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In part 1 we looked at some of the key developments in understanding gluten sensitivity (coeliac and non-coeliac gluten sensitivity) that emerged in 2016. In part 2 now we take a look at some case studies, and small trials that link gluten to a wider range of conditions.
Read time: 18 minutes (2400 words)
When I did my medical training I was examined on clinical diagnostic skills. We students of herbal medicine, like other medical students, were taught that whatever symptoms a patient presented with, our list of possible diagnoses we could always include tuberculosis and syphilis.
These two systemic diseases were called the great imitators due to their potential for affecting any tissue or organ. From back pain, to skin rashes and mental illness, these ancient adversaries of Man could be the cause. Misdiagnosis could be serious in that the wrong treatment might be pursued, and the effective treatment missed. What we are seeing with gluten related disorders is another great imitator at play. The conditions that follow will leave you in no doubt that gluten and/or other factor in cereal grains, can play havoc with every corner of the body and should always be considered, properly tested form and ruled out by the responsible and updated clinician.
In reading this post there are several points to bear in mind:
(1) This is far from an exhaustive list, even of 2016 papers.
(2) Gluten related disorders often go unsuspected, undiagnosed and therefore untreated for many many years and 80% of coeliacs remain undiagnosed!
(3) Gluten can affect any system or tissue type of the body and should always be considered as part of a differential diagnosis even if there are no intestinal symptoms. A full gluten blood test, not just the standard NHS coeliac tests, should be used, or a minimum of a 6 week exclusion diet.
(4) The true extent of the gluten iceberg’s sub-surface volume has yet to be established. These reports give some insight into the extent of the murky mass.
I have seperated these reports into those related to coeliac – where there is adaptive immunity and/or autoimmune factors involved and non coeliac gluten sensitivity (NCGS) – where the innate immune system is principally involved. The latter is particularly important as it indicates the propensity of gluten to affect potentially anyone.
- Coeliac hepatitis: hepatic fibrosis, advanced steatohepatitis and cirrhosis
- In a Nov 2016 case study, a 20 year old woman with coeliac disease and severe liver cirrhosis had a near complete reversal once placed on a gluten-free diet.The author called this a “hepatomiracle” [Gaur, Nov 2016]
- An Iranian study published in Jul 2016 found that the prevalence of coeliac disease among patients with epilepsy was 6% – about five times higher than in the general population. [Bashiri, Jul 2016]
- Chronic Hepatitis C Virus (CHV)
- CHV infection can lead to autoimmune diseases and shares one of the same genetic loci as coeliac disease (HLA-DQ2). Liver disease also leads to anti-tissue transglutaminase antibodies (anti-tTG). Some CHV patients develop coeliac disease during interferon therapy. There is a complex relationship with many overlapping features between these two conditions, although it is not yet clear whether the incidence of coeliac disease is higher in CHV or not [Association between celiac disease and chronic hepatitis C, 2016].
- Distal Renal Tubular Acidosis Associated with Celiac Disease and Thyroiditis
- A case report of a 12 year old girl with a particular form of kidney disease, (distal renal tubular acidosis, RTA) with autoimmune diseases, which is extremely rare in children. [Indian Pediatrics, Nov 2016] “Despite resolution of acidosis on bicarbonate, she continued to have poor growth and delayed puberty. Investigations revealed autoimmune thyroiditis and celiac disease. Levothyroxine and gluten-free diet were initiated. Child gained height and weight and had onset of puberty after gluten withdrawal.”
- Psychiatric Case
- The BMJ recently published a case study of a girl admitted to a psychiatry ward suffering with suicidal behaviours who then developed an agitated catatonic state. She was unresponsive to antidepressants, anxiolytics, antipsychotics and electroconvulsive therapy, but improved significantly when a gluten-free diet was started [Oliveira-Maia, Dec 2016]. Another recent paper The progression of coeliac disease: its neurological and psychiatric implications, Campagna G, Dec 2016, explores the current understanding of the neurological implications of coeliac disease.
- Burning Tongue
- An elderly woman presented with complaints of a burning tongue for the past two years as well as occasional loose stools and fatigue. Tests revealed iron deficiency anemia, zinc deficiency and an abnormal celiac panel. Ten weeks on a gluten free diet led to complete symptom resolution [Sherman, Jun 2016].
- Macrophage activation syndrome
- A case report in Pediatric Rheumatology Online Journal, reports on a six year old girl who was diagnosed with Macrophage activation syndrome – an autoinflammatory or rheumatic disease involving hyper inflammation and an ineffective immune response. Serology indicated coeliac disease and symptoms stabilised with the introduction of a gluten-free diet. Authors state that “Clinicians should have a low threshold for screening children with other autoimmune diseases for coeliac disease.” [Palman, Dec 2016].
- Coeliac like disease in dogs
- The Veterinary Record [Lowrie, Dec 2016] reports on a case of “gluten-sensitive dyskinesia (previously termed canine epileptoid cramping syndrome) is a condition of Border terriers in which the leading manifestation is neurological… responsive to a gluten-free diet.” As such, the authors suggest that gluten sensitivity in Border terriers “may manifest as a multisystem disease in a similar manner to that seen in human beings.” There is another paper on this topic: Gluten exposure and multisystem disease in dogs [Davies M, Dec 2016], but I have been unable to access it.
- Gluten free diet in pregnancy and type 1 diabetes in offspring
- As we have previously discussed, gluten has a significant role in the development of type 1 diabetes. A study in the Journal of Diabetes Research [Antvorskov JC, Aug 2016] investigated the a mouse model of type 1 diabetes. Withholding gluten during pregnancy prevented the subsequent development of type 1 diabetes in offspring, even when exposed to gluten after birth. However, the effect disappeared if the mother received a gluten-free diet prior to pregnancy.
- Aortic stiffness may explain increased cardiovascular risk
- Many studies show an increased risk of cardiovascular disease in coeliac patients which cannot be explained by traditional risk factors. A study from Antalya, Turkey used echocardiograms to compare the aortic function of 81 coeliac patients with that of 63 healthy volunteers. They found an increased level of aortic stiffness and inflammation in coeliac patients. Whilst inflammation decreased with adherence to a gluten free diet, aortic stiffness did not, suggesting that increased cardiovascular risk may persist despite a gluten-free diet. [Bayar, Mar 2016]
- Hemophagocytic lymphohistiocytosis
- Hemophagocytic Lymphohistiocytosis and is a life-threatening immunodeficiency. It affects people of all ages and ethnic groups. Common symptoms are fevers, enlarged spleen, low blood counts and liver abnormalities. [ref] A recent paper [Fordham NJ Sep 2016] reports a case that did not respond to standard treatment, but following blood tests established undiagnosed coeliac disease. “She initially responded to chemoimmunotherapy specific for hemophagocytic lymphohistiocytosis but relapsed within a few months of cessation of treatment and then achieved complete remission on gluten withdrawal alone.”
- Down’s Syndrome
- A study in Poland identified high levels of diagnosed coeliac disease among patients with Down’s syndrome (5.4% vs 1% in general population). The authors emphasise that tests for coeliac disease should be carried out in all (Polish) patients with Down’s syndrome, regardless of the clinical picture. [Szaflarska-Popławska, 2016]
- Multiple autoimmune syndrome with celiac disease
- Reumatologia published a case report of a 32 year old woman who had four co-existing autoimmune diseases: autoimmune hypothyroidism, Sjögren’s syndrome, systemic lupus erythematosus (SLE) and celiac disease which leads to the final diagnosis of multiple autoimmune syndrome type 3 with celiac disease. The authors point out that patients with single autoimmune disorders are at 25% risk of developing other autoimmune disorders. The case emphasises the need for continued surveillance for the development of new autoimmune disease in predisposed patients. [Harpreet, Dec 2016]
2. Non-coeliac Gluten Sensitivity (NCGS)
NOTE: I am using NCGS as a looser category than is currently accepted to include any studies where withdrawal of gluten or wheat showed clinical benefit.
- Intestinal cell damage and systemic immune activation in NCGS
- A study published in the BMJ’s journal Gut at the end of 2016, examined serum from 80 individuals meeting the criteria for NCGS (although the authors use the term Non Celiac Wheat Sensitivity). They found increased levels of lipopolysaccharide binding protein – indicating that these patients had raised levels of gut bacteria products passing through a damaged gut wall, known as ‘leaky gut’. Associated with this was raised markers of systemic immune activation. The researchers went on to find raised levels of fatty acid binding protein, indicative of intestinal cell damage. As NCGS patients do not have villous atrophy (which is characteristic of celiac disease) it had been assumed that there is no intestinal damage taking place in NCGS, however, this study shows that damage is indeed taking place. The authors speculate that damage in NCGS may be taking place in the mid section of the small intestine, the jejunum, rather than the first section, the duodenum, from which biopsies are usually taken. Finally, these markers were found to improve with the initiation of a gluten free diet. [Melanie Uhde, 2016]
- Psychotic Illness
- Schizophrenia has previously been linked to raised kynurenine and reduced tryptophan [Chiappelli, Nature, 2016], both of which are related to the production of Vitamin B3. Researchers hypothesised that this imbalance could be caused by inflammatory immune mediators such as gluten. They found schizophrenic patients had raised levels of anti-gliadin antibodies (IgG) which correlated with kynurenine/tryptophan ratios. They concluded “Our results connect nonceliac gluten sensitivity with the KYN pathway of TRP metabolism in psychotic illness” [Okusaga, 2016]. This links to an long used treatment of schizophrenia which is goodly doses of Vitamin B3 (niacin), the production of which may be getting interfered with by gluten in these patients.
- Atopic Dermatitis (Eczema)
- A recent study sent 169 atopic dermatitis patients a 61-question survey asking about dietary modifications they had tried and their perceptions and outcomes of such trials. The most common foods eliminated were ‘junk foods’ (68%), dairy (49.7%), and gluten (49%). The best improvement in skin was reported when removing white flour products (37 of 69, 53.6%), gluten (37 of 72, 51.4%) and the nightshade family of vegetables, i.e. potatoes, tomatoes, aubergines, peppers, chilli and paprika (18 of 35, 51.4%). [Nosrati, 2017]
- Lymphocytic colitis
- (This condition is characterised by chronic watery diarrhoea yet with normal colon cells when sent to the histology lab, but with an accumulation of lymphocytes in the colonic epithelium/lining)
A study in the journal PLoS One found that 91% of lymphocytic colitis patients who were identified as NCGS responded to a double blind gluten challenge indicating a causative role for gluten in these patients. [Rosinach M, Jul 2016]
- Nephrotic Syndrome
- This is a rare condition in childhood that presents with proteinuria, hypoalbuminemia, and oedema. Kidney function is usually normal however. Most children (>90%) respond to an initial course of oral steroids and are designated as having steroid-sensitive nephrotic syndrome (ssNS). A study in Pediatrics placed 8 children with difficult-to-manage disease (characterized by steroid dependence or frequent relapses) on a gluten-free diet. They all had clinical improvement enabling reduction or discontinuation in steroids. The role of gluten in this condition was confirmed through relapse following re-exposure to gluten. The authors conclude “Elimination of gluten from the diet, may reduce the need for potentially toxic immunosuppressant therapies” [Lemley KV, Jul 2016]
- Microscopic colitis
- – A new clinical and pathological entity (“lymphocytic enterocolitis”)?
Of patients with Marsh 1 duodenal damage, but no coeliac serology (i.e. negative for anti-endomysium and anti-tissue transglutaminase), half were found to have microscopic colitis. Although this study was not specifically looking at gluten, 14 patients tried a gluten free diet for at least one month and 3 of them (21%) had improvements. [Bonagura, Nov 2016]
- Postural orthostatic tachycardia syndrome (POTS)
- A study published in the European Journal of Gastroenterology and Hepatology found that 4% of PoTS patients had coeliac antibodies, yet 42% reported gluten sensitivity, suggesting that many POTS patients are NCGS. [Penny HA, Dec 2016]
- Eosinophilic oesophagitis
- Eosinophilic oesophagitis (also called EoE for those who spell oesophagus without the ‘o’) is a chronic inflammatory oesophageal disease triggered predominantly by food antigens. Although considered a food allergy, EoE is unique in not involving the immunoglobulin IgE antibody response. A recent review identifies milk and gluten elimination as the most promising cure strategies. [Molina-Infante, Dec 2016] How is EoE caused? Until recently it was considered that the oesophagus was relatively impermeable to food antigens and allergic diseases of the oesophagus were unknown. Researchers from the Mayo Clinic wondered if food antigens were present in the oesophageal tissue of sufferers. In a recently published paper they report finding increasing levels of gliadin (gluten) in the oesophageal tissue with increased severity of disease, whilst none was present amongst controls. This suggests a direct causative role of gluten in EoE.
- Effect of a gluten-free diet in children with autism spectrum disorders
- In this randomised clinical trial [Ghalichi F, Nov 2016] 80 children with ASD were randomised to gluten-free diet  or regular diet .
“In the GFD group, the prevalence of gastrointestinal symptoms decreased significantly (P<0.05) after intake of GFD (40.57% vs. 17.10%) but increased insignificantly in the RD group (42.45% vs. 44.05%). GFD intervention resulted in a significant decrease in behavioral disorders (80.03±14.07 vs. 75.82±15.37, P<0.05) but an insignificant increase in the RD group (79.92±15.49 vs. 80.92±16.24).”
- Alcohol related cerebellar degeneration
- Alcohol-related cerebellar degeneration is one of the commonest acquired forms of cerebellar ataxia, however, the mechanism by which alcohol causes this damage is unknown. The cerebellum is the back part of the brain, responsible for many basic things including walking. ‘Ataxia’ is difficulty in walking. In a recent study from Royal Hallamshire Hospital, Sheffield, England, a group of 38 patients with ataxia were studied. 34% were found to have circulating anti–gliadin antibodies vs. 12 % in healthy controls, and 39 % were found to have antibodies to transglutaminase 6 (which are neurological antibodies) vs. 4 % of healthy controls. The authors suggest that chronic alcohol abuse increases gut permeability exposing the immune system to increased levels of gluten peptides to which these two antibodies are raised. They conclude “Alcohol induced tissue injury to the central nervous system leading to cerebellar degeneration may also involve immune mediated mechanisms, including sensitisation to gluten.” [Shanmugarajah PD, Oct 2016]
We are in the middle of an epidemic of gluten related disease that have crept up on us over the last few decades. Our European culture has lived with wheat and its associated diseases, for thousands of years, and we have named and described them, yet only now are we becoming aware of the true cost to our health. At the same time, many Central America countries (Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, and Panama), which historically have had very low rates of coeliac disease, are transitioning from a diet based on maize to one increasingly centred around wheat. Maize too has its problems but the prolamine in maize, zein, is less likely to cause immune reactions than is the prolamine in wheat, namely gluten.
A paper published in the journalNutrients [Amado Salvador Peña* and Jakob Bart Arie Crusius, Sep 2015] provides a salutary reminder of the scope of the problem:
[these] changes permit a prediction of an increase of celiac disease and other autoimmune diseases such as type I diabetes and thyroid disease.– Amado Salvador Peña and Jakob Bart Arie Crusius, Central America in Transition: From Maize to Wheat. Challenges and Opportunities (Nutrients, Sep 2015)
The aim of this review is to… alert authorities responsible for the planning of education and health, to find possibilities to avoid a rise in these disorders before the epidemics start.