Light chain amyloidosis

Amyloid light chain (AL) amyloidosis or immunoglobulin light chain amyloidosis is a systemic amyloidosis and a plasma cell proliferative disorder characterized by deposition of misfolded monoclonal kappa or lambda light chains produced by clonal plasma cells ^1-6.

Epidemiology

Amyloid light chain amyloidosis is a rare disease with an estimated incidence of less than 1/100000 per year ^1-3, but also the most common form of systemic amyloidosis ^1-3. Women and men are equally affected ². However, at this point, epidemiological data still varies significantly among different countries ². The majority of patients have some degree of cardiac or renal involvement or both ^1-6.

Associations

Light chain amyloidosis might be associated with the following clinical conditions ^1-6:

• multiple myeloma: up to 10-15% ⁴

• monoclonal gammopathy of undetermined significance: up to 9% ⁴

• smoldering myeloma

• Waldenström macroglobulinemia

• chronic lymphocytic leukemia

• non-Hodgkin lymphoma

Diagnosis

The diagnosis includes the following ^1,4,6-10:

• histopathological diagnosis with amyloid typing (e.g. by determination of precursor protein by mass spectrometry)

• identification of clonal disease ⁸

  • serum free light chain measurements

  • serum and urine immunoelectrophoresis

• disease extent evaluation

  • cardiac involvement: characteristic cardiac imaging findings with or without elevated NT-proBNP (>332 ng/L) ⁴

  • renal involvement: >0.5 g albumin in 24 h urine collection, renal insufficiency/positive biopsy result ⁴

  • hepatic involvement: serum alkaline phosphatase >1.5 x upper normal limit, liver span >15 cm ⁴

Clinical presentation

Symptoms are usually vague, unspecific and variable. Presentations include fatigue, dizziness and/or weight loss as well as organ-related signs and symptoms such as ^1,4,5:

• heart failure

• nephrotic syndrome

• hepatomegaly

• macroglossia

• bleeding disorders including periorbital bruising

• peripheral neuropathies or carpal tunnel syndrome

• autonomic neuropathy

Other possible but less common symptoms include gastroparesis and intestinal pseudoobstruction, xerostomia and jaw claudication ¹.

Serum alkaline phosphatase might be elevated ¹ as well as NT-proBNP in the setting of cardiac involvement ².

ECG might show decreased limb QRS voltage (≤5 mV) ^4,5.

Complications

Complications often evolve from organ involvement and include the following ^3,4,11:

• heart failure

• arrhythmias

• sudden cardiac death

Pathology

Light chain amyloidosis is characterized by the deposition of monoclonal kappa or lambda light chains in the extracellular space of the affected tissues ^1-5 and accumulation in various organs ¹¹.

Location

Amyloid light chain amyloidosis occurs in the systemic form organ involvement is frequent and might include the following organs ⁴:

• cardiac involvement

• renal involvement

• peripheral and autonomic nervous system

• hepatic involvement

• gastrointestinal involvement

• pulmonary involvement

• soft tissues

The heart and the kidneys are the two most commonly involved organs ¹.

Microscopic appearance

The histopathological diagnosis is based on the Congo red affinity of amyloid associated with apple green birefringence under polarized light demonstrating the amyloid fibril ultrastructure ^1,11.

Immunophenotype

Due to the variability of the light chains, immunohistochemistry stains are associated with false positive and false negative results ^1,9.

Radiographic features

Radiographic features of cardiac amyloidosis, in general, include an unexplained increased wall thickness, thickening of the right ventricular free wall, interatrial septum or atrioventricular valves as well as biatrial enlargement ^7-11. See also: cardiac amyloidosis.

Additional common findings include pericardial and pleural effusions ^7-10,12.

Echocardiography

Echocardiography serves as a first-line imaging tool in the evaluation of cardiac involvement of amyloidosis.  Echocardiographic criteria for cardiac amyloidosis in general include an increased wall thickness (≥12 mm) and other characteristic features such as ^7-9:

• diastolic dysfunction

• decreased tissue Doppler s’, e’ and a’ wave velocities (<5 cm/s)

• decreased global longitudinal left ventricular strain with apical sparing ¹²

Another common feature is a ‘speckled pattern’ of the myocardium ^1,12 and biatrial enlargement ⁸.

MRI

Cardiac MRI might reveal a mildly increased left ventricular mass, increased native T1 and ECV on myocardial mapping and a variably diffuse often global subendocardial or transmural late enhancement in a nonischaemic pattern as well as abnormal blood pool gadolinium kinetics ^7,8.

Signal characteristics

• IRGE/PSIR: often global subendocardial enhancement, but can be absent ^12,13

• T1 mapping: markedly increased native T1

• ECV: markedly increased (≥40%) ^7,8

It is worth noting that a reliable differentiation between AL and ATTR is not possible with MR imaging ^7-10. However, imaging features favoring AL amyloidosis over ATTR amyloidosis have been described ^12,14:

• symmetrical wall thickening

• very high native T1 mapping values

• extracellular volume values in the range of 40-50% as opposed to extremely high values

• lower interventricular septum and right ventricular wall thickness

• lower left ventricular mass <100 g/m²

• late gadolinium enhancement is less extensive often global subenocardial with a QALE score <13

Nuclear medicine

Bone scintigraphy with Perugini grading is often negative in the setting of cardiac AL-amyloidosis, where patients often show no or minimal uptake in the myocardium ^5,6. A Perugini grade of 2 or 3 thus points more to ATTR amyloidosis ^5-7.

However, in a significant number of patients (>10%) bone scintigraphy has been also reported to be positive ^6,8.

Radiology report

The radiology report should include a description of the following:

• morphology and functional analysis

• wall motion abnormalities

• left ventricular wall thickness

• abnormal strain patterns (if measured)

• valvular thickening and atrial enlargement (if present)

MRI

• myocardial tissue properties including:

  • presence, pattern and distribution of late gadolinium enhancement

  • alteration of blood-pool gadolinium kinetics

  • abnormal T1 and T2 mapping and ECV values (if performed/calculated)

Treatment and prognosis

Management of amyloidosis depends entirely on the amyloid type therefore amyloid typing is crucial ⁴. Both treatment and prognosis will mostly depend on the degree of organ involvement, but also on other factors such as age, performance status as well as bone marrow findings ¹⁶. The main goal in treatment is maximal reduction of circulating light chains and recovery of affected organs with improvement and maintenance of organ function ¹. Except for a few localized forms all forms of systemic AL amyloidosis require systemic treatment ³. Options are autologous stem cell transplantation, alkylator-based regimens such as melphalan/dexamethasone, newer agent-based treatments, that include the anti-CD39 monoclonal antibody daratumumab and/or the proteasome inhibitor bortezomib as well as supportive care ^1-4,16.

Compared to other forms AL amyloidosis is associated with the poorest outcome, with survival rates in the absence of treatment of less than 2 years ³. Myocardial infiltration is associated with the worst prognosis ³ and transmural late gadolinium enhancement as well as the presence of myocardial edema are considered predictors of mortality ^9-11.

History and etymology

Amyloid is derived from the Latin ‘starch-like’ and was originally introduced for botanical purposes. It was first used for medical purposes by Rudolf Virchow in 1854, who initially considered amyloid to be starch-based extracellular deposits ^17-19.

Patient-related case descriptions with presumed amyloidosis reach back to 17^th century ¹, and the history of AL amyloidosis includes further descriptions including the discovery of Bence Jones proteins in urine. Finally, in 1867, the physician H Weber described the autopsy of a patient with non-traumatic fractures in the sternum,  where he found cells of unclear dignity in the bone marrow and identified amyloid in the hypertrophied heart, spleen and kidneys, the latter indicating a setting of myeloma associated with amyloidosis ^17-20.

Differential diagnosis

The main differential diagnosis of AL amyloidosis includes the following ^3,5,8,17:

• other infiltrative cardiomyopathies such as

  • ATTR amyloidosis

  • Fabry disease

• hypertensive heart disease

• aortic stenosis

• hypertrophic cardiomyopathy

Practical points

• diagnosis of AL amyloidosis is often delayed and even longer in patients with a prior diagnosis of plasma cell proliferative disorders ¹

• diagnosis requires a high index of suspicion and a testing sequence, there is no single test for the disease ¹

• multiorgan involvement at the time of the diagnosis is very common ^2,3

• macroglossia or periorbital bruising is considered almost pathognomonic in the presence of typical findings on cardiac MRI or echocardiography ⁵

• usually requires multidisciplinary collaboration with a designated coordinator, most frequently a hematologist ⁸

• the PSIR sequence is an option to better deal with the difficulties of nulling myocardium ^12,13

• less than 10% have symptomatic multiple myeloma at presentation or fulfill the CRAB criteria ¹

• histology can be obtained from the affected organ but also from periumbilical fat aspirates, bone marrow or labial salivary gland specimens ^1,4