Wild-type (senile) amyloidosis differential diagnosis

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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]

Differentiating Wild-type (Senile) Amyloidosis from other Diseases

Differentials Based on Cardiac Involvement (Heart Failure)

Wild-type (senile) amyloidosis 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

Differentials Based on Presentation As a Multi-Organ System Dysfunction Disorder

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).