Version May 2024
INTRODUCTION — Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of subunits of a variety of normal serum proteins. These fibrils have a predominantly antiparallel beta-pleated sheet configuration (noted on x-ray diffraction), and can be identified on biopsy specimens both by their characteristic appearance on electron microscopy and by their ability to bind Congo red (leading to green birefringence under polarized light) and thioflavine T (producing an intense yellow-green fluorescence).
More than 30 distinct low molecular weight proteins are recognized to form amyloid fibrils. The four most common causes of systemic amyloid deposition are:
●Immunoglobulin light chain (AL) amyloidosis (historically referred to as primary amyloidosis) in which the fibrils are composed of fragments of monoclonal light chains. Affected patients may have amyloidosis alone or in association with other plasma cell dyscrasias (multiple myeloma, Waldenström macroglobulinemia). All forms of systemic amyloidosis in which the fibrils are derived from monoclonal light chains, regardless of the nature of the underlying plasma cell disorder (eg, monoclonal gammopathy of undetermined significance, multiple myeloma, or Waldenström macroglobulinemia) are considered AL amyloidosis.
●Wild type transthyretin amyloidosis (ATTRwt, historically referred to as age-related [senile] amyloidosis) typically involves the heart and causes a restrictive cardiomyopathy. It is caused by deposition of normal unmutated transthyretin (TTR), which appears to be an inherently amyloidogenic protein. (See "Overview of amyloidosis", section on 'Wild-type transthyretin systemic amyloidosis'.)
●Hereditary (familial) amyloidosis (ATTRmt) are the result of mutations in genes coding for several different proteins that are normally present in the body. The most common "amyloidogenic proteins" implicated in hereditary amyloidosis are mutated forms of TTR, the alpha chain of fibrinogen A, apolipoprotein AI and AII, lysozyme, and gelsolin. (See "Genetic factors in the amyloid diseases".)
●AA amyloidosis in which the fibrils are composed of fragments of the acute phase reactant serum amyloid A. AA amyloidosis is typically reactive (secondary) to chronic inflammation. (See "Pathogenesis of AA amyloidosis".)
Because AL amyloidosis is a clonal plasma cell disorder, it is treated with chemotherapy to eradicate the underlying clone. AL amyloidosis must be differentiated from other forms of amyloidosis (eg, AA amyloidosis, ATTRmt amyloidosis, and ATTRwt amyloidosis) since the latter are non-neoplastic and will not benefit from chemotherapy.
AL amyloidosis is a systemic disorder that can present with a variety of symptoms or signs, including heavy proteinuria (usually in the nephrotic range), edema, hepatosplenomegaly, otherwise unexplained heart failure, and the carpal tunnel syndrome. Although virtually all patients have multisystem amyloid deposition, it is not uncommon to present with evidence of mainly one organ being affected. (See "Renal amyloidosis" and "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management" and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
The clinical presentation, diagnosis, and differential diagnosis of AL amyloidosis will be discussed here. An overview of the amyloid disorders as well as the pathogenesis, prognosis, and treatment of AL amyloidosis are presented separately.
●(See "Overview of amyloidosis".)
●(See "Monoclonal immunoglobulin deposition disease".)
●(See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)
EPIDEMIOLOGY — AL amyloidosis is an uncommon disorder and the exact incidence is unknown. In the United States, the incidence appears to be stable at approximately 9 to 14 cases per million person-years [1-3].
AL amyloidosis is a disease of older adults. As with other plasma cell dyscrasias, the age-specific incidence rates increase in each decade of life after age 40 years [1]. The median age at diagnosis is 64 years, and less than 5 percent of patients are under the age of 40 [4-8]. There is a male predominance with men accounting for 65 to 70 percent of patients.
AL amyloidosis occurs in all races and all geographic locations; however, there are few data regarding whether the incidence varies by ethnicity or geography.
Relation to other plasma cell disorders — Some patients who ultimately show clinical evidence of AL amyloidosis present with what appeared to be monoclonal gammopathy of undetermined significance (MGUS). Once a diagnosis of AL amyloidosis is made, such patients are no longer considered to have MGUS. Over time, a small number of patients with MGUS eventually develop symptoms or signs of AL amyloidosis, multiple myeloma (MM), or Waldenström macroglobulinemia (WM), at a rate of approximately 1 percent per year [9]. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Disease progression'.)
AL amyloidosis can also occur in patients with other plasma cell dyscrasias, including MM and WM, which are malignant disorders of plasma cells or lymphoplasmacytic cells, respectively. Less frequently, AL amyloidosis may be associated with marginal zone lymphoma or another non-Hodgkin lymphoma subtype [10].
When MM and AL amyloidosis are diagnosed in the same patient, the myeloma is typically diagnosed before or around the time of the amyloidosis diagnosis. Less commonly, myeloma develops more than six months after the diagnosis of amyloidosis (delayed progression):
●In a series of 1596 patients with AL amyloidosis seen at the Mayo Clinic between 1960 and 1994, only six (0.4 percent) showed delayed progression (at 10 to 81 months) to overt myeloma [11]. This usually occurred in patients without cardiac or hepatic amyloidosis who lived long enough to develop myeloma.
●In a series of 4319 patients seen at the Mayo Clinic between 1990 and 2008 with a diagnosis of myeloma who had at least six months of follow-up, there were 47 patients (1.1 percent) in whom the diagnosis of AL amyloidosis followed the diagnosis of myeloma by at least six months [12]. Outcome of these patients was poor, especially in those with cardiac involvement, with a median survival after the diagnosis of AL amyloidosis of nine months (95% CI 4-14 months).
In patients with AL amyloidosis, hypercalcemia, bone pain, or lytic bone lesions is suggestive of the combination of clinical myeloma and amyloidosis. The diagnosis of coexisting MM is reserved for patients with amyloidosis who would otherwise meet diagnostic criteria for MM, usually with clonal bone marrow plasmacytosis ≥10 percent and one or more myeloma-defining events (MDEs) such as osteolytic bone lesions [13]. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnostic criteria'.)
Although AL amyloidosis is not an MDE, outcomes of patients with AL amyloidosis who have clonal bone marrow plasmacytosis ≥10 percent are comparable to patients meeting criteria for coexisting MM due to the presence of MDEs [14]. Therefore, such patients with AL amyloidosis without clinical myeloma who have a higher plasma cell burden (≥10 percent) should be managed more intensively than their low tumor burden counterparts. Although typical myeloma regimens are often not well tolerated in patients with AL amyloidosis, induction and maintenance strategies should be considered for those who meet the current criteria for coexistent myeloma.
CLINICAL PRESENTATION
Systemic presentations — The clinical presentation in AL amyloidosis depends on the number and nature of the organs affected. In some patients only one organ is affected, while in others there is extensive multi-system involvement. However, even in patients with more than one organ affected, it is usually possible to identify one organ as the "dominant" site of involvement. A more complete overview of the clinical manifestations of amyloidosis in general can be found elsewhere. (See "Overview of amyloidosis", section on 'Clinical manifestations'.)
Non-specific systemic symptoms, including fatigue and unintentional weight loss, are common in patients with AL amyloidosis [15]. Other common clinical presentations of AL amyloidosis include the following:
●Nephrotic syndrome – Renal involvement occurs in approximately 70 percent of patients and most often presents as asymptomatic proteinuria or clinically apparent nephrotic syndrome (50 percent). (See "Renal amyloidosis".)
●Restrictive cardiomyopathy – Cardiac involvement is seen in approximately 60 percent of patients and is typically characterized by thickening of the interventricular septum and ventricular wall (movie 1). This can lead to systolic or diastolic dysfunction and the symptoms of heart failure. Other manifestations that can occur include sudden death or syncope due to arrhythmia or heart block, and rarely angina or infarction due to accumulation of amyloid in the coronary arteries. Elevations in N-terminal serum brain natriuretic peptide (BNP) in patients with AL amyloidosis are seen before the onset of clinical heart failure and are a marker of cardiac involvement. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)
●Peripheral neuropathy – Mixed sensory and motor peripheral neuropathy (20 percent) and/or autonomic neuropathy (15 percent) is a prominent feature in AL amyloidosis. Symptoms of numbness, paresthesia, and pain are frequently noted, as in peripheral neuropathy of many other causes. Compression of peripheral nerves, especially the median nerve within the carpal tunnel, can cause more localized sensory changes. Symptoms of bowel or bladder dysfunction and findings of orthostatic hypotension may be due to autonomic nervous system damage.
●Hepatomegaly, with elevated liver enzyme levels – Hepatomegaly with or without splenomegaly is seen in as many as 70 percent of patients. A cholestatic pattern with elevated liver enzymes is seen in approximately 25 percent. Clinical gastrointestinal involvement appears to be less common than in other forms of amyloidosis, with clinically apparent disease occurring in only 1 percent of patients [16]. Because amyloidosis is a systemic disease, rates of positive gastrointestinal biopsies are much higher; in days past, rectal biopsy was considered a safe and simple method of diagnosing systemic amyloidosis with a sensitivity of 75 percent [15]. For symptomatic patients potential gastrointestinal manifestations include bleeding (due to vascular fragility and loss of vasomotor responses to injury), gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction resulting from dysmotility. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management".)
●Macroglossia and involvement of other muscles – Amyloid infiltration of skeletal muscles may cause visible enlargement (ie, pseudohypertrophy). A large tongue (ie, macroglossia), or lateral scalloping of the tongue from impingement on the teeth, is characteristic of AL amyloidosis (picture 1). Arthropathy may be due to amyloid deposition in joints and surrounding structures. The "shoulder pad" sign is visible enlargement of the anterior shoulder due to fluid in the glenohumeral joint and/or amyloid infiltration of the synovial membrane and surrounding structures. (See "Musculoskeletal manifestations of amyloidosis", section on 'Muscle involvement in AL amyloid'.)
●Purpura and other skin manifestations – Purpura, characteristically elicited in a periorbital distribution (raccoon eyes) by a Valsalva maneuver or minor trauma, is present in only a minority of patients, but is highly characteristic of AL amyloidosis (picture 2) [17]. Other signs of skin involvement include waxy thickening, easy bruising (ecchymoses) (picture 3), and subcutaneous nodules or plaques. Infiltration of the subcutaneous fat is generally asymptomatic but provides a convenient site for biopsy.
●Bleeding diathesis – Amyloidosis may be directly associated with a bleeding diathesis [18-22]. In one report of 337 patients, abnormal bleeding and abnormal coagulation tests were seen in 28 and 51 percent, respectively [19]. Proposed mechanisms include factor X deficiency due to binding to amyloid fibrils primarily in the liver and spleen; decreased synthesis of coagulation factors in patients with advanced liver disease; and acquired von Willebrand disease. However, some patients with abnormal bleeding have no abnormality in any coagulation test [18]. In such patients, amyloid infiltration of blood vessels may contribute to the bleeding diathesis. (See "Acquired von Willebrand syndrome" and "Pathophysiology of von Willebrand disease", section on 'Causes of reduced VWF in acquired VWS'.)
Nearly 10 percent of patients will have clinical manifestations of coexisting MM characterized by anemia, hypercalcemia, and/or lytic bone lesions [14]. Such patients may present with signs and symptoms related to the MM, such as bone pain and infection. (See 'Relation to other plasma cell disorders' above and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Clinical presentation'.)
IgM-associated AL amyloidosis — AL amyloidosis is an uncommon complication of immunoglobulin M (IgM)-associated monoclonal gammopathies, such as Waldenström macroglobulinemia [23-28]. IgM-related AL amyloidosis appears to be a distinct clinical entity with less cardiac involvement and a higher incidence of lymph node and soft tissue involvement (eg, liver damage, peripheral and autonomic neuropathy) when compared with non-IgM-related AL amyloidosis. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Amyloidosis'.)
In the largest retrospective study, 131 of 250 patients with IgM-associated systemic AL amyloidosis had a clearly identified lymphoproliferative disorder, 39 of which predated the amyloidosis diagnosis [27]. The most common identified conditions were lymphoplasmacytic lymphoma and non-Hodgkin lymphoma, not specifically classified. Rare cases of associated chronic lymphocytic leukemia and follicular lymphoma were seen. The involved light chain was kappa in 40 percent. The most commonly involved organs were:
●Kidney (68 percent)
●Soft tissue (35 percent, including lymph nodes in 20 percent)
●Liver (17 percent)
●Peripheral nervous system (15 percent)
●Autonomic nervous system (13 percent)
●Gastrointestinal system (9 percent)
On multivariate analysis, adverse prognostic features included older age, high NT-proBNP, elevated troponin T, liver involvement, and the presence of neuropathy. These features were combined into a novel prognostic score.
IgD-associated AL amyloidosis — It is extremely rare for patients with AL amyloidosis to have a monoclonal immunoglobulin D (IgD) at the time of diagnosis. The largest single center retrospective case series of 3955 patients with Ig light chain amyloidosis identified 53 patients (1.3 percent) with a serum IgD monoclonal protein [29]. When compared with non-IgD AL amyloidosis, patients appeared to have a lower frequency of renal and cardiac involvement. At the time of presentation, the most common signs and symptoms were fatigue (60 percent), lower extremity edema (43 percent), paresthesias (32 percent), weight loss (32 percent), dyspnea on exertion (28 percent), and carpal tunnel syndrome (26 percent). Survival appeared similar to that of non-IgD AL amyloidosis.
PATHOLOGIC FEATURES
Tissue biopsy
Choosing a biopsy site — The diagnosis of AL amyloidosis requires the demonstration of amyloid fibrils upon histologic evaluation of an affected organ (eg, kidney, liver) or a surrogate site (eg, abdominal fat pad, bone marrow). We suggest initial evaluation with an abdominal fat pad aspirate and bone marrow biopsy because of their ease, convenience, and high yield (algorithm 1). Either or both are positive in 90 percent of patients with AL amyloidosis. If AL amyloidosis is still suspected in the setting of negative fat pad aspirate and bone marrow biopsy, then the affected organ should be biopsied.
The choice of initial biopsy site must take into consideration the expected yield, accessibility of the site, and the risks associated with the procedure. Kidney or liver biopsy is positive in over 90 percent of cases; however, a high success rate can also be achieved by less invasive procedures, such as abdominal fat pad aspirate (60 to 80 percent), rectal biopsy (50 to 70 percent), bone marrow biopsy (50 to 55 percent), or skin biopsy (50 percent) [15,30-33].
We do not perform gingival biopsy because it is uncomfortable for the patient, and skin biopsies are generally negative unless there is clinical involvement or if a considerable amount of fat is taken with the skin. In addition, some patients have a bleeding diathesis (eg, acquired factor X deficiency), which may limit the safety of biopsy of major internal organs. (See "Overview of amyloidosis", section on 'Hematologic abnormalities'.)
Identifying amyloid — On hematoxylin- and eosin-stained biopsy sections, amyloid appears as a pink, amorphous, waxy substance with a characteristic 'cracking' artifact (picture 4) [34]. The presence of amyloid fibrils can be confirmed by their characteristic appearance on electron microscopy (picture 5) and by their ability to bind Congo red (leading to green birefringence under polarized light) (picture 6A-B) or thioflavine-T (producing an intense yellow-green fluorescence) [35]. The estimated sensitivity and specificity of Congo red staining on light microscopy for amyloid are 79 and 80 percent, respectively [36]. The sensitivity for kappa (74 percent) is lower than that for lambda (84 percent). Of importance, biopsy sections that are very thin (ie, 6 microns or less) may not stain appropriately with Congo red despite the presence of amyloid fibrils on electron microscopy.
Determining the type of amyloid — Once the histologic diagnosis of amyloid is made (typically based on the Congo red stain), there are a number of laboratory and histologic findings that may distinguish AL amyloidosis from other forms of amyloidosis on tissue specimens. Mass spectrometry is the preferred method since immunohistochemistry and immunofluorescence have a greater risk of false positive and false negative results. However, this test is not widely available, and appropriate tissue samples need to be sent to referral centers for such testing. If available, immunoelectron microscopy is an acceptable alternative to mass spectrometry.
The following describes the use of each of these methods:
●Laser microdissection with mass spectrometry (MS) combines tissue sampling by laser microdissection along with tandem mass spectrometry-based proteomic analysis [37-40]. This technique is able to efficiently and accurately identify all types of amyloid, including rare subtypes, with 100 percent specificity [8]. In a study of 50 cases of amyloidosis well-characterized by gold standard clinicopathologic criteria (training set) and an independent validation set comprising 41 cases of cardiac amyloidosis, this technique identified the amyloid type with 100 percent specificity and sensitivity in the training set and 98 percent in the validation set [37].
●Immunohistochemical staining (eg, for kappa and lambda light chains, transthyretin, and serum amyloid A component) of the amyloid can determine the type of amyloidosis [41]. Positive staining for kappa or lambda indicates AL amyloidosis; positive staining for transthyretin indicates hereditary or wild type transthyretin (ATTRmt or ATTRwt) amyloidosis; positive staining for serum amyloid A component occurs with secondary (AA) amyloidosis. However, immunohistochemical staining should only be done at centers with considerable expertise with the antibodies since false negatives and false positives are common in inexperienced hands.
●Immunoelectron microscopy combines immunohistochemistry and electron microscopy to confirm amyloid deposition and identify the protein within the amyloid fibrils. In one study, when compared with Congo red staining, immunoelectron microscopy had similar sensitivity (76 percent) and higher specificity (100 percent) for amyloid [36]. The sensitivity for kappa (71 percent) was lower than for lambda (83 percent).
●Immunofluorescence microscopy in the kidney or other affected tissue (picture 7) may show deposition of a monoclonal (lambda or kappa) light chain in AL amyloidosis, although some have reported a low sensitivity with renal biopsies (65 percent in one series) [42]. Immunofluorescence using light-chain specific antisera and other specialized techniques can also be used with other tissue specimens to help diagnose AL amyloidosis (picture 8) [43,44].
Chromosomal changes — Patients with AL amyloidosis frequently have chromosomal abnormalities, but there is no single chromosomal change that is diagnostic of this disease. The monotypic plasma cell population in the bone marrow has elements of a neoplastic nature as shown by the frequent finding of numerical chromosomal abnormalities. In a study of bone marrow samples with fluorescence in situ hybridization (FISH) from 21 patients with AL amyloidosis, monosomy of chromosome 18 was the most common abnormality, occurring in 72 percent of cases, but trisomy of a variety of chromosomes was also common [45]. Similar prevalences were found in 19 patients with monoclonal gammopathy of undetermined significance (MGUS). (See "Diagnosis of monoclonal gammopathy of undetermined significance".)
When a myeloma FISH panel is applied to patients with AL amyloidosis, t(11;14)(q13;q32) is the most common abnormality, seen in nearly 50 percent of patients; other commonly seen abnormalities include del(13q14) and gain of 1q21 [46-50]. High-risk FISH abnormalities (eg, 17p13 deletion) are distinctively uncommon. (See "Multiple myeloma: Pathobiology", section on 'Cytogenetic abnormalities' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Cytogenetics'.)
Evidence of monoclonal plasma cells — The diagnosis of AL amyloidosis requires evidence of a monoclonal plasma cell proliferative disorder as displayed by the presence of a serum or urine monoclonal (M) protein, an abnormal serum free light chain ratio, or clonal plasma cells in the bone marrow.
A monoclonal plasma cell proliferative disorder can be assumed if an M protein is detected in the serum or urine. The M protein in AL amyloidosis is IgG in approximately 35 percent, IgA in 10 percent, IgM in 5 percent, IgD in 1 percent, and light chain (lambda or kappa) in the remaining patients [51]. Most patients with AL amyloidosis have little or no intact monoclonal immunoglobulin, but are characterized by the presence of monoclonal free light chain. The monoclonal light chain type is lambda in approximately 70 percent of cases, kappa in 25 percent, and biclonal in 5 percent [52]. Evaluation with serum and urine immunofixation plus a serum free light chain ratio analysis provides the most sensitive measure for this M protein:
●Serum protein electrophoresis (SPEP), which detects intact monoclonal immunoglobulin, will demonstrate a localized band or peak in less than 50 percent of patients with AL amyloidosis. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum protein electrophoresis (SPEP)'.)
●Immunofixation techniques designed to identify light chains will detect a serum or urinary M protein in nearly 90 percent of cases of AL amyloidosis [7]. Of importance, a subset of patients has very small M protein levels that may only be detected by immunofixation (eg, monoclonal IgD) [29]. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum immunofixation'.)
●When serum and urine immunofixation is combined with serum free light chain ratio analysis, an M protein can be detected in virtually all cases [7,52]. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)
Clonal plasma cells can also be identified in the bone marrow. Bone marrow biopsy specimens typically demonstrate a slightly increased percentage of plasma cells that may appear morphologically normal [34]. Less commonly, the bone marrow demonstrates overt myeloma or lymphoplasmacytic lymphoma. A clonal excess of plasma cells (lambda or kappa) can also be demonstrated by immunoperoxidase staining or flow cytometric analysis of specimens of involved bone marrow (picture 7) [53,54]. However, a monoclonal plasma cell staining pattern typical of AL amyloidosis may be missed if the clone is small and masked by normal polyclonal plasma cells.
IMAGING
Serum amyloid P component scintigraphy — Serum amyloid P component (SAP) scintigraphy is a method of measuring the extent of amyloid involvement by using a radiolabeled variant of the SAP found in all amyloid deposits [55,56]. Tissue amyloid deposits are identified by scintigraphy following the intravenous injection of technetium-labeled SAP [57,58]. This test is more accurate in secondary amyloidosis [59] and may be positive even when tissue biopsy has been negative [55].
The value of SAP scintigraphy is limited because it is inconvenient, costly, not widely available, and is less helpful in detecting cardiac amyloidosis. Another limitation is that the SAP is currently obtained from blood donors, thereby carrying a potential infectious risk.
DIAGNOSIS
Evaluation — AL amyloidosis is suspected in a patient presenting with any one of the following (algorithm 1):
●Non-diabetic nephrotic range proteinuria
●Restrictive cardiomyopathy or otherwise unexplained congestive heart failure
●Increased NT-proBNP in the absence of known primary heart disease
●Unexplained edema, hepatosplenomegaly, or carpal tunnel syndrome
●Unexplained facial or neck purpura
●Macroglossia
The initial evaluation of a patient suspected of having AL amyloidosis should consist of serum and urine protein electrophoresis with immunofixation, serum free light chain ratio analysis, and an abdominal fat pad aspirate and bone marrow biopsy [60]. (See 'Choosing a biopsy site' above.)
If AL amyloidosis is still suspected in the setting of negative fat pad aspirate and bone marrow biopsy, then the affected organ (eg, kidney, liver) should be biopsied. Some patients have a bleeding diathesis, which may limit the safety of biopsy of major internal organs. (See "Overview of amyloidosis", section on 'Hematologic abnormalities'.)
The following tests are performed to assess for clinical organ involvement:
●Kidney – 24-hour urine for protein electrophoresis, creatinine, estimated glomerular filtration rate, and serum albumin.
●Heart – Troponin T, NT-proBNP, echocardiography, and electrocardiogram.
●Liver – Alkaline phosphatase; if involvement is suspected clinically, ultrasound or computed tomography to assess liver size.
●Coagulation system – Factor X levels; alternatively, clinicians may choose to check prothrombin time (PT) and partial thromboplastin time (PTT) with plans to check factor X levels in patients with abnormal bleeding or abnormal testing.
●Neuropathy – Patients with neurologic symptoms should be evaluated with electromyography (EMG) and nerve conduction studies. Since the neuropathy is most typically a small fiber neuropathy, these tests are often normal despite patient’s complaint of paresthesia or dysesthesia.
Additional testing is performed after diagnosis as part of the pretreatment evaluation. This described in more detail separately. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Pretreatment evaluation'.)
Diagnostic criteria — Diagnostic criteria for AL amyloidosis have been developed by the Mayo Clinic and the International Myeloma Working Group and require the presence of all of the following four criteria (table 1) [13,61,62]:
●Presence of an amyloid-related systemic syndrome (eg, renal, liver, heart, gastrointestinal tract or peripheral nerve involvement). In order to be included as a diagnostic criterion, the organ damage must be felt to be related to amyloid deposition and not to another common disease, such as diabetes or hypertension. (See 'Systemic presentations' above.)
●Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow or organ biopsy) or the presence of amyloid fibrils on electron microscopy. (See 'Identifying amyloid' above.)
●Evidence that the amyloid is light chain-related established by direct examination of the amyloid using spectrometry-based proteomic analysis or immunoelectron microscopy. (See 'Determining the type of amyloid' above.)
●Evidence of a monoclonal plasma cell proliferative disorder (eg, presence of a serum or urine M protein, abnormal serum free light chain ratio, or clonal plasma cells in the bone marrow). (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)
Approximately 2 to 3 percent of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder listed above; the diagnosis of AL amyloidosis must be made with caution in these patients.
Given the common occurrence of monoclonal gammopathy of undetermined significance (MGUS) in the general population, especially in the elderly, the presence of a monoclonal protein in conjunction with the demonstration of amyloid deposition may not always indicate that the amyloidosis is of the AL type. As an example, a patient may have wild type transthyretin amyloidosis and a concomitant unrelated MGUS, which can be potentially misdiagnosed as AL amyloidosis. As such, the amyloid itself should be examined directly for light chains rather than assuming a diagnosis of AL amyloidosis based on the presence of monoclonal light chains in the serum of a patient with amyloidosis. (See "Diagnosis of monoclonal gammopathy of undetermined significance".)
Patients with AL amyloidosis who have hypercalcemia, bone pain, or lytic bone lesions should be evaluated for coexisting multiple myeloma. (See 'Relation to other plasma cell disorders' above and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Evaluation'.)
DIFFERENTIAL DIAGNOSIS — AL amyloidosis should be distinguished from other forms of amyloidosis, from localized amyloidosis, and from other types of monoclonal immunoglobulin deposition diseases, because the clinical course and therapy are markedly different.
Other forms of amyloidosis — Other forms of amyloidosis include wild type transthyretin amyloidosis, hereditary amyloidosis, and AA amyloidosis. All of these entities will demonstrate staining with Congo red (a characteristic of amyloid), but direct examination of the amyloid material will not reveal immunoglobulin light chains (as seen in AL amyloidosis). A diagnosis of AL amyloidosis cannot be assumed based on the presence of monoclonal light chains in the serum of a patient with amyloid since it is not uncommon for a patient with another form of amyloid to have a concomitant and unrelated monoclonal gammopathy of undetermined significance (MGUS).
ATTRwt amyloidosis (age-related amyloidosis) — Wild type transthyretin amyloidosis (ATTRwt) refers to the deposition of otherwise normal (wild-type) transthyretin (TTR) in the myocardium and other sites of older adults [63,64]. ATTRwt has historically been referred to as age-related or senile amyloidosis. Patients may present with heart failure or an arrhythmia. Recognition is important because survival is better than with AL amyloidosis, and chemotherapy or hematopoietic cell transplantation are contraindicated. Unlike AL amyloidosis, direct examination of the amyloid material in ATTRwt does not reveal immunoglobulin light chains, but rather reveals TTR deposits. (See "Overview of amyloidosis", section on 'Wild-type transthyretin systemic amyloidosis'.)
Hereditary (familial) amyloidosis — Heritable, autosomal dominant amyloidosis results from mutations in genes coding for several different proteins. The most common "amyloidogenic proteins" implicated in hereditary amyloidosis are mutated forms of transthyretin (TTR), the alpha chain of fibrinogen A, apolipoprotein AI and AII, lysozyme, and gelsolin. Hereditary systemic AL amyloidosis not due to a plasma cell dyscrasia has been described in one family [65].
Sporadic cases of hereditary amyloidosis may be confused with AL amyloidosis, and diagnosis requires careful assessment to determine the chemical nature of the amyloid deposits by mass spectroscopy. The frequency with which this might occur was illustrated in a study of 350 patients suspected of having AL amyloidosis by clinical and laboratory findings and the absence of a family history; 34 (9.7 percent) had a mutant gene for an "amyloidogenic" protein, most often involving the alpha chain of fibrinogen A or transthyretin [66]. The presence of low concentrations of monoclonal immunoglobulins (less than 0.2 g/dL) in 8 of these 34 patients may have contributed to the misdiagnosis. (See "Genetic factors in the amyloid diseases".)
A thorough family history and exclusion of these heritable disorders is important, since the treatment used in AL amyloidosis (eg, chemotherapy, hematopoietic cell transplantation) has no role in the treatment of the hereditary amyloidoses, and is dangerous. Unlike AL amyloidosis, direct examination of the amyloid material in hereditary amyloidosis does not reveal immunoglobulin light chains. (See "Overview of amyloidosis", section on 'Diagnosis'.)
AA amyloidosis — AA amyloidosis (previously referred to as secondary amyloidosis) occurs as a complication of a variety of chronic inflammatory conditions, such as rheumatoid arthritis and its variants, bronchiectasis, Crohn's disease and other inflammatory bowel diseases, osteomyelitis, and familial Mediterranean fever. Inflammation leads to increased hepatic production of the acute phase reactant serum amyloid A, which is then degraded in circulating macrophages into smaller amyloid A fragments that are then deposited as fibrils in the tissues. A distinction between AA amyloidosis and AL amyloidosis can be made based on the identification of immunoglobulin light chains upon the direct examination of the amyloid material in AL amyloidosis, a feature that is not seen in secondary amyloidosis. (See "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)
A diagnosis of AL amyloidosis cannot be assumed based on the presence of monoclonal light chains in the serum of a patient with amyloid since it is not uncommon for a patient with other forms of amyloidosis to have a concomitant and unrelated MGUS.
Localized amyloidosis — Localized amyloidosis is the term used for local amyloid deposits in tissues such as the tracheobronchial tree, urinary tract, or skin; these deposits are derived from monoclonal light chains, but are not due to an underlying systemic clonal plasma cell disorder. Patients with localized amyloidosis do not develop systemic disease (ie, cardiac, renal, hepatic, or nerve involvement) and do not require chemotherapy [67].
Localized AL amyloidosis is most commonly found in the upper respiratory tract (nasopharynx), urinary bladder, colon, skin and nails, and orbit [68-74]. In most of these patients, monoclonal immunoglobulins cannot be found in serum or urine, although the amyloid fibrils are usually light chain-derived. These light chains are usually derived from more than one light chain variable family and may not be clonal [8]. While damage to the affected site may occur (eg, nasal or colonic bleeding, tracheobronchial obstruction, hematuria), the clinical course is usually benign and surgical excision may be the only treatment needed [70,75,76]. If there is evidence of a circulating monoclonal protein in patients with localized amyloidosis, it is important to confirm the absence of systemic AL amyloidosis with an investigation for sites of additional disease (ie, liver function tests, 24-hour urine protein, serum creatinine and echocardiography) to ensure appropriate management. (See 'Evaluation' above.)
Other forms of systemic monoclonal immunoglobulin deposition disease — The monoclonal immunoglobulin deposition diseases (MIDD) are a group of disorders characterized by the accumulation of intact or fragmented abnormal immunoglobulin in visceral and soft tissues resulting in organ damage. The MIDD are plasma cell dyscrasias with abnormal immunoglobulin components secreted by plasma cells or a lymphoplasmacytic neoplasm. There are four major groups of MIDD:
●AL amyloidosis
●Light chain deposition disease
●Light and heavy chain deposition disease
●Heavy chain deposition disease
All of these entities will have evidence of a monoclonal plasma cell proliferative disorder and many will demonstrate light chains in the serum. However, only AL amyloidosis will demonstrate staining with Congo red.
Light chain deposition disease — Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease related to AL amyloidosis in which fibril formation does not occur, but fragments of monoclonal light chains are deposited in the tissues [4,35]. LCDD typically presents as nephrotic syndrome and/or renal insufficiency [77]. Most patients with renal involvement progress to end-stage kidney disease requiring dialysis [78-80]. Less frequently, liver involvement can occur with hepatomegaly and liver dysfunction, either alone or in combination with renal involvement. Rarely, LCDD may involve the heart and lead to cardiomyopathy and heart failure or involve the peripheral nerves, salivary glands, gastrointestinal tract, and/or skin. Patients may progress to overt multiple myeloma; some patients may have coexisting multiple myeloma at initial diagnosis. Unlike AL amyloidosis, LCDD does not stain with Congo red. (See "Monoclonal immunoglobulin deposition disease".)
Heavy chain deposition disease — Heavy chain deposition disease (HCDD) is a rare monoclonal immunoglobulin deposition disease that has clinical characteristics that are similar to AL amyloidosis and LCDD. Deposits in HCDD are heavy chains or short (truncated) heavy chains, granular, and do not stain positive with Congo red. (See "Monoclonal immunoglobulin deposition disease".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immunoglobulin light chain (AL) amyloidosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topics (see "Patient education: AL amyloidosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Relation to other plasma cell disorders – Amyloidosis is a generic term that refers to the extracellular tissue deposition of fibrils composed of subunits of a variety of normal serum proteins. AL amyloidosis (previously called primary amyloidosis) is a clonal plasma cell proliferative disorder in which fibrils of monoclonal light chains are deposited in the kidneys, heart, and other tissues. Affected patients may have AL amyloidosis alone or in association with other plasma cell dyscrasias (multiple myeloma, Waldenström macroglobulinemia). (See 'Epidemiology' above.)
●Clinical presentation – The clinical presentation in AL amyloidosis depends on the number and nature of the organs affected. Non-specific systemic symptoms, including fatigue and unintentional weight loss, are common. Other common clinical presentations include nephrotic syndrome, restrictive cardiomyopathy, peripheral neuropathy, and hepatomegaly with elevated liver enzymes. Other less common but suggestive signs are macroglossia, purpura, and an unexplained bleeding diathesis. (See 'Systemic presentations' above.)
●Tissue biopsy – The diagnosis of AL amyloidosis requires a biopsy. An abdominal fat pad aspirate and bone marrow biopsy are the preferred sites to biopsy in patients with suspected AL amyloidosis due to the ease of access and safety of accessing these sites (algorithm 1). Either or both are positive in 90 percent of patients with AL amyloidosis. (See 'Tissue biopsy' above.)
●Diagnostic criteria – Diagnostic criteria for systemic AL amyloidosis require the presence of all of the following (table 1) (see 'Diagnostic criteria' above):
•Presence of an amyloid-related systemic syndrome (eg, renal, liver, heart, gastrointestinal tract or peripheral nerve involvement). (See 'Systemic presentations' above.)
•Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow or organ biopsy). (See 'Identifying amyloid' above.)
•Evidence that the amyloid is light chain-related established by direct examination of the amyloid (eg, using mass spectrometry based proteomic analysis; note that immunohistochemistry results to type amyloid may be unreliable). (See 'Determining the type of amyloid' above.)
•Evidence of a monoclonal plasma cell proliferative disorder (eg, presence of a serum or urine M protein, abnormal serum free light chain ratio, or clonal plasma cells in the bone marrow). (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)
●Differential diagnosis – AL amyloidosis should be distinguished from other forms of amyloidosis, from localized amyloidosis, and from other types of monoclonal immunoglobulin deposition diseases (MIDD) because the clinical course and therapy are markedly different.
Other forms of amyloidosis will demonstrate staining with Congo red (a characteristic of amyloid), but direct examination of the amyloid material will not reveal immunoglobulin light chains (as seen in AL amyloidosis). (See 'Other forms of amyloidosis' above.)
Other forms of MIDD will have evidence of a monoclonal plasma cell proliferative disorder and many will demonstrate light chains in the serum. However, AL amyloidosis is the only MIDD that will demonstrate staining with Congo red. (See 'Other forms of systemic monoclonal immunoglobulin deposition disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed as a Section Editor to an earlier version of this topic review.
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