Celiac Disease, Refractory

What Is Refractory Celiac Disease?

[dropcap]R[/dropcap]efractory celiac disease, formerly called refractory sprue, is a severe complication characterized by persistence of symptoms and intestinal inflammation despite gluten free diet after 12 months.¹

Refractory celiac disease appears in two forms, ulcerative jejunitis (RCD I) and cryptic intestinal T-cell lymphoma (RCD II).

Patients with RCD I seem to profit from immunosuppressive treatment, but positive response to corticosteroid treatment does not exclude underlying enteropathy–associated T-cell lymphoma (EATL).

Patients with RCD II have a high percentage of abberant T-cells and is usually resistant to medical therapies. The presence of an aberrant clonal intraepithelial T-cell population has led to the designation of refractory celiac disease with this population as a cryptic intestinal T-cell lymphoma, characterized by frequent dissemination to the blood and the entire gastrointestinal lining.²

• Refractory sprue may occur after an initial response to gluten free diet or without any evidence of preexisting celiac disease. All other causes of malabsorption must be excluded, such as collagenous colitis.
• In a subgroup of patients with enteropathy-associated T-cell lymphoma (EATL) there is progressive deterioration of a refractory form of celiac disease. The prognosis is poor, although some patients respond to corticosteroids and immunosuppressive agents.³
• A nationwide Finnish study showed that patients of male gender, older age, severe symptoms or seronegativity (negative antibody result) at the diagnosis of celiac disease are at risk of future refractory coeliac disease and should be followed up carefully.⁴
• Chorea has been described as a paraneoplastic phenomenon in patients with non-Hodgkin’s lymphoma and has been described as associated with lymphoma arising from a background of refractory celiac disease. The finding of chorea in association with celiac disease should prompt a search for possible underlying intestinal T-cell lymphoma.⁵

How Prevalent Is Refractory Celiac Disease?

• Refractory celiac disease is a rare occurrence in a subgroup of celiac disease patients.⁶
• A study investigating medical records of 844 patients diagnosed with celiac disease at a celiac disease referral center in North America found that 4% (34 patients) had refractory celiac disease. Five patients (14.7%) were diagnosed with RCD type II and of these, two died of enteropathy-associated lymphoma within 24 months of diagnosis of celiac disease (observed mortality rate 5.9%).⁷
• A nationwide Finnish study found the prevalence of refractory celiac disease (RCD) was 0.31% among diagnosed celiac disease patients and 0.002% in the general population. Of the enrolled 44 RCD patients, 68% had type I and 23% type II; in 9% the type was undetermined. Comparing 886 patients with uncomplicated celiac disease with these 44 patients that developed RCD later in life, the latter were significantly older (median 56 vs 44 years), more often males (41% vs. 24%) and seronegative (30% vs. 5%) at the diagnosis of celiac disease. Patients with evolving RCD had more severe symptoms at the diagnosis of celiac disease, including weight loss in 36% (vs. 16%) and diarrhea in 54% (vs. 38%).⁸

 

What Are The Symptoms Of Refractory Celiac Disease?

Refractory celiac disease is marked by these symptoms:

• Intractable diarrhea.
• Wasting malnutrition.
• Constant fatigue.
• Weight loss.

How Does Refractory Celiac Disease Develop?

• Refractory celiac disease results directly from gluten sensitive enteropathy.
• Malnutrition may predispose to ongoing inflammation, particularly deficiency of vitamin A, vitamin E, and selenium.

Does Refractory Celiac Disease Respond To Gluten-Free Diet?

Refractory celiac disease is poorly responsive to gluten free diet.³ Keeping a diet history is essential to discover inadvertant consumption of gluten as a causative factor.

6 Steps To Improve Refractory Celiac Disease:

• [dropcap]1[/dropcap]Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

[box type=”shadow” ]Treatment. This condition responds to the complete elimination of gluten, which is the required treatment that improves both refractory celiac disease and gut health.

• Gut health is the foundation to restore ALL health. Restored health will enable you to maintain a strict gluten free diet, just as other life tasks will be easier.
• A strict gluten free diet means removing 100% of wheat, barley, rye and oats from the diet.
• Cutting out bread and other obvious sources of gluten is not good enough for recovery. Even 1/8th teaspoon of flour or bread crumb is enough to sustain the inflammation that is damaging your small intestine, causing increased permeability (leaky gut) and allowing undigested gluten to enter your body where it can damage structures and function, and instigate immune inflammatory responses.

Correct Your Individual Nutritional Needs.

• Eat foods that can replenish missing nutrients. Find them under NUTRIENT DEFICIENCIES.
• Take nutritional supplements as needed. Find them under NUTRIENT DEFICIENCIES.

Recovery. You should begin to feel better within a week and notice more energy as inflammation subsides and the  absorbing cells that make up the surface lining of your small intestine are better able to function.

• Intestinal lining cells are replaced every 5 days. The healing process is like sunburn where the damaged surface layer of skin sloughs off and is replaced with new normal cells.
• Leaky gut normally resolves in two month after starting a gluten free diet and brings about a big improvement in health. Improvement in intestinal permeability precedes morphometric recovery (cell appearance and structure) of the small intestine in celiac disease.⁹
• The intestinal lining may take up to a year to heal.[/box]

• [dropcap]2[/dropcap] Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from your diet to reduce an additive effect to gluten. At the same time, try to eat foods that reduce inflammation (anti-inflammatory).

[box type=”shadow” ]Here Are Major Inflammatory Food Types That Reduce Healing:

• Damaging Foods. In susceptible persons, includes corn, dairy (cow), and soy. Lactose, the sugar in any animal milk disrupts intestinal permeability causing leaky gut.¹⁰
• Allergenic Foods. Includes foods that trigger the immune sytem to produce IgE antibodies. Allergy testing is the usual way to discover these offending foods.
• Shelf Stable Processed Foods. Includes any that contain additives and preservatives. Look for them on the nutrition label of the box or package. Additives and preservatives also disrupt intestinal permeability causing leaky gut.¹⁰
• Fats. Limit deep fried foods, trans-fats, saturated fats (animal fat/butter), and EXCESSIVE omega-6 fatty acid oils like corn oil. Rancid fats, sodium caprate (a medium chain fat), and sucrose monester fatty acid (a food grade surfactant) induce significant disruption of the intestinal barrier that causes leaky gut.¹⁰.
• Excessive Refined White Flours (bran layer removed). Includes products made from them such as cookies, bread, cakes, pies. Bran contains the vitamins and minerals that metabolize grains and slows the otherwise rapid entry of sugar from their digestion into the bloodstream. Also disrupt intestinal permeability causing leaky gut.¹⁰
• Refined Sugars.  Includes white sugar, corn fructose and high fructose corn syrup.
• Certain Spices. Includes paprika and cayenne pepper which disrupt intestinal permeability causing leaky gut.¹⁰
• Alcohol and Caffeine. Disrupt intestinal permeability causing leaky gut.¹⁰[/box]

[box type=”shadow” ]Here Are Important Anti-Inflammatory Food Types to Promote Health:

• Fruits. Contain ample amounts of vitamins, minerals and phytochemicals which are naturally occuring components in plants that detoxify toxins, carcinogens (reducing the risk by 50%) and mutagens.
• Non-Starchy Vegetables. Support intestinal integrity and provide ample amounts of vitamins, minerals and phytochemicals. Includes green leafy vegetables such as lettuce and kale, also onion, broccoli, garlic, and others.
• High Quality Complex Carbohydrates. Provide vitamins, minerals, and fiber while boosting serotonin levels to help you relax and feel calm. Includes whole grains, legumes, and root vegetables such as carrots, parsnips, sweet potatoes, turnips, red beets, and others.
• Antioxidants. Protect the body from inflammatory oxidant molecules that continually occur and help us handle stress and reduce irritability. Includes vitamin C-containing foods such as lemon, grapefruit, apricot, Brussels sprouts and strawberries, and others. Also, includes vitamin E-containing foods such as nuts, seeds, avocado, olive oil, and others. Cocoa is good, too.
• Omega-3 Fatty Acids. Balance opposing omega-6 fatty acids and bad fats. Fish sources includes tuna, salmon, cod, and others. Plants sources include flax, chia seeds, canola oil, and others.
• Probiotics. Supply normal microbes needed for colon health and health of the body such as these fermented foods: yogurt, kefir, and unpasteurized apple cider vinegar.
• Prebiotics/ High Fiber Foods.  Food with fiber keeps our population of colonic microbes healthy.
• Protective Herbs and Spices.  See below #6 below for examples.[/box]

• [dropcap]3[/dropcap] Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• [dropcap]4[/dropcap] Manage Your Medications Safely:

[box type=”shadow” ]

Certain medications deplete vitamin A, vitamin E, and selenium that predispose to refractory sprue. Ask your doctor or pharmacist about this possible adverse effect if you are taking any of the drugs listed below. Do not stop prescribed medications without supervision.

This is not a complete listing.

ANTACIDS / ULCER MEDICATIONS

• Pepcid®, Tagamet®, Zantac® deplete  Vitamin A.
• Magnesium and Aluminum Antacid preparations (Gaviscon®, Maalox®, Mylanta®)  Vitamin A.

ANTI-INFLAMMATORIES disrupt intestinal permeability which complicates celiac disease.

• Corticosteroids (Prednisone, Medrol®, Aristocort®, Decadron) deplete Selenium.

ANTICONVULSANTS

• Phenobarbital and Barbituates; and Dilantin®, Tegretol®, Mysoline®, Depakane/Depacon® deplete Selenium.

CHOLESTEROL DRUGS

• Colestid® and Questran® deplete Vitamin A, Vitamin E.

FEMALE HORMONES disrupt intestinal permeability which complicate celiac disease.

• Oral Contraceptives (Norinyl®, Ortho-Novum®, Triphasil®, and others) deplete Selenium.
• Oral Estrogen/Hormone Replacement (Evista®, Prempro®, Premarin®, Estratab® and others) deplete. [/box]

• [dropcap]5[/dropcap]Nutritional Supplements To Help Correct Deficiencies:

[box type=”shadow” ]

The type and quantity of nutritional supplements that may be needed depend on which nutrients are deficient.

• Multivitamin/mineral combination once a day is useful to improve overall nutrient levels. This is a safe dose, but always check with your doctor to avoid interactions with medications.
• Vitamin E as prescribed.
• Vitamin A as prescribed following blood test for status.
• Selenium as prescribed following blood test for status.

Storage Note: Store container tightly sealed, away from heat, moisture and direct light to avoid loss of potency. That is, in a safe kitchen cabinet – not in the bathroom or on the kitchen table.[/box]

• [dropcap]6[/dropcap]Manage Natural Remedies: 

[box type=”shadow” ]Hydration:

• Eight glasses of water are recommended per day unless there is a contraindication such as kidney or heart disease. The Institute of Medicine recommends approximately 2.7 liters (91 ounces) of total water, from all beverages and foods, each day for women and 3.7 liters (125 ounces) daily of total water for men.
• If you are thirsty, drink water. Add fresh, squeezed lemon to water. Lemon is anti-inflammatory, alkalizing and provides vitamin C.
• Hydration Test: Urine should be pale yellow. Fingertips should be plump, without pruning but this may not be reliable when fingers are swollen with edema. Lips should be plump, without puckering. The feeling of thirst can be unreliable.
• What is wrong with soda, coffee, tea, and alcohol? These drinks are dehydrating, increase acid, and deplete nutrients.[/box]

[box type=”shadow” ]Carminatives. The following  anti-inflammatory plant sources called carminitives help heal the digestive tract. They also tone the digestive muscles which improves peristalsis, thus aiding in the expulsion of gas from the stomach and intestine to relieve digestive colic and gastric discomfort.

Carminative Food Remedies:

• Raspberry.
• Carrot is also a cleansing digestive tonic.
• Grape is also bile stimulating and a cleansing remedy for sluggish digestion and laxative.
• Redbeets also stimulate and improve digestion and are easily digested.
• Cabbage also stimulates and improves digestion and is also a liver decongestant.
• Lettuce also stimulates and improves digestion and is also an alterative, meaning it improves the function of organs involved with the digestion and excretion of waste products to bring about a gradual change.
• Potatoes are antispasmodic (due to atropine like properties) and a liver remedy.

Carminative Herb Remedies:

• Sage is also a digestive, astringent, bile stimulant and energy tonic that heals the mucosa.  Drink as tea or use in cooking.
• Chamomile, lemon balm, and fennel, (as a tea) also help relieve nervous tension.
• Parsley also relieves indigestion.
• Rosemary as a tea and in cooking also is a nervous system tonic for stress and fatigue, bile stimulant, and can relieve headaches and indigestion.
• Thyme is also soothing remedy useful for stimulating digestion of rich, fatty foods.

Carminative Spice Remedies:

• Cloves are also antispasmodic.
• Nutmeg is also useful for indigestion.
• Ginger.[/box]

[box type=”shadow” ]Exercise Helps:

Exercise improves circulation and rids the body of toxins.

• Walking is aerobic exercise that reconditions the whole body to improve stamina. Read more about Exercise and Fitness.
• Weight training builds muscle. Read more about Exercise and Fitness.
• Stretching improves flexibilty. Read more about Exercise and Fitness.

Note: Exercise is important, but the amount and type of exercise undertaken depends on your health. Your first priority is to heal. [/box]

What Do Medical Research Studies Tell About Refractory Celiac Disease?

RESEARCH STUDY SUMMARIES

“Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed celiac disease.” This nationwide Finnish study compared the clinical characteristics at diagnosis of celiac disease between the patients with refractory celiac disease (44 patients) and patients with uncomplicated disease (12 243 patients) and adult inhabitants (1.7 million). Results show that refractory celiac disease is very rare in the general population and that patients of male gender, older age, severe symptoms or seronegativity at the diagnosis of celiac disease are at risk of future refractory celiac disease and should be followed up carefully.

The prevalence of refractory celiac disease (RCD) was 0.31% among diagnosed celiac disease patients and 0.002% in the general population. Of the enrolled 44 RCD patients, 68% had type I and 23% type II; in 9% the type was undetermined. Comparing 886 patients with uncomplicated coeliac disease with these 44 patients that developed RCD later in life, the latter were significantly older (median 56 vs 44 years), more often males (41% vs. 24%) and seronegative (30% vs. 5) at the diagnosis of celiac disease. Patients with evolving RCD had more severe symptoms at the diagnosis of celiac disease, including weight loss in 36% (vs. 16%) and diarrhoea in 54% (vs. 38%).⁸

“The incidence and clinical spectrum of refractory celiac disease in a north american referral center.” This study investigating medical records of 844 patients diagnosed with celiac disease at a celiac disease referral center in North America found that 4% (34 patients) had refractory celiac disease (RCD) compared to the general celiac disease population. Unintentional weight loss at diagnosis of RCD was found in 76.5% (26 patients) compared with 16.7% (141 patients) at diagnosis of celiac disease and diarrhea at diagnosis of RCD was found in 79.4% (27 patients) compared with 40.5% (342) at diagnosis of celiac disease. Five patients (14.7%) were diagnosed with RCD type II and of these, two died of enteropathy-associated lymphoma within 24 months of diagnosis of CD (observed mortality rate 5.9%).⁷

CASE REPORT SUMMARIES

“Refractory celiac disease, small-bowel lymphoma and chorea.” This case report describes the development of chorea associated with non-Hodgkin’s T-cell lymphoma in a 58 year old woman who was compliant with a gluten free diet since having been diagnosed with celiac disease eleven years earlier upon being investigated for symptomatic anemia and found to be iron and folate deficient. She had no abdominal symptoms. Distal duodenal biopsies showed subtotal villous atrophy, inflammatory infiltration of the lamina propria and an increase in intraepithelial lymphocytes. Celiac disease was diagnosed and she was started on a gluten-free diet. She gained weight and ceased to be anemic; however, repeat biopsies of her duodenal mucosa showed no improvement in the villous atrophy.

Eleven years later she complained of diarrhea, ankle edema and 7 kg weight loss. Endoscopic duodenal biopsies again showed features consistent with untreated celiac disease, and again a dietitian confirmed adherence to a strict gluten-free diet. A barium follow-through showed a rather featureless jejunal mucosa but no obstructive lesion of the small bowel; nothing abnormal was seen on an ultrasound scan of the abdomen. In view of her worsening symptoms despite a gluten-free diet, she was started on prednisolone, initially 30 mg daily, and over the next year her clinical condition improved, with resolution of her diarrhea and a weight gain of 5 kg.

At the time of discontinuation of prednisolone a year later she developed involuntary writhing movements of her left limbs. On examination she had choreo-athetoid movements involving the left limbs and persistent dysarthria. At that time she was taking digoxin, aspirin, ferrous sulphate and thyroxin; she had never received any neuroleptic medication. No underlying neurological disease to explain her chorea was found.
Her chorea continued and seven months later she developed acute abdominal pain. At emergency laparotomy she was found to have a perforated jejunal tumour, which was resected. It proved to be a non-Hodgkin’s T-cell lymphoma. She had intravenous chemotherapy but deteriorated three months postoperatively and died.

“Although her chorea may have been a neurological association of her refractory celiac disease, an alternative explanation is that it was a paraneoplastic complication of her impending T-cell lymphoma. Chorea has been described as a paraneoplastic phenomenon in patients with non-Hodgkin’s lymphoma, but to our knowledge this is the first case where it has been associated with lymphoma arising from a background of celiac disease. The finding of chorea in association with celiac disease should prompt a search for possible underlying intestinal T-cell lymphoma.”¹¹

Sources:

1. Murray JA, The widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999;69 (3):354-365. [↩]
2. Culliford AN, Green PH. Refractory sprue. Current Gastroenterology Reports. Oct 2003;5(5):373-8. [↩]
3. Culliford AN, Green PH. Refractory sprue. Current Gastroenterology Reports. Oct 2003;5(5):373-8. [↩] [↩]
4. Ilus T, Kaukinen K, Virta LJ, Huhtala H, Mäki M, Kurppa K, Heikkinen M, Heikura M, Hirsi E, Jantunen K, Moilanen V, Nielsen C, Puhto M, Pölkki H, Vihriälä I, Collin P. Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease. Aliment Pharmacol Ther. 2014 Feb;39(4):418-25. doi: 10.1111/apt.12606. [↩]
5. Kitiyakara T, Jackson M, Gorard DA. Refractory coeliac disease, small-bowel lymphoma and chorea. J R Soc Med. 2002 Mar;95(3):133-4. [↩]
6. Catassi C, Bearzi I, Holmes GK. Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology. Apr 2005;128(4 Suppl 1):S79-86. [↩]
7. Roshan B, Leffler DA, Jamma S, Dennis M, Sheth S, Falchuk K, Najarian R, Goldsmith J, Tariq S, Schuppan D, Kelly CP. The incidence and clinical spectrum of refractory celiac disease in a north american referral center. Am J Gastroenterol. 2011 May;106(5):923-8. doi: 10.1038/ajg.2011.104. [↩] [↩]
8. Ilus T, Kaukinen K, Virta LJ, Huhtala H, Mäki M, Kurppa K, Heikkinen M, Heikura M, Hirsi E, Jantunen K, Moilanen V, Nielsen C, Puhto M, Pölkki H, Vihriälä I,Collin P. Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease. Aliment Pharmacol Ther. 2014 Feb;39(4):418-25. doi: 10.1111/apt.12606. [↩] [↩]
9. Cummins AG, Thompson FM, Butler RN, et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clinical Science. Apr 2001;100(4):379-86. [↩]
10. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Journal of Gastroenterology and Hepatology. 2003;18:479-91. [↩] [↩] [↩] [↩] [↩] [↩]
11. Kitiyakara T, Jackson M, Gorard DA. Refractory coeliac disease, small-bowel lymphoma and chorea. J R Soc Med. 2002 Mar;95(3):133-4. [↩]