What every physician needs to know:
Amyloidosis is a term for diseases caused by extracellular deposition of protein fibrils. The accepted nomenclature is “AX”, “A” for amyloidosis, and “X” indicating the precursor protein. If the precursor is an immunoglobulin light chain, the disease is termed AL, the most common of the systemic amyloidoses. If it is familial (AF), the precursor protein can be an inherited mutant serum protein such as transthyretin, abbreviated ATTR, or proteins such as lysozyme, fibrinogen, gelsolin, or apolipoproteins.
The old nomenclature of “primary” and “secondary” is no longer used, although AA amyloidosis, involving formation of fibrils from serum amyloid A (SAA) protein, is truly secondary to chronic inflammatory or infectious states, as SAA is an acute phase reactant.
Are you sure your patient has amyloidosis? What should you expect to find?
The key to diagnosing patients with amyloidosis is having a high degree of clinical suspicion in the setting of multisystem disease, particularly when typical amyloidosis syndromes are present.
The clinical presentation of systemic amyloidosis can include:
Macroglossia or other soft tissue enlargement
Renal disease usually manifest as massive proteinuria with hypoalbuminemia
Restrictive cardiomyopathy with diastolic dysfunction, congestive heart failure, or arrhythmia
Neurologic disease with peripheral or autonomic neuropathy, usually causing orthostasis and gastrointestinal dysmotility
Malabsorption; and periorbital or other ecchymoses due to capillary fragility or clotting factor deficiency.
These syndromes alone or in combination should prompt a work-up for amyloidosis.
Beware of other conditions that can mimic disease amyloidosis:
Differential diagnosis involves excluding more common causes of end organ dysfunction. Does the patient have longstanding hypertension or diabetes, that could cause renal disease, cardiomyopathy, or neuropathy? Is there evidence of vasculitis, lupus, or other multisystem autoimmune disorder?
If another underlying cause of the clinical syndromes described above cannot be identified, a work-up for amyloidosis should be initiated.
Which individuals are most at risk for developing amyloidosis:
The amyloidoses are rare diseases that can affect any population. However, AF, the hereditary or familial forms, often occur with a family history of cardiomyopathy or neuropathy, and in particular ethnic populations (regions of Portugal, Sweden, and Japan for example) where the mutant gene is endemic. AF is inherited as a dominant disease, as a single mutant allele is enough to initiate protein aggregation and fibril formation.
AL usually occurs in the setting of a bone marrow plasma cell dyscrasia or B lymphoproliferative process; cases have been seen as early as the third decade of life. AA can occur in some patients early in the course of chronic infection (tuberculosis, chronic osteomyelitis) or inflammation (poorly controlled rheumatoid arthritis, Crohn’s disease, etcetera.); rare familial periodic fever syndromes such as familial Mediterranean fever or TRAPS (TNF receptor associated periodic syndrome) can also lead to AA amyloidosis. Interestingly, wildtype TTR (transthyretin) can aggregate and misfold, causing cardiomyopathy, usually in males in their 70’s or 80’s.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Twenty years ago, there was no urgency to diagnose amyloidosis, because it was a rare and untreatable condition. With the advent of highly effective therapies, it is incumbent upon clinicians to make a timely diagnosis, before irreversible organ damage has occurred. The diagnosis of amyloidosis rests upon three legs: proving there are amyloid fibrils in tissues, determining the protein precursor forming the fibrils, and assessing organ involvement.
Identification of amyloidosis relies upon histochemical evidence of protein fibrils in tissues. These can be seen using polarized microscopy following Congo red staining, which produces the classical “apple green” birefringence, or by electron microscopy, which reveals fibrillar deposits approximately 10nm in diameter. The easiest place to obtain tissue for examination is from aspiration of abdominal fat using a large gauge needle and local anesthetic. A fat aspirate is positive in more than 80% of cases of systemic amyloidosis. If it is negative and clinical suspicion is high, the next step is biopsy of a clinically involved organ.
All amyloid fibrils appear the same by light and electron microscopy. While routine immunohistochemistry or immunofluorescence can identify the origin of the fibrils, immunostaining of amyloid is fraught with a high rate of false positive and false negative testing. Specialized centers use techniques such as immuno-electron microscopy and mass spectrometry to type amyloid fibrils.
Genetic testing can diagnose AF diseases, and a thorough investigation for evidence of a clonal plasma cell or B cell process should be undertaken to diagnose AL, including serum and urine immunofixation electrophoresis, serum free light chain testing, measurement of quantitative immunoglobulins, and bone marrow examination using immunohistochemistry or flow cytometry to detect a clonal population of plasma cells. Of note, an SPEP (serum protein electrophoresis (SPEP) or UPEP (urine protein electrophoresis) are very insensitive for detecting a paraprotein in AL amyloidosis.
Assessing organ function
Since one cannot biopsy every organ to determine whether amyloid deposits are present, and since imaging techniques are still in development (see below), we rely upon clinical and laboratory testing to assess involved organ function. For renal disease, measurement of proteinuria and creatinine is done. For cardiomyopathy, echocardiography is used to measure wall thickness and to assess systolic and diastolic function; recently, the cardiac biomarkers BNP (B-type natriuretic peptide) and troponin have been showed to have prognostic significance.
Telemetry to screen for atrial or ventricular arrhythmias is important. Liver disease usually manifests as an obstructive pattern, with elevated alkaline phosphatase during the first manifestation.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of amyloidosis?
Currently, there is no highly specific and sensitive imaging test for amyloidosis, although new PET (positron emission tomography) agents being developed for imaging fibrils and plaques in the brain of Alzheimer’s patients may turn out to be useful in systemic amyloidosis. In the United Kingdom, a nuclear medicine scan using radiolabeled SAP (serum amyloid P component) has been developed; it is not available elsewhere.
A characteristic pattern of “delayed gadolinium enhancement” has been described for cardiac magnetic resonance imaging in amyloid cardiomyopathy.
If you decide the patient has amyloidosis, what therapies should you initiate immediately?
The first step in treatment is to optimize medical management of amyloid organ disease. The single most important medication for severe nephrotic syndrome with edema or congestive heart failure due to amyloid cardiomyopathy is a diuretic, coupled with a low salt diet and limitation of fluid intake.
The second most important class of medications are those that should be discontinued in patients with amyloidotic cardiomyopathy. In these patients, beta blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, and other vasodilators are very poorly tolerated, and digoxin can be bound by amyloid fibrils and reach locally toxic levels in the heart.
Other aspects of medical management rely upon subspecialists familiar with these diseases through participation in multidisciplinary evaluation programs at specialized treatment centers.
More definitive therapies?
Definitive therapy for amyloidosis must be tailored to the properly identified protein precursor. The most critical decision, is if and when to initiate cytotoxic chemotherapy in AL amyloidosis, which can be rapidly progressive and fatal, versus consideration of appropriate therapies for other types of amyloid disease.
Treatment of AL amyloidosis
Treatment of AL amyloidosis incorporates anti-plasma cell chemotherapy. Melphalan and prednisone is no longer used, as response rates with dexamethasone instead of prednisone are considerably higher. However, high dose intravenous melphalan, followed by autologous peripheral blood stem cell transplantation produces even higher rates of complete responses that can be very durable and associated with improvement in organ function and quality of life. Novel anti-plasma cell agents such as bortezomib (Velcade), the proteasome inhibitor, and lenalidomide (Revlimid), the immunomodulator, have excellent activity as well.
Clinical trials are ongoing to determine optimal combinations and sequences of therapies, and personalize therapy to reduce toxicity and optimize organ responses. New approaches are being developed with monoclonal antibodies and drugs directed against the accessory protein SAP.
Treatment of ATTR amyloidosis
The only proven therapy that can ameliorate the progression of ATTR is orthotopic liver transplantation. In this approach, the major organ synthesizing the mutant disease-causing protein is removed and replaced with one synthesizing normal TTR. Recently, biophysical studies have identified small molecules that can stabilize TTR, preventing unfolding and aggregation in the test tube. Two of these molecules, the nonsteroidal diflunisal and a derivative tafamidis, are in clinical trials, and hold promise of a medical therapy for this devastating familial disease.
Treatment of AA amyloidosis
For this disease, treating the underlying inflammatory condition or infection will slow or halt the progression of disease. In addition, a small molecule, eprodisate, has been shown to slow the progression of renal dysfunction and is undergoing further testing.
What other therapies are helpful for reducing complications?
The major cause of death from amyloidosis is due to heart disease, either congestive heart failure or arrhythmia. In addition to optimal medical management of these processes, some patients may benefit from an implantable defibrillator, although rigorous evidence to support the efficacy of these devices in amyloidosis patients is lacking. Patients who are young and have isolated amyloid cardiomyopathy should be considered for orthotopic heart transplantation, followed by definitive treatment of the underlying disease.
What should you tell the patient and the family about prognosis?
The key take-home message for doctors, patients, and families is that amyloidosis is now a treatable disease. With timely and accurate diagnosis, many patients can be treated effectively, with great benefits in survival, quality of life, and maintenance of healthy organ function. However, unfortunately, there are not effective treatments for all types of amyloidosis, nor do all patients respond to treatment. Thus, there is an ongoing need for basic and translational research to improve diagnosis and therapy of these rare diseases.
What if scenarios.
The major clinical error is failure to suspect amyloidosis and test for it. It is critical to pursue the diagnosis in patients with one or more of the typical amyloid clinical syndromes: nephrotic syndrome, concentric hypertrophic cardiomyopathy with diastolic dysfunction, unexplained autonomic and/or peripheral neuropathy, macroglossia, and periorbital ecchymoses.
Although the precursor protein and cellular source of amyloid fibrils is different for each disease, a common pathophysiology underlies all of these diseases, as well as Alzheimer’s and other neurodegenerative diseases. In each of these, the protein precursor undergoes partial denaturation that facilitates the formation of intermolecular beta sheet interactions, leading to oligomerization and eventually formation of large protofibrils and then mature fibrils. The “amyloid hypothesis” as it is now understood, involves tissue damage from both the fibrils themselves, and from the oligomeric precursors, which are more readily able to interact with and damage living cells.
What other clinical manifestations may help me to diagnose amyloidosis?
The most common symptom of systemic amyloidosis is generalized fatigue. Patients often have dyspnea on exertion, edema, anorexia, hoarseness, difficulty swallowing, tongue enlargement, lightheadedness, or sensory neuropathy, usually in the feet. Patients can also have changes in bowel habits, nocturia, erectile dysfunction, and easy bruising.
A multitude of physical findings can support the diagnosis of systemic amyloidosis. These include signs of congestive heart failure: râles, edema, and an elevated jugular venous pulse, often with hepatojugular reflux. The liver and spleen may be enlarged, and ascites may be present. Amyloid in soft tissues can lead to macroglossia, hoarseness, salivary gland or submandibular gland enlargement, subcutaneous nodules, lymphadenopathy, or arthropathy. Characteristic periorbital ecchymoses can be seen, or other bruising, due to capillary fragility or deficiency of clotting factor X, which binds to amyloid fibrils.
What other additional laboratory studies may be ordered?
In addition to the algorithm described for identifying and typing amyloidosis as described above, a battery of routine and specialized laboratory tests should be carried out. In most patients, the complete blood count is normal, but the ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein)are elevated. Electrolytes usually are normal, but the BUN (blood urea nitrogen) and creatinine may be elevated, along with liver function tests in an obstructive pattern, with elevated alkaline phosphatase occurring first, followed by elevation of total bilirubin, and rarely the transaminases.
Deposition in endocrine organs can produce hypothyroidism and hypoadrenalism. Amyloid cardiomyopathy can cause a decrease in limb lead voltages on the electrocardiogram, along with a pseudo-infarct pattern, as well as diastolic dysfunction and increased interventricular septal thickness on echocardiography; the “sparkly” appearance is rarely seen with modern high resolution echocardiography. Cardiac magnetic resonance imaging with gadolinium can have a pattern of delayed enhancement in the subendocardium.
What’s the evidence?
Merlini, G, Bellotti, V. “Molecular mechanisms of amyloidosis”. N Engl J Med. vol. 349. 2003. pp. 583-596. [This review addresses general mechanisms of amyloid formation, pathogenesis of disease, classification of the amyloidoses, clinical presentation, and treatment overview.]
Merlini, G, Seldin, DC, Gertz, MA. “Amyloidosis: Pathogenesis and New Therapeutic Options”. J Clin Oncol. vol. 29. 2011. pp. 1924-33. [This review presents updated treatment options for AL amyloidosis, including oral melphalan and dexamethasone, high dose melphalan and autologous stem cell transplantation, and the newer agents including bortezomib and lenalidomide.]
Dispenzieri, A, Gertz, MA, Kyle, RA. “Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis”. J Clin Oncol. vol. 22. 2004. pp. 3751-3757. [Outcomes for patients with AL amyloidosis are dominated by cardiac disease, as severe amyloid cardiomyopathy puts patients at high risk for the development of congestive heart failure, atrial and ventricular arrhythmias, and sudden death. While cardiac disease can be assessed using imaging techniques and functional measures, the availability of circulating biomarkers, troponin and pro-BNP, has allowed the development of a staging system that provides risk stratification and prognostic information for outcome.]
Ruberg, FL, Appelbaum, E, Davidoff, R. “Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in light-chain cardiac amyloidosis”. Am J Cardiol. vol. 103. 2009. pp. 544-549. [Cardiac magnetic resonance imaging with gadolinium can detect the presence of amyloid deposition in the myocardium, based upon abnormal late gadolinium enhancement. In a series of 28 patients, the sensitivity and specificity for cardiac amyloidosis were both 86%.]
Cibeira, MT, Sanchorawala, V, Seldin, DC. “Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients”. Blood. vol. 118. 2011 Oct 20. pp. 4346-52. [Here, a series of 421 consecutive patients treated with HDM/SCT at Boston Medical Center was analyzed. Treatment-related mortality was 11% (5.6% in recent years). The rate of hematologic complete responses was 34% overall and for patients achieving a complete response, median event-free survival and overall survival were 8.3 and 13.2 years respectively. However, testament resulted in a high organ response rate and long survival, even for patients who did not achieve a complete response.]
Reece, DE, Sanchorawala, V, Hegenbart, U. “Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study”. Blood. vol. 114. 2009. pp. 1489-1497. [This multicenter study examined once and twice weekly bortezomib dosing for patients with AL amyloidosis. Toxicities included gastrointestinal events, fatigue, and nervous system disorders. Single agent hematologic responses occurred in 50% of evaluable patients. Responses occurred within one or two cycles.]
Dey, BR, Chung, SS, Spitzer, TR. “Cardiac transplantation followed by dose-intensive melphalan and autologous stem-cell transplantation for light chain amyloidosis and heart failure”. Transplantation. vol. 90. 2010. pp. 905-911. [Options are limited for patients with amyloidosis presenting with severe heart failure. For highly selected patients with isolated cardiac disease, orthotopic heart transplantation may be an option, but must be followed by effective anti-plasma cell chemotherapy to prevent recurrence in the transplanted heart. Here, outcomes for seven patients successfully undergoing heart transplant, followed by treatment with high dose melphalan and autologous stem cell transplantation are described.]
Dember, LM, Hawkins, PN, Hazenberg, BP. “Eprodisate for the treatment of renal disease in AA amyloidosis”. N Engl J Med. vol. 356. 2007. pp. 2349-2360. [In this first successful randomized phase III trial of a small molecule for systemic amyloidosis, investigators demonstrated that eprodisate (Fibrillex or Kiacta) slowed progression of renal failure in patients with AA (secondary) amyloidosis.]
Miller, SR, Sekijima, Y, Kelly, JW. “Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants”. Lab Invest. vol. 84. 2004. pp. 545-552. [Another small molecule approach in clinical trials is based upon the ability of NSAIDs (nonsteroidal anti-inflammatory drugs) and their analogs to dock into the thyroid hormone binding site on transthyretin (TTR), stabilizing the normal tetrameric conformation of TTR. Mutations in TTR causing familial amyloidosis destabilize the tetramer, which then dissociates into monomers that are prone to amyloid formation.]
Bodin, K, Ellmerich, S, Kahan, MC. “Antibodies to human serum amyloid P component eliminate visceral amyloid deposits”. Nature. vol. 468. 2010. pp. 93-97. [Reduction in SAP levels through use of a small molecule, CPHPC, and a monoclonal antibody, is successful in eliminating amyloid deposits in a mouse model of AA amyloidosis.]
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- What every physician needs to know:
- Are you sure your patient has amyloidosis? What should you expect to find?
- Beware of other conditions that can mimic disease amyloidosis:
- Which individuals are most at risk for developing amyloidosis:
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of amyloidosis?
- If you decide the patient has amyloidosis, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose amyloidosis?
- What other additional laboratory studies may be ordered?