Amyloidosis is a rare disease that results from the buildup of misfolded proteins known as amyloids. When proteins that are normally dissolvable in water fold to become amyloids, they become insoluble and deposit in organs or tissues, disrupting normal function. The type of protein that is misfolded and the organ or tissue in which the misfolded proteins are deposited determine the clinical manifestations of amyloidosis.
There are four main types of amyloidosis, each due to the deposition of a specific protein. The most common type is AL amyloidosis, caused by the deposition of light chain proteins produced by plasma cells in different disease states. The second most common is AA amyloidosis due to the accumulation of S amyloid A protein or SAA, which occurs in association with chronic infections – e.g. tuberculosis – or inflammatory illnesses such as rheumatoid arthritis. The third and the fourth type are due to the deposition of a genetically defective or normal form of a protein called transthyretin respectively. Other minor forms of amyloid are also known.
The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved.
Amyloid deposition in the kidneys can cause nephrotic syndrome, which results from a reduction in the kidney’s ability to filter and hold on to proteins. The nephrotic syndrome occurs with or without elevations in creatinine and blood urea concentration, two biochemical markers of kidney injury. In AA amyloidosis the kidneys are involved in 91-96% of people, symptoms ranging from protein in the urine to nephrotic syndrome and rarely renal insufficiency.
Amyloid deposition in the heart can cause both diastolic and systolic heart failure. EKG changes may be present, showing low voltage and conduction abnormalities like atrioventricular block or sinus node dysfunction. On echocardiography the heart shows a restrictive filling pattern, with normal to mildly reduced systolic function. AA amyloidosis usually spares the heart.
People with amyloidosis do not get central nervous system involvement but can develop sensory and autonomic neuropathies. Sensory neuropathy develops in a symmetrical pattern and progresses in a distal to proximal manner. Autonomic neuropathy can present as orthostatic hypotension but may manifest more gradually with nonspecific gastrointestinal symptoms like constipation, nausea, or early satiety.
Deposition of amyloids in the liver can lead to elevations in serum aminotransferases and alkaline phosphatase, two biomarkers of liver injury, which is seen in about one third of people. Liver enlargement is common. In contrast, spleen enlargement is rare, occurring in 5% of people. Splenic dysfunction, leading to the presence of Howell-Jolly bodies on blood smear, occurs in 24% of people with amyloidosis. Malabsorption is seen in 8.5% of AL amyloidosis and 2.3% of AA amyloidosis. One suggested mechanism for the observed malabsorption is that amyloid deposits in the tips of intestinal villi (fingerlike projections that increase the intestinal area available for absorption of food), begin to erode the functionality of the villi, presenting a sprue-like picture.
A rare development is a susceptibility to bleeding with bruising around the eyes, termed “racoon-eyes”. This is caused by amyloid deposition in the blood vessels and a reduced activity of thrombin and factor X, two clotting proteins that lose their function after binding with amyloid.
Amyloid deposits in tissue and causes enlargement of structures. Twenty percent of people with AL amyloidosis have an enlarged tongue, that can lead to obstructive sleep apnea, difficulty swallowing, and altered taste. Tongue enlargement does not occur in ATTR or AA amyloidosis. Enlarged shoulders, “shoulder pad sign”, results from amyloid deposition in synovial space. Deposition of amyloid in the throat can cause hoarseness. Aβ2MG amyldoisis (Hemodialysis associated amyloidosis) likes to deposit in synovial tissue causing chronic synovitis which can be lead to repeated carpal tunnel syndrome.
Both the thyroid and adrenal gland can be infiltrated. It is estimated that 10-20% of individuals with amyloidosis have hypothyroidism. Adrenal infiltration may be harder to appreciate given that its symptoms of orthostatic hypotension and low blood sodium concentration may be attributed to autonomic neuropathy and heart failure.
“Amyloid deposits occur in the pancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic amyloid is a 37-amino acid residue peptide known as islet amyloid polypeptide or amylin. This is stored with insulin in secretory granules in B cells and is co secreted with insulin”. (Rang and Dale’s Pharmacology, 2015).
No one knows what causes amyloidosis, and there may be more than one cause. Hereditary amyloidosis results from genetic changes that cause the body to make abnormal proteins. Age seems to play a role in amyloidosis — researchers think the disease may be triggered by damage that builds up in the body as we get older. This kind of damage may come from the body’s use of oxygen (oxidation) and from free radicals (harmful byproducts formed when cells use energy). Amyloid is also more likely to form in people who have immune system problems. Once amyloid deposits have started, they seem to continue building up in the same location
Diagnosis of amyloidosis requires tissue biopsy. Biopsy is assessed for evidence of characteristic amyloid deposits. The tissue is treated with various stains. The most useful stain in the diagnosis of amyloid is Congo red, which, combined with polarized light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin T stain may be used.
Tissue can come from any involved organ. But in systemic disease first line site of biopsy is subcutaneous abdominal fat, known as a fat pad biopsy, because it’s simple to acquire and less invasive than biopsy of the rectum, salivary gland or internal organs. An abdominal fat biopsy is not completely sensitive and so, sometimes, biopsy of an involved organ (such as the kidney) is required to achieve a diagnosis. For example, in AL amyloidosis only 85% of people will have a positive fatpad biopsy using Congo red stain. By comparison, rectal biopsy has sensitivity of 74-94%.
The type of the amyloid protein can be determined by various ways: the detection of abnormal proteins in the bloodstream (on protein electrophoresis or light chain determination), binding of particular antibodies to the amyloid found in the tissue (immunohistochemistry), or extraction of the protein and identification of its individual amino acids. Immunohistochemistry can identify AA amyloidosis the majority of the time, but can miss many cases of AL amyloidosis. Laser microdissection with mass spectrometry is the most reliable method of identifying the different forms of amyloidosis.
Since AL is the most common variation, diagnoses often begins with a search for plasma cell dyscrasias, memory B cells producing aberrant immunoglobulins or portions of immunoglobulins. Immunofixation electrophoresis of urine or serum is positive in 90% of people with AL amyloidosis. Immunofixation electrophoresis is more sensitive than regular electrophoresis but may not be available in all centers. Alternatively immunohistochemical staining of a bone marrow biopsy looking for dominant plasma cell can be sought in people with a high clinical suspicion for AL amyloidosis but negative electrophoresis.
ATTR is suspected in people with family history of idiopathic neuropathies or heart failure who lack evidence of plasma cell dyscrasias. ATTR can be identified using isoelectric focusing which separates out mutated forms of transthyretin. Findings can be corroborated by genetic testing to look for specific known mutations in transthyretin that predispose to amyloidosis.
AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases. AA can be identified by immunohistochemistry staining.
Prognosis varies with the type of amyloidosis. Prognosis for untreated AL amyloidosis is poor with median survival of one to two years. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like troponin and BNP. Survival diminishes with increasing stage, with estimated survival of 26, 11 and 3.5 months at stage I, II and III.
Outcomes in a person with AA amyloidosis depends on the underlying disease and correlates with the concentration of serum amyloid A protein.
People with ATTR have better prognosis and may survive for over a decade.
Senile systemic amyloidosis was determined to be the primary cause of death for 70% of people over 110 who have been autopsied.
Treatment depends on the type of amyloidosis that is present. Treatment with high dose melphalan, a chemotherapy agent, followed by stem cell transplantation has showed promise in early studies and is recommended for stage I and II AL amyloidosis. However, only 20-25% of people are eligible for stem cell transplant. Chemotherapy and steroids, with melphalan plus dexamethasone, is mainstay treatment in AL people not eligible for transplant.
In AA, symptoms may improve if the underlying condition is treated; eprodisate has been shown to slow renal impairment by inhibiting polymerization of amyloid fibrils.
In ATTR, liver transplant is curative therapy because mutated transthyretin which forms amyloids is produced in the liver.
People affected by amyloidosis are supported by multiple organizations, including the Amyloidosis Foundation, Amyloidosis Support Groups Inc., and Amyloidosis Australia, Inc.