Reversible dilated cardiomyopathy caused by primary hyperparathyroidism: A case report

Abstract

BACKGROUND

Dilated cardiomyopathy (DCM) is a common cause of systolic heart failure, and is the most prevalent type of non-ischemic cardiomyopathy. Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and excessive secretion of parathyroid hormone (PTH). Generally, PHPT is asymptomatic and is incidentally identified during routine laboratory assessments.

CASE SUMMARY

This case report details a 52-year-old man diagnosed with DCM and refractory hypercalcemia, who presented with clinical manifestations including dyspnea, recurrent anorexia, and abdominal distention. Laboratory investigations indicated an elevated serum PTH level, and the sestamibi scan suggested the presence of a parathyroid adenoma. Hence, the patient underwent a parathyroidectomy, which pathologically confirmed the diagnosis of a parathyroid adenoma. Postoperatively, the patient's hypercalcemia was corrected, the dimensions of the cardiac chambers were reduced, and there was a marked improvement in cardiac function.

CONCLUSION

Our findings emphasize the importance of PTH assessment in patients with DCM and concurrent hypercalcemia.

Key Words: Dilated cardiomyopathy; Primary hyperparathyroidism; Hypercalcemia; Parathyroid hormone; Parathyroid adenoma; Heart failure; Chronic kidney disease; Case report

Core Tip: This case report highlights a rare instance of reversible dilated cardiomyopathy (DCM) secondary to primary hyperparathyroidism, characterized by persistent hypercalcemia and elevated parathyroid hormone (PTH) levels. Surgical resection of the parathyroid adenoma led to normalization of calcium and PTH levels, along with remarkable improvement in cardiac function. This case underscores the importance of evaluating PTH in patients with DCM and hypercalcemia, as early recognition and intervention may lead to full cardiac recovery.

INTRODUCTION

Dilated cardiomyopathy (DCM) is defined by a dilated left ventricular (LV) chamber with systolic LV dysfunction[1]. Despite significant progress in the treatment of DCM, the prognosis remains fairly poor[1]. Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder caused by defective calcium sensing in parathyroid gland tumors, resulting in hypercalcemia and excessive secretion of parathyroid hormone (PTH)[2]. PHPT is commonly associated with an elevated risk of cardiovascular morbidity and mortality, as well as various cardiovascular risk factors including hypertension, dyslipidemia, and metabolic syndrome[3]. The association between PHPT and DCM was first reported in 1992 in a patient who presented with severe cardiac arrhythmias, a rapid decline in physical capacity, and dyspnea. Notably, the patient's condition demonstrated significant improvement following the surgical resection of the parathyroid adenoma[4]. In 2006, Kiernan et al[5] further documented a case of DCM associated with PHPT. In this report, we present a case involving a patient with chronic kidney disease who is afflicted with DCM as a consequence of PHPT.

CASE PRESENTATION

Chief complaints

A two-year history of progressive exertional dyspnea.

History of present illness

A 52-year-old male patient was admitted to our hospital, presenting with a two-year history of progressive exertional dyspnea consistent with New York Heart Association (NYHA) functional class III symptoms. Additional symptoms included leg edema, orthopnea, generalized fatigue, anorexia, and abdominal distention for over three years.

History of past illness

The patient's medical history was notable for chronic gout and alcohol consumption. One year prior, the patient was diagnosed with heart failure and exhibited a reduced glomerular filtration rate of 42.4 mL/minute, elevated serum creatinine levels (160.7 μmol/L), and increased PTH levels (206 pg/mL) and hypercalcemia (2.85 mmol/L).

Personal and family history

No reported history of hypertension, diabetes, or smoking, etc.

Physical examination

Physical examination identified an enlarged cardiac silhouette, diminished heart sounds, a grade II/VI pansystolic murmur indicative of mitral regurgitation, positive hepatojugular reflux, and bilateral pitting edema in the lower extremities.

Laboratory examinations

Laboratory tests showed the following: (1) High-sensitivity cardiac troponin I: 137.7 ng/L; (2) Brain natriuretic peptide: 2583.9 pg/mL; (3) PTH: 284 pg/mL; (4) Serum calcium: 2.78 mmol/L; (5) Serum phosphate: 0.95 mmol/L; (6) Creatinine: 210.4 μmol/L; and (7) A urine albumin to creatinine ratio of 42.27 μg/mg.

Imaging examinations

Electrocardiogram showed sinus tachycardia with high LV voltage and diffuse ST-T changes (Figure 1). Repeat transthoracic echocardiography revealed LV systolic dysfunction [LV ejection fraction (LVEF) 22%], dilated cardiac chambers (end-diastolic diameter 65 mm for the LV, 44 mm for the left atrium, 26 mm for the right ventricle, and 52 mm × 44 mm for the right atrium), moderate mitral regurgitation, and mild tricuspid regurgitation (gradient: 28.09 mmHg) (Figure 2). The interventricular septum was 10 mm and LV posterior wall thickness was 10 mm. Magnetic resonance imaging revealed a dilated left ventricle (short axis: 68 mm), accompanied by myocardial thinning and a significant decrease in LVEF (15.2%). Delayed enhanced images demonstrated linear enhancement within the interventricular septum. An ultrasonographic examination of the parathyroid gland revealed a hypoechoic nodule approximately 13 mm × 8 mm in size, located on the surface of the lower pole of the right deep lobe of the thyroid gland, which was indicative of parathyroid hyperplasia (Figure 3). Technetium-99m sestamibi scintigraphy identified a hypodense nodule approximately 9.6 mm × 5.9 mm in size, located posterior to the inferior pole of the right thyroid lobe, indicative of a functional parathyroid adenoma.

Figure 1 Electrocardiogram showing sinus tachycardia with high voltage in the left ventricle and diffuse ST-T changes.

Figure 2 Transthoracic echocardiogram of preoperation and postoperation obtained in July 2021 and May 2023 respectively. Parasternal long-axis (M-mode) and apical four-chamber views show significant changes in left ventricle, left atrium, and left ventricular ejection fraction from preoperation to postoperation. EF: Ejection fraction.

Figure 3 Findings on parathyroid ultrasonography. A: A hypoechoic, well-circumscribed mass located posteriorly inferiorly to the lower pole of the right thyroid lobe; B: Color doppler scan showing increased vascular flow.

FINAL DIAGNOSIS

DCM, parathyroid adenoma, and chronic renal insufficiency (Figure 4).

Figure 4 Histopathology of the parathyroid adenoma in this patient. A and B: Original magnification 10.0 × and 40 ×. In the tissue of parathyroid adenoma, the structures of main cells and eosinophils are clearly distinguishable on hematoxylin and eosin stained sections, and eosinophils aggregate into clusters, significantly increasing compared to normal parathyroid glands. Orange: Eosinophils, blue: Main cell. The dashed line indicates the boundary between eosinophil clusters and main cells; C and D: Positive precipitates of parathyroid hormone immunohistochemistry (IHC) staining can be seen in the cytoplasm of main cells and eosinophils. Among them, the cytoplasmic positivity intensity of the main cells is high, eosinophil positive particles are mainly distributed at the top of the cells, and negative around the nucleus. Black: Positive staining of main cells, blue: Positive staining of eosinophils. The dashed line indicates the boundary between eosinophil clusters and main cells; E and F: The strong positive result of synaptophysin IHC can be seen in the cytoplasm of the main cells. Some eosinophils are weakly positive, while others are negative. Black: Positive staining of main cells, blue: Positive staining of eosinophils, light blue: Negative eosinophils. The dashed line indicates the boundary between eosinophil clusters and main cells.

TREATMENT

The pharmacological intervention, palmon calcitonin injection, and parathyroidectomy.

OUTCOME AND FOLLOW-UP

Within two days after surgery, PTH and calcium levels recovered to 20.9 pg/mL and 2.25 mmol/L, respectively, confirming the initial diagnosis. The patient was discharged without complications and continued to receive heart failure medications, including sacubitril/valsartan (50 mg twice daily), metoprolol succinate (47.5 mg once daily), spironolactone (10 mg once daily), and empagliflozin (10 mg once daily). A follow-up transthoracic echocardiography performed in May 2023 indicated a significant improvement in LVEF (53%) with normalization of previously dilated cardiac chambers. Specifically, the end-diastolic diameters measured were 47 mm for the left ventricle, 36 mm for the left atrium, 20 mm for the right ventricle, and 44 mm × 37 mm for the right atrium (Figure 5). Meanwhile, the patient exhibited a PTH level of 56.4 pg/mL, a serum calcium level of 2.44 mmol/L, and an N-terminal-pro-brain natriuretic peptide level of 104.0 pg/mL (Table 1). Follow-up assessment revealed that the patient's clinical symptoms were significantly relieved and the NYHA functional class recovered to class I.

Figure 5 Under emission computed tomography scanning, the color of the parathyroid adenoma is darker and darker than that of the thyroid gland. The green dashed circle indicates the thyroid tissue, and the blue dashed circle indicates the parathyroid adenoma tissue.

Table 1 Clinical information for the patient in this report.

	The first hospitalization before PTX (January 2020)	The second hospitalization before PTX (July 2021)	After PTX (May 2023)
Left ventricular ejection fraction (%)	13	22	53
Left ventricular end-diastolic diameter (mm)	65	65	47
Right ventricle (mm)	29	26	20
Left atrium (mm)	42	44	36
Right atrium (mm)	53 × 49	52 × 44	44 × 37
Parathyroid hormone (pg/mL)	206	284	56.4
Brain natriuretic peptide (pg/mL)	2555.5	2583.9
Corrected calcium(mmol/L)	2.85	2.78	2.44
Phosphate (mmol/L)	1.17	0.95
Creatinine (μmol/L)	160.7	210.4	171.2
Estimated glomerular filtration rate (mL/minute)	42.4	30.2	38.2

PTX: Parathyroidectomy.

DISCUSSION

Patients with PHPT frequently exhibit LV hypertrophy and diastolic dysfunction. However, the occurrence of LV dilatation and systolic dysfunction in these PHPT patients is exceedingly rare, with only two documented cases in the literature: (1) One by Koch et al[4]; and (2) Another by Kiernan et al[5] (Table 2). These two cases of DCM were characterized by persistent hypercalcemia and elevated serum PTH levels, and clinically presented with symptoms of dyspnea, arrhythmia, and heart failure[4,5]. Furthermore, it is noteworthy that the patient reported by Koch et al[4] underwent a parathyroidectomy, with pathological confirmation of a parathyroid adenoma. Postoperatively, the patient's hypercalcemia was corrected, the dimensions of the cardiac chambers were reduced, and there was a significant improvement in cardiac function. Similarly, in our case, cardiac function markedly improved and the cardiac chambers returned to normal following the resection of the parathyroid adenoma. This indirectly supports the hypothesis that PHPT may be a causative factor for DCM. To the best of our knowledge, this report represents the first documented instance of DCM caused by PHPT in China.

Table 2 Clinical features of the present patient and the two patients already reported in the literature.

	Age and gender	Clinical characteristics	Serum calcium (mmol/L)	Treatment of primary hyperparathyroidism	Pathologic diagnosis	Postoperative efficacy
Our patient	52-year-old male	Dyspnea, fatigue, anorexia and abdominal distention	2.78-3.03	Surgery	Parathyroid adenoma	Improvement of cardiac function
Koch et al[4]	55-year-old male	Dyspnea, diarrhea and arrhythmia	3.0-3.2	Surgery	Parathyroid adenoma	Improvement of cardiac function and arrhythmia decreased
Kiernan et al[5]	65-year-old female	Cardiogenic shock, dyspnea, anorexia, nausea and fatigue	3.2	-	-	-

However, our findings differ in some aspect from those previously reported[4,5]. This discrepancy may be attributed to the presence of a chronic kidney disease history, which could potentially lead to the misdiagnosis of PHPT as secondary or tertiary hyperparathyroidism. It has been documented that 12%–20.6% of patients with PHPT exhibit an estimated glomerular filtration rate of less than 60 mL/minute[6]. Furthermore, it should be noted that nephropathy induced by hyperuricemia is a common complication of hyperuricemia and gout, which causes renal dysfunction in patients, and our patient had a history of gout. Therefore, the renal insufficiency observed in our patient may be attributable to the combined effects of PHPT and gout. It is pertinent to mention here that chronic renal impairment can disrupt mineral metabolism, often resulting in secondary hyperparathyroidism, which is characterized by elevated PTH levels, hyperphosphatemia, and hypocalcemia[6]. Whereas, our patient exhibited hypercalcemia and normophosphatemia, a profile that deviates from the typical clinical presentation. Tertiary hyperparathyroidism generally presents in individuals with end-stage renal disease or following renal transplantation[7], neither of which were observed in our patient. Thus, we hypothesized that the patient is experiencing PHPT concomitant with renal insufficiency, rather than secondary or tertiary hyperparathyroidism.

DCM arises from either primary (genetic) or secondary etiological factors[8]. Studies have shown that various endocrine diseases, such as thyroid disease, pheochromocytoma, and aldosteronoma, are associated with the development of DCM[9,10]. PHPT is the third most common endocrine disease after diabetes mellitus and thyroid disorders[9,11]. Both our results and previous studies indicate that PHPT is also an important cause of DCM. The two previously documented cases of PHPT-related DCM demonstrate clinical characteristics akin to those observed in typical DCM cases[4,5]. Nonetheless, due to the hypercalcemia and high PTH levels, symptoms such as anorexia, nausea, fatigue, and irritability may be more pronounced and manifest earlier, and the presence of these symptoms may potentially mask the clinical symptoms of heart failure. Patients with DCM typically present with myocardial fibrosis. Conversely, individuals with PHPT predominantly manifest with calcium deposition within cardiac muscle tissue, encompassing the valves, mitral rings, myocardium, and arteries. Additionally, other complications of PHPT, such as nephrolithiasis, osteoporosis, and fractures, may also serve as diagnostic indicators for PHPT-related DCM[12,13]. The symptoms of heart failure observed in our patient, including dyspnea and edema, align with those reported in two previously cases[4,5]. However, gastrointestinal symptoms manifested earlier and were more pronounced in our patient. Additionally, our patient demonstrated a lower incidence of potentially malignant arrhythmias compared to the previously reported cases, which may be attributable to his relatively mild elevation in serum calcium levels.

Currently, the molecular mechanisms of PHPT-associated DCM remain unclear[14-17], but previous studies have proposed several hypotheses[18-21]. One prominent hypothesis is that PTH induces overactivation of the renin-angiotensin-aldosterone system. This overactivation leads to systemic vasoconstriction and sodium and water retention[14], while promoting myocardial fibrosis via the transforming growth factor-β/suppressor of mother against decapentaplegic signaling pathway[15]. The second mechanism involves hypercalcemia and myocardial calcium overload. Hypercalcemia has been identified as an important trigger for calcium deposition, endothelial cell injury, and inflammation. This condition leads to myocardial apoptosis, necrosis, and fibrosis by increasing myocardial oxygen demand, impairing mitochondrial function, and inducing oxidative stress and inflammation[17]. The third mechanism involves impaired insulin secretion and action. Studies have demonstrated that elevated PTH hormone levels impair insulin secretion and induce insulin resistance in adipocytes[19-21], leading to impaired glucose tolerance and subsequent myocardial injury. However, the effects of elevated PTH on the cardiovascular system and its underlying mechanisms remain poorly understood and warrant further investigation.

It is noteworthy that there have been inconsistencies in the literature regarding the relationship between PHPT and cardiac function. Best et al[22] conducted a systematic analysis of echocardiographic data following parathyroidectomy in patients with PHPT and reported no significant improvement in LV systolic function, as measured by LVEF. However, contrasting findings have been reported in other studies. For instance, Agarwal et al[23] observed a significant improvement in LVEF six months post-parathyroidectomy in a cohort of 56 patients with PHPT. Furthermore, Kepez et al[24] and Atasever et al[25] observed significantly elevated global longitudinal strain six months post-parathyroidectomy using speckle tracking echocardiography, indicating an improvement in LV systolic function despite the absence of a statistically significant difference in LVEF. We speculate that this inconsistency may be due to differences in the measurement methods used and the population tested.

CONCLUSION

In this study, we have identified a rare case of patients with DCM complicated by renal insufficiency secondary to PHPT, which presented with chronic cardiac insufficiency and hypercalcemia. In contrast to individuals with primary DCM, patients with DCM secondary to PHPT frequently present with earlier and more pronounced gastrointestinal symptoms, and these patients are often accompanied by calcification or vascular sclerosis. Our findings emphasize the critical need to evaluate PTH levels in patients with DCM who also exhibit hypercalcemia. Further research is necessary to elucidate the varied pathological impacts of PHPT on the cardiovascular system.