amyloidosis

amyloidosis
Field	Hematology, Nephrology, Cardiology, Neurology

amyloidosis is a group of diseases characterized by the extracellular deposition of misfolded proteins into insoluble, toxic aggregates known as amyloid fibrils. These deposits can accumulate in various organs and tissues, disrupting their normal architecture and function. The condition encompasses multiple distinct types, each defined by the specific precursor protein involved, leading to a wide spectrum of clinical manifestations. The disease process can affect virtually any organ system, including the heart, kidneys, liver, and nervous system.

Definition and classification

The disease is formally defined by the presence of amyloid deposits, which exhibit apple-green birefringence under polarized light when stained with Congo red. Classification is primarily based on the biochemical nature of the fibril-forming protein. The most common systemic form is AL amyloidosis, where the precursor protein is derived from immunoglobulin light chains produced by a clonal plasma cell disorder, often associated with multiple myeloma. Another major type is ATTR amyloidosis, caused by the transthyretin protein, which can be hereditary due to mutations in the TTR gene or acquired (wild-type) in older adults. Other forms include AA amyloidosis, secondary to chronic inflammatory conditions like rheumatoid arthritis or tuberculosis, and rare hereditary types involving proteins such as apolipoprotein A1 or fibrinogen.

Pathophysiology

The fundamental mechanism involves the misfolding of normally soluble precursor proteins into abnormal, beta-sheet-rich structures that aggregate into rigid, linear fibrils. In AL amyloidosis, this results from the overproduction of aberrant light chains by a B cell clone. For ATTR amyloidosis, instability of the transthyretin tetramer leads to monomer misfolding. These insoluble fibrils deposit in the extracellular space of tissues, directly causing physical disruption and inducing oxidative stress and apoptosis. Organ damage arises from both the replacement of functional parenchyma and direct cytotoxic effects, with particular vulnerability in highly vascularized organs and those with limited regenerative capacity.

Clinical presentation

Symptoms are notoriously nonspecific and depend entirely on the organs involved, often leading to delayed diagnosis. Cardiac involvement, common in AL amyloidosis and wild-type ATTR amyloidosis, manifests as heart failure, arrhythmias, and features mimicking hypertrophic cardiomyopathy. Renal deposition typically presents with nephrotic syndrome and progressive renal failure. Neurological symptoms, prominent in hereditary ATTR amyloidosis, include peripheral sensory-motor neuropathy and autonomic dysfunction affecting the gastrointestinal tract. Other signs may include macroglossia, periorbital purpura (raccoon eyes), hepatomegaly, and carpal tunnel syndrome, often seen years before systemic diagnosis.

Diagnosis

Diagnosis requires a high index of suspicion and hinges on histological confirmation of amyloid deposits in a tissue biopsy, with abdominal fat pad aspiration or bone marrow biopsy often serving as initial, less invasive sites. The definitive test is demonstration of green birefringence in Congo red-stained tissue viewed under polarized light microscopy. Typing of the amyloid protein is critical and is achieved through techniques like immunohistochemistry, immunofluorescence, or, most definitively, mass spectrometry-based proteomic analysis. Ancillary tests include serum free light chain assay, immunofixation electrophoresis of blood and urine, and genetic testing for hereditary forms. Imaging with echocardiography, cardiac magnetic resonance imaging (particularly with gadolinium enhancement), and technetium pyrophosphate scintigraphy is vital for assessing organ involvement.

Treatment and management

Therapy is directed at the underlying amyloidogenic process to suppress production of the precursor protein. For AL amyloidosis, treatment mirrors that for plasma cell dyscrasias and may involve regimens like cyclophosphamide-bortezomib-dexamethasone, with autologous stem cell transplantation considered for eligible patients. For ATTR amyloidosis, novel therapies include tafamidis and patisiran, which stabilize the transthyretin tetramer or silence its gene expression via RNA interference. Supportive care is paramount and involves managing heart failure with diuretics, treating nephrotic syndrome, and providing nutritional support. In select cases, organ transplantation, such as heart transplantation or liver transplantation (for hereditary ATTR amyloidosis), may be considered.

Prognosis

Prognosis varies dramatically by type, extent of organ involvement, and the timeliness of therapy. AL amyloidosis historically carried a poor prognosis, especially with advanced cardiac disease, but survival has improved significantly with modern chemotherapy and transplantation strategies. The course of AA amyloidosis is closely tied to control of the underlying inflammatory disorder. Wild-type ATTR amyloidosis typically follows an indolent progression over many years, while hereditary forms can be more aggressive. Early diagnosis before irreversible organ damage occurs is the single most important factor influencing outcomes. Multidisciplinary management at specialized centers, such as the Amyloidosis Center at Boston University or the National Amyloidosis Centre in the United Kingdom, is associated with improved survival.

Category:Blood disorders Category:Rare diseases Category:Protein-folding diseases