A Guide To AL (Light Chain) Amyloidosis Authored by Ravi Mareedu and Raymond Q. Migrino What is amyloidosis? Amyloidosis is a disorder in which misfolded native proteins de- posit extracellularly and lead to organ damage. Although the various types of amyloidoses share in common the deposition of misfolded proteins that aggregate as fibrils in tissue, they differ in actual protein composition, organ involvement, prognostic implication and most importantly, treatment. It is therefore critically important to determine the type of amyloidosis a pa- tient has in order to provide the appropriate treatment. There are at least 23 different proteins associated with amyloi- dosis. The most common type of amyloidosis and the one that is associated with a poor prognosis if left untreated is called AL amyloidosis and due to the deposition of clonal immunoglobu- lin light chains produced by plasma cells in the bone marrow. There are several types of hereditary amyloidoses, most com- mon of which is mATTR amyloidosis, an autosomal dominant disease that results from misfolding of mutant transthyretin, a protein produced in the liver containing a single point gene mu- tation. More than 100 different transthyretin mutations are known to cause amyloidosis. The wild-type transthyretin can also misfold and aggregate as amyloid fibrils in tissues, usually the heart in the elderly Caucasian men, causing wtTTR amyloido- sis (also called senile systemic amyloidosis). Other types of amyloidoses include the following. Chronic in- flammatory conditions such as rheumatoid arthritis or chronic infections (such as bronchiectasis) are associated with excessive production of the inflammatory protein, serum amyloid A (SAA) that may misfold and lead to AA amyloidosis. Misfolding and amyloid deposition of atrial natriuretic peptide may lead to AANP amyloidosis located in the left atrium and increase the risk of atrial fibrillation. Other mutant proteins causing hereditary amyloidoses include apolipoproteins AI and AII, cystatin C, fi- brinogen Aα-chain, lysozyme, and gelsolin. This pamphlet will concentrate on the most common type of amyloidosis, AL (light chain) amyloidosis with special emphasis on the cardiac findings. For further reference on ATTR amyloido- sis, please refer to a similar pamphlet from the Amyloidosis Foundation on this topic. What is AL (light chain) amyloidosis ? AL amyloidosis is the disease caused by abnormal immunoglobu- lin light chains (LCs) produced by clonal plasma cells in the bone marrow. The abnormal LCs subsequently misfold, aggregate, and deposit in tissues as amyloid fibrils. It is part of a spectrum of clonal plasma cell proliferative disorders that include multiple myeloma, monoclonal gammopathy of undetermined signifi- cance, Waldenstrom’s macroglobulinemia and heavy chain dis- ease. Multiple myeloma is associated with an excessive number of bone marrow plasma cells (30% or more) producing immu- noglobulin proteins, however, only about 10-15% of patients with multiple myeloma develop AL amyloidosis. Patients with AL amyloidosis usually have only a modest increase in the popula- tion of plasma cells (5-20%) in the bone marrow.. How common is AL amyloidosis? Although AL amyloidosis is commonly thought of as a rare dis- ease, the incidence is similar to diseases not considered rare such as Hodgkin’s disease or chronic myelocytic leukemia. There are approximately 2000-2500 new cases per year in the United States. Increased awareness of the associated physical findings in amyloidosis by physicians and the better technology at the present time for recognition of LC abnormalities in blood and urine is leading to the diagnosis of AL amyloidosis at an earlier stage . How do abnormal light chains cause pathology? Several mechanisms probably play a role in tissue and organ in- jury caused by abnormal LCs. LC proteins produced by the clonal plasma cell are structurally unstable and transition through a se- ries of intermediate conformations (monomers, dimers, oli- gomers) eventually attaining a non-native assembly that favors self-aggregation in tissues. Several factors have been implicated as contributing to the predisposition to form amyloid fibrils in- cluding specific amino acid substitutions, thermodynamic insta- bility and post-translational protein modifications. The mass of amyloid deposits limits the ability of the tissue to function nor- mally. In addition, the deposition of amyloid proteins in the ex- tracellular space including the perivascular space in organs such as the heart, liver, gastrointestinal tract, kidneys and peripheral nerves is associated with evidence of apoptotic injury and oxida- tive stress. Perivascular deposition in arterioles is associated with ischemic injury in the setting of occlusive disease but is also seen even without flow limiting stenosis. Evidence from cell cul- ture studies, animal studies and clinical changes in patients fol- lowing chemotherapy suggest that circulating amyloidogenic light chains (not yet deposited as fibrils) have a toxic effect and cause direct tissue injury. What organ systems are affected by AL amyloidosis? AL amyloidosis is a systemic illness and can affect nearly every organ, including the heart, kidneys, lung, gastrointestinal system (liver and intestines), peripheral and autonomic nerves, and soft tissues. The presence of cardiac involvement and heart failure connotes the worst prognosis. Recent data from cardiac MRI suggests that about 3/4 of patients with AL amyloidosis have car- diac involvement. What are the common manifestations of AL amyloidosis? Patients most frequently present with signs and symptoms of cardiac or renal disease. Proteinuria is a common initial finding, often associated with nephrotic syndrome and severe edema. Symptoms of heart failure, such as dyspnea on exertion or at rest and orthopnea are also common. These may be accompa- nied by signs of right heart failure such as peripheral edema. The patient may complain of chest discomfort or chest pain, both typical and atypical of angina-like pain. This may be related to impaired myocardial flow reserve associated with small vessel perivascular involvement even in the absence of significant oc- clusive epicardial coronary stenosis. An elevated troponin level is common suggesting myocyte necrosis. Although the direct cause of necrosis is not known, direct myocyte toxicity by the amyloid proteins or small vessel ischemia may be playing a role. A patient may present with varying types of arrhythmias. Atrial fibrillation is common. Sudden death is a mode of demise in pa- tients with AL or any cardiac amyloidosis thought due to cardiac electromechanical dissociation or ventricular arrhythmias. Syn- cope and dizziness are common manifestations and may be due to either arrhythmias or autonomic neuropathy. Less than 5% of patients with light chain amyloidosis involving the heart have isolated cardiac involvement and it is the pres- ence of associated non-cardiac symptoms that will point to a sys- temic disease rather than a purely cardiac pathology. Systemic manifestations include weight loss, easy bruising, brittle and slow-growing nails and periorbital purpura. A subtle change in voice, such as hoarseness may occur and be related to vocal cord involvement. Macroglossia or enlargement and stiffening of the tongue is soft tissue involvement of amyloidosis that occurs only in the AL type of amyloidosis. In advanced cases, this may inter- fere with swallowing, eating or breathing. Other soft tissue in- volvement includes lymph nodes, salivary glands which may pre- sent as submandibular swelling, carpal tunnel syndrome, nail dystrophy, and amyloid arthropathy. Gastrointestinal manifestations include right upper quadrant dis- comfort either from chronic passive hepatic congestion or he- patic amyloid infiltration (often massive). Decreased or in- creased bowel motility may occur with autonomic neuropathy. Peripheral nerves are often affected and patients may present with paresthesias of peripheral sensory nerves and occasionally with motor neuropathy. Signs of autonomic neuropathy include: dizzy spells and syncope due to orthostatic hypotension, gastric atony, diarrhea or constipation, and impotence. On occasion, a previously hypertensive patient on multiple blood pressure medications may report spontaneous resolution of hypertension at the time of presentation. The presence of abnormalities in two or more organ systems of- ten leads the physician to consider the diagnosis of amyloidosis. Key Summary Point 1: It is essential that a patient presenting with symptoms and signs of heart failure be investigated for ac- companying systemic manifestations that will provide clues as to the presence of AL amyloidosis. In particular, a history of carpal tunnel syndrome or surgery for carpal tunnel syndrome, or- thostatic hypotension or dizziness, reduced need for antihyper- tensive medications, hoarseness or change in voice, tongue enlargement and skin changes should alert a physician to rule out AL amyloidosis. What are the pertinent physical examination and car- diac findings in AL amyloidosis? Signs of heart failure include jugular venous distension, periph- eral edema, ascites, pulmonary crackles and signs of pleural effu- sion. A right ventricular S3 sound may be heard suggestive of right ventricular dysfunction. Because of atrial infiltration and dysfunction, it is uncommon to hear a fourth heart sound. Blood pressure is often low and orthostatic hypotension is common. Hepatomegaly is common and if due to amyloid infiltration the liver can be hard but non-tender, in contrast to a firm and tender liver when due to chronic passive congestion. As mentioned pre- viously, tongue enlargement, submandibular swelling and nail dystrophy may be seen in some patients. Perhaps the most important clue to the diagnosis of cardiac amy- loidosis is the combined finding of low voltage on electrocardio- gram (defined as <5 mm in height in all limb leads, Figure 1) in the setting of left ventricular thickening on echocardiography. It is essential that echocardiographic findings of left ventricular thickening and diastolic dysfunction, especially with concomitant pericardial and pleural effusion be paired with evaluation of the electrocardiogram to determine if the thickening is due to left ventricular hypertrophy (e.g. due to hypertensive heart disease or hypertrophic cardiomyopathy, associated with increased ECG voltage) or due to myocardial infiltration (such as amyloidosis, with low voltage ECG). This singular act will lead to the earlier diagnosis of amyloidosis. Figure 1. Typical electrocardiogram of a patient with amyloidosis with cardiac involvement demonstrating low limb lead voltages and pseudoinfarct pattern. Figure 2. Typical echocardiographic findings demonstrating thick- ening of the left ventricle and valves, atrial enlargement and presence of pericardial effusion. Echocardiographic findings include ventricular thickening, small cavity size, significant or advanced (i.e. restrictive filling) diastolic dysfunction and often preserved or hyperdynamic systolic func- tion (although left ventricular ejection fraction may be impaired in more advanced cases). The previously described granular sparkling myocardial appearance on echocardiography is often not helpful because it is very subjective and because similar fea- tures are commonly seen with the advent of harmonic imaging on echocardiography. The valve leaflets, atria and atrial septum may appear thick due to amyloid infiltration. Important con- comitant clues usually not associated with hypertensive heart disease but are common in light chain amyloidosis include the presence of pericardial and pleural effusion. Magnetic resonance imaging demonstrates structural findings similar to echocardiography. In addition, the presence of cardiac amyloid infiltration is demonstrated by the presence of enhance- ment of the myocardium (as well as atria and valves) following gadolinium injection (late gadolinium enhancement) (Figure 3). Gadolinium is an extracellular contrast agent that attains a high volume of distribution in myocardial regions where myocytes are replaced or displaced by infiltrates, fibrosis or inflammation. The