eMedicine Specialties > Rheumatology > Metabolic and Bone Disease

Amyloidosis, Transthyretin-Related: Differential Diagnoses & Workup

Author: Jefferson R Roberts, MD, Rheumatology Fellow, Walter Reed Army Medical Center, Washington, DC
Coauthor(s): Robert John Oglesby, MD, Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Contributor Information and Disclosures

Updated: Sep 15, 2009

Differential Diagnoses

Amyloidosis, AA (Inflammatory)
Amyloidosis, Beta2M (Dialysis-Related)
Amyloidosis, Familial Renal
Amyloidosis, Immunoglobulin-Related

Workup

Laboratory Studies

Nonspecific findings found in different types of amyloidosis include normochromic normocytic anemia, electrolyte abnormalities secondary to heart failure or malabsorption, and evidence of varying degrees of proteinuria and diminished glomerular filtration rate in patients with renal deposition.

• Biopsy with Congo red staining and with immunostaining
  • Amyloidosis (of all types) is diagnosed definitively based on demonstration of Congo red binding material in a biopsy specimen. For many years, rectal biopsy was the favored procedure when systemic amyloidosis was suspected. Now, the capillaries in subcutaneous fat are known to be involved often in ATTR and in some other types of systemic amyloidosis; therefore, subcutaneous fat aspiration often provides sufficient tissue for diagnosing amyloid, as well as for further studies such as immunostaining. On the other hand, biopsy of an organ with impaired function, such as the heart or gastrointestinal tract, has the advantage of definitively establishing a cause-and-effect relationship between organ dysfunction and amyloid deposition.
  • ATTR deposition in the peripheral nerves leads to axonal degeneration of the small nerve fibers, causing polyneuropathy. Diagnosis can often be made with sural nerve biopsy, although the deposits may be proximal to the sural nerve and therefore not found in biopsy samples.
  • Other potential biopsy sites include the myocardium, stomach, rectum, or other organ suspected of heavy involvement.
  • Amyloid should not be assumed to be of the TTR type based solely on the Congo red staining and clinical picture. After Congo red staining establishes a diagnosis of amyloidosis, the specific type of amyloidosis must be determined with immunostaining of a biopsy specimen using commercially available antiserum against TTR. Control antisera against other types of amyloid precursors, including immunoglobulin light chains and amyloid A protein, should also be performed to confirm staining specificity. Even patients known to carry a TTR variant should ideally have the diagnosis confirmed with immunostaining to rule out the possibility of a different type of amyloidosis.
  • Distinguishing between ATTR and AL cardiac amyloidosis on clinical grounds alone is particularly difficult. Without immunologic identification of the deposited protein, an incorrect diagnosis of ATTR in a patient with AL, or the reverse, could lead to ineffective or harmful treatment.
    
    

    

    Congo Red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light.

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    Congo Red staining of a cardiac biopsy specimen containing amyloid, viewed under polarized light.

Imaging Studies

• Radiolabeled P-component scanning
  • This test is available in a few European centers. Where it is available, radiolabeled P-component scanning is a very useful means of evaluating the total body burden of amyloid and is a sensitive noninvasive means of diagnosing amyloid in most organs. Serial studies are useful for monitoring the response to therapy in many settings.
  • One drawback is that P-component scanning is not useful for diagnosing or monitoring cardiac amyloid because the concentration of label in the intracardiac blood pool obscures the weaker signal from the labeled molecule bound to myocardial amyloid.
• Cardiac imaging
  • Cardiac deposition is, in many patients, the most serious complication of ATTR; thus, cardiac involvement usually should be assessed and monitored by imaging studies.
  • No noninvasive test is sufficiently sensitive or specific to make a definitive diagnosis of cardiac amyloidosis, although 2-dimensional echocardiography and electrocardiography, particularly when combined, can strongly suggest cardiac amyloidosis (of any type).
  • The most useful noninvasive diagnostic test for cardiac amyloidosis is echocardiography, which enables visualization of increased ventricular wall thickness, increased septal thickness, and an appearance of granular "sparkling." This finding is neither sensitive nor specific enough to be diagnostic but is highly suggestive when present. Amyloid deposits in the heart occur in the ventricular interstitium, leading to thickening of the ventricular walls and interventricular septum without an increase in the intracardiac volume. Evaluation of diastolic function by Doppler echocardiography reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration. The ejection fraction is preserved until late in disease. Other echocardiographic findings include valvular thickening, valvular insufficiency, and atrial enlargement. The combined use of electrocardiography plus echocardiography appears to be of the most diagnostic value.
  • Other cardiac imaging studies include computerized tomography scanning and nuclear scintigraphy.

Other Tests

• Electrocardiography: The classic finding on electrocardiography is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material. In some cases, loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy. Various arrhythmias are observed and can be life threatening.⁸
• Nerve conduction studies: In patients with amyloid neuropathy, serial nerve conduction studies can be useful for objectively monitoring the course of disease and for assessing response to treatment such as liver transplantation.¹²
• Genetic studies
  • Genetic studies to look for a TTR variant can be helpful in many patients with ATTR, particularly in younger patients not known to belong to a kindred carrying a defined TTR variant. These studies generally are not available through routine clinical laboratories.
  • One approach is to perform DNA-based testing, using the polymerase chain reaction (PCR), to look for known, common TTR variants. This approach is most useful if the likely TTR variant can be surmised based on the clinical history and genetic background of the patient. These studies are performed by PCR amplifying regions of the TTR gene followed by digestion with restriction enzymes.
  • If a TTR variant is suspected, but initial screening results for a few common known variants are negative, more comprehensive analysis for a TTR variant can be performed. Either the protein can be isolated from the serum and studied using methods such as electrospray ionization mass spectrometry (ESIMS) or the gene can be studied by PCR and such methods as single-strand conformation polymorphism analysis and/or direct sequencing.
  • Determination of whether a TTR variant is present is important because the treatment options for variant-sequence ATTR differ from those for normal-sequence ATTR. Information about a TTR variant also can be of use to other family members at risk.

Histologic Findings

Biopsy of an affected organ followed by routine hematoxylin and eosin staining reveals homogeneous interstitial eosinophilic material. Amyloid material stained with Congo red and viewed under polarized light appears bright green. Specific staining with antibodies against TTR proves the diagnosis of ATTR, as opposed to other types of amyloidosis that have similar appearance after hematoxylin and eosin or Congo red staining.

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