Abstract
Summary
Autoimmune polyglandular syndrome (APS) type 2 is characterized by the presence of Addison’s disease (AD) along with autoimmune thyroid disease and/or type 1 diabetes. APS type 2 is known as Schmidt’s syndrome when autoimmune adrenal insufficiency is associated with chronic lymphocytic thyroiditis. We report a very rare case of a 28-year-old female patient who had Schmidt’s syndrome revealed by a thyroid storm (TS) concomitant with an acute adrenal crisis. The onset of AD resulted in a surgical emergency. The patient presented with cardiogenic shock and an acute abdomen. The precipitation factor was Hashitoxicosis presented as TS. This life-threatening condition was successfully reversed with aggressive medical therapy based on antithyroid drugs and intravenous glucocorticoids. This hyperthyroid phase lasted for a period of 8 months. The patient eventually developed hypothyroidism, suggesting that Hashimoto's thyroiditis was the most likely diagnosis. She was started on levothyroxine replacement therapy and remained euthyroid on levothyroxine. The case we describe had several diagnostic pitfalls that are discussed both at the start as well as during the evolution.
Learning points
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Autoimmune diseases can appear concomitantly or succeed each other over time. The clinician must be vigilant to detect these diseases in time in order to avoid a misdiagnosis of a life-threatening emergency such as adrenal insufficiency or thyroid storm.
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Thyroid storm is an uncommon but life-threatening manifestation of hyperthyroidism. Diagnosis is dependent on clinical symptoms, and no specific laboratory tests are available.
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Glucocorticoids should be used in the treatment of thyroid storm because they have an inhibitory effect on peripheral conversion of T4 to T3.
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In patients who have severe thyrotoxicosis, especially in conjunction with hypotension, treatment with glucocorticoids has become standard practice because of the possibility of relative adrenal insufficiency or the possibility of undiagnosed Addison’s disease.
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The differential diagnosis of hyperthyroidism can be challenging. Graves’ disease can be discussed in view of the severity of the clinical presentation and the prolonged duration of the hyperthyroid phase. Hashitoxicosis is the initial hyperthyroid phase in chronic autoimmune thyroiditis. The hyperthyroid phase is always followed by definitive resolution, with persistent euthyroidism and no hyperthyroid relapses.
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Synthetic antithyroid drugs may be prescribed during the hyperthyroid phase of Hashimoto thyroiditis if the clinical presentation is severe and the duration of the hyperthyroid phase is prolonged.
Background
Autoimmune polyglandular syndrome (APS) type 2 is rare, with an estimated prevalence of 1.4–2.0 per 100 000. Addison’s disease (AD) is a key criterion for diagnosis and is present in 100% of the patients (1, 2, 3).
In this report, we present a very rare case of acute adrenal crisis and thyroid storm (TS) in a 28-year-old female patient revealing APS type 2.
She presented with a life-threatening medical emergency, which was completely reversed with correction of the underlying endocrine disturbance. This case makes us aware of the importance of the recognition of multisystem signs and symptoms associated with autoimmune polyendocrinopathy.
Case presentation
A 28-year-old Caucasian patient, with no past medical history, presented to the emergency room with fever, palpitation, vomiting and abdominal pain that had progressed for 3 days. She had not had her period for 2 months. She also reported a significant weight loss of 20 kg over the same period. Vital signs on presentation were as follows: blood pressure 60/40 mmHg, heart rate 140 bpm, temperature 38.6°C and respiratory rate 14 bpm. She was confused and had abdominal guarding. General examination did not show hyperpigmentation of skin or mucosa.
Investigation
On initial presentation, laboratory workup showed biologic inflammatory syndrome, hyponatremia, hyperkalemia, acute functional renal failure with increased uremia, elevated transaminase levels and serum calcium at the upper limit of normal (Table 1).
Laboratory investigation in a patient with an autoimmune polyendocrinopathy revealed by a thyroid storm concomitant with an acute adrenal crisis and evolution of biochemical changes during the course of treatment.
Parameters | Normal values | Initial presentation | D2 | D8 | D15 | After 8 months |
---|---|---|---|---|---|---|
White blood cells, × 103/µL | 4000–10000 | 14 280 | 6500 | |||
C-reactive protein, mg/L | <6 | 118 | 67 | 5.2 | ||
Serum sodium, mEq /L | 135–145 | 121 | 130 | 142 | ||
Serum potassium, mEq /L | 3.5–4.5 | 4.8 | 4.8 | 3.9 | ||
AST, IU/L | <45 | 98 | 39 | |||
ALT, IU/L | <45 | 87 | 34 | |||
Serum creatinine, µmol/L | 50–110 | 139 | 39 | |||
Urea, mmol/L | 2.5–7.5 | 18.3 | 4.3 | |||
Serum calcium, mmol/L | 2.2–2.6 | 2.59 | 2.3 | |||
Albumin, g/L | 34–54 | 40 | 38 | |||
TSH , µIU/mL | 0.4–4 | <0.005 | >100 | |||
FT4, pmol / L | 10–20 | 65 | 44 | 3 | ||
Anti-TSH receptor antibody, IU/L | <1.75 | 1.4 | ||||
Anti-TPO, IU/mL | <34 | 488.3 | ||||
Baseline cortisol, ng/mL | 69–194 | 43 | 56 | 14.7 |
AST, aspartate aminotrasferase; ALT, alanine aminotransferase; FT4, free thyroxine.
Treatment
The patient was treated with intravenous hydrocortisone, 50 mg administered every 6 h, but without improvement after a few hours. Given the hypovolemic shock, the abdominal guarding and the delayed period, the patient was operated on to rule out a gynecological emergency (an ectopic pregnancy). The exploratory laparotomy was negative, and the patient was transferred to the intensive care unit (ICU) with respiratory support.
The hormonal assay showed a free thyroxine (FT4) level at 65 pmol/L and thyroid stimulating hormone ultrasensitive (TSHus) level <0.005 µIU/mL. The diagnosis of TS was made with a score of 70. Methimazole (40 mg/day) and propanolol (60 mg/day) were prescribed with good clinical outcome. The patient was extubated on D7 of hospitalization and was transferred to the internal medicine department.
Outcome and follow-up
On examination on D8, the patient had no signs of Graves' ophthalmopathy, pretibial myxedema or goiter. Thyroid peroxidase antibodies (TPOAbs) were positive. The TSH receptor antibody (TRAb) titer values were not checked initially but was measured later in the clinical course and were negative (Table 1). Ultrasound revealed a normal-sized thyroid with heterogeneous echogenicity. Neither radioactive iodine or technetium uptake measurements were performed. However, as Doppler studies did not reveal increased vascularization, and TPO antibodies were positive, hashitoxicosis (HTX) was initially assumed as the cause for hyperthyroidism.
Baseline cortisol levels at D15 of hospitalization had returned to 56 ng/mL. A computerized tomography scan of the abdomen revealed bilateral adrenal atrophy, consistent with autoimmune adrenal failure. A final diagnosis of AD was made.
The patient was discharged from the hospital after few days with the following medical regimen: methimazole (10 mg/day), propranolol (30 mg/day), orally administered hydrocortisone (25 mg/day) and fludrocortisones (50 μg/day).
The hyperthyroid phase lasted for a period of 8 months. The patient eventually developed hypothyroidism, after antithyroid drug discontinuation, suggesting that Hashimoto's thyroiditis (HT) was the most likely diagnosis. She was started on levothyroxine replacement therapy 3 months later and remained euthyroid on levothyroxine thereafter. An adrenocorticotrophic hormone (ACTH) assay was done during the follow-up while the patient was under hydrocortisone. The ACTH level came back to 70 pg/mL. ACTH was therefore not decreased, which confirms the primary origin of the adrenal insufficiency.
A diagnosis of Schmidt’s syndrome associating AD and HT was therefore finally made.
Discussion
Clinically, the most frequent combination of diseases associated with APS type 2 is AD with HT (56%), and the least frequent is the triad of AD, Graves’ disease (GD) and type 1 diabetes mellitus (3%) (4).
Our patient had the two major components of APS type 2 with an acute onset of both of them. We describe an unusual case of a TS and acute adrenal crisis in a woman without a previous diagnosis of hyperthyroidism or AD. The patient presented with cardiogenic shock and an acute abdomen. This life-threatening condition was successfully reversed with aggressive medical therapy based on antithyroid drugs and intravenous glucocorticoids. The case we describe had several diagnosis pitfalls.
First, the diagnosis of TS was challenging, and its clinical course was severe, requiring endotracheal intubation and respiratory support.
The patient developed hypovolemic shock on admission. Hyponatremia and hyperkalemia were strongly suggestive of acute adrenal insufficiency. Given the non-improvement after 24 h of treatment with glucocorticoids, surgical exploration was indicated to rule out a gynecological emergency which could have decompensated the adrenal insufficiency in this patient, but the laparotomy was negative. There was no history of thyroid dysfunction; therefore, an initial presentation of HTX as TS was unexpected, and the diagnosis of TS was not made at first until thyroid function tests confirmed that the patient had hyperthyroidism.
TS is an uncommon but life-threatening manifestation of hyperthyroidism. Diagnosis remains predominantly dependent on clinical symptoms since no specific laboratory tests are available (5, 6).
Burch and Wartofsky have proposed a point scale for the diagnosis of TS, in which a score of 45 and above is highly suggestive of TS (7, 8). Our patient had a score of 70 on admission, sufficient for the diagnosis of TS, and yet the diagnosis was not brought up in time. Thyroid hormones were available 24 h after admission to the ICU and proved indicative of hyperthyroidism, which was associated with clinical findings characteristic of TS.
Second, prompt recognition of TS is essential to initiate treatment, which should be performed in an ICU setting. Patients with TS have increased inpatient mortality rate, overall hospital and ICU length of stay and ventilation requirements compared with those with compensated thyrotoxicosis. The mortality rate of TS ranges from 10% to 20% (9, 10). Our patient did not receive the synthetic antithyroid drugs on time, but most likely what saved her was the administration of glucocorticoids. Glucocorticoids have been used in the treatment of TS because they have an inhibitory effect on peripheral conversion of T4 to T3. Therefore, glucocorticoids can be effective in reducing T3 levels as adjunctive therapy. In patients who have severe thyrotoxicosis, especially in conjunction with hypotension, treatment with glucocorticoids has become standard practice because of the possibility of relative adrenal insufficiency or the possibility of undiagnosed AD. Dosing of glucorticoids in TS can be with hydrocortisone 100 mg intravenously every 8 h, with tapering as the signs of TS improve (8). The 2016 American Thyroid Association Guidelines for the management of TS support that glucocorticoids reduce T4-to-T3 conversion, promote vasomotor stability and possibly treat an associated relative adrenal insufficiency (11).
Third, our case is an example of an unusually prolonged phase of HTX revealed by TS. Most cases of TS are caused by the presence of some triggering condition in conjunction with an underlying thyroid condition. This usually involves untreated or uncontrolled GD but may rarely be due to thyrotoxic disorders such as chronic lymphocytic thyroiditis (12, 13, 14). The differential diagnosis of hyperthyroidism in this case can be challenging. GD can be discussed in view of the severity of the clinical presentation and the prolonged duration of the hyperthyroid phase. Many cases with conversion from GD to HT or vice versa have been reported in the literature. Thus, the existence of such entities needs to be considered (15). Unfortunately, in our patient, TRAbs were evaluated only 1 week after starting antithyroid treatment and were negative. However, this finding might have been secondary to the immunosuppressive effect of methimazole. The unknown pre-existence of HT was based on the positivity of TPOAbs, as data on past thyroid hormones were not available. Nevertheless, the concentrations of TPOAbs are reported to be high in 90% of patients with HT and 75% of patients with GD (16).
In our case, the fact that thyroid sonographic findings and TRAbs were within the reference range argued against the presence of GD. The definitive diagnosis was made in the follow-up period, in which transient thyrotoxicosis followed by hypothyroidism strongly suggested HTX. HTX is the initial hyperthyroid phase in chronic autoimmune thyroiditis. It occurs due to the release of preformed thyroid hormones from the inflamed thyroid gland. Rarely does a patient exhibit signs and symptoms of hyperthyroidism at the initial presentation (17).
The hyperthyroid phase is always followed by definitive resolution, with persistent euthyroidism and no hyperthyroid relapses. A spontaneous and definitive resolution of hyperthyroidism generally occurs few months after HTX presentation (18).The prolonged duration of the hyperthyroid phase in our patient was unusual. Nabhan et al. (19) investigated 69 patients and could not identify any predisposing factor for the development of HTX. Eight of 69 patients with HT (11.5%) initially presented with hyperthyroidism. The duration of hyperthyroidism in these cases was reported to range from 1 to 23 months and to be positively correlated with TPOAb levels at presentation. In the few patients with more severe presentation, methimazole treatment was required (20, 21). Our patient was prescribed methimazole for three reasons: first the severity of the initial presentation: indeed HT was revealed by TS; second the literature review: several teams have prescribed antithyroid drugs for severe presentation of HTX, especially when this phase of hyperthyroidism persisted (for our patient, we kept a low dose of methimazole); third the diagnosis of HT was not easy at the start. The initial presentation was atypical, and the TRAb assay was performed after the administration of antithyroid drugs. In addition, cases with coexistent GD and HT and conversion from GD to HT or vice versa have been reported in the literature (15, 22). In our case, the long-term progression to permanent hypothyroidism was the strongest argument for the diagnosis of HTX.
Fourth, TS triggered an acute adrenal crisis without a previous diagnosis of AD. The diagnosis of a surgical emergency was therefore wrongly made. The hypothalamo–pituitary–adrenal axis has been shown to be impaired in thyrotoxicosis with a decrease in adrenal reserve. Despite increased production of cortisol by the adrenal gland to compensate for accelerated glucocorticosteroid metabolism in hyperthyroid states, a subnormal response of the adrenal glands to adrenocortico-stimulating hormone occurs (7). After successful management of severe thyrotoxicosis during the early stage of TS, doses of corticosteroids should be tapered and discontinued following confirmation of adrenocortical recovery by measuring fasting serum cortisol level (23). Our patient had a very low cortisol level at a distance which allowed us to retain the diagnosis of adrenal insufficiency.
The major endocrine component of APS type 2 is AD. In approximately 40–50% of cases with AD, additional autoimmune endocrine diseases occur. Up to 1 year after the onset of AD, less than 50% of those patients only are detected due to the broad range of unspecific symptoms and the long time interval between the occurrences of the different endocrine components (16). Adult-onset APS manifests sequentially with a large time interval between the occurrence of the first and the second glandular autoimmune disease (24).
Our patient presented with two life-threatening condition, a TS and absolute adrenal insufficiency. De Keulenaer et al. reported a similar case of TS presenting with an absolute adrenal insufficiency in a 57-year-old patient (14).
Conclusion
In conclusion, when patients have a predisposition to autoimmune diseases, all scenarios are possible. Autoimmune diseases can appear concomitantly or succeed each other over time, and the clinician should be cautious to detect these diseases in time in order to avoid a misdiagnosis of a life-threatening emergency such as adrenal insufficiency or TS.
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
A written informed consent has been obtained from the patient for publication of the submitted article.
Author contribution statement
N Lassoued: The first named physician of the patient; W Alaya: The second named physician of the patient; S Rebai: The third named physician of the patient; S Arfa: Collaboration in patient care; B Zantour: Supervision; M H Sfar: Supervision.
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