PROTOZOAL LINK BETWEEN SEVERE ACNE, RISK OF ATTEMPTED SUICIDE AND IMMUNE SUPPRESSION: A direct peripheral blood
test to confirm microparasitic infections
Beldeu Singh
ABSTRACT
Treatment costs are high especially when the underlying causes are not understood or not indentified and eliminated through non-toxic therapies. Equally important is the need to understand the causative factors certain deficiencies such as vitamin B12 deficiency such as consumption of vitamin B12 by protozoa and its association with increasing risk of oxidative damage, including risk of oxidative damage to genetic molecules, as vitamin B12 has an important role in healthy biochemistry such as in the formation of serotonin and dopamine. In a complex biochemical biological system, often, there is a common underlying link among a host of factors that may precipitate a cluster of symptoms but drug therapy may only treat symptoms, not the underlying cause. The basic problems with drug therapy must be understood and where possible these may be integrated with phytomedicine and in other cases effective therapeutic approaches and formulations with phytomolecules must be explored. This research article highlights, for the first time and brings to the fore the link between protozoa, vitamin B12 deficiency, acne and depression that has been used to develop a model for treatment of acne and depression. With a total 27% of affected population, in Europe, the annual cost of neuro-disease burden comes to about one-third of total disease burden.
INTRODUCTION
The world-wide acne treatments cost represents about 12.6% of the annual costs of all the treatments for skin diseases. Add to that burden, the cost of treating migraine. A sudden interest for acne in the adult has surfaced, and consequently each time it is more evident that the psychological, social and physical effects of this condition do not decrease with age. Acne and some of its treatments may lead to depression and other psychiatric problems that, if not properly diagnosed, could have serious consequences.1 Understanding the pathophysiology of acne and migraine will facilitate the development of more effective therapies.
Severe acne and its treatment are known to be associated with depression and attempted suicide and so far "it is difficult to tease out the relation between mental health and isotretinoin because acne itself is associated with psychiatric morbidity, including depression. Isotretinoin (13-cis-retinoic acid) has been used since the 1980s to treat severe recalcitrant nodular acne with good effect, but case reports and spontaneous reporting of adverse drug reactions have suggested an association between isotretinoin, depression, and suicidal behavior.2
There is often a conflict between the host and parasitic protozoa or pathogens that compete directly for minerals like iron3 or vitamin B12.4 There is an association between depressive symptoms and low hemoglobin and anemia.5 The prevalence of ECG abnormalities in patients with anemia was 63% with the prevalence of ST segment depression at 33%.6 Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anemia and has been implicated in a spectrum of neuropsychiatric disorders.7
Vitamin B12 deficiency should be managed aggressively. “Recent evidence suggests that vitamin B12 deficiency in the elderly is more than classic pernicious anemia. Instead, it is a continuum from negative B12 balance to frank deficiency, which can be detected by low serum B12 levels long before changes occur in hemoglobin levels.”8
Propionibacterium acnes is a harmless bacteria. How it becomes a problem in the facial skin with an active role of protozoa that may be associated with some degree of vitamin B12 deficiency that is linked to depression involves a complex but interesting model when the role of protozoa in inducing immune suppression and subsequent proliferation of P acnes is understood together with the role of protozoa and drugs in precipitating some degree of vitamin B12 deficiency which is critical in the production of serotonin and dopamine and maintaining adequate levels of these molecules within the brain.
THE SUNDSTROM OBSERVATIONAL STUDY
The link between increased risk for attempted suicide and severe acne is interesting and may have a biochemical connection with allergens secreted by micro-parasites, including protozoal infections. Certain protozoa have a growth requirement of vitamin B12 or propionate metabolism resembling that in animals9 and this connection deserves proper attention and further research and the hypothesis that people with severe acne may be at a higher risk for attempted suicide regardless of exposure to isotretinoin has a scientific basis. Understanding this connection and its basis provides the structure for a thesis that may turn out to be of immense importance in modern medical science. The Sundström observational study, from the Karolinska Institute10, provides some interesting insights as follows:-
1. During the study period, 128 patients were admitted to the hospital for attempted suicide. The SIR for attempted suicide was increased during the year before treatment: 1.57 (95% confidence interval [CI], 0.86 - 2.63) for all, including repeated attempts, and 1.36 (95% CI, 0.65 - 2.50) for only first attempts.
2. The risk for suicide attempts was further increased during and up to 6 months after treatment, with a SIR of 1.78 (95% CI, 1.04 - 2.85) for all attempts and 1.93 (95% CI, 1.08 - 3.18) for first attempts. At 3 years after treatment was stopped, the observed number of suicide attempts was close to the expected number, and this remained stable during 15-year follow-up, with a SIR of 1.04 (95% CI, 0.74 - 1.43) for all attempts and 0.97 (95% CI, 0.64 - 1.40) for first attempts.
3. Of 32 patients who made their first suicide attempt before treatment, 12 (38%) made a new attempt or committed suicide thereafter, whereas 10 (71%) of the 14 patients who made their first suicide attempt within 6 months after treatment was stopped made a new attempt or committed suicide during follow-up (2-sample test of proportions, P = .034).
4. For 1 additional first suicide attempt to occur, the number needed to harm was 2300 new 6-month treatments per year. For 1 additional repeated attempt, the number needed to harm was 5000 per year.
5. "An increased risk of attempted suicide was apparent up to six months after the end of treatment with isotretinoin which motivates a close monitoring of patients for suicidal behavior for up to a year after treatment has ended.
The interesting and apparent conflict with regard to isotretinoin is that while there is an increased risk of attempted suicide whereas only 32 patients who made their first suicide attempt before treatment, 12 (38%) made a new attempt or committed suicide thereafter, whereas 10 (71%) of the 14 patients who made their first suicide attempt within 6 months after treatment was stopped made a new attempt or committed suicide during follow-up (2-sample test of proportions, P = .034).
Attempted suicide was increased during the year before treatment and the number of patients, who made attempts to commit suicide, after treatment, tends to reduce but the risk for suicide attempts was further increased during the first six months of treatment with isotretinoin. That observation may have everything to do with the primary underlying cause of acne and the properties of isotretinoin. “In an accompanying editorial, Parker Magin and John Sullivan, both from Australia, concur that it is essential for patients treated with isotretinoin for acne to be carefully monitored for depression and suicidal thoughts, especially among patients for whom treatment is unsuccessful” – and it has a sound underlying scientific basis.
RETINOIDS AND FUTURE TREATMENTS
The future trends of long term treatment represent regimens of low dose isotretinoin and new formulations of isotretinoin. Retinoids are considered the first line treatment for acne, being also a maintenance therapy. Topical retinoids are derived from vitamin A and are classified in three groups: non-aromatics - tretinoin and isotretinoin; monoaromatics and polyaromatics - adapalen andtazaroten.11 It was first developed to be used as a chemotherapy medication for the treatment of cancers including brain cancer and pancreatic cancer.
Isotretinoin can increase cholesterol and triglyceride levels and decrease HDL (the good cholesterol) levels and aggravate CVD problems. It can aggravate inflammatory bowel disease (IBD) or cause an unusual or allergic reaction. Its side-effects and the aggravation of IBD and the unusual allergic reaction may point to the fact that it is toxic enough to produce inflammation and it also has anti-parasitic properties and hence more research is required on its activity in the body. The synthetic molecule acts differently in biological systems and is metabolized differently as the body utilizes the natural L-form molecule in its L-form biochemistry. High doses of synthetic vitamin A can lead to vitamin A toxicity and it is known to have teratogenic potential whereas the L-form vitamin A as found in papaya is essential in physiological processes such as cell growth, differentiation, morphogenesis and development. The biological functions of vitamin A are mediated through the retinoid acid receptors (RARs) and retinoid X receptors (RXRs). The problem lies in the fact that metabolism of analogues (D-form: 9-cis-retinoic acid) generate free radicals and “their ability to compete for receptors has been shown to have an inhibitory effect of cells and also alter gene expression and it was established that, synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, activate retinoic acid receptor-γ as an essential for induction of apoptosis of pancreatic cells” and various cancer cells”12 and normal cells may also suffer retinoid-induced apoptosis as “increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity13 with teratogenic potential.14 Natural retinols are antioxidants and have anti-oxidant and anti-inflammatory activity. Research also demonstrated the efficient anticancer ability of natural retinoids on human pancreatic cancer cell lines.15
INFLAMMATORY CONDITIONS AND DEPRESSIONS
An inflammatory disease condition associated with depression is multiple sclerosis (MS). During an MS attack, inflammation occurs in areas of the white matter of the central nervous system in random patches called plaques. This process is followed by destruction of myelin, the fatty covering that insulates nerve cell fibers in the brain and spinal cord. Myelin facilitates the smooth, high-speed transmission of electrochemical messages between the brain, the spinal cord, and the rest of the body; when it is damaged, neurological transmission of messages may be slowed or blocked completely, leading to diminished or lost function. Symptoms of MS may be mild or severe, of long duration or short, and may appear in various combinations, depending on the area of the nervous system affected and affecting bowel or bladder control in some patients. Depression, which is unrelated to cognitive problems, is another common feature of MS. In addition, about 10 percent of patients suffer from more severe psychotic disorders such as manic-depression and paranoia. Five percent may experience episodes of inappropriate euphoria and despair-unrelated to the patient's actual emotional state-known as "laughing/weeping syndrome." It all depends on the area in which the cells are inflamed due to oxidative damage to their cell membranes and the extent of such damage that disturbs healthy biochemistry to various extents.
Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics.16
Attention has been focused recently on the association between vitamin B12 metabolism and the pathogenesis of multiple sclerosis (MS). Several recent reports have documented vitamin B12 deficiency in patients with MS. The etiology of this deficiency in MS is unknown. The majority of these patients do not have pernicious anemia and serum levels of the vitamin are unrelated to the course or chronicity of the disease. Moreover, vitamin B12 does not reverse the associated macrocytic anemia nor are the neurological deficits of MS improved following supplementation with vitamin B12. It has been suggested that vitamin B12 deficiency may render the patient more vulnerable to the putative viral and/or immunologic mechanisms widely suspected in MS. Researchers found that in 45 MS patients, vitamin B12 levels were significantly lower in those who experienced the onset of first neurological symptoms prior to age 18 years (N = 10) compared to patients in whom the disease first manifested after age 18 (N = 35) propose that its deficiency in MS is of critical pathogenic significance.17
It is crucial to understand this strange relationship between MS and B12 deficiency such that its supplementation does not improve the condition, although B12 is required as a fat-soluble antioxidant in nervous tissue and for the formation of myelin and for immune mechanisms which is also “necessary for DNA synthesis.”18 Deficiency of vitamin B12 also results in neurological symptoms such as numbness and tingling of the arms and legs, difficulty in walking, amnesia, depression, disorientation and dementia, with or without mood swings. Up to 30% of patients with depression have vitamin B12 deficiency.
Researchers from the Cleveland Clinic have reported that 13.6% of patients with plasma cell dyscrasias have vitamin B12 deficiency.19
Depression and anxiety also resemble inflammatory states.20 Other researchers also demonstrated decreased antioxidant enzyme activity and increased markers of oxidative stress in subjects with depression when compared with a control group.21 The brain is particularly susceptible to the attack of free radicals caused by its low content of antioxidants, by the considerable content of polyunsaturated fatty acid side chains of the neuronal membrane lipids, and by its high oxygen consumption rate.22 Allergens from protozoa could contribute to the inflammatory process especially when antioxidant levels decline as in old age or in the malnourished.
It has been suggested that proteolytic enzymes (allergens) from protozoa may trigger respiratory allergy.23 In addition, there is growing evidence that protozoan pathogens modify the antigen-presenting and immuno-regulatory functions of dendritic cells, a process that facilitates their evasion of both innate and adaptive immunity.24 Parasitic protozoa are a major cause of global infectious disease. These eukaryotic pathogens have evolved with the vertebrate immune system and typically produce long-lasting chronic infections. A critical step in their host interaction is the evasion of innate immune defenses as they have the ability to avoid attack by humoral effector mechanisms. They do so by remodeling the phagosomal compartments in which they reside and by interfering with signaling pathways that lead to cellular activation. In addition, there is growing evidence that protozoan pathogens modify the antigen-presenting and immuno-regulatory functions of dendritic cells, a process that facilitates their evasion of both innate and adaptive immunity.25 Allergens of micro-parasites play a role in inflammations, allergies, chronic fatigue, bowel disorders, arthritis, hypertension, cancers and immune dysfunction and interfere with the cell signalling process and cause headaches and depression as well.