Over the past few decades, there has been an increase in the number of reports about newly recognized (atypical or unusual) manifestations of Graves' disease (GD), that are related to various body systems. One of these manifestations is sometimes the main presenting feature of GD. Some of the atypical manifestations are specifically related to GD, while others are also similarly seen in patients with other forms of hyperthyroidism. Lack of knowledge of the association between these findings and GD may lead to delay in diagnosis, misdiagnosis, or unnecessary investigations. The atypical clinical presentations of GD include anemia, vomiting, jaundice, and right heart failure. There is one type of anemia that is not explained by any of the known etiological factors and responds well to hyperthyroidism treatment. This type of anemia resembles anemia of chronic disease and may be termed GD anemia. Other forms of anemia that are associated with GD include pernicious anemia, iron deficiency anemia of celiac disease, and autoimmune hemolytic anemia. Vomiting has been reported as a presenting feature of Graves' disease. Some cases had the typical findings of hyperthyroidism initially masked, and the vomiting did not improve until hyperthyroidism has been detected and treated. Hyperthyroidism may present with jaundice, and on the other hand, deep jaundice may develop with the onset of overt hyperthyroidism in previously compensated chronic liver disease patients. Pulmonary hypertension is reported to be associated with GD and to respond to its treatment. GD-related pulmonary hypertension may be so severe to produce isolated right-sided heart failure that is occasionally found as the presenting manifestation of GD. 1. Introduction Graves’ disease (GD) accounts for up to 80% of hyperthyroidism cases and is estimated to affect 0.5% of the population [1]. It usually presents with the common well- known symptoms and signs (goiter, ophthalmopathy, weight loss, nervousness, tremors, palpitations, sweating, etc.) which are the distinctive features of the disease (Table 1). We can observe another group of manifestations, such as periodic paralysis, apathy, or psychosis, which are less common and less distinctive despite being well documented in relation to GD (Table 1). Over the past few decades, there has been an increase in the number of reports about newly recognized (atypical or unusual) manifestations of hyperthyroidism that are related to various body systems and may create a wide range of differential diagnosis [2, 3]. Most of these atypical manifestations are
E. A. Boxall, R. W. Lauener, and H. W. Mcintosh, “Atypical manifestations of hyperthyroidism,” Canadian Medical Association Journal, vol. 91, pp. 204–211, 1964.
M. O. Hegazi and M. R. El-sonbaty, “Unusual presentations of hyperthyroidism,” in Handbook of Hyperthyroidism: Etiology, Diagnosis and Treatment, L. Mertens and J. Bogaert, Eds., pp. 265–270, Nova Publishers, 2011.
A. G. Gianoukakis, M. J. Leigh, P. Richards et al., “Characterization of the anaemia associated with Graves' disease,” Clinical Endocrinology, vol. 70, no. 5, pp. 781–787, 2009.
M. Klein, G. Weryha, P. Kaminsky, M. Duc, and J. Leclère, “Hematological manifestations of hyperthyroidism,” Annales de Medecine Interne, vol. 144, no. 2, pp. 127–135, 1993.
E. Biró, Z. Szekanecz, L. Czirják et al., “Association of systemic and thyroid autoimmune diseases,” Clinical Rheumatology, vol. 25, no. 2, pp. 240–245, 2006.
K. Boelaert, P. R. Newby, M. J. Simmonds et al., “Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease,” American Journal of Medicine, vol. 123, no. 2, pp. 183.e1–183.e9, 2010.
D. Barth and J. V. Hirschmann, “Anemia of endocrine disorders,” in Wintrobe's Atlas of Clinical Hematology, D. C. Tkachuk and J. V. Hirschmann, Eds., p. 6, Lippincott Williams & Wilkins, 2007.
B. Shaw and A. B. Mehta, “Pancytopenia responding to treatment of hyperthyroidism: a clinical case and review of the literature,” Clinical and Laboratory Haematology, vol. 24, no. 6, pp. 385–387, 2002.
M. Duquenne, D. Lakomsky, J. C. Humbert, S. Hadjadj, G. Weryha, and J. Leclère, “Resolutive pancytopenia with effective treatment of hyperthyroidism,” Presse Medicale, vol. 24, no. 17, pp. 807–810, 1995.
R. Akoum, S. Michel, T. Wafic et al., “Myelodysplastic syndrome and pancytopenia responding to treatment of hyperthyroidism: peripheral blood and bone marrow analysis before and after antihormonal treatment,” Journal of Cancer Research and Therapeutics, vol. 3, no. 1, pp. 43–46, 2007.
A. Sato, M. Zakarija, and J. M. McKenzie, “Characteristics of thyrotropin binding to bovine thyroid plasma membranes and the influence of human IgG,” Endocrine Research Communications, vol. 4, no. 2, pp. 95–113, 1977.
B. H. Toh, I. R. van Driel, and P. A. Gleeson, “Mechanisms of disease: pernicious anemia,” The New England Journal of Medicine, vol. 337, no. 20, pp. 1441–1448, 1997.
R. W. Burns and T. W. Burns, “Pancytopenia due to vitamin B12 deficiency associated with Graves' disease,” Missouri Medicine, vol. 93, no. 7, pp. 368–372, 1996.
C. L. Ch'ng, M. K. Jones, and J. G. Kingham, “Celiac disease and autoimmune thyroid disease,” Clinical Medicine and Research, vol. 5, no. 3, pp. 184–192, 2007.
N. Sattar, F. Lazare, M. Kacer et al., “Celiac disease in children, adolescents, and young adults with autoimmune thyroid disease,” Journal of Pediatrics, vol. 158, pp. 272–275, 2011.
T. Ogihara, H. Katoh, H. Yoshitake, S. Iyori, and I. Saito, “Hyperthyroidism associated with autoimmune hemolytic anemia and periodic paralysis: a report of a case in which antihyperthyroid therapy alone was effective against hemolysis,” Japanese Journal of Medicine, vol. 26, no. 3, pp. 401–403, 1987.
D. O'Brien, D. J. Lyons, and J. F. Fielding, “A case of Graves' disease associated with autoimmune haemolytic anaemia,” Irish Journal of Medical Science, vol. 158, no. 6, p. 155, 1989.
M. Mukai, A. Sagawa, I. Watanabe et al., “A case of autoimmune hemolytic anemia associated with Graves' disease,” Nihon Naika Gakkai zasshi Journal, vol. 75, no. 5, pp. 644–649, 1986.
A. B. Andrusenko, T. S. Kamynina, and O. P. Bogatyrev, “Cushing's syndrome associated with toxic goiter and autoimmune hemolytic anemia,” Sovetskaya Meditsina, no. 8, pp. 115–116, 1990.
M. Rajic, S. Djurica, D. P. Milosevic, and N. Markovic, “Autoimmune haemopoietic disturbances simultaneous with autoimmune thyroid diseases,” Srpski Arhiv za Celokupno Lekarstvo, vol. 133, pp. 52–54, 2005.
K. Ikeda, Y. Maruyama, M. Yokoyama et al., “Association of Graves' disease with Evan's syndrome in a patient with IgA nephropathy,” Internal Medicine, vol. 40, no. 10, pp. 1004–1010, 2001.
T. Ushiki, M. Masuko, K. Nikkuni, et al., “Successful remission of Evans syndrome associated with Graves' disease by using propylthiouracil monotherapy,” Internal Medicine, vol. 50, pp. 621–625, 2011.
A. M. McGregor, M. M. Petersen, S. M. McLachlan, P. Rooke, B. R. Smith, and R. Hall, “Carbimazole and the autoimmune response in Graves' disease,” The New England Journal of Medicine, vol. 303, no. 6, pp. 302–307, 1980.
L. Y. Chen, B. Zhou, Z. W. Chen, and L. Z. Fang, “Recurrent severe vomiting due to hyperthyroidism,” Journal of Zhejiang University Science B, vol. 11, no. 3, pp. 218–220, 2010.
M. B. Harper, “Vomiting, nausea, and abdominal pain: unrecognized symptoms of thyrotoxicosis,” Journal of Family Practice, vol. 29, no. 4, pp. 382–386, 1989.
S. Shim, H. S. Ryu, H. J. Oh, and Y. S. Kim, “Thyrotoxic vomiting: a case report and possible mechanisms,” Journal of Neurogastroenterology and Motility, vol. 16, pp. 428–432, 2010.
J. P. Bilezikian and J. N. Loeb, “The influence of hyperthyroidism and hypothyroidism on α- and β-adrenergic receptor systems and adrenergic responsiveness,” Endocrine Reviews, vol. 4, no. 4, pp. 378–388, 1983.
B. Pfaffenbach, R. J. Adamek, D. Hagelmann, J. Schaffstein, and M. Wegener, “Effect of hyperthyroidism on antral myoelectrical activity, gastric emptying and dyspepsia in man,” Hepato-Gastroenterology, vol. 44, no. 17, pp. 1500–1508, 1997.
K. Jonderko, G. Jonderko, C. Marcisz, and T. Golab, “Gastric emptying in hyperthyroidism,” American Journal of Gastroenterology, vol. 92, no. 5, pp. 835–838, 1997.
T. J. Caffrey, “Transient hyperthyroidism of hyperemesis gravidarum: a sheep in wolf's clothing,” Journal of the American Board of Family Practice, vol. 13, no. 1, pp. 35–38, 2000.
J. E. Haddow, M. R. McClain, G. Lambert-Messerlian et al., “Variability in thyroid-stimulating hormone suppression by human chronic gonadotropin during early pregnancy,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 9, pp. 3341–3347, 2008.
T. M. Goodwin, M. Montoro, J. H. Mestman, A. E. Pekary, and J. M. Hershman, “The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum,” Journal of Clinical Endocrinology and Metabolism, vol. 75, no. 5, pp. 1333–1337, 1992.
A. T. Luetic and B. Miskovic, “Is hyperthyroidism underestimated in pregnancy and misdiagnosed as hyperemesis gravidarum?” Medical Hypotheses, vol. 75, no. 4, pp. 383–386, 2010.
American College of Obstetricians and Gynecologists, “ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 37, August 2002. (replaces practice bulletin number 32, November 2001). Thyroid disease in pregnancy,” Obstet Gynecol, vol. 100, pp. 387–396, 2002.
A. Gürlek, V. Cobankara, and M. Bayraktar, “Liver tests in hyperthyroidism: effect of antithyroid therapy,” Journal of Clinical Gastroenterology, vol. 24, no. 3, pp. 180–183, 1997.
M. O. Hegazi, A. Marafie, and M. Alajmi, “Thyrotoxicosis-associated cholestasis in a patient with hepatitis B cirrhosis,” Turkish Journal of Endocrinology and Metabolism, vol. 12, pp. 99–100, 2008.
P. J. Owen, A. Baghomian, J. H. Lazarus, and A. J. Godkin, “An unusual cause of jaundice,” British Medical Journal, vol. 335, no. 7623, pp. 773–774, 2007.
T. L. Fong, J. G. McHutchison, and T. B. Reynolds, “Hyperthyroidism and hepatic dysfunction: a case series analysis,” Journal of Clinical Gastroenterology, vol. 14, no. 3, pp. 240–244, 1992.
S. C. Barnes, J. M. Wicking, and J. D. Johnston, “Graves' disease presenting with cholestatic jaundice,” Annals of Clinical Biochemistry, vol. 36, no. 5, pp. 677–679, 1999.
N. P. Thompson, S. Leader, C. P. Jamieson, W. R. Burnham, and A. K. Burroughs, “Reversible jaundice in primary biliary cirrhosis due to hyperthyroidism,” Gastroenterology, vol. 106, no. 5, pp. 1342–1343, 1994.
M. Enghofer, K. Badenhoop, S. Zeuzem et al., “Fulminant hepatitis A in a patient with severe hyperthyroidism: rapid recovery from hepatic coma after plasmapheresis and total thyroidectomy,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 5, pp. 1765–1769, 2000.
M. Majeed and A. Babu, “Cholestasis secondary to hyperthyroidism made worse by methimazole,” American Journal of the Medical Sciences, vol. 332, no. 1, pp. 51–53, 2006.
M. Chawla and C. S. Bal, “Four cases of coexistent thyrotoxicosis and jaundice: results of radioiodine treatment and a brief review,” Thyroid, vol. 18, no. 3, pp. 289–292, 2008.
K. Hull, R. Horenstein, R. Naglieri, K. Munir, M. Ghany, and F. S. Celi, “Two cases of thyroid storm-associated cholestatic jaundice,” Endocrine Practice, vol. 13, no. 5, pp. 476–480, 2007.
H. Ichikawa, H. Ebinuma, S. Tada et al., “A case of severe cholestatic jaundice with hyperthyroidism successfully treated with methimazole,” Clinical Journal of Gastroenterology, vol. 2, no. 4, pp. 315–319, 2009.
M. Marvisi, P. Zambrelli, M. Brianti, G. Civardi, R. Lampugnani, and R. Delsignore, “Pulmonary hypertension is frequent in hyperthyroidism and normalizes after therapy,” European Journal of Internal Medicine, vol. 17, no. 4, pp. 267–271, 2006.
J. Mercé, S. Ferrás, C. Oltra et al., “Cardiovascular abnormalities in hyperthyroidism: a prospective Doppler echocardiographic study,” American Journal of Medicine, vol. 118, no. 2, pp. 126–131, 2005.
M. O. Hegazi, A. El Sayed, and H. El Ghoussein, “Pulmonary hypertension responding to hyperthyroidism treatment,” Respirology, vol. 13, no. 6, pp. 923–925, 2008.
Y. Paran, A. Nimrod, Y. Goldin, and D. Justo, “Pulmonary hypertension and predominant right heart failure in thyrotoxicosis,” Resuscitation, vol. 69, no. 2, pp. 339–341, 2006.
R. Patel, G. Peterson, A. Rohatgi et al., “Hyperthyroidism-associated coronary vasospasm with myocardial infarction and subsequent euthyroid angina,” Thyroid, vol. 18, no. 2, pp. 273–276, 2008.
A. Yazar, O. D？ven, S. Atis et al., “Systolic pulmonary artery pressure and serum uric acid levels in patients with hyperthyroidism,” Archives of Medical Research, vol. 34, no. 1, pp. 35–40, 2003.
A. Soroush-Yari, S. Burstein, G. W. Hoo, and S. M. Santiago, “Pulmonary hypertension in men with thyrotoxicosis,” Respiration, vol. 72, no. 1, pp. 90–94, 2005.
J. H. Li, R. E. Safford, J. F. Aduen, M. G. Heckman, J. E. Crook, and C. D. Burger, “Pulmonary hypertension and thyroid disease,” Chest, vol. 132, no. 3, pp. 793–797, 2007.
B. Biondi and G. J. Kahaly, “Cardiovascular involvement in patients with different causes of hyperthyroidism,” Nature Reviews Endocrinology, vol. 6, no. 8, pp. 431–443, 2010.
J. W. Chu, P. N. Kao, J. L. Faul, and R. L. Doyle, “High prevalence of autoimmune thyroid disease in pulmonary arterial hypertension,” Chest, vol. 122, no. 5, pp. 1668–1673, 2002.
M. Armigliato, R. Paolini, S. Aggio et al., “Hyperthyroidism as a cause of pulmonary arterial hypertension: a prospective study,” Angiology, vol. 57, no. 5, pp. 600–606, 2006.
T. E. Whitner, C. J. Hudson, T. D. Smith, and L. Littmann, “Hyperthyroidism: presenting as isolated tricuspid regurgitation and right heart failure,” Texas Heart Institute Journal, vol. 32, no. 2, pp. 244–245, 2005.
H. F. Lozano and C. N. Sharma, “Reversible pulmonary hypertension, tricuspid regurgitation and right-sided heart failure associated with hyperthyroidism: case report and review of the literature,” Cardiology in Review, vol. 12, no. 6, pp. 299–305, 2004.
M. Franchini, G. Lippi, and G. Targher, “Hyperthyroidism and venous thrombosis: a casual or causal association? A systematic literature review,” Clinical and Applied Thrombosis/Hemostasis, vol. 17, no. 4, pp. 387–392, 2010.
M. S. Rocha, S. M. Brucki, and A. C. Ferraz, “Cerebral vasculitis and basedow-graves disease: report of two cases,” Arquivos de Neuropsiquiatria, vol. 59, no. 4, pp. 948–953, 2001.
