Primary Systemic Amyloidosis

Primary Systemic Amyloidosis

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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.

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.

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

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]

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. [10]

Primary systemic amyloidosis is a disease of adulthood. In reported cases, the mean patient age of onset is 65 years.

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]

Hayman SR, Bailey RJ, Jalal SM, et al. Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis. Blood. 2001 Oct 1. 98(7):2266-8. [Medline].

Divry P, Florkin M, Firket J. Sur les proprietes otiques de l’amiloide. C R Soc Biol (Paris). 1927. 97:1808-10.

Cohen AS, Calkins E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature. 1959 Apr 25. 183(4669):1202-3. [Medline].

Murtagh B, Hammill SC, Gertz MA, Kyle RA, Tajik AJ, Grogan M. Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement. Am J Cardiol. 2005 Feb 15. 95(4):535-7. [Medline].

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Silverstein SR. Primary, systemic amyloidosis and the dermatologist: where classic skin lesions may provide the clue for early diagnosis. Dermatol Online J. 2005. 11(1):5. [Medline].

McCormick RS, Sloan P, Farr D, Carrozzo M. Oral puprura as the first manifestation of primary systemic amyloidosos. Br J Oral Maxillofac Surg. 2015 Dec 17. [Medline].

Iwahashi N, Tame E, Nagasaka T, Furuta M, Nagashima H, Nimura Y. Massive hemorrhage and pseudo-obstruction of the small intestine caused by primary AL amyloidosis associated with gastric cancer: report of a case. Surg Today. 2004. 34(10):871-4. [Medline].

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Buss SJ, Emami M, Mereles D, Korosoglou G, Kristen AV, Voss A, et al. Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers. J Am Coll Cardiol. 2012 Sep 18. 60(12):1067-76. [Medline].

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Moura CG, Moura TG, Duraes AR, Souza SP. Exuberant macroglossia in a patient with primary systemic amyloidosis. Clin Exp Rheumatol. 2005 May-Jun. 23(3):428. [Medline].

Xavier SD, Bussoloti IF, Muller H. Macroglossia secondary to systemic amyloidosis: case report and literature review. Ear Nose Throat J. 2005 Jun. 84(6):358-61. [Medline].

Summers EM, Kendrick CG. Primary localized cutaneous nodular amyloidosis and CREST syndrome: a case report and review of the literature. Cutis. 2008 Jul. 82(1):55-9. [Medline].

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Emmungil H, Kalfa M, Basarik B, Kahraman H, Tanhan F, Yaman B, et al. Primary systemic Al amyloidosis presenting as temporal arteritis. Case Rep Rheumatol. 2014. 2014:549641. [Medline]. [Full Text].

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Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore). 2008 Mar. 87(2):99-109. [Medline].

Lee JH, Lee GY, Kim SJ, Kim KH, Jeon ES, Lee KH, et al. Imaging Findings and Literature Review of (18)F-FDG PET/CT in Primary Systemic AL Amyloidosis. Nucl Med Mol Imaging. 2015 Sep. 49(3):[Medline].

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Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24. 336(17):1202-7. [Medline].

Shimojima Y, Matsuda M, Ishii W, et al. High-dose melphalan followed by autologous stem cell support in primary systemic AL amyloidosis with multiple organ involvement. Intern Med. 2005 May. 44(5):484-9. [Medline].

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Judit H Nyirady, MD, MBA Adjunct Assistant Professor, Department of Dermatology, Rutgers New Jersey Medical School

Judit H Nyirady, MD, MBA is a member of the following medical societies: American Academy of Dermatology, European Academy of Dermatology and Venereology, Women’s Dermatologic Society

Disclosure: Receiving salary from LEO Pharma Inc. for employment. for: LEO Pharma Inc.

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for MOHS Surgery, Association of Military Dermatologists, Phi Beta Kappa

Disclosure: Nothing to disclose.

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Takeji Nishikawa, MD Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc

Disclosure: Nothing to disclose.

Primary Systemic Amyloidosis

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