AMYLOIDOSIS

AMYLOIDOSIS - Karin S. Leschly, MD
BASICS
DESCRIPTION
• A group of diseases characterized by increased deposition of amyloid fibrils in the tissues. Several different proteins may give rise to amyloid.
• These proteins are present due to their overproduction or decreased clearance. Their deposition may lead to compromise of vital organ function.
• Specific amyloid proteins aggregate mostly in specific organs.
• Primary or idiopathic (AL form): No associated disease
• Secondary, acquired, or reactive (AA form): Associated with chronic diseases, either infectious (tuberculosis, bronchiectasis, osteomyelitis, leprosy) or inflammatory (rheumatoid arthritis, granulomatous ileitis); Hodgkin disease; other tumors; and familial Mediterranean fever.
• Familial (hereditary) amyloidosis: Associated with distinctive types of neuropathy, nephropathy, and cardiopathy; may occur in almost every ethnic group
• Hemodialysis amyloidosis: Associated with renal hemodialysis
• Localized amyloidosis: Associated with Alzheimer disease
• System(s) affected: Cardiovascular; Endocrine/metabolic; Gastrointestinal; Musculoskeletal; Nervous; Pulmonary; Renal/urologic; Skin/exocrine
ALERT
Geriatric Considerations
• In general, older individuals do less well.
• Age may precipitate familial amyloidosis, suggesting an age-related trigger.
EPIDEMIOLOGY
Incidence
• Primary amyloidosis: 1 per 100,000 person-years
• Secondary amyloidosis: Very rare
• Familial amyloidosis: 1 per million person-years
Prevalence
• Predominant age: 60-70
• Predominant sex: Male > Female (2:1)
RISK FACTORS
• Underlying plasma cell dyscrasia
• Underlying chronic inflammatory disease
• Familial Mediterranean fever
• Hemodialysis
Genetics
Only familial amyloidosis can be inherited. The genetics are variable but usually are autosomal dominant.
ETIOLOGY
• The cause of amyloid production and its deposition in tissues is unknown.
• In the different types of amyloidosis, etiologic mechanisms may vary. For example
- Primary amyloidosis: The amyloid consists of immunoglobulin light chains, which are overproduced in plasma-cell disorders.
- Secondary amyloidosis: The amyloid consists of amyloid fibrillary protein formed from serum amyloid protein, which is overproduced in chronic inflammatory conditions.
- Familial (hereditary) amyloidosis: The amyloid consists of abnormal transthyretin protein or lysozyme protein produced in the liver.
- Hemodialysis amyloidosis: The amyloid consists of 2-microglobulin, which is normally cleared by the kidney, but not by hemodialysis.
- Localized amyloidosis: Associated with hormonal proteins or aging, such as -amyloid proteins in Alzheimer disease and other neurodegenerative diseases
ASSOCIATED CONDITIONS
Amyloid may bind Factor X, leading to bleeding problems.


DIAGNOSIS
SIGNS AND SYMPTOMS
Manifestations are nonspecific, determined by the organ or system affected, and often are obscured by the underlying disease, which may be fatal before amyloidosis is suspected.
History
Fatigue, weight loss, gastroparesis, pseudo-obstruction, malabsorption, diarrhea, macroglossia
Physical Exam
• Nephrotic syndrome is the most striking manifestation: Early stages, slight proteinuria; late stages, anasarca, hypoproteinemia, and massive proteinuria
• Hepatic amyloid disease produces hepatomegaly, but rarely jaundice. Occasionally portal hypertension may occur, with esophageal varices and ascites.
• Cardiac involvement is common and may present as cardiomegaly, intractable heart failure, or any common arrhythmia.
• GI amyloid may cause esophageal motility abnormalities, gastric atony, small- and large-intestinal motility abnormalities, gastric atony, small- and large-intestinal motility abnormalities, malabsorption, bleeding, or pseudo-obstruction.
• Peripheral neuropathy, carpal tunnel syndrome
• Lung involvement may be characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits. Patients may present with dyspnea, congestive heart failure, arrhythmia, angina pectoris, or sudden death
• Hilar adenopathy, mediastinal adenopathy
• Amyloid arthropathy may mimic rheumatoid arthritis: Symmetrical polyarthritis, rubbery periarticular soft-tissue swelling
• Skin lesions may be translucent or waxy; purpura (periorbital purpura) may result from amyloidosis of small cutaneous vessels, edema
• Dementia (may have role in Alzheimer disease)
• Macroglossia is common in primary and myeloma-related amyloidosis.
• A firm, symmetric, nontender goiter resembling Hashimoto or Riedel struma may result from amyloidosis of the thyroid gland.
TESTS
Specialized screening for mutant transthyretin
Lab
• Anemia may be present.
• Hypothyroidism may be present due to amyloidosis of the thyroid.
• Renal insufficiency is present in 50%.
• Proteinuria is present in ~80%.
• Primary amyloidosis
- Elevated monoclonal protein level will be found in the serum and/or urine.
• Secondary amyloidosis
- Tests to assess the underlying inflammatory disease will be useful.
• Familial amyloidosis
- An abnormal transthyretin protein may be isolated.
Imaging
Echocardiography (if cardiac involvement is suspected)
Diagnostic Procedures/Surgery
• Amyloidosis is suspected on the basis of symptoms and signs, but can be diagnosed only by biopsy.
• Abdominal fat pad biopsy (up to 85% positive)
• Rectal biopsy (70% positive)
• Bone marrow biopsy (20% positive)
• Endomyocardial biopsy
• Renal biopsy
Pathological Findings
• Demonstration of amyloid deposits in tissues
• With Congo red staining, amyloid produces a green birefringence under polarized light.
• Electron microscopy is the definitive diagnostic tool.
DIFFERENTIAL DIAGNOSIS
• Peripheral neuropathy: Diabetes mellitus, alcoholism, vitamin deficiencies
• Carpal tunnel syndrome: Hypothyroidism, trauma, rheumatoid arthritis, late pregnancy
• Restrictive cardiomyopathy: Acute viral myocarditis, endomyocardial fibrosis, sarcoidosis, hemochromatosis
• Nephrotic syndrome: Glomerulonephritis, renal vein thrombosis
• Renal failure: Glomerulonephritis, obstructive uropathy, toxin- or drug-induced, acute tubular necrosis
• Symmetric polyarthritis: Rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus
• Interstitial lung disease: Connective tissue diseases, infectious, sarcoidosis, drug-induced, pneumoconiosis
• Dementia: Alzheimer disease, multi-infarct dementia, Parkinson disease
TREATMENT
GENERAL MEASURES
• Therapy is 1st directed to underlying cause; such treatment may arrest amyloidosis.
• Management is generally symptomatic.
• Appropriate health care: Outpatient, except for serious complications (CHF, renal failure)
• Hemodialysis amyloidosis: Change to peritoneal dialysis (clears 2-microglobulin).
Diet
• Low-protein, low-salt diet for renal failure patients
• Low-salt diet for CHF patients
Activity
• Fully active as tolerated
• Fatigue/shortness of breath may limit activity
MEDICATION (DRUGS)
• Primary amyloidosis
- Treatment of the underlying plasma-cell disorder may or may not affect the outcome.
- Melphalan and prednisone are among the drugs of choice for plasma-cell disorders.
- Thalidomide also effective
- The role of colchicine is considered less important; it may slow amyloid deposition.
• Secondary amyloidosis
- Treatment of the underlying inflammatory process with disease-specific medications usually improves the outcome (i.e., isoniazid and rifampin for M. tuberculosis, methotrexate for rheumatoid arthritis).
- Donepezil, galantamine, rivastigmine, and memantine have been approved for mild to moderate dementia caused by Alzheimer disease.
- Colchicine, 0.6 mg b.i.d.-t.i.d. may prevent acute attacks in familial Mediterranean fever.
• Familial amyloidosis: None
• Hemodialysis amyloidosis: None
• Precautions
- Melphalan: Bone marrow depression, including agranulocytosis, pancytopenia, thrombocytopenia, or aplastic anemia, may occur with prolonged administration. Monitor CBC periodically. Counsel patient to report symptoms/signs of infection (headache, sore throat, fever).
- Thalidomide: Severe birth defects
- Colchicine: Nausea, diarrhea, blood dyscrasia, rash, alopecia
SURGERY
• Splenectomy may ameliorate this condition by decreasing the amount of amyloid produced.
• Renal transplantation may improve the status of renal amyloidosis. However, amyloid will ultimately recur in a donor kidney.
• Liver transplantation or partial liver transplantation may cure familial (hereditary) amyloidosis.
• Other measures: Treatment of multiple myeloma with bone marrow transplantation is an option for some patients.
• A pacemaker may be indicated in those with amyloid-induced conduction defects.
FOLLOW-UP
PROGNOSIS
• Primary amyloidosis
- The prognosis depends on the underlying disease.
- Once renal failure has developed, the prognosis is usually 1 year.
- CHF has a 4-month prognosis.
- Overall prognosis is poor; reported survival rates are 51% at 1 year and 16% at 5 years.
• Secondary amyloidosis
- The prognosis is better, depending on ability to control the underlying process.
• Familial and hemodialysis amyloidosis
- Highly variable
- A liver transplant may be curative, but it is linked to the duration and severity of the pretransplant illness.
- The deposition of amyloid in the heart may continue even after successful transplantation.
COMPLICATIONS
Despite intervention, worsening renal failure, heart failure, arthropathy, interstitial lung disease, and neuropathy are common.
PATIENT MONITORING
• Primary amyloidosis
- Regular testing of monoclonal protein levels to assess response to therapy
- Regular testing of renal function to assess response to therapy
• Secondary and hemodialysis amyloidosis
- Follow-up to assess control of the underlying disease process
- Regular testing of renal function to assess degree of impairment
REFERENCES
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