Amyloidosis

Signs and symptoms

The presentation of amyloidosis is broad and depends on where amyloid accumulates, with the kidney and heart most commonly involved. Kidney deposition often affects the glomerular capillaries and mesangial regions, leading to proteinuria and nephrotic syndrome; about 20% of AL and 40–60% of AA amyloidosis cases progress to end-stage kidney disease requiring dialysis. Cardiac involvement, especially in AL amyloidosis, can cause diastolic and systolic heart failure, with EKG changes such as low voltage and conduction abnormalities, and echocardiography showing a restrictive filling pattern.

Symptoms of cardiac amyloidosis include shortness of breath, fatigue, and edema. Amyloidosis may also involve the central and peripheral nervous systems. Sensory neuropathy develops symmetrically and progresses from distal to proximal, while autonomic neuropathy can present as orthostatic hypotension or nonspecific gastrointestinal symptoms like constipation, nausea, or early satiety. Central nervous system involvement can lead to life-threatening arrhythmias, cardiac failure, malnutrition, infection, or death.

Peripheral neuropathy may cause erectile dysfunction, incontinence, pupillary dysfunction, and sensory loss depending on the distribution of amyloid along nerves.

Pathogenesis

Amyloidoses are considered protein misfolding diseases. Most amyloid-forming proteins are secreted, so misfolding and aggregation occur in the extracellular space. Of the 37 proteins identified as vulnerable to amyloid formation, only four are cytosolic.

One third of amyloid disease is hereditary, often with early onset, while half are sporadic with late onset, possibly linked to aging-related decline in protein regulation. Amyloid-forming proteins aggregate into fibrils with a beta-sheet structure that is resistant to proteolysis, leading to extracellular deposits. Intermediate oligomeric forms are thought to exist, and both oligomers and fibrils can be toxic to cells and interfere with organ function.

Diagnosis

Diagnosis generally requires tissue biopsy, with the first-line site being subcutaneous abdominal fat (fat pad biopsy) due to ease of acquisition, though it may yield false negatives. Other less invasive biopsy sites include rectal mucosa, salivary gland, lip, or bone marrow, which can achieve a diagnosis in up to 85% of people. The most useful stain is Congo red, which, combined with polarized light, makes amyloid appear apple-green on microscopy; thioflavin T stain may also be used.

Imaging techniques such as nuclear medicine PYP scan, DPD scan, or SAP scan are employed. The type of amyloid protein can be determined by detecting abnormal proteins in blood via protein electrophoresis or light chain determination, immunohistochemistry, or laser microdissection with mass spectrometry, the most reliable method. Immunohistochemistry identifies AA amyloidosis most of the time but can miss many AL cases. For AL, immunofixation electrophoresis of urine or serum is positive in 90% of people, and bone marrow biopsy with immunohistochemical staining for dominant plasma cells may be used if electrophoresis is negative.

Treatment

Treatment depends on the type of amyloidosis. For AL amyloidosis, high-dose melphalan followed by stem cell transplantation is recommended for stage I and II, though only 20–25% of people are eligible. For those not eligible, chemotherapy with cyclophosphamide-bortezomib-dexamethasone-daratumumab (Dara-Cybord) is the recommended option. In AA amyloidosis, symptoms may improve by treating the underlying condition; TNF-alpha inhibitors such as infliximab and etanercept are used for an average of 20 months, and if ineffective, interleukin-1 or interleukin-6 inhibitors may be considered.

For ATTR amyloidosis, both wild-type and variant forms may be treated with tafamidis, which reduces mortality and hospitalization due to heart failure. Other therapies include diflunisal, inotersen, and patisiran. Inotersen blocks gene expression of both wild-type and mutant TTR and has been approved in Canada, the European Union, and the USA for hereditary transthyretin amyloidosis with polyneuropathy.

Did You Know?

• Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied.
• AA amyloidosis is the most common form in developing countries and can complicate longstanding infections such as tuberculosis, osteomyelitis, and bronchiectasis.
• People undergoing long-term hemodialysis (14–15 years) can develop amyloidosis from accumulation of light chains of the HLA 1 complex.