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(Circulation. 1995;91:1269-1271.)
© 1995 American Heart Association, Inc.

Articles

Amyloidosis

Robert A. Kyle, MD

From the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, and Mayo Medical School, Rochester, Minn.

Correspondence to Dr R.A. Kyle, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Key Words: Editorials • proteins • heart failure • biopsy

	Introduction

Top Introduction References

 
Amyloid appears homogeneous and amorphous under the light microscope but in reality consists of rigid, linear, nonbranching, aggregated fibrils 7.5 to 10 nm wide and of indefinite length. Each fibril consists of two to five filaments and is arranged in an antiparallel or cross–ß-pleated sheet configuration, which is responsible for the unique staining and optical features. Congo red produces an apple-green birefringence with a polarized light source and is the most specific stain. Methyl violet, crystal violet, or thioflavin T also produce typical color changes. Electron microscopy reveals the fibrillar pattern. The amyloid fibrils deposit extracellularly and generally resist proteolytic digestion. These deposits lead to loss of normal tissue elements and disorganization of tissue architecture.

In the United States, almost 85% of patients with systemic amyloidosis have the primary type (AL) in which the fibrils consist of monoclonal or light chains.¹ Nephrotic syndrome or renal failure, congestive heart failure, carpal tunnel syndrome, sensorimotor peripheral neuropathy, and orthostatic hypotension are the most common presenting features. Weakness, fatigue, weight loss, edema, paresthesias, light-headedness or syncope, dyspnea, purpura or bleeding, or change in the voice are the most common symptoms. Hepatomegaly occurs in 25% of patients, whereas splenomegaly is present in less than 5% and macroglossia in only 10%. Anemia is infrequent unless multiple myeloma, renal insufficiency, or gastrointestinal bleeding occurs. Thrombocytosis is a diagnostic clue and occurs in 10%. Reduced renal function is present at diagnosis in 50% of patients. The serum protein electrophoretic pattern has a spike in almost one half of patients and hypogammaglobulinemia in one fifth of patients. A monoclonal protein (M protein) is found in the serum or urine in 90%. Light chains are twice as frequent as , whereas the reverse is true in multiple myeloma. Plasmacytosis is present in the bone marrow in more than one half of patients. An M protein in the serum or urine or monoclonal plasma cells in the bone marrow are found in 98% of patients with AL amyloidosis. Biopsy of abdominal fat or bone marrow is positive in 90% of patients.

Congestive heart failure occurs in approximately one fourth of patients with AL. Electrocardiography often shows either low voltage in the limb leads or loss of anterior forces consistent with anterioseptal infarction, but there is no evidence of myocardial infarction at autopsy.² Atrial fibrillation or heart block are common features. Echocardiography is abnormal in two thirds of patients at diagnosis. The major echocardiographic features are increased thickness of the left and right ventricular walls, abnormal myocardial texture (granular sparkling), valvular thickening and regurgitation, atrial enlargement, and pericardial effusion. Early cardiac amyloidosis is characterized by abnormal relaxation, whereas advanced involvement is characterized by restrictive hemodynamics. Eventually, systolic ventricular function fails. Hypertrophic obstructive cardiomyopathy or constrictive pericarditis may be difficult to differentiate from AL. Death is attributed to cardiac involvement from congestive heart failure or arrhythmias in at least one half of AL patients.

The fibrils in secondary amyloidosis (AA) consist of protein A, a nonimmunoglobulin. Rheumatoid arthritis including its variants and chronic inflammatory bowel disease (mainly Crohn's disease) are the most common causes in Western Europe and the United States. Tuberculosis and leprosy are major causes in third-world countries. Renal insufficiency or nephrotic syndrome is seen in 90%, while the heart and peripheral nerves are rarely involved.³

Although familial amyloidosis has been recognized for over four decades, it has been recognized rarely except in the endemic areas of Porto, Portugal, northern Sweden, and Japan until the last decade. Most commonly, familial amyloidosis presents as a sensorimotor peripheral neuropathy involving the lower extremities. Autonomic dysfunction and disturbances of bladder and gastrointestinal functions are prominent. Symptoms begin in the second or third decade of life, but in some patients, late onset is evident and symptoms do not occur until the sixth or seventh decade. In our experience, the median age is 62 years, and in many, a family history was not obtained until after systemic amyloidosis was recognized.⁴ Even in endemic areas, almost one third of patients with this autosomal dominant disorder had asymptomatic parents at the time of diagnosis.⁵ Familial amyloidosis may involve the kidney, as in familial Mediterranean fever, which is characterized by recurrent episodes of fever and abdominal pain and results in nephrotic syndrome and renal insufficiency. In other families, hypertension and renal failure are the major features.

Cardiac amyloidosis producing congestive heart failure was reported in a large Danish family over 30 years ago.⁶ Cardiomyopathy was described in 1987 in a large kindred from the Appalachian region of the United States.⁷ The amyloid fibrils in these patients consist of a mutant of transthyretin (prealbumin). In this issue of Circulation, Booth et al⁸ report an Italian family with a new variant of transthyretin (TTR) associated with hereditary amyloidosis with a cardiac presentation. Almost 50 mutations of the TTR gene have been reported.⁹

It is important to recognize familial amyloidosis because liver transplantation is beneficial. Because the variant TTR is produced by the liver, orthotopic liver transplantation results in disappearance of the variant TTR. Improvement of neurological symptoms and reduction in amyloid deposits have been reported after liver transplantation.¹⁰ In a group of seven patients with familial amyloidosis, only normal TTR was found after surgery. During short-term follow-up, none of the patients had clinical progression of amyloidosis.¹¹ In a worldwide collection of cases, 53 of 64 patients survived a liver transplant for familial amyloidosis. In most of the patients surviving more than a year, the neurological symptoms stabilized and autonomic nervous system symptoms improved.¹² Ideally, liver transplantation should be performed before symptomatic cardiac amyloidosis occurs. If cardiac function is compromised, resulting in congestive heart failure, a cardiac transplant must be done before the liver transplant.

The fibrils in senile cardiac amyloidosis consist of normal TTR. Cardiac amyloid was found in 9 of 40 autopsied patients aged 90 years or over. In four of them, amyloid deposits were extensive and produced chronic congestive heart failure.¹³ Johannson and Westermark¹⁴ studied 12 hearts in which 40% or more of the left ventricle was replaced by amyloid. Atrial fibrillation had been present in 9 patients, while 7 died of congestive heart failure. In a review of 237 autopsies on patients 90 years of age or more, senile cardiac amyloidosis was detected in 154 (65%).¹⁵ Extensive involvement of the atria, ventricles, or heart valves was found in one third of these patients. Amyloidosis was believed to be responsible for death in 22 of the 154 patients.

Although senile cardiac amyloidosis is commonly recognized at autopsy in the elderly, it may be recognized before death.¹⁶ These patients presented with dyspnea, weakness, and fatigue from congestive heart failure or atrial fibrillation. The echocardiogram revealed low voltage and often a pseudoinfarction pattern. The echocardiogram was characterized by increased ventricular wall thickness in the absence of hypertension, thickening of the valves, regurgitation, and pericardial effusion. Endomyocardial biopsy revealed amyloid. The most common cause of amyloidosis in this clinical setting is primary amyloidosis. There are no distinguishing clinical or laboratory features that differentiate patients with senile cardiac amyloidosis from those with nonsecretory immunoglobulin-derived amyloidosis (AL). Two important findings raise the possibility of senile cardiac amyloidosis: (1) the absence of a monoclonal protein in the serum or urine and (2) patients with senile cardiac amyloidosis do not have extracardiac manifestations such as renal insufficiency, nephrotic syndrome, peripheral neuropathy, orthostatic hypotension, steatorrhea, macroglossia, or purpura. Familial amyloidosis must also be distinguished from AL or senile cardiac amyloidosis because hereditary amyloidosis may not present until the sixth or seventh decade, and a positive family history is often lacking.

Differentiation of nonsecretory AL from familial and senile amyloidosis is critical because of the differences in survival and therapy. In our experience, the median survival of patients with AL presenting with congestive heart failure is 4 months, whereas it is 5 years for those with senile cardiac amyloidosis. Furthermore, patients with AL are treated with melphalan and prednisone or other alkylating agents,^{17 18} whereas familial amyloidosis is treated with liver transplantation. No specific therapy exists for senile cardiac amyloidosis.

The clinician usually suspects primary amyloidosis and searches for a monoclonal protein in the serum and urine. When no monoclonal protein is detected, it is often concluded that the patient has nonsecretory primary amyloidosis, which occurs in about 10% of patients with AL. Immunohistochemical staining of the biopsy with antisera to TTR, and light chains, and amyloid A is necessary for accurate classification in this setting.¹⁹ If the stain for TTR is positive, the patient has either familial or senile amyloidosis, and DNA must be examined for a TTR mutation. It is critical that the correct diagnosis be made because of the differences in management and in survival.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

Received December 28, 1994; accepted December 29, 1994.

	References

Top Introduction References

 

1. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45-59. [Medline] [Order article via Infotrieve]
   
2. Smith TJ, Kyle RA, Lie JT. Clinical significance of histopathologic patterns of cardiac amyloidosis. Mayo Clin Proc. 1984;59:547-555. [Medline] [Order article via Infotrieve]
   
3. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine. 1991;70:246-256. [Medline] [Order article via Infotrieve]
   
4. Gertz MA, Kyle RA, Thibodeau SN. Familial amyloidosis: a study of 52 North American-born patients examined during a 30-year period. Mayo Clin Proc. 1991;67:428-440.
   
5. Coelho T, Sousa A, Lourenço E, Ramalheira J. A study of 159 Portuguese patients with familial amyloidotic polyneuropathy (FAP) whose parents were both unaffected. J Med Genet. 1994;31:293-299. [Abstract]
   
6. Frederiksen T, Gøtzsche H, Harboe N, Kiær W, Mellemgaard K. Familial primary amyloidosis with severe amyloid heart disease. Am J Med. 1962;33:328-348. [Medline] [Order article via Infotrieve]
   
7. Benson MD, Wallace MR, Tejada E, Baumann H, Page B. Hereditary amyloidosis: description of a new American kindred with late onset cardiomyopathy: Appalachian amyloid. Arthritis Rheum. 1987;30:195-200. [Medline] [Order article via Infotrieve]
   
8. Booth DR, Tan SY, Hawkins PN, Pepys MB, Frustaci A. A novel variant of transthyretin, 59^ThrLys, associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation. 1995;91:962-967. [Medline] [Order article via Infotrieve]
   
9. Uemichi T, Liepnieks JJ, Altland K, Benson MD. Identification of a novel non-amyloidogenic transthyretin polymorphism (His 74) in the German population. Amyloid: Int J Exp Clin Invest. 1994;1:149-153.
   
10. Holmgren C, Ericzon B-G, Groth C-G, Steen L, Suhr O, Andersen O, Wallin BG, Seymour A, Richardson S, Hawkins PN, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet. 1993;341:1113-1116. [Medline] [Order article via Infotrieve]
    
11. Skinner M, Lewis WD, Jones LA, Kasirsky J, Kane K, Ju S-T, Jenkins R, Falk RH, Simms RW, Cohen AS. Liver transplantation as a treatment for familial amyloidotic polyneuropathy. Ann Intern Med. 1994;120:133-134. [Free Full Text]
    
12. Steen L, Holmgren G, Suhr O, Wikström L, Groth C-G, Ericzon B-G. World-wide survey of liver transplantation in patients with familial amyloidotic polyneuropathy. Amyloid: Int J Exp Clin Invest. 1994;1:138-142.
    
13. Waller BF, Roberts WC. Cardiovascular disease in the very elderly: analysis of 40 necropsy patients aged 90 years or over. Am J Cardiol. 1983;51:403-421. [Medline] [Order article via Infotrieve]
    
14. Johannson B, Westermark P. Senile systemic amyloidosis: a clinicopathological study of twelve patients with massive amyloid infiltration. Int J Cardiol. 1991;32:83-92. [Medline] [Order article via Infotrieve]
    
15. Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc. 1988;63:552-564. [Medline] [Order article via Infotrieve]
    
16. Olson LJ, Gertz MA, Edwards WD, Li C-Y, Pellikka PA, Holmes DR Jr, Tajik AJ, Kyle RA. Senile cardiac amyloidosis with myocardial dysfunction: diagnosis by endomyocardial biopsy and immunohistochemistry. N Engl J Med. 1987;317:738-742. [Abstract]
    
17. Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985;79:708-716. [Medline] [Order article via Infotrieve]
    
18. Kyle RA, Gertz MA, Garton JP, Greipp PR, Witzig TE, Lust JA. Primary systemic amyloidosis (AL): randomized trial of colchicine vs melphalan and prednisone vs melphalan, prednisone, and colchicine. In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle TJ, Young ID, eds. Amyloid and Amyloidosis, 1993. New York: Parthenon Publishing; 1994:648-650.
    
19. Linke RP, Nathrath WBJ, Eulitz M. Classification of amyloid syndromes from tissue sections using antibodies against various amyloid fibril proteins: report of 142 cases. In: Glenner GG, Osserman EF, Benditt EP, Calkins E, Cohen AS, Zucker-Franklin D, eds. Amyloidosis, 1986. New York: Plenum Publishers; 1986:599-605.
    

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