Introduction
The Role of Free Reactive Iron in Psoriasis
Natural Compounds that Help in the Treatment of Psoriasis
Medical Nutrition Therapy in the Treatment of Psoriasis
Biomarkers in Psoriasis
Natural Compounds that Target Biomarkers Involved in Psoriasis
Stress Reduction, Sun Exposure, Homeopathy and Psoriasis
Natural Treatment Strategies for Psoriasis
Introduction
The excess of Th17 cells induce various autoimmune diseases such as psoriasis. Several studies revealed that infections were more common in psoriatics than in healthy individuals. Superantigens released by microorganisms have been suggested as exogenous triggers that stimulate T cells to initiate psoriasis. (Kagami 2011)Psoriasis is a chronic skin disorder characterized by a dense dermal infiltrate, which predominantly consists of T cells, dendritic cells (DCs), natural killer T cells, and macrophages, and affects approximately 0.2% to 2% of the world population. Plasminogen (PLG) is mainly produced in the liver and is activated by PLG activators, other serine proteases, or streptokinase (SK) secreted by group A streptococci (GAS). PLG activators are highly elevated in the lesional skin of psoriasis patients, suggesting that PLG is involved in the pathogenesis of psoriasis. (Li et al 2011)Psoriasis is a chronic IL-23/Th17 pathway-associated skin disease. An increased expression of lesional CCL20 can recruit CCR6+ Th17, and lesional cytokine milieu persistently activates keratinocytes to produce CCL20. (Kim et al 2011)
Psoriasis is a T cell-dependent autoimmune disease of the skin and joints. Disease manifestation is orchestrated by proinflammatory CD4-positive T helper cells producing either interferon-gamma (Th1) or interleukin (IL)-17 (Th17). These Th1 and Th17 cells interact with dermal dendritic cells, macrophages, mast cells, and neutrophils. Together, they cause an inflammation that mainly involves interferon-gamma, tumor necrosis factor, IL-8, IL-12, IL-17, IL-19, and IL-23. (Ghoreschi et al 2007)
Psoriasis is a T cell mediated inflammatory skin disease characterized by hyperproliferation and reduced differentiation of epidermal keratinocytes. In severe cases, the disease can result in an insufficient nutritional status which may even be promoted by nutrient-drug interactions. Both the general diet and single food components have been suggested to play a role in etiology and pathogenesis of psoriasis. (Wolters 2006)
T cell activation and the migration of leukocytes into the epidermis and dermis play a major role in the formation of psoriatic plaques, but this is a normal body response to an antigen, so why this develops into psoriasis and why proliferation remains, is unclear. The specific genes which are upregulated in psoriasis may play a part, these include:
Dendritic cells produce IL-23, act in T- cells to produce IFN-γ.
Signal transducer and activator of transcription 1 (STAT1) is upregulated. This is induced by IFN-γ and causes the production of over 65 pro- inflammatory products such as adhesion molecules, chemokines and release of iNOS, which contribute to the inward migration of leukocytes.
STAT3 has also been implicated in psoriasis. This is believed to be a transducer of the keratinocyte hyperproliferation seen in psoriasis. It is believed that this pathway is activated by epidermal growth factors and IL-6 due to presence of receptors for these on the keratinocyte.
Increased amounts of vasoactive peptide receptors have been shown to be present in keratinocytes in psoriasis, believed to be induced by TNF-α. This is believed to upregulate synthesis of IL-6 and IL-8.
The vascularisation seen in psoriasis is believed to be caused by vascular endothelial growth factor (VEGF) and IL-8, which are released from the keratinocytes on the endothelium. (Zulfakar et al 2007)
Oxidative stress and increased production of free radicals have been related to skin inflammation in psoriasis. Some studies showed that individuals with this disease have high concentrations of malonaldehyde, a lipid peroxidation marker, and an impaired antioxidant status, with reduced levels of -carotene, -tocopherol and selenium. (Araujo et al 2009)
Within the past decade, several putative loci for genetic susceptibility to the disease have been reported on the basis of genome-wide linkage studies, but there has not been widespread replication of the results — a problem that has also been encountered in the investigation of other complex diseases. However, one locus in the major-histocompatibility-complex (MHC) region on chromosome 6 has been replicated in several populations. This locus, termed psoriasis susceptibility 1 (PSORS1), is considered the most important susceptibility locus. On the basis of association studies of three tightly linked susceptibility alleles (HLA-Cw6, HCR*WWCC, and the HLA-associated S gene), PSORS1 appears to be associated with up to 50 percent of cases of psoriasis. Other susceptibility loci are located on chromosomes 17q25 (PSORS2), 4q34 (PSORS3),1q (PSORS4), 3q21 (PSORS5),19p13 (PSORS6), and 1p (PSORS7). Most recently, an additional gene locus for psoriasis susceptibility has been discovered on chromosome 17q25. This locus, a runt-related transcription factor 1 (RUNX1) binding-site variant, encodes for a gene involved in the development of blood cells, including those of the immune system. (Schon & Boehncke 2005)
Psoriatic arthritis is an extracutaneous manifestation that affects at least 5 percent and perhaps as many as 20 percent of patients with psoriasis. The nails are affected in the majority of patients with psoriatic arthritis, but nail involvement can be seen in all types of psoriasis. The fingernails are more frequently affected than are toenails (on average, in 50 percent of patients as compared with 35 percent), and lesions range from pits and yellowish discoloration to severe onycho-dystrophy, a typical complication of acrodermatitis continua suppurativa. (Schon & Boehncke 2005)Infections, particularly streptococcal infections of the upper respiratory tract, have long been recognized as triggers of psoriasis. (Schon & Boehncke 2005)
In addition to the mediators involved in leukocyte recruitment and activation, substances such as neuropeptides appear to be involved in the pathogenesis of psoriasis. These include substance P and nerve growth factor, along with its receptor, the p75 neurotrophin receptor, and tyrosine kinase A. That neuropathogenic mechanisms contribute to the development of psoriasis is further suggested by the increase in terminal cutaneous nerves within psoriatic lesions. Finally, clinical observations, such as the symmetric distribution pattern of psoriatic lesions and the resolution of psoriasis at sites of administration of local anesthesia, are currently interpreted as evidence of the intimate involvement of the nervous system in the pathogenesis of psoriasis. (Schon & Boehncke 2005)
Role of Free Reactive Iron in PsoriasisReduced levels of serum super oxide dismutate (SOD), glutathione peroxidase (GPX), and elevated levels of nitric oxide (NO) have been reported in psoriasis. Low GPX and SOD may help to elevate the level of hydrogen peroxide (H2O2) which causes further break down of hemoglobin within erythrocytes to form hon-heme reactive iron. This free reactive iron can catalyze the Haber-Weiss reaction and generate deadly damaging hydroxyl radicals which in turn damages cellular constituents. Our findings reveal an increase in the level of free reactive iron and lower levels of antioxidant status in psoriasis. Therapeutic use of iron chelators and antioxidant drugs may be investigated for their beneficial role in psoriasis. (Ghosh et al 2008)
Natural Compounds that Increase Glutathione Peroxidase
Vitamin B–12 and Folic Acid – lower homocysteine levels.Lowering Homocysteine levels is important because homocysteine may promote endothelial dysfunction in part by decreasing GPX expression. (Lubos et al 2007)
Lowering Homocysteine levels is important because homocysteine increases the generation of H2O2 and homocysteine decreases the cell’s ability to detoxify H2O2 by reducing intracellular anti-oxidant enzymes specifically GPX. (Upchurch et al 1997)
Holy Basil extract increases Glutathione peroxidase (GPX), Superoxide Dismutase (SOD) and Catalase (Cat) (Kim et al 2010)
Resveratrol and Vitamin E elevated GPX, SOD and Cat – as well as decreasing Il-10, TNF-alpha, VEGF-A and TGF-beta1 levels (Das et al 2010)
Acanthopanax senticocus saponins – raise GPX, SOD and CAT protecting cardio-myocytes against oxidative stress injury induced by H2O2. (Zhongguo Zhi 2009)
Anthocyanins and ellagitannins extracted from blackberries – significantly increased GPX activity in an animal study. (Hassimotto & Lajolo 2010)
Cloudy apple juice – protected the anti-oxidant enzymes GPX, CAT and glutathione reductase in an animal study. (Kujawska et al 2010)
Natural Compounds that Help in the Treatment of Psoriasis
Calcitriol and its analogues have antiproliferative and prodifferentiative effects, which justify their importance in psoriasis. Oral supplementation of vitamin D should be considered in patients with psoriasis who are not on topical treatment with this vitamin. (Araujo et al 2009)
Curcuma longa extract significantly decreased the expression of CSF-1, IL-8, NF-kB2, NF-kB1 and RelA, while Annona squamosa extract significantly lowered the expression of CD40 and NF-kB1. Therefore, this in vitro study suggested that these herbal extracts capable of functioning against psoriasis, might exert their activity by controlling the expression of NF-κB signaling biomarkers. (Saelee et al 2011)
EPA – The rationale of using EPA and/or its metabolites in psoriasis is supported by findings which suggest that it has anti-inflammatory properties and plays an important role in the resolution phase of inflammation. EPA use in psoriasis has also been demonstrated in trials using oral, intravenous, and topical preparations, with generally positive outcomes. Depth profile analysis revealed that EPA and its metabolite, 15-HEPE are deposited in the epidermis, particularly in the metabolically active basal layer. Evidence so far suggests EPA does have a potential role in the treatment of psoriasis, in particular for topical treatments either as an active anti-inflammatory agent by itself, or as a dual action permeation enhancer for other anti-psoriatic treatments. (Zulfakar et al 2007)
Omega-3 fatty acids – Supplementary treatment with omega-3 fatty acids complements topical treatment in psoriasis, and makes a significant contribution to reducing PASI* and NAPSI* and improving DLQI*; and to reducing scalp lesion and pruritus, erythema, scaling, and infiltration of the treated areas. (Balbas et al 2011) *Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI) and Dermatological Life Quality Index (DLQI).
Selenium has immunomodulating and antiproliferative properties. The literature reports that patients with inflammatory skin conditions, malignant melanoma and cutaneous T-cell lymphoma present low concentrations of this element. Selenium low levels may be a risk factor for developing psoriasis, but there are few articles published about it. Decreased levels of selenium are related to severity of the disease and may be due to low food intake or excessive skin scaling. (Araujo et al 2009)
Vitamin D derivatives are one of the pillars of topical treatment of psoriasis. (Balbas et al 2011)
Medical Nutrition Therapy in the Treatment of Psoriasis
Five psoriasis cases, ranging from mild to severe at the beginning of the study, improved on all measured outcomes over a six-month period when measured by the PASI criteria, the PSS, and the lactulose/mannitol test of intestinal permeability. These results suggest a treatment regimen based on Edgar Cayce’s readings on diet and herbal teas or a related type of medical nutritional therapy may be an effective alternative or complementary (not exclusionary of conventional intervention) treatment for psoriasis. This study used a protocol including diet (high in fresh fruits and vegetables, small amounts of protein from fish and fowl, fiber supplements, olive oil, and avoidance of red meat, processed foods, and refined carbohydrates) and herbal teas. (Brown et al 2004)The prevalence and severity of psoriasis decrease during fasting. Low-calorie diets lead to relief of symptoms and might be important adjuvant factors in prevention and treatment of moderate non-pustular psoriasis. Although many mechanisms have been discussed, the direct cause of these positive effects in symptoms are still not clear. The most important explanation is probably reduced intake of arachidonic acid (AA), resulting in lower production of inflammatory eicosanoids. During fasting, there is less activation of the TCD4 cells and increased number and/or function of interleukin (anti-inflammatory cytokine), and calorie restriction leads to reduced oxidative stress. (Araujo et al 2009)
Vegetarian diets may be beneficial to all patients with psoriasis, since there is decreased intake of AA and consequent reduction in inflammatory eicosanoid formation. High concentrations of AA and its pro-inflammatory metabolites were observed in psoriatic lesions, as well as in other autoimmune and inflammatory disorders. A therapeutic option in psoriasis is to replace AA by an alternative fatty acid (FA), especially eicosapentaenoic acid (EPA), which may be metabolized by the same enzyme pathways of AA. (Araujo et al 2009)
Randomized, controlled trials have shown the effectiveness of topical vitamin A and D derivatives, intravenous ω-3 fatty acids, oral inositol, and various combined therapies. Dual therapies of ultraviolet B phototherapy and fish oil, retinoids and thiazolidinediones, and cyclosporine and a low-calorie diet were effective in the treatment of psoriasis in randomized, controlled trials. This contribution also reviews the potential negative effect of alcohol and the potential positive effects of vitamin B(12), selenium, retinoic acid metabolism-blocking agents, and a gluten-free diet in the treatment of psoriasis. (Ricketts et al 2010)
Biomarkers in Psoriasis
Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1Su- Highlights
- HIF-1 is induced by TH17 promoting signals in a Stat3-dependent manner
- HIF-1 cooperates with RORγt, Stat3, and p300 to drive transcription of TH17 genes
- HIF-1 negatively regulates Treg development by mediating Foxp3 protein degradation
- In vitro and in vivo TH17 differentiation is deficient in T cells lacking HIF-1
T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (Treg) and TH17 differentiation. HIF-1 enhances TH17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating TH17 signature genes. Concurrently, HIF-1 attenuates Treg development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of TH17-dependent experimental autoimmune encephalitis associated with diminished TH17 and increased Treg cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies. (Dang et al 2011)Psoriasis pathogenesis is closely associated with disease-inducing Th1 and Th17 cells. Yet, several studies suggest that aberrant keratinocyte or endothelial cell signalling significantly contributes to disease manifestation. Histological hallmarks of psoriatic skin include the infiltration of multiple immune cells, keratinocyte proliferation and increased dermal vascularity. Formation of new blood vessels starts with early psoriatic changes and disappears with disease clearance. Several angiogenic mediators like vascular endothelial growth factor (VEGF), hypoxia-inducible factors (HIF), angiopoietins and pro-angiogenic cytokines, such as tumour necrosis factor (TNF), interleukin (IL)-8 and IL-17, are up-regulated in psoriasis development. (Heidenreich et al 2009)
Angiogenesis is a hallmark of chronic inflammation such as psoriasis. Unraveling the pathogenesis of psoriasis shows that several proangiogenic mediators are activated and highly expressed during psoriasis. Vascular endothelial growth factor, hypoxia- inducible factor, tumor necrosis factor, interleukin-8 and angiopoietins are considered to be the main players responsible for the strong vessel formation in psoriasis. The proangiogenic milieu in the skin seems to result from a proinflammatory immune response initiated by T helper cells.(Heidenreich et al 2008)Psoriasis is a chronic inflammatory skin disease, evolving over time during a complex interplay between environmental and genetic factors. Although, in the past, psoriasis has been considered a primary keratinocyte (KC) disorder, the successful treatment of psoriasis patients with cyclosporin A suggested a potential role of the immune system in the pathogenesis of the disease. The identification of activated CD4+ and CD8+ lymphocytes in psoriatic plaques and blood of psoriatic patients, the detection of clonally expanded T cells, and studies of human skin xenografts in mice supported the growing evidence that activated T cells are the primary modulators in the pathogenesis of psoriasis.
Clinical studies on the therapeutic efficacy of T-cell-targeted drugs further substantiated the role of T cells in psoriasis. Characterization of cells and cytokines involved in the initiation and maintenance of psoriasis showed elevated levels of IFN-γ, tumor necrosis factor (TNF) –α, and IL -12, but not IL-4, IL-5, or IL-10, at both mRNA and protein levels. These observations led to the new definition of psoriasis as a T helper (Th) 1-type disease.Recently, a new population of IL-17-producing Th cells, accordingly named Th17, has been described and its involvement in model systems of autoimmunity shown. Furthermore, the development and maintenance of Th17 cells have been linked to IL-23, a key initiating cytokine in the development of autoimmunity.The findings of elevated levels of IL-23 and Th17-related cytokines in cutaneous lesions and in the serum of psoriatic patients, the association of IL23R gene variants with psoriasis, and the evidence of a functional role of Th17 cells in autoimmunity, provide the basis for a rising interest in the IL-23/Th17 axis in psoriasis. (Di Cesare et al 2009)
IL-23 signaling pathway.
IL-23 is a heterodimeric cytokine composed of p40 and p19 subunits. It binds to its IL-23 receptor complex composed of IL-12R1 and IL-23R subunits, which are associated with the Jak family members, Tyk2 and Jak2, respectively. IL-23 binding to its receptor complex results in Jak2-mediated phosphorylation of tyrosine residues located in the intracellular domain of the IL-23R subunit. Phosphorylated tyrosine residues serve as a docking site for STAT3 molecules, which in turn get phosphorylated. Phospho-STAT3 proteins homodimerize and translocate into the nucleus inducing transcription of cytokines, such as IL-17A, IL-17F, IL-22 and IFN-. Amino acid substitutions, arginine to glutamine (R381Q) and leucine to proline (L310P), in the IL-23R subunit, conferring protection against psoriasis, are shown. (Di Cesare et al 2009)
Model for T helper (Th) or T regulatory (Treg) differentiation from naïve CD4+ T cells.
Th1 cells differentiate in the presence of IL-12, and require activation of the master regulator transcription factor, T-bet, through STAT1. Fully committed Th1 cells express chemokine receptors, CXCR6, CXCR3, and CCR5, and produce IFN- and lymphotoxin through STAT4. They are involved in cell-mediated immunity against intracellular bacteria and viruses. Th2 cells depend on the presence of IL-4, STAT6, and GATA-3, and release IL-4, IL-5, IL-13, and IL-25. Th2 cells express chemokine receptors, CCR3, CCR4, and CCR8, and are important in humoral immunity against parasites and helminthes. Th17 cells require a combination of TGF-1 and proinflammatory cytokines (IL-1, IL-6, and/or IL-21) to differentiate from naïve CD4+, and RORC-(variant) 2 acts as the key transcriptional regulator. Upregulation of the IL-23 receptor makes these cells responsive to IL-23. Human Th17 cells produce, for example, IL-17A, IL-17F, IL-22, and IL-26, and are important in host protection against extracellular pathogens and in autoimmunity. Their surface markers include chemokine receptors, CCR4, CCR6, and CD161. In addition to effector T cells, naïve CD4+ T cells can also differentiate into induced Treg (iTreg) in the presence of IL-2 and TGF-1 or IL-10. iTreg produces immunosuppressive cytokines, TGF-1, IL-10, and IL-35, and express surface markers, GITR, CD25, and CLTA-4. Similar to thymus-derived naturally occurring Treg (nTreg, not shown), iTreg also expresses the master regulator transcription factor, Foxp3. (Di Cesare et al 2009)
Th17 lymphocytes and psoriasis: cellular and molecular interactions with skin-resident cells.
In the ‘IL-23/Th17 axis’ model for psoriasis, Th17 lymphocytes (Th17) interact with skin-resident cells, contributing to the psoriatic phenotype. In the dermis, IL-23, secreted by dermal dendritic cells (DDC), is able to induce Th17 lymphocyte activation with the consequent release of proinflammatory cytokines, such as IL-17A, IL-17F, IL-22, and IL-26. IL-17A, IL-17F, and IL-22 act on keratinocytes (KC) leading to epidermal hyperplasia, acanthosis, and hyperparakeratosis. Dermal CCR5+CXCR3+CXCR6+ Th1 and epidermal VLA-1+ Tc1 lymphocytes are activated by DDCs and produce TNF- and IFN-, contributing to the pathogenesis of the disease. KC hyperproliferation might also be influenced by fibroblasts, which can release keratinocyte growth factor (KGF) through TNF- stimulation. In the context of this proinflammatory milieu, activated KCs might produce IL-23, which could mediate a cross-talk with Th17 lymphocytes in synergy with IL-23 coming from DDC. Th17 cells induce KC to produce IL-8 and antimicrobial peptides (for example, S100A8, S100A9, and defensin 1/2) for recruitment of neutrophils, cathelicidin for activation of plasmacytoid dendritic cells (PDC), and vascular endothelial growth factor (VEGF) with resulting angiogenesis. (Di Cesare et al 2009)
Recent findings have suggested that Th17 cells profoundly participate in the pathogenesis of certain skin disorders, in particular, psoriasis. The concept of the subsets of T cells responsible for psoriasis has been modified in the order of Th1, T cytotoxic 1, and again Thl, and Thl7 cells. IL-22 is the strongest cytokine in the keratinocyte-proliferative ability. Since IL-22 is produced by Th17 cells, they are crucial for the proliferation of keratinocytes. Furthermore, IL-22 with the help of IL-17 can induce the critical events of psoriasis, including signal transducer and activator of transcription 3 (STAT3) activation, cytokine/chemokine (IL-8 etc.) production, and antimicrobial peptide elaboration. For maintaining Th17 cells, IL-23 is required and is released from tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthetase (iNOS)-producing dendritic cells (TIP-DCs). TIP-DCs are activated via an autocrine mechanism by virtue of TNF-alpha. The above cytokine network in the pathogenesis of psoriasis has been proven by the therapeutic effectiveness of cytokine-blocking biologics. Antibodies against TNF-alpha or its soluble receptor have already been widely used in the treatment of psoriasis. (Tokura et al 2010)
Stress Reduction, Sun Exposure, Homeopathy and Psoriasis
There are many factors involved in the induction and/or exacerbation of psoriasis of which stress is a well-known trigger factor in the appearance or exacerbation of psoriasis. Stress reaction in patients with psoriasis is probably mediated by the hypothalamic-pituitary-adrenal relationship with immunologic effects. Stress response involves increased levels of neuroendocrine hormones and autonomic neurotransmitters. Psychological stress or an abnormal response to stressors has been found to modify the evolution of skin disorders such as psoriasis. It can also have substantial psychological, and psychosocial impact on a patient’s quality of life. Treatment regimens include stress-reduction strategies, such as biofeedback, meditation, yoga, and self-help approaches. (Basavaraj et al 2011)Emotional stress may influence the development and exacerbation of psoriasis. The proportion of psoriasis patients who believe stress affects their skin condition (i.e., “stress responders”) is considerably high, ranging from 37% to 78%. Stress may worsen psoriasis severity and may even lengthen the time to disease clearance. Although a pathogenic association appears likely, additional well-controlled studies are necessary to confirm such a causal relationship. Dysregulation of the hypothalamus-pituitary-adrenal and sympathetic adrenomedullary systems has been proposed as one possible underlying cause of stress-induced flares of psoriasis. While stress may be an exacerbating factor, psoriasis itself may contribute to significant adverse psychological sequelae. (Heller et al 2011)
Clinical improvement of psoriasis following sun exposure is preceded by a rapid reduction in local and systemic inflammatory markers, strongly suggesting that immune modulation mediated the observed clinical effect. We cannot completely rule out that other mechanisms, such as stress reduction, may contribute, but it is extensively documented that UV irradiation is a potent inducer of immunosuppression and we therefore conclude that the observed effect was primarily due to sun exposure. (Soyland et al 2011)
Under classical homeopathic treatment, patients with psoriasis improved in symptoms and quality of life. (Witt et al 2009) Consider: Arsenic Alb 200 – 3 times daily for 2-4 weeks. For itchy, burning, scaly, scratching, dry, psoriasis with anxiety. Sepia 200, 3 times a day for itching not relieved by scratching. Sepia and Graphites for psoriasis of the nails and weeping psoriasis. Thyroidinum for psoriasis associated with adiposity.
Natural Treatment Strategies for Psoriasis
- Avoid red meat. This reduces arachidonic acid.
- Get adequate sunshine. Vitamin D reduces psoriasis.
- Supplement with Omega-3 fatty acids, selenium, curcumin, Vitamin D.
- Emphasis on vegetables, fresh fruit, wild-caught salmon and cold-water fish, modified Mediterranean diet.
- Emphasis on botanical formulas which down-regulate the following pathways:
- Emphasis on botanicals and nutrients which increase glutathione peroxidase.
- Customized psoriasis herbal formulas.
- Consider occasional fasting, low-calorie diet, vegetarian diet, gluten free diet, homeopathy.
- Lower stress
- We also need to target any blood work abnormalities that may be revealed in the blood work such as ferritin, iron, ESR, fibrinogen and d-dimer, homocysteine, hs-C-reactive protein (hs-CRP), Vitamin D 25(OH), etc.
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