Hyperthyroidism following hypothyroidism.
Hypothyroidism is commonly thought to be permanent but quite often it may be reversible. This is known to occur in the following situations: antithyroid drug and iodine administration; subacute thyroiditis; auto-immune chronic thyroiditis (after delivery, transition from hypothyroid to hyperthyroid state and in Schmidt's syndrome when treatment with cortisol is initiated); on stopping long term treatment with thyroid hormone; post-operatively in Graves' disease; after radio-iodine treatment; initial primary hypothyroidism changing to Graves' disease; spontaneous recovery from hypothalamic disease; and in newborn infants. We describe below two cases who were initially hypothyroid but became hyperthyroid under observation. One of them has been under observation for over 10 years. Neither had thyroglobulin antibodies in the blood but one used to consume iodochloroxyquinoline over prolonged periods.
Mrs. S. P., aged 50, a mother of 5 children, was seen on 6-3-1968 with the following problem. She had noticed a goitre 2 years earlier and was taking Lugol's iodine, 10 drops daily, for about 1 year. She had also been taking on and off a medication containing iodochloroxyquinoline for alleged dysentery. In January 1968, she started feeling fatigued, could not cope with her housework, and became puffy all over. She also complained of parasthesiae in hands and feet, cold intolerance in winter (of 1967), and of paroxysmal sweating accompanied by hot flushes. She had gained about 6 kg. of weight in a year in 1967, her usual weight having been around 50 kg. Past medical history revealed hysterectomy for menorrhagia in 1960 and two attacks of "dysentery". Her pregnancies and deliveries had been uneventful and she had breast fed all her five children. There was no family history of a goitre or any other thyroid disease. On examination, Mrs. S. P. was of medium build, weighed 56 kg., had a pulse rate of 78 per minute and blood pressure of 130/80 mm of Hg. She had a moderate sized, multinodular goitre without a bruit on it. She had no eye signs of Graves' disease and her face was puffy. Her skin was cool and dry, the ankles showed a little pitting edema and her ankle jerks showed delayed relaxation. The rest of the physical examination did not reveal any abnormality.
Investigations showed the following: Hb: 11.6 g%; Urine: NAD; Electrocardiogram showed low voltage of QRS complexes and flat T waves all over; serum cholesterol 214 mg%; fluoroscopy of the chest showed normal sized heart with poor pulsations. B.M.R. was -20%(Mayo standard). A diagnosis of hypothyroidism (? Iodine induced) was made. The patient was advised to keep off Lugol's iodine and iodochloroxyquinoline medication and to start taking 1-thyroxine sodium. In view of her age, she was advised to begin with a small dose (0.05 mg once a day) and to gradually increase it to 0.2 mg. once a day. With this treatment, most of her symptoms disappeared and her weight gradually returned to 50 kg. Her "dysentery", however, continued and she continued to take various iodochloroxyquinoline medications despite advice to the contrary. She periodically attended for follow up and during one such visit, in March 1970, complained of palpitation. She was prescribed meprobamate and was asked to continue her 1-thyroxine sodium in the dose of 0.2 mg. daily. In March 1971, she was noticed to have tachycardia (100/ minute) and widening of the pulse pressure (120/60 mm of Hg.). She was reassured and asked to continue her 1-thyroxine sodium and meprobamate. She continued to take iodochloroxyquinoline intermittently on her own. In November 1971, she weighed 43 kg. and was found to have moist skin, tachycardia (100/ minute), wide pulse pressure (B.P. 130/50 mm of Hg.) and for the first time, a bruit on her goitre. The goitre had persisted all along. A radio-active iodine tracer test confirmed hyperthyroidism (4 hours uptake 96%, 48 hours uptake 96% and PBIl3I at 48 hours 0.97% of the dose per litre of plasma). She was prescribed carbimazole 30 mg. per day in three divided doses and was asked to omit 1-thyroxine sodium. At first, she was irregular in taking carbimazole but was later persuaded to take it regularly. Her symptoms gradually improved, her tachycardia subsided (pulse rate 80 per minute), blood pressure returned to normal (100/70 mm of Hg.), and by October 1972 she weighed 50 kg.
The patient was next seen in April 1979. She had taken carbimazole for 18 months in 1972-73. She had omitted it when she started feeling well. Ever since then she had kept fit. On examination she weighed 56.5 kg, pulse rate was 80/min. and blood pressure was 130/80 mm of Hg. She had a small, firm and diffuse goitre without a bruit on it. She had no eye signs of Graves' disease. Thus she was clinically euthyroid. The following tests were done at the Radiation Medicine Centre of the Bhabha Atomic Research Centre: serum T4 by R.I.A. 6.4 ug%; serum T8 by R.I.A. 160 ug%; thyroid antibodies were not detected in the serum. The TRH-TSH test was within normal limits. Thus, this patient had now become euthyroid and showed no evidence of autoimmune thyroiditis.
Mrs. D. S., aged 44, a mother of six children, and menstruating regularly, was seen in September 1978 with the following problem. In 1974, she had aches and pains in the hands and feet, bodyache and abdominal discomfort. She had been seen by another physician who diagnosed hypothyroidism and advised treatment with 1-thyroxine sodium. Her symptoms had rapidly disappeared with that treatment. Her electrocardiograms before starting and while on 1-thyroxine sodium are shown in Figure 1. She had continued to take 1-thyroxine sodium ever since and kept well till in early 1978 she started feeling unwell. She tired easily, had palpitation and lost 7 kg. of weight between January and September 1978. Her appetite was good and she had no symptoms to suggest an infective process in the body. Physical examination (20-9-1978) showed a woman of medium build, weighing 49 kg. with a pulse rate of 100 per minute and blood pressure of 13060 mm of Hg. (N.B.: The blood pressure recorded on the electrocardiogram reports in 1974 was 128/ 74 and 120/80 mm of Hg.). Her hands were warm and moist but she had no goitre nor any eye signs of Graves' disease. The rest of the physical examination was negative. Routine laboratory tests were normal: Hb. 14g%; WBC: 7,000/cmm, N: 57%, E: 2%, L: 40%, M: l%; ESR: 12 mm at the end of 1 hour (Westergren); urine and stool: NAD; oral glucose tolerance test was normal.
A suspicion of hyperthyroidism was aroused. The patient was advised to omit all drugs (specifically 1-thyroxine sodium), to avoid any iodine containing medication and to return for re-examination after 2 months.
When seen on 14-11-78, her symptoms had persisted, she had lost a further 2 kgs. of weight, her pulse rate was 100 per minute and blood pressure 120/60 mm of Hg. A radio-iodine (I131) tracer test showed: 2 hour thyroid uptake 38%, 48 hour thyroid uptake 71% and P.B.1.131 at 48 hours 0.66% of the dose per litre of plasma. A diagnosis of hyperthyroidism was made and the patient was advised to take carbimazole 30 mg per day in three divided doses. When seen on 11-1-1979, her tiredness and palpitations had disappeared, she had put on 5 kg. of weight, her pulse rate was 70 per minute and blood pressure 120/80 mm of Hg. She was advised to continue taking carbimazole in a smaller dose and to attend regularly for follow up. When seen on 26-6-79 she had no symptoms of hyperthyroidism. She had been taking 10 mg of carbimazole a day since her previous visit. She had put on another 5 kg. of weight (she now weighed 57 kg.), her pulse rate was 72 per minute and her blood pressure 110/70 mm of Hg. Her plasma was negative for thyroid antibodies.
The occurrence of hyperthyroidism following hypothyroidism is uncommon but documented. It was first reported by Joplin and Fraser in 1959. Doniach et al reported a case in 1960. Zellmann and Sedgwick reported a case of hyperthyroidism occurring in a patient with established autoimmune thyroiditis and thought that the two occurred together by coincidence. Goolden et al and James  described 2 cases each. Gavras and Thomson, documented two cases who developed hyperthyroidism while on thyroxine therapy for hypothyroidism. Bremner and Griep, Hochstein et al and Olczak et al, described one case each.
The mechanism of the change over from hypothyroid to hyperthyroid state is not known with certainty. It has been suggested that the autoimmune process damages the thyroid cells with a consequent increase in pituitary TSH secretion. This fails to keep the patient euthyroid as TSH blocking antibodies render TSH ineffective. The transition from TSH blocking antibodies to thyroid stimulation antibodies may be the cause of hyperthyroidism in some cases. Alternatively, PGE and PGF released by lymphocytes in the thyroid might cause thyroid hyperplasia and hyperthyroidism. Patients who develop hyperthyroidism following initial hypothyroid state fall into two groups: those who have all the features of Graves' disease including the presence of thyroid stimulating immunoglobulin (TSI) in the plasma and others who do not. Patients who are hypothyroid and have a nodule could become hyperthyroid as a result of the nodule becoming autonomous. This has been termed tertiary hyperthyroidism.
Autoimmune thyroiditis may be associated with hyperthyroidism in the initial stage itself. This is called Hashitoxicosis.. It could be due to the regenerating hyperplastic, thyroid follicles being in excess of those that are destroy ed by the cytotoxic autoimmune process. Hyperthyroidism may follow hypothyroidism after many years or it may develop during therapy for hypothyroidism. The other atypical accompaniments of autoimmune thyroiditis are ophthalmic Graves' and hypothyroid Graves' disease. They are probably accounted for by insufficient reserve of thyroid cells to cause clinical thyrotoxicosis. The pseudothyrotoxic cases are those who develop intolerance to thyroxine while on therapy for autoimmune thyroiditis.
Autoimmune thyroiditis covers a wide range of clinical states from hypothyroidism due to destroyed thyroid gland at one end to hyperthyroid Graves' disease at the other. These cases form a continuous spectrum. The hyperthyroid state often gets converted to hypothyroid state spontaneously, after radioactive iodine treatment or after surgery. These are the patients who have lymphocytic infiltration in the thyroid and circulating thyroid antibodies. Less common than this is the transition of the hypothyroid to the hyperthyroid state. If thyroid antibodies are found in patient's plasma, it is easier to explain this occurrence. If no circulating thyroid antibodies are found, the explanation of the phenomenon must elude us.
Case I (SP) probably belongs to the group described by Irvine et al and Olczak et al in that she had no thyroid antibodies in the plasma. She used to consume various iodochloroxyquinoline preparations. Both hypothyroidism and hyperthyroidism have been described during consumption of iodine containing preparations. In fact, Beierwaltes has suggested that excess of iodine may initiate the process of autoimmune thyroiditis. This patient (SP) is of further interest because she showed a spontaneous remission of her hyperthyroid state as well. Case II (D.S) also probably belongs to the group described by Irvine et al and Olczak et al in that the plasma did not show thyroid antibodies.
These two cases demonstrate that it is important to think of the possibility of hyperthyroidism in a hypothyroid patient on replacement therapy, as otherwise symptoms may be glossed over as adverse effects of thyroid medication.
We thank the Dean, Seth G.S. Medical College and K.E.M. Hospital for his permission to publish this material. We also thank the Radiation Medicine Centre, B.A.R.C for the technical assistance.