Description
Amyloidosis is a group of diseases characterised by extracellular deposition of pathologic insoluble fibrillar proteins, known as amyloids, within body tissues and organs. This abnormal accumulation of amyloid proteins disrupts the normal function of organs leading to a wide range of symptoms depending on the location and amount of deposition.
Pathogenesis
Amyloidosis occurs when the body’s protein folding mechanisms fail, allowing misfolded proteins to accumulate. These misfolded proteins form beta-pleated sheets which are resistant to degradation, leading to extracellular deposition of amyloid fibrils. Various precursor proteins, either mutant or wild type, can form amyloids; the type of precursor protein determines the subtype of amyloidosis.
Subtypes
There are several subtypes of amyloidosis which are classified based on the precursor protein that forms the amyloid. They include:
- AL amyloidosis (Amyloid Light chain) – Primary systemic amyloidosis (most common)
- AA amyloidosis (Amyloid A protein) – Secondary amyloidosis
- Hereditary or familial amyloidosis (most commonly transthyretin amyloidosis, ATTR)
- Dialysis-related amyloidosis (beta2-microglobulin)
Epidemiology, Risk Factors & Associations
Primary systemic amyloidosis, also known as AL amyloidosis, is the most common form of systemic amyloidosis in developed countries. It has an estimated incidence of 8 to 12 per million person-years (0.008 to 0.012%). Risk factors include older age and monoclonal gammopathy. It’s commonly associated with plasma cell disorders like multiple myeloma.
Secondary amyloidosis (AA amyloidosis) is usually associated with chronic inflammatory diseases (from most common to least):
- Rheumatoid arthritis
- Inflammatory bowel disease (ulcerative colitis and Crohn’s disease)
- Chronic infections (e.g. tuberculous and osteomyelitis).
Clinical Features
The clinical presentation of amyloidosis is broad, reflecting its systemic nature. Symptoms are typically nonspecific and are related to the organ system involved. Typical manifestations include:
- Nephrotic syndrome, renal failure: kidneys are frequently involved in AL and AA amyloidosis.
- Cardiomyopathy, heart failure: cardiac involvement is frequent in AL amyloidosis.
- Neuropathy: seen in familial (ATTR) amyloidosis and sometimes in AL amyloidosis.
- Hepatomegaly: due to amyloid deposition in the liver.
Complications
Complications depend on the organ involvement. Kidney involvement can lead to chronic kidney disease. Cardiac involvement can result in restrictive cardiomyopathy and heart failure. Autonomic neuropathy can lead to orthostatic hypotension, gastrointestinal motility issues, and sexual dysfunction.
Pathological Features
Morphology
Extracellular deposits of eosinophilic, amorphous, and hyaline material are seen in the affected organs.
Histopathology
Amyloid deposits can be identified histologically by their characteristic apple-green birefringence when stained with Congo red and viewed under polarised light.
Biochemistry
The type of amyloid can be further classified using mass spectrometry or immunohistochemical staining techniques, which are more accurate.
Genetics
Genetic testing may be useful in patients with suspected hereditary amyloidosis, such as in ATTR.
Radiological Features
Cardiac
- Echocardiography: Increased ventricular wall thickness without chamber dilation, ‘granular sparkling’ appearance of the myocardium.
- Cardiac MRI: Global subendocardial late gadolinium enhancement, increased myocardial signal on T1-weighted images, decreased myocardial signal on T2-weighted images due to amyloid deposition.
Pulmonary
- Chest X-ray: Nodular or interstitial opacities, tracheobronchial thickening.
- CT: Multiple pulmonary nodules, thickening of interlobular septa and pleural surfaces, lymphadenopathy.
Renal
- Ultrasound: Increased echogenicity of the renal cortex, kidneys may be normal or large in size.
Gastrointestinal
- Barium swallow: Mucosal irregularity, poor peristalsis in the esophagus.
- CT abdomen: Thickening of the bowel wall or stomach, hepatomegaly with heterogeneous enhancement.
Skeletal
- X-ray: “Punched-out” lytic lesions similar to multiple myeloma, soft tissue masses.
- MRI: Increased marrow signal on T1-weighted images, decreased signal on T2-weighted images due to marrow infiltration.
Soft Tissue and Peripheral Nervous System
- MRI: Enlargement and increased signal of peripheral nerves on T1 and T2-weighted images.
- Ultrasound: Enlarged peripheral nerves with increased echogenicity.
Central Nervous System
- MRI Brain: Multiple white matter hyperintensities on T2-weighted images, cerebral amyloid angiopathy can present with lobar cerebral microhemorrhages on susceptibility-weighted images.
These are general trends; findings can vary based on the subtype of amyloidosis and extent of disease.
Grading and Staging
For AL amyloidosis, the Mayo staging system is used which incorporates cardiac biomarkers (NT-proBNP and troponin T) and free light chain difference.
Management
- The management of amyloidosis is usually multidisciplinary, involving haematologists, nephrologists, and cardiologists, amongst others.
- The therapeutic approach depends on the subtype of amyloidosis, the extent of organ involvement, and the patient’s overall health.
- Treatment usually targets the underlying condition producing the amyloid protein and supportive care for organ dysfunction. For example, chemotherapy is often used in AL amyloidosis to target the underlying plasma cell dyscrasia.