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.

Accumulation 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 2.4% 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.

A rare development is a susceptibility to bleeding with bruising around the eyes, termed "raccoon-eyes," 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 amyloidosis (Hemodialysis associated amyloidosis) likes to deposit in synovial tissue, causing chronic synovitis, which can 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.)

AL amyloidosis can affect a wide range of organs, and consequently present with a range of symptoms. The kidneys are the most commonly affected organ in AL amyloidosis. Symptoms of kidney disease and renal failure can include fluid retention, swelling, and shortness of breath.

In addition to kidneys, AL amyloidosis may affect the heart, peripheral nervous system, gastrointestinal tract, blood, lungs and skin. Heart complications, which affect more than a third of AL patients, include heart failure and irregular heart beat. Other symptoms can include stroke, gastrointestinal disorders, enlarged liver, diminished spleen function, diminished function of the adrenal and other endocrine glands, skin color change or growths, lung problems, bleeding and bruising problems, fatigue and weight loss.

Amyloidosis is a group of diseases in which abnormal protein, known as amyloid fibrils, builds 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 (AL), inflammation (AA), dialysis (AβM), and hereditary and old age (ATTR).

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.

AA amyloidosis is a form of amyloidosis, a disease characterized by the abnormal deposition of fibers of insoluble protein in the extracellular space of various tissues and organs. In AA amyloidosis, the deposited protein is serum amyloid A protein (SAA), an acute-phase protein which is normally soluble and whose plasma concentration is highest during inflammation.

AL amyloidosis can occur spontaneously. It is, however, often associated with other blood disorders, such as multiple myeloma and Waldenström's macroglobulinemia. About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis.

It is usually associated with amyloid beta.

However, there are other types:

- the "Icelandic type" is associated with Cystatin C

- the "British type" is associated with ITM2B

Research is currently being conducted to determine if there is a link between cerebral amyloid angiopathy and ingestion of excessive quantities of aluminum.

Since this can be caused by the same amyloid protein that is associated with Alzheimer's dementia, brain bleeds are more common in people who have a diagnosis of Alzheimer's Disease, however they can also occur in those who have no history of dementia. The bleeding within the brain is usually confined to a particular lobe and this is slightly different compared to brain bleeds which occur as a consequence of high blood pressure (hypertension) - a more common cause of a hemorrhagic stroke (or bleeding in the brain).

Organ-limited amyloidosis is a category of amyloidosis where the distribution can be associated primarily with a single organ. It is contrasted to systemic amyloidosis, and it can be caused by several different types of amyloid.

In almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or instead a downstream consequence of a common idiopathic agent. The associated proteins are indicated in parentheses.

AA amyloidosis is a complication of a number of inflammatory diseases and infections, although only a small portion of patients with these conditions will go on to develop AA amyloidosis. A natural history study of AA amyloidosis patients published in the New England Journal of Medicine reported a number of conditions associated with AA amyloidosis. The most common presentation of AA amyloidosis is renal in nature, including proteinuria, nephrotic syndrome and progressive development of renal insufficiency leading to End Stage Renal Disease (ESRD) and need for renal replacement therapy (e.g. dialysis or renal transplantation).

- Autoimmune diseases

- Rheumatoid arthritis

- Ankylosing spondylitis

- Crohn's disease and ulcerative colitis

- Chronic infections

- Tuberculosis

- Bronchiectasis

- Chronic osteomyelitis

- Autoinflammatory diseases

- Familial Mediterranean fever (FMF)

- Muckle–Wells syndrome (MWS)

- Cancer

- Hodgkin's lymphoma

- Renal cell carcinoma

- Chronic foreign body reaction

- HIV/AIDS

- Silicone-induced granulomatous reaction

The familial amyloid neuropathies (or familial amyloidotic neuropathies, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy) are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.

Most individuals diagnosed with LECT2 amyloidosis in the United States (88%) are of Mexican descent and reside in Southwest region of the United States (New Mexico, Arizona, far Western Texas). Other groups with higher incidence rates of the disorder include First Nation Peoples in Canada, Punjabis, South Asians, Sudanese, Native Americans, and Egyptians. In Egyptians, for example, LECT2 is second most common cause of renal amyloidosis, accounting for nearly 31% of all cases.

ALECT2 amyloidosis is generally diagnosed in individuals between the ages 40 and 90, with a mean age of 67 years old. The disorder commonly presents with renal disease that in general is advanced or at an end stage. Associated signs and symptoms of their renal disease may include fatigue, dehydration, blood in urine, and/or other evidence for the presence of the nephrotic syndrome or renal failure. Further studies may find that these individuals have histological or other evidence of LECT2 amyloid deposition in the liver, lung, spleen, kidney, and/or adrenal glands but nonetheless they rarely show any symptoms or signs attributable to dysfunction in these organs. Unlike many other forms of systemic amyloidosis, LECT2 deposition has not been reported to be deposited in the myocardium or brain of affected individuals. Thus, LECT2 amyloidosis, while classified as a form of systemic amyloidosis, almost exclusively manifests clinically as renal amyloidosis. No familial link has been found in the disorder although there have been several cases described among siblings.

LECT2 Amyloidosis is a form of amyloidosis caused by the LECT2 protein. It was found to be the third most common (~3% of total) cause of amyloidosis in a set of more than 4,000 individuals studied at the Mayo Clinic; the first and second most common forms the disorder were AL amyloidosis and AA amyloidosis, respectively. Amyloidosis is a disorder in which the abnormal deposition of a protein in organs and/or tissues gradually leads to organ failure and/or tissue injury.

Although more than 30 different proteins can cause amyloidosis, the disorder caused by LECT2 is distinctive in three ways. First, it has an unusually high incidence in certain ethnic populations. Second, it is a systemic form of amyloidosis (i.e. amyloid deposited in multiple organs), as opposed to a localized form (amyloid deposits limited to a single organ) but nonetheless injures the kidney without or rarely injuring the other organs in which it is deposited. Third, LECT2 amyloidosis is diagnosed almost exclusively in elderly individuals.

Given its relatively recent discovery, exceptionally strong ethnic bias, limitation to causing kidney disease, and restriction to elderly individuals, LECT2 amyloidosis appears at present to be an under-recognized cause of chronic kidney disease particularly in the ethnic groups that exhibit a high incidence of the disorer.

Familial renal amyloidosis (or familial visceral amyloidosis, or hereditary amyloid nephropathy) is a form of amyloidosis primarily presenting in the kidney.

It is associated most commonly with congenital mutations in the fibrinogen alpha chain and classified as a dysfibrinogenemia (see Hereditary Fibrinogen Aα-Chain Amyloidosis). and, less commonly, with congenital mutations in apolipoprotein A1 and lysozyme.

It is also known as "Ostertag" type, after B. Ostertag, who characterized it in 1932 and 1950.

The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. These proteins include: transthyretin (ATTR, the most commonly implicated protein), apolipoprotein A1, and gelsolin.

Due to the rareness of the other types of familial neuropathies, transthyretin amyloidogenesis-associated polyneuropathy should probably be considered first.

"FAP-I" and "FAP-II" are associated with transthyretin. (Senile systemic amyloidosis [abbreviated "SSA"] is also associated with transthyretin aggregation.)

"FAP-III" is also known as "Iowa-type", and involves apolipoprotein A1.

"FAP-IV" is also known as "Finnish-type", and involves gelsolin.

Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis.

Prognosis is generally poor for all forms of Diabetic angiopathy, as symptomatology is tied to the advancement of the underlying pathology i.e. the early-stage patient displays either non-specific symptoms or none at all.

"Diabetic dermopathy" is a manifestation of diabetic angiopathy. It is often found on the shin.

There is also Neuropathy; also associated with diabetes mellitus; type 1 and 2.

It is also possible to classify angiopathy by the associated condition:

- Diabetic angiopathy

- Congophilic angiopathy

Angiopathy is the generic term for a disease of the blood vessels (arteries, veins, and capillaries). The best known and most prevalent angiopathy is diabetic angiopathy, a common complication of chronic diabetes.

Heredofamilial amyloidosis is an inherited condition that may be characterized by systemic or localized deposition of amyloid in body tissues.

The kidney is the organ most frequently affected. Proteinuria, loss of protein in the urine, is characteristic. More than 90% of people with LCDD develop kidney failure, often with rapid progression of disease.

Light chains may be deposited in many other organs and may or may not result in any symptoms. Other than the kidneys, liver and heart are the most commonly involved organs. Deposition of light chains in the liver may lead to hepatomegaly, an enlarged liver, or rarely portal hypertension or liver failure. The heart is affected in up to 80% of patients with LCDD, and may cause arrythmias and congestive heart failure.

Amyloid purpura is a condition marked by bleeding under the skin (purpura) in some individuals with amyloidosis. Its cause is unknown, but coagulation defects caused by amyloid are thought to contribute.

Amyloid purpura usually occurs above the nipple-line and is found in the webbing of the neck and in the face and eyelids.

Wild-type transthyretin amyloid accumulates mainly in the heart, where it causes stiffness and often thickening of its walls, leading consequently to shortness of breath and intolerance to exercise, called diastolic dysfunction. Excessively slow heart rate can also occur, such as in sick sinus syndrome, with ensuing fatigue and dizziness. Wild-type transthyretin deposition is also a common cause of carpal tunnel syndrome in elderly men, which may cause pain, tingling and loss of sensation in the hands. Some patients may develop carpal tunnel syndrome as an initial symptom of wild-type transthyretin amyloid.

There appears to be an increase in the risk for developing hematuria or blood in the urine due to urological lesions.

Secondary systemic amyloidosis is a condition that involves the adrenal gland, liver, spleen, and kidney as a result of amyloid deposition due to a chronic disease such as Behçet's disease, ulcerative colitis, etc.

Autosomal Dominant Retinal Vasculopathy with Cerebral Leukodystrophy (AD-RVCL) (previously known also as Cerebroretinal Vasculopathy, CRV, or Hereditary Vascular Retinopathy, HVR or Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke, HERNS) is an inherited condition resulting from a frameshift mutation to the TREX1 gene. This genetically inherited condition affects the retina and the white matter of the central nervous system, resulting in vision loss, lacunar strokes and ultimately dementia. Symptoms commonly begin in the early to mid-forties, and treatments currently aim to manage or alleviate the symptoms rather than treating the underlying cause. The overall prognosis is poor, and death can sometimes occur within 10 years of the first symptoms appearing.

AD-RVCL (CRV) Acronym

Autosomal Dominance (genetics) means only one copy of the gene is necessary for the symptoms to manifest themselves.

Retinal Vasculopathy means a disorder that is associated with a disease of the blood vessels in the retina.

Cerebral means having to do with the brain.

Leukodystrophy means a degeneration of the white matter of the brain.

Pathogenesis

The main pathologic process centers on small blood vessels that prematurely “drop out” and disappear. The retina of the eye and white matter of the brain are the most sensitive to this pathologic process. Over a five to ten-year period, this vasculopathy (blood vessel pathology) results in vision loss and destructive brain lesions with neurologic deficits and death.

Most recently, AD-RVCL (CRV) has been renamed. The new name is CHARIOT which stands for Cerebral Hereditary Angiopathy with vascular Retinopathy and Impaired Organ function caused by TREX1 mutations.

Treatment

Currently, there is no therapy to prevent the blood vessel deterioration.

About TREX1

The official name of the TREX1 gene is “three prime repair exonuclease 1.” The normal function of the TREX1 gene is to provide instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme is a DNA exonuclease, which means it trims molecules of DNA by removing DNA building blocks (nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or fragments that may be generated during genetic material in preparation for cell division, DNA repair, cell death, and other processes.

Changes (mutations) to the TREX1 gene can result in a range of conditions one of which is AD-RVCL. The mutations to the TREX1 gene are believed to prevent the production of the 3-prime repair exonuclease 1 enzyme. Researchers suggest that the absence of this enzyme may result in an accumulation of unneeded DNA and RNA in cells. These DNA and RNA molecules may be mistaken by cells for those of viral invaders, triggering immune system reactions that result in the symptoms of AD-RVCL.

Mutations in the TREX1 gene have also been identified in people with other disorders involving the immune system. These disorders include a chronic inflammatory disease called systemic lupus erythematosus (SLE), including a rare form of SLE called chilblain lupus that mainly affects the skin.

The TREX1 gene is located on chromosome 3: base pairs 48,465,519 to 48,467,644

The immune system.

- The immune system is composed of white blood cells or leukocytes.

- There are 5 different types of leukocytes.

- Combined, the 5 different leukocytes represent the 2 types of immune systems (The general or innate immune system and the adaptive or acquired immune system).

- The adaptive immune system is composed of two types of cells (B-cells which release antibodies and T-cells which destroy abnormal and cancerous cells).

How the immune system becomes part of the condition.

During mitosis, tiny fragments of “scrap” single strand DNA naturally occur inside the cell. Enzymes find and destroy the “scrap” DNA. The TREX1 gene provides the information necessary to create the enzyme that destroys this single strand “scrap” DNA. A mutation in the TREX1 gene causes the enzyme that would destroy the single strand DNA to be less than completely effective. The less than completely effective nature of the enzyme allows “scrap” single strand DNA to build up in the cell. The buildup of “scrap” single strand DNA alerts the immune system that the cell is abnormal.

The abnormality of the cells with the high concentration of “scrap” DNA triggers a T-cell response and the abnormal cells are destroyed. Because the TREX1 gene is identical in all of the cells in the body the ineffective enzyme allows the accumulation of “scrap” single strand DNA in all of the cells in the body. Eventually, the immune system has destroyed enough of the cells in the walls of the blood vessels that the capillaries burst open. The capillary bursting happens throughout the body but is most recognizable when it happens in the eyes and brain because these are the two places where capillary bursting has the most pronounced effect.

Characteristics of AD-RVCL

- No recognizable symptoms until after age 40.

- No environmental toxins have been found to be attributable to the condition.

- The condition is primarily localized to the brain and eyes.

- Optically correctable, but continuous, deterioration of visual acuity due to extensive multifocal microvascular abnormalities and retinal neovascularization leading, ultimately, to a loss of vision.

- Elevated levels of alkaline phosphatase.

- Subtle vascular changes in the retina resembling telangiectasia (spider veins) in the parafovea circulation.

- Bilateral capillary occlusions involving the perifovea vessels as well as other isolated foci of occlusion in the posterior pole of the retina.

- Headaches due to papilledema.

- Mental confusion, loss of cognitive function, loss of memory, slowing of speech and hemiparesis due to “firm masses” and white, granular, firm lesions in the brain.

- Jacksonian seizures and grand mal seizure disorder.

- Progressive neurologic deterioration unresponsive to systemic corticosteroid therapy.

- Discrete, often confluent, foci of coagulation necrosis in the cerebral white matter with intermittent findings of fine calcium deposition within the necrotic foci.

- Vasculopathic changes involving both arteries and veins of medium and small caliber present in the cerebral white matter.

- Fibroid necrosis of vessel walls with extravasation of fibrinoid material into adjacent parenchyma present in both necrotic and non-necrotic tissue.

- Obliterative fibrosis in all the layers of many vessel walls.

- Parivascular, adventitial fibrosis with limited intimal thickening.

Conditions with similar symptoms that AD-RVCL can be misdiagnosed as:

- Brain tumors

- Diabetes

- Macular degeneration

- Telangiectasia (Spider veins)

- Hemiparesis (Stroke)

- Glaucoma

- Hypertension (high blood pressure)

- Systemic Lupus Erythematosus (SLE (same original pathogenic gene, but definitely a different disease because of a different mutation in TREX1))

- Polyarteritis nodosa

- Granulomatosis with polyangiitis

- Behçet's disease

- Lymphomatoid granulomatosis

- Vasculitis

Clinical Associations

- Raynaud's phenomenon

- Anemia

- Hypertension

- Normocytic anemia

- Normochromic anemia

- Gastrointestinal bleeding or telangiectasias

- Elevated alkaline phosphatase

Definitions

- Coagulation necrosis

- Endothelium

- Fibrinoid

- Fibrinoid necrosis

- Frameshift mutation

- Hemiparesis

- Jacksonian seizure

- Necrotic

- Necrosis

- Papilledema

- Perivascular

- Retinopathy

- Telangiectasia

- Vasculopathy

- Vascular

What AD-RVCL is not:

- Infection

- Cancer

- Diabetes

- Glaucoma

- Hypertension

- A neurological disorder

- Muscular dystrophy

- Systemic Lupus Erythematosis (SLE)

- Vasculitis

Things that have been tried but turned out to be ineffective or even make things worse:

- Antibiotics

- Steroids

- X-Ray therapy

- Immunosuppression

History of AD-RVCL (CRV)

- 1985 – 1988: CRV (Cerebral Retinal Vasculopathy) was discovered by John P. Atkinson, MD at Washington University School of Medicine in St. Louis, MO

- 1988: 10 families worldwide were identified as having CRV

- 1991: Related disease reported, HERNS (Hereditary Endiotheliopathy with Retinopathy, Nephropathy and Stroke – UCLA

- 1998: Related disease reported, HRV (Hereditary Retinal Vasculopathy) – Leiden University, Netherlands

- 2001: Localized to Chromosome 3.

- 2007: The specific genetic defect in all of these families was discovered in a single gene called TREX1

- 2008: Name changed to AD-RVCL Autosomal Dominant-Retinal Vasculopathy with Cerebral Leukodystrophy

- 2009: Testing for the disease available to persons 21 and older

- 2011: 20 families worldwide were identified as having CRV

- 2012: Obtained mouse models for further research and to test therapeutic agents

Diabetic angiopathy is a form of angiopathy associated with diabetic complications. While not exclusive, the two most common forms are Diabetic retinopathy and Diabetic nephropathy, whose pathophysiologies are largely identical.