Decreased hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda.

To test whether reduced hepatic uroporphyrinogen decarboxylase activity is a specific and intrinsic defect in porphyria cutanea tarda, we measured enzymatic activity in the livers of 17 patients with porphyria cutanea tarda, 12 "normal" control patients without liver disease, and 41 patients with other forms of porphyria, alcoholic liver disease, hemochromatosis, or chronic hepatitis. Enzyme activity in all the patients with porphyria cutanea tarda was lower than in the patients without this disease, except for one patient with alcohol-induced fatty liver. Reduction of hepatic iron stores by phlebotomy did not alter the enzymatic activity in porphyria cutanea tarda. We conclude that reduced hepatic uroporphyrinogen decarboxylase activity is a specific and intrinsic hepatic defect in porphyria cutanea tarda, but modulation of uroporphyrinogen synthesis by extrinsic factors is required for the full biochemical expression of the disease.

Chronic persistent hepatitis and unconjugated hyperbilirubinemia.

The authors studied 12 patients with chronic persistent hepatitis and persistent or intermittent mild unconjugated hyperbilirubinemia. Maximum serum total bilirubin concentration ranged from 2.1 to 3.6 mg/dl. Hemolysis was not evident. Hepatic bilirubin UDP-glucuronyltransferase activity assayed in each patient ranged from 0.16 to 0.39 U (mean +/- SEM = 0.27 +/- 0.02) compared to 0.68-1.99 (1.35 +/- 0.08) in 23 normals, 0.78-2.28 (1.41 +/- 0.05) in 53 patients with acute hepatitis, 0.34-1.74 (0.81 +/- 0.09) in 16 patients with anicteric chronic persistent hepatitis, and 0-0.62 (0.24 +/- 0.03) in 33 patients with Gilbert's syndrome. The mean UDP-glucuronyltransferase activity was significantly lower in anicteric chronic persistent hepatitis compared to normals, but higher than in Gilbert's syndrome. The incidence of unconjugated hyperbilirubinemia among first degree relatives was 0:32 in icteric chronic persistent hepatitis compared to 24:85 (28%) in Gilbert's syndrome. These results show that the likely cause for the unconjugated hyperbilirubinemia associated with chronic persistent hepatitis is an acquired depression of hepatic bilirubin UDP-glucuronyltransferase activity. The data suggest that the enzyme defect is related to chronic persistent hepatitis.

Reduced hepatic bilirubin uridine diphosphate glucuronyl transferase and uridine diphosphate glucose dehydrogenase activity in the human fetus.

Hepatic bilirubin uridine diphosphate glucuronyl transferase (UDPG-T) activity was 0.14 and 0.22 units in two fetuses aged 17 and 22 weeks, respectively, and less than 0.1 unit in 15 fetuses, aged 8--19 weeks compared to 0.68--1.99 units in 21 normal adults. Hepatic uridine diphosphate glucose dehydrogenase (UDPG-D) activity in 14 fetuses, aged 8--18 weeks, ranged from 6.2--15.0 units (mean = 11.3 +/- 0.7) compared to 28.8--49.2 units (mean = 39.6 +/- 2.5) in eight normal adults (P less than 0.001). There was no correlation between UDPG-D activity and gestational age. The hepatic UDPG-D activity was 16.5 units in a 33-day-old full term, female infant, 42.4 and 24.3 units in two 2-year-old infants, respectively, and 24.3 units in a 5.5-year-old child. In three human fetuses, the apparent Km UDPG was 0.54 x 10(-4) M. Thus, both hepatic bilirubin UDPG-T and UDPG-D activity are markedly reduced in the human fetus during the second trimester of gestation. Retarded development of hepatic UDPG-D may extend beyond the first month of life.

Caloric intake and unconjugated hyperbilirubinemia.

Reduction in caloric intake was associated with a greater absolute rise in the serum bilirubin concentration in patients with Gilbert's syndrome and partial hepatic bilirubin uridine diphosphate glucuronyltransferase (UDPG-T) dysfunction compared to patients with hemolytic unconjugated hyperbilirubinemia and normal subjects. Two patients with overt hemolysis but an exaggerated response to caloric deprivation had reduced UDPG-T activities comparable to Gilbert's syndrome. The UDPG-T activities in the other patients with hemolytic jaundice were normal. The combination of fasting and novobiocin in 2 normal subjects produced a greater increase in bilirubin level than either fasting or novobiocin alone. These data suggest that theunderlying UDPG-T dysfunction, rather than the prefasting level of unconjugated hyperbilirubinemia, is responsible for the diet-induced hyperbilirubinemia in Gilbert's syndrome. The diet test appears to differentiate Gilbert's syndrome from hemolytic jaundice as well as from normal subjects, irrespective of the initial serum bilirubin concentration.