Primary amyloidosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Syed Hassan A. Kazmi BSc, MD [2]
Overview
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. Amyloidosis may be classified on the basis of type of amyloidogenic protein and associated clinical syndromes into primary (AL) amyloidosis, secondary (AA) amyloidosis, familial (AF) amyloidosis, transthyretin (ATTRwt) amyloidosis and dialysis-associated (AH) amyloidosis. It can also be classified based on extent of organ system involvement. Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, and in the different connective tissues. Primary (AL) amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones. The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (a component of an antibody). There are approximately 4000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65. The most common risk factor for the development of primary amyloidosis is the presence of an underlying plasma cell dyscrasia. In primary amyloidosis, insoluble fibrils of AL amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with primary amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis or AL amyloidosis, the survival rate depends upon the type of organ involvement and the hematological response to treatment. In AL amyloidosis, untreated individuals have the worst prognosis. In this group of patients, the median survival is one to two years. The diagnostic study of choice in primary amyloidosis is tissue biopsy of the affected organ. Congo Red staining will show apple green birefringence of the tissue sample under polarized light, and subtyping of light chains (for light chain amyloidosis) can be done via mass spectrometry. Bone marrow biopsy and organ-specific laboratory measurements are also important ancillary tests. Symptoms can be quite diverse and range from dyspnea, lethargy, weight loss, fevers/chills to anasarca, bleeding tendency, frothy urine, numbness/tingling and diarrhea/constipation. Common findings in primary amyloidosis include petechiae, ecchymosis, parotid gland enlargement, increased intraocular pressure, enlarged tongue, hepatomegaly, carpal tunnel syndrome, and Raynaud's phenomenon. Laboratory findings in amyloidosis include elevated erythrocyte sedimentation rate, increased BUN level, serum creatinine, protein, casts, or fat bodies in urine. Serum troponin, B-type natriuretic peptide, and beta-2-microglobulin are prognostic markers for heart failure. Amyloid deposits can be identified histologically by Congo red staining and viewing under polarized light where amyloid deposits produce a distinctive 'apple green birefringence'. Alternatively, thioflavin T stain may be used. An abdominal fat pad aspiration, rectal mucosa biopsy, or bone marrow biopsy can help confirm the diagnosis. They reveal positive findings in 80% patients. Findings on electrocardiogram include low voltage QRS complexes, left and right ventricular hypertrophy, left atrial abnormalities, pathological Q waves, and AV block. Echocardiography is critical in the diagnosis of cardiac involvement in primary amyloidosis. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy. Chest x-ray findings in a case of amyloidosis include a coin lesion. 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. Tissue doppler echocardiography and myocardial strain rate imaging has been shown to be very sensitive for the assessment of myocardial dysfunction in restrictive cardiomyopathy. The development of serum amyloid P component (SAP) scans has given physicians the ability to specifically locate amyloid deposits. Patients with systemic AL amyloidosis are not cured with conventional immunosuppressant treatment. However, early mortality rates have decreased and survival has improved as there has been a shift toward earlier diagnosis and therapy aimed at achieving remissions. The most commonly used regimen for AL amyloidosis is CyBorD, which consists of cyclophosphamide, bortezomib, and dexamethasone. 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.
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 may be classified on the basis of type of amyloidogenic protein and associated clinical syndromes into primary (AL) amyloidosis, secondary (AA) amyloidosis, familial (AF) amyloidosis, transthyretin (ATTRwt) amyloidosis and dialysis-associated (AH) amyloidosis. It can also be classified based on extent of organ system involvement.
Pathophysiology
Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, and in the different connective tissues. Primary (AL) amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones.
Causes
The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (a component of an antibody).
Differentiating Primary Amyloidosis From Other Diseases
Primary amyloidosis may affect any organ in the body but the most commonly affected organs are the heart, kidneys and nerves. Involvement of these organ systems may give rise to organ failure, therefore early diagnosis is imperative for optimal treatment. Organ specific amyloidosis should be differentiated from other diseases that mimic amyloidosis and may present as organ dysfunction, specifically, nephrotic syndrome leading to renal failure, cardiac failure and polyneuropathy.
Epidemiology and Demographics
There are approximately 4000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.
Risk Factors
The most common risk factor for the development of primary amyloidosis is the presence of an underlying plasma cell dyscrasia.
Screening
There is insufficient evidence to recommend routine screening for primary amyloidosis.
Natural History, Complications, and Prognosis
In primary amyloidosis, insoluble fibrils of AL amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with primary amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis or AL amyloidosis, the survival rate depends upon the type of organ involvement and the hematological response to treatment. In AL amyloidosis, untreated individuals have the worst prognosis. In this group of patients, the median survival is one to two years.
Diagnosis
Diagnostic Study of Choice
The diagnostic study of choice in primary amyloidosis is tissue biopsy of the affected organ. Congo Red staining will show apple green birefringence of the tissue sample under polarized light, and subtyping of light chains (for light chain amyloidosis) can be done via mass spectrometry. Bone marrow biopsy and organ-specific laboratory measurements are also important ancillary tests.
History and Symptoms
In primary amyloidosis, the range of symptoms depends on specific tissues and organs involved. Symptoms can be quite diverse and range from dyspnea, lethargy, weight loss, fevers/chills to anasarca, bleeding tendency, frothy urine, numbness/tingling and diarrhea/constipation.
Physical Examination
Common findings in primary amyloidosis include petechiae, ecchymosis, parotid gland enlargement, increased intraocular pressure, enlarged tongue, hepatomegaly, carpal tunnel syndrome, and Raynaud's phenomenon.
Laboratory Findings
Laboratory findings in amyloidosis include elevated erythrocyte sedimentation rate, increased BUN level, serum creatinine, protein, casts, or fat bodies in urine. Serum troponin, B-type natriuretic peptide, and beta-2-microglobulin are prognostic markers for heart failure. Amyloid deposits can be identified histologically by Congo red staining and viewing under polarized light where amyloid deposits produce a distinctive 'apple green birefringence'. Alternatively, thioflavin T stain may be used. An abdominal fat pad aspiration, rectal mucosa biopsy, or bone marrow biopsy can help confirm the diagnosis. They reveal positive findings in 80% patients.
Electrocardiogram
Electrocardiogram is particularly useful for cardiac involvement in primary amyloidosis. Findings on electrocardiogram include low voltage QRS complexes, left and right ventricular hypertrophy, left atrial abnormalities, pathological Q waves, and AV block.
X-ray
Chest x-ray findings in a case of amyloidosis include a coin lesion.
Echocardiography and Ultrasound
Echocardiography is critical in the diagnosis of cardiac involvement in primary amyloidosis. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy.
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. However, MRI is more sensitive than CT in the diagnosis of amyloidosis. A cardiac MRI is used when an echocardiogram fails to differentiate amyloidosis from hypertrophic cardiomyopathy.
Other Imaging Findings
Tissue doppler echocardiography and myocardial strain rate imaging has been shown to be very sensitive for the assessment of myocardial dysfunction in restrictive cardiomyopathy. The development of serum amyloid P component (SAP) scans has given physicians the ability to specifically locate amyloid deposits.
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
Patients with systemic AL amyloidosis are not cured with conventional immunosuppressant treatment. However, early mortality rates have decreased and survival has improved as there has been a shift toward earlier diagnosis and therapy aimed at achieving remissions. The most commonly used regimen for AL amyloidosis is CyBorD, which consists of cyclophosphamide, bortezomib, and dexamethasone.
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.
Primary Prevention
There is no role for primary prevention in amyloidosis.
Secondary Prevention
There is no role for secondary prevention in amyloidosis.