A 58-Year-Old Man With Shortness of Breath, Ascites, and Leg Edema
Case Presentation (M. Fedor and D. Schwartz)
The patient is a 58-year-old African American man with past medical history significant for a positive purified protein derivative (PPD) 2 years ago. No treatment was given. He was in his usual state of good health until 6 weeks before admission, when he became aware of breathlessness on mild exertion. Over the ensuing 4 weeks, he noted progressive fatigue; swelling of his lower extremities, particularly on standing; and increasing abdominal girth. His exercise tolerance decreased until he could no longer walk a single city block comfortably. He denied chest pain, palpitations, orthopnea, paroxysmal nocturnal dyspnea, and nocturia. He also denied fever and significant weight loss but did complain of occasional night sweats. The patient was treated with furosemide 20 mg/d without improvement.
His family history was remarkable for a father and a brother who died of unknown heart disease in their 50s. He was married with one healthy son. He immigrated to the United States from St Croix 10 years before admission and worked as a mailroom clerk. He had no significant travel history, was a lifetime nonsmoker, and drank alcohol only socially.
Physical examination revealed an obese African American man in mild respiratory distress. He was afebrile. The heart rate was 80 bpm and regular, and his blood pressure was 120/70 mm Hg. Respiratory rate was 20 breaths per minute. His head was normal except for ill-defined hyperpigmentation periorbitally and bitemporally. His neck was supple without lymphadenopathy. Carotid upstrokes were normal. Jugular venous pressure was estimated at 14 cm water, and there was a Kussmaul's sign; prominent x and y descents were noted. The thyroid gland was normal. There were no gynecomastia and no palpable lymph nodes anywhere. The lungs were clear. Cardiac examination showed a nondisplaced point of maximal intensity and normal S1 and S2. There was a soft S3 gallop and a soft early systolic murmur heard at the lower right sternal border. There was no rub. The abdomen was distended with shifting dullness. The liver span was percussed 18 cm in the midclavicular line, and a spleen tip was palpable. There was pitting edema extending bilaterally from the ankles to midthighs. Genitourinary and rectal examination were unremarkable. The neurological examination was significant for mildly decreased sensation to light touch and proprioception in the lower extremities; the motor examination and reflexes were normal.
The ECG showed normal sinus rhythm, borderline-low QRS voltage, and QS complexes in V1 through V3, suggestive of anteroseptal myocardial infarction. Chest roentgenogram showed mild cardiomegaly and no evidence of effusions or focal infiltrates. Admission laboratory data revealed a normal blood count, blood electrolytes, glucose, blood urea nitrogen, and prothrombin time. Liver function tests showed normal transaminases, alkaline phosphatase of 450 U/L, total bilirubin of 1.7 mg/dL (direct, 0.5 mg/dL), total protein of 6.5 g/dL, albumin of 4 g/dL, and lactic dehydrogenase of 457 U/mL. Ferritin was 81 ng/mL; amylase, 63 U/L; and erythrocyte sedimentation rate, 3 mm/h. Urinalysis showed 3+ protein and no casts or cells.
The patient was placed on a low-sodium diet and given intravenous furosemide. With a net diuresis of 1 L, his peripheral edema decreased by the next morning. A diagnostic paracentesis revealed 3.3 g/dL protein, 88 mg/dL glucose, 109 U/mL lactic dehydrogenase, 63 U/L amylase, and 23 nucleated cells per milliliter (mostly lymphocytes).
A transthoracic echocardiogram (Fig 1⇓) revealed thickened left ventricular (LV) and right ventricular (RV) walls with preserved systolic function, mild left and right atrial dilatation, and moderate tricuspid and mitral regurgitation. A small pericardial effusion was present, and the pericardial reflections were described as echo dense. Mitral inflow pattern consisted of a rapid filling phase with short deceleration time and a diminished A wave (late filling wave corresponding to atrial systole). The pattern of ultrasonic reflection from the myocardium was fine and diffuse without discrete “speckling” or highly refractile pattern.
Cardiac catheterization revealed a pulmonary artery pressure of 60/20 mm Hg, RV pressure of 60/22 mm Hg, LV pressure of 123/24 mm Hg, and mean right atrial pressure of 23 mm Hg, with a tracing showing a prominent y descent. The diastolic pressure tracings in both ventricles exhibited a characteristic square root (dip and plateau) pattern. Left ventriculogram showed an increased ejection fraction and mild mitral regurgitation. Cardiac output was 3.2 L/min, with an index of 1.7 L·min−1·m−2. The coronary arteries were normal.
Serum protein electrophoresis was normal, and urine was negative for Bence Jones protein. A 24-hour urine sample revealed a protein of 141 mg/dL. The patient continued to be treated conservatively with diuretics, with marked weight loss and decreased dyspnea. A diagnostic procedure was performed.
Clinical Discussion (I. Kronzon)
This patient had ankle edema, ascites, and marked neck vein distention. These findings are characteristic of failure of the right side of the heart. In addition, there were symptoms of marked shortness of breath on exertion, which also suggests failure of the left side of the heart. The LV systolic function, which was evaluated by echocardiography and left ventriculography, was increased, with evidence of a hyperkinetic left ventricle. RV systolic function on echocardiography was normal. There were no physical, echocardiographic, or angiographic findings to suggest severe mitral or tricuspid regurgitation. I believe that the differential diagnosis is that of diastolic dysfunction. Indeed, the cardiac catheterization showed significantly elevated diastolic pressure in both ventricles, with equalization of all diastolic pressures. There also was a characteristic square root appearance of the diastolic ventricular pressures and a steep y descent noted on the right atrial pressure curve. Although LV diastolic dysfunction leading to symptoms of failure of the left side of the heart is quite common, this syndrome is frequently associated with hypertension or ischemic heart disease and usually is not associated with failure of the right side of the heart. In this patient, it appears that diastolic dysfunction affects both chambers equally.
Two pathophysiological mechanisms can lead to this clinical picture: restrictive cardiomyopathy and constrictive pericarditis. Differentiation between these two conditions is difficult. In many patients, a comprehensive workup, including noninvasive and invasive techniques, does not solve the clinical puzzle, and the diagnosis finally is made at surgery or sometimes at autopsy. Several clinical hints and a few findings, however, should help differentiate between the two. Table 1⇓ summarizes these findings.
The hallmark of both syndromes is significant, frequently severe failure of the right side of the heart. Jugular venous distention, ankle edema, ascites, hepatomegaly, and elevation of liver enzymes as a result of liver engorgement may be associated with these disorders. In both disorders, most of the ventricular filling occurs in early diastole, with a rapid decrease in right atrial pressure immediately after the opening of the tricuspid valve; therefore, a prominent y descent is noted in the jugular veins. Kussmaul's sign, a paradoxical increase in jugular venous distention during inspiration, also can occur in both conditions. Cardiac examination may be useful. In constrictive pericarditis, the heart (which is encased within a thickened pericardium) is quite quiet. Therefore, the point of maximal intensity frequently is not palpable. By contrast, the point of maximal intensity is usually well detected in patients with restrictive cardiomyopathy. Although S1 and S2 are normal in both conditions, S3 does not occur in constrictive pericarditis. What one can hear is a higher-pitched pericardial knock, which occurs at the end of rapid ventricular filling. A lower pitched S3 is more likely to be present in restrictive cardiomyopathy. However, because the timings for S3 and pericardial knock are similar (approximately 180 ms after S2), the interpretation of the auscultatory findings may be misleading, and one may be mistaken for the other.
Chest roentgenogram and fluoroscopy may be helpful. Approximately 50% of patients with constrictive pericarditis have pericardial calcification. Dramatic cases of encasement of the heart within a calcified “eggshell” are sometimes seen. However, the absence of calcification does not rule out constrictive pericarditis, and pericardial calcification does not necessarily indicate constrictive physiology. Newer tomographic technologies such as CT scanning and magnetic resonance imaging of the heart may help in the differential diagnosis. Pericardial thickening can be detected in most patients with constrictive pericarditis, and it characteristically is absent in restrictive cardiomyopathy. In our patient, however, CT and magnetic resonance imaging of the heart were not performed.
Cardiac catheterization clearly demonstrates the characteristic patterns of diastolic dysfunction. In constrictive pericarditis, the whole heart characteristically is encased within a thickened, noncompliant pericardium that limits its diastolic filling. Filling occurs early in diastole and stops when the nondistensible pericardium is stretched to its limit. At this point, all diastolic pressures are high and equal. Equalization of elevated diastolic pressures is therefore the hallmark of pericardial constriction. In restrictive cardiomyopathy, cardiac catheterization also reveals signs of rapid ventricular filling that reaches a high diastolic pressure plateau (square root sign) as seen in constrictive pericarditis. However, the extent of the process may differ in different chambers; therefore, although both RV and LV diastolic pressures may be elevated, they frequently are not identical. Usually, the LV diastolic pressure is higher than the RV diastolic pressure. Unfortunately, in ≈30% of patients with restrictive cardiomyopathy studied by cardiac catheterization, the diastolic pressures in the left and right chambers are nearly equal. To evaluate these patients, changing of preload or afterload may be useful. Maneuvers such as infusion of 500 cm3 normal saline or exercise will separate right- and left-sided diastolic pressures in patients with restrictive cardiomyopathy. In contrast, the diastolic pressures will increase but remain equal in patients with constrictive pericarditis. We were not told whether such maneuvers were performed in the patient under discussion.
Echocardiography and, in particular, Doppler echocardiographic studies also can be useful in the differential diagnosis. Normal LV function or hyperkinesis is the rule in all cases of constrictive pericarditis and can be present in some cases of advanced restrictive cardiomyopathy in which diastolic dysfunction is dominant. Table 2⇓ compares other characteristic Doppler echocardiographic features of the two disorders. Doppler echocardiography can clearly differentiate between the two disorders. In both disorders (constrictive and restrictive), the flow velocity pattern across an AV valve (best observed by transmitral flow studies) is similar: it stops abruptly after rapid ventricular filling, and thus the deceleration time of transvalvular flow velocity is quite rapid (usually >160 ms). However, the effect of the respiratory cycle on the transvalvular flow differs in the two disorders (see Table 2).⇓ An accurate determination of respiratory variation of flow velocity was not performed in this patient.
The patient had a positive PPD that had been noted 2 years earlier and was not treated. One of the most common causes of constrictive pericarditis is tuberculous pericarditis. The patient did complain of occasional severe night sweats, which also are frequently associated with active tuberculosis. Not infrequently, tuberculous pericarditis may be the only manifestation of tuberculosis. In this patient, however, active tuberculosis seems unlikely because of the lack of fever, normal sedimentation rate, and lack of other radiological or laboratory evidence of chronic infection.
The echocardiographic findings of RV and LV wall thickening are quite remarkable. They occur in the presence of relatively low voltage on the ECG. The combination of significant LV wall thickening, low voltage on the ECG, and failure of the right side of the heart is highly suggestive of restrictive cardiomyopathy secondary to an infiltrative disorder.
Hemodynamic studies showed severe diastolic dysfunction with equalization of all diastolic pressures. A hemodynamic challenge with preload change (by saline infusion or exercise) was not described in this patient. However, the pulmonary artery and RV systolic pressures were markedly elevated, to 60 mm Hg. This finding is unusual in patients with constrictive pericarditis, in which pulmonary artery pressures rarely exceed 40 mm Hg. Thus, the catheterization findings also support the diagnosis of restrictive cardiomyopathy.
Table 3⇓ lists the conditions associated with restrictive cardiomyopathy. Some are congenital and present themselves early in life. Others can be ruled out by this patient's history. Hemochromatosis could be an attractive clinical diagnosis in this patient with vague skin discoloration; however, the normal ferritin level rules this diagnosis out. Sarcoidosis is another possibility; however, massive cardiac sarcoidosis usually presents itself with conduction abnormalities, and systolic dysfunction frequently precedes diastolic dysfunction clinically. There is no clinical or laboratory evidence of secondary spread of neoplasm into the myocardium. Thus, we are left with a common pathogenesis for restrictive cardiomyopathy, namely, cardiac amyloidosis.
Characteristically, cardiac amyloidosis can be associated with dramatic ventricular wall thickening that can be demonstrated by echocardiography and other imaging techniques. A characteristic echocardiographic finding of myocardial speckling has been described, but it is found in only 50% of patients with amyloidosis. Thus, the lack of speckling on this patient's echocardiogram does not rule out amyloidosis. Long-standing amyloidosis can lead to LV systolic dysfunction; however, diastolic dysfunction with well-preserved LV wall motion frequently is an early manifestation of the disorder. Another approach to diagnosing amyloid at this stage is radionuclide imaging. Technetium pyrophosphate characteristically is absorbed by myocardial amyloid, and this technique has been used to demonstrate and diagnose cardiac amyloidosis. This test was not done in this patient.
There are different forms of amyloidosis both clinically and biochemically. They include primary amyloidosis, in which there is no additional known disease; amyloidosis associated with multiple myeloma; secondary amyloidosis associated with conditions such as tuberculosis, osteomyelitis, or leprosy; and amyloidosis associated with heredofamilial disorders, which also is frequently associated with peripheral neuropathy and occasionally with familial Mediterranean fever. Amyloidosis associated with old age also has been described. In this patient, secondary amyloidosis is unlikely. This form of amyloidosis infrequently creates symptomatic heart disease. There is also no clinical evidence of a long-standing, active inflammatory process. The diagnosis of multiple myeloma is not supported because of the protein electrophoresis, absence of Bence Jones protein, and normal sedimentation rate. Amyloidosis associated with aging is unlikely in this 58-year-old patient. This entity also is frequently an incidental finding discovered at autopsy that usually does not cause the severe clinical manifestations observed in this patient. We therefore remain with a primary or, alternatively, a heredofamilial form of amyloidosis. The family history of this patient, with two relatives who died at a relatively young age of vaguely described heart disease, and his peripheral neuropathy may support the latter diagnosis. However, I believe that once the heart is affected by the infiltration of amyloid that is severe enough to cause severe congestive heart failure, the prognosis is poor, and from the cardiologist's clinical point of view, there is little difference. Because this case was diagnosed years ago, I assume that the diagnostic procedure performed was a cardiac biopsy. However, I believe that this procedure is not without danger, and amyloid can be diagnosed in most cases by such procedures as gingival biopsy or, better yet, biopsy of the subcutaneous abdominal fat. Cardiac biopsy should be reserved only for cases in which these biopsies are negative.
Pathological Findings (G. Gallo)
The patient had RV biopsy. The endomyocardial biopsy was stained with Congo red, which showed green birefringence of deposits under polarization microscopy, typical of amyloid (Fig 2A⇓). Frozen sections were incubated with a panel of antibodies against IgG, IgA, IgM (heavy-chain specific), κ light chain, λ light chain (light-chain specific), transthyretin (TTR), amyloid A protein, and amyloid P component. Deposits stained for λ light chain and amyloid P component (Fig 2B)⇓ but were negative for the other proteins tested. The deposits were present diffusely in vessels and around myocardial cells.
Electron microscopy demonstrated randomly oriented fibrils typical of amyloid in the plasmalemmal sheath and interstitially between muscle cells (Fig 3⇓).
Hematology Commentary and Follow-up (D.R. Jacobson)
This patient came to my attention after the diagnosis of amyloidosis was made, and I cared for this patient in the clinic after his discharge from the hospital. Of the comments made so far, the one statement with which I disagree is the comment that because the prognosis of symptomatic cardiac amyloidosis is poor, it makes little difference what type of amyloid is present. Considerable progress has been made recently in understanding amyloid on the molecular level, and this is translating into better approaches to treatment.
First, I would like to address the nomenclature of amyloid because the terms “primary” and “secondary” amyloid are used here. These terms originated long before amyloid was understood on a molecular level, and now that we can determine the specific protein deposited in most patients with amyloidosis, it is recommended that these terms be abandoned and that amyloid be referred to whenever possible by the chemical classification1 2 3 ; unfortunately, the terms “primary” and “secondary” persist in the literature, causing considerable confusion. Historically, secondary amyloidosis referred to the amyloid that accompanied chronic inflammatory processes such as tuberculosis and rheumatoid arthritis. Familial amyloidosis was recognized by the positive family history. All other types of amyloidosis, except that associated with the multiple myeloma, were called primary in the sense of idiopathic; this category included unrecognized inherited forms, secondary amyloidosis without an identified cause, and localized amyloidosis. This classification was based on the assumption that all forms of amyloidosis would consist of a single predominant protein.
We now know that all forms of amyloid consist of a minor glycoprotein, the P (pentagonal) component, which is identical in all types of amyloid, and the major fibrillar component, 15 of which have been identified in human amyloidosis. As a group, the amyloid precursor proteins are small, with molecular weights of 4000 to 25 000 D. Their tertiary structures are characterized by a substantial β-pleated sheet structure, which is thought to play a role in amyloid formation, but the precise mechanisms of fibril formation remain poorly understood. The major protein component defines the type of amyloidosis and determines the pathogenesis of the disease. Classification based on clinical syndromes is now avoided whenever chemical information is available. Thus, in what was called secondary amyloidosis, the amyloid fibrils consist of the amyloid A (AA) protein; these diseases are called AA amyloidosis. The amyloid material consisting of immunoglobulin light chains or light-chain fragments (AL amyloid) originates from a single clone of plasma cells. When this clone has expanded to the extent that the criteria for the diagnosis of multiple myeloma are fulfilled, the disease is called myeloma-associated amyloid; when the clone has a limited proliferative capacity and myeloma criteria are not met, the disease previously was called primary systemic amyloidosis. In such cases, the cause of the patient's disease is essentially the same as monoclonal gammopathy of undetermined significance, with the additional feature that the monoclonal protein happens to be amyloidogenic. From the standpoint of amyloidosis, myeloma-associated amyloidosis and primary systemic amyloidosis are identical processes, and both should instead be referred to as AL amyloid.
Of the various types of amyloid that form deposits in the cardiac ventricles and cause congestive heart failure, the most common are AL and TTR amyloid; cardiac AA occurs less often. TTR is a serum transport protein consisting of four identical subunits of 127 amino acids each. TTR transports thyroxine- and retinol-binding protein and is synthesized primarily in the liver, choroid plexus, and retina. Normal-sequence TTR has a low-grade inherent tendency to form amyloid, and a small amount of TTR amyloid in the cardiac ventricles is found incidentally at autopsy in >25% of people 80 years of age or older.4 This process, usually asymptomatic, has been called senile cardiac amyloidosis. Because other organs may be involved, the alternative name “senile systemic amyloidosis” also is used.
In some patients, the process of TTR amyloid deposition is accelerated, leading to congestive heart failure and/or arrhythmias. Occasionally, patients with large amounts of cardiac TTR amyloid have deposits consisting of normal-sequence TTR5 6 ; in these patients, the stimulus for accelerated deposition is not known. More commonly, the stimulus for symptomatic TTR amyloidosis is a TTR point mutation, changing the conformation of the molecule and leading to increased deposition. Nearly 50 different amyloidogenic TTR mutations are now known, most of which have been described in single kindreds or ethnic groups.7 The most severely affected organs are typically the heart, peripheral nervous system, eye, and gastrointestinal tract. The disease caused by variant TTR typically is called familial amyloid cardiomyopathy or familial amyloid polyneuropathy.1
One amyloidogenic TTR variant, TTR Ile 122, is carried by 4% of African Americans8 (D.R.J. and colleagues, unpublished data, 1995) and has been found in several patients with severe congestive heart failure.9 10 11 The risk of TTR Ile 122 carriers developing symptomatic amyloidosis is not yet known, but it clearly is greater than for people with the normal TTR sequence. When I first saw this patient, immunohistochemistry had not yet been performed, so we did not know the type of amyloid. At the time, I thought that he may have had TTR Ile 122 amyloidosis because there reportedly was no evidence of a monoclonal protein in the serum or urine. While awaiting immunohistochemistry, we performed genetic studies12 and determined that the patient was indeed heterozygous for TTR Ile 122; however, immunohistochemistry demonstrated that the patient's true diagnosis was AL amyloid, and the genetic studies turned out to be a coincidental finding.
After AL amyloidosis was diagnosed, the patient was evaluated for multiple myeloma, as should all patients with AL amyloid. A bone marrow examination revealed 6% plasma cells, and no lytic lesions were seen on skeletal survey; thus, the patient did not have myeloma. Reportedly, only about half of patients with AL amyloid have a monoclonal immunoglobulin protein detectable in the serum or urine. This is really an issue of the practical limitation of the assays used clinically to detect monoclonal proteins. The amyloid precursor, the monoclonal immunoglobulin molecule, is synthesized by monoclonal plasma cells in the bone marrow and is deposited as amyloid in the heart; thus, this protein must travel through the bloodstream. So if a sensitive-enough assay is used, in theory, all patients with AL amyloid must have a monoclonal serum and/or urine protein (free immunoglobulin light chains are small enough to be filtered by the glomerulus and appear in the urine). When we repeated the urine protein immunoelectrophoresis on a concentrated specimen in a research laboratory, the monoclonal protein was detected, even though this test remained negative as reported by the routine clinical laboratory.
So does it matter if we know whether the patient has TTR or AL cardiac amyloid? A decade ago, perhaps not, but in 1996, yes. Chemotherapy is of value for multiple myeloma, so it would seem logical that the same chemotherapy might be of use for AL amyloid even if diagnostic criteria for myeloma are not fulfilled. For many years, reports suggested that chemotherapy is valuable for treating AL amyloid, and two recently randomized, controlled trials have demonstrated a survival advantage for patients receiving chemotherapy,13 14 15 so this should now be standard therapy for patients with AL amyloid, even in the absence of myeloma.
On the other hand, patients with TTR amyloid will not benefit from chemotherapy. For patients with TTR amyloid, studies to determine whether a TTR variant is present can help guide management. Particularly in younger patients, if a TTR variant is present, liver transplantation can be performed as a means of replacing the source of variant TTR with normal-sequence TTR; patients who receive liver transplantations have gradual resolution of their amyloid and may achieve complete resolution of symptoms.16 17 At present, there is no known effective treatment for amyloid consisting of normal-sequence TTR.
This patient's congestive heart failure improved with large doses of diuretics (furosemide and spironolactone), and he improved symptomatically. He also was treated with monthly melphalan and prednisone, and his heart disease appeared to stabilize or even improve. The median survival of patients with symptomatic congestive heart failure resulting from AL amyloidosis is months for patients not receiving or not responding to chemotherapy.18 In a subset of patients, however, chemotherapy leads to resorption of the amyloid, improvement in cardiac function, and longer survival.18 Chemotherapy was discontinued after nearly 2 years because of thrombocytopenia. Shortly thereafter, the patient moved out of town and has been lost to follow-up. The optimal duration of chemotherapy for patients who respond is not known. This patient's clinical stabilization and nearly symptom-free state 2 years after diagnosis clearly demonstrate the value of determining the specific type of amyloid present in each patient and instituting appropriate therapy.
The clinical diagnosis was cardiac amyloidosis, probably heredofamilial.
The final diagnosis is λ light-chain amyloidosis of the myocardium.
This work was supported in part by an Established Scientist Award, American Heart Association, New York City affiliate (Dr Jacobson).
- Copyright © 1996 by American Heart Association
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 colchincine. In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle TJ, Young ID, eds. Amyloid and Amyloidosis 1993. New York, NY: Parthenon Publishing; 1994:648-650.
Skinner M, Anderson J, Wang M, Simms R, Falk R, Jones LA, Cohen AS. Treatment of patients with primary amyloidosis. In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle TJ, Young ID, eds. Amyloid and Amyloidosis 1993. New York, NY: Parthenon Publishing; 1994:232-234.
Gertz MA, Kyle RA. Amyloidosis: prognosis and treatment. Semin Arch Rheum.. 1994;24:124-138.
Gertz MA, Kyle RA, Greipp PR. Response rates and survival in primary systemic amyloidosis. Blood.. 1991;77:257-262.