amyloidosis amyloidosis amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. there are several non-specific and vague signs and symptoms associated with amyloidosis. these include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. in al amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. in wild-type attr amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction. amyloidosisclassic facial features of al amyloidosis with bleeding under the skin (bruising) around the eyesspecialtyhematology, endocrinology, rheumatology, cardiologysymptomsfeeling tired, weight loss, swelling of the legs, shortness of breath, bleeding, feeling light headed with standingusual onset55–65 years oldcausesgenetic or acquireddiagnostic methodtissue biopsytreatmentsupportive care, directed at the underlying cause, dialysis, organ transplantationprognosisimproved with treatmentfrequency3–13 per million per year (al amyloidosis)deaths1 per 1,000 people (developed world) there are about 36 different types of amyloidosis, each due to a specific protein misfolding. within these 36 proteins, 19 are grouped into localized forms, 14 are grouped as systemic forms, and 3 proteins can identify as either. these proteins can become irregular due to genetic effects, as well as through acquired environmental factors. the four most common types of systemic amyloidosis are light chain (al), inflammation (aa), dialysis-related (aβ2m), and hereditary and old age (attr and wild-type transthyretin amyloid). 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 annually from systemic amyloidosis. amyloidosis has been described since at least 1639. signs and symptoms skin features of amyloidosis cutis dyschromica. hyperpigmented and hypopigmented macules on (a) lower legs, (b) back and waist, (c) waist. (d) individual blisters on upper arm. 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 kidney often involve the glomerular capillaries and mesangial regions, affecting the organ's ability to filter and excrete waste and retain plasma protein. this can lead to high levels of protein in the urine (proteinuria) and nephrotic syndrome. several types of amyloidosis, including the al and aa types, are associated with nephrotic syndrome. approximately 20% and 40–60% of people with al and aa amyloidosis respectively progress to end-stage kidney disease requiring dialysis. heart main article: cardiac amyloidosis 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. 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. nervous system 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. neuropathic presentation can depend on the etiology of amyloidosis. people with amyloidosis may experience dysfunction in various organ systems depending on the location and extent of nervous system involvement. for example, peripheral neuropathy can cause erectile dysfunction, incontinence and constipation, pupillary dysfunction, and sensory loss depending on the distribution of amyloidosis along different peripheral nerves. amyloidosis of the central nervous system can have more severe and systemic presentations that may include life-threatening arrhythmias, cardiac failure, malnutrition, infection, or death. gastrointestinal and accessory organs accumulation of amyloid proteins in the gastrointestinal system may be caused by a wide range of amyloid disorders and have different presentations depending on the degree of organ involvement. potential symptoms include weight loss, diarrhea, abdominal pain, heartburn (gastrointestinal reflux), and gi bleeding. amyloidosis may also affect accessory digestive organs including the liver, and may present with jaundice, fatty stool, anorexia, fluid buildup in the abdomen, and spleen enlargement. 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 (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. glands both the thyroid and adrenal glands can be infiltrated. it is estimated that 10–20% of people 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 people who also have 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 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 (>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. attr deposits have been found in ligamentum flavum of patients that underwent surgery for lumbar spinal stenosis. 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". amyloid purpura is 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. some medical treatments are associated with amyloid disease, but this is rare. amyloid-forming proteins aggregate into distinctive fibrillar forms with a beta-sheet structure. the beta-sheet form of amyloid is proteolysis-resistant, meaning it can not be degraded or broken down. as a result, amyloid deposits into the body's extracellular space. 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 mucosa, salivary gland, 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. 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 (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 was previously considered 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 is now considered to be the most common form of amyloidosis. it may be either age related in wild-type attr (attrv) 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