Abnormal processing of pro-IGF-II in patients with hepatoma and in some hepatitis B virus antibody-positive asymptomatic individuals. Hepatomas are a common malignancy in countries with a high prevalence of hepatitis B virus infections. These tumors may present with severe persistent hypoglycemia. We have studied the possible relationship of production of insulin-like growth factor II (IGF-II) by these tumors and the development of hypoglycemia. Mean IGF-II concentration was not significantly higher in 23 patients with hypoglycemia than in nine patients with euglycemia (542 +/- 61 [SE] micrograms/L vs 382 +/- 52 micrograms/L). Serum IGF-I was more suppressed in patients with hypoglycemia (16 +/- 3 micrograms/L) than in patients with euglycemia (57 +/- 18 micrograms/L). Because an increased percentage of IGF-II in serum of patients with hypoglycemia who have other tumors is present as partially processed pro-IGF-II ("big" IGF-II), we passed sera of patients with hypoglycemia and patients with euglycemia with hepatomas through acidic Bio-Gel P-60 columns. We found that 57% +/- 4.6% of the IGF-II in sera from patients with hypoglycemia was present as big IGF-II compared with 22% +/- 3% in patients with euglycemia with hepatomas (not significantly different from that in normal controls). Four of 11 apparently healthy control subjects who were hepatitis B virus positive also had increased percentages of big IGF-II, suggesting that abnormal processing of pro-IGF-II may result from subtle changes in liver function with this infection. It remains to be determined whether these subjects with increased big IGF-II are at increased risk for the development of hepatomas. In conclusion, we have confirmed marked suppression of IGF-I in the sera of patients with hepatoma and hypoglycemia. 