Cardiac amyloidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Cardiac amyloidosis is a well-known progressive condition, which has been reported with varying incidence rates. It refers to extracellular deposition of light chains of some serum proteins, that assume a beta pleated structure. Myocardial involvement results in congestive heart failure and fatal arrhythmias and is the leading cause of death in patients with amyloidosis. Systemic amyloidosis of AL and TTR type is often associated with amyloid deposition in heart valves, in addition to blood vessels and myocardium. In this classical type of valvular amyloidosis, the deposits occur in previously unaltered valves. There is also another type of cardiac amyloidosis restricted entirely to the heart valves (surgically removed for chronic valvular disease) or only the atria (also called isolated atrial amyloidosis). This condition is heavily under-diagnosed because the thickening of ventricles from extracellular deposition of amyloid material in the heart is mostly attributed to chronic hypertension, which is also a feature of cardiac amyloidosis. Cardiac amyloidosis should be suspected in the following scenarios:

• Congestive heart failure and an increase in left ventricular wall thickness (> 12 mm) in the absence of hypertension or other causes of increased left ventricular mass

• Congestive heart failure and an increase in left ventricular wall thickness (> 12 mm) in the absence of hypertension or other causes of increased left ventricular mass in an African-American > 60 years old

• Congestive heart failure with preserved left ventricular ejection fraction fraction (HFPEF) in an individual > 60 years old

• Congestive heart failure in an individual (particularly an elderly male) with unexplained neuropathy, bilateral carpal tunnel syndrome without risk factors, atrial fibrillation

• Signs or symptoms in an individual with a family history of amyloidosis

• Individuals with hyperenhancement on Cardiac Magnetic Resonance (CMR) or echogenicity on echocardiography

In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.

Cardiac amyloidosis can be classified based on the type of amyloid that infiltrates the heart. The types of amyloid that commonly deposit in the heart are immunoglobulin light chain (AL) and transthyretin (ATTR). These two types of amyloid can result in cardiac AL amyloidosis and cardiac transthyretin amyloidosis.

The characteristic feature of cardiac amyloidosis is abnormal deposition of abnormally folded light chains of several serum proteins, making them insoluble and leading to their accumulation in various organs. This abnormal folding of proteins is most commonly a result of genetic mutations or excessive formation. Involvement of cardiac muscle can lead to heart failure, arrhythmias, and advanced cardiac conduction disorders.

The causes of cardiac amyloidosis vary based on the cause of the systemic amyloidosis.

Cardiomyopathy with congestive heart failure is the most common presentation of cardiac amyloidosis. Other common causes of cardiomyopathy should be excluded, and cardiac amyloidosis should be considered in the absence of a history of myocaridal ischemia, myocardial infarction, or presence of coronary artery disease risk factors. Cardiac amyloidosis should be included in the differential diagnoses in patients with unexplained congestive heart failure who have no history of valvular heart disease, long-standing hypertension, or myocardial ischemia.

The incidence rate increased from 18 to 55 per 100,000 person-years from 2000 to 2012. The prevalence rate increased from 8 to 17 per 100 000 person-years from 2000 to 2012. Cardiac amyloidosis commonly presents in adults more than 40 years old. The incidence and prevalence of cardiac amyloidosis have increased among blacks from 2000 to 2012. Over the years, both incidence and prevalence of cardiac amyloidosis have increased among men.

The most common risk factor for the development of cardiac amyloidosis is the presence of an underlying plasma cell dyscrasia.

There is insufficient evidence to recommend routine screening for cardiac amyloidosis.

The presence or absence of cardiac involvement with amyloid is the most important prognostic factor. Untreated cardiac amyloidosis is associated with a very poor prognosis and a high mortality rate. The most common cardiac complications include heart failure, sudden cardiac death due to electromechanical dissociation and pericardial effusion.

A cardiac biopsy that reveals amyloid, confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis of a systemic involvement. Amyloidosis is frequently confirmed by biopsy of abdominal fat, rectal submucosa, kidney, or bone marrow.

Amyloidosis is a multi-system disease involving many organs simultaneously. Approximately 50% of patients with cardiac amyloidosis present with right heart failure symptoms. The most common symptoms observed in patients with cardiac amyloidosis include fatigue, weight loss, and periorbital purpura.

Cardiac amyloidosis is difficult to diagnose. More than 50% of the patients with cardiac amyloidosis present with signs and symptoms suggestive of right heart failure. Common physical exam findings include elevated jugular venous pressure, third heart sound and pedal edema.

There is no single specific diagnostic test that can be used to diagnose amyloidosis and the diagnosis is based upon the totality of the data. Hence, awareness of the disease is necessary to identify patients with amyloidosis.

The combination of low voltage electrocardiographic pattern and increased thickness of the left ventricular posterior wall and interventricular septum on echocardiogram is highly specific for cardiac amyloidosis. Conduction and rhythm disturbances are common in cardiac amyloidosis, however direct infiltration of the specialized conduction tissue of the heart by the amyloid does not account for the majority of these disturbances.

Amyloidosis is an infiltrative disease resulting in deposition of amyloid in the extracellular spaces of the tissues. Amyloid infiltration of the heart leads to expansion of these extracellular spaces resulting in retainment of gadolinium dye during cardiac magnetic resonance imaging. This retainment of gadolinium leads to signal enhancement in the late washout phase during delayed enhanced cardiac imaging.

Transthoracic echocardiography is most commonly used in the initial evaluation of cardiac amyloidosis. The most common echocardiographic finding is thickening of the left ventricle. Echocardiographic findings strongly correlate with the degree of cardiac dysfunction and disease progression with mildly or moderately increased wall thickness in the early asymptomatic phase and severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum in clinically apparent cardiac dysfunction. Echocardiographic findings have both diagnostic and prognostic importance.

Nuclear cardiac scans like MUGA and radionuclide ventriculography (RNV) are not used routinely early in the diagnosis of cardiac amyloidosis. However, when performed, these scans show increased uptake of technetium by the myocardium correlating well with the degree of involvement.

A cardiac biopsy that reveals amyloid confirms the diagnosis. Biopsy of other tissues may also confirm the diagnosis. Amyloidosis is frequently confirmed by biopsy of abdominal fat, rectal submucosa, kidney, or bone marrow.

Major cardiac manifestations of systemic amyloidosis include heart failure and fatal arrhythmias. Therefore treatment of cardiac amyloidosis includes treatment of heart failure and arrhythmias and treatment of the underlying disease. Treatment of heart failure associated with cardiac amyloidosis differs from therapy usually attempted in patients with systolic or diastolic dysfunction.

When heart function is very poor, a heart transplant may be considered for some patients, but not those with AL type amyloidosis since their disease compromises many organs. In one type of secondary amyloidosis, liver transplantation is also required.

New therapies targeting the serum amyloid protein (SAP), which is an excellent immunogen and a universal component of all amyloid deposits, using monoclonal antibodies are currently being investigated.

Template:WikiDoc Sources CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.

• In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis.^[1]
• In 1854, Rudolph Virchow introduced the term “amyloid” as a macroscopic abnormality in some tissues.^[2]
• In 1867, Weber reported the first case of amyloidosis associated with multiple myeloma.^[1]
• In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.^[3]
• In 1959, Cohen and Calkins used ultrathin sections of amyloidotic tissues and assessed by electron microscopy, explained the presence of non-branching fibrils with indeterminate length and variable width.^[2][1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Cardiac amyloidosis can be classified based on the type of amyloid that infiltrates the heart. The types of amyloid that commonly deposit in the heart are immunoglobulin light chain (AL) and transthyretin (ATTR). These two types of amyloid can result in cardiac AL amyloidosis and cardiac transthyretin amyloidosis.

• Cardiac amyloidosis can be classified based on the type of amyloid that infiltrates the heart.^[1][2]
• The types of amyloid that commonly deposit in the heart are immunoglobulin light chain (AL) transthyretin (ATTR).
• Based on the above mentioned information, we can classify cardiac amyloidosis into:

• Cardiac AL amyloidosis
• Cardiac transthyretin amyloidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]Sabawoon Mirwais, M.B.B.S, M.D.[4]

The characteristic feature of cardiac amyloidosis is abnormal deposition of abnormally folded light chains of several serum proteins, making them insoluble and leading to their accumulation in various organs. This abnormal folding of proteins is most commonly a result of genetic mutations or excessive formation. Involvement of cardiac muscle can lead to heart failure, arrhythmias, and advanced cardiac conduction disorders.

• Amyloidosis is characterized by the deposition and extracellular accumulation of fibrillary proteins, leading to the loss of normal tissue architecture.^[1]
• Serum proteins are capable of undergoing abnormal beta pleated folding to form amyloid protein.
• The most common culprit proteins responsible for forming amyloid deposits are the light chains of immunoglobulins produced by plasma cells in the bone marrow.^[2]
• Cardiac amyloidosis is a disease of the myocardium and it is characterized by extracellular amyloid deposition in the heart.^[3]
• The infiltration of the myocardium, resulting in the thickening of ventricular walls, leads to concentric ventricular remodelling and diminished cardiac output.
• The resulting elevated pressure in the atria causes atrial dilatation and the conduction system of the heart can also get affected.^[4]
• Intramyocardial vessels can also be infiltrated by the amyloid and this can cause reduced perfusion of the myocardium.^[5]
• The most frequent types of amyloidosis involving the heart include:

• Acquired monoclonal immunoglobulin light-chain amyloidosis (Primary amyloidosis)
• Familial or hereditary transthyretin (TTR)-related form
• Systemic senile amyloidosis (Non-mutant TTR-related amyloidosis, Wild-type ATTR)

• All these forms frequently involve the myocardium, with the light chain amyloidosis (AL) being the most common.^[6][7]

• Monoclonal gammopathy of benign type is the most common form associated with AL cardiac amyloidosis.
• Abnormally folded light chains, produced by defective plasma cells, deposit in tissues resulting in disruption of tissue architecture by causing free radical damage and organ dysfunction.
• Severity of the cardiac dysfunction determines the morbidity and mortality.^[8]
• Bone marrow filled with plasma cells by more than 5 – 10% is a poor prognostic indicator.
• The lambda (λ) chains are more likely to be involved in amyloid deposit formation than the kappa (κ) chains.

• The hereditary or familial form of cardiac amyloidosis is inherited in an autosomal dominant pattern. Mutations leading to substitution of a single amino acid on the protein chain can cause abnormal spacial configuration of the protein, leading to its abnormal deposition in the inter-cellular space.
• The mutations in the genes producing various proteins like transthyretin, fibrinogen, apolipoprotein A1 and A2 are responsible. However, the transthyretin mutation is by far the most common cause of hereditary cardiac amyloidosis.
• Transthyretin, a protein tetramer synthesized in the liver, is responsible for transport of the thyroid hormone and vitamin A in the body. The extent of myocardial involvement varies with the gene sequence mutated in the transthyretin gene.
• About 90 to 100% of patients with “Thr60Ala” mutation, where alanine is substituted for threonine at the 60th position on the transthyretin protein and the “Val122Ile”, in which isoleucine is substituted for valine at the 122nd amino acid position, have severe restrictive cardiomyopathy at presentation.
• The “Val30Met” mutation of transthyretin has cardiac involvement only in the elderly patients, with peripheral and autonomic nervous system being the primary target. The Val30Met mutation is normally present in 3.9% of all African Americans and in about 23% of African Americans with cardiac amyloidosis.^[9]
• Cardiac involvement is rare in other variant ATTR like mutations in apolipoprotein A1 and secondary amyloidosis. These more often involve the liver and kidneys.

• Amyloid deposits are found in the hearts of approximately 25% of elderly patients at autopsy.^[9] The clinical significance of these amyloid deposits has not been elucidated, although excess deposition leading to symptoms has been shown to be associated with increased mortality, with a median survival of 7 years following the onset of symptoms.^[10][11][12]
• This type of amyloidosis predominantly involves the heart, with the exception of Carpal tunnel syndrome , which presents about 3 to 4 years before cardiac failure.
• This disorder shows male preponderance and commonly presents after 60 years of age. This condition is often misdiagnosed as chronic hypertension, but recent diagnostic techniques like cardiac MRI have made possible the diagnosis of this condition. It is probably the most common form of amyloidosis in the United States.
• Senile systemic amyloidosis has been associated with increased incidence of myocardial infarctions^[13] and atrial fibrillation^[14] in various studies. The association of tau protein with occurrence of this condition has raised the question of correlation of senile systemic amyloidosis with Alzheimer’s disease.

• In isolated atrial amyloid deposition the deposition is limited solely to the atria.
• This condition most commonly results from excess production of abnormally folded atrial natriuretic peptide, like in congestive cardiac failure and valvular heart disease. The amount of amyloid deposited in the atrium correlates with patient’s age and P wave duration, which is associated with the magnitude of delay in atrial conduction.^[15][16]
• The incidence of this condition increases with age with a female preponderance.^[17] IAA first presents in the fourth decade of life, and there is an increased incidence of 15 to 20% per decade of life. More than 90% of the patients with isolated atrial amyloidosis are in their ninth decade of life.^[15]
• Increased incidence of atrial fibrillation^[18] and other tachyarrhythmias has been noted in patients with isolated atrial amyloidosis.^[19]

• Chronic inflammation causing systemic AA amyloidosis involves the heart tissue in only 2% of the patients, causing heart failure and arrhythmias.
• The incidence of this type of cardiac amyloidosis is progressively decreasing signifying better treatment of rheumatological disorders and chronic infections.

• Autonomic imbalance, degenerative tissue changes, alterations in intercellular matrix and fibrosis increase the likelihood of developing atrial fibrillation in patients with cardiac amyloidosis. Increased amounts of fibrous tissue in the extracellular space disturbs the cell-to-cell coupling, thereby directly affecting conduction.
• In a study done by Leone et al.^[20] in patients with chronic persistent AF, amyloid deposits were found mainly in the left atrial appendages. On microscopic analysis, the deposition was predominantly along the sarcolemma of myocytes with minimal involvement of the endocardium.

• Cardiac amyloidosis, in the setting of familial or hereditary amyloidosis, can involve mutations in the following genes:^[21]
  • LYZ gene
  • Fibrinogen A alpha polypeptide gene
  • FGA gene
  • APOA1 gene
  • Lysozyme gene
  • B2M gene

• Conditions associated with AL cardiac amyloidosis include:
  • Multiple myeloma
  • Macroglobulinemia
  • Lymphomas

Cardiac amyloid deposits are most commonly seen in the myocardium, but can also be seen in the atria, pericardium, endocardium and microvasculature.

• On gross examination, the myocardium is thicker, firm and rubbery in consistency. More than half of myocardium involvement is common in the AL type of cardiac amyloidosis.
• The size of the ventricular cavity remains unchanged, however filling of the ventricles is restricted (causing restrictive cardiomyopathy) because of stiffening of the ventricular wall as a result of deposition of amyloid material.
• Pericardial effusion and valvular dysfunction is common from pericardial and endocardial involvement. Intracardiac thrombus formation is frequently seen and may result in fatal thromboembolism.^[22][23][24]

Images shown below are courtesy of Professor Peter Anderson and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

• Under light microscope, extracellular deposits of hyaline like amyloid material are evident. Resultant myocardial fibrosis restricts the movement of the ventricle, compromising complete filling of the ventricle during diastole.
• Amyloid deposits are also seen in the vasculature, particularly the microvasculature thereby sparing the large epicardial vessels. This leads to myocardial ischemia and tissue infarction.

Template:WikiDoc Sources CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

The causes of cardiac amyloidosis vary based on the cause of the systemic amyloidosis.

• The causes of cardiac amyloidosis vary based on the cause of the systemic amyloidosis.
• Enlisted below are the types of the systemic amyloidosis that are more likely to involve the heart:

• Primary amyloidosis^[1][2]
• Familial or hereditary transthyretin (TTR)-related form
• Systemic senile amyloidosis (Non-mutant TTR-related amyloidosis, Wild-type ATTR)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Raviteja Guddeti, M.B.B.S. [3]; Aarti Narayan, M.B.B.S [4]; Lakshmi Gopalakrishnan, M.B.B.S. [5]

Cardiomyopathy with congestive heart failure is the most common presentation of cardiac amyloidosis. Other common causes of cardiomyopathy should be excluded, and cardiac amyloidosis should be considered in the absence of a history of myocaridal ischemia, myocardial infarction, or presence of coronary artery disease risk factors. Cardiac amyloidosis should be included in the differential diagnoses in patients with unexplained congestive heart failure who have no history of valvular heart disease, long-standing hypertension, or myocardial ischemia.

Cardiac amyloidosis should be differentiated from the following:

• Hypertension
• Anderson-Fabry disease
• Hypertrophic cardiomyopathy
• Cardiac sarcoidosis
• Cardiac lymphoma

Cardiac Amyloidosis is Differentiated from the Above Disorders by the Presence of the following:

• Presence of low voltage on the EKG. Other causes of a low QRS voltage are shown here.
• Echo features such as:
  • Diffuse increased echogenicity
  • Valve thickening
  • Thickened interatrial septum
• Global late gadolinium enhancement (LGE) on MRI

Cardiac amyloidosis (AL and TTRwt) should be differentiated from other causes of heart failure:

Differential Diagnosis	History and Symptoms	Physical Examination	Laboratory Findings	Imaging Findings
Cardiac amyloidosis	Fatigue Dyspnea Dizziness Orthopnea Peripheral edema Weight loss due to cardiac cachexia Ascites Syncope on exertion Transthyretin (TTR) associated more common in African-Americans during sixth to seventh decade of life	Elevated jugular pressure Periorbital purpura: Often occurs with sneezing, coughing or with minor trauma. Indicates capillary involvement of AL type amyloidosis. Macroglossia Abnormal phonation Hepatomegaly Ascites may be present in the setting of heart failure Valvular involvement murmurs of mitral and tricuspid regurgitation (systolic).	Normocytic mormochromic anemia Serum free-light-chain assay positive Increased BNP, ANP and β2 microglobulin Voltage-to-mass ratio is more sensitive than EKG, 2D Echo and nuclear scanning alone	Granular or sparkling appearance of the left ventricular (LV) myocardium Increased left and right atrial volumes and reduced atrial function on cardiac MRI Atrial septal thickening Dynamic LV flow Mildly or moderately increased wall thickness in the early asymptomatic phase and severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum
Cardiac sarcoidosis	Asymptomatic conduction abnormalities Chest pain Congestive heart failure symptoms: Fatigue Syncope Dyspnea Chest pain. Irregular heartbeats Palpitations edema	Ventricular tachyarrhythmia Heart block Valvular regurgitation Pericardial effusion Constrictive pericarditis or temponade	Serum markers that have been reported as markers of sarcoidosis in general are: Serum amyloid A (SAA) Soluble interleukin-2 receptor (sIL-2R) Lysozyme Angiotensin-converting enzyme (ACE) Gycoprotein KL-6 Hypercalcemia Hypercalciuria (noncaseating granulomas secrete 1,25 vitamin D)	Radionuclide examinations Thallium‐201 scintigraphy Gallium‐67 scintigraphy Positron emission tomography Magnetic resonance imaging Samples of myocardium with sarcoidosis shows the following: Non‐caseating, multinucleated giant cell granuloma in the subendocardium Trichrome stain can show a dense band of collagen fibers, encasing aggregate of granulomas and inflammatory cells
ST Segment Elevation Myocardial Infarction	Chest pain with possible radiation to left arm and lower jaw Squeezing, crushing chest pain Sweating Nausea and vomiting	Anxious patient in pain with diaphoresis Signs of heart failure may be present Arrhythmia	ST elevation, new left bundle branch block, and Q wave on EKG Elevated cardiac biomarkers	Either complete or subtotal occlusion of an epicardial coronary artery on coronary angiography Confluent hyperenhancement extending from the endocardium
Non ST Elevation Myocardial Infarction	Crushing, left-sided substernal chest pain or pressure that radiates to the neck or left arm	Same as ST-elevation MI	ST-segment depression or T-wave inversion on EKG Elevated cardiac biomarkers
Pericarditis	Chest pain relieved by sitting up and leaning forward and worsened by lying down Fever, anxiety, difficulty breathing	Pericardial friction rub Signs of cardiac tamponade may be present	PR segment depression and electrical alternans on EKG	A flask-shaped, enlarged cardiac silhouette on CXR Pericardial thickness of more than 4 mm on MRI Pericardial effusion and cardiac chamber indentation or collapse on echo when cardiac tamponade is present
Alcoholic Cardiomyopathy	History of alcohol abuse Fatigue, weakness, anorexia, palpitations, and shortness of breath on activity Leg swelling and pedal edema	Signs of heart failure such as presence of S3 and S4 heart sounds, pedal edema, and jugular venous distension Signs of alcoholic liver disease may be present	Elevated MCV and MCHC on CBC Elevated LDH, AST, ALT, creatine kinase, gammaglutamyl transpeptidase, malic dehydrogenase, and alpha-hydroxybutyric dehydrogenase Q waves and non specific ST and T wave changes on EKG	Cardiomegaly, pulmonary congestion, and pleural effusions on CXR Left ventricular dilatation on echo

Primary amyloidosis may affect any organ in the body but the most commonly affected organs are the heart, kidneys and nerves. Involvement of these organ systems may give rise to organ failure, therefore early diagnosis is imperative for optimal treatment. Organ specific amyloidosis should be differentiated from other diseases that mimic amyloidosis and may present as organ dysfunction, specifically, nephrotic syndrome leading to renal failure, cardiac failure and polyneuropathy. The differentials include the following:

Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Nephrotic Syndrome and Renal Failure	Primary (AL) Amyloidosis	Monoclonal plasma cell proliferation Extracellular amyloid fibril deposition	Anasarca Bleeding tendency Swelling of lower limbs Frothy urine Chest pain Numbness or tingling Early satiety Joint pains Enlarged tongue Taste loss Hoarseness of voice Hair loss	Increased erythrocyte sedimentation rate (ESR) Increased alanine aminotrasnferase (ALT) and aspartate aminotrasnferase (AST) Increased cardiac troponins Increased brain natriuretic peptide (BNP) Increased blood urea nitrogen (BUN) and creatinine Proteinuria Urinary hyaline and fatty casts Hypercholesterolemia	Biopsy: Diffuse glomerular deposition of amorphous hyaline material (nodular pattern – 8 to15 nm in diameter), in mesangium (weakly staining with periodic acid-Schiff (PAS)	Melphalan–prednisone/dexamethasone Dexamethasone plus Cyclophosphamide–thalidomide Stem cell transplantation Kidney transplantation
	Diabetic Nephropathy	Hyperfiltration Constriction of efferent arteriole Microalbuminuria Mesangial proliferation	Nocturia Fatigue Pruritis Peripheral edema	Hyperglycemia (random plasma glucose ≥200 mg/dL) Proteinuria Glucosuria HbA1C ≥6.5% (48 mmol/mol).	Biopsy: PAS positive Kimmelstiel-Wilson nodules Glomerulosclerosis	ACE inhibitors Angiotensin receptor blockers Glycemic control
	Minimal Change Disease	Upper respiratory tract infection Allergy to bee sting NSAID Gold Penicillamine Ampicillin Mercury Hodgkin’s and non-Hodgkin’s lymphoma	Peripheral edema Hypertension Peripheral edema	Proteinuria Hypertension Hyperlipidemia Hypoalbuminemia Microscopic hematuria	Biopsy: Fused podocytes/effacement	Prednisone with taper ACE inhibitors Angiotensin receptor blockers Salt restriction
	Focal Segmental Glomerulosclerosis	HIV Parvovirus B19 Cytomegalovirus Heroin Interferon alpha Lithium Pamidronate/aledronate Anabolic steroids Diabetes mellitus Hypertension Obesity Cyanotic congenital heart disease Sickle cell anemia	Peripheral edema Hypertension Peripheral edema	Proteinuria Hypertension Hyperlipidemia Hypoalbuminemia Microscopic hematuria	Biopsy: Podocyte foot process effacement Capillary lumen abolished by the segmental increase in matrix	Prednisone Calcineurin inhibitors (Cyclosporin, tacrolimus) Rituximab Cyclophosphamide/chlorambucil Mycophenolate motefil
	Fabry’s Disease	Deficient alpha galactosidase A	Abdominal pain Arthralgia Febrile episodes Angiokeratomas Burning pain and tingling (peripheral neuropathy) Hypohidrosis X-linked recessive inheritance	Deficient alpha galactosidase A Increased ceramide trihexoside (globotriaosylceramide)	Alpha-galactosidase A activity GLA gene analysis for heterozygotes	Enzyme replacement therapy ACE inhibitors Gabapentin, carbamazepine Migalastat
	Light Chain Deposition Disease	Multiple myeloma Waldenström’s macroglobulinemia Monoclonal gammopathy of undetermined significance	Asymptomatic Fatigue Weight loss Dyspnea Peripheral edema	Proteinuria Portal hypertension Increased ALT, AST	Biopsy: Non-amyloid granules	Bortezomib Autologous stem cell transplantation Immunomodulatory drugs Kidney transplant
	Membranous Glomerulonephritis	Hepatitis B and C HIV Non-Hodgkin`s lymphoma Chronic lymphocytic leukemia Hodgkin`s lymphoma Solid tissue tumors Schistosomiasis Leprosy Hydatid disease Loaiasis (filaria) Quartan malaria Systemic lupus erythematosis (SLE)	Headache Edema affecting any area of the body Foamy appearance of urine Weight gain Poor appetite Nocturia Fatigue Hematuria	Proteinuria Hypertension Hyperlipidemia Hypoalbuminemia Microscopic or gross hematuria Hypoalbuminemia ANA and anti-dsDNA positivity	Biopsy: IgG and C3 deposits with thickened basement membrane with spikes and vacuolization Glomerulosclerosis	Prednisone Methylprednisolone with cyclophosphamide Tacrolimus with a six-month taper Rituximab
	Fibrillary-Immunotactoid Glomerulopathy	Idiopathic Hepatitis C	Microscopic or gross hematuria	Proteinuria Hypertension Increased blood urea nitrogen (BUN) and creatinine	Biopsy: Polycloncal IgG deposits Infiltration of glomerular structures by amorphous acellular material (nonbranching fibrils 12-24nm in diameter) Ig heavy-chain and one light-chain subclass
Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Polyneuropathy	POEMS syndrome (Demyelinating)	Monoclonal plasma cell proliferation Cytokine storm (IL-1, IL-6, IL-12, TNF alpha, VEGF)	Symmetrical, ascending chronic progressive polyneuropathy with both sensory (pin-prick and vibration) and motor disability (motor > sensory) Generalized/extermity pain Areflexia	Increased number of thrombocytes Increased number of erythrocytes Elevated cerebrospinal fluid (CSF) protein content Increased number of leukocytes High levels of IgG lambda or IgA lambda M-protein in the serum Increased number of plasma cells in the bone marrow Increased serum VEGF level Elevated levels of antitiroglobulin antibody and antithyroid peroxydase antibody	International Myeloma Working Group (IMWG) clinical and laboratory diagnostic criteria
	Metabolic Syndrome (Axonal pathology)	Diabetes mellitus	Symmetric sensorimotor distal polyneuropathy Asymmetric proximal neuropathy 3rd nerve palsy Carpel tunnel syndrome Autonomic neuropathy “Glove and stocking” type pain Muscle wasting Hammer toes Polyuria Polydipsia	Uncontrolled hyperglycemia Slowed nerve conduction Small fiber dysfunction Monofilament testing	Fasting blood sugar level greater than equal to 126 mg/dl on 2 separate occasions	Anti-diabetic therapy Gabapentin Carbamazepine Foot care
	Vitamin Deficiencies (Axonal Pathology)	Vitamin B12 deficiency (Decreased S-adenosyl methionine) Vitamin B1 deficiency	Primarily sensory deficits Vibration and proprioception affected Gait abnormalities Cognitive impairment Irritability Glossitis	Anemia (megaloblastic in case of B12 deficiency) Decreased serum Vitamin B12 levels (< 200 pg/ml) Elevated methylmalonic acid	Serum Vitamin B12 levels Methylmalonic acid levels Intrinsic factor antibodies	Vitamin B12 supplement (parenteral)
	Guillain-Barre Syndrome (Demyelinating)	Anti-ganglioside and anti-myelin antibodies Viral infections: Epstein Barr virus HIV Cytomegalovirus Varicella Zoster virus Bacterial infections: Campylobacter infection Mycoplasma pneumoniae	Rapid onset and quick progression Progression stops after 2-3 weeks Bilateral ascending paraesthesias and paralysis (generalized) Weakness Ataxia Areflexia No fever 4 sub-types: Acute inflammatory demyelinating polyneuropathy Acute motor axonal neuropathy Acute motor and sensory axonal neuropathy Miller Fisher syndrome	Delayed F waves	Clinical diagnostic criteria (progressive weakness of more than two limbs, areflexia, and progression for no more than four weeks)	Intravenous immunoglobulins Plasma exchange Respiratory support DVT/PE prevention
	Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (Mixed axonal and demyelinatiing)	Abnormal immune response (both IgG based humoral and T-Cell mediated) response to unknown antigen (possible culprits include myelin proteins P0, P2 and PMP22)	Slow onset and gradual progression Relapsing and remitting course Symmetrical proximal and distal motor and sensory weakness (legs>arms) Foot drop Numbness, tingling and pain Areflexia	Elevated CSF protein (oligoclonal bands with normal WBCs) Slowed motor nerve conduction velocities Prolonged distal motor latencies (period between F wave and initial stimulation) Delayed F wave latencies (recorded from the feet, hence called “F” waves) MRI contrast enhancement and enlargement of T2 spinal segments	EFNS/PNS criteria Koski criteria	Corticosteroids Intravenous immunoglobulin (IVIG) Immunosupressants (Alemtuzemab Azathioprine Cyclophosphamide Cyclosporin Etanercept Interferon-alpha)
	Multifocal Motor Neuropathy	Abnormal immune response (Anti ganglioside GM-1 IgM antibodies)	Progressive, asymmetric, distal and upper limb predominant weakness No significant sensory abnormalities Areflexia	Elevated CSF protein	Clinical criteria (EFNS/PNS): Slowly progressive or step-wise progressive, focal, asymmetric limb weakness; i.e., motor involvement in the motor nerve distribution of at least two nerves for > 1 month. No objective sensory abnormalities except for minor vibration sense abnormalities in the lower limbs	Intravenous immunoglobulins Cyclophosphamide Rituximab
Organ System Involvement	Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
Organomegaly (Hepatosplenomegaly and Lymphadenopathy)	Malaria	Plasmodium falciparum P. ovale P. malariae P. knowlesi	Tertian (vivax, ovale, falciparum), quartan (malariae), quotidian fever (knowlesi) Vector is female Anopheles mosquito Hepatosplenomegaly Lymphadenopathy Jaundice Icterus Tachycardia Tachypnea Productive cough Hematuria Altered mental status	Microcytic anemia Thick and thin blood films (Giemsa staining) Rapid diagnostic test (antigen detection Polymerase chain reaction (PCR) Enzyme linked immunosorbent assay (ELISA)	Thick and thin films	Non-falciparum species: Chloroquine (in susceptible) Artemisinin plus mefloquin or lumefantrine (in chloroquine resistant) Falciparum species: Chloroquine (in susceptible) Artemether plus lumefantrine (in chloroquin resistant) OR Artesunate plus mefloquin OR Artesunate plus sulfadoxine-pyrimethamine Atovaquone plus proguanil
	Kala-azar	Leshmania donovani L. infantum L. chagasi	Fever Vector is sandfly Hepatosplenomegaly Lymphadenopathy Hyperpigmentation	Anemia Direct agglutination test (DAT) rk39 dipstick ELISA	Splenic aspiration	Liposomal amphotericin B Sodium stibogluconate Pentamidine
	Infective Hepatitis	Hepatitis A virus (HAV) HBV HCV HDV (co-infection with HBV) HEV	Fever Transmitted via fecal-oral route (HAV, HBV, HDV, HEV), infected sera (HCV), sexual contact with infected individuals Hepatosplenomegaly (may become shrunken in cases of cirrhosis due to chronic infection) Lymphadenopathy Jaundice Palmar erythema Spider angiomata Gynecomastia Arthritis-dermatitis syndrome	Antigen and antibody detection Total and direct bilirubin (increased) Severe disease is often associated with persistent bilirubin levels >340 mmol/L ALT and AST (increased) Alkaline phosphatase (normal or mildly elevated) Prothrombin time (prolonged from synthetic defect, caused by hepatocellular necrosis) Total protein (decreased) Globulin (mildly elevated) Initial lymphopenia and neutropenia, followed by relative lymphocytosis Low hemoglobin	Antigen and antibody detection	Interferon (IFN) Nucleoside analogs Nucleotide analogs
	Chronic Myelogenous Leukemia (CML)	BCR/ABL gene fusion product due to translocation mutation t(9;22)(q34;q11)	Fever Weight loss Hepatosplenomegaly Lymphadenopathy Bruises Petechiae Ulcers Vesicles Malaise Early satiety	Anemia Leukocytosis (median of 100,000/µL) with a left shift Thrombocytosis Blasts usually <2% Absolute basophilia Absolute eosinophilia Monocytosis Thrombocytosis Thrombocytopenia suggests an alternative diagnosis or the presence of advanced stage Elevated uric acid Elevated histamine levels	Fluoroscent insitu hybridization (FISH)	Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Cytarabine HDAC (high-dose cytarabine) Hydroxyurea Busulfan Busulfex Stem cell transplantation
	Lymphoma	Various causes based on type: Hodgkin’s Non-Hodgkin’s	Fever Weight loss Lymphadenopathy Hepatosplenomegaly Night sweats, constant fatigue Purplish scaly rash in cases of cutaneous lymphoma	Elevated ESR Increased CRP Increased LDH Anemia of chronic disease	Lymph node biopsy
	Primary (AL) Amyloidosis	Aggregation and deposition of immunoglobulin light chains that are usually produced by plasma cell clones	Nephrotic syndrome (peripheral edema) Restrictive cardiomyopathy (fatigue, dyspnea, syncope) Peripheral neuropathy (numbness, tingling) Hepatomegaly with elevated liver enzymes Macroglossia Purpura Bleeding diathesis	Typical green birefringence under polarized light after Congo red staining (appears in red under normal light)	Congo red staining	Melphalan-prednisone/dexamethasone Dexamethasone plus Cyclophosphamide-thalidomide Stem cell transplantation
	Gaucher’s Disease	GBA gene mutation Aberrant metabolism of glucocerebroside (lipid)	Hydrops fetalis Dry, scaly skin (ichthyosis) or other skin abnormalities Hepatosplenomegaly Distinctive facial features Neurological problems Gall stones Growth retardation	Hypocholesterolemia Splenic nodules Cytopenias (especially thrombocytopenia) Increased ferritin levels Increased tartarate resistant acid phosphatase (TRAP) levels	Enzyme assay for glucocerebrosidase DNA analysis for GBA mutation	Enzyme replacement Splenectomy Blood transfusion
Organ System Involvement	Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
Cardiac Failure	Cardiac amyloidosis (AL and ATTRwt)	Monoclonal plasma cell proliferation Extracellular amyloid fibril deposition	Fatigue Dyspnea Dizziness Orthopnea Peripheral edema Weight loss due to cardiac cachexia Ascites Syncope on exertion Transthyretin (ATTRwt) associated more common in African-Americans during sixth to seventh decade of life	Normocytic mormochromic anemia Serum free-light-chain assay positive Increased BNP, ANP and β2 microglobulin Voltage-to-mass ratio is more sensitive than EKG, 2D Echo and nuclear scanning alone	Biopsy: Diffuse deposition of amorphous hyaline material (nodular pattern – 8 to15 nm in diameter), in mesangium (weakly staining with periodic acid-Schiff (PAS)	Supportive care Tafamidis Melphalan-prednisone/dexamethasone Dexamethasone plus Cyclophosphamide-thalidomide
	Cardiac sarcoidosis	The causes are not fully known. Over-reaction of the immune system after exposure to an infectious agent (bacteria or viruses), chemical, or allergen. Excessive inflammation and the clustering of white blood cells.	Asymptomatic conduction abnormalities Chest pain Congestive heart failure symptoms: Fatigue Syncope Dyspnea Chest pain. Irregular heartbeats Palpitations edema	Serum markers that have been reported as markers of sarcoidosis in general are: Serum amyloid A (SAA) Soluble interleukin-2 receptor (sIL-2R) Lysozyme Angiotensin-converting enzyme (ACE) Gycoprotein KL-6 Hypercalcemia Hypercalciuria (noncaseating granulomas secrete 1,25 vitamin D)	Biopsy: samples of myocardium with sarcoidosis shows the following: Non‐caseating, multinucleated giant cell granuloma in the subendocardium Trichrome stain can show a dense band of collagen fibers, encasing aggregate of granulomas and inflammatory cells	Corticosteroid treatment Antiarrhythmic treatment Pacemakers and defibrillators Cardiac transplantation
	Hypertrophic obstructive cardiomyopathy	Mutation in sarcomeric protein (beta myosin heavy chain and myosin binding protein C) Autosomal dominant inheritance	Chest pain (also known as angina) Dizziness Dyspnea (shortness of breath) which is due to increased stiffness of the hypertrophied left ventricle Exercise intolerance Fainting, presyncope or frank syncope, especially during exercise Fatigue) Light-headedness Shortness of breath Reduced activity tolerance Shortness of breath Sudden cardiac death	Increased BNP Increased creatine kinase	Echocardiography: Left ventricular asymmetric hypertrophy Parasternal long axis shows relationship of the septal hypertrophy and the outflow tract Left ventricular diastolic dysfunction SAM (systolic anterior motion) of the mitral leaflet Mid-systolic closure of the aortic valve Late peaking, high velocity flow in the outflow tract Variability of obstruction with maneuvers (exercise, amyl nitrate inhalation, and post-PVC beats)	Beta blockers Calcium channel blockers Septal myectomy
	Alcoholic cardiomyopathy	Alcohol consumption	Exercise intolerance Fainting, presyncope or frank syncope, especially during exercise Fatigue) Light-headedness Shortness of breath Reduced activity tolerance Shortness of breath	Elevated mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCHC) Mild thrombocytopenia Elevated LDH, AST, ALT, creatine kinase, malic dehydrogenase and alpha-hydroxybutyric dehydrogenase Elevated gammaglutamyl transpeptidase Serum concentrations of magnesium and zinc may be reduced	Endomyocardial biopsy	Restriction of dietary salt ACE inhibitors or angiotensin II receptor blockers Beta blockers Diuretics Digoxin
	ST-elevation myocardial infarction	Myocardial ischemia Atherosclerosis	Exercise intolerance Fainting, presyncope or frank syncope, especially during exercise Fatigue) Light-headedness Shortness of breath Reduced activity tolerance Shortness of breath	Increased cardiac troponins Increased LDH Leukocytosis ST segment elevation on EKG	Elevation of cardiac troponins	Percutaneous coronary intervention or coronary artery bypass graft Aspirin Clopidogrel Beta blockers Diuretics
	Pericarditis	HIV Dressler’s syndrome Tuberculosis Uremia Radiation Malignancy	Chest pain (relieved by sitting up and leaning forward and is worsened by lying down) Cough (either dry or productive) Fever Fatigue Anxiety Breathlessness	Creatine kinase: Acute pericarditis may be associated with a modest increase in serum creatine kinase-MB (CK-MB) depending upon the extent of involvement of the underlying myocardium. Increased cardiac troponin-I (cTnI) Increased LDH Increased serum myoglobin Increased SGOT (AST)	Two of the following four criteria: Pericarditic chest pain Pericardial rub New widespread ST-segment elevation or PR depression New or worsening pericardial effusion. Supporting findings can include elevation of inflammatory markers (C-reactive protein, ESR, white blood cell count), and evidence of pericardial inflammation on imaging(CT scan and cardiac MRI).
Organ System Involvement	Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
Plasma Cell Dyscrasias	Multiple myeloma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Diffuse bone pain and tenderness with osteolytic lesions Renal failure Hypercalcemia Anemia	Anemia Thrombocytopenia Leukopenia Decreased albumin (reversed albumin:globulin ratio) Increased serum creatinine, urea Hypercalcemia Elevated ESR Normal-low alkaline phosphatase RBC rouleaux formation Bence-Jones proteins in urine	Clonal plasma cells on bone marrow exam greater than equal to 10% AND Any one of the following: Evidence of end-organ damage Hypercalcemia (>11 mg/dl) Renal insufficiency Anemia (Hb < 10 mg/dl) Bone lesions Greater than 1 lesions on MRI	Induction chemotherapy with bortezomib, lenalidomide, and dexamethasone Bisphosphonates RANK ligand inhibitors (denosumab) Autologous stem cell transplantation
	Monoclonal gammopathy of undetermined significance (MGUS)	Chromosomal aberrations or other genetic insults Clonal plasma cell proliferation	Asymptomatic	Serum M protein of <3 g/L Fewer than 10% plasma cells in the bone marrow No evidence of bone or organ damage	Serum M protein (IgG or IgA) <3g/dl AND Clonal bone marrow plasma cells < 10% AND No end-organ damage	Observation
	Asymptomatic Plasma Cell Myeloma (Smoldering and Indolent plasma cell myeloma)	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Asymptomatic	Serum M protein of greater than equal to 3 g/L Greater than 10% plasma cells in the bone marrow No evidence of bone or organ damage	Serum M protein (IgG or IgA greater than equal to 3 g/dl OR Urinary M protein greater than equal to 500 mg/24 h AND/OR Clonal bone marrow plasma cells 10-60% AND No end-organ damage	Observation
	Plasmacytoma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells	Solitary bone plasmacytoma (bone) Extramedullary plasmacytoma (soft tissues) Clinical manifestations related to tumor mass and compression symptoms	On biopsy: Solitary infiltrate of clonal plasma cells in bone (SBP) or soft tissue (EMP). No evidence of infiltration by clonal plasma cells. Negative skeletal survey plus MRI/CT spine and pelvis except for the solitary lesion. Lack of hypercalcemia, renal insuffieciency, anemia, multiple bone lesions which would suggest MM	Diagnosis of exclusion	Radiotherapy
Skin Changes	Scurvy	Vitamin C deficiency Malabsorption Hemodialysis	Gum disease such as gum bleeding Loose teeth Easy bruising Impaired immune response Impaired wound healing			Vitamin C supplementation Citrus fruits

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]Sabawoon Mirwais, M.B.B.S, M.D.[4]

The incidence rate increased from 18 to 55 per 100,000 person-years from 2000 to 2012. The prevalence rate increased from 8 to 17 per 100 000 person-years from 2000 to 2012. Cardiac amyloidosis commonly presents in adults more than 40 years old. The incidence and prevalence of cardiac amyloidosis have increased among blacks from 2000 to 2012. Over the years, both incidence and prevalence of cardiac amyloidosis have increased among men.

• The incidence rate increased from 18 to 55 per 100,000 person-years from 2000 to 2012.^[1]
• There were 4746 incident cases of cardiac amyloidosis in the US in 2012.^[2]

• The prevalence rate increased from 8 to 17 per 100 000 person-years from 2000 to 2012.^[3]
• There were 15,737 prevalent cases of cardiac amyloidosis in 2012.

• In the United States, it has been estimated that there are 1.3 million gene carries and that there are approximately 150,000 carriers over the age of 60 years.
• Cardiac amyloidosis commonly presents in adults more than 40 years old.
• Senile type of cardiac amyloidosis typically presents after 60 years of age, most commonly after 70 years of age.
• Various mutations of proteins involved in amyloid deposition may present anytime between 30 to 70 years of age.
• The incidence and prevalence of cardiac amyloisosis have significantly increased among the elderly after 2006.^[4]

• 3-4% of African-Americans carry the most common mutation that causes the substitution of Ile for Val at position 122 and is known to contribute to the incidence of familial amyloidotic cardiomyopathy.^[5][6]
• After the age of 60, isolated cardiac amyloidosis is four times more common among blacks than whites in the United States.^[7]
• The incidence and prevalence of cardiac amyloidosis have increased among blacks from 2000 to 2012.^[8]

• Over the years, both incidence and prevalence of cardiac amyloidosis have increased among men.^[9]

Template:WikiDoc Sources CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The most common risk factor for the development of cardiac amyloidosis is the presence of an underlying plasma cell dyscrasia.

The most common risk factor for the development of cardiac amyloidosis is the presence of an underlying plasma cell dyscrasia.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

There is insufficient evidence to recommend routine screening for cardiac amyloidosis.

There is insufficient evidence to recommend routine screening for cardiac amyloidosis.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]; Cafer Zorkun, M.D., Ph.D. [4]; Lakshmi Gopalakrishnan, M.B.B.S. [5]

The presence or absence of cardiac involvement with amyloid is the most important prognostic factor. Untreated cardiac amyloidosis is associated with a very poor prognosis and a high mortality rate. The most common cardiac complications include heart failure, sudden cardiac death due to electromechanical dissociation and pericardial effusion.

• Untreated cardiac amyloidosis is associated with high rate of cardiac complications and eventually death.
• Cardiac involvement in AL amyloidosis is associated with a higher mortality rate compared with that in senile amyloidosis and familial forms of amyloidosis.^[1]
• Also, heart failure in AL type amyloidosis is more difficult to treat as compared with that associated with TTR type amyloid.

The following are the complications of cardiac amyloidosis:

• Congestive heart failure^[2][3]
• Sudden cardiac death (SCD)^[4]
  • Largely due to electromechanical dissociation; unlike other disease states where sudden cardiac death is predominantly due to other causes such as ventricular arrhythmia
• Myocardial infarction^[5]
• Pericardial effusion^[6]
• Cardiac tamponade^[7]
  • It should be noted, however, that the classic echocardiographic signs of cardiac tamponade, such as right atrial indentation and right ventricular compression, are not seen in cardiac tamponade associated with cardiac amyloidosis due to the stiffness of the atrial and ventricular walls. Therefore a high degree of suspicion should be maintained in patients with heart failure and a mild to moderate pericardial effusion.^[6]
• Valvular heart diseases, with aortic stenosis being the most common followed by mitral regurgitation
• Atrial fibrillation^[8]
• Tachyarrhythmias^[9]
• Ventricular arrhythmias^[10]
• Sick sinus syndrome (occasionally)
• Heart blocks and other conduction defects
  • Higher degree blocks are unusual in cardiac amyloidosis associated with AL type amyloidosis, but in the TTR type, progressive conduction system disease is common and requires pacemaker implantation. Frequently, the electrophysiologic function appears to be abnormal in the His-Purkinje system. Prolonged infra-His conduction time is an independent predictor of sudden death in these patients. ^[11]
• Syncope or presyncope^[5]
• Increased sensitivity to digoxin with the potential for digoxin toxicity and digoxin related arrhythmias
  • The amyloid protein tends to bind the digoxin and increase its local concentration in the conduction system for instance.
• Ascites (fluid accumulation in the abdomen)
• Stroke and claudication due to intracardiac thrombus causing thromboembolism.^[12][13]
  • Risk factors include:
    • Atrial fibrillation
    • Atrial dysfunction due to infiltration of the atria by amyloid
    • Left ventricular diastolic dysfunction
    • Increased right ventricular wall thickness
    • Tachycardia

• Cardiac amyloidosis is a chronic and progressive condition.
• A cardiologist may estimate the prognosis according to the thickness of the left ventricle and to the degree of restriction in the heart (diastolic dysfunction).
• The extent of cardiac involvement is the most important predictor of survival in patients with AL amyloidosis.^[1]

• Studies have shown that cardiac troponin T and N-terminal proBNP are powerful prognostic indicators in AL amyloidosis.
• Based on the combined levels of both the indicators, a staging system has been developed for risk stratification of patients with AL amyloidosis.
• Two prognostic models for risk stratification were designed using threshold values for troponins and NT-proBNP.
• The threshold values used for the markers were: NT-proBNP < 332 ng/L, cTnT < 0.035 μg/L, and cTnI <0.1 μg/L.^[14][15]

Stage	NT-proBNP	cTnT/cTnI	Median Survival (months)
Stage I	Low	Low	26.4 – 27.2
Stage II	Low or Elevated	Elevated or Low	10.5 – 11.1
Stage III	Elevated	Elevated	3.5 – 4.1

Updated Staging System

• In 2009 another staging system was proposed which incorporates serum free light chain (serum FLC) levels into the Mayo staging system.
• The threshold values used for the table below are:
  • NT-proBNP <332 ng/L
  • cTnT <0.035 μ<g/L
  • Serum FLC <500mg/L

Stage	NT-proBNP	cTnT	Serum FLC
Stage I	Normal	Normal	Low
Stage II	High	Normal	Low
Stage III	High	Normal	High
Stage IV	High	High	High

Mortality increased as the stage increased.

Prognosis Based on Pathologic Findings

The presence of nodular deposits, thick perimyocytic layers of amyloid, and small myocyte diameters on endomyocardial biopsy are associated with a worse prognosis. ^[16]

Template:WikiDoc Sources CME Category::Cardiology