Could iron-chelation with EDTA and bloodletting/transfusion be a therapeutic option in COVID-19 worst scenario? Proposal for a protocol

COVID-19 is a complex, multi-organ disease where lungs are primarily affected, resulting in a form of ARDS in the later stages. In fact, a relevant role has been attributed to iron dysmetabolism and series of literature data highlight a clear-cut alteration in a few related parameters; significantly high figures of ferritin, hepcidin, red blood cell width distribution, lactate dehydrogenase and lactate, in combination with low levels of serum iron and transferrin, have been repeatedly reported in patients affected by Sars-Cov-2 infection at later stages. Overall, these alterations have a negative prognostic value, indicating a pattern of ferroptosis and of a possible dysfunctional hemoglobin, with pro-coagulant and pro-inflammatory repercussions. Different pathomechanisms have been proposed, from erythrocyte attack and an hepcidin-mimetic action of the viral spike proteins, to a more general iron and calcium deregulated intracellular accumulation. Iron chelation has been advocated as one of the possible treatments of COVID-19 and CaNa2ethylendiaminetetraacetic acid (EDTA) is known as a safe and effective mineral-chelator. In this review the authors propose an EDTA-based therapeutic protocol for those patients in most critical stages and admitted to intensive care unit, with the aim to reduce intracellular and blood ferritin overload. Bloodletting and blood transfusion have proved to be beneficial in patients with viral disease-associated iron accumulation. The inclusion of these two procedures in the proposed protocol aims at improving oxygenation by new normo-functioning hemoglobin, while decreasing toxic hyperferritinemia and interleukins. Lastly, a few specific compounds are also taken into consideration to synergistically complement EDTA infusion. A series of technical details are provided for the possible use of the protocol in clinical practice.

Marker of Bone Resorption in Acute Response to Exogenous or Endogenous Parathyroid Hormone

Parathyroid hormone (PTH) changes morphology of osteoclasts within minutes after its systemic administration. The aim of our study was to test in healthy men whether both exogenous and endogenous PTH could change acutely (minutes to hours) the serum cross-linked C-telopeptide of type I collagen (beta CTX), which is released during osteoclastic resorption of bone. Twelve healthy men (age range 24–34 yr) were each studied during 180 min on a control period, after a single subcutaneous injection of teriparatide, and after 30 min EDTA infusion to stimulate endogenous PTH secretion. The tests were started after overnight fast, 3 h after a standard calcium load. The EDTA infusion induced a significant decrease in serum ionized calcium (by 8.5% at 33 min) and a significant increase in plasma PTH (by 305% at 33 min). Both the EDTA and teriparatide resulted in a significant increase in beta CTX (p < 0.001) with maximum increases of 64% and 80%, respectively. A mild, but significant decrease in beta CTX was observed during the control test period. In conclusion, single-dose teriparatide injection as well as a stimulation of endogenous PTH in healthy men results in an acute increase of the bone resorption marker.

Role of acidosis-induced increases in calcium on PTH secretion in acute metabolic and respiratory acidosis in the dog

Recently, we showed that both acute metabolic acidosis and respiratory acidosis stimulate parathyroid hormone (PTH) secretion in the dog. To evaluate the specific effect of acidosis, ionized calcium (iCa) was clamped at a normal value. Because iCa values normally increase during acute acidosis, we now have studied the PTH response to acute metabolic and respiratory acidosis in dogs in which the iCa concentration was allowed to increase (nonclamped) compared with dogs with a normal iCa concentration (clamped). Five groups of dogs were studied: control, metabolic (clamped and nonclamped), and respiratory (clamped and nonclamped) acidosis. Metabolic (HCl infusion) and respiratory (hypoventilation) acidosis was progressively induced during 60 min. In the two clamped groups, iCa was maintained at a normal value with an EDTA infusion. Both metabolic and respiratory acidosis increased ( P < 0.05) iCa values in nonclamped groups. In metabolic acidosis, the increase in iCa was progressive and greater ( P < 0.05) than in respiratory acidosis, in which iCa increased by 0.04 mM and then remained constant despite further pH reductions. The increase in PTH values was greater ( P < 0.05) in clamped than in nonclamped groups (metabolic and respiratory acidosis). In the nonclamped metabolic acidosis group, PTH values first increased and then decreased from peak values when iCa increased by >0.1 mM. In the nonclamped respiratory acidosis group, PTH values exceeded ( P < 0.05) baseline values only after iCa values stopped increasing at a pH of 7.30. For the same increase in iCa in the nonclamped groups, PTH values increased more in metabolic acidosis. In conclusion, 1) both metabolic acidosis and respiratory acidosis stimulate PTH secretion; 2) the physiological increase in the iCa concentration during the induction of metabolic and respiratory acidosis reduces the magnitude of the PTH increase; 3) in metabolic acidosis, the increase in the iCa concentration can be of sufficient magnitude to reverse the increase in PTH values; and 4) for the same degree of acidosis-induced hypercalcemia, the increase in PTH values is greater in metabolic than in respiratory acidosis.

Parathyroid Responsivity in Postmenopausal Women with Osteoporosis During Treatment with Parathyroid Hormone1

Endocrine systems may be affected permanently by administration of supraphysiologic doses of hormone. This is a well known complication of glucocorticoid treatment where the pituitary/adrenal axis may never fully recover, especially when large doses of steroids are needed during significant physical stress. The goal of this investigation was to determine whether responsivity of the parathyroid gland was normal after use of (1–34)PTH daily as an investigational therapy for osteoporosis. Patients were all postmenopausal osteoporotic women treated with estrogen and enrolled in a 3-yr trial of (1–34)PTH by daily subcutaneous injection (400 IU/day) in addition to their estrogen therapy. A volunteer subgroup (n = 10) of this population was recruited for this investigation. All patients had an EDTA-provoked hypocalcemic challenge before beginning PTH treatment. The same patients had repeat EDTA-challenge tests at various times during the 3-yr PTH treatment trial. Three patients had 2 infusions while on PTH treatment (interim and at the end of 3 yr). Ionized calcium declined identically before and during PTH treatment in response to the EDTA stimulus. PTH(1–84) responses were identical before and during PTH therapy. Furthermore, there were no differences in 1,25(OH)2D elevation or in phosphorus reduction over the course of the EDTA infusion during daily PTH treatment. Osteocalcin levels were higher during PTH treatment, as expected, but responsivity to acute endogenous PTH elevations was the same after PTH treatment. We conclude that 1–34PTH therapy, at 400 IU/day for up to 3 yr, does not suppress parathyroid responsivity and should therefore (at least within this period of treatment) have no permanent adverse effect on the ability of the body to maintain calcium homeostasis. Additionally, there is no difference in target organ responsivity to acute endogenous elevations of PTH after exogenous PTH therapy.

Measurement of intact parathyroid hormone in the diagnosis of hyperparathyroidism

Plasma levels of parathyroid hormone were determined pre-operatively in 27 consecutive patients with clinical and biochemical signs of primary hyperparathyroidism, by the use of one assay recognizing the intact PTH molecule and one assay recognizing the mid-portion of PTH. Plasma levels of mid-molecule PTH were normal in 5 of the patients with primary hyperparathyroidism. In 4 of these patients, plasma levels of intact PTH were raised. Conversely, in 6 patients with primary hyperparathyroidism, intact PTH were normal pre-operatively. In 5 of these cases, plasma levels of mid-molecule PTH were raised. The EDTA infusion test was performed in 6 patients with normal baseline plasma level of intact PTH pre-operatively. The test correctly predicted all the patients in this group who were found to have primary hyperparathyroidism, as well as a patient with normal parathyroid glands found at operation. We conclude that some patients with primary hyperparathyroidism have normal baseline plasma levels of intact PTH. In these patients, plasma levels of mid-molecule PTH and an EDTA infusion test provide further diagnostic information.

Persistent hyperactivity of the parathyroid glands in treated hypothyroid patients

Twelve untreated hypothyroid patients were submitted to EDTA infusion and the parathyroid hormone response to the induced hypocalcemia was studied with an amino-terminal specific assay. Eight of these patients were retested 6 months after achieving clinical and laboratory euthyroidism. The PTH response in the pretreatment condition was significantly higher than that obtained in a group of 10 normal individuals; this increased response had not normalized after 6 months of euthyroidism. This persisting hyperresponsiveness can be a contributory factor to the bone hypersensitivity to thyroid hormone replacement seen in hypothyroid patients.