Role of Transition Metals in Onset of Thyroid Diseases

Corresponding Author: Aurelian Udristioiu, MDaurelianu2007@yahoo.comSorina Comisel, UMF Craiova, Medicine Faculty, Endocrinology, Craiova, Romania, E-mail: sorinacomisel@hotmail.comCristina Popescu, Medistar S.R.L Targu-Jiu, Biochemist Departement , Romania, kristinapopescu@yahoo.com

• Many disease conditions are associated with thyroid diseases, but

of all these diseases, the one with the highest association is anemia. Anemia is usually caused by a deficiency of hemoglobin which is the oxygen carrying molecule in the red blood cell.

• It is believed that, the mineral deficiencies, which lead to hypothyroidism and hyperthyroidism bear remarkable similarity to the mineral deficiencies which lead to the two main types of anemia. Iron-deficiency anemia and hypothyroidism are similar in that in both iron is more deficient than copper. Copper-deficiency anemia and hyperthyroidism are similar in that in both copper is more deficient than iron.   

• It is an easy step to postulate that anemia is the single most important pre-existing and causative condition in the etiology of hypothyroidism and hyperthyroidism. 

• Hypothyroidism may be the result of iron-deficiency anemia and hyperthyroidism may be the result of copper-deficiency anemia. Since iron is needed by the body in amounts approximately five times that of copper, then iron deficiency probably occurs more often than copper deficiency. This may be one of the reasons that hypothyroidism is more common than hyperthyroidism.

ANEMIA AND HYPERTHYROIDISM • In a random test of 100 patients with hyperthyroidism with clinical

and paraclinical ascertainment of the diagnosis in 38 cases normo-hypochromic, normocytary anaemia of different expression were found. In the patients with anaemia the serum hormone values were statistically significantly higher than in the 62 patients without anaemia.

•  Also cardiotoxic and hepatotoxic findings were more frequently to be proved in patients with anaemia. A causal iron deficiency, deficit of vitamin B12 or folic acid as well as a haemolytic component of the induction of anaemia could vastly be excluded. 

• By means of the treatment of the basic disease and metabolic balance a normalisation of hemoglobin was achieved without additional medication. From the results of the examinations is concluded that above all at hypreotoxic damage is responsible for the development of the anaemia. In cases of oligo-symptomatic hyperthyroidism part from hepatotoxicity and cardiotoxicity also anaemia may become a leading symptom.

• ANEMIA AND HYPOTHYROIDISM

• The following study states that 20-60% of patients with hypothyroidism are anemic. It also states that "Anemia is often the first sign of hypothyroidism."  Very important is the observation that anemia in hypothyroidism is often not diagnosed because hypothyroids have a lower volume of plasma which causes a false high estimation of the amount of hemoglobin in the blood. 

• Real values of the degree of anemia are estimated by radioisotopic analysis due to the lower volume of plasma in hypothyroidism causing false high levels of hemoglobin in blood. Anemia is often the first sign of hypothyroidism. [Figure 3 ].

• Diagnosis of hypothyroidism should be considered in every case of anemia with uncertain etiology because sometimes signs of overt hypothyroidism needn't necessarily be evident. Microcytic, macrocytic and normocytic are regularly described anemias.

• Macrocytic anemia is caused by malabsorption of vitamin B12, folic acid, pernicious anemia and inadequate nutrition. Pernicious anemia occurs 20 times more frequently in patients with hypothyroidism than generally.

•

• Macrocytosis is found in up to 55% patients with hypothyroidism and may result from the insufficiency of the thyroid hormones themselves without nutritive deficit.

• Normocytic anemia, so-called uncomplicated anemia, arises due to thyroid hormones deficit itself not followed by nutritive deficit. This type of anemia is considered to be an adaptation to a decreased basal metabolism.

• Thyroid hormones directly or indirectly, through erythropoietin, stimulate growth of erythroid colonies (BFU-E, CFU-E).

• Acanthocytosis findings in cytologic blood smear suggest hypothyroidism in about 90% of cases.

• Anemia in infants with congenital hypothyroidism diagnosed by neonatal screening.

• Women in their child-bearing years need more iron and copper than  women at other ages and men at any age because of the monthly blood loss during menstruation.  Pregnancy, child-birth, and nursing place additional mineral drains on this group of women. This age group of women is the same group that is 8-10 times more likely to get thyroid diseases and autoimmune diseases.

• . When a woman develops hyperthyroidism during pregnancy or breast feeding, it also indicates a deficiency of Fe. (SLIDE with Fe.)

• Although anemia is a common finding in adult hypothyroid patients, there are no studies on anemia in hypothyroid infants. Was reviewed the hematologic status during the first year of life in 50 infants with congenital hypothyroidism detected through the regional neonatal screening program.

• The mean age at diagnosis was 23.7 +/- 6.5 days and treatment was initially begun with a mean L-thyroxine dose of 6.8 +/- 1.3 micrograms/kg/day. Clinical and haematological assessments were performed at diagnosis, 3, 6 and 12 months of age. (SLIDE with Fe)

• Mean Hb levels at 3 months of age were correlated with

mean serum T4 at diagnosis (r = 0.30, p < 0.05). The present results indicate that anemia is a frequent finding in infants with congenital hypothyroidism and is depended on the degree of neonatal hypothyroidism and imply that hypothyroidism during development may produce persisting changes even after thyroid replacement has begun.

• The symptoms of anemia listed above should be watched for so that you can more closely monitor the effects of your supplement and eating programs on your thyroid disease. By eating to correct anemia, you should be able to correct your thyroid disease.  

• Subclinical hypothyroidism should be treated in patients with iron deficiency anemia when both conditions exist, as it may provide a desired therapeutic response to oral iron replacement.

• Evaluation of increased serum ferritin levels in patients with hyperthyroidism.

• To further elucidate the mechanism of increased serum ferritin levels in hyperthyroidism, the changes in erythrocytes and serum iron and total iron-binding capacity levels were examined in addition to serum ferritin levels in 13 hyperthyroid patients. 

• The mean values of hemoglobin, red blood cells, and packed cell volume were increased by anti-thyroid therapy. While the serum levels of iron did not change, those of total iron-binding capacity increased significantly after achieving a euthyroid state. Increased serum ferritin levels returned to normal through antit-hyroid therapy.

• Furthermore, the serum ferritin levels of four anemic patients were significantly higher than those of nine nonanemic patients. Thus it is concluded that the increase in serum ferritin levels in patients with hyperthyroidism may be due to the direct action of thyroid hormones on its synthesis, while in some cases complicated with anemia impaired iron utilization by erythropoietic cells may also be involved.. Iron is used for staining tissue for the demonstration of glycosaminoglycan (GAG) deposition in the skin, which is seen in pretibial myxedema of Graves' Disease

• Researchers randomly assigned 51 patients with coexisting iron deficiency anemia and subclinical hypothyroidism to 240 mg per day of oral iron alone or 240 mg per day of oral iron plus 75 mcg per day of levothyroxine.

• Measurements were taken for hemoglobin, hematocrit, red blood cell count, serum iron levels, ferritin, total iron-binding capacity, thyroid-stimulating hormone and free thyroxine. Addition of levothyroxine resulted in improvement of serum iron and blood count variables, according to the study.

• These findings support our clinical observation regarding the presence of a group of patients resistant to oral iron because of their coexisting subclinical hypothyroidism. These patients might benefit from addition of levothyroxine to their treatment regimen, and this might be an indication for treating subclinical hypothyroidism in iron deficiency anemia patients.

• • In the iron group, mean hemoglobin levels increased

by 0.4 g/dL (95% CI, 0.2-0.7) compared with the iron/levo-thyroxine group (1.9 g/dL; 95% CI, 1.5-2.3). Serum iron was greater by a mean of 47.6 mcg/dL (95% CI, 34.5-60.6) in the iron/levothyroxine group, according to the researchers.

• Hemoglobin, red blood cells, hematocrit and serum ferritin levels were greater in the iron/levo-thyroxine group after treatment (P<.0001).

• A negative correlation was observed (P for starting hemoglobin and an increase in hemoglobin in the iron/levothyroxine group =.006).

• The endemic goiter region had a high prevalence of both disorders, indicating the benefit of treating subclinical hypothyroidism, according to the researchers. Resistance to oral iron treatment indicates the need to test for thyroid function, especially in regions with endemic goiter.

• Effect of dietary aluminum on tissue nonheme iron and ferritin levels in the chick.

• Aluminum toxicity is well documented but the mechanism of action is poorly understood. In renal failure patients with aluminum overload, disturbances in iron metabolism leading to anemia are apparent. Few animal models, however, have been used to study the effects of dietary aluminum on iron metabolism. (SLIDE with Al)

• Ferritin levels were reduced by aluminum intake in all tissues studied. The decreases in tissue ferritin levels were proportionately more than the decreases in tissue nonheme iron levels.

• These findings are consistent with the interpretation that, in the growing chick, dietary aluminum can inhibit iron absorption, disrupt the regulation of tissue ferritin levels by iron, and potentially alter the compartmentalization and protective sequestration of iron within cells.

• The balance of the three minerals, copper, zinc, and iron, is critically important in preventing and correcting thyroid diseases.  Each of these three minerals antagonizes and can deplete the other two.  Many times the antagonistic and depletion effects are not due to competition in absorption, but because these minerals work together.

•

• For example, if zinc gets too high in the body, copper and iron will get depleted with the result of anemia and (probably) hyperthyroidism.  If two of the three minerals are high, then the third mineral will get very depleted. 

• For example, high intake of both iron and copper could deplete zinc and cause hypothyroidism. An interesting pair to look at is copper and iron.  Copper and iron work together to form hemoglobin, the oxygen-carrying molecule in the red blood cell. 

• The two minerals have to be present is a balanced amount, usually about 5:1, and if one of the two is supplied in higher amounts it can cause the other to be depleted.

• An interesting pair to look at is copper and iron. Copper and iron work together to forms molecules of hemoglobin with role of oxygen-carrying in the red blood cells.

• SLIDE with Cu).

• Milk increases the bioavailability of Hg++. In suckling rats Hg is bound to a greater extent to ligands in the erythrocytes. Methyl-Hg concentrations in breast milk reach 5% of those in maternal plasma and that is a severe hazard for breastfed children of exposed mothers.

• Toxic Pb concentrations can lead to Pb encephalopathia. A high percentage of surviving children have seizures and show signs of mental retardation. Anemia and reduced intelligence scores were recently observed in children after exposure to very low levels of Pb. Pb absorption is increased in children and after co-administration of milk.

• Lymphocytopenia may be induced by manganese, lead, toluene and industrial noise. Neutropenia was marked after exposure to carbon disulphide, arsenic compounds, benzene and electromagnetic fields. Only a few reports concern the lymphocyte T3, T4 and T8 subpopulations. Electromagnetic fields (microwaves) cause an imbalance of that subpopulation, consisting of a decrease in the T8 cell count.

• The following study concludes "that during thyrotoxicosis the supply of iron into erythroblasts is greater than the amount used for haemoglobin synthesis."  Since hemoglobin production also requires copper, this is indicative of a copper deficiency in hyperthyrodism.

• Zinc status relates to hematological deficits in middle-aged women.

• • According to the researchers, zinc supplementation might increase

the immune response by boosting phagocytosis averting apoptosis of T lymphocytes and was showed that zinc deficiency compromises immunity through a number of mechanisms, such as T cell dysfunction. [SLIDE cu T cytotoxic].

• Also Zn status to some extent can account for hematological abnormalities in middle-aged women. At least 5.0% of middle-aged Japanese women may have Zn deficiency. Normocytic anemia with low TIBC levels may serve as a good indicator of a marginal Zn deficiency (22, 23).

• If zinc gets too high in the body, copper (Cu) and iron will get depleted with the result of anemia and (probably) hyperthyroidism. The next generation of anticancer drugs will be defined by compounds that selectively kill cancer cells while leaving normal cells undisturbed. We developed an in silico screening methodology that identified such a compound that selectively kills cancer cells with a p53R175 mutation. (SLIDE cu Zn).

• Rescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy in all types of cancer, inclusively cancer of thyroid.. Using the National Cancer Institute’s anticancer drug screen data, we identified two compounds from the thio-semicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53R175 mutant.

• This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53R175 mutant reactivator and as a lead compound for p53-targeted drug development. [SLIDE with p53}.

• Zinc Ion Chelation and Redox Changes are important for the NSC319726-Mediated p53R175 Reactivation Mechanism Thiosemicarbazones are metal ion chelators with a strong

• affinity for iron, copper, and zinc (Yu et al., 2009). They have been investigated as anticancer agents and have been shown to inhibit DNA synthesis by inhibiting the iron-dependent enzyme ribonucleotide reductase (RR) but at much higher concentrations than are employed to inhibit the growth of p53R175 mutant cells

•

• Structural studies of the p53 DNA binding domain indicate that the zinc ion is coordinated by four amino acids (C176, H179, C238, and C242; Cho et al., 1994; Joerger et al., 2005; Wong et al., 1999).

• Mutations in any of these residues result in the inability to coordinate zinc. In contrast, the R175H mutant is not directly involved in zinc binding. It is generally believed that a histidine residue at this location induces structural distortions in the protein that prevent it from binding zinc (Joerger and Fersht, 2007).

• Yu X, Vazquez A, Levine JA, Carpizo1 RD. Allele-Specific Mutant p53 Reactivating Compound. Cancer Cell 2012; (5): 21: 614-625, Copyright © 2012 Elsevier Inc.

• Zn status to some extent can account for hematological abnormalities in middle-aged women. At least 5.0% of middle-aged Japanese women may have Zn deficiency. Normocytic anemia with low TIBC levels may serve as a good indicator of a marginal Zn deficiency.

• The toxicological estimation of the heavy metal content (Cd, Hg, Pb) in food for infants and small children

• There are differences between young and adult organisms regarding toxokinetic aspects and clinical manifestations of heavy metal intoxications. Chronically, toxic Cd intake causes a microcytotic hypochromic anemia in young rats at lower exposure levels and after shorter exposure periods than in adult animals. Cd absorption is increased by co-administration of milk and in conjunction with iron deficiency. 

• After long exposure periods toxic Cd concentrations accumulate in the kidney cortex; this process starts very early in life. In 3-year-old children Cd concentrations in the kidney can reach up to one-third of those found in adults. 

• Hg++ and methyl-Hg can cause Hg encephalopathia, and frequently cause mental retardation in adults. Correspondingly, Hg++ accumulation in the brains of suckling rats is approx. 10 times higher than in grown animals. (SLIDE cu Hg).

• Sideroblasts and haemosiderin in thyrotoxicosis.

• Bone marrow sideroblasts and haemosiderin were studied in 19 thyrotoxic patients before therapy and in the euthyroid state. The proportion of sideroblasts and the amount of haemosiderin were significantly higher in the hyperthyroid than in the euthyroid phase. Pathological sideroblasts with coarse perinuclear iron granules were found before therapy but not in the euthyroid phase. 

• It is concluded that during thyrotoxicosis the supply of iron into erythroblasts is greater than the amount used for haemoglobin synthesis.

• Because aluminum interferes with iron metabolism, studies have found that people who eat food cooked in aluminum pots get anemia. Getting these people to switch to iron cookware greatly reduces the rate of anemia.

• Effect of consumption of food cooked in iron pots on iron status and growth of young children: a randomised trial. In less-developed countries, novel strategies are needed to control iron-deficiency anaemia, the most common form of malnutrition

• • Ethiopian foods cooked in iron, aluminium, and clay

pots. 407 children, one per household, entered the study. The change in haemoglobin concentration was greater in the iron-pot group than in the aluminium-pot group (mean change to 12 months 1.7 [SD 1.5] vs 0.4 [1.0] g/dL; mean difference between groups 1.3 g/dL [95% Cl 1.1-1.6]).

• The laboratory study showed that total and available iron was greatest in foods cooked in iron pots, except for available iron in legumes for which there was no difference between types of pot.

• INTERPRETATION: Ethiopian children fed food from iron pots had lower rates of anaemia and better growth than children whose food was cooked in aluminium pots. Provision of iron cooking pots for households in less-developed countries may be a useful method to prevent iron-deficiency anaemia. SLIDE with Al).

• A particularly sneaky absorption blocker is coffee. Hypothyroid patients tend to be tired, especially if they are also anemic. They will often tell you that a morning cup (or pot) of coffee is essential. Coffee lowers thyroid hormone absorption by about a third. I've started telling my coffee-drinking hypothyroid patients to take their thyroid at night. It's actually better absorbed that way..

• There's been a long tradition of switching people from synthetic T-4 thyroid hormone to naturally derived combinations of T-4 and T-3. Lately, it's become common to use synthetic combinations of T3 and T-4.

• There are various theories to justify doing this. The most popular explanation is that due to inadequate conversion of T-4 to T-3, the patient still feels tired.

• Siegmund, et al., compare duo thyroid hormone therapies against traditional T-4 monotherapy and tell us that it doesn't help the patient feel better: "Replacement therapy of hypothyroidism with T4 plus T3 does not improve mood and cognitive performance compared to the standard T4 monotherapy.

Thanks for your assistance !