View source for AL amyloidosis

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{{Infobox medical condition (new)
| name            = AL amyloidosis
| synonyms        = Primary systemic amyloidosis (PSA), primary amyloidosis
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| field           = [[Hematology]]
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'''Amyloid light-chain''' ('''AL''') '''amyloidosis''', also known as '''primary amyloidosis''', is the most common form of [[Systemic disease|systemic]] [[amyloidosis]].<ref name="Baker">{{cite journal | vauthors = Baker KR | title = Light Chain Amyloidosis: Epidemiology, Staging, and Prognostication | journal = Methodist DeBakey Cardiovascular Journal | volume = 18 | issue = 2 | pages = 27–35 | date = 2022 | pmid = 35414848 | pmc = 8932379 | doi = 10.14797/mdcvj.1070 | doi-access = free }}</ref> The disease is caused when a person's [[antibody]]-producing cells do not function properly and produce abnormal protein fibers made of components of antibodies called [[immunoglobulin light chain|light chains]]. These light chains come together to form amyloid deposits which can cause serious damage to different organs.<ref name="urlAmyloidosis Causes, Diagnosis, Symptoms, and Treatment on MedicineNet.com">{{cite web |url=http://www.medicinenet.com/amyloidosis/article.htm |title=Amyloidosis Causes, Diagnosis, Symptoms, and Treatment on MedicineNet.com }}</ref><ref>{{cite web|url=http://kidney.niddk.nih.gov/kudiseases/pubs/amyloidosis/|title=Amyloidosis and Kidney Disease|publisher=[[National Institute of Diabetes and Digestive and Kidney Diseases]]|access-date=23 November 2011|archive-date=20 November 2011|archive-url=https://web.archive.org/web/20111120050858/http://kidney.niddk.nih.gov/kudiseases/pubs/amyloidosis/|url-status=dead}}</ref> An abnormal light chain in [[urine]] is known as [[Bence Jones protein]].

==Signs and symptoms==
AL amyloidosis can affect a wide range of organs, and consequently present with a range of symptoms. Non-specific symptoms may include fatigue and weight loss.<ref name="Sanchorawala 2024">{{cite journal |last1=Sanchorawala |first1=Vaishali |title=Systemic Light Chain Amyloidosis |journal=New England Journal of Medicine |date=27 June 2024 |volume=390 |issue=24 |pages=2295–2307 |doi=10.1056/NEJMra2304088|pmid=38924733 }}</ref> The kidneys are commonly affected in systemic AL amyloidosis with 60–70% of people having kidney involvement.<ref name="Sanchorawala 2024" /><ref>{{cite journal | vauthors = Feitosa VA, Neves PD, Jorge LB, Noronha IL, Onuchic LF | title = Renal amyloidosis: a new time for a complete diagnosis | journal = Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas | volume = 55 | pages = e12284 | date = 2022-10-03 | pmid = 36197414 | pmc = 9529046 | doi = 10.1590/1414-431X2022e12284 }}</ref> Symptoms of kidney disease and [[kidney failure]] can include fluid retention, swelling, and shortness of breath.<ref name=UNC1/> Other manifestations of kidney involvement may include protein loss in the urine, low albumin levels in the blood and secondary hyperlipidemia ([[nephrotic syndrome]]). Kidney damage in AL amyloidosis may progress to end stage disease requiring [[Kidney dialysis|dialysis]].<ref name="Sanchorawala 2024" /> 

70–80% of those with AL amyloidosis have heart involvement, and heart involvement is the leading cause of death.<ref name="Sanchorawala 2024" /> Heart complications, include [[heart failure]] and [[Arrhythmia|irregular heart beat]]. Early heart involvement in AL amyloidosis may present as low voltage electrical rhythms on an [[electrocardiograph]], concentric [[left ventricular hypertrophy]] and diastolic dysfunction.<ref name="Sanchorawala 2024" /> A person may progress to overt heart failure due to cardiomyopathy as amyloid fibril deposition in the heart muscle progresses. Further signs of cardiac involvement in AL amyloidosis include heart arrhythmias ([[bradycardia]], [[ventricular tachycardia]]) which may necessitate [[pacemaker]] or [[implantable defibrillator]] placement and reduced contractility of the [[atrium (heart)|atria]], with the associated risk of atrial blood clots.<ref name="Sanchorawala 2024" />

AL amyloidosis may also cause nerve damage ([[neuropathy]]) which may present as pain, discomfort or loss of sensation in the extremities in instances of [[peripheral neuropathy]] or gastrointestinal motility disorders, difficulties regulating blood pressure with changes in position or [[neurogenic bladder]] in instances of dysfunction of the [[autonomic nervous system]].<ref name="Sanchorawala 2024" /> Other organ systems that may be involved include gastrointestinal tract, blood, lungs and skin. Other symptoms can include [[stroke]], gastrointestinal disorders, [[Hepatomegaly|enlarged liver]], [[Hyposplenism|diminished spleen function]], [[Adrenal insufficiency|diminished function of the adrenal]] and other [[endocrine gland]]s, skin color change or growths, lung problems, or [[Coagulopathy|bleeding and bruising problems]].<ref name="UNC1"/><ref name=UM1>{{cite web|url=http://www.umm.edu/altmed/articles/amyloidosis-000007.htm|title=Amyloidosis|publisher=[[University of Maryland Medical Center]]|access-date=23 November 2011|archive-date=30 November 2011|archive-url=https://web.archive.org/web/20111130144044/http://www.umm.edu/altmed/articles/amyloidosis-000007.htm|url-status=dead}}</ref> An enlarged tongue, or [[macroglossia]], is sometimes seen in AL amyloidosis.<ref name="Sanchorawala 2024" />

==Causes==
AL amyloidosis is caused by the deposition of abnormal antibody free light chains.  The abnormal light chains are produced by monoclonal [[plasma cell]]s, and, although AL amyloidosis can occur without diagnosis of another disorder, it is often associated with other [[Plasma cell dyscrasias|plasma cell disorders]], such as [[multiple myeloma]] and [[Waldenström's macroglobulinemia]].<ref name="UNC1">{{cite web|url=http://www.unckidneycenter.org/kidneyhealthlibrary/amyloidosis.html |title=AL Amyloidosis |author=UNC |author-link=University of North Carolina at Chapel Hill |publisher=[[University of North Carolina at Chapel Hill|UNC]] |access-date=22 November 2011 |url-status=dead |archive-url=https://web.archive.org/web/20111222004808/http://www.unckidneycenter.org/kidneyhealthlibrary/amyloidosis.html |archive-date=22 December 2011 }}</ref> About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis.<ref>{{cite journal | vauthors = Madan S, Dispenzieri A, Lacy MQ, Buadi F, Hayman SR, Zeldenrust SR, Rajkumar SV, Gertz MA, Kumar SK | title = Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma | journal = Mayo Clinic Proceedings | volume = 85 | issue = 3 | pages = 232–238 | date = March 2010 | pmid = 20194151 | pmc = 2843113 | doi = 10.4065/mcp.2009.0547 }}</ref> AL amyloidosis is not considered to be [[hereditary]].<ref>{{cite journal |vauthors=Enqvist S, Mellqvist UH, Mölne J, Sletten K, Murphy C, Solomon A, Stevens FJ, Westermark P |title=A father and his son with systemic AL amyloidosis |journal=Haematologica |volume=94 |issue=3 |pages=437–9 |date=March 2009 |pmid=19176364 |pmc=2649366 |doi=10.3324/haematol.13640 }}</ref>

==Diagnosis==
Diagnosis of AL amyloidosis requires identification of amyloid deposits within a [[biopsy|tissue sample]] and confirmation of a plasma cell disorder.<ref name="Sanchorawala 2024" /> Both blood and urine can be tested for the light chains which form amyloid deposits, however the diagnosis requires a sample of an amyloid deposit.<ref name=UNC1/><ref>{{cite journal | vauthors = Sanchorawala V | title = Light-chain (AL) amyloidosis: diagnosis and treatment | journal = Clinical Journal of the American Society of Nephrology | volume = 1 | issue = 6 | pages = 1331–1341 | date = November 2006 | pmid = 17699366 | doi = 10.2215/cjn.02740806 | doi-access = free }}</ref> A [[fine needle aspiration]] (FNA) may be done of the abdominal fat pad (which commonly contains amyloid deposits) to aid in the diagnosis of AL amyloidosis. The abdominal fat pad is much more easily accessed for biopsy than the target organs affected by amyloid (such as the heart or kidneys) and confirmation of amyloid light chain deposits in the abdominal fat pad is used as a diagnostic surrogate of amyloid deposits in other organs when combined with imaging. FNA of the abdominal fat pad shows amyloid deposits in 70-75% of cases of suspected AL amyloidosis and diagnosed 85% of cases when combined with a bone marrow biopsy.<ref name="Sanchorawala 2024" /> Other peripheral areas such as the [[salivary glands]], [[gingiva]], [[rectum]] or skin may also be biopsied, however in some cases a biopsy of the target organ may be needed.<ref name="Sanchorawala 2024" /> On microscopic exam of biopsy specimens, amyloid deposits appear green ("apple-green birefringence") when stained with [[Congo Red]] dye and viewed under polarized light.<ref name="Sanchorawala 2024" /><ref>{{cite web |title=AL Amyloidosis |url=https://amyloidosis.org/facts/al/ |website=Amyloidosis Foundation |access-date=9 January 2022}}</ref>

Disordered plasma cells with a monoclonal protein product (immunoglobulin light chains) are confirmed in AL amyloidosis using [[serum protein electrophoresis|serum]] or [[urine protein electrophoresis]], [[Serum free light-chain measurement|immunoglobulin free light-chain assays]] or identification of lambda or kappa restricted plasma cells on a bone marrow biopsy.<ref name="Sanchorawala 2024" /> The precursor protein that is forming the amyloid fibrils may be identified using [[Immunohistochemistry|immunohistochemical studies]] such as immunofluorescence or immunostaining, [[Immunogold labelling|immunogold electron microscopy]] or [[mass spectroscopy]] (which is not widely available).<ref name="Sanchorawala 2024" /> Mass spectroscopy has a sensitivity of 88% and a specificity of 96% in identifying the precurosor protein in AL amyloidosis.<ref name="Sanchorawala 2024" />

Cardiac involvement in AL amyloidosis may be assessed using [[echocardiography]], [[cardiac magnetic resonance]] (cardiac MRI) or [[positron emission tomography]] (PET scan).<ref name="Sanchorawala 2024" />

==Treatment==
The most effective treatment is [[Autologous stem-cell transplantation|autologous bone marrow transplants with stem cell rescues]]. However many patients are too weak to tolerate this approach.<ref name="pmid15070667">{{cite journal | vauthors = Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G | title = Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation | journal = Blood | volume = 103 | issue = 8 | pages = 2936–2938 | date = April 2004 | pmid = 15070667 | doi = 10.1182/blood-2003-08-2788 | doi-access = free }}</ref><ref name="urlBU">{{cite web|url=http://www.bu.edu/amyloid/doctors/features/clinical-al.html |title=BU: Amyloid Treatment & Research Program |url-status=dead |archive-url=https://web.archive.org/web/20080720042602/http://www.bu.edu/amyloid/doctors/features/clinical-al.html |archive-date=2008-07-20 }}</ref>

Other treatments can involve application of [[chemotherapy]] similar to that used in multiple myeloma, which targets the plasma cells responsible for producing the misfolded light chain proteins.<ref name = urlBU/> The most widely used regiment, and first line therapy, for those ineligible for a stem cell transplant is [[cyclophosphamide]], [[bortezomib]] and [[dexamethasone]] (CyBorD) with [[daratumumab]] added.<ref name="Sanchorawala 2024" /> Daratumumab, a monoclonal antibody to CD38, a protein that is expressed on plasma cells, was approved in US and EU for AL Amyloidosis in 2021.<ref>{{cite journal | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-darzalex-faspro-newly-diagnosed-light-chain-amyloidosis | archive-url=https://web.archive.org/web/20210730085101/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-darzalex-faspro-newly-diagnosed-light-chain-amyloidosis | url-status=dead | archive-date=July 30, 2021 | title=FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis | journal=FDA | date=11 June 2021 }}</ref><ref>{{cite web | url=https://www.ema.europa.eu/en/medicines/human/EPAR/darzalex | title=Darzalex | date=17 September 2018 }}</ref> CyBorD with daratumumab has a 78% very good partial hematologic response rate or better as well as a 55-55% organ response rate (reductions in organ damage) at 18 months, with the addition of daratumumab to CyBorD being associated with improved outcomes.<ref name="Sanchorawala 2024" /><ref name="Kastritis 2021">{{cite journal |last1=Kastritis |first1=Efstathios |last2=Palladini |first2=Giovanni |last3=Minnema |first3=Monique C. |title=Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis |journal=New England Journal of Medicine |date=July 2021 |volume=385 |issue=1 |pages=46–58 |doi=10.1056/NEJMoa2028631|pmid=34192431 |hdl=11585/865219 |hdl-access=free }}</ref> CyBorD may be used alone, or bortezomib–[[melphalan]]–dexamethasone may be used in resource limited settings where daratumumab is not available.<ref name="Sanchorawala 2024" />

[[Birtamimab]] and [[anselamimab]] are monoclonal antibodies which are currently undergoing trials. The two antibodies work by targeting the misfolded immunoglobulin light chains making up the amyloid fibrils and designating them for destruction by [[macrophages]], thus degrading amyloid microfibril deposits.<ref name="Sanchorawala 2024" />

Supportive care in AL amyloidosis consists of salt restriction and [[diuretics]] in those with heart failure or kidney involvement.<ref name="Sanchorawala 2024" /> An [[angiotensin converting enzyme inhibitor]] (ACEi) or [[angiotensin receptor blocker]] (ARB) may be used in those with significant proteinuria due to kidney disease.<ref name="Sanchorawala 2024" /> [[Amiodarone]] or an implantable defibrillator are sometimes needed for those with cardiomyopathy due to AL amyloidosis who are at risk of ventricular arrhythmias.<ref name="Sanchorawala 2024" /> Those with AL amyloidosis and kidney disease may require dialysis if kidney involvement progresses.<ref name="Sanchorawala 2024" />

==Prognosis==
Median survival for patients diagnosed with AL amyloidosis was 13 months in the early 1990s, but had improved to about 40 months a decade later with 5 year survival rates also increasing from 15% in the 1980s to 48% in the mid 2010s .<ref name=Wech>{{cite journal | vauthors = Wechalekar AD, Hawkins PN, Gillmore JD | title = Perspectives in treatment of AL amyloidosis | journal = British Journal of Haematology | volume = 140 | issue = 4 | pages = 365–377 | date = February 2008 | pmid = 18162121 | doi = 10.1111/j.1365-2141.2007.06936.x | doi-access = free }}</ref><ref name="Sanchorawala 2024" /> Heart involvement is associated with a worse prognosis.<ref name="Al Hamed 2021">{{cite journal |last1=Al Hamed |first1=Rama |last2=Bazarbachi |first2=Abdul Hamid |last3=Bazarbachi |first3=Ali |last4=Malard |first4=Florent |last5=Harousseau |first5=Jean-Luc |last6=Mohty |first6=Mohamad |title=Comprehensive Review of AL amyloidosis: some practical recommendations |journal=Blood Cancer Journal |date=18 May 2021 |volume=11 |issue=5 |page=97 |doi=10.1038/s41408-021-00486-4|pmid=34006856 |pmc=8130794 }}</ref>

==Epidemiology==
AL amyloidosis is a rare disease; only 1200 to 3200 new cases are reported each year in the United States, and between 500 and 600 in the UK. Two thirds of patients with AL amyloidosis are male and less than 5% of patients are under 40 years of age.<ref name="UNC1"/><ref name=AF1>{{cite web|url=http://www.amyloidosis.org/TreatmentInformation/primaryAL.html |title=Primary AL |publisher=Amyloidosis Foundation |access-date=23 November 2011 |url-status=dead |archive-url=https://web.archive.org/web/20111003174753/http://www.amyloidosis.org/TreatmentInformation/primaryAL.html |archive-date=3 October 2011 }}</ref><ref name="APIS">{{cite web |title=Understanding AL Amyloidosis |url=https://www.amyloidosis.org.uk/about-amyloidosis/al-amyloidosis/understanding-al-amyloidosis/ |website=Amyloidosis Patient Information Site |access-date=27 September 2023}}</ref>

== See also ==
*[[Light chain deposition disease]]

== References ==
{{Reflist}}

== External links ==
{{Medical resources
|  DiseasesDB      = 315  
|  ICD10           = {{ICD10|E|85||e|70}}  
|  ICD9            = {{ICD9|277.3}}  
|  ICDO            =  
|  OMIM            = 254500  
|  MedlinePlus     = 000533 
|  eMedicineSubj   = med  
|  eMedicineTopic  = 3363  
|  MeshID          = 
}}

{{Amyloidosis}}
{{Immunoproliferative immunoglobulin disorders}}

[[Category:Amyloidosis]]