Pediatric Pulmonary Arterial Hypertension and Hyperthyroidism: A Potentially Fatal Combination

Abstract

Context:

Patients with pulmonary arterial hypertension (PAH) who develop hyperthyroidism are at risk for acute cardiopulmonary decompensation and death.

Cases and Setting:

We present a series of eight idiopathic PAH/heritable PAH pediatric patients who developed hyperthyroidism between 1999 and 2011. Institutional Review Board approval was obtained; informed consent was waived due to the retrospective nature of the series. All eight patients were receiving iv epoprostenol; five of the eight patients presented with acute cardiopulmonary decompensation in the setting of hyperthyroidism. In the remaining three patients, hyperthyroidism was detected during routine screening of thyroid function tests. The one patient who underwent emergency thyroidectomy was the only survivor of those who presented in cardiopulmonary decline.

Evidence Synthesis:

Aggressive treatment of the hyperthyroid state, including emergency total thyroidectomy and escalation of targeted PAH therapy and β-blockade when warranted, may prove lifesaving in these patients. Prompt thyroidectomy or radioactive iodine ablation should be considered for clinically stable PAH patients with early and/or mild hyperthyroidism to avoid potentially life-threatening cardiopulmonary decompensation.

Conclusions:

Although the association between hyperthyroidism and PAH remains poorly understood, the potential impact of hyperthyroidism on the cardiopulmonary status of PAH patients must not be ignored. Hyperthyroidism must be identified early in this patient population to optimize intervention before acute decompensation. Thyroid function tests should be checked routinely in patients with PAH, particularly those on iv epoprostenol, and urgently in patients with acute decompensation or symptoms of hyperthyroidism.

Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by sustained elevations in pulmonary arterial pressure (mean >25 mm Hg by catheterization) and increased pulmonary vascular resistance with normal pulmonary capillary wedge pressure (1). Even with optimal therapy, PAH carries a guarded prognosis. For pediatric patients on chronic epoprostenol therapy, 39% die within 10 yr of diagnosis (2).

There is thought to be an autoimmune component to the pathogenesis of PAH; autoimmune diseases are common in patients and family members (3). The association between PAH and thyroid disease has been described; however, the exact link has not been well-characterized. There are descriptions of elevated pulmonary pressures measured by echocardiography in hyperthyroid adults that often improve with treatment directed at the thyroid disease (4, 5). For individuals with preexisting PAH, there is a known association with autoimmune thyroid disease (AITD). Chu et al. (6) found that 49% of adults with PAH had AITD, and four of 18 newly diagnosed patients had Graves' disease.

Less is known about the association between PAH and thyroid disease in children, although the prevalence of thyroid disease is higher in the pediatric PAH population as well. A small Japanese series found that 44% of idiopathic PAH (IPAH) patients had AITD (7). In a cohort of 78 pediatric PAH patients at our institution, 12% had thyroid disease, four of whom developed thyrotoxicosis after initiation of epoprostenol (8). Those authors and others have speculated that epoprostenol might promote or unmask AITD in this at-risk population (9, 10).

In patients with preexisting PAH, hyperthyroidism can lead to acute hemodynamic decline and death. We believe that this potentially fatal complication is underrecognized. We report a series of eight consecutive pediatric patients (one of whom is described below in detail) with PAH who developed hyperthyroidism between 1999 and 2011 and describe treatment and outcomes for these patients.

Case Report

Our patient (no. 7; Table 1) was a 17-yr-old girl with IPAH who presented to the emergency department for worsening dyspnea on exertion, pleuritic chest pain, diarrhea, and hematemesis.

Table 1.

Clinical characteristics of eight pediatric patients with PAH and hyperthyroidism

Subject no.	1	2	3	4	5	6	7	8
PAH subtype	IPAH, ASD	IPAH, ASD	IPAH	HPAH	HPAH	IPAH	IPAH	HPAH
Age (in yr) at PAH diagnosis (year)	4 (1993)	2 (1998)	14 (1999)	11 (2000)	11 (2000)	6 (2002)	16 (2009)	17 (2009)
Duration of epoprostenol treatment before hyperthyroidism (yr)	1.5	2	1.5	4	3.5	4.5	0.5	2
Age (in yr) at hyperthyroid presentation (year)	9 (1999)	6 (2001)	18 (2002)	15 (2004)	15 (2004)	11 (2007)	17 (2010)	19 (2011)
PAH severity (WHO functional class)
Before hyperthyroidisma	II	II	III	I	I	II	III	III
At hyperthyroid presentation	II	II	IV	IV	IV	II	IV	IV
Genetics	NA	NA	NA	BMPR2+	BMPR2+	NA	NA	BMPR2+
Treatment of hyperthyroidism	MMI	MMI	Esmolol	PTU, esmolol	PTU, esmolol, corticosteroids	MMI	PTU/MMI, SSKI, corticosteroids, esmolol	PTU/MMI, SSKI, corticosteroids, esmolol
Final outcome	Thyroidectomy, clinically stable	Clinically stable at transfer of care	Death	Death	Death	Clinically stable	Death	Thyroidectomy, clinically stable

ASD, Atrial septal defect; BMPR2, bone morphogenetic protein receptor 2; NA, not available.

^aMost recent pulmonary hypertension clinic visit before diagnosis of hyperthyroidism.

The patient had been diagnosed with IPAH 4 months earlier and was started on continuous iv epoprostenol urgently. Past medical history was significant for hypothyroidism diagnosed 8 yr ago at an outside institution. No information was available regarding her thyroid function tests (TFT) or antibody status at that time; she was treated with levothyroxine 50 μg/d. Other medications included sildenafil, digoxin, warfarin, omeprazole, and ondansetron. Family history was significant for maternal ulcerative colitis and paternal multiple sclerosis but was negative for PAH or thyroid dysfunction.

On admission, she was afebrile, tachycardic to the 130s, tachypneic in the 20s, with an oxygen saturation of 92–94% on room air. No exophthalmos or goiter was documented. Cardiac exam was significant for a loud S2 and grade II/VI systolic murmur at the left upper sternal border.

Three weeks before admission, at a routine appointment, she was considered stable from a cardiopulmonary standpoint and was euthyroid (while on levothyroxine): TSH, 0.58 μIU/ml; total T₄, 9.89 μg/dl; free T₄, 1.37 ng/dl; and T₃, 106 ng/dl (see references ranges in Table 2 legend). No adjustment was made to her levothyroxine dose at that time. No recent iodine load preceded decompensation.

Table 2.

Thyroid data and exam findings

Subject no.	1	2	3	4	5	6	7	8
Year	1999	2001	2002	2004	2004	2007	2010	2011
Initial hyperthyroid presentation
TSH (μIU/ml)	<0.05	<0.03	<0.03	<0.03	0.08	0.25	<0.04	<0.04
Total T4 (μg/dl)	20.37	23.60	18	15.72	15.44	13.14	20.75	21.70
Free T4 (ng/dl)	NA	NA	NA	2.60	1.90	1.46	4.65	3.69
Total T3 (ng/dl)	155	322	121	146	145	156	417	507
FTI	19.59	27.76	24.28	NA	14.30	NA	NA	NA
Thyroid antibodies
Anti-TPO/antimicrosomal	−	+	+	−	−	+	−	+
Anti-TG	NA	+	−	+	−	−	+	+
TSI	NA	NA	NA	−	−	−	+	+
TBII	NA	+	+	NA	NA	+	+	+
Goiter	Present	Present	Present	Present	Present	Present	Present (small)	Present
Exophthalmos	Mild	Not present	Not present	Not present	Not present	Not present	Not present	Not present
Iodine uptake and scan	NA	NA	24-h 123I uptake, 73.7%	NA	NA	NA	NA	NA
Thyroid ultrasound	NA	NA	Enlarged	Enlarged, mildly heterogenous	NA	NA	NA	NA

Reference values for subjects 1–5: TSH, 0.34–4.25 μIU/ml; total T₄, 5.41–11.66 μg/dl; free T₄, 0.9–1.4 ng/dl; total T₃, 76.91–134.74 ng/dl; free T₄ index (FTI), 6.66–10.88; TSI, less than 125%; TBII, 0–14; anti-thyroglobulin (anti-TG), less than 10 IU/ml; anti-thyroperoxidase (anti-TPO), 0–2 IU/ml; thyroid uptake, 0.75–1.15. Reference values for subjects 6–9: TSH, 0.32–4.05 μIU/ml; total T₄, 5.41–11.66 μg/dl; free T₄, 0.7–1.24 ng/dl; total T₃, 94–170 ng/dl; TBII, less than 1.0 U/liter (negative), 1.1–1.5 U/liter (equivocal), greater than 1.5 U/liter (positive); TSI, ≤109% (negative), 110–129% (indeterminate), ≥130% (positive); anti-TG, less than 40 IU/ml; anti-TPO, less than 35 IU/ml. NA, Not available.

Labs on the day of admission documented a mild leukopenia, mild anemia, and thrombocytopenia with platelets of 76 × 10⁹/liter. Troponin-I was normal. Blood and viral cultures were negative. Portable chest radiograph showed mild cardiomegaly and moderate pulmonary artery enlargement with clear lungs. Electrocardiogram showed sinus tachycardia with right ventricular hypertrophy. Echocardiogram revealed a severely dilated right atrium and right ventricle, moderate right ventricular hypertrophy with severely diminished systolic function, as well as moderate to severe tricuspid regurgitation.

The patient was admitted to the pediatric intensive care unit. She was continued on levothyroxine 50 μg/d. Aggressive intervention, including inotropic support, was initiated to stabilize her cardiovascular status.

On hospital d 2, TFT were sent due to continued tachycardia. TSH was less than 0.04 μIU/ml, total T₄ was 20.75 μg/dl, free T₄ was 4.65 ng/dl, and T₃ was 417 ng/dl. Thyroid-stimulating Ig (TSI) were 430% (reference range, 0–129%), anti-thyroglobulin antibodies were 2881 IU/ml (reference range, <40 IU/ml), anti-thyroid peroxidase antibodies were less than 10 IU/ml (reference range, <35 IU/ml), and TSH binding inhibitory Ig (TBII) was 3.5 U/liter (positive, >1.5 U/liter). B-Type natriuretic peptide was 1169.8 pg/ml (reference range, 0–100 pg/ml; value 1 month earlier, 496.8 pg/ml). Pediatric endocrinology recommended discontinuation of levothyroxine, as well as initiating therapy with propylthiouracil (PTU) 300 mg every 6 h orally, saturated solution of potassium iodide (SSKI) 150 mg every 8 h orally, dexamethasone 2 mg every 6 h iv, and a continuous esmolol infusion. Due to the concern for ongoing cardiopulmonary decline from her hyperthyroidism, urgent total thyroidectomy was also recommended once the patient's clinical status stabilized.

The patient's cardiopulmonary function continued to decline, leading to extracorporeal membrane oxygenation on hospital d 4 and balloon atrial septostomy on hospital d 5. Free and total T₄ levels normalized within 1 wk. PTU was switched to methimazole (MMI) on hospital d 4; SSKI was discontinued on hospital d 12. Despite improvement in her TFT, her condition was not sufficiently stable to permit thyroidectomy.

The patient continued to decline and developed hypotension with associated ST changes, elevated troponin, severe thrombocytopenia, pulmonary hemorrhage, worsening hypoxemia, and kidney failure. The patient suffered cardiopulmonary arrest on hospital d 47 and died despite attempts at resuscitation.

The Columbia Experience

Our hospital is a major referral center for children and adults with PAH. Between 1999 and 2011, we estimate that over 200 pediatric PAH patients were treated at our center. Table 1 describes the clinical characteristics of eight pediatric PAH patients with hyperthyroidism who presented during that time period. These patients had a mean age of 10.7 yr (range, 2 to 17 yr) at the time of PAH diagnosis. Hyperthyroidism was diagnosed at a mean age of 14.1 yr (range, 6 to 19 yr). There was no prior history of thyroid disease in any of the patients, except for patient no. 7 as described. Table 2 outlines the laboratory data for the patients.

All of the patients were female. All were treated with continuous iv epoprostenol before presentation with hyperthyroidism. The mean duration of epoprostenol treatment before the development of hyperthyroidism was 2.4 yr (range, 0.5–4.5 yr). Although amiodarone is associated with thyroid dysfunction in PAH patients (11), none of the patients received it before development of hyperthyroidism. Of the three patients in our series for whom genetic information is available, all had heterozygous mutations of the BMPR2 gene. Three of the eight patients had other autoimmune diagnoses (no. 4, type I diabetes mellitus, Henoch-Schonlein purpura; no. 6, ulcerative colitis; no. 7, hypothyroidism).

At the most recent clinic visit before diagnosis of hyperthyroidism, patients had a median World Health Organization (WHO) functional class of II, which worsened to a median of IV at the time of presentation. Five of the eight patients were admitted with acute decline in functional status, thought to have been exacerbated by the hyperthyroidism. Four died while hospitalized. One severely symptomatic patient (no. 8) underwent emergency total thyroidectomy; she survived to discharge and remains clinically stable.

Three patients were asymptomatic or mildly symptomatic when diagnosed with hyperthyroidism and were initially treated with PTU or MMI. Patient no. 1 underwent total thyroidectomy due to intolerance of medical therapy with thionamide-related rash. Patient no. 2 was admitted for initiation of additional PAH therapy and was noted to be hyperthyroid on admission labs, but did not have an acute decline in cardiopulmonary status. She was started on MMI and at last follow-up was clinically stable before transfer of care to another facility. Patient no. 6 continues to receive close monitoring on MMI.

Natural History of Pediatric PAH

The pathogenesis of PAH in childhood is poorly understood, but pulmonary vascular cell proliferation, inflammation, vasoconstriction, and in situ thrombosis have been associated (12). PAH can be subdivided into several categories: IPAH (formerly primary pulmonary hypertension), heritable PAH (HPAH), drug or toxin-associated PAH, PAH associated with systemic conditions, and persistent pulmonary hypertension of the newborn (13). In the pediatric population, IPAH and HPAH are most common. Although the precise mechanism of injury in PAH is unknown, inflammatory and/or autoimmune mechanisms are believed to be responsible (3). In addition to AITD, PAH has been associated with autoimmune hepatitis (14), autoimmune hemolytic anemia (15), and autoimmune polyendocrine syndromes (16, 17).

There are a number of treatment modalities available for patients diagnosed with PAH, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and prostanoids. Typically, prostanoids such as epoprostenol are used in patients who have severe, advanced disease (WHO functional class III or IV) or in those with an inadequate response to other therapies (18).

Natural History of Pediatric Graves' Disease and Hyperthyroidism

Although it is not certain that all of our PAH patients had hyperthyroidism due to Graves' disease, Graves' disease is the most common cause of hyperthyroidism in both pediatric and adult patients in the United States. Toxic adenomas, multinodular goiter, acute or subacute thyroiditis, and chronic lymphocytic thyroiditis (Hashimoto's disease) are also uncommon causes of hyperthyroidism in children (19). The incidence of Graves' disease in the pediatric population is estimated at 1:10,000, with a female predominance (20).

Untreated hyperthyroidism can lead to deleterious physical and behavioral effects in children, although it is important to note that the effects are usually reversible with treatment and Graves' is rarely fatal. Graves' may present with goiter, effects on growth and puberty, weight loss despite hyperphagia, exophthalmos, palpitations, impaired skeletal mineralization, or proximal muscle weakness (19). Although Graves' ophthalmopathy is milder in children compared with adults, 50–75% of children will have evidence of ophthalmopathy (21, 22). The most pronounced effects of increased thyroid hormone levels may be on the cardiovascular system (23).

A suppressed or undetectable serum TSH yields the best sensitivity and specificity of any single test as an initial screen for hyperthyroidism (24). The addition of a free T₄ measurement greatly improves the accuracy of diagnosis (23). Serum T₃ is typically elevated as well. It is important to note that symptom severity does not appear to correlate with laboratory findings (23).

Treatment options for pediatric Graves' disease include antithyroid drugs (thionamides), thyroidectomy, and radioactive iodine (RAI) (20, 25). Only a minority of children treated medically will achieve lasting remission from disease (26), which must be an important consideration when discussing potential therapy. The thionamides (PTU and MMI) control the hyperthyroid state by preventing the binding and oxidation of iodide, but they are not curative and carry risk for hepatotoxicity, agranulocytosis, and allergic reactions. Irreversible hepatic failure has been associated with the use of PTU; thus, MMI is first-line drug therapy in children (20).

The goal of definitive therapy with RAI or thyroidectomy is to render permanent hypothyroidism, which is easily treated with thyroid hormone replacement. Studies of ¹³¹I ablation have reported success rates of greater than 95% in children. Total thyroidectomy is effective in treating hyperthyroidism; however, potential complications include hypoparathyroidism (both transient and permanent), recurrent laryngeal nerve damage, and scarring (20).

Disease Management

The high mortality rate (50%) in our series of eight pediatric patients with PAH and hyperthyroidism underscores the need for vigilant monitoring of thyroid function in pediatric patients with PAH. Our experience further suggests that emergent intervention, possibly with thyroidectomy, to effect immediate resolution of the hyperthyroid state may result in improved outcomes.

These authors believe that clinicians caring for children with PAH should monitor TFT, including thyroid antibodies (anti-thyroglobulin antibody, anti-thyroid peroxidase antibody, TSI), at the time of diagnosis of PAH and at regular intervals. At our center, TFT are measured at each visit in all children with PAH. We believe that regular monitoring of TFT is vital because the incidence of hyperthyroidism in our series (8:200) far exceeds the expected rate of Graves' disease in a pediatric population.

PAH patients treated with epoprostenol may be more vulnerable to thyroid disease. Chadha et al. (9) examined a group of 54 adult PAH patients and noted three who developed hyperthyroidism, all of whom were treated with epoprostenol. They hypothesize that epoprostenol may directly stimulate thyroid tissue. Basic science work has described the presence of “thyrotropic prostaglandins” (27), and experimental models have shown that exposure to prostaglandins, independent of TSH, can increase intracellular cAMP-dependent kinase activity that leads to downstream thyroid hormone synthesis and secretion (28). This is almost certainly not the only explanation for hyperthyroidism in PAH patients, and autoimmunity likely plays a role because many patients have antithyroid antibodies (10). Others have suggested that those with a positive BMPR2 mutation may be more prone to thyroid disease (29).

Any PAH patient with abnormal thyroid findings, in particular a low TSH, presence of positive thyroid antibodies, and/or goiter should be urgently evaluated by an endocrinologist experienced in the management of thyroid disease. This applies even in the absence of an elevated T₃ or T₄, because our experience shows that frank hyperthyroidism can develop rapidly and that once cardiopulmonary status declines, the window for intervention and reversal may be closed. Even slightly abnormal TFT in a patient with PAH should alert physicians to a potentially critical situation. Furthermore, all patients with PAH who present with an exacerbation of cardiopulmonary symptoms without an identifiable trigger should have TFT checked urgently. Emergency department and primary care physicians must also be aware of the association between PAH and hyperthyroidism because they are often the physicians to whom these patients first present.

In asymptomatic PAH patients for whom hyperthyroidism is an incidental finding, initial treatment with MMI may be sufficient. Definitive treatment with RAI or thyroidectomy must be considered sooner rather than later for these patients, given the concerns regarding thionamide therapy and the particular worry in PAH patients for potentially life-threatening complications from thyroid disease. RAI therapy may be a viable option for the older asymptomatic child, although there have been reports of thyroid storm in pediatric patients after RAI (30) and, depending on the dose of ¹³¹I used, it can take 2–3 months to see the full effects of therapy. This delay may not prove optimal in this patient population. Elective thyroidectomy is a potential treatment option, but one must weigh the risks and benefits of a surgical procedure in these patients. The literature highlights the need for an experienced surgeon and surgical center to maximize postsurgical outcomes (20).

Based on our experience, early aggressive treatment of PAH patients with hyperthyroidism, regardless of etiology, may prove lifesaving. For patients who have presented with PAH exacerbation and cardiovascular instability in the setting of hyperthyroidism, it is vital to render the patient euthyroid as quickly as possible. We have typically initiated treatment with iv short-acting β-blockers as tolerated, SSKI, corticosteroids, and PTU. The choice of thionamide drug in this setting is not a settled issue. A recent randomized, controlled trial comparing the efficacy of PTU and MMI in adult patients with severe Graves' found that high-dose MMI was superior in normalizing thyroid function with fewer side effects (31). Given that SSKI should be discontinued after 4–7 d of treatment to prevent breakthrough hyperthyroidism (escape from Wolff-Chaikoff effect), there is an urgency to consider surgical intervention. PAH patients admitted with hyperthyroidism require close monitoring in an intensive care unit setting with frequent clinical and laboratory evaluation.

Conclusion

We present a series of eight pediatric patients with PAH receiving iv epoprostenol who developed hyperthyroidism to underscore the need for timely diagnosis of thyroid abnormalities to prevent significant morbidity and mortality. Although the exact mechanism of this association and its relation to treatment with iv epoprostenol is not certain, children with PAH should have TFT checked on a routine basis and urgently in the setting of acute decompensation or clinical evidence of hyperthyroidism. In our experience, patients with PAH who develop hyperthyroidism must be rendered euthyroid urgently; elective or emergency total thyroidectomy may prove lifesaving.