Amyloidosis (ORPHA:69)
A vast group of rare systemic diseases characterized by the presence of insoluble fibrillar protein deposits in tissues. Amyloidoses are classified according to biochemical type of amyloid protein involved.
Epidemiology
AL amyloidosis's estimated global incidence of 1/95,800 people, with males preponderance. Hereditary ATTR amyloidosis (or ATTRv) mid-global prevalence estimate is of 1/450,000 people (range 1/120,000-830,000). In Tuscany, the incidence of ATTR wild type (ATTRwt) and ATTRv is 1/37,500 and 1/370,000, respectively, with male preponderance. AA amyloidosis estimated incidence is 1-2/1,000,000, but is decreasing.
Clinical description
The most frequent forms are AL amyloidosis, involving all organs except the brain, ATTR amyloidosis, ATTRwt involving the heart and ATTRv involving nerves and heart, and AA amyloidosis involving mainly kidneys, thyroid and GI tract. Progression is usually severe, as affected organs' functions are progressively destroyed. Localized amyloidosis usually has a benign course.
Etiology
AL amyloidosis is caused by plasma cell clone producing misfolded immunoglobulin LC that deposits as fibrils in vital organs. ATTR amyloidosis is caused by transthyretin, produced mainly by the liver, the retina epithelial cells and choroid plexus. ATTRv is associated with >130 mutations in the transthyretin gene. In the elderly, particularly in men, ATTRwt causes cardiac amyloidosis. AA amyloidosis is caused by persistent high concentration of serum amyloid A (SAA) in chronic inflammatory diseases.
Diagnostic methods
Diagnosis can be facilitated by clinical red flags. Once the suspicion of amyloidosis is made, the first step is the search for the monoclonal protein. In the presence of a monoclonal protein, a biopsy of abdominal fat, or salivary glands, or target organs is necessary. Typing of amyloid deposits is mandatory, using mass spectrometry, or immunoelectron-microscopy and immunohistochemistry. In the absence of monoclonal protein, scintigraphy with bone tracers can diagnose cardiac ATTR.
Differential diagnosis
The various types of systemic amyloidosis have a similar clinical presentation, and can be misdiagnosed as each other with catastrophic therapeutic consequences. Misdiagnosis with common diseases, such as type 2 diabetes and congestive heart failure, can occur. ATTRv amyloidosis can be misdiagnosed with chronic inflammatory demyelinating polyneuropathy.
Antenatal diagnosis
Prenatal diagnosis is available for severe forms, mainly Portuguese amyloid neuropathies.
Genetic counseling
Genetic counseling is recommended in patients with hereditary forms of amyloidosis and in their at-risk relatives. Pre-symptomatic genetic testing can be offered in the context of genetic counseling. Clinical monitoring of asymptomatic TTR mutation carriers should start ten years before the predicted age of onset of the disease according to genotype.
Management and treatment
Effective therapies are now available for the three major types of amyloidosis. Frontline treatments vary greatly depending on the type of amyloidosis; careful diagnosis must be performed beforehand. For all types of amyloidosis, supportive therapy plays a fundamental role. Appropriate management of the cardiac, renal, liver, gastrointestinal, nutritional, and neurological manifestations requires concerted action with specialists.
Prognosis
The recent development of effective therapies has dramatically improved the outlook of patients with the most common systemic amyloidosis. For AL amyloidosis patients, the median survival is >6 years, with ∼1/3 of patients achieving long-term survival (>10 years) without sign of active disease. The same applies to ATTR amyloidosis. The median survival of patients presenting with polyneuropathy is ∼10 years, and ∼4-5 years for those presenting with cardiac involvement. Disease-modifying therapies recently introduced are expected to significantly improve outcomes. In AA amyloidosis, the prognosis depends on the nature of the underlying disease. Biologic therapies have dramatically improved the prognosis.

                            Last update: 
                            April 2023


                            - Expert reviewer(s): 
                            Pr Giampaolo MERLINI | RITA*


                                * European Reference Network