Initiation of levothyroxine in a patient with hypothyroidism inducing adrenal crisis requiring VA ECMO: a tale of preventable disaster

Abstract

A 31-year-old man with a recent diagnosis of hypothyroidism presented to the emergency department as a transfer from the clinic for severe hypotension and hypoglycaemia. The patient endorsed a 2-week history of severe fatigue, weight loss, nausea and non-bloody emesis. He was aggressively hydrated and vasopressors were initiated. Despite these measures, the patient remained hypotensive and went into pulseless electrical activity. Return of spontaneous circulation was achieved via advanced cardiac life support protocol, and venous arterial extracorporeal membrane oxygenation (ECMO) was initiated. On day 3 of hospitalisation, the patient was weaned off ECMO support, and subsequent autoimmune work-up confirmed the diagnosis of autoimmune polyglandular syndrome type 2 with positive antiperoxidase antibodies (267 IU/mL), supporting the diagnosis of Hashimoto’s thyroiditis.

Background

Our intention is to highlight the importance of recognising autoimmune polyglandular syndrome type 2 (APS-2) and its subtle symptomatology that can be easily misdiagnosed and improperly managed leading to fatal consequences. In addition to this we would also like to illustrate the acuity of the disease progression in the setting of initiation of levothyroxine for hypothyroidism in the outpatient setting.

In brief, APS-2 is a rare polyendocrinopathy defined by failure of multiple endocrine glands as well as non-endocrine organs that is caused by an immune-mediated destruction of tissues. As internists, we often see a constellation of symptoms such as fatigue, nausea, vomiting, decreased appetite and weight loss, which tend to be overlooked or misdiagnosed in the setting of an overt issue such as heart failure, sepsis or in the setting of malignancy. This case highlights the importance of careful history taking and diligent physical exam, which can lead to a more accurate diagnosis and proper management.

Case presentation

Our patient is a 31-year-old man recently diagnosed with hypothyroidism without any further autoimmune work-up who presented to the emergency department (ED) from the clinic for severe hypotension and hypoglycaemia. In the ED he endorsed a 15-day history of severe fatigue, poor oral intake, weight loss (2.26kg in 1 week), nausea and non-bloody emesis with each meal, all occurring after the initiation of levothyroxine 25 μg daily. On arrival at the ED the patient’s Glasgow Coma Scale score was 15, his blood pressure was 64/38 mm Hg, heart rate was 82 beats per minute, respiratory rate was 22 per minute and temperature was 35°C. On physical exam, he was a thin man in no acute distress, appropriately oriented to person, place and time. Other pertinent physical findings included a goitre on the right side and hyperpigmentation of the face, oral mucosa and nails. Prior to arrival at the ED, the patient was noted to have blood glucose of 62 mg/dL, slight hypothermia at 35°C, and systolic blood pressures between high 80s and low 90s. It was initially thought that the patient was in a hypothyroid crisis, with hypoglycaemia, hypothermia and hypotension in the setting of elevated thyroid stiulatating hormone.

At first, he was given myxoedema dose of levothyroxine 91 μg intravenously daily, liothyronine 2.5 mg every 8 hours and stress-dose hydrocortisone 100 mg every 8 hours. Despite these measures, along with 5 L of crystalloid fluid and being on four different vasopressors (norepinephrine 50 μg/min, vasopressin 0.04 units/min, dobutamine 20 μg/kg and epinephrine 30 μg/min), the patient continued to have refractory hypotension. Further work-up revealed undetectable random cortisol, <0.04 μg/dL, prior to any steroids being given and severe metabolic acidosis. Arterial blood gas analysis revealed a pH of 7.14, HCO of 37 mm Hg, PCO2 of 21 mm Hg and PaO2 of 101 mm Hg. He was subsequently intubated for increased work of breathing and impending respiratory failure secondary to hypoxia. Shortly after this, he became increasingly hypotensive with systolic blood pressure in the 40s, eventually losing his pulse. Cardiopulmonary resuscitation (CPR) was initiated, and after several rounds of CPR and epinephrine return of spontaneous circulation was achieved. Bedside echocardiogram showed diffuse hypokinesis with poor ejection fraction <25%. In the setting of cardiovascular collapse, the patient was immediately started on venous arterial extracorporeal membrane oxygenation (VA ECMO). After 3 days of VA ECMO support and stress-dose steroids, the patient was decannulated from ECMO and extubated. On day 4, the patient was transferred to the medical floor from the intensive care unit (ICU).

Investigations

Pertinent autoimmune work-up included anti-Thyroid Peroxidase and 21-hydroxylase antibodies, which were positive. The patient was found to be negative for anti-glutamic acid decarbosylase, islet cell and anti-insulin antibody.

Differential diagnosis

A 31-year-old man with no significant medical history other than hypothyroidism presenting with hypoglycaemia and hypotension prompts a broad differential including sepsis, myxoedema coma, insulinoma, hypoadrenalism, anaphylaxis, cardiogenic versus septic shock, or a combination of polyendocrinopathies, among others.

Treatment

In addition to the ECMO support, the patient was also continued on intravenous hydrocortisone 50 mg every 6 hours and intravenous levothyroxine. The patient was discharged on fludrocortisone 0.1 mg daily by mouth, hydrocortisone every morning 15 mg and 5 mg by mouth in the evening, and levothyroxine 100 μg by mouth.

Outcome and follow-up

The patient was taken off VA ECMO on day 3. On day 4, he was transferred out of the ICU and to the medical floor. He was noted to have positive TPO antibodies, anti-21 hydroxylase antibodies and mildly positive parietal cell antibodies at 1:80. The clinical and laboratory findings supported the diagnosis of APS-2 with components of Addison’s disease and Hashimoto’s thyroiditis. The patient was discharged on day 11 of hospitalisation. On discharge, he was scheduled to follow up with pulmonology and endocrinology. The patient is currently on hydrocortisone 15 mg every morning and 5 mg every evening, fludrocortisone 0.1 mg every morning, and levothyroxine 100 μg daily. The patient had a negative work-up for autoimmune diabetes mellitus type 1, and is frequently monitored for signs and symptoms of type 1 diabetes mellitus.

Discussion

APS-2 is characterised by adrenal insufficiency associated with autoimmune thyroid disease and/or diabetes mellitus type 1. Adrenal insufficiency is the initial manifestation in about half of all cases. Around 20% of the time, thyroid disease or diabetes is also seen concurrently. APS is divided into two main categories: APS type 1 (APS-1) and APS type 2 (APS-2). APS-1 usually first manifests as hypoparathyroidism or as chronic mucocutaneous candidiasis with hypogonadism usually developing at age 10–15. Hypogonadism is also seen 60% of the time in APS-1. APS-2 has a prevalence of 1 in 100 000.¹ It occurs more commonly in women with a ratio of at least 3:1 compared with men.² Other less common autoimmune diseases associated with APS-2 include hypergonadotropic hypogonadism, coeliac disease, chronic atrophic gastritis, vitiligo, stiff man syndrome, myasthenia gravis and alopecia. APS-2 has a multifactorial pathogenesis, including complex polygenetic disease and environmental factors, and often has its onset in adulthood with a peak incidence between 20 and 60 years.³ Multiple major histocompatibility complex haplotypes have been associated with APS-2, including HLA-B8, HLA-DR3 and HLA-DR4, with links to MICA and MICB gene polymorphisms.³ Inheritance patterns have been noted, with APS-2 primarily being an autosomal dominant pattern with incomplete penetrance.

Moreover, primary adrenal insufficiency is the main manifestation of APS-2, in addition to autoimmune thyroid disease and autoimmune-related diabetes mellitus. Our patient presented acutely after starting on levothyroxine for hypothyroidism. This case illustrates the dangers of starting patients on levothyroxine who also exhibit manifestations of adrenal insufficiency. Physiologically, the hypothyroid state is a catabolic state requiring lower cortisol levels. When the body’s thyroid hormone levels are repleted, an anabolic state ensues requiring higher doses of cortisol. In a patient with low cortisol levels and limited production reserves, the introduction of exogenous levothyroxine can precipitate acute primary adrenal crisis. In addition, thyroid hormone plays an important role in cortisol clearance. Initiation of levothyroxine can enhance the clearance of cortisol, exacerbating any underlying adrenal insufficiency contributing to the possibility of adrenal crisis.⁴

We recommend a thorough history and detailed physical exam in any patient with overt signs and symptoms of adrenal insufficiency to ensure that the patient is appropriately screened for APS-2. For example, our patient had skin and mucosal hyperpigmentation, abnormal weight loss, nausea, emesis and lack of energy. These were all signs and symptoms suggestive of adrenal insufficiency. Early recognition of these signs and symptoms can alert providers to perform complete autoimmune work-up in young adults prior to initiating treatment.

Unfortunately, the delayed diagnosis of primary adrenal deficiency is still relatively common. According to a cross-sectional study involving 216 patients with adrenal insufficiency, on average less than 50% of them were diagnosed within the first half year of symptom onset, and for about 20% of the patients it took over 5 years after initial symptom onset to be correctly diagnosed with adrenal insufficiency.^{5 6} One of the primary barriers to the correct diagnosis of APS-2 is the delayed presentation of the various autoimmune disorders, and objective data such as circulating autoantibodies often precede clinical manifestations. Therefore, a high index of suspicion must be maintained. Awareness of APS-2 and of the potential danger of starting patients with hypothyroidism on levothyroxine could lead to an earlier appropriate diagnosis and avoidance of potentially life-threatening adrenal crisis.

This young, otherwise healthy patient in refractory cardiogenic shock secondary to adrenal crisis not responding to stress steroids and vasopressors rendered him an ideal candidate for mechanical circulatory support using VA ECMO. In our literature search and to our knowledge, this is one of the rare scenarios where VA ECMO has been used in adrenal crisis. We would like to highlight the vital role of VA ECMO in stabilising the haemodynamics of cardiogenic shock secondary to adrenal crisis while steroid replacement is taking effect.

Learning points.

• Acknowledging the diagnosis of autoimmune polyglandular syndrome type 2 and being able to make the association of hypothyroidism and primary adrenal insufficiency.

• Careful history and physical exam with regard to recognising subtle signs and symptoms of adrenal insufficiency prior to starting patients on levothyroxine for hypothyroidism.

• Understanding that initiating levothyroxine can induce an anabolic state requiring more cortisol and inducing adrenal crisis in patients with adrenal insufficiency.

• Initiating the early use of venous arterial extracorporeal membrane oxygenation for refractory cardiogenic shock secondary to adrenal crisis, allowing sufficient time for corticosteroids to take effect.