Plasma exchange as a rescue therapy for treatment-resistant thyroid storm with concurrent heart failure: a literature review based on a case report

Abstract

Introduction

Thyroid storm or severe hyperthyroidism can present with various signs and symptoms. They are mostly controlled by general treatment, such as anti-thyroid drugs and other medications to control clinical features. However, in rare cases, they are more severe, and they only respond to more aggressive treatments, such as plasmapheresis and total thyroidectomy. The final histopathological features, such as the loci of differentiated thyroid carcinoma, are sometimes surprising.

Case presentation

Here, we present a 40-year-old female who presented with severe palpitation, diaphoresis, and chest pain. After taking the initial steps of treatment and stabilizing the patient, the history, physical exam, and laboratory results confirmed the diagnosis of a thyroid storm in the background of Graves’ disease that is accompanied by heart failure with reduced ejection fraction (HFrEF). She was admitted to an ICU setting and received principal treatment of thyroid storm. However, the systematic treatment was not effective, and finally, plasmapheresis and total thyroidectomy were performed. Histopathologic evaluation following surgery confirmed the presence of foci of papillary thyroid carcinoma (PTC) in the background of the grave’s disease.

This case underscores the complexity of managing Grave’s induced thyroid storm in severe cases, which might lead to plasmapheresis and total thyroidectomy. Urgent and invasive treatment may be necessary in rare cases when normally applied treatment modalities are not able to control the situation and result in life-threatening critical health conditions. In such a severe case, it can result in serious cardiovascular complications such as decompensated heart failure with a high rate of mortality.

Key clinical message

Thyroid storm, though rare, can be accompanied by severe medical conditions such as heart failure and death. In cases in which primary medical and symptomatic therapies do not work, more aggressive treatment (such as plasmapheresis and total thyroidectomy) should be considered. On the other hand, precise histopathologic evaluation of the thyroid tissue is necessary.

Introduction

Thyroid storm is a potentially life-threatening (8–25% mortality despite current advancements) and acute type of hyperthyroidism, which includes severe involvement of organ(s). It is the extreme spectrum of thyrotoxicosis with rare incidence but very severe presentation [1, 2]. This condition was seen for the first time in 1962 and was presented as an exaggerated Grave’s seen as exophthalmia and goiter [3, 4]. There is a new definition for thyroid storm, including two criteria: 1) exaggerated hyperthyroidism symptoms and signs, and 2) signs of severe multi-organ failure such as declined cardiac function, severe hyperpyrexia, and change in mental status [1, 5]. This condition is most commonly seen in untreated or insufficiently treated Grave’s disease, while there are definite triggers that can contribute to this condition [1]. These conditions include a) abrupt cessation of anti-thyroid medications, b) acute infections and other illnesses, c) trauma or accidents, d) loss of function in other organs such as heart or kidneys, e) change in nutritional habits, f) using radioiodine contrasts, g) pregnancy or hyperemesis gravidarum, h) using medications such as amiodarone, salicylates, and anesthetic medications [6,7,8,9,10]. However, almost one-fourth to half of these cases happen without finding any specific trigger. In the United States, this critical condition’s incidence ranged from 6 to 8 cases per a million in normal population and almost 50–60 in a million of hospitalized patients [11].

The pathophysiology of thyroid storm is still to be completely understood, partly attributed to the rapid release of thyroid hormones (or increased production) during any of the mentioned risk factors [12]. They cause increased metabolism in the cells and increased catecholamine release in the blood, which results in altered metabolism and the presentation of thyroid storms. The diagnosis of thyroid storm is based on clinical features and laboratory data. However, determining the underlying cause, as well as the management, is not always straightforward, and it might be accompanied by a high rate of morbidity and mortalities [12, 13].

The present case report presents a patient whose features are diagnostic for severe refractory thyrotoxicosis, namely thyroid storm. However, her treatment progression becomes complicated and refractory to usual treatment, needing aggressive therapeutic interventions.

Case presentation

A 40-year-old female presented to the emergency department with complaints of palpitations, chest pain, perspiration, severe shortness of breath, and loss of consciousness. She reported that her symptoms had progressively worsened over the past two months after discontinuation of medications that she has been taking for treatment of Graves' disease, including Methimazole (60 mg/day) and Propranolol (80 mg/day). The patient was admitted with poor adherence to her drug regimen, noting that she had discontinued treatment several times after experiencing mild symptom relief. However, she complained of exertional dyspnea, orthopnea, and unintentional weight loss of 10 kg over the last month. Her past medical history included a diagnosis of Graves' disease two years prior to admission, for which she had been taking Methimazole and Propranolol. Despite this, she had a history of non-compliance with medication. There was no notable family history of thyroid disease or other autoimmune disorders.

On examination, the patient appeared visibly anxious and in acute distress, with noticeable diaphoresis. Her vital signs were concerning, showing a blood pressure of 160/100 mmHg, a heart rate of 130 beats per minute (tachycardia), a respiratory rate of 30 breaths per minute, and an oxygen saturation of 85% on room air. She was febrile, with an oral temperature of 38.2°C. Auscultation of the heart revealed irregularly irregular heart sounds, and a transient episode of AF was noted on the ECG. Bilateral crackles were present at the lung bases. Examination of the neck revealed a diffusely enlarged thyroid gland with a palpable bruit, and her eyes exhibited prominent bilateral proptosis with periorbital edema. Her skin was warm, moist, and inflamed, consistent with hyperthyroidism. Neurologically, she was confused and disoriented, with a GCS score of 13, reflecting altered mental status.

Methods and materials

The patient was admitted to the ICU with a provisional diagnosis of thyroid storm based on her clinical presentation of severe hyperthyroid symptoms, including tachycardia, altered mental status, and cardiovascular instability. Laboratory results confirmed severe thyrotoxicosis with suppressed TSH and elevated levels of T4 and T3 (Table 1). The radioactive iodine scan demonstrated an enlarged thyroid gland with homogenous increased radiotracer uptake in both lobes, consistent with hyperactivity of the thyroid tissue and Graves’ disease (Fig. 1). Initial treatment included 60 mg of Methimazole (20 mg three times daily), 80 mg of Propranolol (twice daily), and 8 mg of intravenous Dexamethasone per day. This regimen is standard for managing thyroid storm, aiming to block thyroid hormone synthesis (Methimazole), control cardiovascular symptoms (Propranolol), and reduce inflammation (Dexamethasone). Additional treatment measures included 900 mg of Lithium to inhibit thyroid hormone release, IV hydration with dextrose saline solution to maintain fluid balance, and Lugol’s iodine drops (10 drops three times daily) further to inhibit thyroid hormone release by the thyroid gland.

Table 1 Comparison of key laboratory values upon admission and at discharge

Fig. 1

The thyroid gland is enlarged, demonstrating relatively homogenous increased radiotracer uptake in both lobes. There is notably reduced uptake in the salivary glands and background, suggesting hyperactivity of the thyroid tissue

Despite these aggressive interventions, the patient showed no improvement in her symptoms within the first 12 hours of treatment. Echocardiography revealed a low left ventricular ejection fraction (25%) and global hypokinesia, indicating heart failure, while CXR showed signs of pulmonary edema. Transient AF was also observed on the ECG, further complicating her cardiovascular status.

Given the severity and refractory nature of the condition and hemodynamic instability, daily plasmapheresis, a procedure to remove circulating thyroid hormones and immune complexes, was initiated along with albumin replacement therapy. After two plasmapheresis sessions, the patient's clinical status improved significantly with the stabilization of her vital signs. However, cognitive dysfunction persisted, and her mental status remained altered. Due to the recurrent and refractory nature of her thyroid storm, she was considered a candidate for therapeutic and diagnostic total thyroidectomy. The removal of the thyroid gland in such cases is often the last resort when medical management fails, as it eliminates the source of excess thyroid hormone. Despite the recommendation, the patient initially refused surgery. A psychiatric evaluation was performed by a psychiatrist, which revealed declined capacity. Interviews were conducted with the patient to assess her understanding of her current situation and consider and compare available therapeutic options. She was alert to time and place but was not aware of her medical conditions and could not comprehend the pros and cons of each recommended treatment. She was very anxious and concerned about the surgical option. Considering her impaired decision-making capacity, likely due to her severe illness, after discussing the possible options with the patient's next of kin (based on the ethical protocols of the hospital) and shared decision-making, inpatient medical management continued for 8 days. During that time, her condition improved sufficiently, and the dosages of her medications were reduced. Ultimately, the patient consented to undergo a total thyroidectomy.

Conclusion and follow-up

The postoperative course was uneventful. Histopathological evaluation of the thyroid tissue revealed a diagnosis of papillary thyroid cancer (Table 2) (Fig. 2), which, although not commonly, can be seen in association with thyroid storm. The patient was discharged five days postoperatively without complications and with the resolution of her symptoms. The mutation analysis of the cancerous tumor was not feasible due to the patient’s economic limitations.

Table 2 Pathologic findings of the patient in histopathological evaluation

Fig. 2

Histopathological evaluation of the thyroid biopsy revealed both classic and follicular subtypes of papillary thyroid carcinoma. Panel A (×400) and Panel B (×40) demonstrate detailed cellular architecture, while Panel C (×40) and Panel D (×10) provide an overview of the tissue morphology at lower magnifications

During follow-up over the next year, the patient remained asymptomatic, with no recurrence or signs of metastatic disease.

Discussion

This case underscores the importance of considering refractory and resistant to treatment severe thyrotoxicosis as a potentially life-threatening condition that should be managed promptly. Otherwise, it can result in severe organ dysfunction (such as declined cardiac contractility and its severe consequences) [14,15,16,17]. Plasmapheresis and also total thyroidectomy are viable options in refractory cases and can be life-saving [18, 19]. The presented case is clinically rare in several aspects, such as being presented with critical cardiovascular complications, which were dramatically responsive to plasmapheresis and then total thyroidectomy. The lack of decision-making compliance and disturbed judgment despite improving physical symptoms and signs is another useful and noticeable point. It demonstrates that all signs and symptoms are not necessarily resolved simultaneously and might differ in their treatment responses.

The histopathologic examination of the removed thyroid should be taken seriously, and in case of detection of any malignancy, more detailed follow-up is necessary. The main features that should be considered for diagnosing the thyroid storm are clinical signs and symptoms, which can be confirmed by the laboratory indexes [20]. The main symptoms might vary between different cases, seen as constitutional symptoms (generalized weakness and fatigue), excessive heat sensation, diaphoresis, fever, weight loss despite abnormally high appetite, mental instability (anxiety and emotional lability), cardiovascular symptoms (palpitations and exertional dyspnea), gastrointestinal symptoms such as diarrhea, and skin and hair changes (hair loss) in most cases [20,21,22]. In the physical exam, there are also signs that are compatible with the mentioned signs (Table 3) [21, 23].

Table 3 Signs and symptoms frequently seen in thyroid storm [21,22,23,24]

There are no definite changes in laboratory findings regarding the diagnosis of thyroid storm. However, there is a combination of clinical and laboratory data introduced by the Japanese Thyroid Association [25], which categorizes suspicious cases into two groups of

• 1. Definite thyroid storm: increased FT3 and or FT4 + ≥1 CNS manifestation+≥1 other symptom or at least 3/5 of Fever, GI/Hepatic, CHF, Tachycardia

• 2. Probable thyroid storm: ≥2/5 of tachycardia, CHF, GI, Hepatitis, or a goiter patient with an exophthalmos

  • Therapeutic strategies for thyroid storm

There are two lines of treatment which are proven to be effective against thyroid storm:

• 1- The first step of treatment includes two levels of: [22]

  • A) Supportive measures: Rest, Mild sedation. Fluid and electrolyte replacement. Nutritional support and vitamins as needed, Oxygen therapy, Nonspecific therapy as indicated, Antibiotics, Cardio-support, Cooling, blankets, and medications

  • B) Specific therapy: Beta-blockers (Propranolol 60-80 mg Q4h, 1-3 mg IV Q4h, or esmolol in ICU

  • C) Propylthiouracil (PTU, 500-1000 mg load and 250 mg Q4H) or methimazole (60-80 mg daily). They should be tapered as the patient’s condition improves

  • D) Iodide Potassium (One hour after the loading dose of antithyroid+250, Orally every 6 hours)

  • E) IV Hydrocortisone 300 mg load+ 100 mg every 8 hours (Preventing peripheral conversion of T4 to T3)

  • F) Treating background etiology (Infection, MI)

  • G) Definitive treatment: Radioiodine and/or surgical therapy

• 2- Secondary line treatment: For those does not respond to the first line treatment [22]

  • A) Plasmapheresis

  • B) Dialysis

  • C) Lithium for those who cannot take iodine

  • D) Oral T3-T4 binding resins (Colestipol, cholestyramine)

  • E) Thyroidectomy

Plasmapheresis, which has been used in the treatment of thyroid storms in this patient, is normally used in refractory cases and in cases that are not responsive to the first-line treatment. This method is accompanied by a rapid decline in thyroid hormone and TSI, which reveals the symptoms. The safety and efficacy of preoperative treatment with plasmapheresis have been proven [26]. Total thyroidectomy is another option used for the treatment of refractory thyroid storm. Even performing this procedure when the patient is in critical conditions, such as ECMO, has been shown to be life-saving and effective [27]; the obtained thyroid tissue should be evaluated histopathologically to make sure no malignancy is present and if it is work-up for metastasis should be performed. In the presented case, the histopathological examination showed a PTC without any margin or capsule invasion or lymph node metastasis.

PTC typically follows an indolent course with a favorable prognosis, particularly when diagnosed early [28]. However, in certain cases, aggressive disease behavior can emerge, leading to distant metastases and life-threatening complications such as brain or bone metastasis [29]. This case exemplifies a rare and severe presentation where Graves' disease is not properly treated, triggering a refractory thyroid storm and subsequent cardiac failure, underscoring the importance of a prompt, multidisciplinary therapeutic strategy to manage such complex scenarios.

PTC is derived from the follicular cells of the thyroid and is known for its well-differentiated nature [30]. The BRAF p.V600E mutation is the most prevalent genetic alteration in PTC, found in about 70% of cases. It is associated with a poorer prognosis, particularly when combined with TERT promoter mutations. Additionally, mutations in genes such as RAS, PIK3CA, and TP53 accumulate during the progression of PTC, contributing to tumor growth, invasiveness, and resistance to treatment [31]. The tumor typically spreads via lymphatic vessels, with cervical lymph node involvement being common. However, distant metastases, especially to the lungs and bones, occur in about 5-10% of cases, often leading to a poorer prognosis [32]. As seen in this case, the development of a thyroid storm is a rare but life-threatening manifestation of hyperthyroidism that requires immediate attention [33]. It is precipitated by excessive thyroid hormone release, which triggers systemic complications, particularly in the cardiovascular system [34]. In the context of PTC, factors like poorly controlled hyperthyroidism, metastatic spread, and underlying thyroid dysfunctions such as Graves' disease can further exacerbate this crisis [35, 36].

The diagnosis of PTC is typically confirmed by fine-needle aspiration (FNA) biopsy, guided by ultrasound, which remains the gold standard. However, for patients presenting with suspected thyroid storm or metastatic disease, a multimodal approach is necessary [37,38,39,40]. Ultrasound is commonly used to assess cervical lymph node metastasis in PTC because it is non-invasive and accessible. However, it has limitations, especially for deep or mediastinal areas. Contrast-enhanced CT complements ultrasound by detecting metastasis in areas hidden by anatomical structures and providing detailed tumor imaging, which is vital for surgical planning in advanced cases [41, 42]. MRI can provide additional information by distinguishing between histological subtypes of thyroid cancer, such as anaplastic, poorly differentiated, and PTCs, particularly when assessing tumor margins, extrathyroidal extension, and intertumoral characteristics on T2-weighted images [43, 44]. In cases like this, nuclear imaging with radioactive iodine (RAI) can be particularly useful in detecting and treating metastatic PTC, as these tumors often retain iodine-absorbing ability [45].

In managing thyroid storm, antithyroid drugs like propylthiouracil (PTU) or methimazole are used to inhibit hormone synthesis, while beta-blockers manage cardiovascular symptoms. Iodine preparations, such as radioactive iodine, are crucial for post-surgical ablation or persistent disease in thyroid cancer. Corticosteroids may be used in inflammatory cases, and targeted therapies are considered for resistant or advanced cases [40, 46]. Plasmapheresis, an extracorporeal therapy that rapidly removes circulating thyroid hormones, is indicated in cases of thyroid storm that are refractory to conventional treatments or when drug toxicity limits their use [47].

The management of PTC has shifted toward less aggressive treatments following the 2009 and 2015 American Thyroid Association (ATA) guidelines. Thyroid lobectomy (TL) is now preferred for low-risk tumors under 4 cm, reducing the need for total thyroidectomy (TT) and RAI therapy. The use of RAI has significantly declined, especially in low-risk cases, where it is no longer routinely recommended, contributing to a reduction in overtreatment [48]. Postoperative surveillance, including serum thyroglobulin and neck ultrasonography, is emphasized for long-term monitoring, while the ATA also recommends ongoing risk stratification to tailor follow-up and treatment decisions based on the patient’s response to initial therapy. The adoption of these ATA-driven changes has been more rapid in academic centers, intending to reduce treatment risks while maintaining favorable outcomes [40]. In cases of non-iodine-avid tumors or radioiodine-refractory metastatic disease, TKIs such as lenvatinib or sorafenib are recommended [49].

Untreated or poorly managed thyroid storm can lead to severe, life-threatening complications, such as heart failure. In this case, heart failure developed due to the hypermetabolic state caused by excessive thyroid hormones, which leads to high-output cardiac failure, arrhythmias, and cardiomyopathy. Early recognition and prompt treatment are crucial to prevent irreversible myocardial damage [50]. Other systemic complications of poorly managed thyroid storm can include acute liver failure, pulmonary edema, and shock [51]. The metastatic spread of PTC further complicates the management, as bone and lung metastases can lead to respiratory compromise, fractures, and severe pain, impacting the patient’s quality of life [52, 53].

The prognosis of PTC is generally favorable, with a 10-year survival rate exceeding 90% for localized disease, according to the NCCN 2022 Clinical Practice Guidelines. However, the prognosis significantly worsens in cases where PTC has metastasized or when complicated by severe conditions such as thyroid storm. These advanced and aggressive disease courses present challenges in management and often lead to poorer outcomes [54]. Distant metastases in PTC significantly reduce survival. The 5-year survival rate drops from 77.6% for single-organ metastasis to 15.3% for multi-organ involvement. When metastasis involves critical organs like the brain or liver, survival outcomes are even poorer [55].

Kwon et al. (2023) reported a case of thyroid storm caused by metastatic PTC in a patient post-total thyroidectomy. Despite aggressive treatment, including antithyroid medications, the patient succumbed to multi-organ failure within six days of hospitalization. This case highlights the importance of early recognition and management of thyrotoxicosis in patients with metastatic PTC, particularly when complicated by severe conditions like heart failure [39]. Similar cases can be found in Table 4 of the study, which outlines other patients who presented with thyroid storms under similar circumstances.

Table 4 Similar presentations of papillary thyroid carcinoma reported in the literature review

Conclusion

This case highlights the rare but potentially life-threatening medical condition called thyroid storm, which can result in unresponsiveness to regular treatment and final use of plasmapheresis and thyroidectomy. This study also underscores PTC as a potential cause of refractory thyroid storm. Early recognition and aggressive multidisciplinary management are crucial to prevent rapid deterioration and death. Untreated PTC complicated by thyroid storm is a life-threatening condition that requires prompt diagnosis and treatment.