Pitfalls with paraproteins

We were recently consulted on a patient with a history of multiple myeloma who had developed severe hypercalcemia and acute renal failure. The calcium on admission was 15mg/dl (albumin 2.6) and the patient was treated aggressively with IV fluids, diuretics, bisphosphonates and calcitonin. Despite this, the calcium remained elevated and the patients renal function continued to deteriorate. The patient was discharged from the hospital on iv diuretics but returned a few days later with bleeding gums and loose teeth. At this stage, the creatinine was 4mg/dl and his calcium was 11mg/dl.  Paraprotein levels were extremely high at 9g/dl and it was felt that the patient might have a hyperviscosity syndrome so was started on plasmapheresis. The morning after the plasmapheresis, the calcium dropped to 6mg/dl. What could explain this dramatic fall?

It turns out that his calcium was never truly elevated. The ionized calcium was not checked during his first admission but just before starting plasmapheresis it came back low at 1.0mmol/l. It turns out that this is just one of the many artifactual results produced by paraproteins in the serum. Some IgG paraproteins can bind calcium in a similar manner to albumin. While the total calcium is elevated, the ionized calcium remains normal and so treating this hypercalcemia is inappropriate. Obviously, most hypercalcemia related to MM is real and related to the disease itself – this demonstrates the importance of checking the ionized calcium in these cases.

There are a number of ways in which paraproteins interfere with lab assays:

- By interfering with the lab assay in vitro

- By interaction with a specific target in vivo

Increased sample viscosity:

This is usually due to an IgM paraprotein and its effect on an assay depends on whether the turbidity related to the paraprotein dissipates early or late in the processing and can lead to artificially high (PO4, GGT, Bili, CRP) or low (HDL, Glucose, Paracetamol) results. It can be prevented by pre-dilution of the sample and these results are not usually reported as most lab analyzers will detect that there is something amiss with the reaction kinetics and report and error.

Reaction with the assay:

Pseudohypocreatininemia has been reported due to IgG paraproteins interfering with the Jaffe reaction. Similarly, as reported in an earlier post, pseudohypercreatininemia has been seen in some patients with Waldenstrom’s Macroglobulinemia due to interference by the IgM paraprotein with the enzymatic method for measuring creatinine. Binding of paraproteins to the assay constituents can also lead to falsely low TSH and CRP levels. These errors are not easily picked up and are usually detected because they do not correlate with the clinical picture.

Pseudohyponatremia:

This is a well-described consequence of high paraprotein levels. It has been mentioned in previous blog posts and is due to the reduction in the plasma water fraction because of the increased total protein concentration. This can be detected by directly measuring the serum sodium concentration on a blood gas analyzer.

Binding to cations and anions:

Along with calcium, some paraproteins can bind copper or phosphate, raising the total blood levels without altering the free levels. Depending on the substance, they may or may not be biologically active. Similarly, paraproteins can bind hormones such as T4 or insulin (leading to increased insulin requirements, or delayed hypoglycemia if the insulin is slowly released from the paraprotein).

Finally, paraproteins can interfere with the anion gap. IgG paraproteins act as cations at physiological pH leading to retention on chloride and a reduction in the anion gap. In contrast, IgA paraproteins act as anions at the same pH and as a result will cause an increase in the anion gap.