Localized amyloidosis of cardiac and skeletal muscle: investigate promptly where it manifests.

To the Editor: A negative biopsy may not rule out amyloidosis, as seen in the following case. We report the case of a patient with cardiac and muscular manifestations of amyloidosis, who had a normal rectal mucosal biopsy. The diagnosis of amyloidosis was only established at autopsy.

A 58-year-old male was admitted with pulmonary edema. He had experienced lower limb weakness, muscle cramps, and easy fatigability for 2.5 years, and had a 6 month history of shortness of breath. In addition, he had a history of arterial hypertension and was a previous smoker. Clinical examination revealed pulmonary rales and leg edema. Electrocardiography showed Q-waves in the posterolateral leads. Chest x-ray revealed pulmonary congestion. Troponin-T (semiquantitatively) and creatine kinase (188 U/L, normal <80 U/L) were elevated. Coronary angiography revealed a 90% stenosis of the left anterior descending artery. Echocardiography (Fig.) showed a thickened, echodense left ventricular myocardium (13 mm, normal < 11 mm) and an enlarged left atrium (43 mm, normal < 40 mm). Systolic function was normal (fractional shortening 25%), but pulsed wave Doppler sonography of the transmitral flow showed a deceleration time of less than 150 milliseconds and an E-velocity of 1.16 m/s with an E/A ratio > 2, indicating restrictive cardiomyopathy. Dipyridamol stress echocardiography revealed reversible hypokinesis of the midseptal and apicoseptal segments, and coronary bypass grafting was considered. The patient was discharged with acetylsalicylic acid, metoprolol and ramipril. The patient's restrictive cardiomyopathy was suspected to be due to amyloidosis since there were no indications for endomyocardial fibrosis, sarcoidosis, hemochromatosis, Fabry or Gaucher disease, Hurler syndrome, or glycogen storage disease. Bone marrow aspiration revealed 20% plasma cells. Immunohistochemistry exhibited a dominance of [kappa]-positive plasma cells, but no evidence of clonal light-chain restriction, being confirmed by a polyclonal pattern of immunoglobulin gene rearrangement on polymerase chain reaction for the VDI heavy chain locus.

Due to complaints of dizziness, muscle pain in the limbs, weakness of the upper eyelids and chewing muscles after physical stress, as well as worsening heart failure, the patient was readmitted after 10 weeks. Clinical examination revealed massive peripheral edema, dyspnea, and a weight gain of 8 kg. Creatinine was 1.6 mg/dL (normal < 1.1 mg/dL) and creatine-kinase was repeatedly elevated (80-103 U/L, normal < 80 U/L). Serum troponin-T was normal. Brain natriuretic peptide was 11,070 pg/mL (normal < 227 pg/mL). Fractional shortening had deteriorated to 15% (normal > 24%). Systolic blood pressure was 80 mm Hg. Rectal biopsy, light chains, and Bence-Jones protein were negative. Considering the bone marrow findings, immunologic and molecular biologic results, and the lack of serologic evidence of gammopathy, plasmacytosis was assumed reactive. Clinical neurologic examination revealed postural tremor, exaggerated tendon reflexes on the lower limbs and positive Babinski sign. Nerve conduction studies of the left median nerve revealed slightly reduced amplitude of the compound muscle action potential on distal and proximal superficial stimulation. Repetitive stimulation of the left median nerve was normal. Acetylcholine receptor antibodies were normal. Needle electromyography of the right rectus femoral muscle revealed shortened mean motor unit action potential duration. Myopathy and polyneuropathy were suspected and a muscle biopsy was performed. Two days before the muscle biopsy, however, the patient died suddenly at home. Autopsy, confined to histologic examination of the myocardium, showed interstitial deposition of Congo red positive material subendocardially and in the intramyocardial artery walls. Immunohistochemistry revealed a positive staining for antibodies against amyloid P, absent staining with antibodies against amyloid A and no reaction with antibodies against kappa or lambda chains. Due to autolysis, the amyloid could not be further investigated. The patient's sister, children, and nephews had normal clinical cardiological examinations, electrocardiographies, and echocardiographies.

Amyloidosis may be acquired or hereditary, localized, or systemic. (1,2) Most likely the patient suffered from either primary systemic (AL)-amyloidosis or from senile amyloidosis. Rapid progression of the disease, however, favors AL-amyloidosis. (2) History and investigations of the relatives excluded familial amyloidosis. Chronic infection was excluded by history and instrumental investigations. Cardiac involvement occurs frequently in AL, hereditary, and senile amyloidosis. (3) Deposition of amyloid in the myocardial interstitial space, vessel walls, valves, and conduction system may lead to myocardial thickening, coronary stenosis, valve abnormalities, arrhythmias, and diastolic dysfunction. (1,4) A restrictive filling pattern predicts poor outcome. (1) It remains uncertain, however, whether the coronary stenosis was due to amyloidosis or arteriosclerosis and whether the patient's sudden death was due to myocardial ischemia or conduction system affection. (4)

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In our patient, amyloidosis was missed due to the fact that no clinically affected organs were biopsied. (Rectal biopsy in AL-amyloidosis is positive in only 60-89% of cases.) In addition, skeletal muscle affection was neglected, and diagnostic management was too slow, facing the rapid progression and poor outcome of the disease. (1) The patient might have profited from heart transplantation if amyloidosis had been detected earlier. As soon as cardiac amyloidosis is suspected, prompt diagnosis is essential.

Claudia Stollberger, MD

Christina Steger, MD

Marion Avanzini, MD

Second Medical Department

Krankenanstalt Rudolfstiftung

Vienna, Osterreich

Hans Feichtinger, MD

Department of Pathology

Krankenanstalt Rudolfstiftung

Vienna, Osterreich

Robert Ullrich, MD

Department of Pathology

Allgemeines Krankenhaus

Vienna, Osterreich

Josef Finsterer, MD

Krankenanstalt Rudolfstiftung

Vienna, Osterreich

References

1. Falk RH, Comenzo RL, Skinner M. The systemic amyloidosis. N Engl J Med 1997;337:898-909.

2. Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 1996;101:395-400.

3. Dubrey SW, Cha K, Simms RW, et al. Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol 1996;77:313-315.

4. Palladini G, Malamani G, Co F. et al. Holter monitoring in AL amyloidosis: prognostic implications. Pacing Clin Electrophysiol 2001;24:1228-1233.

5. Mandl LA, Folkerth RD, Pick MA, et al. Amyloid myopathy masquerading as polymyositis. J Rheumatol 2000;27:949-952.