Amyloidosis

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue There are several types with varying symptoms; signs and symptoms 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 forms, and systemic ones. The four most common types of systemic amyloidosis are light chain (AL), inflammation (AA), dialysis-related (Aβ2M), and hereditary and old age (ATTR and familial amyloid polyneuropathy.
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 to the physician why this might be so. 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 annually 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. Cardiac amyloidosis can present with symptoms of heart failure including shortness of breath, fatigue, and edema. As cardiac amyloidosis progresses, the amyloid deposition can affect the heart's ability to pump and fill blood as well as its ability to maintain normal rhythm, which leads to worsening heart function and decline in people's quality of life.
===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." (Rang and Dale's Pharmacology, 2015.)
===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 (over 80 years), there is significant risk of wild-type transthyretin amyloid deposition in synovial tissue of knee joint, but predominantly in old age deposition of wild type transthyretin is seen in cardiac ventricles. In beta 2-microglobulin amyloidosis, males have high risk of getting carpal tunnel syndrome. Aβ2MG amyloidosis (Hemodialysis associated 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. Vertebral 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==
Amyloidoses can be considered protein misfolding diseases. The vast majority of proteins that have been found to form amyloid deposits are secreted proteins, so the misfolding and formation of amyloid occurs outside cells, in the extracellular space. Of the 37 proteins so far identified as being vulnerable to amyloid formation, only four are cytosolic. Most amyloid-forming proteins are relatively small, but otherwise there is currently no evidence of structural or functional similarities among proteins known to form disease-associated amyloids. One third of amyloid disease is hereditary, in which case there is normally an early age of onset. Half of amyloid-related diseases are sporadic and have a late age of onset – in these cases, the protein aggregation may be associated with aging-related decline in protein regulation. Rarely, some medical treatments are associated with amyloid disease.
Amyloid-forming proteins aggregate into distinctive fibrillar forms with a beta-sheet structure. The process of forming amyloid fibrils is thought to have intermediate oligomeric forms. Both the oligomers and amyloid fibrils can be toxic to cells and can interfere with proper organ function. The relative significance of different aggregation species may depend on the protein involved and the organ system affected.
==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.
A sample of tissue can be biopsied or obtained directly from the affected internal organ, but the first-line site of biopsy is subcutaneous abdominal fat, known as a "fat pad biopsy", due to its ease of acquisition. An abdominal fat biopsy is not completely sensitive and may result in false negatives, which means a negative result does not exclude the diagnosis of amyloidosis.However, direct biopsy of the affected organ may still be unnecessary as other less invasive methods of biopsy can also be used, including rectal salivary gland biopsy, lip, or bone marrow biopsy which can achieve a diagnosis in up to 85% of people.
In the amyloid deposition of the joints, there will be a decreased signal in both T1 and T2 weighted MRI images.
The type of the amyloid protein can be determined in 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.
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 (i.e., idiopathic) amyloidosis, in which no associated clinical condition was identified, and secondary amyloidosis (i.e., secondary to chronic inflammatory conditions). 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 (e.g., senile amyloidosis), 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 (affecting many different organ systems) 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 (termed AL amyloidosis), or with continuous overproduction of acute phase proteins in chronic inflammation (which can lead to AA amyloidosis).
About 60 amyloid proteins have been identified so far.
The names of amyloids usually start with the letter "A". Here is a brief description of the more common types of amyloid:
Abbr. 	Amyloid type/Gene 	Description 	OMIM
AL 	amyloid light chain 	AL amyloidosis / multiple myeloma. Contains immunoglobulin light-chains (λ,κ) derived from plasma cells. 	
AA 	Serum amyloid A 	Serum amyloid A protein (SAA) is an acute-phase reactant that is produced in times of inflammation. 	
Aβ 	β amyloid/Amyloid precursor protein	Found in Alzheimer disease brain lesions. 	
ALECT2 	LECT2 amyloidosis 	In LECT2 amyloidosis, the LECT2 protein deposits in the kidneys and various other tissues but only kidneys show signs or symptoms; these are typical those of kidney failure. 	
ATTR 	transthyretin 	Transthyretin is a protein that is mainly formed in the liver that transports thyroxine and retinol binding protein. A mutant form of a normal serum protein that is deposited in the genetically determined familial amyloid polyneuropathies. TTR is also deposited in the heart in wild-type transthyretin amyloidosis, also known as senile systemic amyloidosis. Also found in leptomeningeal amyloidosis.	
Aβ2M 	β2 microglobulin 	Not to be confused with Aβ, β2m is a normal serum protein, part of major histocompatibility complex (MHC) Class 1 molecules. Haemodialysis-associated amyloidosis 	
AIAPP 	amylin 	Found in the pancreas of people with Diabetes mellitus type 2 	
APrP 	prion protein 	In prion diseases, misfolded prion proteins deposit in tissues and resemble amyloid proteins. Some examples are Creutzfeldt–Jakob disease (humans), BSE or "mad cow disease" (cattle), and scrapie (sheep and goats). A recently described familial prion disease presents with peripheral amyloidosis causing autonomic neuropathy and diarrhea. 	
AGel 	gelsolin 	Finnish type amyloidosis 	
ACys 	Cystatin C 	Cerebral amyloid angiopathy, Icelandic-type 	
AApoA1 	APOA1 	Familial visceral amyloidosis 	
AFib 	Fibrinogen alpha chain 	Familial visceral amyloidosis 	
ALys 	LYZ 	Familial visceral amyloidosis 	
? 	OSMR 	Primary cutaneous amyloidosis 	
ABriADan	ITM2B 	Cerebral amyloid angiopathy, British-typeDanish-type 	
APro 	prolactin 	Prolactinoma 	
AKer 	keratoepithelin 	Familial corneal amyloidosis 	
AANF 	atrial natriuretic factor 	Senile amyloid of atria of heart 	
ACal 	calcitonin 	Medullary carcinoma of the thyroid 	
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
*Systemic amyloidoses affect more than one body organ or system. Examples are AL, AA, and Aβ2m.
*Localised amyloidoses affect only one body organ or tissue type. Examples are Aβ, IAPP, [Atrial natriuretic factor (in isolated atrial amyloidosis), and Calcitonin (in medullary carcinoma of the thyroid).
Another classification is primary or secondary.
*Primary amyloidoses arise from a disease with disordered immune cell function, such as multiple myeloma or other immunocyte dyscrasias.
*Secondary (reactive) amyloidoses occur as a complication of some other chronic inflammatory or tissue-destroying disease. Examples are reactive systemic amyloidosis and secondary cutaneous amyloidosis.
Additionally, based on the tissues in which it is deposited, it is divided into mesenchymal (organs derived from mesoderm) or parenchymal (organs derived from ectoderm or endoderm).
==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.
Management of ATTR amyloidosis will depend on its classification as wild type or variant. Both may be treated with tafamidis, a low toxicity oral agent that prevents destabilization of correctly folded protein. Studies showed tafamidis reduced mortality and hospitalization due to heart failure. Previously, for variant ATTR amyloidosis, liver transplant was the only effective treatment. However, newer therapies including diflunisal, an anti-inflammatory drug, and inotersen and patisiran, drugs which prevent misfolded protein formation, have shown early promises in slowing disease progression. The latter two drugs have shown their benefit in neurological impairment scores and quality of life measures. However, their role in cardiac ATTR amyloidosis is still being investigated.
In 2018, patisiran was not recommended by NICE in the UK for hereditary transthyretin-related amyloidosis. It was approved for this use in the United States however.
In 2018, inotersen was approved by the European Medicines Agency to treat polyneuropathy in adult patients with hereditary transthyretin amyloidosis. 
In 2021, in a clinical trial using the CRISPR gene-editing technique, several participants had an "80% to 96% drop in TTR levels, on par or better than the average of 81%" who were given patisiran.
===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 and the affected organ system. Prognosis for untreated AL cardiac amyloidosis is poor, with a median survival of six months. More specifically, AL amyloidosis can be classified as stage I, II or III based on cardiac biomarkers like Nt-proBNP and cardiac troponin. Survival diminishes with increasing stage, however recent advancements in treatments have improved median survival rates for stages I, II, and III, to 91.2, 60, and 7 months 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==
Amyloidosis has a combined estimated prevalence of 30 per 100,000 persons with the three most common forms being AL, ATTR, and AA. The median age at diagnosis is 64.
AL has the highest incidence at approximately 12 cases per million persons per year and an estimated prevalence of 30,000 to 45,000 cases in the US and European Union.
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 (14–15 years) 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 (patisiran) or antisense inotersen, the former having recently received FDA approval.<Research into treatments for ATTR amyloidosis have compared liver transplantation, oral drugs that stabilize the misfolding protein (including tafamidis and diflunisal), and newer therapeutic agents still being investigated (including patisiran).
==As the final diagnosis==
In Informed Consent, cardiac scientist Ezra Powell is admitted after losing consciousness due to weakness of his heart. Although he resists treatment, he is eventually diagnosed with Amyloidosis. However, it is an untreatable form of AA Amyloidosis and Powell soon dies from his conditions.
==In other episodes==
*In The Jerk, House suspects amyloidosis because it would explain the patient's obnoxious personality as well as his other symptoms. However, it is soon ruled out.
*In You Don't Want to Know, the patient's sense of doom, high immunoglobulin levels, and failing kidneys point to amyloidosis, However, Foreman, who is temporarily in charge, believes the treatment is too dangerous.
*In Dying Changes Everything, a biopsy points to amyloidosis, but they can't find a cause for it.
*In Lucky Thirteen, Remy Hadley believes the patient has amyloidosis, but the biopsy is negative.
*In Simple Explanation, Chris Taub suggests that Charlotte Novack has amyloidosis, but it would not explain muscle atrophy.
*In Sports Medicine, the patient's elevated Beta 2 proteins pointed to amyloidosis, but House rejected the diagnosis in favour of steroid abuse.
*In Epic Fail, the patient asks to be treated for amyloidosis after crowd-sourcing the differential. A biopsy seems to confirm it but when he develops a high fever they realize that it can't be amyloidosis.
*In Insensitive, several symptoms point to amyloidosis and they agree to do a biopsy.
*In Remorse, Remy Hadley suggests amyloidosis but a MRI had already ruled it out.
*In Act Your Age, Lucy is checked for amyloidosis early in the differential.
*In Whatever It Takes, Remy Hadley suggest amyloidosis, but Taub notes the progression was too fast. They do a biopsy and it is negative.
*In The Softer Side, the failure of the patient's kidneys and liver point to amyloidosis, but it was ruled out due to normal protein levels.
*In Selfish, the patient's kidney failure points to amyloidosis, but it is ruled out when the patient starts coughing up blood.
*In Changes, the patient is treated for amyloidosis, but a heart attack rules it out.
*In You Must Remember This, the patient's failing kidneys point to amyloidosis. However a previous nuclear study ruled it out.
Amyloidosis at Wikipedia - This article uses text from Wikipedia used under a Creative Commons license
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Amyloidosis
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