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AMYLOIDOSIS


AMYLOIDOSIS
Amyloidosis is a multi-system disease in which amyloid protein fibrils deposit and accumulate in various organs, where they cause progressive dysfunction. A wide range of signs and symptoms may be seen depending on the specific organ systems involved.


AMYLOIDOSIS

PATHOPHYSIOLOGY
Amyloid fibrils are rigid, nonbranching, linear fibrils that are 8 to 10 nm wide. They are composed of normally soluble proteins that become misfolded, resulting in structural abnormalities that promote aggregation. Several factors can lead to protein misfolding and fibril formation, such as aging (i.e., transthyretin in senile amyloidosis); elevated serum concentrations (i.e., 2 microglobulin in dialysis-related amyloidosis); and inherited mutations (i.e., hereditary amyloidosis). Over 20 different proteins have been identified to have amyloidogenic potential. The amyloid fibril structure is the same irrespective of the precursor protein.
In addition to the misfolded proteins, all amyloid fibrils contain a glycoprotein called serum amyloid P component (SAP), which renders them resistant to proteolysis. In addition, fibrils contain glycosaminoglycans, such as heparan sulfate, that play an important role in fibril assembly and the binding of fibrils to target tissues.
It is not entirely clear how deposition of amyloid fibers leads to organ dysfunction. It appears probable, however, that fibril accumulation disrupts normal tissue architecture, and that protofibrils (intermediate fibril structures) cause oxidative stress that triggers apoptosis.
The particular organ distribution of amyloid fibrils appears to depend on poorly understood features of the precursor protein. The amyloid fibrils most often associated with renal disease are formed either by immunoglobulin light chains (AL amyloidosis) or serum amyloid A (AA amyloidosis).
AL (primary) amyloidosis occurs in the setting of an abnormal clonal proliferation of plasma cells. During this proliferation, the light chains acquire proamyloidogenic mutations. Such mutations do not always occur when light chains are overproduced, as evidenced by the fact that only a minority of patients with multiple myeloma develop AL amyloidosis. The annual incidence of AL amyloidosis is 4.5 cases per 100,000 individuals, and it is the most common systemic amyloidosis in North America. It typically affects patients over the age of 40.
AA (secondary) amyloidosis occurs in the setting of chronic inflammatory diseases. The precursor protein is serum amyloid A (SAA), an acute phase reactant that is overproduced in chronic inflammatory states. Through a complex, incompletely understood mechanism, SAA is cleaved and undergoes a conformational change that leads to fibril formation. About half of AA amyloidosis cases are associated with rheumatoid arthritis. Other causes of secondary amyloidosis include ankylosing spondylitis, psoriatic arthritis, chronic pyogenic infections, inflammatory bowel disease, cystic fibrosis, neoplasms, and familial Mediterranean fever.
In both AA and AL amyloidosis, the renal manifestations depend on the location of fibril deposition. In the majority of renal amyloidosis cases, amyloid fibrils deposit in the glomerulus, causing proteinuria that is typically in the nephrotic range. Additional signs and symptoms are often consistent with the nephrotic syndrome (see Plate 4-7), including edema, hypercholesterolemia, and hypoalbuminemia. Renal function is usually preserved or only slightly impaired. Urine sediment may reveal lipids or fatty casts but should not contain cells or cellular casts. In a small number of cases, amyloid may deposit in the renal microvasculature, causing a slowly progressive loss of renal function without proteinuria. In even rarer cases, fibrils may deposit in the tubules, causing functional defects such as distal renal tubular acidosis, nephrogenic diabetes insipidus, or the renal Fanconi syndrome.
Both AL and AA amyloidosis may also cause disease in other organ systems. Myocardial deposition is common, resulting in signs and symptoms of restrictive cardiomyopathy. Hepatic deposition leads to hepatomegaly and abnormal liver function tests. Peripheral nervous deposition can cause sensory, motor, and autonomic abnormalities. Soft tissue deposition may manifest as macroglossia and carpal tunnel syndrome.

PRESENTATION AND DIAGNOSIS
Amyloidosis should be on the differential diagnosis for any adult who presents with idiopathic nephrotic syndrome, especially in the presence of unexplained heart failure and peripheral and/or autonomic neuropathy. The presence of a chronic inflammatory process, such as rheumatoid arthritis, suggests possible secondary amyloidosis. A monoclonal paraprotein spike on immunofixation electrophoresis of serum or urine suggests the diagnosis of AL amyloidosis.
A tissue diagnosis is the gold standard for diagnosis, and a renal biopsy may be performed in adults with renal manifestations.
Light microscopy reveals nodular glomerulosclerosis, with deposits of amorphous material seen in the mesangium and extending into the capillary loops. The mesangial depositions can resemble Kimmelstiel-Wilson nodules seen in diabetic nephropathy, but they stain periodic acid-Schiff (PAS) more weakly. A characteristic feature of amyloid fibrils is their ability to stain with Congo Red, which causes them to exhibit characteristic apple-green birefringence under polarized light. AL and AA amyloidosis can be differentiated by immunofluorescence (IF) staining, which is positive for lambda or kappa light chains in AL amyloidosis, and for SAA in AA amyloidosis.
Electron microscopy reveals the presence of randomly organized amyloid fibrils in the mesangium and glomerular basement membrane. The fibrils are approximately 8 to 10 nm in diameter and can be differentiated from the fibrils of immunotactoid and fibrillary glomerulonephritis by their distribution and size. The fibrils in immunotactoid glomerulonephritis are composed of hollow tubules 30 to 50 nm in size, arranged in parallel stacks, whereas the fibrils in fibrillary glomerulonephritis range from 16 to 24 nm.
Somewhat less invasive diagnostic tests than a renal biopsy include abdominal fat or rectal biopsy. These are highly specific but only moderately sensitive (70% to 80%). Thus if amyloidosis is strongly suspected based on clinical history, these superficial biopsies may be performed before renal biopsy. If these tests are negative, however, renal biopsy should be performed.
If AL amyloidosis is diagnosed on tissue biopsy, bone marrow biopsy is typically performed to determine the plasma cell burden and rule out the presence of multiple myeloma and other dyscrasias.

AMYLOIDOSIS

TREATMENT
In general, there are two major approaches to the treatment of amyloidosis. The most common approach is to reduce the production of precursor protein. AL production can be targeted using chemotherapy (often using some combination of melphalan, thalidomide, proteosome inhibitors, and steroids) or stem cell trans- plantation. AA production can be reduced by treating the underlying inflammatory disease. In rheumatoid arthritis, for example, anticytokine therapy may be helpful. In chronic infections, eradication of the focus of infection with appropriate measures, including anti-microbial agents, should be the focus.
The second approach is to destabilize the amyloid fibril by targeting its SAP or glycosaminoglycan component. An example of this approach is the compound eprodisate, which attaches to the glycosaminoglycan binding sites of amyloid fibrils in tissues, leading to fibril destabilization.
No matter how the primary disease process is treated, patients should receive conservative management for symptoms of nephrotic syndrome, including diuretics and salt restriction.

PROGNOSIS
In AL amyloidosis, the prognosis depends on the degree of systemic involvement (especially cardiac involvement) and the degree to which therapy reduces free light chain production. Although AL amyloidosis was previously considered a rapidly fatal disease, patient survival appears to be increasing with current treatment regimens.
In AA amyloidosis, the prognosis depends on the activity of the underlying disease, and infections are the major cause of death. There have been well-documented cases of remission of AA amyloidosis with control of the infectious source.