BASICS
DESCRIPTION
- Very uncommon disorder in which proteins change conformation, aggregate, and form fibrils that infiltrate tissues, leading to organ failure and death. Deposition of amyloid in the extracellular spaces of various organs leads to varied manifestations. Diagnosis is usually delayed, as presenting features are subtle or mimic other more common conditions.
- Classification based on the nature of precursor plasma proteins that form fibril deposits:
- >20 precursor proteins are known to form amyloid fibrils; most common are immunoglobulin light chains, mutant transthyretin (TTR), wild-type (nonmutant) TTR, mutant fibrinogen, and mutant apolipoprotein A1.
- Primary (AL): plasma cell dyscrasia (including multiple myeloma and monoclonal gammopathy of undetermined significance [MGUS]) and other clonal lymphoid processes; deposition of protein derived from immunoglobulin light chain fragments. It is the most common form of systemic amyloidosis.
- Secondary or reactive (AA): complicates chronic infections or inflammatory diseases; deposition of serum amyloid A (SAA) protein; effective treatment of underlying inflammatory condition has reduced incidence in developed countries. Tuberculosis, chronic osteomyelitis, malaria, and leprosy are among the most common precipitating diseases in undeveloped parts of the world, as well as rheumatoid arthritis.
- Heritable or familial (AF): Many different types of variant plasma proteins (most commonly formed from mutations of TTR) form amyloid deposits beginning in midlife; primarily involves nervous system, especially autonomic
- Dialysis related: deposition of fibrils derived from β2-microglobulin; predilection for osteoarticular structures
- Senile systemic (SSA): deposition of otherwise normal TTR in myocardium and other sites; typically in elderly men; more indolent course, especially lungs and carpal ligaments
- Localized or organ specific: deposition isolated to one organ, resulting in specific syndromes; most common is Alzheimer disease caused by cerebral amyloid plaques; also endocrine, heart, bronchial tree, urinary tract, or skin
EPIDEMIOLOGY
Incidence
- AL: 1,275 to 3,200 new cases annually in the United States
- AA: rare in the United States; occurs in <5% of patients with chronic inflammatory diseases
Prevalence
- AF: rare, <1/100,000 population
- AL: most common type in North America, 4.5/100,000 population:
- Predominant age: 60 to 70 years
- AA: more prevalent in third-world countries; also more prevalent in Turkey and Middle East in association with familial Mediterranean fever (FMF)
ETIOLOGY AND PATHOPHYSIOLOGY
- AL: fibril formation by monoclonal antibody light chains; secondary to multiple myeloma, monoclonal gammopathies, and light chain disease; 15% of patients with multiple myeloma have symptomatic AL (1)
- AA: During inflammation, proinflammatory cytokines (e.g., interleukin [IL]-1, IL-6) stimulate liver synthesis of SAA.
- AF: Mutant proteins, derived from TTR (amyloidogenic transthyretin [ATTR]) are present from birth.
- Abnormal amyloid proteins are produced by different mechanisms, but each ultimately results in a change in conformation, then aggregation to form fibrils.
Genetics
- Only familial amyloidosis can be inherited; usually autosomal dominant; particularly of kinships originating in Portugal, Japan, Sweden, Finland, Italy, and Greece.
- FMF (risk factor for secondary or reactive amyloidosis) is an autosomal-recessive disorder.
RISK FACTORS
Depends on type of systemic amyloidosis:
- Age (SSA/Alzheimer)
- Heredity (AF/AA)
- Underlying plasma cell dyscrasia (AL)
- Untreated chronic infections (AA)
- Long-term hemodialysis
GENERAL PREVENTION
Early detection and treatment of underlying disorders (i.e., plasma cell dyscrasias, chronic inflammatory conditions, chronic infections)
COMMONLY ASSOCIATED CONDITIONS
- AL
- Multiple myeloma
- Non-Hodgkin lymphoma
- Rarely, Waldenstr ¶m macroglobulinemia
- AA
- Chronic inflammatory arthritides
- Most commonly seen in adult and juvenile rheumatoid arthritis (RA)
- Spondyloarthropathies: ankylosing spondylitis, psoriatic arthritis
- Rarely in systemic lupus erythematosus (SLE), Sj ¶gren syndrome, and vasculitides
- Periodic fever syndromes:
- FMF, tumor necrosis factor (TNF) receptor-associated periodic syndrome, Muckle-Wells syndrome
- Chronic infections: bronchiectasis, tuberculosis, osteomyelitis
- Crohn disease
- Neoplasms, particularly renal cell cancer
- Castleman disease
DIAGNOSIS
HISTORY
- Four essential steps in diagnosing AL:
- Consider the diagnosis.
- Make the diagnosis by tissue biopsy.
- Determine the precursor protein.
- Define the extent of involvement (2)[A].
- Careful family history to assess for familial AL: Familial TTR amyloidosis (ATTR) can present as syndromes of
- Familial amyloidotic polyneuropathy
- Familial amyloidotic cardiomyopathy
- Suspect AA if inflammatory disease is uncontrolled for >5 years.
- Symptoms are determined by the organ or system involved and can often be obscured by the underlying disease:
- Renal and cardiac involvement are most common.
- AL can affect all organs except the central nervous system (CNS).
- Heritable (ATTR) similar to AL but with more neuropathic symptoms and less renal involvement.
- AA: mostly kidney, liver involved
PHYSICAL EXAM
- Renal involvement common; proteinuria or nephrotic syndrome, particularly in AL type; microscopic hematuria more prominent in AA
- Cardiac involvement common, with diastolic dysfunction and conduction abnormalities
- Neurologic manifestations are especially prominent in the heredofamilial amyloidoses: peripheral neuropathies; autonomic dysfunction; Alzheimer dementia due to localized, organ-specific type of AL
- Amyloid deposition can rarely lead to hepatomegaly and splenomegaly late in the disease process: jaundice, portal hypertension, sequestration
- GI amyloid may cause motility abnormalities, gastric atony, malabsorption, bleeding, or pseudo-obstruction.
- Endocrine glands may be infiltrated but rarely the cause of dysfunction unless the gland becomes largely replaced by amyloid.
- Articular structures can directly, although rarely, be involved; almost exclusively AL type and dialysis-related type; involves synovium, cartilage; in these cases, can mimic rheumatologic conditions by presenting as a symmetric arthritis of small joints.
- Respiratory system may develop accumulations of amyloid in sinuses, larynx, and trachea. The lower respiratory tract is the most frequently involved in primary (AL) disease; amyloid deposition may resemble a neoplasm in the lung parenchyma and bronchi.
- Due to infiltration of soft tissue by amyloid:
- Macroglossia (pathognomonic for primary AL)
- Shoulder pad sign (muscle)
- Nail dystrophy, alopecia
- Hoarse, weak voice (vocal cord infiltration)
- Corneal opacities, vitreous infiltration
- Vascular infiltration (endothelial damage) can lead to raccoon eyes or spontaneous purpura.
- Hematologic changes may include fibrinogenopenia and selective deficiency of clotting factors.
DIFFERENTIAL DIAGNOSIS
- Distinguish different forms of amyloidosis after biopsy with protein fibril typing-using immunofluorescence or immunohistochemical staining for SAA protein, TTR, light chains; mass spectrometry becoming more available
- Particularly, distinguish AL from genetic, senile, and localized amyloidosis because management and prognosis vary considerably.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- CBC, chemistry panel, urinalysis
- Consider electrocardiography, echocardiography, renal ultrasound (US), bone scan, liver/spleen imaging as clinically indicated. Cardiac MRI reliably differentiates between myocardial hypertrophy and expansion of interstitial space by amyloid deposition (3)[C].
- Monitor for early evidence of AL in patients being treated for multiple myeloma or MGUS with serial BNP, urinary albumin.
Follow-Up Tests & Special Considerations
- AL: serum and urine protein electrophoresis with immunofixation; serum free light chain analysis; bone marrow examination and imaging; brain natriuretic peptide (BNP) if symptoms of congestive heart failure
- AA: tests to further evaluate for underlying inflammatory disease:
- ESR, C-reactive protein (CRP), rheumatoid factor (RF), anticyclic citrullinated peptide, antinuclear antibody (ANA)
- Gene testing for FMF, TNF receptor-associated periodic syndrome (TRAPS)
- AF: Abnormal ATTR may be isolated.
Diagnostic Procedures/Other
- Confirmation of diagnosis requires presence of amyloid deposits on biopsy.
- Less invasive and first line: abdominal fat pad aspirate; rectal, bone marrow, or skin biopsy
- If negative, biopsy of affected organs has higher sensitivity: kidney, liver, sural nerve
- Fibril typing is critical in deciding appropriate therapy: performed by immunohistochemistry, immunoelectron microscopy, or mass spectrometry (1)[A]
- Radiolabeled serum amyloid P component (SAP) scintigraphy: quantitatively monitors accumulation of amyloid deposits. Available only at specialized centers.
Test Interpretation
- Light microscopy: demonstration of amyloid deposits as amorphous, nodular hyaline material
- Fibrils bind to Congo red, leading to apple-green birefringence under polarized light.
TREATMENT
GENERAL MEASURES
- Familial (ATTR): liver transplant to remove site of synthesis of the mutant protein
- Hemodialysis and renal transplantation for renal amyloid
- Hemodialysis-related amyloidosis: Change to peritoneal dialysis.
MEDICATION
First Line
- Current treatment aimed at reducing level of amyloid proteins (e.g., immunosuppression in AA amyloidosis, chemotherapy in AL amyloidosis, supportive care)
- The novel immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib have changed the standard treatment of multiple myeloma.
- AL
- Autologous stem cell transplantation (ASCT), preceded by 3 to 4 cycles of dexamethasone plus combinations of either lenalidomide + bortezomib, or thalidomide + bortezomib (4)[B]
- For patients considered ineligible for ASCT:
- Standard-risk patients: melphalan, prednisone, and thalidomide
- High-risk patients: melphalan, prednisone, and bortezomib (4)[A]
- AA
- Control of underlying inflammatory disease.
- Consider anticytokine therapy for autoimmune diseases (5)[A].
- Colchicine for FMF
Second Line
- Primary AL: melphalan + prednisone, followed by ASCT
- Bendamustine (an alkylator with a novel mechanism of action) + prednisone is useful in relapsed/refractory AL disease (1)[B].
ADDITIONAL THERAPIES
- Eprodisate for secondary AA:
- Interferes with AA amyloid protein interaction with glycosaminoglycans, disrupting fibril formation
- Diflunisal for familial amyloidosis (6)[C]
- There is growing interest in developing therapeutic antibodies to directly target amyloid deposits (1).
SURGERY/OTHER PROCEDURES
For localized amyloidosis of lip, skin, nasopharynx, or urinary tract, removal or excision at site of occurrence may be sufficient.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Acute nephrotic syndrome/renal failure
- Cardiomyopathy/acute CHF
- Hepatic failure, pseudo-obstruction
- GI hemorrhage
- Respiratory failure
- Superimposed infections
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Routine monitoring of renal function
- Monitor adverse effects of medications.
- AA: Maintenance of low SAA protein levels correlates to better outcome.
- AL: Prognostic indicators to follow are N-terminal prohormone of BNP, cardiac troponin T and I, serum-free light chains.
DIET
- Low-protein, low-salt diet for patients with renal disease
- Low-salt cardiac diet for CHF patients
PATIENT EDUCATION
- The Amyloidosis Support Network: http://www.amyloidosis.org/
- Amyloid Research Group of Indiana University: http://www.iupui.edu/~amyloid/
PROGNOSIS
- In general, older patients do less well.
- AL: Median survival is 1 to 2 years after diagnosis:
- Cardiac involvement (CHF): 6 months (sudden death, presumably due to arrhythmias, is common)
- Renal involvement: 21 months
- AA: based on underlying disease, mean survival = 133 months
- ATTR: 5 to 15 years, based on precursor protein (80% 5-year survival following liver transplant)
REFERENCES
11 Mahmood S, Palladini G, Sanchorawala V, et al. Update on treatment of light chain amyloidosis. Haematologica. 2014;99(2):209-221.22 Dispenzieri A, Gertz MA, Buadi F. What do I need to know about immunoglobulin light chain (AL) amyloidosis? Blood Rev. 2012;26(4):137-154.33 Dubrey SW, Comenzo RL. Amyloid diseases of the heart: current and future therapies. QJM. 2012;105(7);617-631.44 Morabito F, Gentile M, Mazzone C, et al. Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs. Eur J Haematol. 2010;85(3):181-191.55 Keersmaekers T, Claes K, Kuypers DR, et al. Long-term efficacy of infliximab treatment for AA-amyloidosis secondary to chronic inflammatory arthritis. Ann Rheum Dis. 2009;68(5):759-761.66 Dember LM. Modern treatment of amyloidosis: unresolved questions. J Am Soc Nephrol. 2009;20(3):469-472.
SEE ALSO
Multiple Myeloma
CODES
ICD10
- E85.9 Amyloidosis, unspecified
- E85.3 Secondary systemic amyloidosis
- E85.2 Heredofamilial amyloidosis, unspecified
- E85.8 Other amyloidosis
- E85.4 Organ-limited amyloidosis
- E85.1 Neuropathic heredofamilial amyloidosis
- E85.0 Non-neuropathic heredofamilial amyloidosis
ICD9
- 277.30 Amyloidosis, unspecified
- 277.39 Other amyloidosis
- 277.31 Familial Mediterranean fever
SNOMED
- Amyloidosis (disorder)
- Secondary amyloidosis
- AL amyloidosis (disorder)
- Familial non-neuropathic amyloidosis
- age-related amyloidosis (disorder)
- AA amyloidosis (disorder)
CLINICAL PEARLS
- The most commonly affected organs resulting in symptoms are heart, kidneys, skin, peripheral and autonomic nerves, and liver; early detection is key to improved survival; respective means of presentation are as follows:
- Normal ejection fraction with diastolic dysfunction, left ventricular (LV) hypertrophy with low-voltage ECG
- Nephrotic syndrome with preserved glomerular filtration rate (GFR)
- Purpura, most notably around the eyes and neck
- Small-fiber peripheral neuropathy characterized by dysesthesia
- Orthostatic hypotension
- Hepatomegaly often with a cholestatic rise in LFTs
- Consider amyloidosis in patients with multiple myeloma, RA, juvenile RA, FMF, and other long-standing chronic inflammatory conditions.
- Biopsy for definitive diagnosis: Congo red stain demonstrates apple-green birefringence under polarized light.