Primary Systemic Amyloidosis

Updated: Aug 11, 2023
  • Author: Judit H Nyirady, MD, MBA; Chief Editor: Dirk M Elston, MD  more...
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Practice Essentials

Systemic amyloidosis can be classified as follows: (1) primary systemic amyloidosis, 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. [1]

The current nomenclature refers to amyloidoses based on a capital A (for amyloid), followed by an abbreviation for the fibril protein. 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. For discussion of

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. [2]  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.

Other common types of amyloidosis involve amyloid A protein (AA amyloidosis) and amyloid transport protein transthyretin (ATTR amyloidosis). For discussion of those disorders, see AA (Inflammatory) Amyloidosis and Transthyretin-Related Amyloidosis.

Signs and symptoms

Clinical manifestations of systemic amyloidosis reflect the organ or organs most prominently involved, which is most commonly the kidneys or heart, either individually or together.

Presenting symptoms and signs include the following:

  • Fatigue
  • Weight loss
  • Paresthesias
  • Hoarseness
  • Edema

Classically, patients present with the following:

Clinically evident mucocutaneous involvement may provide an early clue to the existence of an underlying plasma-cell dyscrasia. Petechiae and ecchymoses are the most common skin findings, because of cutaneous blood vessel involvement. The face is most commonly affected; minor trauma sometimes precipitates eyelid and periorbital purpura (pinch purpura or raccoon eyes sign).

The most characteristic skin lesion in primary systemic amyloidosis consists of waxy papules, nodules, or plaques that may be evident in the eyelids, retroauricular region, neck, or inguinal and anogenital regions. Plaques may coalesce to form large tumefactive lesions.

Cardiac infiltration may cause angina, infarction, arrhythmias, or orthostatic hypotension. Renal amyloidosis usually manifests as proteinuria, often resulting in nephrotic syndrome.

See Presentation for more detail.


The workup for systemic (AL) amyloidosis includes the following [3] :

  • Serum protein electrophoresis with immunofixation (SPEI), to assess for clonal immunoglobulin production
  • Urine protein electrophoresis with immunofixation (UPEI), to assess for clonal light chain production
  • Serum free light chain (FLC) kappa-to-lambda ratio, to detect low-level clonal light chain production

The diagnosis is confirmed by Congo red and immunologic staining of a biopsy specimen from the abdominal fat pad or an affected organ (eg, endomyocardial biopsy for cardiac involvement, kidney biopsy for renal involvement). Staging is determined on the basis of cardiac biomarkers: N-terminal pro–B-type natriuretic peptide (NT-proBNP) or brain natriuretic peptide (BNP), troponin T or I, FLC ratio. [2]

See Workup for more detail.


Pharmacologic therapy is targeted against the abnormal plasma cell clone. Daratumumab plus hyaluronidase, in combination with cyclophosphamide, bortezomib, and dexamethasone is the current standard treatment regimen. Autologous stem cell transplantation is performed in eligible patients, especially those with an incomplete response to drug therapy. [4]

See Treatment  and Medication for more detail.

Also see Amyloidosis.



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. [5]

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. [6]




Primary systemic amyloidosis is a plasma-cell dyscrasia characterized by an autonomous proliferation of plasma cells with an overproduction of a monoclonal Ig protein. 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. [7, 8] 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. [9] The most characteristic skin lesions consist of papules, nodules, and plaques that are waxy, smooth, and shiny. [10] Scalp involvement may be evident with hair loss. Mucocutaneous changes in the oral cavity include localized rubbery papules, petechiae, and ecchymoses/purpura [11] . 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, [12] 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.




Precisely defining the epidemiologic characteristics of amyloidosis is difficult because the disease is often undiagnosed or misdiagnosed. A systematic review of the diagnosed incidence and prevalence of AL amyloidosis in 2018 for the United States, Europe, Canada, Brazil, Japan, South Korea, Taiwan, and Russia found an estimated 74,000 cases had been diagnosed in the preceding 20 years with a prevalence of 51 cases per million. The estimated annual incidence in 2018 ranged from 6.7 cases per million in Brazil to 14.3 cases per million in Japan. The US incidence was 9.9 cases per million. [13]   

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. [14]

Race-, sex-, and age-related demographics

Note the following:

  • No racial predilection is reported for the development of primary systemic amyloidosis.
  • 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. [15]
  • Primary systemic amyloidosis is a disease of adulthood. In reported cases, the mean patient age of onset is 65 years.


Theraperutic advances have markedly improved the prognosis for patients with systemic (AL) amyloidosis over the last two decades. With current treatment regimens, patients in all but the highest risk group have a median survival of >4 years and some groups have a median survival of >10 years12. However, median survival in stage 4 patients remains poor (around 6 months)

The prognosis in patients with AL amyloidosis depends on the extent of disease and the response to therapy. Cardiac involvement occurs in approximately 70% of patients with AL amyloidosis, and the severity of cardiac involvement is the primary driver of survival in these patients. Consequently, survival can be predicted through the measurement of cardiac biomarkers that are released into the circulation with cardiac involvement (ie, troponins I and T, brain natriuretic peptide [BNP], N-terminal pro-brain natriuretic peptide [NT-proBNP]). Using a staging system that includes cardiac biomarkers (see Workup/Staging), Kumar et al reported median overall survival duration and estimated 4-year survival rate by stage as follows [16] :

  • Stage I: Not reached; 73%
  • Stage II: 62.8 months; 52%
  • Stage III: 16.8 months; 31%
  • Stage IV: 5.8 months; 10%

Reduced abnormalities in cardic biomarker levels and free light chain ratios correlates with improved survival after 3 to 6 months of treatment. [17] Lilleness et al reported that cardiac response to treatment, as indicated by BNP measured before and at 6 months after treatment, provides survival information. Cardiac response and corresponding median overall survival (OS) was as follows:

  • Cardiac response (BNP decrease by ≥50 pg/mL and ≥30% change in BNP): OS not reached
  • Cardiac stability (BNP decrease by < 50 pg/mL and < 30% change in BNP): OS 9.2 years
  • Cardiac progression (≥50 pg/mL or ≥30% increase in BNP): OS 2.8 years