Managing thyrotoxicosis in the acute medical setting

44 Review Article Managing thyrotoxicosis in the acute medical setting C Napier MBBS MRCP (UK) Endocrine Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle Upon Tyne, NE1 4LP UK Email: c.napier2@newcastle. ac.uk Thyrotoxicosis is common and can present in numerous ways with patients exhibiting a myriad of symptoms and signs. It affects around 1 in 2000 people annually in Europe 1. The thyroid gland produces two thyroid hormones - thyroxine (T4) and triiodothyronine (T3). Thyroxine is inactive and is converted by the tissues and organs that need it into tri-iodothyronine. In health, the production of these thyroid hormones is tightly regulated by the secretion of thyroid stimulating hormone (TSH; thyrotropin) from the pituitary gland. The term thyrotoxicosis refers to the clinical manifestations of hyperthyroidism. Linking clinical presentation to aetiology The commonest cause of hyperthyroidism in the UK is Graves disease (GD), which accounts for around 75% of cases of thyrotoxicosis 2. GD exhibits a particularly strong female preponderance (F:M, 6:1), in common with other autoimmune disorders. It usually presents between 30-50 years of age, but can occur in both sexes and at any age. Other common causes are a single toxic nodule or a multinodular goitre, and together, GD and nodular thyroid disease account for well over 90% of all cases of hyperthyroidism. Nodular thyroid disease is more often seen with advancing age. Histologically these nodules are follicular adenomas and excess thyroid hormone is secreted in an unregulated manner. Rarer causes of thyrotoxicosis include subacute, silent or post-partum thyroiditis; these conditions occur when inflammatory destruction of thyroid follicles causes a release of preformed thyroid hormones into the circulation, resulting in transient thyrotoxicosis. Subacute thyroiditis is usually caused by a viral infection and is characterised by fever and pain or thyroid tenderness. Painless thyroiditis can occur during or after treatment with lithium, cytokines (e.g. interferon alpha), tyrosine kinase inhibitor therapy, highly active retroviral therapy or in the postpartum period and appears with differing frequency between studied populations 3. A destructive (but nevertheless painless) thyroiditis occurs in 5-10% of patients on amiodarone 3. Abnormal thyroid biochemistry (with or without symptoms) is becoming more common with the wider use of biological therapies to treat cancer or other conditions. Almost all patients with thyroiditis should be referred for endocrine input, although symptomatic management can be instigated in the acute setting. Table 1 summarises the causes of thyrotoxicosis. In the acute setting, it is important to recognise that elderly patients with thyrotoxicosis may have a subtle presentation with fewer typical symptoms and signs; apathy and apparent depression may be the only clinical features. In any patient, symptoms of rapid onset (1-2 days duration) are more likely to suggest a diagnosis of thyroiditis rather than GD or nodular thyroid disease. All patients with unexplained weight loss, tachycardia or atrial fibrillation (AF) should have a diagnosis of thyrotoxicosis considered. Clinical features of hyperthyroidism Symptoms of thyrotoxicosis are often nonspecific and patients may present in numerous ways 2,4,5. In GD, onset is often gradual and poorly defined; most individuals have felt unwell for 3 to 6 months before they seek medical attention. If the onset of thyrotoxic symptoms is rapid or can be pinned down to a single day or a few days, the diagnosis is much more likely to be thyroiditis. In GD, the commonest precipitant of thyrotoxicosis, weight loss (despite an increase in appetite) is found in most patients. In a minority, the increase in appetite coupled with the free availability of calorie-dense food, leads to weight gain. Pervasive exhaustion is common but patients may find this alternates with periods of restlessness and hyperactivity. Heat intolerance is a typical feature and sweating at night is characteristic. Poor sleep with mental overactivity and physical hyperkinesis is often found. Palpitations at rest or on minimal exertion or shortness of breath during light exercise are common at all ages. Intestinal transit-time is shortened, leading to more frequent defecation. Menstrual bleeding may Table 1. Causes of Thyrotoxicosis Causes of thyrotoxicosis Autoimmune thyroid disease Graves disease Nodular thyroid disease Solitary toxic nodule Multinodular goitre Thyroiditis Viral Post-partum Drug-induced

45 Table 2. Symptoms and Signs of Thyrotoxicosis Symptoms and signs of thyrotoxicosis SYMPTOMS Tremor Palpitations Fatigue Heat intolerance Weight loss Breathlessness Increased frequency of defecation Anxiety Muscle aches Menstrual disturbance *Signs only seen in Graves disease SIGNS Tremor Palmar erythema Onycholysis Tachycardia Atrial fibrillation Brisk reflexes Orbitopathy* proptosis, eyelid retraction Goitre smooth or nodular Thyroid bruit Hypertension and signs of cardiac failure Weight loss Pretibial myxoedema* be light, decreased in frequency, or absent. Thyroid tenderness or pain is not a feature. Less commonly reported symptoms are thirst, nausea, generalised itch, and hair loss. In 5 10% of people, the first symptoms are due to Graves orbitopathy (GO) with itchy, gritty, or watering eyes, or an abnormal appearance 6. Thyrotoxicosis with extra-thyroidal features, such as orbitopathy or pretibial myxoedema, is pathognomic of GD. In the elderly, there may be little to suggest a diagnosis of hyperthyroidism, or the onset of AF may precipitate a cardiac presentation with dyspnea and/ or congestion. Table 2 lists the symptoms and signs of thyrotoxicosis. During clinical assessment, a thyrotoxic patient may struggle to sit still, with constant fidgeting and apparent anxiety or apprehension. The face, neck, and upper chest wall may be flushed. The palms may be warm and sweaty, with a symmetrical fine tremor when hands are outstretched. In GD, a smooth, diffuse goitre can be visible or palpable, with a systolic phase bruit audible over the gland due to increased blood flow. In nodular thyroid disease, a discrete nodule or uneven, multinodular goitre may be easily palpable. Patients with subacute thyroiditis may complain of tenderness on palpation. In all thyrotoxic patients, tachycardia (unless beta-blockers are already being taken) and rapid atrial fibrillation may be present, with an elevated systolic blood pressure. Hepatomegaly or splenomegaly may be found. Hyperreflexia is common and proximal musculature can be weak. Late features of thyrotoxicosis are frank spasticity and pseudobulbar paresis. Rapid onset of severe and generalized muscle weakness should raise suspicion of the possibility of hypokalemic periodic paralysis, a syndrome most common in men of Asian descent that is precipitated by thyrotoxicosis. In GD, pretibial myxoedema (infiltrative dermopathy) is usually manifest as discrete violaceous plaques on the shin or dorsum of the foot. Signs of GO include lid retraction, lid or conjunctival redness, periorbital oedema and proptosis. Rare signs of GD include chorea, onycholysis, or acropachy of the nails. Investigations in hyperthyroidism Hyperthyroidism can be easily and quickly confirmed on biochemical testing with elevation of one or both serum-free thyroid hormones (FT3, FT4) together with a low or undetectable TSH. Serum TSH measurement has the highest sensitivity and specificity of any single blood test used in the evaluation of suspected thyrotoxicosis and should be used as an initial screening test 3. However, when there is strong clinical suspicion of thyrotoxicosis, it is much more pragmatic to combine TSH testing with measurement of free thyroid hormones for diagnostic accuracy 3. About 5% of subjects, most commonly elderly, present with elevation of FT3 alone, with normal FT4 and undetectable TSH - this T3 thyrotoxicosis is often a manifestation of relatively mild hyperthyroidism. Elevation of free T4 alone, with normal free T3 and undetectable TSH, may be found in someone with co-existing major illness (a combination of thyrotoxicosis and sickeuthyroid syndrome), but is also typical of iodineinduced thyrotoxicosis or exogenous levothyroxine use. If there is doubt about the chronicity or severity of symptoms, then it is good practice to repeat the abnormal thyroid function tests after a short period, as a rapid fluctuation may be the clue to the diagnosis of destructive (silent) thyroiditis. If the TSH is low but still detectable, the diagnosis is almost certainly not GD and further investigations are needed 7. Individuals with a persistently undetectable TSH but normal free thyroid hormones (in the absence of pituitary disease and drug effects) are said to have subclinical hyperthyroidism (SH) and need further

46 Symptoms or signs of thyrotoxicosis If TSH low or undetectable with elevated FT4 +/- FT3 Refer to endocrinology; send TRAb Start beta blockers if symptomatic or tachycardic* Discharge unless features of thyroid storm or clinically unwell** Figure 1. Algorithm for Managing Suspected Thyrotoxicosis on the Acute Medical Unit * If any contraindications to beta blockade, diltiazem can be used as an alternative ** Patients with AF will need consideration re. anticoagulation investigation (i.e., serum thyroid antibodies, Holter monitor, DEXA bone scan) 7. There is little clear evidence to guide treatment in this situation and intervention depends on the degree of SH and the sequelae 7,8 - the presence of atrial fibrillation or established osteoporosis will mean patients are more likely to warrant treatment. In the setting of clear extrathyroidal signs of GD, no further testing beyond free thyroid hormones and TSH is necessary. In the absence of features of GO or pretibial myxoedema, it is useful to attempt to secure an aetiological diagnosis. The gold-standard test is a highly sensitive TSHR-stimulating antibody assay or TSH receptor antibodies (TRAb) 4,5. Other serum antibody tests, including indirect assay of TSH-stimulating antibodies by TSH-binding inhibitory immunoglobulin (TBI or TBII) or TPO antibody assay can be employed to confirm GD (TPO antibodies are also positive in autoimmune hypothyroidism). Imaging Imaging of the thyroid should not be routinely requested for all patients, even in the presence of a goitre. It is often beneficial if the antibody test is negative or if a nodular thyroid is found on palpation, but the decision about the indication for imaging and optimum imaging modality should ideally be left until the time of endocrine review. Although an ultrasound examination may demonstrate a single nodule or a multinodular goitre, radionuclide imaging with either technetium (99 Tc) or iodide (123 I) is often more useful because it gives practical data regarding the presence and distribution of functioning thyroid tissue. Other investigations, often routinely done on medical admission, will be worthwhile depending upon the clinical situation and likely treatment plan. An ECG should be documented in all thyrotoxic patients with tachycardia and a more detailed cardiac evaluation should be performed in those with AF. A full blood count with a white cell differential at baseline is helpful if antithyroid drug (ATD) treatment may be instigated in the future. A pregnancy test should be documented in women of childbearing age and a negative pregnancy test is absolutely mandatory if radioiodine treatment is later the chosen treatment modality. In thyrotoxic patients, microcytosis, elevation of serum alkaline phosphatase, and mildly deranged liver enzymes are often found on biochemical testing; mild hypercalcemia can also be present. Figure 1 outlines a suggested algorithm for the investigation of patients with suspected thyrotoxicosis. Managing hyperthyroidism Symptomatic management All thyrotoxic patients should gain symptomatic benefit from beta blockade (Propranolol 40mg TDS or Propranolol LA 80mg daily); this is contraindicated in those with asthma and caution should be exercised in patients with diabetes where beta blockade can mask the symptoms of hypoglycaemia. If beta blockade is contraindicated, diltiazem can be used in thyrotoxic patients with tachycardia. Treatment The treatment options for hyperthyroidism secondary to GD or nodular thyroid disease include ATDs (Carbimazole or Propylthiouracil in the UK), radioiodine therapy, or thyroid surgery. Each modality has its own pros and cons, and patient preference is frequently a deciding factor. Decisions regarding treatment should be taken in conjunction with the endocrine team and are usually made at the time of endocrine review. The pathway for this will vary between secondary and tertiary care settings; some acute medicals units can rapidly access endocrine telephone advice or review, whereas others will refer for outpatient clinic follow-up.

47 ATDs should only be started in conjunction with endocrine input mainly to ensure robust (verbal and written) warnings regarding the rare but serious and potentially lethal risk of agranulocytosis with Carbimazole (CBZ) or Propylthiouracil (PTU). This thionamide-induced agranulocytosis occurs in around 1 in 300 people 9 : symptoms include a sore throat and mouth ulcers and those affected will often have a high fever. Patients should be warned to stop the ATD immediately in the presence of these symptoms and have a full blood count taken on the same day. Agranulocytosis is most likely to occur in the early months after starting treatment. Liaising with the endocrine team will also help ensure that patients have a timely follow-up plan in place; those who start ATDS can become rapidly euor hypothyroid within a matter of weeks. The pros and cons of ATD treatment vs. radioactive iodine vs. surgery will be discussed at the time of endocrine review. If patients opt to complete a course of ATD therapy, then block and replace vs. a dose-titration regimen will be decided upon. Thyrotoxicosis in the context of thyroiditis is transient. Patients are likely to have a hyperthyroid phase followed by a hypothyroid phase and then spontaneous resolution. Patients with subacute thyroiditis may have pain and fever - analgesia (NSAIDs will be most effective) should be administered and a short course of systemic steroids may be helpful: advice on this can be taken from the endocrine team. ATDs are ineffective. The management of drug-induced thyrotoxicosis is more complex and is best managed by endocrinology (in conjunction with the cardiology team in the case of amiodarone-induced thyrotoxicosis). Other drugs may produce a self-limiting thyroiditis or a more complex picture a joint decision regarding management can be taken by the endocrine team in conjunction with the specialist prescribing the drug. When to admit The vast majority of thyrotoxic patients will not require hospital admission, and can be safely discharged once beta blockade has been instigated. The decision on when to admit should be based upon clinical features rather than serum biochemistry. Free thyroid hormone levels above the upper limit of the reference range are one indicator of severe hyperthyroidism, but should not alone prompt admission. Many patients who present with thyrotoxicosis will be tachycardic; this alone is not an indication for acute admission, although a cardiovascular examination should be performed and an ECG should be documented. Patients with clinical features which are suspicious of a thyroid storm should be admitted for close monitoring, supportive care and urgent endocrine input. In addition, those patients with significant tachycardia, AF or features of cardiac failure will require a short admission until any concern regarding cardiovascular instability has resolved. Special considerations Subclinical hyperthyroidism A number of patients may be found to have a low serum TSH (particularly if TSH testing is performed without specific clinical indication) this, in conjunction with normal levels of free thyroid hormones, is defined as subclinical hyperthyroidism (SH). Depending on the TSH assay cut-off value and the iodine intake of the population, SH may be found in up to 10% of the population 10. SH can be caused by endogenous thyroid disease, drug effects and nonthyroidal illness. A low or undetectable TSH is associated with significant morbidity and mortality in longitudinal epidemiological surveys 7. There is a paucity of evidence to guide the assessment or management of patients with SH, but they should be flagged for repeat biochemical assessment; if TFTs remain abnormal, a referral to endocrinology is appropriate. It is useful to assess for other causes of a low TSH including non-thyroidal illness, drugs that suppress TSH (glucocorticoids, dopaminergic medication, or octreotide) and drugs that alter thyroid hormone secretion (amiodarone, lithium or iodine-containing contrast dyes). If a cause is not found, TFTs should be repeated in 3-6 months (or earlier if the patient is elderly or has cardiovascular disease. If non-thyroidal illness is suspected to be the cause, it would be appropriate to arrange repeat testing after a shorter interval 11. Drug-induced thyroid dysregulation Amiodarone-induced thyrotoxicosis (AIT) encompassing type I, where excess thyroid hormone is synthesised and released, and type II, when a destructive thyroiditis prompts the release of preformed thyroid hormone - occurs in around 20% of patients on the drug. Distinguishing between type I and type II can be challenging: each subtype requires tailored management and endocrine input should be sought. Patients on lithium can present with hypothyroidism or thyrotoxicosis (via the effect of lithium on thyroid cells, or by inducing painless thyroiditis) 12. More recently, the increasing use of immune-checkpoint inhibitors in the management of cancer has resulted in greater numbers of patients presenting with drug-induced thyroid dysfunction (thyrotoxicosis can be secondary to thyroiditis or Graves disease). In drug-induced thyrotoxicosis,

48 the precipitating drug should not necessarily be stopped; endocrine input is paramount to ensure an appropriate management plan is promptly instigated. Thyroid storm A thyroid storm is a rare but life threatening condition. Signs include fever, tachycardia, agitation and altered mental state, deranged liver function tests and features of cardiac failure. It can be precipitated by infection, surgery, trauma childbirth or poor compliance to treatment. Pregnant women Untreated hyperthyroidism in pregnancy poses serious risks to both mother and baby. If uncontrolled, restricted foetal growth and low birthweight is likely 13,14. Maternal sequelae can include hypertension, congestive cardiac failure and thyroid storm 14 and obstetric complications may occur. The longer the duration of uncontrolled hyperthyroidism, the higher the likelihood of a detrimental impact on maternal and foetal outcome. Pregnant women with suspected hyperthyroidism should be urgently referred to medical obstetrics team or endocrinology for prompt assessment. Not all cases of apparent hyperthyroidism in pregnancy are pathological - high levels of ß human chorionic gonadotrophin can lead to gestational hyperthyroidism, with absent TSH receptor antibodies, no extrathyroidal features and no goitre; this will resolve by 20 weeks gestation. Conflict of Interest Nothing to declare. References 1. Garmendia Madariaga A et al; The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab 2014; 99(3):923-31. 2. Vaidya B and Pearce SHS; Diagnosis and management of thyrotoxicosis. BMJ 2014; 349:g5218. 3. Ross DS et al; American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid 2016; 26(10):1343-1421. 4. Burch HB and Cooper DS; Management of Graves Disease: A Review. JAMA 2015; 314(23):2544-54. 5. Smith TJ and Hegedüs L; Graves Disease. N Engl J Med 2016; 375(16):1552-1565. 6. Mitchell AL et al; Diagnosis of Graves orbitopathy (DiaGO): results of a pilot study to assess the utility of an office tool for practicing endocrinologists. J Clin Endocrinol Metab 2015; 100(3):E458-62. 7. Mitchell AL and Pearce SHS; How should we treat patients with low serum thyrotropin concentrations? Clin Endocrinol 2010; 72(3):292-6. 8. Biondi B et al; The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism. Eur Thyroid J 2015; 4(3):149-63. 9. Watanabe N et al; Antithyroid-drug induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves disease. JCEM 2012; 97:E49-53. 10. Carle A et al; Management of Endocrine Disease: Subclinical thyrotoxicosis: prevalence, causes and choice of therapy. EJE 2017; 176:325-337. 11. NICE CKS Hyperthyroidism June 2016 Accessed via www.cks. nice.org.uk [November 2017]. 12. Pearce EN et al; Thyroiditis. N Engl J Med 2003; 348(26):2646-2655. 13. Laurberg P et al; Management of Graves hyperthyroidism in pregnancy: Focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur Jour Endocrinol 2009; 160(1):1-8. 14. Rivkees SA and Mandel SJ; Thyroid disease in pregnancy. Horm Res Paediatr 2011; 76 (supp.1):91-96.