MARINE-LENHART SYNDROME. CASE REPORT AND LITERATURE REVIEW

Transcription

1 Case Report MARINE-LENHART SYNDROME. CASE REPORT AND LITERATURE REVIEW Elena Balmes 1, Alice Burcea 1, Mariana Belgun 1, Daniela Alexandrescu 1, C. Badiu *,1,2 1 Institute of Endocrinology, University Clinical Department: Thyroid related disorders, 2 Carol Davila University of Medicine and Pharmacy, Bucharest Graves disease and toxic nodular goiter both cause thyrotoxicosis by different pathophysiological mechanisms. Rare cases associates both etiologies are undertaken by the diagnosis of Marine-Lenhart syndrome. A woman aged 38, with Graves unilateral ophthalmopathy and a solitary, echo-dense thyroid nodule, developed thyrotoxicosis within the following 3 months. The diagnosis was certified by suppressed TSH (0.002 miu/l), high ft4 (5.6 ng/ml) associated with elevated TRAb (3.5 IU/L), moderately elevated TPOAb (63.1 IU/mL) and ATGl (248 IU/mL). The thyroid radioiodine scan revealed a solitary hot nodule in the left lobe with an elevated radioiodine uptake. Methyl prednisolone was started by oral and pulse therapy, with stabilization of ophthalmopathy within 5 months. After four months with antithyroid drug therapy followed by radioiodine (25 mci 131 I), the thyroid scan revealed diffuse radioiodine uptake. Nine months after radioiodine therapy, the patient was in clinical and biochemical hypothyroidism and substitutive therapy was instituted. A broad literature review suggested that in such rare cases, underlying autoimmune mechanisms might be involved in the development of thyroid nodules with variable function and proliferation activity. Key words: Autonomous thyroid nodule, Graves ophthalmopathy, TRAb, Marine- Lenhart syndrome. INTRODUCTION The most common causes of hyperthyroidism are autoimmunity and autonomous thyroid tissue. Among the most frequent forms of thyrotoxicosis, Graves disease includes diffuse goiter, hyperthyroidism, ophthalmopathy as well as other autoimmune associated disorders. The mechanism involved is stimulation of TSH receptor by specific antibodies, as a consequence of cellular autoimmune disturbances. On the contrary, the autonomous thyroid tissue is dependent upon iodine input while extranodular thyroid function depends upon pituitary-thyroid feed-back system. Such nodules might be multiple or single, hot or cold on isotope uptake and are determined by constitutive mutations on TSH receptor or other pathways of controlling the thyrocyte division. Association between Graves disease and thyroid nodules occurs in *Correspondence to: Corin Badiu, MD, Department of Thyroid-Related Disorders, Institute of Endocrinology, Bucharest, , Romania, badicrin@yahoo.co.uk. Acta Endocrinologica (Buc), vol. III, no. 2, p ,

2 Elena Balmes et al %, mostly with cold nodules (1), but a single toxic hot nodule can also be associated with the Graves disease, defining the Marine-Lenhart syndrome (2). Thyroid nodules are present in up to 30% of Graves thyroids. Most of the nodules are cold, benign and multiple (3), but there are 1-2.5% associated with hot autonomous nodules (2). They are caused by mutations in the thyrocytes proliferation control mechanisms, mostly in mutational hot spots of the TSH receptor loops (4). The main causes of the mutations are suspected as radiations but also the low iodine diet can facilitate propagation of spontaneously occurring mutations, through high-normal TSH values. However, once the hot nodules appeared, they are TSH independent in secretion and proliferation. Therefore, a radical attitude (surgical or radioiodine) is often recommended. CASE REPORT A woman aged 38, from an endemic area with insufficient iodine supply, was admitted in the department of Thyroid disorders in August 2005 for right eye proptosis and lid lag, tremor, high heart rate, weight loss (6 kg in the last month), insomnia, anxiety, asthenia, symptoms progressively installed in the previous 3 months (since May 2005). At admission, she came with several data performed in July. A thyroid ultrasound scan showed a goiter associated with two hypoechoic nodules, one of about 7/10/7 mm in the right lobe and the second of 32/49/30 mm in the left. Table 1 shows the biochemical data. Thyroid hormonal assessment suggested hyperthyroidism, due to high ft4 values 2.49 ng/ml (N= 0.8-2) and diminished TSH 0.25 miu/l (N= ). Specific thyroid autoimmunity was absent, as ATPO=31.5 IU/mL (N<50) and ATgl 248 IU/mL (N< 325 IU/mL) were in the normal range. Table 1. Thyroid function and morphology Parameters July 2005 Aug 2005 Oct Jan Apr Aug 2006 Normal TSH miu/l FT 4 ng/ml (T4) ATPO IU/ml <12 ATgl IU/mL <34 TRAb IU/L <0.55 <1 US Thy scan I 131 Thy scan RAIU 2h/24h 14/42-22/55 11/ /35 Hormonal values for thyroid function using TSH and ft4 expressed innitial hyperthyroidism followed by primary hypothyroidism postradioiodine, while thyroid autoimmunity was in agreement with Graves disease: high TRAb and ATPO; (-) =not done. Thyroid ultrasound (US) showed nodule (+) and I 131 RAIU scan innitialy showed a hot nodule which dissapeared after I

3 Marine Lenhart syndrome The personal medical history showed 2 extrauterine pregnancies with bilateral salpingectomy and uterine leiomioma. The objective examination showed a normoponderal patient (BMI = kg/m 2 ) with unilateral exophthalmos at right eye, lid lag, fine, warm, moist skin, tremulousness, with normal cardiovascular parameters (BP=110/70 mm Hg, AV= 80b/min) no specific abdominal or urogenital abnormalities. Thyroid was multinodular, predominant at the left lobe site, mobile, painless, without lymph nodes or compression phenomena. In addition, a mammary node of 2.5 cm can be felt in the supero-lateral quadrant of the right breast. Biological and hematological data were in normal range. In August 2005, thyroid hormones (ft4= 5.6 ng/ml) and suppressed TSH (0.002 miu/l) confirmed progression of hyperthyroidism. However, evaluation of specific autoimmune antibodies TRAb showed high values, of 3.5 UI/L, confirming the diagnosis of Graves disease. Figure 1. Thyroid scinti scan before radioiodine treatment, showing a hot nodule on the left thyroid lobe. Radioiodine uptake was high (14% at 2h and 42% at 24h), while the scan showed a hot nodule on the left thyroid lobe, without any uptake in the rest of the thyroid (Fig. 1). Thyroid ultrasound shows a multinodular goiter, with several small inhomogeneous nodules of 4/7 mm, on the right thyroid lobe and isthmus. The left lobe is occupied by a big thyroid adenoma (40/26 mm), which is not able to be included completely in the ultrasound field, with cystic areas inside. In addition, several small lymph nodes of 7-8 mm are present on the left side (Fig. 2 a-c). The ophthalmologic exam showed left eye lid lag and mild exophthalmia (OD mm, OS 15.5.mm) without motility or vision changes. Under these circumstances, the diagnosis was of Left thyroid lobe toxic adenoma and Graves ophthalmopathy. Antithyroid drug therapy was started with Metimazole 40 mg/day and pulse therapy with Methyl Prednisolone 500mg/day, associated with beta blockers, tranquilizers, gastric protectors, with rapid 203

4 Elena Balmes et al. improvement of symptoms and exophthalmia with 2 mm. The steroid therapy was continued orally, from 32 mg Methyl Prednisolone to 24 mg /day after 14 days and further reduction with 8 mg every 2 weeks. In addition, metimazole was continued at a rate of 20 mg/day. After 6 weeks, the clinical thyroid status was insignificantly changed; therefore, the Metimazole was increased at 40 mg/day and Methyl prednisolone continued at 8 mg/day. Figure 2. Ultrasonographic aspects before (a) and after (b, c) radioiodine treatment. Note the similar appearance of the nodular left lobe (Lob stg) and the micronodular right lobe (LDT). In October 2005, the thyroid function (TSH=1.28 miu/l) and exophthalmia were under control; therefore a I 131 treatment was decided at a dose of 25 mci. After radioiodine administration, metimazole was restarted at a dose of 5 mg/day. Other 3 months post I 131, the thyroid function is deficient, TSH increased and the RAIU was normal while the I 131 scan shows uptake in the whole formerly suppressed gland, while the left nodule is partially cold (Fig. 3). Thyroid ultrasound scan describes the same inhomogeneous left nodule (Fig. 2). At 6 months post radioiodine, the functional thyroid status is obviously hypothyroid and TSH was 12.8 miu/l, when 50 µg/day T 4 was started. Three months later, she was euthyroid on thyroxin 50 µg/day, with TSH at 1.4 miu/l, ft 4 at 1.21 ng/ml, but the antithyroid peroxidase antibodies were high (904.1 IU/mL). ATgl (167.8 IU/mL) and TRAb (<0.55 IU/L) were normal. A global evolution of therapeutic approach is presented in Table 2. In addition, the patient was submitted to mammary surgery for the right nodular mass which was documented as fibroadenoma. Nowadays, the case is under clinical, thyroid ultrasound and biochemical observation for 6 months, with a stable thyroid and eye disease. 204

5 Marine Lenhart syndrome Figure 3. Thyroid scinti scan after radioiodine treatment. Table 2. Therapeutic approach Parameters July 2005 Aug 2005 Oct Apr Aug 2006 Treatment 20 mg TMZ 40 mg TMZ 5 mg TMZ 100 µg LT 4 50 µg LT 4 ATS TMZ 40-5 mg/day, 5.5 months LT µg/day LT 4 Systemic steroid MPN 32 mg MPN 32 mg MPN 32 mg - - MPN 3 g i.v., than 32-4 mg/day, 5 months Radioiodine 25 mci 131 I TMZ: thyamazole, MPN: Methylprednisolone, T 4 thyroxine DISCUSSION Graves disease can be associated with thyroid nodules in a surprisingly high proportion (25-30%), as proved both by medical and surgical studies (Table 3). The main mechanism of disease involves both cellular (decrease of T suppressor and increase of T helper cells) and humoral autoimmunity, with high TSH receptor (TRAb) and thyroid peroxidase antibodies (TPOAb). In Graves disease, thyroid is out of TSH control, stimulatory immunoglobulin being the trigger for thyrocytes proliferation and goiter, as well as for hyperthyroidism. A similar autoimmune mechanism is proved for Graves ophthalmopathy, with stimulatory effects upon orbit fibroblasts and adipocytes, which eventually affects 205

6 Elena Balmes et al. ocular muscles and decide the degree of proptosis. The thyroid cells are the source of trigger for auto-antibodies (TSH receptor) as well as the target for TRAb, while the main source, -intrathyroid lymphocytes- is located within the thyroid. However, additional extra thyroid sources for antibodies are documented, the cervical lymphatic ganglia and bone marrow (5). Between % Graves disease patients are positive for TRAbs, failure in TRAbs showing a possible wrong initial diagnosis, as in non-autoimmune toxic familial goiter. Table 3. Epidemiological studies for patients with multinodular goiter and Graves disease, addressing the relation between autoimmunity and autonomous nodules. Author et al (M or S), ref.nb. Number of cases Nodules in % Cold /Hot % Autoimmune markers % Lamata et al. (S), (3) NA NA Mishra et al. (S), (6) NA NA Kraimps et al. (S) (1) NA NA Kraimps et al. (S) (7) NA NA Carnell et al. (M) (8) / Cantalamessa et al. (M) (9) NA NA NA - not available; M - Medical management; S - Surgical management Thyroid lymphocytes are early evidence for Graves disease, if using FNAB and are correlated with TRAb blood levels. Antithyroid drug therapy can reduce the intrathyroid lymphocytes as well as TRAb the blood levels; moreover, if TRAb levels remain high after antithyroid drug therapy, the relapse rate is high. On the contrary, long remissions were observed after a long term therapy with antithyroid drugs, which parallels the decrease of thyroid cytokine synthesis, decrease of blood TRAb levels and thyroid lymphocyte infiltration (10). Concomitant positive TPOAb and TglAb shows an underlying autoimmune thyroiditis and double the risk for clinical relevant autoimmune thyroid disease (11). Recent data show a link between immune abnormalities and CTLA4 gene (12). Thyroid nodules are frequent and express a wide range of various disorders. Most of the reports mention thyroid nodules in relation to iodine deficiency, but thyroid malignant lesions are also extremely important. Clinical, ultrasound and scintigraphic behavior are important details and prognostic factors, but pathology brings the main evidence for the final diagnosis and treatment. Mechanisms involved in the development of thyroid nodules are mainly related to mutations. There are more than 30 oncogenes involved in the appearance and development of thyroid nodules, such as c-myc, h-ras, BRAF and retptc (13), but also TSH receptor and gsp. There were considerable debates concerning the role of TSH in the development of thyroid nodules. At the beginning, mutated thyrocytes seems as dependent on TSH as normal thyrocites are, while after the development of a neoplasia, this dependence is much lower. However, thyroid cancer patients are kept under a low 206

7 Marine Lenhart syndrome TSH level in view of this dependence. Whether TSH receptors antibodies can act in nodular Graves disease as a trigger / promoter of development of thyroid neoplasia, current data are controversial. Both disorders can coexist in the same gland, and immune cells are defending every tissue, even for mutated cells from that tissue. Differentiated thyroid cancer is present in 3-10% of Graves patients, and Belfiore et al consider that thyroid cancer is even more aggressive in Graves patients (14). Concerning the rare association between Graves disease and thyroid hot nodules, if the trigger mechanisms involved TRAb, we would expect a higher incidence with TRAb titer, which was not found. Treatment of Graves ophthalmopathy was performed according to the last Eugogo consensus (15, 16), with pulse therapy followed by oral steroids. Treatment of thyroid nodule could have been surgery or radioiodine. Arguments for surgery would have been coexistence of multinodular goiter with a hot macronodule. However, the patient preferred the treatment with radioiodine. Since the 1970 s radioiodine treatment has largely replaced surgery, which is nowadays reserved for children and for patients with exceedingly large goiters. No more than four years after its discovery in 1938, iodine-131 was introduced for the treatment of hyperthyroidism and thyroid cancer. The molecular processes explaining the principles of radioiodine treatment remained unresolved until the genetics and the functionality of the human sodium-iodide symporter (hnis) were recently identified. The thyroid s unique capacity to store iodide, and also radioiodine INa, makes it a natural target for radioiodine therapy (16). For more than 60 years radioiodine has been administered to patients with thyroid diseases. Radioiodine is a safe treatment form for all patients with primary hyperthyroidism. The prevailing dosage strategies for patients with nodular thyroid diseases are rather successful. For patients with Graves disease, however, the therapy outcome is not easily predicted unless ablative doses of radioiodine are being applied. Ablation, however, cures one disease (hyperthyroidism) at the cost of another (hypothyroidism). With non-ablative strategies, both recurrent hyperthyroidism and hypothyroidism are frequently observed treatment outcomes. This empirical fact has led to different opinions with regard to the preferred radioiodine dosage strategy for patients with Graves disease. Nonetheless, the efficacy of prevailing dosage protocols is hardly questioned. This may be illustrated by a beautifully ironic quote from Galenus: All those who drink from this remedy recover in a short time, except those whom it does not help and who all die. Therefore, it is obvious that it fails only in incurable cases. The radioiodine treatment for hot nodules is the preferred initial treatment for patients with Graves hyperthyroidism in North America. In one analysis it was the most cost-effective treatment. A review of the literature indicates that substantial improvement of the present results might be feasible if more consideration is given to the biological state of our patients at the time of radioiodine (17). In conclusion, Marine Lenhart syndrome is a rare association of two pathogenic mechanisms of hyperthyroidism, with possible coincidence and without evidence of a causal relationship. However, it is a model for diagnosis and management of hyperthyroidism. 207

8 Elena Balmes et al. Acknowledgments: Dr. Andrei Goldstein is gratefully acknowledged for performing the thyroid scan and Mrs. Mariana Purice for performing the thyroid hormone measurements. References 1. Kraimps JL, Bouin-Pineau MH, Mathonnet M, De Calan L, Ronceray J, Visset J, Marechaud R, Barbier J. Multicentre study of thyroid nodules in patients with Graves disease. Br J Surg 2000; 87(8): Charkes ND. Graves disease with functioning nodules (Marine-Lenhart syndrome). J Nucl Med 1972; 13(12): Lamata HF, Sanchez BJ, Artigas Marco MC, Gonzalez GM, Martinez DM. [Graves disease with associated thyroid nodules (nodular Graves disease). Clinical, diagnostic and therapeutic considerations]. An Med Interna 2003; 20(8): Nishikawa M, Yoshimura M, Yoshikawa N, Toyoda N, Yonemoto T, Ogawa Y, Mori S, Tabata S, Tokoro T, Sakaguchi N, Inada M. Coexistence of an autonomously functioning thyroid nodule in a patient with Graves disease: an unusual presentation of Marine-Lenhart syndrome. Endocr J 1997; 44(4): Weetman AP, McGregor AM. Autoimmune thyroid disease: developments in our understanding. Endocr Rev 1984; 5(2): Mishra A, Mishra SK. Thyroid nodules in Graves disease: implications in an endemically iodine deficient area. J Postgrad Med 2001; 47(4): Kraimps JL, Bouin-Pineau MH, Marechaud R, Barbier J. [Basedow's disease and thyroid nodules. A common association]. Ann Chir 1998; 52(5): Carnell NE, Valente WA. Thyroid nodules in Graves disease: classification, characterization, and response to treatment. Thyroid 1998; 8(8): Cantalamessa L, Baldini M, Orsatti A, Meroni L, Amodei V, Castagnone D. Thyroid nodules in Graves disease and the risk of thyroid carcinoma. Arch Intern Med 1999; 159(15): Weetman AP. Graves disease. N Engl J Med 2000; 343(17): Vanderpump MP, Franklyn JA. Thyroid function tests and hypothyroidism. Restoring serum TSH to reference range should be goal of replacement. BMJ 2003; 326(7398): Tomer Y, Greenberg DA, Barbesino G, Concepcion E, Davies TF. CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production. J Clin Endocrinol Metab 2001; 86(4): Ciampi R, Nikiforov YE. RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology 2007; 148(3): Belfiore A, Garofalo MR, Giuffrida D, Runello F, Filetti S, Fiumara A, Ippolito O, Vigneri R. Increased aggressiveness of thyroid cancer in patients with Graves disease. J Clin Endocrinol Metab 1990; 70(4): Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active Graves ophthalmopathy. J Clin Endocrinol Metab 2005; 90(9): Wiersinga WM. Management of Graves' ophthalmopathy. Nat Clin Pract Endocrinol Metab 2007; 3(5): van Isselt JW, van Dongen AJ. The current status of radioiodine therapy for benign thyroid disorders. Hell J Nucl Med 2004; 7(2):