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She was well till March 2008 when she presented with lower extremity edema, shortness of breath, fatigue, anorexia, hair loss and weight loss. Her patient's medical history was unremarkable except for cholecystectomy and chronic venous insufficiency. There was no family history of cardiomyopathy, heart failure or sudden cardiac death. She had 5 siblings one of whom suffered from rheumatoid arthritis.
The clinical course was characterized by rapid deterioration. A diagnosis of hypothyroidism was established and thyroxin therapy initiated. Serum iron and markers of inflammation were negative. She did not tolerate beta blocker or ACE inhibitors because of hypotension. The patient initially responded to diuretic therapy but within several months developed bilateral pleural effusions and ascites. The clinical course was complicated by gout requiring steroid therapy.
On presentation LVEF was reported as 50% but echocardiography from December 2008 showed LV wall thickening, moderate to severe systolic dysfunction (LVEF 30-35%), right ventricular hypertrophy with moderately reduced systolic function, bi-atrial enlargement and restrictive LV filling.
Coronary angiography was normal. Right heart catheterization: PA 48/24 mean 32 mmHg, PA wedge 22, LVEDP 25 and mean RA 24 mmHg. After Congo-Red staining of rectal biopsy was negative, a tentative diagnosis of idiopathic restrictive cardiomyopathy was established.
In May 2009 the patient was in NYHA functional class IV. Her ECG is demonstrated in figure 1. An echo-doppler study showed left ventricular hypertrophy (13mm), LVEF 20%, severe diastolic dysfunction, severe right ventricular dysfunction with dilated inferior vena cava, mild tricuspid regurgitation, normal estimated pulmonary artery pressure and small pericardial effusion (figure 2-5). Cardiac MRI was performed, demonstrating a diffuse late gadolinium enhancement (LGE), more pronounced in the subendocardium (figure 6-7). A diagnostic test was performed.
What do you think is the diagnosis in this patient, which further investigations should be performed?
Diagnosis, case resolution and treatment
Free light chains were measured in serum to find LAMBDA Free Light Chain (FLC) level of 263 mg/l (normal 6-26) with reduced F-KAPPA/F-LAMBDA ratio, compatible with Plasma Cell Dyscrasia. Bone marrow biopsy revealed 10% CD-138 positive plasma cells.
The echocardiographic features comprising a hypertrophic, non-dilated left ventricle with severe diastolic dysfunction and rapidly progressive contractile failure are compatible with an infiltrative disease. In the light of the above, the late gadolinium enhancement (LGE) pattern demonstrated on MRI is highly suggestive of cardiac amyloidosis. A diagnosis of amyloidosis was therefore established and the patient was referred to chemotherapy.
The gold standard for diagnosing cardiac amyloidosis still requires a positive Congo Red stain from endomyocardial biopsy or from another tissue in the presence of compatible cardiac morphology and physiology (1,2).
Except for certain geographic regions, the most common type of cardiac amyloidosis is AL, caused by deposition and toxicity of the amyloid in the myocardium. The introduction of a serological test for FLC greatly enhanced the work-up of patients suspected to suffer from amyloidosis. The association with plasma cell dyscrasia: either primary amyloidosis (the majority) or multiple myeloma (the minority) is obvious. FLCs are elevated in 80-90% of patients with cardiac amyloidosis (3). FLC may not be detectable in a minority with a low-level secretion who suffer from a more indolent but still lethal disease. On the other hand, the mere presence of monoclonal immunoglobulin or light chain elevation cannot be accepted as diagnostic of amyloidosis because of it presence in up to 1% of normal elderly population.
Bone marrow, subcutaneous fat pad or rectal biopsy is the preferred mode of tissue diagnosis, in particular when systemic involvement is suspected. However, Congo Red staining itself is not without limitations. Because amyloid deposits may have a patchy distribution, in particular in the initial stage, Congo Red stain of endomyocardial biopsy may be negative due to a sampling error. It also may be negative in the Light Chain Deposition Disease, in particular type KAPPA, where FLCs do not create the classical -sheet layers. Typical extra cellular fibrillar deposits can be detected by an electron microscopic examination even when Congo Red is negative, and therefore a sample in glutaraldehyde should be a routine part of endomyocardial biopsy (1).
Cardiac MRI is a relatively new technique where a distinct pattern of diffuse LGE is found in up to 80% of cardiac amyloidosis patients but is rather rare in other cardiomyopathies (4,5). We therefore believe that a combination of echo-doppler suggestive of infiltrative cardiomyopathy, monoclonal FLC elevation along with typical MRI findings may be diagnostic of amyloidosis even when Congo Red stain is negative/non-available. In our case we considered endomyocardial biopsy to be risky because of advanced conduction disease (see ECG) but were completely confident in the diagnosis established by non-invasive criteria.
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