eMedicine Specialties > Dermatology > Internal Medicine

Amyloidosis, Primary Systemic

Author: Judit Nyirady, MD, MBA, Adjunct Assistant Professor, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Apr 29, 2009

Introduction

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.

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

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. 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,⁷ 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.

Frequency

United States

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.⁸

Mortality/Morbidity

• 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.⁹
• 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.

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.

Clinical

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

• 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.¹¹
• 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.^12,13
• 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).¹⁴
• Villa et al reported on amyloid goiter.¹⁵

Causes

Primary systemic amyloidosis is a plasma-cell dyscrasia characterized by an autonomous proliferation of plasma cells with an overproduction of a monoclonal Ig protein.

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