Endogenous Lithium Levels in Humans

The best replicated and latest data indicate that typical endogenous serum lithium levels are around 0.0003 mmol/l and levels seem to show low variation (~ 0.0001 -0.0005).

We were always taught that naturally (i.e. in people not taking any form of lithium treatment) there was no endogenous lithium the human body, and many doctors may still think that. It is a question of “LODs/LOQs”, limits of detection/quantification: for usual laboratory methods these are way above background levels (i.e. insufficiently sensitive to measure them), which are therefore not detected by medical laboratory tests.

It is helpful to note, at the outset, that the measurement of nanogram levels of endogenous lithium (and other trace metals) in biological tissues and fluids involves technical challenges and difficulties (1) and some reported measurements may require corroboration and replication before one can have confidence in them. The most recent discussion of trace lithium measurement methodology is in Clarke (2) and a recent large sample is from Bochud (3). In the discussion below I have placed more confidence in larger and more recent results, especially those that are most widely replicated.

Various groups have measured the ratio between the human red blood cell and serum lithium, often denoted as R(Li), but any useful rationale behind this is doubtful. Whether it gives an indication of intracellular lithium generally, or neuronal cell levels of lithium, which are presumably more relevant, is uncertain. I suspect the reason it has been done is because red blood cells are easily available and easily separated for measurement. Such results, whether accurate or not, are of unclear relevance or usefulness.

Papers attempting to link red cell/plasma lithium concentration ratio R(Li), values to anything (diagnosis, treatment, prognosis etc. have not yielded useful results, for reviews (none recent) see: (4, 5).

The important paper by Clarke (2) seems to have been uncited since its publication 10 years ago! They gave an R(Li) value (red cell to plasma ratio) of 0.3 from values of plasma at 0.74 and red cells at 0.24 ng/g. That R(Li) value agrees with those obtained at therapeutic lithium levels using atomic absorption methods (6-9). Other accessible papers with data on endogenous lithium in human serum are: (6-13).

The evidence that tap-water constitutes only one tenth of daily lithium intake is relevant because various researchers have sought to link the amount of lithium in tap-water to, among other things, suicide rates and violence (see discussion concerning endogenous lithium and suicide below).

The paper of Bochud et. al. (3), which like Clarke’s work has until now never been cited by any psychiatric publication on lithium, measured both serum & urinary lithium concentrations in 745 subjects and also in the tap-water they consumed (in Belgium & South Africa). The average concentration of lithium in tap water (Belgium 0.01 & South Africa 0.00021 mg/l) and the 24-hour urinary lithium excretion (0.055 mg & 0.021 mg per 24 hours) were much higher and more variable in Belgium than in South Africa (perhaps more variable because a proportion of Belgians consume more bottled water?). Bochud’s results indicate that food, not water, determines the dietary intake of lithium (from my analysis herein that is hardly a surprise, but a welcome substantiation none-the-less). Serum lithium distributions measured in these 745 subjects were (Belgium) 0.3 micro-mol/l or 0.0003 mmol/l (= 0.0022 mg/l) vs. (South Africa) 0.0023 mg/l (i.e. serum levels in the two populations were the same although tap-water levels were hugely different). These serum level means (averages) are effectively identical but the variability is different: that suggests that serum lithium is finely regulated even when there are variations in dietary intake (but only at these low intakes, < 1 mg/day, from natural environmental sources). Remember that at the much higher (x 1000) “therapeutic” intake levels of ~500 mg – 1,000 mg, serum lithium is determined by glomerular filtration rate and is therefore directly proportion to daily dose): i.e. the relationship is linear, so if 500 mg gives a steady state level of 0.3 mmol/l then 1,000 mg will give 0.6 mmol/l.

Other results (for the record, but all minute sample sizes compared to Bochud’d 745): Miller (14) found serum lithium levels around 0.00016 mmol/liter for normal subjects dwelling in the Denver metropolitan area. The mean 24-h excretion rate was 0.005 mmol/day (14). Folkerd (15) healthy volunteers (n = 25), mean 0.00027 +/- 0.02 mmol/l (range 0.00013-0.00055 mmol/l). Lehmann (unreliable?), small sample maximum of 0.06 mg/l (0.009 mmol/l) (16).

Human health

There is now strong evidence that lithium has a beneficial effect on various aspects of human health in concentrations that are relevant, and sometimes much lower than those used for treating manic depressive illness. Evidence has been advanced regarding various effects, especially in nerve cells, for instance: that it enhances the re-myelination of peripheral nerves after various forms of nerve damage (17); has beneficial effects in ameliorating the consequences of oxidative stress (18); protects against ischaemic damage post-stroke (19); reduces inflammation (20); increases expression of brain-derived neurotrophic factor (that may be important in depression); is beneficial in slowing Alzheimer’s dementia  (21-25); protects mitochondrial function from methamphetamine-induced mitochondrial damage (26). Many of these actions have been detailed in a recent review by Manji’s team in Quiroz et al (27).

Lithium and white blood cells

I have long been puzzled by the fact that lithium has not established a wider and more recognised role in the treatment of blood disorders. After a decade or two of relative inaction, more comment and research is now being published (18, 20, 23, 28-30). It was established long ago that patients on lithium had an increased white blood cell count and that lithium increased the number and activity of primitive blood cell precursors thereby increasing the total number of white blood cells and also the entry of white blood cells into tissues (31-33).

Psychiatrists appear to be insufficiently informed concerning the actions of this important drug. In my experience relatively few of them have been aware that it induces leucocytosis, i.e. an increase in white blood cells. I have heard repeated questions throughout my career about why a patient on lithium should have an increased white count.

In the 1% or so of clozapine treated patients who develop neutropenia lithium does appear to be an effective treatment (34-40). Unfortunately most of the literature is case reports with no apparent prospective or long-term studies. This seems a shame since these would be quite simple to do. Probably another example of a little used out of patent drug attracting little funding for research.

However, Bayesian logic suggests that since replicated experimental evidence convincingly demonstrates that lithium affects granulocyte colony-stimulating factor (G-CSF) and promotes white cell production (28, 41) it is a logical course of action. Note that, from a practical clinical point of view, such a combination may have particular problems with toxicity and side effects (42-44) and require close and expert supervision. It is not something to be undertaken without clear, definite and properly documented justification (45).

Endogenous Lithium levels and Suicide

Somewhat dubiously, it has been claimed that violence and the suicide rate is lower in areas where natural lithium intake from water supplies is higher (46-49) and that it has a beneficial effect on various violent and anti-social behaviours (50).

Firstly, it is wise to bear in mind that the lower limit of detection for most hospital laboratories is about 1 mg/l for lithium (0.14 mmol/l), results reported below this level are unlikely to be accurate unless performed in a specialised laboratory. Some papers published in psychiatric journals may not have done that (i.e. used external laboratories with sufficiently accurate assay techniques) and therefore some of the results reported should be taken with a pinch of salt (1).

Over and above that the information below indicates that such speculative associative epidemiology concerning suicide and violence is highly unlikely to be correct or to reveal any cause-effect relationship. In my opinion it definitely falls into the category “better things to do, life is to short to waste time on it”.

A brief examination of one recent paper by Kapusta et al.(47), published in the British J of Psychiatry, a prestigious journal, and a follow up effort (46), will illustrate the kind of nonsensical material that is being published. The paper seeks to make a correlation between population suicide rates and the differing concentrations of lithium in tap-water in various districts in Austria. The majority of the sample were exposed to low levels of lithium in the tap-water in their districts, and also within a relatively narrow range of concentrations (0.002-0.01 mg/l). Since the established range in fresh water is <0.000005 to 0.356 mg/l that constitutes a small window into the overall range.

The most recent best estimate of dietary intake is, as above, around 0.05 mg per day (51), intake from tap-water represents about one tenth of total daily intake. Lithium in food probably contributes ten times as much as tap-water. Not only that, but many of the foods (especially sea-food) and vegetables in peoples’ diet have come from different districts and different countries: which indicates that where you live has little to do with lithium intake.

Furthermore, the consumption of bottled spring-water is a multi-billion dollar industry and bottled waters have five times higher average lithium concentrations: viz. median level of bottled waters is 0.010 mg/l vs. 002 mg/l for tap water. Sales figures suggest that about one thousand bottles of water are sold per person per year (USA: 30 billion bottles in 2008).  In Europe the figure is around 50 l per year, Austrian data indicates around 90 l per year.

Source: http://efbw.eu/bwf.php?classement=07 (European Federation of Bottled Waters).

That makes it likely that a substantial proportion of their sample will have been ingesting more lithium from bottled spring-water than from tap-water, certainly enough to make a nonsense of their data.

Lastly, no attempt was made to measure serum levels of lithium in people exposed to different levels of lithium in their tap-water (or bottled water) and correlate the two: that is the essential and simple requirement needed to establish a relationship between those two variables (see Bochud). That is the key to the whole thing, without which the rest is meaningless and pointless, because correlation is not causation. Not to take that measure is just plain stupid.

Without the correlation between blood levels and lithium concentration in tap-water (which is simply not there, as we can reliably infer from Bochud’s data) it is obvious the paper is of no value. It is laughable and I feel a little sorry for them, but even more sorry for those who wasted money by giving these guys a research grant.

Lastly, in regard to not having accounted for the consumption of lithium either in bottled water, or in the diet, they blithely state: “For obvious reasons, data for both of these factors are not available at aggregate levels; hence we were unable to consider these factors.” That statement was then, and still is, incorrect, because TDS1 had already published results (52). How facile is that? to so blithely dismiss a failure in a key assumption at the heart of the matter. I hope the data and reasoning above persuades any readers that Kapusta et al. are quite obviously incorrect, and that all such similar efforts to correlate lithium in tap-water with suicide, violence or in-growing toenails etc. are fundamentally flawed.

References

 

1.Subramanian, KS, Determination of metals in biofluids and tissues: sample preparation methods for atomic spectroscopic techniques. Spectrochimica Acta Part B: Atomic Spectroscopy, 1996. 51(3): p. 291-319.

 

2.Clarke, WB, Guscott, R, Downing, RG, and Lindstrom, RM, Endogenous lithium and boron red cell-plasma ratios: normal subjects versus bipolar patients not on lithium therapy. Biol. Trace Elem. Res., 2004. 97(2): p. 105-16.

 

3.Bochud, M, Staessen, JA, Woodiwiss, A, Norton, G, et al., Context dependency of serum and urinary lithium: implications for measurement of proximal sodium reabsorption. Hypertension, 2007. 49(5): p. e34.

 

4.Carroll, BJ, Prediction of treatment outcome with lithium. Arch. Gen. Psychiatry, 1979. 36(8 Spec No): p. 870-8.

 

5.Jefferson, JM, Greist, JH, and Ackerman, D, Lithium Encyclopedia for Clinical Practice. 1987: American Psychiatric Press, Washington, DC.

 

6.Elizur, A, Shopsin, B, Gershon, S, and Ehlenberger, A, Intra:extracellular lithium ratios and clinical course in affective states. Clin Pharmacol Ther, 1972. 13(6): p. 947-53.

 

7.Mendels, J and Frazer, A, Intracellular lithium concentration and clinical response: towards a membrane theory of depression. J. Psychiatr. Res., 1973. 10(1): p. 9-18.

 

8.Rybakowski, J, Chlopocka, M, Kapelski, Z, Hernacka, B, et al., Red blood cell lithium index in patients with affective disorders in the course of lithium prophylaxis. Int. Pharmacopsychiatry, 1974. 9(3): p. 166-71.

 

9.Dorus, E, Pandey, GN, Shaughnessy, R, Gaviria, M, et al., Lithium transport across red cell membrane: a cell membrane abnormality in manic-depressive illness. Science, 1979. 205(4409): p. 932-4.

 

10.Frazer, A, Mendels, J, Secunda, SK, Cochrane, CM, et al., The prediction of brain lithium concentrations from plasma or erythrocyte measures. J. Psychiatr. Res., 1973. 10(1): p. 1-7.

 

11.Knorring, L, Oreland, L, Perris, C, and Wiberg, A, Evaluation of the lithium RBC/plasma ratio as a predictor of the prophylactic effect of lithium treatment in affective disorders. Pharmakopsychiatr. Neuropsychopharmakol., 1976. 9(2): p. 81-4.

 

12.Flemenbaum, A, Weddige, R, and Miller, J, Jr., Lithium erythrocyte/plasma ratio as a predictor of response. Am J Psychiatry, 1978. 135(3): p. 336-8.

 

13.Upadhyaya, AK, Varma, VK, Sankaranarayanan, A, and Goel, A, Lithium in prophylactic therapy of manic-depressive illness: biochemical correlates of response. Biol Psychiatry, 1985. 20(2): p. 202-5.

 

14.Miller, NL, Durr, JA, and Alfrey, AC, Measurement of endogenous lithium levels in serum and urine by electrothermal atomic absorption spectrometry: a method with potential clinical applications. Anal. Biochem., 1989. 182(2): p. 245-9.

 

15.Folkerd, E, Singer, DR, Cappuccio, FP, Markandu, ND, et al., Clearance of endogenous lithium in humans: altered dietary salt intake and comparison with exogenous lithium clearance. Am. J. Physiol., 1995. 268(4 Pt 2): p. F718-22.

 

16.Lehmann, K, Endogenous lithium levels. Pharmacopsychiatry, 1994. 27(3): p. 130-2.

 

17.Makoukji, J, Belle, M, Meffre, D, Stassart, R, et al., Lithium enhances remyelination of peripheral nerves. Proc Natl Acad Sci USA, 2012.

 

18.Arraf, Z, Amit, T, Youdim, MB, and Farah, R, Lithium and oxidative stress lessons from the MPTP model of Parkinson's disease. Neurosci. Lett., 2012. 516(1): p. 57-61.

 

19.Kang, K, Kim, YJ, Kim, YH, Roh, JN, et al., Lithium pretreatment reduces brain injury after intracerebral hemorrhage in rats. Neurol. Res., 2012. 34(5): p. 447-54.

 

20.Green, HF and Nolan, YM, GSK-3 mediates the release of IL-1beta, TNF-alpha and IL-10 from cortical glia. Neurochem. Int., 2012.

 

21.Zhang, X, Heng, X, Li, T, Li, L, et al., Long-term treatment with lithium alleviates memory deficits and reduces amyloid-beta production in an aged Alzheimer's disease transgenic mouse model. J Alzheimers Dis, 2011. 24(4): p. 739-49.

 

22.Sudduth, TL, Wilson, JG, Everhart, A, Colton, CA, et al., Lithium treatment of APPSwDI/NOS2-/- mice leads to reduced hyperphosphorylated tau, increased amyloid deposition and altered inflammatory phenotype. PLoS One, 2012. 7(2): p. e31993.

 

23.Forlenza, OV, de Paula, VJ, Machado-Vieira, R, Diniz, BS, et al., Does lithium prevent Alzheimer's disease? Drugs Aging, 2012. 29(5): p. 335-42.

 

24.Nunes, MA, Viel, TA, and Buck, HS, Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimers disease. Curr Alzheimer Res, 2012.

 

25.Moore, GJ, Cortese, BM, Glitz, DA, Zajac-Benitez, C, et al., A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry, 2009. 70(5): p. 699-705.

 

26.Bachmann, RF, Wang, Y, Yuan, P, Zhou, R, et al., Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol, 2009. 12(6): p. 805-22.

 

27.Quiroz, JA, Machado-Vieira, R, Zarate, CA, Jr., and Manji, HK, Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology, 2010. 62(1): p. 50-60.

 

28.Petrini, M and Azzara, A, Lithium in the treatment of neutropenia. Curr. Opin. Hematol., 2012. 19(1): p. 52-7.

 

29.Gold, AB, Herrmann, N, and Lanctot, KL, Lithium and its neuroprotective and neurotrophic effects: potential treatment for post-ischemic stroke sequelae. Curr Drug Targets, 2011. 12(2): p. 243-55.

 

30.Sofola, O, Kerr, F, Rogers, I, Killick, R, et al., Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease. PLoS Genet, 2010. 6(9).

 

31.Boggs, DR and Joyce, RA, The hematopoietic effects of lithium. Semin. Hematol., 1983. 20(2): p. 129-38.

 

32.Hammond, WP and Dale, DC, Lithium therapy of canine cyclic hematopoiesis. Blood, 1980. 55(1): p. 26-8.

 

33.Rossof, AH and Coltman, CA, Jr., The effect of lithium carbonate on the granulocyte phagocytic index. Experientia, 1976. 32(2): p. 238-9.

 

34.Silverstone, PH, Prevention of clozapine-induced neutropenia by pretreatment with lithium. J Clin Psychopharmacol, 1998. 18(1): p. 86-8.

 

35.Blier, P, Slater, S, Measham, T, Koch, M, et al., Lithium and clozapine-induced neutropenia/agranulocytosis. Int. Clin. Psychopharmacol., 1998. 13(3): p. 137-40.

 

36.Sporn, A, Gogtay, N, Ortiz-Aguayo, R, Alfaro, C, et al., Clozapine-induced neutropenia in children: management with lithium carbonate. J. Child Adolesc. Psychopharmacol., 2003. 13(3): p. 401-4.

 

37.Esposito, D, Rouillon, F, and Limosin, F, Continuing clozapine treatment despite neutropenia. Eur. J. Clin. Pharmacol., 2005. 60(11): p. 759-64.

 

38.Kanaan, RA and Kerwin, RW, Lithium and clozapine rechallenge: a retrospective case analysis. J Clin Psychiatry, 2006. 67(5): p. 756-60.

 

39.Mattai, A, Fung, L, Bakalar, J, Overman, G, et al., Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol, 2009. 24(7): p. 584-9.

 

40.Hodgson, RE and Mendis, S, Lithium enabling use of clozapine in a patient with pre-existing neutropenia. Br J Hosp Med (Lond), 2010. 71(9): p. 535.

 

41.Focosi, D, Azzara, A, Kast, RE, Carulli, G, et al., Lithium and hematology: established and proposed uses. J. Leukoc. Biol., 2009. 85(1): p. 20-8.

 

42.Caviness, JN and Evidente, VG, Cortical myoclonus during lithium exposure. Arch. Neurol., 2003. 60(3): p. 401-4.

 

43.Lee, SH and Yang, YY, Reversible neurotoxicity induced by a combination of clozapine and lithium: a case report. Zhonghua Yi Xue Za Zhi (Taipei), 1999. 62(3): p. 184-7.

 

44.Small, JG, Klapper, MH, Malloy, FW, and Steadman, TM, Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol, 2003. 23(3): p. 223-8.

 

45.Whiskey, E and Taylor, D, Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs, 2007. 21(1): p. 25-35.

 

46.Bluml, V, Regier, MD, Hlavin, G, Rockett, IR, et al., Lithium in the public water supply and suicide mortality in Texas. J. Psychiatr. Res., 2013. 47(3): p. 407-11.

 

47.Kapusta, ND, Mossaheb, N, Etzersdorfer, E, Hlavin, G, et al., Lithium in drinking water and suicide mortality. Br J Psychiatry, 2011. 198(5): p. 346-50.

 

48.Kabacs, N, Memon, A, Obinwa, T, Stochl, J, et al., Lithium in drinking water and suicide rates across the East of England. Br J Psychiatry, 2011. 198(5): p. 406-7.

 

49.Ohgami, H, Terao, T, Shiotsuki, I, Ishii, N, et al., Lithium levels in drinking water and risk of suicide. Br J Psychiatry, 2009. 194(5): p. 464-5; discussion 446.

 

50.Dawson, EB, The relationship of tap water and physiological levels of lithium to mental hospital admission and homicide in Texas. Lithium in Biology and Medicine, ed. GN Schrauzer and KF Klippel. 1991, Weinheim: : VCH Verlag.

 

51.Anon, Second French Total Diet Study (TDS 2): Report 1 Inorganic contaminants, minerals, persistent organic pollutants, mycotoxins and phytoestrogens. 2012: p. http://www.tds-exposure.eu/sites/default/files/WP1/RapportEAT2EN1.pdf.

 

52.Leblanc, J-C, Dietary exposure estimates of 18 elements from the 1st French Total Diet Study. Food additives and contaminants 22.7: 624-641. 2005.