Risk of Morbidity in Contemporary Celiac Disease

Nina R Lewis; Geoffrey KT Holmes


Expert Rev Gastroenterol Hepatol. 2010;4(6):767-780. 

In This Article

Neurological & Psychiatric Disorders

The true prevalence of neurological and psychiatric complications of celiac disease is difficult to estimate because of variable definitions of these disorders that have been used and the fact that results have often been based on small groups of patients from tertiary referral centers, which skews the figures.[99] Furthermore, which disorders, if any, are specific for celiac disease is still unknown. In a large population-based study from Sweden using the In-Patient Registry examining the risk of neurological disease in 14,000 celiacs and 70,000 age- and sex-matched controls, celiacs were only at increased risk of polyneuropathy (HR: 3.4 [95% CI: 2.3–5.1].[100] However, even here, ascertainment bias probably influenced the results because the cohort and associated disease was assembled on the basis of admitted patients. It has been estimated that approximately 10% of celiac patients develop neurological complications, but this is almost certainly an underestimate.[101] Retrospective data from the celiac clinic in Derby, UK, which is not a referral center, found 160 neurological and 103 psychiatric problems in 620 patients (some had more than one disorder).[102] The most common three conditions encountered were depression, epilepsy and migraine.[102]


It might be expected that those with a chronic condition, especially if the diagnosis is delayed and the treatment is a restrictive diet that limits social interaction, would result in depression. There is no doubt that depression in celiac disease can be severe to the point where patients may attempt and succeed in suicide.[6] However, whether depression is more common among celiac patients is disputed, with some finding a positive association and some not. Most investigations have included only small numbers of patients, although a large population-based cohort study from Sweden using the In-Patient Registry observed an increased risk of developing depression after the diagnosis of celiac disease was established, with a HR of 1.8 (95% CI: 1.6–2.2).[103] Those with a history of prior depression were at increased risk of a subsequent diagnosis of celiac disease (OR: 2.3 [95% CI: 2.0– 2.8]). An American study of 600 patients with celiac disease, 200 with irritable bowel syndrome and 200 healthy controls found the prevalence of depression similar in all three groups at 17.2, 18.5 and 16%, respectively.[104] A significant increase in depression among celiac patients with coexistent Type 1 diabetes was found at 37%, compared with 16% with celiac disease alone.[104] It seems that having two chronic diseases is enough to tip the balance in favor of depression. However, even these larger studies were not without methodological problems. For example, in the American study, psychiatric records could not be accessed, and in the Swedish one, celiac patients with mood disorders were identified through a hospital-based register, raising the possibility that these were more severely affected than average patients.

A gluten-free diet improves depression and anxiety in some but not all cases.[105,106] As well as a gluten-free diet, vitamin B supplementation is recommended to improve mood.[107] Impaired availability of tryptophan may be important in depressive and behavioral disorders in celiac disease.[105]


Whether patients with celiac disease have an increased risk of developing epilepsy is still not clear, because some studies have reported an association,[108] while others have not.[109] In any event, the association, even if it exists, is probably very weak. A curious combination of celiac disease, bilateral occipital calcifications and epilepsy has been described mainly from centers in Italy.[110] A link between gluten sensitivity and temporal lobe epilepsy with hippocampal sclerosis has been shown.[111]


Migraine may occur in celiac disease and improve or be cured by a gluten-free diet.[112,113]

Other Neurological Conditions

Many other conditions are encountered in celiac disease but only rarely, even in large celiac clinics.[102] These include spinocerebellar and cerebellar disorders and peripheral neuropathy, myelopathy, brainstem encephalitis and chronic progressive leukoencephalopathy. Whether there is a link between schizophrenia and celiac disease has been debated over the last 50 years. Two recent surveys have found an increased risk,[114] and no risk,[115] so this issue still remains controversial. Dementia and cognitive impairment occur in celiac disease, but only 13 patients with the onset of cognitive decline within 2 years of the symptomatic onset or a severe exacerbation of celiac disease could be identified over a 35-year period in a study from the Mayo clinic (MA, USA).[116] Although in some patients cognitive decline and gastrointestinal symptoms were observed to occur simultaneously and a gluten-free diet halted or improved cognitive impairment, the strength of this association is not clear and merits further study. There is no firm link between celiac disease and autism or multiple sclerosis.

At present, it has to be concluded that a neurological or psychiatric disorder specifically associated with celiac disease has not been identified. Most are likely to be chance associations, apart from perhaps certain forms of epilepsy and neuropathy.

Malabsorption does not satisfactorily explain how these disorders arise and progress, because vitamin supplementation is rarely helpful and hypovitaminosis is not always found. Moreover, no neurological abnormality may be detected even in the presence of severe vitamin deficiency. While heredity, infection, toxins, altered autoimmunity, vasculitis and a direct neurotoxic effect of gluten have been implicated in causing these conditions, it has to be conceded that there is still much to be explained.

The effects of a gluten-free diet in these patients ranges from reversal of dysfunction, as is seen in cases with epilepsy and cerebral calcifications, to stabilization of the illness, as may occur in cognitive decline,[116] to making little or no difference. Vitamin deficiencies should be corrected, and this may benefit some patients with cerebellar ataxia (vitamin E) and depression (pyridoxine). Steroids and immunosuppressants in general are of no value.

Gluten Ataxia & Neuropathy

In 1996, investigators from Sheffield, UK, reported gluten sensitivity based on the presence of serum antigliadin antibodies in patients with neurological disorders of unknown cause; the majority of patients had ataxia or peripheral neuropathy.[117] The terms gluten ataxia and gluten neuropathy were coined to describe these disorders. Duodenal biopsy showed celiac disease to be present in only a third of the patients.[118,119] The concept is still controversial because gluten sensitivity has also been found in hereditary ataxias, and response to a gluten-free diet in many patients is lacking.[120] Nevertheless, supporting evidence for idiopathic gluten ataxia continues to accumulate, such as the association with HLA-DQ2 and DQ8, the presence of circulating Purkinje cell antibodies and the presence of anti-tissue transglutaminase antibody in the gut and brain.[119] In addition, 60% of patients have evidence of cerebellar atrophy on MRI scanning and proton MR spectroscopy may also be abnormal, indicating abnormal cerebellar function.[119] Of importance is the observation that improvement of these conditions may occur on a gluten-free diet.[119]

The reason why some patients develop these neurological problems could revolve around a newly identified tissue transglutaminase, transglutaminase 6. Antibodies to transglutaminase 6 have been detected in a group of patients with idiopathic sporadic ataxia.[121] This work further extends the concept of gluten sensitivity beyond the bowel (celiac disease) and the skin (dermatitis herpetiformis) to involve the nervous system. Much of this work has been carried out in one center (Sheffield, UK) and needs to be confirmed by others.


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