Primary amyloidosis differential diagnosis

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

Differentiating Primary amyloidosis from Other Diseases

Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Nephrotic Syndrome and Real Failure	Primary (AL) Amyloidosis	Monoclonal plasma cell proliferation Extracellular amyloid fibril deposition			Biopsy: Diffuse glomerular deposition of amorphous hyaline material (nodular pattern), in mesangium (weakly staining with periodic acid-Schiff (PAS)
	Diabetic Nephropathy
	Minimal Change Disease
	Focal Segmental Glomerulosclerosis
	Fabry's Disease
	Light Chain Deposition Disease
	Membranous Glomerulonephritis
	Fibrillary-Immunotactoid Glomerulopathy
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
		I
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