Immunoglobulin light chain amyloidosis is an uncommon disease, and the exact incidence is unknown. In the United States, the incidence appears to be stable at about 9 to 14 cases per million person-years. Its a disease of the elderly. As with other plasma cell disorders, the age-specific incidence increases every decade after age 40. The median age at diagnosis is 64 years, and less than 5% of patients are under 40 years of age. Males account for 65% to 70% of patients. Clinical presentation ● Nephrotic syndrome-Approximately 70% of patients develop renal involvement, most often presenting with asymptomatic proteinuria or clinically significant nephrotic syndrome (50%). ● Restrictive cardiomyopathy-Approximately 60% of patients present with cardiac involvement, typically characterized by thickening of the septum and ventricular wall. This may lead to systolic or diastolic dysfunction and symptoms of heart failure. Other manifestations that may occur include sudden death or syncope due to arrhythmias or heart block and, rarely, angina or infarction due to amyloid accumulation in the coronary arteries. ● Peripheral neuropathy – Mixed sensory and motor peripheral neuropathy (20%) and/or autonomic neuropathy (15%) is a prominent feature of AL amyloidosis. Symptoms of frequent numbness, sensory abnormalities and pain, as in many other causes of peripheral neuropathy. Compression of peripheral nerves, especially the median nerve in the carpal tunnel, can lead to more localized sensory changes. Symptoms of bowel or bladder dysfunction and findings of postural hypotension may be due to autonomic nervous system injury. ● Hepatomegaly with elevated liver enzyme levels – Up to 70% of patients present with hepatomegaly with or without splenomegaly. A cholestatic pattern of elevated liver enzymes is seen in approximately 25% of patients. Clinical gastrointestinal involvement appears to be less common than other forms of amyloidosis, with only 1% of patients presenting with clinically significant disease. Because amyloidosis is a systemic disease, the rate of positive gastrointestinal biopsies is much higher; rectal biopsy is considered a safe and simple method for diagnosing systemic amyloidosis, with a sensitivity of 75%. In symptomatic patients, potential gastrointestinal manifestations include bleeding (due to vascular fragility and loss of vasodilatory response to injury), gastroparesis, constipation, bacterial overgrowth, malabsorption, and intestinal pseudo-obstruction due to motility disorders. ● Giant tongue and other muscle involvement – amyloid infiltration of skeletal muscle may result in visible enlargement (i.e., pseudohypertrophy). Enlargement of the tongue (i.e., megalingual) or a scalloped shape on the side of the tongue due to impacted teeth is characteristic of AL amyloidosis. Arthropathy may be due to amyloid deposits in the joints and surrounding structures. The “shoulder pad” sign is due to fluid in the glenohumeral joint and/or amyloid infiltration of the synovial membrane and surrounding structures, with a marked enlargement of the anterior shoulder. Purpura and other cutaneous manifestations – Purpura is a characteristic purpura caused by Valsalva maneuvers or minor trauma in the periorbital distribution (raccoon eyes) and is present in only a minority of patients, but is highly characteristic of AL amyloidosis. Other signs of skin involvement include waxy thickening, easy bruising (petechiae), and subcutaneous nodules or plaques. Subcutaneous fatty infiltrates are usually asymptomatic, but provide a convenient site for biopsy. ● Hemorrhagic qualities – Amyloidosis may be directly related to hemorrhagic qualities. Mechanisms include factor X deficiency due to binding to amyloidogenic fibrils primarily in the liver and spleen; decreased synthesis of coagulation factors in patients with advanced liver disease; and acquired vascular hemophilia. However, some patients with abnormal bleeding have no abnormalities in any coagulation test. In such patients, amyloid infiltration of the blood vessels may contribute to the bleeding qualities. IgM-associated AL amyloidosis-AL amyloidosis is a rare complication of immunoglobulin M (IgM)-associated monoclonal gammopathy, such as Waldenstr?m macroglobulinemia. Compared with non-IgM-associated AL amyloidosis, IgM-associated AL amyloidosis appears to be a distinct clinical condition with less cardiac involvement and a higher incidence of lymph node and soft tissue involvement (e.g., liver injury, peripheral and autonomic neuropathy). ● Kidney (68%) ● Soft tissue (35%, including 20% of lymph nodes) ● Liver (17%) ● Peripheral nervous system (15%) ● Autonomic nervous system (13%) ● Gastrointestinal system (9%) IgD-related AL amyloidosis – Patients with AL amyloidosis rarely present with monoclonal immunoglobulin D (IgD) at diagnosis.3955 The largest single-center retrospective case series of patients with Ig light chain amyloidosis identified serum IgD monoclonal protein in 53 patients (1.3%). Patients appeared to have less frequent renal and cardiac involvement compared to non-IgDAL amyloidosis. At presentation, the most common signs and symptoms were fatigue (60%), lower extremity edema (43%), sensory abnormalities (32%), weight loss (32%), exertional dyspnea (28%), and carpal tunnel syndrome (26%). Survival rates were similar to non-IgDAL amyloidosis. Selection of biopsy sites- The diagnosis of AL amyloidosis requires confirmation of the presence of amyloidogenic fibers in the affected organ (e.g., kidney, liver) or in the histologic evaluation of the replacement site (e.g., abdominal fat pad, bone marrow). The use of abdominal fat pad aspiration and bone marrow biopsy is recommended for initial evaluation because of the simplicity, convenience, and high yield. Renal or liver biopsies are positive in more than 90% of cases; however, high success rates can be achieved with minimally invasive procedures such as abdominal fat pad aspiration (60% to 80%), rectal biopsy (50% to 70%), bone marrow biopsy (50% to 55%), or skin biopsy (50%). Gum biopsy is not performed because it is uncomfortable for the patient and skin biopsy is usually negative unless there is clinical involvement or significant fat in the skin. In addition, some patients have a bleeding body (e.g., acquired factor X deficiency), which may limit the safety of major visceral organ biopsies. Unilateral bone marrow aspiration biopsy, immunohistochemical staining for kappa and lambda, and Congo red staining for amyloid. Evidence of monoclonal If M protein is detected in serum or urine, monoclonal plasma cell proliferative disease can be assumed. approximately 35% of M protein in AL amyloidosis is IgG, 10% is IgA, 5% is IgM, 1% is IgD, and the rest of patients have light chains (lambda or kappa). Most patients with AL amyloidosis have little or no intact monoclonal immunoglobulins, but are characterized by the presence of monoclonal free light chains. In about 70% of cases, the monoclonal light chain type is λ, 25% is kappa, and 5% is biclonal. Serum and urine immunofixation and evaluation of serum free light chain ratio analysis provide the most sensitive measures of this M protein. Diagnostic criteria: ● Presence of amyloid-associated systemic syndrome (e.g., renal, hepatic, cardiac, gastrointestinal, or peripheral nerve involvement). In order to be used as a diagnostic criterion, the organ damage must be considered to be related to amyloid deposition and not to other common conditions such as diabetes or hypertension. ● Positive amyloid staining for Congo red in any tissue (e.g., fat aspirate, bone marrow, or organ biopsy) or the presence of amyloidogenic fibrils on electron microscopy. ● Evidence that amyloid is associated with light chains is established by direct examination of amyloid using spectroscopy-based proteomic analysis or immunoelectron microscopy. (See ‘Determining the type of amyloid’ above.) ● Evidence of monoclonal plasma cell proliferative disease (e.g., presence of serum or urine M protein, abnormal serum free light chain ratio, or clonal plasma cells in the bone marrow). Approximately 2% to 3% of patients with AL amyloidosis do not meet the above requirements for evidence of monoclonal plasma cell disease; caution must be exercised in making the diagnosis of AL amyloidosis in these patients. Given the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in the general population, particularly in the elderly, the presence of monoclonal proteins with evidence of amyloid deposition may not always indicate that the amyloidosis is AL. For example, a patient may have wild-type transthyretin amyloidosis and concomitant unrelated MGUS, which may be misdiagnosed as AL amyloidosis. Therefore, the light chains of the amyloid itself should be examined directly rather than assuming a diagnosis of AL amyloidosis based on the presence of monoclonal light chains in the serum of patients with amyloidosis. Differential diagnosis Other forms of amyloidosis – Other forms of amyloidosis include wild-type transthyretin amyloidosis, hereditary amyloidosis, and AA amyloidosis. All of these entities will show Congo red staining (characteristic of amyloid), but direct examination of amyloid material will not reveal immunoglobulin light chains (as seen in AL amyloidosis). The diagnosis of AL amyloidosis cannot be assumed based on the presence of monoclonal light chains in the serum of a patient with amyloid, as it is not uncommon for patients with another form of amyloid to also have unrelated monoclonal gammopathy of unknown significance (MGUS).) . ATTRwt amyloidosis (age-related amyloidosis) – wild-type transthyretin amyloidosis (ATTRwt) refers to the deposition of normal (wild-type) transthyretin (TTR) protein in the myocardium and other sites in the elderly.ATTRwt has historically been referred to as age-related or geriatric amyloidosis. Patients may present with heart failure or arrhythmias. Recognition is important because survival is better than in AL amyloidosis and chemotherapy or hematopoietic cell transplantation is contraindicated. Unlike AL amyloidosis, direct examination of amyloid in ATTRwt will not show immunoglobulin light chains, but rather TTR deposits. Hereditary (familial) amyloidosis – heritable, autosomal dominant amyloidosis is caused by mutations in genes that encode several different proteins. The most common “amyloid proteins” associated with hereditary amyloidosis are mutated forms of thyroxine transport protein (TTR), the alpha chain of fibrinogen A, apolipoproteins AI and AII, lysozyme, and aggrecan. Hereditary systemic AL amyloidosis not due to plasmacytoid malignancy has been described in one family [65]. AA amyloidosis-AA amyloidosis (formerly known as secondary amyloidosis) is a complication of several chronic inflammatory diseases, 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 into smaller amyloid A fragments in circulating macrophages and then deposited as protofibrils in tissues.The distinction between AA amyloidosis and AL amyloidosis can be based on the identification of immunoglobulin light chains when directly examining the amyloid in AL amyloidosis, a secondary amyloidosis in which a feature not seen in secondary amyloidosis. Focal amyloidosis-Local amyloidosis is defined as localized 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 underlying systemic clonal plasma cell disease. Patients with localized amyloidosis do not progress to systemic disease (i.e., cardiac, renal, hepatic, or neurologic involvement) and do not require chemotherapy. Focal AL amyloidosis is most commonly found in the upper respiratory tract (nasopharynx), bladder, colon, skin and nails, and eye sockets. In most of these patients, no monoclonal immunoglobulins are found in the serum or urine, although the amyloidogenic fibrils are usually light chain-derived. These light chains are usually derived from multiple light chain variable families and may not be clonal. Although damage to the affected site may occur (e.g., nasal or colonic bleeding, tracheobronchial obstruction, hematuria), the clinical course is usually benign, and surgical excision may be the only treatment required. If there is evidence of circulating monoclonal proteins in patients with localized amyloidosis, it is important to ensure appropriate management by investigating other sites of disease (i.e., liver function tests, 24-hour urine protein, serum creatinine, and echocardiography). Other forms of systemic monoclonal immunoglobulin deposition diseases – Monoclonal immunoglobulin deposition diseases (MIDD) are a group of diseases characterized by the accumulation of intact or fragmented abnormal immunoglobulins in internal organs and soft tissues, resulting in organ damage.MIDD are plasma cell malignancies with an abnormal immunoglobulin component secreted by plasma cell or lymphoplasmacytic tumors. There are four major categories 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 monoclonal plasma cell proliferative disease and many will show light chains in the serum. However, only AL amyloidosis will show Congo red staining. Light chain deposition disease – Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease associated with AL amyloidosis in which no protofibril formation occurs but monoclonal light chain fragments are deposited in the tissues.LCDD usually presents with nephrotic syndrome and/or renal insufficiency. Most patients with renal involvement progress to end-stage renal disease requiring dialysis. Less commonly, liver involvement may be associated with hepatomegaly and liver dysfunction, 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 the time of initial diagnosis. Unlike AL amyloidosis, LCDD does not stain with Congo red). Heavy chain deposition disease – Heavy chain deposition disease (HCDD) is a rare monoclonal immunoglobulin deposition disease with clinical features similar to those of AL amyloidosis and LCDD. deposits in HCDD are heavy or short (truncated) heavy chains that are granular and do not stain positively for Congo red. Staging of immunoglobulin light chain (AL) amyloidosis Model Risk factor threshold Stage Risk of death ratio (95% CI)* Mayo 2004[1] Troponin: Cardiac TnT ≥ 0.035 mcg/L or Cardiac TnI ≥ 0.1 mcg/L or High sensitivity cardiac TnT ≥ 50 ng/L BNP: NT-proBNP ≥ 332 ng/L or BNP ≥ 81 ng/L Stage I No risk factor Reference Stage II 1 risk factor 2.5 (1.9-3.5) Stage III 2 risk factor 6.7 (5.0-9.1) Mayo2004 with European modifications [2] Troponin: Cardiac TnT ≥ 0.035mcg/L or Cardiac TnI ≥ 0.1mcg/L or High-sensitivity cardiac TnT ≥ 50ng/L L BNP Paribas: NT-proBNP ≥ 332ng/L or BNP ≥ 81 ng/L Stage I No risk factor Reference Stage II 1 Risk factor 2.5 (1.9-3.5) Mayo 2012[3] Troponin Cardiac Troponin T ≥ 0.025mcg/L or High sensitivity cardiac Troponin T ≥ 40ng/L BNP Paribas: NT- proBNP ≥ 1800ng/L or BNP ≥ 400 ng/L dFLC ≥ 18 mg/dL Stage I No risk factor Reference Stage II 1 risk factor 1.7 (1.2-2.3) Stage III 2 risk factor 4.1 (3.1-5.5) Stage IV 3 risk factor 6.3 (4.8-8.3) Boston University [4] Troponin: Cardiac Troponin I > 0.10 ng/mL BNP: BNP > 81 pg/mL Stage I No risk factors Median OS > 12 years Stage II 1 risk factors Median OS 9.4 years Stage IIIA 2 risk factors BNP > 81 pg/mL Median OS 4.3 years Stage IIIB 2 risk factors BNP > 700 pg/mL Median OS 1 year TnT: Troponin T; TnI: troponin I; BNP: brain natriuretic peptide; NT-proBNP: N-terminal pro-brain natriuretic peptide; dFLC: difference between involved and uninvolved serum free light chain; OS: overall survival. *The risk ratios presented reflect the use of cardiac troponin T and NT-proBNP. Treatment Objective-Patients with systemic AL amyloidosis cannot be cured by conventional therapy. However, early mortality has decreased and survival has improved as there has been a shift toward early diagnosis and treatment to achieve profound remission. Although remission can be achieved, relapse is common. It is essentially the same as multiple myeloma. Almost all patients with systemic AL amyloidosis require treatment at the time of diagnosis. In patients with localized forms of AL amyloidosis (e.g., tracheobronchial, genitourinary, isolated carpal tunnel, and non-purpuric skin lesions), systemic therapy is also not required. These deposits are not due to underlying systemic clonal plasma cell disease and do not progress to systemic disease. In general, patients should meet all of the following criteria to be eligible for autologous HCT in AL amyloidosis: ● Physiologic age ≤ 70 years ● Troponin T < 0.06 ng/mL ● Systolic blood pressure ≥ 90 mmHg ● Creatinine clearance ≥ 30 mL/min (unless on long-term stable dialysis) ● Eastern Cooperative Oncology Group (ECOG) physical status ≤ 2 ● New York Heart Association ( NYHA) functional status class I or II (see table below for details) ● No more than two significantly involved organs (liver, heart, kidney, or autonomic nerves) ● No massive pleural effusion ● No dependence on oxygen therapy These are guidelines; the decision for transplantation should be based on a risk-benefit assessment and the patient's needs and desires. Importantly, the transplant-related mortality (TRM) in patients with severe (<25%) factor X deficiency approaches 50%. To increase factor X levels prior to HCT, splenectomy can be performed in such patients. NYHA (New York Heart Association) and other cardiovascular disability classifications Grading NYHA functional classification[1] Canadian Cardiovascular Society functional classification[2] Specific activity scale[3] I. Patients with heart disease but unrestricted physical activity. Ordinary physical activity does not cause excessive fatigue, palpitations, dyspnea or angina. Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina, strenuous or rapid prolonged exertion at work or play. The patient can complete any activity requiring ≥7 metabolic equivalents (i.e., can move 24 pounds (1 lb = 0.9 pounds) up 8 steps; perform outdoor work [shoveling snow, shoveling]; perform recreational activities [skiing, basketball, squash, handball, jogging/walking 5 miles (1 km = 1.6 km)/hour]). Second, heart patients cause slight limitations in physical activity. They are comfortable at rest. Ordinary physical activity leads to fatigue, palpitations, dyspnea or angina. Ordinary activities are slightly limited. Rapid walking or stair climbing, uphill, walking or stair climbing after meals, in the cold, wind, or when emotionally stressed, or only for a few hours after waking up. Walking more than 2 blocks on a horizontal surface at normal speed and under normal conditions (1 block = 500 m) and climbing more than 1 flight of ordinary stairs. The patient can complete any activity requiring ≥ 5 metabolic equivalents (e.g., uninterrupted sexual intercourse, gardening, raking, weeding, roller skating, foxtrot, walking on level ground at 4 mph) but cannot and does not complete activities requiring ≥ 7 metabolic equivalents. Third, patients with heart disease cause significant limitations in physical activity. They are comfortable at rest. Unusual physical activity can lead to fatigue, palpitations, dyspnea, or angina. Common physical activity is significantly limited. Walking 1 to 2 blocks on a horizontal surface and climbing 1 flight under normal conditions.