Hypocalcemia in COVID-19: Prevalence, clinical significance and therapeutic implications

Abstract

COVID-19 extra-pulmonary features include several endocrine manifestations and these are becoming strongly clinically relevant in patients affected influencing disease severity and outcomes. At the beginning of COVID-19 pandemic no population data on calcium levels in patients affected were available and in April 2020 a first case of severe acute hypocalcemia in an Italian patient with SARS-CoV-2 infection was reported. Subsequently, several studies reported hypocalcemia as a highly prevalent biochemical abnormality in COVID-19 patients with a marked negative influence on disease severity, biochemical inflammation and thrombotic markers, and mortality. Also a high prevalence of vertebral fractures with worse respiratory impairment in patients affected and a widespread vitamin D deficiency have been frequently observed, suggesting an emerging “Osteo-Metabolic Phenotype” in COVID-19. To date, several potential pathophysiological factors have been hypothesized to play a role in determining hypocalcemia in COVID-19 including calcium dependent viral mechanisms of action, high prevalence of hypovitaminosis D in general population, chronic and acute malnutrition during critical illness and high levels of unbound and unsaturated fatty acids in inflammatory responses. Since hypocalcemia is a frequent biochemical finding in hospitalized COVID-19 patients possibly predicting worse outcomes and leading to acute cardiovascular and neurological complications if severe, it is reasonable to assess, monitor and, if indicated, replace calcium at first patient hospital evaluation and during hospitalization.

The emerging osteo-metabolic phenotype of COVID-19: clinical and pathophysiological aspects

“…Some papers have now highlighted an emerging osteo-metabolic phenotype of COVID-19, which might influence COVID-19 severity and clinical outcomes. This phenotype is typically characterized by widespread acute hypocalcaemia and chronic hypovitaminosis D, as well as a high prevalence of morphometric vertebral fractures 2 – 4 .…”

“…This report suggested that COVID-19 was a possible precipitating cause of subclinical post-surgical hypoparathyroidism 5 . Interestingly, previous reports on patients with SARS and Ebola virus infection had described hypocalcaemia as a highly prevalent biochemical abnormality, ranging from 60% of patients at hospital admission to 75% during hospitalization 2 .…”

“…Following the first reported case of acute hypocalcaemia in a patient with COVID-19, several studies worldwide showed a very high prevalence of hypocalcaemia in hospitalized patients with COVID-19, ranging from 62.6% to 87.2%, depending on the definition criteria 2 . Furthermore, low calcium levels were associated with worse disease outcomes, increased levels of markers for biochemical inflammation and thrombosis (such as C-reactive protein, lactate dehydrogenase, IL-6 and D -dimer) and an increased risk of in-hospital short-term and 28-day mortality 2 . Hypocalcaemia, detected at first evaluation on admission to an emergency department for COVID-19, was also identified as a significant independent risk factor for hospitalization 6 .…”

“…Several pathophysiological mechanisms have been investigated to clarify COVID-19-related hypocalcaemia. These mechanisms include increased calcium depletion due to the calcium-dependent mechanisms of action of the virus, acute malnutrition during critical illness, the role of calcium ions in coagulation and prothrombotic status, high levels of unbound and unsaturated fatty acids in the inflammatory response and hypovitaminosis D 2 . In addition, as hypocalcaemia also seems to be a distinctive biochemical feature of COVID-19 (ref.…”

“…For instance, vitamin D replacement in the general population (particularly in high risk patients with vitamin D deficiency) and avoiding discontinuation of anti-osteoporotic treatment. Calcium supplements should be considered in patients with acute hypocalcaemia admitted to hospital with COVID-19, particularly in those with severe hypocalcaemia owing to its potentially harmful effects on the cardiac and central nervous systems 2 .…”