Hypogammaglobulinemia in a family with Crohn ’ s disease

Serum immunoglobulins in most Crohn’s disease patients are normal; however, there are occasional reports of Crohn’s patients with hypogammaglobulinemia (1). Low immunoglobulin levels are usually transient, and after appropriate therapy for the disease they increase. We report a case of hypogammaglobulinemia associated with Crohn’s disease that did not resolve with appropriate therapy. Furthermore, when her family was screened, there was a strong correlation between family members with Crohn’s disease and hypogammaglobulinemia.


Hypoglammaglobulinémie chez les patients atteints de maladie de Crohn
the terminal ileum.Due to impending surgery, preoperative blood work, including a protein electrophoresis, was done.Because the protein electrophoresis demonstrated low gamma globulins (3.0 g/L), immunoglobulin levels were analyzed.Serum immunoglobulins IgA and IgM were normal, but the IgG level was 4.49 g/L (normal 6.39 to 13.49).She subsequently had an ileal resection of histologically proven Crohn's disease.Repeat IgG after the surgical resection was 3.61 g/L.Low levels of IgG persisted on repeat measurements over the next two years.
Abdominal symptoms resolved and 5-ASA maintenance therapy was initiated.Two years later she required admission for atypical pneumonia, and pulmonary function testing demonstrated findings consistent with chronic obstructive lung disease.Testing revealed that serum immunoglobulins were again low.
A diagnosis of hypogammaglobulinemia was made, and family screening was done (Figure 1).Four of the six family members with Crohn's disease had low serum immunoglobulins.Of these four, three had low IgG and one had low IgM.Only two family members without Crohn's disease were available to have serum immunoglobulins measured and these results were normal.The results demonstrate that the case outlined above was the index case in a family who appear to have coexistent Crohn's disease and hypogammaglobulinemia (Table 1).

DISCUSSION
Gastrointestinal disturbances such as Crohn's disease have been known to occur in patients with immunedeficient states (2).Some researchers have preferred to call these lesions 'regional enteropathy-like' states to denote their similarity to Crohn's disease (1).Others have simply called the lesions Crohn's disease and felt that it was associated with hypogammaglobulinemia (3).Despite normal levels of B lymphocytes, patients with hypogammaglobulinemia still have low immunoglobulin levels (4).One explanation is that there is intrinsic abnormality in the B lymphocyte function, which results in low immunoglobulin production.A second theory argues that there is stimulatory dysfunction, so B lymphocytes are not encouraged to produce appropriate levels of immunoglobulins; this theory is supported by several studies that demonstrated that when B cells from affected individuals are isolated and stimulated with specific cytokines, they produce appropriate levels of immunoglobulins.When T cells from affected patients are added to the matrix, immunoglobulin production decreases.Therefore, it appears that the defect in hypogammaglobulinemia may rest in abnormal T cell suppressor activity (4)(5)(6)(7)(8)(9).
Only occasional individual reports of hypogammaglobulinemia associated with Crohn's disease have been published (5,8).This case is unique in that our index patient had six first-degree relatives with Crohn's disease, four of whom had low levels of immunoglobulins.Three of these four had low serum IgG, and one had low serum IgM and borderline low IgA.These findings are similar to common variable hypo-gammaglobulinemia, in which it is common to have low IgM, IgA and IgG, especially in siblings.Furthermore, our index case developed chronic obstructive lung disease, common in patients with hypogammaglobulinemia.In some reported cases of hypogammaglobulinemia in Crohn's disease, serum immunoglobulins returned to normal when the patient had the active disease treated.This did not occur in our index case; she had persistently low serum immunoglobulins after surgical correction and appropriate medical therapy.

CONCLUSIONS
The presented index case led us to evaluate further her family, and four other members were subsequently shown to have Crohn's disease and hypogammaglobulinemia.Serum immunoglobulins measured in the only two available family members without Crohn's disease were normal.It appears that in this family, Crohn's disease and hypogammaglobulinemia are closely linked.This finding deserves further study because its elucidation may help to define the pathogenesis of Crohn's disease more clearly.