Amyloidosis

Amyloidosis

Amyloidosis is a term for a group of diseases that are due to the extracellular deposition of insoluble polymeric protein fibrils in organs and tissues. Clinical manifestations depend on anatomic distribution and intensity of amyloid protein deposition and range from local deposition with little significance to involvement of virtually any organ system with severe pathophysiologic consequences.

CLASSIFICATION

Amyloid diseases are defined by the biochemical nature of the protein in the fibril deposits and are classified according to whether they are systemic or localized, acquired or inherited, and by their clinical patterns. The accepted nomenclature is AX where A indicates amyloidosis and X is the protein in the fibril.

  • AL (immunoglobulin light chains): Primary amyloidosis; most common form of systemic amyloidosis; arises from a clonal B cell disorder, usually multiple myeloma.
  • with almost any chronic inflammatory state [e.g., RA, SLE, familial Mediterranean fever (FMF), Crohn’s disease] or chronic infections.
  • AF (familial amyloidoses): number of different types that are dominantlytransmitted in association with a mutation that enhances protein misfolding and fibril formation; most commonly due to transthyretin.
  • Aβ2M: composed of β2 microglobulin; occurs in end-stage renal disease of long duration.
  • Localized or organ-limited amyloidoses: most common form is Aβ found in Alzheimer’s disease derived from abnormal proteolytic processing of the amyloid precursor protein.

CLINICAL MANIFESTATIONS

Clinical features are varied and depend entirely on biochemical nature of the fibril protein. Frequent sites of involvement:

  • Kidney—seen with AA and AL; proteinuria, nephrosis, azotemia.
  • Liver—occurs in AA, AL, and AF; hepatomegaly.
  • Skin—characteristic of AL but can be seen in AA; raised waxy papules.
  • Heart—common in AL and AF; CHF, cardiomegaly, arrhythmias.
  • GI—common in all types; GI obstruction or ulceration, hemorrhage, protein loss, diarrhea, macroglossia, disordered esophageal motility.
  • Joints—usually AL, frequently with myeloma; periarticular amyloid deposits, “shoulder pad sign”: firm amyloid deposits in soft tissue around the shoulder, symmetric arthritis of shoulders, wrists, knees, hands.
  • Nervous system—prominent in AF; peripheral neuropathy, postural hypotension, dementia. Carpal tunnel syndrome may occur in AL and A2M.
  • Respiratory—lower airways can be affected in AL; localized amyloid can cause obstruction along upper airways.

DIAGNOSIS

Diagnosis relies on the identification of fibrillar deposits in tissues and typing of the amyloid. Congo red staining of abdominal fat will demonstrate amyloid deposits in >80% of patients with systemic amyloid.

PROGNOSIS

Outcome is variable and depends on type of amyloidosis and organ involvement. Average survival of AL amyloid is ~12 months; prognosis is poor when associated with myeloma. Cardiac dysfunction associated with death in 75% of patients.

TREATMENT

For AL most effective treatment is high-dose intravenous melphalan followed by autologous stem-cell transplantation. Only 50% are eligible for such aggressive treatment and peritransplant mortality is higher than for other hematologic diseases because of impaired organ function. In patients who are not candidates for hematopoietic cell transplant, cyclic melphalan and glucocorticoids can decrease the plasma cell burden, but produces remission in only a few percent of patients with a minimal improvement in survival (median 2 years). Treatment of AA is directed towards controlling the underlying inflammatory condition. Colchicine (1–2 mg/d) may prevent acute attacks in FMF and thus may block amyloid deposition. One study found that eprodisate slowed the decline of renal function in AA, but had no significant effect on progression to end-stage renal disease or risk of death. In certain of the forms of AF, genetic counseling is important and liver transplantation is a successful form of therapy.

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