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Reversible Systolic Heart Failure and Deep Jaundice in Hyperthyroidism
Case Report: Reversible Systolic Heart Failure and Deep Jaundice 1n Hyperthyroidism TSUNG-MING LEE, MD, SUNG-HSIN KUO, MD, YUAN-TEH LEE, MD
ABSTRACT: Systolic heart failure because of hyperthyroidism in patients without preexisting heart disease is not common. Thyrotoxic systolic heart failure is rarely diagnosed during life. Reports about thyrotoxicosis-related systolic heart failure have been diagnosed postmortem. However, antemortem diagnosis of this fatal disease has important clinical implications because if detected early, thyrotoxicosis-related systolic heart failure is reversible. Here is a report a patient with Graves' disease, systolic heart failure, and deep jaundice, which resolved after the treatment of antithyroid drugs. KEY INDEXING TERMS: Hyperthyroidism; Jaundice; Systolic heart failure. [Am J Med Sci 1996;312(5):246248.]
C
ongestive heart failure caused by hyperthyroidism in patients without preexisting heart disease is not common. 1 Most of these patients are hyperkinetic and have high cardiac output heart failure. Patients with systolic heart failure caused by hyperthyroidism . are rarely reported in the English literature. 1 •2 Thyrotoxic systolic heart failure is rarely diagnosed during life, but reports about thyrotoxicosis-related systolic heart failure have been diagnosed, postmortem. However, antemortem diagnosis of this fatal disease has two important clinical implications. First, if detected late, prognosis is grave because thyrotoxicosis-related systolic heart failure responds poorly to the conventional treatments for heart failure: digoxin, diuretics, and angiotensin-converting enzyme inhibitors. Second, if detected early, thyrotoxicosis-related systolic heart failure is reversible as proven in animal studies. Hyperthyroidis m is a rare but recognized cause of hepatic dysfunction. Jaundice in patients with hyperFrom the Center for Cardiovascular Research, College of Medicine, National Taiwan University, Department of Internal Medicine, National Taiwan Un iversity Hospital, Taipei, Taiwan. Submitted May 30, 1996; accepted in revised form June 21, 1996. Correspondence: Tsung-Ming Lee, MD, Department of Internal Medicine, National Taiwan University H ospital, Taipei, Taiwan, 10002.
246
thyroidism may come from hyperthyroidism alone or from hyperthyroidism complicated by heart failure or autoimmune disease. Jaundice in patients with hyperthyroidism is reported to be severe only when associated with either heart failure or autoimmune chronic active hepatitis. 3 Here, a patient with Graves' disease and both systolic heart failure and deep jaundice is reported. A good response of systolic heart failure to treatment with carbimazole and propanolol and a decrease in bilirubin levels from 294.1 to 17.1 JLmol/L (or 17.2-1.0 mg/dL) in 1 month were evidenced. Case Report A 46-year-old woman with no history of heart disease reported progressive lower leg edema a nd t hen exertional dyspnea 1 week before admission. Graves' disease was diagnosed 2 years previously. She was treated with carbimazole, but had stopped taking the medicine 6 months before admission because of drug-related gastritis. Two to three months before admission, nervousness, heat intolerance, easy fatigability, and a weight loss of 20 kg were reported. On physical examination, the patient was a markedly emaciated woman of 162 em tall and 29 kilograms in body weight. Her blood pressure was 130/90 mm H g and she had an irregular pulse rate of 136 beats per minute. Mild fever was also noted. The sclera was icteric and neither exophthalmos nor staring gaze were noted. The t hyroid gland was diffusely enlarged. Jugular vein distention was noted at a tilt of 45°. The lungs were dull by percussion examinations and chest auscultation showed moist rales at both lung fields. Heart auscultation showed a grade II/IV pansystolic murmur at the apical site, and a grade 1/IV diastolic murmur at the aortic area. The liver a nd spleen were enlarged. Marked bilateral pedal lower leg edema was n oted. Laboratory data showed a triiodothyronine level of 400 ng/dL (normal, 80- 200 ng/ dL) , a thyroxine level of> 30 !lg% (normal, 4.512 llg% ), and depressed thyroid stimulating hormone level of< 0.002 IJ.IU/ml (normal, < 5.0 IJ.IU/ml) by sen sitive radioimmunoassay method. Antithyroglobulin (titer > 20480) and antimicrosomal (titer > 20480) antibodies were a lso markedly positive. Serum antimitochondrial antibody was 1:20. The bilirubin level was 4.5 mg/dL (76.5 !J.mol/L) ; a lkaline phosphate, 339 U/L (normal, 64-238 U/L), aspartate am inotransferase, 75 U/L (normal, 5-31 U/L); glutamic pyruvic transaminase, 24 U/L (normal, 0-31 U/L); zinc turbidity test, 20.3 K.U.(normal , 4- 12 K.U.); and albumin , 3.1 g/dL (normal, 3.75.2 g/dL). There was no evidence of hemolysis. Serum hepatoglobulin, direct and indirect Coombs' tests, antiDNA, and antiENA test results were all within norma l ranges. Viral ma rkers for hepatitis A, B, a nd C were negative. Abdominal sonography showed hepatic vein, inferior vein cava engorgement, minimal ascites, and hepatic congestion , all compatible with congestive heart failure. Echocardiographic examination showed minimal pericardia! effusion, mild severity of aortic regurgitation, a nd tricuspid regurgitation and depressed ejection fraction (48.1 %) of the left ventricle. There was no evidence of valvular dysfunction November 1996 Volume 312 Number 5
Lee, Kuo, and Lee
that could explain heart failure. Radionuclide angiography showed that the ejection fraction of the left ventricle was 35.2%. Thyroid sonography showed diffuse enlargement of the thyroid gland with the size of the right thyroid lobe as 3.8 X 2.7 X 2.2 em and of the left thyroid lobe as 4.3 X 3.1 X 2.3 em. Initially treatment with digoxin, furosemide, and angiotensinconverting enzyme inhibitor proved to be ineffective in reversing clinical symptoms of heart failure. The level of bilirubin was rapidly exacerbated from 76.5 to 294.1/Lmol/L (4.5-17.2 mg/dL) in two weeks, with a direct bilirubin form of around 80%. No drugs were responsible for the elevated bilirubin. She had persistent mild fever, progressive nausea, and vomiting. Her blood pressure was· 150/100 mm Hg, and body temperature was 38.5° C. The patient was suspected to have an impending thyroid storm and treatment ~as started with carbimazole at 40 mg/day in divided doses and propanolol at 40 mg/day. Her lower leg edema and dyspnea improved dramatically. The jaundice greatly faded from a bilirubin level of 294.1 to 100.3 ILmolfL (17.2- 5.9 mg/dL) 10 days after the antithyroid treatment. She had no additional weight loss. The proximal weakness of extremities was entirely resolved. No more fever was noted. One month later, repeat bilirubin was normal (1.0 mg/dL) . Follow-up echocardiography showed improvement of the ejection fraction (58.9 % ) of the left ventricle. The patient recovered well and has continued to do so.
Discussion
Thyroid hormone may enhance left ventricular function in humans. 4 The enhancement of myocardial contractility in hyperthyroidism may be explained either by an enhanced accumulation and release of calcium by the sarcoplasmic reticulum during excitationcontraction coupling or by the stimulation of synthesis of a new myosin that has a higher level of adenosine triphosphatase activity. 5 Both systolic contraction and diastolic relaxation are enhanced and cardiac output is increased in hyperthyroidism. Therefore, high cardiac output failure is more common in patients with hyperthyroidism. Excessive thyroid hormone may cause myocardial damage. Hyperthyroidism, if left untreated, can damage the myocardium through a postreceptor site. 6 The clinical effects of hyperthyroidism are similar to those associated with catecholamine-induced cardiomyopathy. Increased tissue sensitivity to catecholamine was suggested in experimental hyperthyroidism of increased numbers of beta-adrenergic receptors in myocardial tissue. An increased number of adrenergic receptors has also been found in skeletal and adipose tissue. However, catecholamine levels are not related to hyperthyroidism. 7 In summary, although the specific mechanism is unclear, excessive thyroid hormone produces toxic effects in myocytes and focal necrosis. Physiologic changes can produce abnormal myocardial structure and function and life-threating myocardial failure . On histopathologic examination, there are no distinctive myocardial lesions unique to hyperthyroidism. Interstitial fibrosis, leukocyte infiltration, myocardial necrosis, and abnormal separation of myocardial fibers have been reported. 8 In addition, some alternations in mitochondrial ultrastructure have been identified in some animals with a thyrotoxic state. These changes completely disappeared when the animal was allowed THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
to return to a euthyroid state. It has been suggested that pathophysiologic abnormality of the thyrotoxic heart may be reversible. Abnormal liver function is rarely noted in patients with hyperthyroidism. 9 The degree of jaundice in patients with hyperthyroidism without congestive heart failure or after the treatment of congestive heart failure has been mild. Thompson et al 10 studied 85 patients with hyperthyroidism. Among those, there were 31% with an elevated bilirubin level and the highest bilirubin value was 3.5 mg/dL. A recent report9 described a few patients with hyperthyroidism whose bilirubin may have been as high as 19.4 mg/dL. The mechanism of hyperbilirubinemia in hyperthyroidism has not fully understood. A study 11 of hyperthyroid Wistar rats showed that hyperthyroidism lowers the conjugated/ total bilirubin ratio, contrary to this study. Meyer et al 12 speculated that increased splanchnic blood flow in the face of normal hepatic flow would result in hepatic hypoxia and impaired liver function. There are many different causes of hepatic and extrahepatic jaundice. In this patient's case, persistent fever, nausea, vomiting, and progressive jaundice could have been signs of impending thyrotoxic crisis. Thyrotoxicosis-related systolic heart failure may complicate and worsen the severity of jaundice. Therefore, jaundice may result from hyperthyroidism alone or a complication of heart failure. Without a liver biopsy, it is difficult to sort out the contributions of thyrotoxicosis-related and heart failure-related mechanisms in pathogenesis of jaundice in this patient. Jaundice was not improved until antithyroid drugs were used while the patient was still taking the cardiac medications. Therefore, the worsening jaundice before antithyroid treatment was not caused by the drug effect. Thyrotoxic heart failure may respond poorly to conventional standard therapy unless the hyperthyroid state is controlled. Valko et al 13 described a patient with Graves' disease who developed systolic heart failure after delivery. She responded well to standard treatment of heart failure consisting of digoxin, diuretics, and angiotensin-converting enzyme inhibitors. However, no proof of heart failure related to Graves' disease was confirmed. Wilson et al 1 described a patient with Graves' disease who developed systolic heart failure because of hyperthyroidism. This patient was treated with antithyroid drugs of propylthiouracil and radioactive iodide similar to the current case. Marti et al 14 described a patient with hyperthyroidism, heart failure, and depressed ejection fraction in whom myocardial damage was evidenced by ln 111 -labelled monoclonal antimyosin antibodies. Both myocardial damage and left ventricular dysfunction disappeared after antithyroid therapy. Therefore, thyrotoxic heart failure should be suspected in patients who poorly respond to therapy of heart failure with the use of digoxin, diuretics, and angiotensin-converting enzyme inhibitors. 247
ABSTRACT: Systolic heart failure because of hyperthyroidism in patients without preexisting heart disease is not common. Thyrotoxic systolic heart failure is rarely diagnosed during life. Reports about thyrotoxicosis-related systolic heart failure have been diagnosed postmortem. However, antemortem diagnosis of this fatal disease has important clinical implications because if detected early, thyrotoxicosis-related systolic heart failure is reversible. Here is a report a patient with Graves' disease, systolic heart failure, and deep jaundice, which resolved after the treatment of antithyroid drugs. KEY INDEXING TERMS: Hyperthyroidism; Jaundice; Systolic heart failure. [Am J Med Sci 1996;312(5):246248.]
C
ongestive heart failure caused by hyperthyroidism in patients without preexisting heart disease is not common. 1 Most of these patients are hyperkinetic and have high cardiac output heart failure. Patients with systolic heart failure caused by hyperthyroidism . are rarely reported in the English literature. 1 •2 Thyrotoxic systolic heart failure is rarely diagnosed during life, but reports about thyrotoxicosis-related systolic heart failure have been diagnosed, postmortem. However, antemortem diagnosis of this fatal disease has two important clinical implications. First, if detected late, prognosis is grave because thyrotoxicosis-related systolic heart failure responds poorly to the conventional treatments for heart failure: digoxin, diuretics, and angiotensin-converting enzyme inhibitors. Second, if detected early, thyrotoxicosis-related systolic heart failure is reversible as proven in animal studies. Hyperthyroidis m is a rare but recognized cause of hepatic dysfunction. Jaundice in patients with hyperFrom the Center for Cardiovascular Research, College of Medicine, National Taiwan University, Department of Internal Medicine, National Taiwan Un iversity Hospital, Taipei, Taiwan. Submitted May 30, 1996; accepted in revised form June 21, 1996. Correspondence: Tsung-Ming Lee, MD, Department of Internal Medicine, National Taiwan University H ospital, Taipei, Taiwan, 10002.
246
thyroidism may come from hyperthyroidism alone or from hyperthyroidism complicated by heart failure or autoimmune disease. Jaundice in patients with hyperthyroidism is reported to be severe only when associated with either heart failure or autoimmune chronic active hepatitis. 3 Here, a patient with Graves' disease and both systolic heart failure and deep jaundice is reported. A good response of systolic heart failure to treatment with carbimazole and propanolol and a decrease in bilirubin levels from 294.1 to 17.1 JLmol/L (or 17.2-1.0 mg/dL) in 1 month were evidenced. Case Report A 46-year-old woman with no history of heart disease reported progressive lower leg edema a nd t hen exertional dyspnea 1 week before admission. Graves' disease was diagnosed 2 years previously. She was treated with carbimazole, but had stopped taking the medicine 6 months before admission because of drug-related gastritis. Two to three months before admission, nervousness, heat intolerance, easy fatigability, and a weight loss of 20 kg were reported. On physical examination, the patient was a markedly emaciated woman of 162 em tall and 29 kilograms in body weight. Her blood pressure was 130/90 mm H g and she had an irregular pulse rate of 136 beats per minute. Mild fever was also noted. The sclera was icteric and neither exophthalmos nor staring gaze were noted. The t hyroid gland was diffusely enlarged. Jugular vein distention was noted at a tilt of 45°. The lungs were dull by percussion examinations and chest auscultation showed moist rales at both lung fields. Heart auscultation showed a grade II/IV pansystolic murmur at the apical site, and a grade 1/IV diastolic murmur at the aortic area. The liver a nd spleen were enlarged. Marked bilateral pedal lower leg edema was n oted. Laboratory data showed a triiodothyronine level of 400 ng/dL (normal, 80- 200 ng/ dL) , a thyroxine level of> 30 !lg% (normal, 4.512 llg% ), and depressed thyroid stimulating hormone level of< 0.002 IJ.IU/ml (normal, < 5.0 IJ.IU/ml) by sen sitive radioimmunoassay method. Antithyroglobulin (titer > 20480) and antimicrosomal (titer > 20480) antibodies were a lso markedly positive. Serum antimitochondrial antibody was 1:20. The bilirubin level was 4.5 mg/dL (76.5 !J.mol/L) ; a lkaline phosphate, 339 U/L (normal, 64-238 U/L), aspartate am inotransferase, 75 U/L (normal, 5-31 U/L); glutamic pyruvic transaminase, 24 U/L (normal, 0-31 U/L); zinc turbidity test, 20.3 K.U.(normal , 4- 12 K.U.); and albumin , 3.1 g/dL (normal, 3.75.2 g/dL). There was no evidence of hemolysis. Serum hepatoglobulin, direct and indirect Coombs' tests, antiDNA, and antiENA test results were all within norma l ranges. Viral ma rkers for hepatitis A, B, a nd C were negative. Abdominal sonography showed hepatic vein, inferior vein cava engorgement, minimal ascites, and hepatic congestion , all compatible with congestive heart failure. Echocardiographic examination showed minimal pericardia! effusion, mild severity of aortic regurgitation, a nd tricuspid regurgitation and depressed ejection fraction (48.1 %) of the left ventricle. There was no evidence of valvular dysfunction November 1996 Volume 312 Number 5
Lee, Kuo, and Lee
that could explain heart failure. Radionuclide angiography showed that the ejection fraction of the left ventricle was 35.2%. Thyroid sonography showed diffuse enlargement of the thyroid gland with the size of the right thyroid lobe as 3.8 X 2.7 X 2.2 em and of the left thyroid lobe as 4.3 X 3.1 X 2.3 em. Initially treatment with digoxin, furosemide, and angiotensinconverting enzyme inhibitor proved to be ineffective in reversing clinical symptoms of heart failure. The level of bilirubin was rapidly exacerbated from 76.5 to 294.1/Lmol/L (4.5-17.2 mg/dL) in two weeks, with a direct bilirubin form of around 80%. No drugs were responsible for the elevated bilirubin. She had persistent mild fever, progressive nausea, and vomiting. Her blood pressure was· 150/100 mm Hg, and body temperature was 38.5° C. The patient was suspected to have an impending thyroid storm and treatment ~as started with carbimazole at 40 mg/day in divided doses and propanolol at 40 mg/day. Her lower leg edema and dyspnea improved dramatically. The jaundice greatly faded from a bilirubin level of 294.1 to 100.3 ILmolfL (17.2- 5.9 mg/dL) 10 days after the antithyroid treatment. She had no additional weight loss. The proximal weakness of extremities was entirely resolved. No more fever was noted. One month later, repeat bilirubin was normal (1.0 mg/dL) . Follow-up echocardiography showed improvement of the ejection fraction (58.9 % ) of the left ventricle. The patient recovered well and has continued to do so.
Discussion
Thyroid hormone may enhance left ventricular function in humans. 4 The enhancement of myocardial contractility in hyperthyroidism may be explained either by an enhanced accumulation and release of calcium by the sarcoplasmic reticulum during excitationcontraction coupling or by the stimulation of synthesis of a new myosin that has a higher level of adenosine triphosphatase activity. 5 Both systolic contraction and diastolic relaxation are enhanced and cardiac output is increased in hyperthyroidism. Therefore, high cardiac output failure is more common in patients with hyperthyroidism. Excessive thyroid hormone may cause myocardial damage. Hyperthyroidism, if left untreated, can damage the myocardium through a postreceptor site. 6 The clinical effects of hyperthyroidism are similar to those associated with catecholamine-induced cardiomyopathy. Increased tissue sensitivity to catecholamine was suggested in experimental hyperthyroidism of increased numbers of beta-adrenergic receptors in myocardial tissue. An increased number of adrenergic receptors has also been found in skeletal and adipose tissue. However, catecholamine levels are not related to hyperthyroidism. 7 In summary, although the specific mechanism is unclear, excessive thyroid hormone produces toxic effects in myocytes and focal necrosis. Physiologic changes can produce abnormal myocardial structure and function and life-threating myocardial failure . On histopathologic examination, there are no distinctive myocardial lesions unique to hyperthyroidism. Interstitial fibrosis, leukocyte infiltration, myocardial necrosis, and abnormal separation of myocardial fibers have been reported. 8 In addition, some alternations in mitochondrial ultrastructure have been identified in some animals with a thyrotoxic state. These changes completely disappeared when the animal was allowed THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
to return to a euthyroid state. It has been suggested that pathophysiologic abnormality of the thyrotoxic heart may be reversible. Abnormal liver function is rarely noted in patients with hyperthyroidism. 9 The degree of jaundice in patients with hyperthyroidism without congestive heart failure or after the treatment of congestive heart failure has been mild. Thompson et al 10 studied 85 patients with hyperthyroidism. Among those, there were 31% with an elevated bilirubin level and the highest bilirubin value was 3.5 mg/dL. A recent report9 described a few patients with hyperthyroidism whose bilirubin may have been as high as 19.4 mg/dL. The mechanism of hyperbilirubinemia in hyperthyroidism has not fully understood. A study 11 of hyperthyroid Wistar rats showed that hyperthyroidism lowers the conjugated/ total bilirubin ratio, contrary to this study. Meyer et al 12 speculated that increased splanchnic blood flow in the face of normal hepatic flow would result in hepatic hypoxia and impaired liver function. There are many different causes of hepatic and extrahepatic jaundice. In this patient's case, persistent fever, nausea, vomiting, and progressive jaundice could have been signs of impending thyrotoxic crisis. Thyrotoxicosis-related systolic heart failure may complicate and worsen the severity of jaundice. Therefore, jaundice may result from hyperthyroidism alone or a complication of heart failure. Without a liver biopsy, it is difficult to sort out the contributions of thyrotoxicosis-related and heart failure-related mechanisms in pathogenesis of jaundice in this patient. Jaundice was not improved until antithyroid drugs were used while the patient was still taking the cardiac medications. Therefore, the worsening jaundice before antithyroid treatment was not caused by the drug effect. Thyrotoxic heart failure may respond poorly to conventional standard therapy unless the hyperthyroid state is controlled. Valko et al 13 described a patient with Graves' disease who developed systolic heart failure after delivery. She responded well to standard treatment of heart failure consisting of digoxin, diuretics, and angiotensin-converting enzyme inhibitors. However, no proof of heart failure related to Graves' disease was confirmed. Wilson et al 1 described a patient with Graves' disease who developed systolic heart failure because of hyperthyroidism. This patient was treated with antithyroid drugs of propylthiouracil and radioactive iodide similar to the current case. Marti et al 14 described a patient with hyperthyroidism, heart failure, and depressed ejection fraction in whom myocardial damage was evidenced by ln 111 -labelled monoclonal antimyosin antibodies. Both myocardial damage and left ventricular dysfunction disappeared after antithyroid therapy. Therefore, thyrotoxic heart failure should be suspected in patients who poorly respond to therapy of heart failure with the use of digoxin, diuretics, and angiotensin-converting enzyme inhibitors. 247