Amyloidosis is defined as the clinical syndrome associated with deposition of amyloid. Amyloid in tissue is defined by its tinctorial properties of a homogeneous, eosinophilic, hyaline material when viewed by hematoxylin and eosin staining.

• A heterogeneous group of disorders characterized by the extracellular deposition of protein in an abnormal fibrillar form.
• Amyloid stains specifically with Congo red, demonstrating a deep pink amorphous composition. Although Congo red staining is the sine qua non for the diagnosis of amyloid, many pathology laboratories prefer the use of sulfated Alcian blue or crystal violet for screening. A second requirement is that the Congo red–positive histologic finding must demonstrate apple-green birefringence when observed under polarized light.
• By electron microscopy, amyloid has been shown to be fibrillar in origin with an approximate diameter of 9.5 nm and as being linear nonbranching and comprised of protofilaments. The Congo red binding occurs because the protein misfolds from the physiologic configuration of the α-helix into a β-pleated sheet, which is directly responsible for its insolubility and resistance to proteolysis. Amyloid is highly resistant to solubilization unless it is subjected to the harshest denaturation conditions. This insolubility in physiologic solution likely contributes to amyloid's ability to disrupt normal organ function and leads to the clinical disease amyloidosis, the clinical syndrome associated with deposition of amyloid.
• AL amyloidosis represents 60% of all patients seen with amyloidosis.
• Hereditary amyloidosis now accounts for 10% of patients, localized amyloidosis 8.5% of patients, senile systemic amyloidosis 18% of patients, and secondary amyloidosis 2.5% of patients.
  • The localized forms generally do not require any systemic chemotherapy.

Clinical Manifestations

• The clinical features are caused by involvement of the heart in more than 50% of patients usually with a restrictive cardiomyopathy, kidneys in 30%, tongue, gastrointestinal tract, peripheral nerves and autonomic nervous system.
• The most common symptoms associated with amyloidosis are fatigue, anorexia, lower extremity edema (may be cardiac or renal), unexplained weight loss (often leading to search for occult malignancy), exertional dyspnea, orthostatic hypotension, paresthesias, peripheral neuropathy or carpal tunnel syndrome.

• The physical findings that are known to be associated with light-chain amyloidosis include macroglossia (15%) and periorbital purpura (12%).
  • Major indentations on the underside of the tongue from the patients' teeth and from the continuous pressure that the tongue exerts against their lower jaw.
  • Development of purpura simply by rubbing of the eyelids.
  • Highly specific when recognized.
  • Lack sensitivity because nearly 80% of patients with amyloidosis lack both of these physical features.

• Even when nephrotic range proteinuria is seen, amyloidosis, which is known to cause nephrotic syndrome in 10% of adults who are nondiabetic, is infrequently considered in the differential diagnosis, which would include minimal change glomerulopathy, as well as membranous and membranoproliferative glomerulopathy.

  • Nephrotic range proteinuria + a monoclonal protein or an abnormal free light-chain ratio:
    • Myeloma cast nephropathy: globulinuria
    • Immunoglobulin light-chain amyloidosis of the kidney: λ light chain, albuminuria
    • κ light-chain deposition disease of the kidney

• Hepatomegaly is seen in approximately 10% of patients with amyloidosis, but it is nonspecific, and imaging of the liver will show homogeneous enlargement without filling defects.

• Occasionally, patients will have widespread vascular amyloid that will result in claudication of the calf, buttock, upper extremities, and jaw.

• The rarest physical finding in amyloidosis is periarticular infiltration of the synovium in the upper extremities, leading to the “shoulder pad” sign. This causes a continuous, chronic, low-grade pain caused by the periarticular infiltration. Diagnosis in this setting requires arthrocentesis and the demonstration of Congo red–positive deposits in the synovial fluid.

Diagnosis

• Evidence of a monoclonal plasma cell proliferative disorder (serum monoclonal protein, abnormal free light chain ratio, or clonal plasma cells in the bone marrow)

  • The level of paraprotein may be very low and is not always detectable in serum or urine but the serum free light chain ratio is usually abnormal.

• Presence of an amyloid-related systemic syndrome  (e.g., renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement)

  • In patients who have renal, cardiac, hepatic, and peripheral nerve amyloid, biopsy of the affected organs has a very high sensitivity of demonstrating amyloid. However, these biopsies are not required if amyloid is considered in the differential diagnosis.

• Positive amyloid staining by Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy)

  • Subcutaneous fat aspirate in an experienced laboratory will demonstrate amyloid deposits in 75% of patients tested.
  • Staining of the bone marrow biopsy for amyloid deposition in blood vessels is positive in 50%.
  • It is possible to have a positive biopsy for amyloid and a coincidental monoclonal protein when the amyloid itself is unrelated to immunoglobulin light-chain amyloidosis.
  • Even when light-chain amyloidosis exists, the use of anti-κ and anti-λ antibodies frequently will not be able to identify the type of amyloid in tissue section.

• Evidence that amyloid is light-chain-related established by direct exmination of the amyloid using mass spectrometry-based proteomic analysis or immunoeletronmicroscopy