A patient was recently referred to me for elevated IgG of 2137(700-1600) and IgA 831(91-414). Normal IgM and IgE of 8. There were drawn as he had elevated total serum proteins. No M spike noted. Patient is healthy no symptoms and no evidence of infections. Hepatitis was ruled out. The only significant history was for empyema of left chest cavity following motor vehicle accident 2 years ago and he had thoracotomy. Repeat labs show elevated IgG and IgA normalIgM, CRP is normal Sed rate slightly elevated at 40(0-30. How should I proceed with further investigation?


Thank you for your inquiry.

The history you presented is of an asymptomatic patient with a polyclonal gammopathy. Unfortunately, the differential diagnosis of a polyclonal gammopathy is extremely extensive. There are at least 10 separate classifications of conditions associated with a polyclonal gammopathy, and many separate causes under each classification. The most common causes are probably chronic liver disease, connective tissue disorders, chronic infections, and lymphoproliferative disorders. Perhaps less common are other hematologic conditions, nonhematologic malignancies, neurological conditions, “diseases with immune system abnormalities,” (ulcerative colitis, autoimmune pancreatitis, et cetera), drugs, and finally, miscellaneous. And, as mentioned, each one of these major categories has a number of diseases within their classification.

Thus, to begin a workup for these conditions in a patient who is asymptomatic is a formidable task, and may not uncover a cause of any of these conditions in their early phase. And, like monoclonal gammopathies, many times there is no detectable cause at the time of the investigation.

However, to begin a workup, one would of course start with the most common causes, and I think the best reference to guide you in this regard is the series from the Mayo Clinic. I have copied below the abstract of the Mayo Clinic publication of this series. It is a retrospective cohort study of 148 patients with polyclonal gammopathy. In addition, there is a very good succinct annotation of this series available to you online at no charge. A link to this article is also copied below. Evidently you have already looked at liver disease, the most common cause. If you want to proceed further (rather than just observe the patient for a while before doing any tests), using this article as a guide you would next look for connective tissue diseases, then chronic infections, then immunologic disorders followed by nonhematologic malignancies.

As you can see, once again, this is a very daunting task, and in an asymptomatic patient, it is not unlikely that you would not uncover anything at this stage.

For a comprehensive look at the vast majority (but perhaps not all) of conditions which can cause a polyclonal gammopathy, here is a link to a book chapter, entitled “Classification of diseases with increased immunoglobulins.”

Obviously, with this formidable differential diagnosis, a detailed discussion of what one would do to rule out each classification is beyond the scope of our website.

In summary, the two best references, of which I am aware, for you to at least look at the differential diagnoses of a monoclonal gammopathy and begin an initial search are copied below. In many instances, in the early stages of any polyclonal gammopathy, you may not be able to identify a cause. And such a workup at this time may not be helpful.

Also, a polyclonal gammopathy is not necessarily permanent. If a patient had a source of inflammation which has resolved, the gammopathy may in turn resolve, and therefore, since your patient is asymptomatic, you might consider simple observation at this time after looking at the references cited below.

Thank you again for your inquiry and we hope this response is helpful to you.

Adapted from Mayo Clinic Proceedings 76:476-487, 2001.
Mayo Clin Proc. 2001 May;76(5):476-87.
Retrospective cohort study of 148 patients with polyclonal gammopathy.
Dispenzieri A, Gertz MA, Therneau TM, Kyle RA.
Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Objective: To quantify clinical conditions and laboratory values associated with moderate to marked polyclonal gammopathy.
Patients and Methods: Patient characteristics, laboratory correlates, evolving disease states, and survival of all patients seen at the Mayo Clinic, Rochester, Minn, during 1991 with a polyclonal gamma globulin level of 3.0 g/dL or higher were reviewed in this retrospective cohort study.
Results: One hundred forty-eight patients were identified (median age, 58 years; 59% female). In 130 patients (88%), only 1 diagnosis was identified. Liver disease was the most common single disease association in 79 (61%) of 130 patients, followed by connective tissue diseases in 28 (22%), chronic infections in 8 (6%), hematologic disorders in 6 (5%), and nonhematologic malignancies in 4 (3%). No difference in gamma globulin levels existed between groups. With a median follow-up of 67 months, 90 (63%) of 143 patients for whom follow-up was available were alive. By multivariate analysis, age, albumin concentration, disease group, and platelet count were predictive of survival. No patient developed myeloma or a clonal plasmaproliferative disorder.
Conclusion: Moderate to marked polyclonal gammopathy may reflect an underlying condition: liver disease, connective tissue disease, hematologic disorder, infection, or malignancy.

Phil Lieberman, M.D.

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