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Iron anemia with paradoxical elevations of iron storage and metabolic iron utilization challenges.

Author Note

This paper describes iron anemia coexisting with paradoxical syndromes of iron overload as a consequence of altered or impaired bioavailability of iron. Iron anemia frequently occurs in the presence of iron mis-utilization syndromes or iron overload as these clinical and sub-clinical conditions exist as a continuum instead of as separate or distinct conditions. The broad, yet vague, diagnostic term "anemia of chronic disease" best categorizes the complexity of events that lead to paradoxical disorders related to iron metabolism. Nutritional biochemistry applications contribute a pivotal role in identifying and prioritizing diagnostic criteria for improving accuracy and corrective prioritization of therapeutic interventions that transcend the complexity and variability of these syndromes. Once understood, earlier and more successful conservative interventions may be achieved.

Abstract

Characteristics of iron anemia are frequently superimposed on those of iron overload, creating a diagnostic and therapeutic challenge. Disorders that promote an anemic state exist in a reciprocal "cause and effect" continuum of disorders that promote an iron overload state. (14) It is not uncommon to encounter a clinical situation where symptoms, clinical signs, and laboratory chemistry markers indicate an iron anemia, yet also imply a situation of iron overload. Key considerations involve attention to hepatic and renal pathologies, alimentary and lifestyle inventories, toxic and immunological burdens, and genetic predispositions that may amplify or promote an iron metabolism dysfunction. Greater than 10% of the aging population at 65 years of age or older and greater than 20% at 85 and older have IDA (Iron-deficiency anemia). (16)

Anemia of chronic disease is thought to account for nearly a nearly a fifth of anemia cases (19.7%) in older adults (US data). (15) American Diabetes Association data reports a prevalence of 1 in 200 for hereditary hemochromatosis. The prevalence of CKD (chronic kidney disease) is reported to be 7.2% to 35.8% depending on age. (21) Specific and relevant dietary and micronutrient interventions involving the addition or cessation of relevant foods and micronutrient(s) may be employed to resolve or improve the condition(s).

Keywords: IDA, CKD, ACD, hepcidin, iron overload, anemia of chronic disease, nutritional anemias, micronutrients.

Iron deficiency anemia is the most common micronutrient deficiency worldwide. (2) By definition, "anemia is present when individual hemoglobin concentrations fall below two standard deviations of the distribution mean for hemoglobin in a healthy population of the same gender and age and living at the same altitude." (1,3) Therefore, it is less a term for a disease entity, and more a term for a symptom of many different and divergent disorders that may have a varied convergent set of symptoms. Within the context of the very broad context of "anemias," there exist at least 12 different categories, and at least 38 different subtypes of anemia organized within those categories. (12) Iron is only one of several factors and micronutrients involved in manifestations of micronutrient-related anemia which include; vitamin B6, vitamin B12, folate, copper, zinc, vitamin C, proteins, and several other cofactors. Situational anemias related to micro-bleeding from gastrointestinal disease, gastrointestinal malabsorption syndromes, inflammatory syndromes, menstruation, pregnancy, and those related to bleeding from trauma can also occur. Hereditary and genetic anemias and autoimmune anemias also exist within the context of the definition. Anemia may manifest as reduced blood cell formation including red blood cells, platelets, white blood cells, as well as the hemoglobin concentration and maturation of blood cells. (1,3)

The condition has many manifestations and causes, due to the variability and superimposed dysfunction in multiple organ systems, its metabolic utilization and co-utilization with other micronutrients, and its interdependent cofactor and micronutrient relationships in enzymatic reactions. (1,2,5) In this case, poor binding, transport, or utilization of alimentary iron (or a combination of these physiological conditions) may deprive the bloodstream and tissues of bioavailable iron. The sensitivity and integrity of the signaling of the iron-regulating protein, hepcidin, plays a key role in how iron is managed. (1,2,11,13,20,23) (Fig. 3) Iron anemia exists worldwide, whether from alimentary unavailability, or the presence of dietary availability of iron. The aging population is particularly vulnerable to IDA, and diagnosis has frequently been overlooked and trivialized as a normal part of aging.

Iron overload disorders can occur from metabolic conditions or situations that impair the gastrointestinal absorption and transport, transmembrane and hepatic binding and transport, excessive iron supplementation, or copper deficiency or utilization problem. (1,2,8,20) It can also occur as a hereditary genetic disorder known as HH (Hereditary Hemochromatosis), of which there are four known types. There are at least 20 known subtypes of iron overload subdivided within the categories of primary and secondary types. (20) HH Type 1 is the most common, and involves impaired HFE gene regulation of intestinal absorption of iron. Type 2 HH is rare, and involves mutations impairing hemojuvelin or hepcidin function. (2) Type 3 HH involves impaired transferrin receptor 2 gene, and HH Type 4 impairs ferroportin's transmembrane transport role in exporting iron from cells (Ferroportin disease) in a copper-dependent coupling with hephaestin or ceruloplasmin to oxidize the iron. Type 4 HH is the next most prevalent, secondary to Type 1. (1,2) A hereditary hemochromatosis condition may be stable depending on the health of the individual and adaptive capacity, or unstable and clinically evident in an individual with comorbidities discussed in this paper. Also, the zygosity and genetic penetrance of the hereditary disorder would have an influence on how and how much it would be expressed. (6) In iron overload conditions and hemochromatosis, the iron that is not actively bioavailable becomes highly oxidative and reactive material in both its stored capacity and in its circulating state. (1,2) Within the context of paradoxical iron metabolism conditions, there exists an overlap between nutritional anemias and those from organic and metabolic causes. (Fig. 1 & 2)

Anemia of Chronic Disease (ACD) presents as iron anemia combined with iron overload, with or without evidence of genetic hereditary forms of hemochromatosis. It's observed to be a multi-factorial consequence of adaptive responses; some of which may be necessary and beneficial. (14) It is believed that the loss of integrity of the regulation of EPO (erythropoietin) is a major "cause" of ACD in aging. (19) However, it is likely that it is not the cause, but a symptom of the same metabolic conditions that influence the overall regulation of inflammation and biochemical events discussed here. (13) (Fig. 1,2, 3)

The result of the presence of these two conditions involves a paradoxical combination of iron anemia and of iron overload. The former involves impaired processes of erythropoiesis that would eventually lead to the many variations of cellular, tissue and organ system impairment once homeostatic adaptive systems have failed. (13,14) These can be categorized into disorders that manifest as a consequence of cellular, tissue, or eventual organ hypoxia, and the adaptive burdens involved to promote molecular pump activity and mitochondrial energy production. At the cellular level, the mitochondria involved in cytochrome activity, ATP production, and electron transport become diminished in numbers and function. (2) The latter can be categorized into disorders that involve oxidative damage to cells, tissues, organs and consequences that result where one condition promotes the other. (14)

Iron, a divalent cation, is involved in multiple enzyme and protein reactions in physiological functions, and is a highly oxidative and reactive micronutrient. Most notably, it is involved in transporting oxygen from blood to tissues, production of energy, DNA synthesis, and integrity of the activities of proteins that carry, transport, and store iron. It is also necessary for the function of peroxidase and cytochrome function. (2) There is a narrow balance of homeostasis between the micronutrients zinc, copper and iron (also divalent) with respect to cellular and molecular physiology and in gene interactions that they are involved in as cofactors. (4,10)

Conditions involving CKD, xenobiotic exposures that impair iron metabolism, inflammatory conditions that promote unregulated chronic cytokine activation or auto-immunity, hepatic diseases that impair iron transport and transmembrane binding, synergistic micronutrient deficiencies such as copper, excessive micronutrient competition, and dietary iron-binding interruptors explain this paradoxical phenomenon. Certain immune challenges, such as bacterial, viral, fungal, and parasitic infections may also disrupt iron utilization, both as a direct effect of the pathogen's affinity to the iron and as a consequence of the immune regulatory changes. There are also genetic variants that, individually or combined with a genetic homozygous or heterozygous hemochromatosis, can disrupt iron metabolism. The common denominator in the development of the paradoxical disorder, in the absence of nutritional deficiencies, bleeding, or absolute genetic disorders, is that of liver dysfunction. Hepatic protein-binding, transport mechanisms are entirely dependent on the integrity of hepatic function.

CKD, or Chronic Kidney Disease involves impairment of erythropoietin and renal tubular dysfunction to regulate mineral balance. According to 2016 statistics from the National Institute of Diabetes and Digestive and Kidney Diseases, 14% of the general population have CKD in at least one of the five CKD stages. The prevalence of CKD in the U.S. ranges from 1.5% to 15.6%, depending on co-morbidities and lifestyle factors. (19) Anemia of chronic disease is typically as a consequence of an inflammatory condition, an autoimmune or neoplastic condition, prolonged illness, trauma, chronic infection involving parasitic, fungal, bacterial, or viral loads, and, in the elderly or ill, polypharmacy. ACD may be the eventual manifestation of chronic impaired absorption of iron in the digestive tract (due to the above causes) and stored iron release and transport (molecular binding and transport functions) becomes impaired or inhibited by the exposure to chronic inflammatory events. Inflammation up-regulates Hepcidin, the primary hepatic iron absorption regulating protein, which inhibits the activity of Ferroportin at the intestinal basolateral cell membrane to transport iron out of storage for utilization. (1,2) CKD does not usually exist in isolation and is a condition of multiple comorbidities, particularly in the context of chronic metabolic conditions and polypharmacy. (18) In cases of superimposed hereditary or genetic channelopathy variants, such as HPP (hyperkalemic periodic paralysis) where deficient potassium channels are dysfunctional and potassium levels rise. These types of disorders tend to be progressive and may not be clinically evident or discovered until the "perfect storm" of inflammatory events de-compensates the regulatory systems that would normally be adapting to such a variant. (7,14)

The paradoxical syndromes of anemia and iron overload are attributed to hepatic dysfunction, as the integrity of the formation and function of the transport and binding proteins involved in metabolism and utilization of iron depend on hepatic integrity. The inherent adaptive homeostatic feedback responses contribute significantly to the paradoxical relationships between anemia and overload. (14)

Clinically, routine laboratory testing on a CBC/differential might reveal shifts in one or a combination of markers indicating iron anemia, such as low Hgb, low hematocrit, low MCV, low WBC, low RBC, low MCHC. Routine chemistry panels might reveal (or not, due to compensatory and adaptive responses (14)) evidence of renal stress or liver stress. Routine iron studies might reveal, individually or in combination, reduced serum iron, transferrin (% iron saturation), ferritin and elevated TIBC and/or UIBC. (Ferritin, TIBC, and UIBC values are clues as to the nature of the disorder, based on iron binding, free-form iron availability, and storage activity). Routine urine microscopy tests are also useful in revealing emerging kidney pathology. Contrary to the assertions of many clinicians, authors and papers that ferritin is a sufficient marker for establishing iron deficiency or overload, serum ferritin is inaccurate and over-relied upon in the absence of additional markers. (20)

Clinically, I have encountered many cases of anemia and overload with ferritin well within normal ranges, with the accessory markers re-vealing the dysfunction. Even an established clinical anemia can easily be overlooked by attending only to the most basic of routine tests and by excluding a routine iron study. Non-routine and more exotic tests are very useful in these scenarios. Cystatin-C, zinc protoporphyrin, urine creatinine clearance testing, ASO antibody titers, anti-DNAase antibody titers, microsomal antibodies, urine microalbumin, urine cultures for crystals and bacterial burdens, for example, are useful in uncovering suspected renal impairment. For hepatic impairment, when routine chemistries are equivocal, microsomal antibodies, viral load and antibody tests, and additional enzyme tests, to name a few, are useful.

Genetic testing for uncovering SNP's and variants related to channelopathies and specific disorders are also useful when more routine clinical testing is not revealing. Organic acid testing and micronutrient testing are available and quite useful for more in-depth, realtime diagnostics, as are toxic metals, porphyrins, and environmental chemicals tests. Ideally, however, a more convenient and accurate methodology of quantifying and monitoring therapeutic progress using ferritin is the "Point Strip ferritin-3000" test, which can be done in-office as a baseline score (in concert with other markers), and as a follow-up on its own. Testing at a range of 300-3,000 ng/dL, it is more accurate than the standard reagents that measure ferritin at 10-500 ng/mL, which is not sensitive enough to capture functional, emerging, and well-adapted iron overload conditions. (22) However, an established, but not yet routine screening test is the serum Hepcidin, which seems to have the most useful diagnostic applications. Adding serum Hepcidin as a routine diagnostic test is becoming a coveted target for iron uncovering utilization challenges. (1,2,23) Since serum ferritin and hepcidin also act as acute-phase inflammatory responders, C-reactive protein and fibrinogen are recommended to identify inflammatory events as a source of paradoxical iron utilization. (1)

Clinical intervention strategies should include: Identifying and therapeutically reducing or eliminating intake of foods that may challenge iron absorption and binding. Identifying and removing xenobiotic substances and exposures that may challenge iron binding, transport, and utilization. Identifying and removing immunological loads and correcting resultant immune activity if either insufficient or chronically persistent. Identifying and correcting kidney and liver pathologies. Identifying and correcting metabolic conditions, such as diabetes. Identifying and correcting micronutrient imbalances, both supplemental and dietary. If chronic, and refractory to what is prioritized symptomatically and clinically for hepatic, renal, immune, dietary, xenobiotic interventions, identifying the most probable genetic variants that may be responsible for disrupting iron metabolism and determining if they are modifiable for treatment options. Examples of other genetic variants that tend to confound a clinical iron utilization disorder are the AAT (alpha-1 - antitrypsin deficiency) and Wilson's disease. (8,9)

Treatment plans depend on the prioritization of the individual's set of conditions leading to the disorder. The challenge lies in the accurate identification of the individual priority in a clinical setting and the strategic management of the condition's priority, given the symptomatic and clinical variables that are superimposed. Selecting and de-selecting testing and treatment direction is dependent on the accuracy of evaluation. Some genetic variants have no known modifiable treatment. Relevant and specific dietary modifications, supplemental micronutrient additions or deletions, botanical medicines, pharmaceutical chelation strategies and therapeutic venipuncture to reduce circulating iron loads are a key to resolving an immunological dis-regulation or a chronic pathogen burden. When applicable, non-pharmaceutical interventions for iron overload would circumvent the possible adverse consequences of medications. (20) Dietary avoidance of, or reduction in, foods that contain a high concentration of phytic acids, soy protein, tannins, oxalic acids, phosvitins, divalent cation supplements (Ca++, Zn++, MN++), and polyphenolic compounds. (1,2) (Table 1) Dietary modifications with respect to sources of heme-iron from meats red meats, fish, poultry) versus non-heme sources of iron (plant sources, dairy, meats, and foods fortified with iron salts). Also, non-heme iron absorption is known to be enhanced by the actions of sugars such as fructose and sorbitol, acids (ascorbic acid, citric acid, lactic acid, tartaric acid), mucin, and meats such as red meats, poultry, and fish. (1,2) (Table 1) Modifications are based on the condition priority and may be applied as either additions or subtractions, or strategic combining of foods to avoid or enhance inhibiting/enhancing qualities of micronutrient attributes. (1,2) (Table 1) Ideally, a food journal or dietary inventory during the intervention period would be maintained. Iron supplementation is best avoided if not absolutely necessary. It would be indicated only if/when there is no evidence of a utilization problem, overload, anemia from blood loss or absolute deficiency, or significant chronic or acute inflammatory events. Heme sources of supplemental iron are preferable, however, iron in the forms of ferrous sulfate heptahydrate or monohydrate, ferrous gluconate or fumarate. (2) Zinc supplementation for conditions involving ACD from CKD (5,10) to exploit its iron-competing properties, preferably in the forms of zinc acetate, gluconate, picolinate, and sulfate. (2) Vitamin D for CKD anemia (17) for its role in kidney health and mineral utilization properties, in the form of cholecalciferol, or vitamin D3. Vitamin C (at least 100-300 mg/day) to enhance absorption of non-heme iron by overcoming formation of insoluble iron compounds and for enhanced reduction of ferric iron to ferrous iron. (1) Astragalus is useful for iron overload syndromes, as it stimulates hepcidin activity. (25) Dong Quai (Angelica sinensis) possesses properties that suppress activity of hepcidin that may be useful in IDA, in paradoxical conditions where iron is best not supplemented. (26) Lactoferrin, an iron-binding glycoprotein extracted from bovine colostrum and whey protein isolates, has both iron-binding properties and immune modulating in conditions involving chronic inflammation, infection, and trauma. (24) Hepatic, digestive, and renal support support formulations (depending on the condition priority) are recommended, provided they are derived from whole food and non-synthetic, quality-controlled sources, and that their constituents meet the condition criteria discussed.

Follow-up care involves re-testing relevant clinical laboratory markers in two to four month intervals to monitor evidence of change as well as soliciting changes in symptoms. Relevant routine in-office exam inventories are also re-checked for evidence of clinical change within a reasonable time in which to expect changes to occur, e.g., two to four months' time.

References

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(8.) Zhou, H., Fischer, H.P. (2008). Hereditary hemochromatosis, alpha-1-antitrypsin deficiency and Wilson's disease.

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(18.) Fraser, S.D.S., Roderick, P.J., May, C.R., McIntyre, N., McIntyre, C., Fluck, R.J., Shardlow, A., Taal, M.W. (2015). The burden of comorbidity in people with chronic kidney disease stage 3: a cohort study. BMC Nephrol. 16: 193.

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(22.) Shibusa, K., Hatayama, M., Toki, Y, Yamamoto, M., Ito, S,. Shindo, M., Fujiya, M., Niizeki, N., Tomoda, Y, Kawai, Y, Addo, L., Ikuta, K. (2015). Evaluation of Basic Performance of "Point Strip ferritin-3000" for Simple and Rapid Quantification of Serum Ferritin. Rinsho Byori. Dec;63(12):1371-6.

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(26.) 26. Zhang, Y., Li, M.M., Zen, F., Ya, C., Wang, K.P. (2012). Study to establish the role of JAK2 and SMAD1/5/8 pathways in the inhibition of hepcidin by polysaccharides from Angelica sinensis. J Ethnopharmacol. Nov 21;144(2):433-40. doi:10.1016/j.jep.2012.09.040.

by: Aaron Root, DC, DACNB, FACFN, Dipl. Ac.

Nutrition Institute - University of Bridgeport, Bridgeport, CT

Table 1. Food & micronutrient interactions with iron

Foods            Heme  Non-  Enhance Non-  Inhibit Non-  Oxylat  Phytat
                       Hem   Heme Iron     Heme Iron     es      es
                       e     Absorption    Absorption

Meats            [??]        [??]
Red meats,
chicken, Fish
Dairy                  [??]
Shellfish,                   [??]
Mollusks
Plant-based            [??]  [??]          [??]
foods
Acidic foods                 [??]
Coffee & teas                              [??]
spinach, chard,        [??]                [??]          [??]
berries,
chocolate, teas
legumes, whole         [??]                [??]                  [??]
grains, nuts,
seeds, maize
Eggs
[Zn.sup.++]                                [??]
[CU.sup.++]                  [??]
[Ca.sup.++]                                [??]
Vitamin C                    [??]

Foods            Polyphen  Phosvi
                 ols &     tin
                 Tannins

Meats
Red meats,
chicken, Fish
Dairy
Shellfish,
Mollusks
Plant-based
foods
Acidic foods
Coffee & teas    [??]
spinach, chard,
berries,
chocolate, teas
legumes, whole
grains, nuts,
seeds, maize
Eggs                       [??]
[Zn.sup.++]
[CU.sup.++]
[Ca.sup.++]
Vitamin C
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Date:Mar 1, 2017
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