Background
Systemic amyloidosis can be classified as follows: (1) primary systemic amyloidosis (PSA), usually with no evidence of preceding or coexisting disease, paraproteinemia, or plasma-cell dyscrasia; (2) amyloidosis associated with multiple myeloma; or (3) secondary systemic amyloidosis with evidence of coexisting previous chronic inflammatory or infectious conditions.
The current nomenclature refers to amyloidoses based on a capital A (for amyloid), with an abbreviation for the fibril protein following. Primary systemic amyloidosis is referred to as AL amyloidosis, with the A signifying amyloid and the L designating it as light-chain amyloidosis. Terms such as AL describe the protein (light chain), but do not necessarily describe the clinical phenotype.
Primary systemic amyloidosis involves mainly mesenchymal elements, and cutaneous findings are observed in 30-40% of patients. Secondary systemic amyloidosis does not involve the skin, whereas localized amyloidosis does.
Primary systemic amyloidosis involves the deposition of insoluble monoclonal immunoglobulin (Ig) light (L) chains or L-chain fragments in various tissues, including smooth and striated muscles, connective tissues, blood vessel walls, and peripheral nerves. [1] The amyloid of primary systemic amyloidosis is made by plasma cells in the bone marrow. These L-chains are secreted into the serum. Unlike the normal L-chain and the usual form seen in patients with myeloma, these L-chains are unique in that they undergo partial lysosomal proteolysis within macrophages, and they are extracellularly deposited as insoluble amyloid filaments attached to a polysaccharide. Sometimes, instead of an intact L-chain, this amyloid has the amino-terminal fragment of an L-chain.
In 1838, Mathias Schleiden (a German botanist) coined the term amyloid to describe the normal amylaceous constituent of plants. In 1854, Rudolf Virchow used the term amyloid. Virchow described its reaction with iodine and sulfuric acid, which, at the time, was a marker for starch; thus, the term amyloid or starchlike is used. Virchow adopted the term to describe abnormal extracellular material that is seen in the liver during autopsy.
Some 70 years after Virchow's description, Divry and associates recognized that the amyloid deposits showed apple-green birefringence when specimens stained with Congo red were viewed under polarized light. This observation remains the sine qua non of the diagnosis of amyloidosis. [2]
In 1959, with the use of electron microscopy, Cohen and Calkins first recognized that all forms of amyloidosis demonstrated a nonbranching fibrillar structure. Electron microscopy remains the most sensitive method for recognizing the disorder. [3]
Also see Amyloidosis.
Pathophysiology
The final pathway in the development of amyloidosis is the production of amyloid fibrils in the extracellular matrix. The process by which precursor proteins produce fibrils appears to be multifactorial and differs among the various types of amyloidosis.
The fibrils in primary systemic amyloidosis are composed of Ig L-chain material (protein amyloid L) consisting of intact L-chains, L-chain fragments (particularly the variable amino-terminal region), or both. Amyloid deposition occurs as a result of plasma-cell dyscrasia.
The diagnosis depends on the demonstration of amyloid deposits in tissue. The organs most commonly involved are the kidneys or heart, either individually or together. [4, 5] Autonomic and sensory neuropathies are relatively common features.
About 30-40% of patients with primary systemic amyloidosis have cutaneous findings. Mucocutaneous involvement provides early evidence of the existence of an underlying plasma-cell dyscrasia. Petechiae, purpura, and ecchymoses that occur spontaneously or after minor trauma are the most common skin signs and are found in about 15-20% of patients. [6] The most characteristic skin lesions consist of papules, nodules, and plaques that are waxy, smooth, and shiny. [7] Scalp involvement may be evident with hair loss. Mucocutaneous changes in the oral cavity include localized rubbery papules, petechiae, and ecchymoses/purpura [8] . Xerostomia may result from the infiltration of the salivary glands. Macroglossia is reported in 19% of patients with primary systemic amyloidosis.
Primary systemic amyloidosis accounts for 7% of nonhematological malignancies, [9] but few cases of gastric carcinoma in patients with primary amyloidosis have been described. Although acute pseudoobstruction is an uncommon clinical manifestation of amyloidosis, the coexistence of both gastrointestinal hemorrhage and pseudoobstruction of the small intestine should alert the clinician to a diagnosis of gastrointestinal amyloidosis.
Etiology
Primary systemic amyloidosis is a plasma-cell dyscrasia characterized by an autonomous proliferation of plasma cells with an overproduction of a monoclonal Ig protein.
Epidemiology
US frequency
Precisely defining the epidemiologic characteristics of amyloidosis is difficult because the disease is often undiagnosed or misdiagnosed. The age-adjusted incidence of primary systemic amyloidosis and secondary systemic amyloidosis is estimated to be 5.1-12.8 cases per million person-years, which means that approximately 1275-3200 new cases occur annually in the United States. In a large series of 236 cases of systemic amyloidosis, Kyle and Bayrd reported that 56% were primary cases and 26% were multiple myeloma cases. [10]
Race
No racial predilection is reported for the development of primary systemic amyloidosis.
Sex
No sexual predilection is reported for primary systemic amyloidosis; however, Kyle and Greipp reported a slight male dominance in a large series of 182 patients with primary systemic amyloidosis. [11]
Age
Primary systemic amyloidosis is a disease of adulthood. In reported cases, the mean patient age of onset is 65 years.
Prognosis
The prognosis of primary systemic amyloidosis is generally poor. Cardiac failure and renal failure are the major causes of death. The median survival in most reported cases is as long as 14.7 months. The prognosis depends on the response to therapy and the extent of disease. The presence of congestive heart failure is associated with a median survival of 7.7 months.
In the report by Skinner et al, the overall survival of all patients was 8.4 months from their entry into the study. In the group receiving only colchicine and the group treated with melphalan, prednisone, and colchicine, the survival was 6.7 and 12.2 months, respectively (P = .087). The cardiac subgroup of both treatment groups had poor survival, and the renal subgroup had the longest survival. [12]
In another trial, Kyle and Greipp reported the effectiveness of combined melphalan and prednisone therapy compared with placebo therapy. [11] The overall survival rates for the 2 groups were not substantially different, although the nephrotic syndrome improved in a number of individuals receiving the active medications.
In a prospective observational study involving 206 consecutive patients with biopsy-proven systemic light-chain amyloidosis, Buss et al found that reduced left ventricular longitudinal function independently predicted survival and offered incremental prognostic information beyond that offered by standard clinical and serological parameters. [13] More recently, targeted therapy including daratumumab has been investigated. [14]
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Amorphous eosinophilic interstitial amyloid observed on a renal biopsy.
