Lithium Carbonate in the Preoperative Preparation of Graves' Disease

Tsukasa TSUNODA a , Nobuo MOCHINAGA 1, Toshifumi ETO 1, Minoru YAMAGUCHI 1, Ryoichi TSUCHIYA 1 and Motomori IZUMI ~

ABSTRACT: Lithium carbonate was given in the preoperative preparation of !2 patients with Graves' disease, the reasons for its use being side effects o f thi0namide in: 9 patientS; insufficient Control by thionamide in 1 and psychic symptoms in 2. Lithium carbonate was often used in combination Mth o ther drugs, namely; thionamide in 4 patients, beta-adrenergic blockades in 5, reserpine in 5 and glucoc0rfic0id in 1. This preoperative control significantly decreased the mean serum T~ and T 4 levels from 656 + 55 ng/d l to 180 +_ 16 ng /d l and from 25.9 + 2.1 pg /d l to 9.7 + 1.5 pg/dl , respectively. The only adverse effect of lithium carbonate was pollakisuria observed in one patient. All patients underwent subtotal thyroidectomy uneventfully. It is concluded that the administration of lithium carbonate alone or in combinat ion with other durgs is an effective method of preoperatively controlling hyperthyroidism when convent ional antithyroid drugs show adverse effects.

KEY WORDS: lithium carbonate, Graves' disease, preoperative prepara- tion

INTRODUCTION

l .n the surgical treatment of hyperthyroid- ism, preoperative control of the hyperthyroid state is necessary tO avoid the intra- and post- operative thyroid storm. The conventional method using thionamide is effective in achieving a euthyroid state before surgery in the majority of cases, however, it occasionally causes such adverse effects as skin eruptions and disturbance of liver function. In these cases, propranolol or :corticosteroids have been used as alternative drugs. 1-4

~The Second Department of Surgery and 2the First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan

Reprint requests to: Tsukasa Tsunoda, MD, The Second Department of Surgay, Nagasaki University School of Medicine, 7-i, Sakamoto, Nagasaki 852,

Japan

Some investigators of thyroid disease be- came interested in lithium after Schou re- ported a high incidence of goiter in manic- depressive patients treated with lithium in 1968. 5 In 1970, Berens confirmed that lithium inhibited the thyroid function, and that its inhibition depended on the release of the thyroid ho rmone? Since then, several trials of lithium treatment in patients with hyper- thyroidism have been reported7 -1~ We also employed lithium carbonate for the pre- operative prepara t ion o f hyperthyroidism and the purpose of this paper is to review our experience o f lithium treatment as a pre- operative preparation for hyperthyroidism.

PATIENTS AND METHODS

Between January, 1976 and December, 1989, 132 patients with Graves' disease were treated surgically in our department, 12 of

JAPANESE JOURNAL OF SURGERY, VOL. 21, No. 3 pp. 292-296, 1991

Volume 21 Number 3 Lithium in surgery for hyperthyroidism 293

whom (9.1 per cent) received lithium treat- ment before their operation. There were 10 females and 2 males whose ages ranged f rom 16 to 58 years with an average age of 30.8 years. T h e cases were reviewed with special reference to the reasons for administration, doses, intervals o f administration, effective- ness, and adverse effects o f lithium carbon- ate. The serum level o f lithium was measured by atomic absorption spectroscopy 11 and Student's t-test was used for statistical analysis o f the data.

RESULTS

Details concerning the lithium treatment employed in this study are summar ized in Table 1. The reasons for administrat ion of lithium were: adverse affects o f thionamide in 9 cases, insufficient control by thionamide in 1 and psychic symptoms in 2. The adve r se effects o f thionamide included skin erup- tions, fever, disturbance of liver function, leukocytopeni a and agranulocytosis. The mean administration dose of lithium car-

Table 1. Patients Treated with Lithium Carbonate

Reasons Dose* Interval Drugs in Combination Case Age/Sex for Use (mg/day) (days) (Dosage or days)

1. 16/F psychic symptoms 300 105 MMI (30), Reser (0.4) LS (8)

2. 26/F psychic symptoms 1000 1250 PTU (100), LS (7)

3. 24/F skin eruption by MMI, 600 39 Reser (0.3), IS (8) fever by PTU

4~ 32/M ahnomal liver 600 41 Reser (1.0) function by PTU

5. 24/F skin eruption by MMI, 450 53 None skin eruption & agra- nulocytosis by PTU

insufficient 300 36 control by PTU

skin eruption by 400 80 both MMI & PTU

joint pain by MMI, 600 i6 skin eruption by PTU

skin eruption, fever, 1200 107 abnormal liver func- tion by both MMI &.PTU

skin eruption by MMI 900 58

skin eruption by MMI, 1200 48 leukocytopenia by PTU

skin eruption & fever 1200 43 by MMI, fever by PTU

6. 58/F

7. 23/F

8. 35/F

9. 46/F

10. 27/F

11. 34/M

12. 24/F

PTU (300), LS ~8)

MMI (60), Prop (30) Pred (20), IS (8)

Reser (0.5), LS (8)

Metop (60), Reser (016), I s (8)

Prop (30), IS (8)

Prop (30), LS (8)

Prop (30), Pred (10) IS (14)

* The final dose of lithium carbonate used. MMI, Methylmevcaptoimidazole (mg/day); PTU, Prophyltyiouracil (mg/day); Reser, Reserpine (mg/day); LS, Lugol's solution (days administered); Prop, Propranolol (mg/day); Metop, MetoproiO1 (mg/day); Pred;' Prednisolone (mg/day)

294 Tsunoda et al.

Table 2. Results of Treatment with Lithium Carbonate

Jpn. J. Surg. May 1991

Serum T 3 (ng/dl) Serum T 4 (/lg/dl) Serum Levels WBC (per mm s) Case pre end pre end of Li + (mEq/1) pre end

1. 248 8.4 10900 2. 190 7.9 7500 3. 556 25.2 4700 5700 4. 483 236 22.4 11.1 7300 8200 5. 605 203 32.0 12.9 4400 11600 6. 681 154 18.1 1.3 0.13 3200 4000 7. 564 152 21.7 8.3 0.25 5600 7200 8. 480 108 26.8 7.0 0.47 5200 6000 9. 1030 216 38.9 12.6 0.58 7300

10. 746 176 23.0 11.6 0.41 5100 9500 11. 668 246 27.4 16.1 0.62 4800 7200 12. 647 129 22.6 6.1 0.82 4800 10200

Mean_SE 656• 180• 25.9• 9.7• 0.44• 5011• 7733•

pre, before preparation; end, end of preparation; *,**~*** p<0.01; Li § lithium

bonate was 729 mg per day, ranging f rom 300 mg to 1200 mg. The interval required for preoperat iv e preparat ion ranged f rom 16 to 107 days, except for case 2 in whom lithium had been administered by a psychiatrist unde r the presumptive diagnosis o f psychic disease, not hyperthyroidism. In addition to lithium carbonate, thionamide, beta-adrener- gic blockade, reserpine and glucocorticoid were utilized alone or in several combina- tions. All but 2 patients received Lugol's solution for a short period of between 7 and 14 days, just prior to their operation. Only one case (No. 5) was treated with lithium alone.

Thyrotoxic symptoms and signs were effectively controlled in all patients before surgery. The results o f lithium treatment are shown in Table 2. The s e rum concentrat ion of thyroid ho rmone was determined in 9 cases both before and at the end of the preoperative preparation. The mean (• serum T 3 level, which was 656 • 55 ng /d l before preparation, the normal range being 80-180 ng/dl , significantly decreased to 180 • 16 ng /d l at the end of the prepara t ion (p~0.01). The mean (• serum T 4 level which was 25.9 • 2 .1 / tg /dl before prepara- tion, the normal range being 6-13 /zg/dl,

also significantly decreased to 9.7 • 1.5/~g/dl at the end of the preparat ion (p<0.01).

With regard to the adverse effects of lithium carbonate, only pollakisuria, up to 37 times per day, developed in 1 patient. How- ever, this disappeared quickly after with- drawal of the drug, and readministration did not cause pollakisuria or any other adverse effect. Leukocytosis was the only abnormal finding in the laboratory data, the mean WBC count before administrat ion ,be ing 5011 • 363 /mm 3 which significantly in creased to 7733 • 799 /mm 3 at the end of administration (p<0.01).

The serum lithium level during adminis- tration was measured in the 7 most recent cases. The values ranged f rom 0.13 to 0.82 mEq/1 and the serum concentrat ions of lithium in cases 6 and 7 were relatively low because th ionamide was administered simul- taneously. All o f the 12 patients underwent successful subtotal thyroidectomy. The fol- lowing is a description of one patient (case 5) treated with only lithium carbonate before her operation.

A 24 year old J apanese woman was ad- mitted to our hospital on April 14, 1982 for the surgical t reatment of Graves' disease. The diagnosis had initially been made at

Volume 21 Lithium in surgery for hyperthyroidism 295 Number 3

ano ther hospital on January 4, 1982 and t reatment with methimazole (30 mg per day) been started. One month later, a skin erup- tion had developed and the medication was changed to propylthiouracil (300 mg per day). However, further skin eruption and agranulocytosis developed on the first and third t reatment days, respectively.

The patient was transferred to our hospital for surgical t reatment of the disease. Serum T 3 and T, levels were 605 ng /d l and 32.0 / tg/dl at that time. She had had an allergic reaction to iodide, which led us to abandon the use o f Lugol's solution. Thus, lithium t rea tment (300 mg per day) was started for preoperat ive preparation. One month after the beg inn ing o f treatment, the dose of lithium carbonate was increased to 450 mg pe r day to obtain sufficient control o f the hyperthyroid state. After administration of this dose for 3 weeks, the serum T 3 and T 4 levels decreased to 203 ng /d l and 12.9/~g/dl. respectively. The pulse rate stabilized be- tween 60/rain and 80/min, and her body weight increased f rom 38.0 kg to 41.5 kg. Subtotal thyroidectomy was per formed un- eventfully on June 11,1982 without any other drugs be ing used for the preoperat ive prepa- ration. Serum T 3 and T 4 levels 2.5 hours after the opera t ion were 237 ng /d l and 14.8 ktg/dl respectively. The patient was discharged f rom hospital on the 8th postoperative day without any complications.

DISCUSSION

Since the antithyroid effect o f lithium was first discovered, 6 several trials of lithium treatment on thyrotoxic patients have been reported. 7-1~ However,~ none o f the authors r e c o m m e n d e d lithium as first choice in the rout ine m a n a g e m e n t of hyperthyroidism, because it can cause various adverse effects. 7 Its side effects in , the therapeutic range of serum Li § 0.5-1.5 ~ mEq/1 are reported to be nausea, vomiting, anorexia, diarrhea, ab- dominal pain, .fatigue, hand tremor, thirst, polyuria, leukocytosis, changes on electro-

cardiograms and so forth. In the toxic range, being serum Li + of more than 2.0 mEq/l , neurogenic symptoms such as stupor, coma, ataxia, dysarthria, seizures or dysfunction of the kidney can occur. However, no symp- tomatic adverse effects of lithium were ex- per ienced in this study except for a short episode of pollakisuria in case 7. Although the increase in the WBC count was observed in the laboratory studies of our series, it is considered to be useful ra ther than adverse, especially in patients who show leukopenia induced by thionamide. The iodine type "escape" p h e n o m e n o n reported by Lazarus 8 was not observed in our study. T h e few abverse effects that were noticed in our series may have been caused by the relatively low serum lithium levels even in the ther- apeutic range.

Read reported a case of postoperative thyroid storm occurring after lithium prepa- ration. 12 He described an abrupt rise in the serum thyroid h o r m o n e level and speculated that the postoperative thyrotoxic crisis might have been due to the release of stored thyroid hormone , which was caused by intra- operative manipulat ion of the thyroid or anesthesia. However, we encountered no such experience in any of our 12 patients. In case 5, the patient was treated with lithium carbonate alone for preoperative prepara- tion and the serum thyroid h o r m o n e levels did not increase after the operation.

We employed lithium carbonate mainly because of the adverse effects of th ionamide . When thionamide is inappropriate, other drugs such as propranolol , corticosteroids, iodine and lithium carbonate can be used alone or in various combinations. The re- sults o f the present study indicate that lithium carbonate is useful for the preopera- tive preparat ion of hyperthyroidism as the hyperthyroid state of all of our 12 patients was controlled well, allowing us to per form successful subtotal thyroidectomies. Lithium is not difficult to administer in a hospital environment, 7 even though it is potentially toxic. When lithium is used, its serum con-

296 Tsunoda et al. 1991

c e n t r a t i o n s h o u l d b e fo l lowed up c losely a n d kep t lower t h a n 1.5 m E q / l .

I n c o n c l u s i o n , l i t h i u m c a r b o n a t e is a n effect ive d r u g for p r e o p e r a t i v e p r e p a r a t i o n i n t h e surgica l t r e a t m e n t o f h y p e r t h y r o i d i s m w h e n c o n v e n t i o n a l a n t i t h y r o i d d ru g s s h o w

adve r se effects.

(Rece ived fo r p u b l i c a t i o n o n Mar. 29, 1990)

I~EFERENCES

1. Lee TC, Coffey RJ, Mackin J, Cobb M, Routon J, CanaryJJ. The use of propranolol in the surgical treatment of thyrotoxic patients. Ann Surg 1973; 177: 643-647.

2. Toft AD, Irvine WJ, Sinclair I, McIntosh D, Seth J, Cameron EHD. Thyroid function after surgical treatment of thyrotoxicosis. A report of 100 cases treated with propranolol before operation. N Engl J Med 1978; 298: 643-647.

3. FeelyJ, Crooks J, ForrestAL, Hamilton WF, Gnnn A. Propranolol in the surgical treatment of hyper- thyroidism, including severely thyrotoxic patients. BrJ Surg 1981; 68: 865-869.

4. Ozawa Y, Daida H, Shimizu T, Shishiba Y. Rapid improvement of thyroid function by using gluco-

corticoid indicated for the preoperative prepara- tion of subtotal thyroidectomy in Graves' disease. EndoclinolJapan 1983; 30: 93-100.

5. Schou M, Amdisen A, Jensen SE, Olsen T. Occur- rence of goitre during lithium treatment. Br MedJ 1968; 3~ 710-713.

6. Berens SC, Bernstein RS, Robbins J, WolffJ. Anti- thyroid effects of lithium. J Clin Invest 1970; 49: 1357-1367.

7. Temple R, Berman M, Carlson HE, RobbinsJ, Wolff J. The use of lithium in Graves' disease. Mayo Clin Proc 1972; 47: 872-878.

8. LazarusJH, Richards AR, Addison GM, Owen GM. Treatment of thyrotoxicosis with lithium carbon- ate. Lancet 1974; 1: 1160-1162.

9. Kristensen O, Harrestrup Andersen H, Pallisgaard G. Lithium carbonate in the treatment of thy- rotoxicosis. A controlled trial. Lancet 1976; 2: 603-605.

10. Balazs C, Leovey A, Szerze P, Bako G, Vertes T . Lithium treatment of Basedow's disease. Ther Hung 1984; 32: 69-73.

11. PybusJ, Bowers GN. Measurement of serum lithium by atomic absorption spectroscopy. Clin Chem 1970; 16: 139-143.

12. Read J, Bradley EL. Postoperative thyroid storm after lithium preparation. Surgery 1985; 98: 983-986.