- Email: [email protected]
Alagille syndrome and pregnancy: anesthetic management for cesarean section
F.C. Rahmoune et al.
355
Alagille syndrome and pregnancy: anesthetic management for cesarean section F.C. Rahmoune, M. Bruye`re, M. Tecsy, D. Benhamou AP-HP, Hoˆpital Biceˆtre, Service d’Anesthe´sie-Re´animation, Le Kremlin-Biceˆtre, France ABSTRACT A 34-year-old multiparous woman with a breech presentation, intrauterine growth restriction and premature rupture of membranes was transferred to our referral unit at 33 weeks of gestation. She was diagnosed with Alagille syndrome soon after birth because of cholestasis and pruritus. Her condition was later complicated by esophageal varices, treated with propranolol, thrombocytopenia, and insulin-dependent diabetes. She had characteristic facies, posterior embryotoxon, ‘‘butterfly’’ vertebrae but had no cardiac or renal abnormalities. Due to the early onset of spontaneous labor, emergency cesarean section under general anesthesia was performed 48 h after admission. This is the first case describing anesthetic care during delivery in a patient with Alagille syndrome. We discuss the anesthetic implications of the syndrome, emphasizing problems associated with portal hypertension and cholestasis, thrombocytopenia and cardiac abnormalities such as pulmonary artery stenosis. c 2011 Elsevier Ltd. All rights reserved.
Keywords: Alagille syndrome; Portal hypertension; Cholestasis; Pregnancy; General anesthesia; Cesarean section
Introduction Alagille syndrome (AS) is a multi-system hereditary disorder described by Watson and Miller in 19731 and Alagille in 1975.2 The major characteristics of this arteriohepatic dysplasia include hepatic, cardiac, ophthalmic, skeletal, renal and craniofacial abnormalities.3 Its incidence lies between 1 in 70 000 and 1 in 100 000 births.4 It has an autosomal dominant pattern of inheritance, linked to a mutation in the Jagged1 gene (JAG1)5 which is found in 70–90% of cases. The management of cholestasis, which results from intrahepatic bile duct paucity, is symptomatic and includes the use of dietary measures, fat-soluble vitamin (ADEK) supplementation, and the administration of ursodeoxycholic acid in the case of pruritus. Morbidity and early mortality are linked to cardiac abnormalities.6 The severity of liver disease determines the prognosis in adult patients.4 We report the anesthetic management of a patient with AS for cesarean section (CS).
Case report A 34-year-old G3P2 woman was transferred to our maternity unit with premature rupture of membranes at 31 weeks of gestation, intrauterine growth restriction (IUGR) and a breech presentation. She had been diagnosed with AS at birth. Clinical features present during adulthood were cholestasis, pruritus treated with ursoAccepted June 2011 Correspondence to: Pr. Dan Benhamou, Service d’Anesthe´sie-Re´animation, 78 Rue du Ge´ne´ral Leclerc, 94275 Le Kremlin-Biceˆtre, France. E-mail address: [email protected]
deoxycholic acid, portal hypertension with grade II esophageal varices treated with propranolol, thrombocytopenia with platelet counts ranging from 40 · 109/L to 55 · 109/L of mixed origin (anti-platelet antibody positive and hypersplenism), and facial deformity. The patient had no cardiac abnormalities. She had been diagnosed with insulin-dependent diabetes at five years of age. During the postpartum period following her first pregnancy, the patient had presented with acute pulmonary edema, requiring mechanical ventilation for seven days. For the delivery of her second child, she had a CS under spinal anesthesia with intraoperative platelet transfusion because of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Investigation for the JAG1 genetic mutation was negative for the first infant and positive for the second. During the course of her disease she required several admissions to hospital for jaundice and disturbances of liver function but her cholestasis had remained stable in recent years. During her current pregnancy, hepatobiliary ultrasound performed at 14 weeks of gestation and biological parameters were unchanged. However, because of increasing severity of pruritus, the dose of ursodeoxycholic acid was increased to 600 mg/day. Laboratory examination on admission showed cholestasis, moderate anemia and normal coagulation (Table 1). A multidisciplinary staff meeting concluded that because of esophageal varices, together with a scarred uterus, breech presentation, IUGR and thrombocytopenia, expulsive efforts were contraindicated. It was decided to perform an elective CS at 34 weeks under general anesthesia. However, as the woman went into
356
Alagille syndrome
spontaneous labor, emergency CS was performed 48 h after admission. General anesthesia was induced using a rapid-sequence induction with cricoid pressure with thiopental 350 mg and succinylcholine 80 mg; tracheal intubation was uneventful (Cormack and Lehane grade II). A 1060-g female infant with Apgar scores of 8, 8 and 9 at 1, 5 and 10 min, respectively, was delivered and transferred to the neonatal resuscitation unit. Anesthesia was maintained with desflurane and atracurium 40 mg. Following delivery, sufentanil 15 lg, carbetocin 100 lg and co-amoxiclav 2 g were administered intravenously. A prophylactic transfusion of six platelet concentrates was given intraoperatively. Lactated Ringer’s solution 1000 mL and 5% dextrose 200 mL were also infused. Estimated blood loss was 200 mL. Postoperatively, hemodynamic parameters were stable. After consultation with a hematologist, a second transfusion of five platelet concentrates was given due persistent moderate bleeding. The immediate postoperative results showed unchanged liver function and a satisfactory coagulation profile (Table 1). Propranolol was administered before CS and was continued after surgery. Postoperative analgesia was managed with nefopam and intravenous morphine. Non-steroidal anti-inflammatory drugs and paracetamol were avoided. Elastic compression stockings and early mobilization were used for thromboprophylaxis and anticoagulants were not administered initially because of thrombocytopenia. Hemodynamic parameters remained stable and neither worsening of cholestasis nor changes in renal function were detected by the fifth postoperative day. Four months after delivery, the baby was well and her JAG1 mutation was positive.
Discussion The features of AS are listed in Table 2. There is little documentation concerning anesthetic management of adult patients with AS with most reported cases relating to children under five years of age undergoing liver surgery.7–9 For females with AS who reach adulthood, de-
Table 1
tailed management during pregnancy and childbirth have rarely been documented.10,11 Cholestasis, resulting from intrahepatic bile duct paucity, is the main manifestation of AS and appears in the first three months of life in 45–75%, and in the remainder before three years of age.4 Cholestasis can progress to cirrhosis in 10–15% of cases. The resulting vitamin K deficiency may be responsible for coagulopathy with prolonged prothrombin time (PT). Thrombocytopenia, secondary to hypersplenism and splenomegaly is often found.4 Liver transplantation is indicated in 15–50% of cases depending on the severity of jaundice and pruritus.12 Liver failure and portal hypertension may also occur. In women with cirrhosis caused by liver failure, the combination of portal hypertension and pregnancy is rare because of subfertility due to disruption of estrogen metabolism.13 In the context of non-cirrhotic portal hypertension, as in our case, fertility is similar to that of the general population.13 The main fetal complications are early abortion (3–13%) and prematurity (18– 20%).14 On the maternal side, gastrointestinal bleeding may occur with an incidence of 6–22%.15 Some physiological changes unique to pregnancy may trigger esophageal variceal rupture. These include an increase in cardiac output, splanchnic and portal compression, and particularly uterine development which raises intra-abdominal pressure, leading to an accentuation of portal pressure in the esophageal venous system.16 b-Blocker therapy can effectively prevent these complications, explaining why it is maintained throughout pregnancy despite a known risk of IUGR. Endoscopic management (sclerotherapy and ligation) of esophageal varices rupture is possible without maternal and fetal impact.16 Infection and hepatotoxic drugs should also be avoided as they may cause gastrointestinal bleeding.16 During delivery, obstetric trauma and expulsive efforts should be minimized and forceps or suction delivery are recommended.16 In patients with AS, cardiac anomalies are found in 85–95% of cases.7 Localized stenosis of peripheral branches of the pulmonary arteries is the most common anomaly (75–90%),5,9 although non-progressive and
Maternal blood results
AST (U/L) [normal 10–35] ALT (U/L) [normal 5–35] LAP (U/L) [normal 35–105] GGT (U/L) [normal 5–40] Hemoglobin (g/dL) Platelets (·109/L) Prothrombin time (%) aPTT (s) [normal < 41 s]
Admission
Pre-op
1 h postop
6 h postop
48 h postop
85 77 500 273 10.2 42 100 32/35
80 70 443 287 10.7 52 100 31/35
65 54 396 200 8.9 96 91 31/35
83 55 404 176 8.4 85 98 33/35
68 54 451 176 8.6 81 100a 36/35a
AST: aspartate aminotransferase; ALT: alanine aminotransferase; LAP: leukocyte alkaline phosphatase; GGT: gamma-glutamyl transferase; aPPt: activated partial thromplastin time.a Obtained at 60 h.
F.C. Rahmoune et al. Table 2
357 Major and minor findings of Alagille syndrome
Major
Minor
Chronic cholestasis Cardiac abnormalities (most commonly pulmonary artery stenosis) Posterior embryotoxon Butterfly-like vertebral arch defects Characteristic facies (forehead convexity, deeply set eyes, moderate hypertelorism, small chin pointed anteriorly, and saddle or straight nose)
Renal abnormalities High-pitched voice
usually without hemodynamic consequence. It is diagnosed because of an audible murmur and confirmed by echocardiography. More widespread pulmonary artery stenoses are extremely uncommon, as well as pulmonary artery hypoplasia, but they can lead to pulmonary hypertension. Other more complex abnormalities such as Tetralogy of Fallot (8–12% of cases),6 ventricular septal or inter-atrial defects, aortic coarctation, and valvular defects have also been described,6 and are responsible for morbidity and premature mortality.5 They should be assessed and, if required, corrected surgically. Among other major features in AS, the characteristic ‘‘triangle’’ facial appearance, involves a prominent forehead, deep-set eyes, moderate hypertelorism, a straight or saddle nose and a small pointed chin.1,2 Vertebral anomalies also are frequent in AS (33–87%),2 and the most characteristic anomaly is the sagittal cleft or ‘‘butterfly’’ vertebrae in which affected vertebral bodies are split sagittally into paired hemivertebrae due to failure of fusion of the anterior arch, mostly at the dorsal level.4 Of the ocular abnormalities, posterior embryotoxon is the most important but has no clinical relevance, except for diagnosing the condition. It occurs in 89% of patients with AS4 and consists in abnormal prominence of Schwalbe’s line, formed by the junction of Descemet’s membrane with the uveal trabecular meshwork of the angle of the anterior chamber. Renal function changes are found in 40–50% of cases.17 Perioperatively, renal perfusion must be maintained and nephrotoxic products avoided. Cerebral vascular abnormalities are also common and often asymptomatic (23%),18 but intracranial hemorrhage has been described and may be associated with a high mortality (30–50%).18 IUGR and premature rupture of membranes may occur,10 resulting in delivery of a preterm infant. The etiology of IUGR is unclear but chronic maternal hepatic dysfunction may be a contributing factor.10 AS has an autosomal dominant pattern of inheritance, with a 50% risk of transmission in each pregnancy but the clinical phenotype cannot be predicted. When one parent presents with the genetic mutation, antenatal diagnosis can be obtained by amniocentesis or chorionic villus
Growth restriction
sampling. When prenatal diagnosis has not been performed, the disease can be identified shortly after birth in an infant presenting with prolonged jaundice and/or cardiac abnormalities. It is important to make the diagnosis of AS early to avoid unnecessary surgical intervention for hepatobiliary disease. AS is diagnosed when P3 main features of the condition are found. Our patient presented with chronic cholestasis, portal hypertension associated with esophageal varices, characteristic facies, a posterior embryotoxon, and ‘‘butterfly’’ vertebrae; fortunately, she had no cardiac or renal abnormalities. There is no evidence of interaction between cholestasis and anesthetic agents.19 One study found worsening of liver function attributed to propofol given to a patient with AS during gynecological surgery;20 whereas another study did not find any deterioration.21 Because many anesthetic agents undergo hepatic metabolism, the use of muscle relaxants that do not rely on the liver, such as cisatracurium and atracurium, is preferable. For major liver surgery, which is common in patients with AS, hemodynamic changes and reduced cardiac output may cause mesenteric vasoconstriction with decreased regional blood flow. To avoid altering liver perfusion, inhalation anesthetic agents, such as isoflurane, sevoflurane and desflurane, which are associated with less myocardial depression and better preservation of hepatic blood flow, are preferred.22,23 Neuraxial anesthesia in patients with AS has rarely been reported;24 a two-year-old child underwent ileal exclusion and ileocolostomy under general anesthesia with epidural analgesia. During our patient’s second pregnancy, she developed HELLP syndrome and CS was performed under spinal anesthesia with preoperative platelet transfusion to achieve a platelet count above 80 · 109/L.25 We believe that this approach was justified at that time, given the additional risk of difficult intubation associated with preeclampsia. For the current delivery, general anesthesia was preferred to a neuraxial technique after correction of thrombocytopenia, although we admit that a strategy similar to the one used in the previous delivery could have been used. We were also aware that no cases involving difficult ventilation or intubation had been reported in the literature. There was indeed no difficulty in tracheal intubation
358
Alagille syndrome
suggesting that the facial appearance is unlikely to cause difficulty in airway management. In conclusion, the management of adult patients with AS may become more frequent, either after liver transplantation or in less severe forms of the condition as in our case. Obstetric anesthesiologists may increasingly encounter women with AS and normal fertility. Cholestasis, coagulopathy, portal hypertension and multiple organ system involvement, notably cardiac, spinal and facial, can worsen during pregnancy and have implications for anesthetic management.
References 1. Watson GH, Miller V. Ateriohepatic dysplasia. Familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child 1973;48:459–66. 2. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development and cardiac murmur. J Pediatr 1975;86:63–71. 3. Alagille D. Alagille syndrome today. Clin Invest Med 1996;19:325–30. 4. Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987;110:195–200. 5. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997;16:243–51. 6. Mc Elhinney DB, Krantz ID, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG 1 mutation and/or Alagille syndrome. Circulation 2002;106:2567–74. 7. Cardona J, Houssin D, Gauthier F, et al. Liver transplantation in children with Alagille syndrome – a study of twelve cases. Transplantation 1995;60:339–42. 8. Png K, Veyckemans F, De Kock M, et al. Hemodynamic changes in patients with Alagille’s syndrome during orthotopic liver transplantation. Anesth Analg 1999;89:1137–42. 9. Choudhry DK, Rehman MA, Schwartz RE, et al. The Alagille’s syndrome and its anaesthetic considerations. Paediatr Anaesth 1998;8:79–82. 10. Romero R, Reece A, Riely C, Hobbins JC. Arteriohepatic dysplasia in pregnancy. Am J Obstet Gynecol 1983;147:108–9.
0959-289X/$-see front matter c 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2011.07.012
11. Albayram F, Stone K, Nagey D, Schwarz KB, Blakemore K. Alagille syndrome: prenatal diagnosis and pregnancy outcome. Fetal Diagn Ther 2002;17:182–4. 12. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;127:220–4. 13. Andey EK, Cohen A. Liver disease associated with pregnancy. Ann Clin Lab Sci 1990;20:233–8. 14. Cheng YS. Pregnancy in liver cirrhosis and or hypertension. Am J Obstet Gynecol 1977;128:812–20. 15. Paternoster DM, Floreani AR, Paggioro A, Laureti E. Portal hypertension in a pregnant woman. Minerva Gynecol 1996;48:243–5. 16. Aggarwal N, Sawhney H, Vasishta K, Dhiman RK, Chawla Y. Non-cirrhotic portal hypertension in pregnancy. Int J Gyn Obst 2001;71:1–7. 17. Tolia V, Dubois RS, Watts FB, Perrin E. Renal abnormalities in paucity of interlobular bile ducts. J Pediatr Gastroenterol Nutr 1987;6:971–6. 18. Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 2004;109:1354–8. 19. Sahin H, Pirat A, Arslan G. Anaesthesia and surgery in patients with abnormal preoperative liver enzymes. Eur J Anaesthesiol 2007;24:465–7. 20. Muller C, Jelinek T, Endres S, et al. Severe protracted cholestasis after general anesthesia in a patient with Alagille syndrome. Gastroenterology 1996;34:809–12. 21. Murray JM, Trinick TR. Hepatic function and indocyanine green clearance during and after prolonged anaesthesia with propofol. Br J Anaesth 1992;69:643–4. 22. Merin R, Bernard JM, Doursout MF. Comparison of the effects of isoflurane and desflurane on cardiovascular dynamics and regional blood flow in the chronically instrumented dog. Anesthesiology 1991;74:568–72. 23. Bernard JM, Doursout MF, Wouters P, et al. Effects of sevoflurane on hepatic circulation in the chronically instrumented dog. Anesthesiology 1992;77:541–5. 24. Subramaniam K, Myers LB. Combined general and epidural anesthesia for a child with Alagille syndrome: a case report. Paediatr Anaesth 2004;14:787–91. 25. Recommandations de la Socie´te´ Franc¸aise d’Anesthe´sie Re´animation: les blocs pe´ri me´dullaires chez l’adulte. SFAR 2006. http:// www.sfar.org/article/187/les-blocs-perimedullaires-chez-l-rsquoadulte-rpc-2006 accessed 31.08. 10.
355
Alagille syndrome and pregnancy: anesthetic management for cesarean section F.C. Rahmoune, M. Bruye`re, M. Tecsy, D. Benhamou AP-HP, Hoˆpital Biceˆtre, Service d’Anesthe´sie-Re´animation, Le Kremlin-Biceˆtre, France ABSTRACT A 34-year-old multiparous woman with a breech presentation, intrauterine growth restriction and premature rupture of membranes was transferred to our referral unit at 33 weeks of gestation. She was diagnosed with Alagille syndrome soon after birth because of cholestasis and pruritus. Her condition was later complicated by esophageal varices, treated with propranolol, thrombocytopenia, and insulin-dependent diabetes. She had characteristic facies, posterior embryotoxon, ‘‘butterfly’’ vertebrae but had no cardiac or renal abnormalities. Due to the early onset of spontaneous labor, emergency cesarean section under general anesthesia was performed 48 h after admission. This is the first case describing anesthetic care during delivery in a patient with Alagille syndrome. We discuss the anesthetic implications of the syndrome, emphasizing problems associated with portal hypertension and cholestasis, thrombocytopenia and cardiac abnormalities such as pulmonary artery stenosis. c 2011 Elsevier Ltd. All rights reserved.
Keywords: Alagille syndrome; Portal hypertension; Cholestasis; Pregnancy; General anesthesia; Cesarean section
Introduction Alagille syndrome (AS) is a multi-system hereditary disorder described by Watson and Miller in 19731 and Alagille in 1975.2 The major characteristics of this arteriohepatic dysplasia include hepatic, cardiac, ophthalmic, skeletal, renal and craniofacial abnormalities.3 Its incidence lies between 1 in 70 000 and 1 in 100 000 births.4 It has an autosomal dominant pattern of inheritance, linked to a mutation in the Jagged1 gene (JAG1)5 which is found in 70–90% of cases. The management of cholestasis, which results from intrahepatic bile duct paucity, is symptomatic and includes the use of dietary measures, fat-soluble vitamin (ADEK) supplementation, and the administration of ursodeoxycholic acid in the case of pruritus. Morbidity and early mortality are linked to cardiac abnormalities.6 The severity of liver disease determines the prognosis in adult patients.4 We report the anesthetic management of a patient with AS for cesarean section (CS).
Case report A 34-year-old G3P2 woman was transferred to our maternity unit with premature rupture of membranes at 31 weeks of gestation, intrauterine growth restriction (IUGR) and a breech presentation. She had been diagnosed with AS at birth. Clinical features present during adulthood were cholestasis, pruritus treated with ursoAccepted June 2011 Correspondence to: Pr. Dan Benhamou, Service d’Anesthe´sie-Re´animation, 78 Rue du Ge´ne´ral Leclerc, 94275 Le Kremlin-Biceˆtre, France. E-mail address: [email protected]
deoxycholic acid, portal hypertension with grade II esophageal varices treated with propranolol, thrombocytopenia with platelet counts ranging from 40 · 109/L to 55 · 109/L of mixed origin (anti-platelet antibody positive and hypersplenism), and facial deformity. The patient had no cardiac abnormalities. She had been diagnosed with insulin-dependent diabetes at five years of age. During the postpartum period following her first pregnancy, the patient had presented with acute pulmonary edema, requiring mechanical ventilation for seven days. For the delivery of her second child, she had a CS under spinal anesthesia with intraoperative platelet transfusion because of HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Investigation for the JAG1 genetic mutation was negative for the first infant and positive for the second. During the course of her disease she required several admissions to hospital for jaundice and disturbances of liver function but her cholestasis had remained stable in recent years. During her current pregnancy, hepatobiliary ultrasound performed at 14 weeks of gestation and biological parameters were unchanged. However, because of increasing severity of pruritus, the dose of ursodeoxycholic acid was increased to 600 mg/day. Laboratory examination on admission showed cholestasis, moderate anemia and normal coagulation (Table 1). A multidisciplinary staff meeting concluded that because of esophageal varices, together with a scarred uterus, breech presentation, IUGR and thrombocytopenia, expulsive efforts were contraindicated. It was decided to perform an elective CS at 34 weeks under general anesthesia. However, as the woman went into
356
Alagille syndrome
spontaneous labor, emergency CS was performed 48 h after admission. General anesthesia was induced using a rapid-sequence induction with cricoid pressure with thiopental 350 mg and succinylcholine 80 mg; tracheal intubation was uneventful (Cormack and Lehane grade II). A 1060-g female infant with Apgar scores of 8, 8 and 9 at 1, 5 and 10 min, respectively, was delivered and transferred to the neonatal resuscitation unit. Anesthesia was maintained with desflurane and atracurium 40 mg. Following delivery, sufentanil 15 lg, carbetocin 100 lg and co-amoxiclav 2 g were administered intravenously. A prophylactic transfusion of six platelet concentrates was given intraoperatively. Lactated Ringer’s solution 1000 mL and 5% dextrose 200 mL were also infused. Estimated blood loss was 200 mL. Postoperatively, hemodynamic parameters were stable. After consultation with a hematologist, a second transfusion of five platelet concentrates was given due persistent moderate bleeding. The immediate postoperative results showed unchanged liver function and a satisfactory coagulation profile (Table 1). Propranolol was administered before CS and was continued after surgery. Postoperative analgesia was managed with nefopam and intravenous morphine. Non-steroidal anti-inflammatory drugs and paracetamol were avoided. Elastic compression stockings and early mobilization were used for thromboprophylaxis and anticoagulants were not administered initially because of thrombocytopenia. Hemodynamic parameters remained stable and neither worsening of cholestasis nor changes in renal function were detected by the fifth postoperative day. Four months after delivery, the baby was well and her JAG1 mutation was positive.
Discussion The features of AS are listed in Table 2. There is little documentation concerning anesthetic management of adult patients with AS with most reported cases relating to children under five years of age undergoing liver surgery.7–9 For females with AS who reach adulthood, de-
Table 1
tailed management during pregnancy and childbirth have rarely been documented.10,11 Cholestasis, resulting from intrahepatic bile duct paucity, is the main manifestation of AS and appears in the first three months of life in 45–75%, and in the remainder before three years of age.4 Cholestasis can progress to cirrhosis in 10–15% of cases. The resulting vitamin K deficiency may be responsible for coagulopathy with prolonged prothrombin time (PT). Thrombocytopenia, secondary to hypersplenism and splenomegaly is often found.4 Liver transplantation is indicated in 15–50% of cases depending on the severity of jaundice and pruritus.12 Liver failure and portal hypertension may also occur. In women with cirrhosis caused by liver failure, the combination of portal hypertension and pregnancy is rare because of subfertility due to disruption of estrogen metabolism.13 In the context of non-cirrhotic portal hypertension, as in our case, fertility is similar to that of the general population.13 The main fetal complications are early abortion (3–13%) and prematurity (18– 20%).14 On the maternal side, gastrointestinal bleeding may occur with an incidence of 6–22%.15 Some physiological changes unique to pregnancy may trigger esophageal variceal rupture. These include an increase in cardiac output, splanchnic and portal compression, and particularly uterine development which raises intra-abdominal pressure, leading to an accentuation of portal pressure in the esophageal venous system.16 b-Blocker therapy can effectively prevent these complications, explaining why it is maintained throughout pregnancy despite a known risk of IUGR. Endoscopic management (sclerotherapy and ligation) of esophageal varices rupture is possible without maternal and fetal impact.16 Infection and hepatotoxic drugs should also be avoided as they may cause gastrointestinal bleeding.16 During delivery, obstetric trauma and expulsive efforts should be minimized and forceps or suction delivery are recommended.16 In patients with AS, cardiac anomalies are found in 85–95% of cases.7 Localized stenosis of peripheral branches of the pulmonary arteries is the most common anomaly (75–90%),5,9 although non-progressive and
Maternal blood results
AST (U/L) [normal 10–35] ALT (U/L) [normal 5–35] LAP (U/L) [normal 35–105] GGT (U/L) [normal 5–40] Hemoglobin (g/dL) Platelets (·109/L) Prothrombin time (%) aPTT (s) [normal < 41 s]
Admission
Pre-op
1 h postop
6 h postop
48 h postop
85 77 500 273 10.2 42 100 32/35
80 70 443 287 10.7 52 100 31/35
65 54 396 200 8.9 96 91 31/35
83 55 404 176 8.4 85 98 33/35
68 54 451 176 8.6 81 100a 36/35a
AST: aspartate aminotransferase; ALT: alanine aminotransferase; LAP: leukocyte alkaline phosphatase; GGT: gamma-glutamyl transferase; aPPt: activated partial thromplastin time.a Obtained at 60 h.
F.C. Rahmoune et al. Table 2
357 Major and minor findings of Alagille syndrome
Major
Minor
Chronic cholestasis Cardiac abnormalities (most commonly pulmonary artery stenosis) Posterior embryotoxon Butterfly-like vertebral arch defects Characteristic facies (forehead convexity, deeply set eyes, moderate hypertelorism, small chin pointed anteriorly, and saddle or straight nose)
Renal abnormalities High-pitched voice
usually without hemodynamic consequence. It is diagnosed because of an audible murmur and confirmed by echocardiography. More widespread pulmonary artery stenoses are extremely uncommon, as well as pulmonary artery hypoplasia, but they can lead to pulmonary hypertension. Other more complex abnormalities such as Tetralogy of Fallot (8–12% of cases),6 ventricular septal or inter-atrial defects, aortic coarctation, and valvular defects have also been described,6 and are responsible for morbidity and premature mortality.5 They should be assessed and, if required, corrected surgically. Among other major features in AS, the characteristic ‘‘triangle’’ facial appearance, involves a prominent forehead, deep-set eyes, moderate hypertelorism, a straight or saddle nose and a small pointed chin.1,2 Vertebral anomalies also are frequent in AS (33–87%),2 and the most characteristic anomaly is the sagittal cleft or ‘‘butterfly’’ vertebrae in which affected vertebral bodies are split sagittally into paired hemivertebrae due to failure of fusion of the anterior arch, mostly at the dorsal level.4 Of the ocular abnormalities, posterior embryotoxon is the most important but has no clinical relevance, except for diagnosing the condition. It occurs in 89% of patients with AS4 and consists in abnormal prominence of Schwalbe’s line, formed by the junction of Descemet’s membrane with the uveal trabecular meshwork of the angle of the anterior chamber. Renal function changes are found in 40–50% of cases.17 Perioperatively, renal perfusion must be maintained and nephrotoxic products avoided. Cerebral vascular abnormalities are also common and often asymptomatic (23%),18 but intracranial hemorrhage has been described and may be associated with a high mortality (30–50%).18 IUGR and premature rupture of membranes may occur,10 resulting in delivery of a preterm infant. The etiology of IUGR is unclear but chronic maternal hepatic dysfunction may be a contributing factor.10 AS has an autosomal dominant pattern of inheritance, with a 50% risk of transmission in each pregnancy but the clinical phenotype cannot be predicted. When one parent presents with the genetic mutation, antenatal diagnosis can be obtained by amniocentesis or chorionic villus
Growth restriction
sampling. When prenatal diagnosis has not been performed, the disease can be identified shortly after birth in an infant presenting with prolonged jaundice and/or cardiac abnormalities. It is important to make the diagnosis of AS early to avoid unnecessary surgical intervention for hepatobiliary disease. AS is diagnosed when P3 main features of the condition are found. Our patient presented with chronic cholestasis, portal hypertension associated with esophageal varices, characteristic facies, a posterior embryotoxon, and ‘‘butterfly’’ vertebrae; fortunately, she had no cardiac or renal abnormalities. There is no evidence of interaction between cholestasis and anesthetic agents.19 One study found worsening of liver function attributed to propofol given to a patient with AS during gynecological surgery;20 whereas another study did not find any deterioration.21 Because many anesthetic agents undergo hepatic metabolism, the use of muscle relaxants that do not rely on the liver, such as cisatracurium and atracurium, is preferable. For major liver surgery, which is common in patients with AS, hemodynamic changes and reduced cardiac output may cause mesenteric vasoconstriction with decreased regional blood flow. To avoid altering liver perfusion, inhalation anesthetic agents, such as isoflurane, sevoflurane and desflurane, which are associated with less myocardial depression and better preservation of hepatic blood flow, are preferred.22,23 Neuraxial anesthesia in patients with AS has rarely been reported;24 a two-year-old child underwent ileal exclusion and ileocolostomy under general anesthesia with epidural analgesia. During our patient’s second pregnancy, she developed HELLP syndrome and CS was performed under spinal anesthesia with preoperative platelet transfusion to achieve a platelet count above 80 · 109/L.25 We believe that this approach was justified at that time, given the additional risk of difficult intubation associated with preeclampsia. For the current delivery, general anesthesia was preferred to a neuraxial technique after correction of thrombocytopenia, although we admit that a strategy similar to the one used in the previous delivery could have been used. We were also aware that no cases involving difficult ventilation or intubation had been reported in the literature. There was indeed no difficulty in tracheal intubation
358
Alagille syndrome
suggesting that the facial appearance is unlikely to cause difficulty in airway management. In conclusion, the management of adult patients with AS may become more frequent, either after liver transplantation or in less severe forms of the condition as in our case. Obstetric anesthesiologists may increasingly encounter women with AS and normal fertility. Cholestasis, coagulopathy, portal hypertension and multiple organ system involvement, notably cardiac, spinal and facial, can worsen during pregnancy and have implications for anesthetic management.
References 1. Watson GH, Miller V. Ateriohepatic dysplasia. Familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child 1973;48:459–66. 2. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development and cardiac murmur. J Pediatr 1975;86:63–71. 3. Alagille D. Alagille syndrome today. Clin Invest Med 1996;19:325–30. 4. Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987;110:195–200. 5. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997;16:243–51. 6. Mc Elhinney DB, Krantz ID, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG 1 mutation and/or Alagille syndrome. Circulation 2002;106:2567–74. 7. Cardona J, Houssin D, Gauthier F, et al. Liver transplantation in children with Alagille syndrome – a study of twelve cases. Transplantation 1995;60:339–42. 8. Png K, Veyckemans F, De Kock M, et al. Hemodynamic changes in patients with Alagille’s syndrome during orthotopic liver transplantation. Anesth Analg 1999;89:1137–42. 9. Choudhry DK, Rehman MA, Schwartz RE, et al. The Alagille’s syndrome and its anaesthetic considerations. Paediatr Anaesth 1998;8:79–82. 10. Romero R, Reece A, Riely C, Hobbins JC. Arteriohepatic dysplasia in pregnancy. Am J Obstet Gynecol 1983;147:108–9.
0959-289X/$-see front matter c 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2011.07.012
11. Albayram F, Stone K, Nagey D, Schwarz KB, Blakemore K. Alagille syndrome: prenatal diagnosis and pregnancy outcome. Fetal Diagn Ther 2002;17:182–4. 12. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;127:220–4. 13. Andey EK, Cohen A. Liver disease associated with pregnancy. Ann Clin Lab Sci 1990;20:233–8. 14. Cheng YS. Pregnancy in liver cirrhosis and or hypertension. Am J Obstet Gynecol 1977;128:812–20. 15. Paternoster DM, Floreani AR, Paggioro A, Laureti E. Portal hypertension in a pregnant woman. Minerva Gynecol 1996;48:243–5. 16. Aggarwal N, Sawhney H, Vasishta K, Dhiman RK, Chawla Y. Non-cirrhotic portal hypertension in pregnancy. Int J Gyn Obst 2001;71:1–7. 17. Tolia V, Dubois RS, Watts FB, Perrin E. Renal abnormalities in paucity of interlobular bile ducts. J Pediatr Gastroenterol Nutr 1987;6:971–6. 18. Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 2004;109:1354–8. 19. Sahin H, Pirat A, Arslan G. Anaesthesia and surgery in patients with abnormal preoperative liver enzymes. Eur J Anaesthesiol 2007;24:465–7. 20. Muller C, Jelinek T, Endres S, et al. Severe protracted cholestasis after general anesthesia in a patient with Alagille syndrome. Gastroenterology 1996;34:809–12. 21. Murray JM, Trinick TR. Hepatic function and indocyanine green clearance during and after prolonged anaesthesia with propofol. Br J Anaesth 1992;69:643–4. 22. Merin R, Bernard JM, Doursout MF. Comparison of the effects of isoflurane and desflurane on cardiovascular dynamics and regional blood flow in the chronically instrumented dog. Anesthesiology 1991;74:568–72. 23. Bernard JM, Doursout MF, Wouters P, et al. Effects of sevoflurane on hepatic circulation in the chronically instrumented dog. Anesthesiology 1992;77:541–5. 24. Subramaniam K, Myers LB. Combined general and epidural anesthesia for a child with Alagille syndrome: a case report. Paediatr Anaesth 2004;14:787–91. 25. Recommandations de la Socie´te´ Franc¸aise d’Anesthe´sie Re´animation: les blocs pe´ri me´dullaires chez l’adulte. SFAR 2006. http:// www.sfar.org/article/187/les-blocs-perimedullaires-chez-l-rsquoadulte-rpc-2006 accessed 31.08. 10.