Hypergammaglobulinemia

What hypergammaglobulinemia means

Blood proteins fall into two main groups: albumin and globulins. Globulins include the gamma globulins, which are antibodies made by plasma cells (a type of white blood cell). There are five classes of antibody: IgG, IgA, IgM, IgD and IgE. IgG is by far the most abundant.

When a routine blood test shows a high total protein or a high globulin level (often above about 3.5 g/dL, or 35 g/L), doctors look for the reason. The usual next test is serum protein electrophoresis (SPEP), which separates the proteins into bands on a strip.

Polyclonal vs monoclonal hypergammaglobulinemia

This distinction is the central step in the approach to hypergammaglobulinemia. A broad bulge sends the doctor looking for inflammation. A spike sends them looking for a plasma cell disorder.

Causes of polyclonal hypergammaglobulinemia

The immune system makes more antibodies of many kinds when it is chronically stimulated.

Liver disease

• Cirrhosis from any cause. The scarred liver fails to filter gut bacteria and their products, which keep stimulating the immune system. A characteristic "bridging" pattern between the beta and gamma bands is common.
• Autoimmune hepatitis, which typically raises IgG strongly.
• Chronic viral hepatitis B and C.

Chronic infections

• HIV infection, which commonly causes polyclonal increases even in early stages.
• Tuberculosis, endocarditis, osteomyelitis and other long-lasting bacterial infections.
• Parasitic infections such as malaria, leishmaniasis (kala-azar) and schistosomiasis, often with very high levels.

Autoimmune and inflammatory diseases

• Sjögren's syndrome, often with dry eyes and mouth. Very high IgG levels are typical.
• Systemic lupus erythematosus.
• Rheumatoid arthritis.
• Sarcoidosis.
• IgG4-related disease, which raises IgG4 and causes swollen glands, pancreas or other organs.

Blood and lymph node disorders

• Castleman disease, a rare lymph node disorder.
• Some lymphomas and chronic lymphocytic leukemia, although these can also lower antibodies.

Rare inherited syndromes

• Hyper-IgE syndrome (Job syndrome): very high IgE with eczema, recurrent skin abscesses and lung infections.
• Hyper-IgM syndrome: high or normal IgM but low IgG and IgA, causing frequent infections. Despite the name, it is an immunodeficiency.
• Hyper-IgD syndrome (mevalonate kinase deficiency): recurrent fevers starting in childhood.

Causes of monoclonal gammopathy

• Monoclonal gammopathy of undetermined significance (MGUS): a small M-protein without symptoms or organ damage. It is found in about 3% of people over 50 and becomes more common with age. The risk of progressing to myeloma or a related cancer is roughly 1% per year.
• Multiple myeloma: a cancer of plasma cells that can damage bones, kidneys and blood counts.
• Waldenström macroglobulinemia: a lymphoma that produces large IgM molecules, which can thicken the blood.
• Smoldering myeloma, AL amyloidosis and some lymphomas.

Symptoms of hypergammaglobulinemia

The extra antibodies themselves usually cause no symptoms. Most people are diagnosed after a routine blood test. Symptoms, when present, come from the underlying cause:

• Liver disease: jaundice, swelling of the belly or legs, easy bruising.
• Autoimmune disease: dry eyes and mouth, joint pain, rashes, mouth ulcers, fatigue.
• Chronic infection: fevers, night sweats, weight loss, swollen lymph nodes.
• Myeloma: bone pain (especially the back), fatigue from anemia, frequent infections, kidney problems and high calcium (thirst, constipation, confusion).

Hyperviscosity syndrome

Very high antibody levels, especially IgM in Waldenström macroglobulinemia, can make the blood thick and slow. This hyperviscosity causes blurred vision, headaches, dizziness, nosebleeds and bleeding gums, and in severe cases confusion or stroke-like symptoms. It is a medical emergency treated with plasma exchange. It is rare with polyclonal hypergammaglobulinemia but can occur with extremely high levels in Sjögren's syndrome.

Other effects

• Purpura: some people with Sjögren's syndrome develop small, raised purple spots on the lower legs, called hypergammaglobulinemic purpura of Waldenström.
• Kidney effects: monoclonal light chains can damage the kidneys.
• Lab quirks: high protein can cause falsely low sodium readings on some analyzers and a raised ESR (sedimentation rate).

How hypergammaglobulinemia is investigated

1. Total protein and albumin: the globulin level is calculated from the difference. A high globulin with normal albumin starts the workup.
2. Serum protein electrophoresis (SPEP): shows whether the rise is polyclonal (broad) or monoclonal (spike).
3. Immunofixation: identifies the class of a monoclonal protein (for example IgG kappa).
4. Serum free light chains: measures kappa and lambda light chains. An abnormal ratio supports a clonal disorder.
5. Quantitative immunoglobulins: measures IgG, IgA and IgM separately. A rise in one class can hint at the cause, such as IgA in alcohol-related liver disease or IgM in primary biliary cholangitis.

For a polyclonal pattern, the next tests look for the cause: liver tests and ultrasound, HIV and hepatitis B and C tests, autoantibodies (ANA, anti-Ro and anti-La, rheumatoid factor) and inflammatory markers.

For a monoclonal pattern, doctors check the blood count, kidney function and calcium, and may order a skeletal survey or low-dose CT, and a bone marrow biopsy, depending on the protein level and symptoms.

Hypergammaglobulinemia treatment

There is no treatment aimed at the antibody number itself in most cases. Treatment targets the cause, and the level falls as the cause is controlled.

• Liver disease: treating hepatitis, stopping alcohol, or immunosuppression for autoimmune hepatitis.
• HIV: antiretroviral therapy usually lowers the gamma globulin level over time.
• Other infections: antibiotics, antiparasitic or antifungal drugs.
• Autoimmune disease: medicines such as hydroxychloroquine, steroids or other immunosuppressants, depending on the diagnosis.
• MGUS: no treatment, but regular monitoring with blood tests, usually 6 months after diagnosis and then every 1 to 2 years if stable and low risk.
• Myeloma and Waldenström: specialist treatment with targeted drugs, chemotherapy or stem cell transplant.
• Hyperviscosity: urgent plasma exchange (plasmapheresis) to remove the excess antibody.

Outlook

The outlook depends almost entirely on the cause. Polyclonal hypergammaglobulinemia is a marker of inflammation and often improves with treatment of the underlying disease. Most people with MGUS never develop cancer, but they need lifelong follow-up because a small proportion do.

Frequently asked questions

What are the symptoms of hypergammaglobulinemia?

Most people have none. The raised antibodies are usually found on a routine blood test. Symptoms come from the cause, such as fatigue, joint pain or dry eyes in autoimmune disease, or bone pain and anemia in myeloma. Very high levels can rarely thicken the blood, causing blurred vision, headaches and nosebleeds.

What is the most common cause of polyclonal hypergammaglobulinemia?

Chronic liver disease, especially cirrhosis, is one of the most common causes. Others include chronic infections such as HIV and hepatitis, and autoimmune diseases such as Sjögren's syndrome, lupus and rheumatoid arthritis. A doctor finds the cause with liver tests, infection screening and autoantibody tests.

Is hypergammaglobulinemia cancer?

Polyclonal hypergammaglobulinemia is not cancer. It reflects an active immune system. A monoclonal rise can be associated with blood cancers such as multiple myeloma or Waldenström macroglobulinemia, but it is most often MGUS, a benign condition that needs monitoring. Electrophoresis tells the two apart.

How is hypergammaglobulinemia treated?

By treating its cause. Controlling hepatitis, HIV, autoimmune disease or other infections usually brings the level down. MGUS is monitored without treatment. Myeloma and Waldenström macroglobulinemia need cancer treatment. Plasma exchange is used only for hyperviscosity, when thick blood causes symptoms.

What does a high globulin level on a blood test mean?

A high globulin level means there are more proteins other than albumin in the blood, usually antibodies. It may reflect inflammation, infection, liver disease or a plasma cell disorder. Protein electrophoresis is the usual next test to find out which.

Can dehydration cause high gamma globulin?

Dehydration concentrates the blood, so total protein and globulin readings can rise slightly while albumin rises too. This does not change the electrophoresis pattern. A true, persistent rise in gamma globulins with normal hydration needs investigation.