Hyperthyroidism and Thyrotoxicosis
- The management strategy for thyroid storm revolves around preventing peripheral effects of raised thyroid hormone levels, and preventing the ongoing increase of said levels by inhibiting the synthesis and release of thyroid hormone.
- The mainstay agents are propylthiouracil, carbimazole (or methimazole), potassium iodide and a beta-blocker such as propanolol.
- One cannot forget to mention corticosteroids, as there is always some relative adrenal insufficiency.
- Other potentially useful agents include lithium and cholestyramine.
- Severe refractory disease may call for extracorporal clearance of thyroid hormone by plasma exchange or charcoal haemoperfusion.
Question 25 from the second paper of 2013 asks for some drugs which are used in the management of thyrotoxic crisis. Also, Question 15.1 from the first paper of 2017 presents a cas of a patient whose TSH-secreting adenoma was massaged a little too much by the surgeon during the trans-sphenoidal resection, resulting in a post-operative thyroid storm in the recovery room.
In brief, the goals of pharmacotherapy in thyrotoxicosis are as follows:
- Prevent synthesis of T3 and T4:
- Thiouracils: propylthiouracil - blocks synthesis of T3 and T4 as well as peripheral T4-T3 conversion
- Imidazoles: carbimazole - block synthesis of T3 and T4
- Prevent T3 and T4 release:
- Inorganic iodine therapy, eg. potassium iodide (given after synthesis is blocked)
- Block peripheral T3 and T4 activity:
- β-blockade: propanolol (which also decreases T4-T3 conversion)
- Corticosteroids: also decrease T4-T3 conversion
A reasonable reference to base one's srtudy notes upon would be Chapter 60 of Oh's Manual, Thyroid emergencies by Jonathan M Handy and Alexander M Man Ying Li (pp. 652). The summary below is based largely on their work. Emphasis was given to the content of the Blue Boxes, as these tend to be mined by the examiners. They are a rich source of lists, and lists are easily made into SAQs ("name six causes of this or that, etc"). If more detail is required, one should find
Definition, diagnosis and clinical features of thyroid storm
Definition of thyroid storm
Like the electrical storm of ventricular arrhythmias, this has no fixed scientific definition. It is not a clinical entity of its own right, but rather part of the spectrum of hyperthyroidism. Hyperthyroidism becomes thyroid storum when its manifestations become lifethreatening.
Precipitants of thyroid storm:
We can devise a table to classify these precipitants:
Clinical features of thyroid storm
- Goitre: possible airway compromise)
- Tachypnoea due to increased CO2 production;
Increased O2ER (increased metabolic fuel use)
Atrial fibrillation and ventricular arrhythmias
Hypertension (early), hypotension (late)
Agitation, progressing to encephalopathy, coma and seizures.
There is the phenomenon of "apathetic thyrotoxicosis" which presents with weakness
- Low potassium and magnesium (particularly in "apathetic thyrotoxicosis")
Serum cortisol should be elevated. If it is not, one might consider a relative adrenal insufficiency, and supplement some hydrocortisone.
- Rhabdomyolysis may be present; CK may be elevated. This is "thyrotoxic myopathy"
- Diarrhoea, nausea and vomiting
Increased metabolic rate; increased demand for metabolic substrate.
Nutritional requirements are increased
Hyperglycaemia may be apparent in the non-diabetic patient
Jaundice may develop
- Leukocytosis; a left shift
- Fever:in fact, may go up to 41°C. This is apparently the most characteristic feature.
Diagnostic criteria for thyroid storm
An attempt has been made to produce some diagnostic criteria (Burch and Wartofsky, 1993); the authors proposed a scoring system whereby one attributes points to different clinical features.
If one scores over 45, thyroid storm is very likely, and a score of 25-44 suggests that it is imminent.
Diagnostic investigations and their characteristic findings
- Raised T3 and T4
- Low TSH
- Deranged LFTs
- Ultrasound of the thyroid:
- Hypervascularity (eg. "thyroid inferno" of Graves disease)
- Solid masses (eg. nodular goitre)
Management of thyroid storm
Prevention of thyroid hormone synthesis
Thiouracils: propylthiouracil blocks synthesis of T3 and T4 as well as peripheral T4-T3 conversion. In the thyroid gland, propythiouracil blocks the organification of iodide by inhibiting thyroperoxidase, the enzyme responsible for oxidising the iodide anion. Thus, iodide cannot be added to tyrosine residues of thyroglobulin, and thyroid hormone synthesis dies off. It is therefore important to give the patient some propylthiouracil before giving them iodide.
Imidazoles: methimazole or carbimazole (which is metabolised into methimazole) also block synthesis of T3 and T4 by interfering with the action of thyroperoxidase. it has a longer half-life than propylthiouracil.
Imidazoles should probably be the first-line choice in patients who are not critically ill. Nakamura et al (2013) compared the efficacy of methimazol and propylthiouracil in a prospective randomised study of non-storming patients with Graves disease. The authors concluded that even lowish-dose methimazole (15mg/d) is very effective, and that propylthiouracil cannot be recommended as an initial treatment because of poor efficacy and severe side effects.
On the other hand, propylthiouracil is also able to block peripheral T4-T3 conversion. UpToDate (American) authors recommend propylthiouracil over methimazole in thyroid storm because of this factor. There is also some evidence of more rapid action - T3 levels decrease more quickly with propylthiouracil (Cooper et al, 1982). Therefore, propylthiouracil should be the first choice in the ICU setting.
Given that the two drugs compete for the same enzyme, there may be no synergistic effect in giving both at the same time.
Prevention of thyroid hormone release
Inorganic iodine therapy, eg. potassium iodide (given after synthesis is blocked with propylthiouracil or methimazole) is effective because iodine blocks the release of T4 and T3 from the gland within hours. Also, large doses of iodine can inhibit the organification of iodine, which is called the Wolff-Chaikoff effect (Abrahams, 2005). However, the iodide transport system soon adapts to higher concentrations of iodine, and there may be an "escape" effect where thyroid hormone synthesis starts again. This is why iodide therapy is best combined with a syntheis blocking agent like methimazole.
Lithium has also been used to block the release of thyroid hormone (Bogazzi et al, 2002). Shek et al (2006) also demonstrated satisfactory control of thyrotoxicosis in non-storming patients who had contraindications to propylthiouracil and carbimazole. The authors both complained that the response was slow. The savvy candidate should be aware of this agent for the exams, but its use for thyroid storm is hampered by its pointlessness and by the existence of less toxic agents. One can potentially envision a situation where a patient who is for some reason intolerant of potassium iodide might benefit from lithium instead.
Blockade of peripheral T4⇒T3 conversion
Many drugs block peripheral T4-T3 conversion.
- Iodinated contrast
Of these, iodinated contrast agents are probably the most potent. Roti et al (1988) had demonstrated a significant and rapid decrease in circulating T3 levels with sodium ipodate, which normally goes by the name Gastrograffin.
Of course, this arm of the therapy is not a very effective pathway, as it only works on the small pool of potentially harmful T4. Treatments which prevent the synthesis of T4 and block its release are probably more effective in the long run, and in the short term more good will be done by focusing on blocking the peripheral effects of thyroid hormone.
Blockade of the peripheral effects of thyroid hormone
β-blockade with propanolol (which also decreases T4-T3 conversion) is the standard of acute care. Most of the immediately life-threatening consequences of thyoroid storm are cardiovascular. Propanolol is effective in controlling heart rate; with a slower rate the cardiac failure may actually improve and the blood pressure may paradoxically increase. The alternative agent is the easily titratable esmolol, but you miss out on the peripheral T4-T3 conversion blockade.
Management of coexisting adrenal insufficiency
Corticosteroids are routinely used in thyroid storm to address the coexisting hypoadrenal state. Their peripheral effects on T4-T3 conversion are trivial and probably have little influence on their effectiveness in thyrotoxicosis. Thyroid disease (particularly long-standing hyperthyroidism) is associated with a diminished adrenal reserve (Tsatsoulis et al, 2000) and the addition of a small amount of hydrocortisone seems to correct this. An additional benefit is the treatment of whatever autoimmune disease is responsible (Graves, Hashimoto, etc)
Blockade of enterohepatic recirculation of thyroxine
Cholestyramine is a bile acid sequestrant which prevents the reabsorption of thyroid hormone which is excreted with the bile. The normal metabolism of T3 involves conjugation with glucuronide and sulfate, and the excretion of this product in the bile. Free thyroid hormones are released in the intestine and are then reabsorbed. This recirculation makes the gut a potentially massive reservoir of thyroid hormones. The addition of cholestyramine to other medical management strategies tends to decrease the levels of circulating T3 and T4 (Solomon et al, 1993). The key is not to administer it together with other medications (it may bind them and reduce their efficacy).
Extracorporeal clearance of circulating thyroid hormone
Plasma exchange is an effective treatment for this problem, and is one of the efective last resort measures in severe thyroid storm with multiorgan system failure. Experience with it is based on case series only, albeit encouraging ones. Binimelis et al (1987) reported that the rate of T4 clearance was about thirty times higher than with standard medical management (that was a case series of six patients with massive thyroxine overdose).
Haemoperfusion is even better than plasma exchange. Binimelis et al (1987) reported that with charcoal haemoperfusion the clearance rate for T3 was even higher than with plasmapheresis. This technique has been known about since the ancient times (Herrmann et al, 1977), but more recently there has ben a resurgence in interest with the development of safer filters. Kreisner et al (2010) report a more recent case. Three 2-hour sessions were required.
This seems drastic, but it may be the only choice in patients who have failed medical therapy. Weber et al (1999) presents such a case series, where all medically refractory patients underwent subtotal thyroidectomy and did well therafter.