DEFINITION GENERALITY
Amyloidosis was first described in the 19th Century.
Amyloidosis is now known to be a group of diseases in which one or more organ systems in the body accumulates protein deposits.
abnormal protein that may be deposited in any of your body's tissues or organs.
This abnormal protein comes from cells in the bone marrow.
disabling or life threatening.
The disease known as amyloidosis (pronounced am-i-loy-do'-sis) results when enough amyloid protein builds up in one or more organs to cause the organ(s) to malfunction.
The heart,
kidneys,
nervous system
spleen
adrenal
gastro-intestinal tract are most often affected.
the site of deposition depend on the type of amyloidosis primary or secondary.
![](Symb075c00b700f000000000.png) Amyloidosis is a bone marrow disease.
![](Symb075c00b700f000000000.png) bone marrow makes protective antibodies.
![](Symb075c00b700f000000000.png) After they have served their function, these antibodies are broken down and recycled by the system.
![](Symb075c00b700f000000000.png) In the amyloidosis, cells in the bone marrow produce antibodies that cannot be broken down.
![](Symb075c00b700f000000000.png) These antibodies then begin to build up in the bloodstream.
![](Symb075c00b700f000000000.png) Ultimately, they leave the bloodstream and can deposit in your tissues as amyloid.
![](Symb075c00b700f000000000.png) amyloid is a hyalin substance that stains specifically with congo red, when examined with ME is found to be composed of fibers lacking periodicity [see specificity chapter]
![](Symb075c00b700f000000000.png) amyloid is produced by the reticulum endothelial system and is deposited extracellularily.
recognition in 3 categories:
typical amyloidosis
![](Symb075c00b700f000000000.png) slpeen
![](Symb075c00b700f000000000.png) kidney
![](Symb075c00b700f000000000.png) liver
![](Symb075c00b700f000000000.png) adrenal
![](Symb075c00b700f000000000.png) intestinal mucosa [rectal bipsy for diag]
atypical amyloidosis
![](Symb075c00b700f000000000.png) any organ in addition to those mentioned [amyloidosis of the age affecting more the heart , 3% over 70 years old]
tumor forming amyloidosis
![](Symb075c00b700f000000000.png) nodules of infiltrates by plasma cells may occurs [tongue]
![](Symb075c00b700f000000000.png) tumor like deposits [pancreas islets and c cell thyroid tumors [calcitonin producing cells]
There are three major etiologic types, all very different from each other.
1. Primary Amyloidosis
familial mediterranean fever = typical amyloidosis
neuropathic amyloidosis = atypical amyloidosis
Primary amyloidosis is a plasma cell disorder and occasionally occurs with multiple myeloma.
This is the most common type of amyloidosis in the United States and is usually treated (conventionally) with chemotherapy.
Primary amyloid is not associated with any other diseases.
In primary amyloidosis, the organs most often involved include:
![](Symb075c00b700f000000000.png) the heart, kidneys,
![](Symb075c00b700f000000000.png) nervous system,
![](Symb075c00b700f000000000.png) gastrointestinal tract.
![](Symb075c00b700f000000000.png) Amyloid deposits in these organs cause:
shortness of breath,
fatigue,
edema (swelling of ankles and legs),
dizziness upon standing,
a feeling of fullness in the stomach (especially after eating),
diarrhea,
weight loss,
enlarged tongue,
numbness of the legs and arms,
and protein in the urine.
2. Secondary Amyloidosis
Secondary amyloid is caused by a chronic infection or inflammatory disease.
tuberculosis is present in 50% of the cases of amyloidosis
osteomyelitis 12%
chronic lung infection 10%
other chronic infections 12% = hyperimmunization
primary chronic polyarthritis 20% of cases show amyloidosis
Treatment of the underlying chronic infection or inflammatory disease can slow down or stop the progression of this type of amyloid.
In secondary amyloidosis, symptoms caused by the underlying chronic infection or inflammatory disease are complicated by the development of amyloid deposits in the kidney.
This may cause protein in the urine, edema, and fatigue
3. Hereditary Amyloidosis
Familial amyloid is the only type of amyloidosis that is inherited.
It is rare and is found in families of nearly every ethnic background.
In hereditary amyloidosis, the nervous system and gastrointestinal tract are often involved.
This can cause numbness and tingling in the arms and legs, dizziness upon standing, and diarrhea.
Families have their own pattern of organ involvement and symptoms.
The transmission is autosomal dominant, which means that if you have this type of amyloidosis each of your children has a 50% chance of inheriting the disease.
If your child does not inherit the gene, he/she cannot pass it on to future generations.
4. Other types of amyloidosis
include localized amyloid, b2 microglobulin amyloid, and Alzheimer's disease.
Localized types of amyloidosis are associated with hormones, proteins, aging, and specific areas of the body, and are not found with systemic involvment.
The type of amyloidosis which is due to the b2 microglobulin protein may affect people who have been on dialysis for a significant length of time.
In Alzheimer's disease, the amyloid protein in the brain is called the b-amyloid protein.
Amyloidosis can only be diagnosed by a positive biopsy; that is, an identification of the amyloid deposits in a piece of tissue.
![](Symb075c00b700f000000000.png) Amyloidosis is rare, affecting about 8 persons per million annually. Its cause is not known.
![](Symb075c00b700f000000000.png) It can affect anyone, but the majority of people who get amyloidosis are over the age of 40.
![](Symb075c00b700f000000000.png) Primary amyloidosis is not contagious or inherited.
![](Symb075c00b700f000000000.png) It is not known how many people have this disease.
![](Symb075c00b700f000000000.png) About 10 percent of patients who have multiple myeloma (a form of bone marrow cancer), develop amyloidosis.
![](Symb075c00b700f000000000.png) Although amyloid is an abnormal protein, diet and the amount of protein you eat play no role in the development of the disease.
![](Symb075c00b700f000000000.png) Also, there is no recognized link between amyloidosis and stress or occupation.
ACQUIRED AMYLOIDOSIS
Protein
![](Symb075c00b700f000000000.png) AL: Immunoglobulin light chains; k or l
Clinical
![](Symb075c00b700f000000000.png) Most common in middle aged males
![](Symb075c00b700f000000000.png) Associated disorders
![](Symb075c00b700f0ff000000.png) Paraproteinemia ( M-protein)
![](Wing0a73006f00f000000000.png) In 90% when serum & urine tested by immunofixation
![](Wing0a73006f00f000000000.png) Most common in nephrotic syndrome
![](Wing0a73006f00f000000000.png) Least common in polyneuropathy
![](Wing0a73006f00f000000000.png) Light chain in 1/3
![](Wing0a73006f00f000000000.png) Intact immunoglobulin in 2/3
![](Wing0a73006f00f000000000.png) l light chains: AL type
![](Wing0a73006f00f000000000.png) k light chains: Multiple myeloma; MGUS
![](Symb075c00b700f000000000.png) Multiple myeloma : May present 10-81 months after diagnosis of AL
![](Symb075c00b700f000000000.png) Polyneuropathy: Occurs in 20% of patients with light chain amyloid
![](Symb075c00b700f000000000.png) Distal; Symmetric
![](Symb075c00b700f000000000.png) Predominantly sensory
![](Wing0a73006f00f000000000.png) Pain & temperature loss most prominent
![](Wing0a73006f00f000000000.png) Distal weakness may develop later
![](Symb075c00b700f000000000.png) Autonomic
![](Wing0a73006f00f000000000.png) Orthostatic hypotension
![](Wing0a73006f00f000000000.png) Hypoactive pupils
![](Wing0a73006f00f000000000.png) Hypohydrosis
![](Wing0a73006f00f000000000.png) Bladder dysfunction
![](Wing0a73006f00f000000000.png) Impotence
![](Symb075c00b700f000000000.png) Carpal tunnel syndrome in 25%
Myopathy
![](Symb075c00b700f000000000.png) Systemic features
![](Symb075c00b700f000000000.png) Purpura: Periorbital
![](Symb075c00b700f000000000.png) Submandibular swelling
![](Symb075c00b700f000000000.png) Cardiac
![](Symb075c00b700f000000000.png) Renal: Nephrotic syndrome
Muscle enlargement ± weakness
![](Symb075c00b700f000000000.png) Gastrointestinal: Diarrhea
![](Symb075c00b700f000000000.png) Anemia associated with multiple myeloma
Amyloidoma
![](Symb075c00b700f000000000.png) Laboratory
![](Symb075c00b700f000000000.png) CSF: Protein mildly elevated
![](Symb075c00b700f000000000.png) Electrodiagnostic: Axonal neuropathy
![](Symb075c00b700f000000000.png) Biopsy: Axonal loss; Amyloid
![](Symb075c00b700f000000000.png) Prognosis
![](Symb075c00b700f000000000.png) Gradual progression
![](Symb075c00b700f000000000.png) Survival of 1 to 10 years depending on organ involvement
![](Symb075c00b700f000000000.png) Shortest survival with cardiac (< 1 year) & renal dysfunction
![](Symb075c00b700f000000000.png) HEREDITARY PNS AMYLOIDOSIS
![](Symb075c00b700f000000000.png) Mutations in serum proteins that can form b-pleated sheets
![](Symb075c00b700f000000000.png) Protein forming the amyloid is identified by immunocytochemistry
![](Symb075c00b700f000000000.png) Liver transplantation may be effective therapy
ATTR: Transthyretin (Prealbumin)
![](Symb075c00b700f0ff00ff00.png) l Chromosome 18q11.2-q12.1; Dominant
![](Symb075c00b700f000000000.png) ATTR gene
![](Symb075c00b700f000000000.png) 4 exons: Exon 1 codes for signal peptide
![](Symb075c00b700f000000000.png) Mutations
![](Wing0a73006f00f000000000.png) General locations
![](Symb075c00b700f000000000.png) Exon 1: Only 1 mutation (Val20Ile); Not in signal peptide
![](Symb075c00b700f000000000.png) > 70 in other 3 exons
![](Wing0a73006f00f000000000.png) Specific mutations: Variable clinical presentation
![](Symb075c00b700f000000000.png) Val30Met: Most common; Onset 25 to 65 years; Small fiber & autonomic D
![](Symb075c00b700f000000000.png) Val28Met: 7th decade onset neuropathy with impotence; No FH
![](Symb075c00b700f000000000.png) Database: HGMD
![](Wing0a73006f00f000000000.png) Types: Most are missense point mutations
![](Symb075c00b700f000000000.png) ATTR Protein
![](Symb075c00b700f000000000.png) 127 amino acids
![](Symb075c00b700f000000000.png) Present in plasma
![](Symb075c00b700f000000000.png) Binds: Thyroxine (20%); Retinol binding protein
![](Symb075c00b700f000000000.png) Clinical syndromes
![](Symb075c00b700f000000000.png) Heterogeneous, with some relation to:
![](Wing0a73006f00f000000000.png) Point mutation & Ethnic background
![](Symb075c00b700f000000000.png) Signs include:
![](Wing0a73006f00f000000000.png) Peripheral nerve
![](Symb075c00b700f000000000.png) Polyneuropathy: Sensory, Autonomic, ± Motor
Carpal tunnel syndrome
![](Wing0a73006f00f000000000.png) Systemic: Cardiomyopathy, Vitreous opacities, Renal failure
![](Wing0a73006f00f000000000.png) Rare CNS
![](Symb075c00b700f000000000.png) Glycine 18: Meningocerebrovascular syndrome sparing eyes
![](Symb075c00b700f000000000.png) Glycine 30: Oculoleptomeningeal syndrome
![](Symb075c00b700f000000000.png) Ile107Val: Autonomic; Carpal tunnel; CNS; Multisystem (Cardiomyopathy; Lung; Joint; Angiopathy)
![](Symb075c00b700f000000000.png) General signs: Hearing loss; Migraine; Dementia; Cerebellar; Seizures; Stroke; Myelopathy
![](Symb075c00b700f000000000.png) Onset 17-78 years
![](Wing0a73006f00f000000000.png) Earlier: Portuguese; Japanese endemic Val30Met foci
![](Wing0a73006f00f000000000.png) Later: Swedish; Sporadic Japanese Val30Met patients
![](Wing0a73006f00f000000000.png) ? Anticipation: Not explained by triplet repeats
![](Symb075c00b700f000000000.png) Homozygotes & heterzygotes with same clinical manifestations
![](Symb075c00b700f000000000.png) Penetrance: Variable: 30% to 95%
![](Symb075c00b700f000000000.png) FAP I
![](Symb075c00b700f000000000.png) Presentation: Generalized Autonomic & Sensory Polyneuropathy
![](Wing0a73006f00f000000000.png) Onset: Legs
![](Wing0a73006f00f000000000.png) Painful dysesthesias
![](Symb075c00b700f000000000.png) Most common point mutation: Val30Met
![](Wing0a73006f00f000000000.png) Onset: 20 to 80 years
![](Symb075c00b700f000000000.png) Later: Sporadic Japanese cases; Swedish endemic foci
![](Symb075c00b700f000000000.png) Earlier: Japanese & Portugese endemic foci
![](Wing0a73006f00f000000000.png) Penetrance
![](Symb075c00b700f000000000.png) High: Endemic Japanese foci
![](Symb075c00b700f000000000.png) Low: Scattered, sporadic cases; Swedish endemic foci
![](Wing0a73006f00f000000000.png) Male > Female: Especially in late onset sporadic cases
![](Wing0a73006f00f000000000.png) Weakness: Distal; Legs > Arms
![](Wing0a73006f00f000000000.png) Sensory loss
![](Symb075c00b700f000000000.png) Early onset: Pain & Temperature loss most prominent
![](Symb075c00b700f000000000.png) Late onset: Distal; Symmetric; All modalities; Paresthesias
![](Wing0a73006f00f000000000.png) Tendon reflexes: Reduced or Absent
![](Wing0a73006f00f000000000.png) Autonomic failure
![](Symb075c00b700f000000000.png) Severe in early onset patients
![](Symb075c00b700f000000000.png) Mild in late onset patients
![](Wing0a73006f00f000000000.png) Progression: Death in 7 to 10 years
![](Wing0a73006f00f000000000.png) CSF protein: Moderately é in 20%
![](Wing0a73006f00f000000000.png) Sural nerve biopsy
![](Symb075c00b700f000000000.png) Axonal loss: Myelinated axons especially in older onset patients
![](Symb075c00b700f000000000.png) Amyloid: Most prominent in sympathetic ganglia, dorsal root ganglia & proximal nerve trunks
![](Wing0a73006f00f000000000.png) Treatment: Liver transplantation
![](Symb075c00b700f000000000.png) Also > 23 other mutation
![](Symb075c00b700f000000000.png) "Portuguese, Swedish & Japanese" types
![](Symb075c00b700f000000000.png) FAP II
![](Symb075c00b700f000000000.png) Onset:
![](Wing0a73006f00f000000000.png) Upper extremities, esp carpal tunnel syndrome
![](Wing0a73006f00f000000000.png) 5th decade
![](Symb075c00b700f000000000.png) Most common mutation: Ser77Tyr
![](Wing0a73006f00f000000000.png) Onset
![](Symb075c00b700f000000000.png) 51 to 67 years
![](Symb075c00b700f000000000.png) Carpal tunnel syndrome: May be only manifestation for 1 to 2 decades
![](Wing0a73006f00f000000000.png) Generalized polyneuropathy
![](Symb075c00b700f000000000.png) Pain & Paresthesias
![](Symb075c00b700f000000000.png) Weakness: Symmetric; May become severe
![](Wing0a73006f00f000000000.png) Restrictive cardiomyopathy: Arrhythmia; Cardiac insufficiency
![](Wing0a73006f00f000000000.png) Autonomic: Intestinal malabsorption; Hypotnesion
![](Wing0a73006f00f000000000.png) No renal or ocular involvement
![](Wing0a73006f00f000000000.png) Progression
![](Symb075c00b700f000000000.png) Variable: Some stable; Others rapidly progressive
![](Symb075c00b700f000000000.png) Survival high
![](Symb075c00b700f000000000.png) Severe disability may develop
![](Wing0a73006f00f000000000.png) Treatment: Liver transplantation for disabled < 65 years
![](Symb075c00b700f000000000.png) > 6 other point mutations
![](Symb075c00b700f000000000.png) "Indiana & Maryland " types
![](Symb075c00b700f000000000.png) Other point mutations present with Cardiomyopathy or Renal disease
![](Symb075c00b700f000000000.png) Cardiomyopathy: Val122Ile mutation
![](Wing0a73006f00f000000000.png) Common in black population
![](Wing0a73006f00f000000000.png) Late onset: > 60 years
AApoA1: Apolipoprotein A-1 (FAP III; "Iowa" type)
![](Symb075c00b700f0ff00ff00.png) l Chromosome 11q23.3; Dominant
![](Symb075c00b700f000000000.png) Gene
![](Symb075c00b700f000000000.png) Neuropathic amyloid: Point mutation Gly26Arg
![](Symb075c00b700f000000000.png) Other amyloid mutations: Trp50Arg; Insertions & deletions
![](Symb075c00b700f000000000.png) Protein
![](Symb075c00b700f000000000.png) Transports cholesterol from tissues to liver
![](Symb075c00b700f000000000.png) Major plasma & chylomicron protein
![](Symb075c00b700f000000000.png) Clinical features (Iowa type): Similar to FAP I
![](Symb075c00b700f000000000.png) Polyneuropathy
![](Symb075c00b700f000000000.png) Nephropathy
![](Symb075c00b700f000000000.png) Gastric Ulcer
![](Symb075c00b700f000000000.png) Other non-neuropathic amyloid syndromes
![](Symb075c00b700f000000000.png) Hepatic failure
![](Symb075c00b700f000000000.png) Cardiac ± Cutaneous: Leu90Pro; Arg173Pro; Leu174Ser
AGel: Gelsolin (FAP IV; "Finnish" (also Japanese) type )
![](Symb075c00b700f0ff00ff00.png) l Point mutations amino acid 187; Chromosome 9q32-q34; Dominant
![](Symb075c00b700f000000000.png) Protein
![](Symb075c00b700f000000000.png) Binds to:
![](Wing0a73006f00f000000000.png) Actin: barbed end of filaments; Prevents monomer exchange
![](Wing0a73006f00f000000000.png) Fibronectin
![](Symb075c00b700f000000000.png) Intracellular: Muscle; Phagocytes; Fibroblasts; Platelets
![](Symb075c00b700f000000000.png) Clinical features
![](Symb075c00b700f000000000.png) Onset: 4th decade
![](Symb075c00b700f000000000.png) Cranial Neuropathies
![](Wing0a73006f00f000000000.png) Facial paresis (Upper)
![](Wing0a73006f00f000000000.png) Also: V; XII; VIII
![](Symb075c00b700f000000000.png) Corneal lattice dystrophy: Also see Lattice corneal dystrophy IIIA
![](Symb075c00b700f000000000.png) Sensory neuropathy (Vibration loss) ± autonomic
![](Symb075c00b700f000000000.png) Skin: Laxity
![](Symb075c00b700f000000000.png) No cardiac involvement
![](Symb075c00b700f000000000.png) Homozygotes: Rapidly progressive disease & Renal failure
What are the symptoms of amyloidosis in general?
Symptoms of amyloidosis depend on the organs it affects. The wide range of symptoms often makes amyloidosis difficult to diagnose. You may have no symptoms. Symptoms can include:
![](Symb075c00b700f000000000.png) Swelling of ankles and legs
![](Symb075c00b700f000000000.png) Weakness
![](Symb075c00b700f000000000.png) Weight loss
![](Symb075c00b700f000000000.png) Shortness of breath
![](Symb075c00b700f000000000.png) Numbness or tingling in the hands or feet
![](Symb075c00b700f000000000.png) Diarrhea
![](Symb075c00b700f000000000.png) Severe fatigue
![](Symb075c00b700f000000000.png) Enlarged tongue
![](Symb075c00b700f000000000.png) Feeling of fullness after eating smaller amounts of food than usual
![](Symb075c00b700f000000000.png) Dizziness upon standing
How is amyloidosis diagnosed?
Physical examination is necessary to find out if your organs are functioning properly.
Blood, urine and bone marrow tests may also be done.
A small tissue sample (biopsy) may be taken from your rectum, abdominal fat or bone marrow to determine if you have amyloidosis.
Occasionally, samples are taken from the liver, nerve, heart or kidney.
Blood or urine tests can detect the protein, but only bone marrow tests or other small samples of tissue can positively establish the diagnosis of amyloidosis
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