagnose celiac disease (43).

If someone has positive bloodwork and positive genotype but showed no damage on a duodenal biopsy, it might be wise to have them get a video capsule endoscopy to look for damage in other areas.

Video capsule endoscopy can also be used for people who cannot have a biopsy. 50% will show damage with this method, and should be treated w. a gluten-free diet (44, 45)

Optional Step 3: Genetic Testing

People with suspected celiac disease can also get genetic testing for the HLA-DQ2 or DQ8 genes (95% of people with celiac disease have at least one of these genes) (46). This is not required but may add clarity to the clinical picture.

If someone tests positive for these genes, they are genetically susceptible to developing celiac disease. However, it is NOT diagnostic.

A negative test can effectively rule out celiac disease and prompt a physician to look for other causes of villous atrophy (3).

Getting a Positive Diagnosis

Classic celiac disease diagnosis = Elevated antibodies + positive biopsy + positive genetics + symptoms

There are also several other subtypes of celiac disease that may be diagnosed (3):

• “Potential” celiac disease: Elevated antibodies + a negative biopsy + positive genetics, with or without symptoms (10% of all diagnoses) (1, 47)
• “Seronegative” celiac disease: Normal antibodies + a positive biopsy + positive genetics + symptoms + response to GF diet after 1 year (2-3% of all diagnoses, average age of diagnosis 50 years old) (48)
• “Non-classical” celiac disease: Elevated antibodies + a positive biopsy + positive genetics + no symptoms

If someone with celiac disease does not feel better and regrow healthy villi after 12 months on a strict gluten-free diet (and other possible causes have been ruled out), they are diagnosed with “refractory” or “non-responsive” celiac disease (1 to 1.5% of diagnoses) (49).

There are two types of refractory celiac disease, Type 1 and Type 2, which differ based on the types of immune cells seen in the IELs during biopsy (49). Type 2 has a high risk of developing into intestinal lymphoma, so it is important to screen properly and have consistent follow-ups (50, 51).

Proposed “4 out of 5 rule” – If the patient meets all 4 of the following, the doctor can diagnose without a biopsy (52).

1. Has the symptoms of celiac disease
2. Positive anti-tTG antibodies at high titer (10x the cutoff)
3. HLA-DQ2 and/or DQ8 genes
4. Responds well to a gluten-free diet

It is also important to note that celiac disease can spontaneously develop at any time. Just because someone tested negative in the past does NOT mean that they won’t get celiac disease in the future. Retesting, usually based on symptoms, may be needed.

Non-recommended tests:

Anti-gliadin antibodies are no longer used due to poor specificity (53). Stool tests for anti-gliadin antibodies (like offered by EnteroLab) are also not recommended (54).

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What additional labs are recommended?

The following labs are recommended upon diagnosis (3, 40):

• Anti-tTG IgA (or IgG in case of IgA deficiency) (helps monitor compliance/response to GF diet)
• Antinuclear antibodies to check for other autoimmune diseases
• Bone density scan (recommended in adults after 12 to 18 months of being gluten-free)
• Complete blood count (CBC) (check for anemias)
• Ferritin, folate, B12, zinc, copper, and vitamin D3 (info on possible anemias, deficiencies, and bone health)
• TSH + TPO and thyroglobulin antibodies (screen for Hashimoto’s)
• Comprehensive metabolic panel (electrolytes, calcium, blood sugar, liver and kidney function)

Follow-up biopsies are not typically recommended unless refractory celiac disease is suspected, however some physicians choose to do them to check for villi regrowth (55).

Urine testing for gluten antibodies is currently being studied as a possible way to detect adherence to a gluten-free diet, but more research is needed (56).

For people who experience complications, the following labs can also be added (3):

• Beta-2 microglobulin testing (tumor marker)
• Lactate dehydrogenase (sign of cell damage in the body)
• Protein electrophoresis (cancer screening)
• Upper endoscopy with new biopsies
• CT/MR-enterography
• PET
• Capsule endoscopy
• Enteroscopy

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What are the long term complications of celiac disease?

Late diagnosis (around the age of 50) or not following a gluten-free diet after diagnosis is linked to greater mortality than the general population (57). It is also linked to a greater risk of cancer (58).

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What are some factors associated with increased risk of celiac disease?

The following are associated with increased risk of developing celiac disease:

1. Genetic predisposition

At least 95% of people with celiac disease have 2 specific genes: HLA class II haplotypes DQ2 and/or DQ8 (46).

However, just because someone HAS the genes for celiac disease doesn’t mean they are actively being expressed. Plenty of healthy people have these genes and do NOT have celiac disease (59).

Genetic tests can help rule out celiac disease (if you don’t have the genes), but cannot diagnose it.

2. Family history

People with a first-degree relative with celiac disease have a 10 – 15% chance of getting celiac disease themselves (3).

In identical twins, if one has celiac disease, there is a 75 – 80% the other will develop it as well (strong heritability) (60).

3. Autoimmune diseases

Approximately 10% of people with type 1 diabetes will eventually develop celiac disease (61). This may be because they share predisposing genes (62).

Other autoimmune conditions linked to celiac disease include (3):

• Addison’s disease
• Alopecia
• Autoimmune atrophic gastritis
• Autoimmune hemolytic anemia
• Autoimmune hepatitis
• Dermatitis herpetiformis
• Grave’s disease
• Hashimoto’s thyroiditis
• IgA deficiency
• IgA nephropathy (Berger’s disease)
• Myasthenia gravis
• Polymyositis
• Primary biliary cholangitis
• Primary sclerosing cholangitis
• Psoriasis
• Rheumatoid arthritis
• Scleroderma
• Sjogren’s syndrome
• Systemic erythematosus lupus
• Vitiligo

4. Other medical conditions

Some non-autoimmune conditions are also associated with celiac disease (3):

• Atopy
• Cerebellar ataxia
• Cerebral atrophy
• Chronic inflammatory intestinal diseases
• Dilated cardiomyopathy
• Down syndrome
• Epilepsy with or without occipital calcifications
• Multiple myoclonic seizures
• Multiple sclerosis
• Peripheral neuropathy
• Sarcoidosis
• Turner syndrome
• William’s syndrome

5. Gut infections

One study found that children between the ages of 1 – 4 years old who had gastrointestinal infections had a 33% greater risk of developing celiac disease in the following 3 months (63).

There is some evidence that a rotavirus infection can trigger celiac disease in susceptible children and that a vaccine against the rotavirus may be helpful for prevention in children (64).

6. Gut dysbiosis

Preliminary studies have found that children with celiac disease have more gram-negative bacteria, fewer gram-positive bacteria, and less bacterial diversity in their intestines than healthy children, even when following a strict gluten-free diet (65, 66, 67, 68, 69).

Antibiotic use appears to be linked to dysbiosis and increased risk of celiac disease (70).

Some researchers have also proposed a link between glyphosate intake, gut dysbiosis, and increased prevalence of celiac disease (71).

7. New wheat strains

The development of wheat strains with greater amounts of gluten is hypothesized to play a role in the increased prevalence of celiac disease, but so far, this is just a correlation and has not been shown to be causative (72, 73).

8. Gluten intake in early childhood

Since gluten in the diet is the known trigger for the autoimmune response in celiac disease, exposure to gluten is required in order to develop celiac disease.

A newly published longitudinal study found that children with the highest gluten intakes when they were 1 and 2 years old had a 2x greater risk of developing celiac disease over the following 24 years than the children with the lowest intakes. There was a 5% increased risk for every additional gram of gluten per day in the diet at the age of 1 (2 grams = roughly 1 slice of bread) (74).

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What are the nutrition interventions for celiac disease?

Dietitians often recommend the following:

1. Gluten-Free Diet

The primary treatment for celiac disease is following a strict gluten-free diet, begun under the guidance of a dietitian, for life.

With 100% compliance, diarrhea should resolve within days, and most symptoms will disappear in about 4 weeks (75). Antibodies should return to normal within 12 months (up to 24 months in cases w. extremely high titers) (76).

The small intestinal villi should also grow back, but you can’t tell whether this is happening just by looking at antibodies. Approximately 20% of children with normalized antibodies will still have persistent enteropathy after 1 year on a gluten free diet (77).

In nearly half of the cases of non-responsive celiac disease, the persistent enteropathy is due to poor adherence to the gluten free diet, (often accidental). However, in some cases, the intestinal damage is actually from other lingering conditions, like microscopic colitis or SIBO, and not celiac disease (78).

According to one study, it takes… (79)

• 6 months for people newly diagnosed with celiac disease to feel confident in distinguishing between gluten-containing and gluten-free foods
• 1 – 2 years to feel confident in explaining celiac disease and the gluten-free diet to friends and family
• 3 – 5 years to identify gluten in medications and supplements
• More than 5 years to learn how to travel internationally on a gluten free diet

So ongoing support is helpful!

It is recommended that newly diagnosed patients have a follow-up visit 6 months after starting a gluten-free diet and then every 1 to 2 years afterward to monitor for compliance with the GF diet, monitor nutrition-related labs, check antibodies, and monitor for potential complications.

If complications arise, follow-ups should be every 3 to 6 months (3).

2. Lactose-Free Diet (as needed) 

Since lactase (the enzyme that breaks down lactose) is produced on the brush border of the small intestines, lactose intolerance often develops in people with celiac disease.

Often times it is just temporary and the ability to properly digest lactose can return once the villi regenerate.

While the gut is healing, a lactose-free diet may be recommended (usually during the first 3 to 6 months on a gluten-free diet) (80).

3. Address Nutrient Deficiencies

Vitamin and mineral deficiencies are very common in celiac disease, often due to malabsorption.

A 2018 paper published in JAMA recommends iron, B-vitamins, vitamin D, zinc, and magnesium supplementation for people with celiac disease until deficiencies are repleted (81). If bone health is compromised, then calcium and vitamin K2 should be supplemented as well.

Newer data has shown that copper deficiency is also common (82)

Micronutrient testing can be done to develop customized protocols for each person.

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Emerging Advances:

Over 40% of people with celiac disease are unhappy following a gluten-free diet and would be interested in exploring other treatment options (84).

Studies are underway for medications/supplements that would further reduce symptoms for people following a gluten free diet and/or make it possible for them to eat small amounts of gluten without harm.

Emerging areas of celiac disease research include:

1. Improving the gut barrier

One compound being studied is larazotide acetate, a synthetic peptide that acts as a zonulin antagonist and prevents tight junctions in the gut from becoming “leaky” (83).

The idea is that by improving gut integrity, food sensitivity reactions would be reduced and symptoms would improve for people who still feel bad while on a gluten free diet (85).

2. Gluten-specific protease supplements

Another potential therapy is taking protease supplements (ALV003) that specifically degrade gluten within the stomach, before it reaches the small intestine. The idea is to help prevent symptoms from consuming small amounts of gluten. However, so far, the results have been mixed (86, 87).

3. Antibody treatments

IL-15 antibodies (PVR-015/AMG 714) are being investigated as a possible way to blunt the immune response that occurs in celiac disease, but so far, only animal studies have been conducted (88).

4. Vaccines

A vaccine (Nexvax2) was in development to help desensitize people with celiac disease to gliadin, but phase 2 trials found that it was no more effective than placebo and development was discontinued as of June 2019 (89).

5. Drug repurposing

Some researchers have found similarities between defective proteostasis in cystic fibrosis and celiac disease and hypothesize that some drugs may have therapeutic overlap (but research is needed) (90, 91, 92).

6. Genetically engineered wheat

Some researchers are even working on genetically engineered wheat that express and store proteases within their grains that can degrade gluten. A recent experimental strain was able to reduce the amount of gliadin by ~70% (93).