Clinical presentation
A 69-year-old Caucasian female with a past medical history significant for hypertension, gastroesophageal reflux disease, obstructive sleep apnea, and carpal tunnel syndrome was referred with new onset atrial fibrillation and congestive heart failure (CHF). She presented with fatigue, dyspnea on minimal exertion, and had recently been discharged from the hospital after an admission for acute on chronic CHF (NYHA III). Prior workup for coronary artery disease, including angiography, was unremarkable. She had been experiencing significant peripheral edema despite high doses of intravenous loop diuretics. There was no history of diabetes, chronic diarrhea, bleeding, or bruising. She had a 3-pack-year smoking history and admitted to drinking alcohol socially. Family history was notable for premature coronary artery disease (CAD) in both parents, cardiac arrest in a brother at age of 55, and another brother with a history of pulmonary embolism in the context of antiphospholipid antibody syndrome.
On examination, she was afebrile, hemodynamically stable, and had a body mass index (BMI) of 35. Head and neck exam was significant for a moderate macroglossia. No periorbital edema or lymphadenopathy were noted. Cardiac examination revealed irregular heart sounds and a mid systolic murmur. Auscultation of the chest revealed decreased air entry over the bases bilaterally. There was no hepatosplenomegaly. Bilateral pretibial edema was noted. Pertinent laboratory findings are summarized in Table
1.
Table 1
Pertinent laboratory findings
WBC | 15.7 × 109/L (3.5–10.5) |
ANC | 10.8 × 109/L (2.0–7.5) |
Hemoglobin | 123 g/L (115–155) |
Platelets | 343 × 103/L (150–450) |
Creatinine | 107 mmol/L (< 75) |
Ionized calcium | 1.09 mmol/L (1.12–1.3) |
Albumin | 31.8 g/L (34–50) |
Bilirubin | 20 μmol/L (3–17) |
LDH | 340 IU/L (< 234) |
Troponin | 0.02 ng/L (< 0.1) |
NT-proBNP | 980 ng/L (< 100) |
24-hour urine protein | 0.22 g (< 0.2) |
24-hour urine albumin | 0.09 g (< 0.03) |
Gammopathy workup: | |
IgG | 7.83 g/L (7–15) |
IgM | 0.72 g/L (0.6–3) |
IgA | 1.79 g/L (0.6–4) |
Serum protein electrophoresis | No quantifiable monoclonal protein |
Serum immunofixation | Discrete band of IgD lambda |
Serum free light chains | Lambda: 186.4 mg/L (5.7–26.3) Kappa: 7.54 mg/L (3.3–19.4) Lambda/kappa: 24.6 |
Imaging
Computed tomography (CT) chest with pulmonary embolism (PE) protocol was negative, but showed small-to-moderate bilateral pleural effusions. Abdominal ultrasound showed no hepatosplenomegaly. X-ray skeletal survey did not show any lytic lesions. A transthoracic echocardiogram showed mild concentric hypertrophy of the left ventricle (LV) with normal systolic function (ejection fraction of 65–70%), grade 1 diastolic dysfunction with impaired relaxation pattern, mild pulmonary hypertension [right ventricular systolic pressure (RVSP), 44 mmHg], moderate aortic sclerosis, mild bilateral atrial enlargement, interventricular septal enlargement at 12 mm (6–9 mm), and dilated inferior vena cava (IVC) with diminished inspiratory collapse consistent with increased right atrial pressure (RAP) of 15–20 mmHg (2–6 mmHg). Features suggestive of constrictive pathology were noted. Further workup with cardiac magnetic resonance imaging (MRI) showed mild concentric left ventricular (LV) hypertrophy. However, classic feature of cardiac amyloidosis (diffuse sub endocardial delayed enhancement) was not seen.
Pathology
Abdominal fat pad biopsy showed benign fatty tissue with negative staining for Congo Red. Bone marrow aspiration and biopsy showed a slightly hypercellular marrow with 10% monoclonal (lambda-restricted) plasma cells. Further pathology revealed rare blood vessels within the periosteum with amorphous deposit positive for Congo Red stain, suggestive of amyloidosis. Proteomic analysis by mass spectrometry of Congo Red positive material indicated amyloid deposition consistent with light chain immunoglobulin type (AL) amyloidosis. Although cardiac MRI did not show classic sign of cardiac amyloidosis, right ventricular biopsy revealed features consistent with infiltrative cardiomyopathy with Congo Red staining positive for amyloid deposits, which was confirmed to be AL amyloidosis by mass spectrometry.
Management and clinical course
Patient was diagnosed with systemic amyloidosis with bone marrow and cardiac involvement, stage III on the basis of elevated NT-proBNP [980 ng/L (< 100)] and troponin [0.02 ng/L (< 0.1)], with an associated median survival of 4.1 months [
9]. Patient was enrolled in a phase III clinical trail with cyclophosphamide, bortezomib, and dexamethasone with or without daratumumab. Unfortunately, her disease course was complicated by acute on chronic renal impairment requiring hemodialysis 2 weeks into her treatment, and 2 weeks afterwards, the patient and her family decided to make her comfortable and she was transitioned to hospice.
Discussion
Immunoglobulin D (IgD) monoclonal gammopathy is rare, affecting only 0.5% of patients with monoclonal gammopathy [
12]. Interestingly, the presence of monoclonal IgD is almost always associated with multiple myeloma (MM), AL amyloidosis, or plasma cell leukemia; with only case reports of IgD monoclonal gammopathy of undetermined significance (MGUS) present in the literature [
12]. Patients with IgD MM tend to present younger, have more severe disease, and are more likely to have extra medullary disease and poorer prognosis [
13,
14]. Though not well studied, IgD AL amyloidosis is estimated to make up 1.3% of cases of AL amyloidosis and does not seem to have a survival disadvantage as in IgD MM [
15]. However, patients with IgD MM are more likely to have concurrent AL amyloidosis (19–44%) when compared with non-IgD MM [
16‐
18].
Cardiac amyloidosis is often the best predictor of mortality and morbidity [
19] in systemic amyloidosis compared with other organ involvement [
6]. It is an infiltrative disease that can be caused by many subtypes of systemic amyloidosis, with greater than 98% being caused by transthyretin (ATTR) or AL amyloidosis [
20]. The former is reported to involve the heart in almost all cases, depending on the mutation, while the latter affects the heart 50–70% of the time [
3,
20]. Cardiac AL amyloidosis can usually be diagnosed when there is evidence of monoclonal gammopathy, amyloidosis in another organs (usually via fat pad biopsy) and classic imaging evidence of cardiac involvement, particularly MRI. However, as in this case, ventricular biopsy is sometimes required for diagnosis, especially when classic MRI changes are not evident [
3,
20]. Cardiac AL amyloidosis has a median survival of 24 months after diagnosis, compared to 31–69 months in ATTR amyloidosis [
20]. The presence of heart failure at the time of diagnosis, as in this case, is associated with a poor median survival of 6 months [
20]. Treatment is the same as with other organ involvement and is targeted at the underlying plasma cell dyscrasia [
3,
20].
This patient presented with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation; two hallmarks of amyloid cardiac involvement [
3,
9]. A past medical history of bilateral carpal tunnel and macroglossia on physical examination are also specific signs for systemic amyloidosis [
3,
9]. Traditional echocardiography has a low sensitivity of 25–35% [
21], and is particularly challenging in patients with hypertension, which can also cause concentric hypertrophy and HFpEF [
21]. This patient had a negative cardiac MRI, despite its high sensitivity of 85–90% [
7]. This highlights the importance of pursuing a tissue diagnosis when clinical suspicion is high. Interestingly, this patient also had a negative fat pad biopsy, which is positive in 78–100% of patients with cardiac AL amyloidosis [
22].
Finally, family history of cardiac arrest in her brother at the age of 55 would have been a good reason to look for cardiac transthyretin (ATTR) amyloidosis, which is a familial genetic disorder. However, this patient had mass-spectrometry-confirmed cardiac AL amyloidosis, making further workup for other types of cardiac amyloid unnecessary.