Amyloidosis

Definition, Etiology, PathogenesisTop

Amyloidosis is a group of diseases sharing the common feature of the extracellular accumulation of insoluble fibrous proteins called “amyloid” in tissues and organs. Etiology and pathogenesis are not fully understood.

Amyloidosis may be systemic (see below) or localized (eg, accumulation of amyloid beta in Alzheimer disease and cerebral amyloid angiopathy). Types of amyloidosis differ with respect to the structure of proteins that form amyloid fibrils as well as clinical features and natural history of the disease. Some of the more common forms of amyloidosis (>30 are described) include:

1. AL amyloidosis (primary amyloidosis) occurs in patients with monoclonal gammopathies. Amyloid fibrils are formed by monoclonal immunoglobulin light chains.

2. AA amyloidosis (secondary, reactive amyloidosis) results from chronic inflammation (mainly rheumatoid arthritis, spondyloarthritis) or infection. The precursor of amyloid A is the acute-phase protein serum amyloid A (SAA).

3. A beta2-M amyloidosis is caused by long-term dialysis. The precursor of amyloid fibrils is beta2-microglobulin.

4. Familial amyloidosis is rare. The majority of different types of familial amyloidosis are autosomal dominant and caused by mutations in genes encoding various proteins. Most frequently this involves the transthyretin gene and leads to ATTR amyloidosis.

Clinical Features and Natural HistoryTop

1. AL amyloidosis: Symptoms depend on the location and number of amyloid deposits.

2. AA amyloidosis: Features of the underlying condition and nephrotic syndrome causing progressive renal failure, diarrhea, malabsorption, and rarely features of cardiomyopathy.

3. A beta2-M amyloidosis: Carpal tunnel syndrome (usually the presenting symptom, often bilateral), joint pain and swelling (particularly affecting large joints), pathologic fractures.

4. ATTR amyloidosis: In all affected families the age of onset is similar. The presenting feature is peripheral sensory and motor neuropathy (starting in the lower extremities), cardiomyopathy (arrhythmia may be the only manifestation of cardiac involvement), or both; autonomic neuropathy usually presents with diarrhea and orthostatic hypotension.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests reveal proteinuria (the most frequent presenting feature; occurs in AA and AL amyloidosis as well as in some rare familial forms), elevated serum creatinine levels, elevated gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) liver isoenzyme levels (in AL amyloidosis), presence of a monoclonal protein and free light chains in serum or urine (in 90% of patients with AL amyloidosis).

2. Histologic examination: Usually biopsy specimens are collected from abdominal subcutaneous adipose tissue. Congo red staining and apple-green birefringence under polarized microscopy are part of the diagnostic algorithm.

3. Immunohistochemical studies are used to establish the type of amyloidosis.

Diagnostic Criteria

Diagnosis is based on clinical features, examination of biopsy specimens, and immunohistochemical studies. In patients with suspected amyloidosis and negative results of subcutaneous adipose tissue biopsy, perform biopsy of another organ, such as the kidney, liver, minor salivary glands in the lower lip, or gastrointestinal mucosa (eg, rectal or duodenal).

TreatmentTop

1. Treatment of AL amyloidosis: Treatment of underlying monoclonal gammopathies.

2. Treatment of secondary amyloidosis (treatment in a specialized setting required):

1) Treatment of the underlying condition.

2) Specific treatment:

a) Reducing the production of amyloid precursor proteins using anti-inflammatory and immunosuppressive drugs (the effectiveness of this approach has not been confirmed).

b) Low-quality data suggest prevention of amyloid accumulation using oral colchicine 0.5­ to 1 mg/d in monotherapy (in patients with a low erythrocyte sedimentation rate [ESR] and serum C-reactive protein [CRP] levels and no clinical features of amyloidosis) or in combination with cyclophosphamide (in patients with symptomatic amyloidosis).Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the sparsity and observational nature of data. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986 Apr 17;314(16):1001-5. PubMed PMID: 3515182. Chevrel G, Jenvrin C, McGregor B, Miossec P. Renal type AA amyloidosis associated with rheumatoid arthritis: a cohort study showing improved survival on treatment with pulse cyclophosphamide. Rheumatology (Oxford). 2001 Jul;40(7):821-5. PubMed PMID: 11477289.

c) Orthotopic liver transplant in patients with familial ATTR amyloidosis was performed in selected cases to prevent organ damage, although progression of cardiac disease could still occur.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Benson MD. Liver transplantation and transthyretin amyloidosis. Muscle Nerve. 2013 Feb;47(2):157-62. doi: 10.1002/mus.23521. Epub 2012 Nov 21. Review. PubMed PMID: 23169427.

3. Treatment of organ involvement depends on the location and symptoms.

4. Symptomatic treatment, as dictated by specific organ involvement.

PrognosisTop

The estimated mean survival in patients with AA amyloidosis is ~10 years. Renal failure is the most common cause of death. Untreated patients with AL amyloidosis survive up to a year from the diagnosis. Cardiac involvement is a poor prognostic factor.