Amyloidosis

Amyloidosis

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as an insoluble proteinaceous material in the extracellular matrix of tissue. At least 30 human precursor proteins can form amyloid. The deposits may be localized to one organ or may be systemic. Amyloid deposition may be subclinical or may produce a diverse array of clinical manifestations.

1. Systemic amyloidosis is protean in its manifestations and can mimic more common rheumatic conditions such as seronegative rheumatoid arthritis (RA).

2. Abdominal fat pad aspiration is the easiest and safest method of obtaining tissue to examine for amyloid deposition.

3. Diagnosis is established by tissue biopsy and polarized microscopy of Congo red-stained tissue. Immunohistochemical stains can identify the specific amyloid protein subunit.

4. Treatment varies depending on the type of amyloidosis: AL by eliminating clonal B cells; AA by controlling chronic inflammation; ATTR by liver transplantation or lowering transthyretin (TTR) levels; localized amyloidosis by surgical or laser excision.

Key Points

• Amyloidosis is broadly classified as primary, secondary, or hereditary 
• Clinical presentation varies widely depending on organ or organs affected 
  • Nephrotic syndrome with features including proteinuria and edema
  • Congestive heart failure, which may lead to severe fatigue, palpitations, dyspnea, or weakness
  • Autonomic neuropathy affecting blood pressure, bladder function, temperature control, and digestion
• Diagnosis requires a high index of suspicion based on clinical features
  • Definitive diagnosis of amyloid deposition is made by tissue biopsy, which is used for Congo red staining to identify fibril accumulation using cross-polarized light (gold standard)
  • Mass spectrometry can identify the specific type of amyloid protein present
• Cornerstone therapy for primary light chain amyloidosis (the most common type of amyloidosis) is high-dose chemotherapy with autologous stem cell transplantation if disease is in the early stage and cardiac failure has not yet developed 
  • A variety of chemotherapeutic regimens are used for patients who present with or develop end-stage organ dysfunction
• Secondary amyloidosis (amyloid A protein) is best treated with the management of the underlying infection or inflammatory disease
  • In rare instances—if kidney, heart, or liver is compromised—organ transplantation is recommended, particularly after achieving control of the underlying inflammatory condition
• Main treatment approach to hereditary amyloidosis is orthotopic liver transplant, sometimes in conjunction with target organ transplant, especially when end-stage organ failure is imminent 
• Prognosis varies with the type of amyloid and organ affected
  • Heart failure is the most common terminal event for primary and hereditary amyloidosis 
  • Median survival of 4.6 to 8 years was reported in patients with primary amyloidosis who were treated with high-dose chemotherapy followed by autologous stem cell transplant 
  • Patients with secondary amyloidosis can see improvement in kidney function, but improvement may take months to years after the underlying inflammation is controlled 

Pitfalls

• Consider amyloidosis in all patients with unexplained cardiomyopathy, nephrotic syndrome, hepatomegaly, peripheral neuropathy, and atypical multiple myeloma 

• Amyloidosis is a group of rare, life-threatening diseases characterized by extracellular deposition and accumulation of abnormal protein fibrils in organs or tissues, which progressively disrupt organ function 
• Most common clinical syndromes associated with amyloidosis are nondiabetic nephrotic syndrome, nonischemic cardiomyopathy, hepatomegaly, and peripheral neuropathy

Classification

• The responsible amyloid protein is designated protein “A” and followed by a suffix that is an abbreviated form of the parent or precursor protein name (eg, in light chain amyloidosis, the fibril protein is designated as “AL” because the precursor protein is a light chain immunoglobulin) 
• International consensus committee recommends that the disease name be expressed as the abbreviated designation for the protein fibril followed by the word amyloidosis (eg, light chain amyloidosis is designated as AL amyloidosis). Nomenclature used in medical literature varies widely and may be confusing 
• Classified as primary, secondary, or hereditary amyloidosis; each affects the function of 1 or more tissues or organs. Some types do not fall neatly within these categories 
  • Primary
    • Light chain amyloidosis (AL amyloidosis)
      • Clonal, nonproliferative plasma cell disorder originating in the bone marrow in which abnormal cells produce antibody (misfolded kappa or lambda light chain) proteins that deposit as amyloid
      • Primarily affects kidneys, heart, and liver, but may involve nerves, gastrointestinal tract, lungs, soft tissue, and bones 
        • Presents with cardiac involvement (50% of cases)—most often restrictive cardiomyopathy, renal insufficiency (47% of cases), and/or proteinuria (73% of cases) 
      • Most common type of amyloidosis in the United States and United Kingdom (68% of cases) 
  • Secondary
    • Amyloid A amyloidosis (AA amyloidosis) 
      • Complication of chronic inflammatory illnesses, such as rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis; can also result from chronic infections, familial Mediterranean fever, Crohn disease, and malignancy
      • Characterized by extracellular deposition of fibrils of serum amyloid A, which is an acute-phase reactant
      • Primarily affects the kidneys but also affects the liver
        • Presents as proteinuria (97% of cases) and/or nephrotic syndrome (54%-63% of cases) 
      • Second most common amyloidosis, accounting for up to 12% of renal amyloid cases in the United Kingdom (30%-40% in Europe overall) and 7% to 12.5% of cases in the United States 
  • Hereditary
    • Autosomal dominant disease associated with a variety of precursor proteins
      • Most common type
        • Mutant/variant or hereditary transthyretin amyloidosis; (mATTR amyloidosis; also known as hATTR amyloidosis), resulting from one of many possible mutations in the TTR gene
          • Deposits tend to occur in the peripheral nervous system and myocardium, causing neuropathy and cardiomyopathy 
      • Uncommon types
        • Fibrinogen Aα-chain amyloidosis (AFib amyloidosis)
          • Accounts for 1.7% of hereditary amyloidosis 
          • Fibrinogen Aα-chain amyloidosis presents as proteinuria in 54% of cases 
        • Several subtypes of apolipoprotein A and apolipoprotein C (AApo AII amyloidosis, AApo AIV amyloidosis, AApo CII amyloidosis, AApo CIII amyloidosis) 
          • Results in a variety of clinical manifestations
  • Other, nonhereditary types
    • Leukocyte chemotactic factor 2 amyloidosis (ALECT2 amyloidosis) 
      • Accounts for 2.7% of renal amyloidosis cases and is the third most common amyloidosis 
    • Wild-type ATTR amyloidosis, formerly called senile systemic amyloidosis (wtATTR amyloidosis) 
      • Age-related nonhereditary systemic amyloidosis resulting from wild-type TTR deposition in various tissues
      • Predominantly affects cardiac function in elderly patients; however, presents as carpal tunnel syndrome in 50% of these cases and precedes cardiac involvement by 8 to 10 years 

Clinical Presentation

History

• History of an asymptomatic MGUS (monoclonal gammopathy of uncertain significance) may be present as an increase in serum levels of free light chains precedes the development of AL amyloidosis by many years 
• Some patients may be asymptomatic (10%-15%), whereas others experience multisystem symptoms with a wide spectrum of variability depending on organ or organs affected 
  • Symptoms of cardiac involvement are usually symptoms of restrictive cardiomyopathy, disproportionately showing symptoms of right ventricular failure 
    • Cardiac involvement is most often diagnosed in patients with light chain (50% of light chain amyloidosis patients) and wild-type or hereditary ATTR amyloidosis
      • Common symptoms are severe fatigue, palpitations, dyspnea, exercise intolerance, presyncope, and syncope
  • Renal involvement is also common in amyloidosis
    • Most commonly occurs in AA amyloidosis (nearly 100% of cases); also occurs in AL amyloidosis (70% of cases), ALECT2 amyloidosis, and AFib amyloidosis 
      • Symptoms include severe edema, especially periorbital and peripheral-dependent edema (ankles and/or feet), and foamy urine
  • Neuropathy
    • Autonomic neuropathy
      • Control of bladder function, temperature, blood pressure, and digestive function are affected
        • Present in AL amyloidosis (20% of patients) and some hereditary types of ATTR amyloidosis
          • Recurrent urinary tract infections
          • Impotence
          • Orthostatic hypotension and syncope
          • Anorexia and early satiety
          • Diarrhea or constipation
          • Malabsorption leading to weight loss
    • Peripheral neuropathy
      • Affects mainly pain and temperature sensitivity 
        • Present in AL amyloidosis (usually in combination with autonomic dysfunction) and hereditary types of ATTR amyloidosis; several TTR mutations are associated with an isolated peripheral neuropathy
      • Carpal tunnel syndrome may develop owing to infiltration of amyloid protein around the median nerve, leading to compression and dysfunction of the nerve
        • Patient will complain of pain that may radiate proximally in the involved hand and paresthesias and/or anesthesia (over thumb, second and third finger, and one-half of the fourth finger)
        • Common in hereditary and wild-type ATTR amyloidosis

Physical examination

• Patients may present with a variety of clinical signs, depending on organ involvement 
  • Soft tissue lesions
    • Seen mainly in AL amyloidosis (12% of cases), these particular signs develop as a result of infiltration of amyloid protein into soft tissue and are highly suggestive of the diagnosis 
      • Macroglossia (14% of patients with AL amyloidosis)
      • Submandibular swelling (15%)
      • Periorbital purpura (11%)
      • Alopecia (5%)
      • Shoulder pad (4%)
      • Nail lesions (3%)
  • Findings consistent with carpal tunnel syndrome may develop in AL amyloidosis (also found in ATTR amyloidosis)
    • Diminished sensation and paresthesias in hand with median nerve distribution (ie, thumb and most of the next 3 adjacent fingers)
    • Grip weakness
    • Atrophy involving thenar eminence of involved hand
  • Cardiovascular effects
    • Reflect development of restrictive cardiomyopathy disproportionately affecting the right side
      • Increased jugular venous pressure (jugular venous distention)
      • Dependent peripheral edema
      • Hepatomegaly
      • Ascites
      • Arrhythmias
      • Hypotension in advanced disease
  • Renal effects
    • Peripheral edema may be present, especially with amyloid A and light chain amyloidosis 
      • Also may be present in patients with wild-type ATTR, ALECT2, and AFib amyloidosis, all of which have potential for renal involvement

Causes

• Mutated, misfolded, or excessive protein production accumulating in organs and tissues and causing dysfunction
  • AL amyloidosis: underlying plasma cell dyscrasia
    • May also occur in association with multiple myeloma, Waldenström macroglobulinemia, and some forms of lymphoma
  • AA amyloidosis: underlying chronic inflammatory conditions
  • Hereditary (mutant) ATTR amyloidosis: autosomal dominant inherited disease
  • AFib amyloidosis: autosomal dominant inherited disease
  • AApo AI, AII, CII, and CIV amyloidosis: autosomal dominant inherited disease
  • Wild-type ATTR amyloidosis: related to aging and not to heredity
  • ALECT2 amyloidosis: uncertain cause

Risk factors and/or associations

Age

• Mean age at AL amyloidosis diagnosis: 65 years 
• Mean age of patients with AA amyloidosis: 10 years 
• Median age at presentation of AFib amyloidosis: 58 years 
• Wild-type ATTR amyloidosis affects 22% to 25% of patients older than 80 years 

Sex

• Male to female ratio of approximately 2:1 

Genetics

• Inherited forms of amyloidosis
  • Result from mutations in the following genes:
    • Transthyretin (TTR) (OMIM *176300)
      • Endemic in Portugal, Sweden, and Japan
      • Val30Met is the most common mutation in the transthyretin gene; however, more than 120 pathogenic mutations are known 
    • Fibrinogen Aα-chain (FGA) (OMIM *134820) 
    • Apolipoprotein A-I (APOAI) (OMIM *107680) 

Ethnicity/race

• Amyloidogenic LECT2 protein predominantly occurs in populations from South Asia, North Africa, the Middle East, and Mexico (88%-92% of all cases in the United States)
• Mutant TTR (due to V122I mutation) is present in 3.2% of Black population. Evaluate Black men older than 50 years who have symptoms of heart failure and echocardiographic findings of thickened ventricular walls for this mutation 

Diagnostic Procedures

Primary diagnostic tools

• History and physical examination rarely suggest amyloidosis as the primary diagnosis; a high index of suspicion is required. Initial evaluation of the symptomatic organ system (eg, basic laboratory tests, urine studies, and/or echocardiogram) generally already has been done when diagnosis is considered 
  • Most common type of amyloidosis in the United States and Europe is AL amyloidosis, with cardiac, kidney, gastrointestinal/hepatic, or peripheral nerve involvement. Consider the diagnosis in patients when initial evaluation reveals the following: 
    • Nephrotic range proteinuria
    • Heart failure with preserved ejection fraction
    • Nonischemic cardiomyopathy with hypertrophy on echocardiography
    • Nondiabetic peripheral neuropathy, especially carpal tunnel syndrome
    • Unexplained hepatomegaly
    • Diarrhea
  • When AL amyloidosis is in the differential diagnosis, obtain the following evaluations:
    • Serum and urine protein electrophoresis with immunofixation
    • Serum immunoglobulin free light chain analysis
      • If immunofixation of serum and urine is negative and the immunoglobulin free light chain (kappa-lambda) ratio is normal (0.26-1.65), AL amyloidosis is unlikely and further evaluation should not be undertaken, unless 1 of the following occurs: 
        • Clinical index of suspicion for AL amyloidosis is very high
        • There is clinical suspicion for another type of amyloidosis for which abnormalities of light chains would not be expected. Normal results do not rule out the possibility of an inherited or other form of amyloidosis
      • If a light chain abnormality is found, biopsy is required to establish the diagnosis
  • Additional cardiac imaging and functional studies, if not already performed, aid in assessing the presence and impact of cardiac amyloidosis
    • ECG
    • Echocardiography 
    • Cardiac MRI 
    • Cardiac radionuclide scan with technetium pyrophosphate scan: for patients with cardiac symptoms and echocardiographic evidence suggesting cardiac amyloidosis (ie, thickened ventricular walls, Doppler evidence of poor diastolic filling, and abnormal longitudinal strain) 
      • Useful in differentiating identifying cardiac ATTR amyloidosis
        • ATTR amyloidosis (both hereditary and wild-type) will result in a positive pyrophosphate scan (2+ or greater); these patients should be screened for mutant TTR gene with autosomal dominant inheritance 
        • AL amyloidosis will result in a negative scan (no uptake)
  • Tissue biopsy is required to diagnose all types of amyloidosis
    • For AL amyloidosis, biopsy of the clinically involved organ is generally unnecessary
      • Combination of subcutaneous fat aspirate and an iliac crest bone marrow biopsy will demonstrate amyloid in 85% of patients
      • Labial salivary gland biopsy is an alternative biopsy site
    • Organ biopsy (eg, renal, endomyocardial, hepatic, peripheral nerve) is reserved for use when alternative biopsy sites are nondiagnostic, yet amyloidosis is still suspected clinically
      • Endomyocardial biopsy has a sensitivity of nearly 100% for cardiac amyloidosis 
    • Diagnosis requires demonstration of amyloid deposits that show green birefringence under cross-polarized light when stained with Congo red
    • Mass spectrometry can confirm composition of the amyloid protein (ie, type of amyloidosis) and can be applied to almost any tissue source, including fat and nerve. It is considered the gold standard and is superior to immunohistochemistry for this purpose 
  • When hereditary amyloidosis is suspected
    • Genetic testing is crucial to confirm; can identify the specific mutation (eg, Val30Met, ATTR Met30, Ala60, Ile122)
  • If AL amyloidosis is confirmed, obtain cardiac troponins and NT-proBNP level; use these values plus serum free light chain levels to calculate a score for staging to guide therapy decision (whether or not to treat with stem cell transplant)
    • Scores are calculated by assigning 1 point for each of the following; total score (0, 1, 2, or 3) equates to the prognostic stage 
      • Cardiac troponin T 0.025 ng/mL or higher
      • N‐terminal probrain natriuretic peptide 1800 pg/mL or higher
      • Difference between involved and uninvolved serum free light chain levels (dFLC) greater than 180 mg/L

Laboratory

• Blood and urine studies
  • Obtain in all patients to assess specific organ involvement
    • Urinalysis
    • 24-hour urine protein
      • Proteinuria is defined as urine protein level above 150 mg/day (10-20 mg/dL) 
      • Up to 97% of patients with amyloid A amyloidosis present with proteinuria exceeding 500 mg/day 
    • Serum creatinine level and estimated GFR
      • Up to 97% of patients with amyloid A amyloidosis present with serum creatinine level higher than 1.5 mg/dL (132.6 μmol/L) 
    • Liver function tests
      • AL amyloidosis
        • Alkaline phosphatase level is elevated in 86% of patients
        • AST and serum glutamate oxaloacetate transaminase levels are elevated in 80% of patients
        • Total bilirubin is increased in 21% of patients
    • Prothrombin time
      • Elevated in 35% of patients with light chain amyloidosis
    • CBC
  • Obtain in all patients suspected of having light chain amyloidosis
    • Required to identify the monoclonal protein that is the basis of amyloid deposits
      • Serum and urine protein electrophoresis with immunofixation 
      • Serum immunoglobulin free light chain analysis (quantifies circulating free light chains) 
        • In light chain amyloidosis, fibrils are found to be lambda light chains 4 times more often than kappa light chains
  • Obtain in all patients to evaluate cardiac involvement
    • Cardiac troponin
      • Elevated troponin levels predict a poor outcome in patients with light chain amyloidosis 
    • NT-proBNP or BNP
      • All patients with AL amyloidosis and cardiac involvement have elevated NT-proBNP levels (100% sensitivity) 
      • BNP testing is more specific, but it is only 89% sensitive 
• Tissue studies
  • Congo red staining of biopsied tissue
    • Gold standard to identify presence of amyloid protein
    • Detects the accumulated β-sheet fibrillar (amyloid) proteins appearing as:
      • Apple-green birefringence under polarized light
      • Orange-red appearance under light microscopy
  • Laser capture mass spectroscopic proteome analysis
    • Gold standard for identification of the amyloid protein subunit
    • Amyloid deposits are directly removed from a glass slide (can be performed on archived paraffin-embedded tissues)
    • Technique serves as a positive control because it also will detect associated proteins always seen in amyloid deposits (eg, serum amyloid P, vitronectin, apolipoprotein E23)
  • When mass spectrometry is not available, immunohistochemistry and immunofluorescence techniques are available to classify the myeloid protein, but the technique has multiple limitations, including limited panels of antisera 

Imaging

• Echocardiography 
  • Obtain for all patients with suspected cardiac amyloidosis
  • Findings in amyloid cardiomyopathy include:
    • Increased wall thickness of right and left ventricles (one-third of patients have normal wall thickness)
      • Increased wall thickness along with a low-voltage ECG has a sensitivity of 72% to 79% and specificity of 91% to 100% for cardiac amyloidosis 
    • Biatrial enlargement
    • Normal to small left-ventricular cavity size
    • Preserved ejection fraction but reduced stroke volume
    • Valvular and papillary muscle thickening
    • Small to moderate pericardial effusions (often present)
    • Doppler studies reveal worsening diastolic dysfunction
      • Doppler echocardiography can be used to monitor progression of cardiac disease
    • Segmental wall motion abnormalities
• Cardiac radionuclide imaging
  • Uses specific radiotracers (eg, technetium TC 99m pyrophosphate); uptake localizes to cardiac amyloid deposits in TTR amyloidosis and differentiates ATTR amyloidosis from light chain amyloidosis
• Cardiac MRI
  • Obtain in patients with suspected cardiac involvement when echocardiogram does not show myocardial thickening or is unable to discern from hypertensive cardiomyopathy
    • Unique pattern of global transmural or subendocardial late gadolinium enhancement is associated with cardiac amyloidosis with high specificity (94% in light chain amyloidosis) 
    • Transmural patterns of late gadolinium enhancement may distinguish TTR cardiac amyloidosis from light chain cardiac amyloidosis with high accuracy
• The American Society of Nuclear Cardiology has released detailed imaging guidelines 

Functional testing

• ECG 
  • Obtain in all patients to screen for cardiac involvement 
  • Low-voltage QRS is present in 50% of all cases of light chain amyloidosis (but not present in senile systemic amyloidosis)
  • 50% of amyloidosis cases show a pseudoinfarction pattern: poor R-wave progression or QS waves in the precordial leads
  • Less common findings
    • First-degree atrioventricular block (21% of cases) and atrial fibrillation or flutter (20% of cases)
    • Nonspecific intraventricular conduction delay (16% of cases)
    • Ventricular tachycardia (5% of cases) and second- or third-degree atrioventricular block (3% of cases)

Procedures

• Demonstrating amyloid deposition in tissue by any of the following procedures may preempt the need for biopsy of the affected organ and/or bone marrow 
  • Fine-needle aspiration of subcutaneous abdominal fat (safest)
    • Aspirate 2 to 5 samples of abdominal fat using a 10-mL syringe and a 10- to 23-gauge needle 
    • 57% to 82% of patients with AL amyloidosis will have an abdominal fat aspiration sample positive for amyloid deposits; specificity is 93% to 100% 
  • Labial salivary gland biopsy
    • Positive finding in 83% to 100% of patients with AL or AA amyloidosis 
  • Rectal biopsy
    • Often positive in AL, AA, and ATTR amyloidosis
    • Sensitivity is 75% to 85% 
    • Biopsy from other portions of the gastrointestinal tract (eg, stomach, colon) also may be useful
• When abdominal fat aspiration and salivary gland (or rectal) biopsy do not demonstrate amyloidal deposition and suspicion of amyloidosis persists, obtain bone marrow biopsy 
• When alternative biopsy sites are nondiagnostic yet amyloidosis is still suspected clinically, obtain specific organ biopsy (eg, endomyocardial, hepatic, or renal biopsy) 
  • Endomyocardial biopsy is obtained via cardiac catheterization
  • Hepatic and renal biopsies are generally obtained percutaneously
• Clinical suspicion of amyloidosis
• Uncorrected coagulopathy or anticoagulation (except with abdominal fat biopsy)
• Bleeding from biopsy site
• Infection at biopsy site
• Hollow cutting needle is used to remove a core of bone containing bone marrow (for core biopsy) or to remove bone marrow fluid (for aspiration biopsy)
  • Adults: typically performed on iliac crest or sternum
  • Children: typically performed on iliac crest, femur, or anterior tibia
• Aspiration and biopsy are usually performed at the same time
  • Aspiration provides sample of marrow cells
  • Biopsy provides marrow cells and cellular framework of marrow
  • Usually performed under conscious (moderate) sedation and/or local anesthesia
• Suspected light chain amyloidosis to evaluate the underlying plasma cell dyscrasia 
• Uncorrected coagulopathy or anticoagulation
• Infection at or near puncture site
• Bleeding from puncture site
• Infection at puncture site
• Pain at biopsy site

Differential Diagnosis

Most common

• Multiple myeloma
  • Malignant plasma cell proliferation
  • Like patients with amyloidosis, those with multiple myeloma may experience fatigue and anemia 
  • Unlike patients with amyloidosis, 80% of those with multiple myeloma have osteolytic skeletal lesions (present on radiograph), 15% have hypercalcemia, and 20% have elevated serum creatinine level (2 mg/dL or higher) 
  • Differentiate by bone marrow biopsy findings: plasma cells with eccentric nuclei, chromatin arranged in a clock face pattern, and prominent Golgi apparatus are seen in multiple myeloma
• Focal segmental glomerulosclerosis
  • Glomerular lesions associated with progressive kidney disease
  • Like patients with amyloidosis, those with focal segmental glomerulosclerosis experience proteinuria and hypertension
  • Unlike those with amyloidosis, patients with focal segmental glomerulosclerosis experience weight gain and low serum albumin levels
  • Differentiate by renal biopsy: presence of lesions under a light microscopic analysis or foot process effacement under electron microscopy analysis of the kidney tissue
    • Additionally, negative results of kidney biopsy with Congo red staining are expected
• Membranous glomerulonephritis
  • Most common cause of adult-onset nephrotic syndrome, which thickens the glomerular basement membrane
  • Similar to amyloidosis, membranous glomerulonephritis presents with proteinuria, edema, hypertension, and end-stage kidney disease
  • Patients with membranous glomerulonephritis also experience excessive urination, weight gain, and poor appetite
  • Differentiate by presence of subepithelial immune deposits identified under electron microscopy analysis of renal biopsy
• Cardiac sarcoidosis
  • Idiopathic disease characterized by presence of noncaseating granulomas affecting the left ventricular free wall and the basal aspect of the interventricular septum
  • Like cardiac amyloidosis, cardiac sarcoidosis clinically presents as asymptomatic electrocardiographic findings, palpitations, syncope, heart failure, and sudden cardiac death
  • Unlike amyloidosis, complete heart block (25%-30% of cases) and pulmonary disease are observed in 90% of patients with cardiac sarcoidosis 
  • Differentiate at later stages with echocardiographic analysis
    • Septal thinning (or thickening) and left ventricle dilation with systolic dysfunction
    • Ventricular aneurysms and papillary muscle thickening
    • Valvular abnormalities and/or pericardial effusions
  • Additionally, negative results of cardiac biopsy with Congo red staining are expected
• Hypertrophic cardiomyopathies
  • Heart muscle becomes thickened with unexplained hypertrophy of the left ventricle
  • Like cardiac amyloidosis, hypertrophic cardiomyopathies present as dyspnea, fatigue, palpitations, dizziness, and syncope
  • Unlike amyloidosis, hypertrophic cardiomyopathy also presents with angina and sudden death
  • Differentiate by echocardiography
    • Asymmetrical hypertrophy, small left ventricular cavity, left ventricular outflow tract obstruction and normal ejection fraction present in hypertrophic cardiomyopathy
• Cardiac hemochromatosis
  • Excessive iron storage within internal organs including the heart; overload of iron in the myocardium leads to systolic dysfunction
  • Like amyloidosis, patients experience acquired anemia, arthritis, fatigue, weakness, and disruption in bladder control
  • Unlike amyloidosis, a specific symptom from moderate to severe iron overload is skin hyperpigmentation
  • Differentiate by liver biopsy as definitive test for iron overload and/or serum ferritin and transferrin saturation

Treatment Goals

• Reduce and/or eliminate abnormal amyloid production (not possible for some types of amyloid protein)
• Control symptoms
• Preserve organ function
• Maintain quality of life
• Prolong survival

Admission criteria

Patients with significant end-organ involvement (eg, congestive heart failure, end-stage kidney disease, cardiac autonomic neuropathy)

Criteria for ICU admission

• Multiorgan failure
• Significant cardiac dysfunction (eg, heart failure)
• Requirement for renal replacement therapy

Recommendations for specialist referral

• Refer all patients who have suspected amyloidosis to a hematologist-oncologist or specialized referral center that coordinates care among multiple specialists

Treatment Options

Main focus of treatment is suppressing synthesis of the amyloid protein (not possible for some types of amyloid protein) in conjunction with supportive care and managing organ dysfunction

AL amyloidosis

• In preparation for treatment
  • Herpes zoster prophylaxis for patients who will be treated with proteasome inhibitors or daratumumab
  • Test for hepatitis B before starting carflizomib or daratumumab
  • Screen for HIV and hepatitis C as clinically indicated
• First step is careful evaluation of patient for stem cell transplant eligibility. This is important because there is significant treatment-related mortality risk
  • Disease stage (using troponin and NT-proBNP), patient age, and kidney function are relevant factors
    • Although several studies have demonstrated that patients with advanced cardiac disease should be excluded from stem cell transplant studies, good outcomes with stem cell transplantation have been reported when performed before onset of advanced congestive heart failure 
    • Patients in stage 1 are good candidates for stem cell transplantation, but they represent a minority of patients with AL amyloidosis
• For eligible patients, high-dose melphalan followed by autologous stem cell transplantation is recommended 
  • Good hematologic and organ response rates have been reported with higher overall survival than that reported for standard chemotherapy 
  • Bortezomib (with high-dose melphalan and stem cell transplant) achieved higher 24-month posttransplant survival than did high-dose melphalan and stem cell transplant 
  • Consolidation therapy with a bortezomib-based regimen may be indicated in some patients based on free light chain response 
• Conventional therapy without stem cell transplant is appropriate for most patients with advanced-stage AL amyloidosis
  • Optimal therapy is unknown; participation in a clinical trial is encouraged 
  • Combination chemotherapy typically results in clinical improvement within 3 to 4 months
  • Stage III/high-risk patients are treated with various chemotherapy regimens 
  • Reassess for stem cell transplant eligibility after 2 cycles 
• Organ transplant (ie, kidney, heart) is appropriate in patients with AL amyloidosis who attain a complete hematologic response (ie, negative serum and urine immunofixation results, normal free light chain kappa-lambda ratio) but develop irreversible end-organ damage 
  • Young patients who present with isolated, severe cardiac involvement may be effectively managed by heart transplant, followed by autologous stem cell transplant or effective chemotherapy

AA amyloidosis

• Managing underlying infection or inflammatory disease leads to stabilizing or reducing serum amyloid A deposition
  • Examples include antibiotic therapy for bronchiectasis or tuberculosis, colchicine for treatment of AA amyloidosis associated with familial Mediterranean fever, biologic treatment of rheumatoid arthritis, and chemotherapy and surgery for a malignant neoplasm
• Treatment aimed at reducing formation of amyloid also may be useful
• In rare instances—if kidney, heart, or liver is compromised—organ transplant is recommended, particularly after achieving control of the underlying inflammatory condition

Hereditary amyloidosis

• Main treatment approach has been organ transplantation
  • Orthotopic liver transplant is the treatment of choice for patients with hereditary ATTR amyloidosis
    • Effective because this removes the source of circulating mutant amyloid
  • Heart transplant with or without orthotopic liver transplant can be performed in patients who have hATTR amyloidosis with significant cardiac involvement
    • Native liver continues to produce mutant TTR, which may continue to deposit in the new heart graft
  • Kidney transplant or combined liver-kidney transplant is offered to patients with AFib amyloidosis
    • Kidney transplant is associated with amyloid recurrence (after median 6.7 years)
    • Combined liver-kidney transplant prevents further amyloid deposition, but is associated with more perioperative complications
• Therapeutic options include patisiran (peripheral neuropathy), inotersen (peripheral neuropathy), tafamidis (cardiac in United States, cardiac or nerve in Europe), and diflunisal (off-label use for variant ATTR amyloid neuropathy) 

Wild-type ATTR amyloidosis

• Primarily involves the heart
  • Cardiac complications, including arrhythmia and cardiomyopathy, are treated medically, like any other arrhythmia or cardiomyopathy
• Usual treatments for other types of amyloidosis (eg, chemotherapy, immunomodulators) have minimal or no effect

Supportive medical therapies for amyloidosis that affect the nervous system may include gabapentin or pregabalin for treatment of neuropathic pain, octreotide for diarrhea caused by autonomic or gastrointestinal involvement 

• Midodrine may help treat hypotension caused by autonomic dysfunction

Nondrug and supportive care

Both heart failure and nephrotic syndrome are treated by restricting salt and carefully using diuretics 

• Heart failure in amyloidosis is right-sided and is dependent on preload; intravascular volume reduction is avoided, particularly in patients with hypoproteinemia and postural hypotension

Autonomic dysfunction is often asymptomatic, but symptomatic hypotension can occur with use of ACE inhibitors; therefore, use these drugs cautiously and use low initial dosing 

• Hypoproteinemia and heart failure may contribute to hypotension
• Midodrine and elastic leotards may benefit patients who have hypotension

Recurrent syncope may require implantation of a pacemaker 

Patients with systemic amyloidosis must maintain good nutritional status 

Procedures

Autologous stem cell transplantation 

General explanation

• Stem cells are collected from the patient’s own bone marrow
• Chemotherapy is provided (in light chain amyloidosis: high-dose melphalan) to eliminate the amyloidogenic plasma cells, after which the patient’s previously collected stem cells are infused

Indication

• Stage I light chain amyloidosis 

Contraindications

• Older than 70 years
• 3 or more organs involved
• Creatinine clearance less than 30 mL/minute

Complications

• Bone marrow suppression
• Systemic infection
• Hepatic veno-occlusive disease
• Interstitial pneumonia
• Cataracts
• Infertility
• Secondary malignancy

Monitoring

• 3 months after autologous stem cell transplant or every 2 chemotherapy cycles, assessment of cardiac and hematologic response is recommended 
  • Obtain cardiac troponin and NT-proBNP levels, serum and urine immunofixation test results, and serum free light chains measurements
    • Hematologic response
      • Complete response: negative serum and urine immunofixation results and normal free light chain kappa-lambda ratio
      • Very good partial response: difference between amyloidogenic and uninvolved free light chain concentration (dFLC) less than 40 mg/L
      • Partial response: difference between amyloidogenic and uninvolved free light chain concentration decrease more than 50% compared to baseline
      • No response: all other patients
    • Cardiac response
      • NT-proBNP level decrease of more than 30% and 300 ng/L in patients with baseline NT-proBNP level greater than or equal to 650 ng/L, or
      • Decrease by at least 2 New York Heart Association classes in patients with baseline class of III or IV
    • Cardiac progression 
      • NT-proBNP level increase of more than 30% and 300 ng/L, or
      • Cardiac troponin level increase of 33% or more compared to baseline, or
      • Decrease of at least 10% of ejection fraction

Complications

• Congestive heart failure
  • Avoid use of β-blockers and ACE inhibitors
    • In heart failure caused by amyloidosis, cardiac output is more dependent on heart rate, which may be slowed by β-blockers and result in decreased output
    • Neurohormonal blockade may cause profound hypotension, thus avoid ACE inhibitors
  • Digitalis and calcium channel blockers are relatively contraindicated because they are believed to selectively bind amyloid fibrils and have an increased risk of toxicity 
• End-stage kidney failure
• Hypoproteinemia
• Hypotension
  • Midodrine or fludrocortisone may be useful to treat autonomic neuropathy that is causing postural hypotension 
• Neuropathy
  • May manifest with sensorineural peripheral neuropathy
  • Autonomic neuropathy can cause gastric emptying disorder or voiding dysfunction
• Liver failure
• Nephrotic syndrome
• Ventricular arrhythmia
• Cardiac conduction defects
  • Implantable cardioverter-defibrillators are considered for patients with rhythm or conduction abnormalities to prevent sudden cardiac death 
• Disease recurrence
• Sudden cardiac death
  • Typically caused by electromechanical dissociation (as opposed to ventricular arrhythmia) 
• Patients with gastrointestinal involvement can develop intestinal obstruction, which may require emergency surgery
• Soft tissue involvement
  • Tongue enlargement
  • Clinical arthropathy
  • Claudication
  • Myopathy
  • Carpal tunnel syndrome

Prognosis

• Primary: light chain amyloidosis
  • Untreated patients have a median survival of 12 months; in untreated patients with cardiac involvement, median survival is less 5 months 
  • Median kidney transplant survival is 5.8 years (5- and 10-year graft survival rates of 74% and 25%, respectively) 
    • 20% to 28% of patients who undergo kidney transplant demonstrate recurrence of renal amyloid 
  • Median survival of 4.6 to 8 years was reported in patients treated with high-dose chemotherapy followed by autologous stem cell transplant 
    • Autologous stem cell transplantation combined with full-dose melphalan is associated with hematologic response in approximately 75% of patients, with complete response in 40% 
    • Patients not eligible for autologous stem cell transplantation, usually treated with melphalan and dexamethasone, experience a hematologic response in 66% of cases with a complete response in 33% of cases 
• Secondary: amyloid A amyloidosis
  • Improvement of renal function may take months to years
  • Up to 28% of patients who undergo kidney transplant demonstrate recurrence of renal amyloid 
  • After kidney transplant, a small study reported 5- and 10-year graft survival rates of 86% and 59%, respectively 
• Hereditary amyloidosis
  • Treatment of hereditary amyloidosis remains unsatisfactory; organ transplant is the major treatment option 
  • Patients with diagnosed fibrinogen Aα-chain amyloidosis who undergo kidney transplant were reported to have 5- and 10-year graft survival rates of 85% and 30%, respectively 
• Wild-type ATTR amyloidosis
  • Generally affects older patients whose prognosis depends on response to medical treatment and existence of comorbidities
  • A study of 102 patients with senile systemic amyloidosis reported that congestive heart failure was a prominent feature in 76% of patients; median survival was 6.7 years from symptom onset 

Screening and Prevention

Screening

At-risk populations

• Patients with monoclonal gammopathies of undetermined significance with altered free light chain kappa-lambda ratio 

Screening tests

• Periodic evaluation (eg, annual or with symptom development) with cardiac biomarkers and urine protein to screen for cardiac and renal involvement, respectively 

References

Wechalekar AD et al: Systemic amyloidosis. Lancet. 387(10038):2641-54, 2016 Reference