Refractory celiac disease is a type of celiac disease that is unresponsive to at least 12 months of a strict gluten-free diet.

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Celiac disease is a common gastrointestinal disorder that most people manage with a gluten-free diet. However, people with refractory celiac disease who omit gluten do not see an improvement in their symptoms and continue to have the hallmark signs of damage to the gut.

This article explores refractory celiac disease and its symptoms and causes. Next, it explains how a doctor diagnoses the condition, potential complications, and treatments. Finally, it answers some frequently asked questions.

Celiac disease is a chronic autoimmune condition. When genetically predisposed people react to gluten, the body mounts an immune response, causing damage to cells in the gut and sometimes elsewhere in the body.

According to a 2019 review of existing research, there are several different types of celiac disease that doctors identify based on their clinical presentations:

  • intestinal, or classic
  • extraintestinal, or nonclassic
  • subclinical
  • potential
  • refractory
  • seronegative
  • gluten-free diet nonresponsive

The review explains that refractory celiac disease causes persistent symptoms and damage to the cells lining the gut after at least 12 months of a strict gluten-free diet.

Additionally, it notes two subtypes of refractory celiac disease, type 1 and 2, whose genetics vary slightly. Type 2 predominantly occurs in adults aged 50 or over.

The 2019 review states the symptoms of refractory celiac disease in adults are:

Experts associate these symptoms with persistent villous atrophy — damage to the gut cells — after at least 1 year on a strict gluten-free diet.

Additionally, people may get symptoms of complications, including:

The exact causes of refractory celiac disease remain unclear. However, experts suggest the following elements of the body’s immune system are involved:

Lymphocytes

Lymphocytes are white blood cells and one of the body’s main types of immune cells. T lymphocytes (T cells) are one of the two main categories of lymphocytes.

Intraepithelial lymphocytes are T cells in the intestinal lining. Doctors refer to the protein on the surface of T cells as the T cell receptor (TCR).

In celiac disease, when the TCR recognizes gluten, the protein activates. With a gluten-free diet, these T cells become inactive, and the intestinal damage heals. However, in the case of refractory celiac disease, intestinal T cells activate without gluten, and intestinal damage persists despite removing gluten from the diet.

Cytokines

Cytokines are small proteins that help regulate communication among the cells of the immune system and other tissues.

Research suggests that people with refractory celiac disease have an increased number of proinflammatory cytokines called interleukin-15 (IL-15). These proteins support inflammation.

IL-15 stimulates another small protein known as interferon-gamma, which increases the toxicity of the T cells in the intestinal lining. As damage occurs to more and more cells in the lining of the intestine, symptoms of refractory celiac disease develop.

Antigens

Approximately 2–3% of people with celiac disease test negative for antibodies. Doctors call this seronegative celiac disease. People with seronegative celiac disease have a higher risk of developing refractory celiac disease.

Celiac disease causes

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) notes that celiac disease may occur in people with specific genes and if a family member has the condition.

People with celiac disease usually have variants of the genes DQ2 and DQ8. People who do not have these gene variants are very unlikely to develop celiac disease.

However, according to the NIDDK, even though around 30% of people have DQ2 or DQ8, only about 3% of these develop celiac disease. Researchers are studying the reasons for this and other genes that may be involved.

A 2019 multinational study of 6,605 children suggests that those who are genetically susceptible and eat gluten early in life may have more risk of developing celiac disease. Infections and changes in the microbiome may also trigger the condition. The microbiome is the body’s habitat, including its microorganisms and surrounding environmental conditions.

While experts estimate that about 2 million people in the United States have celiac disease, many do not have a diagnosis from a doctor.

According to the 2019 review, doctors have traditionally referred to persistent symptoms on a strict gluten-free diet as nonresponsive celiac disease cases.

However, the review notes that this terminology is confusing as the patient may have symptoms due to other associated conditions, such as small intestinal bacterial overgrowth or inflammatory bowel disease (IBD). Therefore, the authors suggest doctors differentiate ongoing active celiac disease and other gastrointestinal conditions.

The review states that refractory celiac disease represents about 10% of all ongoing active celiac disease cases.

Assessment and tests

Doctors diagnose the condition by assessing the symptoms and gut damage for at least a year after beginning a strict gluten-free diet. They confirm a diagnosis with a celiac disease antibody test and by checking for villous atrophy — damage to the cells lining the intestine. They may perform a biopsy to establish this.

Additionally, the review explains that doctors may diagnose either primary or secondary refractory celiac disease depending on whether a person’s symptoms have improved since the beginning of a gluten-free diet.

Furthermore, doctors must define whether a person has subtype 1 or 2, as this affects their outlook.

A doctor may perform various diagnostic tests, including:

The 2019 research review indicates that refractory celiac disease can lead to the following complications:

The subtype of refractory celiac disease that someone has affects their long-term outlook.

The review suggests that subtype 2 has a 5-year mortality rate of 55% compared with 7% for subtype 1. The higher mortality rate for type 2 is mainly due to more people with this form developing intestinal lymphoma.

Currently, the only treatment for celiac disease is a lifelong, strictly gluten-free diet.

Doctors treat refractory celiac disease according to the subtype.

Type 1

Treatments include immunosuppressants such as:

Type 2

Medications may include cyclosporine or chemotherapy. Doctors may also treat this subtype with anti-IL-15 antibodies or, in some instances, stem cell transplantation.

It is necessary for a person to speak to their doctor to obtain a diagnosis and treatment if they have symptoms of either type.

The following section answers some commonly asked questions about this condition.

What is the life expectancy for someone with refractory celiac disease?

A 2016 study suggests a mortality rate of 48% during a 25-year period. It also reports a 5-year survival rate of 28.6% for people with lymphoma.

A research review from 2020 suggests the survival rate depends on the subtype. According to this review, people with type 1 often respond to treatment, with a 5-year survival rate of approximately 80–100%. However, treatment options for type 2 are limited, and the 5-year survival rate is around 50%.

Is refractory celiac disease the same as nonresponsive celiac disease?

The 2020 review indicates that nonresponsive celiac disease may occur due to refractory celiac disease. Still, it can also result from other causes, such as not adhering to a gluten-free diet or having another associated condition, such as irritable bowel syndrome (IBS) or IBD.

Refractory celiac disease is a type of celiac disease characterized by ongoing gut damage and symptoms even with a strict gluten-free diet. However, assessing someone’s gluten ingestion is challenging, and nonadherence may appear as refractory celiac disease. A doctor will also need to rule out other associated conditions, such as IBS or IBD, before making a diagnosis.

Doctors diagnose refractory celiac disease using symptoms, imaging tests, and biological samples. Refractory celiac disease may cause complications, and the outlook for a person with the condition depends on the subtype they have.