AL amyloidosis

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AL amyloidosis
Other namesPrimary systemic amyloidosis (PSA), primary amyloidosis
Specialty Hematology

Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis. [1] 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 light chains. These light chains come together to form amyloid deposits which can cause serious damage to different organs. [2] [3] An abnormal light chain in urine is known as Bence Jones protein.

Contents

Signs and symptoms

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 systemic AL amyloidosis. [4] Symptoms of kidney disease and kidney failure can include fluid retention, swelling, and shortness of breath. [5]

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. [5] [6]

Causes

AL amyloidosis is caused by the deposition of abnormal antibody free light chains. The abnormal light chains are produced by monoclonal plasma cells, and, although AL amyloidosis can occur without diagnosis of another disorder, it is often associated with other plasma cell disorders, such as multiple myeloma and Waldenström's macroglobulinemia. [5] About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis. [7] AL amyloidosis is never hereditary. [8]

Diagnosis

Both blood and urine can be tested for the light chains, which may form amyloid deposits, causing disease. However, the diagnosis requires a sample of an affected organ. [5] [9] Other diagnosis can be tissue biopsy. Tissue biopsy tests a tissue sample to look for amyloid deposits. The tissue is stained with red dye, and under a microscopic examination, amyloid proteins can be detected if the tissue turns an apple-green color. [10]

Treatment

The most effective treatment is autologous bone marrow transplants with stem cell rescues. However many patients are too weak to tolerate this approach. [11] [12]

Other treatments can involve application of chemotherapy similar to that used in multiple myeloma. [12] A combination of melphalan and dexamethasone has been found effective in those who are ineligible for stem cell transplantation, [11] and a combination of bortezomib and dexamethasone is now in widespread clinical use. [13] [14] 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. [15] [16]

Prognosis

Median survival for patients diagnosed with AL amyloidosis was 13 months in the early 1990s, but had improved to c. 40 months a decade later. [17]

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. [5] [18] [8]

See also

Related Research Articles

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include hypercalcemia and amyloidosis.

<span class="mw-page-title-main">Amyloidosis</span> Metabolic disease involving abnormal deposited amyloid proteins

Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight loss, shortness of breath, palpitations, and feeling faint with standing. In AL amyloidosis, specific indicators can include enlargement of the tongue and periorbital purpura. In wild-type ATTR amyloidosis, non-cardiac symptoms include: bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, small fiber neuropathy, and autonomic dysfunction.

<span class="mw-page-title-main">POEMS syndrome</span> Paraneoplastic syndrome

POEMS syndrome is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the disease's major signs and symptoms, as is PEP.

<span class="mw-page-title-main">Cryoglobulinemia</span> Medical condition

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

<span class="mw-page-title-main">Bortezomib</span> Chemical compound

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications. It is given by injection.

<span class="mw-page-title-main">Bence Jones protein</span> Urinary protein

Bence Jones protein is a monoclonal globulin protein or immunoglobulin light chain found in the urine, with a molecular weight of 22–24 kDa. Detection of Bence Jones protein may be suggestive of multiple myeloma, or Waldenström's macroglobulinemia.

<span class="mw-page-title-main">Cardiac amyloidosis</span> Medical condition

Cardiac amyloidosis is a subcategory of amyloidosis where there is depositing of the protein amyloid in the cardiac muscle and surrounding tissues. Amyloid, a misfolded and insoluble protein, can become a deposit in the heart's atria, valves, or ventricles. These deposits can cause thickening of different sections of the heart, leading to decreased cardiac function. The overall decrease in cardiac function leads to a plethora of symptoms. This multisystem disease was often misdiagnosed, with a corrected analysis only during autopsy. Advancements of technologies have increased earlier accuracy of diagnosis. Cardiac amyloidosis has multiple sub-types including light chain, familial, and senile. One of the most studied types is light chain cardiac amyloidosis. Prognosis depends on the extent of the deposits in the body and the type of amyloidosis. New treatment methods are actively being researched in regards to the treatment of heart failure and specific cardiac amyloidosis problems.

<span class="mw-page-title-main">Myeloma protein</span> Abnormal immunoglobulin fragment

A myeloma protein is an abnormal antibody (immunoglobulin) or a fragment thereof, such as an immunoglobulin light chain, that is produced in excess by an abnormal monoclonal proliferation of plasma cells, typically in multiple myeloma or Monoclonal gammopathy of undetermined significance. Other terms for such a protein are monoclonal protein, M protein, M component, M spike, spike protein, or paraprotein. This proliferation of the myeloma protein has several deleterious effects on the body, including impaired immune function, abnormally high blood viscosity, and kidney damage.

In hematology, plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury. Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.

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.

<span class="mw-page-title-main">Plasma cell leukemia</span> Medical condition

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

Free light chains (FLCs) are immunoglobulin light chains that are found in the serum (blood) in an unbound (free) state. In recent decades, measuring the amount of free light chains (FLCs) in the blood has become a practical clinical test. FLC tests can be used to diagnose and monitor diseases like multiple myeloma and amyloidosis.

<span class="mw-page-title-main">Light chain deposition disease</span> Medical condition

Light chain deposition disease (LCDD) is a rare blood cell disease which is characterized by deposition of fragments of infection-fighting immunoglobulins, called light chains (LCs), in the body. LCs are normally cleared by the kidneys, but in LCDD, these light chain deposits damage organs and cause disease. The kidneys are almost always affected and this often leads to kidney failure. About half of people with light chain deposition disease also have a plasma cell dyscrasia, a spectrum of diseases that includes multiple myeloma, Waldenström's macroglobulinemia, and the monoclonal gammopathy of undetermined significance premalignant stages of these two diseases. Unlike in AL amyloidosis, in which light chains are laid down in characteristic amyloid deposits, in LCDD, light chains are deposited in non-amyloid granules.

<span class="mw-page-title-main">LECT2 amyloidosis</span> Medical condition

LECT2 Amyloidosis (ALECT2) is a form of amyloidosis caused by the LECT2 protein. It was found to be the third most common 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.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Daratumumab/hyaluronidase, sold under the brand name Darzalex Faspro, is a fixed-dose combination medication for the treatment of adults with newly diagnosed or relapsed/refractory multiple myeloma. It is a combination of daratumumab and hyaluronidase. It is administered via subcutaneous injection.

Monoclonal immunoglobulin deposition disease, or MIDD, is a disease characterised by the deposition of monoclonal immunoglobulins on the basement membrane of the kidney. Monoclonal immunoglobulins are produced by monoclonal plasma cells, which are found in a variety of plasma cell dyscrasias. The deposition of monoclonal immunoglobulins on the basement membrane of the kidney causes renal impairment. As well as the kidney, MIDD may also affect the liver, heart, peripheral nerves, lung and skin.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

References

  1. ↑ Baker KR (2022). "Light Chain Amyloidosis: Epidemiology, Staging, and Prognostication". Methodist DeBakey Cardiovascular Journal. 18 (2): 27–35. doi: 10.14797/mdcvj.1070 . PMC   8932379 . PMID   35414848.
  2. ↑ "Amyloidosis Causes, Diagnosis, Symptoms, and Treatment on MedicineNet.com".
  3. ↑ "Amyloidosis and Kidney Disease". National Institute of Diabetes and Digestive and Kidney Diseases. Archived from the original on 20 November 2011. Retrieved 23 November 2011.
  4. ↑ Feitosa VA, Neves PD, Jorge LB, Noronha IL, Onuchic LF (2022-10-03). "Renal amyloidosis: a new time for a complete diagnosis". Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas. 55: e12284. doi:10.1590/1414-431X2022e12284. PMC   9529046 . PMID   36197414.
  5. 1 2 3 4 5 UNC. "AL Amyloidosis". UNC. Archived from the original on 22 December 2011. Retrieved 22 November 2011.
  6. ↑ "Amyloidosis". University of Maryland Medical Center. Archived from the original on 30 November 2011. Retrieved 23 November 2011.
  7. ↑ Madan S, Dispenzieri A, Lacy MQ, Buadi F, Hayman SR, Zeldenrust SR, et al. (March 2010). "Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma". Mayo Clinic Proceedings. 85 (3): 232–238. doi:10.4065/mcp.2009.0547. PMC   2843113 . PMID   20194151.
  8. 1 2 "Understanding AL Amyloidosis". Amyloidosis Patient Information Site. Retrieved 27 September 2023.
  9. ↑ Sanchorawala V (November 2006). "Light-chain (AL) amyloidosis: diagnosis and treatment". Clinical Journal of the American Society of Nephrology. 1 (6): 1331–1341. doi: 10.2215/cjn.02740806 . PMID   17699366.
  10. ↑ "AL Amyloidosis". Amyloidosis Foundation. Retrieved 9 January 2022.
  11. 1 2 Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, et al. (April 2004). "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". Blood. 103 (8): 2936–2938. doi: 10.1182/blood-2003-08-2788 . PMID   15070667.
  12. 1 2 "BU: Amyloid Treatment & Research Program". Archived from the original on 2008-07-20.
  13. ↑ Chaulagain CP, Comenzo RL (May 2015). "How we treat systemic light-chain amyloidosis". Clinical Advances in Hematology & Oncology. 13 (5): 315–324. PMID   26352777.
  14. ↑ Kastritis E, Anagnostopoulos A, Roussou M, Toumanidis S, Pamboukas C, Migkou M, et al. (October 2007). "Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone". Haematologica. 92 (10): 1351–1358. doi: 10.3324/haematol.11325 . PMID   18024372.
  15. ↑ "FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis". FDA. 11 June 2021.
  16. ↑ "Darzalex". 17 September 2018.
  17. ↑ Wechalekar AD, Hawkins PN, Gillmore JD (February 2008). "Perspectives in treatment of AL amyloidosis". British Journal of Haematology. 140 (4): 365–377. doi: 10.1111/j.1365-2141.2007.06936.x . PMID   18162121.
  18. ↑ "Primary AL". Amyloidosis Foundation. Archived from the original on 3 October 2011. Retrieved 23 November 2011.
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