Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic

amyloidosis 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, weigh ...

. The disease is caused when a person's

antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

-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. An abnormal light chain in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

is known as

Bence Jones 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 macroglob ...

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. The kidneys are commonly affected in systemic AL amyloidosis with 60–70% of people having kidney involvement. Symptoms of kidney disease and

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

can include fluid retention, swelling, and shortness of breath. Other manifestations of kidney involvement may include protein loss in the urine, low albumin levels in the blood and secondary hyperlipidemia (

nephrotic syndrome Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes proteinuria, protein in the urine, hypoalbuminemia, low blood albumin levels, hyperlipidemia, high blood lipids, and significant edema, swelling. Other symptoms ...

). Kidney damage in AL amyloidosis may progress to end stage disease requiring

dialysis Dialysis may refer to: * Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric po ...

. 70–80% of those with AL amyloidosis have heart involvement, and heart involvement is the leading cause of death. Heart complications, include

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

and irregular heart beat. Early heart involvement in AL amyloidosis may present as low voltage electrical rhythms on an electrocardiograph, concentric

left ventricular hypertrophy Left ventricular hypertrophy (LVH) is thickening of the heart muscle of the left ventricle of the heart, that is, left-sided ventricular hypertrophy and resulting increased left ventricular mass. Causes While ventricular hypertrophy occurs ...

and diastolic dysfunction. 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 Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple ...

) which may necessitate

pacemaker A pacemaker, also known as an artificial cardiac pacemaker, is an implanted medical device that generates electrical pulses delivered by electrodes to one or more of the chambers of the heart. Each pulse causes the targeted chamber(s) to co ...

implantable defibrillator An implantable cardioverter-defibrillator (ICD) or automated implantable cardioverter defibrillator (AICD) is a device implantable inside the body, able to perform defibrillation, and depending on the type, cardioversion and pacing of the he ...

placement and reduced contractility of the

atria Atria may refer to: Science *Atrium (heart) (plural: atria), an anatomical structure of the heart *Atria (genus), a flatworm genus in the family Dendrocoelidae * Atria (star) or Alpha Trianguli Australis, a star in the constellation Triangulum Aus ...

, with the associated risk of atrial blood clots. AL amyloidosis may also cause nerve damage (

neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

) which may present as pain, discomfort or loss of sensation in the extremities in instances of

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

or gastrointestinal motility disorders, difficulties regulating blood pressure with changes in position or

neurogenic bladder Neurogenic bladder dysfunction, often called by the shortened term neurogenic bladder, was technically termed neurogenic lower urinary tract dysfunction by the International Continence Society. It refers to urinary bladder problems due to disease o ...

in instances of dysfunction of the

autonomic nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates viscera, internal organs, smooth muscle and glands. The autonomic nervo ...

. Other organ systems that may be involved include gastrointestinal tract, blood, lungs and skin. Other symptoms can include

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

, gastrointestinal disorders,

enlarged liver Hepatomegaly is enlargement of the liver. It is a non-specific medical sign, having many causes, which can broadly be broken down into infection, hepatic tumours, and metabolic disorder. Often, hepatomegaly presents as an abdominal mass. Dependi ...

, diminished spleen function, diminished function of the adrenal and other

endocrine gland The endocrine system is a network of glands and organs located throughout the body. Along with the nervous system, it makes the neuroendocrine system, which controls and regulates many of the body's functions. Endocrine glands are ductless gland ...

s, skin color change or growths, lung problems, or bleeding and bruising problems. An enlarged tongue, or

macroglossia Macroglossia is the medical term for an unusually large tongue. Severe enlargement of the tongue can cause cosmetic and functional difficulties in speaking, eating, Dysphagia, swallowing and sleeping. Macroglossia is uncommon, and usually occurs ...

, is sometimes seen in AL amyloidosis.

Causes

AL amyloidosis is caused by the deposition of abnormal antibody free light chains. The abnormal light chains are produced by monoclonal

plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...

s, and, although AL amyloidosis can occur without diagnosis of another disorder, it is often associated with other plasma cell disorders, such as

multiple myeloma 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 antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...

and Waldenström's macroglobulinemia. About 10% to 15% of patients with multiple myeloma may develop overt AL amyloidosis. AL amyloidosis is not considered to be

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

Diagnosis

Diagnosis of AL amyloidosis requires identification of amyloid deposits within a

tissue sample In medicine, sampling is gathering of matter from the body to aid in the process of a medical diagnosis and/or evaluation of an indication for treatment, further medical tests or other procedures. In this sense, the sample is the gathered matter ...

and confirmation of a plasma cell disorder. 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. A

fine needle aspiration Fine-needle aspiration (FNA) is a diagnostic procedure used to investigate lumps or masses. In this technique, a thin (23–25 gauge (0.52 to 0.64 mm outer diameter)), hollow needle is inserted into the mass for sampling of cells that, ...

(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. Other peripheral areas such as the

salivary glands The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of Duct (anatomy), ducts. Humans have three paired major salivary glands (Parotid gland, parotid, Submandibular gland, submandibula ...

gingiva The gums or gingiva (: gingivae) consist of the mucosal tissue that lies over the mandible and maxilla inside the mouth. Gum health and disease can have an effect on general health. Structure The gums are part of the soft tissue lining of the ...

rectum The rectum (: rectums or recta) is the final straight portion of the large intestine in humans and some other mammals, and the gut in others. Before expulsion through the anus or cloaca, the rectum stores the feces temporarily. The adult ...

or skin may also be biopsied, however in some cases a biopsy of the target organ may be needed. On microscopic exam of biopsy specimens, amyloid deposits appear green ("apple-green birefringence") when stained with Congo Red dye and viewed under polarized light. Disordered plasma cells with a monoclonal protein product (immunoglobulin light chains) are confirmed in AL amyloidosis using

serum Serum may refer to: Biology and pharmacology *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity *Serous fluid, any clear bodily fluid Places *Serum, Ind ...

urine protein electrophoresis Protein electrophoresis is a method for analysing the proteins in a fluid or an extract. The electrophoresis may be performed with a small volume of sample in a number of alternative ways with or without a supporting medium, namely agarose or poly ...

, immunoglobulin free light-chain assays or identification of lambda or kappa restricted plasma cells on a bone marrow biopsy. The precursor protein that is forming the amyloid fibrils may be identified using

immunohistochemical studies Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...

such as immunofluorescence or immunostaining, immunogold electron microscopy or

mass spectroscopy Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...

(which is not widely available). Mass spectroscopy has a sensitivity of 88% and a specificity of 96% in identifying the precurosor protein in AL amyloidosis. Cardiac involvement in AL amyloidosis may be assessed using

echocardiography Echocardiography, also known as cardiac ultrasound, is the use of ultrasound to examine the heart. It is a type of medical imaging, using standard ultrasound or Doppler ultrasound. The visual image formed using this technique is called an ec ...

cardiac magnetic resonance Cardiac magnetic resonance imaging (cardiac MRI, CMR), also known as cardiovascular MRI, is a magnetic resonance imaging (MRI) technology used for non-invasive assessment of the function and structure of the cardiovascular system. Conditions in wh ...

(cardiac MRI) or

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

(PET scan).

Treatment

The most effective treatment is autologous bone marrow transplants with stem cell rescues. However many patients are too weak to tolerate this approach. Other treatments can involve application of

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

similar to that used in multiple myeloma, which targets the plasma cells responsible for producing the misfolded light chain proteins. The most widely used regiment, and first line therapy, for those ineligible for a stem cell transplant is

cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...

bortezomib 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 ...

and

dexamethasone Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive pulmonary disease (COPD), croup, brain swelling, eye pain following eye su ...

(CyBorD) with

daratumumab Daratumumab, sold under the brand name Darzalex among others, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now ...

added. 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. 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. CyBorD may be used alone, or bortezomib–

melphalan Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma; malignant lymphoma; lymphoblastic and myeloblastic leukemia; childhood neuroblastoma; ovarian cancer; mammary adenocar ...

–dexamethasone may be used in resource limited settings where daratumumab is not available. 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 Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

, thus degrading amyloid microfibril deposits. Supportive care in AL amyloidosis consists of salt restriction and

diuretics A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

in those with heart failure or kidney involvement. An

angiotensin converting enzyme inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as ...

(ACEi) or

angiotensin receptor blocker Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals tha ...

(ARB) may be used in those with significant proteinuria due to kidney disease.

Amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxys ...

or an implantable defibrillator are sometimes needed for those with cardiomyopathy due to AL amyloidosis who are at risk of ventricular arrhythmias. Those with AL amyloidosis and kidney disease may require dialysis if kidney involvement progresses.

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 . Heart involvement is associated with a worse prognosis.

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.

References

External links

{{Immunoproliferative immunoglobulin disorders Amyloidosis