Familial amyloidosis differential diagnosis

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

Overview

Familial 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.

Differentiating Familial Amyloidosis from other Diseases

Familial 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.


Organ System Involvement Differential Diagnosis Causes Clinical Features Laboratory Findings Gold Standard Test Therapy
Nephrotic Syndrome and Real Failure Familial Amyloidosis
  • Genetic mutation
  • Parasthesia
  • Muscle weakness
  • Sexual problems
  • Constipation/ diarrhea
  • Urination problems
  • Weakness
  • Fatigue
  • Edema
  • Palpitation
  • Dizziness
  • ncreased:I
  • Biopsy:
    • Apple green birefringence of the tissue sample under polarized light with Congo red stain.
  • Liver transplant for TTR amyloidosis
  • Organ specific transplant
  • Tafamidis
  • Patisiran and Inoteresen
  • Diflunisal
  • Epigallocathechin-3-gallate
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
Light Chain Deposition Disease
  • Biopsy:
    • Non-amyloid granules
Membranous Glomerulonephritis
Fibrillary-Immunotactoid Glomerulopathy
  • 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


  • 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
  • Alcohol consumption


ST-elevation myocardial infarction
Pericarditis



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


References



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