Pulmonary arterial hypertension in primary amyloidosis

Abstract Abstract

Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.

Case description

A 53-year-old woman was referred for evaluation of dyspnea. She had a history of κ light chain amyloidosis,¹ diagnosed 2 years earlier when she presented with mild hypercalcemia and proteinuria. She had multisystem involvement: bone marrow biopsy demonstrated 20% κ-restricted plasmacytosis along with prominent amyloid, kidney biopsy demonstrated light chain deposition, and clinical findings indicated that she had hepatomegaly with infiltration of the liver. The patient underwent high-dose melphalan chemotherapy followed by autologous hematopoietic cell transplant and subsequently initiated bortezomib-thalidomide-dexamethasone maintenance therapy. Due to neurotoxicity, thalidomide was discontinued with the second cycle, but bortezomib-dexamethasone was given for a total of 16 cycles. The patient had an excellent response with persisting normalization of light chains within 2 months after treatment initiation and a significant reduction of bone marrow plasma cells to <5%. Although the patient had experienced mild dyspnea for some time, before cycle 17 of therapy, she reported a significant progression of symptoms. Over a 2-month period, she developed exertional dyspnea after walking only ~15 m on flat ground. She denied episodes of chest pain. Electrocardiogram findings showed right axis deviation, and transthoracic echocardiogram findings indicated severe pulmonary hypertension on the basis of estimated right ventricular systolic pressures (eRVSP). Echocardiogram findings also included mild left ventricular (LV) and moderate right ventricular (RV) wall thickening in addition to impaired LV relaxation and severe RV dilation. Biventricular systolic function was within normal limits. There was no pericardial effusion, valvular thickening or dysfunction, increased echogenicity, or LV strain dissociation, findings that are often implicated in cardiac amyloidosis.^2,3 Cardiac magnetic resonance imaging performed at the initial diagnosis of multiple myeloma was negative for cardiac amyloidosis, but this study was performed approximately 15 months before onset of dyspnea and not repeated. Right and left heart catheterization confirmed the elevated pulmonary artery pressures with normal pulmonary capillary wedge pressure (Table 1). Right ventricular biopsy revealed only minimal, focal amyloid deposition within the cardiac interstitium (Fig. 1).

Table 1.

Invasive hemodynamic measurements from right heart catheterization

Hemodynamic measurement	Value
RA (mmHg)	3
PA (mmHg)	89/24
mPAP (mmHg)	46
PCWP (mmHg)	6
CO (L/min)	5.5
PVR (WU)	7.3
SBP (mmHg)	118/70
SVR (dyn × s−1 × cm−5)	1,250

^NoteCO: cardiac output; mPAP: mean pulmonary artery pressure; PA: pulmonary artery; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RA: right atrium; SBP: systemic blood pressure; SVR: systemic vascular resistance.

Figure 1.

Right ventricular biopsy with congophilic amyloid deposition in small vessels (arrowhead) and interstitium (arrow), Congo red stain, ×100.

With pulmonary arterial hypertension (PAH) identified on hemodynamic assessment, the patient was evaluated further for an underlying etiology. She had normal spirometry with moderately decreased diffusion capacity consistent with pulmonary vasculopathy.⁴ The patient had negative testing for schistosomiasis and denied a family history of pulmonary hypertension, premature death, bleeding disorders, or fenfluramine-phentermine use. She had test results that were negative for HIV and denied sleep apnea. She endorsed a remote history of rheumatoid arthritis (RA), but rheumatoid factor was <10, and chest computed tomography (CT) findings were negative for features of RA-related interstitial lung disease.

Because of etiologic uncertainty and several possible contributing factors, further diagnostic evaluation was pursued to help guide treatment of the patient’s PAH. The patient underwent video-assisted wedge biopsy of the left upper and lower lung lobes. Histopathological examination revealed significant intimal and medial concentric hypertrophy of the small and medium-size pulmonary arteries (Fig. 2A), consistent with PAH. The luminal narrowing was moderate overall but with focal severe narrowing, particularly of the smaller vessels (Fig. 2B). On polarizable light microscopy, Congo red special staining identified apple-green birefringence in small, medium, and large arteries, consistent with amyloid deposition (Fig. 2C). Interestingly, the vasculopathy did not correlate linearly with the degree or presence of amyloid, as some vessels had only faint or no evidence of amyloid deposition but significant myointimal thickening (Fig. 2D). Additionally, minimal patchy mononuclear interstitial inflammation and rare vasculitis of small and medium-size arteries were identified, suggesting the possibility of bortezomib-related toxicity (Fig. 3).^5,6

Figure 2.

Left upper and lower lobe wedge resections. A, Marked myointimal concentric hypertrophy of medium-size vessel, routine hematoxylin and eosin stain, ×400. B, Small vessels with severe luminal narrowing, routine hematoxylin and eosin stain, ×400. C, Prominent, but focal and asymmetric, congophilic and birefringent amyloid deposition in medium-size vessel, Congo red stain, ×400. D, Medium-size artery with fairly marked myointimal hypertrophy but only faint congophilic and birefringent amyloid deposition, Congo red stain, ×400.

Figure 3.

Vasculitis of small to medium-size vessel, routine hematoxylin and eosin stain, ×400.

In light of the finding of significant intimal and medial concentric hypertrophy of vessels within the lung, the patient received a diagnosis of group 1 PAH and initiated therapy with the phosphodiesterase 5 inhibitor, sildenafil,⁷ which she tolerated well with improvement of symptoms. Ambrisentan therapy was added but not tolerated because of adverse effects, so therapy was switched to macitentan to maintain a dual-agent therapeutic regimen.⁸ Most recently, sildenafil was switched to tadalafil for ease of once-daily dosing. The patient recovered to World Health Organization functional class I, with improvement in 6-minute walk test from 448 m (at diagnosis) to 549 m at her last follow-up visit, approximately 1 year after starting PAH-targeted therapy. Bortezomib-dexamethasone treatment was held at the onset of dyspnea and has not been restarted in the absence of elevated serum free light chains. Repeat hemodynamic examination has not been performed in light of significant functional improvement.⁵

Discussion

In this report, we highlight the diagnostic difficulty presented by PAH in a patient with primary light chain amyloidosis and multiple potential confounders, including medication exposure. In patients with primary amyloidosis, the most common etiologies of pulmonary hypertension are left-sided restrictive cardiomyopathy from amyloid deposition (group II pulmonary hypertension) or diffuse lung disease (group III pulmonary hypertension).^9,10 The patient in this case had normal pulmonary capillary wedge pressure, making diastolic dysfunction a very unlikely cause of her pulmonary hypertension. Additionally, the heart biopsy demonstrated only very focal and minimal interstitial amyloid deposition. Chest CT was negative for a diffuse parenchymal process, spirometry was normal, and lung biopsy showed no convincing evidence for diffuse parenchymal lung disease.

Group I PAH is a rare but reported complication of primary amyloidosis.^9,10 Although pulmonary vascular amyloid deposition is nearly always identified in the systemic forms of amyloidosis, symptomatic pulmonary hypertension is infrequently described and, when present, is typically associated with progressive disease and poor outcomes.^9,11 Moreover, previously described cases had extensive vascular deposition in quantity sufficient to explain changes in pulmonary hemodynamic characteristics.^10,12 In this case, however, histopathologic specimens demonstrate mild patchy amyloid deposition but diffuse, moderate to focally severe myointimal hypertrophy, which is inconsistent with earlier reports. There are limited data demonstrating that amyloid deposition in vessel walls may result in systemic endothelial dysfunction⁹ and subsequent smooth muscle cell hypertrophy, which could explain the seemingly discordant findings in this case. The required burden of vascular amyloid deposition and associated pathologic changes corroborating such a hypothesis have yet to be published.

Review of our patient’s risk factors for PAH reveals two medication exposures, both associated with pulmonary vascular disease: thalidomide and bortezemib. Our patient received only a single dose of thalidomide, and the diagnosis of PAH was delayed by several months, but there are cases in the literature of prompt development of pulmonary hypertension after only a few days of thalidomide therapy.^13-16 Similarly, acute, reversible PAH has been reported in a patient treated with bortezomib, thought secondary to drug-induced vasculitis.^5,6 In case reports, PAH promptly resolved with cessation of both medications and did not recur, contrary to the course of our patient.^6,13-16 Interestingly, other studies suggest rather beneficial effects of bortezomib on PAH.^17,18 Our patient also endorsed a remote history of rheumatoid arthritis. She had no evidence of active joint disease at the time of evaluation, and rheumatoid factor was within the normal range. Autoimmune and connective tissue disease are known risk factors for pulmonary vascular complications, but PAH is usually associated with progressive and active disease.^19,20 Rheumatoid arthritis–related pulmonary hypertension is typically a result of significant parenchymal lung involvement, but, rarely, isolated vasculopathy has been described.^21,22 In our case, the mild, patchy mononuclear interstitial inflammation and rare vasculitis of small and medium-size vessels does raise the possibility of either drug-related toxicity or an underlying connective tissue disease as putative causes.

In this case, the exact etiology remains unknown, and accordingly, the patient’s disease was classified as idiopathic PAH. The patient responded well to pulmonary vasodilator therapy and is not currently receiving therapies targeting amyloidosis. She has had a slight increase in κ free light chains but a steadily decreasing κ/λ ratio with <5% plasma cell dyscrasia (by immunohistochemistry) on last bone marrow biopsy and is followed closely by the oncology department for recurrence. The patient’s 6-minute walk test result has improved to normal, and her eRVSP has decreased from 89 mmHg to 48 mmHg on her most recent echocardiogram.

This report further emphasizes the importance of a multidisciplinary approach to the care of patients with pulmonary hypertension, particularly when multiple underlying factors must be considered. In our patient, amyloidosis was given primary consideration because of the multitude of known complications in this unique patient population, including pulmonary and cardiac involvement. Additional studies examining the relationship between amyloidosis and PAH are needed to characterize the proposed effects of amyloid on endothelial dysfunction and subsequent pulmonary vascular disease.

Source of Support: Nil.

Conflict of Interest: None declared.