Continued part 1, part 2 of ebook Clinical rounds in endocrinology (Volume I - Adult endocrinology) provide readers with content about: extra-thyroidal manifestations of autoimmune thyroid disease; thyroid disorders during pregnancy; disorders of mineral homeostasis; hyperparathyroidism; osteoporosis; type 1 diabetes mellitus;... Please refer to the part 2 of ebook for details!
Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 11.1 11 Case Vignette A 60-year-old man presented with history of weight loss, palpitations, and tremor for the last months He also had protrusion of both eyes, which was gradually progressive For the last weeks, he developed retrobulbar pain and redness of both eyes There was no history of diplopia or visual loss He denied history of smoking On examination, his pulse rate was 128/min, regular, BP 140/60 mmHg, and had diffuse, soft, grade I goiter He had proptosis (24 mm) of both eyes with marked chemosis and swelling of eyelids with a clinical activity score of 6/7 and severity score moderate to severe Ocular movements were restricted in all the quadrants bilaterally He had normal visual acuity and color vision, and there was no papilledema Pupillary reflexes were normal He had no evidence of dermopathy or acropachy On investigation, serum T3 was 3.4 ng/ml (0.8–1.8), T4 20.4 μg/dl (4.8–12.6), and TSH 0.001 μIU/ml (0.45–4.2), and TPO antibodies were 200 IU/ml (5 mm) with sparing of tendons and increased volume of retro-orbital tissue without any evidence of apical crowding He was diagnosed to have Graves’ disease with active and moderate to severe thyroid-associated orbitopathy He was advised artificial teardrops, sunglasses with side cover and elevation of head end of bed while sleeping He was initiated on carbimazole 30 mg once a day and propranolol 40 mg thrice daily along with pulse methylprednisolone therapy A week later, he had improvement in clinical activity score (4/7) and symptoms of toxicosis Liver function tests were monitored periodically and were within normal limits Repeat thyroid function test at weeks revealed serum T3 2.2 ng/ml, T4 14.6 μg/dl (4.8–12.6), and TSH 0.001 μIU/ ml (0.45–4.2) He was continued with 30 mg carbimazole and propranolol A cumulative dose of 4.5 g methylprednisolone was administered over a period of 12 weeks Subsequently at months, he had resolution of clinical symptoms and normalization of T3 and T4; however, TSH remained suppressed Dose of carbimazole was decreased to 20 mg per day, and β-blockers were discontinued His clinical activity score (CAS) improved further (2/7); proptosis remained static, and there was no © Springer India 2015 A Bhansali, Y Gogate, Clinical Rounds in Endocrinology: Volume I - Adult Endocrinology, DOI 10.1007/978-81-322-2398-6_11 249 250 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease deterioration in vision during follow-up He was continued on carbimazole for years with close monitoring of thyroid function tests Later, he was subjected to decompressive eye surgery for severe proptosis after months of consistently inactive disease On follow-up, he is doing fine a b c Fig 11.1 (a) Clinically active, moderate–severe TAO in a patient with Graves’ disease (b) CT scan of the orbit showing thickening of extraocular muscles (medial rectus) and sparing of tendons with bilateral proptosis (c) Improvement in clinical activity score and proptosis following pulse methylprednisolone therapy 11.2 Stepwise Analysis Long duration of symptoms of thyrotoxicosis, presence of diffuse goiter and orbitopathy are consistent with the diagnosis of Graves’ disease Further, he had CAS of 6/7 which indicates the presence of active (CAS ≥3/7) thyroid-associated orbitopathy Disease was moderate to severe as proptosis was >20 mm, and there was severe 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 251 soft tissue involvement He had marked restriction of eyeball movements (frozen globe) without any cranial nerve involvement Orbital CT was done to exclude the presence of orbital apex syndrome as he had severe TAO Imaging features were consistent with the diagnosis of TAO (extraocular muscle belly thickening with tendon sparing) without any evidence of dysthyroid optic neuropathy Thyroid function test confirmed the diagnosis of thyrotoxicosis, and he was started on carbimazole and propranolol Presence of active eye disease suggests ongoing inflammation and merits glucocorticoid treatment Surgery is indicated only in patients with dysthyroid optic neuropathy, corneal breakdown, and globe subluxation who not respond to glucocorticoids within 1–2 weeks He was started on methylprednisolone therapy The reduction in CAS from 6/7 to 4/7 within a week’s time suggests significant response to therapy and predicts favorable outcome Further, absence of smoking in the index case appears to be complimentary for the long-term outcome It is important to monitor liver function test as pulse methylprednisolone therapy can rarely induce fatal hepatic failure Further, thyroid function test was closely monitored in the index case as hypothyroidism may lead to worsening of TAO He was continued on antithyroid drugs for years Rehabilitative surgeries are undertaken once the eye disease is consistently inactive for months; therefore, the patient was subjected to decompressive eye surgery after months of persistently inactive eye disease 11.3 Clinical Rounds What are the extra-thyroidal manifestations of autoimmune thyroid diseases? The extra-thyroidal manifestations of autoimmune thyroid disease include thyroid-associated orbitopathy, infiltrative dermopathy, and thyroid acropachy What is thyroid-associated orbitopathy? Thyroid-associated orbitopathy (TAO) is an autoimmune disorder characterized by immuno-inflammation of the extraocular muscles and retro-orbital tissue, and invariably occurs in the presence of autoimmune thyroid disease, irrespective of presence of hyper-, hypo-, or euthyroidism Autoimmune thyroid disease is the prerequisite for the development of TAO as evidenced by consistent presence of antithyroid antibodies (TRAbs, TPO, or anti-Tg antibodies) in these patients and absence of TAO in patients with thyroid aplasia and toxic multinodular goiter Ninety percent of patients with TAO have hyperthyroidism, while 6–10% are euthyroid, and 3–4% have hypothyroidism Hyperthyroid or euthyroid patients with TAO commonly have Graves’ disease, while those with hypothyroidism have Hashimoto’s thyroiditis or rarely Graves’ disease with blocking antibodies TAO associated with hyperthyroidism is usually moderate to severe, bilateral, and symmetrical, while TAO with hypothyroidism is milder and tends to be asymmetrical 252 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease Is there any difference between Graves’ orbitopathy and thyroid-associated orbitopathy? Yes The term thyroid-associated orbitopathy denotes orbitopathy associated with autoimmune thyroid disease, either Graves’ or Hashimoto’s thyroiditis, while Graves’ orbitopathy is a specific term for orbitopathy associated with Graves’ disease Is Graves’ ophthalmopathy and Graves’ orbitopathy synonymous? No Although the terms Graves’ ophthalmopathy and Graves’ orbitopathy are used interchangeably, they are not synonymous The ocular manifestation in patients with thyroid disorder is due to involvement of retro-orbital tissue and ocular muscles Therefore, the term “Graves’ ophthalmopathy” is a misnomer as it does not address orbital involvement in the disease process Hence, the appropriate term should be Graves’ orbitopathy Why is the onset of TAO not always synchronous with development of hyperthyroidism? Onset of TAO can precede, follow, or may occur concurrently with hyperthyroidism in patients with Graves’ disease Therefore, TAO and hyperthyroidism were considered as different diseases in the past However, patients with euthyroid TAO often have subtle thyroid function abnormalities, and there is a qualitative correlation between the presence of TRAbs and the occurrence of TAO and thyrotoxicosis Hence, it has been reconciled that both TAO and hyperthyroidism are spectrum of same autoimmune thyroid disease Differential responsiveness of orbital fibroblast to circulating TRAbs as compared to thyroid follicular cells, variability in TSH receptor density and affinity in the target tissue, and co-expression of IGF1 receptor along with TSH receptor in the orbital fibroblast may explain the discordance between the onset of TAO and hyperthyroidism in patients with Graves’ disease What are the extra-thyroidal effects of TSH? TSH regulates growth and development of thyroid gland and stimulates thyroid hormone synthesis by upregulation of expression of sodium iodide symporter, activation of thyroid peroxidase and augmentation of thyroglobulin proteolysis In addition to its thyrotrophic effects, TSH has various extra-thyroidal actions It acts as a lipolytic hormone by activating hormone-sensitive lipase TSH receptors are present on osteoblasts and osteoclasts, and TSH has been shown to inhibit bone remodeling TSH receptors are also expressed in ovary and testes, and it may play a role in the development of multicystic ovaries and macroorchidism in primary hypothyroidism In addition, the presence of TSH receptors on orbital fibroblasts, extraocular muscles, adipocytes, and dermal fibroblasts explains its role in the pathogenesis of TAO and dermopathy 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 253 What are the risk factors for the development of Graves’ orbitopathy? Risk factors for Graves’ orbitopathy include old age, male sex, severe thyrotoxicosis at presentation, large goiter, persistent elevation of TRAbs, smoking, and use of radioiodine In addition, use of drugs like pioglitazone may worsen TAO due to orbital adipocyte proliferation What are the characteristic features of Graves’ orbitopathy? Clinically evident orbitopathy is seen in nearly one-third of patients with Graves’ disease, although imaging may show evidence of orbitopathy in almost all However, sight-threatening orbitopathy occurs in only 3–5% of patients Graves’ disease is highly prevalent in women with a female to male ratio of 10:1, while the ratio of female to male for Graves’ orbitopathy (GO) is narrowed to 2:1 It is usually bilateral, but may be asymmetrical in 10–15% and is rarely unilateral Further, GO may precede, accompany, or follow hyperthyroidism The most common muscles involved in GO are inferior rectus and medial rectus and are characterized by involvement of muscle belly with sparing of tendons What is the natural history of Graves’ orbitopathy? Natural history of Graves’ orbitopathy in a treatment-naive patient is characterized by an initial active phase of 6–12 months, followed by a plateau for 1–3 months and eventually an inactive phase lasting 1–2 years The clinical activity of disease progressively declines over time; however, parameters of severity like exophthalmos, diplopia, and lid retraction may not remit completely Further, once disease remits it is unlikely to relapse 10 What is clinically active TAO? Pain on eye movement, spontaneous retro-orbital pain, conjunctival and eyelid injection, and swelling of eyelid, conjunctiva, and caruncle are the parameters used for the assessment of clinical activity of TAO A score of ≥3/7 is considered to be clinically active and requires immunosuppressive therapy 11 How to assess severity score in a patient with TAO? Lid retraction, soft tissue involvement, proptosis diplopia, corneal exposure, and optic nerve dysfunction are the parameters used for assessment of severity of TAO Mild TAO is defined as presence of lid retraction 3 mm above the reference range, and inconstant or constant diplopia The presence of corneal breakdown and optic nerve dysfunction indicates sight-threatening TAO 254 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 12 What is the difference between clinical activity score and severity score? The objective parameters for the assessment of TAO include clinical activity score (CAS) and severity score (SS) Clinical activity score represents acute inflammation in the orbit with extension into anterior region of eye Clinical activity is the result of cytokine-mediated injury to retro-ocular and ocular tissues, and venous outflow obstruction Severity score represents anatomical/ functional aberrations and is due to retro-orbital fibroblast and adipocyte proliferation and thickening of extraocular muscles along with glycosaminoglycan deposition in a closed retro-orbital space and thereby compressing neighboring tissues including optic nerve Patients with clinically active disease (CAS ≥3/7) requires immunosuppressive therapy, while those with moderate–severe TAO and CAS 20 mm is considered as moderate–severe proptosis In TAO, proptosis is due to proliferation of retro-orbital fibroblasts and adipocytes along with deposition of glycosaminoglycans (GAG) in the retrobulbar space and extraocular muscles In addition ocular muscle tone, that normally retracts the globe, is lost in TAO due to deposition of GAG in extraocular muscles leading to proptosis 16 What is “frozen globe”? “Frozen globe” is a clinical entity in which there is restriction of movements of eyeball in all quadrants It commonly occurs due to ocular cranial nerve 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 255 involvement However, in patients with Graves’ disease, “frozen globe” can occur due to involvement of extraocular muscles per se without any cranial nerve palsy 17 What are the causes of ptosis in patients with Graves’ disease? Ptosis is uncommon in patients with Graves’ disease, and if present, the patient should be evaluated for myasthenia gravis Other causes include superior orbital fissure syndrome, orbital apex syndrome, and rarely mechanical failure of levator palpebrae superioris due to long-standing severe proptosis Ptosis can occur either due to involvement of the Muller’s muscle or levator palpebrae superioris, innervated by sympathetic nerve fibers and 3rd cranial nerve, respectively Ptosis is usually mild with sympathetic nerve involvement, whereas it is severe with oculomotor nerve palsy 18 What is superior orbital fissure syndrome? Superior orbital fissure is a passage for oculomotor, trochlear, and abducens nerves, ophthalmic branch of trigeminal nerve, inferior and superior ophthalmic veins, and sympathetic fibers Superior orbital fissure syndrome (SOFS) is characterized by ptosis, proptosis, ophthalmoplegia, fixed and dilated pupil, and sensory loss involving upper eyelid and forehead The close differential diagnosis of SOFS is orbital apex syndrome It shares all the features of SOFS, and in addition, there is visual loss due to optic nerve involvement as optic nerve passes through optic canal which lies in close proximity to superior orbital fissure 19 What are the causes of vision loss in patients with thyroid-associated orbitopathy? Causes of vision loss in patients with thyroid-associated orbitopathy are exposure keratitis with severe corneal involvement and dysthyroid optic neuropathy either due to optic nerve compression or stretching of optic nerve 20 What is dysthyroid optic neuropathy? Dysthyroid optic neuropathy (DON) is characterized by reduced visual acuity, loss of color vision, visual field defects, papilledema, relative afferent pupillary defect, and apical crowding on imaging Optic neuropathy is caused by compression of optic nerve due to crowding of retro-orbital tissue and thickened extraocular muscles at the apex (orbital apex syndrome) and/or stretching of optic nerve either due to severe proptosis or subluxation of the globe This is an important cause of visual loss in patients with GO and is an urgent indication to initiate pulse methylprednisolone therapy (1 g intravenous for consecutive days) If there is no improvement in optic nerve function after 1–2 weeks of glucocorticoid therapy, orbital decompression is recommended Orbital radiotherapy is not recommended as a monotherapy in the management of DON; however, it may be used as an adjunct to glucocorticoids 256 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 21 How does smoking exacerbate thyroid-associated orbitopathy? Smoking is associated with increased incidence of TAO, severe eye disease, poor response to therapy, and risk of worsening of TAO post-radio-ablation Smoking exacerbates TAO by causing local hypoxia and increased free radical generation resulting in fibroblast proliferation and increased deposition of glycosaminoglycans In addition, increased production of interleukin-1 in smokers has been shown to induce orbital adipogenesis and may worsen orbitopathy Therefore, complete cessation of smoking is recommended in all patients with Graves’ disease 22 What are the indications of orbital imaging in a patient with thyroidassociated orbitopathy? Patients with unilateral or asymmetrical proptosis, clinically suspected DON, euthyroid/ hypothyroid orbitopathy, and TAO associated with ptosis should undergo orbital imaging In addition, patients who are planned for rehabilitative surgery need imaging for anatomical details of the orbit Lastly, in the presence of atypical clinical features, imaging must be done to exclude alternative diagnosis, e.g., orbital tumors, orbital myositis, orbital mycosis, or granulomatous infiltrative disease of the eye 23 What are the imaging characteristics of thyroid-associated orbitopathy? Imaging modalities available for detection of thyroid-associated orbitopathy (TAO) are A/B mode ultrasonography, CT scan, and MRI MR imaging is the best available modality for the detection of TAO Imaging features of TAO include proptosis, thickening of extraocular muscles (>5 mm) with sparing of tendons (Coca-Cola bottle sign), increased retro-orbital fat, intracranial fat prolapse, and apical crowding Inferior and medial recti are the most common muscles to be affected, although any ocular muscle can be involved Tendon sparing is due to decreased expression of TSH receptors over the tendons as compared to belly of the muscle Intracranial fat prolapse is a surrogate evidence of raised retro-orbital tension 24 What are the indications for glucocorticoids in the management of thyroidassociated orbitopathy? The indications for glucocorticoids in the management of thyroid-associated orbitopathy are clinically active disease and dysthyroid optic neuropathy 25 How to treat clinically active thyroid-associated orbitopathy? Clinically active TAO is defined as CAS ≥3/7 and mandates immunosuppressive therapy Glucocorticoids are the drug of choice and intravenous therapy is preferred over oral therapy The effect of intravenous therapy is dramatic and sustained with higher response rate (77% vs 51%), better tolerance, and reduced risk of Cushing’s syndrome The preferred regimen is pulse therapy 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 257 with intravenous methylprednisolone, administered over a period of 12 weeks with a dose schedule of 500 mg weekly for weeks followed by 250 mg weekly over the next weeks with a cumulative dose of 4.5 g Rarely, fulminant hepatitis may occur with pulse methylprednisolone therapy; therefore, liver function tests should be monitored Alternatively, oral prednisolone may be administered at a dose of mg/kg/day for 4–6 weeks and tapered over the next 4–6 weeks If there is no response to steroids after months of therapy, other treatment options like rituximab, azathioprine, cyclosporine, etanercept, somatostatin analogues, and immunoglobulin may be considered However, data with the use of these drugs is scanty and not encouraging Orbital radiotherapy is another option available for the management of TAO a b Fig 11.2 (a) Unilateral active disease (CAS 7/7) with keratitis in a patient with TAO Note the proptosis in other eye with CAS 0/7 (b) Posttreatment image of the same patient showing marked reduction in CAS of the right eye to 1/7 along with corneal opacity 26 How to treat mild TAO with CAS 2/7? Thyroid-associated orbitopathy with mild severity is treated with artificial tears, dark protective glasses with side cover and use of prism, if diplopia is present In addition, elevation of head end of the bed at nighttime improves disease activity by reducing venous congestion As the disease is clinically inactive (CAS