Congenital Dyserythropoietic Anemia and the Dubin-Johnson Syndrome

Vol. 67 , No.4

GASTROENTEROLOGY 67:686-690, 1974 Copyright@ 1974 by The Williams & Wilkins Co.

Printed in U.S.A.

CONGENITAL DYSERYTHROPOIETIC ANEMIA AND THE DUBIN-JOHNSON SYNDROME A case report J.-P.

CLAUVEL,

M .D.,

:"ND

S.

ERLINGER,

M.D.

Service du Pr.Jean Bernard, Hopital Saint Louis , Paris, France, and Unite de Recherches de Physiopdthologie Hepatique (INSERM), Hopital Beaujon, Clichy, France

A patient with type II congenital dyserythropoietic anemia and the Dubin-Johnson syndrome is reported. Serum conjugated bilirubin concentration was above 30 mg per 100 ml; this was interpreted as a result of both increased production of bilirubin and decreased elimination due to the hepatic excretory defect. This association has not previously been reported and may be expected to be extremely rare. The Dubin-Johnson syndrome is a chronic, benign, familial, idiopathic jaundice with conjugated hyperbilirubinemia, bilirubinuria, and a brown pigment in the liver cells. 1 - 4 Congenital dyserythropoietic anemia is a rare condition defined by therapy-refractory anemia with an ineffective erythropoiesis and characteristic morphological alterations of the erythroblasts. s- 9 On the basis of bone marrow morphology, three types, designated I, II, and III, have been distinguished. 5 This report describes the clinical and laboratory features of a patient suffering from the Dubin-Johnson syndrome and type II congenital dyserythropoietic anemia. Case Report M . S. (who is patient 5 in ref. 8) is a 26-year-old male patient, born of Algerian parents. He has one brother and one sister, neither of whom have jaundice. Deep jaundice, with dark urine and normally colored stools, was Received November 20, 1973. Accepted February 20, 1974. Address requests for reprints to: Dr. Serge Edinger, Unite de Recherches de Physiopathologie Hepatique, H6pital Beaujon, 92110 Clichy, France. The authors thank Dr. A. Gajdos for urinary coproporphyrin determinations, Professor P. Boivin for red cell enzymes assays, and Professor F. Potet for liver biopsy interpretation.

noted at birth; it decreased progressively during the first 6 months of life, aJ;J.d a moderate jaundice is said to have persisted thereafter . At the age of 4, he was admitted to the hospital. Jaundice and bilirubinuria were present; total bilirubin was 15.8 mg per 100 ml and unconjugated bilirubin 6.4 mg per 100 ml; the red blood cells were 3,760,000 per J.Ll, hemoglobin, 12.2 g per 100 ml; reticulocytes , 53,000 per J.Ll, leukocytes, 6,400 per J.Ll; the bone marrow showed 62% erythroblasts . At the age of 9, the spleen was found to be markedly enlarged and a splenectomy was performed. Jaundice has persisted, with variable intensity. At the age of 26, he was admitted to the hospital for additional investigation of the jaundice. His general condition was good. His liver was 14 em on the midclavicular line. His urine was dark, and the stools were normally colored. Clinical examination was otherwise normal.

Laboratory Findings Hematology. Hemoglobin was 12.5 g per 100 ml; red blood cells were 4,300,000 per J.Ll; mean corpuscular volume was 102 J.Lm 3 ; reticulocytes were 45,000; leukocytes, 10,500; and platelets 550,000 per J.LL Red cell enzymes (hexokinase, glucose-6-phosphate dehydrogenase, glucose phosphate isomerase, phosphofructokinase, glyceraldehyde phosphate dehydrogenase, phosphoglycerate kinase, enolase, pyruvate kinase, 6-phosphogluconate dehydrogenase) ,

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DYSERYTHROPOIESIS AND DUBIN-JOHNSON SYNDROME

and hemoglobin electrophoresis were normal. Serum iron was 350 J.Lg per 100 ml, and total iron-binding capacity was 480 J.,Lg per 100 ml. The bone marrow was hypercellular (fig. 1), with 62% erythroblasts, most of them oxyphilic; 25% of the erythroblasts, chiefly the more mature forms, had two nuclei, sometimes more or multilobulated nuclei. At electron microscopy, a double cell membrane, probably originating from the endoplasmic reticulum, was seen in the periphery of most of the late erythroblasts. At phase contrast microscopy of the ghost, pieces of this membrane remained in 43% of the mature red cells. Serology. The acidified serum test 6 was positive. The red cells were strongly agglutinated by anti-i and anti-I sera. Coombs test was negative. Erythrokinetics (table 1). Red cells survival, estimated with the patient's red cells, labeled with 51 Cr, in his own circulation, was slightly shortened . 59 Fe

b

~o 7

FIG. 1. Aspect of a bone marrow smear. Note the erythroblastic hyperplasia and binuclearity.

TABLE

1. Erythrokinetics (normal values in

parentheses) Red cell survival (patient's own cells) "Cr t~; (days) Plasma "Fe clearance, t ~; (min) "Fe incorporation after 15 days

22 (30 ± 4) 62 (61- 114) 30 (75-85)

(%)

Calculated peripheral hemolysis

2.5-3 (0.85)

(%)

incorporation 10 into erythrocytes was decreased and surface counting showed predominant bone marrow uptake. Biochemical data and liver biopsy. Serum total bilirubin was 44 mg per 100 ml, and unconjugated bilirubin was 3.3 mg per 100 ml. Serum glutamic pyruvic transaminase was 110 Karmen units, and alkaline phosphatase was 11 King-Armstrong units. The plasma disappearance curve of bromsulphalein, determined by the method of Seligson et al. 11 to avoid the error due to the high bilirubin levels, showed a slightly delayed decay during the first 30 min, and a secondary rise after 45 min (fig. 2). Total urinary coproporphyrins were 504 J.,Lg per liter (normal less than 300 J.Lg per liter); coproporphyrin I was 75%, and coproporphyrin III 25%. Histological examination of a needle biopsy specimen (fig. 3) showed normal liver architecture and the presence, chiefly periportal, of abundant dark brown pigment in hepatocytes; there was slight portal fibrosis , mild steatosis, and iron in periportal liver cells. A duodenoscopic cholangiography, aimed at verifying the patency of the common bile duct, was normal.

Discussion The hematological findings of this patient correspond well with those of type II congenital dyserythropoietic anemia as classified by Heimpel and Wendt, 5 also designated hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS) 9 ; anemia was moderate and well tolerated; the spleen was enlarged when it was removed when the patient was 9; the bone marrow showed characteristic binuclearity within numerous oxyphilic erythroblasts and characteristic ultrastruc-

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CLAUVEL AND ERLINGER

Vol . 67, No . 4

100

PLASMA [BSP] mg.l- 1 50

T112

10 min

K1

0.07

10

oJ~------~--------~----

o 60 120 min FIG. 2. Bromsulphalein (ESP) plasma disappearance curve, after a single injection of 5 mg per kg. Note a slightly delayed disappearance during the first 20 min, and the rise in plasma concentration after 45 min. (t "'' half-time; K" plasma disappearance rate; normal, 0.11 to 0.16). tural abnormalities. 12 Acidified serum test 6 (i.e., lysis of the patient's red cells by acidified normal sera) was positive; this indicates the presence, on the patient's red cells, of an antigen which reacts with an agglutinating allo-antibody present in a high proportion of normal sera, and it has been observed in patients with type II congenital dyserythropoietic anemia. 6 Peripheral red cell survival was moderately shortened, and erythrokinetic studies with 59 Fe showed that anemia was mostly due to ineffective erythropoiesis . Patients with this condition usually have a variable jaundice due to unconjugated hyperbilirubinemia. 9 The patient had deep jaundice, first noted at birth, due mainly to conjugated hyperbilirubinemia with bilirubinuria. The common bile duct was patent, as demonstrated by duodenoscopic cholangiography, and the most likely explanation for the conjugated hyperbilirubinemia was the existence of a congenital transport defect of bilirubin. Three types of congenital conjugated hyperbilirubinemia, have, so far, been described: the Dubin-Johnson syndrome, 1 - 4 the Rotor syndrome, 1 3 and the "hepatic storage disease." 14 • 15 The laboratory findings in this patient are consistent with the Dubin-Johnson syndrome ; a secondary rise in plasma bromsulphalein concentration after a single injection, characteristic of the Dubin-Johnson syn-

drome 16 - 18 was seen; such a secondary rise is not observed in the hepatic storage disease 14 • 15 and has not been reported in the Rotor syndrome 1 3 • 19 ; the brown pigment observed at optical microscopy in parenchymal liver cells was also characteristic of the Dubin-Johnson syndrome, and likewise has not been observed in the Rotor and hepatic storage types 13 - 1 5 ; moreover, no such pigment was found in patients with type II congenital dyserythropoietic anemia in whom a liver biopsy was performed .9 • 20 - 22 The iron deposition in periportal liver cells, slight periportal fi· brosis, as well as the slightly elevated serum glutamic pyruvic transaminase activity, were probably the result of iron overload: the patient did not ingest alcohol , and iron deposits, 22 which may be associated with fibrosis or cirrhosis, 9 have already been observed in patients with type II congenital dyserythropoietic anemia. Finally, the urinary coi:noporphyrin pattern, with predominant co· proporphyrin I excretion, has also been observed in patients with the Dubin~John· son syndrome and their relatives .23 ' 25 Bilirubinemia in patients with congenital dyserythropoietic anemia is moderately elevated, usually less than 6 mg' per 100 ml. 9 Bilirubinemia in this patient was above 30 mg per 100 ml; when bilirubi· nemia exceeds 25 mg per 109 ml, increased

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DYSERYTHROPOIESIS AND DUBIN-JOHNSON SYNDROME

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the Dubin-Johnson syndrome. In view of the rarity of both conditions, the probability of such an association may be expected to be extremely low. However, whether the association is not fortuitous in our patient is unknown. REFERENCES

FIG. 3. Liver biopsy specimen. Note the dark pigment in hepatocytes, around a centrolobular vein (at the lower part of the field) (Ziehl stain, x 400) .

bilirubin production or renal failure are likely to be present 26 ; in our patient, although studies of bilirubin metabolism were not performed, the association of an increased bilirubin production (chiefly as a result of ineffective erythropoiesis), and of an impaired biliary excretion of bilirubin (as a,, result of the Dubin-Johnson syndrome), probably accounted for the very high bilirubin levels. This is, to the best of our knowledge, the first example of an association between congenital dyserythropoietic anemia and

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