Definition

Amyloidosis is a term for a group of protein misfolding disorders characterized by the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. Clinical manifestations depend on anatomic distribution and intensity of amyloid protein deposition; they 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 their clinical patterns. The accepted nomenclature is AX where A indicates amyloidosis and X is the protein in the fibril (Table 108-1, HPIM-20).

• AL (immunoglobulin light chains): primary amyloidosis; most common form of systemic amyloidosis; arises from a clonal B-cell disorder, usually multiple myeloma.
• AA (serum amyloid A): secondary amyloidosis; can occur in association with almost any chronic inflammatory state (e.g., RA, SLE, periodic fever syndromes such as familial Mediterranean fever [FMF], Crohn's disease) or chronic infections.
• AF (familial amyloidoses): number of different types that are dominantly transmitted 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 Aβ₂M.
• 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 (Fig. 170-1. Algorithm for the Diagnosis of Amyloidosis and Determination of Type). Congo red staining of abdominal fat will demonstrate amyloid deposits in >80% of pts with systemic amyloid.

Prognosis

Outcome is variable and depends on type of amyloidosis and organ involvement. Average survival of AL amyloid without treatment is ∼1-2 years; cardiac involvement is the leading cause of death with a median survival of ∼6 months without treatment.