Amyloidosis


Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. Symptoms depend on the type and are often variable. They may include diarrhea, weight loss, feeling tired, enlargement of the tongue, bleeding, numbness, feeling faint with standing, swelling of the legs, or enlargement of the spleen.
There are about 30 different types of amyloidosis, each due to a specific protein misfolding. Some are genetic while others are acquired. They are grouped into localized and systemic forms. The four most common types of systemic disease are light chain, inflammation, dialysis, and hereditary and old age.
Diagnosis may be suspected when protein is found in the urine, organ enlargement is present, or problems are found with multiple peripheral nerves and it is unclear why. Diagnosis is confirmed by tissue biopsy. Due to the variable presentation, a diagnosis can often take some time to reach.
Treatment is geared towards decreasing the amount of the involved protein. This may sometimes be achieved by determining and treating the underlying cause. AL amyloidosis occurs in about 3–13 per million people per year and AA amyloidosis in about 2 per million people per year. The usual age of onset of these two types is 55 to 60 years old. Without treatment, life expectancy is between six months and four years. In the developed world about 1 per 1,000 people die from amyloidosis. Amyloidosis has been described since at least 1639.

Signs and symptoms

The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved.

Kidneys

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 chronic kidney disease.

Heart

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.

Brain

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.

Liver

Accumulation of amyloid proteins 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 2.4% of AA amyloidosis. One suggested mechanism for the observed malabsorption is that amyloid deposits in the tips of intestinal villi, begin to erode the functionality of the villi, presenting a sprue-like picture.

Glands

Both the thyroid and adrenal glands 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."

Musculoskeletal system

Amyloid proteins deposit most commonly inside the knee, followed by hands, wrists, elbow, hip, and ankle, causing joint pain. In males with advanced age, there is significant risk of wild-type transthyretin amyloid deposition in synovial tissue of knee joint. In beta 2-microglobulin amyloidosis, males have high risk of getting carpal tunnel syndrome. Aβ2MG amyloidosis tends to deposit in synovial tissue, causing chronic inflammation of the synovial tissue in knee, hip, shoulder and interphalangeal joints. Amyloid light chains deposition in shoulder joint causes enlarged shoulders, also known as "shoulder pad sign". Amyloid light chain depositions can also cause bilateral symmetric polyarthritis.
The deposition of amyloid proteins in the bone marrow without causing plasma cell dyscrasias is called amyloidoma. It is commonly found in cervical, lumbar, and sacral vertebrae. Those affected may be presented with bone pain due to bone lysis, lumbar paraparesis, and a variety of neurological symptoms. Vertebrae fractures are also common.

Eyes

A rare development is amyloid purpura, a susceptibility to bleeding with bruising around the eyes, termed "raccoon-eyes", caused by amyloid deposition in the blood vessels and reduced activity of thrombin and factor X, two clotting proteins that lose their function after binding with amyloid.

Oral cavity

Amyloid deposits in tissue can cause 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. Deposition of amyloid in the throat can cause hoarseness.

Pathogenesis

The cells in the body have two different ways of making proteins. Some proteins are made of one single piece or sequence of amino acids; in other cases, protein fragments are produced, and the fragments come and join together to form the whole protein. But such a protein can sometimes fall apart into the original protein fragments. This process of "flip flopping" happens frequently for certain protein types, especially the ones that cause amyloidosis.
The fragments or actual proteins are at risk of misfolding as they are synthesized, to make a poorly functioning protein. This causes proteolysis, which is the directed breakdown of proteins by cellular enzymes called proteases or by intramolecular digestion; proteases come and digest the misfolded fragments and proteins. The problem occurs when the proteins do not dissolve in proteolysis because the misfolded proteins sometimes become robust enough such that they are not dissolved by normal proteolysis. When the fragments do not dissolve, they get spit out of proteolysis and aggregate to form oligomers. The reason they aggregate is that the parts of the protein that do not dissolve in proteolysis are hydrophobic β-pleated sheets. They are usually sequestered in the middle of the protein, while parts of the protein that are more soluble are found near the outside. When they are exposed to water, these hydrophobic pieces tend to aggregate with other hydrophobic pieces. This ball of fragments gets stabilized by GAGs and SAP, a component found in amyloid aggregations that is thought to stabilize them and prevent proteolytic cleavage. The stabilized balls of protein fragments are called oligomers. The oligomers can aggregate together and further stabilize to make amyloid fibrils.
Both the oligomers and amyloid fibrils are toxic to cells and can interfere with proper organ function.

Diagnosis

Diagnosis of amyloidosis generally requires tissue biopsy. The 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. A number of imaging techniques such as a DPD scan or SAP scan are also in use.
Tissue can come from any involved organ, but in systemic disease the first-line site of the biopsy is subcutaneous abdominal fat, known as a "fat pad biopsy", due to its ease of acquisition versus biopsy of the rectum, salivary gland or internal organs. An abdominal fat biopsy is not completely sensitive, and sometimes, biopsy of an involved organ 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%.
In the amyloid deposition of the joints, there will be a decreased signal in both T1 and T2 weighted MRI images. In amyloidoma, there will be low T1 signal with gadolinium injection and low T2 signal.
The type of the amyloid protein can be determined in various ways: the detection of abnormal proteins in the bloodstream ; binding of particular antibodies to the amyloid found in the tissue ; 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.
AL is the most common form of amyloidosis, and a diagnosis often begins with a search for plasma cell dyscrasia, 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 cells can be sought in people with a high clinical suspicion for AL amyloidosis but negative electrophoresis.
ATTR, or familial transthyretin-associated amyloidosis, 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 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.

Classification

Historical classification systems were based on clinical factors. Until the early 1970s, the idea of a single amyloid substance predominated. Various descriptive classification systems were proposed based on the organ distribution of amyloid deposits and clinical findings. Most classification systems included primary amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis. Some classification systems included myeloma-associated, familial, and localized amyloidosis.
The modern era of amyloidosis classification began in the late 1960s with the development of methods to make amyloid fibrils soluble. These methods permitted scientists to study the chemical properties of amyloids. Descriptive terms such as primary amyloidosis, secondary amyloidosis, and others, which are not based on cause, provide little useful information and are no longer recommended.
The modern classification of amyloid disease tends to use an abbreviation of the protein that makes the majority of deposits, prefixed with the letter A. For example, amyloidosis caused by transthyretin is termed "ATTR". Deposition patterns vary between people but are almost always composed of just one amyloidogenic protein. Deposition can be systemic or organ-specific. Many amyloidoses are inherited, due to mutations in the precursor protein.
Other forms are due to different diseases causing overabundant or abnormal protein production – such as with overproduction of immunoglobulin light chains, or with continuous overproduction of acute phase proteins in chronic inflammation.
About 60 amyloid proteins have been identified so far. Of those, at least 36 have been associated with a human disease.
The names of amyloids usually start with the letter "A". Here is a brief description of the more common types of amyloid:
As of 2010, 27 human and 9 animal fibril proteins were classified, along with 8 inclusion bodies.

Alternative

An older clinical method of classification refers to amyloidoses as systemic or localised
Another classification is primary or secondary.
Additionally, based on the tissues in which it is deposited, it is divided into mesenchymal or parenchymal.

Treatment

Treatment depends on the type of amyloidosis that is present. Treatment with high dose melphalan, a chemotherapy agent, followed by stem cell transplantation has shown 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 a curative therapy because mutated transthyretin which forms amyloids is produced in the liver.
In 2018, patisiran was not recommended by NICE in the UK for hereditary transthyretin-related amyloidosis. As of July 2019 further review however is occurring. It was approved for this use in the United States however.

Support groups

People affected by amyloidosis are supported by organizations, including the Amyloidosis Research Consortium, Amyloidosis Foundation, Amyloidosis Support Groups, and Amyloidosis Australia.

Prognosis

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 stages I, II and III, respectively.
Outcomes in a person with AA amyloidosis depend on the underlying disease and correlate with the concentration of serum amyloid A protein.
People with ATTR have a 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.

Epidemiology

The three most common forms of amyloidosis are AL, AA, and ATTR amyloidoses. The median age at diagnosis is 64.
In the western hemisphere, AL is the most prevalent, comprising 90% of cases. In the United States it is estimated that there are 1,275 to 3,200 new cases of AL amyloidoses a year.
AA amyloidoses is the most common form in developing countries and can complicate longstanding infections with tuberculosis, osteomyelitis, and bronchiectesis. In the west, AA is more likely to occur from autoimmune inflammatory states. The most common causes of AA amyloidosis in the West are rheumatoid arthritis, inflammatory bowel disease, psoriasis, and familial Mediterranean fever.
People undergoing long-term hemodialysis can develop amyloidosis from accumulation of light chains of the HLA 1 complex which is normally filtered out by the kidneys.
Senile amyloidosis resulting from deposition of normal transthyretin, mainly in the heart, is found in 10–36% of people over 80.

Research

Treatments for ATTR-related neuropathy include TTR-specific oligonucleotides in the form of small interfering RNA or antisense inotersen, the former having recently received FDA approval.