Case Presentation: A 58 year old male with a history of NASH cirrhosis, diabetes mellitus, and obstructive sleep apnea presented due to multiple symptoms that had been present for the past 3 months, including severe fatigue, generalized weakness, headaches, intermittent confusion, recurrent epistaxis, and multiple episodes of blurry vision that spontaneously resolved.  He also reported a tendency to have prolonged bleeding from wounds (which in the past had been attributed to thrombocytopenia caused by liver cirrhosis).  His father died of a “blood cancer,” and a paternal aunt died of leukemia. 

Initial physical exam was remarkable for mild tachypnea (respiratory rate 22).  He had wheezing in his lung fields, and right lower extremity edema and erythema (which were attributed to cellulitis).  Vancomcyin was started for treatment of the cellulitis. His initial labs were remarkable for hemoglobin 8.9, hematocrit 29.3, and platelets 68.  Also, his total serum protein was 10.0 and serum albumin was 2.2, to give a globulin gap of 7.8.  Serum and urine protein electrophoresis (SPEP and UPEP) were ordered to investigate the etiology of his elevated globulin gap, and a monoclonal IgM kappa spike was identified in his SPEP.  Subsequently, a bone marrow biopsy was performed, and this demonstrated lymphoplasmacytic lymphoma, which is diagnostic of Waldenström macroglobulinemia. 

Discussion: In this case, the patient’s elevated globulin gap provided the impetus to obtain additional tests that led to a definitive diagnosis.  The globulin gap (known alternatively as either the “paraprotein gap” or “gamma gap”) is the difference between the total protein and albumin, and a value above 4 g/dL is considered to be elevated.  Some disease states, such as acute HIV infection and plasma cell dyscrasias, and also generalized inflammation, can cause an elevated globulin gap.  However, the finding of a monoclonal band on SPEP generally indicates the presence of a plasma cell dyscrasia or other B cell disorder, such as multiple myeloma or Waldenström macroglobulinemia.  The patient’s symptoms of blurry vision, and intermittent confusion and headaches were attributable to hyperviscosity syndrome, which may be seen in up to thirty percent of patients who have Waldenström macroglobulinemia.  The patient was relieved to know that a definite diagnosis had been established, although the fact that he had a newly diagnosed malignancy was emotionally unsettling.

Conclusions:   The presence of an elevated globulin gap has a wide differential, but it is never normal, and it should be worked up appropriately.