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Arquivos Brasileiros de Endocrinologia & Metabologia

On-line version ISSN 1677-9487

Arq Bras Endocrinol Metab vol.57 no.7 São Paulo Oct. 2013 



Lithium and phosphorilation cell reactions


Lítio e reações celulares de fosfo/defosforilação



Roberto Lozano

Hospital Real Ntra Sra de Gracia, Espanha

Correspondence to



Having read with great interest your excellent review of endocrine aspects of lithium treatments (1), I would like to contribute and share data extracted from our particular clinical experience, concerning to the effect of lithium on the thyroid gland and its mechanism of action. Being in complete agreement with your review about the relationship between lithium and alterations of the thyroid gland, we go further by stating that almost 100% of patients treated with lithium, in a dose-related manner, have decreased FT4 levels compared with baseline values; although, in absolute terms, these values ​​are within the normal range, coinciding our data about thyroid disorders with the results described in your article (goitrogenic potential of Lithium can be manifested in up to 50% of patients).

This dose-dependent decrease in FT4 levels  has allowed us to use it as Surrogate Biomarker, for patients treated with lithium salts. It is also useful to calculate the dosing regimens of the patients by adjusting the dose up to FT4 values: 1.0-1.1 mcg/mL, its Clinical Surrogate Endpoint. If this level of FT4 is achieved and TSH values rise above 4 mcIU/mL, it should be valued starting treatment with 25-50 mcg of levothyroxine, as we have explained in Biomarker (2), as follows:

All the pharmacological activity of lithium salts is carried out by the insolubilization of intracellular inorganic phosphate salts by means of the formation of inorganic lithium phosphates. These phosphates have much lower solubility than their sodium salts (e.g., the solubility of Li3PO4 in water is 0.03821 g/dL/20°C versus that of Na3PO4, which is 8.8 g/dL/25ºC), leading to a decrease in the amount of intracellular inorganic soluble phosphates (Pi), and consequently causing a decrease in intracellular phosphate stored in organic compounds (Po), and a slowdown in all metabolic reactions that involve exchange of inorganic phosphates, mainly those using ATP, but also those using other nucleotides with capacity for phosphate storage, as we know now, affecting, in a hierarchically manner, several intracellular pathways of activation and/or inhibition. Among others, those of GSK and inositol-phosphates are the first to be affected.

In the case of the thyroid gland, lithium salts cause a dose-dependent decrease in serum free thyroxine (FT4) due to the very low solubility of inorganic lithium phosphates formed in the interior of target cells by action of lithium, which lead to a decrease in the intracellular pH and pH-dependent tyrosine iodination reaction, with consequent decrease in FT4 levels, because the iodination of phenols is a direct reaction of iodine (I2) with the phenolate ion, which is very sensitive to changes in pH, decreasing exponentially the rate of iodination when pH decreases.

Due to lithium elimination by glomerular filtration, the population analysis conducted by Kernel's test has allowed us to detect two subpopulations related to serum creatinine and, therefore, with lithium clearance, caused by the presence of MDR1 polymorphisms, altering the aldosterone level and therefore the creatinine clearance, obtaining a equi-effective dose ratio (genotype: wild type/genotype: MDR1 polymorphic) in the range of 1.5-2.



1. Giusti CF, Amorim SR, Guerra RA, Portes ES. Endocrine disturbances related to the use of lithium. Arq Bras Endocrinol Metab. 2012;56(3):153-8.         [ Links ]

2. Lozano R, Marin R, Pascual A, Santacruz MJ, Lozano A, Sebatian F. Biomarkers and therapeutic drug monitoring in psychiatry. In: Kumar T (Ed.), Biomarker, InTech, 2012, p. 182.         [ Links ]



Correspondence to:
Roberto Lozano
Pharmacy Service,
Hospital Real Ntra Sra de Gracia
C/ Ramon y Cajal 50
50003 – Zaragoza, Spain

Received on July/6/2012
Accepted on Ago/9/2012



Disclosure: no potential conflict of interest relevant to this article was reported.

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