eMedicine Specialties > Rheumatology > Miscellaneous Inflammatory Arthritis

Amyloidosis, AA (Inflammatory): Differential Diagnoses & Workup

Author: Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Coauthor(s): Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine; Eisha Mubashir, MD, Fellow in Rheumatology, Department of Medicine, Fellow, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport; Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute
Contributor Information and Disclosures

Updated: Nov 21, 2008

Differential Diagnoses

Amyloidosis, Familial Renal
Amyloidosis, Immunoglobulin-Related
Glomerulonephritis, Membranous
Renal Vein Thrombosis

Workup

Laboratory Studies

  • The overwhelming factor in diagnosing amyloid A (AA) amyloidosis is considering the possibility that it is present. The development of proteinuria in any individual with chronic inflammatory disease or any of the associated conditions listed in Causes should prompt a search for tissue AA deposition, most commonly in the kidney.
  • No specific tests for AA amyloidosis exist.
    • While the SAA precursor is usually elevated, prolonged elevation does not necessarily indicate tissue deposition because many patients with inflammatory disease have very high levels of SAA without developing amyloidosis.
    • Serum immunoglobulins should be evaluated because the presence of a monoclonal serum or urine protein suggests AL amyloidosis as a more likely diagnosis.
    • Patients with AA amyloidosis tend to show polyclonal hypergammaglobulinemia, reflecting their underlying inflammatory condition.
  • Evaluate the parameters of renal function to monitor the course of the nephrotic syndrome or renal failure.
    • Occasionally, patients show renal tubular acidosis as an early manifestation of renal involvement.
    • Deterioration of a patient with the nephrotic syndrome may indicate progression of the amyloid renal disease, but consider the possibility of renal vein thrombosis because this complication can be observed in nephrotic syndrome due to any cause.
    • A serum creatinine level greater than 2 mg/dL and/or a serum albumin level less than 2.5 g/dL have been associated with diminished survival rates, including renal survival.

Imaging Studies

  • Avoid intravenous pyelography in patients with suspected amyloidosis because dye exposure has been associated with more frequent renal failure in individuals with substantial proteinuria.
  • Ultrasonography is useful in establishing renal size; however, kidneys may be large, small, or normal size in patients with renal amyloidosis.
  • CT scanning may be useful because technetium occasionally binds to soft-tissue amyloid deposits. This was originally reported as an incidental finding. However, CT scanning does not yield great sensitivity, and reports concerning the specificity of CT scanning have varied considerably. If results are positive, CT scanning can be used to monitor gross progression of the deposition in a given organ.
  • MRI may have a role in amyloidosis diagnosis in the future, but, currently, no formal studies have reported its use in a large series of patients.
  • Radiolabeled P-component gamma scanning has been used in centers in London and France to demonstrate the total body burden of amyloid and its disappearance after successful treatment of the primary disease. This test has been most useful in AA amyloidosis because the major sites of deposition, ie, liver, kidneys, spleen, and adrenal glands, are readily accessible to the imaging agent.

Other Tests

  • In the 10% of cases of AA amyloidosis in showing cardiac involvement, conventional parameters of cardiac dysfunction, measured using electrocardiography, echocardiography, and cardiac catheterization with endomyocardial biopsy, provide the appropriate diagnostic information and tissue for the demonstration of AA (or other amyloid) deposition in the myocardium or coronary vessels.

Procedures

  • Biopsy with Congo red staining and immunostaining: The tissue with the highest yield, particularly in the presence of proteinuria or renal failure, is the kidney. Technically adequate samples have a diagnostic yield close to 100%. Stain the tissue with an alkaline solution of Congo red, and examine it under polarized light, where positive (green) birefringence is detectable in the presence of amyloidosis of any type. The nature of the fibril precursor can be established by immunohistochemical staining with antibodies specific for the major amyloid precursors (AA, immunoglobulin L chains of k or l type, antitransthyretin). In AA amyloidosis, only the AA is positive. The amyloid nature of the deposit can by confirmed by staining with an antiserum specific for serum amyloid P-component (SAP).
  • If renal biopsy is deemed too risky for a specific patient or if amyloidosis without renal disease is suspected, 2 sites have been shown to be useful in obtaining tissue for histologic and immunochemical analysis. Subcutaneous fat aspiration is positive in approximately 60% of individuals with AA amyloidosis, except in the case of FMF, when it is rarely, if ever, positive.
  • Rectal biopsy is more useful than subcutaneous fat aspiration in AA amyloidosis. It has been found to produce positive results (assuming that submucosa is included in the biopsy specimen) in 80-85% of patients ultimately found to have tissue amyloid at a clinically relevant site. Samples from either the subcutaneous fat aspirate or the rectal biopsy can be stained as conventional tissue biopsies to determine the presence and nature of the amyloid precursor. Occasionally, patients have positive results on subcutaneous fat aspirates in the presence of a negative result on rectal biopsy, while others may have deposits in the rectal tissue and not in the aspirate. Use of both procedures may increase the yield to 90%. Abdominal subcutaneous fat biopsy results are not very sensitive in AA amyloidosis caused by FMF and in dialysis-related amyloidosis. The results are usually negative, probably because beta2-microglobulin does not accumulate in this tissue.
  • Series from individual centers have shown that the labial gland or gastric mucosal biopsies can also be high-yield procedures, but these have not been used widely for amyloidosis, and their general utility remains to be definitively established.
  • In the past, liver biopsy was a common procedure in the investigation of AA amyloidosis. Several reports of fatal liver rupture or bleeding, as well as the availability of sampling procedures with little or no morbidity and mortality, have resulted in its decreased use.
  • Once histological diagnosis of amyloidosis has been established, the amyloid type should be defined based on immunohistochemical analysis and genetic testing. Immunoelectron microscopy characterizes the amyloid deposits by co-localizing the specific proteins with the fibrils and can be performed on abdominal fat samples.

Histologic Findings

Infiltrated tissues show homogeneous eosinophilic staining with hematoxylin and eosin. The earliest deposits are usually vascular. In the kidney, early deposits may be mesangial, but, late in the course, entire glomeruli may be obliterated. Distinguishing these from glomerulosclerosis and from other causes is difficult prior to Congo red staining. Congo red binding by itself may be observed in other states, particularly in collagen-rich tissues, but the green birefringence is characteristic on examination with polarized light and the amyloid nature of the deposit can be demonstrated by observing the characteristic beta pleated sheet on electron microscopy. The nature of the precursor can be established with certainty using antisera specific for various amyloid precursors. In this case, staining with anti-AA serum is positive, as described above.

Staging

No formal staging system has been proposed for any of the amyloidoses.

More on Amyloidosis, AA (Inflammatory)

Overview: Amyloidosis, AA (Inflammatory)
Differential Diagnoses & Workup: Amyloidosis, AA (Inflammatory)
Treatment & Medication: Amyloidosis, AA (Inflammatory)
Follow-up: Amyloidosis, AA (Inflammatory)
References
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References

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Further Reading

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Keywords

amyloidosis, secondary amyloidosis, amyloid A amyloidosis, AA amyloidosis, inflammatory amyloidosis, systemic amyloidosis, inflammation-associated amyloidosis, tissue amyloid deposition, AA deposition, renal amyloidosis, amyloid renal disease, amyloid nephropathy, rheumatoid arthritis, RA, familial Mediterranean fever, FMF, serum amyloid A protein, SAA protein

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Contributor Information and Disclosures

Author

Richa Dhawan, MD, Faculty, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Science Center at Shreveport
Richa Dhawan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin, American College of Physicians-American Society of Internal Medicine, and American College of Rheumatology
Disclosure: Nothing to disclose.

Coauthor(s)

Mohammed Mubashir Ahmed, MD, Associate Professor, Department of Medicine, Division of Rheumatology, University of Toledo College of Medicine
Mohammed Mubashir Ahmed, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Federation for Medical Research
Disclosure: Nothing to disclose.

Eisha Mubashir, MD, Fellow in Rheumatology, Department of Medicine, Fellow, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport
Disclosure: Nothing to disclose.

Joel Buxbaum, MD, Professor, Department of Molecular and Experimental Medicine, The Scripps Research Institute
Joel Buxbaum, MD is a member of the following medical societies: American Society for Clinical Investigation, American Society of Human Genetics, and Association of American Physicians
Disclosure: Nothing to disclose.

Medical Editor

Robert E Wolf, MD, PhD, Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport
Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

 
 
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