Presentation and outcome of Alagille syndrome in paediatric patients at State Academic Hospital in South Africa

Abstract

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder in which patients may have characteristic facial features and involvement of the liver, heart, vessels, bones, eyes, kidneys and central nervous system. As there is little published data on ALGS in Africa, our aim was to describe the presentation and outcomes of ALGS in South Africa. The study constitutes a retrospective analysis of 25 patient medical records diagnosed as ALGS at Chris Hani Baragwanath Academic Hospital Pediatric Gastroenterology clinic between January 1992 and January 2020. Twenty-five patients met the diagnostic criteria for ALGS over the period investigated. Eighteen (72%) patients were less than 1 year old at first presentation. Seven patients (28%) had all five main clinical manifestations of ALGS, and the rest had an equal proportion of four and three main clinical manifestations. Cholestasis, one of the main clinical manifestations, was present in 72%; 80.0% had the typical Alagille facial features; 64% had cardiovascular disease, 36% had ocular abnormalities and 40% had skeletal abnormalities. Of the 16 patients, (64%) who presented with cardiovascular disease, seven patients presented with more than one cardiac lesion. As of January 2020, 8 (32%) patients are still being followed up at the pediatric GIT clinic, 13 (52%) patients were lost to follow-up and four patients (16%) were demised. Low- to middle-income countries, with no readily available access to genetic testing, need to rely on diagnostic criteria to make a diagnosis of Alagille syndrome in infants who present with cholestasis.

INTRODUCTION

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder in which patients may have characteristic facial features and involvement of the liver, heart, vessels, bones, eyes, kidneys and central nervous system. Cases were first reported by Alagille et al in 1969, subsequently by Watson and Miller in 1973, and again by Alagille et al in 1975, leading to the creation of the current diagnostic criteria and the occasional referral to the syndrome as the Alagille–Watson syndrome. The prevalence is reported in the literature to be 1:70000, and this was based on the presence of neonatal liver disease; however, this is most probably an underestimation as people without overt liver disease were not included. The use of genetic testing increased the prevalence to 1:30000 [1,2,3].

The diagnosis of ALGS has been based on liver biopsy histology demonstrating a paucity of intrahepatic bile ducts (PIHBDs), associated with three out of five main clinical abnormalities [4]. These are cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial features. The presence of at least two main clinical abnormalities and a confirmed diagnosis of ALGS in a first-degree relative may be enough to make a diagnosis of ALGS [4]. As ALGS is one of the causes of neonatal cholestasis, it is important to differentiate it from extrahepatic biliary atresia to avoid unnecessary surgical intervention (Kasai portoenterostomy) [1,4].

Approximately 97% of the patients have JAG1 gene mutation on the 20p11.2-20p12 chromosome, which encodes a ligand for the Notch transmembrane receptor; rarely, deletions may take place at this locus [2]. A small percentage (approximately 1%) of the ALGS patients have NOTCH2 mutations [5]. The prognosis and risk of mortality of ALGS depend on the type and severity of organ involvement. Early mortality is related to cardiac or liver disease, and later mortality is related to vascular accidents [6].

The liver outcome of ALGS showed survival to early adulthood with native liver in only 24% of children at 18 years. Clinical manifestations of cholestasis (pruritus and xanthomas) were frequent in early childhood and improved in transplant-free survivors after the age of 5 years. Only 20%–30% of individuals with ALGS require liver transplantation [7]. A ‘second wave’ of hepatic disease occurring in later childhood in ALGS with the development of portal hypertension, despite improvement in cholestasis, was documented [7]. To the best of our knowledge, there is little published data on ALGS in Africa. This study aimed to assess the clinical and biochemical presentation and outcome of ALGS in patients presenting to a state hospital with limited resources in South Africa. In addition to increasing awareness of the condition, the study would provide information on Alagille syndrome in Africa.

MATERIALS AND METHODS

Retrospective analysis of 25 patient medical records diagnosed with ALGS at Chris Hani Baragwanath Academic Hospital (CHBAH) Pediatric Gastroenterology clinic between January 1992 and January 2020. The liver clinic at CHBAH, the region’s biggest and oldest specialised liver clinic, was established in 1992. ALGS was diagnosed in patients with three of the five clinical characteristics (or two if there was a family history) plus a histological diagnosis of paucity of intrahepatic bile ducts. Five patients diagnosed clinically as ALGS but still waiting for liver biopsy or with less than three diagnostic criteria were excluded. A liver biopsy is part of the diagnostic work-up for neonatal cholestatic jaundice. Patients with suspected ALGS routinely undergo ophthalmological and cardiac evaluation [including cardiac echocardiography (ECHO)] and chest and spine X-rays. Demographic and clinical and biochemical data were collected, including age at onset of symptoms and presentation; gender and clinical features at presentation. Biochemical data collected included total and direct bilirubin; albumin; alanine transaminase (ALT); aspartate transaminase (AST); alkaline phosphatase (ALP); gamma glutamyl transferase (GGT); international normalisation rate and total serum cholesterol.

Clinical data collected included the presence of jaundice, cardiac defects, skeletal anomalies, ophthalmological assessment, facial manifestations [deep-set and widely spaced eyes (hypertelorism), a pointed chin, broad forehead, low-set malformed ears] and other abnormalities including those involving the renal and vascular systems. Clinical associations with cholestasis such as pruritus and xanthomata were noted. Progression to cirrhosis and portal hypertension were recorded.

Data on medical and surgical management were collected. These included surgical management (Kasai portoenterostomy, biliary diversion and liver transplantation) and medical management of complications of portal hypertension. Outcomes, in terms of mortality, and loss to follow-up were also collected.

Statistics

Data were entered in the computer using the IBM Statistical Package for the Social Sciences (SPSS^®) for Windows, version 22.0 (SPSS Inc., Armonk, New York, United States). Continuous data were checked for normality using the Shapiro–Wilk test. As none of the data were normally distributed, they were expressed as median and interquartile ranges. Frequency and proportions were used to describe the categorical data.

RESULTS

Between January 1992 and January 2020, 30 patients met the diagnostic criteria of ALGS. The majority (23 patients, 92%) of the cases were black, with almost equal distribution between sexes (male 48% vs female 52%). Eighteen (72%) patients were less than 1 year old at first presentation. Seven patients (28%) had all five main clinical manifestations of ALGS, and an equal proportion had four and three main clinical manifestations, nine in each group.

Most patients had cholestasis as one of the main clinical manifestations, with 72% presenting with neonatal cholestasis. Eighty percent of the patients had typical facial features, 64 % had cardiovascular disease, 36% had ocular abnormalities and 40% had skeletal abnormalities (Figure 1).

Figure 1.

Main clinical manifestations of Alagille syndrome at Chris Hani Baragwanath Academic Hospital, South Africa.

One patient had sensorineural deafness. Two patients (8%) presented with vascular complications – both had arterio-venous cerebral malformation complicated with stroke and hemiplegia. Of the 16 patients (64%) who presented with cardiovascular disease, seven patients presented with more than one cardiac lesion. The most common cardiac lesion was peripheral pulmonary stenosis (PPS, 81%), followed by patent ductus arteriosus (PDA, 19%), the other cardiac lesions are listed in Table 1.

Table 1.

Cardiac abnormalities in patients with Alagille syndrome at Chris Hani Baragwanath Academic Hospital, South Africa 1992–2020.

	Frequency	Percentage
Peripheral pulmonary stenosis	13	81.25
Patent ductus arteriosus	3	18.75
Ventricular septal defect	2	12.5
Tetralogy of fallot	2	12.5
Atrial septal defect	1	6.25
Bicuspid aortic valve	1	6.25

Eight (32%) patients had renal disease, which included renal tubular acidosis, dysplastic kidney and focal segmental glomerulosclerosis. With regards to hepatobiliary complication, (Table 2) eight patients (32%) had xanthomata, 21 patients (84%) had pruritus and 15 patients (60%) were diagnosed with portal hypertension, either clinically when they presented with upper gastrointestinal bleeding from esophageal varices or by Doppler ultrasound. Three (12%) patients in this study underwent Kasai portoenterostomy in early infancy (misdiagnosed as biliary atresia, two of whom subsequently required (67%) liver transplantation). Two (8%) patients underwent internal biliary diversion surgery. Eight (32%) patients are still being followed up at the pediatric GIT clinic, 13 (52%) patients were lost to follow-up and four patients (16%) were demised. Pruritus and failure to thrive were the most common complications noted during clinic follow-up visits.

Table 2.

Liver outcomes/complications in patients with Alagille syndrome at Chris Hani Baragwanath Academic Hospital, South Africa.

	Number	Percentage
Kasai operation	3	12
Biliary diversion	2	8
Liver transplant	2	8
Death	4	16
Loss to follow up	13	52
Being followed-up	8	32
Xanthoma	8	32
Pruritis	21	84
Portal hypertension	15	60
Esophageal varices/bleeding	4	16

Biochemical investigations done at first presentation (Table 3), confirmed conjugated hyperbilirubinemia in 23 patients, while bilirubin, ALT and AST were normal in the other two patients. GGT was normal in 4 patients, but ALP was high in all patients. Synthetic function was normal in all patients at first presentation. Serum cholesterol was checked in 17 out of the 25 patients, with 13 of the patients demonstrating high cholesterol levels at first presentation.

Table 3.

Biochemical data in patients with Alagille syndrome at Chris Hani Baragwanath Academic Hospital, South Africa.

	Median	Interquartile range
Total bilirubin, µmol/l	207	102–254
Direct bilirubin, µmol/l	126	76–186
Aspartate transaminase, U/l	292	133–389
Alanine transaminase, U/l	188	124–327
Alkaline phosphatase, U/l	755	582–1,288
Gamma-glutamyl transferase, U/l	272	145–606
Albumin, g/l	39	34–41
International Normalisation rate	1.02	0.9–1.2
Cholesterol, mmol/l	9.2	7.2–11.5

DISCUSSION

The presence of the main clinical features of ALGS in the current study is comparable to the previously published studies in terms of the presence of cholestasis and skeletal abnormalities (Table 4). In contrast, ocular abnormalities, characteristic facial features and cardiac lesions are less common [1,4,8]. The presence of other non-main clinical manifestations of ALGS, which include renal involvement, is comparable to reports from previously published studies. However, these figures could be higher if renal workup was included in the routine workup of any patient suspected of having ALGS. Cardiovascular involvement, which is significantly lower in our study compared to previous studies, is possible because screening for cardiovascular involvement is only done if a patient presents with a complaint [1]. In a resource-poor setting, with limited access to genetic studies, ALGS may be misdiagnosed as extrahepatic biliary atresia. This information is particularly relevant for low-income countries, where access to genetic studies is limited due to availability and high costs. The cost of single-gene testing in these regions ranges from $200 to $1,000 USD, which is approximately double the price in high-income countries [9]. The incidence of biliary atresia in South Africa is one of the highest in the world: 2500-1:8000, with the majority of the patients coming from the black ethnic group [10]. Six percent of cases of neonatal cholestasis are due to ALGS [11]. All the patients in this study underwent liver biopsy, which confirmed PIHBD. However, if a liver biopsy was done early in the disease, histology may show ductal proliferation and portal inflammation, which are characteristic findings in biliary atresia. This may have led to unnecessary Kasai portoenterostomy in three patients in our study [12]. Paying attention to the diagnostic criteria for ALGS may prevent patients from undergoing unwarranted surgery [4]. PIHBD is defined histologically in a full-term and older infant as a ratio of bile ducts to portal tracts of <0.9 in a liver biopsy with an adequate number of portal tracts (at least 6) [8].

Table 4.

Comparison of the main clinical features of Alagille syndrome to the previous published studies.

	Cholestasis	Typical facial feature	Cardiac disease	Skeletal abnormalities	Ocular abnormalities
Our data	96	80	64	40	36
Alagille et al. [13]	91	95	85	87	88
Deprettere et al. [14]	93	70	96	33	56
Emerick et al. [15]	97	96	97	51	78
Subramaniam et al. [8]	89	77	91	37	61

The presence of the main clinical features of ALGS compared to the previously published studies is equal in terms of cholestasis and skeletal abnormalities, whereas ocular abnormalities, characteristic facial features and cardiac disease are less common. The reasons for these differences may be due to the fact that characteristic faces may be difficult to recognise in an infant [13,16] and echocardiography may not detect stenotic changes if they are confined to distal pulmonary artery branches [17,18]. In addition, ocular abnormalities (posterior embryotoxon) may only be detected by an ophthalmologist who has the expertise in looking specifically for the lesion in the anterior chamber [19,20].

The liver outcomes in ALGS include living with a native liver with or without complications including portal hypertension with all its sequelae, pruritis, xanthomata, survival with a native liver with biliary diversion and liver transplantation. Three patients were misdiagnosed as having extrahepatic biliary atresia and underwent Kasai portoenterostomy; two of them underwent liver transplantation due to liver cirrhosis. Biochemical investigations, except for serum cholesterol, are usually non-specific. Conjugated hyperbilirubinemia associated with high GGT and ALP may also occur in biliary atresia and it is important to not miss these cases. Some of the challenges with regard to the liver outcome are assessing the progression of liver disease using biochemical investigations and the timing of surgical intervention (biliary diversion or liver transplantation), as ALGS-related cholestasis can resolve or stabilise [1,4]. Total and direct bilirubin levels in children with ALGS aged 6 and ≤12 months were identified as a prognostic marker for long-term hepatic outcomes, with a total bilirubin level of more than 170 umol/l associated with 15.6-fold increased risk of chronic liver disease and increased chance for needing liver transplantation compared to those with total serum bilirubin less than 85 umol/l [1,21]. This finding was also applicable to patients in our study, where those with the highest levels of total bilirubin developed liver complications and required liver transplantation. All children with cholestasis and ALGS will not inevitably require liver transplantation; therefore, there is a strong need for early predictors.

The high number of patients who were lost to follow-up may indicate less severe liver disease or early death. South Africa currently has one of the largest centers for liver transplantation in Africa at The Wits Donald Gordon Medical Centre. The hepatology services at public hospitals refer suitable patients to the Centre for Assessment and Liver Transplantation. Liver disease secondary to ALGS may not be as severe, considering that only 2 patients from this cohort underwent liver transplantation.

Post-transplant survival in ALGS patients is comparable to other indications, with 5-year survival rates of 80%-90% in experienced centers. Quality of life improves significantly after transplantation, particularly regarding pruritus and growth. Liver transplantation resolves cholestasis, improves growth and normalises fat-soluble vitamin levels. Other complications such as cardiovascular, renal and vascular disease show no change or even worsen especially renal complications due to the starting of nephrotoxic immunosuppression medication [22].

To the best of our knowledge, this is the first study describing the clinical presentation and complications of ALGS in Africa. Study limitations include a small sample size, numbers loss to follow-up and the retrospective nature of the study.

CONCLUSION

Countries with low income and no access to genetic studies need to have diagnostic guidelines for cholestatic infants with high ALP and GGT. This includes examination for characteristic facial anomalies [deeply set and widely spaced eyes (hypertelorism), a pointed chin, broad forehead and low-set, malformed eyes], comprehensive cardiac and ophthalmologic evaluations, and vertebral X-rays to exclude Alagille syndrome.

CONFLICT OF INTEREST

The authors have indicated that they have no conflicts of interest to disclose.

FUNDING

No external funding was received.

ETHICAL APPROVAL

The study received ethical approval from the Human Research Ethics Committee of the University of Witwatersrand: Reference No. (M 200618). Confidentiality of information was kept at all levels. Date of approval of ethical clearance 4/7/2020 and valid for 5 years.