Recovery from AA amyloidosis-cardiomyopathy complexed with unicentric Castleman disease
- 1 Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, Japan
- 2 Department of Internal Medicine, Sakura-jyuji Yatsushiro Rehabilitation Hospital, Yatsushiro, Japan
- 3 Department of Life Science, Shokei University, Kumamoto, Japan
- 4 Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Correspondence to Sunao Kojima; kojimas@kumamoto-u.ac.jp
Abstract
We report a case of cardiac amyloid A (AA) amyloidosis due to unicentric Castleman disease (UCD) in a patient whose cardiac function was restored 15 years after surgical resection of the mesenteric lymph node lesion. A man in his 40s had recurrent palpitations and fainting spells. ECG revealed torsades de pointes. Increased C-reactive protein, interleukin-6 and serum AA levels, and marked concentric thickening of the left ventricular (LV) wall with diastolic restrictive filling pattern were observed. Duodenal biopsy revealed AA amyloid deposits. He had a mesenteric tumour, comprising many plasma cells. He was diagnosed with plasma cell-type UCD associated with secondary AA amyloidosis. C-reactive protein, interleukin-6 and serum AA levels were normalised 2 months postresection. Episodes of lethal ventricular arrhythmias decreased. LV wall thickness was gradually reduced. Approximately 15 years postresection, the LV wall thickness nearly normalised and ventricular arrhythmias disappeared. Better outcomes are expected following surgical tumour resection.
Background
Cardiac amyloidosis is a life-threatening disease caused by deposition of amyloid fibrils in the myocardial interstitium.1 The prognosis varies among the subtypes of amyloidosis, and cardiopathy is a major prognostic factor.2 3 Delay in diagnosis results in progressive heart disease and, consequently, poor outcomes.4 Treatment may improve prognosis; however, heart failure remains a fatal complication of amyloidosis, and cardiopathy is generally considered irreversible.
Castleman disease (CD) is a rare lymphoproliferative disorder and is classified based on lymphadenopathy lesions into unicentric CD (UCD) and multicentric CD (MCD). Amyloid A (AA) amyloidosis is a minor complication of CD, and CD-associated amyloidosis accounts for only 4% of cases of AA amyloidosis.5 Diseased lymph node resection (mostly for UCD) and interleukin-6 (IL-6)-blocking therapies (for MCD) improve renal function and prognosis.6–8 However, AA amyloidosis-associated cardiopathy, which has an impact on patient outcomes, has yet to be examined. Here, we present a case of cardiac AA amyloidosis because of UCD in a patient whose cardiac function was restored 15 years after surgical resection of the mesenteric lymph node lesion.
Case presentation
A man in his early 40s, who was a smoker, presented with complaints of repeated palpitations and fainting spells for over 3 months, and he was immediately admitted to a regional hospital. ECG revealed torsades de pointes, and he underwent cardioversion (figure 1A). Thereafter, he had bradycardia-type atrial flutter, underwent an external pacemaker insertion (figure 1B), and was referred to our hospital. His blood pressure was 98/62 mm Hg, and his pulse rate was 72 bpm and irregular.
Examination of the heart. (A) ECG at initial presentation showing torsades de pointes and at the time of cardioversion (yellow arrowhead). (B) ECG after insertion of an external pacemaker showing bradycardia-type atrial flutter. (C) The cardiothoracic ratio is 50%, and there is no pulmonary congestion or effusion on chest radiography. (D) Transthoracic echocardiograph of long axis view showing left ventricular concentric thickening (white arrowhead). (E) Transthoracic echocardiograph of short axis view showing left ventricular concentric thickening (white arrowhead). IVSTd, 17.4 mm; LVPWTd, 16.5 mm. IVSTd, interventricular septum thickness in diastole; LVPWTd, left ventricular posterior wall thickness in diastole.
Investigations
The cardiothoracic ratio was 50% on chest radiography (figure 1C). Although transthoracic echocardiography showed preserved left ventricular (LV) ejection fraction and valvular movement, the interventricular septum thickness in diastole (IVSTd) was 17.4 mm, and LV posterior wall thickness in diastole (LVPWTd) was 16.5 mm (figure 1D,E), indicating a marked concentric thickening of the LV wall. A high ratio of early diastolic transmitral (DT) flow velocity to atrial transmitral flow velocity (E/A ratio) (1.84) and short deceleration time of early DT flow velocity (138 ms) indicated restrictive movements of the heart. Laboratory examinations showed high levels of plasma C-reactive protein (CRP) (11.75 mg/dL), IL-6 (125 pg/mL) and serum amyloid A (SAA) (429 µg/mL), as well as renal function impairment, anaemia and increased levels of liver enzymes (table 1).
Laboratory findings before and after tumour resection
| Item (normal range) | Before tumour resection | 10 days after tumour resection | 2 months after tumour resection | 12 years after tumour resection |
| AST (13–30 U/L) | 79 | 49 | 27 | 26 |
| ALT (10–42 U/L) | 137 | 42 | 26 | 22 |
| ChE (240–486 U/L) | 69 | 105 | 153 | 289 |
| Cr (0.65–1.07 mg/dL) | 1.77 | 2.87 | 2.74 | 1.73 |
| eGFR (>90 mL/min/1.73 m2) | 35.5 | 20.9 | 22 | 33.9 |
| CRP (<0.14 mg/dL) | 11.75 | 1.78 | <0.05 | 0.06 |
| IL-6 (<8.0 pg/mL) | 125 | – | 2.4 | – |
| SAA (<8.0 µg/mL) | 429 | 4.7 | <2.5 | <0.5 |
| WBC (3300–8600 /µL) | 5000 | 4600 | 3500 | 4800 |
| RBC (435–555 x 104 /µL) | 311×104 | 448×104 | 354×104 | 466×104 |
| Haemoglobin (13.7–16.8 g/dL) | 7.4 | 12 | 10.2 | 15.6 |
| Platelet (158–348 x 103 /µL) | 362×103 | 309×103 | 197×103 | 159×103 |
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; ChE, cholinesterase; Cr, creatinine; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; IL-6, interleukin-6; RBC, red blood cell; SAA, serum amyloid A; WBC, white cell count.
Treatment
We suspected AA amyloidosis and performed a biopsy of the thickened duodenal wall. Congo red-positive deposits were observed in the duodenal tissue (figure 2A) and identified as amyloid fibrils (figure 2B), suggesting that AA amyloidosis was the cause of the heart, liver and kidney dysfunction. A tumour measuring 53×41 mm was observed in the lower abdomen on ultrasound scanning (figure 3A) and CT (figure 3B) and suspected to be associated with AA amyloidosis; thus, the tumour, including the adjacent part of the jejunum involved, was resected. The tumour was an enlarged mesenteric lymph node (figure 3C) composed of many plasma cells (figure 3D). The patient was finally diagnosed with plasma cell-type UCD complicated by secondary AA amyloidosis affecting the heart, liver and kidneys. After tumour resection, the CRP, IL-6, SAA and liver enzyme levels decreased to normal levels within 2 months (table 1). After undergoing catheter ablation for atrial flutter and cardioverter defibrillator (ICD) implantation for lethal ventricular arrhythmias, the patient was discharged home.
Microscopic images of the biopsied duodenal tissue. (A) Congo red staining. Amyloid deposits are present in the perivascular and interstitial areas (black arrowhead). (B) Immunohistochemistry for serum amyloid A revealing AA deposition in the duodenal tissue (yellow arrowhead). AA, amyloid A.
Images of the mesenteric tumour. (A) Abdominal ultrasound scanning image showing the tumour in the left lower abdomen behind the transverse colon (yellow arrowheads). (B) CT image of the mass in the right part of the mesentery (white arrowhead). (C) Macroscopic image of the resected mesenteric tumour presenting an enlarged lymph node appearance. (D) Microscopic image of the tumour that consisted of a large amount of plasma cells.
Outcome and follow-up
Our patient came for follow-up visits at our hospital twice a year for 15 years and was not prescribed IL-6 blocking medicines at any time point. In the 15-year period following the resection of the mesenteric plasma cell tumour, ventricular tachycardia has occurred six times, with decreasing incidence over time (four times in the first 5 years and twice in the next 5 years; no incidence was recorded in the recent 5 years). The LV wall thickness reduced gradually and was recently restored to almost normal (IVSTd, 11.7 mm; LVPWTd, 11.8 mm); the diastolic restrictive pattern persisted (E/A ratio, 1.48; DT, 111 ms) (figures 4 and 5).
Chronological changes of parameters examined by transthoracic echocardiography. The LV wall thickness gradually reduced and returned to almost normal at 15 years after resection of the mesenteric tumour. There is no significant change in mitral inflow pattern (DT, e’ and E/A ratio). DT, early diastolic transmitral flow velocity deceleration time; e’, peak early diastolic mitral annulus velocity; E/A, ratio of early diastolic transmitral flow velocity to atrial transmitral flow velocity; IVSTd, interventricular septum thickness in diastole; LV, left ventricle; PLVWd, left ventricular posterior wall thickness in diastole.
Transthoracic echocardiograph obtained at 15 years after resection of the tumour showing an almost normal thickness of the left ventricular wall (white arrowhead). (A) Transthoracic echocardiograph of long axis view showing left ventricular thickening (white arrowhead). (B) Transthoracic echocardiograph of short axis view showing left ventricular thickening (white arrowhead). IVSTd, 11.7 mm; LVPWTd, 11.8 mm. IVSTd, interventricular septum thickness in diastole; LVPWTd, left ventricular posterior wall thickness in diastole.
Discussion
We have presented the case of a patient with AA amyloidosis-associated cardiomyopathy (figure 2) complicated by UCD (figure 3). CD, an uncommon underlying disease in patients with AA amyloidosis,5 frequently involves the kidney but rarely the heart.5 9 Elevated levels of CRP, IL-6 and SAA are clinical features of CD-associated AA amyloidosis. A rapid decrease in the proteins following surgical resection of the mesenteric plasma cell tumour (table 1) indicates that the tumour-induced inflammatory mediators of precursor protein (SAA) and deposition of amyloid fibrils to the heart, thereby leading to cardiac amyloidosis. Approximately 15 years after tumour resection, the thickness of the enlarged LV wall returned to within the normal range (figures 4 and 5), and ventricular arrhythmias ceased. Thus, AA amyloidosis is presumed to be attributable to cardiopathy in our patient. Approximately 60 cases of AA amyloidosis complexed with CD have been reported in the literature,5 10 but only one patient developed cardiopathy and died of heart block and renal failure.11 To the best of our knowledge, our patient is the first to have recuperated from AA amyloidosis-associated cardiomyopathy.
Atrial flutter is common in cardiac amyloidosis,12 and torsades de pointes has been reported in a patient with amyloid-associated cardiomyopathy.13 A comparatively low voltage QRS (figure 1B) for the marked concentric thickening of the LV wall (figure 1D,E) appears to agree with the diagnosis of cardiac amyloidosis rather than hypertensive cardiomyopathy. Myocardial restrictive movement is characteristic of cardiac amyloidosis.12 AA amyloid was deposited in the duodenum (figure 2B), and elevated SAA and IL-6 levels were normalised after resection of the mesenteric tumour; the myocardial deterioration disappeared (table 1). Therefore, it is most likely that the cardiopathy was caused by AA amyloid deposition, although the deposition was not confirmed by immunohistochemistry of the myocardial tissue.
Inflammatory cytokine (such as IL-610 14 or tumour necrosis factor-α15)-blocking therapy for AA amyloidosis complexed with rheumatoid arthritis, resolved cardiopathy and other symptoms, including impaired renal function. These agents eventually suppress AA amyloid production and deposition. However, surgical resection of a causative lymph node or tumour led to the complete cessation of AA amyloid production and deposition in organs. Moreover, tocilizumab was associated with a reduction in LV mass weight and disappearance of duodenal AA amyloid deposits in the case complexed with rheumatoid arthritis.14 Thus, the disappearance of ventricular tachycardia and restoration of normal LV wall thickness in our patient presumably resulted from the disappearance of heart AA amyloid deposits following tumour resection. The E/A ratio decreased in 15 years; however, the diastolic restrictive pattern remained. One explanation is that residual AA amyloid deposits are affecting myocardial movement; however, collagen fibres might increase during the recovery phase of cardiac AA amyloidosis, replacing the amyloid deposits and impairing the elasticity of the myocardium.
This case report has a limitation. Myocardial biopsy was not performed because an unstable state, such as torsades de pointes, was observed and the patient continued to have low blood pressure. A marked concentric thickening of the LV wall and restrictive cardiac movement were observed. The CRP, IL-6 and SAA levels were high and AA deposits were detected in the biopsied duodenal tissue. Our patient had a mesenteric tumour composed of plasma cells diagnosed as UCD complicated by secondary AA amyloidosis. Generally, pathological information can be obtained from the tissues or organs related to the symptoms in patients with systemic amyloidosis.16 It is acceptable to make a diagnosis of cardiac amyloidosis when amyloid protein is detected from non-cardiac organs in suspected amyloidosis patients with clinical and imaging findings.16
In conclusion, this case demonstrates recovery from cardiac AA amyloidosis complicated by UCD. Cardiac AA amyloidosis is caused by the deposition of AA amyloid in the myocardium, leading to restrictive cardiac movement and lethal ventricular arrhythmias. Better outcomes are expected following successful surgical resection of the tumour, because loss of continuous AA amyloid production and deposition interferes with the progression and development of cardiac AA amyloidosis.
Learning points
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Castleman disease is a lymphoproliferative disorder that is rarely associated with AA amyloidosis, in which the onset of cardiopathy is uncommon.
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Cardiac AA amyloidosis is caused by the deposition of AA amyloid in the myocardium, leading to cardiac restriction and lethal ventricular arrhythmias.
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Better outcomes are expected following successful surgical resection of the tumour, because cessation of AA amyloid production interferes with the development of cardiac amyloidosis.
Ethics statements
Patient consent for publication
Acknowledgments
The authors thank Hiroki Usuku and Toshiro Yokoyama (Department of Laboratory Medicine, Kumamoto University Hospital), Fumi Oike (Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University) and Junjiro Koyama (Department of Cardiovascular Medicine, Saiseikai Kumamoto Hospital) for their contributions in caring for the study patient.
Footnotes
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Contributors First Author: KI, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, Japan. Co First Author: SK, Department of Internal Medicine, Sakurajyuji Yatsushiro Rehabilitation Hospital, Yatsushiro, Japan. Second Author: TI, Department of Life Science, Shokei University, Kumamoto, Japan. Third Author: KT, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. We hereby certify that submitted work, titled 'Recovery from AA amyloidosis-cardiomyopathy complexed with unicentric Castleman disease’, to BMJ Case Reports journal is written by above four authors. Any work that is not our work has been referenced. All references and sources of information have been clearly cited within the text. We can confirm that KI and SK gathered the clinical data including the photograph following gaining written consent for the patient. KI and SK contributed equally in writing the paper following planning, researching and interpreting the results. Hence, KI and SK are considered as first authors. TI contributed in writing of the paper, editing and optimising the image. TI is considered as the second author. KT contributed in submitting the paper to BMJ Case Reports journal. KT is considered as the third author.
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Funding This study was funded by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (21K07356).
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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