Thread by @ValHartmann

A link between HAPE (High-Altitude Pulmonary Edema) and COVID-19 is Aldosterone. Glucocorticoids may help preserve endothelial cell membrane.

"The plasma aldosterone level rose continuously and on the last day of altitude was significantly elevated."

pubmed.ncbi.nlm.nih.gov/6780338/

2/ "A possible explanation is that inhaled budesonide, as a glucocorticoid agent, preserved the integrity of pulmonary endothelial cell membrane.."

ncbi.nlm.nih.gov/pmc/articles/P…

3/ Acclimatization at high altitude is dependent upon a response reducing Aldosterone.

"Indeed it is a relatively consistent finding that if this response does not occur and plasma aldosterone is elevated then this is associated with increased fluid retention and AMS."

4/ "It is the significant inter-individual variation in this endocrine response that may underpin the variable susceptibility to both poor acclimatization and AMS (Acute Mountain Sickness)."

researchgate.net/publication/51…

5/ "Endothelial cells regulate inflammatory cell infiltration and adhesion via MR-dependent mechanism. Aldosterone increases expressions of ICAM1, vascular cell adhesion molecule (VCAM)-1 and inflammatory markers such as COX-2 and MCP-1 in the endothelium"
ncbi.nlm.nih.gov/pmc/articles/P…

6/ "Downstream effectors of these receptors such as MAPK/ERK1/2/p38 pathways mediate vascular biology and physiology, particularly, vascular remodeling, inflammation, fibrosis, and vascular tone."

7/ "Aldosterone’s cardiopathological effects include myocardial fibrosis and hypertrophy and vascular remodeling and fibrosis."

hindawi.com/journals/iji/2…

"If hypersecretion of aldosterone indeed is involved in the pathogenesis of high altitude sickness, and if raised aldosterone concentrations...occur only in young subjects, then this would explain the higher incidence of altitude sickness in young people."
link.springer.com/article/10.100…

9/ "Okazaki et al reported significant increase in aldosterone on arrival at a simulated altitude of 6000m. This increased level appeared to be due to increased ACTH because the concentrations of serum cortisol were also elevated significantly."

jpma.org.pk/article-detail…

10/ "Aldosterone exerts direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, and fibrosis."
karger.com/Article/FullTe…

11/ "When ACE1 activity is increased and ACE2 inhibited, intact angiotensin II acts via the angiotensin 1 receptor (AT1R) or AT2R to exert pro-inflammatory responses and stimulate aldosterone [..] increasing the risk of respiratory distress syndrome."

nature.com/articles/s4157…

12/ Negative effects of hyperaldosteronism on immunity and autoimmunity.

"These studies clearly suggest that MR stimulation or antagonism plays a role not only in innate immune activation, but also in the polarization of the adaptive immune response."
ncbi.nlm.nih.gov/pmc/articles/P…

13/ Aldosterone decreases Nitric Oxide, and vice-versa.
NO is a treatment for HAPE and acclimatisation failure.
Inhabitants of high-altitude regions are shown to have higher levels of NO.
journals.sagepub.com/doi/10.1177/14…

14/ "In general, prolonged exposure of endothelial cells to aldosterone decreases NO bioavailability."

 sciencedirect.com/science/articl…

15/ "To confirm the increases in NO, the researchers subjected the Tibetan samples to sensitive high performance liquid chromatography, where the results verified the 10-fold increase of NO in the blood."

eurekalert.org/pub_releases/2…

16/ "Mechanism of nitric oxide regulation in high-altitude Tibetans" | National Science Review | Oxford Academic

academic.oup.com/nsr/article/5/…

17/ "Evidence suggests that failure to acclimatize may be related to insufficient NO production. A potentially fatal response is high altitude pulmonary edema (HAPE) characterized by an exaggeration of the normal constriction of pulmonary blood vessels.."
ncbi.nlm.nih.gov/pmc/articles/P…

18/ NO inhibited in APS:
"Impaired synthesis of the vasodilatory factor NO has been described in patients with APS. Patients displaying thrombosis exhibited low plasma levels of nitrites and nitrates, which are the stable metabolites of NO breakdown."
ncbi.nlm.nih.gov/pmc/articles/P…

19/ Antiphospholipid antibodies have been found in COVID-19 patients, with symptoms which could correlate with symptoms of antiphospholipid syndrome (APS).

nejm.org/doi/full/10.10…

20/ "Patients with APS may present with diffuse alveolar hemorrhage resulting in mild to life threatening symptoms. Prompt and thorough evaluation to confirm the diagnosis and treatment with corticosteroids usually leads to rapid improvement."
pubmed.ncbi.nlm.nih.gov/10229400/

21/ APS may include antiphospholipid lung syndrome (ALS).
Possible symptoms = pulmonary microthrombosis, lung artery thromboembolism, pulmonary hypertension, ARDS, intra-alveolar hemorrhages, pulmonary capillaritis, recurrent microvascular thrombosis.
pubmed.ncbi.nlm.nih.gov/8371225/

22/ "Early diagnosis and aggressive therapy is essential to the management of CAPS (catastrophic APS), ARDS, and DAH because the mortality rates are high. Generally, the aim of CAPS treatment is to reduce thrombotic events and suppress cytokine cascade."

23/ "The treatment of CAPS includes a combination of anticoagulants, systemic glucocorticoids, plasma exchange, and intravenous Ig.."

emjreviews.com/rheumatology/a…

24/ Viral infections have been linked with APS antibodies.

"Many infections have been found to be associated with antiphospholipid antibodies (aPL)[...]
It is assumed that many of the “triggering” factors for catastrophic APS are viral and not bacterial."
ard.bmj.com/content/62/5/3…

25/ The link between hyperaldosteronism and autoimmunity has often been underlined.

"..the clear association of hyperaldosteronism with autoimmune diseases and detection of stimulatory autoantibodies warrants further evaluation/research for the causal relationship and...."

26/ ...."effect on the progression of the disease and associations, which would in turn aid in the evaluation and management of such autoimmune diseases."

hindawi.com/journals/crie/…

27/ Articles on viral infections triggering antiphospholipid antibodies.

ncbi.nlm.nih.gov/pubmed/18926604

ncbi.nlm.nih.gov/pubmed/28945149

28/ Environmental triggers of EPS, including infections.

ncbi.nlm.nih.gov/pmc/articles/P…

29/ "Skin infections (18%), human immunodeficiency virus (HIV) infection (17%), pneumonia (14%), hepatitis C virus (HCV) (13%), and urinary tract infections constituted the most common infections found as “triggering” factors in the most recent review."

ncbi.nlm.nih.gov/pmc/articles/P…

30/ HIV and other viral infections are linked to a state of hyperaldostronism.

"It is now known that the HIV has rennin-like properties. Therefore, HIV infection itself can inappropriately alter the Aldosterone:Renin Ratio (ARR)."

pubmed.ncbi.nlm.nih.gov/16041202/

31/ Antiphospholipid syndrome can also be triggered by high altitudes, but it is not clear in the literature if this indicates an undiagnosed, pre-existing susceptibility in the individual.

the-rheumatologist.org/article/antiph…

32/ Link between high Aldosterone (COVID-19, HAPE) and G6PD deficiency.

"Aldosterone-mediated inhibition of G6PD activity results in a G6PD deficient phenotype in the vascular endothelium in the absence of a genetic cause for deficient G6pd activity."

ncbi.nlm.nih.gov/pmc/articles/P…

33/ #COVID-19 is causing endothelial damage via aldosterone-induced G6PD inhibition?

"Aldosterone-mediated inhibition of G6PD represents a unifying mechanism by which aldosterone may impair EC function and vasodilation."....

34/ "Aldosterone is known to influence gene transcription and inhibition of G6PD, in turn, will result in decreased NO. levels and increased vascular OS to promote EC dysfunction."

grantome.com/grant/NIH/K02-…

35/ Blocking Aldosterone and the RAS system restores G6PD function in diabetic, hypertensive rats.

"..a mineralocorticoid receptor blocker, Spironolactone, would improve nephropathy in hypertensive diabetic rats by restoring G6PD deficiency.."

journals.sagepub.com/doi/10.1177/14…

36/ "We could not find a definite cause of hypoxia, and it was difficult to explain the rapid deterioration following the hypoxic event. The patient was conscious with good respiratory efforts, and regular suctioning was being done to prevent mucous plugging from tracheal..."

37/ "...secretions.
Glucose-6-phosphate dehydrogenase deficiency has been considered as a benign condition and the only emphasis till date has been on the prevention of oxidative injury and acute hemolytic crisis.There is no literature on the mortality and morbidity of..."

38/ "..patients admitted in the ICU with this enzyme deficiency. In our patient, an episode of transient hypoxia during weaning from mechanical ventilation could have led to the production of oxidants by injured lung parenchymal cells which further promoted neutrophil.."

39/ "...infiltration and development of lung edema and inflammation [..]
In a patient with G-6-PD deficiency, the level of reduced glutathione is inadequate, and the deficient erythrocytes are unable to handle the oxidized form."

ncbi.nlm.nih.gov/pmc/articles/P…

40/ "Alterations in diamide-induced band 3 Tyr-P levels are a measure of preexisting membrane status modifications, like those observed in G6PD-deficient patients having chronic impairment of antioxidant defenses.."

academic.oup.com/jcem/article/9…

Cortisol as an Aldosterone competitor.
"Can or Cort did not induce any alteration in the above parameters, but when added with Aldo prevented Aldo-related effects."

academic.oup.com/jcem/article/9…

42/ "These findings demonstrate that aldosterone induces a G6PD-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6PD activity."

nature.com/articles/nm1545

43/ G6PD appears to play a role in the initial phase of cortisol production.

"The mean cortisol levels observed in the first hour after ACTH stimulation in the G-6-PD-deficient patients were significantly (p = 0.03) lower than in the control group."

pubmed.ncbi.nlm.nih.gov/1655604/

44/ "However, little consideration has been given to G6PD as a metabolic marker in steroidogenic organs in relation to ageing. Trout (1974) found G6PD activity to be greater in the adrenal glands of female than of male Wistar rats."

joe.bioscientifica.com/view/journals/…

45/ G6PD function increases markedly with increase in cortisol.

"Glucose-6-phosphate dehydrogenase showed marked increase in activity after corticotrophin administration."

eje.bioscientifica.com/view/journals/…

46/ "These data demonstrate that there are changes of DHEAS and cortisol in acute stage of #Kawasaki disease and the dis-equilibrium between two steroids may be relevant in the T cell immune response induction of Kawasaki disease."

e-cep.org/m/journal/view…

47/

https://twitter.com/ValHartmann/status/1262014032816607233?s=20

48/ DHEA is high in children with Kawasaki. Both DHEA and aldosterone are potent inhibitors of G6PD enzyme function. Inhibition of the G6PD enzyme can potentially lead to oxidative stress and hemolytic anemia.

ncbi.nlm.nih.gov/pubmed/15177053

49/ DHEA is high via unopposed ACE?
"..ACE inhibitor use in older hypertensive men was associated with significantly lower serum DHEA [..]
Overall, these findings suggest that ACE activity may be involved in the adrenal production of androgen precursors."
ncbi.nlm.nih.gov/pmc/articles/P…

50/ DHEA vs aldosterone levels.

"..activity of the sympathetic nervous
system or the hypothalamus pituitary adrenal axis,
including enzymatic steps within the adrenal gland,
may very well affect endogenous levels of aldosterone
and DHEAS in parallel."
ncbi.nlm.nih.gov/pmc/articles/P…

51/ Children with #Kawasaki have high DHEA.
Inhibition of G6PD by high-dose DHEA causes severe autoinflammatory MKD/Kawasaki-like response in dogs.
Dogs closely model the human adrenal androgen system.
Please look at endocrine effects on G6PD in #COVID.Thx
hindawi.com/journals/crive…

52/ "The autoinflammatory reaction observed closely resembles mevalonate kinase deficiency (MKD), a rare autosomal recessive disease in humans characterized by recurrent febrile attacks, arthralgia, skin rash, and aphthous ulcers of mucocutaneous tissues."
hindawi.com/journals/crive…

53/ An autoimmune illness which "closely ressembles mevalonate kinase deficiency (MKD)" also ressembles #Kawasaki disease; they can be mistaken for one another.
(See prior tweets on G6pd and DHEA).
pubmed.ncbi.nlm.nih.gov/24470648/

54/ An interesting paper on #G6PD deficiency and immunity.

"That patients with G6PD deficiency are susceptible to infection may involve a novel mechanism that includes impaired inflammasome activation."

sciencedirect.com/science/articl…

@threadreaderapp unroll