Extra-intestinal manifestations of non-celiac gluten sensitivity: An expanding paradigm

Table 1 Studies reporting the prevalence of people avoiding gluten-containing foods

Ref.	Country	Population	Sample size	Avoidance rate of gluten-based products
Tanpowpong et al[60], 2012	New Zealand	Pediatric	916	5.2%
Rubio-Tapia et al[61], 2013	United States	Pediatric	7798	0.7%
DiGiacomo et al[62], 2013	United States	National Health and Nutrition Examination Survey	7762	0.6%
Lis et al[63], 2014	Australia	Adults	910	41.2%
Golley et al[64], 2015	Australia	Adults	1184	10.6%
Mardini et al[65], 2015	United States	Pediatric	14701	1%
Aziz et al[59], 2014	United Kingdom	Adults	1002	3.7%
Van Gils et al[8], 2016	The Netherlands	Adults	785	6.2%
Carroccio et al[7], 2017	Italy	Adolescents	548	2.9%

Table 2 Main studies exploring the effect of gluten free diet in irritable bowel syndrome

Ref.	Country	Population	Outcome
Wahnschaffe et al[67], 2001	Germany	102 IBS-D	Stool frequency/bowel movement improved in DQ2-8 positive subjects
Aziz et al[68], 2016	United Kingdom	40 IBS-D	A 6-wk GFD reduced symptoms in 70%
Vazquez-Roque et al[69], 2013	United States	45 IBS-D	Stool frequency/bowel movement reduced in patients under GFD
Di Sabatino et al[5], 2015	Italy	59 IBS with self-diagnosis of NCGS	A challenge with 4 g/d of gluten worsened symptoms compared to placebo
Shahbazkhani et al[70], 2015	Iran	72 IBS	Worsening of intestinal symptoms with gluten compared to placebo
Zanwar et al[71], 2016	India	60 IBS	A 4-wk GFD improved a visual-analogue scale of symptoms
Elli et al[72], 2016	Italy	140 IBS with self-diagnosis of NCGS	Only the 14% showed a response to GFD as well as challenge test
Barmeyer et al[73], 2017	Germany	34 IBS	The 34% showed clinical improvement to GFD and continued for one year

GFD: Gluten free diet; IBS-D: Irritable bowel syndrome, diarrhea subtype; NCGS: Non celiac gluten sensitivity.

Table 3 Main extra-intestinal manifestations of non-celiac gluten sensitivity and associated disorders

Manifestations	Extra-intestinal manifestations	Level of evidence	Associated disorders	Level of evidence
General symptoms	Tiredness	4	Aphthous stomatitis	4
	Lack of wellbeing	4
	Foggy mind	4
	Joint or muscle pain	4
	Arm/leg numbness	4
Neurologic manifestations			Ataxia	3b
			Neuropathy	3b
			Encephalopathy	3b
			Epilepsy	4
			Miopathy	4
			Myelopathy	4
			Demyelinating disease	4
Psychiatric manifestations	Depression	1c	Bipolar disorder	4
	Anxiety	1c	Gluten psychosis	4
			Autism	2b
			Schizophrenia	4
Other autoimmune diseases and rheumatologic diseases			Psoriasis	2b
			Autoimmune thyroiditis	2b
			Rheumatoid arthritis	4
			Scleroderma	4
			Sjogren syndrome	4
			Raynaud phenomenon	4
Skin diseases			Dermatitis herpetiformis	2b
			Contact dermatitis	2b
			Rash and undetermined dermatitis	2b
Functional disorders			Fibromyalgia	1c
			Irritable bowel syndrome	1c
Nutritional imbalance	Anemia	4
	Osteoporosis	2b
Other			Interstitial cystitis	4
			Ingrown hairs	4
			Rhinitis, asthma	4
			Postural tachycardia syndrome	2b
			Oligo- or polymenorrhea	4

The level of evidence was expressed according to the Oxford consensus[85]