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Original Studies |
Departments of Chemical Pathology (T.W.L.M.), Medicine and Therapeutics (C.-C.C.), and Psychiatry (Y.K.W., S.L.), The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories; and the Department of Pathology, Queen Elizabeth Hospital (C.-C.S.), Kowloon, Hong Kong
Address all correspondence and requests for reprints to: Dr. Tony W. L. Mak, Department of Clinical Pathology, Tuen Mun Hospital, Tuen Mun, Hong Kong. E-mail: makwl{at}ha.org.hk
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Abstract |
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Introduction |
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Cross-sectional studies have shown that lithium therapy affects bone mineral metabolism (1, 4, 5, 6, 7). However, an increased serum calcium level was reported by some (1, 4, 5), but not by others (6). Likewise, PTH was found to be elevated only by some investigators (1, 4, 5, 7). Prospective studies were scanty, of short duration, and performed on a small number of patients (8, 9, 10, 11). Elevated serum PTH and calcium after lithium therapy were more commonly reported (8, 9, 10), but, again, there were exceptions (9, 10, 11).
The mechanism by which lithium affects PTH secretion has been studied in both in vivo and in vitro experiments. Lithium ions decreased the sensitivity of cultured parathyroid cells to calcium, so that more PTH was secreted for the same level of calcium (12, 13). This phenomenon of "set-point error" has recently been reproduced in an in vivo study (14).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Free diet was allowed throughout the study. Clinical and laboratory assessments were started immediately before lithium therapy and were repeated at 1, 6, 12, and 24 months after treatment. Collection of a 24-h urine specimen was started 1 day before each visit. At each visit, a fasting, double void, 2-h (from 0800–1000 h) urine specimen was collected. A blood specimen was taken at 0900 h. Patients were maintained at serum lithium levels of 0.4–1.2 mmol/L. Noncompliance was defined by a lithium level of 0.3 mmol/L or less and/or a clinical history of not taking lithium for 3 or more consecutive days. Such patients were excluded from the study. All specimens were stored deep frozen at -70 C in aliquots until analysis in a single batch, except for PTH, which was determined in three batches on 3 consecutive days.
Serum samples were analyzed for creatinine, albumin, total calcium, inorganic phosphate (PO4), and total alkaline phosphatase (ALP) by a Dimension AR analyzer (DuPoint, Wilmington, DE). The intraassay coefficients of variation for all analytes measured on the Dimension AR analyzer were less than 4.1%. Serum intact PTH was analyzed by a chemiluminescence immunometric method using a Magic Lite Analyzer (Chiron Corp., East Walpole, MA). The reference range for the PTH assay was 1.16–5.67 pmol/L. The intraassay coefficients of variation were 7.6% and 7.8% at PTH concentrations of 2.49 and 41.5 pmol/L, respectively. The interassay coefficients of variation were 9.3% and 8.7% at the same concentrations. The serum total calcium concentration adjusted for albumin (alb-adj Ca) was calculated by: alb-adj Ca = [(40 - albumin) x 0.025 + total calcium]. Urinary calcium, phosphate, and creatinine levels were determined with a Hitachi 911 analyzer (Boehringer Mannheim, Mannheim, Germany). The intraassay coefficients of variation were less than 4.0% for the urine tests.
Twenty-four-hour urinary calcium excretion (24UCaE) and phosphate excretion (24UPO4E), adjusted for creatinine clearance, were derived by multiplying the 24-h urinary calcium and phosphate concentrations, respectively, by the 24-h urine volume and then dividing by creatinine clearance. Creatinine clearance was estimated from the serum creatinine concentration, 24-h urinary creatinine concentration, and volume. Fasting urinary calcium excretion adjusted for creatinine clearance (UCaE) was derived by the formula: UCaE = (CaU x CrS)/CrU (16). Tubular reabsorption of calcium relative to the filtered load, adjusted for creatinine clearance (CaR), was estimated from the formula: CaR = [1 - (CaU x CrS)/(CaSCorr x CrU)] x 100% (9, 16), where CaU is the 2-h urinary calcium concentration, CrS is the serum creatinine concentration, CaSCorr is the serum alb-adj Ca x 0.56, and CrU is the 2-h urinary creatinine concentration. Maximum tubular reabsorption of phosphate in relation to GFR (TmP/GFR) was derived by Walton and Bijvoet’s method (17).
Statistical evaluation was performed using SPSS for Windows (SPSS Inc., Chicago, IL). Data were given as the mean ± SD unless otherwise specified. The normality of the data was evaluated by Shapiro-Wilk test and Kolmogorov-Smirnov test. Square root transformation was employed when necessary. Between-group differences were analyzed by ANOVA with Tukey’s adjustment for multiple comparisons. Non-Gaussianly distributed data, despite transformation, were evaluated by Kruskal-Wallis analysis for differences. Correlations between parameters were determined using Spearman’s rank test. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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). Compared to baseline (2.8 ± 1.2
pmol/L), PTH levels were higher at 1 month (3.3 ± 1.6 pmol/L;
P = NS, by Tukey’s adjustment), 6 months (3.7 ±
1.4 pmol/L; P < 0.005), 12 months (3.7 ± 1.3
pmol/L; P < 0.01), and 24 months (3.9 ± 1.5
pmol/L; P < 0.005). There was no statistically
significant difference among the 4 posttreatment PTH levels. All PTH
results were within the reference range before lithium therapy. Of the
4 posttreatment visits, 13 patients had a total of 16 (7.3%) PTH
results higher than the reference range (Fig. 1).
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). All measurements for alb-adj Ca were within the reference range,
except in one patient. The alb-adj Ca was 2.70 mmol/L at 24 months for
that patient, whereas the concurrent PTH, PO4, and ALP
levels were normal.
CaR increased at all four posttreatment visits compared to
the baseline value (P < 0.0005, by ANOVA; Fig. 2). UCaE dropped
substantially after lithium therapy at the first 3 posttreatment
visits (P < 0.0005, by ANOVA). At 24 months, the
differences were no longer significantly different from the baseline
(Fig. 2). 24UCaE decreased significantly 1 month after
treatment compared to the baseline (P < 0.0005, by
ANOVA; Fig. 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The changes in the urinary calcium indexes were of interest. In sporadically occurring primary hyperparathyroidism, CaR, UCaE, and 24UCaE all increase (16) as a result of the physiological action of PTH. Many factors affect CaR (16), but PTH is the dominant one. Our finding of increased CaR is consistent with elevated PTH, which enhances renal tubular reabsorption of calcium physiologically.
Fasting UCaE reflects net bone turnover, which is promoted by PTH through the induction of higher bone resorption (16). Interestingly, UCaE was reduced in our study during the first three posttreatment visits. This was opposite the expected physiological effect of increased PTH. Serum ALP, a bone formation marker, did not show any change. The lower UCaE, therefore, suggests that there was reduced bone resorption after lithium therapy.
24UCaE represents net calcium balance in the previous 24 h and is affected by changes in dietary intake of calcium, intestinal absorption, and bone turnover. Primary hyperparathyroidism leads to higher intestinal absorption of calcium and net bone turnover and, consequently, higher 24UCaE (16). 24UCaE in our study decreased substantially at the first posttreatment visit, again the opposite of the expected effect of increased PTH. Although we did not standardize the dietary intake of calcium, this is unlikely to be the cause of the profound reduction. We also did not estimate the intestinal absorption of calcium. It has been demonstrated in a PTH infusion study that lithium enhanced intestinal calcium absorption (18). Our finding of reduced fasting UCaE, which indicates decreased bone resorption, is the most likely explanation for the observed decreased U24CaE result.
Lithium therapy disturbed the homeostatic relationship between calcium and PTH. The lack of change in serum calcium despite the substantial increase in PTH suggests that there was a counterregulating factor offsetting the hypercalcemic effect of PTH. The increase in CaR indicates that the effect of PTH on renal tubular reabsorption of calcium was maintained. Other researchers have shown that intestinal absorption of calcium is enhanced after lithium therapy (18). In contrast, the changes in UCaE and 24UCaE strongly indicate that bone resorption is reduced rather than enhanced as in primary hyperparathyroidism. The correlation of serum lithium with 24UCaE suggests that lithium might be the cause of the reduced bone resorption.
All evidence considered, we postulate that a counterregulating factor offset the hypercalcemic action of PTH by reducing bone resorption. The serum calcium concentration is influenced by two opposite forces, PTH and the postulated factor, on bone resorption and calcium balance. Lithium, acting directly or indirectly, is the most likely candidate. The metabolism of vitamin D, which we did not study, could also play a role. In susceptible patients, the effect of PTH may become dominant and lead to hypercalcemia. Future studies should examine the metabolism of vitamin D, the mechanism of reduced bone resorption, and direct markers of bone turnover, such as osteocalcin and deoxypyridinoline, after lithium therapy.
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Acknowledgments |
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Footnotes |
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Received April 13, 1998.
Revised June 8, 1998.
Accepted July 29, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and 24UCaE adjusted for creatinine clearance (
)
before and 1, 6, 12, and 24 months after lithium therapy. GF,
Glomerular filtrate. Data were shown as the mean and SEM
(error bars). *, P < 0.05; @,
P < 0.005; #, P < 0.0005.