Introduction:

• It is a condition in which level of gamma-globulin is increased
• Detection of one or several monoclonal bands within polyclonal background is not unusual. Small bands frequently disappear in such cases. 
• If clonal plasma proliferative disorder is suspected, immunofixation electrophoresis should be performed.

Causes

• Polyclonal gammopathy (IL6 and IL10 are usually involved. If they cause symptomatic hypervisosityplasmapheresis with/without glucocorticoids are indicated)
  • Liver disease- Autoimmune hepatitis, primary biliary cirrhosis, primary sclerosingcholangitis, viral hepatitis, Alcoholic liver disease. Alpha 1 antitrypsin  deficiency, hemochromatosis
  • Connective tissue disorders: Sjogren syndrome, SLE, ankylosingspondylitis, rheumatoid arthritis.
  • Hyper immunoglobinemia D
  • Tumor necrosis factor receptor-1 associated periodic syndrome.
  • Infections- HIV, subacute bacterial endocarditis, tuberculosis, perinephric abscess, Lyme disease, variety of parasitic infections.
  • Hematological disorders- CLL, large granular lymphocytic leukemia, hairy cell leukemia, angioimmunoblastic T-cell lymphoma, MDS, CMML, AML.
  • Solid tumors: Ovarian carcinoma, hepatocellular carcinoma, carcinoma colon.
  • Others- Asbestos exposure, hypersensitivity pneumonitis, idiopathic interstitial pneumonia.
• Monoclonal gammopathy:
  • Plasma cell and related disorders- MGUS, Solitary plasmacytoma, Multiple myeloma, Waldenstrommacroglobulinemia, Primary amyloidosis
  • Other hematological disorders- Acquired vWD, Goucher disease, Pernicious anemia, Pure red cell aplasia, MPN, MDS, NHL, HL, Castleman's diseaseetc
  • Connective tissue disorders- SLE, Inclusion body myositis, Polymyositis, Rheumatoid arthritis, Scleroderma
  • Neurological disorders- POEM syndrome, Peripheral neuropathy, Myasthenia gravis, Amyotrophic lateral sclerosis, Alzheimer's disease
  • Dermatological disorders- Schnitzler syndrome, Scleroderma, Pyodermagangenosum
  • Infections- HIV, HCV, CMV, Mycobacterium tuberculosis
  • Immunosuppression following Renal transplant, Liver transplant, Heart transplant and Bone marrow transplant

Clinical manifestations (For both malignant and non malignant causes)

• Cryoglobulinemia (Common with Waldenstorm’smacroglobulinemia)
  • Reynaud’s phenomenon
  • Skin changes
  • Glomerulonephritis
• Hemorrhages in to skin, retina, epistaxis, hemoptysis, malena etc
• Thrombosis- Pulmonary, renal, mesenteric arteries
• Peripheral neuropathy
• Articular manifestations
• Fever and chills usually provoked by cold
• Hemostatic abnormalities (15% of myeloma, 60% of macroglobulinemia )
• Inhibitors of factors – V,VII,VIII,XI,XII, fibrinogen
• Platelet defects –Due to increased membrane bound IgG
• Vascular damage – By toxic / autoimmune damage by abnormal protein
• Itching, stinging, erythema, leading to purpura (In cryoglobulinemia lesions are usually seen in exposed areas such as nose, ears, face, and extremities)
• Hyperviscosity syndrome
  • Viscosity is ability of fluid to resist flow
  • Common with increased IgM levels
  • Presents with – Headache, vertigo, somnolence, seizures, coma

Investigations

• Serum immunofixation electrophoresis
• Serum free light chain assay
• Complete hemogram
  • Rouleaux formation in myeloma
  • Cold agglutinin – RBC agglutination
  • Neutropenia
  • Thrombocytopenia
  • Leucoerythroblastic blood picture
• Urine protein electrophoresis
• Serum cryoglobulins
• RFT with electrolytes including calcium
• Bone marrow aspiration and biopsy- Flow cytometry if needed
• Skeletal survey- X ray of axial skeleton, skull, femora,, humeri and chest X ray
• Biopsy of  approachable tumor
• CT Chest, abdomen and pelvis
• Abdominal fat pad biopsy for amyloidosis