Perth Haematology :: Dr Steven Ward
Amyloidosis results from a sequence of changes in protein folding that leads to the deposition of insoluble amyloid fibrils, mainly in the extracellular spaces of organs and tissues. Depending upon the biochemical nature of the amyloid precursor protein, amyloid fibrils can be deposited locally or may involve virtually every organ system of the body. Amyloid fibril deposition may have no apparent clinical consequences or may be associated with severe disease. All amyloid fibrils share an identical secondary structure, the β-pleated sheet. All amyloid deposits contain the pentraxin serum amyloid P (SAP) and glycosaminoglycans. Abnormal protein folding and assembly can also result in protein deposition (e.g., in brain or kidney) that lacks the classic fibrillar morphology of amyloid and the presence of SAP.
The amyloidoses are classified according to the identity of the fibril-forming protein (See below). Systemic amyloidoses are neoplastic, inflammatory, genetic, or iatrogenic in origin, while localized amyloidoses or organ-limited amyloidoses are associated with aging and diabetes and occur in isolated organs without evidence of systemic involvement.
Despite their biochemical and clinical differences, the various amyloidoses share common pathophysiologic features:
Note: Proteins in italics are preliminary.
aADan comes from the same gene as ABri and has identical N-terminal sequence. It will be a matter of further discussion whether ADan should be included in the nomenclature as a separate protein (see text)
bTo be named.
Light Chain Amyloidosis (AL)
Amyloid A Amyloidosis (AA)
Clinical Features of Systemic Amyloidosis
Renal involvement may consist of mild proteinuria or frank nephrosis. The renal lesion is usually not reversible and in time leads to progressive renal failure and death. The prognosis does not appear to be related to the degree of the proteinuria. Treatment by peritoneal dialysis or hemodialysis or kidney transplantation improves the prognosis considerably. Hypertension is rare, except in long-standing amyloidosis.
Cardiac amyloidosis can present as intractable heart failure.
With respect to systemic amyloidoses, cardiac amyloidosis is common in primary (AL) and heredofamilial amyloidosis and very rare in the secondary (AA) form. In systemic amyloidosis, cardiac manifestations consist primarily of congestive failure and cardiomegaly (with or without murmurs) and a variety of arrhythmias.
While hepatic involvement is common except in heredofamilial amyloidosis of the TTR type, liver function abnormalities are minimal and occur late in the disease. Portal hypertension occurs but is uncommon. Intrahepatic cholestasis has been noted in about 5% of patients with AL (primary) amyloidosis. Hepatomegaly is common, and AL hepatic amyloid is usually accompanied by the nephrotic syndrome and congestive heart failure with poor prognosis. Amyloidosis of the spleen characteristically is not associated with leukopenia and anemia.
Involvement of the skin is one of the most characteristic manifestations of primary (AL) amyloidosis. In AL amyloidosis, the usually non-itchy lesions may consist of slightly raised, waxy papules or plaques that are usually clustered in the folds of the axillae, anal, or inguinal regions; the face and neck; or mucosal areas such as ear or tongue. Periorbital ecchymoses ("black eye" or "raccoon syndrome") have been reported.
Gastrointestinal symptoms are common in all systemic types of amyloidosis either from direct involvement of the gastrointestinal tract at any level or from infiltration of the autonomic nervous system with amyloid. Symptoms include obstruction, ulceration, malabsorption, haemorrhage, protein loss, and diarrhoea. Infiltration of the tongue is characteristic of primary amyloidosis (AL) or amyloidosis accompanying multiple myeloma and occasionally leads to macroglossia (large tongue). Gastrointestinal bleeding may occur from any of a number of sites, notably the esophagus, stomach, or large intestine, and may be severe. A malabsorption syndrome is common.
Neurologic manifestations, especially prominent in the heredofamilial amyloidoses, may include peripheral neuropathy, postural hypotension, inability to sweat, Adies's pupil, hoarseness, and sphincter incompetence. The cranial nerves are generally spared, except in the Finnish hereditary amyloidosis (AGel). Carpal tunnel syndrome may be caused by several amyloidoses, especially primary (AL) and chronic hemodialysis (Aβ2M) amyloid. Peripheral neuropathy is frequent in the former type.
Amyloid may infiltrate the thyroid or other endocrine glands but rarely causes endocrine dysfunction.
Joints and Muscles
Amyloid can directly, although rarely, involve articular structures by its presence in the synovial membrane and synovial fluid or in the articular cartilage. In these cases it is almost always of the AL type and associated with multiple myeloma. Amyloid arthritis can mimic a number of the rheumatic diseases because it can present as a symmetric arthritis of small joints with nodules, morning stiffness, and fatigue. Amyloid infiltration of muscle may lead to a pseudomyopathy.
The nasal sinuses, larynx, and trachea may be involved by accumulation of AL amyloid, which blocks the ducts, in the case of the sinuses, or the air passages. Amyloidosis of the lung involves the bronchi and alveolar septa diffusely. The lower respiratory tract is affected most frequently in primary (AL) amyloidosis and in the disease associated with dysproteinemia. Pulmonary symptoms attributable to amyloid are present in about 30% of cases. Amyloid may be localized in the bronchi or pulmonary parenchyma and may resemble a neoplasm. In these cases, local excision should be attempted and, when successful, may be followed by prolonged remissions.
Hematologic changes may include hypofibrinogenoaemia, increased fibrinolysis, and selective deficiency of clotting factors. Deficient factor X seems to be due to non-specific calcium-dependent binding to the poly-anionic amyloid fibrils. Splenectomy in the patient with such a factor X deficiency can relieve the deficiency and the associated bleeding disorder, since factor X has been shown to bind to the large masses of splenic amyloid. Endothelial damage together with the clotting abnormalities lead to a propensity toward abnormal bleeding.
Generalized amyloidosis is usually a slowly progressive disease that leads to death if untreated. The average survival in most large series of AL amyloid is 12 months and in familial amyloidosis is 7 to 15 years. A number of individuals with amyloid have been followed 5 to 10 years and longer. The course of amyloidosis is difficult to document, because dating the time of origin of the disease is rarely possible.
Rational therapy should be directed at (1) reducing precursor production, (2) inhibiting the extracellular deposition of amyloid fibrils, and (3) promoting lysis or mobilization of existing amyloid deposits.
There are new specific therapies for the various amyloidoses. In certain of the heredofamilial amyloidoses, genetic counselling is an important aspect of treatment, and the removal of the site of synthesis of the mutant protein by liver transplantation has proven remarkably successful. The utilization of chronic hemodialysis and of kidney transplantation has clearly improved the prognosis of renal amyloid.
In the case of AL amyloid, the fact that immunoglobulin light chain is made by plasma cells has led to the use of alkylating agents. However, these agents are toxic and not very effective. The most effective form of treatment currently is stem cell transplantation and immunosuppressive drugs (melphalan). Several long-term remissions have been reported, but serious complications, even death, can occur.
Colchicine has been shown to be effective in preventing acute attacks and amyloidosis in patients with FMF.
The major causes of death are heart disease and renal failure. Sudden death, presumably due to arrhythmias, is common. Occasionally, gastrointestinal haemorrhage, respiratory failure, intractable heart failure, and superimposed infections are the terminal events.