Ongoing symptoms and complications

In people with coeliac disease there is a small increased risk of intestinal malignancy. Undiagnosed coeliac disease is associated with an increased risk of non-Hodgkin’s and Hodgkin’s lymphoma and small bowel cancer, but overall rates are low. It is recommended that serological testing should be offered to any children or adults with lymphoma. 

Enteropathy associated T cell lymphoma (EATL) 

EATL is a very rare type of non-Hodgkin’s lymphoma affecting around 1 in a million people in the general population. It makes up less than 1% of all non-Hodgkin’s lymphomas.

The main symptoms linked with EATL are gut problems including chronic diarrhoea, abdominal pain and unexplained weight loss. People with coeliac disease have a slightly higher risk of developing EATL because this affects the same part of the gut that is affected in coeliac disease. However, even with this slightly increased risk, overall the likelihood of developing this type of cancer is still very rare.

Non-adherence to a strict gluten free diet increases the risk of complications of coeliac disease including intestinal malignancy. Research suggests that the risk of intestinal malignancy decreases after ten years on a gluten free diet to nearly the same risk as in the general population. 

People with Type 2 RCD are at an increased risk of developing malignancy, particularly enteropathy-associated T-cell lymphoma (EATL). 

Other cancers 

There appears to be a lower risk of developing breast cancer and lung cancer in people with coeliac disease. 

Diagnosis of non-responsive coeliac disease requires dietary assessment for ongoing gluten ingestion and a review of the diagnosis of coeliac disease and exclusion of other conditions which may be causing symptoms. 

The NHS Rare Disease Collaborative Network for non-responsive and refractory coeliac disease can provide clinical support with diagnosis and care of patients with non-responsive and refractory coeliac disease. 

There are two types of refractory coeliac disease which can be distinguished by the presence (RCD type 2) or absence (RCD type 1) of an aberrant population of intraepithelial lymphocytes (IELs), 

People with RCD type 2 have an increased risk of malignancy, particularly enteropathy-associated T-cell lymphoma (EATL). 

A publication by the RDCN team provides a clinical overview of management of patients with persisting symptoms. 

We have developed resources to support you and your patients. 

Rare Disease Collaborative Network for non-responsive and refractory coeliac disease 

Specialist teams led by Prof David Sanders in Sheffield and Dr Jeremy Woodward in Cambridge have been approved by the NHS for a Rare Disease Collaborative Network (RDCN) to provide support with the diagnosis and care of those difficult cases of non-responsive or refractory coeliac disease.  

The RDCN will provide facilities for a national registry for patients with refractory coeliac disease, a reference diagnostic pathway and will share experience to improve understanding and management of this condition. 

These two centres will provide clinical support at the level that the referring clinician would wish. This could involve reviewing notes, histological review, telephone consultation (with patient or clinician) or by seeing the patient and assessing small bowel biopsy for monoclonal lymphocyte population, as well as endoscopic intervention (capsule endoscopy or enteroscopy).  

This ensures a comprehensive assessment which can lead to discussions about therapeutic options. Therapeutic intervention can either be provided by the RDCN or the referring site. The most important issue is to ensure that patients have a standardised care and that the RDCN can support colleagues in a collaborative manner. 

The RDCN National Register will provide prospective data on such patients. This may allow consideration for novel treatments such as Interleukin-15 or stem cell transplantation. 

Non-responsive coeliac disease 

Most individuals with coeliac disease report a rapid clinical improvement after starting a gluten free diet and symptoms usually improve within a few weeks. However, there are a number of people with coeliac disease who do not respond to the gluten free diet or who respond initially and then see a recurrence in their symptoms. 

The first step is to review the certainty of the original diagnosis through review of histology and serology. HLA typing may be useful to rule out coeliac disease. Repeat gastroscopy with duodenal biopsies should be carried out once the diagnosis of coeliac disease is confirmed.  

Persisting villous atrophy in coeliac disease usually occurs because of ongoing gluten ingestion (inadvertant or purposeful) and it is important that this is ruled out before considering alternative diagnoses. 

Other reasons for ongoing symptoms should also be considered including: 

• Co existent inflammatory bowel disease.
• Microscopic or inflammatory colitis.
• Small bowel bacterial overgrowth.
• Lactose intolerance.
• Functional bowel disorders. 
• Giardiasis.
• Slow response to treatment. 

Refractory coeliac disease 

Symptoms of refractory coeliac disease (RCD) include persistent severe diarrhoea, abdominal pain and sudden unexplained weight loss. The true prevalence of RCD is unknown, but estimates suggest that around 0.3 to 4.0% of people with coeliac disease may have RCD.  

A diagnosis of RCD is extremely rare before 30 years of age and in most cases, it is diagnosed over the age of 50.  

There are two types of RCD, type 1 and type 2, which differ in presentation, diagnosis and mortality. Detailed analysis of cell populations in the duodenal mucosa using immunohistochemistry and flow cytometric analysis is required on fresh biopsy samples, services which are offered via the specialist centres in Cambridge and Sheffield. 

Diagnosis 

RCD is diagnosed if the original diagnosis of coeliac disease has been confirmed, and exposure to gluten and any co existing conditions have been excluded as the cause of continuing symptoms. People with RCD should be referred to a specialist centre for further investigation. 

There are two types of RCD which can be distinguished by the presence (RCD type 2) or abscence (RCD type 1) of an abberant population of intraepithelial lymphocytes (IELs) that lack the usual expression of CD3 and CD8 on the cell surface but do express intracellular CD3. The phenotype of this IEL subset is present in the healthy population, uncomplicated coeliac disease and RCD type 1, but at lower frequencies to that found in RCD type 2. Therefore, clonality testing alone is not an adequate indicator of RCD type 2, which requires quantification of the aberrant IEL subset within the small intestine. 

Complications 

RCD is associated with a higher risk of complications and mortality, especially with Type 2 RCD. People with Type 2 RCD are at an increased risk of developing malignancy, particularly enteropathy-associated T-cell lymphoma (EATL) and prognosis is poor. Aberrant intraepithelial lymphocytes in Type 2 RCD are considered a premalignant cell population from which EATL can evolve. Nutrition will be impaired because of ongoing malabsorption. 

Treatment 

Due to the rarity of RCD limited clinical trials have been carried out. Treatments are based on case reports, observational reports and expert opinion. 

When a patient is not responding to a gluten free diet it is essential that a dietitian performs a dietary evaluation. Regular dietetic input is important to assess nutritional adequacy and despite not responding to the diet it is essential that someone with RCD continues to follow a strict gluten free diet as part of their management plan. 

Admission to hospital may be needed to monitor adherence to the gluten free diet. Nutritional treatment should include incorporating strategies to address any nutritional deficiencies. 

Drug treatments may include steroids, immunosuppressive drugs, chemotherapy or a combination of these. However, these have had varying results and whichever treatment is chosen ongoing review from the healthcare team is essential. 

• Type 1 – Prednisolone, budesonide or a combination of prednisolone and azathioprine can be given to induce clinical remission and mucosal recovery in most people with Type 1 RCD. In a few individuals with Type 1 RCD an elemental diet has been shown to induce long term immunopathologic, histologic and clinical improvement. However, more research is required before this can be considered a valid treatment option for Type 1 RCD.
• Type 2 – Treatment for Type 2 RCD is more difficult and the consensus on treatment can vary. The majority of people with Type 2 RCD respond clinically to steroids however mucosal recovery is less likely and steroid treatment does not appear to prevent the development of EATL. Due to the possibility of developing overt lymphoma, there is a need for close monitoring and follow up. Large randomised controlled trials which would require collaboration between several specialist centres are needed to provide an evidence base for the treatment of Type 2 RCD.  

Explaining RCD to patients 

It can be difficult to explain RCD to your patients, and they may find the diagnosis upsetting and worrying. More information about RCD aimed at our Members is available which may help to explain it more easily to your patients.

Most women with treated coeliac disease do not seem to have a greater risk of fertility problems than women without coeliac disease. However, undiagnosed coeliac disease may be an underlying cause of unexplained subfertility. 

Testing for coeliac disease should be considered in people with unexplained subfertility and in women with recurrent miscarriage. 

Explaining fertility problems to patients 

We have information on fertility on our main site for you to help you to explain to patients. 

Coeliac disease is a frequent cause of secondary lactose intolerance.  

Untreated coeliac disease results in damage to the lining of the gut. The enzyme lactase is found in the brush border of the small intestine. This is why people with coeliac disease can be deficient in lactase at diagnosis.  

Once established on a gluten free diet, the gut can heal and lactose digestion returns to normal. Lactose intolerance is therefore usually temporary. However, it can take up to a couple of years for lactase production to return to normal depending on how long it takes the gut to heal.  

Lactose intolerance is treated by avoiding or restricting lactose. The amount of lactose people can manage in the diet depends on the degree of lactase deficiency. People with lactose intolerance should be given dietary advice to make sure there is enough calcium in their diet from non-dairy sources. Some people may need to take calcium supplements. Individuals should have their diet assessed and advice should be given on an individual basis by the healthcare team. We have information on lactose intolerance you can use to help your patients. 

The NICE guideline on the recognition, assessment and management of coeliac disease recommends that testing for coeliac disease is considered in anyone with reduced bone mineral density or osteomalacia. 

The risk of osteoporosis is higher for those who are diagnosed with coeliac disease late in life due to chronic malabsorption of calcium prior to diagnosis. Treatment is important to avoid complications of osteoporosis such as fractures. There is evidence that early diagnosis and management of coeliac disease in childhood allows normal bone mass to be achieved.

Who is at risk of osteoporosis? 

There are many risk factors for osteoporosis including endocrine, metabolic and nutritional disorders, as well as some prescription medication. 

Risk factors related to coeliac disease 

• Late or delayed diagnosis of coeliac disease in adult life. 
• Lapses from the gluten free diet.
• Persistent villous atrophy.
• Lactose intolerance.
• Low BMI.

How common is osteoporosis in coeliac disease? 

There are studies reporting evidence of reduced bone mineral density, in up to 75% of patients at diagnosis. Adhering to a gluten free diet is important to promote healing of the gut lining and to optimise absorption of calcium from the diet. Therefore, strict adherence to a gluten free diet can improve bone mineral density (BMD). The prevalence of reduced bone mineral density after one year of following a gluten free diet is similar to that after three years. This suggests that the extent of bone mass gain in the first year of dietary treatment is indicative of overall BMD improvement. 

Causes of loss of bone mass in coeliac disease 

The cause of changes in bone health in coeliac disease is multifactorial – both systemic and local mechanisms may play a role. 

• Chronic malabsorption – intestinal damage seen in untreated coeliac disease can lead to chronic malabsorption of nutrients including calcium. Calcium malabsorption and subnormal levels of serum calcium result in damage to bone health. Intestinal malabsorption can also result in a reduced BMI. Hypocalcaemia (low serum calcium) can lead to secondary hyperparathyroidism. Hyperparathyroidism leads to high levels of parathyroid hormone which results in further loss of calcium from the bones. 
• Reduced calcium intake – some people with coeliac disease reduce their intake of calcium rich dairy foods e.g. milk and milk products due to secondary lactose intolerance. Dietary advice to replace calcium rich foods is essential in this situation. 
• Bone formation – osteoblasts play a role in the formation of bone. Osteoclasts are cells which are responsible for the removal of bone. The balance of osteoblasts and osteoclasts is important for bone repair. Pro-inflammatory cytokines are responsible for osteoclast activation. Cytokines can have an impact on both normal and abnormal bone formation. In coeliac disease increased resorption (where old bone is removed from the skeleton) is not balanced out by increased bone formation. These changes in bone are similar to those seen in Crohn’s disease. 
• Gynaecological disorders – in women with coeliac disease, the role of associated gynaecological disorders should be considered. Amenorrhoea is a more common finding in coeliac disease than the general population and sex hormone imbalance represents an important risk factor for the development of osteoporosis. 

Diagnosing low bone mineral density 

Diagnosis of osteoporosis in people with coeliac disease is determined by a Dual energy X-ray absorptiometry (DEXA) scan which measures bone density. The World Health Organisation (WHO) recommends using measurements from a T-score for determining bone mass. 

The T-score is an index representing the number of standard deviations by which the patient value differs from the average peak bone mass of a young adult reference population. A diagnosis of osteopenia is made when the T-score is between -1 and -2.5. A diagnosis of osteoporosis is made when the T-score is less than -2.5. 

DEXA scan follow up and calcium supplementation 

The need for a DEXA scan and calcium supplementation should be assessed on an individual basis as part of the annual review. NICE guideline for coeliac disease (2015) recommends the need for a dual-energy X-ray absorptiometry (DEXA) scan should be assessed in line with the NICE guideline on osteoporosis: assessing the risk of fragility fracture or active treatment of bone disease.