NEWS & VIEWS COELIAC DISEASE
Noncoeliac gluten sensitivity —food for thought Imran Aziz and Marios Hadjivassiliou
Patients with noncoeliac gluten sensitivity (NCGS) can experience a range of gastrointestinal and extraintestinal symptoms. A study has now demonstrated that gluten is independently associated with depression in patients with NCGS. NCGS-associated depression might share similar pathophysiological mechanisms to other neurological manifestations observed in gluten-related disorders, such as ataxia and encephalopathy. Aziz, I. & Hadjivassiliou, M. Nat. Rev. Gastroenterol. Hepatol. 11, 398–399 (2014); published online 17 June 2014; doi:10.1038/nrgastro.2014.91
In the past 5 years, there has been an exponential rise in the use of a gluten-free diet (GFD), which has exceeded levels predicted by the prevalence of coeliac disease. This increase is a result of individuals who selfreport intestinal and extraintestinal symptoms after gluten ingestion, but who exhibit no diagnostic markers of coeliac disease, perhaps with the exception of elevated serum levels of antigliadin antibodies.1 The intestinal complaints are similar to those of IBS, and the extraintestinal manifestations can include cognitive difficulties, fatigue, skin rash, headaches, musculoskeletal pains, sensory symptoms, poor balance and depression.1
‘‘
…gluten is independently associated with depression in patients with NCGS
’’
A consensus document has led to this clinical entity being described as non coeliac gluten sensitivity (NCGS), which is now regarded as the new frontier of glutenrelated disorders.2 Peters et al. assessed the mental state of 22 patients with NCGS in a small double-blind cross-over study. 3 The duration of gluten challenge was short (3 days) and the patients’ mental state at the end of the challenge was assessed using a validated tool (Spielberger State Trait Personality Inventory). Such short-term exposure to gluten was associated with higher depression scores than in the placebo group.3 The investigators concluded that the
findings might explain why patients with NCGS reportedly feel better on a GFD, 3 a suggestion supported by the absence of somatization in NCGS when gluten is eliminated.4 Future studies need to validate such findings in larger patient numbers, using a longer duration of gluten challenge. Furthermore, the pathophysiological mechanisms as to how gluten induces depression are yet to be established. Depression in NCGS may share similar pathophysiological mechanisms to those of already established neuropsychiatric disorders associated with gluten-related disorders. Even in the absence of enteropathy, gluten has been shown to cause neurological dysfunction manifesting as cerebellar ataxia, neuropathy and encephalopathy.5 Gluten ataxia is the most common neurological disorder studied so far. In a case series of 500 patients with progressive ataxia evaluated in the Sheffield Ataxia Centre, UK, 101 of 215 (47%) patients with idiopathic sporadic ataxia had evidence of gluten sensitivity as shown by positive test results for antigliadin antibodies, compared with 12% in a healthy population.5 More than 90% of patients with gluten ataxia do not have gastrointestinal symptoms and two-thirds demonstrate normal histology on duodenal biopsy samples.5 Furthermore, 39% will be negative for deamidated-gliadin peptide and tissue transglutaminase‑2 antibodies,5 but up to 73% have circulating antibodies to tissue transglutaminase‑6 (a trans glutaminase isozyme primarily expressed in the brain).6 60% of patients with gluten
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
ataxia have evidence of cerebellar atrophy on MRI, with MR spectroscopy of the cerebellum suggesting abnormal cerebel lar neuronal physiology independent of atrophy.5 Post-mortem examination from patients with gluten ataxia shows patchy loss of Purkinje cells throughout the cerebellar cortex. Immune-mediated pathogenesis has been favoured in view of the diffuse infiltration of mainly T lymphocytes seen within the cerebellar white matter, as well as marked perivascular cuffing with inflammatory cells.5 Furthermore, widespread IgA deposits against tissue transglutaminase-2 have been found around the blood vessels of the brain in patients with gluten ataxia.5 The deposition is most pronounced in the cerebellum, pons and medulla. There is some evidence suggesting that there might be transglutaminase and gliadin antibody cross-reactivity with antigenic epitopes on Purkinje cells (antigliadin and trans glutaminase antibodies have been shown to react with Purkinje cells in human and rat cerebellar tissue).5 The clinical response to a GFD depends on the duration of ataxia as long-term exposure to gluten results in irreversible loss of Purkinje cells with atrophy of the cerebellum. The response is independent of the presence or not of enteropathy. As a result, early diagnosis and prompt treatment with a GFD are essential for optimal neurological recovery.5 Similar observations have been made in gluten-induced peripheral neuropathy and encephalopathy.5 In a UK-based study, 34% of patients with idiopathic sporadic neuro pathy had circulating antigliadin antibodies, of which 74% did not have any evidence of enteropathy.5 In patients who undertook a GFD, circulating antigliadin antibodies were eliminated and neurop athy substantially improved compared with those who maintained gluten consumption. The improvement was again irrespective of the presence of enteropathy.5
‘‘
In the last 5 years there has been an exponential rise in the use of a gluten-free diet…
’’
Gluten-induced encephalopathy refers to a combination of intractable headaches, VOLUME 11 | JULY 2014
NEWS & VIEWS detection of abnormal brain matter on MRI and improvement or elimination of the headaches on a GFD. Possible cognitive deficits associated with such MRI findings remain to be explored. In this group of patients, 43% do not have enteropathy, yet a GFD arrests progression of white matter brain abnormalities visible with MRI.5 A connection between NCGS and schizo phrenia has also been proposed following reports showing a reduction in psychotic symptoms in a subset of patients on a GFD.7 Since then, two independent groups have shown an increased prevalence of anti gliadin antibodies in patients with schizophrenia.8,9 Cascella et al. identified 323 of 1,401 (23.1%) patients with schizophrenia to have elevated antigliadin antibodies, compared with 28 of 900 (3.1%) healthy control individuals. Tissue transglutaminase‑2 antibodies were present in 5.4% of patients with schizophrenia, as opposed to 0.8% of healthy control individuals, although these findings were not paralleled by an increased prevalence of endomysial antibodies.8 Dickerson et al. also noted an increased prevalence of antigliadin antibodies in patients with schizop hrenia compared with healthy control individuals, but found no increase in levels of deamidated-gliadin peptide
JULY 2014 | VOLUME 11
or tissue transglutaminase‑2 antibodies, thereby arguing against any association with coeliac disease.9 Further analysis has now revealed an increased prevalence of tissue transglutaminase‑6 antibodies in patients with schizophrenia and raised antigliadin antibodies, even in the absence of tissue transglutaminase‑2.10 Whether this particular group will benefit from a GFD remains to be elucidated. In summary, data suggest that NCGS might be associated with depression and schizophrenia along the same lines as neurological manifestations such as ataxia, encephalopathy and neuropathy. Further insight into the pathophysiology of extraintestinal manifestations of NCGS might be gained by measuring antigliadin and tissue transglutaminase‑6 antibodies, as previously demonstrated in gluten-related neurological dysfunction. Department of Gastroenterology (I.A.), Department of Neurosciences (M.H.), Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK, Correspondence to: [email protected]; [email protected] Competing interests The authors declare no competing interests
1.
Volta, U. & De Giorgio, R. New understanding of gluten sensitivity. Nat. Rev. Gastroenterol. Hepatol. 9, 295–299 (2012). 2. Catassi, C. et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 5, 3839–3853 (2013). 3. Peters, S. L., Biesiekierski, J. R., Yelland, G. W., Muir, J. G. & Gibson, P. R. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity—an exploratory clinical study. Aliment. Pharmacol. Ther. 39, 1104–1112 (2014). 4. Brottveit, M., Vandvik, P. O., Wojniusz, S., Løvik, A., Lundin, K. E. & Boye, B. Absence of somatization in non-coeliac gluten sensitivity. Scand. J Gastroenterol. 47, 770–777 (2012). 5. Hadjivassiliou, M. et al. Gluten sensitivity: from gut to brain. Lancet Neurol. 9, 318–330 (2010). 6. Hadjivassiliou, M. et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 80, 1740–1745 (2013). 7. Kalaydjian, A. E., Eaton, W., Cascella, N. & Fasano, A. The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr. Scand. 113, 82–90 (2006). 8. Cascella, N. G. et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr. Bull. 37, 94–100 (2011). 9. Dickerson, F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol. Psychiatry 68, 100–104 (2010). 10. Cascella, N. G. et al. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr. Bull. 39, 867–871 (2013).
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
Noncoeliac gluten sensitivity —food for thought Imran Aziz and Marios Hadjivassiliou
Patients with noncoeliac gluten sensitivity (NCGS) can experience a range of gastrointestinal and extraintestinal symptoms. A study has now demonstrated that gluten is independently associated with depression in patients with NCGS. NCGS-associated depression might share similar pathophysiological mechanisms to other neurological manifestations observed in gluten-related disorders, such as ataxia and encephalopathy. Aziz, I. & Hadjivassiliou, M. Nat. Rev. Gastroenterol. Hepatol. 11, 398–399 (2014); published online 17 June 2014; doi:10.1038/nrgastro.2014.91
In the past 5 years, there has been an exponential rise in the use of a gluten-free diet (GFD), which has exceeded levels predicted by the prevalence of coeliac disease. This increase is a result of individuals who selfreport intestinal and extraintestinal symptoms after gluten ingestion, but who exhibit no diagnostic markers of coeliac disease, perhaps with the exception of elevated serum levels of antigliadin antibodies.1 The intestinal complaints are similar to those of IBS, and the extraintestinal manifestations can include cognitive difficulties, fatigue, skin rash, headaches, musculoskeletal pains, sensory symptoms, poor balance and depression.1
‘‘
…gluten is independently associated with depression in patients with NCGS
’’
A consensus document has led to this clinical entity being described as non coeliac gluten sensitivity (NCGS), which is now regarded as the new frontier of glutenrelated disorders.2 Peters et al. assessed the mental state of 22 patients with NCGS in a small double-blind cross-over study. 3 The duration of gluten challenge was short (3 days) and the patients’ mental state at the end of the challenge was assessed using a validated tool (Spielberger State Trait Personality Inventory). Such short-term exposure to gluten was associated with higher depression scores than in the placebo group.3 The investigators concluded that the
findings might explain why patients with NCGS reportedly feel better on a GFD, 3 a suggestion supported by the absence of somatization in NCGS when gluten is eliminated.4 Future studies need to validate such findings in larger patient numbers, using a longer duration of gluten challenge. Furthermore, the pathophysiological mechanisms as to how gluten induces depression are yet to be established. Depression in NCGS may share similar pathophysiological mechanisms to those of already established neuropsychiatric disorders associated with gluten-related disorders. Even in the absence of enteropathy, gluten has been shown to cause neurological dysfunction manifesting as cerebellar ataxia, neuropathy and encephalopathy.5 Gluten ataxia is the most common neurological disorder studied so far. In a case series of 500 patients with progressive ataxia evaluated in the Sheffield Ataxia Centre, UK, 101 of 215 (47%) patients with idiopathic sporadic ataxia had evidence of gluten sensitivity as shown by positive test results for antigliadin antibodies, compared with 12% in a healthy population.5 More than 90% of patients with gluten ataxia do not have gastrointestinal symptoms and two-thirds demonstrate normal histology on duodenal biopsy samples.5 Furthermore, 39% will be negative for deamidated-gliadin peptide and tissue transglutaminase‑2 antibodies,5 but up to 73% have circulating antibodies to tissue transglutaminase‑6 (a trans glutaminase isozyme primarily expressed in the brain).6 60% of patients with gluten
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
ataxia have evidence of cerebellar atrophy on MRI, with MR spectroscopy of the cerebellum suggesting abnormal cerebel lar neuronal physiology independent of atrophy.5 Post-mortem examination from patients with gluten ataxia shows patchy loss of Purkinje cells throughout the cerebellar cortex. Immune-mediated pathogenesis has been favoured in view of the diffuse infiltration of mainly T lymphocytes seen within the cerebellar white matter, as well as marked perivascular cuffing with inflammatory cells.5 Furthermore, widespread IgA deposits against tissue transglutaminase-2 have been found around the blood vessels of the brain in patients with gluten ataxia.5 The deposition is most pronounced in the cerebellum, pons and medulla. There is some evidence suggesting that there might be transglutaminase and gliadin antibody cross-reactivity with antigenic epitopes on Purkinje cells (antigliadin and trans glutaminase antibodies have been shown to react with Purkinje cells in human and rat cerebellar tissue).5 The clinical response to a GFD depends on the duration of ataxia as long-term exposure to gluten results in irreversible loss of Purkinje cells with atrophy of the cerebellum. The response is independent of the presence or not of enteropathy. As a result, early diagnosis and prompt treatment with a GFD are essential for optimal neurological recovery.5 Similar observations have been made in gluten-induced peripheral neuropathy and encephalopathy.5 In a UK-based study, 34% of patients with idiopathic sporadic neuro pathy had circulating antigliadin antibodies, of which 74% did not have any evidence of enteropathy.5 In patients who undertook a GFD, circulating antigliadin antibodies were eliminated and neurop athy substantially improved compared with those who maintained gluten consumption. The improvement was again irrespective of the presence of enteropathy.5
‘‘
In the last 5 years there has been an exponential rise in the use of a gluten-free diet…
’’
Gluten-induced encephalopathy refers to a combination of intractable headaches, VOLUME 11 | JULY 2014
NEWS & VIEWS detection of abnormal brain matter on MRI and improvement or elimination of the headaches on a GFD. Possible cognitive deficits associated with such MRI findings remain to be explored. In this group of patients, 43% do not have enteropathy, yet a GFD arrests progression of white matter brain abnormalities visible with MRI.5 A connection between NCGS and schizo phrenia has also been proposed following reports showing a reduction in psychotic symptoms in a subset of patients on a GFD.7 Since then, two independent groups have shown an increased prevalence of anti gliadin antibodies in patients with schizophrenia.8,9 Cascella et al. identified 323 of 1,401 (23.1%) patients with schizophrenia to have elevated antigliadin antibodies, compared with 28 of 900 (3.1%) healthy control individuals. Tissue transglutaminase‑2 antibodies were present in 5.4% of patients with schizophrenia, as opposed to 0.8% of healthy control individuals, although these findings were not paralleled by an increased prevalence of endomysial antibodies.8 Dickerson et al. also noted an increased prevalence of antigliadin antibodies in patients with schizop hrenia compared with healthy control individuals, but found no increase in levels of deamidated-gliadin peptide
JULY 2014 | VOLUME 11
or tissue transglutaminase‑2 antibodies, thereby arguing against any association with coeliac disease.9 Further analysis has now revealed an increased prevalence of tissue transglutaminase‑6 antibodies in patients with schizophrenia and raised antigliadin antibodies, even in the absence of tissue transglutaminase‑2.10 Whether this particular group will benefit from a GFD remains to be elucidated. In summary, data suggest that NCGS might be associated with depression and schizophrenia along the same lines as neurological manifestations such as ataxia, encephalopathy and neuropathy. Further insight into the pathophysiology of extraintestinal manifestations of NCGS might be gained by measuring antigliadin and tissue transglutaminase‑6 antibodies, as previously demonstrated in gluten-related neurological dysfunction. Department of Gastroenterology (I.A.), Department of Neurosciences (M.H.), Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK, Correspondence to: [email protected]; [email protected] Competing interests The authors declare no competing interests
1.
Volta, U. & De Giorgio, R. New understanding of gluten sensitivity. Nat. Rev. Gastroenterol. Hepatol. 9, 295–299 (2012). 2. Catassi, C. et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients 5, 3839–3853 (2013). 3. Peters, S. L., Biesiekierski, J. R., Yelland, G. W., Muir, J. G. & Gibson, P. R. Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity—an exploratory clinical study. Aliment. Pharmacol. Ther. 39, 1104–1112 (2014). 4. Brottveit, M., Vandvik, P. O., Wojniusz, S., Løvik, A., Lundin, K. E. & Boye, B. Absence of somatization in non-coeliac gluten sensitivity. Scand. J Gastroenterol. 47, 770–777 (2012). 5. Hadjivassiliou, M. et al. Gluten sensitivity: from gut to brain. Lancet Neurol. 9, 318–330 (2010). 6. Hadjivassiliou, M. et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 80, 1740–1745 (2013). 7. Kalaydjian, A. E., Eaton, W., Cascella, N. & Fasano, A. The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr. Scand. 113, 82–90 (2006). 8. Cascella, N. G. et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials of intervention effectiveness study population. Schizophr. Bull. 37, 94–100 (2011). 9. Dickerson, F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol. Psychiatry 68, 100–104 (2010). 10. Cascella, N. G. et al. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr. Bull. 39, 867–871 (2013).
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
