Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients.

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10-4) and small HDL particles (p=6.0x10-5) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10-3) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10-3, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.

The role of carbonic anhydrase in the pathogenesis of vascular calcification in humans.

Carbonic anhydrases are a group of isoenzymes that catalyze the reversible conversion of carbon dioxide into bicarbonate. They participate in a constellation of physiological processes in humans, including respiration, bone metabolism, and the formation of body fluids, including urine, bile, pancreatic juice, gastric secretion, saliva, aqueous humor, cerebrospinal fluid, and sweat. In addition, carbonic anhydrase may provide carbon dioxide/bicarbonate to carboxylation reactions that incorporate carbon dioxide to substrates. Several isoforms of carbonic anhydrase have been identified in humans, but their precise physiological role and the consequences of their dysfunction are mostly unknown. Carbonic anhydrase isoenzymes are involved in calcification processes in a number of biological systems, including the formation of calcareous spicules from sponges, the formation of shell in some animals, and the precipitation of calcium salts induced by several microorganisms, particularly urease-producing bacteria. In human tissues, carbonic anhydrase is implicated in calcification processes either directly by facilitating calcium carbonate deposition which in turn serves to facilitate calcium phosphate mineralization, or indirectly via its action upon γ-glutamyl-carboxylase, a carboxylase that enables the biological activation of proteins involved in calcification, such as matrix Gla protein, bone Gla protein, and Gla-rich protein. Carbonic anhydrase is implicated in calcification of human tissues, including bone and soft-tissue calcification in rheumatological disorders such as ankylosing spondylitis and dermatomyositis. Carbonic anhydrase may be also involved in bile and kidney stone formation and carcinoma-associated microcalcifications. The aim of this review is to evaluate the possible association between carbonic anhydrase isoenzymes and vascular calcification in humans.