Primary Systemic Amyloidosis 

Updated: Aug 05, 2019
Author: Judit H Nyirady, MD, MBA; Chief Editor: Dirk M Elston, MD 

Overview

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] 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.[5] The most characteristic skin lesions consist of papules, nodules, and plaques that are waxy, smooth, and shiny.[6] Scalp involvement may be evident with hair loss. Mucocutaneous changes in the oral cavity include localized rubbery papules, petechiae, and ecchymoses/purpura[7] . 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,[8] 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.[9]

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.[10]

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.[11]

In another trial, Kyle and Greipp reported the effectiveness of combined melphalan and prednisone therapy compared with placebo therapy.[10] 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.[12]  More recently, targeted therapy including daratumumab has been investigated.[13]

 

Presentation

History

The symptoms of a patient with primary systemic amyloidosis (PSA) are rarely helpful in making the diagnosis because they are often too nonspecific. Therefore, the diagnosis is often delayed.

Presenting symptoms include the following:

  • Fatigue

  • Weight loss

  • Paresthesias

  • Hoarseness

  • Edema

Classically, patients present with symptoms of the following:

  • Carpal tunnel syndrome

  • Macroglossia

  • Mucocutaneous lesions

  • Hepatomegaly

  • Edema

The organs most commonly involved are the kidneys or heart, either individually or together. The patients' symptoms reflect the organ or organs most prominently involved.

Physical Examination

Clinically evident mucocutaneous involvement occurs in 30-40% of patients with primary systemic amyloidosis, and it provides 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). Purpuric lesions are found in flexural regions such as the nasolabial folds, neck, and axillae.

At times, bullae form; these may be hemorrhagic.

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.

Diffuse infiltrates may resemble infiltrates of scleroderma or myxedema.

Scalp involvement may appear as diffuse or patchy alopecia.[14]

Dystrophic nail changes include brittleness, crumbling, and subungual striation.

The tongue may be infiltrated, resulting in macroglossia. Macroglossia is a classic feature of primary systemic amyloidosis. The tongue may extrude through gaps between the teeth to produce unique irregular indentations. The presence of amyloid in the oral cavity is often revealed by localized, soft, elastic papules.[15, 16]

Amyloid deposition in the smooth and striated muscles, connective tissue, blood vessel walls, and peripheral nerves may result in myocardial insufficiency, which is the most common cause of death in this fatal disease.

Cardiac infiltration may cause angina, infarction, arrhythmias, or orthostatic hypotension.

Blood vessel infiltration may lead to claudication of the legs or jaw.

Renal amyloidosis usually manifests as proteinuria, often resulting in nephrotic syndrome.

Edema is frequently found and may be the result of cardiac failure or nephrotic syndrome.

Amyloid infiltration of the gastrointestinal tract may result in hemorrhage or malabsorption. Gut bleeding may also be fatal.

Hepatomegaly occurs in about 50% of patients with primary systemic amyloidosis, but splenomegaly is present in less than 10% of patients.

Autonomic and sensory neuropathies are relatively common features. Autonomic neuropathy may result in symptomatic postural hypotension, impotence, and disturbances in gastrointestinal motility.

Summers and Kendrick reported and association with CREST syndrome (ie, calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia syndrome).[17]

Villa et al reported on amyloid goiter.[18]

Complications

The presence of diffuse skin infiltrates and the loss of scalp hair can be distressing.

Macroglossia may be associated with painful dysphagia.

Cardiac involvement may cause angina, infarction, arrhythmias, or orthostatic hypotension.[19, 20]

Congestive heart failure or arrhythmias account for death in about 40% of the cases of primary systemic amyloidosis.

Blood vessel infiltration may lead to claudication of the legs or jaw. A case of temporal arteritis also has been described.[21]

Amyloid infiltration of the gastrointestinal tract may result in hemorrhage that can cause malabsorption or even death.[22]

 

DDx

Diagnostic Considerations

Terrier et al reported on immunoglobulin M – related amyloidosis, which is a rare and little known complication of monoclonal immunoglobulin M – associated disorders.[23]

Differential Diagnoses

 

Workup

Laboratory Studies

In a review of 132 primary systemic amyloidosis cases, Kyle and Bayrd reported that laboratory studies revealed anemia in less than 50% of the cases.[9] The white cell count was usually within the reference range, and the erythrocyte sedimentation rate was higher than 50 mm/h in one half of the cases. Hepatic function was abnormal, and the serum creatinine level was increased in 50% of patients. Proteinuria was present in more than 90% of the cases.

Conventional urine heat testing and electrophoresis of serum and urine samples may fail to demonstrate small quantities of monoclonal paraprotein or Bence-Jones protein. Immunoelectrophoresis of serum and concentrated urine samples is essential.

Imaging Studies

Echocardiography is valuable in the evaluation of amyloid heart disease. It usually reveals a concentrically thickened left ventricle and often a thickened right ventricle, with a normal-to-small cavity.

Doppler studies are useful and may show abnormal relaxation early in the course of the disease. Advanced involvement is characterized by restrictive hemodynamics.

18F-Fluorodeoxyglucose positron-emission tomography has been used in primary systemic amyloidosis evaluation.[24]

Procedures

Biopsy of a cutaneous lesion, if present, has the advantage of safety and a high diagnostic yield.

Biopsy results in clinically normal skin may be positive in as many as 50% of cases of primary systemic amyloidosis.

Findings from abdominal fat aspiration are positive in almost 80% of patients.

Rectal biopsy reveals positive findings in about 80% of patients.

If specimens from the biopsy sites are negative for amyloid, tissue should be obtained from an organ or area with suspected involvement, such as the kidney, liver, heart, or sural nerve.[25]

Histologic Findings

The best way to identify amyloid is to stain paraffin-embedded sections with alkaline Congo red and to examine them with polarized light to elicit a green fluorescence. Routine hematoxylin-eosin staining may show a homogenous, faintly eosinophilic mass if enough amyloid is present. See the image below.

Amorphous eosinophilic interstitial amyloid observ Amorphous eosinophilic interstitial amyloid observed on a renal biopsy.

Analysis of a skin biopsy specimen of a papule reveals an amorphous or fissured eosinophilic mass in the papillary dermis with associated thinning or obliteration of the rete ridges. Nodules and plaques may demonstrate diffuse amyloid deposition in the reticular dermis or subcutis. Amyloid depositions are usually not associated with an inflammatory infiltrate.

The appearance of amyloid infiltration of the blood vessel walls, pilosebaceous units, arrector pili muscles, and lamina propria of sweat glands and infiltration around individual fat cells in the subcutis (known as amyloid rings) are characteristic findings. Amyloid may be deposited in the nail bed of dystrophic nails.

The finding of light chain–restricted plasma cells with amyloid may be a manifestation of myeloma or a marginal cell lymphoma. Clinical correlation is required.[26]

 

Treatment

Medical Care

The treatment of primary systemic amyloidosis (PSA) is directed toward the affected organ and the specific type of the disease. In studies of different regimens of intermittent oral melphalan and prednisone, Skinner et al and Kyle et al reported that the response rates were low, with an increased survival from a median of approximately 7-9 months in patients who did not receive chemotherapy to approximately 12-18 months in those receiving chemotherapy.[11, 27]

Shimojima et al reported a patient with primary systemic amyloidosis who achieved partial hematological response after 2 courses of the VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone) chemotherapy regimen and subsequent high-dose melphalan followed by autologous peripheral blood stem cell transplantation despite involvement of multiple organs, including the heart.[28] When amyloidosis-related dysfunction is seen in multiple organs, intensive chemotherapy might be a possible therapeutic option, although several modifications in the regimen and careful management are necessary.

The nephrotic syndrome requires supportive therapy and diuretics, and renal failure can be successfully treated with dialysis.

Congestive heart failure may respond to diuretics, but larger doses are often required as the disease progresses. The use of calcium channel blockers, beta-blockers, and digoxin are contraindicated in cardiac amyloidosis, because they may cause toxicity at therapeutic levels.

Gastrointestinal involvement and neuropathy are treated symptomatically.

 

Medication

Medication Summary

The treatment of primary systemic amyloidosis is often unsatisfactory. No reliable method for the accurate assessment of the total amount of amyloid in the body exists. Investigations are limited to the evaluation of organ function and the measurement of monoclonal protein levels in the serum and urine.

The similarity between primary systemic amyloidosis and multiple myeloma suggests that chemotherapy may be useful. Using different regimens of intermittent oral melphalan and prednisone, 2 groups of investigators[11, 27] confirmed the effectiveness of this therapy compared with no therapy or therapy with colchicine alone. However, the response rate was low, with an increased survival from a median of approximately 7-9 months in patients who did not receive chemotherapy to approximately 12-18 months in those receiving chemotherapy.

In another trial, Kyle and Greipp reported the effectiveness of combined melphalan and prednisone therapy compared with placebo therapy.[29] Although the nephrotic syndrome improved in a number of individuals receiving the active medications, overall survival rates for the active and placebo groups were not substantially different.

Colchicine has also been used in the treatment of primary systemic amyloidosis. Colchicine may inhibit amyloid deposition by blocking the formation of amyloid-enhancing factors, and it also inhibits the secretion of amyloid from hepatocytes.

Based on encouraging results in myeloma patients, Dispenzieri et al reported results of a clinical trial of lenalidomide therapy with or without dexamethasone in patients with primary systemic amyloidosis.[30] As a single agent, lenalidomide had modest activity in primary systemic amyloidosis. This activity was significantly enhanced when lenalidomide was used in conjunction with dexamethasone.

Immunosuppressants

Class Summary

These agents inhibit key factors in the immune system that are responsible for inflammatory responses.

Prednisone (Deltasone, Orasone, Meticorten)

Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dexamethasone (Decadron)

Dexamethasone has many pharmacologic benefits but also significant adverse effects. It stabilizes cell and lysosomal membranes, increases surfactant synthesis, increases serum vitamin A concentration, and inhibits prostaglandin and proinflammatory cytokines (eg, TNF-alpha, IL-6, IL-2, and IFN-gamma). The inhibition of chemotactic factors and factors that increase capillary permeability inhibits recruitment of inflammatory cells into affected areas. Dexamethasone suppresses lymphocyte proliferation through direct cytolysis and inhibits mitosis. It breaks down granulocyte aggregates and improves pulmonary microcirculation. It is an important chemotherapeutic agent in the treatment of ALL. It is used in induction and reinduction therapy and given as intermittent pulses during continuation therapy.

Adverse effects are hyperglycemia, hypertension, weight loss, GI bleeding or perforation synthesis, cerebral palsy, adrenal suppression, and death. Most of the adverse effects of corticosteroids are dose or duration dependent.

Dexamethasone is readily absorbed via the GI tract and metabolized in the liver. Inactive metabolites are excreted via the kidneys. It lacks the salt-retaining property of hydrocortisone.

Patients can be switched from an intravenous to oral regimen in a 1:1 ratio.

Antineoplastic agents

Class Summary

These agents inhibit cell growth and proliferation.

Melphalan (Alkeran)

Melphalan inhibits mitosis by cross-linking DNA strands.

Uricosuric agents

Class Summary

These agents may inhibit the events involved in the inflammatory response associated with the disease.

Colchicine

Colchicine decreases leukocyte motility and phagocytosis in inflammatory responses.

Immunomodulators

Lenalidomide (Revlimid)

Lenalidomide is structurally similar to thalidomide. It elicits immunomodulatory and antiangiogenic properties. It inhibits proinflammatory cytokine secretion and increases anti-inflammatory cytokines from peripheral blood mononuclear cells.

 

Questions & Answers

Overview

What is primary systemic amyloidosis (PSA)?

What is the pathophysiology of primary systemic amyloidosis (PSA)?

What causes primary systemic amyloidosis (PSA)?

What is the prevalence of primary systemic amyloidosis (PSA) in the US?

What are the racial predilections of primary systemic amyloidosis (PSA)?

What are the sexual predilections of primary systemic amyloidosis (PSA)?

Which age group has the highest prevalence of primary systemic amyloidosis (PSA)?

What is the prognosis of primary systemic amyloidosis (PSA)?

Presentation

Which clinical history findings are characteristic in primary systemic amyloidosis (PSA)?

What are the signs and symptoms of primary systemic amyloidosis (PSA)?

Which physical findings are characteristic of primary systemic amyloidosis (PSA)?

What are the possible complications of primary systemic amyloidosis (PSA)?

DDX

Which conditions are included in the differential diagnoses of primary systemic amyloidosis (PSA)?

What are the differential diagnoses for Primary Systemic Amyloidosis?

Workup

What is the role of lab tests in the workup of primary systemic amyloidosis (PSA)?

What is the role of imaging studies in the workup of primary systemic amyloidosis (PSA)?

What is the role of biopsy in the workup of primary systemic amyloidosis (PSA)?

Which histologic findings are characteristic of primary systemic amyloidosis (PSA)?

Treatment

How is primary systemic amyloidosis (PSA) treated?

Medications

What is the role of medications in the treatment of primary systemic amyloidosis (PSA)?

Which medications in the drug class Immunomodulators are used in the treatment of Primary Systemic Amyloidosis?

Which medications in the drug class Uricosuric agents are used in the treatment of Primary Systemic Amyloidosis?

Which medications in the drug class Antineoplastic agents are used in the treatment of Primary Systemic Amyloidosis?

Which medications in the drug class Immunosuppressants are used in the treatment of Primary Systemic Amyloidosis?