How should I approach standard endocrine evaluation in patients with coeliac disease?

Authors


Correspondence: Catherine Napier, Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. Tel.: +44 191 233 6161;

E-mail: catherine.napier@nuth.nhs.uk

Summary

Endocrine evaluation is an important consideration in the longitudinal assessment of patients with coeliac disease (CD). In addition to wide-ranging nutritional implications, this common autoimmune disorder has a significant impact on bone health. A strategy to prevent osteomalacia, in conjunction with regular assessment of bone mineral density, is essential to minimize the possibility of increased fracture risk. Clinicians should readily acknowledge that patients with CD have a higher risk of developing a coexisting autoimmune condition. A considered clinical assessment and timely biochemical evaluation, as indicated in the wider context of continued emphasis on a gluten-free diet, will ensure optimal patient management.

Introduction

Coeliac disease (CD) is commonly encountered within both the adult and paediatric populations, with a prevalence of approximately 1%.[1] The condition arises as the result of interplay between host genetic make-up, immunological factors, and exposure to dietary derivatives of gluten.[1]

Endocrine evaluation is an important component of the management of patients with CD. Calcium and Vitamin D malabsorption is a chronic problem, and appropriate management is paramount to minimize the long-term impact on bone health. There is a clear association between CD and other autoimmune conditions (Table 1), including hypothyroidism, type 1 diabetes and Addison's disease.[1] Monitoring and treatment of these associated conditions may be impaired in the context of malabsorption, emphasizing the need for strict adherence to a gluten-free diet (GFD).

Table 1. Prevalence of CD in organ-specific autoimmune conditions
Autoimmune conditionPrevalence of CD (%)
  1. a

    The quoted prevalence of CD in patients with Addison's disease should be interpreted with caution. Published studies contain small patient numbers (41,17 patients).

Autoimmune hypothyroidism2–7[1, 4, 5]
Type 1 diabetes2–7[1, 4, 5]
Addison's diseasea6–12[25, 26]

Background

Coeliac disease is an autoimmune disease characterized by chronic inflammation of the proximal small intestinal mucosa due to an immunologically mediated response to the gluten glycoprotein, prolamin. In susceptible patients, ingestion of a gluten-containing diet will result in the production of highly specific IgA and IgG autoantibodies to tissue transglutaminase (tTG).[2] The enzymatic function of tTG in the intestine results in deamidation of gliadin peptides, with ensuing increased immunogenicity and an inflammatory cascade causing tissue damage.[3] The resulting intestinal villous atrophy can impair digestion and absorption of nutrients.[1] Deficiencies of iron, folate, calcium, B12 and fat-soluble vitamins D, E and K are common, and subsequent anaemia and osteomalacia are frequently encountered.[4]

Insidious onset of symptoms hampers the diagnosis of CD, and a significant latent period of malabsorption is the norm. A protracted time-scale of calcium and vitamin D malabsorption and ensuing secondary hyperparathyroidism (SHPT) often results in significantly reduced bone mineral density (BMD) by the time the diagnosis is confirmed.[5] Screening for metabolic bone disease, including dual-energy X-ray absorptiometry (DEXA), should be performed in all individuals following confirmed diagnosis.[5] Early recognition of osteopenia allows prompt treatment, with an opportunity to minimize further bone loss.[4] Identifying those patients with low BMD (either at diagnosis, or subsequently, with a progressively falling BMD) is essential to allow intervention – patients with CD have a modest but definite increase in fracture risk.[6] Previous studies report varied incidence of this[7-14] depending on multiple factors, including site of fracture, and whether or not patients have overt or subclinical disease. There is clear evidence that adherence to a gluten-free diet is associated with an improvement in BMD, and in adults, this benefit is detectable at 1 year.[4]

Metabolic bone disease, a significant and common complication of CD, will clearly predispose patients to fragility fractures.[15] Although screening with bone densitometry is sensitive for detecting reduced bone mass, it will not demonstrate underlying bone pathology.[15] The mechanisms of disturbance in BMD in CD are not fully understood,[16] and significant osteomalacia can be present even in the context of normal BMD. In a previous case series, 50% of patients with CD who underwent bone biopsy had confirmed osteomalacia, frequently coupled with characteristic biochemistry and secondary or tertiary hyperparathyroidism.[15] Patients with untreated CD who have features of SHPT at diagnosis have more significantly reduced BMD, and this is less likely to return to normal after adherence to a GFD.[16] In addition to the impact of CD on absorption of vitamin D and calcium, dietary intake may be insufficient.[5] Supplementation of both is frequently indicated, and frank osteomalacia will usually improve, even with oral administration.[5]

Unfortunately, even severely reduced BMD may remain occult until symptomatic fracture occurs.[15] In all cases, the identification of bone disease in a patient with CD should alert the clinician to re-evaluate adherence to a GFD.

In addition to the consideration of nutritional factors and bone health, clinicians should be alert to the possibility of a coexisting autoimmune condition in these patients. Individuals with type 1 diabetes have a 4–7% chance of having concomitant CD,[4] and both conditions can share the same HLA-DQ2/8 susceptibility alleles.[1] In fact, approximately 95% of patients with CD carry HLA-DQ2, and the remainder mostly DQ8, suggesting the link between associated autoimmune conditions and CD is on the basis of these shared HLA susceptibility genes.[1]

The prevalence of CD in autoimmune thyroid disease is similar[17, 18] where it is consistently reported to coexist in 2%–7% of these patients.[1] Detecting symptoms that herald the onset of associated endocrinopathies can be challenging, and clinicians should consider utilizing relevant biochemical markers where appropriate, for example changes in the circulating lipid profile which may be observed in patients with subclinical hypothyroidism. As a result of the much lower prevalence of Addison's disease in the general population, patients with concurrent autoimmune Addison's and CD are seen much less frequently, but this combination of conditions is of high clinical significance. Crossover of symptoms between those representing adrenocortical insufficiency, and those indicating malabsorption (e.g. weight loss, abdominal discomfort, fatigue), could compound and delay diagnosis, alongside the possibility of regular steroid administration potentiating an atypical presentation of CD.

The timely recognition and diagnosis of associated autoimmune conditions may play a key role in optimizing outcomes in certain patient groups. The hypothesis that adherence to a GFD will reduce the likelihood of additional autoimmune diseases developing exists, although published data surrounding this is conflicting. The potential impact of duration of exposure to gluten on this is also controversial.[19-21]

Clinical approach

Nutrition

Strict adherence to a GFD is the cornerstone of management in CD[1, 4] and underlies the principle of maintaining bone health and minimizing associated complications. UK guidelines advise annual testing of full blood count, serum calcium, ferritin, folate and B12,[4] and addition of relevant supplementation where required. A GFD may negate the need for this,[5] but a daily multivitamin is a practical consideration. Persistent high titres of tTG antibodies are an important indicator of poor dietary compliance.

Bone health

The beneficial impact of a GFD on bone health should be highlighted as the core management strategy for preventing osteoporosis[22] and ultimately reducing fracture risk. Although improvements in BMD vary between anatomical sites, there is evidence that measurements at the forearm, spine and hip will increase during the first year of compliance to dietary recommendations.[22] The initial assumption should be that BMD will improve following adherence to a GFD, with or without supplementation of vitamin D and calcium, as appropriate.

At diagnosis, vitamin D insufficiency and/or calcium malabsorption will have been present for many years, leading to chronic SHPT; plasma PTH concentrations may take months or years to normalize, even in the context of optimal management. Alkaline phosphatase (ALP) and serum 25-hydroxyvitamin D measurements should be performed annually. Vitamin D should be replaced aggressively where indicated; daily oral colecalciferol is usually sufficient, without the need for parenteral administration. Moderate oral doses (i.e. 2000 IU daily) are usually adequate for maintenance. Once the patient is rendered vitamin D replete, oral calcium should be added in the presence of persisting hypocalcaemia. Bisphosphonates should not be routinely used in younger patients.

All patients should have a formal BMD assessment at presentation. Subsequently, females with normal bone density should be re-assessed after the menopause, and males at age 55.[4] Those with abnormal bone density should be re-assessed every 3[4]–5 years, with the application of appropriate intervention in the interim, as advised in Fig. 1.

Figure 1.

Algorithm for endocrine evaluation in patients with CD.

Preventing fractures in CD should be underlined by measures applicable to the general population – educating patients regarding the importance of lifestyle factors, such as smoking cessation, regular weight-bearing exercise and avoiding alcohol excess, is still necessary.

Autoimmune disease surveillance

The possibility of patients with CD developing an associated autoimmune disease should be readily acknowledged by clinicians. This will ensure timely investigation and appropriate onwards referral where indicated.

Lifelong follow-up (usually on an annual basis) should include monitoring for associated autoimmune conditions, in addition to review of dietary adherence and corresponding serological monitoring.[23] Routine antibody screening of these patients is not worthwhile, but targeted serological testing on the basis of suggestive symptoms should be performed where clinical suspicion arises. This may be difficult to detect where there is insidious onset of an associated autoimmune condition, for example subtle changes in the symptom profile of patients developing concurrent subclinical hypothyroidism. Targeted testing is appropriate in selected scenarios where prompt recognition and treatment can result in significant clinical benefit, for example thyroid serology in a woman of reproductive age who is considering pregnancy. A low threshold for detecting symptoms that may represent an underlying autoimmune disorder is imperative, and educating patients with regards to alarm symptoms, which could herald their emergence, is worthwhile.

Where CD and hypothyroidism coexist, fluctuating serum TSH levels may signify suboptimal dietary compliance. In these patients, increased doses of levothyroxine are often required to render the patient biochemically euthyroid, although this is generally reversible following adherence to a GFD.[24] Conversely, screening for covert CD in patients with hypothyroidism and high levothyroxine dose requirements is a relevant consideration. Patients taking thyroid hormone replacement should be reminded of the need to administer any iron- or calcium-containing preparations at an alternative time of day.

In the instance of coexisting Addison's disease, there are similar considerations for patient management. Potentially altered pharmacokinetics of ingested steroids may pose a significant challenge in achieving an optimal replacement regimen. Again, a GFD is crucial to minimize malabsorption and ameliorate this complication.

Conclusion

A long-term strategy for evaluating and managing endocrine complications in CD is essential. We recommend rigorous assessment of markers of bone health, with active treatment and continued longitudinal assessment of BMD, in the wider context of emphasis on nutritional factors. This should be accompanied by close surveillance for concurrent autoimmune conditions. A raised index of suspicion in patients with CD is appropriate, and timely detection and comprehensive evaluation will ensure optimal management of coexisting conditions.