Immunoglobulin light chain amyloidosis is characterized by a clonal population of bone marrow plasma cells that produces a monoclonal light chain of the κ or λ type, as either an intact molecule or a fragment. The light chain protein, instead of conforming to the α-helical configuration of most proteins, misfolds and forms a β-pleated sheet. This insoluble protein is deposited in tissues and interferes with organ function. The β-pleated sheet configuration is responsible for the tinctorial properties; when the protein is stained with Congo red and viewed under polarized light, apple-green birefringence is demonstrated and is required for the diagnosis. Systemic light chain amyloidosis (AL) must be distinguished from the much less common amyloidosis associated with chronic infection and inflammatory arthropathies (secondary amyloidosis or AA) or with inherited amyloid cardiomyopathies and neuropathies (familial amyloidosis or AF).
Amyloidosis is particularly difficult to diagnose and is a challenge for internists. The presenting symptoms can be diverse and are mimicked by far more common disorders. The signs include tongue enlargement with dental indentations and “pinch” or periorbital purpura, a result of vascular fragility. The signs are specific but lack sensitivity in that they are present in no more than 20% of patients. No single imaging procedure or laboratory study is diagnostic for the disease. The clinician must therefore be aware of the possibility of amyloidosis, or it may be overlooked. The kidney is commonly involved in amyloidosis (50% of cases). The diagnosis should be suspected in any patient who presents with nondiabetic nephrotic-range proteinuria. One third of patients with amyloidosis have nephrotic syndrome that is manifested with dramatic increases in the blood cholesterol level (median, 270 mg/dL), and urinalysis for proteinuria should be done in patients with a sudden increase in the serum cholesterol level. A patient with nondiabetic proteinuria may receive an empirical course of corticosteroids for possible minimal-change glomerulopathy. This treatment delays the diagnosis of amyloidosis and allows other organs to become involved. Ten percent of renal biopsy specimens from patients with nondiabetic nephrotic syndrome are subsequently shown to be involved by amyloidosis. The incidence of bleeding after percutaneous renal biopsy is not increased in patients with AL.
Symptoms and signs
- Common symptoms: fatigue, edema, dyspnoea, anorexia, paresthesias
- Rare symptoms: claudication, joint pain and stiffness, sicca syndrome
- Common signs: periorbital purpura, glossomegaly, hepatomegaly
Rare signs: waxy infiltration of eyelids, shoulder pad sign
- Nondiabetic nephrotic syndrome
- Nonischemic cardiomyopathy with an echocardiogram showing “hypertrophy”
- Hepatomegaly or increased alkaline phosphatase with no imaging abnormality
- Peripheral neuropathy with monoclonal gammopathy of undetermined significance or chronic inflammatory demyelinating polyneuropathy with autonomic features
- Atypical myeloma with monoclonal light chains and modest marrow plasmacytosis
The heart is involved in approximately 50% of patients with amyloidosis, and the presentation is subtle because fatigue is often the only manifestation. Because amyloid heart disease is a disorder of diastolic failure, the typical findings of cardiomyopathy (enlarged cardiac silhouette on chest radiography, depressed ejection fraction by echocardiography, and pulmonary vascular redistribution) are absent. The effect of amyloidosis on the heart is poor filling during diastole. Patients have low end-diastolic volume and, as a consequence, poor stroke volume, despite a completely normal ejection fraction. Electrocardiography frequently shows a pseudoinfarct pattern, which can be interpreted as demonstrating silent ischemic infarction; this finding leads to coronary angiography, which is invariably negative (unless there is coincidental coronary artery disease). Echocardiography, which shows thickening of the heart walls due to amyloid infiltration, is frequently interpreted as showing left ventricular hypertrophy, and the cause of heart failure can be ascribed to silent hypertension or, alternatively, hypertrophic cardiomyopathy. Restrictive cardiomyopathy has been confused with pericardial disease, and patients have undergone unnecessary pericardiectomy, without clinical benefit. The classic granular sparkling appearance on the echocardiogram is not a useful diagnostic finding. Patients with amyloidosis rarely have symptoms of ischemic heart disease. Enhancement on magnetic resonance imaging with gadolinium is delayed in 69% of patients with cardiac amyloidosis. Myocardial enhancement is associated with increased ventricular mass and impaired left ventricular systolic function.
The liver is involved in 13% of patients. The typical presentation is hepatomegaly and an increased serum alkaline phosphatase value. Increased transaminase values and hyperbilirubinemia are late signs. Imaging is not helpful, and liver uptake is homogeneous. Many patients undergo evaluation for metastatic malignant disease. Liver biopsy is not associated with an increased rate of bleeding and is not contraindicated in the presence of hepatic amyloidosis. Rarely, patients present with spontaneous splenic rupture. Acquired deficiency of coagulation factor X is specific to AL and can be associated with clinically severe haemorrhage. Levels of coagulation factor X improve with effective therapy because the cause of low levels of circulating factor X is binding of factor X to the amyloid fibrils.
The peripheral neuropathy associated with amyloidosis begins in the lower extremities, is symmetrical, and is generally sensory or mixed sensorimotor. When a monoclonal protein is recognized, frequent diagnoses are chronic inflammatory demyelinating polyneuropathy and neuropathy associated with monoclonal gammopathy of undetermined significance because amyloidosis has not been considered in the differential diagnosis. Associated autonomic neuropathy occurs in approximately 4% of patients and can be characterized by orthostatic hypotension, which may be misattributed to cardiac failure. Autonomic dysmotility of the bowel is a common associated finding. It can be upper intestinal, leading to pseudo-obstruction and recurrent emesis, or lower intestinal, characterized by alternating obstipation and faecal incontinence. Diarrhoea caused by autonomic failure has been misdiagnosed as collagenous colitis when eosinophilic deposits are found in the bowel mucosa on haematoxylin-eosin staining in the absence of Congo red staining. Carpal tunnel syndrome occurs in approximately 13% of patients; it is not clinically distinguishable from the syndrome associated with repetitive stress injury but frequently fails to improve after surgical release. Rarely, interstitial lung disease, pseudoclaudication, periarticular deposits, and unexplained weight loss are presenting symptoms.
Systemic amyloidosis can be confused with early multiple myeloma. Patients who present with vague symptoms of fatigue and edema are found to have a monoclonal protein in the urine, and a bone marrow biopsy specimen shows a clonal plasmacytosis with a median of 5% plasma cells in the bone marrow; however, a quarter of patients have more than 10% plasma cells in the bone marrow, a finding that qualifies as a diagnosis of multiple myeloma. These patients are often considered to have atypical multiple myeloma when the underlying amyloid syndrome is undetected. In these patients, a misdiagnosis of myeloma kidney or demyelinating neuropathy is made when an adequate diagnostic evaluation to exclude amyloidosis has not been performed.
In a patient with nondiabetic proteinuria, cardiomyopathy without ischemic risk factors, unexplained hepatomegaly, peripheral or autonomic neuropathy, or carpal tunnel syndrome, amyloidosis is not the most likely cause. The disorder occurs in only 8 per million persons per year, and routine biopsy is not appropriate whenever consistent symptoms are found. The classic physical finding of periorbital purpura occurs in only 10% of patients, is often limited to petechial eruptions over the eyelids, and is easily overlooked. Enlargement of the tongue occurs in 10 to 15% of patients; therefore, although it is specific, it is not sensitive for the diagnosis. Amyloidosis in patients with enlarged tongues may be unrecognized, or these patients may be evaluated for acromegaly or undergo unnecessary tongue biopsies because of the suspicion of squamous cell cancer. If biopsy is not an appropriate screening technique, what algorithm should be used to recognize AL?
By definition, amyloidosis is a plasma cell dyscrasia; therefore, virtually all patients have a detectable immunoglobulin abnormality by immunofixation of the serum or urine, or they have abnormal results on a serum immunoglobulin free light chain assay. When a patient presents with a compatible clinical syndrome, these diagnostic studies should be completed before invasive diagnostic studies are performed. Simple electrophoresis without immunofixation is inadequate because the monoclonal proteins are quantitatively very small in most patients and will not cause a detectable peak on serum protein electrophoresis. When these three diagnostic studies are used in combination, the sensitivity is 100%. If a monoclonal protein is detected, further investigations for amyloid should proceed, as described later. If a monoclonal protein is not found, three possibilities exist: (1) the patient does not have amyloidosis; (2) if the patient is known to have amyloidosis, it may be localized rather than systemic; or (3) if the patient is known to have systemic amyloidosis, it may be the senile systemic or familial type rather than the light chain type.
In view of the grave prognosis associated with AL, the diagnosis must be confirmed by biopsy (with Congo red staining) in all cases. Although it is reasonable to biopsy the kidney when proteinuria is the presenting symptom, the heart when cardiomyopathy is recognized, the liver when there is hepatomegaly and increased alkaline phosphatase, or the nerve when there is a sensorimotor functional loss, these invasive and occasionally risky procedures are not required. Subcutaneous fat aspiration is an outpatient procedure that has a 24-hour turnaround time and recognizes amyloid deposits in 70% of patients. Bone marrow is a second convenient biopsy site, and this test is often required to exclude the possibility of associated multiple myeloma. Bone marrow biopsy is positive in 50% of patients. When both subcutaneous fat aspiration and bone marrow biopsy are done, amyloid is detected in 83% of patients. The remaining patients should have biopsy of the appropriate organ.
Once amyloid deposits are detected in tissues, further diagnostic evaluation is required. The presence of a monoclonal protein in the serum or urine and the presence of congophilic deposits in tissue do not verify that amyloidosis is light chain in origin. Further diagnostic studies are essential to classify the type of amyloid before therapy is initiated. Immunohistochemical studies on the tissue may be useful, but misfolding of the amyloid light chain often prevents epitopes from being recognized by commercial antisera; thus, false-negative results are common. Mass spectrometric analysis of the amyloid deposit can be done on paraffin-embedded tissue and validates the type of amyloid by direct amino acid sequencing, leaving no question about the origin of the amyloid protein as an immunoglobulin light chain. The incidence of monoclonal gammopathies in the elderly ranges from 3 to 5%. Therefore, that fraction of patients with senile systemic, localized, and familial amyloidosis could be expected to have an associated monoclonal gammopathy, which would be misleading. Mass spectrometric analysis is feasible on subcutaneous fat tissue.
Amyloidosis was previously thought to be untreatable and invariably fatal. With current therapy, response rates of about 70% regularly occur, and the median duration of survival is reportedly upward of 5 years. Agents to reverse the misfolding of the protein and render it soluble would be ideal, but they are not available. The source of the immunoglobulin light chain is the clonal plasma cell population in the bone marrow. All known therapies are directed at destruction of the plasma cell clone.
The two treatment choices are generally traditional-dose chemotherapy and high-dose chemotherapy with autologous stem cell transplantation. Most patients are not candidates for high-dose therapy because of age, advanced cardiac dysfunction, or renal insufficiency. High-dose melphalan is a feasible approach in selected patients with cardiac AL and is associated with a high rate of hematologic and organ responses that lead to prolonged survival. Current therapies include combinations of melphalan, cyclophosphamide, dexamethasone, bortezomib, and lenalidomide. Treatment with a combination of bortezomib (1.5 mg/m 2 weekly or 1.3 mg/m 2 on days 1, 4, 8, and 11 every 28 days), cyclophosphamide (300 mg/m 2 orally weekly), and dexamethasone (40 mg weekly) has produced rapid and complete hematologic responses in the majority of patients with AL with few side effects. Effective therapy has been associated with resolution of nephrotic syndrome, cardiac failure, and hepatomegaly. Imaging has shown amyloid deposits to regress after the suppression of light chain synthesis.
A systematic review and meta-analysis indicated that autologous hematopoietic stem cell transplantation does not appear to be superior to conventional chemotherapy in improving overall survival in patients with AL amyloidosis, although the quality of evidence was deemed low.
The serum immunoglobulin free light chain assay has been cited as a useful screening test for patients with a compatible clinical syndrome. This assay is also used to measure the therapeutic effect of intervention because the light chain level is quantifiable and reproducible. On the basis of current hematologic response criteria, successful therapy is characterized by a 50% reduction in the abnormal free light chain level. Because the tissue toxicity associated with amyloid is related to the deposition of small amounts of light chain, it is unclear whether a successful outcome requires complete eradication of the light chain product. Studies have shown that patients achieving complete normalization of the free light chain have a better outcome, but it is uncertain whether patients who do not achieve this level of response should be subjected to more intensive treatment in an effort to remove this pathogenic amyloid serum precursor.
The outcome of patients with AL depends on the extent of cardiac involvement. With the advent of routine haemodialysis for this population, death due to renal failure is uncommon. The greater the involvement of the heart, the shorter a patient’s survival. Echocardiography provides useful information about the ejection fraction, the thickness of the ventricular septum and left ventricular free wall, and the strain percentage (the rate at which wall shortening occurs). Doppler echocardiography allows quantitative measurements of diastolic function and reflects the slowing of blood flow into the ventricular chamber as the noncompliant left ventricle fills. This “stiffness,” measured by the deceleration time, provides useful information and correlates well with survival.
Cardiac biomarkers are extremely sensitive measures of myocardial function, are reproducible, and can be used not only for prognosis but also to follow cardiac response after effective therapy. The serum troponin value is a powerful predictor of survival in patients with amyloidosis, and the N-terminal pro–brain natriuretic peptide value predicts survival after a diagnosis of amyloidosis. A staging system has been developed with these two cardiac biomarkers and the difference between involved and uninvolved free light chain levels to accurately predict survival.
Localized amyloidosis can be confused with systemic amyloidosis, but it has a much better prognosis. Localized AL amyloidosis represents a true plasma cell neoplasm and not a pseudotumor. However, patients with localized amyloidosis generally do not require systemic therapy; management can be supportive or localized to the deposition. The location of the amyloid deposits can be a clue to the localized nature. Typical sites for localized amyloid deposition include the ureter, bladder, urethra, and prostate. Therapy entails cystoscopic resection or intravesical instillation of dimethyl sulfoxide. Most forms of cutaneous amyloidosis are localized, although nodular cutaneous amyloidosis has occurred in systemic AL. Tracheobronchial and laryngeal amyloidosis and nodular pulmonary amyloidosis are localized, are not associated with a plasma cell dyscrasia, and generally require only local therapy. Nodular pulmonary amyloidosis is often diagnosed after thoracotomy for a presumed malignant pulmonary nodule. Most cases of laryngeal amyloidosis are found when the patient presents to an otorhinolaryngologist with hoarseness and amyloid deposits are found on endoscopic biopsy. Patients with localized amyloidosis do not have a demonstrable monoclonal protein in the serum or urine and have a normal free light chain ratio. The localized amyloidosis found in Alzheimer disease is chemically unrelated to AL, and AL patients have no increased risk of dementia.
Senile systemic amyloidosis results from the deposition of a normal serum protein, transthyretin (TTR), in the myocardium. It has a much better prognosis than cardiac AL and generally necessitates endomyocardial biopsy for diagnosis; most patients are older than 70 years. When a monoclonal protein is present, it is incidental, and confirmation of type generally requires analysis of the amyloid-laden tissues. Therapy is supportive. The clinical presentation of senile systemic amyloidosis is not distinguishable from that of cardiac AL.
AF is uncommon in the United States and represents only 3% of cases of systemic amyloidosis. Patients present with the full clinical spectrum associated with amyloidosis, including cardiomyopathy, peripheral neuropathy, and proteinuria. Patients do not have a monoclonal protein because the deposited precursor is a mutant form of TTR, fibrinogen, lysozyme, or apolipoprotein A. Diflunisal (250 mg twice daily) can slow the rate of progression of the AF associated polyneuropathy. Selected patients with AF with polyneuropathy have benefited from liver transplantation because this disease is characterized by systemic accumulation of polymerized TTR in the peripheral nerves and systemic organs and liver transplantation stops the major production of amyloidogenic TTR. In one hospital, the estimated probability of 10-year survival in patients with familial amyloid polyneuropathy was 100% after liver transplantation compared with 56% for the nontransplantation group, with the survival curves diverging at 6 years.
One important form of AF in the United States is associated with an allele of the normal serum protein TTR in which isoleucine is substituted for valine at position 122 (TTR Val-122-Ile). The prevalence of this mutation in blacks in the United States is as high as 3.9%. Heterozygous inheritance of this mutant TTR is associated with late-onset cardiomyopathy in this population. Wall thickening is found on echocardiography. Heart failure is often mild at onset. The prognosis is far better than that of cardiac AL, and its recognition has important implications for genetic counselling.
Systemic AA is the rarest form in Western countries. Previously, it was a consequence of uncontrolled sustained inflammation, usually infectious, and causes included tuberculosis and osteomyelitis. Cystic fibrosis, bronchiectasis, decubitus ulcers, and skin abscesses related to subcutaneous injection of illicit drugs are modern-day infectious causes. Today it occurs primarily in patients with difficult-to-control inflammatory syndromes, including Crohn’s disease, juvenile arthritis, and ankylosing spondylitis. Organ damage results from the extracellular deposition of proteolytic fragments of the acute phase reactant serum amyloid A (SAA) as amyloid fibrils. However, because only a minority of patients with chronic inflammatory disorders actually develop this complication, disease-modifying factors must be also operative. The best characterized of these is the SAA1 genotype. There has been a recent decline in numbers of patients presenting with AA amyloidosis due to rheumatic diseases, at least in part due to the use of disease-modifying antirheumatic therapy.
The large majority of these patients present with proteinuria, nephrotic syndrome, or renal dysfunction. Diarrhoea related to intestinal involvement (22%) and thyromegaly (9%) also occur.
Suppression of the inflammatory process results in regression of tissue amyloid deposits. Early diagnosis and rapid control of the underlying inflammatory disease are critical to prevent irreversible organ damage and to improve survival of patients with AA amyloidosis. Therefore, monitoring of patients with chronic, active inflammatory disease by serial testing of SAA, C-reactive protein, microalbuminemia, proteinuria, and other indicators of amyloid development, as well as possibly determination of the SAA1 genotype, can guide approach to management. Anti– tumour necrosis factor-α agents have markedly reduced the incidence of AA from inflammatory arthritis. There are familial forms of AA associated with familial periodic fever syndromes, the most common being familial Mediterranean fever due to mutations in the tumour necrosis factor receptor. Interleukin-1 inhibitors (anakinra) have been used successfully in these inherited periodic fever syndromes.