Increased Neuropathy Risk in Celiac Disease

Pauline Anderson

May 14, 2015

Having celiac disease (CD), an autoimmune disorder characterized by a sensitivity to gluten, more than doubles the risk for neuropathy, a new study shows.

"In patients with neuropathy and no obvious cause, celiac disease should be considered," said Jonas Ludvigsson, MD, PhD, professor of clinical epidemiology, Karolinska Institutet, a pediatrician at Örebro University Hospital, Stockholm, and president, Swedish Pediatric Society.

As well, said Dr Ludvigsson, physicians managing patients with CD should be aware of their increased risk for neuropathy.

Dr Jonas Ludvigsson

The study was published online May 11 in JAMA Neurology.

Lasting Risk

In Sweden, at least 90% of patients suspected of having CD undergo a small-intestine biopsy before diagnosis. Researchers linked nationwide data on biopsy-verified CD from Swedish pathology registers to data on neuropathy from the Swedish National Patient Register. The diagnosis was validated through examination of medical records for a diagnosis of villous atrophy, which is almost exclusively caused by CD.

Researchers also linked data on CD to information from the Prescribed Drug Register in Sweden.

The analysis included 28,232 patients with CD and 139,473 controls matched for age, sex, calendar year, and county. Among patients with CD, the median age of diagnosis was 29 years.

During a median of 10 years, 198 patients with CD were diagnosed with neuropathy (0.7%) compared with 359 controls (0.3%). The absolute risks of neuropathy were 64 per 100,000 person-years for patients with CD and 15 per 100,000 person-years for controls, which corresponded to a hazard ratio (HR) of 2.5 (95% confidence interval [CI], 2.1 - 3.0; P < .001).

Adjusting for educational level, socioeconomic status, country of birth, type 2 diabetes, several autoimmune disorders associated with CD (including type 1 diabetes, thyroid disease, and rheumatoid arthritis), vitamin deficiencies, and alcoholic disorders had only a marginal effect on the risk estimate (HR, 2.3; 95% CI, 1.9 - 2.7).

The risk was highest in the first year after a CD diagnosis, when physicians might have been more prone to investigate for neuropathy, but there was also a significantly increased risk after the first year. For example, the HR for developing neuropathy in patients with CD at more than 5 years of follow-up was 2.2.

There were no differences in increased neuropathy risk between male and female patients with CD. Age at diagnosis also didn't influence risk estimates for neuropathy.

When the outcome was restricted to neuropathy in those with a record of neuropathy-associated medications, the association between CD and neuropathy remained.

The risk varied according to type of neuropathy. Celiac disease was most strongly associated with mono-neuritis multiplex (with an HR of 7.6). The next strongest link was to autonomic neuropathy (HR, 4.2). There was no association between CD and acute inflammatory demyelinating polyneuropathy (HR, 0.8).

The study did not have enough statistical power to examine the association between CD and multifocal motor neuropathy, which has been reported by other researchers.

Bidirectional Association

There also seemed to be a bidirectional association between CD and neuropathy in that the association existed before the CD diagnosis.

"That is probably because some patients have undiagnosed celiac disease and are then at increased risk of neuropathy — and only after the neuropathy diagnosis is the celiac disease detected," commented Dr Ludvigsson. "But it could also mean that celiac disease and polyneuropathy share a common cause or risk factor."

Other possible mechanisms linking celiac disease with neuropathy include chronic inflammation and malnutrition. A deficiency of vitamin B12 has been found to be associated with CD and with neuropathy, suggesting that this deficiency may help explain the connection between the two conditions, said Dr Ludvigsson.

However, the authors noted that the influence of vitamin deficiencies did not significantly affect the risk estimate in the study.

The researchers didn't investigate whether a strict gluten-free diet would prevent neuropathy in patients with CD, but according to Dr Ludvigsson "that would make an interesting study."

Given the autoimmune nature of CD, the data reinforce the potential role of immunologic mechanisms for the development of neuropathy, said the authors.

While other studies have found a similar association between celiac disease and neuropathy, this new analysis used a nationwide sample of patients, so it included "average patients" with CD, commented Dr Ludvigsson. "Some earlier studies primarily studied patients with celiac disease in specialist centers, which makes it is difficult to calculate a correct risk for neuropathy."

The size of the study sample also enabled researchers to calculate a more precise risk estimate than was the case in the past, according to Dr Ludvigsson. The large number of patients also allowed investigators to study subtypes of neuropathy. "That has not been done on a large scale before," he said.

Future related research should include electrophysiologic studies, thorough serum evaluations, prior drug histories, and skin biopsies to evaluate for small-fiber neuropathy, said the authors. The study results suggest that screening could be beneficial in patients with neuropathy, they concluded.

"In patients with neuropathy where there is a plausible cause, such as high alcohol consumption or type 1 diabetes, looking for celiac disease may not be necessary," said Dr Ludvigsson. "But in cases where there is no obvious cause for the neuropathy, I think screening for celiac disease is appropriate."

The estimated prevalence of CD is 1%. Research indicates that about 60% of patients with CD are women.

The association between CD and neuropathy was first reported in 1966. Other autoimmune disorders also increase the risk for neuropathy.

Strong Case

Asked to comment, Shamik Bhattacharyya, MD, Department of Neurology, clinical fellow in neurology, Massachusetts General Hospital, Brigham & Women's Hospital, and Harvard Medical School, Boston, noted the study's strengths, particularly the very large number of participants in both study groups, and the duration of follow-up.

The study also makes a strong case for the increased risk for neuropathy in patients with CD relative to the general population, said Dr Bhattacharyya. However, he pointed out that the absolute risk remains small at 64 people per 100,000 patients followed for 1 year.

"For the larger population of patients with neuropathy without symptoms of celiac disease such as diarrhea, the role of testing for disease, if any, remains unclear."

Any person with neuropathy is also at relatively increased risk for CD — again a small absolute risk — but who those patients are remains unknown, added Dr Bhattacharyya.

But what he found "particularly provocative" about the study was that the risk for neuropathy remained increased for years after the diagnosis of celiac disease.

"The patients in this study probably were treated for celiac disease with a gluten-free diet. Since their risk remained elevated even with this diet, we really don't know whether this treatment even has any effect on the risk of neuropathy. This is particularly relevant for patients with neuropathy without diarrhea who test positive for antibodies associated with celiac disease."

Dr Ludvigsson and Dr Bhattacharyya have disclosed no relevant financial relationships.

JAMA Neurol. Published online May 11, 2015. Abstract


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