The Case of the Fatal Fibril

Introduction

An 85-year-old woman was brought to the Emergency Department after falling at home with brief loss of consciousness. The patient had previously been treated for hypertension, taking metolazone, furosemide, lisinopril, carvediol, and spironolactone as well as meclizine (unknown doses), but medications were recently reduced because of documented low blood pressures. There was no history of cardiac ischemia, cerebrovascular disease or diabetes. There was a remote history of uterine cancer.

When seen in the Emergency Department, she was alert, hypothermic (35.9?C) and hypotensive (72/44 mmHg). Her heart rate was 63 beats/min (sinus rhythm). The right ocular orbit was ecchymotic, fine inspiratory crackles were heard bilaterally, heart sounds were distant and there was trace pedal edema. The neurologic examination was grossly intact.

She was mildly pancytopenic: white blood cell count was 3.3; hemoglobin, 10; and platelets, 128,000. Chemistries were remarkable for serum urea nitrogen of 100; creatinine, 3.3; b-type natriuretic peptides, 2,880; and troponin, 0.54. Urinalysis showed 2+ proteinuria, and a 24-hour collection had 1.148 grams of protein. Her chest x-ray showed mild vascular congestion. Initial cultures of blood and urine were negative.

Her blood pressure did not respond to fluids and she was placed on a dopamine drip. One week into the hospitalization, she became markedly dyspneic and obtunded. She was intubated. The chest x-ray was consistent with pulmonary edema. Diuretics were administered. Her blood pressure did not respond to pressors. A family conference was held and life support was withdrawn. A morphine drip was titrated to comfort and the patient died on the second day in the intensive care unit. Blood cultures drawn the day prior to death grew Streptococcus pneumoniae. Serum protein electrophoresis showed a monoclonal peak in the beta region.

On autopsy, amyloid deposition was seen in blood vessels, kidneys, stomach, intestine and liver. Specifically, amyloid deposits were seen in the intracardiac vessels and surrounding the cardiomyocytes. The bone marrow was hypercellular with 30% plasma cells. Flow cytometry demonstrated IgA λchains. Final diagnoses were smoldering myeloma, systemic amyloidosis, acute and chronic lung injury, severe coronary disease, ventricular hypertrophy secondary to hypertension and pneumococcal sepsis.

Discussion

This patient had light chain amyloidosis (AL), the most common form and that associated with multiple myeloma. Amyloid takes its name from Rudolf Virchow's finding in 1854 that certain tissues stained with iodine similar to complex carbohydrates such as starch. The substance was later found to be birefringent, with intensification after Congo Red staining.¹ Amyloid forms fibrils in tissue, which are then thought to interfere with various cellular functions. These were first identified by electron microscopy in 1959. The fibrils are variable in length with widths80? to 100?. Over 20 different varieties are now known to be associated with human disease.^2,3 Recent advances in the molecular structure of amyloid fibrils has defined some basic commonalities that relate the various forms of amyloid seen in myeloma, familial Mediterranean fever, familial amyloidoses, Alzheimer's dementia, Down's Syndrome and dialysis-related amyloid.⁴

Amyloid fibrils arise from conformation changes in naturally soluble proteins, rendering them insoluble. These configuration changes lead to aggregation of identical protein molecules into fibrils. The environment favoring these conformational changes appears to occur more readily with age (transthyretin). Sequence changes due to mutation (lysozyme), enzyme cleavage (ApoA-I) or increased concentration (dialysis) lead to other aggregating proteins.^1,3 The soluble native proteins associated with the different amyloid-related diseases vary widely in composition and are not related. When aggregated, however, the fibrils all display a characteristic conformation in their spines, with segments forming a double beta sheet (Figure 1). These double beta sheets have been nicknamed "steric zippers" because of their ability to link the protein molecules into fibril. The fibrils bind Congo Red, resulting in the classic birefringence which identifies amyloid in tissue.

Figure 1. Molecular structure of the pleated double beta sheet.Reprinted with permission from Eisenberg et al.⁶

Studies of a wide range of proteins suggest that the ability to form fibrils under the proper conditions is by no means limited to the proteins recognized to be associated with specific diseases and, in fact, this property has been known for decades.^5,6 These fibrils are not crystalline and exact tructural information is difficult to obtain. However, a small 7-residue yeast prion (GNNQQNY) with the double beta sheet structure has been shown to aggregate into amyloid-like fibrils whose structure could be analyzed by x-ray crystallography.⁷ Alzheimer's disease is associated with amyloid resulting from cleavage of a precursor protein (APP) the so-called amyloid-β-peptide (Aβ₄₂). Human amylin, or islet amyloid peptide, found in 90% of Type 2 diabetics, is a 37-residue peptide cleaved from a precursor molecule.⁵

Amyloid cardiomyopathy typically presents as congestive heart failure poorly responsive to therapy with a median survival around 6 months. Interestingly, studies of cardiomyocytes in vitro demonstrate that amyloid light chains impair contractility in the absence of fibril formation. This effect appears to be calcium-independent and possibly related to increased oxidative stress.⁸ Patients with amyloid cardiomyopathy are "preload dependent," vitiating the effectiveness of diuresis. Treatment of the underlying myeloma with traditional regimens is usually too gradual to restore contractility.⁹

Amyloidosis occurs in only 12% to 15% of myeloma patients, implying that not all light chains have the propensity to form fibrils.³ It is well known that λchains (as were found in this patient) are more frequently amyloidogenic than κchains. The tissue effects of amyloid fibrils are a subject of considerable debate. They appear to have poorly understood cytotoxic properties and the equilibrium between the fibrils and their soluble precursors may also be important in pathogenesis.³

This patient's terminal course appears to represent the rapid evolution of amyloid cardiomyopathy. Its relationship to her pneumococcal sepsis is not obvious. On the other hand, the hypoimmunoglobulin and granulocyte effects associated with myeloma put her at increased risk for infection with S pneumoniae.

The authors thank Dr. David Eisenberg for helpful comments.

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Submitted on June 6, 2007