Hyperammonemia in Multiple Myeloma

Abstract

Two patients with multiple myeloma who appeared to be producing ammonia are reported. Both patients showed hyperammonemia and amino acid disturbances, such as a low Fischer ratio. One patient had Bence Jones protein (λ) type myeloma and became comatose, but the hyperammonemia and disturbance of consciousness were improved by chemotherapy for the myeloma. The other patient had IgA gκ type myeloma and somnolence and died of malignant pleurisy despite intensive chemotherapy. Autopsy showed widespread multiple myeloma and an almost normal liver. Ammonia levels in the supernatant of cultured myeloma cells from the patient’s pleural effusion increased almost linearly from the time of cell seeding. These observations showed that ammonia was produced at a high level by these human myeloma cells. We also found that one of the common myeloma cell lines, RPMI 8226, could produce ammonia as well.

In vitro excess ammonia production in human myeloma cell lines

“…In addition, hyperammonemia has also been reported to be associated with urinary tract infections, 59,60 valproic acid treatment, 61,62 portacaval shunts in cases with gastric cancer 63 and high-dose cytoreductive chemotherapies for cases with hematological malignancies. 64 Recently, there have been several reports of cases with myeloma associated with hyperammonemia, [21][22][23][24][25][26][27][28][29][30] most of whom have been Japanese. This hyperammonemia was not considered to be due to liver dysfunction, because most of these cases had normal hepatic function and some showed different patterns of serum amino acid distributions than that of liver failure.…”

“…This hyperammonemia was not considered to be due to liver dysfunction, because most of these cases had normal hepatic function and some showed different patterns of serum amino acid distributions than that of liver failure. 23,28,29 However, there has been no apparent observation of ammonia production by myeloma cells. Although one cell line, KHM-4, was reported to have produced ammonia in vitro, 25 it was clarified that ornithine transcarmanylase derived from infected mycoplasma in this cell line was the major factor that produced ammonia in culture.…”

“…In another report concerning ammonia production by a myeloma cell line in which RPMI8226 was used, 29 no description of mycoplasma status was given and ammonia production was not measured according to proliferating cell numbers.…”

“…Although one cell line, KHM-4, was reported to produce ammonia in vitro, 25 it has been clarified that ornithine transcarmanylase derived from infected mycoplasma in this cell line played a major role in the production of ammonia in culture. 31 In the only other report concerning ammonia production by a myeloma cell line, RPMI8226, 29 there was no description of mycoplasma status and ammonia production was not measured according to proliferating cell numbers. Therefore, there has been no apparent observation of ammonia production by myeloma cells in vitro so far.…”

Human Myeloma Cell Line (KHM-4) Established from A Patient with Multiple Myeloma Associated with Hyperammonemia.

“…It may also occur as a complication of urinary tract infection (8), asparaginase therapy (9), valproic acid therapy (10), and systemic carnitine deficiency (ll). Recently, we encountered and reported two patients with multiple myeloma who had hyperammonemia, serum amino acid disturbances, and disturbance of consciousness (12). Malignant plasma cells have proved to be very difficult to establish; however, we established a myeloma cell line (KHM-4) from one patient with hyperammonemia.…”