Light chain deposition disease (LCDD) is a rare blood cell disease which is characterized by deposition of fragments of infection-fighting

immunoglobulins 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 bacteria and viruses, including those that cause di ...

, 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 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 ...

, Waldenström's macroglobulinemia, and the

monoclonal gammopathy of undetermined significance Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is u ...

premalignant stages of these two diseases. Unlike in

AL amyloidosis Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein fibers ...

, in which light chains are laid down in characteristic

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

deposits, in LCDD, light chains are deposited in non-amyloid granules.

Signs and symptoms

Light chain deposition disease can affect any organ. Renal involvement is always present and can be identified by microscopic

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with ...

and

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...

. Due to the gradual buildup of light chains from plasma filtration, renal function rapidly declines in the majority of patients with LCDD as either acute tubulointerstitial nephritis or rapidly progressing

glomerulonephritis Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...

. This condition can include

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 ...

, and/or

renal 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 ...

. Regardless of the degree of light chain excretion,

happens with a comparable frequency. Furthermore,

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

may be present at the time of diagnosis in patients with LCDD. Deposits may form in the skin,

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

, thyroid glands,

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

s, and

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...

s. Extrarenal deposition with symptoms is uncommon. It is unclear if localized LCDD is a real condition or if it is the first sign of a silent systemic LCDD. The

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

is the most common extra-renal site in LCDD, although involvement is not always limited to this organ. There appears to be no relationship between the degree of light chain deposition within the liver and the severity of liver dysfunction. In addition to

portal hypertension Portal hypertension is defined as increased portal venous pressure, with a hepatic venous pressure gradient greater than 5 mmHg. Normal portal pressure is 1–4 mmHg; clinically insignificant portal hypertension is present at portal pressures 5� ...

and hepatic insufficiency, affected patients may die from hepatic failure. Cardiac involvement may be linked to paroxysmal atrial fibrillation, severe

congestive 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 fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...

, and

restrictive cardiomyopathy Restrictive cardiomyopathy (RCM) is a form of cardiomyopathy in which the walls of the heart are rigid (but not thickened). Thus the heart is restricted from stretching and filling with blood properly. It is the least common of the three original s ...

. The lungs are rarely affected by light chain deposition disease, which typically damages the

parenchyma upright=1.6, Lung parenchyma showing damage due to large subpleural bullae. Parenchyma () is the bulk of functional substance in an animal organ such as the brain or lungs, or a structure such as a tumour. In zoology, it is the tissue that ...

; bronchial involvement seems to be extremely uncommon. However recent reports have indicated that the major airways are involved. There have been descriptions of nodular as well as diffuse pulmonary interstitial diseases; however, the literature has only reported seven occurrences of pulmonary nodular-type LCDD to date. The effects of systemic protein deposition on the nerves are comparable to those of

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 ...

, which is clinically characterized by

polyneuropathy Polyneuropathy () is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may prog ...

. Deposits may form in the

choroid plexus The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central ...

and along

nerve fibers A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the electrochemical nerve impulses called ...

. Additionally, isolated LCDD within the brain has been reported.

Cause

LCDD develops as a result of overproduction and thus deposition of abnormal

. About 60% of cases develop in the context of

plasmacytoma Plasmacytoma is a plasma cell dyscrasia in which a plasma cell tumour grows within soft tissue or within the axial skeleton. The International Myeloma Working Group lists three types: Plasma cell dyscrasia#Solitary plasmacytoma, solitary plasma ...

, and other

lymphoproliferative disorders Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised ...

. However, in many cases, an underlying cause cannot be identified.

Mechanism

The main light chain structure in LCDD presumably dictates how the disease manifests in the body. Though κI-IV has been described, the sequenced kappa light chains in LCDD are more likely to belong to the V-region subtype, of which VκIV appears to be overrepresented. The pathogenicity of these proteins has not been linked to any particular structural pattern or residue, but a number of recurring characteristics have been identified. Firstly,

somatic mutation A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline muta ...

s, not

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

s, are the source of the amino acid substitutions. Secondly, the region that determines complementarity is where substitutions happen most frequently. Third, hydrophobic residues are more likely to be introduced by the mutations reported in both the kappa and light chains. This could disrupt protein-protein interactions and destabilize the protein, leading to protein deposition in tissues. The propensity for aggregation is exemplified in a

murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...

model of LCDD where light chain deposition was observed in the kidney of transfected mice using vectors that contained kappa light chain sequence from an individual with LCDD with the VκIV subtype. Lastly, because some patients with LCDD have isolates of kappa light chains with mutations that produce new

N-glycosylation ''N''-linked glycosylation is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), i ...

sites, posttranslational modification can be linked to the creation of pathologic light chains. It is possible that the new hydrophobic residues along with

sites will make it more likely for the light chains to accumulate in the affected tissues'

basement membrane The basement membrane, also known as base membrane, is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between epithelial tis ...

s. The

mesangial cell Mesangial cells are specialised cells in the kidney that make up the mesangium of the glomerulus. Together with the mesangial matrix, they form the vascular pole of the renal corpuscle. The mesangial cell population accounts for approximately ...

is also thought to play a role in the pathogenesis of LCDD.

Diagnosis

A number of laboratory tests are required in order to assist in diagnosing LCDD. Blood and urine samples are collected for evaluation of kidney and liver function and determination of the presence of a monoclonal protein. Imaging studies such as

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 ...

and an

ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...

of the abdomen will be performed. A

CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...

, magnetic resonance imaging (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) may also be indicated. Patients suspected of having LCDD should be evaluated using the screening panel for plasma cell proliferative disorders. However, the sensitivity of laboratory testing strategies for detecting monoclonal gammopathies has increased with the development of quantitative serum assays to test for immunoglobulin free light chain; this increased diagnostic sensitivity is easily noticeable in the monoclonal light chain diseases. The most recent diagnostic screening guidelines state that serum immunofixation in addition to immunoglobulin free light chain is an adequate screening panel for plasma cell proliferative disorders apart from

and LCDD due to the increased sensitivity for free light chain diseases. It is advised, nevertheless, that urine immunofixation be used in addition to LCDD and

screening. The immunohistologic examination of tissue from an afflicted organ—which is not congophilic in nature—confirms the diagnosis of LCDD. The tissue's light chain restriction evaluation will determine whether the heavy or light chain is monoclonal. An

abdominal ultrasound Abdominal ultrasonography (also called abdominal ultrasound imaging or abdominal sonography) is a form of medical ultrasonography (medicine, medical application of ultrasound technology) to visualise abdomen, abdominal anatomy, anatomical structu ...

and

should be part of the workup when an individual is diagnosed with LCDD in order to evaluate the

, and

s. A bone marrow aspirate as well as biopsy are necessary to rule out light amyloidosis and/or

. Similar to cardiac amyloid,

diastolic dysfunction Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the ...

and a decrease in myocardial compliance may be discovered via

and

catheterization In medicine, a catheter ( ) is a thin tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Catheters are man ...

. By using specific light chain stains in glomeruli as well as negative Congo red stain, tubular

s, and punctate amorphous, ground-pepper-like appearance of deposits on

electron microscopy An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...

, LCDD can be differentiated from other causes of nodular sclerosis and mesangial expansion.

Diabetic nephropathy Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) and end-stage renal disease ...

exhibits no deposits; fibrillary

is Congo red negative and has a proliferative appearance along with polyclonal

immunoglobulin G Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...

; other monoclonal immunoglobulin deposition disease exhibit both light and heavy chain staining or just heavy chain staining. Additional reasons for a membranoproliferative glomerulonephritis pattern exhibit

appearances and

immunofluorescence Immunofluorescence (IF) is a light microscopy-based technique that allows detection and localization of a wide variety of target biomolecules within a cell or tissue at a quantitative level. The technique utilizes the binding specificity of anti ...

specific to the disease.

Treatment

Decreasing production of the organ-damaging light chains is the treatment goal. Options include chemotherapy using bortezomib,

autologous stem cell transplantation Autologous stem-cell transplantation (also called autogenous, autogenic, or autogenic stem-cell transplantation and abbreviated auto-SCT) is the autologous transplantation of stem cells—that is, transplantation in which stem cells ( undifferen ...

, immunomodulatory drugs, and

kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...

. There is no standard treatment for LCDD. High-dose melphalan in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of bortezomib 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 ...

has also been examined.

Outlook

Different light chain deposition does not appear to have an impact on the clinical course of LCDD patients, as the clinical presentation is known to depend on the quantity and type of affected organs. The median survival time is roughly four years. Following a median follow-up of 27 months, the most comprehensive series to date found that 59% of cases resulted in death and 57% of cases reached

uremia Uremia is the condition of having high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess in the blood of amino acid and protein metabolism end products, such as urea and creatinine, which ...

. LCDD prognostic factors include age, extrarenal light chain deposition, and plasma cell myeloma.

Epidemiology

Being a relatively rare condition, LCDD is commonly misdiagnosed as a protein disease. Up to 50% of patients receive an LCDD diagnosis as a result of

such as

. LCDD is diagnosed at a median age of 58 years. LCDD affects men 2.5 times more than women and is frequently linked with monoclonal gammopathies of unknown significance in 17% of patients.

References

External links

National Institutes of Health Genetic and Rare Diseases Information Center

Emedicine
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