Amyloidosis
BASIC INFORMATION
Amyloidosis is a disorder of protein metabolism in which there is an extracellular deposition of pathological insoluble fibrillar proteins in organs and tissues. Characteristically, the amyloid protein consists of b-pleated sheets that are responsible for its insolubility and resistance to proteolysis. Amyloidosis can be acquired or inherited. Classification is based on the nature of the precursor plasma proteins (at least 20) that form the fibrillar deposits. The process for the production of these fibrils appears to be multifactorial and differs amongst the various types of amyloid.
AL amyloidosis (immunoglobulin light chain-associated)
This is a plasma cell dyscrasia, related to multiple myeloma, in which clonal plasma cells in the bone marrow produce immunoglobulins that are amyloidogenic. This may be the outcome of destabilization of light chains owing to substitution of particular amino acids into the light chain variable region. There is a clonal dominance of amyloid light (AL) chains - either the dominant k or l isotype - which are excreted in the urine (Bence Jones proteins). This type of amyloid is often associated with lymphoproliferative disorders, such as myeloma, Waldenstrom’s macroglobulinaemia or non-Hodgkin’s lymphoma. It rarely occurs before the age of 40 years. The clinical features are related to the organs involved. These include the kidneys (presenting with proteinuria and the nephrotic syndrome) and the heart (presenting with heart failure). Autonomic and sensory neuropathies are relatively common, and carpal tunnel syndrome with weakness and paraesthesia of the hands may be an early feature. Sensory neuropathy is common. There is an absence of central nervous system involvement. On examination, hepatomegaly and rarely splenomegaly, cardiomyopathy, polyneuropathy and bruising may be seen. Macroglossia occurs in about 10% of cases and periorbital purpura in 15%.
This is a plasma cell dyscrasia, related to multiple myeloma, in which clonal plasma cells in the bone marrow produce immunoglobulins that are amyloidogenic. This may be the outcome of destabilization of light chains owing to substitution of particular amino acids into the light chain variable region. There is a clonal dominance of amyloid light (AL) chains - either the dominant k or l isotype - which are excreted in the urine (Bence Jones proteins). This type of amyloid is often associated with lymphoproliferative disorders, such as myeloma, Waldenstrom’s macroglobulinaemia or non-Hodgkin’s lymphoma. It rarely occurs before the age of 40 years. The clinical features are related to the organs involved. These include the kidneys (presenting with proteinuria and the nephrotic syndrome) and the heart (presenting with heart failure). Autonomic and sensory neuropathies are relatively common, and carpal tunnel syndrome with weakness and paraesthesia of the hands may be an early feature. Sensory neuropathy is common. There is an absence of central nervous system involvement. On examination, hepatomegaly and rarely splenomegaly, cardiomyopathy, polyneuropathy and bruising may be seen. Macroglossia occurs in about 10% of cases and periorbital purpura in 15%.
Familial amyloidoses (transthyretin-associated (ATTR))
These are autosomally dominant transmitted diseases where the mutant protein forms amyloid fibrils, starting usually in middle age. The most common form is due to a mutant - transthyretin - which is a tetrameric protein with four identical subunits. It is a transport protein for thyroxine and retinolbinding protein and mainly synthesized in the liver. Over 80 amino acid substitutions have been described; for example, a common substitution is that of methionine for valine at position 30 (Met 30) in all racial groups, and alanine for threonine (Ala 60) in the English and Irish. These substitutions destabilize the protein, which precipitates following stimulation, and can cause disorders such as familial amyloidotic polyneuropathy (FAP), cardiomyopathy or the nephrotic syndrome. Major foci of FAP occur in Portugal, Japan and Sweden.
These are autosomally dominant transmitted diseases where the mutant protein forms amyloid fibrils, starting usually in middle age. The most common form is due to a mutant - transthyretin - which is a tetrameric protein with four identical subunits. It is a transport protein for thyroxine and retinolbinding protein and mainly synthesized in the liver. Over 80 amino acid substitutions have been described; for example, a common substitution is that of methionine for valine at position 30 (Met 30) in all racial groups, and alanine for threonine (Ala 60) in the English and Irish. These substitutions destabilize the protein, which precipitates following stimulation, and can cause disorders such as familial amyloidotic polyneuropathy (FAP), cardiomyopathy or the nephrotic syndrome. Major foci of FAP occur in Portugal, Japan and Sweden.
Other less common variants include mutations of apoprotein A-I, gelsolin, fibrinogen Aa and lysozyme. Clinically, peripheral sensorimotor and autonomic neuropathy are common, with symptoms of autonomic dysfunction, diarrhoea and weight loss. Renal disease is less prevalent than with AL amyloidosis. Macroglossia does not occur. Cardiac problems are usually those of conduction. There may be a family history of unidentified neurological disease. Other hereditary systemic amyloidoses include other familial amyloid polyneuropathies (e.g. Portuguese, Icelandic, Dutch). There is a familial Creutzfeldt-Jakob disease. In familial Mediterranean fever, renal amyloidosis is a common serious complication.
Reactive systemic (secondary AA) amyloidoses
These are due to amyloid formed from serum amyloid A (SAA), which is an acute phase protein. It is, therefore, related to chronic inflammatory disorders and chronic infection. Clinical features depend on the nature of the underlying disorder. Chronic inflammatory disorders include rheumatoid arthritis, inflammatory bowel disease and untreated familial Mediterranean fever. In developing countries it is still associated with infectious diseases such as tuberculosis, bronchiectasis and osteomyelitis. AA amyloidosis often presents with chronic kidney disease, with hepatomegaly and splenomegaly. Macroglossia is not a feature and cardiac involvement is rare. The degree of renal failure correlates with the SAA level in a more favourable outcome in patients with low normal levels.
Cerebral amyloidosis, Alzheimer’s disease and transmissible spongiform encephalopathy
The brain is a common site of amyloid deposition, although it is not directly affected in any form of acquired systemic amyloidosis. Intracerebral and cerebrovascular amyloid deposits are seen in Alzheimer’s disease. Most cases are sporadic, but hereditary forms caused by mutations have been reported. In hereditary spongiform encephalopathies several amyloid plaques have been seen. Amyloid deposits are frequently found in the elderly, particularly cerebral deposits of A4 protein. This is also seen in Down’s syndrome. Apoprotein E (involved in LDL transport) interacts directly with b-A4 protein in senile plaques and neurofibrillary tangles in the brain. The gene for apoprotein E is on chromosome 19 and may be a susceptibility factor in the aetiology of Alzheimer’s disease.
Reactive systemic (secondary AA) amyloidoses
These are due to amyloid formed from serum amyloid A (SAA), which is an acute phase protein. It is, therefore, related to chronic inflammatory disorders and chronic infection. Clinical features depend on the nature of the underlying disorder. Chronic inflammatory disorders include rheumatoid arthritis, inflammatory bowel disease and untreated familial Mediterranean fever. In developing countries it is still associated with infectious diseases such as tuberculosis, bronchiectasis and osteomyelitis. AA amyloidosis often presents with chronic kidney disease, with hepatomegaly and splenomegaly. Macroglossia is not a feature and cardiac involvement is rare. The degree of renal failure correlates with the SAA level in a more favourable outcome in patients with low normal levels.
Cerebral amyloidosis, Alzheimer’s disease and transmissible spongiform encephalopathy
The brain is a common site of amyloid deposition, although it is not directly affected in any form of acquired systemic amyloidosis. Intracerebral and cerebrovascular amyloid deposits are seen in Alzheimer’s disease. Most cases are sporadic, but hereditary forms caused by mutations have been reported. In hereditary spongiform encephalopathies several amyloid plaques have been seen. Amyloid deposits are frequently found in the elderly, particularly cerebral deposits of A4 protein. This is also seen in Down’s syndrome. Apoprotein E (involved in LDL transport) interacts directly with b-A4 protein in senile plaques and neurofibrillary tangles in the brain. The gene for apoprotein E is on chromosome 19 and may be a susceptibility factor in the aetiology of Alzheimer’s disease.
Local amyloidosis
Deposits of amyloid fibrils of various types can be localized to various organs or tissues (e.g. skin, heart and brain).
Dialysis-related amyloidosis This is due to the b2-microglobulin producing amyloid fibrils in chronic dialysis patients. It frequently presents with the carpal tunnel syndrome.
EPIDEMIOLOGY & DEMOGRAPHICS
• Amyloidosis affects primarily males between the ages of 60 and 70 yr.
• There are between 1500 and 3500 new cases annually in the U.S.
• The most common type in the U.S. is immunoglobulin light chain related (AL).
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Findings are variable with organ system involvement. Symmetric polyarthritis, peripheral neuropathy, and carpal tunnel syndrome may be present with joint involvement.
• Signs and symptoms of nephrotic syndrome may be present with renal involvement.
Deposits of amyloid fibrils of various types can be localized to various organs or tissues (e.g. skin, heart and brain).
Dialysis-related amyloidosis This is due to the b2-microglobulin producing amyloid fibrils in chronic dialysis patients. It frequently presents with the carpal tunnel syndrome.
EPIDEMIOLOGY & DEMOGRAPHICS
• Amyloidosis affects primarily males between the ages of 60 and 70 yr.
• There are between 1500 and 3500 new cases annually in the U.S.
• The most common type in the U.S. is immunoglobulin light chain related (AL).
PHYSICAL FINDINGS & CLINICAL PRESENTATION
• Findings are variable with organ system involvement. Symmetric polyarthritis, peripheral neuropathy, and carpal tunnel syndrome may be present with joint involvement.
• Signs and symptoms of nephrotic syndrome may be present with renal involvement.
• Fatigue and dyspnea may occur with pulmonary involvement.
• Diarrhea, macroglossia (20% of patients), malabsorption, hepatomegaly, and weight loss may occur with GI involvement.
• Cardiac involvement is common and can lead to predominantly right-sided CHF, JVD, peripheral edema, and hepatomegaly.
• Vascular involvement can result in easy bleeding and periorbital purpura (“racoon-eyes”).
ETIOLOGY
In patients with amyloidosis, a soluble circulating protein (serum amyloid P [SAP]) is deposited in tissues as insoluble b-pleated sheets. The source of amyloid protein
is a population of monoclonal plasma cells in the bone marrow. There are several chemically documented amyloidoses that can be principally subdivided into:
1. Acquired systemic amyloidosis (immunoglobulin light chain, multiple myeloma, hemodialysis amyloidosis)
2. Heredofamilial systemic (polyneuropathy, familial Mediterranean fever)
3. Organ-limited (Alzheimer’s disease)
4. Localized endocrine (pancreatic islet, medullary thyroid carcinoma)
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
This is based on clinical suspicion and, if possible, on tissue histology. Amyloid in tissues appears as an amorphous, homogeneous substance that stains pink with haematoxylin and eosin and stains red with Congo red. It also has a green fluorescence in polarized light. Tissue can be obtained from the rectum, gums or abdominal fat. The bone marrow may show plasma cells in amyloidosis or a lymphoproliferative disorder. A paraproteinaemia and proteinuria with light chains in the urine may also be seen in AL amyloidosis. In secondary or reactive amyloidosis there will be an underlying disorder. Scintigraphy using 123I-labelled serum amyloid P component is useful for the assessment of AL, ATTR and AA amyloidosis, but it is not widely available and is expensive.
Variable, depending on the organ involvement:
• Renal involvement (toxin- or drug-induced necrosis, glomerulonephritis, renal vein thrombosis)
• Interstitial lung disease (sarcoidosis, connective tissue disease, infectious etiologies)
• Restrictive cardiac (endomyocardial fibrosis, viral myocarditis)
• Carpal tunnel (rheumatoid arthritis, hypothyroidism, overuse)
• Mental status changes (multiinfarct dementia)
• Peripheral neuropathy (alcohol abuse, vitamin deficiencies, diabetes mellitus)
WORKUP
Diagnostic approach is aimed at demonstration of amyloid deposits in tissues. This may be accomplished with rectal biopsy (positive in >60% of cases). Renal, myocardial, and bone marrow biopsy are other options. Abdominal fat pad biopsy can also be diagnostic.
LABORATORY TESTS
• Initial laboratory evaluation should include CBC, TSH, renal functions studies, ALT, AST, alkaline phosphatase, bilirubin, urinalysis, and serum and urine protein immunoelectrophoresis.
• Various laboratory abnormalities include proteinuria (found in >70% of cases), anemia, renal insufficiency, liver function abnormalities, hypothyroidism (10% to 20% of patients), and elevated monoclonal proteins. The finding of a monoclonal light chain in the serum or urine is very useful for diagnosis.
• DNA analysis is necessary for the diagnosis of hereditary amyloidosis.
IMAGING STUDIES
• Chest x-ray may reveal hilar adenopathy and mediastinal adenopathy.
• Two-dimensional Doppler echocardiography to study diagnostic filling is useful to evaluate for cardiac involvement.
• Nuclear imaging with technetium-labeled aprotinin may detect cardiac amyloidosis. SAP scintigraphy has high sensitivity for the detection of amyloid deposits in liver, spleen, kidneys, adrenal glands, and bones.
TREATMENT
This is symptomatic or the treatment of the associated disorder. The nephrotic syndrome and congestive cardiac failure require the relevant therapies. Treatment of any inflammatory source or infection should be instituted. Colchicine may help familial Mediterranean fever. Eprodisate, which interferes with interactions between amyloid proteins and glycosaminoglycans inhibits polymerization of amyloid fibrids; it slows the fall in renal function in AA amyloidosis. Chemotherapy with nephalan plus dexamethasone is showing some efficacy in AL amyloidosis. In ATTR amyloidosis where transthyretin is predominantly synthesized in the liver, liver transplantation (when there would be a disappearance of the mutant protein from the blood) is considered as the definitive therapy.
ACUTE GENERAL Rx
• Therapy is variable, depending on the type of amyloidosis. Amyloidosis associated with plasma cell disorders may be treated with melphalan and prednisone, along with colchicine. Colchicine may also be effective in renal amyloidosis.
• Promising results have been found with the use of a molecule known as CPHPC given IV or SC in amyloidosis. This molecule has been shown effective in reducing circulating levels of SAP.
CHRONIC Rx
Renal transplantation is needed in patients with renal amyloidosis. Peritoneal dialysis in place of hemodialysis in patients with renal failure may improve hemodialysis amyloidosis by clearing b-2 microglobulin.
DISPOSITION
Prognosis is determined primarily by the presence or absence of cardiac involvement and with the form of amyloidosis:
• In reactive amyloidosis, eradication of the predisposing disease slows and can occasionally reverse the progression of amyloid disease. Survival of 5 to 10 yr after diagnosis is not uncommon.
• Patients with familial amyloidotic polyneuropathy generally have a prolonged course lasting 10 to 15 yr.
• Amyloidosis associated with immunocytic processes carries the worst prognosis (life expectancy <1 yr).
• The progression of amyloidosis associated with renal hemodialysis can be improved with newer dialysis membranes that can pass b-2 microglobulin.
• Median survival in patients with overt CHF is approximately 6 mo, 30 mo without CHF.
• Diarrhea, macroglossia (20% of patients), malabsorption, hepatomegaly, and weight loss may occur with GI involvement.
• Cardiac involvement is common and can lead to predominantly right-sided CHF, JVD, peripheral edema, and hepatomegaly.
• Vascular involvement can result in easy bleeding and periorbital purpura (“racoon-eyes”).
ETIOLOGY
In patients with amyloidosis, a soluble circulating protein (serum amyloid P [SAP]) is deposited in tissues as insoluble b-pleated sheets. The source of amyloid protein
is a population of monoclonal plasma cells in the bone marrow. There are several chemically documented amyloidoses that can be principally subdivided into:
1. Acquired systemic amyloidosis (immunoglobulin light chain, multiple myeloma, hemodialysis amyloidosis)
2. Heredofamilial systemic (polyneuropathy, familial Mediterranean fever)
3. Organ-limited (Alzheimer’s disease)
4. Localized endocrine (pancreatic islet, medullary thyroid carcinoma)
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
This is based on clinical suspicion and, if possible, on tissue histology. Amyloid in tissues appears as an amorphous, homogeneous substance that stains pink with haematoxylin and eosin and stains red with Congo red. It also has a green fluorescence in polarized light. Tissue can be obtained from the rectum, gums or abdominal fat. The bone marrow may show plasma cells in amyloidosis or a lymphoproliferative disorder. A paraproteinaemia and proteinuria with light chains in the urine may also be seen in AL amyloidosis. In secondary or reactive amyloidosis there will be an underlying disorder. Scintigraphy using 123I-labelled serum amyloid P component is useful for the assessment of AL, ATTR and AA amyloidosis, but it is not widely available and is expensive.
Variable, depending on the organ involvement:
• Renal involvement (toxin- or drug-induced necrosis, glomerulonephritis, renal vein thrombosis)
• Interstitial lung disease (sarcoidosis, connective tissue disease, infectious etiologies)
• Restrictive cardiac (endomyocardial fibrosis, viral myocarditis)
• Carpal tunnel (rheumatoid arthritis, hypothyroidism, overuse)
• Mental status changes (multiinfarct dementia)
• Peripheral neuropathy (alcohol abuse, vitamin deficiencies, diabetes mellitus)
WORKUP
Diagnostic approach is aimed at demonstration of amyloid deposits in tissues. This may be accomplished with rectal biopsy (positive in >60% of cases). Renal, myocardial, and bone marrow biopsy are other options. Abdominal fat pad biopsy can also be diagnostic.
LABORATORY TESTS
• Initial laboratory evaluation should include CBC, TSH, renal functions studies, ALT, AST, alkaline phosphatase, bilirubin, urinalysis, and serum and urine protein immunoelectrophoresis.
• Various laboratory abnormalities include proteinuria (found in >70% of cases), anemia, renal insufficiency, liver function abnormalities, hypothyroidism (10% to 20% of patients), and elevated monoclonal proteins. The finding of a monoclonal light chain in the serum or urine is very useful for diagnosis.
• DNA analysis is necessary for the diagnosis of hereditary amyloidosis.
IMAGING STUDIES
• Chest x-ray may reveal hilar adenopathy and mediastinal adenopathy.
• Two-dimensional Doppler echocardiography to study diagnostic filling is useful to evaluate for cardiac involvement.
• Nuclear imaging with technetium-labeled aprotinin may detect cardiac amyloidosis. SAP scintigraphy has high sensitivity for the detection of amyloid deposits in liver, spleen, kidneys, adrenal glands, and bones.
TREATMENT
This is symptomatic or the treatment of the associated disorder. The nephrotic syndrome and congestive cardiac failure require the relevant therapies. Treatment of any inflammatory source or infection should be instituted. Colchicine may help familial Mediterranean fever. Eprodisate, which interferes with interactions between amyloid proteins and glycosaminoglycans inhibits polymerization of amyloid fibrids; it slows the fall in renal function in AA amyloidosis. Chemotherapy with nephalan plus dexamethasone is showing some efficacy in AL amyloidosis. In ATTR amyloidosis where transthyretin is predominantly synthesized in the liver, liver transplantation (when there would be a disappearance of the mutant protein from the blood) is considered as the definitive therapy.
ACUTE GENERAL Rx
• Therapy is variable, depending on the type of amyloidosis. Amyloidosis associated with plasma cell disorders may be treated with melphalan and prednisone, along with colchicine. Colchicine may also be effective in renal amyloidosis.
• Promising results have been found with the use of a molecule known as CPHPC given IV or SC in amyloidosis. This molecule has been shown effective in reducing circulating levels of SAP.
CHRONIC Rx
Renal transplantation is needed in patients with renal amyloidosis. Peritoneal dialysis in place of hemodialysis in patients with renal failure may improve hemodialysis amyloidosis by clearing b-2 microglobulin.
DISPOSITION
Prognosis is determined primarily by the presence or absence of cardiac involvement and with the form of amyloidosis:
• In reactive amyloidosis, eradication of the predisposing disease slows and can occasionally reverse the progression of amyloid disease. Survival of 5 to 10 yr after diagnosis is not uncommon.
• Patients with familial amyloidotic polyneuropathy generally have a prolonged course lasting 10 to 15 yr.
• Amyloidosis associated with immunocytic processes carries the worst prognosis (life expectancy <1 yr).
• The progression of amyloidosis associated with renal hemodialysis can be improved with newer dialysis membranes that can pass b-2 microglobulin.
• Median survival in patients with overt CHF is approximately 6 mo, 30 mo without CHF.
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