This article has been divided into two parts.
Part one discusses the concept of overlapping syndromes (OLS) and evaluates different ‘terminology’ used between conventional medicine and functional medicine as it could be argued that ‘overlapping syndromes’ are not well studied.
The gut/brain axis and psychoneuroimmunology are further evaluated within this context. Imbalances as well as shared and non-shared pathology are recorded throughout the first part by using the functional medicine model.
Part two looks more closely at one of these conditions - Gulf War Syndrome. The efficacy of nutritional intervention and screening is evaluated and the work carried out by the US Medical Centre on over 69,000 Gulf war veterans is also discussed.
There are significant ethical, social and cultural roles, which need to be taken into consideration when working with those who experience Gulf War Syndrome, and these are also highlighted.
Background of the overlapping syndrome concept - what is it?
Overlapping syndromes (OLS) is a term coined by Hooper (2000; 2007) and includes a wide variety of disorders and diseases including autism, Parkinson’s disease, irritable bowel syndrome, chronic fatigue, fibromyalgia and multiple chemical sensitivities, Gulf War Syndrome (GWS) as well as learning disorders and mental illnesses.
When searching the term on PubMed retrieved papers show overlapping syndromes to focus on a wide variety of overlaps including genetic mutations, this suggests the term as Hooper describes, is not widely recognised within the scientific literature, and therefore perhaps the medical establishment. However, similar terminology is Affective Spectrum Disorder, used to understand links between mood and anxiety disorders, IBS and fibromyalgia (Goddard et al., 2007) as well as Functional Somatic Syndrome which encompasses several medically unexplained syndromes, such as irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome (Myaoka et al., 2009).
After further investigation, evidence supports Hooper’s terminology of ‘overlapping syndromes’ within the contexts of contributory factors. The gut-brain axis is a bi-directional communication system between the gut and the brain and is essential in maintaining homeostasis, it is regulated at the hormonal, neural and immunological level (Cryan & O’Mahony, 2011) – alterations in this system affect the stress response, overall behaviour and have been implicated in a variety of conditions for example autism (Wakefield, 2002; Reichelt & Knivsberg, 2009) Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS) (Cryan & O’Mahony, 2011; Grenham et al., 2011) and Chronic Fatigue Syndrome (CFS) (Lakhan & Kirchgessner, 2010). When searching the term “gut-brain axis” it is easy to find information with a large number of papers published in well-respected peer reviewed journals. The main area of research is currently around the impact of gut flora and its relation to altering communication between the gut and the brain.
A disrupted Hypothalamic-Pituitary-Adrenal (HPA) axis with disordered inflammatory states shows shared pathophysiology between depression, anxiety, IBS, CFS, fibromyalgia and migraines (Goddard et al., 2007). Again it is relatively easy to find data on how a disrupted HPA axis affects inflammation and the links with mental health disorders as well as the above syndromes however there is less data in relation to autism. The impacts of gut, immune and brain interactions have been documented within Multiple Sclerosis and Parkinson’s Disease (Berer & Krishnamoorthy, 2012; Mosley et al., 2012). Psychoneuroimmunology (PNI) has an abundance of academic literature discussing overlapping symptomology and functional imbalances, and it is discussed in many papers in relations to IBS, CFS and mental health issues but less so in MS, PD and autism. In the case of GWS it could be argued that PNI was used as a “cover-up” for toxicity that was not acknowledged.
Functional Medicine Matrix
By using the functional medicine matrix (FMM) the imbalances of overlapping syndromes may be more clearly distinguished and are described below.
It has been demonstrated that there are multiple gene defects in autism (with an environmental catalyst) (Cusco et al., 2009) however not one single gene has been found that can account for more than 2% of those affected by autism (Seneff et al., 2012). In CFS polymorphisms have been identified in relation to 5-HT receptors but not one single gene has been identified (Smith et al., 2008). In ADHD, CHRNA7 has only been implicated in as much as 1.25% of the affected population. This gene overlaps with schizophrenia, autism and depression; in all of these cases the reaction to stress alters the release of dopamine, affecting nicotinic acetylcholine receptors (Ross, 2012). Life experiences, attitudes and beliefs are all important throughout health, disease and recovery. The effects of PNI have been shown to affect inflammation, wound-healing time, stress, diet, and intestinal permeability (Haroon et al., 2012; Vedhara, 2012).
A genetic disposition does not necessarily result in one of the above syndromes however attitudes and beliefs towards life play a significant role. This area is of primary importance when working within a clinical setting, yet is still being debated within conventional medicine.
"Attitudes and beliefs towards life play a significant role in health and wellbeing."
Digestive, absorption and microbial imbalances are common in all aspects of OLS (Hooper, 2000) the loss of digestive efficiency and gut membrane integrity may lead to the cascading multi-system failure encouraging gastrointestinal irritability, dysbiosis, toxin production, allergies, intestinal permeability and systematic stress, this impacts production of neurotransmitters thus affecting the gut–brain-axis, HPA and inflammatory response as previously discussed (Jones & Quinn, 2006). Inflammation of the gastrointestinal tract has been documented in autism (Wakefield, 2002) CFS (Lakhan & Kirchgessner, 2010), mental illnesses (Fetissov & Dechelotte, 2011) and multiple chemical sensitivities (Luca et al., 2011) When working with FMM and OLS it is apparent that digestive function is of primary importance yet interesting to note that many in the medical establishment still do not accept that gut membrane integrity is vital to health.
Immune and inflammatory imbalances appear to be widespread throughout all of the syndromes, and appear as allergies or intolerances, either to foods, chemicals or both. Inflammation is present in CFS, mental illness, IBS, GWS, autism, fibromyalgia, MS and PD. Underlying factors may include viruses, autoimmune disorders, lowered secretory IgA, or excess production of nitric oxide (Hooper, 2007; Fetissov & Dechelotte, 2011; Israeli, 2012). The following paragraph could also be considered under neurotransmitter imbalances as a disordered HPA axis and an over or under production of cortisol results in either an over or under stimulated inflammatory response. Abnormal levels of inflammatory cytokines have been reported in mental illness, IBS, CFS and migraines (Goddard et al., 2007) in some cases this may be connected to the excess-opioid-theory, discussed below.
It is well documented that CFS is accompanied by increased oxidative stress this is also accompanied by lowered levels of L-glutathione thus leading to a vicious cycle, inflammation may cause further damage to mitochondria as well as fatty acids and proteins (Lakhan & Kirchgessner, 2010). Stress, viral, bacterial, psychological, physical (including exposure to chemicals) stimulate responses that raise nitric oxide (NO) and its oxidant, peroxynitrite (ONOO-), once chronically elevated they form a cycle known as NO/ONOO-, this acts on a cellular basis which can lead to different variation and distribution of symptoms, these include CFS, MCS, MS, autism, GWS and fibromyalgia (Pall, 2007, pp. 3-10).
Toxic exposure leads to decreases in phase1 and 2 enzyme activity, this affects sulphation which may impact on cell structure and neurotransmitter communication. Exposure to high levels of mercury due to amalgam fillings is a trigger in some cases of MCS and CFS and toxic metals have been implicated in Parkinson’s, MS and depressive disorders (Watts, 2009, p40; Luca et al., 2011). Gulf War Syndrome has also been connected to high levels of toxins and chemical exposure (Israeli, 2012) similarly with autism, however Wakefield (2002) also highlighted that the liver in autistic children may be unable to metabolize or eliminate toxic compounds even if they derived from the gut. The gut-liver axis refers to hepatocytes transforming gut-derived compounds into safe by-products before excreting them, the hepatic phase 1 and 2 reactions occur in the intestinal mucosa with the gut flora playing a role in biotransformation. Imbalances result in systemic toxicity and/or inflammatory responses (Jones & Quinn, 2006).
Expressions of hormonal and neurotransmitter imbalances could include, depression, fatigue, headaches, memory problems, disturbed sleep, anxiety and gastrointestinal issues. All of these are indicated in OLS. This may be due to disordered tryptophan metabolism, derangements in the gamma-aminobutyric acidergic (Wakefield, 2002) and serotonergic systems. Hyperactivity of the serotonergic system and hypo-activity of the HPA axis have been implicated in CFS (Smith et al., 2008).
The opioid excess theory includes similar conditions to that in the OLS, such as autism, CFS/ME, MCS, GWS, fibromyalgia and IBS. A recent review by Mulloy et al., (2010) summarised that the evidence for using gluten free/casein free diet in autism was limited and weak however they did go on to say that practitioners should consider testing children with autism for food allergies and intolerances, which suggests that more standardised research may strengthen the evidence of this theory that was first introduced in 1979.
Stress if left unresolved may lead to adrenal insufficiency, stress in itself reduces SIgA, increases the permeability of the gut membrane and the blood brain barrier (Nicolle & Beirne, 2010, p93). Stress influences hormonal balance leading to impaired hormone metabolism, which is linked, with MCS and the clinical expression of thyroid hormone dysfunctions (Luca et al., 2011). Stress is related to the pathogenesis of autoimmune disease and alters cytokine production as previously mentioned.
Within the overlapping syndromes there are a variety of structural imbalances, muscle and joint pain are commonly found in those who suffer with CFS, MS, fibromyalgia, GWS, and they may be present in those with autism (Hooper, 2007; Arck et al., 2009). Lipids make up bilayer of cellular structure and dysfunctional lipid metabolism has been implicated in ADHD, fatigue, MS, depression and other mental illnesses this may affect cells function and signaling of hormones and neurotransmitters (Nicolle & Beirne, 2010, pp.106-115).
Now moving on - and focusing on Gulf War Syndrome
Gulf War Syndrome affected hundreds of thousands of veterans, and 17% of UK deployed military personnel, they suffered from fatigue, memory loss, joint pain, depression, lack of concentrations, headaches, rashes, coughs and abdominal pains (Kilshaw, 2009). Debates raged about the nature and cause of this illness, with many suggesting that it is a psychiatric condition. The controversies continued as more evidence was highlighting this new disorder may be linked to chemical warfare agents provided by the US government (Kilshaw, 2009, p2). In 1997 a paper was published titled “Is there a Gulf War Syndrome…?” This studied six syndrome factors and concluded that there were clusters of overlapped syndromes reflecting a spectrum of disorders (Haley et al., 1997). According to Pall (2007) “GWS is a combination of CFS, MCS, FM and Post Traumatic Stress Disorder”, there is no data showing elevated NO/ONOO- cycle biochemistry in humans (Pall, 2007, p159), however data shows elevation of nitrates/nitrites in those with MCS (Luca et al., 2011).
Factors to consider when working with this population include high levels of stress, deteriorating health, alcohol abuse or dependency and feelings of vulnerability due to the vast range of symptoms.
Women veterans are more likely to have increased risk of trauma in association with deployment, combat and sexual traumas, this is independently associated with an elevated risk of IBS (White et al., 2010). A longitudinal study following nearly 9,000 Gulf war veterans observed that over a 10-year period their health worsened compared to those not deployed (Li et al., 2011).
In a recent study unexplained multi-symptom illness, and chronic fatigue syndrome were more frequent among veterans from the Gulf War with problem drinking than those without problem drinking (Couchlin et al., 2011). Alcohol abuse and dependence in the military is a well-documented health issue (Armed Forces Health Surveillance Center, 2011).
These clients may be not be forthcoming for nutritional support, and when they do may be wary. They have experienced the trauma of war, living and working in a toxic environment, and in some cases being raped or assaulted. On returning home their symptoms may have been dismissed and they are likely to have been told they are just somatic. For males working in this environment their masculinity may have been questioned and in many cases their fertility has been affected. Due to the many symptoms they may be experiencing, the foods they eat, products they buy and places they can visit may be very limited. Care and sensitivity needs to take priority when working together. Goals may need to be small and recommendations realistic.
"On returning home their symptoms may have been dismissed and they are likely to have been told they are just somatic."
Nutritional Intervention in Gulf War Syndrome
The National Veterans Affairs Medical Council (NVAMC) recommended a treatment based on other successful interventions. This was a multi-system approach and included a controlled environment (chemical and toxin free), nutritional support, psychological support, education, and exercise/sauna programme. A 30-day period was used and free time was spent meditating or playing games such as chess or backgammon. Over 69,000 veterans participated and 73% self reported that their health was now “alright” or “good” (United States Congress House of Representatives, 2010, pp18-44). The details of this programme were released in 2010 to help the public understand the support given by the US military.
The NVAMC expected approximately 80% of patients would have food sensitivities therefore identification and elimination was essential and undertaken with an elimination/rotational diet. Common allergenic foods were removed for the first weeks, such as gluten, dairy, beef, pork and veal and nuts. Organic foods were consumed. Spring water was used for drinking. Many biochemical tests were carried out and liver sulphation pathways were assumed to be affected therefore oligo-antigenic liquids were provided. These contained white rice protein, as well as nutrients to unregulated P450 enzyme activity, zinc, copper, manganese, molybdenum, iron, B-vitamins, L-cysteine, glutathione, N-acetyl cysteine, tocopherol, carotenoid and ascorbate.
(United States Congress House of Representatives, 2010, pp18-44).
The programme above offers sound evidence for the recommendation of removing allergens and replacing with healing foods, these will be client specific but are likely to include low allergenic foods, protein such as plant proteins, fish, chicken and in some cases whey. Luca et al., (2011) tabulate data from peer-reviewed literature, which shows success with similar strategies. In a one-to-one situation the primary focus would be on ensuring the client is able to follow the programme as they may be in a severely debilitated condition. After the removal of allergens supporting detoxification was the main focus on the intervention used by the NVAMC. It could be enhanced by the inclusion of essential fats, and sulphuric foods (onions, garlic, broccoli) as well as natural chelators such as cilantro or chlorella.
In addition to the above, the following interventions may also be considered:
Repopulate gut flora by including pre/probiotics (Lactobacillus rhamnosus and Bifidobacterium longum have been well studied), these not only alleviate dysbiosis, modulate inflammatory and immune responses but have also been shown to influence the gut-brain axis and normalize alterations in the HPA axis (Collins et al., 2009; Cryan & O’Mahoney, 2011; Lee & Chua, 2011). Repair the gut to alleviate dysbiosis and support anti-inflammatory actions. Including foods and herbs with mucilage properties such as okra, aloe vera or marshmallow root. Oxidative stress may be addressed by the inclusion of multi-coloured fruits and vegetables to offer a wide range of antioxidants.
Testing considerations in Gulf War Syndrome
Genova Diagnostics were contacted regarding evidence for tests specifically for GWS, they replied that even though there was evidence for the Adrenal Stress index on PTSD, they had no data relating directly to GWS.
However, the following functional tests could be considered.
Please note: The information below was correct at time of writing (2012) - subsequently prices and companies may have changed. Testing should always be client specific, the below is not suggesting a testing ‘protocol’.
ONE Test – Genova Diagnostics costs £260 includes an amino acid and metabolic analysis profile, it measures the full range of amino acids as well as many cellular processes, including digestive function, dysbiosis, cellular and mitochondrial energy, neurotransmitter metabolism, sulphur status, the test highlights metabolic inhibitions and may be best suited to those with signs of disordered energy metabolism over predominantly digestive complaints. This test leads direction for future developments, and according to Luca et al., (2011) metabolic analysis contributes substantially to the establishment of evidence-based personalised medicine.
Comprehensive Digestive Stool Analysis (with optional additional parasitology test) measures, fermentation, digestive adequacy, intestinal flora, and secretory IgA and butyrate. Military personnel are usually deployed overseas and may have a higher risk of contracting parasites so it may be advisable to include this option. Genova Diagnostics = CDSA+P costs £156 and if inflammatory markers are also required then CDSA 2.0+P costs £225. Metametrix = GI Effects costs £249 and includes inflammatory markers, SIgA, adiposity levels and absorption. Bacteria are identified by DNA analysis, which is now the gold standard in clinical microbiology (Metametrix, 2012). The test is recommended for those who have chronic fatigue syndrome, food or environmental sensitivities, IBS, alcoholism or other autoimmune disorders (Lord and Bralley, 2008, p446) three stool samples are required. Both tests have a turnaround time of 14 days.
Routine blood chemistry (including full blood count) available via the NHS can be beneficial to measure renal and liver function (and to exclude serious liver disease) as well as red and white blood counts. A useful test to monitor impact of intervention and may collaborate communication between client, GP and therapist.
Gut Permeability test is simple and inexpensive urine sample, it is useful to use as a repeat test to monitor success of the nutritional intervention. It is well recognised and assesses permeability of the small intestine and colon by measuring mannitol and lactulose (Camilleri, et al., 2010). Genova Diagnostics - Intestinal Permeability Assessment costs £68. Turnaround time is 14 days.
Biolab - Gut Permeability Profile costs £75.
And to conclude...
Overlapping syndromes are complex and even though the term may not be widely recognised by conventional medicine when delving further there is evidence that supports Hooper’s terminology.
The gut-brain-axis, HPA axis, effects of stress and PNI are well documented and when categorised under the Functional Medicine Matrix the interactions may be clearly observed, often intertwining with one another – scientific papers agree on the complex nature of these syndromes.
Wide subject areas were covered from genetics, to digestion and its affects on gut-brain-axis, micro-flora and the excess-opioid-theory. Taking a closer look at neurotransmitters, from tryptophan metabolism to the effects of stress and its impact on inflammation and oxidative stress and highlighting the impact of the NO/OHNO- cycle. Also the effects of detoxification and biotransformation, either from heavy metal, chemicals or toxins, including toxins derived from gut bacteria, were evaluated.
Gulf War Syndrome is a complex condition consisting of four of the overlapping syndromes. The programme operated by NVAMC offered a huge amount of information with over 69,000 participants, and 73% with an improvement in symptoms, this data is hard to ignore. In GWS testing is likely to be essential, detoxification needs to be assessed, as does gastrointestinal health. Psychological support would also need to be considered if this is not already in place. Clinicians need to be aware of the vulnerability of this group and make appropriate interventions accordingly.
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