Amyloidosis
Amyloidosis is a group of protein-misfolding disorders characterized by the extracellular deposition of insoluble polymeric protein fibrils in tissues in organs. Tend to form beta-pleated structural conformations. Named after amylum (STARCH) by Virchow due to microscopic appearance resembling starch.
Amyloid diseases are classified according to whether they are systemic or localized, acquired or inherited, and the clinical patterns of disease. The standard nomenclature is AX, where X represents the protein present in the fibril.
Diagnosis and Workup of Amyloidosis
- Biopsy is required for systemic amyloidosis.
- While the clinically involved organs can be biopsied, an abdominal fat pad biopsy is positive in more than 80% of systemic amyloidosis and therefore allows avoidance of a more invasive sample. When negative, an invasive tissue biopsy of the affected organ is required.
- deposits show "apple green" birefringence under polarized light
- further tests (mass spectrometry, etc)are done to determine the involved protein in the amyloid plaques
- Assess for monoclonal gammopathy with SPEP + IFE + FLC, UPEP
AL Amyloidosis
Usually caused by clonal expansion of BM plasma cells that secrete monoclonal Ig LC that deposits as amyloid fibrils. If the LC misfolds --> AL amyloidosis, if the LC folds properly --> MM spectrum. This depends on the primary sequences of the clonal LC and other genetic factors. AL amyloidosis can occur with MM, other B lymphoproliferative disease including NHL, and Waldenstrom macroglobulinemia.
The most common systemic amyloidosis diagnosed in NA. Usually occurs after age 40 and often rapidly progressive and fatal if untreated.
Widespread clinical manifestations generally from lambda-subtype light chain disease.
| Manifestation | Note |
|---|---|
| Constitutional symptoms | |
| Renal amyloidosis (70-80%) | Often with nephrotic range proteinuria. Interstitial nephritis. |
| Cardiac Amyloidosis | Leading cause of death in AL amyloid |
| Neuroamyloidosis | Peripheral sensorimotor neuropathy, autonomic dysfunction |
| Macroglossia (10% but pathognomonic) |  |
| Hepatic/splenic | cholestasis, HSM, functional hyposplenism |
| Coagulopathy | Easy bruising due to capillary disease and Factor X binding. Classic raccoon eyes  |
| Nail dystrophy | |
| Alopecia | |
| Amyloid arthropathy | wrist and shoulders |
SPEP/UPEP are not sufficient as there generally is no M spike; immunofixation will detect a clonal light chain population.
Treatment of AL Amyloidosis
AL amyloid is an aggressive disease (1-2 years without treatment prognosis, 6 months with cardiac involvement). Therapies target the clonal etiology of the disorder, using principles for Myeloma:
- High dose melphalan --> SCT
- Melphalan + dexamethasone
- Anti-plasma cell agents (lenalidomide, thalidomide, bortezomib, etc)
- Cardiac transplantation
Always remember to treat the manifestations separately (Cardiac Amyloidosis, Nephrotic Syndrome, etc).
AA Amyloidosis
AA amyloid is a disease of chronic inflammation (RA, IBD, FMF, Castleman's, etc...) and infection (TB, subacute endocarditis...). The protein in question is the SAA protein, which is an acute phase apoprotein made in the liver.
Clinically this can overlap with AL amyloidosis. Organ involvement generally involves the kidney first and progresses to HSM, autonomic neuropathy. Cardiac AA amyloid is a late presentation.
Treatment: treat the underlying disease. Colchicine is only effective in FMF.
ATTR Amyloidosis
The familial amyloidoses are autosomal dominant. Rare and generally present in mid-life.
ATTRm is the most common form and is due to transthyretin mutation ("prealbumin"). Mutation V122I has a 4% carrier frequency in African-Americans, and prompts consideration for ATTR amyloidosis in African-American patients with concentric cardiac hypertrophy and evidence of diastolic HF.
ATTRwt (wild type TTR) is due to unmutated precursor protein that occurs with aging. Increases in frequency in older men. Found in 25% of heart autopsies done in men older than age 80 -- extremely prevalent with age.
Clinical presentation: ATTRm associated with familial amyloidotic polyneuropathy, cardiomyopathy. Vitreous opacities are pathognomonic for ATTR amyloid. Ruptured biceps tendon (Popeye sign) is specific for ATTRwt.
Treatment: Without treatment, the survival period after onset of ATTR disease is 5-15 years. Liver transplantation removes the major source of variant TTR production (best done in younger patients).
Aβ2M Amyloidosis
Beta2-microglobulin is the invariant chain of MHC class 1 and produces rheumatologic manifestations in patients on dialysis, because it is usually excreted by the kidney. In ESRD levels become elevated. Declining incidence due to newer membranes and high-flow dialysis techniques. Historically not filtratable by the dialyser filter
Clinical presentation: most often first presents with carpal tunnel syndrome (frequently bilateral). Can have persistent joint effusions (large joints, noninflammatory) with amyloid protein present in the synovial fluid.
There is no specific therapy for this disease. May improve after renal allograft and stopping dialysis.
References
- Harrison's 21E, Chapter 112