Rotor's syndrome. A distinct inheritable pathophysiologic entity.

Urinary total, isomer I and isomer III coproporphyrin excretion was determined in 11 patients with Rotor's syndrome, 23 phenotypically normal family members, 16 patients with the Dubin-Johnson syndrome and 20 normal control subjects. Control subjects excreted 24.8 +/- 1.3 per cent (mean SEM) of urinary coproporphyrin as isomer I. Patients with the Dubin-Johnson syndrome excreted 88.9 +/- 1.3 per cent as urinary coproporphyrin I, and patients with Rotor's syndrome excreted 64.8 +/- 2.5 per cent as urinary coproporphyrin I, significantly different from the control subjects and the patients with the Dubin-Johnson syndrome (p less than 0.001). Eight phenotypically normal parents and children of patients with Rotor's syndrome excreted 42.9 +/- 5.4 per cent as urinary coproporphyrin I, intermediate between results in patients with Rotor's syndrome and control subjects (p less than 0.001). Total urinary coproporphyrin excretion was markedly increased in patients with Rotor's syndrome (332 +/- 86 mug/g creatinine) as compared to that in control subjects (p less than 0.001) or obligate heterozygotes (p less than 0.025). With respect to urinary coproporphyrin excretion, Rotor's syndrome and Dubin-Johnson syndrome are both inherited as autosomal recessive traits and are separate pathophysiologic entities. Study of rare but distinct inheritable disorders, such as these, provide insight into the functional dissociation of hepatic transport mechanisms.

Relevance of urinary coproporphyrin isomers in hereditary hyperbilirubinemias.

Porphyrin metabolism is impaired in Dubin-Johnson syndrome (DJS), Rotor's syndrome (RS), and Gilbert's syndrome (GS). Urinary coproporphyrin (CP) isomer I is increased in these hereditary hyperbilirubinemias to different degrees: in DJS to 85%, in RS to 70%, and in GS to 50% in the homozygous state (p less than 0.001 compared to controls with isomer I of 27%). Intermediate isomer proportions were found in heterozygote carriers of DJS. An overlapping distribution of the isomer I/III ratio is observed in DJS and RS carriers, homozygous subjects with GS, and individuals suffering from alcohol-related intrahepatic cholestasis. The diagnosis of DJS and RS can be based mainly on porphyrin analysis, but the detection of carriers (heterozygotes) requires additional criteria to distinguish them from patients with intrahepatic cholestasis of a different etiology.

Defective hepatobiliary leukotriene elimination in patients with the Dubin-Johnson syndrome.

The Dubin-Johnson syndrome (DJS) is characterized by a hereditary conjugated hyperbilirubinemia and a typical dark pigment accumulation in liver parenchymal cells. In the present study the renal excretion of leukotrienes in five patients with histologically established DJS and five age- and sex-matched healthy subjects was investigated. Endogenous urinary leukotrienes were separated by high-performance liquid chromatography and subsequently quantified by immunoassays and gas chromatography-mass spectrometry. Patients with DJS excreted significantly (P < 0.01) greater amounts of cysteinyl leukotriene, LTE4 (8-fold), the omega-oxidation product omega-carboxy-LTE4 (15-fold) and the beta-oxidation metabolite omega-carboxy-tetranor-LTE3 (26-fold) into urine than healthy controls. These results imply that in DJS leukotriene elimination into bile is defective, leading to a compensatory renal leukotriene elimination and a typical excretion pattern of urinary leukotriene metabolites. Analysis of endogenous urinary leukotrienes seems to be a new approach to the noninvasive diagnosis of this disease.

A new diagnostic approach to the Dubin-Johnson syndrome.

Dubin-Johnson syndrome (DJS), a congenital metabolic disorder of bilirubin excretion, was classically diagnosed by the bromsulfalein (BSP) curve and needle hepatic biopsy methods. We present three cases of DJS and propose a new diagnostic approach which could conceivably become a substitute for more aggressive techniques. The results of the 24-h urine coproporphyrin determination and 99mTc-Disofenin scintigraphy gave, together, enough data for an accurate diagnosis.

Dubin-Johnson syndrome in a neonate.

We described the clinical and biochemical findings in a 32 day-old boy with the Dubin-Johnson syndrome. Only two other patients diagnosed as having the Dubin-Johnson syndrome during neonatal period have been reported in the literature. The ratio of urinary coproporphyrin isomer I of our patient was 97% and that of his parents were carrier level, confirming that increased urinary excretion of coproporphyrin isomer I is of diagnostic value in neonates with the Dubin-Johnson syndrome.

Uroporphyrinogen III cosynthetase in liver and blood in the Dubin-Johnson syndrome.

The activities of uroporphyrinogen III cosynthetase in blood lysates from five patients with the Dubin-Johnson syndrome (DJS) and four control subjects and in liver homogenates from four patients and four control subjects were determined. No significant difference was found in enzyme activity between the two groups in either blood lysate or liver homogenate. These results indicate that low urinary coproporphyrin III output in the DJS is not due to deficiency of uroporphyrinogen III cosynthetase in the liver and the erythropoietic system.

Metabolic fate of exogenous delta-aminolevulinic acid in Dubin-Johnson syndrome.

The underlying mechanism of abnormal urinary distribution of CP isomers in DJS is unknown. We administered ALA to DJS patients and carriers as well as to normal controls, and urinary and biliary porphyrins and plasma bilirubin were studied. In sharp contrast to the remarkable increase in urinary CP-III excretion in normal controls (2234 nmol/gm creatinine during the first 2 hr) after ALA, very small increase was observed in DJS patients (19 nmol). In DJS carriers the increase took intermediate values (1122 nmol). The increments in urinary CP-I were smallest in DJS patients, and the peak of its increase was delayed. These data are compatible with the hypothesis that a carrier-mediated mechanism in transporting CP-gen isomers I and III from the liver cells to the plasma may be anomalous in DJS hepatocytes and that the increased urinary CP-I characteristic of DJS may be the result of a disturbance in the uptake process of CP-gen I, derived mainly from the erythropoietic tissues, by DJS liver cells. Although the biliary percent of CP-I in controls decreased after ALA, it remained unchanged in DJS, suggesting the existence of a bile canalicular barrier against CP-gen-III in DJS. The elevated biliary porphyrins and plasma bilirubin after ALA in DJS patients favor an idea that there may be no major enzymatic derangements in the metabolic sequences from ALA to bilirubin. The increased excretion of PP in DJS bile after ALA remained to be explained.