Transthyretin amyloidosis
Synonyms and keywords:

# Overview

# Historical Perspective
- In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis.
- In 1854, Rudolph Virchow introduced the term "amyloid" as a macroscopic abnormality in some tissues.
- In 1867, Weber reported the first case of amyloidosis associated with multiple myeloma.
- In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.
- In 1959, Cohen and Calkins used ultrathin sections of amyloidotic tissues and assessed by electron microscopy, explained the presence of non-branching fibrils with indeterminate length and variable width.

# Classification
Transthyretin amyloidosis is one of the subtypes of familial amyloidosis. Familiar amyloidosis may be classified according to the type of mutant protein into 7 subtypes:
- Transthyretin (TTR)
- Apolipoprotein AI
- Apolipoprotein AII
- Fibrinogen Aa
- Lysozyme
- Gelsolin
- Cystatin C

# Pathophysiology

## Pathogenesis
- It is understood that amyloidosis is the result of deposition of Amyloid.
- Amyloid is an abnormal insoluble extracellular protein which may cause organic dysfunction and a wide variety of clinical syndromes.
- These abnormal amyloids are derived from misfolding and aggregation of normally soluble proteins.
- Amyloid depositions also have glycosaminoglycans and serum amyloid P component (SAP) which alter the propensity for amyloid formation.
- Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.
- Genetic mutations in Apolipoprotein AI gene may lead to misfolding protein product.

## Genetic
- Familial ATTR amyloidosis is transmitted in autosomal dominant pattern but it can have a heterogeneous nature of presentation.
- Genes involved in the pathogenesis of Familial ATTR amyloidosis include:
Transthyretin amyloidosis (ATTR)
The most common type of familial amyloidosis.
Single nucleotide substitution on transthyretin gene on chromosome 18 leads to nonfunctional transthyretin protein.
Transthyretin protein is responsible for thyroid hormone and vitamin A transport and is produced by liver.
We can find normal transthyretin protein deposition in aged individuals (senile cardiac amyloid).
Mutant transthyretin protein accelerate the process of deposition and leads to early onset disease.
- Transthyretin amyloidosis (ATTR)
The most common type of familial amyloidosis.
Single nucleotide substitution on transthyretin gene on chromosome 18 leads to nonfunctional transthyretin protein.
Transthyretin protein is responsible for thyroid hormone and vitamin A transport and is produced by liver.
We can find normal transthyretin protein deposition in aged individuals (senile cardiac amyloid).
Mutant transthyretin protein accelerate the process of deposition and leads to early onset disease.
- The most common type of familial amyloidosis.
- Single nucleotide substitution on transthyretin gene on chromosome 18 leads to nonfunctional transthyretin protein.
- Transthyretin protein is responsible for thyroid hormone and vitamin A transport and is produced by liver.
- We can find normal transthyretin protein deposition in aged individuals (senile cardiac amyloid).
- Mutant transthyretin protein accelerate the process of deposition and leads to early onset disease.

# Causes
Common cause of Apolipoprotein AI amyloidosis is genetic mutation.

# Differentiating Transthyretin amyloidosis from Other Diseases
 must be differentiated from other diseases that cause , , and , such as , , and .
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 must be differentiated from , , and .

# Epidemiology and Demographics
- The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide.
- The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.
- Apolipoprotein AI amyloidosis commonly affects individuals older than 30.
- Hereditary amyloidosis subtypes include a substitution of an amino acid that is detected in approximately 4% of the african american population.
- Men are more commonly affected by amyloidosis than women.

# Risk Factors
Common risk factors in the development of apolipoprotein AI amyloidosis include:
- Older age
- Male gender
- African american race
- Positive family history

# Screening
There is insufficient evidence to recommend routine screening for .
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According to the , screening for  is not recommended.
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# Natural History, Complications, and Prognosis
If left untreated, % of patients with  may progress to develop , , and .
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Common complications of  include , , and .
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Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with  is approximately %.

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of  is made when at least  of the following  diagnostic criteria are met: , , , and .
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The diagnosis of  is based on the  criteria, which include , , and .
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The diagnosis of  is based on the  definition, which includes , , and .
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There are no established criteria for the diagnosis of .

## History and Symptoms
The majority of patients with  are asymptomatic.
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The hallmark of  is . A positive history of  and  is suggestive of . The most common symptoms of  include , , and . Common symptoms of  include , , and . Less common symptoms of  include , , and .

## Physical Examination
Patients with  usually appear . Physical examination of patients with  is usually remarkable for , , and .
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Common physical examination findings of  include , , and .
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The presence of  on physical examination is diagnostic of .
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The presence of  on physical examination is highly suggestive of .

## Laboratory Findings
An elevated/reduced concentration of serum/blood/urinary/CSF/other  is diagnostic of .
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Laboratory findings consistent with the diagnosis of  include , , and .
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 is usually normal among patients with .
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Some patients with  may have elevated/reduced concentration of , which is usually suggestive of .
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There are no diagnostic laboratory findings associated with .

## Electrocardiogram
There are no ECG findings associated with .
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An ECG may be helpful in the diagnosis of . Findings on an ECG suggestive of/diagnostic of  include , , and .

## X-ray
There are no x-ray findings associated with .
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An x-ray may be helpful in the diagnosis of . Findings on an x-ray suggestive of/diagnostic of  include , , and .
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There are no x-ray findings associated with . However, an x-ray may be helpful in the diagnosis of complications of , which include , , and .

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound  findings associated with .
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Echocardiography/ultrasound  may be helpful in the diagnosis of . Findings on an echocardiography/ultrasound suggestive of/diagnostic of  include , , and .
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There are no echocardiography/ultrasound  findings associated with . However, an echocardiography/ultrasound  may be helpful in the diagnosis of complications of , which include , , and .

## CT scan
There are no CT scan findings associated with .
OR
 CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of  include , , and .
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There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and .

## MRI
There are no MRI findings associated with .
OR
 MRI may be helpful in the diagnosis of . Findings on MRI suggestive of/diagnostic of  include , , and .
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There are no MRI findings associated with . However, a MRI may be helpful in the diagnosis of complications of , which include , , and .

## Other Imaging Findings
There are no other imaging findings associated with .
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 may be helpful in the diagnosis of . Findings on an  suggestive of/diagnostic of  include , , and .

## Other Diagnostic Studies
There are no other diagnostic studies associated with .
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 may be helpful in the diagnosis of . Findings suggestive of/diagnostic of  include , , and .
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Other diagnostic studies for  include , which demonstrates , , and , and , which demonstrates , , and .

# Treatment

## Medical Therapy
There is no treatment for ; the mainstay of therapy is supportive care.
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Supportive therapy for  includes , , and .
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The majority of cases of  are self-limited and require only supportive care.
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 is a medical emergency and requires prompt treatment.
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The mainstay of treatment for  is .
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The optimal therapy for  depends on the stage at diagnosis.
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 is recommended among all patients who develop .
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Pharmacologic medical therapy is recommended among patients with , , and .
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Pharmacologic medical therapies for  include (either) , , and/or .
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Empiric therapy for  depends on  and .
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Patients with  are treated with , whereas patients with  are treated with .

## Surgery
Surgical intervention is not recommended for the management of .
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Surgery is not the first-line treatment option for patients with . Surgery is usually reserved for patients with either , , and 
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The mainstay of treatment for  is medical therapy. Surgery is usually reserved for patients with either , , and/or .
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The feasibility of surgery depends on the stage of  at diagnosis.
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Surgery is the mainstay of treatment for .

## Primary Prevention
There are no established measures for the primary prevention of .
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There are no available vaccines against .
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Effective measures for the primary prevention of  include , , and .
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 vaccine is recommended for  to prevent . Other primary prevention strategies include , , and .

## Secondary Prevention
There are no established measures for the secondary prevention of .
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Effective measures for the secondary prevention of  include , , and .