Primary amyloidosis differential diagnosis

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

Overview

  • 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
Diabetic Nephropathy
Minimal Change Disease
Focal Segmental Glomerulosclerosis
  • Biopsy:
    • Podocyte foot process effacement
    • Capillary lumen abolished by the segmental increase in matrix
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
  • Lymphoproliferative
  • 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)
Metabolic Syndrome (Axonal pathology)
Vitamin Deficiencies (Axonal Pathology)
Guillain-Barre Syndrome (Demyelinating)
  • Delayed F waves
  • Clinical diagnostic criteria (progressive weakness of more than two limbs, areflexia, and progression for no more than four weeks)
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (Mixed axonal and demyelinatiing)
  • EFNS/PNS criteria
  • Koski criteria
Multifocal Motor Neuropathy
  • Progressive, asymmetric, distal and upper limb predominant weakness
  • No significant sensory abnormalities
  • Areflexia
  • 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
Organ System Involvement Differential Diagnosis Causes Features Laboratory Findings Gold Standard Test Therapy
Organomegaly (Hepatosplenomegaly and Lymphadenopathy) Malaria
Kala-azar
Infective Hepatitis
Chronic Myelogenous Leukemia (CML)
Lymphoma
Primary (AL) Amyloidosis
  • 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
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
Hypertrophic obstructive cardiomyopathy
  • Mutation in sarcomeric protein (beta myosin heavy chain and myosin binding protein C)
  • Autosomal dominant inheritance


  • 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)
Alcoholic cardiomyopathy
ST-elevation myocardial infarction
Pericarditis
Non-ST-segment elevation myocardial infarction
Organ System Involvement Differential Diagnosis Causes Features Laboratory Findings Gold Standard Test Therapy
Plasma Cell Dyscrasias Multiple myeloma
  • 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
Monoclonal gammopathy of undetermined significance (MGUS)
  • 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)

  • 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
  • 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