Hyperproteinaemia

Hyperproteinaemia is a serum total protein concentration above the reference range (about 83 g/L), usually from raised globulins rather than raised albumin. It is a laboratory finding that prompts a search for a monoclonal or polyclonal increase in immunoglobulins, haemoconcentration, or other causes.

• Pseudo hyperproteinaemia from haemoconcentration: dehydration, vomiting, diarrhoea, diuretics, burns, prolonged tourniquet time (albumin and globulin both raised, with a raised haematocrit and urea).
• Raised albumin occurs only with dehydration.
• Raised globulins (albumin normal or low, with a protein gap over 35 to 40 g/L):
  • Monoclonal gammopathy: monoclonal gammopathy of undetermined significance (about 3 percent of adults over 50), multiple myeloma, Waldenstrom macroglobulinaemia, AL amyloidosis, lymphoma, and chronic lymphocytic leukaemia.
  • Polyclonal gammopathy: chronic infections (HIV, hepatitis B and C, TB, malaria, kala azar, schistosomiasis, brucellosis, chronic bacterial infections), chronic liver disease and cirrhosis, autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome), sarcoidosis, and chronic inflammatory disease.
• Cryoglobulinaemia and other paraproteins can also raise total protein.
• Hyperproteinaemia can produce spurious laboratory results (pseudohyponatraemia with indirect ion selective electrodes and artefactual hypercalcaemia or low anion gap).

• Often asymptomatic, found on routine blood tests.
• Symptoms of myeloma: bone pain, fractures, fatigue, recurrent infections, weight loss, thirst, constipation, confusion, and renal failure; hyperviscosity symptoms (headache, visual blurring, nosebleeds, confusion).
• Chronic infection: fever, weight loss, night sweats, cough, diarrhoea, hepatosplenomegaly, travel and endemic exposure.
• Autoimmune: joint pain, rash, dry eyes and mouth.
• Liver disease: jaundice, spider naevi, ascites.
• Dehydration: thirst, dry mucous membranes, tachycardia, orthostatic hypotension, concentrated urine.
• Red flags: bone pain, anaemia, hypercalcaemia, renal impairment (the "CRAB" features of myeloma), neuropathy, recurrent infections, hyperviscosity symptoms, or unexplained weight loss.

• Repeat sample (avoiding prolonged tourniquet); calculate the globulin fraction (total protein minus albumin) and the protein gap (over 40 g/L suggests a paraprotein).
• Serum protein electrophoresis with immunofixation: monoclonal band (paraprotein) versus polyclonal increase in gamma globulins; quantitative immunoglobulins (IgG, IgA, IgM); serum free light chains with kappa/lambda ratio (normal 0.26 to 1.65); urine protein electrophoresis or Bence Jones protein on a 24 hour or spot urine.
• Basic tests: FBC with film (rouleaux), ESR (very high in myeloma), urea, creatinine, calcium, albumin, beta-2 microglobulin, lactate dehydrogenase, CRP, urinalysis.
• If a paraprotein is present: skeletal survey or whole body low dose CT, and bone marrow biopsy if concern for myeloma (IgG over 15 g/L, IgA or IgM paraprotein, abnormal free light chain ratio, or CRAB features).
• Polyclonal pattern: HIV, hepatitis B and C, TB tests, ANA, rheumatoid factor, liver function, abdominal ultrasound, chest X-ray, malaria, schistosomiasis, brucellosis and leishmaniasis testing according to endemicity.
• Plasma viscosity if hyperviscosity is suspected.
• Differentials: dehydration, monoclonal gammopathy of undetermined significance, smouldering myeloma, multiple myeloma, polyclonal hypergammaglobulinaemia, and laboratory artefact.

Dehydration or haemoconcentration

• Rehydrate orally (oral rehydration solution 200 to 400 mL per hour) or intravenously (0.9 percent sodium chloride 1 litre over 1 to 2 hours, adjusted to response and cardiac status); treat vomiting and diarrhoea; stop or reduce diuretics; recheck protein in 24 to 72 hours.

Monoclonal gammopathy of undetermined significance (paraprotein under 15 g/L IgG, normal free light chain ratio, no CRAB)

• Annual follow up (protein electrophoresis, FBC, calcium, creatinine) for life, or every 6 months in the first year; risk of progression to myeloma is about 1 percent a year; no treatment; refer to haematology if the paraprotein rises (over 15 g/L), abnormal free light chain ratio, or symptoms develop.

Myeloma, Waldenstrom macroglobulinaemia, amyloidosis and lymphoma

• Urgent referral to haematology (within 24 hours if hypercalcaemia, renal failure, spinal cord compression, or hyperviscosity). Initial supportive care: hydration (3 litres a day), correct hypercalcaemia (intravenous zoledronic acid 4 mg over 15 minutes, dose adjusted to renal function, plus hydration), analgesia (paracetamol, avoid NSAIDs), allopurinol if tumour lysis risk, antibiotics for infection, and dexamethasone 40 mg daily for 4 days under specialist advice for cord compression or severe disease.
• Hyperviscosity syndrome: plasmapheresis (plasma exchange) as an emergency; avoid red cell transfusion before pheresis.
• Definitive treatment (specialist): bortezomib, lenalidomide and dexamethasone combinations, daratumumab, autologous stem cell transplantation in eligible patients, rituximab based therapy for Waldenstrom macroglobulinaemia.

Polyclonal hypergammaglobulinaemia

• Treat the cause: antiretroviral therapy for HIV; antivirals for hepatitis B (tenofovir 300 mg daily) and C (sofosbuvir-velpatasvir 400/100 mg daily for 12 weeks); antituberculous therapy; antimalarial or antiparasitic treatment (liposomal amphotericin B for visceral leishmaniasis; praziquantel 40 mg/kg for schistosomiasis); immunosuppression for autoimmune disease; liver disease management.
• Recheck protein levels 3 to 6 months after treating the cause.

Follow up

• Repeat total protein and electrophoresis in 4 to 12 weeks after rehydration or treatment of the cause; refer to haematology for any monoclonal band.