Ocular myasthenia gravis, Hashimoto's thyroiditis, iron deficiency anemia, and reactive hypoglycemia/Okuler myastenia gravis, Hashimoto tiroiditi, demir eksikligi anemisi ve reaktif hipoglisemi.
Abstract: Myasthenia gravis (MG) may occur in association with other organ- specific or nonspecific autoimmune diseases. In our study, we present a patient with ocular myasthenia, Hashimoto s thyroiditis, and iron deficiency anemia who later developed reactive hypoglycemia. A 25-year-old woman with complaints of fluctuating extraocular muscle weakness, ptosis, and diplopia was examined. MG, type I (ocular MG), was confirmed by an elevated titer of anti-acetylcholine receptor antibodies in serum (7 nmol/I, normal <0.6) and positive edrophonium test. Nerve conduction studies, needle electromyography, repetitive stimulation tests, and mediasten MRI were normal. The coexistence of Hashimoto's thyroiditis was diagnosed by the presence of a diffuse thyroid enlargement, elevated titers of anti-thyroglobulin antibodies (211.8 IU/ml, normal 0-115), thyroid peroxidase antibodies (356.4 IU/ml, normal 0-34), thyroid stimulating hormone (8.21 ulU/ml, normal 0.27-4.2), and a decreased titer of free-T4 (1.03ng/dl normal 1.8-4.6). Diplopia and ptosis have regressed with 180 mg/day pyridostigmine bromide. On her follow-up period, 8 months later, reactive hypoglycemia has been diagnosed. The coexistence of myastenia gravis, Hashimoto s thyroiditis and reactive hypoglycemia was not found in the literature. We should take into consideration the association and the importance of recognizing and treating these pathologies in myastenia gravis. Turk Jem 2009, 13: 31-3

Key words: Myasthenia gravis, Hashimoto s thyroiditis, hypoglycemia

Myastenia gravis (MG) diger organ spesifik veya nonspesifik otoimmun hastaliklar ile birliktelik gosterebilir. Calismamizda okuler myasteni, Hashimoto tiroiditi ve demir eksikligi anemisi olup daha sonra reaktif hipoglisemi gelisen hastayi sunmaktayiz. Fluktuasyon gosteren ekstraokuler kas gucsuzlugu, pitoz ve diplopi sikayetleri olan 25 yasindaki bayan hasta incelendi. Artmis serum antiasetilkolin reseptor antikor titresi (7 nmol/l, normal <0.6) ve edrophonium testinin pozitif olarak saptanmasi ile MG tip 1 (okuler myasteni) tanisi konuldu. Sinir ileti calismasi, igne EMG, repetetif sinir uyarimi ve mediaten MRI tetkikleri normal idi. Difuz tiroid genislemesi ile anti-tiroglobulin antikor (211.8 IU/ml, normal 0-115), tiroid peroxidase antikor (356.4 IU/ml, normal 0-34) ve tiroid stimulan hormon (8.21 ulU/ml, normal 0.27-4.2) duzeylerinin yuksekligi ve serbest T4 (1.03ng/dl normal 1.8-4.6) dozeyinin dusuk olmasi ile Hashimoto tiroiditinin eslik ettigi saptandi. Di plopi ve pitoz 180 mg/gon piridostigmine bromide ile geriledi. Takip doneminde 8 ay sonra reaktif hipoglisemi saptandi. Myastenia gravis, Hashimoto thyroiditi, demir eksikligi anemisi ve reaktif hipoglisemi birlikteligi literaturde bulunamamistir. Myastenia gravis olan hastalarda bu patolojilerin birlite olabilecegi, taninmalari ve tedavi edilmelerinin onemi goz onune alinmalidir. Turk Jem 2009; 13: 31-3

Anahtar kelimeler: Myastenia gravis, Hashimoto tiroiditi, hipoglisemi
Article Type: Case study
Subject: Thyroiditis, Autoimmune (Risk factors)
Thyroiditis, Autoimmune (Diagnosis)
Thyroiditis, Autoimmune (Care and treatment)
Thyroiditis, Autoimmune (Patient outcomes)
Hypoglycemia (Risk factors)
Hypoglycemia (Diagnosis)
Hypoglycemia (Care and treatment)
Hypoglycemia (Research)
Iron deficiency anemia (Diagnosis)
Iron deficiency anemia (Care and treatment)
Myasthenia gravis (Risk factors)
Myasthenia gravis (Diagnosis)
Myasthenia gravis (Care and treatment)
Myasthenia gravis (Patient outcomes)
Myasthenia gravis (Case studies)
Authors: Domac, Fusun Mayda
Misirli, Handan
Boylu, Ece
Ozer, Beratgul
Pub Date: 06/01/2009
Publication: Name: Turkish Journal of Endocrinology and Metabolism Publisher: Galenos Yayincilik Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Galenos Yayincilik ISSN: 1301-2193
Issue: Date: June, 2009
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: Turkey Geographic Code: 7TURK Turkey
Accession Number: 208535236
Full Text: Introduction

Autoimmune diseases (AD) are conditions in which there is a development of antibodies against self cells and/or organs. AD could either be organ-specific or non-organ specific (systemic) in clinical presentation (1). Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular transmission due to circulating antiacetylcholine receptor autoantibodies (AchRAb) (2). The clinical expression of MG varies ranging from a mild localized disease, such as ocular, to a severe generalized disease. In epidemiological studies autoimmune thyroid disease (AITD) has been observed in approximately 5-10% of MG patients, and a higher frequency of thyroid antibodies has been observed in ocular myastenia gravis (OMG) compared to generalized myastenia gravis (GMG), whereas a fairly low incidence of MG (0.2%) has been reported in patients with AITD (2,3,4). In our study, we present a patient with ocular myasthenia, Hashimoto's thyroiditis, and iron deficiency anemia who later developed reactive hypoglycemia.

Case Report

A 25- year-old woman with complaints of fluctuating extraocular muscle weakness, ptosis, and diplopia since 3 years was examined. Physical and the remaining neurological examination were normal. Myasthenia gravis (MG), type I (ocular MG according to Osserman criteria), was confirmed by an elevated titer of anti-acetylcholine receptor antibodies in serum (7 nmol/I, normal <0.6 nmol/I) and a clear improvement in eye muscle weakness a few seconds after the administration of edrophonium. Nerve conduction studies, needle electromyography, repetitive stimulation tests, and mediastinal magnetic resonance imaging were normal. The coexistence of Hashimoto's thyroiditis was diagnosed by the presence of a diffuse thyroid enlargement on thyroid ultrasonography, elevated titers of anti-thyroglobulin antibodies, thyroid peroxidase antibodies, thyroid stimulating hormone, and a decreased titer of free-T4 in blood samples (Table 1) and lymphocytic infiltration on fine needle aspiration biopsy. Hyperlipidemia and iron deficiency anemia were also noted (Table 1). The other biochemical parameters were within normal ranges. The patient was also examined for unusual combination of autoimmune conditions. The computed tomography of the abdomen and pelvis, and transduodenal endoscopic ultrasound were negative for insulinoma. The levels of C-reactive protein, anti-streptolysin O, rheumatoid factor, anti-SLE in blood samples were normal. Diplopia and ptosis have regressed with 180 mg/day pyridostigmine bromide. Hypothyroidism has been treated with L-Thyroxine sodium 0.25 mg/day. Routine hematological and biochemical blood tests were repeated every 2 months. Iron deficiency anemia has been treated with ferroglycerine sulfate 450mg/day for 2 months and 225 mg/day for 4 months, and thyroid function tests were not affected during this treatment.

Eight months later, as autonomic findings like sweating, palpitation and hunger have developed postprandially, oral glucose tolerance test (OGTT) using 75 g of glucose has been applied and her blood sugar was periodically measured every hour. The plasma glucose reached a nadir of 0.48 g/I at the end of the 3rd hour and hypoglycemic symptoms have been examined (Table 2). Fasting insulin level was 6.91 j IU/mL, while the postprandial insulin level has reached a nadir of 87 j IU/mL and reactive hypoglycemia has been diagnosed. The OGTT test has been repeated a month later and the similar results have been detected. The computed tomography of the abdomen and pelvis were normal, and transduodenal endoscopic ultrasound was negative for insulinoma. She was treated by avoidance of sweets and high-sugar foods, and eating meals at regular times. On her follow-up period, at the end of the 24th months, diplopia and ptosis did not recur under the treatment of pyridostigmine bromide and she did not develop generalized muscle involvement. Routine hematological and biochemical tests were also in normal ranges.

Discussion

Genetic, immune, hormonal, and environmental factors are associated with the multifactorial origin of autoimmunity. When one or more of these factors are altered, a "switch" from one autoimmune condition to another can occur (2). Chronic autoimmune thyroidism (Hashimoto's), as well as immunogenic hyperthyroidism (Graves-Basedow) are frequently associated with autoimmune diseases of other organs, such as: chronic insufficiency of salivary glands (Sjogren's), autoimmune hemolytic anemia, megalocytic pernicious anemia, thrombocytopenia, rheumatoid arthritis, diabetes mellitus (more often type 2, but also type 1), and other autoimmune diseases such as systemic diseases of connecting tissue (Systemic Lupus erythematosus-SLE, Sclerodermia) (1,4).

Autoimmune thyroid disease (AITD) is a multifactorial, genetic disease that is the sequelae of impaired immunoregulation, tolerance and poor recognition of one's own proteins, oligopolysaccharides and polypeptides, due to development of somatic lymphocyte mutations (4). AITD is manifested by different clinical and morphological entities, inter-related by etiopathogenetic association, i.e., all of them are caused by disorder of immune system regulation. Hashimoto's thyroiditis (HT) and MG are infrequently associated, while Graves' disease is a quite frequent phenomenon in MG (5). Though it was suggested that AITD occurs in approximately 5-10% of MG patients, in another study, 46 patients with MG were investigated and it was observed that two (4%) had Graves' disease, five (12%) were euthyroid with autonomously functioning thyroid tissue, the remaining 39 patients had no thyroid disease. One year earlier, the same authors reported a somewhat higher incidence of thyroid disease in a larger series (n=104) of MG patients (6% with thyrotoxicosis, 2% with hypothyroidism, 12% had antithyroglobulin antibodies and 28% had antimicrosomal antibodies) (6). Marino et al found a prevalence of AITD in their MG series as 28.5% (26/91): 4.4% (4/91) with hyperthyroid Graves' disease (GD), 3.3% (3/91) with euthyroid GD, 10.9% (10/91) with euthyroid Hashimoto's thyroiditis (HT), and 9.9% (9/91) with hypothyroid HT or idiopathic myxedema (2).

In some studies, an increased association of autoimmune disorders was found in OMG than GMG, while a higher frequency in GMG compared to OMG was found by others (2). Several hypotheses have been considered for the increased association between OMG and thyroid autoimmunity. First, OMG and GMG might actually represent separate diseases with different spectra of associated diseases, and different pathogenetic mechanisms are responsible for them. Second, as several experimental data suggest that thyroid antigens are present in ocular tissues, an immunological cross-reactivity against epitopes or autoantigens shared by the thyroid and the eye muscles might be the basis of this association. Third, they might share a common peculiar genetic background (7,8,9). Weissel et al have investigated 74 consecutive patients with MG, and found only 1 euthyroid patient on L-thyroxine therapy with HT and another patient with mildly elevated TSH without elevated thyroid antibodies, and they have suggested that autoimmune thyroid disease may be associated with MG, but the occurrence of thyroid dysfunction induced by autoimmunity is a very rare phenomenon in MG (10).

The coexistence of Hashimoto's thyroiditis and myastenia gravis can be diagnosed by the presence of a diffuse thyroid enlargement, anti-thyroglobulin and anti-microsomal antibodies and a lowered thyroidal 131-I uptake (2). Since HT as well as MG has an abnormality of T lymphocyte regulatory function, and the autoimmune process in both diseases is directed against cell membrane receptors, they can be considered as pathogenetically related (8). Unrecognized HT progressively leads to hypothyroidism with hyperlipidemia, blood vessel changes, osteoporosis, deformities, invalidity which substantially reduces the quality of life of the patient and requires medical attention (10).

In the literature there are few cases with MG and HT who also developed an unusual combination of autoimmune conditions. One of these patients with Type 1 diabetes mellitus has developed generalized MG, Addisonian pernicious anaemia, adrenalitis and thyroiditis which did not fit into the Type 1 or Type 2 classical polyendocrine deficiency syndromes (11). Another patient with generalized MG was complicated by sarcoidosis and HT, while one patient was complicated by type 1 DM, autoimmune hepatitis and HT, suggesting that the common underlying immunological abnormalities for these disorders, such as a certain defective cellular immunity, are responsible for the pathomechanism to induce the patient condition (5,12,13).

Several minerals and trace elements, such as iodine and iron, are essential for normal thyroid hormone metabolism. Though patients with AITD have a higher prevalence of vitamin B12 deficiency and pernicious anemia, studies in animals and adults have indicated iron deficiency anemia to be associated with altered thyroid hormone metabolism. Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase (14). Chen et al have reported the occurrence of megaloblastic anemia in a young woman with chronic autoimmune thyroiditis, who has presented with iron deficiency anemia that has been diagnosed initially (15). Our patient has been diagnosed as ocular myastenia, and during the investigations a coexistence with Hashimoto's thyroiditis was observed. She also had an iron deficiency anemia, and during her follow-up period reactive hypoglycemia has developed. The coexistence of myastenia gravis, Hashimoto's thyroiditis and reactive hypoglycemia was not found in the literature.

In conclusion, we should take into consideration the association and the importance of the recognition of the above-mentioned pathologies with myastenia gravis, and by early diagnosis and multidisciplinary treatment, to take secondary preventive measures, and in that way, to avoid the development of comorbidity and complications. This suggests that the autoantibody, biochemical and haematological screening of affected individuals should be extended to anticipate a wider range of potential autoimmune conditions.

References

(1.) Talabi OA, Owolabi MO, Osotimehin BO. Autoimmune diseases in a Nigerian woman-a case report. West Afr J Med 2003; 22: 361-3.

(2.) Marino M, Ricciardi R, Pinchera A, et al. Mild clinical expression of myasthenia gravis associated with autoimmune thyroid disease. J Clin Endocrinol Metab 1997; 82: 438-43.

(3.) Peacey SR, Belchetz PE. Graves disease associated with ocular myasthenia gravis and thymic cyst. J R Soc Med. 1993; 86: 297-8.

(4.) Lapcevic M. Autoimmune thyroid disease and associated diseases. Srp Arh Celok Lek 2005;133: 84-7.

(5.) Werneck AL, Checcacci-Balod T, Tuma G. Scleroderma, thyroiditis, and myastenia gravis: a study of a case. Arq Neuropsiquiatr 1993; 51: 549-53.

(6.) Kiessling WR, Finke R, Kotulla P, Schleusener H Circulating TSH-binding inhibiting immunoglobulins in myasthenia gravis. Acta Endocrinol 1982;101: 41-6.

(7.) Kanazawa M, Shimohata T, Tanaka K, Nishizawa M. Clinical features of patients with myasthenia gravis associated with autoimmune diseases. Eur J Neurol. 2007; 14:1403-4.

(8.) Mengitsu M, Lukes YG, Nagy HB, et al. TSH receptor gene expression in retroocular fibroblasts. J Endocrinol Invest 1994;17: 437-41.

(9.) Zimmermann CW, Eblen F. Repertoires of autoantibodies against homologous eye muscle in ocular and generalized myasthenia gravis differ. Clin Invest 1993; 71: 445-51.

(10.) Weissel M, Mayr N, Zeitlhofr J. Clinical significance of autoimmune thyroid disease in myasthenia gravis. Exp Clin Endocrinol Diabetes 2000;108 :63-5.

(11.) Green ST, Ng JP, Chan-Lam D. Insulin-dependent diabetes mellitus, myasthenia gravis, pernicious anemia, autoimmune thyroiditis and autoimmune adrenalitis in a single patient. Scott Med J 1988; 33: 213-4.

(12.) Nishida H, Tanaka Y, Nakao N, Ibi T, Sahashi K. A case of myasthenia gravis following sarcoidosis and Hashimoto s Thyroiditis. Rinsho Shinkeigaku 2000; 40: 797-800.

(13.) Asakawa H, Kashibara T, Fukuda H, Yamamoto M. A patient with thymoma and four different organ-specific aotuimmune diseases. Neth J Med 2002; 60: 266-8.

(14.) Tienboon P, Unachak K. Iron deficiency anaemia in childhood and thyroid function. Asia Pac J Clin Nutr 2003;12:198-202.

(15.) Chen SH, Hung CS, Yang CP, Lo FS, Hsu HH. Coexistence of megaloblastic anemia and iron deficiency anemia in a young woman with chronic lymphocytic thyroiditis. Int J Hematol 2006; 84: 238-41.

Fusun Mayda Domac, Handan Misirli, Ece Boylu *, Beratgul Ozer

Haydarpasa Numune Training and Research Hospital, Department of 1st Neurology, Istanbul, Turkey

* GATA Haydarpasa Training Hospital, Department of Neurology, Istanbul, Turkey

Address for Correspondence: Fusun Mayda Domac, MD, Haydarpapa Numune Training and Research Hospital, Department of 1st Neurology, lkkodar, Turkey Phone: +90 216 455 67 58 Gsm: +90 532 282 59 50 E-mail: fusundomac@yahoo.com.tr Recevied: 08.04.2009 Accepted: 06.08.2009

Turkish Journal of Endocrinology and Metabolism, published by Galenos Publishing. All rights reserved.
Table 1. Pathological blood parameters

                                       Serum levels of the patient

Anti-acetylcholine receptor antibody        7 nmol/L [up arrow]
Anti-thyroglobulin antibody              211.8 IU/mL [up arrow]
Thyroid peroxidase antibody              356.4 IU/mL [up arrow]
Thyroid stimulating hormone              8.21 uIU/mL [up arrow]
Free-T4                                   1.03 ng/dL [down arrow]
Hemoglobin                                 10.4 g/dL [down arrow]
Iron                                        18 ng/dL [down arrow]
Total iron binding capacity            417 [micro]g/dL [up arrow]
Ferritin                                  7.28 ng/dL [down arrow]
Total cholesterol                          266 mg/dL [up arrow]
Trygliseride                               191 mg/dL [down arrow]
LDL cholesterol                             174mg/dL [up arrow]
VLDL cholesterol                             38mg/dL [up arrow]
HbA1c                                             5.53
Insulin (postprandial)                  87 [micro]U/mL [up arrow]

                                             Normal levels

Anti-acetylcholine receptor antibody           <0.6 nmol/L
Anti-thyroglobulin antibody                   0-115 IU/mL
Thyroid peroxidase antibody                    0-34 IU/mL
Thyroid stimulating hormone                  0.27-4.2 IU/mL
Free-T4                                      1.8-4.6 ng/dL
Hemoglobin                                   11.7-15.5g/dL
Iron                                          25-145 ng/dL
Total iron binding capacity                  187-395 [micro]g/dL
Ferritin                                      13-150 ng/dL
Total cholesterol                            110-200 mg/dL
Trygliseride                                   <150 mg/dL
LDL cholesterol                                <160mg/dL
VLDL cholesterol                                <30mg/dL
HbA1c                                            %<6.0
Insulin (postprandial)                    2.6-24.9 [micro]U/mL

Table 2. Results of oral glucose tolerance test

OGTT                g/I

Glucose (fasting)   0.86
30 minute           1.37
60 minute           1.21
120 minute          1.09
180 minute          0.46 [down arrow] *
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