Section 15

Section Editor: Sujit Jha Endocrinology

197. Interpretation of Thyroid Function Tests 202. Evaluation of Non-Diabetic Polyuria Dheeraj Kapoor, Ruchi Kapoor, Abhishek Goyal Indira Maisnam, Soumita Mandal 198. Cognitive Aspects of Hypothyroidism 203. Postgraduate Clinic on Non-Thyroidal Anubha Srivastava, Anurag Varma, Kachnar Varma Illness Syndrome 199. Thyroid Myopathy—An Update Pankaj Kumar Agarwal NS Neki 204. Common Mistakes in Thyroid Disorders 200. Impact of Altered Thyroid Status on Diabetes: Y Bhasker Partners in Metabolic Malfunction 205. Glucocorticoids-induced Osteoporosis Swati Srivastava Saurabh Jain 201. Thyrotoxicosis: Evaluation and Management Manoj Saluja

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Interpretation of Thyroid 197 Function Tests

Dheeraj Kapoor, Ruchi Kapoor, Abhishek Goyal

Abstract Thyroid disorders have various etiologies and presentations. Pertinent treatment needs a conclusive diagnosis and is influenced by variety of coexisting medical conditions. This chapter delineates how to interpret thyroid hormones, referring to various evidence-based clinical guidelines for the management of thyroid disorders. In depth research of relevant literature and evidence-based approach has been taken to simplify interpretation of thyroid hormone levels. Topics addressed include thyroid hormone assays, thyroid antibodies levels, hyper- and hypothyroidism along with thyroid dysfunction in pregnancy.

Introduction available, and hence permitting an accurate diagnosis of thyroid condition to be made in majority of case. Thyroid is a small butterfly shaped endocrine organ However, analytical inference still stands a major hurdle. located anteriorly in the lower part of neck. On an average The interpretation of thyroid function tests is generally it weighs around 25–30 g in an adult. It produces the straight forward; through sometimes the reports may seem thyroid hormones, which are released into the blood fairly clear but are in fact misleading. This article aims to stream and then transported to different tissues in the address the interpretation of thyroid functions test. body. They have an effect on each and every cell and organ of the body. Their main function is to maintain homeostasis in various functions ranging from controlling Thyroid-stimulating Hormone the metabolic rate, the muscle mass, digestive functions, TSH is secreted by anterior pituitary and is central to the development of brain, and bone maintenance. negative feedback mechanism for secretion of thyroid Thyroid gland chiefly synthesizes the hormone hormones. It shows a diurnal variance, presenting a peak thyroxine (T4) and small quantity of triiodothyronine soon after midnight and a nadir by late noon, with peak (T3). T3 being the active form with a short half life is values sometimes even twice the value seen in nadir. converted from T4 with removal of an iodine atom mainly TSH may vary in between measurements to the extent of in liver and in small quantities in heart, gut, muscle, and up to 20% without any change in thyroid state.1,2 nerves. The gland is controlled by a feedback regulation TSH is now considered as the first diagnostic test for from the pituitary, which releases thyroid-stimulating assessment of thyroid condition.3 It presents as a foremost hormone (TSH), which in turn is controlled by the irregularity in case of thyroid disorders when the other thyroid-releasing hormone (TRH) released from the test are normal. When TSH is used to confirm patients hypothalamus. with suspected thyroid diseases in an Endocrine clinic it Progress in technology over time has improved carries high sensitivity of up to 98% and a specificity of up the sensitivity and specificity of thyroid function test to 92%. But in cases of mass screening the sensitivity and

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—— Non-thyroidal illness Conditions associated with high risk for thyroid BOX 1 disease in which screening is recommended —— Drugs, e.g., glucocorticoids, dopamine „„ Increased TSH levels— zz All new borns (neonatal screening) —— Primary hypothyroidism zz Those with strong family history of thyroid disease —— Pituitary adenoma (TSH producing)—secondary zz Those having an autoimmune disease, such as type 1 diabetes hyperthyroidism mellitus —— zz Genetic conditions (e.g., Down’s syndrome, Turner’s syndrome) Pituitary resistance to thyroid hormone (TSH zz Past history of neck irradiation unreliable) zz Drug therapies such as lithium and amiodarone —— Generalized thyroid hormone resistance zz Elderly patients —— Old age zz Women over age 35 —— Drugs, e.g., amiodarone zz Pregnant women during the first trimester —— Recovery phase after severe systemic illness zz Women at 6 weeks to 6 months postpartum zz Dyslipidemia zz Atrial fibrillation Thyroid Hormone Assays zz Depression zz Reduced bone mineral density Serum Thyroxine T4 levels are elevated in patients of hyperthyroidism. Hence, in the course of treatment their levels are measured positive predictive value is low due to underlying diseases to ascertain the degree of thyroid dysfunction and titration or health of the individual screened, hence making the of doses of anti-thyroid medication, because serum TSH interpretation of test result problematic. As a routine now, values may remain suppressed for a continued duration value of TSH is considered low when less than 0.1 mU/L during the course of therapy.6 and high when more than 6.5 mU/L. Serum T4 values are also important in diagnosis Using TSH as an ace standard does help to categorize of patients suffering from secondary hypothyroidism. patients in over 95% cases. But, TSH alone can be used Because a case of normal TSH and suppressed T4 should only if the pituitary thyroid axis is intact. In case of pituitary direct the clinical toward a possible diagnosis of secondary diseases (hyperthyroidism secondary to TSH producing hypothyroidism, justifying the assessment of pituitary pituitary adenoma), non-thyroidal illness, HAMA hormone levels for further investigations. antibody, drugs (glucocorticoids, tyrosine kinase inhibitor, octreotide, etc.), lab results can be misleading and difficult Serum Triiodothyronine to interpret. Aberrant TSH levels may persist for up to few Evaluation of T3 levels is not suggested routinely because months even after initiation of thyroid treatment. of its short half life and normal levels of it influenced by the The American Thyroid Association recommends endocrine homeostasis. Despite this it is of values in cases routine screening for thyroid disorders in all adults by of T3 toxicosis, in which patients have low TSH, normal measurement of serum TSH starting from the age of 35 T4, and features of hyperthyroidism. This condition is years and then every 5 years, with more frequent screening observed in a small fraction of patients suffering from 4 in high risk or symptomatic person. The American Graves’ disease. A ratio of T3:T4 > 20 ng/mL is indicative Association of Clinical Endocrinologists recommend of Graves’.6 routine measurement of serum TSH in all women of child bearing age before they conceive or during the first Free Thyroxine and Free Triiodothyronine trimester of pregnancy (Box 1).5 Merely a meagre portion of thyroid hormones circulate Conditions associated with abnormal TSH levels: in free form not bound to protein. These free form of „„ Decreased TSH levels— thyroid hormones are physiologically more important. —— Primary hyperthyroidism Their quantification is of value in conditions where levels —— Pituitary or hypothalamic disease—secondary or of thyroid-binding globulin (TBG) are altered. Levels of tertiary hypothyroidism TBG influence the levels of T3 and T4 in direct proportion

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TABLE 1 Conditions associated with altered TBG6 Thyroid Antibodies Estimation of thyroid antibodies is advisable in altered Increased binding Decreased binding thyroid functions. They help to determine if patient is Oral contraceptives Nephrotic syndrome having an autoimmune thyroid dysfunction. Various Pregnancy Active acromegaly antibodies exist against thyroid antigens. The ones of Neonates Major systemic illness importance include Anti Thyroperoxidase antibody (Anti- Acute intermittent porphyria Genetic factors TPO Ab), antithyroglobulin antibody and TSH receptor Hepatitis, biliary cirrhosis Asparaginase antibody (TSH-RAb). HIV infection Drugs—androgens, large dose glucocorticoids Anti-thyroperoxidase Antibody (Anti-TPO Ab) Drugs—estrogen supplements, tamoxifen Anti-TPO is also known as thyroid microsomal antibodies. They cause hypothyroidism by two distinctive mechanisms. First by blocking the thyroid peroxidase without any change in hormone activity, more TBG falsely thereby hindering the synthesis of T3 and T4 and secondly more T3, T4, and low TBG presenting as falsely low T3 and by antibody dependent cell toxicity and inflammation T4 (Table 1). of thyroid gland.7 Anti-TPO Ab levels facilitate in the diagnosis of subclinical hypothyroidism and helps in Free Thyroxine evaluation of autoimmune thyroiditis. fT4 is performed for optimizing thyroxine therapy in patients of newly diagnosed hyperthyroidism. It is also TSH Receptor Antibody (TSH-RAb) prescribed in diagnosis of secondary hypothyroidism and TSH-RAb may either stimulate of block the TSH receptor. in cases of end organ thyroid hormone resistance. If they stimulate they cause Grave’s disease and associated Conditions associated with decreased fT4: ophthalmopathy. If they act as blocking anti-antibodies 7 „„ Primary hypothyroidism (thyroid hypofunction) they may lead to hypothyroidism. „„ Secondary hypothyroidism (pituitary hypofunction) Measurement of TSH-RAb is helpful in confirming the „„ Tertiary hypothyroidism (hypothalamic hypofunction) cause of hyperthyroidism and radioactive iodine therapy is not an option. This assay if of particular importance in Conditions associated with increased fT4: managing pregnant patients with Grave’s disease as high „„ Graves’ disease concentrations is a fair predictor of fetal and neonatal „„ Plummer’s disease (toxic thyroid adenoma) thyrotoxicosis.8 „„ Early phase of subacute thyroiditis „„ Struma ovarii „„ Thyrotroph hyper function—secondary hyper­ Thyroglobulin thyroidism It is a large glycoprotein, secreted along with the thyroid hormone. Raised thyroglobulin levels is not a reliable Free Triiodothyronine marker or a screening test for thyroid carcinoma; however, fT3 levels are rarely required. it gains importance as an important marker of remaining or recurrent malignancy in patients who undergo total Conditions associated with decreased fT3: thyroidectomy or radioactive thyroid ablation for papillary „„ Critically ill patients or follicular carcinoma. „„ Patients on high dose steroids „„ Patients on beta blockers Thyroid Function in Pregnancy „„ Severe hypothyroidism During pregnancy there is a paradigm shift in level of Conditions associated with increased fT3: thyroid hormones leading to an increase in T4 levels and „„ T3 toxicosis a reciprocal decrease in level of TSH. The reason for this „„ Hyperthyroidism physiological change is linked to—

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„„ Human chorionic gonadotropin has an alpha subunit TABLE 3 ??? Hypothyroidism similar to TSH, which binds to TSH receptor. This Elevated TSH levels with low fT4 suggest a diagnosis of High fT4 Primary Non thyroid illness Secondary leads to an increased production of T4, which gives primary hypothyroidism, primarily autoimmune in nature hyperthyroid or patient on hyperthyroid a negative feedback to the pituitary resulting in but can also be a result of previous surgery or radio iodine thyroxine reduction of TSH.9 ablation of thyroid gland. The prevalence of high TSH with Normal fT4 Subclinical Euthyroid Subclinical „„ Estrogen produced by the placenta leads to increased hyperthyroid hypothyroid 7 secretion of sex hormone binding globulin (SHBG) raised antibody levels is more common in elderly women. Low fT4 Secondary Non thyroid illness Primary by the liver. This SHBG increases secretion of T4 from Raised TSH in presence of normal fT4 indicates hypothyroid hypothyroid thyroid. autoimmune thyroid condition. When TSH levels are Low TSH Normal TSH High TSH „„ Pregnancy being a hypermetabolic state leads to more than 4 μIU/mL but less than 10 μIU/mL without any increased glomerular filtration rate; hence, increased clinical sign, it represents subclinical hypothyroidism. secretion of T4 by thyroid due to augmented Treatment is warranted in this condition in presence elimination by the kidneys. of thyroperoxidase antibody, pregnancy, goitre, or dyslipidemia. TSH levels more that 10 μIU/mL require Detecting Thyroid Dysfunction treatment. There exist an inverse log relationship between TSH and Low or normal TSH usually excludes the diagnosis of T4 levels. Elevated TSH levels indicate hypothyroidism and primary hypothyroidism. However, presence of low TSH low TSH indicate hyperthyroidism.10 Analysis of thyroid and low fT4, low fT3 should indicate toward secondary function test can be a challenge in case of hypothalamic hypothyroidism, most commonly seen in cases of Sick pituitary disease (low TSH, low T4), systemic illness, Euthyroid syndrome. starvation (low TSH, low T3). Thyroxine replacement in hypothyroid patient should be titrated to maintain a TSH of about 2 μIU/mL. Hyperthyroidism Guidelines recommend that test for thyroid function An elevated fT4 and low TSH is indicative of thyrotoxicosis. and changes in dose of thyroxine should not be done Most of the young age group patients with these levels before 6 weeks unless clinically indicated because it presents as Grave’s disease while the elderly are more takes this much time for the body to accomplish reliable prone for nodular thyroid disease. T4 levels. Patients who are less compliant to medication In cases of subclinical hyperthyroidism TSH levels usually have tendency to replenish the dose before the may be borderline suppressed in the presence of normal scheduled visit. This presents as a raised TSH but normal fT3 and fT4. Treatment of subclinical hyperthyroidism is fT4. warranted in the presence of underlying condition like Patients suffering with differentiated thyroid increased age, cardiac condition like atrial fibrillation, cancers are given suppressive doses of thyroxine to 7 recent history of stroke, and osteoporosis. maintain TSH levels below 0.1 μIU/mL to prevent flare Temporary or short lived thyrotoxicosis can be ups. Those who initially had a high risk disease but are presented in the form of viral thyroiditis. Most patients now disease free post-treatment are advised to maintain have a recent history of viral upper respiratory tract TSH levels between 0.1 and 0.5 μIU/mL for at least 5–10 infection. This usually responds to anti-inflammatory years.7,11 medication. Prompt diagnosis of the condition stands as a key to treatment. Sick Euthyroid Syndrome A small subset of patients may present with low TSH and normal fT4 thereby representing T3 toxicosis. In these This is referred as a thyroid-related change that occurs cases measurement of T3 levels is of value. If in case fT3 is during systemic illness in the absence of an intrinsic not raised then fT4 and TSH should be rechecked. thyroid disease. The syndrome is acute, reversible, and High fT4 with normal or raised TSH depicts a T4 to T3 occurs commonly after surgery, starvation and in many conversion defect, or an analysis error. acute febrile illnesses. These changes may be observed During the course of treatment, TSH may remain in up to 75% of hospitalized patients. Any abnormality in suppressed for varied amount of time; in this case fT4 is hormone level is possible, but the most common observed measured every 6–8 weeks to monitor the treatment. abnormality is low fT3.

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TABLE 2 Interpretation of thyroid function test7

TSH fT4 fT3 Thyroid antibodies Normal ↔ ↔ ↔ ↔ Primary hypothyroidism ↑ ↓ ↓ ↑ Subclinical hypothyroidism ↑ ↔ ↔ ↑ Hyperthyroidism ↓ ↑ ↑ ↑ Subclinical hyperthyroidism ↓ ↔ ↔ ↔ Pituitary diseases ↓ ↓ ↓ ↔ T3 toxicosis ↔ ↓ ↔ ↑ Variable ↔ Normal, ↑ High, ↓ Low

Conclusion function tests. 2006. Available from: http://www.british-thyroid- association.org/info-for-patients/Docs/TFT_guideline_final_ Diseases of thyroid gland are common and initial test to be version_July_2006.pdf done for assessment of this condition is serum TSH. fT4 is 4. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association indicated as a second line test, but the reference range for fT4 guidelines for detection of thyroid dysfunction [erratum and TSH are not universal and reference interval provided by appears in Arch Intern Med. 2001;161(2):284]. Arch Intern Med. the lab should be acknowledged. Results of thyroid function 2000;160(11):1573-5. . 5 AACE Thyroid Task Force. American Association of Clinical test are interpreted in light of clinical status of patients: Endocrinologists medical guidelines for clinical practice for the hypothyroid, euthyroid, or hyperthyroid. Subclinical thyroid evaluation and treatment of hyperthyroidism and hypothyroidism. diseases are commonly encountered and present with an Endocrine Prac. 2002;8:457-69. abnormal TSH and normal fT4. Awareness of associated . 6 Kurian ME, Kapoor N. Interpretation of thyroid function tests. conditions can serve as a guide for further investigations and Current Medical Issues. 2018;16(2):34-8. management. Confounding factors should be excluded before 7. Mortimer RH. Thyroid function tests. Aust Prescr. 2011;34(1):12-5. embarking upon further biochemical, radiological, or genetic 8. Barbesino G, Tomer Y. Clinical review: clinical utility of TSH receptor testing (Table 2). antibodies. J Clin Endocrinol Metab. 2013;98:2247-55. . 9 Ballabio M, Poshychinda M, Ekins RP. Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as References putative regulator of maternal thyroid. J Clin Endocrinol Metab. . 1 Weeke J, Gundersen HJ. Circadian and 30 minutes variations 1991;73:824-31. in serum TSH and thyroid hormones in normal subjects. Acta 10. Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association Endocrinol (Copenh). 1978;89(4):659-72. guidelines for detection of thyroid dysfunction. Arch Intern Med. 2. National Academy of Clinical Biochemistry. Laboratory Support for 2000;160:1573-5. the Diagnosis and Monitoring of Thyroid Disease. Washington, DC: 11. Cooper DS, Doherty GM, Haugen BR, et al. Revised American AACC Press; 2003. Thyroid Association management guidelines for patients with . 3 Association for Clinical Biochemistry, British Thyroid Association, thyroid nodules and differentiated thyroid cancer. Thyroid. British Thyroid Foundation. UK guidelines for the use of thyroid 2009;19:1167-214.

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Cognitive Aspects of 198 Hypothyroidism

Anubha Srivastava, Anurag Varma, Kachnar Varma

Abstract Hypothyroidism is associated with myriad of neuropsychiatric manifestations in clinical practice. Due to its variable and wide clinical presentation it sometimes poses a dilemma for the treating physician and consultation—liaison should be considered when treating patients with neurocognitive symptoms.

Introduction inflammatory markers or of second messengers is yet to be established and a direct correlation between the more Disorders of Thyroid are one of the common endocrine specific marker of the disease, that is, thyroid peroxidase problems encountered in clinical practice; the antibodies (TPOAb) or of thyroglobulin antibodies (TGAb) hypothalamic-pituitary-thyroidaxis is needed to maintain is still an ongoing research. the normal functioning of various organs and systems, including the central nervous system.1 Thyroid dysfunction affects the nervous system Epidemiology and produces a wide and variable spectrum of clinical Due to improvements in diagnosis and treatment of the presentation due to alterations in cognition and emotions.2 hormonal disorders and universal iodine supplementation As early as 1888 Clinical Society of London had described of common salt the most severe neuropsychiatric myxoedema and its association with behavior and syndromes in endocrine diseases are not as frequent psychological disturbances.3 as in the past although psychiatric and subtle cognitive disturbances are still seen.6 Data shows that 1–4% Pathophysiology of patients diagnosed with affective disorders have overt hypothyroidism and 4–40% may have subclinical The hypometabolism of brain has been postulated to be hypothyroidism (SCH). However, majority of patients associated with cognitive decline.4 Thyroid hormones diagnosed with major depression have normal thyroid exert their influence on the central nervous system function.7 through a variety of mechanisms like modulation of gene expression of several groups of proteins and the influence on serotonin and noradrenergic neurotransmission. Overt Hypothyroidism Antithyroid antibodies are also postulated to play a Overt hypothyroidism by definition is an elevation causativerole.5 In autoimmune Hashimoto’s thyroiditis of serum thyroid stimulating hormone (TSH) level link with Unipolar and Bipolar Depressive disorders is with a low-free thyroxine (fT4) level.2 Autoimmune established; however, the exact pathophysiology, role of thyroiditis (Hashimoto’s) is the most common cause of

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hypothyroidism which is commonly seen in middle age itself. Hence, the diagnosis of hypothyroidism may be females.8 clinically missed. The most common presenting complaints are Traditionally, Myxoedema used to be known as a fatigue and impaired quality of life. Due to advances reversible cause of dementia in the elderly. There occurs in interventional and functional imaging the subtle progressive neurocognitive decline leading to impaired changes in cognition in specific domain like working social and cognitive functioning. Elderly patients tend memory and executive function are now more commonly to have problems with recent memory though remote diagnosed along with the more commonly seen anxiety memory and overall intelligence remains intact other and depression. common problems observed are lack of attention and emotional liability with easy fatigability leading also to a Neurocognitive Effects Seen in lot of family and caregiver burden. There is decline in auditory acuity which might Overt Hypothyroidism contribute indirectly to memory impairment due to Cognition sensory deprivation and poor registration usually seen Cognition is referred to as mental activities involved in the in uncontrolled hypothyroidism which can partially be reversed with thyroxine. TSH levels and risk of developing acquisition, storage, retrieval and use of information. 9,12 Memory is most commonly affected domain with Alzheimer’s disease may also show some correlation.

specific deficits seen in verbal memory. Hypothyroid 10 individuals have also shown deficits in visuospatial and Other Neurological Complications executive functions. Cerebellar dysfunction and motor coordination like ataxia, The other cognitive domains affected include general intention tremors are usually mild and more commonly intelligence, complex attention and concentration, seen in children and may result in poor outcomes in language, learning and memory along with perceptual motor functions in later childhood if delayed treatment or and visuospatial functions. The frontal lobe executive inadequate hormone replacement is done. functions like reasoning, problem solving, decision- Neuropathy: Hypothyroidism is associated with peripheral making may be affected. There are various psychological nerve demyelination and decreased nerve conduction tests and measures available for evaluation of these velocity (NCV). 4 individual cognitive domains. Entrapment neuropathy, like Carpal tunnel syndrome In congenital hypothyroidism irreversible cognitive and polyneuropathy, is also seen but the bilateral and deficits may happen if hypothyroidism is left untreated or distal sensorimotor neuropathy is the most common. intervention started belatedly after the critical window of With thyroxine replacement therapy the symptoms and brain development. signs of neuropathy along with changes in NCV usually In adolescents who develop hypothyroidism again normalize in adulthood but those who have symptoms cognitive domains are affected and those who were treated of longer duration may show some residual symptoms of with Thyroxine Replacement Therapy (TRT) were found to peripheral neuropathy. have improved performance on a battery of cognitive tests Myopathy can occur when associated with symptoms including reading performance and block design but the or signs of hypothyroidism such as poor linear growth patterns of recovery are not definitive. or global developmental delay with pain and muscle In adults with hypothyroidism again vocational and weakness along with elevation of creatine phosphokinase. occupational pursuit may be affected whereas specific The delayed acquisition of early motor milestones tests of cognitive domains are often seen to be not may be a sign of missed congenital or early acquired significantly impaired. hypothyroidism in young children and investigation of thyroid function should be performed in them. Dementia Hashimoto’s encephalopathy (HE) is a rare neuro­ In geriatric population there may be an overlap of endocrine disorder to be associated with autoimmune symptoms seen in hypothyroidism and due to old age, thyroiditis (Hashimoto thyroiditis). Hashimoto’s

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encephalopathy is frequently seen in women and presents certain symptoms like weight gain, hypersomnolence with symptoms of seizures, myoclonus, stroke, and also or insomnia and impoverished quality of life may give psychiatric manifestations mainly depressive disorders a clue toward diagnosis of hypothyroidism but they are and even psychosis. These symptoms usually recover with also common in mood disorders. An overlap of anxiety treatment but relapses can also be seen. and mood disorders can be seen leading to variety of Thyroid tests are usually normal. Neuroimaging is often emotional disturbances.2,7,15 normal. The diagnosis of Hashimoto’s encephalopathy Psychotic disorders: Severe hypothyroidism in 5–15% may is made with classical clinical picture with positivity present as melancholic depression with mood congruent of antithyroid peroxidase antibodies. Treatment of psychotic features, rarely frank psychosis, delusions, and 11 Hashimoto’s encephalopathy is corticosteroids. hallucinations. These features are often seen in Myxedema Anxiety disorders: These disorders present as restlessness, madness. inability to concentrate, irritability, distraction, increased Capgras syndrome a delusional disorder has also sweating, muscular tension, and insomnia. The most been associated with hypothyroidism where psychotic prevalent anxiety disorders are social anxiety disorder, symptoms are preceded by symptoms of hypothyroidism generalized anxiety and panic disorder, the incidence even months to years of diagnosis. of which is increased in hyperthyroidism and also in hypothyroidism.2,7 Effects of Thyroxine Replacement Mood disorders: Depression has a prevalence of 10–15% Therapy on Hypothyroidism in the general population and may be more common After supplementation of thyroxine replacement therapy in people with thyroid disorders. The normal circadian there may occur incomplete normalization of subjective secretion of TSH peaks from 11 pm to 4 am. In depressive neuropsychiatric symptoms even on reaching euthyroid patients there is a dysregulation of Hypothalamic- state. There is no rationale of using combination of Pituitary-Adrenal axis; hence, the nocturnal surge is absent Levothyroxine (LT4) and Liothyronine (LT3) treatment which may point to functional central hypothyroidism in for hypothyroidism who still complained of depressive some depressed patients. symptoms. In these subsets of individual revaluation of It has been seen that self-knowledge of mildly elevated other chronic medical condition and consultation liaison TSH may be associated with poor quality of life or fatigue with psychiatrist should be sought. known as (“labeling effect”). Major depressive disorder can also happen Subclinical Hypothyroidism in hyperthyroidism although more common in “Subclinical” hypothyroidism (SCH) by definition hypothyroidism, presence of antithyroid antibodies may is an elevation of TSH with a normal fT42. In young have an etiopathological role and severity in causing adults and middle age, the symptoms of depression are depression. There are further complications as Lithium more frequent along with mild cognitive impairment, the gold standard medicine of Bipolar disorders leads to difficulty in learning and selective attention. Subclinical Hypothyroidism on prolonged use. hypothyroidism is prevalent in as many as 20% of post- Depression is characterized with cognitive distortion menopausal women and in older patients many of whom in form of hopelessness, helplessness, and worthlessness already have some cognitive decline.14 The correction of this may lead to suicidal ideation and in few cases lead to the subclinical hypothyroid state with neuropsychiatric self-harm and suicide. symptoms still remains elusive.9 Many cognitive symptoms like poorer memory, in There have been no improvements in symptoms of attentiveness, slower thinking and speech, impaired Subclinical hypothyroidism on thyroxine replacement concentration and apathy is seen in both the diseases. The therapy diagnosed with depression who are biochemically common symptoms of being easily tired, lack of interest, euthyroid. Various studies have shown no significant and pleasure along with loss of appetite, decrease libido, clinical improvement with coadministration of and constipation may pose a difficulty in diagnosis though Levothyroxine (LT4) and Selective Serotonin Reuptake

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Inhibitors (SSRI) in depressed patients when compared 9 Though these changes may be subtle in patients of SCH with SSRI alone. and may not show major changes on mood and cognition, SCH Congenital hypothyroidism (CH) is a common and have been seen to be associated with mild deficits in working treatable cause of preventable intellectual disability with memory and executive function especially in elderly. a prevalence of approximately 1 in 2,000–4,000 new born. The treatment with thyroxine replacement is the Thyroxine is an essential hormone during pregnancy cornerstone and is always indicated in overt hypothyroidism. especially during first trimester as it is required for fetal There have been improvements in physical symptoms along brain development at around 12 weeks postconception. with resolution of deficits in mood or cognition though Deficiency of thyroxine may lead to abnormal dendrite- complete recovery may not be seen. The treatment of SCH is genesis and synaptogenesis leading to congenital elusive and it depends upon the decision of treating physician. hypothyroidism in neonates. The neuropsychiatric symptoms with mild hypothyroidism should be evaluated and treated as independent diagnosis Congenital hypothyroidism can impair cognition with consultation liaison. but also cause arrange of other neurological sequelae There appears significant merit in recommending universal including abnormal muscle tone, ataxia and strabismus thyroid screening for all pregnant females along with testing and motor in coordination the most severe forms of for any young infant or child with global neurocognitive or congenital hypothyroidism may include alterations in neuromuscular dysfunction. domains of attention, memory, arithmetic, verbal skills, Also, emphasis on thyroid testing for patients presenting memory, and behavior. with neuropsychiatric disorders and conversely assessment of In severe cases mental retardation, deafness, and mental health for all patients diagnosed with thyroid disorders spastic diplegia can be seen. There is also presence of can be instrumental for good clinical management as the other clinical features such as short stature, delayed timely intervention may improve quality of life among thyroid puberty, and craniofacial abnormalities. disorder patients with comorbidities. For prevention of neurobehavioral effects of Neuroplasticity more often favors infant rather than older individual. Thyroxine replacement therapy remains the main congenital hypothyroidism supplementation of iodine stay of treatment but the extent and duration of recovery preconceptually may be advised. The immediate goal of especially neurocognitive domains is often incomplete and thyroxine replacement is to normalize T4 within 2 weeks inconsistent. There is global decline in cognition if thyroxine and TSH within 1 month of birth to ensure growth and replacement therapy is delayed or absent. Hence, universal neurodevelopmental outcomes as close as possible to screening of TSH in pregnant women should be emphasized. their genetic potential.13 Hypothyroidism has also been associated with attention deficit hyperactivity disorder (ADHD) and this References may persist even in adults. . 1 Bauer M, Goetz T, Glenn T, et al. The thyroid-brain interaction The preventive measures of congenital hypothyroidism in thyroid disorders and mood disorders. J NeuroEndocrinol. may be early identification and early initiation of 2008;20(10):1101-14. treatment, which has shown improvement in tests for . 2 Samuels MH. Psychiatric and cognitive manifestations of hypothyroidism. Curr Opin Endocrinol Diabetes Obes. formal intelligence. But certain domains of neurocognition 2014;21(5):377-83. may persist in late childhood and adolescence. Some . 3 Russell T. The Thyroid Axis and Psychiatric Illness. Report on domains like language, motor skills, attention, and Myxoedema Transactions of the Clinical Society of London. 21;18. visuospatial processing may be affected even after 4. Bégin ME, Langlois MF, Lorrain D, et al. Thyroid function and cognition becoming euthyroid.9,10 during aging. Curr Gerontol Geriatr Res. 2008;2008:474868. . 5 Placidi M, Boldrini A, Patronelli E, et al. Prevalence of psychiatric disorders in thyroid disease patients. Neuropsychobiology. Conclusion 1998;38(4):222-5. 6. Kathol RG. Endocrine disorder. The American Psychiatric Publishing Overt hypothyroidism is associated with myriad of symptoms Textbook of Consultation-Liaison Psychiatry, 2nd edition. 2005. pp. ranging from fatigue affecting quality of life to mood and 563-7. behavior changes along with cognition. Among the cognitive . 7 Feldman AZ, Shrestha RT, Hennessey JV, et al. Neuropsychiatric impairment seen in hypothyroidism is its effect on memory. manifestations of thyroid disease. Endocrinol Metab Clin North Am. 2013;42(3):453-76.

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8. Pelúcio L, Nardi AE, Ornelas AC, et al. Psychiatric disorders and quality 12. De Sousa AD, Shrivastava A. Neurocognition and hypothyroidism: of life in patients with hypothyroidism. J Depress Anxiety. 2016;5:3. critical points. Ann Indian Psychiatry. 2017;1:118-9. . 9 DugbarteyAT. Neurocognitive aspects of hypothyroidism. Arch 13. Agrawal P, Philip R, Saran S, et al. Congenital hypothyroidism. Indian Intern Med. 1998;158(13):1413-8. J EndocrinolMetab. 2015;19(3):436-7. 10. Nandi-Munshi D, Taplin CE. Thyroid-related neurological disorders 14. Bajaj S, Sachan S, Misra V, et al. Cognitive function in subclinical and complications in children. Pediatr Neurol. 2015;52(4):373-82. hypothyroidism in elderly. Indian J Endocr Metab. 2014;18(6):811-4. 11. Mocellin R, Walterfang M, Velakoulis D, et al. Hashimoto’s 15. Bathla M, Singh M, Relan P, et al. Prevalence of anxiety and encephalopathy: epidemiology, pathogenesis and management. depressive symptoms among patients with hypothyroidism. Indian CNS Drugs. 2007;21(10):799-811. J EndocrMetab. 2016;20(4):468-74.

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Thyroid Myopathy— 199 An Update

NS Neki

Abstract Muscular complaints are common symptoms of thyroid disorder: hypothyroidism or hyperthyroidism. About 79% of hypothyroid patients and 67% of hyperthyroid patients develop neuromuscular symptoms. However, muscle stiffness is more common in hyperthyroidism while muscle weakness is observed commonly both in hypothyroidism and hyperthyroidism. The onset of weakness is usually insidious and proximal muscles are predominantly affected in both types of thyroid myopathy. Thyroid myopathy occurs as a result of either deficiency or overproduction of thyroid hormone, i.e., Thyroxine. Skeletal muscle is a major target of thyroid hormone. Patients with untreated or uncontrolled hypothyroidism and hyperthyroidism can develop severe myopathy resulting in severe functional limitations. These symptoms subside completely with proper diagnosis and appropriate treatment.

Introduction complication of uncontrolled or untreated hypothyroidism involving about 79% of patients. It is seen in both congenital Abnormal thyroid functions/disorder either too increased and acquired hypothyroidism. Sometimes subclinical or too low can result in neuromuscular manifestations hypothyroidism manifests as HM. HM can occur at an age including hypothyroid myopathy, hyperthyroid but most common age is 40–70 years and involves both (thyrotoxic) myopathy, thyrotoxic periodic paralysis, and sexes. However, females are predominantly affected than thyroid associated ophthalmopathy because the skeletal males.3 muscle is a major target of thyroid hormone. Muscular complaints are common symptoms of thyroid dysfunction, Pathogenesis: The exact pathogenesis of HM is not known. especially muscle stiffness more so in hyperthyroidism Thyroid hormones markedly influence the cellular and muscle weakness in both hypothyroidism and metabolism and their deficiency results in cellular hyperthyroidism. The prevalence of neuromuscular functional impairment. Thyroxine (T4) deficiency in manifestations varies between 20% and 50%. Most of these hypothyroidism causes: studies were retrospective and were done before FT4 and „„ Abnormal glycogenolysis 1,2 TSH assays were available. „„ Reduced mitochondrial oxidation „„ Insulin resistant state of the cell Types of Myopathy Ultimately this causes selective atrophy of Type 2 muscle fibers (fast twitching type) because these muscle Hypothyroid Myopathy fibers are dependent on glycolysis for energy. Finally, it Various manifestations of hypothyroidism are observed in results in slowing of muscle contraction which may be clinical practice. Hypothyroid myopathy (HM) occurs as a observed clinically. However, compensatory mechanism

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occurs from accumulation of glycosaminoglycans in the Clinical features of HM include cramps, muscle muscle further causing muscle hypertrophy. Myopathy weakness, myalgia, stiffness, myxedema, and hyporeflexia. symptoms in HM result from low muscle carnitine. Various Muscle hypertrophy, wasting, and rhabdomyolysis factors causing muscle involvement in hypothyroidism are are unusual features.9 Rhabdomyolysis is a rare life due to threatening complication being precipitated by trauma, „„ Deposition of glycosaminoglycans exercise, alcohol, and electrolyte disturbances. Rarely „„ Low myosin ATPase activity HM may present as acute compartment syndrome being „„ Changes in muscle fibers from fast twitching Type 2 to precipitated by thrombosis, surgery, trauma, or IV drug slow twitching Type 1 fibers abuse. „„ Decrease in ATP turnover in skeletal muscle Differential diagnosis of calf muscle (gastrocnemius) „„ Structural muscle injury. A significant feature is that hypertrophy include Duchenne and Becker muscular degree of muscle weakness does not always correlate dystrophy, sarcoidosis granuloma, amyloid, and focal 10 with the severity of thyroid hormone deficiency. Rise myositis. in serum muscle enzymes in the absence of clinical Myoedema is a classical sign of HM but is uncommon manifestations or structural alterations results from and hence is mostly missed by clinicians. It is demonstrated changes in the muscle cell membrane permeability. by percussion or applying pressure stimulus with thumb Thyroid hormone may have a role in regulating gene and index finger on the muscles of arm, especially biceps expression of skeletal muscle proteins like myosin belly. This causes the muscle to form a visible palpable, ATPase thus favoring the role of thyroid hormone nontender, firm, localized swelling around the site of deficiency in the pathogenesis of TM.4 stimulus. The swelling reaches its maximum size after 1–2 seconds and gradually subsides over 5–10 seconds Thyroid myopathy is of four types: so that the muscle regains its normal contour with no „„ Myasthenic syndrome: It is associated with Ptosis and palpable localized hardening. The swelling does not marked weakness. It is commonly seen in children. spread elsewhere along the muscle. Myoedema is due to „„ Atrophic type: It is seen in severe muscle atrophy. prolonged muscle contraction caused by delayed calcium „„ Kocher-Debre-Semelaigne syndrome: It is commonly reuptake by the sarcoplasmic reticulum after the stimulus seen in children. Clinical features include myxedema, causes release of local calcium. Differential diagnosis short stature, cretinism, and generalized muscle of myoedema is from malnutrition, hypoalbuminemia, hypertrophy. hypovitaminosis, and hypothyroidism.11 „„ Hoffman syndrome (HS): It occurs in adults. Clinical features include pseudohypertrophy of Hyperthyroid Myopathy muscles, proximal muscle weakness, stiffness, and Various names are Graves myopathy, thyrotoxic myopathy, painful spasms. Commonly involved muscles are Basedow myopathy, or Basedow paraplegia. It was tongue, arm, and leg muscles. The pathogenesis of described in early nineteenth century by Graves and pseudohypertrophy is not exactly known but may be Von Basedow documented in severe hyperthyroidism. due to deposition of glycosaminoglycans and increased There are two types of muscle fibers—Type 1 or Slow 5 muscle fiber size. Few cases of HS have been reported fibers are required for sustained effort like standing, while from India.6,7 HS was first described by Hoffman in Type 2 fibers are fast fibers required for short rapid bursts 1897 in an adult who developed muscle stiffness and like sprinting. In hyperthyroidism, there is increased difficulty in relaxation of muscles after thyroidectomy.8 production of ATP and reuptake of calcium. This results in Usually the cause of HS is primary hypothyroidism very rapid contraction and relaxation. When this process (Hashimoto thyroiditis) but rarely secondary. Muscle occurs repeatedly, the structure and mechanics of slow biopsy is usually not required to confirm the diagnosis. fibers is changed to fast fibers so that muscles lose their Muscle MRI may be helpful. Prognosis is good in HS. endurance, become fatigued, weak, and wasted. Muscle enlargement usually regresses over time, but Hyperthyroid (thyrotoxic) myopathy occurs due to may persist in a few cases. overproduction of thyroid hormone, that is, thyroxine.

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Etiology includes mostly multinodular goiter and Graves’ Other theory of hyperthyroid myopathy is decrease disease. Clinical features consist of muscle weakness, in protein kinase affinity to cAMP within muscle fibers fatigue and heat intolerance, difficulty in climbing stairs, resulting in increase in cAMP within muscle fibers, which and proximal myopathy. If untreated, it can lead to marked ultimately causes increased release of calcium from debilitating condition and rarely death.12 muscle fibers’ sarcoplasmic reticulum. Finally, it results in Hyperthyroid myopathy can be acute or chronic. Acute more muscle contractions.15 hyperthyroid myopathy is rare than chronic hyperthyroid Chronic hyperthyroid myopathy can be so severe myopathy. It occurs due to rapid degradation of muscle that the patient may develop winging of scapula. If fibers so that patients complain of severe muscle pain, the myopathy progresses untreated, then patient may muscle cramps, blurring of vision, and bulging eyes. It may have involvement of muscles of face, swallowing, and present with more severe proximal and distal weakness respiration. and rarely quadriplegia with bulbar and respiratory Ocular myopathy: It is also called dysthyroid ophthalmo­ involvement. Patients develop rhabdomyolysis and severe pathy, or exophthalmic ophthalmoplegia. It is more respiratory failure requiring artificial ventilation. common in females. It may or may not be associated with Chronic hyperthyroid myopathy develops after 6 chronic thyrotoxic myopathy. It may occur even after months of onset so that symptoms appear slowly in the treatment for hyperthyroidism. In severe cases it may form of increased fatigue and difficulty in performing result in blindness and severe residual deficit. certain tasks. Some patients in thyrotoxic myopathy may have involvement of upper motor neurons related Thyrotoxic periodic paralysis: It is a rare clinical entity to pyramidal tract dysfunction as well as lower motor mostly occurring in young adult Asian males in age neuron symptoms related to peripheral neuropathy. This group of 25–30 years. It manifests as sudden episodes may overlap with those of amyotrophic lateral sclerosis of muscle weakness involving muscles of trunk and (ALS).13 However, there is no association found between limbs, developing over a few minutes to hours, and hyperthyroidism and motor neuron disease. lasting for hours to a few days. It is due to altered muscle Some patients of hyperthyroid myopathy may membrane excitability secondary to hypokalemia. It present with sensory polyneuropathy, carpal tunnel reverses spontaneously or requires potassium. Patient syndrome, headache, seizures, ischemic cardiovascular may die due to cardiac arrhythmias. Many cases have been disease especially in patients of hyperthyroidism with reported in the literature.16 atrial fibrillation, as well as cerebral venous thrombosis Diagnosis: Laboratory investigations include CBC, FT3, occurring as a result of hypercoagulable state, and auto FT4, TSH, serum sodium, serum potassium, serum immune mechanisms. Rarely, Guillain-Barré syndrome calcium, serum phosphorus, blood glucose, blood urea, and chronic inflammatory demyelinating polyneuropathy serum creatinine, serum vitamin B12, serum folic acid, have been associated with hyperthyroid patients. ECG, auto antibodies against thyroid disease, CPK, CPK- MB levels (muscle enzymes), lipid studies, ultrasound of Pathophysiology thyroid, hand-held dynamometry, EMG, nerve conduction Excess of thyroid hormone, that is, thyroxine, causes study, and muscle biopsy, if needed. Normal levels of CPK degradation of muscle fibers, especially at the motor end may reveal early stages of progression while increased plates of neuromuscular junction. There occurs low level levels indicate late stages of progression. of acetylcholinesterase (AChE), which breaks down ACh EMG findings of thyroid myopathy include polyphasic in neuromuscular junction. Decrease in AChE blocks action potential with early recruitment full interference degradation of ACh causing Ach to overstimulate motor pattern. Electromyography (EMG) findings in HM end plates of muscle fiber. Ultimately overstimulation may show low/small amplitude potentials suggesting of motor end plate leads to more sustained muscle myopathic changes although it may be normal in half of contraction resulting in fatigue, muscle weakness and the patients. degradation occurring as a result of overproduction of The distal muscles in thyrotoxic patients may show thyroxine.14 EMG findings of a rather neuropathic process. EMG is used

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to diagnose myopathies by comparing muscle contraction References responses to electrical stimulus. Response may be . 1 Khaleeli AA, Gohil K, Mc Phail G, et al. Muscle morphology and normal or myopathic. Muscle biopsy findings in case of metabolism in hypothyroid myopathy: effects of treatment. J Clin HS include muscle fiber hypertrophy, increased nuclei, Pathol. 1983;36(5):519-26. mucous deposits at places with increased inter fiber 2. Sozay S, Gokce-Kutsal Y, Celiker R, et al. Neuroelectrophysiological ground substance consistent with thyroid myopathy. evaluation of untreated hyperthyroid patients. Thyroid Clin Ex. Muscle biopsy in hyperthyroid myopathy is not specific 1994;6(2):55-9. 3. Sindon A, Rodolico C, Pappalardo MA, et al. Hypothyroid myopathy: but may show mild atrophic changes and type 2 fiber a peculiar clinical presentation of thyroid failure. Review of predominance. Management of HM consists of thyroid literature. Rev Endocr Metab Disord. 2016;17(4):499-519. hormone administration and hyperthyroid myopathy . 4 Vignesh G, Balachandran K, Kamalanathan S, et al. Myoedema: treatment consists of antithyroid drugs (propylthiouracil, a clinical pointer to hypothyroid myopathy. Indian J Endocrinol methimazole), radioactive iodine or surgery in the Metab. 2013;17(2):352. 5. Achappa B, Madi D. Hoffman syndrome. a rare form of hypothyroid form of partial or total thyroidectomy. Treatment of myopathy. J Clin Diagn Res. 2017;11(5):1-2. thyroid myopathy is carried out by multidisciplinary . 6 Neki NS, Singh I, Kumar J, et al. Hypothyroidism presenting as team consisting of neurologist, endocrinologist, Hoffman syndrome—case report. J Med Bangladesh. 2015;16: surgeon, ophthalmologist, and physical therapist. Aim 112-4. in hyperthyroid myopathy is to reduce overproduction . 7 Neki NS. Hypothyroidism presenting as Hoffman syndrome of thyroxine from the thyroid gland. While in HM aim is pictorial CME. J Ayub Med Coll. 2014;26(2). . 8 Sidibe EH, Diop AN, Thiama A, et al. Hoffman’s syndrome in to correct thyroid hormone deficiency by administration hypothyroid myopathy. Report of a case in an African. Joint Bone of thyroid hormone. Thyroid replacement usually leads Spine. 2001;68(1):84-5. to resolution of laboratory abnormalities and symptoms . 9 Bhansali A, Chandan V, Ramesh J, et al. Acute myxedema: an over a few weeks. However, weakness may take months unusual presenting manifestation of hypothyroid myopathy. for recovery. Ultimate goal is to restore normal hormone Postgrad Med J. 2000;76(892):99-100. 10. Praveen KA, Aslam S, Dutta TK, et al. Hoffman syndrome: a rare homeostasis. neurological presentation of hypothyroidism. Int J Nutr Pharmacol Neurol Dis. 2011;1(2):201-3. Conclusion 11. Cakir M, Samanci N, Balci N, et al. Musculoskeletal manifestations in patients with thyroid disease. Clin Endocrinol (Oxf.). 2003;59(2): Neuromuscular symptoms and signs are common in 75% 162-7. of hypothyroid patients and 67% of hyperthyroid patients 12. Horak HA, Pourmand R. Endocrine myopathies. Neurol Clin. because the skeletal muscle is a major target of thyroid 2000;18(1):203-13. hormone.17 It is uncommon for a patient with hypothyroidism 13. Fisher M, Mateer JE, Ullrich I, et al. Pyramidal tract deficits to present with muscle weakness as the chief complaint. and polyneuropathy in hyperthyroidism. Combination Patients of hyperthyroid myopathy usually report after the age clinically mimicking amyotrophic lateral sclerosis. Am J Med. 1985;78(6.1):1041-4. of 40 years unlike patients of hypothyroidism. Clinical suspicion 14. Kazakov VM, Katinas GS, Skorometz AA, et al. Pathogenesis of supported by laboratory investigations is needed to diagnose experimental thyrotoxicosis myopathy. Eur Neurol. 1986;25(3): patients of both hypo- and hyperthyroid myopathy. Weakness 212-24. in hyperthyroid myopathy develops early but resolves 15. Kazakov VM, Kovalenko TM. Experimental thyrotoxic myopathy— completely during treatment, thus suggesting a functional auto radiography of protein synthesis in skeletal muscle and motor muscular disorder. neurons of spinal cord. Neuromuscul Disord. 1995;5(1):47-52. 16. Neki NS. Thyrotoxic periodic paralysis—a case report. J Int Med Sci Acad. 2010;23(2):87-8. 17. Duyff RF, Van Den Bosch J, Laman DM, et al. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry. 2000;68(6):750-5.

MU-199.indd 1286 29-01-2021 15:33:15 CHAPTER Impact of Altered Thyroid Status on Diabetes: Partners 200 in Metabolic Malfunction

Swati Srivastava

Abstract Diabetes and thyroid dysfunction have impact on each other and mutual interdependence has been a matter of interest since long. The prevalence of thyroid disorder in people with diabetes was found to be higher than in general population. Diabetic patients with hyperthyroidism experience a deterioration of glycemic control. Thyroid hormone excess can sometimes precipitate ketoacidosis in diabetic patients. About half of the patients with Grave’s disease exhibit glucose intolerance of variable degree and about 2–3% may develop overt diabetes. Hypothyroidism is the most frequently encountered thyroid disease in patients with diabetes. Studies have found the occurrence of hypothyroidism in 5.7% patients suffering from diabetes. In individuals with T1DM, repetitive events of hypoglycemia hint toward hypothyroidism.

Introduction Epidemiological studies have shown similar genetic background for diabetes mellitus and thyroid The two most often seen endocrine disorders in disorders. However, the common genes identification medical experience are diabetes mellitus and thyroid is presently focused on the autoimmune etiology. The abnormalities. Thyroid dysfunction is found to occur more closest connection seen amongst type 1 diabetes and frequently in patients with diabetes as compared to the autoimmune thyroid diseases have relation with HLA class general society.1,2 Diabetes and thyroid dysfunction have II sequences.3 There is evidence to propose the likelihood impact on each other and mutual interdependence has of impact of intracellular T3 on insulin sensitivity.4 been a matter of interest since long. Increasing body of It is said that rectification of abnormal thyroid status evidence suggests a pattern of multiform combination of in individuals with diabetes will enhance blood glucose biochemical, inherited, and endocrinal defects leading to levels, diminish cardiac and other complications chances, this pathophysiological interdependence. Epidemiologic and improve overall health. However, there is dearth data reveal that thyroid dysfunction is seen in 13.4% of of unanimity concerning timing and periodicity about diabetic population. Amongst the patients with diabetes, thyroid assessment to be conducted in standard approach the subgroup having maximum prevalence of thyroid to diabetes management.5 dysfunction were females with type 1 diabetes (31.4%) and minimum were males with type 2 diabetes (6.0%).1 Thyroid hormones play role in metabolism, energy disbursement Hyperthyroidism and Glucose Metabolism as well as insulin sensitivity. Vis-a-vis diabetes impacts Thyroid hormones may affect glycemia secondary to their TSH responsiveness to thyrotropin releasing hormone influence on glucose metabolism. Hyperthyroidism is and causes low T3. The reciprocal interlinkage between known to increase blood sugar levels.6 thyroid hormone levels and diabetes mellitus has clinical Increase in thyroid hormones lead to enhanced connotation. intestinal absorption of glucose, insulin clearance,

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glycogenolysis and gluconeogenesis.7 The hepatic glucose Hypothyroidism and Diabetes Mellitus output is increased with decreased insulin action and The most often thyroid disease that we come across increased lipolysis.7 in diabetes is hypothyroidism. Studies have found the Hyperthyroid patients encounter decline in blood occurrence of hypothyroidism in 5.7% patients suffering sugar control if they are also suffering from diabetes 1 from diabetes. The most common etiology in iodine mellitus. Thyroid hormone excess can also sometimes 8 sufficient regions being autoimmune thyroiditis. precipitate diabetic ketoacidosis in diabetic patients. In individuals with T1DM, repetitive events Also, the clinical features of hypermetabolic state of of hypoglycemia hint toward hypothyroidism. It has thyrotoxicosis and those due to hyperglycemia may been shown that treatment with thyroxine lowers the be confused among each other leading to missing the blood glucose variations.12 It is documented that insulin diagnosis. resistant condition is seen in both overt as well subclinical About half the patients of Grave’s disease exhibit hypothyroidism.13 glucose intolerance of variable degree and about 2–3% The impact of reduced levels of thyroid hormone 6 may develop overt diabetes. on metabolism in diabetic patients is contrary to that There is an escalated β-cells reaction to blood observed in hyperthyroidism.5 Reduced thyroid hormones sugar levels/catecholamines perhaps secondary to lead to reduced glucose absorption from gastrointestinal expanded β-cell volume. Patients with elevated thyroid tract. Extended peripheral glucose accretion, lessened hormones may also have enhanced removal of insulin. hepatic glucose yield, gluconeogenesis and lower Hyperthyroidism leads to increased glucose output from peripheral glucose use is witnessed in hypothyroidism.5 the liver and upregulates glycogenolysis producing glucose The insulin stimulated glucose transport and GLUT 9,10 intolerance (Flowchart 1). It has been advocated that expression are lowered. Insulin clearance is reduced and there is hypothalamic sympathetic impact on liver along less hunger further decreases insulin. A combination of with enhanced expression of hepatic GLUT 2 transporters all these metabolic alterations in patients with diabetes with resultant increase of plasma-free fatty acids.5 This and coexistent hypothyroidism lead to reduction in situation accounts for magnification of elevated blood blood sugar with increased frequency of hypoglycemia glucose levels in diabetics. Thyrotoxicosis can also result (Flowchart 2).14 Studies have also shown reduction and in state of ketoacidosis in patients with diabetes. This benefit in hypoglycemic episodes following treatment of is secondary to the accelerated lipolytic activity and hypothyroidism.15 Studies have correlated hypothyroidism escalated liver β-oxidation.7,11 with lowered insulin sensitivity.

Flowchart 1: Effects of hyperthyroidism on blood glucose Flowchart 2: Effects of hypothyroidism on glucose metabolism

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Other factors: Lipid profile disturbances are recognized in patients „„ Role of thyroid hormones in lipid metabolism has been with hypothyroidism. Elevated total cholesterol, LDL studied by many authors. cholesterol, apolipoprotein B, and decreased HDL are 19 „„ They work along with controlling route for energy the typical findings. Altered thyroid status has been equilibrium and directly modify insulin equipoise and correlated with dyslipidemia and insulin resistance glucose disbursement by tissues. in several studies. Literature also shows relation of „„ Triggering of melanocortin receptor type 4 (MC4R) hypothyroidism and obesity. Blood pressure changes in brings about lowering of food ingestion and elevation patients with hypothyroidism have also been studied by in energy disbursement. Hypothalamic TRH neurons authors. Increase in systemic vascular resistance leading express these receptors which play role in central to high diastolic blood pressure has been documented pathways of energy control.16 in hypothyroidism.20 Studies documenting higher „„ Thyroxine relates to adipocytokines and gut hormones intima media thickness in hypothyroid patients suggest disturbing carbohydrate metabolism. endothelial dysfunction resulting in increased chances of „„ Ghrelin hormone which impacts insulin sensitivity has CV risk. been observed to have counter alliance with T3. The escalated peripheral vascular resistance and „„ The β-cell activity of insulin secretion mediated by drop in cardiac output witnessed in subclinical and overt glucose also is reduced in low thyroid hormone status. hypothyroidism put them to increased susceptibility to nephropathy. The diabetic patients with concurrent Does Diabetes Mellitus Modify low thyroid hormones observed good renal response Dysfunctional Thyroid Status? to therapeutic thyroid correction. Retinopathy seen in patients with diabetes was of greater intensity in Diabetic patients have dampened diurnal TSH climax subclinical and overt hypothyroid individuals than occurring at night. Also, there is weakened TSH response 21 euthyroid people. The above findings of high renal and to TRH. Low T3 levels are witnessed in individuals with eye complications documented in coexisting thyroid unchecked diabetes mellitus. It is seen that in diabetic dysfunction in patients with type 2 diabetes provides individuals with unrestrained blood glucose, there may be rationale for assessing thyroid dysfunction in patients with blunted T4 to T3 conversion leading to low T3 state, which type 2 diabetes mellitus. corrects with normalization of hyperglycemia. Evidence suggests that reduced insulin sensitivity and hyperinsulinemia may cause multiplicative sequel on Effect of Metformin on Thyroid Function thyroid tissue resulting in thyromegaly and nodularity. Studies document impact of metformin on thyroid Presence of concomitant diabetes also changes therapeutic function. Metformin given as therapeutic intervention response to thyroxine in hypothyroidism. Patients with for diabetes resulted in subduing of TSH in a study.22 Grave’s orbitopathy have an increased prevalence of type Another study conducted on thyroid nodules revealed a 1 diabetes mellitus as compared to general population. decrease in nodule size with use of metformin in patients Dysthyroid optic neuropathy has higher occurrence with with insulin resistance.23 The studies show the effect to patients with diabetes mellitus and Grave’s orbitopathy as be without any changes in LT4 and LT3. Studies have also compared to those without diabetes mellitus.17 shown that following withdrawal of metformin there was some rebound rise in TSH levels. Does Thyroid Dysfunction Affect Diabetic Complications? Do Hypothyroid Individuals have Diabetes is a well established individual predisposing Factitious Spike in HbA1c? cause for cardiac ailments. Hypothyroidism is known to „„ Rising HbA1c in hypothyroid patients was witnessed in have independent association with atherosclerotic cardiac non-diabetic subjects also in a study.24 The possibility diseases.18 Coexistence of these disorders augment the of false spike probably owing to the lower hemoglobin cardiovascular risk of the patient. levels in hypothyroid subjects was suggested.

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„„ This questions the validity of using glycosylated „„ On similar grounds, in those with abnormal lipid hemoglobin for diagnosis of diabetes and management profile, age more than 50, TSH is proposed. in cases with concomitant thyroid abnormalities. „„ A recent analysis by Kadiyala et al. suggested a Summarizing diabetes mellitus and thyroid cross­ comprehensible perspective to this matter. An initial linking: TSH and TPO antibody assessment in patients with „„ Diabetes + Euthyroid Reduced T3, reduced diabetes was advocated. Accordingly a high-risk group responsiveness to TRH could be identified. This group would be consisting „„ Diabetes + Hyperthyroid Glycemic control of T1DM patients, those with elevated TSH and those worsens with TPO antibody positive. An annual TFT evaluation „„ Non-diabetic + Hyperthyroid Proceeds to glucose in this subset would be more likely to be cost effective intolerance in half and yielding desired results.4 cases „„ Diabetes + Hypothyroidism More events of Conclusion hypoglycemia There is a multifaceted linkage between thyroid defects and diabetes mellitus. In individuals with normal blood Is there any Difference in Diagnosis of glucose status, high thyroid hormones bring about glucose Hypothyroidism in Coexistent Diabetes? intolerance whereas amongst those with established diabetes the metabolic control gets disturbed. On the other hand, „„ The elucidation of tests of thyroid function in individuals hypothyroidism increases the susceptibility of hypoglycemic with unrestrained diabetes may be erroneous. episodes in diabetic individuals. Increased insulin resistance „„ Typical alterations include a low-serum T3, a low- is another important feature associated with hypothyroidism. serum T4 caused by decreased protein binding, and a Obscure thyroid defects would have unfavorable consequence low-serum TSH level. not only on diabetes but also on its complications. Therapeutic „„ The similar symptoms of pallor, fatigue, edema, and interventions of subclinical hypothyroidism in patients with increase in weight being common to renal disease diabetes would be advantageous. A structured and well related to diabetes and hypothyroidism may cause outlined approach to thyroid testing in diabetic subjects overlooking the diagnosis of the other disorder if one is suitable; nevertheless, there is a paucity of categorical is suspected. specifications in this direction. When should we screen diabetics for thyroid dysfunction: References „„ The significant interdependence seen between thyroid . 1 Perros P, McCrimmon RJ, Shaw G, et al. Frequency of thyroid function and metabolic status in T1DM patients dysfunction in diabetic patients: value of annual screening. Diabet warrants timely and adequate monitoring of thyroid Med. 1995;12(7):622-7. levels in these subset of patients. 2. Kordonouri O, Klinghammer A, Lang EB, et al. Thyroid autoimmunity „„ Regarding T2DM patients, the consensus regarding in children and adolescents with type 1 diabetes: a multicenter thyroid testing is less lucid. There are either no clear survey. Diabetes Care. 2002;25(8):1346-50. cut recommendations regarding once a year screening . 3 Huber A, Menconi F, Corathers S, et al. Joint susceptibity to type 1 diabetes and autoimmune thyroiditis: from epidemiology to or in opposition to routine annual estimation of mechanisms. Endocr Rev. 2008;29(6):695-725. thyroid status in these patients. . 4 Kadiyala R, Peter R, Okosieme OE. Thyroid dysfunction in patients „„ More often testing for thyroid abnormalities in diabetic with diabetes: clinical implications and screening strategies. Int J individuals is approved. Clin Practice. 2010:64(8):1130-9. „„ Similarly, some associations endorse analysis of thyroid . 5 Ray S, Ghosh S. Thyroid disorders and diabetes mellitus: double trouble. J Dia Res Ther. 2016;2(1):2016. Available from doi http:// status in pregnancy with diabetes. They propose TSH dx.doi.org/ 10.16966/2380-5544.113. estimation along with palpation of the thyroid gland at 6. Maxon HR, Krienes KW, Goldsmith RE, et al. Long term observations identification of diabetes, with systematic observation of glucose tolerance in thyrotoxic patients. Arch Intern Med. thereof in individuals with positive results. 1975;135(11):1477-80.

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. 7 Potenza M, Via MA, Yanagisawa RT. Excess thyroid hormone and 16. Vaisse C, Clement K, Durand E, et al. Melanocortin-4 receptor carbohydrate metabolism. Endocr Pract. 2009;15(3):254-62. mutations are a frequent and heterogeneous cause of morbid . 8 Bhattacharyya A, Wiles PG. Diabetic ketoacidosis precipitated by obesity. J Clin Invest. 2000;106(2):253-62. thyrotoxicosis. Postgrad Med J. 1999;75(883):291-2. 17. Kalman R, Mourits MP. Diabetes mellitis: a risk factor in Grave’s 9. Kemp HF, Hundal HS, Taylor PM. Glucose transport correlates with Orbitopathy. British J Opthalmol. 1999;83(4):463-65. GLUT2 abundance in rat liver during altered thyroid status. Molecul 18. Steinberg AD. Myxedema and coronary artery disease—a Cellul Endocrinol. 1997:128(1-2):97-102. comparative autopsy study. Ann Intern Med. 1968;68(2):338-44. 10. Mokuno T, Uchimura K, Hayashi R, et al. Glucose transporter 2 19. Pearce EN. Hypothyroidism and dyslipidemia: modern concepts concentrations in hyper- and hypothyroid rat livers. J Endocrinol. and approaches. Curr Cardiol Rep. 2004;6(6):451-6. 20. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J 1999;160(2)285-9. Clin Endocrinol Metab. 2003;88(6):2438-44. 11. Chaoxun W. The relationship between type 2 diabetes mellitus and 21. Yang GR, Yang JK, Zhang L, et al. Association between subclinical related thyroid diseases. J Diabetes Res. 2013;2013:390534. hypothyroidism and proliferative diabetic retinopathy in type 12. Leong KS, Wallymahmed M, Wilding J, et al. Clinical presentation 2 diabetic patients: a case-control study. Tohoku J Exp Med. of thyroid dysfunction and Addison’s disease in young adults with 2010;222(4):303-10. type 1 diabetes. Postgrad Med J. 1999;75(886):467-70. 22. Zolk O. Current understanding of the pharmacogenomics of 13. Vyakaranam S, Vanaparthy S, Nori S, et al. Study of insulin resistance Metformin. Clin Pharmacol Ther. 2009;86(6):595-8. in subclinical hypothyroidism. Int J Health Sci Res. 2014;4(9):147-53. 23. Rezonicco J, Rezonicco M, Pusiol E, et al. Metformin treatment for 14. Mouradian M, Abourizk N. Diabetes mellitus and thyroid disease. small benign thyroid nodules in patients with insulin resistance. Diabetes Care. 1983;6(5):512-20. Metab Synd Relat Disord. 2010;9(1):69-75. 15. Mohn A, Di Michele S, Di Luzio R, et al. The effect of subclinical 24. Christy AL, Manjerakar P, Babu RP, et al. Elevation of HbA1C in hypothyroidism on metabolic control in children and adolescents non-diabetic hypothyroid individuals: is anaemia the connecting with type 1 diabetes mellitus. Diabet Med. 2002;19(1):70-3. link?—a preliminary study. J Clin Diagn Res. 2013;7(11):2442-4.

MU-200.indd 1291 29-01-2021 15:22:38 CHAPTER

Thyrotoxicosis: Evaluation and 201 Management

Manoj Saluja

Abstract Thyrotoxicosis, or inappropriately high circulating thyroid hormone concentration causing surplus action at the tissue level, may present as a constellation of clinical manifestations. Causes vary depending on various factors like iodine intake, age, and geography. Diagnosing the entity begins with detailed history and clinical examination aided by tests like thyroid hormone profile, radio and nuclear imaging, Doppler sonogram, serology for antibodies. While management differs according to cause and patient, the target is to control symptoms (beta blockers, glucocorticoids) and treating the cause (surgery, anti-thyroid drugs, radiotherapy). Latest researches on autoimmunity and molecular targets have opened new horizons in term of diagnosis and management as well.

Introduction (painless thyroiditis seen in 0.5% of cases in Denmark, 22% in Wisconsin)1,2 (Flowchart 1). Thyrotoxicosis, characterized by inappropriately high circulating thyroid hormone concentration causing surplus action at the tissue level, may present as a constellation Approach to a Patient with of clinical manifestations.1,2 Hyperthyroidism, a clinical Suspected Thyrotoxicosis subset of thyrotoxicosis, indicates inappropriately high Combined and balanced assessment of history, clinical 1,2 synthesis and secretion of hormone(s) by the thyroid. examination, and investigations guides the physician to Effective management of the disease demands an diagnosis and management. intricate knowledge of the etiologies, pathophysiology, and treatment options. A basic understanding of approaching History a patient, clinical, and lab parameters is important, as is the knowledge about various therapeutic regimens. Clinical presentation, like medical and obstetric history, drug and diet intake, familial clustering of similar disease, is important. This provides an organized approach in less Etiology time, money, and resources. A multitude of causes have been identified, differing in Thyrotoxicosis has specific stigmata (Flowchart 2)5 frequency—depending on iodine intake (Graves’ disease and may be suspected in presence of given signs and predominates in iodine sufficient regions, nodular thyroid symptoms, concomitant type 1 diabetes/autoimmune disease in iodine deficient regions), age (toxic nodular diseases, new-onset atrial fibrillation, unexplained goiter increases with age; autoimmune thyrotoxicosis anxiety or change in behavior. Thyrotoxicosis typically is common in young and middle aged), and geography presents with low thyroid stimulating hormone (TSH),

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Flowchart 1: Causes of thyrotoxicosis2-4 Measurement of TRAb, especially in thyrotoxicosis without nodular signs/orbitopathy, distinguishes between GD and other etiologies. Young age, pre-existing autoimmune diseases, a positive family history are indications for antibody assays. Reduced cost and faster diagnosis have been proven in some studies when compared to RAIU.1 99mTc pertechnetate scan is used in nodular thyroid. Ratio of total T3 to T4 is useful in assessing hyperthyroidism. A hyperactive gland produces more T3 than T4, elevating T3 above the upper limit of normal more than T4. Vice versa is true in thyroiditis1 and thyrotoxicosis factitia (exogenous levothyroxine). Acute phase reactants indicate active inflammation, as in subacute and infectious thyroiditis.

Management We will discuss management of some of the common etiologies with a protocol for follow-up (Flowchart 4).

Graves’ Disease Follow two steps—one, symptom control and second, treat AIT2, amiodarone-induced thyroiditis type 2; PD-1, programmed cell death the underlying illness. Beta-blockers are used to abate 1; TKI, tyrosine kinase inhibitor; TSH, thyrotropin; TSHR, TSH receptor. symptoms (caused by overstimulation of beta adrenergic receptors). Propranolol (non-selective) additionally inhibits with (overt) or without (subclinical thyrotoxicosis) raised peripheral conversion of T4 to T3.2 Glucocorticoids may be fT3 and fT4. used in thyroid storm. For the underlying illness, radioactive The Flowchart 3 shows the approach to a patient with 3 iodine (RAI), ATD, and thyroidectomy are potential options. suspected thyrotoxicosis. ATDs should be stopped 12–18 months after initiation to Laboratory Investigations/Imaging look for remission—defined as no recurrence of GD after 12 months without treatment (Table 1).2 While thyroid profile (TSH, fT3, and fT4) is done to detect GD may be associated with ophthalmopathy, but the disease, further workup assists in determining the only 5% develop severe symptoms (diplopia, visual underlying cause. field defects, and blurred vision). Mild symptoms like Radioactive iodine uptake (RAIU) using 123I has photophobia, irritation, and tearing can be solved using become mainstay in diagnosing GD (diffuse uptake of radioactive iodine by the gland) and nodular thyroid tight fitting sunglasses, saline drops/gel, and application disease (focal increased and decreased uptake in TMNG; of paper tape (at night) to avoid exposure keratitis. In uptake only in the nodule in TA). Anti-thyroid drugs (ATD) case of corneal abrasion due to the tape, goggles are is given only in patients showing increased dye uptake, recommended. Medical emergency may ensue if orbital implying hyperthyroid state (Fig. 1). edema causes optic nerve compression. In such cases, Color Flow Doppler Study (CFDS) is safe and efficient, high dose glucocorticoids and orbital decompression particularly useful when RAIU is contraindicated surgery are considered. (pregnancy/breastfeeding). It distinguishes between Dermopathy-nonpitting erythematous edema on thyroid hyperactivity (increased flow) from destructive anterior shin is due to glycosaminoglycan accumulation thyroiditis and between the two types of amiodarone- in dermis. High potency local steroid cream with nightly induced thyroiditis (AIT).1 occlusive plastic wraps may be advised.6

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Flowchart 2: Signs and symptoms (hyperthyroidism)

Young females may benefit from RAI and surgery to this pathophysiology, ATDs show less satisfactory more than ATD (better remission rates of former, high results and no remission despite long-term use. RAI teratogenicity of latter), but comorbid condition/ and thyroidectomy are feasible and better management pregnancy or refusal to undergo RAI/surgery are options. Selective uptake of the radioactive dye, as indications to initiate ATDs.2 opposed to diffuse destruction as seen in GD, makes RAI first-line therapy unless contraindicated.2 Risk of Toxic Adenoma and Toxic persistent hyperthyroidism is 11–20% with RAI and <1% Multinodular Goiter with near-total/total thyroidectomy, but hypothyroidism at 5 years occurs in 16% and100%, respectively.2 Toxic adenoma (TA) (benign monoclonal thyroid tumor) secretes excess thyroid hormones due to activating mutation in TSH receptor gene (increasing adenylyl Miscellaneous cyclase independent of TSH). TMNG or Plummer’s disease Amiodarone-induced thyroiditis, caused by direct toxicity manifests as multiple autonomous nodules. Owing of amiodarone and its iodine content, is treated with

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Flowchart 3: Approach to patient with thyrotoxicosis

long-term high dose ATDs and potassium perchlorate Thyrotoxicosis without Hyperthyroidism (type-1) or high dose prednisone (40–60 mg/day) for Subacute thyroiditis, seen post-viral infections due to 1–3 months then tapered (type 2). Thyrotropin secreting antigenic mimicry, is painful but resolves spontaneously pituitary adenoma is suspected if raised TSH with high over a span of 2–3 months. It undergoes phases of T3, T4 is noted. Pituitary imaging (MRI) confirms the diagnosis. Apart from radiotherapy and/or radiosurgery, hormonal changes: initially thyrotoxicosis caused by several new pharmacotherapies are being explored. preformed hormone release followed by hypothyroidism Somatostatin receptors 2 and 5 on tumor cells have due to the lack of new hormone synthesis during the advocated somatostatin analogues as a possible cure or disease period. Painless thyroiditis (seen in iodine at least as a preoperative adjunct.2,7 They also express sufficient areas), postpartum thyroiditis (seen after dopamine receptors, but agonists have produced variable delivery/miscarriage) share an autoimmune etiology results.2 with a positive family history found more often than not. Hydatidiform mole, choriocarcinoma, testicular germ Supportive treatment is indicated beta-blockers, NSAIDs, cell tumor, metastatic follicular thyroid cancer primarily and prednisone (for pain relief). During the latter part require symptom control and multimodal approach to of disease, levothyroxine should be supplemented and eradicate the root cause via surgery, radiation, or RAI. tapered gradually while monitoring the hormone levels Detailed discussion is beyond the scope of this article. every 3–4 weeks. Selenium therapy has been tried in some

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Fig. 1: Radioactive I123 uptake images

cases with inconsistent results.2,8 Drug induced thyroiditis trimester pregnancy. Methimazole and carbimazole have (sunitinib, sorafenib, ipilimumab, and pembrolizumab)2,9 longer duration of action with once daily dosing, ensuring demands removal of offending agent and beta-blockers. better compliance. Owing to teratogenicity (cutis aplasia), they are less preferred in first trimester of pregnancy, but Exogenous Thyrotoxicosis may be restarted post 12 weeks gestation.1,2,6 This may be accidental or intentional (thyrotoxicosis ATDs should be titrated every 4 weeks. Adverse factitia). Intentional overdose needs appropriate reactions are mild—include fever, rash, urticarial and counseling2 along with beta-blockers, iopanoic acid and arthralgia, usually seen within first week of treatment. cholestyramine. In extreme cases, plasmapheresis may be Grave side effects include agranulocytosis, aplastic required.2,10 anemia, hepatic failure, lupus like vasculitis. Except agranulocytosis, all are more common with PTU. Antithyroid Pharmacotherapy Granulocyte colony-stimulating factor (G-CSF) appears ATD (methimazole, carbimazole, and propylthiouracil) to accelerate recovery in patients with agranulocytosis. inhibit formation of iodotyrosines in thyroglobulin (takes Dipping prevalence of these side effects from 30/1,000 2–8 weeks). PTU remains drug of choice in thyroid storm to 1/1,000 at the end of 30 and 180 days, respectively, (due to its peripheral inhibition of T4 to T3) and in first establishes safety in long-term therapy, especially in GD.1,2

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Flowchart 4: Management and follow-up of thyrotoxicosis4

(A)With cascading--measuring FT4 in the same sample if TSH above reference range, and FT4 and FT3 in the same sample if TSH below reference range

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TABLE 1 Treatment of Graves’ disease

Treatment Mechanism Dosing Remission Adverse effects Pregnancy rate (%) ATDsa Block TPO Initial dose proportional to 30–60 Dose and duration MMI zz MMI degree of elevation of thyroid dependent ↑ Risk of congenital zz PTUb hormones, symptoms, and Rash, elevated liver abnormalities; recommended goiter size enzymes, agranulocytosis in 2nd and 3rd trimester. (0.3%), vasculitis (<0.1%) PTU Lower teratogenic risk, ↑ risk of hepatotoxicity; recommended in 1st trimester All ATDs ↑ Risk of fetal hypothyroidism Radioactive Thyroid follicular Fixed or calculated dose based 80–90 Worsening thyrotoxicosis/ Contraindicated iodine I131 cell necrosis on goiter size and uptake orbitopathy, Thyroiditis Thyroid Removal of Total thyroidectomy 100 Hypoparathyroidism, Done in 2nd trimester surgery thyroid tissue laryngeal nerve injury a ATDs, anti-thyroid drugs; MMI, methimazole; PTU, propylthiouracil; TPO, thyroid peroxidase; T3, triiodothyronine; T4, thyroxine; ↑, increased. b Blocks TPO and peripheral T4 to T3 conversion.

Monitoring of liver function and explaining the possible Thyroidectomy reactions to the patients are quintessential. Up to 750 Subtotal, near-total, total thyroidectomies are mg/day of PTU or 20 mg/day of methimazole in lactating various options available. Severe hyperthyroidism mothers does not affect infants’ thyroid function.11 in children, pregnant females noncompliant or intolerant Severe thyrotoxicosis calls for use of additive therapy to ATDs, patients with large goiters, severe ophthalmo­ with saturated solution of potassium iodide (SSKI) at a pathy, suspicious nodules, refractory AIT, and dosage of 10 drops twice daily, iopanoic acid at 1 g/day, patients with unstable cardiac conditions are common cholestyramine (enhances enterohepatic clearance of indications.6 thyroid hormone) up to 12 gm in three divided doses (for Prior to the surgery, euthyroid state should be achieved 4 weeks).1,2 using beta-blockers (target heart rate <80/minute), ATDs (4–8 weeks) and stable (cold) iodine treatment. SSKI Radioactive Iodine Therapy (1–2 drops twice daily for 10–14 days) is administered RAI is effective, safe, avoids hospitalization with higher after ATDs and before the procedure. It reduces cure and lower recurrence rates. It causes thyroid hormone secretion and decreasing gland vascularity 2 131 specific fibrosis of the gland over weeks to months. I is (moderates intraoperative blood loss). Preoperative single administered at 75–200 µCi/g of estimated thyroid tissue dose dexamethasone (8 mg) is suggested avoid post- 123 1 divided by percent of I uptake in 24 hours. procedure nausea, vomiting, and pain.1,2,6 Laryngeal It is absolutely contraindicated in children (<5 years), nerve injury and hypoparathyroidism are possible pregnancy (as it causes fetal hypothyroidism) and complications. Hormone levels are checked every in lactating mothers. Patients are counseled to avoid 4–8 weeks and T4 is titrated accordingly (started at 50–75 conception for 3–6 months post RAI therapy. Severe µg/day). ophthalmopathy could be exacerbated, so is either Endoscopic technique is a novel approach with better avoided or given with concomitant glucocorticoid therapy cosmetic satisfaction, lesser complications, and reduced (prednisone 0.4 mg/kg for 1 month with subsequent time. Any surgical procedure, open, or endoscopic, 2 taper). To diminish the risk of worsened thyrotoxicosis, yields better result if performed by a high-volume thyroid pretreatment with ATD (methimazole than PTU) may be surgeon (>25 surgeries/year)2,6,12 considered for 3–5 days.

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Pitfalls, Controversies, and References Unanswered Questions . 1 Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of Biotin has proven to cause spurious diagnosis of GD, hyperthyroidism and other causes of thyrotoxicosis. Thyroid. especially at a dose of more than 10 mg/day, hence should 2016;26(10):1343-421. be avoided for at least 12 hours prior to testing.13 Second . 2 Sharma A, Stan MN. Thyrotoxicosis: Diagnosis and Management; Mayo Clinic Proceedings. 2019;94(6):1048-64. common pitfall is misdiagnosing iodine deficiency for . 3 Pearce EN. Diagnosis and management of thyrotoxicosis. BMJ. thyrotoxicosis under the setting of increased radioiodine 2006;332(7554):1369-73. uptake by the gland. Amplified uptake but normal T3/ . 4 Available from https://www.guidelines.co.uk/eye-ear-nose-and- T4/TSH implies iodine deficiency than endogenous throat/thyroid-disease-assessment-and-management/455108.article. . 5 Fazal-Sanderson V, Karavitaki N, Mihai R, et al. Hyperthyroidism hyperthyroidism. in adults. In: Llahana S, Follin C, Yedinak C, Grossman A (Eds). Treatment of subclinical thyrotoxicosis has been a Advanced Practice in Endocrinology Nursing. Springer, Cham; 2019. matter of debate for long. Current guidelines recommend . 6 Available from https://emedicine.medscape.com/article/121865- 12 treatment. treatment in case TSH is persistently <0.1 Mu/L. Risk . 7 Yoshihara A, Isozaki O, Hizuka N, et al. Expression of type 5 reduction of atrial fibrillation and low bone density in somatostatin receptor in TSH-secreting pituitary adenomas: a postmenopausal women is seen. possible marker for predicting long-term response to octreotide Questions concerning optimum dose and duration therapy. Endocr J. 2007;54(1):133-8. . 8 Negro R, Greco G, Mangieri T, et al. The influence of selenium of ATD in GD, use of ATDs before and after RAI therapy, supplementation on postpartum thyroid status in pregnant risk benefit ratio of block replacement regimen during women with thyroid peroxidase autoantibodies. J Clin Endocrinol RAI therapy, role of rituximab, lanreotide remain largely Metab. 2007;92(4):1263-8. unanswered. Immunomodulatory therapy is being tested 9. Morganstein DL, Lai Z, Spain L, et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed for GD. death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol (Oxf). 2017;86(4):614-20. 10. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Conclusion Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American The evaluation for cause should begin from the clinical picture Thyroid Association Guidelines Task Force on Thyroid Nodules and itself to be supported by biochemical tests, nuclear medicine, Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133. and ultrasound imaging. Increased gland function remains an 11. Azizi F, Khoshniat M, Bahrainian M, et al. Thyroid function and important aspect for therapy selection. GD and MNG remain intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab. 2000;85(9):3233-8. the common causes. Long-term ATDs have replaced RAI and 12. Zhang Y, Dong Z, Li J, et al. Comparison of endoscopic and surgery for managing GD, except in special circumstances, conventional open thyroidectomy for Graves’ disease: a meta- while nodular goiter fare less well with ATDs. Thyroiditis analysis. Int J Surg. 2017;40:52-9. constitutes major cause of thyrotoxicosis in absence of a hyper- 13. Kummer S, Hermsen D, Distelmaier F, et al. Biotin treatment functioning gland. Thyroid autoimmunity has huge scope for mimicking Graves’ disease [letter]. N Engl J Med. 2016;375(7):704-6. developing novel therapies, particularly GD by addressing the pathophysiology itself. From redressal of less effective therapies to identifying newer targets at a molecular level, we have definitely come a long way with even better prospects in near future.

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Evaluation of Non-Diabetic 202 Polyuria

Indira Maisnam, Soumita Mandal

Abstract Polyuria is defined as urinary output more than 50 mL/kg/day or 3–3.5 L/day. It should be differentiated from increased urinary frequency by proper history and documentation of increased urinary volume. Polyuria can be due to solute diuresis or water diuresis. In most cases of solute diuresis the etiology is evident from history, physical examination and baseline laboratory investigations. For water diuresis a detailed history and physical examination and a number of tests consisting of serum sodium and other electrolytes, paired plasma and urine osmolality, water deprivation test, hypertonic saline infusion, and plasma copeptin levels help establish the diagnosis.

Introduction ascending loop of Henle thereby producing hypertonic renal medullary interstitium. The sensation of thirst and Polyuria is defined as urinary output more than 50 mL/ ADH secretion is suppressed upon normalization of ECF kg/day or 3–3.5 L/day.1 It should be differentiated from volume and serum osmolality (280–295 mOsm/kg). increased urinary frequency. Polyuria can interrupt daily activities, disturb sleep, and cause bed-wetting in children. The two major types of polyuria are solute and Determinants of Daily Urine Output water diuresis. The daily urine output is dependent on solute load and concentrating ability of the nephron. Polyuria can Water Homoeostasis therefore be solute diuresis, water dieresis, or both. Extracellular fluid balance is under control of two factors: Solute diuresis due to excess saline/hypertonic saline Antidiuretic hormone (ADH) also known as arginine infusion, protein excess with urea generation, glucose, vasopressin (AVP) and thirst. A rise in serum osmolality and mannitol produces concentrated urine. Water diuresis (most sensitive to serum sodium) and hypovolemia (polyuria-polydipsia syndrome) producing dilute urine sensed by baroreceptors stimulate ADH secretion and is of two types: diabetes insipidus (DI) and primary thirst. ADH (V2) receptors are located at the luminal side polydipsia (PP). In central diabetes insipidus (CDI), there of collecting duct of the kidney. On receptor binding, ADH is partial or complete ADH deficiency; in nephrogenic leads to cAMP production with translocation of aquaporin DI (NDI), there is resistance ADH action. Excessive 2 channels to luminal membrane, allowing reabsorption water intake in absence of physiological stimulus, often of water from lumen forming concentrated urine. Water in the background of psychiatric disorders is seen in PP. moves out of the tubule along the concentration gradient Sometimes solute and water diuresis coexist, for example, created and maintained by reabsorption of solutes in thick ADH deficiency/resistance with solute diuresis. Chronic

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TABLE 1 Causes of polyuria

Osmotic diuresis Water diuresis (polyuria-polydipsia syndrome) Central diabetes insipidus (CDI) Nephrogenic diabetes insipidus (NDI) Primary polydipsia (PP) Glucosuria Tumors Congenital Psychogenic Urea diuresis zz Craniopharyngioma zz V2 receptor mutation Psychiatric illness zz zz zz Resolving phase of acute Pituitary tumor with suprasellar AQ2 channel mutation Antipsychotics extension kidney injury Drugs zz Causing dry mouth zz High protein diet zz Germinoma zz Lithium zz Glucocorticoid excess → zz Metastasis zz Amphotericin protein breakdown → Trauma zz Cidofovir urea generation zz Traumatic brain injury zz Foscarnet Sodium diuresis zz Pituitary surgery Electrolyte imbalance zz Large volume of saline/ zz Pituitary apoplexy zz Hypercalcemia hypertonic saline Infiltrative/Autoimmune zz Hypokalemia zz Post release of bilateral zz Lymphocytic hypophysitis Renal disease urinary tract obstruction zz Langerhans cell histiocytosis zz Medullary cystic kidney Mannitol zz Sarcoidosis zz Adult polycystic kidney disease zz IGF4 mediated (ADPKD) zz Immune check point inhibitors Obstructive uropathy Congenital/Genetic Systemic diseases zz Familial CDI zz Sjogren’s syndrome zz Septo-optic dysplasia zz Renal amyloidosis zz Congenital hypopituitarism zz Sickle cell disease zz Wolfram syndrome Idiopathic Hypoxic encephalopathy

renal failure, infiltrative renal parenchymal disease and suggests urea-induced diuresis. In glucocorticoid excess relief of longstanding urinary obstruction sometimes have states, polyuria occurs due to hyperglycemia and protein a mixed solute and water diuresis. Sometimes DI is seen breakdown with urea generation. A detailed medication in pregnancy due to placental vasopressinase increasing history, history of head injury, or central nervous system ADH breakdown and transient ADH resistance in second surgery is important. Mannitol and hypertonic saline half of pregnancy (Table 1). cause solute diuresis; many drugs cause NDI. Patients with DI prefer cold water; in CDI symptoms develop almost Approach to a Patient with Polyuria suddenly (as urine concentrating capacity is maintained until ADH synthesis decreases to 10–15% of normal); in History PP symptoms develop gradually. Patients with PP may A detailed history regarding age and mode of onset, have coexisting psychiatric illness. These are not precise progression, and duration of polyuria and family history discriminating criteria and overlap exists in clinical should be taken. Polyuria should be differentiated from features of CDI, NDI, and PP. The etiology of DI may be increased urinary frequency. Hereditary NDI typically evident at presentation. Polyuria in a non-diabetic patient has a neonatal presentation; most craniopharyngiomas with breast cancer could be due to metastasis to posterior present in childhood and adolescence; infiltration, tumors, pituitary or hypercalcemia of malignancy. Metastasis and metastasis present in any age. Polyuria with weight to posterior pituitary is more common than to anterior loss with family/personal history of diabetes mellitus pituitary as the systemic circulation supplies the posterior suggests diabetes mellitus/uncontrolled hyperglycemia; pituitary whereas the hypophyseal portal system supplies polyuria after recent acute kidney injury, high protein diet/ the anterior pituitary. DI due to craniopharyngioma may supplement and after release of urinary tract obstruction present with growth retardation and visual impairment.

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Often the etiology is not obvious on presentation and volume of dilute urine. Urine osmolality less than 300 unfolds as investigations progress, for example, infiltrative mOsm/kg with normal, or slightly elevated serum, disorders, tumors, hypercalcemia, hypokalemia in Bartter osmolality suggests DI. To ascertain DI type; confirmatory syndrome, etc. tests like water deprivation test and hypertonic saline In most patients with DI, presence of intact thirst infusion test are required. The water deprivation test mechanism ensures that sodium levels are within normal. is labor intensive and both tests entail some risk in However, DI may present with hypernatremia in patients susceptible individuals. Fortunately, the water deprivation with limited access to water or unable to express thirst, for and hypertonic saline tests are not indicated in every example, elderly people living alone, patients admitted patient with polyuria. in intensive care, infants, and in adipsic (impaired thirst) hypernatremia. Typically, patients with DI visiting a Polyuria in Hypernatremic Patients physician in out-patient setting complaining of polyuria Hypernatremic patients with polyuria, with urine have normal sodium levels; whereas those in intensive osmolality less than 300 mosmol/kg, have DI and care setting, infants and elderly living alone may have water deprivation test is not required as ADH is already hypernatremia. stimulated to maximally concentrate urine. The next step Physical Examination is differentiation between NDI and CDI by evaluating response to desmopressin (Box 1). Clinical examination is unremarkable in most cases; Hypernatremic polyuric patients with urine osmolality however, one should look for wasting (diabetes, more than 600 mosmol/kg have solute diuresis; however, malignancy), evidence of glucocorticoid excess, and mixed osmotic and water diuresis may be present. enlarged kidneys on abdominal palpation. Anthropometric If on giving hypotonic fluids despite normalization evaluation in a child and confrontation perimetry is to be of serum sodium, urine osmolality remains more done when history or physical examination suggests sellar than 600 msomol/kg, diagnosis is solute diuresis. If or suprasellar mass. Hypernatremic patients may have on giving hypotonic fluids, urine osmolality falls to irritability, disorientation, unconsciousness, seizures, and 300–600 msomol/kg before sodium comes down to less focal neurologic deficits. than 145 mEq/L, diagnosis is mixed osmotic and water Investigations diuresis. If on giving hypotonic fluids, urine osmolality falls to less than 300 msomol/kg before sodium comes down Confirm Polyuria While evaluating any case of polyuria, one must confirm Assessing desmopressin response to differentiate it by advising patients to maintain a home fluid intake BOX 1 between CDI, NDI, and PP and output record. A 24-hour urine output and creatinine measurements help confirm polyuria and adequacy of zz Desmopressin is given at a dose of 10 μg by nasal insufflation urine collection, respectively. or 2–4 μg subcutaneously or intravenously. Urine osmolality is measured every 30 minutes for the next 2 hours. Baseline Investigations zz Complete NDI: Urine osmolality rises <15% to a value <300 mOsmol/kg Baseline investigation include plasma glucose, HbA1c, zz Partial NDI: Urine osmolality rises 15–45% to a value <300 urea, creatinine, complete hemogram, thyroid function mOsmol/kg tests, sodium, potassium, calcium, potassium, plasma and zz Complete CDI: Urine osmolality rises >100% to a value >300 urine osmolality, urine routine examination including mOsmol/kg zz Partial CDI: Urine osmolality rises to 15–100% to a value >300 specific gravity (normal 1.010–1.025; low in DI); and other mOsmol/kg tests as history and physical examination suggest. zz Non-diagnostic: Minimal or no rise in urine osmolality to a value >300 mOsmol/kg. In most cases non-diagnostic results are seen Paired Serum and Urine Osmolality in partial CDI and PP Baseline paired serum and urine osmolality gives valuable zz A baseline (without desmopressin) plasma copeptin >21.4 pmol/L suggest NDI information. The hallmark of DI is production of large

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to less than 145 mEq/L, diagnosis is DI. Desmopressin at normal is diagnosed as CDI, NDI, and PP, respectively. response will determine DI type (Box 1). However, AVP measurement provided a correct diagnosis Hypernatremic polyuric patients with urine osmolality in only 38% cases and was especially weak in differentiating 300–600 mosmol/kg may have solute or water diuresis. A partial CDI from PP.2 AVP limitations include its platelets total daily osmolar output (urinary osmolality × 24-hour binding, instability in isolated plasma even at –20°C and urine output in litres) more than 1,000 mosmol indicates insensitivity of commercially available assays.3 Copeptin solute diuresis and less than 900 mosmol suggests water a 39-amino acid peptide is the C-terminal glycoprotein diuresis (DI). Desmopressin response will determine the moiety of AVP prohormone pre-pro-vasopressin. It DI type (Box 1). is cosecreted in equimolar amounts with AVP and neurophysin II. Copeptin is a surrogate marker for AVP Polyuria in Normonatremic Patients secretion because of long half-life, insignificant diurnal Normonatremic patients with urine osmolality more than variation, and absence of extraction step or pre-analytical 4 600 mosmol/kg have osmotic diuresis. The diagnosis procedures for testing. is frequently obvious from history and laboratory investigations. Water Deprivation Test Normonatremic patients with urine osmolality 300– Before subjecting patient to the test, moderate fluid 600 mosmol/kg may have solute diuresis, DI, or PP. A total restriction for few days re-establishes medullary daily osmolar output more than 1,000 mosmol indicates hypertonicity, which might have been lost (medullary solute diuresis and lesser suggest water dieresis. washout) due to excessive water intake in psychogenic Normonatremic patients with urine osmolality of less causes. This could have led to persistent serum than 300 mosmol/kg suggest water diuresis. hypoosmolality with wash out of solutes from medulla; hindering ADH mediated water reabsorption. Determining the Cause of Water Diuresis in All fluids are withheld during the test to induce Normonatremic Patients dehydration to stimulate maximal ADH secretion. It is The next step in water diuresis is to determine the cause important to ensure patients have no access to drinking namely CDI, NDI, and PP. water during the test (to avoid surreptitious drinking); If history and investigations suggest NDI, for example, avoid cigarette and caffeine in preceding 24 hours; and bilateral urinary tract obstruction, hypercalcemia, long- are free from non-osmotic stimuli for ADH release (e.g., term lithium use, and presenting in infancy with family nausea and vomiting). In patients with severe symptoms history of DI; water deprivation test may not be done. A (e.g., complete forms of DI), few hours of fluid restriction baseline plasma copeptin level or desmopressin response cause sufficient dehydration. Thus, the test can be started may be directly evaluated to confirm NDI (Box 1). in the morning. In mild disorders (e.g., PP), it can take In other cases of normonatremic polyuria [urine several hours for sufficient dehydration, the test may need osmolality <300 mosmol/kg (and where NDI is not the to begin the previous night. Duration of fluid deprivation obvious etiology) and total daily osmolar output <1,000 may range 4–18 hours. mosmol)]; water deprivation or thirsting test is done to At the beginning of test, patient is asked to void urine raise the serum sodium more than 145 mEq/L and plasma and initial body weight measured. Hourly monitoring osmolality more than 295 mosmol/kg to stimulate ADH to of body weight, serum sodium, urine volume, and maximally concentrate urine. urine osmolality is done. The test is terminated when The adequacy of ADH secretion and/or action can be dehydration is sufficient enough determined by body assessed indirectly or directly. In indirect testing, at end weight reduction of 3%, serum sodium more than 145 water deprivation or hypertonic saline infusion, the urine mEq/L or no further increase in urine osmolality (three osmolar response to exogenous AVP or desmopressin is consecutive urine samples with osmolality <30 mOsm/ assessed to classify the diuresis as CDI, NDI, and PP. In kg variability).5 At test, termination plasma sodium, direct test, direct measurement of AVP or copeptin is done osmolality, and AVP/copeptin are measured. The patient upon osmotic stimulation. Plasma AVP below, above, and is administered AVP or desmopressin and response

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assessed. Giving exogenous AVP (or desmopressin) mosmol/kg, diagnosis is PP. If the urine osmolality less before serum sodium is more than 145 mEq/L cannot than 700 mosmol/kg it can be CDI, NDI, or PP. distinguish CDI from PP, since in both cases ADH levels „„ Assess desmopressin response, if urine osmolality of are submaximal and will anyway respond to exogenous less than 700 mosmol/kg to differentiate CDI, NDI, or AVP or desmopressin. Therefore, maximum endogenous PP (Box 1). ADH secretion should be ensured by increasing serum „„ Plasma copeptin more than 4.9 pmol/L at end of the sodium (>145 mEq/L) and osmolality (>295 mosmol/kg) test (when serum sodium was >145 mEq/L) suggests before response to AVP or desmopressin is assessed. PP and lower value suggests partial CDI. „„ Therapeutic trial of desmopressin help differentiates Hypertonic Saline Infusion Test PP from partial CDI. Desmopressin 10 μg/day is given Hypertonic saline infusion maybe used in place of water intranasally for 3 days. Patients are advised to limit deprivation or may be used to supplement the water fluid intake to 1.5–2 liters/day. Thirst and polyuria deprivation when it is insufficient to raise the serum are assessed; and urine osmolality and plasma osmolality to more than 295 mOsmol/kg and serum sodium measured twice daily. In partial CDI, there is sodium more than 145 mEq/L (often in primary polydipsia resolution of symptoms of thirst and polyuria; whereas or partial DI). 3% NaCl is infused @ 0.1 mL/kg/minute for persistent thirst, non-adherence to fluid restriction, 1–2 hours till serum osmolality and sodium are more than and development of hyponatremia suggest PP. 295 mOsm/kg and more than 145 mEq/L, respectively. Hypertonic saline infusion should be avoided in high-risk individuals. Polyuria in Hyponatremic Patients Hyponatremia, low urine osmolality (less than half of 6,7 Interpretation plasma osmolality) in polyuric patients, suggests water „„ If at the end of water deprivation and/or hypertonic overload due to PP. Hyponatremia, polyuria, and high saline infusion test the urine osmolality more than 700 urine osmolality suggests osmotic (solute) diuresis.

Flowchart 1: A simplified approach to polyuria

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A Simplified Approach to Polyuria Conclusion Patients with polyuria should initially be classified as The diagnosis of polyuria can be challenging and needs to be solute or water diuresis. In solute diuresis the cause is differentiated from increased urinary frequency. A systematic often obvious from history, physical examination, and approach, including detailed history, physical examination, baseline investigations. To further classify water diuresis, and appropriate laboratory testing, helps in diagnosis in most more tests are needed. Due to limitations of the indirect cases. tests and increasing availability and reliability of copeptin measurements, a simplified approach to water diuresis is suggested (Flowchart 1).6 References 1. Robertson GL. Diabetes insipidus. Endocrinol Metab Clin North Am. 1995;24(3):549-72. Additional Testing 2. Christ-Crain M, Fenske W. Copeptin in the diagnosis of vasopressin- The polyuria type will determine additional testing. If dependent disorders of fluid homeostasis. Nat Rev Endocrinol. history, physical examination, and laboratory evaluation 2016;12(3):168-76. suggest osmotic diuresis; the differential diagnosis are . 3 Szinnai G, Morgenthaler NG, Berneis K, et al. Changes in plasma copeptin, the c-terminal portion of arginine vasopressin during narrowed to diabetes mellitus, urea, saline/hypertonic water deprivation and excess in healthy subjects. J Clin Endocrinol saline, and mannitol. If evaluation suggests partial or Metab. 2007;92(10):3973-8. central DI, MRI focusing on the hypothalamus and . 4 Morgenthaler NG, Struck J, Alonso C, et al. Assay for the pituitary is required. It may show mass lesions; and loss measurement of copeptin, a stable peptide derived from the of posterior pituitary bright spot in CDI. The bright spot precursor of vasopressin. Clin Chem. 2006;52(1):112-9. . 5 Barthel B. Clinical disorders of vasopressin. Manual Endocrinol results from T1-shortening effects of AVP stored in the Metab, 5th edition; 2020. pp. 100-15. neurosecretory granules. In PP the bright spot is usually . 6 Christ-Crain M. EJE AWARD 2019: new diagnostic approaches seen. However, sometimes in NDI the bright spot maybe for patients with polyuria polydipsia syndrome. Eur J Endocrinol. absent due to prolonged stimulus for vasopressin release. 2019;181(1):11-21. If evaluation suggest NDI; offending drugs, anatomic . 7 Zerbe RL, Robertson GL. A comparison of plasma vasopressin lesions of kidney and other systemic illness should be measurements with a standard indirect test in the differential diagnosis of polyuria. N Engl J Med. 1981;305(26):1539-46. looked for. In PP no further testing other than counseling is required.

MU-202.indd 1305 29-01-2021 15:22:28 CHAPTER Postgraduate Clinic on Non-Thyroidal Illness 203 Syndrome

Pankaj Kumar Agarwal

Abstract Abnormalities in thyroid function test in a hospitalized patient are not always carried forward from the past; some do develop during the course of current systemic illness as well. Such abnormalities, where thyroid gland by itself is not at fault, are categorized under the heading, non-thyroidal illness syndrome. The commonest amongst such abnormalities is lowering of serum T3. Sometimes, serum T4 and TSH may also be reduced. These may develop because of alteration in synthesis, transportation, metabolism, or regulation of these hormones at different levels of hypothalamus-pituitary-thyroid axis. Most of these changes gradually return back to normal but the extent of correction and its exact course can’t yet been defined very well. Therapeutic interventions in these cases have been found to be largely futile in most cases though T3 supplementation has been shown to be of partial help in some cardiac patients.

Introduction of the Clinical Case Answer: Normal TFT, and also normal T3, 2 months back suggests that the lady was not carrying any thyroid disorder Abnormalities in thyroid hormone tests (TFT) are a in the past. Low T3 observed during cerebrovascular event frequent finding in patients admitted in ICU or wards can therefore suggest that it might have been produced because of various systemic illnesses. Many of them by the effect of systemic non-thyroidal illness (NTI) on have had normal TFT in the past and some are found the thyroid hormones (TH) rather than being produced with normal TFT in follow-up as well. This poses a because of any organic disorder of the thyroid gland itself. question upon the genesis of these abnormalities in Such abnormalities in TFT, which arise after any NTI patients suffering from systemic illnesses. Today, in this and are not produced by the disorder of thyroid gland Postgraduate Clinic, we will discuss about a similar patient itself, are called non-thyroidal illness syndrome (NTIS). and will try to understand the disorder in a thorough Considering TFT to be normal before and after the NTI, manner. such abnormalities in the past were also known as sick A 63-year-old female was admitted in near ICU for euthyroid syndrome. The nomenclature has now been altered sensorium and right hemiplegia, two days back. discarded because normalcy cannot be assured in future, Her TFT revealed low serum T3, low normal serum T4 and always.1,2 mid normal serum TSH. Her family members informed that her TFT was absolutely within normal limits, just Question: Name some disorders which can make a person 2 months back. prone for NTIS. Answer: NTIS can be observed in as high as 70% patients Question: Given this scenario, how would you interpret admitted in the ICU.3 Some common disorders associated current low T3? with NTIS are as follows:

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„„ Severe critical illnesses: Such as pneumonia, septicemia, T4 into T3, D1 is also responsible for metabolism of reverse MI, CHF, respiratory failure, IBD, cirrhosis, CRF, DKA, T3. Downregulation of D1 in NTIS reduces its metabolism and malignancies. as well which is the main reason behind rise in reverse 7 „„ Trauma and major surgeries: Such as CABG T3 in NTIS. T4 metabolism in NTIS, thus is diverted „„ Deprivation of calories: Such as starvation and anorexia toward the formation of bio-inactive reverse T3 in place of nervosa4 bioactive T3. Inhibition of TH uptake into the cell and binding of Question: Does NTIS affect serum T3 only or it has any T3 with its nuclear receptor—Numerous cytokines can other clinical characteristics as well? be produced during systemic illnesses such as IFN- Answer: Clinical characteristics observed in NTIS are gamma and Nonesterified fatty acids (NEFA). These may actually that of NTI and not because of abnormalities interfere with the entry of TH into the target cell and their in TFT. Even total deficiency of TH may take as long interaction with TH receptor. It creates a situation of tissue as 2–3 weeks in producing its effects. So, even with the hypothyroidism in NTIS.8 given abnormality of TFT, most patients appear to be Low T4 syndrome (downregulation of T4 content in clinically euthyroid. In the absence of any discernible circulation)—Fall in serum T4 is an indicator of rising clinical finding specific for the thryoid, NTIS is classified severity of NTIS. This can be produced because of two according to its laboratory characteristics only. main reasons. Low T3 syndrome—This is the commonest presentation Increased metabolism of T4—Systemic illnesses are of NTIS, which is seen in nearly 70% (40–100%) cases. It is often associated with fall in tissue perfusion. This may be often associated with elevated serum reverse T3 levels. associated with expression of D3 which converts T4 into Serum T4 and TSH levels are usually normal in the reverse T3.7 This leads to rise in serum reverse T3 level and beginning.3-5 fall in serum T4 level. Low T4 syndrome—With the progression of systemic Inhibition of binding of T4 to TH binding proteins—Not illness, serum T4 level also starts declining along with only the metabolism, but the circulatory transportation serum T3.1 of T4 is also affected in NTIS. As an acute phase reactant, Low TSH—Acute incident events such as major serum albumin concentration falls in any acute illness. trauma, MI, or surgery are immediately associated with NEFA, which is otherwise bound to this albumin; therefore, transient TSH elevation but progression of systemic illness increases in circulation. It displaces TH from TBG, which may lead to fall in serum TSH levels in nearly 10% of such leads to fall in total T4 (and total T3) concentrations.5 cases.1 Free T4 and T3 hormone concentrations largely remain Question: What could be the pathophysiology of unaffected.8,9 abnormalities in TFTs in NTIS? Low TSH (central downregulation of hypothalamic Answer: NTI may affect every aspect of TH including its TRH and pituitary TSH release)—NTIS may be associated secretion, peripheral metabolism, and action. with reduction in sensitivity of thyrotrophs toward TRH Low T3 syndrome (downregulation of T3 content in leading to fall in TSH secretion. This too may arise out of target tissues)—Low serum T3 is the initial feature of NTIS, two reasons. which is associated with fall in tissue T3 concentration and Cytokines induced direct suppression of TSH— its effects. It can be produced because of following factors. Cytokines, especially interleukins (mainly IL6), tumor Inhibition of conversion of T4 into T3—Approximately necrosis factor (TNF alpha) and interferons (IFN beta), can 80% of circulatory T3 is derived from the deionization of T4 directly suppress thyrotrophs to reduce TSH secretion.5 by 5’-deiodinase type 1 (D1). NTIS leads to downregulation Reduced stimulation of TSH secretion—Thyrotrophs of D1 leading to reduced T4 to T3 conversion and therefore possesses a different set of enzyme, deiodinase type low serum T3.6 2 (D2), which converts intra-pituitary T4 into T3. T3 Inactivation of T3 and production of reverse T3— thus produced within the thyrotrophs is responsible for Another enzyme, 5’-deiodinase type 3 (D3), converts T4 negative feedback and suppression of TSH secretion. into reverse T3. This is upregulated in NTIS leading to This D2 is up regulated in NTIS, leading to rise in intra- increased synthesis of reverse T3. In addition to converting pituittary T3 and suppression of TSH secretion.6 NTIS,

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thus is associated with exactly opposite effects on tissue T3 associated with significant morbidities but have been concentrations. Tissue T3 concentration falls in peripheral found to carry 1.8× higher risk of total mortality and 2.5× tissues but rises in thyrotrophs. higher risk of cardiac mortality as well.10 Reduced T3 concentration in target tissues and its Low T4 level with NTI actually points toward a much reduced binding with TH receptors favors the hypothesis grave prognosis. Serum T4 <4 mcg/dL may increase that NTIS is not merely an adaptive response to the systemic mortality by 50% and level <2 mcg/dL may increase it up illness but is an actual state of “tissue hypothyroidism.” to 80%.1,5,8,10-13 Initial changes could be the compensatory responses Question: If low T3, T4, and TSH are so clearly linked with toward a systemic illness but prolongation of this poorer clinical outcomes then should these patients be adaptation definitely becomes harmful in the long term.8 offered TH supplementation? Question: What are the differential diagnoses for various Answer: NTIS was earlier thought to be just compensatory abnormalities found in TFT in NTIS? adaptation of acute systemic illnesses only but the view is Answer: In fact, abnormalities in TFT, seen in NTIS, may gradually changing. Now we know that this adaptation is mimic any organic disorder of the thyroid gland. not always beneficial for the patient. Many clinical studies Low or low normal serum T3, T4, and elevated serum have been performed in recent past to look for the effects TSH level, sometimes found in the initial course of the of TH supplementation in such cases. disease may mimic Hashimoto thyroiditis and subclinical Intravenous T4 therapy—Intravenous T4 therapy or overt hypothyroidism. (1.5 mcg/kg/d IV) has been tried in some critically ill Midnormal or low normal serum T3, T4, and low TSH patients with low serum T4 concentration. Contrary to the level, often seen in advanced NTIS may mimic subclinical presumptions, it could not reduce total mortality rate.14,15 thyrotoxicosis or central hypothyroidism. Inability to normalize serum T3 level was opined to be the NTIS may not only produce new changes in TFT, reason for its inefficacy.8 which may mimic organic disorders of thyroid gland, but T3 Therapy—In an attempt to normalize serum T3 may also interfere with the detection of its preexisting levels, T3 supplementation was also tried but this too organic disorders as well. Chronic severe NTIS and use of could not reduce mortality.16 dopamine or glucocorticoid therapy may lead to marked Till date, clinical benefits of TH supplementation have suppression of TSH secretion. This may interfere with been observed in cardiac patients only.17 Its hypothesized the diagnosis of untreated or partially treated thyroprivic that IV T3 supplementation should at least be tried in hypothyroidism. Similarly, low serum T3 in NTIS will patients with NTIS in whom serum T4 level is less than change the reflection of T3+T4 thyrotoxicosis into T4 4 mcg/dL. With clinical recovery in NTI, it can be switched toxicosis alone.1,8 to oral T4 supplementation.8 Raised serum T3, low serum reverse T3, markedly TRH therapy—Knowing that the hypothalamo- disturbed serum TSH (>20 mIU/L or <0.1 mIU/L) and pituitary set point is low in patients with NTIS, TRH therapy presence of antithyroid antibodies may be the indicators of has also been tried in it. It could successfully normalize organic thyroid disorders along with systemic illnesses.5,8 serum TSH, T4, T3, and reverse T3 levels. Considering Above mentioned facts preclude the policy of routine the catabolic state of these ill patients, addition of growth screening of critically ill patients for thyroid dysfunctions. hormone to TRH has been found to be more effective in In fact, during any critical systemic illness, only those raising anabolic activities in these patients.13,18 patients should be screened for thyroid dysfunctions in whom there is a high degree of clinical suspicion of any Conclusion organic disorder of thyroid gland. It can clearly be understood that systemic illnesses can affect Question: Does NTIS carry any prognostic significance as TFT in variety of manners. Many of these affections have well? been recognized well and there pathogenesis have also been Answer: Serum T3 levels have been found to be inversely deciphered up to some extent. Yet, there are still many unseen proportional to the severity of NTI. Low serum T3 levels facets of this disorder which are restricting us from offering any observed during coronary angiography are not only meaningful therapy to our patients.

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References 10. Coceani M, Iervasi G, Pingitore A, et al. Thyroid hormone and coronary artery disease: from clinical correlations to prognostic . 1 Bravermen LE, Cooper DS (Eds). Werner and Ingbar’s The Thyroid: implications. Clin Cardiol. 2009;32(7):380-5. A Fundamental and Clinical text, 10th edition. Philadelphia: 11. Tognini S, Marchini F, Dardano A, et al. Non-thyroidal illness Lippincott Williams and Wilkins; 2013. p. 10. syndrome and short term survival in a hospitalised older population. . 2 Aytug S. Euthyroid sick syndrome. 2020. Available from: https:// Age Ageing. 2010;39(1):46-50. emedicine.medscape.com/article/118651-overview 12. Bello G, Pennisi MA, Montini L, et al. Non-thyroidal illness syndrome . 3 Gutch M, Kumar S, Gupta KK, et al. Prognostic value of thyroid and prolonged mechanical ventilation in patients admitted to the profile in critical care condition. Indian J Endocrinol Metab. ICU. Chest. 2009;135(6):1448-54. 2018;22(3):387-91. 13. Van Den Berghe G, Wouters P, Weekers F, et al. Reactivation . 4 Ganesan K, Wadud K. Euthyroid sick syndrome. In: StatPearls. of pituitary hormone release and metabolic improvement by Treasure Island (FL): StatPearls Publishing; 2020. Available from: infusion of growth hormone releasing peptide and thyrotropin https://www.ncbi.nlm.nih.gov/books/NBK482219/ [Updated 2019 releasing hormone in patients with protracted clinical illness. J Clin Dec 17]. Endocrine Metab. 1999;84(4):1311-23. . 5 Meyer S, Schuetz P, Wieland M, et al. Low triiodothyronine 14. Brent GA, Hershman JM. Thyroxine therapy in patients with severe syndrome: a prognostic marker for outcome in sepsis? Endocrine. 2011;39(2):167-74. non thyroidal illness and low serum thyroxine concentration. J Clin . 6 Michalaki M, Vagenakis AG, Makri M, et al. Dissociation of the Endocrine Metab. 1986;63(1):1-8. early decline in serum T3 concentration and serum IL-6 rise and 15. Debaveye Y, Ellger B, Mebis L, et al. Effects of substitution and high TNFalpha in non-thyroidal illness syndrome induced by abdominal dose thyroid hormone therapy on deionisation, sulfoconjugation, surgery. J Clin Endocrine Metab. 2001;86(9):4198-205. and tissue thyroid hormone levels in prolonged critically ill rabbits. . 7 Jameson JL, Fauci AS, Kasper DL, et al. Harrison’s Principles of Endocrinology. 2008;149(8):4218-28. Internal Medicine, 20th edition. New York: McGraw Hill, Health 16. Becker RA, Vaughan GM, Ziegler MG, et al. Hypermetabolic Professions Division; 2018. p. 20. low triiodothyronine syndrome of burn injury. Crit Care Med. . 8 DeGroot LJ. The non-thyroidal illness syndrome. In: Feingold KR, 1982;10:870-5. Anawalt B, Boyce A, et al. (Eds). Endotex. South Dartmouth (MA): 17. Kaptein EM, Sanchez A, Beale E, et al. Thyroid hormone therapy MDText.com, Inc.; 2000. Available from: https://www.ncbi.nlm.nih. for postoperative non thyroidal illnesses: a systematic review and gov/books/NBK285570/ [Updated 2015 Feb 1]. synthesis. J Clin Endocrine Metab. 2010;95(10):4526-34. . 9 Chopra IJ. Simultaneous measurement of free thyroxine and free 18. Van Den Berghe G, Baxter RC, Weeker F, et al. The combined 3,5,3’-triiodothyronine in undiluted serum by direct equilibrium administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH dialysis/radioimmunoassay: evidence that free thyroxine and to men with prolonged critical illness evokes superior endocrine free triiodothyronine are normal in many patients with the low and metabolic effects compared to treatment with GHRP-2 alone. triiodothyronine syndrome. Thyroid. 1998;8(3):249-57. Clin Endocrinol. 2002;56(5):665-9.

MU-203.indd 1309 29-01-2021 15:22:22 CHAPTER

Common Mistakes in 204 Thyroid Disorders

Y Bhasker

Abstract The knowledge on practical management of thyroid disorders with precision is ever expanding as a huge number of cases are detected because of easy availability of investigation facility. However, all the cases with abnormal results of thyroid function do not require treatment immediately, or nor ever. In this chapter, brief analysis of relevant investigation and modalities of treatment on such entities of thyroid disorders is presented.

Introduction further appropriate investigations, final diagnosis, plan of long-term treatment, and management. This article For long time, the diagnosis of hypothyroidism was only focuses on discussed issues of thyroid functional disorders clinical. It used to be suspected only after manifestation of myxedema (spotters in undergraduate examination) and to guide the physician approach. hyperthyroidism on development of features of Graves or hypermetabolic state. Later indirect tests like effective Common Mistakes thyroxine ratio was available, but not within reach. Hence, „„ Proceeding further without recheck of the laboratory clinical parameters were only the guidance to manage results the cases until availability of triiodo thyroxine (T3), „„ Not ordering further investigations tetraiodo thyroxine (T4), and thyroid stimulating hormone (TSH).1 „„ Starting on medicines on certain thyroid disorders, Ever since direct hormone assay (T3, T4, TSH) is which spontaneously remit widely available for past three decades, there is great „„ Use and abuse of iodine leap in detection of number of thyroid disorders and „„ Under utilization of radioisotope scanning of thyroid management precision. In the last decade, diagnosis „„ Hurry to start on medicines in subclinical hypo- and of thyroid disorders clinically has become a rarity and hyperthyroidism physician is encountered with abnormal reports of thyroid „„ Monitoring of treatment of hyperthyroidism by TSH function tests for opinion. This is because the thyroid levels function tests are done as routine in non-thyroid illness „„ Selection of modalities of treatment (anti-thyroid drugs, and sometimes on self motivation. Potentially misleading radioiodine ablation, surgery) in hyperthyroidism reports may result in mistakes of management. In such „„ Pregnancy versus thyroid disorders a scenario, physician is expected to guide the patient for „„ Diet restriction

MU-204.indd 1310 29-01-2021 15:22:18 Common Mistakes in Thyroid Disorders CHAPTER 204 1311

Common Abnormalities in Disorders with Increased TSH, Normal/Abnormal Thyroid Function Test (TFT) T3, and T4 „„ Hashimoto’s/autoimmune thyroiditis, atrophic „„ Increased TSH, normal/abnormal T3, T4 thyroiditis (end stage). It can present as hyper/ „„ Decreased TSH, normal/abnormal T3, T4 hypothyroidism/normal. Investigations—TPO „„ Goiter or swelling of thyroid with normal TSH, T3, T4 antibodies positive, Ultrasound, FNAC-lymphocytic Further investigations: infiltration suggestive of autoimmune thyroiditis. „„ Confirm the abnormality by repeating first line „„ Iodine deficiency/endemic goiter—Not seen nowadays, investigation TFT, since the treatment is prolonged diagnosed epidemiologically. Urine iodine levels are and/or destructive less than 50 ng/L. Treat by iodine supplementation. „„ Estimation of thyroid antibodies Iodine has complex effects on thyroid. Chronic —— Thyroid peroxidase antibodies (TPO) administration of iodine causes hypothyroidism due —— Thyroglobulin antibodies (Tg-Ab) to increased iodine content in thyroid. Paradoxically —— TSH receptor antibodies (Tr-Ab), assay form of it can also precipitate thyrotoxicosis.2,3 Hence, there is thyroid receptor stimulating immunoglobulin hardly any necessity to recommend iodine for healthy 2 (TSI) used to predict neonatal thyrotoxicosis persons. The above antibodies tests are neither 100% sensitive „„ Goitrogens—Intake of cassava root, cabbage, nor specific.2,3 TPO assay is commonly done to assess cauliflower—due to presence of thiocyanate, causes the immune status of the disease, rest of the tests are not hypothyroidism, diagnosed epidemiologically.3 Treat routinely done and expensive. TPO and Tg-Ab present in by thyroxine supplementation. There is no evidence normal population, auto immune hypothyroidism, Grave’s based study to recommend routine restriction of disease, multinodular goiter (MNG), transient thyroiditis. cabbage, cauliflower, in all cases of hypothyroidism. Where as Tr-b is absent in normal population, MNG, „„ Miscallaneous causes are—Iaotrogenic, infiltrative transient thyroiditis, and present in Grave, autoimmune disorders like amyloidosis, sarcoidosis. hypothyroidism. Goiter and TPO-Ab are absent in secondary hypothyroidism. Disorders with Low/Undetectable TSH, Normal/ „„ Ultrasound neck—It is done to know the size of thyroid, Abnormal T3, and T4 nodules in the thyroid gland, and for the presence of „„ Subacute thyroiditis/De quervain’s—due to viral increased vascularity seen in Grave’s disease. etiology. There is release of stored hormones due to „„ Fine needle aspiration cytology (FNAC) usually inflammation.3 Spontaneous remission in 6 weeks. If ultrasound guided is done to differentiate benign thyroid antibodies are positive, suggests risk of ultimate and malignant lesions and also to note lymphocytic progression to hypothyroidism. When prolonged infiltration suggestive of autoimmune thyroiditis. abnormal levels of TFT, isotope scan—a low uptake „„ Radioisotope scanning of thyroid—It is very specific confirms transient thyroiditis. Symptomatic treatment investigation in differentiation of hyperthyroidism with NSAID/prednisolone. etiologically. Transient thyroiditis like sub-acute, „„ Silent/postpartum thyroiditis—Presence of TPO viral, postpartum thyroiditis shows low uptake antibodies follow for autoimmune thyroiditis. of tracer because of follicular damage. In Grave’s Isotope scanning—negligible uptake. No role for disease, gland is enlarged with homogenous increased glucocorticoids. Recovery is rule. Sometimes, uptake of tracer. Toxic adenoma shows focal areas pregnancy may be masking autoimmune thyroiditis. of increased uptake of tracer and suppressed uptake No role for anti-thyroid drugs. Symptomatic treatment in the remainder of the gland. Toxic multi-nodular with propranolol.3 gland is enlarged with increased and decreased uptake „„ Grave’s disease—Autoimmune disorder. Monitoring of tracer. Cold nodule (absence of uptake of tracer) for life long. Ultrasound—increased vascularity. suggestive of neoplastic lesion.2 Thyroid antibodies—TPO, Tr-Ab, Tg-Ab all are positive.

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Isotope scanning—homogenous and diffuse high based on the levels of T4, since TSH levels take longer time uptake confirms the diagnosis. Ideal management by to reach normal. anti-thyroid drugs, sometimes with remission after 2-4 12–18 months of treatment. Pregnancy—Thyroid Disorders „„ Toxic adenoma/solitary nodule—Ultrasound and FNAC to confirm the nodule. Isotope scan is the choice There is altered metabolism of thyroid hormones and of investigation—focal uptake with hyper-functioning thyroid–pituitary axis stability. Hence trimester specific 2,6 nodule and diminished uptake in the rest of the gland. normal ranges of TSH, T3, and T4, to be followed. Treatment of choice is radioiodine ablation.2,4 „„ Toxic multinodular goiter—Ultrasound and FNAC, Case Reports—Author’s Own Experience isotope scanning ideal investigation—heterogenous Case 1 uptake with multiple regions of increased and „„ Female 35 years; Engineer in Govt. Service decreased uptake of tracer. Radioiodine ablation is the „„ Incidental finding of low TSH, high T4, and normal T3 treatment of choice. Alternate treatment is surgical if „„ Ultra sound neck FNAC—Cystic colloid nodule compressive symptoms are present. „„ One month later—Persistent low TSH, TPO positive Goiter or Swelling of Thyroid with Normal TSH, „„ Isotope scanning of thyroid showed normal uptake of T3, and T4 tracer. Not started on any treatment because of normal 2 uptake of tracer. Two months later repeat TFT showed „„ Simple goiter—unknown stimulus 3 raised TSH—26.02 µIU/mL. „„ Juvenile goiter—teenagers „„ Started on thyroxine. What started as hyperthyroidism „„ Non-toxic adenoma turned to be autoimmune hypothyroidism over a „„ Non-toxic multinodular goiter If ultrasound, FNAC, and thyroid antibodies are period of 2 months. negative, these conditions require follow-up with Case 2 monitoring of TFT periodically. No medical treatment „„ Male 40 years general check-up before leaving for Gulf. is necessary. Surgical treatment if compressive signs develop. Decrease TSH and increased T4 and T3. „„ Ultrasound neck diffuse enlargement of both lobes, Sick Euthyroidism or Non-thyroid Illness or increased vascularity. FNAC suggestive of autoimmune Low T3 Syndrome thyroid. TPO positive. Isotope scanning—intense Thyroid gland is normal, Abnormal TFT (Low T3, Low or homogenous uptake of tracer 11.28% (normal is normal T4, Low or normal TSH) due to acute systemic 0.5–4%). illness, causing failure of peripheral conversation of T4 „„ Diagnosis—Graves disease under management with to T3. Needs to be re-evaluated after recovery from acute antithyroid drugs. illness for thyroid disorder.3 Case 3 Subclinical Thyroid Disease „„ Male 58 years presented with increased appetite, Subclinical hypothyroidism with high TSH, normal palpitations, tremors. T3, T4, and Subclinical hyperthyroidism with low TSH, „„ Decreased TSH and increased T4 and T3. normal T3, and T4 are milder forms of the disease. „„ Ultrasound small colloid cyst left lobe of thyroid. Isotope No universally accepted guidelines for treatment and scanning—diffuse increased tracer uptake—28.1%. case to be managed depending on symptoms, age, and Diagnosis Graves disease. comorbidities. Excessive treatment to be avoided.3,5 „„ Clinically this case suggestive of hyperthyroidism, ultrasound showed colloid cyst but isotope scanning Monitoring of Therapy is in favor of Graves disease. For the above three cases Treatment of hypothyroidism is monitored based on the of hyperthyroidism isotope scanning is the clinching levels of TSH. Treatment of hyperthyroidism is monitored investigation.

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Conclusion References It is obvious TFT reports suggestive of hypothyroidism . 1 Maenhaut C, Christophe D, Vassart G, et al. Ontogeny, Anatomy, Metabolism, Physiology of the thyroid disease; 2015. irrespective of etiology, the treatment is thyroxine replacement . 2 Strachan MWJ, Well price JN, Ian D, et al. Penman Davidson except in iodine deficiency hypothyroidism. Whereas TFT Principles and Practice of Medicine, 22nd edition. London: Elsevier reports suggestive of hyperthyroidism, the treatment differs. Churchill Livingstone; 2014. Transient thyroiditis—No treatment, spontaneous recovery 3. Kasper DL, Fasu AL, Hauser S L, et al. Harrison’s Principles of Internal mostly. Medicine, 19th edition. New York: McGraw Hill Education Medical; Grave’s disease—Antithyroid drugs or Radioiodine ablation. 2015. Toxic adenoma/solitary nodule and Toxic multinodular . 4 Leo DE, Lee SY, Braverman LE, et al. Hyperthyroidism. Lancet. goiter—Radioiodine ablation is the treatment of choice. To 2016;388(10047):906-18. differentiate above disorders of hyperthyroidism, isotope scan . 5 Surks M, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: is the investigation of choice. scientific review and guide lines for diagnosis and management. JAMA. 2004;291(2):228-38. . 6 Glinoer D. The regulation of thyroid function in pregnancy: path ways of endocrine adaptation from physiology to pathology. Endocr Rev. 1997:18(3):404-33.

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Glucocorticoids-induced 205 Osteoporosis

Saurabh Jain

Abstract Prolonged use of Glucocorticoids is associated with several adverse effects including Osteoporosis. High daily dose of GC (>7.5 mg), cumulative dose >5 gm both lead to increased risk of fractures. Vertebral fractures are most common. Often asymptomatic, these are found as incidental findings on routine chest X-rays. The fracture risk assessment tool – FRAX considers several risk factors for osteoporosis (including GC use) with the bone mineral density and gives us an estimate of the 10-year risk of major osteoporotic fracture and hip fracture in patients who are more than 40 years old. Prevention of GC-induced fractures requires identifying the high risk patient, and initiating them on preventive strategies like weight-bearing exercises, maintenance of normal weight, smoking cessation, and limitation of alcohol consumption. Bisphosphonates are considered as first-line agents for the management of Glucocorticoid induced osteoporosis. Treatment with an anabolic agent such as teriparatide or abaloparatide and Denosumab (human IgG2 monoclonal antibody specific to RANKL) should be followed by an antiresorptive agent. Patients experiencing treatment failure or having contraindications to conventional medications are considered of third line agents like raloxifene or with calcitonin. Raloxifene (a selective estrogen-receptor modulator) is approved by the FDA for the prevention and treatment of GC-induced osteoporosis in postmenopausal women. Pharmacologic treatment to prevent fractures are not recommended in pregnant ladies.

Introduction inflammatory or neoplastic conditions.1 GC use over long term is associated with various adverse effects. Amongst Glucocorticoids (GC) are used in many inflammatory and them fracture is the most common preventable side effect autoimmune conditions. While being used to treat an which is often serious.2-4 Increase in the dose and duration underlying disease, GC are associated with appreciable of GC increases the risk of fracture.5-7 risk of bone loss and increase the risk of fractures, which is actually more pronounced during the initial few months Risk Factors for Fractures of use. Related to Glucocorticoid Use „„ High daily dose of GC (e.g., >7.5 mg of prednisone Epidemiology daily) The association of GC and osteoporosis was first described „„ Cumulative dose of GC >5 g 80 years ago. The US data suggests that approximately „„ Current or recent (<3 month) use of GC 3% of adults older than 50 years and almost 1% of all „„ GC-associated myopathy (increases the risk of falls) adults receive GC either for allergic conditions or various „„ GC-induced hypogonadism

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Related to Underlying Condition fractures is increased significantly. But, high doses if used intermittently (total cumulative dose of <1 g) had less Rheumatoid arthritis, ankylosing spondylitis, etc. are 8 independent risk factors. fracture risk. High-dose inhaled GC (dose equivalent to ≥1 mg fluticasone) when used for more than 4 years showed a marginal increase in the risk of fracture.9 Related to Risk of Osteoporosis Also worth remembering is that GC can cause avascular Advance age; white race; female sex; menopause; smoking; necrosis. alcohol use (>2 units per day); bone mineral density T-score less than −1.5; previous fracture. Pathophysiology (Flowchart 1) Vertebral fractures are the most common GC induced Specifically related to bone, GC receptors are found on all fractures and are often asymptomatic. These are diagnosed cells except osteoclast. GC use sends negative feedback as incidental finding on chest or abdominal radiograph. effect on the hypothalamus and pituitary gland. It acts as In patients who have asymptomatic vertebral fracture an exogenous cortisol, so elevated GC levels reduce the there is often no history of preceding trauma. The typical secretion of ACTH, along with FSH and LH. Reduction in symptomatic patient presents with acute back pain ACTH results in reduced endogenous steroid hormone after sudden bending, coughing, or lifting. The risk of production from the adrenal glands including cortisol and vertebral fracture increases within 3 months of starting the androgens. treatment and is maximum at 12 months.7,8 Low FSH and LH reduce production of androgens and Studies, having a follow-up of 6 months to 10 years, estrogen from the gonads. Low androgens and estrogens have shown that with high dose of GC, risk of vertebral increase the risk of osteoporosis.

Flowchart 1: Pathophysiology of glucocorticoid-induced osteoporosis

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Bones contain three main types of cells. Osteocytes— Clinical Evaluation the mature bone cells formed by osteoblasts, Osteoblasts— The fracture risk assessment tool—FRAX considers several the bone building cells, and Osteoclasts—bone eating risk factors for osteoporosis (including GC use) with the cells. And in our case, immature osteoclast termed bone mineral density and gives us an estimate of the 10- pre-osteoclasts. GC stimulates osteocyte apoptosis, with year risk of major osteoporotic fracture and hip fracture in long-term use. The predominant effect of GC on the patients who are more than 40 years old.11 skeleton is actually reduction in bone formation. The One of the limitation of the FRAX score calculation is decline in bone formation is mediated by direct inhibition that it uses bone mineral density at the hip joint, which of osteoblast proliferation and differentiation, and by an can give false values as GC have the greatest detrimental increase in the apoptotic rate of mature osteoblasts and effect on the vertebrae. Also in patients, receiving very osteocytes. High GC levels stimulate RANKL synthesis high doses of prednisone may underestimate the risk of by osteoblasts thus supporting osteoclast differentiation fracture. and net bone resorption. In normal condition there is this molecule called osteoprotegerin, which regulates this osteoblast-osteoclast interaction, by binding to the Treatment RANKL and preventing osteoclast stimulation. However, Prevention of GC-induced fractures requires identifying GC increases osteoclastic activity by suppressing synthesis the high-risk patient, and initiating them on preventive of osteoprotegerin and also by increasing production strategies. of RANKL, which is required for osteoclastogenesis. So RANKL binds onto osteoclasts stimulating osteoclastic Nonpharmacologic Options activity, it becomes active osteoclast, which will breakdown „„ Weight-bearing exercise bone minerals and this is termed bone resumption. In „„ Maintenance of normal weight addition GC increases bone resorption by decreasing „„ Smoking cessation secretion of androgens and estrogens. The net bone „„ Limitation of alcohol consumption resorption by osteoclast reduces bone mineral density and „„ Assessment and management of fall risks bone remodeling, thereby increasing the risk of fractures. „„ Minimizing GC use Bone resorption leads to an increase in serum calcium and phosphate levels due to the breakdown of bone minerals. Calcium and Vitamin D Now when you have a high serum calcium the body Because GC increases the excretion of urinary calcium, does not want to keep it. High serum calcium reduces dietary intake of calcium (1,000 mg per day) and vitamin D intestinal absorption of calcium and also increases urinary (600–800 IU) is commonly suggested to patients receiving calcium excretion because you want to get rid of all the GC. calcium in your body, now this will cause hypocalcemia. A Cochrane meta-analysis suggested that the bone Hypocalcemia stimulates the parathyroid gland to mineral density at the lumbar spine was significantly release parathyroid hormone. Parathyroid hormone better in patients receiving calcium and vitamin D works by binding onto parathyroid hormone receptors supplementation in comparison with the placebo group.12 on osteoblasts, which stimulates expression of RANKL, which will further promote osteoclastgenesis and so Pharmacologic Treatment increase bone resorption further. Indirect GC effects that also predispose patients to an increased risk of fractures Bisphosphonates include reduced muscle mass and weakness, both leading Multiple randomized trials have suggested that in patients to an increase in the risk of fall. receiving GC, the use of bisphosphonates is associated After discontinuation of GC treatment, the risk with an increase in the bone mineral density.13 A 2016 of fracture also downtrends. It was also reaffirmed Cochrane review involving 12 RCTs showed that in the in a prospective study where within 6 months after group receiving bisphosphonates the risk of new vertebral discontinuation of GC, lumbar spine showed significant fractures was lower by 43% in comparison to those who recovery in bone mineral density.10 received either calcium or vitamin D, or both. In patients

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receiving bisphosphonate treatment over a period of Hence in patients on immunosuppressive medicines or 3–5 years, there was less incidence of serious adverse biologicals, denosumab is generally not recommended. events (like osteonecrosis of the jaw and atypical femoral Denosumab, in dosages that is used to treat osteoporosis, fractures).14 Due to their good safety profile and affordable is associated with minimal risk of osteonecrosis of the cost, oral bisphosphonates are recommended as first-line jaw and atypical fractures.13 However, similar to anabolic agents to prevent GC induced fractures unless they are agents, after its discontinuation there is a rapid increase contraindicated or have undesirable adverse effects. in the rates of vertebral fracture, especially in patients Patients who are not able to tolerate the oral with a previous history of vertebral fracture. Here also an formulation, or who for some reasons are not adherent alternative antiresorptive therapy should be initiated after to oral bisphosphonate regime, are offered intravenous its discontinuation.19 bisphosphonates. Third-line Agents Other Recommended Agents Patients experiencing treatment failure or having Teriparatide and abaloparatide are anabolic molecules contraindications to conventional medications are and increases bone formation.15 In a study of 428 patients considered of third-line agents like raloxifene or with on GC, receiving either teriparatide or alendronate were calcitonin. Raloxifene (a selective estrogen-receptor followed for 36 months. Patients receiving teriparatide modulator) is approved by the FDA for the prevention and showed better improvement in bone mineral density at treatment of GC-induced osteoporosis in postmenopausal the spine, than alendronate. They also had lesser rate of women. A study done in postmenopausal women receiving radiographic vertebral fractures. However, no significant GC showed that raloxifene significantly increased absolute difference was noted in the rates of nonvertebral fracture in bone mineral density at the lumbar spine by 1.3%, in the two groups.16 In the teriparatide group, 21% of patients comparison to Calcium and Vit D supplementation.20 had hypercalcemia, as compared to 7% in the alendronate However, no difference in bone mineral density was group. In a smaller study, effects of teriparatide and noted at the femoral neck between the treatment groups. risedronate were noted on middle-aged men receiving Studies have shown that raloxifene use is associated GC. Teriparatide group showed higher bone mineral with decreased risk of estrogen-receptor–positive breast 21 density and lower rate of fractures.17 However, after cancer; however, it can cause serious complications like 22 discontinuation of teriparatide, bone loss and fractures venous thromboembolism, and fatal stroke. occurred at a rapid rate. Hence, after discontinuation Calcitonin-Salmon is a man-made form of the of teriparatide, it is prudent to initiate an antiresorptive hormone. A meta-analysis of nine trials with 500 patients agent such as bisphosphonate or denosumab. In severe on GC, compared the effects of calcitonin with calcium osteoporosis where bone mineral density T score is less and Vit D supplementation, concluded that calcitonin than −2.5 in patients with a past history of fracture, initial improved the bone mineral density at the lumbar spine treatment with an anabolic agent such as teriparatide or (but not hip); however, there was no difference in the 23 abaloparatide should be followed by an antiresorptive risk of vertebral fracture in both the groups. Calcitonin agent. is available as injectables which can be administered Denosumab is human IgG2 monoclonal antibody subcutaneously and also as a nasal spray. Hypocalcemia specific to RANKL. By binding to RANKL, it suppresses the and Vit D deficiency must be corrected before initiating development of osteoclasts. In a trial involving patients the treatment. In clinical trials among calcitonin treated on GC, denosumab was compared with risedronate. patients, overall incidence of malignancies are reported to Denosumab group showed superiority with respect to be higher in comparison with placebo. increase in spinal bone mineral density at 12 months and noninferiority in terms of rates of fracture.18 Few Treatment in Women of Childbearing Age studies have reported higher risk of infection with Pharmacologic treatment to prevent fractures is not denosumab in comparison to bisphosphonates which recommended in pregnant ladies. A summary of case may be attributed to its immunomodulatory effects.19 study involving 65 women receiving bisphosphonate

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before or in the first trimester of pregnancy showed „„ Adults ≥30 years taking very-high-dose GC (≥30 mg no clinically significant adverse effects in the fetus.24 daily) However, there is a reluctance to treat women in child „„ High cumulative use (>5 g in 1 year) bearing age with bisphosphonates as it may cause long- Pharmacologic interventions: term retention of these agents in bone and may have affect „„ First-line therapy: oral bisphosphonates on the fetal skeleton later when these ladies conceive. If „„ Second-line therapies (in order of preference): intra­ treatment has to be offered owing to their risks, agents venous bisphosphonates, teriparatide, denosumab, having a shorter half-life and lesser retention in bone raloxifene (only in postmenopausal women when other are generally recommended such as risedronate and listed second-line medications are not appropriate) teriparatide. Animal’s studies have shown that denosumab has teratogenic effects and should be used with caution in Duration of pharmacologic intervention: 25 women of childbearing age. „„ If continuing to receive GC >5 years, continue treatment if having moderate to high risk Guidelines/Recommendations „„ If GC is discontinued before 5 years, continue treatment for osteoporosis for 5 years if moderate to high risk The 2017 Guidelines of the American College of „„ Discontinue treatment for osteoporosis when GC are 26 Rheumatology recommend the following: discontinued if low risk. Which patient requires intervention? „„ All adults taking ≥2.5 mg of prednisone daily for >3 Conclusion months Long-term use of Glucocorticoids is known to cause many Whom to test and monitor for changes in BMD? adverse effects and it is essential to identify the high risk individuals. After lifestyle change and correction of calcium and „„ All adults ≥40 years of age and adults <40 years with a vitamin D, initiation of appropriate anti-resorptive medicines history of fragility fracture or other risk factors; can prevent long-term debilitation and morbidity associated „„ Test within 6 months after initiation of GC; with osteoporosis. „„ Repeat testing every 2–3 years and every 1–3 years in adults ≥40 years receiving GC without treatment for osteoporosis. References Correction used with the FRAX tool to adjust risk 1. Overman RA, Yeh JY, Deal CL, et al. Prevalence of oral glucocorticoid estimate for prednisone dose >7.5 mg: usage in the United States: a general population perspective. „„ Risk of major osteoporotic fracture is increased by 15% Arthritis Care Res (Hoboken). 2013;65(2):294-8. and risk of hip fracture is increased by 20% 2. Hoes JN, Jacobs JW, Verstappen SM, et al. Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a Calcium and Vit D supplementation: meta-analysis. Ann Rheum Dis. 2009;68(12):1833-8. 3. Weinstein RS. Glucocorticoid-induced bone disease. N Engl J Med. „„ 800–1,000 mg of calcium daily and 600–800 IU of 2011;365(1):62-70. vitamin D daily . 4 Weinstein RS. Glucocorticoid-induced osteoporosis and osteo­ Threshold for pharmacologic treatment: necrosis. Endocrinol Metab Clin North Am. 2012;41(3):595-611. 5. Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids „„ All adults with a previous fragility fracture and risk of fractures. J Bone Miner Res. 2000;15(6):993-1000. „„ Adults ≥40 years with BMD T score of −2.5 or less or . 6 Kado DM, Browner WS, Palermo L, et al. Vertebral fractures and FRAX risk ≥20% for major osteoporotic fracture or ≥3% mortality in older women: a prospective study. Arch Intern Med. for hip fracture 1999;159(11):1215-20. „„ Consider in adults ≥40 years with FRAX risk 10–19% for . 7 van Staa TP, Leufkens HG, Abenhaim L, et al. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. major osteoporotic fracture or >1–2.9% for hip fracture Rheumatology (Oxford). 2000;39(12):1383-9. „„ Adults <40 years with BMD T score below −3 and >7.5 . 8 De Vries F, Bracke M, Leufkens HG, et al. Fracture risk with mg of prednisone daily intermittent high dose oral glucocorticoid therapy. Arthritis „„ Adults with >10%/year bone loss at hip or spine Rheum. 2007;56(1):208-14.

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. 9 Gonzalez AV, Coulombe J, Ernst P, et al. Long-term use of 18. Toulis KA, Anastasilakis AD. Increased risk of serious infections in inhaled corticosteroids in COPD and the risk of fracture. Chest. women with osteopenia or osteoporosis treated with denosumab. 2018;153:321-8. Osteoporos Int. 2010;21(11):1963-4. 10. Laan RF, van Riel PL, van de Putte LB, et al. Low-dose prednisone 19. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after induces rapid reversible axial bone loss in patients with rheumatoid discontinuation of denosumab: a post hoc analysis of the arthritis: a randomized, controlled study. Ann Intern Med. randomized placebo-controlled FREEDOM trial and its Extension. J 1993;119(10):63-8. Bone Miner Res. 2018;33(2):190-8. 11. Kanis JA, Oden A, Johansson H, et al. FRAX and its applications to 20. Mok CC, Ying KY, To CH, et al. Raloxifene for prevention of clinical practice. Bone. 2009;44(5):734-43. glucocorticoid induced bone loss: a 12-month randomised double- 12. Homik J, Suarez-Almazor ME, Shea B, et al. Calcium and vitamin D blinded placebo-controlled trial. Ann Rheum Dis. 2011;70(5):778-84. for corticosteroid-induced osteoporosis. Cochrane Database Syst 21. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene Rev. 2000;1998(2):000952. on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene 13. Wallach S, Cohen S, Reid DM, et al. Effects of risedronate treatment Evaluation. JAMA. 1999;281(23):2189-97. on bone density and vertebral fracture in patients on corticosteroid 22. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene therapy. Calcif Tissue Int. 2000;67(4):277-85. on cardiovascular events and breast cancer in postmenopausal 14. Khow KS, Shibu P, Yu SC, et al. Epidemiology and postoperative women. N Engl J Med. 2006;355:125-37. outcomes of atypical femoral fractures in older adults: a systematic 23. Cranney A, Welch V, Adachi JD, et al. Calcitonin for the treatment review. J Nutr Health Aging. 2017;21(1):83-91. and prevention of corticosteroid-induced osteoporosis. Cochrane 15. Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide Database Syst Rev. 2000;2:001983. versus alendronate for treating glucocorticoid-induced 24. Green SB, Pappas AL. Effects of maternal bisphosphonate use osteoporosis: thirty-six-month results of a randomized, double- on fetal and neonatal outcomes. Am J Health Syst Pharm. blind, controlled trial. Arthritis Rheum. 2009;60(11):3346-55. 2014;71:2029-36. 16. Glüer CC, Marin F, Ringe JD, et al. Comparative effects of teriparatide 25. Boyce RW, Varela A, Chouinard L, et al. Infant cynomolgus monkeys and risedronate in glucocorticoid-induced osteoporosis in exposed to denosumab in utero exhibit an osteoclast poor men: 18-month results of the Euro GIOPs trial. J Bone Miner Res. osteopetrotic-like skeletal phenotype at birth and in the early 2013;28(6):1355-68. postnatal period. Bone. 2014;64:314-25. 17. Saag KG, Wagman RB, Geusens P, et al. Denosumab versus 26. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of risedronate in glucocorticoid-induced osteoporosis: a multicentre, Rheumatology guideline for the prevention and treatment randomised, double-blind, active controlled, double-dummy, non- of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. inferiority study. Lancet Diabetes Endocrinol. 2018;6(6):445-54. 2017;69(8):1521-37.

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