Hypocalcemia is highly incident in COVID-19

Basis of mechanism and therapeutic relevance of hypocalcemia during severe COVID-19 infection

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2), presents primarily with fever, dry cough, and fatigue or myalgia.¹

Many researches have reported that calcium played a central role in viral infectious and replicative mechanisms of SARS-CoV, MERS-CoV, and Ebolavirus.¹

In a large group of SARS patients in North America, hypocalcemia was detected in 60% of patients at hospital admission and in 70% during hospitalization.² Moreover, data from patients with Ebolavirus infection in United States and European hospitals reported a similar incidence of hypocalcemia.³

Di Filippo et al conducted a retrospective cohort study at IRCCS San Raffaele Hospital, a tertiary health-care hospital in Milan, to investigate the incidence of hypocalcemia in a large single center population of COVID- 19 patients and evaluate its possible clinical implications.

The results of this clinical study revealed that on initial hospital evaluation, median AC level (actually measured levels) was 1.1 mmol/L [1.07–1.15] and SC level (standardized pH of 7.4. levels) was 1.14 mmol/L [1.1–1.17]. Hypocalcemia was found in 462 patients (82%) with AC levels, in 414 (78.6%) patients with SC levels. Using AC levels 18 patients (3.4%) presented a severe hypocalcemia with values lower than 0.99 mmol/L, using SC this was found in 10 patients (1.9%).

In conclusion, since hypocalcemia is highly incident in COVID-19 patients and predicts the need for hospitalization suggest that ionized calcium should always be assessed at initial hospital evaluation in order to identify more severe patients.⁴

However, Singh et al⁵ would like to make aware of the mechanisms that underlie this acute hypocalcemia and its therapeutic relevance.

The salient features linking severe COVID-19 and hypocalcemia are:

• Patients with severe COVID-19 have elevated unbound fatty acids, and unsaturated fatty acids.⁵
• Unsaturated fatty acids can bind calcium with a favorable (−20 KJ/mol) enthalpy and trigger acute hypocalcemia.⁵
• Ionized calcium levels were measured in this study, which is notable, as calcium interacts with fatty acids when in an ionized state.⁶
• During severe COVID-19, hypocalcemia is accompanied by hypoalbuminemia, and both of these can be induced acutely by unsaturated fatty acids, unlike hypoparathyroidism or vitamin D deficiency.⁷
• Chronic vitamin D deficiency states in adults, such as osteomalacia very rarely present with the acute hypocalcemia seen in COVID-19, but as mild baseline chronic hypocalcemia, irrespective of whether the patient has COVID-19 infection.⁵
• The “calcium albumin correction” pseudo-normalizes hypocalcemia concurrent with hypoalbuminemia (for e.g., a serum calcium of 5.9 mg/dl with an albumin of 0.1 gm/dl, to a calcium of 9.0 mg/dl), and should not be applied to COVID-19 associated hypocalcemia.⁷
• Lastly, the therapeutic relevance of this unsaturated fatty acid-calcium interaction lies in correction of calcium (and albumin) deficits early in the disease. By binding and neutralizing the unbound unsaturated fatty acids early in the disease,⁷such a correction may prevent the mitochondrial injury⁸ that results in widespread cell injury, organ failure, and sepsis later during severe COVID-19.⁷ Delayed correction of these deficits after organ failure has set in may be of little help.

The above explanation of acute hypocalcemia during severe COVID-19 to be mechanistically and therapeutically relevant, and realize its value beyond being a prognostic marker.

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References:

1. W.J. Guan, Z.Y. Ni, Y. Hu et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382(18), 1708–1720 (2020).
2. C.M. Booth, L.M. Matukas, G.A. Tomlinson et al. Clinical features and short-term outcomes of 144 patients with SARS in the Greater Toronto area. JAMA 289(21), 2801–2809 (2003).
3. T.M. Uyeki, A.K. Mehta, R.T. Davey Jr et al. Clinical management of Ebola virus disease in the United States and Europe. N. Engl. J. Med. 374(7), 636–646 (2016).
4. L Di Filippo, AM Formenti et al. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine. 2020 Jun;68(3):475-478. doi: 10.1007/s12020-020-02383-5.
5. VP Singh, B Khatua, B El-Kurdi et al. Mechanistic basis and therapeutic relevance of hypocalcemia during severe COVID-19 infection. Endocrine (2020) 70:461–462 https://doi.org/10.1007/s12020-020-02530-y.
6. B. Khatua, et al. Ringer’s Lactate prevents early organ failure by providing extracellular calcium. J. Clin. Med. 9, (2020). https://doi.org/10.3390/jcm9010263.
7. B. El-Kurdi, et al. Mortality from coronavirus disease 2019 increases with unsaturated fat and may be reduced by earlBy calcium and albumin supplementation. Gastroenterology (2020). https://doi.org/10.1053/j.gastro.2020.05.057.
8. S. Navina, et al. Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci. Transl. Med. 3, 107ra110 (2011). https://doi.org/10.1126/scitranslmed.3002573