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. Non-specific symptoms may include fatigue and weight loss. [4] The kidneys are commonly affected in systemic AL amyloidosis with 60–70% of people having kidney involvement. [4] [5] Symptoms of kidney disease and kidney failure can include fluid retention, swelling, and shortness of breath. [6] 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 dialysis. [4]

70–80% of those with AL amyloidosis have heart involvement, and heart involvement is the leading cause of death. [4] Heart complications, include heart failure and 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. [4] 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 atria, with the associated risk of atrial blood clots. [4]

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. [4] Other organ systems that may be involved include gastrointestinal tract, blood, lungs and skin. 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, or bleeding and bruising problems. [6] [7] An enlarged tongue, or macroglossia, is sometimes seen in AL amyloidosis. [4]

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. [6] About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis. [8] AL amyloidosis is never hereditary. [9]

Diagnosis

Diagnosis of AL amyloidosis requires identification of amyloid deposits within a tissue sample and confirmation of a plasma cell disorder. [4] 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. [6] [10] 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. [4] 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. [4] On microscopic exam of biopsy specimens, amyloid deposits appear green ("apple-green birefringence") when stained with Congo Red dye and viewed under polarized light. [4] [11]

Disordered plasma cells with a monoclonal protein product (immunoglobulin light chains) are confirmed in AL amyloidosis using serum or urine protein electrophoresis, immunoglobulin free light-chain assays or identification of lambda or kappa restricted plasma cells on a bone marrow biopsy. [4] The precursor protein that is forming the amyloid fibrils may be identified using immunohistochemical studies such as immunofluorescence or immunostaining, immunogold electron microscopy or mass spectroscopy (which is not widely available). [4] Mass spectroscopy has a sensitivity of 88% and a specificity of 96% in identifying the precurosor protein in AL amyloidosis. [4]

Cardiac involvement in AL amyloidosis may be assessed using echocardiography, cardiac magnetic resonance (cardiac MRI) or positron emission tomography (PET scan). [4]

Treatment

The most effective treatment is autologous bone marrow transplants with stem cell rescues. However many patients are too weak to tolerate this approach. [12] [13]

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. [13] 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. [4] 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. [14] [15] 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. [4] [16] CyBorD may be used alone, or bortezomib–melphalan–dexamethasone may be used in resource limited settings where daratumumab is not available. [4]

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. [4]

Supportive care in AL amyloidosis consists of salt restriction and diuretics in those with heart failure or kidney involvement. [4] An angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) may be used in those with significant proteinuria due to kidney disease. [4] Amiodarone or an implantable defibrillator are sometimes needed for those with cardiomyopathy due to AL amyloidosis who are at risk of ventricular arrhythmias. [4] Those with AL amyloidosis and kidney disease may require dialysis if kidney involvement progresses. [4]

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 . [17] [4] Heart involvement is associated with a worse prognosis. [18]

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. [6] [19] [9]

See also

Related Research Articles

<span class="mw-page-title-main">Serum protein electrophoresis</span> Laboratory test

Serum protein electrophoresis is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.

<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, renal insufficiency, 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> Presence of cold-sensitive antibodies in the blood

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">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">Plasmacytoma</span> Growth of a plasma cell tumour within soft tissue or the axial skeleton

Plasmacytoma is a plasma cell dyscrasia in which a plasma cell tumour grows within soft tissue or within the axial skeleton.

<span class="mw-page-title-main">Monoclonal gammopathy</span> Excess myeloma protein or monoclonal gamma globulin in the blood

Monoclonal gammopathy, also known as paraproteinemia, is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia. The most common form of the disease is monoclonal gammopathy of undetermined significance.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

<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.

The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with normal blood clotting and/or lysis of blood clots. The condition therefore may cause pathological bleeding and/or thrombosis. Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. It is associated primarily with pathological bleeding. Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.

<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.

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.

Smouldering myeloma is a disease classified as intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. In this spectrum of diseases, a clone of plasma cells secreting monoclonal paraprotein causes the relatively benign disease of monoclonal gammopathy of undetermined significance. This clone proliferates and may slowly evolve into more aggressive sub-clones that cause smouldering multiple myeloma. Further and more rapid evolution causes the overtly malignant stage of multiple myeloma and can subsequently lead to the extremely malignant stage of secondary plasma cell leukemia. Thus, some patients with smouldering myeloma progress to multiple myeloma and plasma cell leukemia. Smouldering myeloma, however, is not a malignant disease. It is characterised as a pre-malignant disease that lacks symptoms but is associated with bone marrow biopsy showing the presence of an abnormal number of clonal myeloma cells, blood and/or urine containing a myeloma protein, and a significant risk of developing into a malignant disease.

<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.

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. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Sanchorawala V (27 June 2024). "Systemic Light Chain Amyloidosis". New England Journal of Medicine. 390 (24): 2295–2307. doi:10.1056/NEJMra2304088. PMID   38924733.
  5. ↑ 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.
  6. 1 2 3 4 5 UNC. "AL Amyloidosis". UNC. Archived from the original on 22 December 2011. Retrieved 22 November 2011.
  7. ↑ "Amyloidosis". University of Maryland Medical Center. Archived from the original on 30 November 2011. Retrieved 23 November 2011.
  8. ↑ 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.
  9. 1 2 "Understanding AL Amyloidosis". Amyloidosis Patient Information Site. Retrieved 27 September 2023.
  10. ↑ 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.
  11. ↑ "AL Amyloidosis". Amyloidosis Foundation. Retrieved 9 January 2022.
  12. ↑ 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.
  13. 1 2 "BU: Amyloid Treatment & Research Program". Archived from the original on 2008-07-20.
  14. ↑ "FDA grants accelerated approval to Darzalex Faspro for newly diagnosed light chain amyloidosis". FDA. 11 June 2021.
  15. ↑ "Darzalex". 17 September 2018.
  16. ↑ Kastritis E, Palladini G, Minnema MC (July 2021). "Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis". New England Journal of Medicine. 385 (1): 46–58. doi:10.1056/NEJMoa2028631. hdl: 11585/865219 . PMID   34192431.
  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. ↑ Al Hamed R, Bazarbachi AH, Bazarbachi A, Malard F, Harousseau JL, Mohty M (18 May 2021). "Comprehensive Review of AL amyloidosis: some practical recommendations". Blood Cancer Journal. 11 (5): 97. doi:10.1038/s41408-021-00486-4. PMC   8130794 . PMID   34006856.
  19. ↑ "Primary AL". Amyloidosis Foundation. Archived from the original on 3 October 2011. Retrieved 23 November 2011.
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