Secondary amyloidosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]
Overview
Secondary amyloidosis, also known as reactive amyloidosis is the condition of amyloid deposition particularly in the kidneys secondary to an underlying disorder, most commonly a chronic inflammatory disorder. In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis. AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors. In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis). Causes of secondary amyloidosis can include any persistent inflammatory process such as rheumatologic, autoinflammatory, chronic infectious, and other disorders. Echocardiography is critical in the diagnosis of cardiac amyloidosis. Secondary amyloidosis needs to be differentiated from other conditions causing nephrotic syndrome, hepatosplenomegaly, and peripheral neuropathy. The incidence of AA amyloidosis is approximately 0.16 per 100,000 individuals in 2008 in the united kingdom. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Secondary amyloidosis more commonly affects children. Men are more commonly affected by amyloidosis than women. In amyloidosis, insoluble fibrils of amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. Prognosis is poor and 5-years survival rate is 51.3%.Infection and renal failure are the most common cause of death. The diagnostic study of choice in amyloidosis is tissue biopsy of the affected organ. Urinary protein measurement followed by renal biopsy is the gold standard of the diagnosis. Common physical examination findings of secondary amyloidosis include periorbital edema, pitting edema of the lower extremity, and signs of the underlying inflammatory disorder. An elevated urinary protein is suggestive of secondary amyloidosis. Elevated level of acute phase reactant, abnormal liver function test, and other findings may also be observed. An ECG may be helpful in the diagnosis of secondary amyloidosis. Possible ECG findings associated with the diagnosis of cardiac involvement include low voltage QRS complexes, Left ventricular hypertrophy, Right ventricular hypertrophy, and atrioventricular block. An x-ray may be helpful in the diagnosis of secondary amyloidosis. Findings suggestive of amyloid deposition may include nodular densities. CT scan can be done to assess for amyloid deposition in particular organs. It can also be done to rule out other causes of organ dysfunction. However, MRI is more sensitive than CT in the diagnosis of amyloidosis. MRI is commonly done to assess for amyloid deposition in particular organs. It can also be done to rule out other causes of organ dysfunction. A cardiac MRI is used when an echocardiogram fails to differentiate amyloidosis from hypertrophic cardiomyopathy. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy. Total body SAP component scintigraphy may be used in the workup and follow-up of patients with amyloid deposition. This method has been observed to have high sensitivity (90%) and requires a low radioactive dose which makes it a safe and effective method. The radiolabeled SAP binds to aa amyloid and localizes its deposition semiquantitatively. Medical or surgical treatment of the underlying chronic infection or inflammatory disease is recommended among all patients who develop AA amyloidosis.
Historical Perspective
In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.
Classification
Amyloidosis can also be classified based on the extent of organ system involvement
Pathophysiology
AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors. In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).
Causes
Causes of secondary amyloidosis can include any persistent inflammatory process such as rheumatologic, autoinflammatory, chronic infectious, and other disorders.
Differentiating Amyloidosis from other Diseases
Secondary amyloidosis needs to be differentiated from other conditions causing nephrotic syndrome, hepatosplenomegaly, and peripheral neuropathy.
Epidemiology and Demographics
The incidence of AA amyloidosis is approximately 0.16 per 100,000 individuals in 2008 in the united kingdom. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Secondary amyloidosis more commonly affects children. Men are more commonly affected by amyloidosis than women.
Risk Factors
The most potent risk factor in the development of secondary amyloidosis is a persistent inflammatory disorders. Chronic infections and inflammatory arthritis are among the most common risk factors.
Screening
There is insufficient evidence to recommend routine screening for amyloidosis.
Natural History, Complications and Prognosis
In amyloidosis, insoluble fibrils of amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. Prognosis is poor and 5-years survival rate is 51.3%.Infection and renal failure are the most common cause of death.
Diagnosis
Diagnostic Study of Choice
The diagnostic study of choice in amyloidosis is tissue biopsy of the affected organ. Urinary protein measurement followed by renal biopsy is the gold standard of the diagnosis.
History and Symptoms
Symptoms of secondary amyloidosis may vary depending on the primary disorder and the affected organs. Secondary amyloidosis most commonly presents with kidney involvement and patients usually have a positive history of periorbital edema and frothy urine.
Physical Examination
Common physical examination findings of secondary amyloidosis include periorbital edema, pitting edema of the lower extremity, and signs of the underlying inflammatory disorder.
Laboratory Findings
An elevated urinary protein is suggestive of secondary amyloidosis. Elevated level of acute phase reactant, abnormal liver function test, and other findings may also be observed.
Electrocardiogram
An ECG may be helpful in the diagnosis of secondary amyloidosis. Possible ECG findings associated with the diagnosis of cardiac involvement include low voltage QRS complexes, Left ventricular hypertrophy, Right ventricular hypertrophy, and atrioventricular block.
X-Ray
An x-ray may be helpful in the diagnosis of secondary amyloidosis. Findings suggestive of amyloid deposition may include nodular densities.
CT Scan
CT scan can be done to assess for amyloid deposition in particular organs. It can also be done to rule out other causes of organ dysfunction. However, MRI is more sensitive than CT in the diagnosis of amyloidosis.
MRI
MRI is commonly done to assess for amyloid deposition in particular organs. It can also be done to rule out other causes of organ dysfunction. A cardiac MRI is used when an echocardiogram fails to differentiate amyloidosis from hypertrophic cardiomyopathy.
Echocardiography
Echocardiography is critical in the diagnosis of cardiac amyloidosis. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy.
Other Imaging Findings
Total body SAP component scintigraphy may be used in the workup and follow-up of patients with amyloid deposition. This method has been observed to have high sensitivity (90%) and requires a low radioactive dose which makes it a safe and effective method. The radiolabeled SAP binds to aa amyloid and localizes its deposition semiquantitatively.
Other Diagnostic Studies
A tissue biopsy or fat aspirate should be done to confirm the presence or type of amyloid protein which is involved in the pathogenesis of the disease.
Treatment
Medical Therapy
Medical or surgical treatment of the underlying chronic infection or inflammatory disease is recommended among all patients who develop AA amyloidosis.
Surgery
Organ-specific transplant may need to be done, depending on the organ involved. However, surgery is not commonly done in patients with amyloidosis, since it is usually a systemic disease that requires treatment of the underlying cause.
Prevention
Primary Prevention
There is no role for primary prevention in amyloidosis.
Secondary Prevention
There is no role for secondary prevention in amyloidosis.