The macula is a highly pigmented yellow spot near the center of the retina of the human eye, providing us with the clearest, most distinct vision needed in reading, driving, seeing fine detail, and recognizing facial features. AMD is characterized by the deterioration of the macula which impairs central vision. Both forms of the disease may start from affecting one eye or both eyes simultaneously.

There are two forms of macular degeneration either atrophic (dry) or neovascular (wet). These conditions can be spotted during a regular eye exam. Dry AMD is observed in 80–90% of cases and tends to progress slowly. In 10–20% of people, dry AMD progresses to the wet type.

The "dry" form of macular degeneration shows itself by the presence of yellow deposits, called drusen, in the macula. A few small drusen may not cause changes in vision; but, as they progress in size and/or quantities, their symptoms become more noticeable In advanced stages of dry macular degeneration, the light-sensitive layer of cells in the macula is thinning as well, which leads to atrophy, or tissue death resulting in development of blind spots in the center of the vision.

The "wet" form of macular degeneration is the result of the abnormal growth of the blood vessels underneath the macula. These blood vessels leak blood and fluid into the retina, causing distortion of vision, such as when the straight lines look wavy, or blind spots and loss of central vision. These abnormal blood vessels and their bleeding eventually form a scar and damage the surrounding tissues.

What are the Risk Factors or Causes for Macular Degeneration?

Macular degeneration typically occurs in older ages. Genetic factors and ethnicity play roles, for example AMD is more seen in Americans than African-Americans. Vascular diseases (including cardiovascular disease), hypertension (high blood pressure), smoking, Photo-toxicity (exposure to UV or blue light, oxidative stress, inflammation, poor diet low in B vitamins, Carotenoids, and high consumption of saturated and trans fats; all are important in progression and initiation of the AMD.

The evidence suggests that chronic vascular disease, including cardiovascular disease, as a potential cause. It is believed that slow degradation of the retina's blood vessels may lead to macular degeneration. Blockages and increased pressure of the blood vessels in the vascular layer of the eye (Choroid), possibly due to vascular disease, lead to increased ocular rigidity and less efficiency in retinal blood circulation. Cholesterol exists within the drusen spots. Research suggest that the AMD lesions and its symptoms are due to the accumulation of sub-endothelial apolipoprotein B, which is a similar condition to atherosclerotic coronary artery disease (Curcio 2010) Therefore the predictive bio-markers for cardiovascular risk such as elevated homocysteine, LDL, and C-reactive protein (CRP- Inflammatory marker) levels, are considered risk factors for AMD as well. Drusen accumulations continue to grow with advancing age; Those over 75 are 16 times more likely to develop large drusen compared to those 43-54.

Loss of elastin and collagen in Bruch’s membrane (the barrier between the retina and the choroids) and increased formation of the abnormal blood vessels which are also more fragile than typical blood vessels, cause blood and protein leakage below the macula.

Age-related accumulation of low-molecular-weight, photo-toxins, , metabolic by-products, and reduced enzymatic activity of the photoreceptor cells in the retinal pigment epithelium (RPE) is associated with drusen formation.

Oxidative stress is increased due to bad diet, exposure to UV, and smoking resulting in further inflammation in macula. The retina is susceptible to oxidative stress because of its high consumption of oxygen, high proportion of polyunsaturated fatty acids, and exposure to visible light have consistently shown to contribute to photochemical retinal injury.

Based on the genetic and epidemiology data, those who have a close relative with AMD have a 50% higher risk of eventually developing it compared to 12% for other people.

Natural Medicine For Prevention & Management of AMD

There is a well established the relation between the density of macular pigment (MP) and the onset of AMD. Macular pigments include family of main Carotenoids such as lutein, zeaxanthin, and meso-zeaxanthin(Meso-zeaxanthin is a synthetic form of natural zeaxanthin). These carotenoids are found within the macula, surrounding tissues and vessels. Lutein,& zeaxanthin participate in filtering out UV light and act as antioxidants .

Due to aging levels of these carotenoids decrease; and low levels of MPs are linked to AMD (Johnson 2010). Although there is a decline in all three types, meso-zeaxanthin found to have a sharp decrease in the macula of macular degeneration subjects. All three carotenoids are considered to be very important in maintaining the structural integrity of the macula.

Supplementing with lutein and zeaxanthin is an important preventative measure, but may also help reverse the degeneration process in the long term use. Lutein and zeaxanthin have the tissue-specific characteristic of all carotenoids, their natural tendency is to concentrate in the macula and retina. The denser the pigment, the less likely a retinal tear or degeneration to happen. Zeaxanthin is not easily found in the diet, but when taken as a supplement, it is absorbed into the blood stream and effectively increases macular pigment levels.

Powerful antioxidantsincluding Anthocyanidins and Cyanidin-3-Glucoside (C3G) are found in bilberry. Taking bilberry extract supplements have provided a significat improvement for macular degeneration as well as other eye conditions including diabetic retinopathy, retinitis pigmentosa, glaucoma, cataracts, and poor night vision.

The anthocyanidins in bilberry helps decrease vascular permeability by interacting with blood vessel collagen to slow down the enzymatic damage on the blood vessel wall. This may prevent the leakage from capillaries that is prevalent in wet AMD. Bilberry extract also provides antioxidant properties and adding vitamin E has provided greater benefits .

Anthocyanidins and Cyanidin-3-Glucoside (C3G) are highly bioavailable and enhances each other functions. They protect vessels endothelial cells against peroxynitrite (which cause endothelial dysfunction and vascular failure. They help lowering vascular inflammation while improve the activity of endothelial nitric oxide synthase (eNOS), which helps maintain normal vascular function. These benefits on blood vessels are important for retina's delicate circulation and nerve cells.

Grape Seed Extract is high in bioflavonoid with potent antioxidant properties. Bioflavonoids protect retinal ganglion cells and prevents aggregation of pathologic proteins, which suggests to provide protection against macular degeneration and neurodegenerative disorders. In vitro grape extracts can inhibit angiogenesis in human cells suggesting it may help suppress the abnormal blood vessel growth in wet AMD. In animals Grape seed extract helped reduce rate of ocular blood vessel damage seen in diabetic retinopathy.

Ginkgo Biloba in addition to provide antioxidant benefits, is well known to help improve microcapillary circulation. This property is also beneficial the eyes and slows deterioration of the macula. Ginkgo Biloba helps inhibit platelet aggregation , regulate blood vessel elasticity, and improve blood flow through major blood vessels and capillaries.

Quantities of Glutathione and Vitamin C are substantially decreased in the eyes of AMD patients . Combination of Glutathione and Vitamin C with cysteine (NAC) helps to improve Glutathione synthesis , due to the fact that cysteine remains stable in aqueous solutions and is a precursor to glutathione . Vitamin C absorbs UV radiation, which contributes to cataracts .

R- lipoic acid is considered a universal antioxidant because it is fat and water soluble. It improves the life cycle and activity of other antioxidants. In animals R- lipoic acid helped reduce new abnormal vascular formation in the eyes.

Selenium is an essential trace mineral. It is a co-factor for the activity of the antioxidant enzyme glutathione peroxidase. Selenium is important in slowing the progression of AMD and other eye disorders including cataracts and glaucoma .

L-Carnosine is a naturally occurring antioxidant and anti-glycation agent (glycation is a process through which excessive sugar bound to fat and protein molecules and form highly oxidative compounds). L-carnosine inhibits lipid peroxidation and free radical-induced cellular damage N-acetyl-carnosine helped prevent light-induced DNA damage, repaired damaged DNA strands , and improved visual acuity, glare and lens opacification in animals and humans with advanced cataracts.

A high concentration of Amino Acid Taurine is found in the retina. Taurine deficiency is contributes to alteration of retina's structure and function.

Coenzyme Q10 (CoQ10) may protect against free radical damage within the eye. Mitochondrial DNA (mtDNA) stability is necessary for proper function of mitochondria. In all regions of the eye, mtDNA damage is increased as a consequence of aging and age-related disease. Supplementing with combination of antioxidants including CoQ10, acetyl-L-carnitine, and omega-3 fatty acids helped improve the function of mitochondria in retinal pigment epithelium and subsequently stabilized visual functions in participants with early AMD.

Similar risk factors contribute to both AMD andcardiovascular disease (CVD), especially elevated Inflammatory biomarkers such as CRP and homocysteine. Elevated levels of homocysteine, is associated with low levels of certain B vitamins and increased risk of AMD and vision loss in older. Supplementing with folic acid, B6, and B12 can significantly reduce the risk of AMD in adults with cardiovascular risk factors. Taking daily B vitamin supplementation which included therapeutic dose in bio-available form of folic acid , B6, and B12 helped prevent and reduce risk of developing AMD in participants.

Vitamin B2 (Riboflavin) in B complex vitamin helps reduces oxidization of glutathione and prevent light sensitivity, reduced visual acuity, as well as burning and itching in the eyes.

Fruits with a yellow or orange color such as mangoes, kiwis, oranges, and vegetables of the dark green leafy, orange and yellow varieties are sources of lutein and zeaxanthin. Consuming such foods provide a direct effect on macular pigment density.

Food rich in Omega-3 fatty acids like oily arctic fish such as salmon, mackerel, Alaskan Pollock as well as plant/ algal sourced omega 3s are important for protection against macular degeneration and other diseases . Patients with a high dietary intake of omega-3 fatty acids had a 38% lower risk of late (more advanced) AMD.

References:

1. "Facts About Age-Related Macular Degeneration". National Eye Institute. June 2015. Archived from the original on 22 December 2015. Retrieved 21 December 2015.
2. Seddon JM, Gensler G, Klein ML, Milton RC. C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration. Nutrition. 2006;22(4):441-3.
3. Rochtchina E, Wang JJ, Flood VM, Mitchell P. Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: The Blue Mountains Eye Study. Am J Ophthalmol. 2007 Feb;143(2):344-6.
4. Fraser-Bell S, Wu J, et al. Cardiovascular risk factors and age-related macular degeneration: The Los Angeles Latino Eye Study. Am J Ophthalmol. 2008 Feb;145(2):308.316.
5. Hollyfield JG, Bonilha VL, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nature Medicine. 2008;14:194-198.
6. Haddad S, Chen CA, Santangelo S, Seddon JM. The genetics of age-related macular degeneration: A review of progress to date. Survey of Ophthalmology. 2006 Jul;51(4):316-363.
7. Dzugan SA, Arnold Smith R. Hypercholesterolemia treatment: a new hypothesis or just an accident? Med Hypotheses. 2002 Dec;59(6):751-6.
8. Delcourt C, Carriere I, et al. Dietary fat and the risk of age-related maculopathy: the POLANUT Study. European Journal of Clinical Nutrition. 2007 Nov;61(11):1341-1344.
9. Chong EW, Robman LD, et al. Fat consumption and its association with age-related macular degeneration. Arch Ophthalmol. 2009b May;127(5):674-680.
10. Chong ET, Kreis AJ, Wong TY, et al. Dietary Omega-3 Fatty Acid and Fish Intake in the Primary Prevention of Age-Related Macular Degeneration: A Systematic Review and Meta-analysis. Arch Ophthalmol. 2008;126(6):826-833.
11. Chiu CJ, Klein R, Milton RC, Gensler G, Taylor A. Does eating particular diets alter risk of age-related macular degeneration in users of the age-related eye disease study supplements? Br J Ophthalmology. June 2009. doi:10.1136/bjo.2008.143412.
12. Mehta S (September 2015). "Age-Related Macular Degeneration". Primary Care. 42 (3): 377–91. doi:10.1016/j.pop.2015.05.009. PMID 26319344.
13. Evans JR, Lawrenson JG (July 2017). "Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration". The Cochrane Database of Systematic Reviews. 7: CD000253. doi:10.1002/14651858.CD000253.pub4. PMC 6483250. PMID 28756617 & PMID 28756618.
14. "Melanin aggregation and polymerization: possible implications in age related macular degeneration." Ophthalmic Research, 2005; vol. 37: pp. 136–41.
15. John Lacey, "Harvard Medical signs agreement with Merck to develop potential therapy for macular degeneration Archived 2007-06-07 at the Wayback Machine", 23 May 2006.
16. Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP (September 2005). "Smoking and age-related macular degeneration: a review of association". Eye. 19 (9): 935–44. doi:10.1038/sj.eye.6701978. PMID 16151432.
17. Tomany SC, Cruickshanks KJ, Klein R, Klein BE, Knudtson MD (May 2004). "Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study". Archives of Ophthalmology. 122 (5): 750–7. doi:10.1001/archopht.122.5.750. PMID 15136324.
18. Szaflik JP, Janik-Papis K, Synowiec E, Ksiazek D, Zaras M, Wozniak K, Szaflik J, Blasiak J (October 2009). "DNA damage and repair in age-related macular degeneration". Mutation Research. 669 (1–2): 169–76.
19. Zafra-Stone S, Yasmin T, et al. Berry anthocyanins as novel antioxidants in human health and disease prevention. Molecular Nutrition & Food Research. 2007 Jun;51(6):675-683.
20. Serraino I, Dugo L, Dugo P, et al. Protective effects of cyanidin-3-O-glucoside from blackberry extract against peroxynitrite-induced endothelial dysfunction and vascular failure. Life Sci. 2003 Jul 18;73(9):1097-114.
21. Pergola C, Rossi A, Dugo P, Cuzzocrea S, Sautebin L. Inhibition of nitric oxide biosynthesis by anthocyanin fraction of blackberry extract. Nitric Oxide. 2006 Aug;15(1):30-9.
22. Nakaishi H, Matsumoto H, Tominaga S, Hirayama M. Effects of black currant anthocyanoside intake on dark adaptation and VDT work-induced transient refractive alteration in healthy humans. Alt Med Rev. 2000 Dec;5(6):553-62.
23. Fursova AZ, Gesarevich OG, et al. Dietary supplementation with bilberry extract prevent macular degeneration and cataracts in senesce-accelerated OXYS rats. Adv Gerontology. 2005;16:76-79.
24. Feher J, Kovacs B, Kovacs I, Schveoller M, Papale A, Balacco Gabrieli C. Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10. Ophthalmologica. 2005 May-Jun;219(3):154-66.
25. Milbury PE, Graf B, et al. Bilberry (Vaccinium myrtillus) Anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells. Invest. Ophthalmol. Vis. Sci. 2007 May;48(5):2343-2349.
26. Kaya S, Weigert G, et al. Effect of lutein supplementation on macular pigment optical density in patients with AMD. Acta Ophthalmologica. 2010 Sep;88(s246).
27. Roberts LJ, Oates JA, et al. The relationship between dose of Vitamin E and suppression of oxidative stress in humans. Free Radical Biology and Medicine. 2007 Nov;43(10):1388-1393.
28. Tan AG, Mitchell P, Flood VM, Bulutsky G, Rochtchine E, Cumming RG, Wang JJ. Antioxidant nutrient intake and the long-term incidence of age-related cataract: the Blue Mountains Eye Study. Am J of Clin Nutr. 2008 Jun;87(6):1899-1905.
29. Stahl W. Macular carotenoids: lutein and zeaxanthin. Dev Ophthalmol. 2005;38:70-88.
30. Landrum JT, Bone RA. Lutein, zeaxanthin, and the macular pigment. Arch Biochem Biophys 2001 Jan 1;385(1):28-40.
31. Bone RA, Landrum JT, et al. Lutein and zeaxanthin in the eyes, serum and diet of human subjects. Exp Eye Res. 2000 Sep;71(3):239-45.
32. Bone RA, Landrum JT, Cao Y, Howard AN, Alvarez-Calderon F. Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin. Nutr Metab (Lond). 2007 May 11;4:12.
33. Blasi MA, Bovina C, et al. Does coenzyme Q10 play a role in opposing oxidative stress in patients with age-related macular degeneration? Ophthalmologica. 2001 Jan-Feb;215(1):51-4.
34. Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr. 2003;23:171-201.
35. Chen PN, Chu SC, Chiou HL, Chiang CL, Yang SF, Hsieh YS. Cyanidin 3-glucoside and peonidin 3-glucoside inhibit tumor cell growth and induce apoptosis in vitro and suppress tumor growth in vivo. Nutr Cancer. 2005;53(2):232-43.
36. Acquaviva R, Russo A, Galvano F, et al. Cyanidin and cyanidin 3-O-beta-D -glucoside as DNA cleavage protectors and antioxidants. Cell Biol Toxicol. 2003 Aug;19(4):243-52.
37. Brubaker RF, Bourne WM, et al. Ascorbic acid content of human corneal epithelium. Invest Ophthalmol Vis Sci 2000 Jun;41(7):1681-3.
38. Williams DL, Munday P. The effect of topical antioxidant formulation including N-actetyl carnosine on canine cataract: a preliminary study. Vet Ophthalmol. 2006 Sep-Oct;9(5):311-6.
39. Thiagarajan G, Chandani S, et al. Molecular and cellular assessment of Ginkgo biloba extract as a possible ophthalmic drug. Experimental Eye Research. 2002 Oct;75(4):4231-430.
40. Mahadevan S, Park Y. Multifaceted therapeutic benefits of Ginkgo biloba L.: Chemistry, efficacy, safety and uses. Journal of Food Science. 2008 Jan/Feb;73(1):R14-R19.
41. Tan JS, Wang JJ, Flood V, Mitchell P. Dietary fatty acids and the 10-year incidence of age-related macular degeneration: The Blue Mountains Eye study. Arch Ophthalmol. 2009 May;127(5):656-665.
42. Richer S, Stiles W, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004 Apr;75(4):216-30.
43. Rapp LM, Maple SS, et al. Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina. Invest Ophthalmol Vis Sci. 2000 Apr;41(5):1200-9.
44. Pintea A, Rugina D, Pop R, et al. Antioxidant effect of trans-resveratrol in cultured human retinal pigment epithelial cells. J Ocul Pharmacol Ther. 2011 Aug;27(4):315-21.
45. Kim YH, Kim YS, Roh GS, et al. Resveratrol blocks diabetes-induced early vascular lesions and vascular endothelial growth factor induction in mouse retinas. Acta Ophthalmol. 2012 Feb;90(1):e31-7.
46. King AJ. Should we be considering selenium in glaucoma? Br J Ophthalmol. 2009;93(9):1132-1133. doi:10.1136/bjo.2008.141218.
47. Pfleger CM, et al. Grape-seed polyphenolic extract improves the eye phenotype in a Drosophila model of tauopathy. Int J Alzheimers Dis. 2010 Aug 24;2010. pii: 576357.
48. Liu M, Liu RH, Song BB, Li CF, Lin LQ, Zhang CP, Zhao JL, Liu JR. Antiangiogenetic effects of 4 varieties of grapes in vitro. J Food Sci. 2010 Aug 1;75(6):T99-104.
49. Yi C, Pan X, Yan H, Guo M, Pierpaoli W. Effects of melatonin in age-related macular degeneration. Ann NY Acad Sci. 2005 Dec;1057:384-92.
50. Vine AK, Stader J, Branham K, Musch DC, Swaroop A. Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration. Ophthalmol. Dec 2005;112(12):2076-80.

Usually, abnormal heart rate or arrhythmias are seen in people with other heart conditions; however, healthy hearts also can experience an abnormal rhythm. Some of these arrhythmias are life-threatening, and others are not directly life-threatening but can increase the risks of a stroke.

Diet, lifestyle, and some supplements are found to be important to help to manage and may preventing the conditions related to heart rhythm. What Are Arrhythmias & Risk Factors?

What Are Arrhythmias & Risk Factors?

Irregularities in heart rate or rhythm are referred to as arrhythmias. This is caused when the electrical signaling in the heart is disrupted.

Arrhythmias are commonly classified by their manifestation through slowing or speeding the heart rate, also the area of the heart that is impacted. Different types of arrhythmias may each require different treatments. Tachycardia is a term for when the heart beats too fast, Bradycardia is the term for when the heart beats too slow; and in Fibrillation, the heart beats irregularly or quivers.

About one-third of people with arrhythmias may do not experience any symptoms; but for those who do, symptoms may include: Pounding or racing heart, Chest pain, Shortness of breath, dizziness, lightheadedness, Anxiety, and Reduced capacity for exercise.

A normal range for resting heart rate is within 60-100 beats per minute, with some evidence suggesting that a heart rate at rest over 80 beats per minute may be cause for possible concern for underlying heart disease.

Risk factors for developing arrhythmia include: Other heart conditions such as Coronary artery disease (The narrowing of the heart arteries), Congestive heart failure (The inability of the heart to pump blood), Cardiomyopathy (Damaged or dysfunctional heart muscle), History of Heart Attack, Heart Birth Defects, High Blood Pressure, Imbalance Electrolytes, Overweight, Diabetes, Thyroid conditions, Stress, Use of stimulants like Caffeine, Smoking, Alcohol, Oxidative Stress, Major surgeries, and High-performance sports or in Athletes.

High blood pressure may cause an increase in the thickness and stiffness of the left ventricular walls over time, causing a change in the way in which electrical impulses move through the heart. Also, the heart's electrical conduction could be impacted by any other condition that causes alteration or disturbance of the heart blood circulation(coronary arteries), its oxygenation, and eventually the health or function of its muscle.

The normal conduction of electric impulses and normal heart muscle contractions depend on the levels of different electrolytes in the body. Impulses are generated by the movement of electrolytes through specialized cellular passages on the heart cells called ‘ion channels’. Sodium, potassium, calcium, and magnesium are the major required ions for generating electric impulses under normal conditions. Improper levels of these ions would prevent the formation of impulses, and/or their normal function, leading to the development of arrhythmias. Most treatments for arrhythmia work by modulating these ion channels.

Obesity contributes to increased risk of developing arrhythmia and other cardiac problems; it can affect the heart indirectly, by increasing lipid levels, blood pressure, and glucose intolerance, or directly, by increasing the blood volume, which elevates cardiac output and causes thickening of the heart muscle in the left ventricle.

One of the common complications after a major surgery is the onset of arrhythmic disorders, which is especially frequently observed in the elderly. Both cardiac and non-cardiac surgeries carry this risk. Local and systemic inflammation, Nervous system and hormonal changes after surgical trauma, anesthesia, injury to the heart and surrounding tissues during cardiac surgery, effects of the medical procedures, and electrolyte disturbances all play a role. These types of arrhythmias may occur in the first four days after surgery but can last much longer.

Athletes are at increased risk for developing arrhythmia which is often seen in middle-aged than young athletes. The alteration in the Autonomic nervous system, Systemic inflammation, and increased atrial size are some of the contributing factors.

Arrhythmia is different than Palpitations. Palpitations are feelings of a racing or pounding heart that may be felt in the chest, neck, or throat. These may or may not be accompanied by an abnormal heart rhythm. Often they are harmless, and in up to 16% of cases, no underlying cause can be found. Palpitations could be caused by non-cardiac conditions such as anxiety, low blood sugar, electrolyte imbalance, fever, caffeine, alcohol, tobacco, substance abuse, and certain treatments. By avoiding these triggers the condition may resolve. An electrocardiogram can be used to help find out the cause of palpitations.

Which Targeted Natural Therapies Can Help?

Omega-3 fatty acids are essential & health-promoting lipids found in certain fish as well as specific plant sources.

Omega-3 fatty acids may help protect the heart from arrhythmias. Omega 3 participates in stabilizing the electrical activity in the heart by reducing the sodium and calcium currents inside heart muscle cells. From 11 324 cases of acute myocardial infarction, those participants who within 3 months after treated with an omega-3 fatty acid of 850 mg of EPA and DHA showed reduced nonfatal heart attack and nonfatal stroke rates, as well as reduced cardiovascular death.

Similarly, a reduction in ventricular arrhythmia episodes was observed in 1014 cases of clinically diagnosed heart attack and diabetes who were given a combination of DHA, EPA, and alpha-linolenic acid (ALA; a plant-based precursor of EPA).

In 2012, a study analyzing plasma levels of various omega-3 fatty acids in a population of 3326 individuals concluded that higher levels of omega-3 fatty acids and DHA contributed to a lower risk of atrial fibrillation in older patients.

However, for those with implanted devices, it is strongly recommended to only supplement as per advice and under regular supervision of their medical practitioner to avoid unwanted risks or interactions.

Magnesium

Magnesium deficiency may result in heart disease, hypertension, and angina. The American Heart Association recommends intravenous administration of magnesium sulfate as part of treatment for some types of ventricular arrhythmias.

The addition of oral magnesium oxide to a regimen of beta-blockers helped to improve some markers of imminent ventricular tachyarrhythmia.

93.3% of participants who were given oral magnesium ( up to 3 grams daily for 30 days) had improved symptoms of premature ventricular and supraventricular complexes; while, only 16.7% of those in the placebo group.

Potassium

Potassium plays an important role in cardiac electrical stability. Alterations (deficiency or excess) in serum potassium levels, which can be caused by diuretics, may contribute to cardiac arrhythmias.

Studies support that if in an arrhythmia, the assessment of blood potassium levels indicates the low levels, increasing potassium intake through supplementation can help to improve the condition.

Both magnesium and potassium play a key role in the stability of the heart’s electrical function, thus monitoring and maintaining their normal blood levels and ratios are critical for a healthy heart. Low blood concentrations of magnesium and potassium are associated with an increased risk of developing ventricular arrhythmias.

Antioxidants

Oxidative stress and inflammation contribute to the development of arrhythmia particularly post-operative atrial fibrillation; thus studies have attempted to find out how and which antioxidants would be useful.

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a powerful antioxidant and an important component of cellular energy production. A number of studies have noted a therapeutic role for CoQ10 involving heart conditions.

Evidently, CoQ10 possess antiarrhythmic action. In conditions such as impaired cardiac function or metabolic disease like type 2 diabetes, supplementation was beneficial in reducing premature ventricular contractions.

In 2500 patients with heart failure, 3 months of supplementation with CoQ10 daily ranging from 50 – 150 mg helped improving the arrhythmia signs and symptoms in 62% of subjects.

CoQ10 supplementation for 7 days preceding scheduled coronary artery bypass was associated with lower markers of oxidative stress and significantly lower incidence of ventricular fibrillation.

In a controlled clinical trial, patients of heart attack, who were given28 days of CoQ10 supplementation had a 2.6 times less occurrence of arrhythmias, overall less evidence of oxidative stress, with increased blood levels for their other antioxidants such as vitamins A, C, and E.Vitamins C and E

Data analysis suggests Vitamins C and E may also provide a protective effect due to their antioxidant properties. Vitamin therapy helped with a significant reduction in the incidence of postoperative atrial fibrillation and all-cause arrhythmia. This effect was independent of the type of surgery.

Evidently, also there is a synergistic effect between antioxidant vitamins and beta-blockers. In 100 patients undergoing bypass surgery combination of oral vitamin C (2 grams on the night prior to surgery and 2 grams daily for 5 days thereafter) and a beta-blocker was more effective in preventing postoperative atrial fibrillation than the beta-blocker treatment alone. The incidence was only 4% in the vitamin C group; while, at 26% in the control group. Similar other studies observed similar results.

In other clinical studies, pre-operative treatment with vitamin E for 28 days followed by vitamin C on days 27-29 reduced the incidence of arrhythmias in patients undergoing bypass surgery.

Resveratrol

Resveratrol is known for its antioxidant and anti-inflammatory properties. In animals resveratrol can weaken inflammatory responses and oxidative stress after myocardial infarction; and significantly suppressed myocardial infarction-induced ventricular arrhythmias and improved long-term survival.

It is suggested that Resveratrol works in a concentration-dependent manner, by inhibiting the calcium current, which reduces the intracellular calcium overload, or opening certain potassium channels.

N-acetyl-cysteine

The beneficial effects of N-acetyl-cysteine (NAC) treatment are attributed to its antioxidant and anti-inflammatory properties (Ozaydin 2008). Data analysis concluded that NAC supplementation may effectively reduce the incidence of postoperative atrial fibrillation. In a trial Postoperative atrial fibrillation was found in only three patients from the NAC-treated group, as compared with 12 patients from the placebo group.

Hawthorn

Hawthorn is rich in antioxidants such as flavonoids and anthocyanins. Also, it is suggested that hawthorn may help support heart and vascular health by modulating the ions such as calcium and potassium channels, blood flow, inflammation, and oxygen utilization.

In animals model, after deprivation and subsequent reinstitution of blood supply to the heart (mimicking a heart attack), infusions of hawthorn extracts reduced the number of arrhythmias compared to control group.

In a 24-week long human clinical trial of 1000 patients with heart failure, hawthorn supplementation helped improve heart function and reduced symptoms such as fatigue and palpitations. Supplementation also helped increase the duration of their heart rhythms remaining normal.

Rhodiola

Experimental pre-clinical research suggests that taking rhodiola may help improve several indicators of cellular health in heart following induced ischemic injury (oxidative stress) in animals.

Dietary and Lifestyle Considerations:

Studies have found that the type of diet & vitamin intake, do have an effect on the incidence of arrhythmias. In the clinical studies those participants with low adherence to the mediterranean diet had more occurrences of atrial fibrillation; while in participants with high adherence with the diet, spontaneous conversion back to normal electrical impulses in the heart were observed. Although the are more studies to further clarify these findings, high adherence to a Mediterranean diet may potentially help prevent occurrences of arrhythmias.

Other changes in lifestyle also have shown to help reduce risk of arrhythmia. Adequate exercise, maintaining a healthy body weight , reducing stress, reducing blood lipids, lowering sugar intake, keeping inflammation in check, avoiding stimulants, lowering caffeine intake, quitting smoking , and cutting back on alcohol all have shown to improve overall heart health and help prevent development of arrhythmias.

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3. How to Maintain and Restore Healthy Blood Lipids Level
4. Vital Scientific Facts to Maintain an Ideal Cardiovascular Health!
5. Essential Nutrients For Healthy Thyroid Function
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Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

Select References:

1. Mayo Clinic. Heart arrhythmias. Definition. Available at: mayoclinic.com/health/heart-arrhythmias/ds00290 Last updated Feb 11, 2011a. Accessed June 26, 2012.
2. Weirich J, Wenzel W. [Current classification of anti-arrhythmia agents&91;. Zeitschrift fur Kardiologie. 2000;89 Suppl 3:62-67.
3. Mayo Clinic. Heart arrhythmias. Risk factors. Available at: mayoclinic.com/health/heart-arrhythmias/ds00290 Last updated February 11, 2011d. Accessed December 4, 2012.
   
4. Mayo Clinic. Heart arrhytmias. Causes. Available at: mayoclinic.com/health/heart-arrhythmias/ds00290 Last updated February 11, 2011c. Accessed December 4, 2012.
   
5. Merriam-Webster. Tacchyarrhythmia. Avialable at: merriam-webster.com/dictionary/ tochyarrhythmia Accessed 12/5/2012.
   
6. National Heart Lung and Blood Institute. What is an arrhythmia? Available at: nhlbi.nih.gov/health/health-topics/topics/arr/. Last updated July 1, 2011a. Accessed 06/26/2012.
   
7. Nauman J, Nilsen TI, Wisloff U, Vatten LJ. Combined effect of resting heart rate and physical activity on ischaemic heart disease: mortality follow-up in a population study (the HUNT study, Norway). Journal of epidemiology and community health. Feb 2010;64(2):175-181.
8. National Heart Lung and Blood Institute. What are palpitations? Available at: nhlbi.nih.gov/health/health-topics/topics/hpl/. Last updated July 1, 2011c. Accessed December 4, 2012.
   
9. National Institutes of Health. Heart Palpitations. Available at: nlm.nih.gov/medlineplus/ency/articel/ 003081 Last updated 03 June, 2012c. Accessed 09/17/2012.
   
10. Raviele A, Giada F, Bergfeldt L, et al. “Management of patients with palpitations: a position paper from the European Heart Rhythm Association.” EP Europace (2011): 920-934.
11. Abdel-Qadir HM, Tu JV, Yun L, Austin PC, Newton GE, Lee DS. Diuretic dose and long-term outcomes in elderly patients with heart failure after hospitalization. American heart journal. Aug 2010;160(2):264-271 e261.
12. Fazio S, Palmieri EA, Lombardi G, et al. “Effects of thyroid hormone on the cardiovascular system.” Recent Prog Horm Res 59 (2004): 31-50.
13. Jeong EM, Liu M, Sturdy M, Gao G, Varghese ST, Sovari AA, Dudley SC, Jr. Metabolic stress, reactive oxygen species, and arrhythmia. Journal of molecular and cellular cardiology. Feb 2012;52(2):454-463.
14. Magri D, Piccirillo G, Quaglione R, et al. "Effect of Acute Mental Stress on Heart Rate and QT Variability in Postmyocardial Infarction Patients." ISRN Cardiol 2012 (2012): 912672.
15. Taggart P, Boyett MR, Logantha S, et al. “Anger, emotion, and arrhythmias: from brain to heart.” Front Physiol 2 (2011): 67.
16. Peretto G, Durante A, Limite LR, Cianflone D. Postoperative arrhythmias after cardiac surgery: incidence, risk factors, and therapeutic management. Cardiology research and practice. 2014;2014:615987-615987.
17. Turagam MK, Velagapudi P and Kocheril AG “Atrial fibrillation in athletes.” Am J Cardiol 109 (2012): 296-302.
18. Maisel WH. Autonomic modulation preceding the onset of atrial fibrillation. J Am Coll Cardiol. 2003;42(7):1269-70.
19. Mathew B, Francis L, Kayalar A, et al. “Obesity: effects on cardiovascular disease and its diagnosis.“ J Am Board Fam Med 21 (2008): 562-568.
20. Rasoli S, Kakouros N, Harling L, et al. "Antioxidant vitamins in the prevention of atrial fibrillation: what is the evidence?" Cardiol Res Pract 2011 (2011): 164078.
21. Sali A and Vitetta L. "Integrative medicine and arrhythmias." Aust Fam Physician 36 (2007): 527-528.
22. Gallego J, Gil Alzueta MC. [Dabigatran: a new therapeutic alternative in the prevention of stroke&91;. Neurologia (Barcelona, Spain). Mar 2012;27 Suppl 1:39-45.
23. Brouwer IA, Raitt MH, Dullemeijer C, et al. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. European Heart Journal. 2009;30:820-26.
24. Pepe M and Recchia FA. "Omega-3 fatty acids for the prevention of myocardial infarction and arrhythmias." Cardiovasc Ther 28 (2010): e1-4.
25. Wu JH, Lemaitre RN, King IB, et al. Association of plasma phospholipid long-chain omega-3 fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study. Circulation. 2012 Mar;125(9):1084-93.
26. Kromhout D, Geleijnse JM, De Goede J, et al. "n-3 fatty acids, ventricular arrhythmia-related events, and fatal myocardial infarction in postmyocardial infarction patients with diabetes." Diabetes Care 34 (2011): 2515-2520.
27. Jenkins DJA, Josse AR, Beyene J, et al. Fish-oil supplementation in patients with implantable cardioverter defibrillators: a meta-analysis. CMAJ. 2008;178(2): 157-64.
28. Lavie CJ, Milani RV, Mehra MR, et al. "Omega-3 polyunsaturated fatty acids and cardiovascular diseases." J Am Coll Cardiol 54 (2009): 585-594.
29. Marik PE and Varon J. "Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review." Clin Cardiol 32 (2009): 365-372.
30. Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 Drug Surveillance Investigators. The Clinical investigator. 1993;71(8 Suppl):S145-149.
31. Chello M, Mastroroberto P, Romano R, et al. Protection by coenzyme Q10 from myocardial reperfusion injury during coronary artery bypass grafting. The Annals of thoracic surgery. Nov 1994;58(5):1427-1432.
32. Singh RB, Wander GS, Rastogi A, et al. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. Sep 1998;12(4):347-353.
33. Singh U, Devaraj S, Jialal I. Coenzyme Q10 supplementation and heart failure. Nutrition reviews. Jun 2007;65(6 Pt 1):286-293.
34. Harling L, Rasoli S, Vecht JA, et al. "Do antioxidant vitamins have an anti-arrhythmic effect following cardiac surgery? A meta-analysis of randomised controlled trials." Heart 97 (2011): 1636-1642.
35. Hung LM, Su MJ and Chen JK. “Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms.” Free Radic Biol Med 36 (2004): 774-781.
36. Xin P, Pan Y, Zhu W, et al. “Favorable effects of resveratrol on sympathetic neural remodeling in rats following myocardial infarction.” Eur J Pharmacol 649 (2010): 293-300.
37. Korantzopoulos P, Kolettis TM, Kountouris E, et al. "Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation." Int J Cardiol 102 (2005): 321-326.
38. Rodrigo R, Vinay J, Castillo R, et al. "Use of vitamins C and E as a prophylactic therapy to prevent postoperative atrial fibrillation." Int J Cardiol 138 (2010): 221-228.
39. Bachman DM "Oral magnesium ion shortens prolonged QTc interval." J Clin Psychiatry 64 (2003): 733-734.
40. Falco CN, Grupi C, Sosa E, et al. "Successful improvement of frequency and symptoms of premature complexes after oral magnesium administration." Arq Bras Cardiol (2012): 480-487.
41. Guerrera MP, Volpe SL and Mao JJ. "Therapeutic uses of magnesium." Am Fam Physician 80 (2009): 157-162.
42. Gu WJ, Wu ZJ, Wang PF, Aung LH, Yin RX. N-Acetylcysteine supplementation for the prevention of atrial fibrillation after cardiac surgery: a meta-analysis of eight randomized controlled trials. BMC cardiovascular disorders. 2012;12:10.
43. al Makdessi S, Sweidan H, Dietz K, Jacob R. Protective effect of Crataegus oxyacantha against reperfusion arrhythmias after global no-flow ischemia in the rat heart. Basic research in cardiology. Apr 1999;94(2):71-77.
44. Rigelsky JM, Sweet BV. Hawthorn: pharmacology and therapeutic uses. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. Mar 1 2002;59(5):417-422.
45. Chang WT, Dao J, Shao ZH. Hawthorn: potential roles in cardiovascular disease. The American journal of Chinese medicine. 2005;33(1):1-10.
46. Tadic VM, Dobric S, Markovic GM, Dordevic SM, Arsic IA, Menkovic NR, Stevic T. Anti-inflammatory, gastroprotective, free-radical-scavenging, and antimicrobial activities of hawthorn berries ethanol extract. Journal of agricultural and food chemistry. Sep 10 2008;56(17):7700-7709.
47. Edwards JE, Brown PN, Talent N, Dickinson TA, Shipley PR. A review of the chemistry of the genus Crataegus. Phytochemistry. Jul 2012;79:5-26.
48. Maimeskulova LA and Maslov LN. "[Anti-arrhythmic effect of phytoadaptogens&91;." Eksp Klin Farmakol 63 (2000): 29-31.
49. Mattioli AV, Miloro C, Pennella S, et al. "Adherence to Mediterranean diet and intake of antioxidants influence spontaneous conversion of atrial fibrillation." Nutr Metab Cardiovasc Dis. 2011 Jul 26. [Epub ahead of print&91;
50. Chamberlain AM, Agarwal SK, Folsom AR, et al. "Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study." Heart Rhythm 8 (2011): 1160-1166.
51. D'Alessandro A, Boeckelmann I, Hammwhöner M, et al. “Nicotine, cigarette smoking and cardiac arrhythmia: an overview,” Eur J Prev Cardiol 19 (2012): 297-305.
52. Kodama S, Saito K, Tanaka S, et al. "Alcohol consumption and risk of atrial fibrillation: a meta-analysis." J Am Coll Cardiol 57 (2011): 427-436.
53. Mattioli AV, Bonatti S, Zennaro M, et al. "Effect of coffee consumption, lifestyle and acute life stress in the development of acute lone atrial fibrillation." J Cardiovasc Med (Hagerstown) 9 (2008): 794-798.
54. Ziegelstein RC. “Acute emotional stress and cardiac arrhythmias.” JAMA 298 (2007): 324-329.

Gallstones are hard deposits made of cholesterol or bilirubin found in bile. Gallstones can develop in the gallbladder or bile ducts. Bile is produced by the liver and flows into the gallbladder to be stored and released to help with the digestion and absorption of fat . Gallstones are commonly formed due to excessive amounts of cholesterol in the bile which causes bile to thicken and crystallize.

Gallstones are formed in a variety of sizes, from tiny grains of sand to golf ball-sized particles. Often those small stones cause the most trouble. These little stones can leave the gallbladder and get trapped in the bile duct. Larger stones tend to remain in the gallbladder. Many people who have gallstones are never bothered by them and may not be aware of their formation.

Gallstones cause inflammation of the gallbladder which manifests itself in the form of dull pain and indigestion. Moving stones, however, result in acute and often severe pain if they block bile flow. Gallstones may result in inflammation of the gallbladder, liver, or pancreas and in rare occasions may become life-threatening.Gallstones are also linked to increased risk of certain cancers and cardiovascular diseases.

What is the gallbladder?

The gallbladder is a small pear shaped, muscular pouch beneath the liver, on the right side of the body. It is about three to six inches long. The gallbladder’s job is to receive, store, and dispense bile produced by the liver cells.

Bile moves through a network of small ducts within the liver. The connection of these small ducts forms the right hepatic duct (which drains bile from the right half of the liver) and the left hepatic duct (which drains bile from the left half of the liver). The junction of the left and right hepatic ducts forms the common hepatic duct. The common hepatic duct from one side is connected directly to the common bile duct and the duodenum (the first part of the small intestine); while from another side, it connects to cystic duct leading to the gallbladder. This entire system of ducts is called the biliary system.

The gallbladder stores bile, which is available to be used for digestion on very short notice. Between meals, the gallbladder is relaxed, but during meals, signals from the digestive tract stimulate contractions of the gallbladder and some stored bile is released into the common bile duct where it’s passed into the small intestine to mix with food.

What is bile?

Bile is a dark-green-to-yellowish-brown fluid which is continuously produced by the liver. It is a combination of cholesterol, bilirubin, bile salts and lecithin. Bile helps break down fat during the digestion process. Bile reaches the duodenum directly from the hepatic duct (from the liver) or from the gallbladder.

Bile in addition to being an important part of digestion, carries waste products from the liver to be eliminated through the digestive tract

The two main pigments of bile are bilirubin, which is orange–yellow, and its oxidized form biliverdin which is green. When mixed, they are responsible for the brown colour of the stool.

What are the gallstones?

Gallstones are hard deposits formed from bile components. Gallstones can be categorized based on their cholesterol content:

Cholesterol stones; are usually made up of more than 70 % cholesterol and are the most common type of gallstones.

Pigment Stones; are mainly made of bilirubin and formed due to high levels of bilirubin. Pigment stones contain less than 30 % cholesterol. Calcium salts are also found in higher concentrations in pigment gallstones.

Pigment stones usually form when there is increased level of bilirubin in the bile. Conditions such as liver cirrhosis, certain blood disorders, parasitic infections, and narrowing of bile ducts can cause increased bilirubin in the bile, contributing to pigment gallstones formation.

Mixed stones; are referred to the stones with the cholesterol content between 30% and 70%.

Majority of gallstones are cholesterol stones or mixed stones which are linked to diets consisting of high amounts of cholesterol and saturated fats. People with gallstones often have high levels of oxidized lipids in their blood.

At the very beginning stage of the stone formation, gallbladder muscles are weakened which reduces the gallbladder response to the signals from digestive tract to empty the bile. Therefore, the thicken bile and the cholesterol sludge remain in the gallbladder to create gallstones over time.

Gallstones are most found in the gallbladder, but they can travel from the gallbladder to the common bile duct, which is the largest duct in the liver.

What conditions are associated with gallstones?

The bile duct stones are much less common but can create more serious medical situations than just gallstones that stay in the gallbladder. Common bile duct stones can block the common bile duct, resulting in a serious infection known as cholangitis; inflammation of the gallbladder, pancreatitis (inflammation of the pancreas), and Choledocholithiasis occur when one or more gallstones trapped in the common bile duct. Biliary pain is the most common symptom of gallstone disease, which is commonly described as acute, severe pain in the upper-right or upper-mid region of the abdomen, radiating to the right shoulder or between the shoulder blades; and it may last for minutes to hours especially after eating.

Cholecystitis (inflammation of the gallbladder) causes biliary pain, fever, and nausea. In its chronic form causes digestive symptoms such as gas, bloating, nausea, and gag. These symptoms are usually worse after eating fatty foods.

cholangitis is Infection& inflammation of the bile ducts due to an obstruction, causing abdominal pain, fever, and jaundice.

pancreatitis is the inflammation of the pancreas due to blockage of the pancreatic duct. It symptoms include biliary pain , and potential life-threatening condition in which causes the inflammation of the lining of the inner abdominal wall (peritonitis).

Ileus is another rare condition that can be caused by larger stones. Ileus is the lack of intestinal movement that leads to a buildup with potential blockage of food material, and an intestinal obstruction. This means no food material, gas, or liquids can not get through.

Why do the gallstones form?

Gallstones can develop for several reasons involving genetic, ethnicity, gender, age, family history, diet, and environmental factors. When there is a critical concentration of cholesterol or bilirubin in the bile, slow gallbladder that does not empty the bile, liver diseases, blood disorders, aging, during pregnancy, rapid weight loss, fasting, obesity, high blood sugar or diabetes, high blood lipids, hormonal imbalance, hormone therapy, and certain medications increase the risk of gallstone formation.

High caloric foods, carbohydrates, saturated fats, and sugar along with low intake of fiber have been linked to increased risk, while consumption of polyunsaturated fats, fiber, fish, fruits and vegetables, and nuts have been associated with lower risk.

While gradual weight loss may reduce gallstone risk, rapid weight loss increases the risk of gallstone formation. Prolonged fasting and weight cycling often seen in inconsistent dieting are also contribute to higher cholesterol gallstone risk.

Evidently, food allergies and intolerances promote gallstone formation by triggering gallbladder inflammation and slowing gallbladder emptying. One week of the elimination diet helped to resolve the gallbladder symptoms in all participants. Suspected food allergens such as dairy (milk, cheese, and ice cream), wheat (gluten), soy, corn, preservatives, and chemical food additives, and Eggs, especially, may irritate the gallbladder. Your practitioner may recommend testing for food allergies.

Risk of developing cholesterol and pigmented stones increases with age, due to lower bile acid production which is leading to greater concentration of cholesterol in the gallbladder. Also, aging may also be associated with reduced gallbladder motility.

Additional hormone exposure through oral contraceptives and post-menopausal hormone therapy may increase the risk of gallstone formation. Data analysis suggests that that hormone therapy increased risk of gallstones. Estrogen seems to be responsible for this negative effect, and adding the progesterone to estrogen therapy does not reduce the risk. Topical bioidentical estradiol also demonstrated the same negative effect on bile cholesterol saturation and crystallization time after eight weeks of use.

Gallstones are more common during pregnancy due to decreased gallbladder motility and increased cholesterol saturation of bile. Added estrogen in the body can lead to an increased amount of cholesterol in the bile, while also reducing gallbladder contractions (cholestasis of pregnancy).

Individuals with iron-deficiency anemia are at a higher risk of gallstones than those with normal iron levels. This relationship has been verified in the reverse as well: gallstone patients have been found to be more likely to have low serum iron levels than healthy individuals . Iron deficiency may alter the activities of several liver enzymes, leading to increased cholesterol saturation in bile and increased cholesterol crystallization, and it also negatively impacts gallbladder motility. In addition, it is possible that gallstone disease contributes to iron malabsorption and poor iron status. Only those with iron deficiency should consider iron supplementation to reduce the risk of gallstones.

High levels of iron due to break don of red blood cells in certain diseases and also due to high intake of specially Heme iron or Iron from the red meat is associated with higher risk of pigment gallstone formation.

Several pharmaceuticals are known to increase the risk of gallstones, such as estrogens, oral contraceptives, anti-biotics, diuretics (used mainly to treat high blood pressure), and some blood cholesterol lowering agents.

Which natural medicine can help prevent gallstone formation?

Individuals with higher risk factors of ethnicity, age, family history, hormone therapy, or medical factors such as high blood lipids (cholesterol & triglycerides), high blood sugar, liver conditions like none alcoholic fatty liver, viral hepatitis, or history of some parasitical infections, slow digestion, dyspepsia, gas, bloating, and those with known silent gallstones, or the history of them may want to consider supplements to reduce their risk.

Vitamin C is necessary for the conversion of cholesterol into bile acids . The link between vitamin C deficiency and gallstones has been recognized decades ago. Low vitamin C level causes increased cholesterol saturation in the bile. In a group of candidate of gallbladder removal those who supplemented with vitamin C showed better bile consistency and delayed formation of further cholesterol crystals than those without vitamin C.

Supplementing with omega-3 fatty acids of high EPA and DHA may help prevent gallstones by improving bile composition and the gallbladder function.

A study looked at gallbladder function in individuals with obesity and high insulin levels found that those who took omega3 supplement or ate fish had a better gallbladder function than those who did not, concluding omega 3 helps lowering their risk for gallbladder problems.

Omega-3 helps to encourage the gallbladder to empty itself regularly, something that is considerably helpful if an individual also has high triglyceride levels which have been associated with gallstone development. Supplementing for roughly six weeks makes a difference in how the gallbladder is reacting.

Data from other studies suggest that supplementing with 3.7g omega 3 daily helped to reduce the ratio of cholesterol to phospholipids in bile; and lowered super saturation with cholesterol, thus helped to prevent precipitation of cholesterol crystals in bile of gallstone patients.

S-Adenosyl-L-Methionine (SAMe) is a natural compound and methyl group donor that supports the methylation cycle, glutathione production, and gene expression. Methylation is fundamental for the elimination of certain toxins. Chronic liver disorders and alcohol consumption inhibit the ability to produce an adequate amount of SAMe. SAMe supplementation helps to improve the bile flow. SAMe is also beneficial for women with an increased bile cholesterol saturation after starting oral contraceptives; supplementing with SAMe for two cycles has helped to reduce the bile cholesterol saturation in participants.

Curcumin helps reduce the possibility of gallstone formation by improving cholesterol and lipid metabolism. Curcumin has also been shown to improve gallbladder motility, reduce gallbladder inflammation, and normalize bile acid metabolism. Curcumin may also be helpful in recovery after cholecystectomy and reduces the need for pain relievers.

Milk thistle is often used as a natural treatment for liver conditions such as cirrhosis, jaundice, hepatitis, and gallbladder disorders. Silymarin is the main active ingredient in milk thistle. Silymarin provides both anti-inflammatory and antioxidant benefits. Silymarin and silybin, its major active compound, have been noted to reduce bile cholesterol content in human, suggesting its potential value in gallstone prevention and treatment. Milk thistle in general is considered safe and well-tolerated .

Dandelion is regarded one of the finest liver remedies. It enhances the flow of bile, and helps improving liver congestion, bile duct inflammation, hepatitis, gallstones, and jaundice. Supplementing with dandelion root extract helps to increase bile production in the liver causing greater flow of bile to the gallbladder (choleretic effect). In addition, it causes contraction and release of stored bile in the gallbladder (cholagogue effect).

The active ingredient in Artichoke is cynarin, which like silymarin demonstrates significant liver protective and regenerative effects. It also creates a choleretic effect, with acts to decongest the liver.

The other most common natural medicine for the liver diseases is the artichoke (Cynara scolymus L., family Asteraceae. Cynarin is one of the important bioactive constituents of artichoke. Clinical treatments have confirmed the therapeutic properties of this plant, especially in hypercholesterolemia, digestive disorders and irritable bowel syndrome. Currently, the raw material is used for the production of medicinal preparations for liver failure, inflammation of the gallbladder, cholangitis, cholelithiasis and disorders of lipid metabolism. Furthermore, it was shown that extracts from artichoke leaves indirectly reduces hepatic cholesterol biosynthesis.

Cynarin compound stimulates bile secretion and helps to reduce blood cholesterol which in turn helps prevent gallstones forming, it said in a press release.

A high-fiber diet helps prevent gallstones. In several publications, it has been recommended for women to take 25 grams of fiber daily and men consume 38 grams of fiber.

Those who followed the high fiber diet accumulated less gallbladder sludge, which reduced their risk of developing gallbladder disease. This suggests that a high fiber diet can help prevent gallbladder disease in individuals who need to lose weight quickly, and perhaps overall.

Results from clinical studies have supported effectiveness of specific homeopathic remedies. However, a professional homeopath may recommend one or more of the treatments for gallbladder disease based on clinical experience considering totality of person's signs and symptoms including all the physical plus emotional status of the patient to choose appropriate treatment plan.

Some of the most common homeopathic medicines for gallbladder conditions are including; Colocynthis, for colicky abdominal pains which get better by pressure or bending. Chelidonium, for when the abdominal pain that radiated to the shoulder area. Lycopodium, for when abdominal pain gets worse with deep breaths. Remedies, doses, and potencies may vary depending on the stage of the condition.

What lifestyle and dietary factors would help to prevent gallstone formation?

Dietary factors are very important when it comes to preventing cholesterol gallstone formation. High calorie diets including high fat, sugar, refined carbohydrates, saturated fat, cholesterol, trans fats, fried foods, highly processed foods (doughnuts, cookies, white bread), High fat dairy products (milk, butter, cheese, ice cream), Processed meats (bacon, ham, sausage), and alcohol increase risk of gallstones and the related complications.

Diet rich in fiber, vegetables, plant based proteins, omega3 fats, , and legumes is associated with lower risks of gallstone formation.

In overweight individuals weight management strategies are very important to reduce the risk of gallstones; however, a rapid weight loss increases the possibility of gallstone formation.

Physical activity may help prevent cholesterol gallstone formation by improving the motility of the digestive system and by helping with cholesterol metabolism.

During pregnancy keeping a healthy diet rich in fiber, Good fats like omega3's and unsaturated fats, and low in refined carbohydrates, and saturated fat such as those found in animal products may help reduce risk of gallbladder symptoms. This can help keep you and your baby healthy. But always keep your healthcare practitioner informed if you do have symptoms that involve your gallbladder.

Related Articles:

• How to Maintain and Restore Healthy Blood Lipids Level
• How to lose weight successfully and maintain it!
• The best way to know your liver and protect it!
• How to maintainhealthy blood sugar & improve diabetic conditions?

Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

References:

1. Fogel ELS, S. Diseases od the Gallbladder and Bile Ducts. In: Goldman L, Schafer A, eds. Goldman-Cecil Medicine. 25th edition. Philadelphia: Pennsylvania: Elsevier/Saunders; 2016:1038–1048. 2016.
2. Housset C, Chretien Y, Debray D, Chignard N. Functions of the Gallbladder. Comprehensive Physiology. Jun 13 2016;6(3):1549-1577.
3. Jones MW, Ghassemzadeh S. Gallbladder, Gallstones (Calculi). StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2018.
4. Hundt M, John S. Physiology, Bile Secretion. StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2018.
5. University of Maryland Medical Center; Gallstones and Gallbladder Disease - Risk Factors; June 26, 2009
6. Jiang ZY, Sheng X, Xu CY, et al. Gallbladder gallstone disease is associated with newly diagnosed coronary artery atherosclerotic disease: a cross-sectional study. PLoS One. 2013;8(9):e75400.
7. International Journal of Clinical Chemistry"; Triglycerides and Gallstone Formation; A. Smelt; November 2010
8. https://europepmc.org/article/med/1398503 gallstone disease.
9. Kaufman HS, Magnuson TH, Pitt HA, Frasca P, Lillemoe KD. The distribution of calcium salt precipitates in the core, periphery and shell of cholesterol, black pigment and brown pigment gallstones. Hepatology. May 1994;19(5):1124-1132.
10. Vitek L, Carey MC. New pathophysiological concepts underlying pathogenesis of pigment gallstones. Clinics and research in hepatology and gastroenterology. Apr 2012;36(2):122-129.
11. Chen Y, Kong J, Wu S. Cholesterol gallstone disease: focusing on the role of gallbladder. Laboratory investigation; a journal of technical methods and pathology. Feb 2015;95(2):124-131.
12. Di Ciaula A, Wang DQ, Bonfrate L, Portincasa P. Current views on genetics and epigenetics of cholesterol gallstone disease. Cholesterol. 2013;2013:298421.
13. Wang HH, Liu M, Li X, Portincasa P, Wang DQ. Impaired intestinal cholecystokinin secretion, a fascinating but overlooked link between coeliac disease and cholesterol gallstone disease. European journal of clinical investigation. Apr 2017;47(4):328-333.
14. Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut and liver. Apr 2012;6(2):172-187.
15. Ko, CW. Prefac: Gallbladder disease. Gastroenterol Clin North Am. 2010;39(2):xiii.
16. Shaffer EA. Gallstone disease: Epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol. 2006;20(6):981-96.
17. Karłowicz-Bodalska K, Bodalski T. Role of plant crude drugs in treatment of liver diseases. Post Fitoter 2007; 3:155-167.
18. Boroń-Kaczmarska A, Morańska I, Kruszewski T. Hepatic disorders, therapy recommendations. Nowa Klin 1999; 6(1):45-48.
19. Krauze M. Arnika, karczoch, kozieradka w laboratorium. Panacea 2004; 2(7):32.
20. Gawęcki J, Hryniewiecki L. Żywienie człowieka. Podstawy nauki o żywieniu. Wydawnictwo PWN S.A., Warszawa 2004; 198-206.
21. Baiu I, Hawn M. Gallstones and Biliary Colic. JAMA. 2018; 320(15): 1612. Accessed 10/15/2019.
22. US Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases. Gallstones. Accessed 10/15/2019.
23. US Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases. Endoscopic Retrograde Cholangiopancreatography (ERCP). Accessed 10/15/2019.
24. American Academy of Family Physicians. Gallstones. Accessed 10/15/2019.
25. Nemours, KidsHealth. A to Z: Cholelithiasis (Gallstones). Accessed 10/15/2019.
26. American Family Physician. Gallstones: What are they? How are they treated? Accessed 10/15/2019.
27. American Gastroenterological Association. Gallstones. Accessed 10/15/2019.
28. Merck Manual. Gallstones. Accessed 10/15/2019.
29. American Heart Association. Cooking to Lower Cholesterol. Accessed 10/15/2019.
30. Could Your Abdominal Pain Actually Be Gallstones? Cleveland Clinic. May 13, 2019.
31. Gallstones. National Institute of Diabetes and Digestive and Kidney Diseases.
32. Bari O, Wang T, Liu M, Paik C, Portincasa P, Wang D. Cholesterol cholelithiasis in pregnant women: Pathogenesis, prevention and treatment. Ann Hepatol. 2014;13(6):728-745. doi:10.1016/s1665-2681(19)30975-5
33. Jessri, M. & Rashidkhani, B. (2015). Dietary patterns and risk of gallbladder disease: A hospital-based case-control study in adult women. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438...
34. Lander, E. M., et al. (2016). Vegetable protein intake is associated with lower gallbladder disease risk: Findings from the Women’s Health Initiative prospective cohort. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902...
35. Stokes CS, Gluud LL, Casper M, Lammert F. Ursodeoxycholic acid and diets higher in fat prevent gallbladder stones during weight loss: a meta-analysis of randomized controlled trials. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. Jul 2014;12(7):1090-1100.e1092; quiz e1061.
36. Erlinger S. Gallstones in obesity and weight loss. European journal of gastroenterology & hepatology. Dec 2000;12(12):1347-1352.
37. Fraquelli M, Pagliarulo M, Colucci A, Paggi S, Conte D. Gallbladder motility in obesity, diabetes mellitus and coeliac disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. Jul 2003;35 Suppl 3:S12-16.
38. Overview: Gallstones. (2018). https://www.nhs.uk/conditions/gallstones/.
39. Sulaberidze, G., et al. (2014). Dietary fiber’s benefit for gallstone disease prevention during rapid weight loss in obese patients [Abstract&91;. https://www.ncbi.nlm.nih.gov/pubmed/25020181
40. Fraquelli M, Pagliarulo M, Colucci A, Paggi S, Conte D. Gallbladder motility in obesity, diabetes mellitus and coeliac disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. Jul 2003;35 Suppl 3:S12-16.
41. Lee HS, Chung MJ, Park JY, Bang S, Park SW, Song SY, Chung JB. Urgent endoscopic retrograde cholangiopancreatography is not superior to early ERCP in acute biliary pancreatitis with biliary obstruction without cholangitis. PloS one. 2018;13(2):e0190835.
42. Zimmer V, Lammert F. Acute Bacterial Cholangitis. Viszeralmedizin. Jun 2015;31(3):166-172.
43. Setiawan VW, Pandol SJ, Porcel J, Wei PC, Wilkens LR, Le Marchand L, . . . Monroe KR. Dietary Factors Reduce Risk of Acute Pancreatitis in a Large Multiethnic Cohort. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Feb 2017;15(2):257-265.e253.
44. Turner AR, Bhimji SS. Ileus, Gallstone. StatPearls. Treasure Island (FL): StatPearls Publishing LLC.; 2018.
45. Di Ciaula A, Wang DQ, Bonfrate L, Portincasa P. Current views on genetics and epigenetics of cholesterol gallstone disease. Cholesterol. 2013;2013:298421.
46. Macias B, Gomez-Pinilla PJ, Camello-Almaraz C, Pascua P, Tresguerres JA, Camello PJ, Pozo MJ. Aging impairs Ca(2+) sensitization pathways in gallbladder smooth muscle. Age. Aug 2012;34(4):881-893.
47. Wang S, Wang Y, Xu J, Chen Y. Is the oral contraceptive or hormone replacement therapy a risk factor for cholelithiasis: A systematic review and meta-analysis. Medicine. Apr 2017;96(14).
48. Wang F. Oral contraceptives and risk of gallbladder disease. CMAJ. 2011:183(13):1517
49. Breneman JC. Allergy elimination diet as the most effective gallbladder diet. Annals of allergy. Feb 1968;26(2):83-87.
50. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease? Expert opinion on drug safety. Jan 2006;5(1):117-129.
51. Simonsen MH, Erichsen R, Froslev T, Rungby J, Sorensen HT. Postmenopausal estrogen therapy and risk of gallstone disease: a population-based case-control study. Drug safety. Dec 2013;36(12):1189-1197.
52. Liu B, Beral V, Balkwill A. Childbearing, breastfeeding, other reproductive factors and the subsequent risk of hospitalization for gallbladder disease. Int J Epidemiol. 2009;38(1):312-8.
53. Gaby AR. Nutritional approaches to prevention and treatment of gallstones. Altern Med Rev. 2009:14(3):258-67.
54. Walcher T, Haenle MM, Kron M, Hay B, Mason RA, Walcher D, . . . Kratzer W. Vitamin C supplement use may protect against gallstones: an observational study on a randomly selected population. BMC gastroenterology. Oct 8 2009;9:74.
55. del Pozo R, Munoz M, Dumas A, Tapia C, Munoz K, Fuentes F, . . . Jungst D. [Effects of vitamin C administration on cholesterol gallstone formation&91;. Revista medica de Chile. Jan 2014;142(1):20-26.
56. Ginter E. Cholesterol: vitamin C controls its transformation to bile acids. Science (New York, N.Y.). Feb 16 1973;179(4074):702-704.
57. Gustafsson U, Wang FH, Axelson M, Kallner A, Sahlin S, Einarsson K. The effect of vitamin C in high doses on plasma and biliary lipid composition in patients with cholesterol gallstones: prolongation of the nucleation time. European journal of clinical investigation. May 1997;27(5):387-391.
58. Simon JA, Hudes ES. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Archives of internal medicine. Apr 10 2000;160(7):931-936.
59. Simon JA, Hudes ES. Serum ascorbic acid and other correlates of gallbladder disease among US adults. American journal of public health. Aug 1998;88(8):1208-1212.
60. Worthington HV, Hunt LP, McCloy RF, Maclennan I, Braganza JM. A pilot study of antioxidant intake in patients with cholesterol gallstones. Nutrition (Burbank, Los Angeles County, Calif.). Feb 1997;13(2):118-127.
61. Walcher T, Haenle MM, Kron M, Hay B, Mason RA, Walcher D, . . . Kratzer W. Vitamin C supplement use may protect against gallstones: an observational study on a randomly selected population. BMC gastroenterology. Oct 8 2009;9:74.
62. Jonkers IJ, Smelt AH, Princen HM, Kuipers F, Romijn JA, Boverhof R, . . . Stellaard F. Fish oil increases bile acid synthesis in male patients with hypertriglyceridemia. The Journal of nutrition. Apr 2006;136(4):987-991.
63. Mendez-Sanchez N, Gonzalez V, Aguayo P, Sanchez JM, Tanimoto MA, Elizondo J, Uribe M. Fish oil (n-3) polyunsaturated fatty acids beneficially affect biliary cholesterol nucleation time in obese women losing weight. The Journal of nutrition. Sep 2001;131(9):2300-2303.
64. Berr F, Holl J, Jungst D, Fischer S, Richter WO, Seifferth B, Paumgartner G. Dietary N-3 polyunsaturated fatty acids decrease biliary cholesterol saturation in gallstone disease. Hepatology. Oct 1992;16(4):960-967. Hepatology (Baltimore, Md.), 30 Sep 1992, 16(4):960-967 DOI: 10.1002/hep.1840160418 PMID: 1398503 .
65. Cho SM, Park JA, Kim NH, Kim DS, Zhang D, Yi H, . . . Shin HC. Effect of eicosapentaenoic acid on cholesterol gallstone formation in C57BL/6J mice. Molecular medicine reports. Jan 2015;11(1):362-366.
66. Almasio P, Bortolini M, Pagliaro L, Coltorti M. Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. Drugs. 1990;40 Suppl 3:111-123.
67. Worthington HV, Hunt LP, McCloy RF, Ubbink JB, Braganza JM. Dietary antioxidant lack, impaired hepatic glutathione reserve, and cholesterol gallstones. Clinica chimica acta; international journal of clinical chemistry. Nov 2004;349(1-2):157-165.
68. Di Padova C, Tritapepe R, Di Padova F, Frezza M, Stramentinoli G. S-adenosyl-L-methionine antagonizes oral contraceptive-induced bile cholesterol supersaturation in healthy women: preliminary report of a controlled randomized trial. The American journal of gastroenterology. Dec 1984;79(12):941-944.
69. Frezza M, Tritapepe R, Pozzato G, Di Padova C. Prevention of S-adenosylmethionine of estrogen-induced hepatobiliary toxicity in susceptible women. The American journal of gastroenterology. Oct 1988;83(10):1098-1102.
70. Li Y, Li M, Wu S, Tian Y. Combination of curcumin and piperine prevents formation of gallstones in C57BL6 mice fed on lithogenic diet: whether NPC1L1/SREBP2 participates in this process? Lipids in health and disease. Sep 3 2015;14:100.
71. Rasyid A, Lelo A. The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Alimentary pharmacology & therapeutics. Feb 1999;13(2):245-249.
72. Rasyid A, Rahman AR, Jaalam K, Lelo A. Effect of different curcumin dosages on human gall bladder. Asia Pacific journal of clinical nutrition. 2002;11(4):314-318.
73. Shubha MC, Reddy RR, Srinivasan K. Antilithogenic influence of dietary capsaicin and curcumin during experimental induction of cholesterol gallstone in mice. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. Apr 2011;36(2):201-209.
74. Yang F, Tang X, Ding L, Zhou Y, Yang Q, Gong J, . . . Yang L. Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation. Scientific reports. Sep 14 2016;6:33052.
75. Crocenzi FA, Sanchez Pozzi EJ, Pellegrino JM, Favre CO, Rodriguez Garay EA, Mottino AD, . . . Roma MG. Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: a study in vivo and in isolated hepatocyte couplets. Hepatology. Aug 2001;34(2):329-339.
76. Natural Medicines Comprehensive Database: "Milk Thistle Monograph." National Center of Complementary and Alternative Medicine (NCCAM): "Milk Thistle."
77. Pittler MH, Thompson CO, Ernst E. Artichoke leaf extract for treating hypercholesterolemia. (Cochrane Review). In: The Cochrane Library, Issue 1, Oxford, 2006.
78. Sulaberidze G, Okujava M, Liluashvili K, Tughushi M, Bezarashvili S. Dietary fiber's benefit for gallstone disease prevention during rapid weight loss in obese patients. Georgian medical news. Jun 2014(231):95-99.
79. Di Ciaula A, Garruti G, Fruhbeck G, De Angelis M, De Bari O, D QHW, . . . Portincasa P. The Role Of Diet In The Pathogenesis Of Cholesterol Gallstones. Current medicinal chemistry. May 29 2017.
80. Aune D, Leitzmann M, Vatten LJ. Physical Activity and the Risk of Gallbladder Disease: A Systematic Review and Meta-Analysis of Cohort Studies. Journal of physical activity & health. Jul 2016;13(7):788-795.
81. Walcher T, Haenle MM, Mason RA, et al. The effect of alcohol, tobacco and caffeine consumption and vegetarian diet on gallstone prevalence. Eur J Gastroenterol Hepatol. 2010;22(11):1345-51.

About one in every seven men are diagnosed with prostate cancer making it the most common cancer in Men. Treatments such as surgery, radiation, and hormone therapy are utilized to remove or destroy cancer cells; however, all of these treatments cause side effects which often impact men's sexual performance, also create erectile dysfunction (ED), and infertility.

Prostate cancer treatments both physically and mentally affect libido. Hormone treatment during cancer therapy lowers the testosterone level leading to low desire, weight gain, and loss of muscle mass. Prostate surgery as well as the radiation will affect not only the nerve and vessel tissues in the area but also the sperm and semen production, considered main causes for ED and Infertility.

Other than Cancer, other common factors such as aging, hypertension (High blood pressure), imbalance male hormones, obesity, diabetes, sedentary lifestyle, psychological conditions (anxiety, depression, stress,...), multiple sclerosis (MS), and even medication side effects are all major contributors to ED, and poor male performance.

Common cardiovascular conditions including Atherosclerosis and High blood pressure accounts for a high percentage of ED cases by impacting blood flow. Coronary artery disease strikes epidemic numbers of aging humans. Erectile dysfunction can be one of the earliest symptoms of heart disease. Reduced libido and loss of fertility are also potential predictors of vascular disease. Diabetes due to poor blood flow and nerve damage is also another main contributor.

Many aspects of male sexual function depend upon male hormones (androgens) such as testosterone. Maintaining healthy levels of testosterone helps support the production of nitric oxide, improved libido and ED condition. High aromatase enzyme activity contributes to the conversion of testosterone into estrogen which is called aromatization; therefore, aromatase inhibitors allow testosterone levels to rise without being converted into excess estrogen.

Which natural & Integrative solutions can help improve male performance?

The essential amino acid L-arginine participates in many metabolic functions. It is one of the major contributors to the formation of the vasodilator nitric oxide and blood flow. Healthy endothelial cells release nitric oxide synthase, an enzyme that catalyzes production of the chemical compound nitric oxide from the amino acid L-arginine. L-arginine supplementation also helps to reduce endothelial dysfunction associated with high cholesterol and coronary heart disease. Thus, L-arginine is used as one of the main factors to improve penile blood flow, restore libido, help revert ED, enhance sperm quality and quantity, and Increased male fertility.

Combination of L-arginine with Pycnogenol®, a bioactive compound derived from French maritime pine bark with vasodilatory properties, has helped to significantly improve ED condition in male participants when compared with placebo group. This combination included 80 mg of Pycnogenol® and 1.7 grams of L- arginine daily. Further increase in amount of Pycnogenol® to120 mg per day, achieved up to 92.5 % rate of successful outcomes within 3 months.

Carnitine (including acetyl-L-carnitine ) is a natural amino acid compound associated to a variety of positive effects among men with low testosterone, including improved erection and general sexual well-being. Carnitines may have testosterone-like effects in the body. Daily intake of Carnitine compounds along with 2500 mg of L-arginine and 20 mg of niacin for 3 months contributed to improvement of erectile dysfunction in to 40 % of participants, while nearly 77% of men reported a partial response.

Carnitine also may help improve endothelial function by acting as antioxidants making them beneficial for cardiovascular health, this is especially useful for those patients whose erectile dysfunction is caused by underlying endothelial disorders, such as diabetes.

Panax Ginseng continues to be a popular natural medicine with multiple benefits. Ginsenosides, the principle active constituents in ginseng, providing cardio-protective, immune-stimulatory, anti-fatigue, hepato-protective, and antioxidant effects. In addition, they also increase the synthesis of nitric oxide and potentially increase testosterone levels. Male participants who took 1000 mg two times daily reported improved erectile function, libido, and overall sexual satisfaction when compared to control group.

Maca (Lepidium meyenii) is grown in high altitudes in Peru. Maca's dried root is a rich source of amino acids, iodine, iron, and magnesium. Maca helps to stimulates metabolism, control body weight, increases energy, improves memory, and reduces stress and depression. In participants maca helped to enhance the production of sex hormones, increased libido, and improved overall well-being. These benefits are suggested to be due its action on central nervous system.

Ginkgo biloba leaves' extract has a long history of use for treatment of asthma, fatigue, circulatory problems, and vertigo; but it recently has also been associated with neuroprotective properties, enhanced sexual desire, excitement. The sexual benefits of ginkgo were discovered when male geriatric patients who were given Ginkgo biloba extract for memory enhancement reported improved erections.

Ginkgo biloba extract can increase penile blood supply and improve erectile function in humans. Ginkgo contributes to increased blood flow by increasing nitric oxide bioavailability to vascular smooth muscles. Supplementing with 120-240 mg of Ginkgo biloba extract helped 76% improvement in sexual dysfunction among men being treated with antidepressants.

Plant Epimedium (horny goat weed) has been used in traditional Chinese medicine as a natural aphrodisiac and for the treatment of erectile dysfunction. It contains a bioactive compound known as icariin, which helps to improve nitric oxide levels, support endothelial integrity, and improve penile blood flow. Icariin also provides testosterone-like properties.

Muira Puama supplementation in 262 men suffering from poor sexual desire resulted in 60% reported improvements. Muira Puama’s mechanism of action is suggested to be related to its plant sterol content. Plant sterols may contribute to increased synthesis of testosterone.

Vitamin D, B vitamins, and Vitamin E insufficiencies may be risk factors for erectile dysfunction. Insufficient serum vitamin D contributes to arterial stiffness and vascular dysfunction. Optimizing the Vitamin D level potentially helps reduce certain risk factors for erectile dysfunction, such as arterial stiffness, diabetes mellitus, hypertension, and inflammation of the endothelium. Vitamin D also stimulates the production of nitric oxide.

Low B vitamins specially folate, B6, and B12 are associated with elevated Homocysteine level. Homocysteine is a metabolic derivative that damages endothelial cells and contributes to cardiovascular disease. Homocysteine also impairs smooth muscle relaxation. Both of these conditions are risk factors for developing ED. Supplementing with B vitamins helps keep homocysteine levels in a healthy range.

Oxidative stress which impairs endothelial function and reduces nitric oxide bioavailability is also a risk factor for ED. Vitamin E enhances endothelial cell function, scavenges free radicals, improves nitric oxide-mediated relaxation, preserves nerve function, and help maintain healthy blood pressure. Therefore, taking Vitamin E is considered beneficial for men with ED caused by aging and hypertension.

Lifestyle And Male Sexual Performance

Lack of physical activity, obesity, alcohol, tobacco, eating unhealthy meals with low antioxidants are part of diagnosis for poor sexual health and erectile dysfunction. Exercising and physical activity improve erectile function, sexual response, and overall cardiovascular health.

Obesity nearly doubles the risk of cardiovascular disease and erectile dysfunction. Weight control and adoption of a healthier diet rich in antioxidants, vegetables, healthy fats, and fibre; while low intake of refined grains, sugar, and trans fats would not only greatly benefit those with metabolic syndrome or diabetes but also significantly improve male sexual health and fertility.

Related Articles:

• How to Prevent Prostate Cancer Naturally?
• Keep Healthy Testosterone Level in Adult Men
• Important Nutrients Men Should Include in a Daily Routine
• How To Improve Conditions of Obesity In Men ?

References:

1. Ewane KA, Lin HC, Wang R. Should patients with erectile dysfunction be evaluated for cardiovascular disease? Asian J Androl. 2012;14(1):138-144.
2. Gandaglia G, Salonia A, Passoni N, Montorsi P, Briganti A, Montorsi F. Erectile dysfunction as a cardiovascular risk factor in patients with diabetes. Endocrine. Sep 5 2012.
3. Giles TD. Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. J ClinHypertens. 2006;8(12 Suppl 4):2-16.
4. Nunes KP, Labazi H, Webb RC. New insights into hypertension-associated erectile dysfunction.CurrOpinNephrolHypertens. 2012;21(2):163-170.
5. Jackson G. Prevention of cardiovascular disease by the early identification of erectile dysfunction. Int J Impot Res. 2008 Dec;20 Suppl 2:S9-14.
6. Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol. 2003 Aug;170(2 Pt 2):S46-S50.
7. Garcia-Cruz E, Piqueras M, Gosalbez D, Perez-Marquez M, Peri L, Izquierdo L, . . . Alcaraz A. [Erectile dysfunction and its severity are related to the number of cardiovascular risk factors&91;. Actasurologicasespanolas. May 2012;36(5):291-295.
8. Hannan JL, Maio MT, Komolova M, Adams MA.Beneficial impact of exercise and obesity interventions on erectile function and its risk factors. J Sex Med. 2009;3:254-261.
9. Kellis JT, Jr., Vickery LE.Inhibition of human estrogen synthetase (aromatase) by flavones.Science. Sep 7 1984;225(4666):1032-4.
10. Morales A. Androgens are fundamental in the maintenance of male sexual health. CurrUrol Rep. 2011;12(6):453-460.
11. Diaz-Arjonilla M, Schwarcz M, Swerdloff RS, Wang C. Obesity, low testosterone levels and erectile dysfunction. Int J Impot Res. 2009 Mar-Apr;21(2):89-98
12. Mehraban D, Naderi GH, Yahyazadeh SR, Amirchaghmaghi M. Sexual dysfunction in aging men with lower urinary tract symptoms. Urol J. 2008 Fall;5(4):260-4.
13. Montorsi F, Salonia A, Deho F, Briganti A, Rigatti P. The ageing male and erectile dysfunction. World J Urol. 2002 May;20(1):28-35.
14. Fowler CJ, Miller JR, Sharief MK, et al. A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005 May;76(5):700-5.
15. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. The Journal of urology. Jan 1994;151(1):54-61.
16. Fode M, Krogh-Jespersen S, Brackett NL, Ohl DA, Lynne CM, Sønksen J. Male sexual dysfunction and infertility associated with neurological disorders. Asian J Androl. 2012 Jan;14(1):61-8.
17. Nowosielski K, Drosdzol A, Sipiński A, Kowalczyk R, Skrzypulec V. Diabetes mellitus and sexuality--does it really matter? J Sex Med. 2010 Feb;7(2 Pt 1):723-35.
18. Blonde L. Sildenafil citrate for erectile dysfunction in men with diabetes and cardiovascular risk factors: a retrospective analysis of pooled data from placebo-controlled trials. Curr Med Res Opin. 2006 Nov;22(11):2111-20.
19. Fortney L. (2012) Chapter 60: Erectile Dysfunction (pg 560). In: Rakel D. (Ed.), Integrative Medicine (3rd ed). Saunders, An Imprint of Elsevier.
20. Masuda H. Significance of nitric oxide and its modulation mechanisms by endogenous nitric oxide synthase inhibitors and arginase in the micturition disorders and erectile dysfunction.Int J Urol. 2008;15(2):128-134.
21. Mathers MJ, Brandt AS, Rundstedt F, Roth S, Sommer F, Klotz T. [Metabolism of nitric oxide (NO) and arginine: significance for male health&91;. Aktuelle Urol. 2009;40(4):235-241.
22. Aoki H, Nagao J, Ueda T, et al. Clinical assessment of a supplement of Pycnogenol(R) and L-arginine in Japanese patients with mild to moderate erectile dysfunction. Phytother Res. 2012;26(2):204-7.
23. Stanislavov R, Nikolova V. Treatment of erectile dysfunction with pycnogenol and L-arginine. J Sex Marital Ther. 2003;29(3):207-213.
24. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004;63(4):641-646.
25. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24(2):139-143.
26. Yeh KY, Pu HF, Kaphle K, et al. Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats. HormBehav. 2008;53(1):225-231
27. Cybulska-Heinrich AK, Mozaffarieh M, Flammer J. Ginkgo biloba: an adjuvant therapy for progressive normal and high tension glaucoma. Mol Vis. 2012;18:390-402.
28. Gonzales GF, Cordova A, Vega K, et al. Effect of Lepidiummeyenii (MACA) on sexual desire and its absent relationship with serum testosterone levels in adult healthy men. Andrologia. 2002;34(6):367-372.
29. Hudson T. Maca: new insights on an ancient plant. Integrative Medicine: A Clinician’s Journal 2008;7(6):54-57.
30. Brooks NA, Wilcox G, Walker KZ, Ashton JF, Cox MB, Stojanovska L. Beneficial effects of Lepidium meyenii (Maca) on psychological symptoms and measures of sexual dysfunction in postmenopausal women are not related to estrogen or androgen content. Menopause. 2008 Nov-Dec;15(6):1157-62.
31. Gonzales GF, Córdova A, Vega K, Chung A, Villena A, Góñez C. Effect of Lepidium meyenii (Maca), a root with aphrodisiac and fertility-enhancing properties, on serum reproductive hormone levels in adult healthy men. J Endocrinol. 2003 Jan;176(1):163-8.
32. Shin BC, Lee MS, Yang EJ, Lim HS, Ernst E. Maca (L. meyenii) for improving sexual function: a systematic review. BMC Complement Altern Med. 2010;10:44.
33. Shindel AW, Xin ZC, Lin G, et al. Erectogenic and neurotrophic effects of icariin, a purified extract of horny goat weed (Epimedium spp.) in vitro and in vivo. J Sex Med. 2010;7(4 Pt 1):1518-1528.
34. Zhang ZB, Yang QT. The testosterone mimetic properties of icariin. Asian J Androl. 2006 Sep;8(5):601-5.
35. Zenico T, Cicero AFG, Valmorri L, Mercuriali M, Bercovich E. Subjective effects of Lepidiummeyenii (Maca) extract on well-being and sexual performances in patients with mild erectile dysfunction: a randomised, double-blind clinical trial. Andrologia. 2009;41(2):95-99.
36. Ning H, Xin ZC, Lin G, Banie L, Lue TF, Lin CS. Effects of icariin on phosphodiesterase-5 activity in vitro and cyclic guanosine monophosphate level in cavernous smooth muscle cells. Urology. 2006 Dec;68(6):1350-4.
37. Liu WJ, Xin ZC, Xin H, Yuan YM, Tian L, Guo YL.Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats.Asian J Androl. 2005;7(4):381-388
38. Jang DJ, Lee MS, Shin BC, Lee YC, Ernst E. Red ginseng for treating erectile dysfunction: a systematic review. Br J ClinPharmacol. 2008;66(4):444-450.
39. Kim TH, Jeon SH, Hahn EJ, et al. Effects of tissue-cultured mountain ginseng (Panax ginseng CA Meyer) extract on male patients with erectile dysfunction. Asian J Androl. 2009;11(3):356-361.
40. Nair R, Sellaturay S, Sriprasad S. The history of ginseng in the management of erectile dysfunction in ancient China (3500-2600 BCE). Indian J Urol. 2012;28(1):15-20.
41. Hong B, Ji YH, Hong JH, Nam KY, Ahn TY. A double-blind crossover study evaluating the efficacy of korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol. 2002 Nov;168(5):2070-3.
42. de Andrade E, de Mesquita AA, Claro Jde A, et al. Study of the efficacy of Korean Red Ginseng in the treatment of erectile dysfunction. Asian J Androl. 2007;9(2):241-244.
43. Ernst E, Posadzki P, Lee MS. Complementary and alternative medicine (CAM) for sexual dysfunction and erectile dysfunction in older men and women: an overview of systematic reviews. Maturitas. 2011;70(1):37-41.
44. Sorenson M, Grant WB. Does vitamin D deficiency contribute to erectile dysfunction? Dermatoendocrinol. 2012;4(2):128-136.
45. Ushiyama M, Kuramochi T, Yagi S, Katayama S. Antioxidant treatment with alpha-tocopherol improves erectile function in hypertensive rats. Hypertens Res. 2008;31(5):1007-1013.
46. Helmy MM, Senbel AM.Evaluation of vitamin E in the treatment of erectile dysfunction in aged rats. Life Sci. 2012;90(13-14):489-494.
47. Lombardo F, Tsamatropoulos P, Piroli E, et al. Treatment of erectile dysfunction due to C677T mutation of the MTHFR gene with vitamin B6 and folic acid in patients non responders to PDE5i. J Sex Med. 2010;7(1 Pt 1):216-223.
48. Esposito K, Ciotola M, Giugliano F, et al. Mediterranean diet improves erectile function in subjects with the metabolic syndrome. Int J Impot Res. 2006;18(4):405-410.
49. Giugliano F, Maiorino MI, Bellastella G, et al. Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes. J Sex Med. 2010;7(5):1911-1917.
50. Zhang Q, Radisavljevic ZM, Siroky MB, Azadzoi KM. Dietary antioxidants improve arteriogenic erectile dysfunction. Int J Androl. 2011;34(3):225-235.

Ninety percent of all people get at least one cold sore in their life. Cold sores are caused by a virus, but not a cold virus; instead, they happen because of an infection with the herpes simplex virus (HSV). Cold sores, can appear anywhere on the body. They're most likely to appear on the outside of the mouth and lips, but they can also be found on the nose, cheeks, or fingers. The sores usually last 7 to 10 days and could spread to other people. Cold sores generally are not serious, but the infection may be life-threatening for anyone with low immune system, elderly, kids, or when the infection spreads to the eyes and brain. Those with skin conditions such as eczema may experience a larger spread of the cold sores on their body.

How Cold Sore Starts?

Cold sores are small, painful, fluid-filled blisters or sores that appear on the lips, mouth, or nose caused by a virus . Unlike most viral infections, the cold sore virus is not completely eliminated by the body defenses. For this reason they often recur.

There are two types of herpes simplex virus that can cause cold sores: HSV type 1 and HSV type 2. Cold sores are usually caused by HSV type 1.

Individuals catch HSV when come into contact with people or things that carry the virus. For example, from kissing someone who's infected or when sharing eating utensils, towels, or razors.

One of the most important properties of herpes virus (Herpesviridae) is its ability to form a latent infection, which means that the virus can stay dormant in the body and becoming “re-activated” under certain conditions, showing symptoms long after the initial infection.

Triggers to the reactivation of herpes virus are suggested to be a local injury, or systemic factors such as emotions, stress, fatigue, fever, trauma, allergies, certain foods, sunlight exposure, and hormone changes such as during menstrual periods. But perhaps the most prominent factor among older adults, is general age-related decline in immune function.

Infection with any member of the herpes virus family involves several steps. First, the virus attaches to the receptors on the external surface of human cells and enters into the cell. Then Virus uses the human cell to make many copies of itself (replicate). This stage is known as the primary infection, and while it can cause a period of illness, person may also be without any symptoms and unaware of the infection.

In addition to using the cell to replicate, herpes viruses are equipped with certain class of gene products known as latency-associated transcripts (LATs), which remain in the body and can reactivate the viral replication process.

Members of the herpes virus family typically travel across sensory nerves until they reach large nerve clusters called ganglia, where they replicate undetected by the host.

HSV-1 is the common cause of oral herpes. Herpes spreads by skin-to-skin contact of an individual that has been infected with the virus. Many cases initially contract this virus as an infant or child. The virus gains access to the body through mucous membranes or breaks in the skin.

Infection with either herpes virus can initially show as small fluid-filled blisters on the skin. Once the initial infection wares off, the virus spreads to the nerve cells where it stays dormant until it is reactivated. The frequency of the recurrent outbreaks differs from person to person; some individuals never experience any outbreaks (asymptomatic carriers), while others may have monthly or occasional outbreaks. It is unknown why some individuals are asymptomatic while others have outbreaks, but both asymptomatic and symptomatic patients are able to infect others.

Signs & Symptoms of Cold Sores:

Usually the first oral infection with HSV causes painful sores to appear in or around the mouth, which is also known as herpetic gingivostomatitis. In some cases swollen gums are the only symptom, and other times no symptoms may develop at all. The most common locations for these sores are the lips, the area around the mouth, and the tongue, however the blisters can appear on any skin-covered area. .

Before these sores appear, the skin may itch, tingle, or burn . The sores usually appear for the first time 1 to 3 weeks after contact with the infected person and may last up to 14 days. It can be accompanied with fever, a sore throat, and swollen neck lymph nodes, especially during the first episode, which can make eating and drinking difficult. When cold sores recur, the blisters stage is usually short. Blisters dry up rapidly and leave scabs that last anywhere from a day to several days, depending on the severity of the infection.

Herpes infections can also cause several complications by spreading to one or both eyes, and when the cornea is affected, it causes pain, sensitivity to light, a gritty feeling in the eye, and discharge ; which if left without treatment, it may result in scarring, cloudy vision or even blindness, requiring corneal transplantation .

Herpes infections may affect fingers via breaks in the skin, causing a condition known as herpetic whitlow, in which the fingertip becomes swollen, red, and painful. Herpes can also infect the brain, leading to herpes encephalitis. Other internal organs, such as the lungs and esophagus, can be infected as well, but this is rare.

Which Natural Medicine Can Help Relief Cold Sore Symptoms?

Cold sores are caused by the Herpes simplex virus which stays dormant in the nervous system. Immune system can no longer keep this virus inactive when we are under stress. This could be the common cold, certain foods, work or emotional upset. People who are prone to cold sore should get to know what triggers them to help reduce the number of out breaks. Tingling, burning, or itching may be felt around the lips for several hours or a day prior to cold sore appear, this is the best time to begin treating cold sore. The best approach to treat cold sore is to take care of it early before even it can be seen. Treating cold sore in its earliest stage can result in smaller sore that heals quickly. Ideally, the cold sore may be stopped in its track so it doesn't appear. 

There are several natural treatments which may help reduce the frequency of outbreaks and provide quicker relief by helping to maintain healthy immune system they would provide a great help to prevent outbreaks. Certain Vitamins such as Vitamin C, Vitamin D, and Vitamin A provide immune protection, and antioxidant benefits. In addition, It is recommended to use a proper sunscreen and avoid sun exposure to help prevent the outbreaks triggered by sun.

Vitamin C (ascorbic acid) is a great antioxidant and has natural antiviral properties. In Vitro Vitamin C has helped to prevent HSV-1 from replicating. In vivo those participants with active HSV-1 breakouts who took a formula containing vitamin C prevented the HSV-1 outbreaks when taken within 48 hours of onset of tingling or itching at the outbreak site. Also, when the vitamin C formula was taken after this period of time, it helped reduce the severity and the duration of the outbreaks.

More recent studies suggest that vitamin D may play a role as a potent immunomodulator. Vitamin D deficiency is associated with impaired immune function and increased susceptibility to infections. Vitamin D is able to increase the levels of an immunologic antimicrobial peptide called cathelicidin, which has antiviral properties against HSV-1 and other viruses. Vitamin D level is apparently associated with antibody levels to several viruses, including herpes viruses, in children with multiple sclerosis. Higher vitamin D levels corresponded with more antibodies among children with multiple sclerosis.

Vitamin A and its precursor, beta-carotene, are potent antioxidants and may provide some benefits relevant to HSV infections. Beta-carotene can help protect the skin from sunlight damage, which is a known trigger of HSV-1 outbreaks. Plus, serum vitamin A levels appear to help reduce HSV viral shedding. Low vitamin A levels were associated with increased shedding of HSV. This suggests that vitamin A may help prevent the transmission of herpes to others.

Zinc is a key role player in many aspects of the immune system. Zinc deficiency is associated with immune dysfunction and an increased risk of infection. Zinc levels tend to decrease with age, in parallel with declining immune health. In vitro, zinc sulfate has prevented the HSV-1 replication up to a 98%. Topical zinc ointments (Zinc Oxide) have been used successfully to treat skin outbreaks of herpes simplex in humans. Topical ointments containing zinc oxide along with other natural ingredients have helped to significantly improve oral herpes lesions.

The herpes simplex virus appears to require high amounts of the amino acid arginine to replicate. Amino acid Lysine has a similar structure to arginine and therefore woks against its effects, making it harder for HSV to replicate. Diets rich in lysine and low in arginine have helped suppress HSV replication. Participants who took one gram of L-lysine three times per day for 6 months reduced their frequency, duration, and severity of herpes outbreaks. L-lysine supplementation can reduce the frequency of cold sores that occur during HSV-1 infection. It appears regularly taking lysine is able to reduce the intensity and the frequency of HSV flare-ups.

Lactoferrin is a type of protein found in both cow and human milk. Lactoferrin provides natural antimicrobial properties by helping to protect the body from bacterial, fungal, parasitic, and viral infections. Particularly, lactoferrin is able to suppress HSV-1 and HSV-2 replication, and block the virus from entering cells.

The reishi mushroom (Ganoderma lucidum) is a kind of medicinal fungus which some of its components appear to have antiviral benefits. Amongst reishi compounds GLPG (Ganoderma lucidum proteoglycan) and APBP (acidic protein bound polysaccharide), has provided strong antiviral activities against both HSV-1 and HSV-2 in vitro.

In participants with resistance to regular treatments against herpes and shingles infections, supplementation with reishi extract helped to reduce pain and to shorten the duration of symptoms.

Part of the reishi’s benefits may be due to its ability to overcome declining immune system due to aging. Combination of compounds in reishi including; a group of long-chain carbohydrates called polysaccharides, a unique protein named LZ-8, and a small group of steroid-like molecules called triterpenes help promote healthy immune responses against viral, bacterial, or fungal infections, while assist to reduce inflammation and therefore its unwanted impacts on immune health.

Variety of immune enhancing properties are identified from reishi including: promoting specialized dendritic cells and macrophages which are essential to react to new pathogens, vaccines, and cancer cells. Encouraging development of bone marrow, where most immune cells are born. Increasing numbers and functions of many cell lines in the immune system, such as natural killer cells, B Cells, and T cells for rapid response to a new or "remembered" antigen. Suppressing inflammatory markers produced during chronic inflammation, which is seen for instance, in rheumatoid arthritis, while maintaining normal inflammatory responses.

Lemon balm (Melissa officinalis) extract in lab has provided a variety of antiviral activities against both HSV-1 and HSV-2. Topical lemon balm preparations in participants helped to improve symptoms of oral herpes compared to placebo.

Antioxidants help protect against damage to immune cells, this is more important for the elderly, whose immune systems function less optimally than in younger individuals. Supplementation with antioxidants may help overcome age related immune decline and help prevent certain nutritional deficiencies, which are common among the elderly.

Participant who supplemented Coenzyme Q10, Vitamin E, Selenium and Methionine in the treatment of Chronic Recurrent Viral Mucocutaneous Infections, experienced a significantly faster healing with reduced incidence of relapses as compared to control groups, which was confirmed by decreased viral load and increased antiviral cytokine and peroxynitrite plasma levels.

Employing correct homeopathic remedy at the first sign, helps to prevent the outbreak; and if the cold sore is already a little advanced, then the correct remedy will help to speed up the healing. Repeated use of the remedy may also contribute to less frequent infections. If you are a cold sore sufferer, then you might want to have one of the following remedies on hand.

Nat mur It’s a fantastic remedy for cold sores that erupt on the lips specially after being in the sun. It can have large vesicles which burns, can develop with numbness and be tingling. The lips may have a tendency to be dry and cracked. there can be a craving for salt.

If cold sores tend to appear around menses then Sepia could be a great remedy. Feeling very tired, foggy and irritable before period would considered an indication for this remedy. The cold sores themselves will tend to be crusty and scabby at their worst. They may also appear around the nose and inside. Sepia is seen to help stop blistering and oozing from cold sores. If cold sores are particularly intense, Sepia might be a great choice.

Rhus tox is another great remedy for cold sores. When cold sores appear red, burning and itching. There may be some neuralgic pain in the face. The glands in the throat may also be slightly swollen. The vesicles may weep a yellow fluid. Rhus tox promotes a ‘crusting’ over the sore itself, that can stop additional blistering, bleeding, and oozing. Once the cold sore has crusted over, it can begin to heal.

Certain essential oils can be useful for treating cold sores. Essential oils can be harmful if taken orally and when used to treat cold sore they should be diluted with carrier oil before being applied on the skin.

Applying a few drops of the peppermint essential oil mixed with almond oil has helped participants to stop activity of both herpes virus type 1 and type 2, with less recurrence.

Eucalyptus essential oil may help to treat cold sore and speed up healing due to its anti-inflammatory benefits. Eucalyptus oil is known to cause allergies and also only should be used after mixed with carrier oils.

Clove oil may have an antimicrobial and antiviral effect on the herpes simplex virus. It also may decrease pain associated with a cold sore. Clove oil is irritating and should be diluted with other oils before application.

Chamomile oil and lemon Balm oil both appear to prevent the adhesion of virus to the cells and might be used for resistant herpes simplex, but yet again it has to be mixed with carrier oils before application.

Teat tree oil is another great essential oil with ability to stop and kill herpes virus, Pure teat Tree oil also needs to be mixed with a carrier oil before use.

Recurrent cold sores usually do not require medical care. A few people may have cold sores that come so frequently that may need a daily medicine to reduce the number of attacks. It is not possible to predict for how long the treatment should continue, because the virus continues to live in the ganglion. Therefore, stopping suppressive treatment is usually a trial and error procedure. People who have very weak immune systems from cancer treatments or other causes may have very severe outbreaks of cold sores. Medical care should be considered to avoid complications.

Herpes can be spread from a cold sore to another area of the body, which is called "autoinoculation." Autoinoculation is common during the primary infection when viral shedding is high and the immune system is still trying to contain it. The antibodies that are made after primary infection are usually; but not always; help preventing autoinoculation during the recurrent attack. To prevent spreading the virus to other parts of the body, it is important to keep high levels of hygiene, and wash hands after touching the sore. A more serious complication is an ocular herpes, which causes sores and severe pain around the eye. If untreated, ocular herpes can lead to serious eye damage or even blindness. Cold sores may cause genital herpes which acquired through sexual contacts.

Related Articles:

Natural Solutions to Quick Recovery from Common Cold

Key Steps to De-stress and Improve Your Energy and Focus

Medicinal Mushrooms and their Immune boosting power

Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

References:

1.Albrecht, Mary. "Clinical Manifestations of Varicella-zoster Virus Infection: Herpes Zoster."UpToDate. UpToDate, July 2012c. Web. 02 Jan. 2013. <http://www.uptodate.com/contents/clinical-manifestations-of-varicella-zoster-virus-infection-herpes-zoster>.

2.Chida Y, Mao X. Does psychosocial stress predict symptomatic herpes simplex virus recurrence? A meta-analytic investigation on prospective studies. Brain, behavior, and immunity, 2009;23(7):917-925.

3.Hill JM, Sedarti F et al. Herpes Simplex Virus Latent Phase Transcription Facilitates in Vivo Reactivation. Virology, 1990; 174: 117-125.

4.Imai Y, Apakupakul K et al. Investigation of the Mechanism by Which Herpes Simplex Virus Type 1 LAT Sequences Modulate Preferential Establishment of Latent Infection in Mouse Trigeminal Ganglia. Journal of Virology, 2009; 83(16): 7873-7882.

5.Randall, Brian. "Lifestyle Changes to Manage Cold Sores." Munson Healthcare. Munson Healthcare, Sept. 2012. Web. 16 Jan. 2013. < http://www.munsonhealthcare.org/Taxonomy/RelatedD...>

6.Yarnell E, Abascal K et al. Herbs for Herpes Simplex Infections. Alternative and Complementary Therapies, 2009; 15(2): 69-74.

7.Zwaagstra JC, Ghiasi H et al. Activity of Herpes Simplex Virus Type 1 Latency-Associated Transcript (LAT) Promoter in Neuron-Derived Cells: Evidence for Neuron Specificity and for a Large LAT Transcript. Journal of Virology, 1990; 64(10): 5019-5028.

8.Brinkevich SD, Boreko EL et al. Radical-Regulating and Antiviral Properties of Ascorbic Acid and its Derivatices. Bioorganic and Medicinal Chemistry Letters, 2012; 22: 2424-2427.

9.Byun SH, and Jeon Y. Administration of Vitamin C in a Patient with Herpes Zoster - A case report. The Korean journal of pain, 2011;24(2):108-111.

10.Furuya A, Uozaki M, Yamasaki H, Arakawa T, Arita M, Koyama AH. Antiviral effects of ascorbic and dehydroascorbic acids in vitro. International Journal of Molecular Medicine, 1998;22(4): 541-545.

11.Aranow C. Vitamin D and the Immune System. Journal of Investigational Medicine, 2011; 59(6): 881-886.

12.Beard JA, Bearden A et al. Vitamin D and the Anti-Viral State. Journal of Clinical Virology, 2011;50: 194-200.

13.Lang PO, Samaras N et al. How Important is Vitamin D in Preventing Infections? Osteoporosis International, 2012. [Epub ahead of print&91;

14.Mowry EM, James JA et all. Vitamin D status and Antibody Levels to Common Ciruses in Pediatric-Onset Multiple Sclerosis. Multiple Sclerosis, 2011; 17(6): 666-671.

15.Naeem Z. Vitamin D deficiency- an ignored epidemic. International Journal of Health Sciences (Qassim), 2010;4(1):V-VI.

16.Antoine TW, Mishra YK et al. Prophylactic, Therapeutic and Neutralizing Effects of Zinc Oxide Tetrapod Structures Against Herpes Simplex Virus Type-2 Infection. Antiviral Research, 2012; 96: 363-375.

17.Bourne N, Stegall R et a. Efficacy and Toxicity of Zinc Salts as Candidate Topical Microbicides Against Vaginal Herpes Simplex Virus Type 2 Infection. Antimicrobial Agents and Chemotherapy, 2005; 49(3): 1181-1184.

18.Godfrey HR, Godfrey NJ et al. A Randomized Clinical Trial on the Treatment of Oral Herpes with Topical Zinc Oxide/Glycine. Alternative Therapies, 2001; 7(3): 49-55.

19.Haase H and Rink L. The Immune Sysytem and the Impact of Zinc During Aging. Immunity and Aging, 2009; 6(9).

20.Overbeck S, Rink L et al. Modulating the Immune Response by Oral Zinc Supplementation: A Single approach for Multiple Diseases. Archives of Immunological Therapy Experiments, 2008; 58: 15-30.

21.Prasad AS. Zinc in Human Health: Effect of Zinc on Immune Cells. Molecular Medicine, 2008; 14(5-6): 353-357.

22.Andersen JH, Jenssen H, Sandvik K, Gutteberg TJ. Anti-HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface. Journal of Medical Virology, 2004;74(2):262-271.

23.Berlutti F, Pantanella F et al. Antiviral Properties of Lactoferrin---A Natural Immunity Molecule. Molecules, 2011; 16: 6992-7018.

24.Jennsen H, Sandvik K et al. Inhibition of HSV Cell-To-Cell Spread by Lactoferrin and Lactoferricin. Antiviral Research, 2008; 79: 192-198.

25.Jennsen H. Anti Herpes Simplex Virus Activity of Lactoferrin/Lactoferricin-An Example of Antiviral Activity of Antimicrobial Protein/Peptide. Cellular and Molecular Life Sciences, 2005; 62: 3002-3013.

26.Marr AK, Jennsen H et al. Bovine Lactoferrin and Lactoferricin Interfere with Intracellular Trafficking of Herpes Simplex Virus-1. Biochimic 2009; 91: 160-164.

27.Valenti P and Antonini G. Lactoferrin: An Important Host Defence Against Microbial and Viral Attack. Cellular and Molecular Life Sciences, 2005; 62: 2576-2587.

28.EBSCO CAM Review Board "Lysine." NYU Langone Medical Center. NYU, June 2011. Web. 03 Jan. 2013. <http://www.med.nyu.edu/content?ChunkIID=21791>.

29.Griffith RS, Walsh DE et al. Success of L-Lysine Therapy in Frequently Recurrent Herpes Simplex Infection. Dermatologica, 1987; 175: 183-190.

30.Astani A, Reichling J, Schnitzler P. Melissa officinalis extract inhibits attachment of herpes simplex virus in vitro. Chemotherapy. 2012;58(1):70-77.

31.Dimitrova Z, Dimov B, Manolova N, Pancheva S, Ilieva D, Shishkov S. Antiherpes effect of Melissa officinalis L. extracts. Acta microbiologica Bulgarica. 1993;29:65-72.

32.Geuenich S, Goffinet C, Venzke S, Nolkemper S, Baumann I, Plinkert P, . . . Keppler OT. Aqueous extracts from peppermint, sage and lemon balm leaves display potent anti-HIV-1 activity by increasing the virion density. Retrovirology. 2008;5:27.

33.Schnitzler P, Schuhmacher A, Astani A, Reichling J. Melissa officinalis oil affects infectivity of enveloped herpesviruses. Phytomedicine : international journal of phytotherapy and phytopharmacology. Sep 2008;15(9):734-740.

34.Vahabpour-Roudsari R, Shamsi-Shahrabadi M et al. Evaluation of Potential Antiviral Activity of the Hydroalcoholic Extract of Lemon Balm L. Against Herpes Simplex Virus Type 1. Iranian Journal of Virology, 2010; 4(3&4): 52-57.

35.Wolbling RH, Leonhardt K. Local therapy of herpes simplex with dried extract from Melissa officinalis. Phytomedicine : international journal of phytotherapy and phytopharmacology. Jun 1994;1(1):25-31.

36.Chan WK, Lam DT, Law HK, Wong WT, Koo MW, Lau AS, . . . Chan GC. Ganoderma lucidum mycelium and spore extracts as natural adjuvants for immunotherapy. Journal of alternative and complementary medicine (New York, N.Y.). Dec 2005;11(6):1047-1057.

37.Dudhgaonkar S, Thyagarajan A, Sliva D. Suppression of the inflammatory response by triterpenes isolated from the mushroom Ganoderma lucidum. International immunopharmacology. Oct 2009;9(11):1272-1280.

38.Hijikata Y and Yamada S. Effect of Ganoderma Lucidum on Postherpetic Neuralgia. American Journal of Chinese Medicine, 1998; 26: 375.

39.Jan RH, Lin TY, Hsu YC, Lee SS, Lo SY, Chang M, . . . Lin YL. Immuno-modulatory activity of Ganoderma lucidum-derived polysacharide on human monocytoid dendritic cells pulsed with Der p 1 allergen. BMC immunology. 2011;12:31.

40.Jeurink PV, Noguera CL, Savelkoul HF, Wichers HJ. Immunomodulatory capacity of fungal proteins on the cytokine production of human peripheral blood mononuclear cells. International immunopharmacology. Aug 2008;8(8):1124-1133.

41.Ji Z, Tang Q, Zhang J, Yang Y, Liu Y, Pan YJ. Immunomodulation of bone marrow macrophages by GLIS, a proteoglycan fraction from Lingzhi or Reishi medicinal mushroom Ganoderma lucidium (W.Curt.:Fr.) P. Karst. International journal of medicinal mushrooms. 2011;13(5):441-448.

42.De Luca C, Khareva Z et al. Coenzyme Q10, Vitamin E, Selenium and Methionine in the Treatment of Chronic Recurrent Viral Mucocutaneous Infections. Nutrition, 2012; 28(5): 509-514.

43.Hughes D. Dietary Antioxidants and Human Immune Function. Nutrition Bulletin, 2000; 25: 35-41

44.Gaby AR. Natural remedies for Herpes simplex. Alternative Medicine Review, 2006;11(2):93-101.

45.Khan MT, Ather A et al. Extracts and Molecules from Medicinal Plants Against Herpex Simplex Viruses. Antiviral Research, 2005; 67: 107-119.

46.Singh BB, Udani J et al. Safety and Effectiveness of an L-Lysine, Zinc and Herbal-Based Product on the Treatment of Facial and Circumoral Herpes. Alternative Medicine Review, 2005; 10(2): 123-127.

47.Astani A1, Reichling J, Schnitzler P. Melissa officinalis extract inhibits attachment of herpes simplex virus in vitro.Chemotherapy. 2012;58(1):70-7. doi: 10.1159/000335590. Epub 2012 Feb 23.https://www.ncbi.nlm.nih.gov/pubmed/22377592.

48.Koch C1, Reichling J, Kehm R, Sharaf MM, Zentgraf H, Schneele J, Schnitzler P. Efficacy of anise oil, dwarf-pine oil and chamomile oil against thymidine-kinase-positive and thymidine-kinase-negative herpesviruses.J Pharm Pharmacol. 2008 Nov;60(11):1545-50. doi: 10.1211/jpp/60.11.0017.https://www.ncbi.nlm.nih.gov/pubmed/18957177.

49.Athbi Alqareera, Asma Alyahya, Lars Andersson. The effect of clove and benzocaine versus placebo as topical anesthetics.Journal of Dentistry Volume 34, Issue 10, November 2006, Pages 747-750.

50.Schuhmacher A1, Reichling J, Schnitzler P. Virucidal effect of peppermint oil on the enveloped viruses herpes simplex virus type 1 and type 2 in vitro. Phytomedicine. 2003;10(6-7):504-10.

51.Columbia University College of Dental Medicine: "Cold Sores and Fever Blisters."

52.Stuart-Harris C. The epidemiology and clinical presentation of herpes virus infections. The Journal of Antimicrobial Chemotherapy, 1983;12 Suppl B:1-8.

53.Cernik, C., K. Gallina, and R.T. Brodell. "The Treatment of Herpes Simplex Infections: An Evidence-Based Review." Arch Intern Med 168.11 June 9, 2008: 1137-1144.

54.Sucato G, Celum C et al. Demographic rather than behavioral risk factors predict herpes simplex virus type 2 infection in sexually active adolescents. The Pediatric Infectious Disease Journal, 2001;20(4):422-426. 

Changing of the seasons for many, signals the start of allergies. Runny nose, itchy skin, asthma, watery and red eyes are just some of the symptoms that many people face each year as the pollen from trees, grass, flowers, and plants are appearing in the air. For some relief is just a drugstore counter away; however, studies suggest that there are variety of all-natural and effective treatments for an increasing number of allergies without many of the troubling side effects associated with usual allergy drugs.

Allergy is a result of an intense response of the Immune system to mainly non harmful substances in the environment (Allergens). Allergens could affect different parts of the body including our mucus membranes, respiratory system, skin, and digestive system.

Inhalant allergens are such as dust, pollen, mold, and those sourced from animals or pets, while some of the examples of ingested allergens include dairy, eggs, shellfish. gluten, nuts, and heavy metals.

An allergic reaction could be very rapid (within minutes after contraction) or delayed (within 2-3 days after exposure). Symptoms of allergy vary from mild to severe. Severe allergic reaction is called anaphylaxis.

In recent years allergies have become a public health concern. Number of allergy cases have increased during the past decade. 500 million of world population suffer from food allergies and about 30 % of adults and 40% of children are diagnosed with asthma. Furthermore, existence of one type of allergy increases the risk of developing other allergies. For example infants with atopic dermatitis are more likely to develop allergic rhinitis and asthma later in their life.

Allergic diseases are including atopic dermatitis, allergic rhinitis, asthma, hives, edema (angioedema), insect allergy, food and drug allergy.

Genetic tendency to develop classic allergy disease is called Atopy. Atopic dermatitis is usually the first signal for the allergic disease and many cases develop allergic rhinitis and asthma in the future. Symptoms of atopic dermatitis includes red and itchy rashes on the body, face, behind the knees, and the inner elbows. The rashes may be scaly, and affected by temperature, humidity, food, stress, clothing material, and chemicals.

Allergic Rhinitis is one of the major respiratory issues affecting many adults; but it is more common in children. Allergic rhinitis considers a risk to develop asthma.Common symptoms of Allergic rhinitis include runny and stuffy nose, itchy eyes, throat, and skin, and coughing. Allergic rhinitis is categorized to 4 levels based on the severity and frequency of the symptoms. And depending on the type of allergen it is classified to two types of Seasonal and Perennial.

New studies are associating allergies and asthma. Many people suffer from both seasonal allergies and asthma. In fact, it's been found that the rough and thick lung tissue in asthmatic cases is connected to the repeated episodes of allergies in the upper airways. Probably lung tissue is changing due to the constant higher than normal presence of the immune cells and the inflammation in the area. Failure to control seasonal and year-round allergies pose a real danger of causing permanent structural damage to lung tissue.

Asthma is a chronic inflammatory disease. Narrowed airway because of inflammation and structural changes in the lung tissue and air ways results in difficulty breathing and shortness of breath. Children with allergy are 30 % more in risk of developing asthma. Exposure to allergens, viral infections like cold and flu, heavy exercise, certain foods, and smoking affect the severity of the asthmatic symptoms.

Food Allergy is one of the common causes of anaphylaxis cases brought to hospitals. Main food allergens are such as egg, nuts, dairy (cow milk in particular), soy, seafood, and wheat.Symptoms of food allergy are including edema, nausea, vomiting, skin rash, diarrhea, and swelling of the mucus membranes. These symptoms may appear within hours to days after exposure to allergens.

Frequent exposure to the food allergens triggers inflammation in the mucous layer of the digestive tract weakening the intestinal wall and eventually it leads to much severe reactions and other serious health issues like colitis and leaky gut syndrome. Therefore, maintaining and restoring the health of digestive tract are very important to improve its function and prevent it from being further damaged.

Studies suggest supplementing with natural medicines and nutrients is useful in managing and improving allergic associated symptoms.

Quercetin is one of the flavonoids with the ability to reduce allergy symptoms and inflammation. Studies showed in cases with allergic rhinitis using nasal spray containing quercetin and artemisia abortanum provides a rapid relief from nasal symptoms, and taking quercetin supplement for 2 months reduces the allergic symptoms significantly. Another flavonoid called hesperidin has shown to provide relief and/or partial improvement of the allergic symptoms.

Based on studies Supplementing with Rosmarinic Acid can significantly reduce the symptoms of allergy in allergic rhinitis as well as in seasonal allergy. Rosmarinic acid is named for one of its source plants, rosemary, it is also found in perilla, oregano, marjoram, thyme, and basil. According to preliminary pharmacology research, rosmarinic acid influences immune system and inflammation indicators including IL-4, IL-8, IgE, IGg, and histamine which all are involved in allergic reactions. Perilla extract containing 20% rosmarinic acid is shown to be effective for seasonal allergies. Perilla seed is also rich in omega fatty acids which could even be more helpful in reducing inflammation. In another research topical application of rosmarinic emulsion in 2 months improved the atopic dermatitis symptoms of dryness and redness.

Research has found that stinging nettle is able to inhibit histamin receptors as well as those enzymes involving with allergic and inflammatory reactions. As a result, stinging nettle has been helpful to decrease allergic symptoms.

Omega 3 Fatty Acids including EPA and DHA provide anti-inflammatory benefits.

Low levels of omega 3 fatty acids are associated with dermatitis and allergic skin reactions. Evidence suggests maternal supplementation with omega 3 during pregnancy reduces the risk of asthma and /or food allergy in children.

Studies indicate that vitamin D deficiency is associated with higher frequency and severity of asthma and allergy symptoms. Moreover, it is shown that supplementing with vitamin D during pregnancy reduces the risks of developing childhood dermatitis and asthma.

The relation between the vitamin E intake and allergy and asthma is supported by several researches. Taking vitamin E shows to improve symptoms of skin irritation, redness, scaling and scaring associated with eczema. However, low levels of vitamin E during pregnancy has been linked to a higher risk of developing asthma in children.

Intestinal micro flora play an important role in supporting and protecting the intestinal wall and balancing the Immune system throughout the body. About 75% of our Immune cells are in the digestive tract and the intestinal micro flora are able to communicate with them via number of bio-chemicals. Food allergies and food sensitivities cause constant inflammation in the intestinal wall damaging the digestive tract and interrupting its function. Probiotics are able to modulate the gut immune system and inflammation by lowering the impact of allergens on the intestinal tract and overall immune system net work.

Randomized trials and studies support the fact that probiotic could offer a significant benefits to adults as well as children with allergic rhinitis, and other allergic disease. Lactobacillus Casei, Lactobacillus gasseri, Bifidobacterium longum BB536 ,Lactobacillus rhamnosus GG, and many other probiotics have shown to be effective in improving symptoms of allergy and reducing the frequency of the reactions. Infants with allergy to cow milk who was given Lactobacillus rhamnosus for 12 months more likely acquired tolerance to dairy in comparison to the placebo group.

Managing allergic disease and its related symptoms starts with identifying the allergens and try to avoid them as much as possible. Changing life style and taking healthy steps toward better food choices and improving our environment is helping to reduce the impact of the allergens and inflammation on the body.

Measuring blood IGg antibodies specially for food allergies and food sensitivities, heavy metal testing, and measuring blood omega fatty acids are effective ways to identify allergens and deficiencies. These tests help individuals and practitioners to better understand the issue and find a proper way of restoring health. (all of these tests are provided at health palace. to find out more about them please do not hesitate to contact us).

Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

Reference:

1.Bousquet J, Khaltaev N, Cruz AA, Denburg J, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008 Apr;63Suppl 86:8-160.

2.Ziment I, Tashkin LP. Alternative medicine for allergy and asthma. J Allergy Clin Immunol. 2000 Oct;106(4):603-14.

3.Garg A et al. Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 2001 Dec;15(8):655-69.

4.Guex JJ et al. Quality of life improvement in Latin American patients suffering from chronic venous disorder using a combination of Ruscusaculeatus and hesperidin methyl-chalcone and ascorbic acid (quality study). IntAngiol. 2010 Dec;29(6):525-32.

5.Osakabe N, Takano H, Sanbongi C, et al. Anti-inflammatory and anti-allergic effect of rosmarinic acid (RA); inhibition of seasonal allergic rhinoconjunctivitis (SAR) and its mechanism. Biofactors. 2004;21(1-4):127-31.

6.Sanbongi C, et. al., Rosmarinic acid in perilla extract inhibits allergic inflammation induced by mite allergen, in a mouse model, Clinical and Experimental Allergy 2004; 34(6): 971–977.

7.al Sereiti MR, Abu-Amer KM, Sen P. Pharmacology of rosemary and its therapeutic potentials. Indian J Exp Biol. 1999 Feb;37(2):124-0.

8.Takano H, Osakabe N, Sanbongi C, et al. Extract of Perilla frutescens enriched for rosmarinic acid inhibits seasonal allergic rhinoconjunctivitis in humans. Exp Biol Med. 2004 Mar;229(3):247-54.

9.Makino T, Furuta Y, Wakushima H, Fujii H, Saito K, Kano Y. Anti-allergic effect of Perilla frutescens and its active constituents. Phytother Res. 2003 Mar;17(3):240-3.

Sanbongi C, Takano H, Osakabe N, et al. Rosmarinic acid in perilla leaf extract inhibits allergic inflammation induced by mite allergen, in a mouse model. Clin Exp Allergy. 2004 Jun;34(6):971-7

10.CederholmTE et al. Low levels of essential fatty acids are related to impaired delayed skin hypersensitivity in malnourished chronically ill elderly people. Eur J Clin Invest. 1994 Sep;24(9):615-20.

11.Klemens CM, Berman DR, Mozurkewich EL. The effect of perinatal omega-3 fatty acid supplementation on inflammatory markers and allergic diseases: a systematic review. BJOG. 2011 Jul;118(8):916-25.

12.Chinellato I, Piazza M, Sandri M, et al. Vitamin D serum levels and markers of asthma control in Italian children. J Pediatr 2011;158:437–441.

13.Erkkola M, Kaila M, Nwaru BI, et al. Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children. ClinExp Allergy 2009;39:875–882.

14.Javanbakht MH, Keshavarz SA, Djalali M, et al. Randomized controlled trial using vitamins E and D supplementation in atopic dermatitis. J Dermatolog Treat. 2011 Jun;22(3):144-50. Epub 2010 Jul 24.

15.Centanni S, Santus P, Di Marco F, et al. The potential role of tocopherol in asthma and allergies: modification of the leukotriene pathway. Biodrugs . 2001;15(2):81–6.

16.Devereux G, Turner SW, Craig LCA, et al. Reduced maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J RespirCrit Care Med. 2006;174;499-507.

17.Boyle RJ, Ismail IH, Kivivuori S, et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial.Allergy. 2011 Apr;66(4):509-16.

18.Calder PC. Polyunsaturated fatty acids and inflammation. BiochemSoc Trans . 2005 Apr; (pt 2): 423–7.

19.Berni Canani R, Nocerino R, Terrin G, et al. Effect of Lactobacillus GG on tolerance acquisition in infants with cow's milk allergy: A randomized trial. J Allergy ClinImmunol. 2011 Nov 10.

20.Cross ML, Gill HS. Can immunoregulatory lactic acid bacteria be used as dietary supplements to limit allergies? Int Arch Allergy Immunol . 2001 Jun;125(2):112–9.

Which Factors Would Compromise The Health of The Hair, Skin, and Nails?

Aging impacts the collagen, elastin, keratin, and melanin (skin pigments). Biological process of aging causes changes in the structure and the function of skin, hair, and nail tissue leading to changes such as wrinkled, dry, and thinner skin; grey and thinner hair; and brittle lifeless looking nails.

Skin cells and tissues responsible for maintaining the structure and function of the skin are influenced by hormones including growth, female, and male hormones, as well as DHEA. Hormones and hormonal levels play an important role to the changes on the hair, skin, and nail. High blood sugar, and inflammation are damaging collagen structure and interrupt its production.

Glycation is a major contributor to skin aging. Glycation is when the sugar molecules bound with protein and fat molecules in the body. This reaction is significantly accelerated when blood sugar is elevated. Attachment of the sugar to collagen and elastin proteins cause them change into advanced glycation end products (AGEs), interrupting the skin’s structure. In addition, glycation encourages the inflammation in the body as well as in the skin cells.

Inflammation interferes with collagen synthesis and actually promotes collagen breakdown partly via activation of an enzyme known as matrix metalloproteinases.

A group of skin cells called fibroblasts produce collagen-rich connective tissue providing the important structure and function of the skin. These collagen-producing fibroblasts in the skin work based on the signaling factors called transforming growth factor betaandconnective tissue growth factor. The levels of these growth factors decline as we age causing loss of collagen and thin, fragile skin.

Other group of the skin cells are called Melanocytes responsible for producing skin and hair pigments known as melanin. Usually the number of melanocytes decrease by 10-20 % in each decade.

Pollution in general, toxins, chemicals in the cosmetics, strong soaps, smoking, and increased free radicals all would damage the skin. UV exposure enhances the activity of the enzymes which break down collagen and elastin.

UV radiation from the sun is one of the most damaging external factors to the skin. Sun exposure is suggested to contribute to 80% of facial skin aging. UV light creates large number of free radical in the skin tissue, targeting the Collagen and elastin fibers in the skin. UV light also activates certain enzymes which speed up the collagen degradation.

Those with exposure to air pollution experience rapid skin aging which includes a 20% increase in pigment spots on the cheeks and forehead, and significantly more pronounced wrinkles. Cleansing and detoxification helps by reducing the volume of pollutants and therefore their unwanted effects on the organs such as skin.

Lack of sleep promotes chronic low-grade inflammation. Short sleep duration of 5 hours or less is associated with higher skin aging scores and longer recovery time from exposure to UV light. Stress can trigger or worsen different inflammatory skin conditions such as psoriasis, acne, dermatitis, as well as the skin aging. Stress promotes release of stress hormones. Constantly high levels of cortisol accelerates the loss of collagen and elastin contributing to dry thinner skin, delayed wound healing, and easy bruising.

The external factors like sun, internal causes, or just natural aging process, all would result in damaged skin which is characterized by dryness, discoloration such as appearance of age spots, thinning, wrinkling, and low elasticity.

What Could Help to Maintain Youthful Qualities Of The Skin?

Supporting the skin's inherent defense mechanism by employing different science based interventions helps to slow and / or reverse skin damage.These include positive lifestyle habits, healthy eating, using sunscreen, quality sleep, lowering stress, effective and natural ingredients that help support skin structure from the inside out.

Diet is being recognized as a contributing factor to skin diseases such as acne, atopic dermatitis, psoriasis, and aging. For example, a diet high in sugar and starch would keep blood sugar levels high and promotes glycation and production of AGEs damaging the cells and tissues contributing to structural changes in the skin such as loss of elasticity and increased stiffness. Spices like cinnamon can help reduce the production of advanced glycation end products (AGEs).

Plant-based foods are rich in nutrients such as polyphenols, carotenoids, omega-3 fatty acids, and vitamins A, C, and E, providing protection against UV radiation.

Sunscreens and sunblocks are different important skin-care products and commonly used to prevent skin photoaging caused by UV radiation from the sun. Sunscreens and sunblocks should provide broad-spectrum protection against both UVA and UVB radiation. Sunblock is opaque and stronger than sunscreen, since it is able to block most of the UVA/UVB rays and radiation from the sun, and does not need to be reapplied several times in a day. Titanium dioxide and zinc oxide are two of the important ingredients in sunblock.

Sunscreen is more transparent once applied to the skin and also has the ability to protect against UVA/UVB rays. It is important to allow some time for sunscreen to be absorbed into the skin before sun exposure. It is recommended to apply sunscreen 30 minutes before going outside. The sunscreen's ingredients have the ability to break down at a faster rate once exposed to sunlight, and some of the radiation is able to penetrate to the skin. In order for sunscreen to be more effective it is necessary to consistently reapply and use one with a higher sun protection factor.

Collagen is one of the main proteins in the skin, hair, and nail. Collagen in hair contributes to its strength and growth. In fact, certain types of collagen produced by hair follicles in higher levels than in the skin.  Apparently, age-related hair thinning and loss is related to a loss of collagen. Taking collagen peptide supplement has helped to improve skin moisture, elasticity, and reduce wrinkles. There was a 65% improvement in collagen and 18% improvement in elastin synthesis in the skin of the treatment group compared with the placebo group.

Collagen protein supplementation provides spectrum of amino acids from which the body can make keratin. Taking hydrolyzed collagen, for three months has helped to return healthy appearance and normal structure to brittle, soft, peeling, and easily broken nails.

Biotin is a B vitamin that helps improve skin, hair, and nail health. Participants with brittle nails who took minimum of 2.5 mg of biotin for several months had thicker, firmer and healthier nails when compared with the placebo.

Hair loss is a symptom associated with biotin deficiency. Individuals with sever types of hair loss such as found in alopecia would require much higher doses of Biotin. Participants who were given Biotin and Zinc in combination with their regular treatment after one year had 33% of complete hair re-growth, compared with none from the group with the regular treatment alone.

Zinc is an essential mineral for healthy skin and hair. Zinc has high concentration in hair follicles. Zinc helps to stabilize cell membranes, and it is necessary for proper wound healing. Zinc has been employed to treat alopecia for several months to even a few years. Zinc has also helped improve dry and scaly skin conditions.

Nicotinamide, also known as niacinamide, is a form of vitamin B3 found in food and used as a dietary supplement.  As a supplement, it is taken by mouth to prevent and treat pellagra which is a disease caused by a lack of the niacin (vitamin B3). While nicotinic acid (niacin) may be used for this purpose, nicotinamide has the benefit of not causing skin flushing. Nicotinamide (niacinamide) has been successfully used orally as a safe treatment for a variety of inflammatory skin conditions including acne, rosacea, ageing skin, dermatitis, skin cancer, the side-effects of UV, and chemotherapy.

There are two types of B3 deficiencies, a diet poor in vitamin B3; and a poor ability to absorb the niacin from the diet. This is seen in high alcohol consumption, long term diarrhea, and the usage of certain antibiotics. Nicotinamide increases the production of ceramides in human keratinocytes (skin cells) in vitro and improves the epidermal permeability barrier in vivo.

In 2015 in a trial of 12 months, taking nicotinamide helped reduce the rate of new non-melanoma skin cancers and actinic keratoses in a group of people at high risk for the conditions.

Nicotinamide is also the precursor of nicotinamide adenine dinucleotide (NAD+), a compound required for energy (ATP) production. UV radiation suppresses DNA repair by depleting cellular energy. Nicotinamide by increasing levels of NAD+ helps with energy production and DNA repair. In rodents Nicotinamide helped prevent the UV light induced skin cancer .

Pantothenic acid (vitamin B5), is an essential nutrient in the diet and is important to wound healing. Vitamin B5 deficient mice develop gray fur and skin irritation, which resolved with vitamin B5 supplementation.

Silica (Silicon) is an essential trace mineral participating in connective tissue health and it s considered a factor in structural integrity of hair, nails, and skin. Silica is involved in the synthesis and stabilization of collagen. Silica deficiency would result in lower collagen concentration. Brittle hair, skin, and nails may improve by silica supplementation. Silica is required for the function of an enzyme (prolyl hydroxylase) which participates in formation of collagen in bone & cartilage.

Ceramides are an essential part of the protective layer of the skin. Ceramides are a family of waxy lipid molecules.  Although present in other tissues, ceramides are especially concentrated in the skin where they help maintain normal skin hydration and barrier function; this layer of the skin is composed of 50% ceramides, 25% cholesterol, and 15% free fatty acids.  Altogether ceramides with cholesterol and saturated fatty acids, create a water-resistant, protective organ to prevent excessive water loss due to evaporation as well as a barrier against the entry of microorganisms.

In psoriasis the water permeability barrier is compromised. It is very well known that the low ceramide level is a key contributing factor to variety of the skin conditions, as well as the age-related skin dysfunction which could be a result of ceramide deficiency. Ceramide concentrations decrease with age and exposure to UV radiation in sunlight.  A clinical trial using ceramide-rich wheat extract showed increased skin hydration in those taking the extract rather than the placebo.

Ceramides are found as ingredients of some topical skin treatments to complement treatment for skin conditions such as eczema. They are also used in cosmetic products such as some soaps, shampoos, skin creams, and sunscreens.

Omega-3 fatty acids provide photo-protective and anti-skin-aging effects helping to protect skin against the damaging effects of UV light.  Omega 3 high in EPA, would replace the Omega 6 (arachidonic acid) in the cell membranes, and that helps to reduce the possibilities of the production of arachidonic acid-derived inflammatory markers due to UV exposure or other stimulants.

Hyaluronic acid, a natural component of many tissues. Hyaluronic acid plays an important role in keeping the skin properly moisturized. Ingesting HA increased skin moisture and improved treatment outcomes for participants with dry skin. HA appears to get absorbed by the body and distributed, in part, to the skin. Ingested HA also encourages the of HA and promotes cell proliferation in fibroblasts. These effects show that ingestion of HA moisturizes the skin and is expected to improve the quality of life for people who suffer from dry skin.

Topically applied hyaluronic acid has improved skin hydration and elasticity while also significantly reducing wrinkle depth.

DMAE (2-dimethylaminoethanol) It is a colorless liquid. DMAE has been used as an ingredient in skin care, and as a supplement to improve cognitive function, and mood. DMAE is actually a lesser-known compound in fish and it is similar to choline. Topical application of DMAE gel formulation has helped to increase skin firmness.

DMAE may enhance water retention in connective skin tissue, and / or may improve the skin’s ability to transmit acetylcholine which promotes a form of muscle tightening in the skin. DMAE may not completely reverse existing facial sagging, but it may reduce its further progression while a cumulative effect with continued use it has been achieved.

Liver spots or Age spots also may respond effectively to DMAE in topical or oral form. DMAE helps to stabilize the cell membranes, and reduced the accumulation of lipofuscin deposits inside the cells. Lipofuscin is known as those brownish pigments which are formed from molecular waste due to inefficient metabolism of fatty acids. These pigments are more seen in the cells of older people and are the primarily reason for age spots. DMAE helps to flush excess lipofuscin pigments from the affected skin cells.

Vitamin C is a powerful antioxidant and essential for healthy synthesis of collagen. Concentration of vitamin C in the skin reduces by age, therefore; taking vitamin C or using topical vitamin C helps to restore its decline. It is suggested that topical application of vitamin C improves its concentrations in the skin 20‒40 times more effectively than oral intake. Topical vitamin C has helped to reduce oxidative stress of the skin, fine lines, and wrinkles; while improved subjective and objective appearance of photo damaged and photo aged skin within 3 months.

The human skin is the outer covering of the body and is the largest organ made up of multiple layers. Skin guards the underlying muscles, bones, ligaments and internal organs. The skin interfaces with the environment and is the first line of defense from external factors. Skin is important to maintain immunity by protecting the body against pathogens and excessive water loss. Skin other functions are including insulation, temperature regulation, sensation, synthesis of vitamin D, and the protection of vitamin B folates.

Due to aging skin becomes thinner and more easily damaged. Intensifying this effect is the decreasing ability of skin to heal itself as a person ages. Skin aging is also noted by a decrease in volume and elasticity. There are many internal and external causes to skin aging. For example, aging skin receives less blood flow and lower glandular activity. Clinically skin aging graded based on sagging, wrinkles, and the various demonstrations of photo-aging, including redness, telangiectasia ( tiny veins, or spider veins), dyspigmentation (brown discoloration), solar elastosis (yellow, thickened and deeply wrinkled skin due to chronic exposure to the sun), abnormal skin growths, and poor texture. High cortisol level causes degradation of collagen accelerating skin aging.

Related Articles:

How Does Dry Skin Affect Your Health

How to Remove Toxic Heavy Metals From Body naturally?

How to Reverse Aging and Stay Young Even In the Old Age?

Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

References:

1. Schagen SK, Zampeli VA, Makrantonaki E, Zouboulis CC. Discovering the link between nutrition and skin aging. Dermatoendocrinol. Jul 1 2012;4(3):298-307.
2. "Sunscreen or sunblock". Retrieved July 2015. Check date values in: |accessdate= (help).
3. Hughes MC, Williams GM, Baker P, Green AC. Sunscreen and prevention of skin aging: a randomized trial. Ann Intern Med. Jun 4 2013;158(11):781-790.
4. "Nanotechnology Information Center: Properties, Applications, Research, and Safety Guidelines". American Elements.
5. An update on Suncreens; 2007; P 23- 29.Available at www.aocd.org/resource/resmgr/jaocd/2007aug.pdf.
6. Iannacone MR, Hughes MC, Green AC. Effects of sunscreen on skin cancer and photoaging. Photodermatology, photoimmunology & photomedicine. Apr-Jun 2014;30(2-3):55-61.
7. Pandel R, Poljšak B, Godic A, Dahmane R. Skin Photoaging and the Role of Antioxidants in Its Prevention. ISRN Dermatology. 2013;2013:930164.
8. Phillips TJ, Demircay Z, Sahu M. Hormonal effects on skin aging. Clin Geriatr Med. Nov 2001;17(4):661-672, vi.
9. Angelo G. Oregon State University. Linus Pauling Institute. Micronutrient Center. Essential Fatty Acids and Skin Health http://lpi.oregonstate.edu/mic/micronutrients-hea... February 2.
10. Angelo G. Linus Pauling Institute. Micronutrient Information Center. Minerals and Skin Health. http://lpi.oregonstate.edu/mic/micronutrients-hea... 1/2013. Accessed 5/9/2016.
11. Gkogkolou P, Bohm M. Advanced glycation end products: Key players in skin aging? Dermato-endocrinology. Jul 1 2012;4(3):259-270.
12. Pageon H. Reaction of glycation and human skin: the effects on the skin and its components, reconstructed skin as a model. Pathologie-biologie. Jun 2010;58(3):226-231.
13. Pageon H, Zucchi H, Rousset F, Monnier VM, Asselineau D. Skin aging by glycation: lessons from the reconstructed skin model. Clinical chemistry and laboratory medicine : CCLM / FESCC. Jan 1 2014;52(1):169-174.
14. Hamers L. One reason your hair is thinning? Some of it turns into skin. Science: American Academy for the Advancement of Science. http://www.sciencemag.org/news/2016/02/one-reason... 2/4/2016. Accessed 5/6/2016
15. Morita A. Tobacco smoke causes premature skin aging. J Dermatol Sci. Dec 2007;48(3):169-175.
16. Hagenau T, Vest R, Gissel TN, Poulsen CS, Erlandsen M, Mosekilde L, Vestergaard P. Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. Jan 2009;20(1):133-140.
17. Minocha, R; Damian, DL; Halliday, GM (5 July 2017). "Melanoma and nonmelanoma skin cancer chemoprevention: A role for nicotinamide?". Photodermatology, Photoimmunology & Photomedicine. 34 (1): 5–12. doi:10.1111/phpp.12328. PMID 28681504.
18. Chen, Andrew C.; Damian, Diona L. (2014). "Nicotinamide and the skin". Australasian Journal of Dermatology. 55 (3): 169–175. doi:10.1111/ajd.12163. PMID 24635573.
19. Niren NM. Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review. Cutis. Jan 2006;77(1 Suppl):11-16.
20. Namazi, Mohammad Reza (2003). "Nicotinamide: A potential addition to the anti-psoriatic treatment". The FASEB Journal. 17 (11): 1377–1379. doi:10.1096/fj.03-0002hyp.
21. Chen AC, Martin AJ, Choy B, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. The New England journal of medicine. Oct 22 2015;373(17):1618-1626.
22. Surjana D, Halliday GM, Martin AJ, Moloney FJ, Damian DL. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. The Journal of investigative dermatology. May 2012;132(5):1497-1500.
23. Colombo VE, Gerber F, Bronhofer M, Floersheim GL. Treatment of brittle fingernails and onychoschizia with biotin: scanning electron microscopy. J Am Acad Dermatol. Dec 1990;23(6 Pt 1):1127-1132.
24. Higdon J. Linus Pauling Institute. Micronutrient Information Center. Biotin. http://lpi.oregonstate.edu/mic/vitamins/biotin. Last updated 10/21/2015a. Accessed 5/9/2016.
25. NLM. U.S. National Library of Medicine. Aging changes in hair and nails www.nlm.nih.gov/medicineplus/ency/article.nails. Last updated 8/23/2016a. Accessed 9/13/2016.
    
26. Higdon J. Linus Pauling Institute. Micronutrient Information Center. Pantothenic Acid: Wound Healing. http://lpi.oregonstate.edu/mic/vitamins/pantothen... Last updated 7/2015b. Accessed 5/9/2016
27. Ead RD. Oral zinc sulphate in alopacia areata-a double blind trial. Br J Dermatol. Apr 1981;104(4):483-484.
28. Jugdaohsingh R. Silicon and bone health. The journal of nutrition, health & aging. Mar-Apr 2007;11(2):99-110.
29. Seaborn CD, Nielsen FH. Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver. Biological trace element research. Dec 2002;89(3):251-261.
30. Kadler KE, Baldock C, Bella J, Boot-Handford RP. Collagens at a glance. Journal of cell science. Jun 15 2007;120(Pt 12):1955-1958.
31. Okawa T, Yamaguchi Y, Takada S, et al. Oral administration of collagen tripeptide improves dryness and pruritus in the acetone-induced dry skin model. J Dermatol Sci. May 2012;66(2):136-143.
32. Sudha PN, Rose MH. Beneficial effects of hyaluronic acid. Advances in food and nutrition research. 2014;72:137-176.
33. Bender, David A. (2003). Nutritional Biochemistry of the Vitamins. Cambridge University Press. p. 203. ISBN 978-1-139-43773-8. Archived from the original on 2016-12-30.
34. El-Alfy M, Deloche C, Azzi L, et al. Skin responses to topical DMAE: implications in antiageing treatment? Br J Dermatol. Nov 2010;163(5):968-976.
35. Piccardi N, Manissier P. Nutrition and nutritional supplementation: Impact on skin health and beauty. Dermato-endocrinology. Sep 2009;1(5):271-274.
36. Pilkington SM, Massey KA, Bennett SP, et al. Randomized controlled trial of oral omega-3 PUFA in solar-simulated radiation-induced suppression of human cutaneous immune responses. The American journal of clinical nutrition. Mar 2013;97(3):646-652.
37. Surette ME. The science behind dietary omega-3 fatty acids. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. Jan 15 2008;178(2):177-180.
38. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. Jan 2012;463(1):121-137.
39. Oyetakin-White P, Suggs A, Koo B, Matsui MS, Yarosh D, Cooper KD, Baron ED. Does poor sleep quality affect skin ageing? Clinical and experimental dermatology. Jan 2015;40(1):17-22.
40. Ortonne JP. Pigmentary changes of the ageing skin. Br J Dermatol. Apr 1990;122 Suppl 35:21-28.
41. Evans JA, Johnson EJ. The role of phytonutrients in skin health. Nutrients. Aug 2010;2(8):903-928.
42. Michels AJ. Linus Pauling Institute. Micronutrient Information Center. Micronutrients and Skin Health. http://lpi.oregonstate.edu/mic/micronutrients-hea... 9/2011. Accessed 9/13/2016.
43. WHO Model Formulary 2008 (PDF). World Health Organization. 2009. pp. 496, 500. ISBN 978-924-154765-9. Archived (PDF) from the original on December 13, 2016. Retrieved December 8, 2016.
44. British National Formulary: BNF 69 (69th ed.). British Medical Association. 2015. p. 822. ISBN 978-0-85711-156-2.
45. Knip, M.; Douek, I. F.; Moore, W. P.; Gillmor, H. A.; McLean, A. E.; Bingley, P. J.; Gale, E. A. (2000). "Safety of high-dose nicotinamide: A review" (PDF). Diabetologia. 43 (11): 1337–1345. doi:10.1007/s001250051536. PMID 11126400.
46. MacKay, D.; Hathcock, J.; Guarneri, E. (2012). "Niacin: Chemical forms, bioavailability, and health effects". Nutrition Reviews. 70 (6): 357–366. doi:10.1111/j.1753-4887.2012.00479.x. PMID 22646128.
47. CPCE. Collagen Peptide Clinical Evidence. http://www.humanclinicals.org/collagen-peptide-1/... Accessed 5/9/2016
48. Humbert PG, Haftek M, Creidi P, et al. Topical ascorbic acid on photoaged skin. Clinical, topographical and ultrastructural evaluation: double-blind study vs. placebo. Experimental dermatology. Jun 2003;12(3):237-244.
49. Traikovich SS. Use of topical ascorbic acid and its effects on photodamaged skin topography. Archives of otolaryngology--head & neck surgery. Oct 1999;125(10):1091-1098.
50. Raschke T, Koop U, Dusing HJ, et al. Topical activity of ascorbic acid: from in vitro optimization to in vivo efficacy. Skin Pharmacol Physiol. Jul-Aug 2004;17(4):200-206.
51. Sauermann K, Jaspers S, Koop U, Wenck H. Topically applied vitamin C increases the density of dermal papillae in aged human skin. BMC dermatology. Sep 29 2004;4(1):13.
52. Rabionet M, Gorgas K, Sandhoff R. Ceramide synthesis in the epidermis. Biochimica et biophysica acta. Mar 2014;1841(3):422-434.
53. Siskind LJ, Kolesnick RN, Colombini M (2006). "Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations". Mitochondrion. 6 (3): 118–25. doi:10.1016/j.mito.2006.03.002. PMC 2246045. PMID 16713754.
54. Choi MJ, Maibach HI. Role of ceramides in barrier function of healthy and diseased skin. Am J Clin Dermatol. 2005;6(4):215-223.
55. Feingold KR (2007). "Thematic review series: skin lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis". Journal of Lipid Research. 48 (12): 2531–2546. doi:10.1194/jlr.R700013-JLR200. PMID 17872588.
56. Kim HH, Cho S, Lee S, Kim KH, Cho KH, Eun HC, Chung JH. Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo. Journal of lipid research. May 2006;47(5):921-930.
57. Kim HH, Shin CM, Park CH, Kim KH, Cho KH, Eun HC, Chung JH. Eicosapentaenoic acid inhibits UV-induced MMP-1 expression in human dermal fibroblasts. Journal of lipid research. Aug 2005;46(8):1712-1720.
58. Jennemann R, Rabionet M, Gorgas K, Epstein S, Dalpke A, Rothermel U, Bayerle A, van der Hoeven F, Imgrund S, Kirsch J, Nickel W, Willecke K, Riezman H, Gröne HJ, Sandhoff R (2012). "Loss of ceramide synthase 3 causes lethal skin barrier disruption" (PDF). Human Molecular Genetics. 21 (3): 586–608. doi:10.1093/hmg/ddr494. PMID 22038835.
59. Popa I, Abdul-Malak N, Portoukalian J (2010). "The weak rate of sphingolipid biosynthesis shown by basal keratinocytes isolated from aged vs. young donors is fully rejuvenated after treatment with peptides of a potato hydrolysate". International Journal of Cosmetic Science. 32 (3): 225–232.
60. Kawada C, Yoshida T, Yoshida H, Matsuoka R1, Sakamoto W, Odanaka W, Sato T, Yamasaki T, Kanemitsu T, Masuda Y, Urushibata O.Ingested hyaluronan moisturizes dry skin. Nutr J. 2014 Jul 11;13:70. doi: 10.1186/1475-2891-13-70.
61. Uhoda I, Faska N, Robert C, Cauwenbergh G, Pierard GE. Split face study on the cutaneous tensile effect of 2-dimethylaminoethanol (deanol) gel. Skin Res Technol. 2002 Aug;8(3):164-7.
62. Dylewski DP, Nandy S, Nandy K. Effects of centrophenoxine on lipofuscin in the retinal pigment epithelium of old mice. Neurobiol Aging. 1983;4(1):89-95.
63. Burke KE. Photodamage of the skin: protection and reversal with topical antioxidants. Journal of cosmetic dermatology. Jul 2004;3(3):149-155.
64. Proksch, E; Brandner, JM; Jensen, JM (2008). "The skin: an indispensable barrier". Experimental Dermatology. 17 (12): 1063–72. doi:10.1111/j.1600-0625.2008.00786.x. PMID 19043850.
65. Madison, KC. (2003). "Barrier function of the skin: "la raison d'être" of the epidermis" (PDF). J Invest Dermatol. 121 (2): 231–41. doi:10.1046/j.1523-1747.2003.12359.x. PMID 12880413.
66. Proksch, E; Brandner, JM; Jensen, JM (2008). "The skin: an indispensable barrier". Experimental Dermatology. 17 (12): 1063–72. doi:10.1111/j.1600-0625.2008.00786.x. PMID 19043850.
67. Madison, KC. (2003). "Barrier function of the skin: "la raison d'être" of the epidermis" (PDF). J Invest Dermatol. 121 (2): 231–41. doi:10.1046/j.1523-1747.2003.12359.x. PMID 12880413.
68. Weedon, David (2010). Weedon's Skin Pathology, 3rd Edition. Elsevier. ISBN 978-0-7020-3485-5.
69. Kahan V, Andersen ML, Tomimori J, Tufik S. Can poor sleep affect skin integrity? Medical hypotheses. Dec 2010;75(6):535-537.
70. Cutroneo, Kenneth R.; Kenneth M. Sterling (2004). "How do glucocorticoids compare to oligo decoys as inhibitors of collagen synthesis and potential toxicity of these therapeutics?". Journal of Cellular Biochemistry. 92 (1): 6–15. doi:10.1002/jcb.20030. ISSN 0730-2312. PMID 15095399.
71. Oikarinen, A. (2004). "Connective tissue and aging". International Journal of Cosmetic Science. 26 (2): 107. doi:10.1111/j.1467-2494.2004.213_6.x. ISSN 0142-5463.
72. Dunn JH, Koo J. Psychological Stress and skin aging: a review of possible mechanisms and potential therapies. Dermatology online journal. Jun 2013;19(6):18561.
73. Besdine RW. Merck Manual. Consumer Version. Changes in the Body With Aging. http://www.merckmanuals.com/home/older-people’s-h... Copyright 2016. Accessed 9/13/2016.
74. Calleja-Agius J, Brincat M, Borg M. Skin connective tissue and ageing. Best practice & research. Clinical obstetrics & gynaecology. Oct 2013;27(5):727-740.

5-10 % of the women in childbearing age are affected by PCOS. PCOS is a hormonal condition with variety of signs and symptoms at different severity levels including irregular menstrual cycle, chronic lack of ovulation, enlarged ovaries, excess male hormone production which shows as facial hair, adult acne, and male pattern hair loss.

PCOS is one of the most common female endocrine conditions. The word “syndrome” is commonly used in medicine to describe varied signs and symptoms but does not indicate a precise cause of the condition.

Main conditions associated with PCOS are high blood sugar or diabetes due to increased insulin resistance, Increase LH, weight gain, depression, infertility. Also, women with PCOS are at much higher risk of developing cardiovascular disease.

Key Features Of PCOS:

PCOS causes hormonal imbalances, such as elevated testosterone (male hormone) and estrogen (female hormone), as well as increased insulin levels.

Irregular menstrual cycle which can take more than 35 days, or absent for a few months, and too little or heavy long periods.

Increased androgen levels is a key feature of PCOS, which may result in excess facial and body hair (hirsutism), adult acne and male-pattern baldness (in women). However, the physical signs of androgen excess vary with ethnicity. for example, the hirsutism is seen in at least 40% of European and American females, and it is even more common in darker skin types, while it may not affect the women of oriental descent.

Polycystic ovaries are enlarged ovaries with numerous small cysts that are detected by ultrasound. However, there are some women with the condition while their ovaries appear normal.

Infertility is one of the most common conditions caused by PCOS, as many women with polycystic ovary syndrome experience infrequent ovulation or lack of ovulation altogether . PCOS also is associated with spontaneous abortion and preeclampsia .

Obesity rate in women with PCOS is significantly higher; and about half of all women with PCOS manifest central obesity, in which there is a greater deposition of visceral fat around internal organs in the abdominal region. Accumulation of abdominal fat is associated with increased risk of hypertension, diabetes and lipid abnormalities.

Studies suggest that the insulin resistance and type 2 diabetes are at much higher level in women with PCOS than age and weight-matched controls. A great number of PCOS women is found to develop type 2 diabetes mellitus by the age of 40.

A skin condition known as Acanthosis nigricans which consists of dark, poorly defined, velvety dark patches found on the nape of the neck, armpits, inner thighs, vulva, or under the breasts , is in fact a sign of insulin resistance and higher circulating insulin levels.

How PCOS Is Diagnosed?

A standard diagnostic assessment for PCOS includes a full medical history, looking for signs and symptoms during a physical exam, a comprehensive hormonal tests, and ultrasound to detect "follicular arrest", or the development of small (5–7mm) follicles that never reach the pre-ovulatory size of 16 mm

Blood work is used to measure the levels of several hormones and to exclude the many possible causes of menstrual abnormalities or androgen excess that mimic PCOS. Along with tests used to measure elevated androgen levels, high levels of luteinizing hormones (LH) or an elevation in the ratio of LH to follicle stimulating hormone (FSH), prolactin, thyroid stimulating hormone (TSH), 17-hydroxyprogesterone, testosterone and DHEA-S, AMH, blood glucose level, cholesterol, and triglycerides are all considered.

What Are The Causes & Risk Factors For PCOS?

Anovulation (a menstrual cycle in which ovulation does not occur) and androgen excess have been considered the main diagnostic identifier for PCOS, however, insulin resistance is now considered as a significant contributor to the pathogenesis of PCOS.

Currently there are several contributing key factors to the development of PCOS:

Excessive production of LH triggers premature ovulation, disrupting the follicle’s maturation process and leading to an increase in androgen production by ovarian theca cells. Some research points to increased LH as the driving force for PCOS in slim and normal body-weight women.

High Insulin production also causes high androgen levels. Studies indicate that insulin acts synergistically with LH to enhance androgen production in ovarian theca cells; also Insulin directly and independently reduces the serum sex hormone-binding globulin (SHBG) resulting in more free blood androgen.

Since abnormal theca cells activity seems to be the primary source of excessive androgen production in PCOS, scientists suspect that there may be a genetic basis for PCOS.

An increase in LH, as well as high insulin levels both cause an increase in androgen production by ovarian theca cells. Scientists suspect that the changes in the ovaries, development of the cysts and theca cells' dysfunction seems may be an indication of a genetic basis for PCOS.

Some risk factors are considered to have a significant impact on the progression of PCOS. these risk factors are including; weight gain which is seemed to contribute to the development of PCOS, enlarged fat cells, not being able to regulate insulin, chronic inflammation, exposure to endocrine-disrupting chemicals, autoimmune disorders, especially those involving the ovaries, pancreas, thyroid and adrenal glands, the use of prolactin promoting treatments, and early puberty (under the age of 8).

How Natural Medicine Can Help?

Inositol is a sugar alcohol that comes in variety of forms. The Myo-inositol (MI) is the most common form, while D-chiro-inositol (DCI) makes up a small percentage. Some MI is converted to DCI in the body. Inositol supplementation contributes to improving hormonal and reproductive conditions in women. Inositol is found in cell membrain structure and plays an active role in cell to cell signalling, moreover it improves the insulin signaling.

PCOS participants who have taken Myo-inositol supplementation had improved insulin sensitivity, metabolic markers, reproductive hormone levels, restored menstrual cycles, improved quality and maturity of oocytes, and overall higher pregnancy rates. These improvement are dose dependant, the 4g daily Inositol with 400 mcg folate within 14 weeks produced better results than 1500 mg daily.

N-acetyl-cysteine (NAC) is an antioxidant which is used for production of glutathione, one of the body's most important natural antioxidants and detoxifiers. NAC helps to improve Insulin Sensitivity which is important for PCOS patients. The NAC treatment also helped to reduce testosterone levels and in free androgen in women with PCOS.

NAC may also be useful for improving fertility in women with PCOS. NAC when used in conjunction with infertility treatments improved ovulation rates. In a study of 573 women with PCOS, 52% of the participants who NAC with their regular treatment ovulated, whereas only 18% ovulated on the treatment alone.

Based on multiple studies and research, lipoic acid plays a critical role in maintaining optimal blood sugar levels (by helping the body use glucose), supporting insulin sensitivity. Lipoic acid helps relieve several aspects of metabolic syndrome. It helps to maintain healthy blood pressure and insulin resistance, improves lipid profile, and reduces weight. Therefore liopic acid has been considered to provide therapeutic benefits for those with metabolic syndrome.

Similarly, Lipoic acid at 600 mg twice daily has helped women with PCOS to improve their insulin sensitivity, and a reduction in triglycerides and LDL within 16 weeks.

Chromium is one of the most widely studied nutritional supplements for treatment of glucose and insulin-related irregularities. Chromium picolinate specifically is the form that has been used in a number of studies on insulin resistance. Chromium picolinate at 200 mcg/day improves glucose tolerance when compared with a placebo in women with PCOS.

Unique compounds in cinnamon bark where found to effectively increase sugar metabolism by 20 times in the lab, suggesting these compounds may function as antioxidants, enhancing insulin action, and may be beneficial to control of glucose intolerance and diabetes. Participants who took 1-6 grams of ground cinnamon lowered their fast blood sugar, serum triglycerides, LDL, and total cholesterol during 40 days. Similarly researchers at Columbia University found that cinnamon reduced insulin resistance in women with PCOS after 8 weeks, while it was not observed in placebo group.

Licorice root may help to down regulate androgen production and reduce serum testosterone in females. The authors of the study suggested that licorice could be considered to be used along with other treatments for hirsutism and polycystic ovary syndrome. These finding were further confirmed via follow up studies and it was found that the including licorice along with the routine treatment also helped to reduce the medical side effects of the treatment.

Researchers at Columbia University suggest that Vitamin D combined with calcium supplementation has helped to normalize and maintain menstrual cycles, and improve fertility rate of women with PCOS. It appears that abnormalities in calcium balance may be responsible, in part, for the poor follicular development in women with PCOS and contribute to its pathogenesis. Furthermore, those women with higher blood levels of vitamin D were much less likely to be insulin resistant.

Based on data often women with PCOS have significantly low serum and total magnesium which it could further contribute to the progression of insulin resistance to type 2 diabetes and heart disease. Supplementing with higher doses of magnesium (600 mg -1000 mg elemental magnesium) for 16 weeks combined with regular treatments and diet resulted in higher blood levels of magnesium and improved control of diabetes, as suggested by lower hemoglobin A1c (HbA1c) levels. Since magnesium improves insulin-mediated glucose uptake and insulin secretion in type 2 diabetes patients, it is considered a critical mineral for women with PCOS as well.

Diet and lifestyle:

Daily physical activity and exercise are essential part of treatments to help prevent insulin resistance, and to lower blood sugar, improve weight management, and to decrease testosterone.

A diet that is rich in fiber, vitamins, minerals , phytonutrients, and low in saturated fat is helpful to manage and prevent progression of the PCOS symptoms.

Monounsaturated fats help to increase insulin sensitivity and lower the overall glycemic index. High fiber foods are slowly absorbed, causing less insulin to be released. High fiber diets increase SHBG, which binds to and lowers free testosterone.

A moderate reduction in dietary carbohydrates contributes to lower fasting and post-challenge insulin concentrations among women with PCOS, and improved reproductive and endocrine outcomes.

Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

Related Articles:

Balanced Hormones and Women's Health

Benefits of Hypoallergenic Feminine Hygiene Products & The Risks of Toxic Chemicals in Feminine Hygiene Products

Natural Remedies for Hormonal Imbalance in Females

How to Relieve Yeast Infection Itch Naturally?

References:

1. Dewailly D, Pigny P, Soudan B, et al. Reconciling the definitions of polycystic ovary syndrome: the ovarian follicle number and serum anti-Müllerian hormone concentrations aggregate with the markers of hyperandrogenism. J Clin Endocrinol Metab. 2010 Sep;95(9):4399-405.
2. Diamanti-Kandarakis, E, et al. The role of genes and environment in the etiology of PCOS. Endocrine. 2006 August;30(1):19-26.
3. Fica S, Albu A, Constantin M, Dobri GA. Insulin resistance and fertility in polycystic ovary syndrome. J Med Life. 2008 Oct-Dec;1(4):415-22.
4. Ma YM, Li R, Qiao J, Characteristics of abnormal menstrual cycle and polycystic ovary syndrome in community and hospital populations. Chin Med J (Engl). 2010 Aug;123(16):2185-9.
5. Schuring AN, Schulte N, Sonntag B, Kiesel L. Androgens and insulin--two key players in polycystic ovary syndrome. Recent concepts in the pathophysiology and genetics of polycystic ovary syndrome. Gynakol Geburtshilfliche Rundsch. 2008;48(1):9-15.
6. Artini PG, Di Berardino OM, Simi G, Best methods for identification and treatment of PCOS. Minerva Ginecol. 2010 Feb;62(1):33-48.
7. Azziz R, Carmina E, Dewailly D et al. Androgen Excess Society: Position statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006, 91:4237-4245.
8. Badaway, A, State O, El Gawad S et al. Plasma homocysteine and polycystic ovary syndrome: The missed link. Eur J Obstet Gynecol Reprod Biol. 2007 March; 131(1):68-72.
9. Faloia E, Canibus P, Gatti C, Frezza F, Santangelo M, GarrapaGG, Boscaro M. Body composition, fat distribution and metabolic characteristics in lean and obese women with polycystic ovary syndrome. J Endocrinol Invest. 2004 May;27(5):424-9.
10. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010 Jul-Aug;16(4):347-63.
11. Pellatt L, Rice S, Mason HD. Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high? Reproduction. 2010 May;139(5):825-33.
12. Petríková J, Lazúrová I. Polycystic ovary syndrome and autoimmune diseases. Vnitr Lek. 2010 May;56(5):414-7.
13. Armamani D, et al. Licorice reduces serum testosterone in healthy women. Steroids. 2004 October-November;69(11-12):763-766.
14. Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of myo-inositol supplementation on oocyte's quality in PCOS patients: a double blind trial. European review for medical and pharmacological sciences. May 2011;15(5):509-514.
15. Grundy SM. Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation. 2002;105(23):2696–2698.
16. Guzick DS. Polycystic ovary syndrome. Obstet Gynecol 2004;103:181-193.
17. Wood JR, Nelson VL, Ho C, et al. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem. 2003 Jul 18;278(29):26380-90.
18. Bremer AA and Miller WL. The serine phosphorylation hypothesis of polycystic ovary syndrome: a unifying mechanism for hyperandrogenemia and insulin resistance. Fertil Steril. 2008 May;89(5):1039-48.
19. Gupta A, Jakubowicz D, Nestler JE. Pioglitazone Therapy Increases Insulin-Stimulated Release of d-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome. Metabolic syndrome and related disorders. Oct 2016;14(8):391-396.
20. Lagana AS, Rossetti P, Buscema M, La Vignera S, Condorelli RA, Gullo G, . . . Triolo O. Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols. International journal of endocrinology. 2016;2016:6306410.
21. Artini PG, Di Berardino OM, Papini F, Genazzani AD, Simi G, Ruggiero M, Cela V. Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Apr 2013;29(4):375-379.
22. Kamenov Z, Kolarov G, Gateva A, Carlomagno G, Genazzani AD. Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Feb 2015;31(2):131-135.
23. Unfer V, Nestler JE, Kamenov ZA, Prapas N, Facchinetti F. Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials. International journal of endocrinology. 2016;2016:1849162.
24. Muscogiuri G, Palomba S, Lagana AS, Orio F. Inositols in the Treatment of Insulin-Mediated Diseases. International journal of endocrinology. 2016;2016:3058393.
25. Bevilacqua A, Bizzarri M. Physiological role and clinical utility of inositols in polycystic ovary syndrome. Best practice & research. Clinical obstetrics & gynaecology. Nov 2016;37:129-139.
26. Costantino D et al. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. Eur Rev Med Pharmacol Sci. 2009 Mar-Apr;13(2):105-10.
27. Genazzani AD, Lanzoni C, Ricchieri F, JasonniVM. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol. 2008 Mar;24(3):139-44.
28. Benelli E, Del Ghianda S, Di Cosmo C, Tonacchera M. A Combined Therapy with Myo-Inositol and D-Chiro-Inositol Improves Endocrine Parameters and Insulin Resistance in PCOS Young Overweight Women. International journal of endocrinology. 2016;2016:3204083.
29. Cheang KI, Sistrun SN, Morel KS, Nestler JE. Effect on Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator during Weight Loss in Obese Women with and without Polycystic Ovary Syndrome. International journal of endocrinology. 2016;2016:7631804.
30. Genazzani AD, Prati A, Santagni S, Ricchieri F, Chierchia E, Rattighieri E, . . . Artini PG. Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. Dec 2012;28(12):969-973.
31. Gerli S et al. Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci. 2007 Sep-Oct;11(5):347-54.
32. Papaleo E et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol. 2007 Dec;23(12):700-3.
33. Papaleo E, Unfer V, Baillargeon JP, Chiu TT. Contribution of myo-inositol to reproduction. Eur J Obstet Gynecol Reprod Biol. 2009 Dec;147(2):120-3.
34. Fulghesu, AM, et al. N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Fertil Steril. 2002 June; 77(6):1128-1135.
35. Lucidi RS, et al. Effect of chromium supplementation on insulin resistance and ovarian and menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril. 2005 December; 84(6):1755-7.
36. Rizk AY, Bedaiwy MA, Al-Inany HG. N-acetyl-cysteine is a novel adjuvant to infertility treatment -resistant patients with polycystic ovary syndrome. Fertil Steril. 2005 Feb;83(2):367-70.
37. Masharani U, Gjerde C, Evans JL, Youngren JF, Goldfinel D.Effects of controlled-release alpha lipoic acid in lean, nondiabetic patients with polycystic ovary syndrome. J Diabetes Sci Technol. 2010 Mar 1;4(2):359-64.
38. Pershadsingh HA. Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome. Expert Opin Investig Drugs. 2007 Mar;16(3):291-302.
39. Anderson RA, Broadhurst CL, Polansky MM, et al. Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity. J Agric Food Chem. 2004 Jan 14;52(1):65-70.
40. Cao H, Graves DJ, Anderson RA. Cinnamon extract regulates glucose transporter and insulin-signaling gene expression in mouse adipocytes. Phytomedicine. 2010 Nov;17(13):1027-32.
41. Khan A et al. Cinnamon Improves Glucose and Lipids in People with Type 2 Diabetes. Diabetes Care. 2003;26:3215-18.
42. Wang JG, et al. The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study. Fertil Steril. 2007 July;88(1):240-3. Epub 2007 Feb 12.
43. Armanini D et al. Treatment of polycystic ovary syndrome with spironolactone plus licorice. Eur J ObstetGynecolReprod Biol. 2007 Mar;131(1):61-7.
44. Vitd & calcium:
45. Thys-Jacobs S, Donovan D, Papadopoulos A, et al. Vitamin D and calcium dysregulation in the polycystic ovarian syndrome. Steroids.1999 June;64(6):430-5.
46. Wehr EB et al. Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol. 2011 Mar 9.
47. De Lourdes Lima, M, Cruz T, PousadaJC, Rodrigues LE, Barbosa K, Canguco V. The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care 1998 May; 21: 682-86.
48. Kauffman RP, Tullar PE, Nipp RD, Castracane VD. Serum magnesium concentrations and metabolic variables in polycystic ovary syndrome. Acta Obstet Gynecol Scand. 2011 Jan 4. doi: 10.1111/j.1600-0412.2010.01067.x. [Epub ahead of print&91;
49. Mooren FC, Kruger K, Völker S, Golf W, Wadepuhl M, Kraus A. Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects – a double-blind, placebo-controlled, randomized trial. Diabetes, Obesity and Metabolism. 2011 March; 13 (3): 281-84.
50. Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects. Diabetes Care. 2003 April; 26:1147-52.
51. Douglas CC, et al. Role of diet in the treatment of polycystic ovary syndrome. Fertil Steril. 2006 March; 85(3):679-88.
52. Marsh K, et al. The optimal diet for women with polycystic ovary syndrome? Br J Nutr. 2005 August; 94(2):154-65.
53. Kiddy DS, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol. 1992 January;36(1):105-11. 

The spectrum of gluten-related disorders includes celiac disease, dermatitis, gluten ataxia (Severe body's reaction to gluten impacting central nervous system), wheat allergy and non-celiac gluten sensitivity. The term non-celiac gluten sensitivity (NCGS) describes a clinical condition when the individuals develop symptoms to gluten-containing foods and feel better on the absence of gluten but do NOT have celiac disease.

What is gluten?

Gluten is the Latin word for glue. Gluten is not a single protein but instead a complex combination of proteins, primarily gliadin and glutenin. Gluten is formed in the process of dough making when wheat flour is mixed with water. The combination of gliadin, a viscous (thick) protein, with glutenin, a long, elastic protein, yields gluten with its unique “visco-elastic” properties that are important in baking and food processing. Therefore despite the common interpretation of the term “gluten-containing grains,” in fact, gluten itself is not present in the wheat seed; rather it is created during the process of dough making.

Furthermore, Rye and barley, do not form gluten. These grains contain proteins known as secalin in rye and hordein in barley which both contain fragments acting similar to wheat's gliadin in the body triggering celiac disease.

All three grains—wheat, rye, and barley—are commonly and by error considered “gluten-containing grains”,  just for simplicity and convenient.

Protein compounds of Gliadin (wheat), secalin (rye), and hordein (barley) are rich in two amino acids including proline and glutamine, and thus are called together “prolamins”.

The chemical bonds between proline and glutamine in the gluten protein are resistant to digestion. This prevents complete breakdown of gluten into small, harmless molecules. Instead, big, undigested gluten fragments remain in the digestive tract.

In healthy people, these large, undigested fragments of gluten protein are eventually harmlessly excreted and do not provoke an immune response (Fasano 2009). For people with celiac disease, however, these glutamine-proline rich fragments, or peptides, are toxic.

What Are The Differences Between Wheat Allergy, Celiac Disease, and Non-Celiac Gluten Sensitivity?

While clinical symptoms of these conditions may overlap and make it difficult to differentiate them on the basis of symptoms alone, these disorders are actually three different conditions from distinct processes:

In wheat allergy certain type of antibody (IGE) is produced in reaction to wheat, resulting in the release of histamine and other inflammatory compounds which could cause symptoms such as skin eruptions, runny nose, itching, and in rare cases, anaphylactic reaction.

Wheat allergy is a less common condition in about 0.5% of the general population. IgE antibodies are key players in immediate food allergy reactions which usually occur within minutes to several hours after ingesting the allergenic food, though the reaction can occur up to two days later IgE reactions to foods can be measured by blood or dermal testing. (Available by Health Palace)

Celiac disease is an autoimmune disease, not an allergy. Autoimmune disease reactions are long lasting and highly destructive, whereas allergic reactions can appear and disappear within minutes to hours after contact with an allergen. In celiac disease other than signs and symptoms, there is a strong presence of antibody IGA in the blood sample with positive villous atrophy (damage to small intestine) on biopsy, and positive human leukocyte antigens (HLAs). Blood tests alone are often not considered adequate to confirm a diagnosis of celiac disease. More than 98% of people with celiac disease have at least one of two variants of a gene called HLA DQ2 and/or HLA DQ8 .

Genetic testing for HLA DQ2 and HLA DQ8 is useful due to several reasons; negative tests rule out almost all cases of celiac disease, including those already on a gluten-free diet; negative tests may help clarify the picture when the result of other testing is unclear; and these tests are used to screen close relatives of patients for genetic risk of celiac disease . (available at Health Palace).

Celiac disease is an inflammatory immune disorder in genetically susceptible individuals. In people with celiac disease, ingestion of gluten provokes an immune attack that inflames and damages the lining of the small intestine. Gluten causes damage to the gut of individuals who suffer from celiac disease. This typically results in nutrient malabsorption along with a wide variety of symptoms, ranging from diarrhea and constipation to skin rashes and depression . This reaction to gluten is not an allergy, but rather an internal inflammatory immune condition. Untreated celiac disease contributes to variety of other conditions such as osteoporosis, infertility, neurological disorders, other autoimmune diseases, and in some cases, cancer.

Celiac disease is characterized by increased intestinal permeability (“leaky gut”), which allows gluten to get through the damaged gut barrier and provoke an immune response.

In celiac disease, intestinal damage manifests as a flattening of the villi (finger shape structures of the intestinal cells which are significantly important for the absorption of nutrients ). The villous atrophy reduces the surface area available for nutrient absorption resulting mal-absorption which further contributes to both intestinal disorders such as indigestion and diarrhea, and non-intestinal conditions such as anemia and osteoporosis.

Celiac disease has been associated with a number of other conditions, especially autoimmune-related conditions such as type 1 diabetes and autoimmune thyroid disease, and an increased risk of certain cancers such as non-Hodgkin lymphoma, small intestinal cancer, colon cancer, and basal cell carcinoma.

Brain and nervous system problems are seen in celiac cases. In celiac disease autoimmune antibodies are produced against and enzyme called transglutaminase involving the intestine and skin, however a sub type of this enzyme called transglutaminase 6, is found in the brain and nervous system. Antibodies against this enzyme have been identified in patients with gluten ataxia and schizophrenia. Although, the involvement of these antibodies in other neurological and psychiatric conditions is still under investigation, there is evidence that transglutaminase 6, and the transglutaminase enzyme family in general, may be important in the development of degenerative diseases of the brain. For example, Recently, the prevalence of celiac disease was reported to be 5–10 times higher in a study in patients with multiple sclerosis compared to the general population. All the patients in this study had an excellent response to the gluten-free diet in an average of three years, with regard to both digestive and neurological symptoms.

A case report has shown celiac disease can mimic multiple sclerosis. A patient with a history of diarrhea and colic since youth and neurological symptoms since age 18 was diagnosed with multiple sclerosis at age 34. Later was found the he was positive for HLA DQ2 and DQ8 genetic tests, and under a gluten-free diet both his digestive and neurological symptoms have been improved.

Non-celiac gluten sensitivity (NCGS) is only considered once wheat allergy and celiac disease have been ruled out, and a beneficial response to dietary elimination of gluten-containing foods is observed. Specific antibodies are absent and there is no villous atrophy.

Majority of the cases of Non-celiac gluten sensitivity, the symptoms are reported to the food that contained gluten, not the pure gluten; therefore, suggesting this group are may be actually sensitive to other compounds known as FODMAPs rather than gluten.

FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) are types of carbohydrates that some people cannot digest very well. So the bacteria in the colon ferment these carbohydrates resulting in gas, bloating, abdominal pain and diarrhea. Wheat, barley and rye are high in FODMAP, which may be a contributing factor to these symptoms. Not all carbohydrates are considered FODMAPs, but many types of foods contain them, including foods that are high in fructose, like honey, apples, mangoes, and watermelon; dairy products, like milk and ice cream; and fructans, such as garlic and onions.

In fact, FODMAPs seem more likely than gluten to cause widespread intestinal distress, since bacteria regularly ferment carbohydrates but ferment protein less frequently. Although a FODMAP-free diet is complicated, it permits people to eliminate individual foods temporarily and then reintroduce them systematically to determine which, if any, are responsible for their stomach problems. Furthermore, wheat contains other proteins called amylase/trypsin inhibitors (ATI) that in lab has shown to cause intestinal inflammation.

People with NCGS can experience a spectrum of highly variable symptoms similar to those caused by celiac disease and irritable bowel syndrome such as bloating, abdominal pain, diarrhea, constipation, nausea, acid reflux, and mouth ulcers . These Individuals may have non-intestinal symptoms such as feeling generally unwell, fatigue, headaches, foggy mind, numbness, joint pains, or skin rash. An individual may have one or more symptoms.

Non-celiac gluten sensitivity does not appear to be an autoimmune condition, making it distinct from celiac disease; neither is an allergic condition, which distinguishes it from classical wheat allergy. In fact, there are currently no universally recognized tests or biomarkers for non-celiac gluten sensitivity. A recent randomized controlled trial in 37 patients with NCGS and irritable bowel syndrome found that gluten did not produce negative effects when FODMAPs were restricted in the diet.

What Is A Gluten Free Diet?

A strict, lifelong gluten-free diet is the only established treatment for celiac disease, as even a tiny amount of gluten can lead to intestinal damage in those with celiac disease. In the majority of cases, a strict compliance has helped to reduce their symptoms, to heal the existing intestinal damage, and to prevent further damage.

The gluten-free diet excludes all foods that contain wheat (including spelt, triticale, and kamut), rye, and barley. This means avoiding these grains, as well as pasta, cereals, and processed foods—unless they are labeled “gluten-free.”

It is thought that most celiac patients can eat modest amounts of pure gluten free oats, while some celiac patients do not tolerate oats well.

The gluten-free diet is also recommended for non-celiac gluten sensitivity conditions as well; however, recent studies suggests avoidance of FODMAPs as opposed to gluten. The level of gluten tolerance varies among individuals with NCGS and with rare exceptions, most of these individuals can eat trace amounts of gluten without negative health consequences.

What Can Help To Improve The Gluten Related Conditions?

Certain specific types of protease enzymes derived from plants and microorganisms such as common fungus Aspergillus niger can completely break down gluten peptides into harmless fragments. These enzymes are proline-specific and /or glutamine-specific protease. These enzyme specifically cleaves the proline-rich gliadin peptides, making them less immunogenic.

Experiments with cell cultures suggests that these enzymes are resistant to the strong acidic environment of the stomach, and fully digest gluten and immunogenic peptides and appeared to reduce gluten-induced small intestinal damage in patients with celiac disease who were challenged with up to 2g gluten per day while following a gluten-free diet.

Low pancreatic digestive enzymes, is relatively common in celiac disease patients. Damage to the small intestine impacts on the ability of the pancreas to secrete digestive enzymes. Patients treated with pancreatic enzymes experienced a 75% reduction in symptoms. Another study found that the severity of villous atrophy in the small intestine was greatly associated with laboratory signs of pancreatic enzyme insufficiency.

Celiac patients and those on a gluten free diet due to poor intestinal absorption of nutrients, chronic intestinal inflammation, limited diet, and limited choices due to cross contamination with gluten byproducts, are prone to develop many health conditions related to long term deficiencies of essential nutrients. These conditions often increase the severity of the digestive conditions, despite of being on a restrict diet.

Poor calcium absorption is very common in individuals with celiac disease due to damage to the intestinal lining . This chronic deficiency leads to bone loss, osteopenia, osteoporosis, and increased fracture risk. A calcium deficient gluten free diet is a major cause of low bone mineral density. Therefore, supplementation with calcium is very important for patients with celiac disease or those on the gluten free diet.

Several studies indicate that the celiac Patients and those on the gluten free diet are more at risk of magnesium deficiency as well. Magnesium is an essential mineral involved in many of enzymatic reactions in the body and it is required for proper metabolism of vitamin D and calcium, and therefore for bone health. The significance of the magnesium deficiency in celiac disease was first recognized over fifty years ago. And in later studies it was found that children and adolescents with celiac disease or normal intestinal villi who had been on a gluten-free diet were depleted form magnesium. Taking Magnesium supplements in these individuals resulted in increases in both red blood cell magnesium and bone mineral density. Accordingly, screening for magnesium status and deficiency, and magnesium supplementation and dietary enrichment, are considered essential aspects of care for celiac patients and those on a gluten free diet.

Based on studies 64% of men and 71% of women with celiac disease and on a gluten free diet are found to have significantly low vitamin D levels contributing to range of musculoskeletal disorders including bone pain, muscle disorders (myopathy), loss of bone mineral density, osteopenia, and osteoporosis. Vitamin D supplementation helps to improve the symptoms and prevent deficiencies. Vitamin D also plays important role to particularly modulate the immune system and provides anti-inflammatory benefits. Supplementation with vitamin D and calcium is widely recommended for celiac patients. Lab studies suggests vitamin D potentially decrease systemic inflammation and prevent autoimmune disease in human.

B-deficiency and anemia related to low b12 and folate is very common in celiac cases and on a gluten free diet. Low levels of B12, folate and B6 are also associated with elevated homocycteine levels, which contributes to a damage to lining of blood vessels and promote atherosclerotic disease. Vitamins B12, B6, and folate, are necessary for the metabolism of homocysteine, and their supplementation is shown to help normalize the homocycteine levels and prevent deficiencies in celiac conditions and in individuals on a gluten free diet.

Celiac individuals and those on a poor gluten free diet are prone to deficiency of fat soluble vitamins and nutrients including vitamin A, D, E, K, and omega 3s.

Poor nutrient absorption in celiac condition is associated with vitamin A deficiency. Vitamin A is important for normal immune function, vision, and gene expression. Case studies have pointed out the importance of vitamin A, even in remitted celiac cases on a gluten-free diet. Supplementing with Vitamin A has helped to restore their intestinal symptoms and blurry vision.

Vitamin E is an important fat-soluble vitamin and free radical scavenger that plays a major role in protecting cell membranes from oxidative damage. Vitamin E deficiency has also been linked to the development of neurological symptoms in celiac patients.

Because often patients on the gluten free diet do not get adequate amount of calcium, vitamins K and D, supplementation with vitamin K at the time of diagnosis for these individuals has been recommended. Vitamin K participate in calcium metabolism and therefore it is important for bone health. Furthermore, Vitamin K deficiency can contribute to easy bruising, which is a atypical sign of celiac disease.

Serum concentrations of omega-3 fatty acids are significantly lower in celiac individuals and after one year on a gluten-free diet, levels of omega-3 fatty acids still remaine well below control values. Omega-3 fatty acids significantly contribute to biological anti-inflammatory effects in the body.

In vitro studies on the intestinal epithelial cells cultures suggests that supplementation with DHA would help to reduce intestinal inflammation. Intestinal cells in response to inflammation triggered by gluten, release inflammatory arachidonic acid, while DHA is shown to be able to block its release. Also, omega-3 fatty acids help reduce inflammation by inhibiting the nuclear factor-kappaB (NF-ĸB) which is a pro-inflammatory mediator. Omega 3 is able to stimulate PPAR- Gamma cellular receptor which activates genes that reduce the production of pro-inflammatory markers.

Celiac individuals and those on a gluten free diet are at the higher risk of developing autoimmune thyroid conditions, due to selenium deficiency. Selenium is an integral part of the enzyme glutathione peroxidase which the body's master antioxidant; plus, Selenium is essential for thyroid hormone regulation and conversion.

Glutathione is our body's powerful defenses against free radicals, and is essential to the liver’s detoxification functions. Celiac patients are prone to lower levels of glutathione in their intestinal lining and blood, resulting in elevated lipid peroxides (oxidized fat) which promotes and contributes to oxidative damage to the intestinal tissue and increased risk of cancer. Supplementation with glutathione has shown to help to restore the body's reserve. Also, N-acetyl cysteine as well as alpha-lipoic acid, vitamin c, selenium, and whey protein are helping to improve and maintain proper glutathione level and functions.

Alpha-lipoic acid is naturally produced in the mitochondria of the cell contributing to energy production. It is also a powerful free radical scavenger, and it helps reviving other antioxidants such as glutathione, vitamin C, vitamin E, and coenzyme Q10. Dietary supplementation with alpha-lipoic acid is shown to increase both cellular glutathione concentrations and its activity.

Zinc deficiency is another common condition associated with celiac disease and gluten free diet. Zinc is an essential nutrient which participates in more than 300 enzymatic reactions in the body. Some consider the zinc supplementation a necessary part of celiac treatment and an addition to the gluten free diet. Zinc deficiency negatively impacts growth, immune function, wound healing, and skin problems.

Zinc carnosine in particular appears to help maintain the integrity of the intestinal barrier and inhibit the intestinal permeability in the treatment group.

Since celiac is an inflammatory autoimmune condition, keeping the inflammation and the inflammatory markers at the low level, helps to improve symptoms and the quality of life of those individuals. Anti-inflammatory nutraceuticals such as Curcumin and Boswellia serrata are shown to help with variety of inflammatory conditions including gluten intolerance or celiac disease. Curcumin contributes to suppression of interferon-gamma, an inflammatory marker; while boswellia participates in inhibition of pro-inflammatory pathways involving 5-lipoxygenase, leukotrienes, and TNF-α which both In a similar way, may help reduce the intestinal inflammation in celiac disease.

EGCG a chief constituent of Green tea extract is capable of interrupting inflammatory tissue damage seen in celiac and other autoimmune conditions. Helper T cells are considered a key factor in many autoimmune diseases including celiac disease. EGCG helps to suppress the auto-reactive T cells which consequently reduces production of pro-inflammatory cytokines. Furthermore, EGCG is shown to inhibit interferon-gamma which is a main inflammatory mediator in celiac disease .

Glutamine is the most abundant amino acid in the body and play a key role in protection and repair of the gastrointestinal lining, especially during stress and illness. Oral supplementation with glutamine helps to improve the size of intestinal villi, encourages proliferation of the cells of the intestinal lining, and helps to maintain integrity of the gut lining, prevent excessive permeability, and improve gut barrier function.

Whey protein is source of essential amino acids and it is rich in cysteine which is used to produce glutathione. Whey protein is highly effective for increasing glutathione levels in different types of cells. Whey protein also helps to significantly reduce intestinal permeability. This benefit of whey on gut integrity may be useful in celiac disease, and could be considered to be used in conjunction with gluten-free diet as a source of high-quality protein and glutathione precursors.

Evidently the intestinal micro-biome is greatly altered in celiac individuals and those on a gluten free diet. Probiotics from Lactobacillus and Bifidobacterium Species have shown to improve indigestion, constipation, and acid reflux. Probiotics help to enforce the intestinal barrier, as well as helping to predigest the gluten protein in food. Exposure of the intestinal biopsy of celiac patients to predigested gluten showed to result in less recruitment of immune cells suggesting that the probiotic formulation helped to reduce or eliminate the toxicity of wheat gluten.

Dietary & Lifestyle Changes:

What is most important for the individuals and health care professionals to know is that the diagnosis of non-celiac gluten sensitivity should not be made without excluding celiac disease. A gluten-free diet should NOT be initiated without a proper clinical assessment such as testing for IgA-tissue transglutaminase antibody while the person is on a regular gluten-containing diet, along with a confirming genetic test.

The gluten free diet can be very challenging to follow. In addition, there are concerns about the nutritional adequacy of general gluten free products on the market as they can be high in fat and sugar, and often low in fiber, iron and B vitamins. Thus those requiring or like to initiate a gluten free diet should consult with health care professionals and consider taking nutritional supplements to prevent deficiencies and to help improve their condition.

There are many gluten-free alternatives to wheat such as; amaranth, buckwheat, corn, millet, rice, quinoa, sorghum, teff, yucca, potato, nuts, flax, and all beans and legumes are naturally gluten-free. There are also alternatives to gluten-containing flour, including potato, rice, soy, tapioca, carob, and bean flour.

Gluten free foods usually contain Ingredients like rice starch, cornstarch, tapioca starch, and potato starch which are often used as replacements for white flour. But they are highly refined carbohydrates, and release so much sugar into the bloodstream.

While the gluten-free diet is also used to treat non-celiac gluten sensitivity, the need for strict adherence or permanency is not clear.

Enzyme therapy is one of the a promising intervention to detoxify gluten. Certain protein-digesting enzymes (proteases) derived from plants and microorganisms can completely break down gluten peptides into harmless fragments.

Articles and products featured by Health Palace are collected from a variety of sources and are provided as a service by Health Palace. These newsletters, while of potential interest to readers, do not necessarily represent the opinions nor constitute the advice of Health Palace. Presented materials are only for information purposes and do not intent to treat, cure, or prevent any disease.

Related Articles:

How Digestive Enzyme Can Improve Your Health?

Probiotics and their Several Health Benefits for Human

How to Reduce Inflammation Effectively With Natural Medicine

What is Homocysteine & How Is It Related to Cardiovascular Disease

References:

1.Volta U, Tovoli F, Cicola R, Parisi C, Fabbri A, Piscaglia M, . . . Caio G. Serological tests in gluten sensitivity (nonceliac gluten intolerance). Journal of clinical gastroenterology. Sep 2012;46(8):680-685.

2.Volta U, De Giorgio R. New understanding of gluten sensitivity. Nat Rev Gastroenterol Hepatol. 2012;9:295-299.

3.Volta U, Caio G, Tovoli F, et al. Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness. Cell Mol Immunol. 2013;10:383-392.

4.Veraverbeke WS, Delcour JA. Wheat protein composition and properties of wheat glutenin in relation to breadmaking functionality. Critical reviews in food science and nutrition. 2002;42(3):179-208.

5.Mooney, P; Aziz, I; Sanders, D (2013). "Non-celiac gluten sensitivity: clinical relevance and recommendations for future research". Neurogastroenterology & Motility. 25 (11): 864–871. doi:10.1111/nmo.12216. PMID23937528.

6.Nijeboer, P; Bontkes, H; Mulder, C; Bouma, G (2013). "Non-celiac gluten sensitivity. Is it in the gluten or the grain?". Journal of Gastrointestinal and Liver Disorders. 22 (4): 435–40. PMID24369326.

7.Catassi C, Bai JC, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A (Sep 2013). "Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders". Nutrients. 5 (10): 3839–53.

8.Vahedi K, Mascart F, Mary JY, et al. Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol. 2003;98(5):1079-1087.

9.Snyder CL, O Young D, Green PHR, et al. Celiac Disease. In: GeneReviews. Pagon RA, Adam MP, Amemiya A, et al. eds. Seattle WA: University of Washington, Seattle; 2015. <http://www.ncbi.nlm.nih.gov/books/NBK1727/>.

10.Smith DF, Gerdes LU. Meta-analysis on anxiety and depression in adult celiac disease. Acta Psychiatr Scand. 2012;Mar;125(3):189-93.

11.Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656-676.

12.Marchioni Beery RM, Birk JW. Wheat-related disorders reviewed: making a grain of sense. Expert Rev Gastroenterol Hepatol. 2015;3:1-14. [Epub ahead of print&91;

13.Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. Journal of the American College of Nutrition. 2014;33(1):39-54.

14.UCMC. University of Chicago Medical Center. The University of Chicago Celiac Disease Center. Celiac disease facts and figures. Available at: http://www.cureceliacdisease.org/wp-content/uploa... Updated 2014. Accessed 10/14/2014.

15.UCLA Health. Celiac Disease Program. For Patients page. Celiac vs Gluten-Sensitivity vs Wheat Allergies. Available at: http://gastro.ucla.edu/site.cfm?id=281. Accessed 3/6/2015.

16.Thomas H, Beck K, Adamczyk M, Aeschlimann P, Langley M, Oita RC, . . . Aeschlimann D. Transglutaminase 6: a protein associated with central nervous system development and motor function. Amino acids. Jan 2013;44(1):161-177.

17.Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997;3(7):797-801.

18.Tilley KA, Benjamin RE, Bagorogoza KE, et al. Tyrosine cross-links: molecular basis of gluten structure and function. J Agric Food Chem. 2001;49:2627-2632.

19.Stenman SM, Lindfors K, Venalainen JI, Hautala A, Mannisto PT, Garcia-Horsman JA, . . . Kaukinen K. Degradation of celiac disease-inducing rye secalin by germinating cereal enzymes: diminishing toxic effects in intestinal epithelial cells. Clinical and experimental immunology. Aug 2010;161(2):242-249.

20.Sapone A, Lammers KM, Casolaro V, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011;9:23.

21.Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012;Feb 7;10:13.

22.Carroccio A, Mansueto P, Iacono G, et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012;107(12):1898-906

23.Staudacher HM, Irving PM, Lomer MC, Whelan K. Mechanisms and efficacy of dietary FODMAP restriction in IBS. Nat Rev Gastroenterol Hepatol. Apr 2014;11(4):256-266.

24.Barrett JS, Gibson PR. Fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and nonallergic food intolerance: FODMAPs or food chemicals? Therapeutic advances in gastroenterology. Jul 2012;5(4):261-268.

25.Catassi C, Bai JC, Bonaz B, et al. Non-celiac gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013;Oct;5(10):3839-3853.

26.Tikkakoski S, Savilahti E, Kolho KL. Undiagnosed celiac disease and nutritional deficiencies in adults screened in primary health care. Scand J Gastroenterology. 2007;Jan;’42(1):60-65.

27.Caruso R, Pallone F, Stasi E, et al. Appropriate nutrient supplementation in celiac disease. Ann Med. 2013;Dec;45(8):522-31.

28.Stazi AV, Trinti B. Selenium status and over-expression of interleukin-15 in celiac disease and autoimmune thyroid diseases. Ann Ist Super Sanita. 2010;46(4):389-399.

29.Stazi AV, Trinti B. Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases. Minerva Med. 2008;Dec;99(6):643-53.

30.Sapone A, Lammers KM, Casolaro V, et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011;9:23.

31.Lee SA, Kim HJ, Chang KC, et al. DHA and EPA down-regulate COX-2 expression through suppression of NF-kappaB activity in LPS-treated human umbilical vein endothelial cells. Korean J Physiol Pharmacol. 2009;Aug;13:301-307.

32.Ferretti G, Bacchetti T, Masciangelo S, Saturni L. Celiac disease, inflammation and oxidative damage: a nutrigenetic approach. Nutrients. Apr 2012;4(4):243-257.

33.Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiological Reviews. 2011;Jan1;91(1):151-175.

34.Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005;Sep;2(9):416-22.

35.FARE. Food Allergy Research & Education. About Food Allergies. Wheat Allergy. Available at: http://www.foodallergy.org/allergens/wheat-allerg... Copyright 2015a. Accessed 3/6/2015.

36.Elfström P, Montgomery SM, Kämpe O, et al. Risk of primary adrenal insufficiency in patients with celiac disease. J Clin Endocrinol Metab. 2007;92(9):3595-8.

37.Peters SL, Biesiekierski JR, Yelland GW, et al. Randomized clinical trial: gluten may cause depression in subjects with non-celiac gluten sensitivity – an exploratory clinical study. 2014;May;39(10):1104-12.

38.Toouli J, Blankin AV, Oliver MR, et al. Management of pancreatic exocrine insufficiency: Australasian Pancreatic Club recommendations. Med J Aust. 2010;193(8):461-7.

39.Siegel M, Bethune MT, Gass J, et al. Rational design of combination enzyme therapy for celiac sprue. Chem Biol. 2006;13:649-658.

40.Gass J, Bethune MT, Siegel M, et al. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology. 2007;133:472-480.

41.Hallert C, Grant C, Grehn S, et al. Evidence of poor vitamin status in celiac patients on a gluten-free diet for 10 years. Aliment Pharmacol Ther. 2002;16:1333-1339.

42.Allred LK, Ritter BW. Recognition of gliadin and glutenin fractions in four commercial gluten assays. Journal of AOAC International. Jan-Feb 2010;93(1):190-196.

43.Evans KE, Leeds JS, Morley S, Sanders DS. Pancreatic insufficiency in adult celiac disease: do patients require long-term enzyme supplementation? Digestive diseases and sciences. Oct 2010;55(10):2999-3004.

44.Saibeni S, Lecchi A, Meucci G, et al. Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics. Clin Gastroenterol Hepatol. 2005;3:574-580.

45.Reinken L, Zieglauer H. Vitamin B-6 absorption in children with acute celiac disease and in control subjects. J Nutr. 1978;108:1562-1565.

46.Hadithi M, Mulder CJJ, Stam f, et al. Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease. World J Gastroenterol. 2009;Feb 28;15(8):955-960.

47.Dahele A, Ghosh S. Vitamin B12 deficiency in untreated celiac disease. Am J Gastroenterology. 2001;96(3):745-750.

48.Dickey W, Ward M, Whittle CR, et al. Homocysteine and related B-vitamin status in coeliac disease: effects of gluten exclusion and histological recovery. Scand J Gastroenterol. 2008;43:682-688.

49.Dickey W. Low serum vitamin B12 is common in celiac disease and is not due to autoimmune gastritis. Eur J Gastroenterol Hepatol. 2002;14(4):425-427.

50.Turner J, Pellerin G, Mager D. Prevalence of metabolic bone disease in children with celiac disease is independent of symptoms at diagnosis. J Pediatr Gastroenterol Nutr. 2009;49:589-593.

51.Szymczak J, Bohdanowicz-Pawlak A, Waszczuk E, et al. Low bone mineral density in adult celiac disease. Endokrynol Pol. 2012;63(4):270-6.

52.Pantaleoni S, Luchino M, Adriani A, et al. Bone mineral density at diagnosis of celiac disease and after 1 year of gluten-free diet. Scientific World Journal. 2014;2014:173082.

53.Lucendo AJ, Garcia-Manzanares A. Bone mineral density in adult celiac disease: an updated review. Rev Esp Enferm Dig. 2013;Mar;105(3):154-62.

54.Nikpour S. Neurological manifestations, diagnosis, and treatment of celiac disease: A comprehensive review. Iranian Journal of Neurology. 2012;11(2):59-64.

55.Bianchi ML, Bardella MT. Bone in celiac disease. Osteoporos Int. 2008;19:1705-1716.

56.Blazina S, Bratanic N, Campa AS, et al. Bone mineral density and importance of strict gluten-free diet in children and adolescents with celiac disease. Bone. 2010;Sep;47(3):598-603.

57.Rujner J, Socha J, Wojtasik A, et al. Magnesium status in children and adolescents with celiac disease. Wiad Lek. 2001;54(5-6):277-285.

58.Richards JB, Valdes AM, Gardner JP, Paximadas D, Kimura M, Nessa A, . . . Aviv A. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. The American journal of clinical nutrition. Nov 2007;86(5):1420-1425.

59.Prietl B, Treiber G, Pieber TR, et al. Vitamin D and immune function. Nutrients. 2013;5:2502-2521.

60.Duerksen DR. Dramatic effect of vitamin D supplementation and a gluten-free diet on bone mineral density in a patient with celiac disease. J Clin Densitom. 2012;Jan-Mar;15(1):120-123.

61.Mager DR, Qiao J, Turner J. Vitamin D and K status influences bone mineral density and bone accrual in children and adolescents with celiac disease. Eur J Clin Nutr. 2012;66:488-495.

62.Lerner A, Shapira Y, Agmon-Levin N, et al. The clinical significance of 25OH-vitamin D status in celiac disease. Clinic Rev Allerg Immunol. 2012;42:322-330.

63.Kriegel MA, Manson JE, Costenbader KH. Does vitamin D affect risk of developing autoimmune disease?: a systematic review. Semin Arthritis Rheum. 2011;40:512-531.

64.Karaahmet OZ, Unlu E, Karaahmet F, Gurcay E, Cakci A. Myopathy related to vitamin D deficiency in patient with celiac disease. Muscle & nerve. Jul 2014;50(1):147-148.

65.Agmon-Levin N, Theodor E, Segal RM, et al. Vitamin D in systemic and organ-specific autoimmune diseases. Clinic Rev Allerg Immunol. 2013;45:256-266.

66.Antico A, Tampoia M, Tozzoli R, et al. Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? a systematic review of the literature. Autoimmunity Reviews 2012;12:127-136.

67.Zittermann A. Effects of vitamin K on calcium and bone metabolism. Current opinion in clinical nutrition and metabolic care. Nov 2001;4(6):483-487.

68.Rastogi A, Bhadada SK, Bhansali A, et al. Celiac disease: a missed cause of metabolic bone disease. Indian J Endocrinol Metab. 2012;Sep-Oct;16(5):780-785.

69.Booth SL. Roles for vitamin K beyond coagulation. Annu Rev Nutr. 2009;29:89-110.

70.Vaynshtein G, Rosenbaum H, Groisman GM, Markel A. Celiac sprue presenting as severe hemorrhagic diathesis due to vitamin K deficiency. The Israel Medical Association journal : IMAJ. Dec 2004;6(12):781-783.

71.Higdon J. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Vitamin A. Available at: http://lpi.oregonstate.edu/infocenter/vitamins/vi... Last updated 11/2007a. Accessed 3/5/2015.

72.Alwitry A. Vitamin A deficiency in coeliac disease. The British Journal of Ophthalmology. 2000;84(9):1075-1075.

73.Higdon J. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Vitamin E. Available at: http://lpi.oregonstate.edu/infocenter/vitamins/vi... Last updated 6/2008. Accessed 3/5/2015.

74.Kleopa KA, Kyriacou K, Zamba-Papanicolaou E, et al. Reversible inflammatory and vacuolar myopathy with vitamin E deficiency in celiac disease. Muscle Nerve. 2005;31:260-265.

75.Zapata-Gonzalez F, Rueda F, Petriz J, et al. Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPARgamma: RXR heterodimers: comparison with other polyunsaturated fatty acids. J Leukoc Biol. 2008;84:1172-1182.

76.Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, . . . Zhou R. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity. Jun 27 2013;38(6):1154-1163.

77.Westphal C, Konkel A, Schunck WH. CYP-eicosanoids – a new link between omega-3 fatty acids and cardiac disease? Prostaglandins Other Lipid Mediat. 2011;96:99-108.

78.Surette ME. The science behind dietary omega-3 fatty acids. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. Jan 15 2008;178(2):177-180.

79.Calder PC. Immunomodulation by omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2007;77:327-335.

80.Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et biophysica acta. Apr 2015;1851(4):469-484.

81.Solakivi T, Kaukinen K, Kunnas T, et al. Serum fatty acid profile in celiac disease patients before and after a gluten-free diet. Scand J Gastrolenterol. 2009;44:826-830.

82.Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilizes small bowel integrity and stimulates gut repair processes. Gut. 2007;56:168-175.

83.Jiang X, Dong J, Wang B, Yin X, Qin L. [Effects of organic selenium supplement on glutathione peroxidase activities: a meta-analysis of randomized controlled trials&91;. Wei sheng yan jiu = Journal of hygiene research. Jan 2012;41(1):120-123.

84.Higdon J. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Selenium. Available at: http://lpi.oregonstate.edu/infocenter/minerals/se... Last updated 11/2007b. Accessed 3/5/2015.

85.Zavorsky GS, Kubow S, Grey V, et al. An open-label dose-response study of lymphocyte glutathione levels in healthy men and women receiving pressurized whey protein isolate supplements. Int J Food Sci Nutr. 2007;58(6):429-436.

86.Stojiljkovic V, Todorovic A, Radlovic N, et al. Antioxidant enzymes, glutathione and lipid peroxidation in peripheral blood of children affected by celiac disease. Ann Clin Biochem. 2007;44:537-543.

87.Stojiljkovic V, Pejic S, Kasapovic J, et al. Glutathione redox cycle in small intestinal mucosa and peripheral blood of pediatric celiac disease patients. An Acad Bras Cienc. 2012;84(1):175-184.

88.Stojiljkovic V, Todorovic A, Pejic S, et al. Antioxidant status and lipid peroxidation in small intestinal mucosa of children with celiac disease. Clin Biochem. 2009;Sep;42(13-14):1432-7.

89.Richie JPJ, Nichenametla S, Neidig W, Calcagnotto A, Haley JS, Schell TD, Muscat JE. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. European journal of nutrition. 2014:1-13.

90.Suh JH, Wang H, Liu RM, et al. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys. 2004;423:126-135.

91.Chen P, Ma QG, Ji C, et al. Dietary lipoic acid influences antioxidant capability and oxidative status of broilers. Int J Mol Sci. 2011;12(12):8476-8488.

92.Kolgazi M, Jahovic N, Yuksel M, et al. Alpha-lipoic acid modulates gut inflammation induced by trinitrobenzene sulfonic acid in rats. J Gastroenterol Hepatol. 2007;22:1859-1865.

93.Jones W, Li X, Qu ZC, et al. Uptake recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med. 2002;33(1):83-93.

94.Higdon J. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Lipoic Acid. Available at: http://lpi.oregonstate.edu/infocenter/othernuts/l... Last updated 1/2012b. Accessed 3/5/2015.

95.Higdon J. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Vitamin C. Available at: http://lpi.oregonstate.edu/infocenter/vitamins/vi... Last updated 11/2013c. Accessed 3/5/2015.

96.Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2014;Apr;28(4):579-85.

97.Fahey AJ, Adrian Robins R, Constantinescu CS. Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells. Journal of cellular and molecular medicine. Sep-Oct 2007;11(5):1129-1137.

98.Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41:40-59.

99.Higdon J. Oregon State University. Linus Pauling Institute. Micronutrient Information Center. Curcumin. Available at: http://lpi.oregonstate.edu/infocenter/phytochemic... Last updated 1/2009. Accessed 3/5/2005.

100.Bright JJ. Curcumin and autoimmune disease. Adv Exp Med Biol. 2007;595:425-451.

101.Antony B, Merina B, Iyer VS, et al. Bioavailability of BCM-95 CG (Biocurcumax), a novel bioenhanced preparation of curcumin. Indian J Pharm Sci. 2008;Jul-Aug;70(4):445-9.

102.Ammon HP. Boswellic acids in chronic inflammatory diseases. Planta Med. 2006;72:1100-1116.

103.Sevastiadou S, Malamitsi-Puchner A, Costalos C, et al. The impact of oral glutamine supplementation on the intestinal permeability and incidence of necrotizing enterocolitis/septicemia in premature neonates. J Matern Fetal Neonatal Med. 2011;24(10):1294-1300.

104.Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Alternative medicine review: a journal of clinical therapeutic. Aug 1999;4(4):239-248.

105.Li N, Lewis P, Samuelson D, et al. Glutamine regulates Caco-2 tight junction proteins. Am J Physiol Gastrointest Liver Physiol. 2004;287:G726-G733.

106.Kuhn KS, Muscaritoli M, Wischmeyer P, Stehle P. Glutamine as indispensable nutrient in oncology: experimental and clinical evidence. European journal of nutrition. Jun 2010;49(4):197-210.

107.Nilsen EM, Jahnsen FL, Lundkin KE, et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology. 1998;Sep;115(3):551-63.

108.Wu D, Wang J, Pae M, et al. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol Aspects Med. 2012;33:107-118.

109.Watson JL, Ansari S, Cameron H, et al. Green tea polyphenol (-)-epigallocatechin gallate blocks epithelial barrier dysfunction provoked by IFN-gamma but not byIL-4. Am J Physiol Gastrointest Liver Physiol. 2004;Nov;287(5):G954-61.

110.Molberg O, Kjersti Uhlen A, Jensen T, et al. Mapping of gluten T-cell epitopes in the bread wheat ancestors: implications for celiac disease. Gastroenterology. 2005;128:393-401.

111.Mazzon E, Muia C, Paola RD, et al. Green tea polyphenol extract attenuates colon injury induced by experimental colitis. Free Radic Res. 2005;Sep;39(9):1017-25.

112.Vilela RM, Lands LC, Chan HM, et al. High hydrostatic pressure enhances whey protein digestibility to generate whey peptides that improve glutathione status in CFTR-deficient lung epithelial cells. Mol Nutr Food Res. 2006;50:1013-1029.

113.Alt Med Rev. Therapeutic applications of whey protein. Alternative Medicine Review. 2008;13(4):341-347.

114.Middleton N, Jelen P, Bell G. Whole blood and mononuclear cell glutathione response to dietary whey protein supplementation in sedentary and trained male human subjects. Int J Food Sci Nutr. 2004;55(2):131-141.

115.Benjamin J, Makharia G, Ahuja V, et al. Glutamine and whey protein improve intestinal permeability and morphology in patients with Crohn’s disease: a randomized controlled trial. Dig Dis Sci. 2012;57:1000-1012.

116.Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;May;9:313-323.

117.Pozo-Rubio T, Olivares M, Nova E, et al. Immune development and intestinal microbiota in celiac disease. Clin Dev Immunol. 2012;2012:654143.

118.Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. Aug 2012;4(8):1095-1119.

119.Lindfors K, Blomqvist T, Juuti-Uusitalo K, et al. Live probiotic Bifidobacterium lactis bacteria inhibit the toxic effects induced by wheat gliadin in epithelial cell culture. Clin Exp Immunol. 2008;152:552-558.

120.Zingone F, Capone P, Ciacci C. Celiac disease: Alternatives to a gluten free diet. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2010;1(1):36-39.

121.Thompson T. Folate, iron, and dietary fiber contents of the gluten-free diet. Journal of the American Dietetic Association. Nov 2000;100(11):1389-1396.

122.Shepherd SJ, Gibson PR. Nutritional inadequacies of the gluten-free diet in both recently-diagnosed and long-term patients with celiac disease. J Hum Nutr Diet. 2013;Aug;26(4):349-58.

123.UCMC. University of Chicago Medical Center. The University of Chicago Celiac Disease Center. Jump start your gluten-free diet. Available at: http://www.cureceliacdisease.org/living-with-celi... Updated 2013. Accessed 10/17/2014.

124.Bai JC, Fried M, Corazza GR, et al. World gastroenterology organization global guidelines on celiac disease. J Clin Gastroenterol 2013; Feb;47(2):121-126.