Case 8 -

Cardiac Amyloidosis, Senile Form Henry D. Tazelaar and Marie-Christine Aubry

PDF File (3.1 MB) Clinical History A 73 year-old gentleman presented at the emergency room with vague chest pain. He has a past history of Wegener's granulomatosis and mild well controlled systemic hypertension. He was evaluated for acute ischemic heart disease. He underwent a stress electrocardiogram (ECK) and echocardiogram. The stress ECG was negative and the stress echocardiogram revealed a severe concentric hypertrophy of the left ventricle with severe hypokinesis of the inferior wall of the left ventricle, which remained unchanged during effort. His troponin was negative. The chest pain was considered of non-coronary origin and he was referred to cardiology for further work-up of the ventricular hypertrophy. A cardiac catheterization confirmed the absence of significant coronary disease and a right endomyocardial biopsy was performed. Slides illustrating Case 8 are included in the accompanying PDF of the Powerpoint presentation. At high power, the cardiac myocytes do not show marked increase in their thickness and the nuclei are only focally increased in size with irregular shape, suggesting mild myocyte hypertrophy. However, a dense amorphous eosinophilic material is present, intimately surrounding myocytes as well as forming nodular deposits, accounting for the echocardiographic findings. The material stains strongly with the sulfated alcian blue stain confirming the diagnosis of cardiac amyloidosis. The immunohistochemical study performed on paraffin-embedded tissue show strong reactivity of the amyloid for transthyretin and absence of reactivity for other types of amyloid, including light chains, protein A, and β2 microglobulin. These findings are consistent with either familial or senile amyloidosis. Upon clinical evaluation and follow-up, it was determined that patient had senile amyloidosis. Discussion Amyloidosis refers to a heterogenous group of disorders that share one feature in common: deposition of protein in an abnormal fibrillary form (amyloid) within various organs. If amyloid is histologically quite uniform in all types of amyloidosis, chemically it is heterogeneous with over 15 biochemical forms described. Classification is based on these forms (Table 1). Amyloid deposits can also be focal or generalized, acquired or inherited, thus determining different clinical syndromes. Amyloid,first described by Virchow in 1854, is 95% comprised of fibril proteins. The ultrastructure of the fibrils is identical in all types and characterized by nonbranching fibrils, indefinite in length and with a diameter varying between 7.5-10 nm. However, chemically, these proteins are variable. The most common forms are AL, AA proteins and transthyretin. AL represents complete immunoglobulin light chains, the terminal fragments or both, and most are λ light chains. This type of amyloid is found in primary Table 1 - Classification of amyloidosis (modified from Gillmore et al, BJH 1997) Major Fibril Protein Clinical Syndrome Associated Diseases AL (Ig light chains) Primary systemic amyloidosis Immunocyte dyscrasia (multiple myeloma, monoclonal gammopathy, occult dyscrasia) AL (Ig light chains) Local nodular amyloidosis (lung, larynx, skin, bladder, tongue)   AA Reactive systemic amyloidosis Chronic inflammatory diseases (rheumatoid arthritis, ankylosing spondylitis, IBD) AA Hereditary amyloidosis such as Familial Mediterranean Fever   Transthyretin (normal) Senile systemic amyloidosis   Transthyretin (mutated) Hereditary amyloidosis such as Familial amyloid neuropathies, Familial amyloidotic cardiomyopathy   Aβ2m (β2 microglobulin) Hemodialysis-associated amyloidosis Focal senile amyloidosis of prostate Chronic renal failure with long term dialysis Aβ Focal senile amyloidosis of brain Non-familial Alzheimer's disease Sporadic cerebral amyloid angiopathy   AANF (atrial natriuretic factor) Focal senile amyloidosis of heart   A Cal (calcitonin) Localized to thyroid Medullary carcinoma AIAPP (islet amyloid peptide) Localized to Islet of Langerhans Type II diabetes systemic amyloidosis and complicates most clonal plasma cell dyscrasias, including up to 15% of multiple myeloma. It is also present in some forms of localized amyloidosis such as pulmonary nodular amyloidosis. AA, amyloid associated protein, is derived from a larger precursor protein, serum amyloid A, synthesized by the liver, secondary to an inflammatory condition, thus the type of amyloid seen in reactive systemic amyloidosis. The most common causes in the Western World are chronic inflammatory disease, such as rheumatoid arthritis, ankylosing spondylitis, Reiter's and IBD. Other causes include chronic microbial infections, including tuberculosis and osteomyelitis. AA amyloid can also be deposited in cases of malignant neoplasms such as renal cell carcinoma and Hodgkin lymphoma. Finally, it is also seen in some forms of hereditary amyloidosis. Transthyretin, previously known as pre-albumin, is a normal serum protein that can accumulate in aged individuals (systemic senile amyloidosis) or mutated in some forms of hereditary amyloidosis, with over 59 mutations described. In addition to amyloid fibrils, other minor components (5%) are always present in all types of amyloid and include serum amyloid P component, and highly sulfated glycosaminoglycans. Heart and Amyloidosis (Table 2) Amyloid deposition in the heart occurs in several types of amyloidosis, including primary, familial, senile (systemic and localized) and rarely in reactive systemic amyloidosis. Clinical, therapeutic, prognostic and histologic/immunohistologic features distinguish these different types. Clinical Diseases The most common type of amyloidosis involving the heart is primary amyloidosis. Clinical manifestations of primary amyloidosis are protean since almost any organ can be involved and symptoms reflect the organs most prominently involved, the most common being heart, kidney, followed by gut, spleen, peripheral nervous system, skin and soft tissue, including tongue. The heart is histologically involved in most cases, and cardiac manifestations can be as protean. Indeed, cardiac amyloidosis can simulate constrictive pericarditis, hypertrophic cardiomyopathy, ischemic heart disease and even valvular disease. The most common manifestation is that of a restrictive cardiomyopathy, the presenting feature in up to a third of patients with primary amyloidosis. Cardiac complications lead to death in half of patients. Congestive heart failure (CHF) is the most frequent cardiac symptom. It may be preceded by asymptomatic electrocardiogram (ECG) abnormalities, namely low QRS voltage. CHF is predominantly right-sided with peripheral edema and hepatomegaly. Prominent vascular deposition leading to obstruction can result in a clinical picture of ischemic heart disease, with angina and ECG abnormalities such as bundle branch block and Q wave abnormality, and no significant epicardial coronary disease demonstrated by cardiac catheterism. Deposition within the conduction system can lead to arrhythmias, with nearly all types described and the most common being atrial fibrillation. Echocardiogram may suggest the presence of amyloid with septal and left ventricular wall thickening, and echogenicity described as granular sparkling; the reported sensitivity of the echocardiogram is 87%. Median survival is 12-15 months, and less if associated with myeloma; 50% of deaths are cardiac and if heart failure is evident at presentation median survival drops to 4-6 months. Familial Amyloidosis Hereditary amyloidoses are due to genetic variants of physiologic proteins, including transthyretin. Over 70 specific point mutations in the TTR gene, on chromosome 18, in over 50 different sites, have been described. The course of the prototypical disease usually begins with sensorimotor polyneuropathy due to predominant peripheral nervous system involvement. Cardiac deposition is quite variable, occurring with progressive disease, and reported in at least 27% of patients. Conduction system can be predominantly involved with some type of mutations, while in others infiltrative disease similar to that in AL will dominate the clinical picture. Cardiac involvement is strongly predictive of poor prognosis with up to half of patients dying as a result of arrhythmia or CHF. Familial amyloidotic cardiomyopathy has only been recently described. It is the result of apoint mutation in the transthyretin gene at codon 122, with isoleucine substituted for valine. 3.9% of the black population carries the mutant gene. Late-onset cardiac involvement over the age of 60 years has been described in both homo and heterozygous patients, with a 7.5 times risk greater than the population without the mutation. Senile systemic amyloidosis is the most common form of systemic amyloidosis, occurring in up to 25% of elderly individuals over the age of 80 years. Initially, was thought to be limited to the heart. While cardiac involvement is predominant, small deposits can be found in many organs. Amyloid is comprised of normal transthyretin. Although the disease is usually clinically silent and benign, in some patients, the cardiac deposits can be extensive leading to death in up to 10% of patients. The clinical manifestations of the heart disease are similar to patients with primary systemic amyloidosis, although arrhythmia and ischemic heart disease are less common. The median survival is 5 years. Isolated atrial amyloid. One of the most prevalent type of senile amyloidosis, found in about 80-90% of non-selected autopsies in patients over 80 years of age. Usually it presents as small deposits, coating the myocytes in the atria. The significance and pathogenesis of these deposits are incompletely understood and may be related to aberration involving the storage and release of ANF, since they are more prevalent in patients with chronic CHF, which causes increased plasma concentration of ANF. No definite clinical consequence has been identified; however, these patients are more likely to develop atrial fibrillation. In reactive systemic amyloidosis, amyloid deposition usually starts in the spleen followed by liver and kidney before general deposition in vessels and interstitium. Cardiac involvement is rare and almost never results in CHF. Table 2 - Systemic Amyloidosis Involving the Heart.   Primary Senile systemic Familial Reactive Population 40-60 years old >80 years old 30-60 years old 40-60 years old Clinical manifestations Protean Silent Cardiac Peripheral neuropathy Proteinuria Cardiac involvement: Common Yes Yes Variable No Site Myocardium, conduction system, valves Myocardium mostly Myocardium, conduction system Myocardium Manifestation CHF, arrhythmia, IHD, valvular disease Similar to primary CHF Echocardiogram RCM, HCM RCM, HCM RCM RCM, HCM Type of protein AL Transthyretin Normal Transthyretin Mutated AA Prognosis Poor Median survival 12-15mos Median survival 5 years Median survival < 10 years 5-yr survival of 50% Cause of death Cardiac in 1/2 Cardiac Variable with type of mutation Renal failure Histology The diagnosis of amyloidosis requires histological confirmations. Furthermore, determining cardiac involvement and type of amyloid involving the heart can be important for prognosis and treatment. Although in cases of suspected systemic amyloidosis, commonly biopsied sites include rectal mucosa, abdominal fat pad and labial salivary glands, the reported sensitivity of these non-invasive procedures can be as low as 50%. For rectal mucosa biopsy, the sensitivity ranges from 75-85%. Abdominal fat aspiration is less sensitive, ranging from 55 to 75%, however, is very specific. In patients with suspected cardiac involvement by primary amyloidosis, endomyocardial biopsy has a sensitivity and specificity of 100% and may be the only organ biopsied showing amyloid in up to 27% of patients. Although echocardiogram has a relatively high sensitivity and specificity, 87% and 81% respectively, distinction between senile from primary cardiac amyloidosis can not be always accomplished, even with clinical information. This is particularly important in older patients since both types may coexist in the same patient. Also, approximately 15% of patients with primary amyloidosis are "non-secretors" and do not have demonstrable light chains in their serum or urine, or B-cell clone on bone marrow biopsy, therefore distinction between both types can only be made histologically. Amyloid deposition in the heart can be focal, thus a minimum of four cardiac biopsy samples is necessary to eliminate sampling error. The pattern of amyloid deposition in endomyocardial biopsies overlaps between major forms of amyloidosis, and the deposits can be pericellular, nodular, vascular and endocardial. However, deposits tend to involve predominantly the vessels in primary and familial types, while nodular deposits predominate in the senile form. The conduction system is more commonly involved in primary and familial amyloidosis than senile. Prominent vascular involvement with obstruction is often underestimated in endomyocardial biopsies due to the lack of larger caliber vessels, and best appreciated in explanted or autopsy cardiac specimens. In an autopsy or explanted heart, the myocardium is firm and rubbery. The ventricular cavities are usually normal to moderately dilated, and the wall thickness increased. Amyloid can be found in all cardiac chambers, in conduction system (sinoatrial and atrioventricular nodes and bundle branches), in valves and vessel wall of intramyocardial coronary arteries. Several histochemical stains can be used to identify amyloid, including Congo red, sulfated alcian bleu (SAB) and thioflavin T. At our institution, we prefer using SAB stain because it does not require polarization or fluorescence, and is also used concomitantly to evaluate fibrosis in lieu of a trichrome stain. Immunohistochemical characterization of the different proteins on paraffin- embedded tissue is possible and at our institution, our panel is comprised of protein P, albumin, AA protein, AL chains, transthyretin and beta 2 – microglobulin. Protein P is used as a positive control, since present in all types of amyloidosis, and defines the site of amyloid deposition. AL amyloid contains unique epitopes often not recognized by standard antisera to Kappa and Lambda light chains. The antibody directed against transthyretin does not distinguish the normal from the mutated form, therefore if a familial form is clinically suspected, further tests, including isoelectric focusing of the serum and specific genetic testing to identify specific mutation, are necessary. Treatment: Therapy is directed both at correcting the underlying disorder to reduce the supply of amyloid precursor protein, and supportive treatment of the symptoms. Definitive treatment of the underlying disease is possible only in some cases of familial amyloidosis with orthotopic liver transplantation. Although theoretically, this strategy could apply to patients with familial amyloidotic cardiomyopathy, in practice these patients tend to be elderly and the amyloid infiltrate unlikely to reverse. Treatment for primary amyloidosis is aimed at reducing the plasma cell proliferation, usually with a combination of steroids and melphalan. Differential Diagnosis Histologically , the main differential diagnosis of amyloid deposition is interstitial fibrosis, a non-specific finding often seen in association with myocyte hypertrophy. By H&E, collagen is fibrillary rather than amorphous and has a brighter eosinophilia than amyloid. At our institution, since we perform an SAB routinely on endomyocardial biopsies, collagen is readily differentiated from amyloid by the different tinctorial affinity, with collagen appearing metachromatic and amyloid aqua-green. Clinically, the differential diagnosis of restrictive cardiomyopathy is lengthy (Table 3) and includes several disorders which can be recognized histologically or at least suggested by the pathologist (in bold in Table 3), thus, should be sought for by the pathologist once aware of the clinical indication of the endomyocardial biopsy. The most common etiology in North America is amyloidosis. 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