Hospitalized COVID-19 Patients Typically Exhibit Extreme Hypoaldosteronism


A new study by researchers from University of Cambridge and Cambridge University Hospitals NHS Foundation Trust has found that most hospitalized COVID-19 Patients typically exhibit extreme hypoaldosteronism, a condition characterized by the shortage (deficiency) or impaired function of a hormone called aldosterone.

The study findings were published on a preprint server and are currently being peer reviewed.

As of February 2022 the United Kingdom has recorded in excess of 18.8 million cases of COVID-19, with at least 161,000 cases resulting in death [1]. The speed of onset and severity of the pandemic has spurred a coordinated response from the global biomedical community on a scale not previously seen.

This includes attempts to better understand the pathogenesis of the disease, to identify factors that can be used to predict risk and disease trajectory in individual patients, and to deliver preventative and curative interventions for the world’s population.

Given the key role of angiotensin-converting enzyme 2 (ACE2) in facilitating entry of SARS-CoV-2 virus particles into the lung (alveolar epithelial type II cells), gastrointestinal tract (luminal intestinal epithelial cells) and other tissues [2, 3], exploration of the potential effects on the renin-angiotensin-aldosterone system (RAAS) is of interest in understanding the pathogenesis of COVID-19.

ACE2 inhibits RAAS activation by converting angiotensin II (AngII), to angiotensin 1–7 (Ang 1–7). Ang 1–7 exerts anti-inflammatory, anti-oxidative and vasodilatory effects via binding to the Mas receptor [4]. AngII binds AngII receptor type 1 which then exerts pro-inflammatory, pro-oxidative and vasoconstrictive effects [5].

It may also contribute to pro-fibrotic effects, hypercoagulability and immunothrombosis by inducing tissue factor and plasminogen activator inhibitor-1 expression by endothelial cells. AngII further binds to the angiotensin I receptor on the adrenal glands, stimulating the release of the mineralocorticoid aldosterone.

SARS-CoV-2 has the potential to activate RAAS and the secretion of aldosterone, by preventing this ACE2-Ang1–7 mediated RAAS inhibition. The uninhibited Ang II may then play a role in the pathogenesis of the observed hypertension [6], inflammation, immunothrombosis and possible fibrosis in COVID-19.

While elevated serum cortisol has been identified as a marker of poor prognosis in COVID-19 patients [7], the evidence regarding RAAS activation is less clear. Early studies found evidence of increased RAAS activation [8, 9, 10], but subsequent reports suggested no association [11].

Similarly, there is conflicting evidence regarding serum aldosterone levels, with both increased concentrations [12] and no changes reported [11]. In addition, there have been several case reports of hyporeninemic hypoaldosteronism [13]. A low aldosterone/renin ratio has also recently been suggested as predictive of increased severity [14].

To the best of our knowledge, all published studies measuring aldosterone in COVID-19 patients have used non-extraction immunoassays. These methods lack specificity and are prone to interference, for example the polar aldosterone metabolite Aldosterone-18-glucuronide has been shown to cross react in a non-extraction assay commonly used in clinical laboratories [15, 16].

This is more apparent in patients with renal failure as hydrophilic metabolites accumulate. Mass spectrometric methods for aldosterone are now increasingly available in clinical laboratories and do not suffer this interference. Whilst the clinical effectiveness of non-extraction immunoassays in the diagnosis of primary hyperaldosteronism is still contested [17], mass spectrometric methods are metrologically superior and are more likely to represent the biologically active aldosterone fraction.

During the pandemic we observed low aldosterone levels in a number of patients, which we had not anticipated. Motivated by this observation, in this study we used a tandem mass spectrometric method to estimate serum aldosterone concentration in patients admitted to hospital with SARS-CoV-2 infection.

We correlate these serum aldosterone results with clinical outcomes, and compare results from the tandem mass spectrometric method with re-measurements using immunoassay methods. We also evaluate the association between high cortisol concentrations and 28-day survival, as previously described by Tan et al [7].

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Hypoaldosteronism (HA) is a condition marked by decreased synthesis or diminished release of aldosterone (ALD) from the zona glomerulosa of the adrenal glands, or resistance to its action on target tissues. In conditions of resistance, aldosterone levels are often elevated and termed pseudo-hypoaldosteronism.

Recent advances have unraveled the mechanisms involved in the synthesis, release, and action of aldosterone on target organs. It is important first to understand these concepts to comprehend abnormalities in related diseases. The zona glomerulosa (ZG), which is the outermost layer of the adrenal cortex, is unique in possessing the key gene (CYP11B2) and enzyme (aldosterone synthase) for ALD synthesis which are absent from the other layers of the adrenal cortex. Likewise, the ZG is deficient in the machinery (CYP17 gene and related enzymes) for cortisol synthesis (see image 2).

ACTH and other neuropeptides play a less important role, while potassium (K+) and angiotensin II (Ang II) are the principal regulators of aldosterone. K+ regulates ALD independent of Ang II. The renin-angiotensin-aldosterone (RAA) axis is a feedback system that tightly regulates sodium (Na), K+, water, extracellular compartment fluid (ECF) volume, and blood pressure.

A drop in perfusion will trigger the cells of the macula densa of the juxtaglomerular apparatus to secrete renin, which cleaves the hepatocyte derived protein angiotensinogen to angiotensin I (Ang I). Angiotensin-converting enzyme (ACE) in the vascular endothelium converts Ang I to Ang II, which is the most potent stimulus for aldosterone production and release.

Amiloride sensitive sodium channels are located in the distal renal tubular and collecting duct epithelial cells (ENaC). They are composed of three subunits alfa, beta, and gamma. Aldosterone mediates both genomic (ENaC gene transcription) and non-genomic (decreased ENaC degradation and hence enhanced surface expression of ENaC) effects through the mineralocorticoid receptor (MR) belonging to the family of intracellular nuclear receptors. The ENaC facilitates passive energy independent Na reabsorption. Apart from the kidneys, MR is present in the epithelia of the distal colon, sweat glands, salivary glands, airways, eyes, and nonepithelial cardiovascular and central nervous tissues.[1]

Both cortisol and aldosterone have an equal affinity to the MR. Although cortisol levels are much higher, the 11beta HSD2 in renal tubules converts active cortisol to inactive cortisone, thereby allowing aldosterone to dominate receptor binding.[2][3][4]

reference link :,elevated%20and%20termed%20pseudo%2Dhypoaldosteronism.


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