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Aortic valve replacement in a patient with Dubin-Johnson syndrome
Aortic valve replacement in a patient with Dubin-Johnson syndrome Vincent F. Miscia, M.D., * Irwin B. Boruchow, M.D., ** Federico Pol/icina, M.D., *
and Robert S. Eliot, M.D., * Gainesville, Fla.
Dubin-Johnson syndrome is a disorder characterized by a selective defect in the hepatic excretory mechanism which results in hyperbilirubinemia.': 2, 4, 7 In such patients it would be anticipated that the trauma to red blood cells from cardiopulmonary bypass and implantation of a prosthetic valve would be associated with severe postoperative hyperbilirubinemia. This paper presents the case history of a patient with biopsyproved Dubin-Johnson syndrome who underwent successful aortic valve replacement. To our knowledge, this is the first reported case of prosthetic valve implantation in a patient with this disorder. Postoperatively, hyperbilirubinemia became remarkably exaggerated, but there was no other evidence of liver function abnormality. Case report A 69-year-old white man was admitted to the Gainesville Veterans Administration Hospital on March 7, 1972, with a 1 year history of increasing shortness of breath, chest pain, and syncope. There was no knowledge of rheumatic fever or previous heart disease. Jaundice had been continuously present since he was 17 years old. It was more From the Cardiology and Cardiovascular Surgery Services, Veterans Administration Hospital and the University of Florida School of Medicine, Gainesville, Fla. Received for publication Nov. 13, 1972. Address for reprints: Vincent F. Miscia, M.D., Division of Cardiology, Department of Medicine, University of Nebraska College of Medicine, 42nd and Dewey Ave., Omaha, Nebr. 68105. 'Cardiology Service. • 'Cardiovascular Surgery Service.
prominent during periods of infection and stress. There was no history of ethanol ingestion. Both parents were free of jaundice, but both siblings (a brother and sister) have been intermittently jaundiced since adolescence. A right upper lobectomy had been performed in 1964 for a benign lung cyst. Owing to the life-threatening significance of the symptoms, aortic valve replacement appeared to be an acceptable option. Physical examination. The patient was mildly icteric but in no distress. Blood pressure was 130/80 mm. Hg and equal in both arms. The pulse rate was 76 beats per minute and regular. Clinical findings of tight aortic stenosis were present. A well-healed right thoracotomy scar was noted. The lungs were clear, and there was no clubbing, cyanosis, or edema. The liver was non tender and normal in size. There were no spider angiomata or other stigmata of chronic liver disease. Laboratory data. The hemoglobin value was 13.0 Gm. per 100 mI. with a hematocrit value of 40 volumes per cent and normal red blood cell indices. The leukocyte count was 8,200 with a normal differential. The urine was positive for bilirubin. The total serum bilirubin was 2.5 mg. per 100 ml., with a direct fraction of 1.6 mg. per 100 ml. The levels of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), lactic dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen (BUN), and 2 hour postprandial blood sugar were all within normal limits. A bromsulphthalein (BSP) intravenous test demonstrated 26.3 per cent retention at 30 minutes, decreasing to 19.9 per cent at 45 minutes. A second elevation of 22.2 and 23.4 per cent developed at 60 and 90 minutes, respectively (normal is less than 5 per cent retention at 45 minutes). Chest roentgenogram on admission and serial films of the heart (four views with barium swallow) revealed moderate left ventricular
559
The Journa l of
560
Miscia et al.
Thoracic and Card iovasc ular Surgery
Fig. 1. Liver histology photomicrograph reveals dark brown gr anules in hep atocytes, especially in the centrilobular area. Rem ainder of the section reveals norm al liver histology. enl argement and a ring of calcium in the aort ic valve area . The lung fields displayed redistribution of pulmonary venous flow to the upper lobes. The electrocardiogram showed left ventricular hypertrophy with associated ST-T changes and sinus rhythm . Cardiac catheterization performed I week after after adm ission revealed mild elevation of the veno us and right ventricul ar end-diastolic pressur es, mild pulmonary hypertension, systemic hypertension , and an elevated end -diastolic pre ssure in the left ventricle . The aortic valve was calcified and stenotic, with a peak systolic grad ient of 70 0101. Hg. Study of the left ventricle with contrast medium displayed good contractility. Aortic root injection demonstrated mild aortic regurgitation. The cardiac index was 2.8 L. per minute per squ are meter. Selective coronary artery cineangiographic studies were normal. Hospital course. The gallbladder failed to op acify after a double dose of oral contrast medium. A liver biopsy was performed on the ninth hospital day. Grossly, the specimen was melanot ic. Histologically, the hepatic architecture was normal; how ever, many hepatocytes, particularly in the centrilobular are a, cont ained multiple small irregular gr anules of melanotic pigment consistent with the Dubin-Johnson syndrome. There was no cholestasis or inflammatory reaction (Fig . 1). A preoperative episode of atri al fibrillation with a rapid ventricular response reverted to normal sinus rhythm after digitalis had been given intravenously. Operative findings and postoperative course. On
M arch 22, 1972, the patient underwent openhe art surgery. The he avily calcified aortic valve was replaced with a No. 9 Starr-Edwards ballval ve prosthesis (Seri es 2320) without incident. On the second postoperative day , atrial fibrillation with a rapid ventricul ar response was restored to normal sinu s rhythm by electrical cardioversion. De spite adequate digit aliz ation , bur sts of atrial fibrill ation co ntinued but were subsequently con trolled with quinidine. On the da y after valve repl acement, the total bilirubin level was 2.5 mg. per 100 011. with a d irect fract ion of 1.6 mg. per 100 011. Total bilirubin levels peaked on the fifteenth postoperative day to 31.9 mg. per 100 011. with a direct fraction of 18.7 mg. per 100 ml. At thi s time, the hematocrit value was 35 volumes per cent. Throughout the hospit al course, the alkaline pho sphatase, SGOT, SGPT, LDH, and BUN levels were norm al. The pat ient was disch arged on the nineteenth postoperative day with a total bil irub in level of 22 mg . per 100 011. and a direct fraction of 16.5 mg. per 100 011. At this time the hematocrit value was 36 volumes per cent. Over the next 4 months the patient bec ame asymptomatic. Serum bilirubin levels ha ve de creased slowly since op er at ion to the pre sent values: total bilirubin 8.3 mg . per 100 mI. and direct fraction 5.4 mg . per 100 mI. (Fig . 2). The patient was ho spit alized after 4 months to determine whether the postoperative anemia and bilirubin elevation were due to hemolysis from the aort ic valve prosthesis. The hematocrit value varied from 30 to 32 vo lumes per cent. Serum foli c acid ranged from 15.6 to 16.2 nanogram s
Volume 65
Dubin-Johnson syndrome
Number 4 April,1973
35
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Fig. 2. Total serum bilirubin and direct fractions, represented by open and solid circles, respectively. Note the delay in bilirubin decline after open-heart surgery and the sustained elevation at 90 and 120 days. The postoperative level is higher than the preoperative level. per milliliter (normal is 7 to 16 nanograms per milliliter). Blood levels of vitamin B" were from 1,188 to 1,237 picograms per milliliter (normal is 200 to 900 picograms per milliliter). Urine urobilinogen levels varied from 1.16 to 1.30 mg. per 100 rnl., and reticulocyte counts ranged from 2.0 to 2.8 per cent. Urine hemosiderin and direct and indirect Coombs tests were repeatedly negative. Serum protein electrophoresis was normal. Hepatitis-associated antigen or antibody was not detectable by counterelectrophoresis. Erythrocyte survival studies by radioactive-tagged chromium 51 demonstrated a half life of 1I days (normal is 25 to 35 pays). Haptoglobin was not detectable in the serum (normal is 50 to 150 mg. per 100 mI.). Plasma hemoglobin was 46 mg. per 100 ml. (normally, none is detectable). Serum iron was 77 mg. per 100 mI., and iron binding capacity was 267 mg. per 100 ml. with 29 per cent saturation. (The normal ranges are iron 80 to 160 mg. per 100 ml. and total iron binding capacity 250 to 350 mg. per 100 ml. with 20 to 50 per cent saturation.) Peripheral blood smears revealed evidence of fragmented erythrocytes.
Discussion
The Dubin-Johnson syndrome consists of chronic or intermittent hyperbilirubinemia with darkly pigmented material in otherwise normal liver cells." 2,:; The nature of the pigment is unknown." S The disorder is inherited, and its mode of transmission is unknown, :; It is a lifelong disease with an excellent prognosis.' The patient exhibited chronic hyperbilirubinemia of the Dubin-Johnson type with
no other evidence of liver dysfunction. The disorder is considered to be a defect in the hepatic excretory mechanism which has no effect on tests of synthetic liver function." 4, 7 We are unaware of previously reported cases in which aortic valve replacement, or any other type of cardiac surgery, had been performed in patients with this disease. The diagnosis was suspected because of persistent chronic jaundice of over 50 years' duration, a family history in two siblings, inability to opacify the gallbladder with Telepaque,"- :; and a characteristic "double peak" when BSP was given intravenously." :; The diagnosis of Dubin-Johnson syndrome was unequivocally established by liver biopsy which demonstrated characteristic melanotic pigment in the centrilobular hepatocytes with otherwise normal liver cells. i , :; The normal function tests obtained in this patient were typical of this syndrome,l,:; As there was no histologic evidence of fibrosis, fat, or inflammation, it was considered that the patient had no underlying liver pathology. Predictably, marked jaundice developed postoperatively because of the stress of surgery,? and intravascular hemolysis developed as a result of the cardiopulmonary bypass and the presence of the aortic valve prosthesis.": '0 However, despite the marked bilirubin elevation, the patient did quite welI in
562
The Journal of
Miscia et al.
Thoracic and Cardiovascular Surgery
the postoperative period. In the fourth month after the operation, the total bilirubin was 8.3 mg. per 100 ml., higher than the preoperative level of 2.5 mg. per 100 ml. (Fig. I). This was the result of chronic intravascular hemolysis from the accelerated destruction of red blood cells after implantation of a prosthetic valve in a patient with a congenital defect in the hepatic excretory mechanism. The available evidence supports the concept that accelerated red cell destruction is the result of turbulence around the prosthetic valve.": 10 The extreme degree of postoperative hyperbilirubinemia in DubinJohnson syndrome after aortic valve replacement did not appear to contraindicate valve replacement in the absence of underlying liver pathology. Summary An aortic valve prosthesis was successfully implanted in a patient with known Dubin-Johnson syndrome. Predictably, the stress of surgery combined with the trauma to red blood cells from cardiopulmonary bypass and prosthetic valve implantation was associated with marked postoperative hyperbilirubinemia and hemolysis. There was no evidence of hepatic damage or clinical complication related to the marked bilirubinemia or hemoglobinemia. The experience with this patient suggests that open-heart surgery may be performed in similar patients who have otherwise normal liver function, despite marked postoperative hyperbilirubinemia.
REFERENCES Porush, J. G., Delman, A. J., and Feuer, M. M.: Chronic Idiopathic Jaundice With Normal Liver Histology, Arch. Intern. Med. 109: 302, 1962. 2 Dubin, I. N.: Rotors Syndrome and Chronic Idiopathic Jaundice (Editorial), Arch. Intern. Med. 110: 823, 1962. 3 Mandema, E., De Fraiture, W. H., Nieweg, H. D., and Arends, A: Familial Chronic Idiopathic Jaundice (Dubin-Sprintz Disease), With a Note on Bromsulphthalein Metabolism in This Disease, Am. J. Med. 28: 42, 1970. 4 Shani, M., Gilon, E., Ben-Ezzer, J., and Sheba, C.: Sulfobromphthalein Tolerance Test in Patients With Dubin-Johnson Syndrome and Their Relatives, Gastroenterology 59: 842, 1970. 5 Shani, M., Seligsohn, U., Gilon, E., Sheba, C., and Adam, A: Dubin-Johnson Syndrome in Israel in a Clinical Laboratory and Genetic Aspects of 101 Cases, Q. J. Med. 156: 549, 1970. 6 Farmer, R. G., Hawk, W. A, and Sullivan, B. H., Jr.: Dubin-Johnson Syndrome With Varied Manifestations: Report of Two Cases, Cleve. Clin. Q. 38: 65, 1971. 7 Dubin, I. N.: Chronic Idiopathic Jaundice: A Review of Fifty Cases, Am. J. Med. 24: 26, 1958. 8 Dubin, I. N., and Johnson, F. B.: Chronic Idiopathic Jaundice With Unidentified Pigment in Liver Cells, Medicine 33: 154, 1954. 9 DeCesare, W., Rath, C, and Hufnagel, c.: Hemolytic Anemia of Mechanical Origin With Aortic-Valve Prosthesis, N. Eng!. J. Med. 272: 1045, 1965. 10 Boruchow, I. B., Ramsey, H. W., and Wheat, M. W.: Complications Following Destruction of the Cloth Covering of a Starr-Edwards Aortic Valve Prosthesis, J. THORAC. CARDIOVASCo SURG. 62: 29, 1971.
and Robert S. Eliot, M.D., * Gainesville, Fla.
Dubin-Johnson syndrome is a disorder characterized by a selective defect in the hepatic excretory mechanism which results in hyperbilirubinemia.': 2, 4, 7 In such patients it would be anticipated that the trauma to red blood cells from cardiopulmonary bypass and implantation of a prosthetic valve would be associated with severe postoperative hyperbilirubinemia. This paper presents the case history of a patient with biopsyproved Dubin-Johnson syndrome who underwent successful aortic valve replacement. To our knowledge, this is the first reported case of prosthetic valve implantation in a patient with this disorder. Postoperatively, hyperbilirubinemia became remarkably exaggerated, but there was no other evidence of liver function abnormality. Case report A 69-year-old white man was admitted to the Gainesville Veterans Administration Hospital on March 7, 1972, with a 1 year history of increasing shortness of breath, chest pain, and syncope. There was no knowledge of rheumatic fever or previous heart disease. Jaundice had been continuously present since he was 17 years old. It was more From the Cardiology and Cardiovascular Surgery Services, Veterans Administration Hospital and the University of Florida School of Medicine, Gainesville, Fla. Received for publication Nov. 13, 1972. Address for reprints: Vincent F. Miscia, M.D., Division of Cardiology, Department of Medicine, University of Nebraska College of Medicine, 42nd and Dewey Ave., Omaha, Nebr. 68105. 'Cardiology Service. • 'Cardiovascular Surgery Service.
prominent during periods of infection and stress. There was no history of ethanol ingestion. Both parents were free of jaundice, but both siblings (a brother and sister) have been intermittently jaundiced since adolescence. A right upper lobectomy had been performed in 1964 for a benign lung cyst. Owing to the life-threatening significance of the symptoms, aortic valve replacement appeared to be an acceptable option. Physical examination. The patient was mildly icteric but in no distress. Blood pressure was 130/80 mm. Hg and equal in both arms. The pulse rate was 76 beats per minute and regular. Clinical findings of tight aortic stenosis were present. A well-healed right thoracotomy scar was noted. The lungs were clear, and there was no clubbing, cyanosis, or edema. The liver was non tender and normal in size. There were no spider angiomata or other stigmata of chronic liver disease. Laboratory data. The hemoglobin value was 13.0 Gm. per 100 mI. with a hematocrit value of 40 volumes per cent and normal red blood cell indices. The leukocyte count was 8,200 with a normal differential. The urine was positive for bilirubin. The total serum bilirubin was 2.5 mg. per 100 ml., with a direct fraction of 1.6 mg. per 100 ml. The levels of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), lactic dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen (BUN), and 2 hour postprandial blood sugar were all within normal limits. A bromsulphthalein (BSP) intravenous test demonstrated 26.3 per cent retention at 30 minutes, decreasing to 19.9 per cent at 45 minutes. A second elevation of 22.2 and 23.4 per cent developed at 60 and 90 minutes, respectively (normal is less than 5 per cent retention at 45 minutes). Chest roentgenogram on admission and serial films of the heart (four views with barium swallow) revealed moderate left ventricular
559
The Journa l of
560
Miscia et al.
Thoracic and Card iovasc ular Surgery
Fig. 1. Liver histology photomicrograph reveals dark brown gr anules in hep atocytes, especially in the centrilobular area. Rem ainder of the section reveals norm al liver histology. enl argement and a ring of calcium in the aort ic valve area . The lung fields displayed redistribution of pulmonary venous flow to the upper lobes. The electrocardiogram showed left ventricular hypertrophy with associated ST-T changes and sinus rhythm . Cardiac catheterization performed I week after after adm ission revealed mild elevation of the veno us and right ventricul ar end-diastolic pressur es, mild pulmonary hypertension, systemic hypertension , and an elevated end -diastolic pre ssure in the left ventricle . The aortic valve was calcified and stenotic, with a peak systolic grad ient of 70 0101. Hg. Study of the left ventricle with contrast medium displayed good contractility. Aortic root injection demonstrated mild aortic regurgitation. The cardiac index was 2.8 L. per minute per squ are meter. Selective coronary artery cineangiographic studies were normal. Hospital course. The gallbladder failed to op acify after a double dose of oral contrast medium. A liver biopsy was performed on the ninth hospital day. Grossly, the specimen was melanot ic. Histologically, the hepatic architecture was normal; how ever, many hepatocytes, particularly in the centrilobular are a, cont ained multiple small irregular gr anules of melanotic pigment consistent with the Dubin-Johnson syndrome. There was no cholestasis or inflammatory reaction (Fig . 1). A preoperative episode of atri al fibrillation with a rapid ventricular response reverted to normal sinus rhythm after digitalis had been given intravenously. Operative findings and postoperative course. On
M arch 22, 1972, the patient underwent openhe art surgery. The he avily calcified aortic valve was replaced with a No. 9 Starr-Edwards ballval ve prosthesis (Seri es 2320) without incident. On the second postoperative day , atrial fibrillation with a rapid ventricul ar response was restored to normal sinu s rhythm by electrical cardioversion. De spite adequate digit aliz ation , bur sts of atrial fibrill ation co ntinued but were subsequently con trolled with quinidine. On the da y after valve repl acement, the total bilirubin level was 2.5 mg. per 100 011. with a d irect fract ion of 1.6 mg. per 100 011. Total bilirubin levels peaked on the fifteenth postoperative day to 31.9 mg. per 100 011. with a direct fraction of 18.7 mg. per 100 ml. At thi s time, the hematocrit value was 35 volumes per cent. Throughout the hospit al course, the alkaline pho sphatase, SGOT, SGPT, LDH, and BUN levels were norm al. The pat ient was disch arged on the nineteenth postoperative day with a total bil irub in level of 22 mg . per 100 011. and a direct fraction of 16.5 mg. per 100 011. At this time the hematocrit value was 36 volumes per cent. Over the next 4 months the patient bec ame asymptomatic. Serum bilirubin levels ha ve de creased slowly since op er at ion to the pre sent values: total bilirubin 8.3 mg . per 100 mI. and direct fraction 5.4 mg . per 100 mI. (Fig . 2). The patient was ho spit alized after 4 months to determine whether the postoperative anemia and bilirubin elevation were due to hemolysis from the aort ic valve prosthesis. The hematocrit value varied from 30 to 32 vo lumes per cent. Serum foli c acid ranged from 15.6 to 16.2 nanogram s
Volume 65
Dubin-Johnson syndrome
Number 4 April,1973
35
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120
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Fig. 2. Total serum bilirubin and direct fractions, represented by open and solid circles, respectively. Note the delay in bilirubin decline after open-heart surgery and the sustained elevation at 90 and 120 days. The postoperative level is higher than the preoperative level. per milliliter (normal is 7 to 16 nanograms per milliliter). Blood levels of vitamin B" were from 1,188 to 1,237 picograms per milliliter (normal is 200 to 900 picograms per milliliter). Urine urobilinogen levels varied from 1.16 to 1.30 mg. per 100 rnl., and reticulocyte counts ranged from 2.0 to 2.8 per cent. Urine hemosiderin and direct and indirect Coombs tests were repeatedly negative. Serum protein electrophoresis was normal. Hepatitis-associated antigen or antibody was not detectable by counterelectrophoresis. Erythrocyte survival studies by radioactive-tagged chromium 51 demonstrated a half life of 1I days (normal is 25 to 35 pays). Haptoglobin was not detectable in the serum (normal is 50 to 150 mg. per 100 mI.). Plasma hemoglobin was 46 mg. per 100 ml. (normally, none is detectable). Serum iron was 77 mg. per 100 mI., and iron binding capacity was 267 mg. per 100 ml. with 29 per cent saturation. (The normal ranges are iron 80 to 160 mg. per 100 ml. and total iron binding capacity 250 to 350 mg. per 100 ml. with 20 to 50 per cent saturation.) Peripheral blood smears revealed evidence of fragmented erythrocytes.
Discussion
The Dubin-Johnson syndrome consists of chronic or intermittent hyperbilirubinemia with darkly pigmented material in otherwise normal liver cells." 2,:; The nature of the pigment is unknown." S The disorder is inherited, and its mode of transmission is unknown, :; It is a lifelong disease with an excellent prognosis.' The patient exhibited chronic hyperbilirubinemia of the Dubin-Johnson type with
no other evidence of liver dysfunction. The disorder is considered to be a defect in the hepatic excretory mechanism which has no effect on tests of synthetic liver function." 4, 7 We are unaware of previously reported cases in which aortic valve replacement, or any other type of cardiac surgery, had been performed in patients with this disease. The diagnosis was suspected because of persistent chronic jaundice of over 50 years' duration, a family history in two siblings, inability to opacify the gallbladder with Telepaque,"- :; and a characteristic "double peak" when BSP was given intravenously." :; The diagnosis of Dubin-Johnson syndrome was unequivocally established by liver biopsy which demonstrated characteristic melanotic pigment in the centrilobular hepatocytes with otherwise normal liver cells. i , :; The normal function tests obtained in this patient were typical of this syndrome,l,:; As there was no histologic evidence of fibrosis, fat, or inflammation, it was considered that the patient had no underlying liver pathology. Predictably, marked jaundice developed postoperatively because of the stress of surgery,? and intravascular hemolysis developed as a result of the cardiopulmonary bypass and the presence of the aortic valve prosthesis.": '0 However, despite the marked bilirubin elevation, the patient did quite welI in
562
The Journal of
Miscia et al.
Thoracic and Cardiovascular Surgery
the postoperative period. In the fourth month after the operation, the total bilirubin was 8.3 mg. per 100 ml., higher than the preoperative level of 2.5 mg. per 100 ml. (Fig. I). This was the result of chronic intravascular hemolysis from the accelerated destruction of red blood cells after implantation of a prosthetic valve in a patient with a congenital defect in the hepatic excretory mechanism. The available evidence supports the concept that accelerated red cell destruction is the result of turbulence around the prosthetic valve.": 10 The extreme degree of postoperative hyperbilirubinemia in DubinJohnson syndrome after aortic valve replacement did not appear to contraindicate valve replacement in the absence of underlying liver pathology. Summary An aortic valve prosthesis was successfully implanted in a patient with known Dubin-Johnson syndrome. Predictably, the stress of surgery combined with the trauma to red blood cells from cardiopulmonary bypass and prosthetic valve implantation was associated with marked postoperative hyperbilirubinemia and hemolysis. There was no evidence of hepatic damage or clinical complication related to the marked bilirubinemia or hemoglobinemia. The experience with this patient suggests that open-heart surgery may be performed in similar patients who have otherwise normal liver function, despite marked postoperative hyperbilirubinemia.
REFERENCES Porush, J. G., Delman, A. J., and Feuer, M. M.: Chronic Idiopathic Jaundice With Normal Liver Histology, Arch. Intern. Med. 109: 302, 1962. 2 Dubin, I. N.: Rotors Syndrome and Chronic Idiopathic Jaundice (Editorial), Arch. Intern. Med. 110: 823, 1962. 3 Mandema, E., De Fraiture, W. H., Nieweg, H. D., and Arends, A: Familial Chronic Idiopathic Jaundice (Dubin-Sprintz Disease), With a Note on Bromsulphthalein Metabolism in This Disease, Am. J. Med. 28: 42, 1970. 4 Shani, M., Gilon, E., Ben-Ezzer, J., and Sheba, C.: Sulfobromphthalein Tolerance Test in Patients With Dubin-Johnson Syndrome and Their Relatives, Gastroenterology 59: 842, 1970. 5 Shani, M., Seligsohn, U., Gilon, E., Sheba, C., and Adam, A: Dubin-Johnson Syndrome in Israel in a Clinical Laboratory and Genetic Aspects of 101 Cases, Q. J. Med. 156: 549, 1970. 6 Farmer, R. G., Hawk, W. A, and Sullivan, B. H., Jr.: Dubin-Johnson Syndrome With Varied Manifestations: Report of Two Cases, Cleve. Clin. Q. 38: 65, 1971. 7 Dubin, I. N.: Chronic Idiopathic Jaundice: A Review of Fifty Cases, Am. J. Med. 24: 26, 1958. 8 Dubin, I. N., and Johnson, F. B.: Chronic Idiopathic Jaundice With Unidentified Pigment in Liver Cells, Medicine 33: 154, 1954. 9 DeCesare, W., Rath, C, and Hufnagel, c.: Hemolytic Anemia of Mechanical Origin With Aortic-Valve Prosthesis, N. Eng!. J. Med. 272: 1045, 1965. 10 Boruchow, I. B., Ramsey, H. W., and Wheat, M. W.: Complications Following Destruction of the Cloth Covering of a Starr-Edwards Aortic Valve Prosthesis, J. THORAC. CARDIOVASCo SURG. 62: 29, 1971.