292
~
Alerts, Notices, and Case Reports Severe Thyrotoxicosis Presenting Acute Psychosis
as
TIMOTHY G. CAUDILL, MD CLAUDE K. LARDINOIS, MD Reno, Nevada
ACCIDENTAL EXPOSURE to thyroid hormone products is common.1-4 The American Association of Poison Control Centers Collection System reported more than 2,200 exposures to thyroid hormone products in 1986.5 Classic symptoms of thyrotoxicosis include nervousness, hyperhidrosis, palpitations, fatigue, weight loss, and a fine resting tremor. The psychiatric symptoms may vary from a delirious state to one of hyperexcitability simulating mania. We report the case of a teenaged girl with acute psychosis after probable but unintentional exogenous thyroid ingestion. Report of a Case
The patient,
a
16-year-old adolescent girl,
was
admitted
to the hospital because of severe headaches, confusion, and bizarre behavior for two days. She had been well before the symptoms began, when she was noted to become increas-
ingly more confused and withdrawn, dressing inappropriately, and having bizarre speech. There had been no history of exposure to unusual illness or of drug abuse. Of significance was a medical history of depression, an episode of "hysterical" blindness, and suicidal behavior on at least two previous occasions. She was sexually active and fearful she might be pregnant. She had not had psychiatric treatment. The family history was significant for a sister who was sexually molested by a friend of her stepfather. Another sister was reportedly raped, and the stress associated with this forced the family to move from a small town in Oregon. Her younger brother was also taking several illicit drugs. She was brought by her parents to the emergency department where she was noted to be extremely agitated and uncooperative, necessitating the administration of 100 mg of chlorpromazine hydrochloride (Thorazine). On physical examination her pulse rate was 112 beats per minute, and her blood pressure and temperature were normal. The findings of a neurologic examination were entirely normal, and her toes were downgoing bilaterally. Of note was the absence of a thyroid goiter, resting tremor, or hyperreflexia. Initial laboratory studies revealed a normal complete blood count and chemistry profile except for a cholesterol level of 2.25 mmol per liter (87 mg per dl). A drug screen for major substances of abuse was negative. A serum thyroxine level was markedly elevated at 1,193 nmol per liter (normal, 50 to 154), and the thyroid-stimulating hormone (TSH) level
was below the level of sensitivity in the ultrasensitive assay, strongly suggesting thyrotoxicosis. The free thyroxine level was 97 pmol per liter (normal 10 to 29), and a triiodothyronine value was 25.8 nmol per liter (normal 1.2 to 3.4). Thyroglobulin was undetectable, and a scan using technetium Tc 99m pyrophosphate showed no demonstrable thyroid uptake over a 30-minute period. An electrocardiogram showed sinus tachycardia with occasional premature ventricular contractions. An electroencephalogram showed diffuse activity suggestive of a hypermetabolic state. On admission to the hospital, she was extremely agitated and thrashed around in bed, requiring four-point restraints. She yelled, screamed, bit herself, and showed paranoid behavior. She was confused and disoriented to person, place, and time. Treatment with propranolol hydrochloride (Inderal), 40 mg every four to six hours; dexamethasone (Decadron), 2 mg every six hours; and chlorpromazine, 50 mg every four hours, was instituted. Over the next few days she remained confused, frequently wandered into other rooms, and on several occasions thought she saw her mother sitting in a chair. Additional drug therapy included haloperidol (Haldol) decanoate, thioridazine hydrochloride (Mellaril), and thiothixene hydrochloride (Navane). Over the next several days, she became more alert, less agitated, and oriented to her surroundings. All antipsychotic drugs were discontinued three days before discharge. The results of serial thyroid function tests were monitored closely, as shown in Figure 1. Further questioning of the patient regarding the ingestion of exogenous thyroid hormone revealed no intentional ingestion. None of her immediate family had been taking any thyroid preparations. She had not eaten any hamburger made from neck tissues that might have included beef thyroid. A question of accidental ingestion was raised when she admitted being at a party three days before the onset of her symptoms. The delay in biotransformation of thyroxine to triiodothyronine suggests that the ingestion occurred more than 24 hours previously.
Discussion There are many causes of thyrotoxicosis that a clinican must consider in dealing with a case such as this.6 The more common causes include Graves' disease, toxic adenoma, toxic multinodular goiter, choriocarcinoma, hydatidiform I Decaiwimgmm
PnoW II
1,225
Os
ao 1,050 OI\.
-E 875 c
O1%
o
525
175 n
From the Department of Medicine (Drs Caudill and Lardinois), Division of Physiology (Dr Lardinois), University of Nevada School of Medicine, and the Department of Medicine, Division of Endocrinology, Veterans Affairs Medical Center (Dr Lardinois), Reno, Nevada. Reprint requests to Claude K. Lardinois, MD, Department of Medicine (Ill), VA Medical Center, 1000 Locust St, Reno, NV 89520.
24 I
20 16
\'
700
350
(Caudill TG, Lardinois CK: Severe thyrotoxicosis presenting as acute psychosis. West J Med 1991 Sep; 155:292-293)
28
'h.
TSH,-N mlJ/liter -X
XX
1
-
T3
0
CD
0°
--^-+
_ N Yt , I_
8
cr 12, 2
"
4 ---a
2 3 4 5 6 7 8 9 10 11 12 13 14 Days
In
Figure 1.-Serial changes are shown in thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) concentrations after the administration of dexamethasone and propranolol hydrochloride.
THE WESTERN JOURNAL OF MEDICINE
* SEPTEMBER 1991
* 155 * 3
mole, TSH-secreting pituitary tumor, iodine-induced hyperthyroidism, thyroiditis, and exogenous hormone ingestion. The key test to do to sort out the causes of thyrotoxicosis is the radioiodine uptake of the thyroid gland. A normal or increased uptake ensures that the gland is the source of the thyrotoxicosis, and a low uptake means that the source of the excess thyroid hormone is outside the thyroid gland or that the gland is injured. In the case reported here, the young woman had greatly elevated thyroid hormone levels but, except for the severe agitation and tachycardia, did not show the classic constellation of symptoms suggestive of thyrotoxicosis. Her low thyroid uptake narrowed the differential diagnosis down to exogenous hormone ingestion (thyrotoxicosis factitia) and thyroiditis. Clinicians may differentiate between these two causes of thyrotoxicosis by evaluating a patient's thyroglobulin levels. Thyroglobulin is the thyroid hormone containing protein that is stored in the colloid within the thyroid follicles. During acute inflammation of the thyroid gland, as with thyroiditis, thyroglobulin is released into the serum along with thyroxine and triiodothyronine, resulting in an elevated serum thyroglobulin level. This is not true of exogenous thyroid administration, however, where the thyroglobulin levels are generally undetectable. I The finding of a low thyroglobulin level in our patient excludes the possibility of thyroiditis and strongly suggests the ingestion of exogenous thyroid hormone. Initially it was thought that she might be suffering from euthyroid hyperthyroxinemia of acute psychosis. As many as 30% of patients presenting with acute psychiatric illnesses may have findings consistent with thyrotoxicosis that are indistinguishable from other causes.8 The notably elevated values of her thyroid function tests, however, made this diagnosis unlikely. Current therapy for thyrotoxicosis includes decreasing the thyroid hormone production by the thyroid gland, blocking thyroid hormone release, and reducing the peripheral action of thyroid hormone. In this particular case, the patient responded to a combination of propranolol and dexamethasone. Both of these agents act to decrease the peripheral conversion of thyroxine to the more biologically active triiodothyronine. Propranolol also has the added benefit of blocking the adrenergic effects of the elevated thyroid hormone levels on peripheral tissues such as the myocardium. To our knowledge, this is the first reported case using dexamethasone therapy for thyrotoxicosis factitia. Its use in thyroid storm is well described and is applicable to exogenous thyroid hormone ingestion as well. The acute ingestion of thyroid hormone may not present with the "classic" symptoms of thyrotoxicosis, as illustrated by the case reported here. Clinicians must use their intuition to include thyroid function testing as part of the differential diagnosis when patients present with acute psychosis. REFERENCES 1. Gorman RL, Chamberlain JM, Rose SR, Oderda GM: Massive levothyroxine overdose: High anxiety-Low toxicity. Pediatrics 1988; 82:666-669 2. Nystrom E, Lindstedt G, Lundberg PA: Minor signs and symptoms of toxicity in a young woman in spite of massive thyroxine ingestion. Acta Med Scand 1980;
207:135-136 3. Regan WM: Thyrotoxicosis manifested as mania. South Med J 1988; 81:14601461 4. Braunstein GD, Koblin R, Sugawara M, Pekary AE, Hershman JM: Unintentional thyrotoxicosis factitia due to a diet pill. West J Med 1986; 145:388-391 5. 1986 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1987; 5:405-445 6. Bethune JE: Interpretation of thyroid function tests. DM 1989; 35:551-595
293 7. Mariotti S, Martino E, Cupini C, et al: Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med 1982; 307:410412 8. Spratt DI, Pont A, Miller MB, McDougall IR, Bayer MF, McLaughlin WT: Hyperthyroxinemia in patients with acute psychiatric disorders. Am J Med 1982; 73:4147
Cardiomyopathy Associated With High-Dose Interleukin-2 Therapy ANNA C. BECK, MD JOHN H. WARD, MD ELIZABETH H. HAMMOND, MD ROBERT B. WRAY, MD WOLFRAM E. SAMLOWSKI, MD Salt Lake City, Utah
RECOMBINANT INTERLEUKIN (IL)-2 is active as an antineoplastic agent in the treatment of disseminated renal cell cancer and melanoma.1'2 Treatment with high-dose IL-2 (600,000 IU per kg every eight hours by intravenous bolus) has led to a 20% to 30% response rate, including 8% to 12% complete remissions.3 Unfortunately, high-dose IL-2 therapy has been associated with serious cardiovascular side effects.4-8
A dose-dependent increase in vascular permeability, termed the "vascular leak syndrome," develops in all patients.2 This is accompanied by decreases in intravascular volume and systemic vascular resistance, resulting in hypotension and tachycardia.4`8 Fluid, colloid, or vasopressor support is usually required to maintain adequate tissue perfusion. 1'6 Pulmonary artery catheterization studies have shown that cardiac output and work increase during IL-2 administration.4'7 This "high-output" state may exacerbate underlying ischemic heart disease. '4-6 Transient myocardial dysfunction has been recorded during IL-2 therapy.4'7'8 The cardiac ejection fraction is frequently depressed during IL-2 therapy, despite increased heart rate and decreased systemic vascular resistance. This alteration in cardiac performance is reversible over time. These findings are similar to the cardiovascular manifestations of septic shock, suggesting a related pathophysiology.9 Irreversible heart damage following IL-2 administration is unusual. We report the case of a patient in whom acute cardiomyopathy developed after high-dose IL-2 therapy and who eventually died of probable persistent myocardial
damage. Report of a Case The patient, a 50-year-old woman, saw her physician for the evaluation of an enlarging left buttock mass in January 1989. An excisional biopsy of the mass revealed a poorly differentiated tumor with ultrastructural features suggestive of malignant melanoma. Staging evaluation detected a left (Beck AC, Ward JH, Hammond EH, Wray RB, Samlowski WE: Cardiomy-
opathy associated with high-dose interleukin-2 therapy. West J Med 1991 Sep; 155:293-296) From the Department of Internal Medicine (Drs Beck, Ward, Wray, and Samlowski), University of Utah-Veterans Affairs Medical Center Cancer Immunotherapy Program (Drs Ward and Samlowksi), and the Department of Pathology (Dr Hammond), University of Utah School of Medicine; the Department of Pathology, LDS Hospital (Dr Hammond), and the Department of Veterans Affairs Medical Center (Dr Samlowski), Salt Lake City. Reprint requests to Wolfram Samlowski, MD, Division of Hematology/Oncology, 4c 416 University of Utah Medical Center, Salt Lake City, UT 84132.
~
Alerts, Notices, and Case Reports Severe Thyrotoxicosis Presenting Acute Psychosis
as
TIMOTHY G. CAUDILL, MD CLAUDE K. LARDINOIS, MD Reno, Nevada
ACCIDENTAL EXPOSURE to thyroid hormone products is common.1-4 The American Association of Poison Control Centers Collection System reported more than 2,200 exposures to thyroid hormone products in 1986.5 Classic symptoms of thyrotoxicosis include nervousness, hyperhidrosis, palpitations, fatigue, weight loss, and a fine resting tremor. The psychiatric symptoms may vary from a delirious state to one of hyperexcitability simulating mania. We report the case of a teenaged girl with acute psychosis after probable but unintentional exogenous thyroid ingestion. Report of a Case
The patient,
a
16-year-old adolescent girl,
was
admitted
to the hospital because of severe headaches, confusion, and bizarre behavior for two days. She had been well before the symptoms began, when she was noted to become increas-
ingly more confused and withdrawn, dressing inappropriately, and having bizarre speech. There had been no history of exposure to unusual illness or of drug abuse. Of significance was a medical history of depression, an episode of "hysterical" blindness, and suicidal behavior on at least two previous occasions. She was sexually active and fearful she might be pregnant. She had not had psychiatric treatment. The family history was significant for a sister who was sexually molested by a friend of her stepfather. Another sister was reportedly raped, and the stress associated with this forced the family to move from a small town in Oregon. Her younger brother was also taking several illicit drugs. She was brought by her parents to the emergency department where she was noted to be extremely agitated and uncooperative, necessitating the administration of 100 mg of chlorpromazine hydrochloride (Thorazine). On physical examination her pulse rate was 112 beats per minute, and her blood pressure and temperature were normal. The findings of a neurologic examination were entirely normal, and her toes were downgoing bilaterally. Of note was the absence of a thyroid goiter, resting tremor, or hyperreflexia. Initial laboratory studies revealed a normal complete blood count and chemistry profile except for a cholesterol level of 2.25 mmol per liter (87 mg per dl). A drug screen for major substances of abuse was negative. A serum thyroxine level was markedly elevated at 1,193 nmol per liter (normal, 50 to 154), and the thyroid-stimulating hormone (TSH) level
was below the level of sensitivity in the ultrasensitive assay, strongly suggesting thyrotoxicosis. The free thyroxine level was 97 pmol per liter (normal 10 to 29), and a triiodothyronine value was 25.8 nmol per liter (normal 1.2 to 3.4). Thyroglobulin was undetectable, and a scan using technetium Tc 99m pyrophosphate showed no demonstrable thyroid uptake over a 30-minute period. An electrocardiogram showed sinus tachycardia with occasional premature ventricular contractions. An electroencephalogram showed diffuse activity suggestive of a hypermetabolic state. On admission to the hospital, she was extremely agitated and thrashed around in bed, requiring four-point restraints. She yelled, screamed, bit herself, and showed paranoid behavior. She was confused and disoriented to person, place, and time. Treatment with propranolol hydrochloride (Inderal), 40 mg every four to six hours; dexamethasone (Decadron), 2 mg every six hours; and chlorpromazine, 50 mg every four hours, was instituted. Over the next few days she remained confused, frequently wandered into other rooms, and on several occasions thought she saw her mother sitting in a chair. Additional drug therapy included haloperidol (Haldol) decanoate, thioridazine hydrochloride (Mellaril), and thiothixene hydrochloride (Navane). Over the next several days, she became more alert, less agitated, and oriented to her surroundings. All antipsychotic drugs were discontinued three days before discharge. The results of serial thyroid function tests were monitored closely, as shown in Figure 1. Further questioning of the patient regarding the ingestion of exogenous thyroid hormone revealed no intentional ingestion. None of her immediate family had been taking any thyroid preparations. She had not eaten any hamburger made from neck tissues that might have included beef thyroid. A question of accidental ingestion was raised when she admitted being at a party three days before the onset of her symptoms. The delay in biotransformation of thyroxine to triiodothyronine suggests that the ingestion occurred more than 24 hours previously.
Discussion There are many causes of thyrotoxicosis that a clinican must consider in dealing with a case such as this.6 The more common causes include Graves' disease, toxic adenoma, toxic multinodular goiter, choriocarcinoma, hydatidiform I Decaiwimgmm
PnoW II
1,225
Os
ao 1,050 OI\.
-E 875 c
O1%
o
525
175 n
From the Department of Medicine (Drs Caudill and Lardinois), Division of Physiology (Dr Lardinois), University of Nevada School of Medicine, and the Department of Medicine, Division of Endocrinology, Veterans Affairs Medical Center (Dr Lardinois), Reno, Nevada. Reprint requests to Claude K. Lardinois, MD, Department of Medicine (Ill), VA Medical Center, 1000 Locust St, Reno, NV 89520.
24 I
20 16
\'
700
350
(Caudill TG, Lardinois CK: Severe thyrotoxicosis presenting as acute psychosis. West J Med 1991 Sep; 155:292-293)
28
'h.
TSH,-N mlJ/liter -X
XX
1
-
T3
0
CD
0°
--^-+
_ N Yt , I_
8
cr 12, 2
"
4 ---a
2 3 4 5 6 7 8 9 10 11 12 13 14 Days
In
Figure 1.-Serial changes are shown in thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) concentrations after the administration of dexamethasone and propranolol hydrochloride.
THE WESTERN JOURNAL OF MEDICINE
* SEPTEMBER 1991
* 155 * 3
mole, TSH-secreting pituitary tumor, iodine-induced hyperthyroidism, thyroiditis, and exogenous hormone ingestion. The key test to do to sort out the causes of thyrotoxicosis is the radioiodine uptake of the thyroid gland. A normal or increased uptake ensures that the gland is the source of the thyrotoxicosis, and a low uptake means that the source of the excess thyroid hormone is outside the thyroid gland or that the gland is injured. In the case reported here, the young woman had greatly elevated thyroid hormone levels but, except for the severe agitation and tachycardia, did not show the classic constellation of symptoms suggestive of thyrotoxicosis. Her low thyroid uptake narrowed the differential diagnosis down to exogenous hormone ingestion (thyrotoxicosis factitia) and thyroiditis. Clinicians may differentiate between these two causes of thyrotoxicosis by evaluating a patient's thyroglobulin levels. Thyroglobulin is the thyroid hormone containing protein that is stored in the colloid within the thyroid follicles. During acute inflammation of the thyroid gland, as with thyroiditis, thyroglobulin is released into the serum along with thyroxine and triiodothyronine, resulting in an elevated serum thyroglobulin level. This is not true of exogenous thyroid administration, however, where the thyroglobulin levels are generally undetectable. I The finding of a low thyroglobulin level in our patient excludes the possibility of thyroiditis and strongly suggests the ingestion of exogenous thyroid hormone. Initially it was thought that she might be suffering from euthyroid hyperthyroxinemia of acute psychosis. As many as 30% of patients presenting with acute psychiatric illnesses may have findings consistent with thyrotoxicosis that are indistinguishable from other causes.8 The notably elevated values of her thyroid function tests, however, made this diagnosis unlikely. Current therapy for thyrotoxicosis includes decreasing the thyroid hormone production by the thyroid gland, blocking thyroid hormone release, and reducing the peripheral action of thyroid hormone. In this particular case, the patient responded to a combination of propranolol and dexamethasone. Both of these agents act to decrease the peripheral conversion of thyroxine to the more biologically active triiodothyronine. Propranolol also has the added benefit of blocking the adrenergic effects of the elevated thyroid hormone levels on peripheral tissues such as the myocardium. To our knowledge, this is the first reported case using dexamethasone therapy for thyrotoxicosis factitia. Its use in thyroid storm is well described and is applicable to exogenous thyroid hormone ingestion as well. The acute ingestion of thyroid hormone may not present with the "classic" symptoms of thyrotoxicosis, as illustrated by the case reported here. Clinicians must use their intuition to include thyroid function testing as part of the differential diagnosis when patients present with acute psychosis. REFERENCES 1. Gorman RL, Chamberlain JM, Rose SR, Oderda GM: Massive levothyroxine overdose: High anxiety-Low toxicity. Pediatrics 1988; 82:666-669 2. Nystrom E, Lindstedt G, Lundberg PA: Minor signs and symptoms of toxicity in a young woman in spite of massive thyroxine ingestion. Acta Med Scand 1980;
207:135-136 3. Regan WM: Thyrotoxicosis manifested as mania. South Med J 1988; 81:14601461 4. Braunstein GD, Koblin R, Sugawara M, Pekary AE, Hershman JM: Unintentional thyrotoxicosis factitia due to a diet pill. West J Med 1986; 145:388-391 5. 1986 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1987; 5:405-445 6. Bethune JE: Interpretation of thyroid function tests. DM 1989; 35:551-595
293 7. Mariotti S, Martino E, Cupini C, et al: Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia. N Engl J Med 1982; 307:410412 8. Spratt DI, Pont A, Miller MB, McDougall IR, Bayer MF, McLaughlin WT: Hyperthyroxinemia in patients with acute psychiatric disorders. Am J Med 1982; 73:4147
Cardiomyopathy Associated With High-Dose Interleukin-2 Therapy ANNA C. BECK, MD JOHN H. WARD, MD ELIZABETH H. HAMMOND, MD ROBERT B. WRAY, MD WOLFRAM E. SAMLOWSKI, MD Salt Lake City, Utah
RECOMBINANT INTERLEUKIN (IL)-2 is active as an antineoplastic agent in the treatment of disseminated renal cell cancer and melanoma.1'2 Treatment with high-dose IL-2 (600,000 IU per kg every eight hours by intravenous bolus) has led to a 20% to 30% response rate, including 8% to 12% complete remissions.3 Unfortunately, high-dose IL-2 therapy has been associated with serious cardiovascular side effects.4-8
A dose-dependent increase in vascular permeability, termed the "vascular leak syndrome," develops in all patients.2 This is accompanied by decreases in intravascular volume and systemic vascular resistance, resulting in hypotension and tachycardia.4`8 Fluid, colloid, or vasopressor support is usually required to maintain adequate tissue perfusion. 1'6 Pulmonary artery catheterization studies have shown that cardiac output and work increase during IL-2 administration.4'7 This "high-output" state may exacerbate underlying ischemic heart disease. '4-6 Transient myocardial dysfunction has been recorded during IL-2 therapy.4'7'8 The cardiac ejection fraction is frequently depressed during IL-2 therapy, despite increased heart rate and decreased systemic vascular resistance. This alteration in cardiac performance is reversible over time. These findings are similar to the cardiovascular manifestations of septic shock, suggesting a related pathophysiology.9 Irreversible heart damage following IL-2 administration is unusual. We report the case of a patient in whom acute cardiomyopathy developed after high-dose IL-2 therapy and who eventually died of probable persistent myocardial
damage. Report of a Case The patient, a 50-year-old woman, saw her physician for the evaluation of an enlarging left buttock mass in January 1989. An excisional biopsy of the mass revealed a poorly differentiated tumor with ultrastructural features suggestive of malignant melanoma. Staging evaluation detected a left (Beck AC, Ward JH, Hammond EH, Wray RB, Samlowski WE: Cardiomy-
opathy associated with high-dose interleukin-2 therapy. West J Med 1991 Sep; 155:293-296) From the Department of Internal Medicine (Drs Beck, Ward, Wray, and Samlowski), University of Utah-Veterans Affairs Medical Center Cancer Immunotherapy Program (Drs Ward and Samlowksi), and the Department of Pathology (Dr Hammond), University of Utah School of Medicine; the Department of Pathology, LDS Hospital (Dr Hammond), and the Department of Veterans Affairs Medical Center (Dr Samlowski), Salt Lake City. Reprint requests to Wolfram Samlowski, MD, Division of Hematology/Oncology, 4c 416 University of Utah Medical Center, Salt Lake City, UT 84132.
