Outcome of Liver Disease in Children with Alagille Syndrome: A Study of 163 Patients

Outcome of Liver Disease in Children with Alagille Syndrome: A Study of 163 Patients. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Gut 2001;49:431–435. Summary: This article is a retrospective clinical study that evaluates the role of liver disease in the mortality, morbidity, and long-term outcome of 163 children with Alagille syndrome (AGS) from the Hôpital de Bicêtre (Le Kremlin Bicêtre Cedex, France). The authors examine the relationship between mode of presentation (with or without neonatal jaundice) and long-term prognosis. Chart data was collected which spanned from the time of the patients' presentation to the point of death, liver transplantation or last follow-up visit. The patients were divided into two groups according to their presentation: with neonatal cholestatic jaundice (NJ, n = 132) or without (no-NJ, n = 31). There was a significant difference between the NJ and no-NJ groups in the persistence of: jaundice (77 vs. 16%, p < 0.0001), pruritus (84 vs. 60%, p = 0.0003), xanthomas (30 vs. 0%, p = 0.0004), hepatomegaly (87 vs. 35%, p < 0.001) and splenomegaly (47 vs. 20%, p = 0.0095). In the NJ group jaundice resolved in 20 (23%) whereas it persisted in all patients in the no-NJ group. Pruritus resolved permanently in 20 (15%) patients in the NJ group and in 7 (29%) patients from the no-NJ group. Cirrhosis occurred at a slightly higher, but not statistically significant, rate in the NJ versus the no-NJ groups (46% versus 33%). More NJ patients underwent liver transplantation (33 vs. 0%, p = 0.0002). Death occurred at similar rates and from similar causes in both groups from liver failure, hemorrhage, cardiac abnormalities, and infection. Thirty-three percent of all deaths were related to liver disease. Death after liver transplantation (LT) accounted for 20% of the mortality in the NJ group and corresponded to a survival rate of 77% at 10 years post transplant. Overall patient survival was 68% at 10 years and 62% at 20 years. There was no significant survival difference between the NJ and no-NJ groups, between patients born before or after 1986 (when LT became available) or between patients (n = 60) who did or did not undergo LT once it became available. In the univariate analysis, 10-year survival was worse: in the NJ than in the no-NJ group with native liver (45 vs. 79%, p = 0.0004), in patients with xanthomas than in those without xanthomas (43 vs. 60%, p = 0.017) and in patients who underwent Kasai operation than in those who did not (38 vs. 54%, p = 0.048). However, in a multivariate analysis, neonatal cholestatic jaundice was the only independent prognostic factor for survival. Comment: This large clinical study further clarifies the natural history of AGS liver disease, and reflects the vast experience of the authors. The strength of this study lies in its large sample size. A potential weakness of the study is it does not specifically address the influence of cardiac disease on survival. This report confirms that it is difficult to predict the outcome of liver disease in AGS; some patients will worsen and develop morbid cholestasis, some will develop end-stage liver disease, while others improve. This raises one of the major dilemmas of AGS liver disease, which is when and in which patients with AGS is liver transplantation indicated and justifiable? Liver transplantation (LT) in AGS patients with its own set of accompanying morbidities and 20% risk of early mortality, may not be the best therapy for non–end-stage liver disease. This study concludes that the prognosis of liver disease in AGS is worse in children who present with neonatal jaundice than in those who do not. This finding seems intuitive in many ways. However, as the authors point out, there is a large component of variability within each group of patients and several observations moderate the above conclusion. First, within the neonatal jaundice group was a subgroup that demonstrated reduced cholestasis over time. Second, the overall survival of the two groups of patients was comparable, around 70% at 10 years. It is also encouraging to note little difference in the development of biopsy-proven cirrhosis between the two groups (46% in the neonatal jaundice group versus 33%). This observation was made despite the probable over-representation of the sickest patients given that 50% of the neonatal jaundice biopsies came from ex-plants and overall only 50% of patients were biopsied. Another important finding is that death from end-stage liver disease was comparable between the two groups. This is especially evident when one considers that only 5/44 patients (11%) of the neonatal jaundice group who underwent liver transplantation (LT) had end-stage or life-threatening liver disease but twice that number (10) died after LT. This may suggest that LT increased the early mortality in the neonatal jaundice group. Death due to extra-hepatic causes was frequent in both groups as has been previously demonstrated. Clinically, the most significant difference between the two groups was in the persistence of cholestasis. The major impact of AGS liver disease for the majority of patients is therefore persistent cholestasis and its morbid complications rather than end-stage liver disease. Liver transplantation is a justifiable therapy for end-stage liver disease in AGS, however we are still learning how best to use it for patients with morbid cholestasis. Over the last 10 years numerous centers have had varying thresholds for transplanting patients with AGS and consequently report very different outcomes. The counseling of families regarding LT could vary from strong encouragement to strong warning given that post-transplant survival rates for AGS range from 57 to 100% (Liver Transplantation 1993; 128:337–9, Journal of Pediatrics 1995; 127(2): 220–4). Our inability to predict the course of AGS liver disease coupled with the variable expression of AGS in other organ systems makes it challenging to advise families regarding the risks and benefits of transplantation. For a physician to compare the probable outcome of LT between two AGS patients with similar liver disease but different degrees of heart or kidney disease may be like comparing apples to oranges. The interactions between these co-morbidities on LT outcome may be significantly different. As stated by the authors in this report, “the timing of LT should be considered carefully” because the risk of death of >20% associated with transplantation may not be justified to treat morbid cholestasis. This points to the need to focus research on improved therapies to treat the bone disease, growth failure, and pruritus in AGS patients, which will provide options other than LT. Alagille syndrome outcome and survival is influenced by multiple factors. We know that cardiac disease, hepatic disease, and intracranial bleeding account for the majority of the mortality in AGS (Hepatology 1999; 29(3): 822–9, Journal of Pediatric Gastroenterology and Nutrition 1999; 29 (4): 431–7, Journal of Pediatrics 1995; 127(2): 220–4, Journal of Pediatrics 1987; (110 (2): 195–200). This study however fails to acknowledge the important interaction between liver disease and the other components of AGS. In a previous study, cardiac disease accounted for the majority of early mortality in AGS (Hepatology 1999; 29(3): 822–9). In that analysis, although early jaundice and higher bilirubin suggested worse prognosis, the association between bilirubin and poor outcome was no longer significant when patients with complex congenital heart disease were excluded. This information suggests that the liver disease is only one factor in the AGS survival story and cannot be legitimately considered independently of the co-morbid heart disease because of the interaction between them. This observation has been acknowledged in the AGS transplantation experience where higher mortality has been noted in the setting of peripheral pulmonary stenosis and right ventricular hypertension (Liver Transplantation 1993; 128:337–9). It therefore would be helpful for the interpretation of the survival statistics in this study to clarify the frequency and severity of cardiac disease, particularly in the neonatal jaundice group where there was high early mortality and poor “survival with native liver”. The truth is that AGS, with its myriad of associated vascular and tissue-development abnormalities, is not simply “liver disease” and needs to be thought of as a package of co-morbidities where cardiac, renal and cerebro-vascular involvement play a major and often unpredictable role in outcome. Karan McBride Emerick Children's Memorial Hospital Division of Gastroenterology, Hepatology and Nutrition Chicago, Illinois, U.S.A

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