Lipid and Carbohydrate Metabolism in Acatalasemia

Oxidative stress appears to be involved in degenerative diseases, including atherosclerosis and some forms of diabetes mellitus. The free radicals that damage cellular macromolecules are scavenged by a range of antioxidant enzymes. Superoxide dismutase catalyzes the conversion of superoxide anion into hydrogen peroxide, and catalase (EC 1.11.1.6) provides the main defense against the toxic hydrogen peroxide (1)(2). Despite interest in antioxidant capacity, determination of antioxidants is not routine (3)(4)(5).

In acatalasemia, a genetic deficiency of erythrocyte catalase inherited as an autosomal recessive trait, and in hypocatalasemia, heterozygosity of the acatalasemia gene, the defense system against hydrogen peroxide is diminished; however, no biochemical changes have been reported for this syndrome (6)(7). Furthermore, recent findings concerning the connection of decreased antioxidant enzyme activities and diabetes mellitus lack clarification of the mechanism (8)(9).

We have reported on two acatalasemic sisters in the first Hungarian acatalasemic family (10) and nine hypocatalasemic families (11) with 37 hypocatalasemics. The frequencies for acatalasemia and hypocatalasemia in Hungary are 0.05 in 1000 and 1.8 in 1000.

We describe here the first comprehensive study of the biochemical markers of lipid and carbohydrate metabolism in acatalasemia and hypocatalasemia. We studied one acatalasemic and five hypocatalasemic Hungarian families with 2 acatalasemic females, 28 hypocatalasemic family members (15 females and 13 males), and 28 normocatalasemic family members (15 males and 13 females).

Serum glucose was determined by a glucose oxidase-peroxidase method (glucose test; Reanal), serum fructosamine (Roche Fructosamine Test; Hoffmann-La Roche), blood hemoglobin A_1C (DIAMAT; Bio-Rad), triglycerides (triglyceride GPO-PAP Test; Boehringer Mannheim), cholesterol (cholesterol CHOD-PAP Test; Boehringer Mannheim) on a Boehringer/Hitachi 717 analyzer. LDL-cholesterol was calculated according to the Friedewald formula. Serum apolipoprotein (Apo) A1, Apo B, and lipoprotein(a) [Lp(a)] were measured on a COBAS MIRA analyzer (Hoffmann-La Roche). Oxidative modification of LDL was measured by a microassay of the oxidative resistance of LDL based on the hemin-catalyzed oxidation of LDL (12).

Blood catalase activity was determined spectrophotometrically (10)(11), with a reference mean ± SD of 113.3 ± 16.5 MU/L (n = 1756). We selected a normocatalasemic family member age-matched to each hypocatalasemic family member. The Student t-test was used to evaluate the statistical significance of difference between the two groups.

The results are shown in Table 1⇓ . The increased glucose, hemoglobin A_1C, and fructosamine in the patients reflected the higher incidence of diabetes in the affected members (n = 8) than in controls (n = 0). Seven of the affected members had type 2 diabetes, and one had type 1. Although decreased blood catalase activity in type 1 and type 2 diabetes mellitus has been reported (8)(9)(13)(14)(15), the high frequency (23%) of diabetes mellitus we found in hypocatalasemic and acatalasemic patients is a new finding. The toxic effect of increased hydrogen peroxide concentrations on either the pancreatic cells or the peripheral tissues may be involved in the pathogenesis of the disease. A study using pancreatic insulin-producing cells from rats showed that catalase plays a critical importance for the removal of reactive oxygen species (16).

Significant (P <0.048) changes were detected in cholesterol, LDL-cholesterol, Apo A1, Lp(a), and Apo B concentrations, and LDL oxidative resistance. These values in the diabetic patients did not show a significant (P >0.88) change when compared with those of the control group (cholesterol, 4.79 ± 1.13 vs 4.56 ± 0.89 mmol/L; LDL-cholesterol, 3.04 ± 0.38 vs 2.83 ± 0.97 mmol/L; Apo A1, 1.55 ± 0.29 vs 1.51 ± 0.38 g/L; Apo B, 1.09 ± 0.16 vs 1.05 ± 0.23 g/L; Lp(a), 259 ± 144 vs 212.1 ± 193.8 mg/L). These data suggest that the hypocatalasemia is the main contributor of the lipid abnormalities. The triglyceride and HDL-cholesterol concentrations were similar in the two groups.

In the two acatalasemics (both diabetic), increases (compared with their age- and gender-matched pairs) were also seen in cholesterol (6.39 vs 4.18 mmol/L), LDL-cholesterol (4.14 vs 2.46 mmol/L), Apo A1 (1.69 vs 1.53 g/L), Apo B (1.35 vs 1.10 g/L), and Lp(a) (294 vs 222 mg/L), with lower LDL oxidative resistance (2580 vs 4480 s) and increased glucose (8.6 vs 5.4 mmol/L), fructosamine (256 vs 210 μmol/L), and hemoglobin A_1C (7.1% vs 4.5%). Changes in cholesterol, LDL-cholesterol, Apo A1, Apo B, Lp(a), and LDL oxidative resistance have not been reported for acatalasemic and hypocatalasemic patients and could be attributed to the increased oxidation of cholesterol, especially of LDL-cholesterol. The connection between lipid peroxidation and catalase activity has been reported in other diseases (4)(9)(13)(14). The change in conventional (cholesterol, LDL-cholesterol, and Apo B) and in nonconventional [Lp(a), LDL oxidative resistance] risks may mean a higher risk for these patients.

In addition to the condition itself, hypocatalasemia is seen with increased frequency in other disorders [e.g., anemia, tumors, schizophrenia, and atherosclerosis (4)], yielding a prevalence of ∼1%. We conclude that these acatalasemic and hypocatalasemic subjects are at increased risk of diabetes mellitus and atherosclerosis.

• © 2000 The American Association for Clinical Chemistry