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Hyperproteinemia

  • HYPERPROTEINEMIA: The reason to work up such patient is to diagnose Monoclonal BM Cell Proliferation (MGUS to MM)
    • Differential Diagnosis of Hyperproteinemia
    • Case 29-2011: A 66-Year-Old Woman with Cardiac and Renal Failure
      • Polyclonal Gammopathy
      • MGUS: Not very Significant M protein elevation AND not very significant Plasma Cells in BM with negative CRAB - < 3 g /dL M protein (IgG, IgA, or IgD), AND < 10% BM Plasma Cells
        Case 23-2010: A 49-Year-Old Man with Erythrocytosis, Perinephric Fluid Collections, and Renal Failure
      • MGRS
      • Igb deposition disease: Amyloidosis (see below)
      • Smoldering (Asymptomatic) Myeloma: Significant M protein and / or significant Plasma Cells in BM with negative CRAB - ≥ 3 g /dL M protein, AND/OR ≥  10% BM Plasma Cells; 73% risk of progression to MM at 15 yrs
        • Note: In the absence of end organ damage, amount of M protein needs to higher than certain limits (which is not needed if end organ damage is present)
      • Solitary Plasmacytoma
      • MM: Mostly Secrete M protein or Free light Chain Alone (16%) or Rarely No Immunoglobulin (Ig
        • M-Protein: (Consist of an intact Ig composed of Heavy Chain (IgG, IgA, IgD) and a kappa or lambda light chain
          • Misc
        • Diagnosis: 3 ways to diagnose MM if End-Organ Damage is present Lancet 2014
          • 1. M Protein (any level) with ≥  10% BM Plasma Cells 
          • 2. M protein more than or equal to 3 g/100 mL even if less than 10% BM Plasma Cells 
          • 3. Non-secretary MM:  if greater than 30% BM Plasma Cells or detection of Plasmacytoma on BM biopsy  
            • CRAB Criteria)
              • C Hypercalcemia (28%) (>10.5 mg / dL)
              • R Renal Failure (48%) (S-Cr: > 2 mg/dL)
              • Anemia (73%) (<10g/dL or 2 g/dL below baseline) Leukopenia (20%) Thrombocytopenia (5%)
              • Bony Lytic Lesions (58% of newly diagnosed pt): Bone Pain, Back Pain, Spinal Cord Compression, Vertebral Body Compression Fractures
              • Hyper-viscosity / Recurrent Bacterial Infections / AL
      • Waldenstrom Macroglobulinemia 
        • Diagnosis (NEJM 2006)
          • BM Plasma Cells < 10 % AND 
          • M protein < 3 g / dL AND
          • Clinical Symptoms: Present 
            • Fatigue
            • Weight loss
            • Purpura
            • Nephrotic Syndrome 
            • CHF
            • Peripheral Neuropahty
            • Orthostatic Hypotension
            • Massive Hepatomegaly

      • POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M Protein, and Skin Changes)
        • Rare Paraneoplastic Syndrome associated with Monoclonal Plasma Cell Dyscrasia
        • VEGF induced neovascularization and permeability and IL-12
        • Sclerotic Bone Lesion or Castleman Diseases (Lymphoproliferative Disorder) is present in all cases 
        • DDx: CIDP (POEMS has uniform demyelination, CIDP has multifocal demyelination with more severe in proximal and distal nerve)
    • Diagnostic Tests (JAMA 2014)
      • SPEP ($ 21 per Medicare reimbursement)
      • Serum IFA ($ 31 per Medicare reimbursement)
      • Free Light Chain (FLC) Assay ($31 per Medicare reimbursement)
      • Additional Tests include
        • 24 UPEP and Immunofixation (is more cumbersome)

    • What clinical manifestation can M protein lead to 
      • Igb light chain Amyliodosis Case 2-2016:
      • Monoclonal Igb deposition disease
      • Cryoglobulinemia
      • Peripheral Neuropathy
      • MPGN
      • Osteoporosis
    • When to consider testing for M- protein or FLC  (ref: MKSAP 16)
      • Do not do screening
      • Can be done in following situations
        • Incidently discovered hyperproteinemia
        • Unexplained CRA (of CRAB criteria of MM)
        • Unexplained incidentally discovered LYTIC bone lesion
        • Unexplained Peripheral Neuropathy 
      • What to order
        • SPEP, FLC, serum IFA (as a first line order)
        • If these are negative, order 24 UPEP and 24 Urine IFA
      • Once M protein is detected following tests need to be ordered (if not already performed)
        • CBC; CMP (serum calcium, albumin, and creatinine)
        • UA 
        • Protein electrophoresis and immunofixation performed on serum and a 24-hour urine collection; 
        • Quantitative immunoglobulin measurement (IgG, IgM, IgA); 
        • Serum free light-chain testing; and 
        • A skeletal survey
        • CT scans to assess lymphadenopathy in the thorax and abdomen (if IgM MGUS for Waldenström macroglobulinemia or other B-cell non-Hodgkin lymphoma). 
      • Bone marrow examination should be performed in patients with 
          • findings suspicious for a plasma cell dyscrasia requiring treatment i.e higher risk of progression is there in following scenario, (JAMA 2014)
            • a non-IgG M protein, 
            • an M protein level of 1.5 g/dL or more, or 
            • an abnormal serum free light-chain ratio or 
            • any concern for MM or amyloidosis 
          • What to order in BM examination:
            • BM Core Biopsy: Cell count including Plasma Cells
            • In situ hybridization of mRNA and Flow Cytometry for identification of type of plasma cells (which type of Igb producing)
            • Cytogenetics
      • Follow-up testing for patients with MGUS 
        • Vary depending on the individual circumstances 
        • CBC, CMP, SPEP and S-IFA, 24 hr Urine UEPE, 24 hr Urine- IFA,   S-FLC
      • Some Clinical Situations:
        1. M Protein (< 1.5 g /dL M protein): needs full work up to evaluate for CRAB and BM Bxp only if CRAB is abnormal (can be ordered by PCP) or non-IgG M protein or abnormal FLC ration (higher risk of progression in these situations)
          1. Negative CRAB: MGUS (BM Bxp not done)
          2. BM Bxp < 10% BM Plasma Cells; Positive R: MGRS
          3. BM Bxp < 10% BM Plasma Cells; 
            1. Positive Single Lytic Bone Lesion: Solitory Plasmacytoma
            2. Postive Multiple Lytic Lesions: ?????
          4. BM Bxp < 10% BM Plasma Cells; Positive CA: look for other cause of C and A i.e Primary Amyloidosis (NEJM 2006)
          5. BM Bxp > 10% BM Plasma Cells; Negative CRAB: Smoldering Myeloma
          6. BM Bxp > 10% BM Plasma Cells; Positive CRAB: MM
        2. M Protein (1.5 or more ): needs full work up to evaluate for CRAB and BM Bxp - so initiate the work up as above and refer to Heme/Onc for Bxp
          1. BM Bxp < 10% BM Plasma Cells; Negative CRAB: MGUS if M protein < 3, Smoldering Myeloma if M protein > 3
          2. BM Bxp > 10% BM Plasma Cells; Negative CRAB: Smoldering Myeloma irrespective of level of M protein
          3. BM Bxp < 10% BM Plasma Cells; Positive R: MGRS
          4. BM Bxp < 10% BM Plasma Cells; Positive CAB: 
            1. Not MM as Plasma Cells has to be > 10 %; Look for other cause of CAB i.e Primary Amyloidosis (NEJM 2006)
          5. BM Bxp > 10% BM Plasma Cells; Positive CRAB: MM
        3. M protein and CKD not explained by anything else
          1. Needs full work up including BM Bxp
        4. Abnormal FLC Ratio
          1. Needs full work up including BM Bxp
    • Further reading in IMREFERENCE:
    • References
  • Some Facts
    • Peripheral Neuropathy: Seen in MM complicated by Amyloidosis or in POEMS 
MM and Related Disorder References



AMYLOIDOSIS
  • Type: 
    • AL
    • TTR
    • Wild Type or Age-related
  • Clinical manifestation: The Great Imitator
    • CV / Resp: 
    • Neuro:
      • Autonomic Neuropathy (postural hypotension, diarrhea)
      • Syncope
    • Renal:
      • Nephrotic Syndrome, Associated sudden increase in LDL

    • Soft tissue infiltration 
      • Macroglossia, Carple Tunnel Syndrome,
      • Bleeding (Cutaneous, Periorbital purpora  < 10 %
      • Case 2-2016
    • Resp:
      • Pleural Effusion
    • GI:
      • Malnutrition / Cachexia
  • Diagnosis: 
    • Diagnosis / Lab evaluation :
      • First look for monoclonal protein
      • Once monoclonal protein is seen, to answer the question does this patient have an Amyliodosis, tissue diagnosis is needed
        • Fat pad aspiration, 
        • BM Biopsy and aspiration
          • BM Biopsy: The kappa light-chain restriction and clustering of plasma cells are suggestive of plasma-cell myeloma 
          • BM aspirate: Flow cytometry for CD45−, CD138, and CD38+ plasma cells shows a dominant population of CD56+, CD19−, and CD27dim plasma cells with monotypic kappa light-chain restriction
        • Renal Biopsy. If all negative then in AL-type endomyocardial biopsy is done. 
          • TTR type: We may have to do endomyocardial biopsy upfront
        • Identify the nature of Amyloid (3 major subtypes in Cardiology, but there are > 20 types of Amyloid in total)
        • Congo red staining of the specimen and examination with crossed-polarized light microscopy has high specificity for amyloid. Under crossed-polarized light, the stain shows green birefringence  Case 2-2016
    • Imaging 
      • Caridiac Amyloid
        • EKG abnormalities are very common, eg. Low Voltage EKG in the limb leads despite myocardial thickening (usually in AL type). In Other causes of myocardial thickening, such as hyper- trophy due to hypertension, you would expect to find high voltage in the limb leads on ECG 
        • ECHO 
          • Nondilated left ventricular thickening, right ventricular thickening, prominent valves, and increased echogenicity of the myocardium (with a granular sparkling appearance) is seen. 
          • A restrictive pattern on Doppler echocar- diography and progression of diastolic dysfunc- tion are seen with advanced amyloid heart disease 
        • Cardiac MRI (with contrast is needed):
          • Pattern of contrast enhancement is very characteristic. 
          • Delayed enhancement is not very specific
          • Nulling is very specific (but absence of it does not rule out Amyloid)
  • Treatment (Many present now)
  • Key learning points: 
    • Patients presenting with multiorgan derangement should be screened for amyloidosis. The diagnosis is much more challenging when the patient presents with single-organ involvement as it may mimic more common diseases. A high index of suspicion is often required. Screening should be performed in patients with unexplained heart failure, neuropathy, and nephrotic syndrome. Clues that raise suspicion include low voltage on ECG, severe hypotension without antihypertensive medications, and the presence of neuropathy in combination with other organ involvement. Easy bruisability, especially “raccoon eyes” after procedures or minor trauma, is another hint. Major bleeding can result from factor X and vitamin K-dependent clotting factor deficiency but is much less common.
    • How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing Blood 2012
  • Case Discussion Please read Case 2  of :
  • References:


HYPERVISCOSITY SYNDROME

  • DDx:
  • Waldenstrom Macroglobulinemia (Pentameric Structure of IgM)
  • IgA MM (can also occur in this subtype)

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