Transthyretin amyloidosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Synonyms and Keywords:

Overview

Historical Perspective

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:[4][5][6]

 
 
 
 
 
 
 
 
 
 
 
 
 
Genes involved in familial amyloidosis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transthyretin (TTR)
 
Apolipoprotein AI
 
Gelsolin
 
Lysozyme
 
Cystatin C
 
Fibrinogen Aa-chain
 
Apolipoprotein AII

Pathophysiology

Pathogenesis

  • It is understood that amyloidosis is the result of deposition of Amyloid.[7]
  • 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.[8][9][10]
  • Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.[11]
  • 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.[12][13]
  • Genes involved in the pathogenesis of Familial ATTR amyloidosis include:[14][15][16]
    • Transthyretin amyloidosis (ATTR)[17][18][19]
      • 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.[20][21][22][23]

Differentiating Transthyretin amyloidosis from Other Diseases

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

OR

[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

Epidemiology and Demographics


  • The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide.[24]
  • The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.[25]
  • Hereditary amyloidosis subtypes include a substitution of an amino acid that is detected in approximately 4% of the african american population.[24]
  • Men are more commonly affected by amyloidosis than women.[26]


Risk Factors

Common risk factors in the development of apolipoprotein AI amyloidosis include:[27][28][29]

  • Older age
  • Male gender
  • African american race
  • Positive family history

Screening

There is insufficient evidence to recommend routine screening for [disease/malignancy].

OR

According to the [guideline name], screening for [disease name] is not recommended.

OR

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

OR

The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

OR

The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

OR

Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

OR

[Test] is usually normal among patients with [disease name].

OR

Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

OR

There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

There are no established measures for the secondary prevention of [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

References

  1. 1.0 1.1 1.2 Kyle RA (June 2011). "Amyloidosis: a brief history". Amyloid. 18 Suppl 1: 6–7. doi:10.3109/13506129.2011.574354001. PMID 21838413.
  2. 2.0 2.1 Sipe JD, Cohen AS (June 2000). "Review: history of the amyloid fibril". J. Struct. Biol. 130 (2–3): 88–98. doi:10.1006/jsbi.2000.4221. PMID 10940217.
  3. Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  4. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  5. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  6. Scriver, Charles (2001). The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. ISBN 978-0079130358.
  7. Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  8. Pepys MB, Rademacher TW, Amatayakul-Chantler S, Williams P, Noble GE, Hutchinson WL, Hawkins PN, Nelson SR, Gallimore JR, Herbert J (June 1994). "Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure". Proc. Natl. Acad. Sci. U.S.A. 91 (12): 5602–6. doi:10.1073/pnas.91.12.5602. PMC 44044. PMID 8202534.
  9. Tan SY, Pepys MB (November 1994). "Amyloidosis". Histopathology. 25 (5): 403–14. doi:10.1111/j.1365-2559.1994.tb00001.x. PMID 7868080.
  10. Botto M, Hawkins PN, Bickerstaff MC, Herbert J, Bygrave AE, McBride A, Hutchinson WL, Tennent GA, Walport MJ, Pepys MB (August 1997). "Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene". Nat. Med. 3 (8): 855–9. doi:10.1038/nm0897-855. PMID 9256275.
  11. Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  12. Hund E, Linke RP, Willig F, Grau A (February 2001). "Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment". Neurology. 56 (4): 431–5. doi:10.1212/wnl.56.4.431. PMID 11261421.
  13. Gertz MA (June 2017). "Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges". Am J Manag Care. 23 (7 Suppl): S107–S112. PMID 28978215.
  14. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  15. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  16. Scriver, Charles (2001). The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. ISBN 978-0079130358.
  17. Robbins J (1976). "Thyroxine-binding proteins". Prog. Clin. Biol. Res. 5: 331–55. PMID 61594.
  18. Westermark P, Sletten K, Johansson B, Cornwell GG (April 1990). "Fibril in senile systemic amyloidosis is derived from normal transthyretin". Proc. Natl. Acad. Sci. U.S.A. 87 (7): 2843–5. doi:10.1073/pnas.87.7.2843. PMC 53787. PMID 2320592.
  19. Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S, Andersen O, Karlberg I, Nordén G, Nakazato M (September 1991). "Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30)". Clin. Genet. 40 (3): 242–6. doi:10.1111/j.1399-0004.1991.tb03085.x. PMID 1685359.
  20. Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ (April 1993). "Human lysozyme gene mutations cause hereditary systemic amyloidosis". Nature. 362 (6420): 553–7. doi:10.1038/362553a0. PMID 8464497.
  21. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  22. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  23. Scriver, Charles (2001). The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. ISBN 978-0079130358.
  24. 24.0 24.1 Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  25. Pepys MB (2006). "Amyloidosis". Annu. Rev. Med. 57: 223–41. doi:10.1146/annurev.med.57.121304.131243. PMID 16409147.
  26. Shin YM (March 2011). "Hepatic amyloidosis". Korean J Hepatol. 17 (1): 80–3. doi:10.3350/kjhep.2011.17.1.80. PMC 3304630. PMID 21494083.
  27. Shin YM (March 2011). "Hepatic amyloidosis". Korean J Hepatol. 17 (1): 80–3. doi:10.3350/kjhep.2011.17.1.80. PMC 3304630. PMID 21494083.
  28. Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
  29. Shin YM (March 2011). "Hepatic amyloidosis". Korean J Hepatol. 17 (1): 80–3. doi:10.3350/kjhep.2011.17.1.80. PMC 3304630. PMID 21494083.



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