Digestive and Liver Disease 47 (2015) 86–89
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Correspondence Successful pregnancy in Alagille Syndrome Dear Editor, A 25 year-old woman, clinically diagnosed with Alagille Syndrome (AGS) in childhood and confirmed by genetic testing, was referred to our unit for liver transplantation (LT) evaluation. As past medical history, she underwent endovascular and open heart surgery for pulmonary arterial hypertension secondary to atrial and ventricular septal defects at age 2. During the following years she remained stable, without clinical signs of liver disease, therefore she was not listed for LT. Six months after the initial evaluation, the patient announced she was pregnant, without any prenatal counselling. Biochemical tests revealed normal liver enzymes and bilirubin levels; varices were absent at oesophagogastroduodenoscopy and the Model for End Stage Liver Disease was 8. Foetal ultrasonography excluded cardiac or skeletal malformations suspicious for AGS, and chorionic villous sampling (CVS) performed at week 13 of gestation ruled out the Alagille genotype. During pregnancy, biochemical examinations did not show worsening of liver function and the patient did not complain of pruritus. Due to thrombocytosis, with platelet counts of up to 410 × 109 /L she underwent haematological evaluation, which ruled out the presence of an underlying myeloproliferative disease (genetic tests for JAK-2V617F and BCR/ABL mutation were negative); bone marrow biopsy was not deemed necessary, however prophylaxis with low molecular weight heparin was initiated. Caesarean delivery was performed at week 38, without complications for the
newborn and the mother. During the follow-up after pregnancy a mild elevation of liver enzymes disappeared after correction of hypothyroidism. The increase of gamma-gutamyl-transpeptidase up to 155 U/l, and the elevation of platelet count up to 450 × 109 /L persisted after the delivery. AGS is an inherited autosomal dominant multisystemic disorder with protean clinical manifestations. Classical features include cholestasis due to intrahepatic biliary hypoplasia, cardiac malformations, skeletal abnormalities, posterior embriotoxon and facial dysmorphisms [1]. About 20–30% of paediatric patients develop liver failure and require LT, and only 10% of AGS patients undergo LT in adulthood, at a mean age of 30 years [2]. Pregnancy is unusual in AGS, as in other chronic liver diseases, because of decreased fertility, voluntary abortion and miscarriages. Few cases of successful pregnancy in AGS have been described (Table 1), and stemming from these, several issues should considered before attempting pregnancy; first, the severity of liver disease and the degree of portal hypertension, which could further worsen during pregnancy; second, the degree of cardiac dysfunction and in particular the severity of pulmonary hypertension; third, the high probability of AGS mutation in the foetus, although with variable phenotypic manifestations [3]. For these reasons, appropriate genetic counselling is warranted before conception. Despite guidelines for the management of pregnancy in AGS patients have not been established to date – due to its rarity – CVS could represent a useful tool to routinely screen for the presence of the classical JAGGED1 gene mutation in the foetus of an affected mother, if the associated liver dysfunction does not represent a contraindication. Finally, caesarean section could probably be the delivery route of choice to minimize the risks for the mother and the newborn. After
Table 1 Case reports of successful pregnancies in mothers with Alagille Syndrome. LT before pregnancy
Maternal age (years)
Prenatal counselling
Chorionic villous sampling
Delivery (gestational week)
Delivery (technique)
AGS the newborn
Newborn outcome at 1 year
Witt et al. (2004) Albayram et al. (2002)
NO NO
NA 21
YES NO
YES NO
NA 35
NO YES
NA Death at 3 months
Herr et al. (2002)
NO
NA
NA
NA
36
YES
NA
Rahmoune et al. (2011)
NO
34
YES
NO
34
YES
NA
Maisonneuve et al. (2012) Jung et al. (2007, case series of four pregnancies)
YES
22
NO
YES
37
YES
NA
1 out of 4 mothers
NA
YES
YES
NA
NA Spontaneous vaginal delivery Caesarean section Caesarean section Elective forceps delivery NA
1 out of 4 newborns
Clinically healthya
AGS, Alagille Syndrome; LT, liver transplantation; NA, not available. a Refers to the three newborns without AGS. 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Correspondence / Digestive and Liver Disease 47 (2015) 86–89
87
pregnancy patients should be followed and possibly evaluated for liver transplantation, especially in cases of liver function worsening during the gestational period. Conflict of interest None declared. References [1] Alagille D, Odievre M, Gautier M, et al. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. Journal of Pediatrics 1975;86:63–71. [2] Kamath BM, Schwarz KB, Hadzic N. Alagille syndrome and liver transplantation. Journal of Pediatric Gastroenterology and Nutrition 2010;50:11–5. [3] Kamath BM, Krantz ID, Spinner NB, et al. Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance. American Journal of Medical Genetics 2002;112:194–7.
Alberto Ferrarese Marco Senzolo Patrizia Burra ∗ Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy ∗ Corresponding
author at: Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, Italy. Tel.: +39 0498212892; fax: +39 0498218727. E-mail address: [email protected] (P. Burra)
http://dx.doi.org/10.1016/j.dld.2014.08.047
High-dose (peg)interferon therapy in treatmentnaïve, interleukin-28B rs12979860 CT/TT genotype 1 chronic hepatitis C Dear Editor, Interleukin-28B (IL28B) rs12979860 CT/TT genotype 1 chronic hepatitis C patients exhibit a less-pronounced viral decline during the peginterferon and ribavirin lead-in-phase preceding the starting of a triple combination regimen based on boceprevir compared with IL28B rs12979860 CC genotype 1 patients [1,2]. A greater than 1 log HCV RNA drop after a 4 week peginterferon/ribavirin lead-in period is commonly achieved in rs12979860 CC patients leading to higher sustained virological response (SVR) rates with short 24 week treatment duration, while rs12979860 CT/TT patients achieve this less often and more frequently require 48 week treatments to maximise SVR rates [3]. We examined whether high-dose (peg)interferon induction therapy ameliorates 1st and 2nd phase viral kinetics in treatment-naïve rs12979860 CT/TT genotype 1 patients. We identified 15 rs12979860 CT/TT treatment-naïve genotype 1 mono-infected patients who were treated in 3 pilot studies in our centre with different induction schemes (group A, n = 4: interferon alpha-2a 9 MU/d, group B, n = 4: peginterferon alpha-2a 360 g/w and group C, n = 7: combined regimen interferon-alpha-2a 4.5 MU/d plus peginterferon alpha-2a 180 g/w). The 1st and 2nd phase viral decline patterns during the first 4 weeks in the pilot groups were compared with a historical control group, consisting of 126 genotype 1 treatment-naïve rs12979860
Fig. 1. Second phase log10 decline per day. Observed second phase viral decline between day 7 and week 4 in the 3 pilot groups and the historical control group expressed as log10 IU/ml/day: 0.054, 0.029 and 0.066 in patients treated in pilot groups A, B and C, and 0.065 in the control group respectively (p = 0.61, 0.11, 0.98).
CT/TT HCV patients who were treated with peginterferon alpha2a 180 g/w prior to randomisation in study arms as previously published [4]. Patients in the 3 pilot groups and historical control group all received a similar dose of oral ribavirin of 1000 or 1200 mg for bodyweight below or above 75 kg, respectively. HCV-RNA levels of both pilot studies and historical control group had been determined centrally at Erasmus MC University Medical Center Rotterdam (Cobas Amplicor HCV Monitor Version 2.0, Roche Diagnostics, Branchburg, NJ) and were available at days 0, 1, 4 and 7 followed by weekly determinations until week 4 in all patients. Statistical analysis was performed using SPSS® 20.0 statistical software (SPSS Inc., Chicago, IL, USA) with 2-sided tests and a type I error of 0.05. Baseline characteristics sex, age, body mass index, mean ribavirin dosage per body weight, baseline viraemia, fibrosis stage, alanine aminotransferase, platelet and neutrophil count were comparable across groups. A greater number of patients in the control group exhibited the rs12979860 TT genotype compared with the pilot study groups. A trend towards greater viral decline was observed 24 h after the start of therapy in groups A and C containing short-acting interferon, although not statistically significant when compared with the control group. Within the next days of treatment, the viral decline patterns in rs12979860 CT/TT treatment-naïve patients in all 3 high-dose pilot groups became identical to the values observed in the control group. The mean HCV-RNA log10 declines at day 4 were 0.97, 0.59 and 0.72 in groups A, B and C, respectively, versus 0.80 in the control group (p = 0.62, 0.52, 0.76). The HCV-RNA log10 declines at week 4 were 2.16, 1.10 and 2.22 in groups A, B and C, respectively, versus 2.37 in controls (p = 0.74, 0.04, 0.75). The second phase mean log10 decline/day between day 7 and week 4 did not differ across groups (Fig. 1). Our analysis is the first detailed analysis of the 1st and 2nd phase viral kinetics in treatment-naïve genotype 1 IL28B rs12979860 CT/TT patients who were treated with (peg)interferon doseintensified regimes in combination with oral ribavirin. Our study shows that the suboptimal viral response of treatment-naïve genotype 1 chronic hepatitis C patients with the rs12979860 CT/TT genotype is not amenable for improvement with any of the 3 highdose induction schemes studied. Our data suggest that rs12979860 CT/TT status but not a higher than the current standard dose of (peg)interferon is the main determinant of the observed response
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Correspondence Successful pregnancy in Alagille Syndrome Dear Editor, A 25 year-old woman, clinically diagnosed with Alagille Syndrome (AGS) in childhood and confirmed by genetic testing, was referred to our unit for liver transplantation (LT) evaluation. As past medical history, she underwent endovascular and open heart surgery for pulmonary arterial hypertension secondary to atrial and ventricular septal defects at age 2. During the following years she remained stable, without clinical signs of liver disease, therefore she was not listed for LT. Six months after the initial evaluation, the patient announced she was pregnant, without any prenatal counselling. Biochemical tests revealed normal liver enzymes and bilirubin levels; varices were absent at oesophagogastroduodenoscopy and the Model for End Stage Liver Disease was 8. Foetal ultrasonography excluded cardiac or skeletal malformations suspicious for AGS, and chorionic villous sampling (CVS) performed at week 13 of gestation ruled out the Alagille genotype. During pregnancy, biochemical examinations did not show worsening of liver function and the patient did not complain of pruritus. Due to thrombocytosis, with platelet counts of up to 410 × 109 /L she underwent haematological evaluation, which ruled out the presence of an underlying myeloproliferative disease (genetic tests for JAK-2V617F and BCR/ABL mutation were negative); bone marrow biopsy was not deemed necessary, however prophylaxis with low molecular weight heparin was initiated. Caesarean delivery was performed at week 38, without complications for the
newborn and the mother. During the follow-up after pregnancy a mild elevation of liver enzymes disappeared after correction of hypothyroidism. The increase of gamma-gutamyl-transpeptidase up to 155 U/l, and the elevation of platelet count up to 450 × 109 /L persisted after the delivery. AGS is an inherited autosomal dominant multisystemic disorder with protean clinical manifestations. Classical features include cholestasis due to intrahepatic biliary hypoplasia, cardiac malformations, skeletal abnormalities, posterior embriotoxon and facial dysmorphisms [1]. About 20–30% of paediatric patients develop liver failure and require LT, and only 10% of AGS patients undergo LT in adulthood, at a mean age of 30 years [2]. Pregnancy is unusual in AGS, as in other chronic liver diseases, because of decreased fertility, voluntary abortion and miscarriages. Few cases of successful pregnancy in AGS have been described (Table 1), and stemming from these, several issues should considered before attempting pregnancy; first, the severity of liver disease and the degree of portal hypertension, which could further worsen during pregnancy; second, the degree of cardiac dysfunction and in particular the severity of pulmonary hypertension; third, the high probability of AGS mutation in the foetus, although with variable phenotypic manifestations [3]. For these reasons, appropriate genetic counselling is warranted before conception. Despite guidelines for the management of pregnancy in AGS patients have not been established to date – due to its rarity – CVS could represent a useful tool to routinely screen for the presence of the classical JAGGED1 gene mutation in the foetus of an affected mother, if the associated liver dysfunction does not represent a contraindication. Finally, caesarean section could probably be the delivery route of choice to minimize the risks for the mother and the newborn. After
Table 1 Case reports of successful pregnancies in mothers with Alagille Syndrome. LT before pregnancy
Maternal age (years)
Prenatal counselling
Chorionic villous sampling
Delivery (gestational week)
Delivery (technique)
AGS the newborn
Newborn outcome at 1 year
Witt et al. (2004) Albayram et al. (2002)
NO NO
NA 21
YES NO
YES NO
NA 35
NO YES
NA Death at 3 months
Herr et al. (2002)
NO
NA
NA
NA
36
YES
NA
Rahmoune et al. (2011)
NO
34
YES
NO
34
YES
NA
Maisonneuve et al. (2012) Jung et al. (2007, case series of four pregnancies)
YES
22
NO
YES
37
YES
NA
1 out of 4 mothers
NA
YES
YES
NA
NA Spontaneous vaginal delivery Caesarean section Caesarean section Elective forceps delivery NA
1 out of 4 newborns
Clinically healthya
AGS, Alagille Syndrome; LT, liver transplantation; NA, not available. a Refers to the three newborns without AGS. 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Correspondence / Digestive and Liver Disease 47 (2015) 86–89
87
pregnancy patients should be followed and possibly evaluated for liver transplantation, especially in cases of liver function worsening during the gestational period. Conflict of interest None declared. References [1] Alagille D, Odievre M, Gautier M, et al. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. Journal of Pediatrics 1975;86:63–71. [2] Kamath BM, Schwarz KB, Hadzic N. Alagille syndrome and liver transplantation. Journal of Pediatric Gastroenterology and Nutrition 2010;50:11–5. [3] Kamath BM, Krantz ID, Spinner NB, et al. Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance. American Journal of Medical Genetics 2002;112:194–7.
Alberto Ferrarese Marco Senzolo Patrizia Burra ∗ Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy ∗ Corresponding
author at: Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, Italy. Tel.: +39 0498212892; fax: +39 0498218727. E-mail address: [email protected] (P. Burra)
http://dx.doi.org/10.1016/j.dld.2014.08.047
High-dose (peg)interferon therapy in treatmentnaïve, interleukin-28B rs12979860 CT/TT genotype 1 chronic hepatitis C Dear Editor, Interleukin-28B (IL28B) rs12979860 CT/TT genotype 1 chronic hepatitis C patients exhibit a less-pronounced viral decline during the peginterferon and ribavirin lead-in-phase preceding the starting of a triple combination regimen based on boceprevir compared with IL28B rs12979860 CC genotype 1 patients [1,2]. A greater than 1 log HCV RNA drop after a 4 week peginterferon/ribavirin lead-in period is commonly achieved in rs12979860 CC patients leading to higher sustained virological response (SVR) rates with short 24 week treatment duration, while rs12979860 CT/TT patients achieve this less often and more frequently require 48 week treatments to maximise SVR rates [3]. We examined whether high-dose (peg)interferon induction therapy ameliorates 1st and 2nd phase viral kinetics in treatment-naïve rs12979860 CT/TT genotype 1 patients. We identified 15 rs12979860 CT/TT treatment-naïve genotype 1 mono-infected patients who were treated in 3 pilot studies in our centre with different induction schemes (group A, n = 4: interferon alpha-2a 9 MU/d, group B, n = 4: peginterferon alpha-2a 360 g/w and group C, n = 7: combined regimen interferon-alpha-2a 4.5 MU/d plus peginterferon alpha-2a 180 g/w). The 1st and 2nd phase viral decline patterns during the first 4 weeks in the pilot groups were compared with a historical control group, consisting of 126 genotype 1 treatment-naïve rs12979860
Fig. 1. Second phase log10 decline per day. Observed second phase viral decline between day 7 and week 4 in the 3 pilot groups and the historical control group expressed as log10 IU/ml/day: 0.054, 0.029 and 0.066 in patients treated in pilot groups A, B and C, and 0.065 in the control group respectively (p = 0.61, 0.11, 0.98).
CT/TT HCV patients who were treated with peginterferon alpha2a 180 g/w prior to randomisation in study arms as previously published [4]. Patients in the 3 pilot groups and historical control group all received a similar dose of oral ribavirin of 1000 or 1200 mg for bodyweight below or above 75 kg, respectively. HCV-RNA levels of both pilot studies and historical control group had been determined centrally at Erasmus MC University Medical Center Rotterdam (Cobas Amplicor HCV Monitor Version 2.0, Roche Diagnostics, Branchburg, NJ) and were available at days 0, 1, 4 and 7 followed by weekly determinations until week 4 in all patients. Statistical analysis was performed using SPSS® 20.0 statistical software (SPSS Inc., Chicago, IL, USA) with 2-sided tests and a type I error of 0.05. Baseline characteristics sex, age, body mass index, mean ribavirin dosage per body weight, baseline viraemia, fibrosis stage, alanine aminotransferase, platelet and neutrophil count were comparable across groups. A greater number of patients in the control group exhibited the rs12979860 TT genotype compared with the pilot study groups. A trend towards greater viral decline was observed 24 h after the start of therapy in groups A and C containing short-acting interferon, although not statistically significant when compared with the control group. Within the next days of treatment, the viral decline patterns in rs12979860 CT/TT treatment-naïve patients in all 3 high-dose pilot groups became identical to the values observed in the control group. The mean HCV-RNA log10 declines at day 4 were 0.97, 0.59 and 0.72 in groups A, B and C, respectively, versus 0.80 in the control group (p = 0.62, 0.52, 0.76). The HCV-RNA log10 declines at week 4 were 2.16, 1.10 and 2.22 in groups A, B and C, respectively, versus 2.37 in controls (p = 0.74, 0.04, 0.75). The second phase mean log10 decline/day between day 7 and week 4 did not differ across groups (Fig. 1). Our analysis is the first detailed analysis of the 1st and 2nd phase viral kinetics in treatment-naïve genotype 1 IL28B rs12979860 CT/TT patients who were treated with (peg)interferon doseintensified regimes in combination with oral ribavirin. Our study shows that the suboptimal viral response of treatment-naïve genotype 1 chronic hepatitis C patients with the rs12979860 CT/TT genotype is not amenable for improvement with any of the 3 highdose induction schemes studied. Our data suggest that rs12979860 CT/TT status but not a higher than the current standard dose of (peg)interferon is the main determinant of the observed response
![[Keratoconus in Alagille syndrome].](/assets/img/hold.png)
