Dubin-Johnson Syndrome Research Articles

Neonatal Dubin‐Johnson Syndrome with Severe Cholestasis: Effective Phenobarbital Therapy

We described Dubin-Johnson syndrome (DJS) with severe cholestasis in a 20-day-old Japanese boy. Although neonatal DJS has been sporadically reported. DJS with severe cholestasis has not to our knowledge been described in the English literature. The ratio of urinary coproporphyrin isomer I to urinary total coproporphyrin in our patient was high (93%). Liver histology showed cytoplasmic pigment granules in the liver cells. Administration of phenobarbital (PB) significantly decreased the levels of bilirubin and bile acids in the serum. There was a significant elevation of 1 beta-hydroxylated bile acids in the urine. It is predicted that severe cholestasis in neonatal DJS may cause metabolic abnormalities in both bilirubin and bile acids transport.

Dubin-Johnson syndrome presenting with neonatal cholestasis.

We report a case of Dubin-Johnson syndrome presenting with neonatal cholestasis. Liver histology was studied during the neonatal period and at 6 years of age. Distinct brownish pigment granules in hepatocytes were noted. This case confirms that Dubin-Johnson syndrome is a cause of neonatal cholestasis.

Defective ATP-dependent bile canalicular transport of organic anions in mutant (TR-) rats with conjugated hyperbilirubinemia.

TR- mutant Wistar rats secrete markedly fewer organic anions other than bile acids from the liver into the bile than do control rats. Fluorescence-image analysis of isolated normal and TR- hepatocyte "doublets", which retain a bile canaliculus between them, revealed that normal hepatocytes readily transport a fluorescent bile acid (fluorescein isothiocyanate glycocholate) and a nonbile acid organic anion (carboxydichlorofluorescein diacetate) into the canaliculus. Hepatocyte doublets from TR- rats also transported fluorescein isothiocyanate glycocholate normally, but transport of carboxydichlorofluorescein diacetate into the canaliculus was negligible. Vesicles derived from the canicular domain of the plasma membrane of hepatocytes (CMV) from control and TR- rats were used to characterize the transport process for 35S-labeled bromosulphthalein and 35S-labeled bromosulphthalein glutathione, which represent nonbile acid organic anions. CMV from normal rat hepatocytes had an ATP- and temperature-dependent, saturable transport process for these 35S-labeled compounds that was absent in CMV from TR- rats. CMV from TR- rats retained normal ATP-dependent transport of daunomycin, and immunologic blots with a monoclonal antibody against the multidrug resistance gene product, P-glycoprotein, revealed no difference between normal and TR-CMV. These studies reveal that the bile canaliculus in normal rats contains an ATP-dependent organic anion transport system that is functionally absent in TR- mutant rats. The defect in TR- mutant rats is phenotypically similar to that seen in mutant Corriedale sheep and in the Dubin-Johnson syndrome in man.

Melanosis coli--histochemical and immunohistochemical comparison of the pigments of melanosis coli and Dubin-Johnson syndrome

We compared the pigment of melanosis coli with the pigment of Dubin-Johnson syndrome, melanin, and lipofuscin. The pigment of melanosis coli appeared similar to lipofuscin in that it stained positively with periodic acid-Schiff, oil red-0 and Victoria blue stains and revealed negative reactions to the immunohistochemical stains for S-100 protein and neuron specific enolase, but had similarity to melanin as shown by the positive reaction to Fontana-Masson stain and negative autofluorescence. The pigment of Dubin-Johnson syndrome showed the same histochemical and immunohistochemical characteristics as that of melanosis coli. The results indicate that the pigments of melanosis coli and Dubin-Johnson syndrome are identical and are variants of lipofuscin.

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.

Pericanalicular microfilaments of hepatocytes in patients with familial non-hemolytic hyperbilirubinemia.

We observed pericanalicular webs (PCW) of liver cells in cases with familial non-hemolytic hyperbilirubinemia using electron microscopy. The area and width of PCW were determined by morphometric methods as a way of quantitating this feature. The mean PCW width was 0.175 +/- 0.003 micron (mean +/- SE) in Dubin-Johnson syndrome and 0.184 +/- 0.005 micron in Rotor's syndrome. In both of these syndromes PCW width was significantly larger than that in Gilbert's syndrome (0.124 +/- 0.003 micron) (p less than 0.01). The mean PCW area was 0.585 +/- 0.017 micron 2 in Dubin-Johnson syndrome and 0.582 +/- 0.030 micron 2 in Rotor's syndrome. Values in these two syndromes were significantly larger than that in Gilbert's syndrome (0.382 +/- 0.014 micron 2) (p less than 0.01). Widths and areas of PCW in these three syndromes were not significantly different between central, intermediate, and peripheral zones of the hepatic lobules. There was a positive correlation between serum direct bilirubin levels and widths or areas of PCW in these syndromes. These results suggested that disturbances of bile flow caused by the dysfunction of pericanalicular microfilaments are partly involved in the pathogenesis of Dubin-Johnson syndrome and Rotor's syndrome.

Hepatobiliary function studies on Dubin-Johnson syndrome using 99mTc-pyridoxyl-methyl-tryptophan (PMT).

Hepatobiliary studies on five patients with Dubin-Johnson syndrome were performed using 99mTc-PMT. Time-activity curves of the liver of the patients showed delayed excretion and that plasma elimination in the patients was prolonged compared to that of normal subjects.

Further evidence that the pigment in the Dubin-Johnson syndrome is not melanin.

The pigment in the Dubin-Johnson syndrome (DJS) is shown unequivocally not to be a typical melanin or closely related polymer. In electron spin resonance (ESR) studies of DJS pigment from a hepatoma, it is shown that, unlike true melanins, the pigment associated with the DJS syndrome has no free radical in the absence of light. Exposure to even low levels of visible light over a broad frequency range induces a free radical in the DJS pigment. Previous studies did not appreciate the sensitivity to light of this pigment and therefore erroneously concluded that the DJS pigment had a permanent free radical. The light induced ESR signal in DJS tissue has spectroscopic properties that differ significantly from any known melanins. The pigment is not extracted by lipophilic solvents and is centrifuged down at 50,000g, but not at 5,000g.

Hepatic computerized tomography in the Dubin-Johnson syndrome: Increased liver density as a diagnostic aid

Computed tomography of the liver was performed in I7 patients with Dubin-Johnson syndrome as well as 50 control patients free of liver disease. Multiple readings of liver attenuation values were made in the patients in these two groups and their values compared. The Dubin-Johnson group had liver attenuation values significantly higher than the control group but considerable overlap between the 2 groups existed. It is concluded that computed tomography may be useful as confirmatory evidence of Dubin-Johnson syndrome.

Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport.

A mutant rat strain is described with autosomal recessive conjugated hyperbilirubinemia. Transport of conjugated bilirubin and tetrabromosulfophthalein from liver to bile is severely impaired whereas uptake of organic anions from plasma to liver is normal. During the first 10 days of life, serum bilirubin levels are 147 +/- 11 mumoles per liter with 68.7% diconjugates and 27.9% monoconjugates. In adult rats, serum bilirubin is 33 +/- 8 mumoles per liter with 81.8% diconjugates and 12.1% monoconjugates vs. 0.3 +/- 0.1 mumole per liter unconjugated bilirubin in normal adult rats. Bile acid metabolism is only mildly affected. In young rats, serum bile acid levels are normal. In adult rats, bile acid levels are elevated to 49 +/- 11 mumoles per liter vs. 10 +/- 6 mumoles per liter in normal rats. The bile flow in mutant rats is reduced to about 50%. This might be caused by a reduction of the bile acid-independent bile fraction. Liver marker enzyme activities in mutant rat serum are normal. Liver morphology is also normal. Total urinary coproporphyrin excretion is not elevated but urinary coproporphyrin isomer I excretion is increased, a pattern like that in Dubin-Johnson syndrome in humans. However, unlike Dubin-Johnson syndrome, the mutant rats do not have the characteristic black hepatic pigment. These rats provide a unique model to study mechanisms of bile formation and cholestasis.

The nicotinic acid test in constitutional conjugated hyperbilirubinemias and effects of corticosteroid.

The nicotinic acid test was performed in 5 patients with Dubin-Johnson syndrome, 5 with Rotor syndrome and 13 with Gilbert's syndrome. The increment in serum bilirubin concentration and bilirubin retention 5 hr later differed; the proportion of conjugated bilirubin in the increment of total bilirubin in Dubin-Johnson and Rotor syndromes was greater than in Gilbert's syndrome. These observations suggest that the nicotinic acid test reflects, in part, impaired biliary excretion of conjugated bilirubin. The results did not differentiate the two conjugated hyperbilirubinemias. The nicotinic acid test was also performed before and after corticosteroid treatment in four patients with Dubin-Johnson or Rotor syndrome. Although serum total and unconjugated bilirubin concentrations were reduced by corticosteroids, no significant change occurred in the parameters of the nicotinic acid test, suggesting that corticosteroids may enhance uptake of bilirubin without significantly altering biliary excretion of conjugated bilirubin.

Infantile hepatic cholestasis with maternal Dubin-Johnson syndrome.

A pregnant patient had Dubin-Johnson syndrome. Although the mother had hyperbilirubinemia, there were no untoward fetal effects. The infant's neonatal course, however, was complicated by hepatitis with giant cell transformation.

正常色調の肝臓を有し，胆汁酸の再上昇現象を呈した慢性肝炎合併Ｄｕｂｉｎ‐Ｊｏｈｎｓｏｎ症候群の１例

慢性肝炎を合併したDubin-Johnson症候群(DJS)の1例を報告する.本症例で興味ある点は,1)肝は肉眼的にほぼ正常の色調を呈した,2)胆汁酸負荷試験で再上昇現象を示したことである.症例は22歳の男性.2年前に急性肝炎(非B型)に罹患.トランスアミナーゼの中等度の上昇,直接型優位の高ビリルビン血症およびBSPの再上昇を認め,腹腔鏡検査で肝はほぼ正常の色調を呈した.組織像は慢性肝炎非活動型の所見であり,主に中心帯の肝細胞内に少量の色素顆粒を認めた.空腹時血清総胆汁酸は増加,ウルソデオキシコール酸500mgを経口負荷後,総胆汁酸濃度は30分で最高値をとった後低下し,90分より再上昇を示した.空腹時総胆汁酸の増加は合併している慢性肝炎の影響も考えられたが,再上昇現象はDJSの胆汁酸代謝異常によるものと考えられた.

The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia.

A directly reacting fraction of bilirubin that is probably covalently bound to albumin (albumin-bound bilirubin) has recently been described. To determine its clinical importance we used a new high-performance liquid-chromatography technique to measure it in the serum of 200 patients with hyperbilirubinemia from various causes. Albumin-bound bilirubin was an important fraction (8 to 90 per cent) of total bilirubin in patients with hepatocellular and cholestatic jaundice as well as in patients with the Dubin-Johnson syndrome. It was not detected in normal volunteers, neonates with physiologic jaundice, or patients with Gilbert's disease or hemolysis. Thus, albumin-bound bilirubin appears in serum when hepatic excretion of conjugated bilirubin is impaired. It becomes a larger component of serum bilirubin as jaundice subsides, delaying resolution of this disorder and causing bilirubin to persist in plasma after it has disappeared from the urine.

99mTc-HIDA Cholescintigraphy in Children with Dubin-Johnson Syndrome

Tc-HIDA cholescintigraphy in Dubin-Johnson syndrome (DJS) demonstrates intense prolonged homogeneous visualization of the liver, together with delayed visualization of the gall bladder and extrahepatic ducts. Such a cholescintigram has not been described for any other hyperbilirubinemic state. Because it is a noninvasive and easy technique, it is recommended for the evaluation of children suspected of having DJS.

99mTc‐HIDA Cholescintigraphy in Children with Dubin‐Johnson Syndrome

SummaryTc‐HIDA cholescintigraphy in Dubin‐Johnson syndrome (DJS) demonstrates intense prolonged homogeneous visualization of the liver, together with delayed visualization of the gall bladder and extrahepatic ducts. Such a cholescintigram has not been described for any other hyperbilirubinemic state. Because it is a nonin‐vasive and easy technique, it is recommended for the evaluation of children suspected of having DJS.

99mTc-HIDA Cholescintigraphy in Children with Dubin-Johnson Syndrome

Tc-HIDA cholescintigraphy in Dubin-Johnson syndrome (DJS) demonstrates intense prolonged homogeneous visualization of the liver, together with delayed visualization of the gall bladder and extrahepatic ducts. Such a cholescintigram has not been described for any other hyperbilirubinemic state. Because it is a nonin-vasive and easy technique, it is recommended for the evaluation of children suspected of having DJS.

Clinicopathological studies of the Dubin-Johnson syndrome complicated with chronic hepatitis

Eleven patients with Dubin-Johnson syndrome (DJS) were studied clinicopathologically. In three patients with DJS, concomitant chronic hepatitis was observed. They showed long-standing jaundice with the symptoms of general fatigue and anorexia. Laboratory tests revealed mild hypertransaminasemia, elevated serum bilirubin (over 5.0 mg/dl) and a high level of serum Bromsulphalein (BSP) retention at 45 min (above 18%). Two patients complicated with chronic hepatitis showed a rather slow secondary rise in the BSP excretion curve in comparison with the patients who had no complication. One patient accompanied with the most severe fibrosis showed no secondary rise in the BSP excretion curve. After the treatment of the patient with phenobarbital, however, a secondary rise in the BSP excretion curve appeared and the serum BSP level was also significantly decreased at all points on the BSP excretion curve. Histological examination of the liver revealed the decreased number of the Dubin-Johnson pigments in the patients complicated with chronic hepatitis. Laparoscopically, a patient with a chronic aggressive hepatitis showed a dark gray decololization of the liver surface and another patient with a chronic aggressive hepatitis showed a black color of the liver surface with partial nodule formation.

The hepatic excretion of 131I-rose bengal and 99mTc-IDA derivatives in Rotor's syndrome.

Bilirubin kinetics and hepatobiliary excretion of some exogenous anions (BSP, 131I-rose bengal, diethyl and parabutly-IDA labeled with 99mTc) were studied in three patients presenting with Rotor's syndrome. Two were brothers; a nonjaundiced fraternal twin of one of them was also evaluated. The hepatic clearance of the radiopharmaceuticals was impaired in the affected patients but the degree of impairment was different among the tested anions, i.e., maximal for 99mTc-diethyl-IDA and minimal for 131I-rose bengal. Parabutyl-IDA was cleared better than the diethyl derivative. The metabolic derangement seems to be at the level of transfer from plasma to liver and of the hepatic storage, rather than at the level of hepatocyte excretory pathways, as in the case of Dubin-Johnson syndrome.

99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes.

99mTc-HIDA cholescintigraphy was performed in 6 patients with Dubin-Johnson syndrome and 1 patient with Rotor syndrome. In the patients with Dubin-Johnson syndrome, the cholescintigrams had a characteristic pattern of delayed visualization or nonvisualization of the gallbladder and bile ducts in the presence of intense, homogeneous, and prolonged visualization of the liver. In the patient with Rotor syndrome, the hepatobiliary system was not visualized at all. It is concluded that 99mTc-HIDA cholescintigraphy may be helpful in the diagnosis of Dubin-Johnson syndrome and Rotor syndrome and in the differential diagnosis between these two conditions.