US Pharm. 2022;47(2):17-24.
ABSTRACT: Cardiac amyloidosis is challenging to diagnose and treat, as the symptoms may be unspecific and the different disease subtypes require appropriate treatment selection. The accumulation of pathologic amyloid protein within the heart muscle generally leads to multiple complications and a poor prognosis. If the disease is systemic, interprofessional collaboration is required. Recent years have seen advances in diagnostic techniques and therapeutic possibilities for the most common forms of cardiac amyloidosis (immunoglobulin light-chain–induced cardiac amyloidosis and transthyretin amyloidosis, both wild-type and mutant), resulting in improved prognosis. Understanding, diagnosing, and treating early-stage cardiac amyloidosis are necessary for cardiologists, pharmacists, and other practitioners involved in the clinical management of these patients.
Amyloidosis comprises a group of rare diseases characterized by the extracellular accumulation of insoluble fibrinous protein, called amyloid, in tissues and organs.1 The different types of amyloidosis are described in the following sections. Cardiac amyloidosis is a clinical condition wherein amyloid accumulates in the heart muscle and impairs cardiac function, leading to cardiomyopathy (CM), heart failure (HF), abnormal heart rhythm, and orthostatic hypotension.2 If the amyloid deposit accumulates in a different part of the body, it may cause another organ to malfunction. Previously, amyloidosis was mostly undiagnosed and had poor survival.3 Disease awareness allows for early and noninvasive diagnosis and the ability to distinguish between different forms of the disease. Cardiac amyloidosis is challenging to diagnose and treat, as the symptoms may be unspecific and the different subtypes require appropriate treatment selection.
Etiology and Pathophysiology
Immunoglobulin light-chain (AL) amyloidosis is likely the result of the abnormal breakdown of antibodies that occurs when the plasma-cell clone produces a light chain that is prone to misfolding. These proteins enter the bloodstream and cling to various organs. Amyloid A (AA) amyloidosis may be a consequence of complications from inflammatory disease. A slightly rarer form of the disease is hereditary amyloidosis, which is a result of a genetic mutation.1
Amyloid, a pathologic substance usually produced in the bone marrow, is generated by normally soluble proteins that assemble to form insoluble fibers that are resistant to degradation. The amyloidosis types differ in the structure of proteins forming amyloid fibers and in their different clinical course.4 Complex mechanisms are involved in the formation of amyloid, such as precursor protein mutations resulting in changes in physical properties; defective proteolysis responsible for the formation of beta-structural fibers; the affinity of these fibers for specific tissues and organs; and participation of other proteins and molecules in the formation of deposits.5
Epidemiology
Amyloidosis is sometimes called an orphan disease. It is estimated that there are approximately 4,000 new cases of AL amyloidosis in the United States each year, but because the disease is underdiagnosed, the actual incidence may be higher. The incidence is equal in males and females, but more males are referred to amyloid centers. Amyloidosis may be diagnosed in young persons, but diagnosis typically occurs between ages 50 and 65 years. AA amyloidosis is diagnosed in fewer than 5% of cases.3 Amyloidosis caused by a transthyretin (TTR) mutation occurs in approximately one in 100,000 Caucasians in the U.S., and it is more common in African Americans (3%-3.9% in that population).3,6 Symptoms usually begin between ages 40 and 65 years. Familial amyloidosis and AA amyloidosis occur less frequently than AL amyloidosis. Wild-type transthyretin amyloidosis (ATTRwt) is probably more common, but it is considerably underdiagnosed.3 AL-induced cardiac amyloidosis and ATTR are the cause of 95% of all cases of cardiac amyloidosis.7
Risk Factors
Risk factors may be specific for different amyloidosis subtypes. The main risk factors for the development of the disease include being older than age 50 years, duration of the underlying disease, long-lasting clinical or biochemical disease activity, and coexisting infections and diseases.7
Patients with chronic inflammatory diseases such as rheumatic arthritis, psoriatic arthritis, chronic juvenile arthritis, ankylosing spondylitis (in children), inflammatory bowel disease, and familial Mediterranean fever are at higher risk for developing AA amyloidosis. Tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis, and chronic pyelonephritis may lead to the development of AA amyloidosis. Other diseases, such as multiple myeloma, Hodgkin’s lymphoma, lymphoma, medullary thyroid cancer, Whipple’s disease, Crohn’s disease, osteomyelitis, Reiter’s syndrome, leprosy, early-onset Alzheimer’s disease, and Waldenstrom’s macroglobulinemia, may be associated with amyloidosis.3
ATTR-CM is inherited as an autosomal-dominant trait caused by mutations in the genes encoding different proteins, and ATTRwt is linked to aging.8
Clinical Presentation
Symptoms of amyloidosis depend on where the protein accumulates. Sometimes it is local and affects only one organ; in other cases, amyloid deposition occurs in several organs, which results in a generalized form of the disease, or systemic disease. The deposited protein impairs the functioning of a given organ.1 Amyloidosis affects the kidneys in 70%, the heart muscle in 50%, and the nervous system in 30% of all diagnosed patients.7
The clinical picture of amyloidosis depends on the form. The patient may feel general bodily weakness and lose body weight quickly despite an absence of eating disorders. Amyloidosis most often manifests in the following ways:
• Enlarged liver or spleen (frequently, this is the first symptom)
• Edema associated with proteinuria
• HF (usually congestive HF with preserved ejection fraction)
• CM
• Arrhythmias
• Nephrotic syndrome or progressive renal failure
• Orthostatic hypotension
• Nervous-system manifestations (e.g., sensory neuropathy, numbness, tingling, general muscle weakness, carpal tunnel syndrome)
• Diarrhea or constipation due to autonomic nervous system dysfunction
• Malabsorption syndrome
• Erectile dysfunction
• Macroglossia
• Nail dystrophy
• Enlarged salivary glands1-3
Amyloidosis may induce frequent bleeding because of the blood-vessel fragility caused by the sizable accumulation of amyloid protein. The clinical picture also involves a disorder of blood coagulation: factor X deficiency. Amyloid binds factor X to the amyloid fibers.1
Symptoms of AA amyloidosis vary depending on the presence of ongoing rheumatic diseases and the severity of the alterations in tissues or organs. AA amyloidosis sometimes overlaps with the already-existing organ changes that occur in the course of the underlying disease.1
Patients with cardiac amyloidosis may present with lower-extremity edema, elevated jugular venous pressure, hepatic congestion, ascites, and dyspnea, which are caused by restrictive cardiomyopathy with predominantly right ventricular failure; symptoms and signs of low cardiac output (diminished pulse pressure and diminished capillary refill); and angina. Syncope may be present because of bradyarrhythmia, advanced atrioventricular block, or ventricular arrhythmia.9 Patients with AL amyloidosis and atrial fibrillation have an increased risk of cardiac thromboembolism.10
If hereditary amyloidosis is present, it takes a characteristic course. In each individual family, hereditary amyloidosis begins at a similar age in each family member who develops the disorder. Hereditary amyloidosis is characterized by sensory and motor neuropathy, and the only symptom of myocardial involvement may be arrhythmias. Patients with ATTR (wt or hereditary) often develop progressive conduction-system disease.10
Diagnosis
Amyloidosis was first described in 1854 by Rudolf Virchow, who thought that the amyloid material was similar to starch (amylin). The disease owes its name to the navy blue color of the deposits when stained with Lugol’s solution (iodine), which suggested a relationship to starch.11
Amyloid may resemble other deposits (e.g., fibrin). Therefore, when disease is suspected, a determination is made via staining techniques, such as Congo red (typical apple-green birefringence); microscopic techniques; or immunohistochemical reactions.12
Diagnosis is made by performing noninvasive tissue biopsy with Congo red staining of abdominal fat or other tissue, or invasive tissue biopsy with Congo red staining for affected major organs. It is important to exclude other diseases, including multiple myeloma.13 Serum kappa/lambda free light-chain ratio analysis, serum protein immunofixation, and urine protein immunofixation are performed to detect the presence of monoclonal protein. If monoclonal protein is present, subsequent bone-marrow biopsy is recommended.13
To diagnose cardiac amyloidosis in a patient, noncardiac biopsy and cardiovascular MRI are conducted. If amyloidosis is suspected, echocardiography (ECHO) is recommended in order to detect present reduction in global longitudinal strain (a measure of systolic function). This measure is one of the earliest markers of cardiac amyloidosis and presents with a characteristic pattern of relative apical sparing of longitudinal strain. Additionally, infiltration of ventricular walls produces an appearance of hypertrophy.13
The deposits look similar under polarizing (birefringent) and electron microscopy. In routine staining with hematoxylin and eosin, the deposits present as a glassy, slightly eosinophilic material that enlarges the intercellular spaces over time, causing the surrounding cells to disappear.13
Later in the process, mass-spectrometry laser microdissection is used to determine the type of amyloid. Chemically, the deposits are not homogeneous, as they have a number of different forms and accompany various diseases.13 In the electron-microscope image (not correlating with classifications), the deposits have the appearance of filaments with a diameter of up to approximately 10 nm.14
The most common forms of amyloid are AL, in which amyloid light chain is produced by stimulated bone-marrow plasma cell clone; AA (amyloid-associated acute-phase reactant protein serum amyloid A [SAA]), occurring in the setting of chronic inflammatory or infectious diseases; and amyloid beta (AB), which is produced from the beta precursor protein and is present in the brain in Alzheimer’s disease.1
A number of other proteins have been found in amyloid deposits. One of these, TTR, which occurs in ATTR, is normally found in blood serum; the liver synthesizes the protein that circulates as a stable tetramer and transports thyroid hormone and retinol (vitamin A). Another protein, beta2 macroglobulin (AB2M), is found in the course of chronic dialysis.1
Radiolabeled serum amyloid P scanning is a technique that demonstrates the distribution and amount of amyloid in the organs throughout the body without the need for biopsy. This method is available in some centers in Europe for amyloidosis diagnosis and monitoring.3
Monitoring
Patients should be monitored for worsening of signs and symptoms of disease. Regular monitoring of these elements should be performed:
• Cardiac biomarkers, troponin, and N-terminal pro–brain natriuretic peptide (NT-proBNP)
• Increasing left-ventricular-wall thickness (identified by cardiac imaging, such as ECHO) and QRS voltage
• Kidney function, elevations of serum blood urea nitrogen and creatinine, possible albuminuria
• Liver biochemical abnormalities, possible elevation of serum bilirubin
• Alkaline phosphatase
• Functioning of other organs
• Excessive diuresis (when diuretics are used)
• Effectiveness, side effects, and toxicity of the patient’s medications10
Disease Subtypes and Therapeutic Considerations
A number of different amyloidosis subtypes have been recognized, and all of them may have cardiovascular involvement.
AL Amyloidosis: This subtype, the most common form of amyloidosis, is characterized by the dyscrasia of plasmocytes as a result of the formation of clones of these cells in the bone marrow. The amyloid fiber deposits are composed of monoclonal immunoglobulin light chains, which consist of fragments of the variable part of immunoglobulins. AL amyloidosis usually affects the heart, kidneys, liver, and nerves. In untreated AL amyloidosis, survival is only about a year, and is up to 6 months with severe heart damage.1 It should be remembered that the earlier diagnosis is made and treatment is started, the better the chances of long-term survival.
In this subtype, the goal of treatment is to destroy the clone of plasmocytes that produce the monoclonal protein converted to amyloid. The method of treatment depends on the patient’s general condition, age, and clinical symptoms; the number of organs involved; and the degree of their failure (with particular emphasis on assessment of heart function).14 The most important criteria to consider before treatment is implemented are the patient’s fitness level and cardiac indicators (troponin and NT-proBNP).10
The most effective—but also the most aggressive—method of treatment, high-dose chemotherapy followed by autologous bone-marrow stem-cell transplant (ASCT), is appropriate for patients in generally good condition without serious heart damage. In some cases, the bone marrow shows an increased percentage of plasmocytes. In approximately 10% of patients, treatment begins with chemotherapy and the ASCT procedure is performed after a few months, after the bone-marrow infiltration has been reduced.7 Those patients ineligible for ASCT are offered chemotherapy based on drugs used in myeloma.10
Currently, no single regimen is known to be the most effective. The use of melphalan with prednisone or dexamethasone has limited benefit in cardiac involvement. Some patients receive chemotherapy, such as bortezomib regimens.10 In 2021, the FDA approved the use of SC daratumumab plus hyaluronidase in combination with bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed AL amyloidosis.15
Patients with heart damage have a greater risk of heart complications from these drugs. Other drugs that have been used for myeloma are also being investigated for amyloidosis. Immunomodulatory drugs such as lenalidomide, pomalidomide, and thalidomide may be used, but caution should be exercised because of a higher risk of side effects than with myeloma.13 Some patients with AL amyloidosis have added doxycycline to their treatment regimen. Doxycycline, an anthracycline antibiotic, has proven additional protective effects on the heart in these patients.13,16
AA Amyloidosis: This subtype is the consequence of chronic inflammation, such as an infection. Amyloid fibers are derived from the plasma AA precursor, an acute-phase protein that is produced in the liver and transported in the plasma by HDL. The sudden increase in the concentration of SAA protein and C-reactive protein is associated with the rapid accumulation of amyloid deposits. Also, a high concentration of tumor necrosis factor–alpha promotes development of amyloidosis. Average survival is more than 10 years. Eliminating the inflammation stops or slows the deposition of amyloid, significantly improving the prognosis. In AA amyloidosis, it is important to address the inflammation.7
ATTR-CM: This subtype is caused by the deposition of misfolded monomers or oligomers of TTR fibrils in the myocardium, and it results in CM and symptoms of HF. For this subtype, death is usually related to cardiac causes, including sudden death and HF.7
Hereditary, Mutated ATTR (ATTRm): Hereditary amyloidosis is an inherited disorder that involves the nerves, heart, and kidneys. This autosomal-dominant disease is most commonly due to abnormal TTR protein made by the liver.7
ATTRwt: ATTRwt primarily affects the heart, and it can also cause carpal tunnel syndrome.17
Treatment
The treatment of amyloidosis involves the alleviation of symptoms in order to maintain a good quality of life for the patient while also suppressing the production of amyloid protein. Proposed treatments may alter the natural course of the disease if they are implemented before irreversible organ damage occurs.
The amyloid protein stabilizers (diflunisal and tafamidis) are used to prevent the conversion of normal TTR protein into amyloid.18 Patisiran is employed for the treatment of polyneuropathy in patients with hereditary TTR-mediated amyloidosis, and inotersen is utilized to treat nerve damage in adults with hereditary TTR-mediated amyloidosis.19,20 In some situations, liver transplantation may be considered in order to stop the production of misfolded proteins by the liver.21
Owing to extensive health problems, patients with amyloidosis require the cooperation of specialists from various fields of medicine. In the case of heart damage, cardiologist consultation is necessary to eliminate potentially harmful effects in this type of CM, recommend a set of drugs appropriate for the patient, and order tests for additional cardiovascular risk factors. Of the cardiac drugs, diuretics that protect against bodily overhydration (which may lead to worsening of circulatory-failure symptoms) and agents for heart-rhythm control (in the case of disorders related to damage to the conduction system) are the most important and should be used carefully. Loop diuretics (e.g., furosemide) are usually used in combination with a mineralocorticoid receptor antagonist (e.g., spironolactone). Calcium channel blockers are contraindicated owing to their significant negative inotropic effect. Nondihydropyridine calcium channel blockers can bind to amyloid fibrils and cause high-degree heart block and shock. Recent studies recommend the use of digoxin at lower doses (0.125 mg/day or lower) with frequent drug-concentration monitoring (target digoxinemia of 0.5-0.8 ng/mL). The use of beta-blockers has no survival effect. Anticoagulation with warfarin or novel oral anticoagulants is recommended for cardiac amyloidosis, as patients exhibit a high frequency of intracardiac thrombosis. Amiodarone is indicated as antiarrhythmic therapy.22,23
In the presence of kidney damage, and depending on the disease stage, a nephrologist should make drug adjustments, recommend adequate daily fluid intake, and advise on dietary restriction of salt. Diuretics are the most important class of drugs for treating kidney damage from amyloidosis. Some ACE inhibitors also have been proven effective for reducing proteinuria, but these drugs should be used cautiously with concomitant cardiac amyloidosis. In some cases, it may be necessary to institute renal replacement therapy.22
A gastroenterologist should make recommendations regarding constipation or diarrhea if there are infiltrates in the patient’s digestive tract. Owing to food malabsorption, it is advisable to use additional nutritional therapy involving vitamin supplementation. Parenteral nutrition must be included in the case of protein and energy depletion. It should be noted that patients may experience gastrointestinal bleeding.24
A neurologist’s involvement is recommended when the patient exhibits damage to the nervous system. The primary classes of agents used for neuropathies are anticonvulsants, antidepressants, topical treatments, and nonspecific analgesics. Gabapentin and pregabalin possess the strongest evidence for efficacy. Two antidepressant classes, the tricyclics and the serotonin-norepinephrine reuptake inhibitors, are commonly used for the treatment of neuropathic pain that is caused by amyloidosis.25
Transplantation to replace organs irreversibly damaged by amyloidosis is a possibility. However, this procedure is generally considered when hematologic treatment has resulted in at least a very good partial response; otherwise, the risk that the transplanted organ would be quickly destroyed by the disease is too high. Heart transplantation is a serious procedure and typically is considered in younger patients. Kidney transplantation is performed more frequently.26
Prognosis
The patient’s prognosis depends largely on the disease type and the degree of organ damage. The greatest determinant of a patient’s fate is the state of the heart, as this organ determines how intensively the patient can be treated. In some patients, it is possible to partially reverse or stop the disease process.27
Conclusion
The treatment of amyloidosis consists in extending the patient’s life, stopping the disease progression, and supporting the treatment of affected organs. It is essential to recognize amyloidosis at an early stage. Timely diagnosis, appropriate treatment of the underlying disease (adapted to the risk level), close monitoring, and supportive therapy are of key importance to the effectiveness of amyloidosis treatment.
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