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Alagille syndrome (ALGS) also known as arteriohepatic dysplasia is a rare genetic multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart, eyes, skeleton, face, kidneys, liver, and vasculature with the paucity of intrahepatic bile ducts associated with variable degrees of chronic cholestasis, characteristic facial features, structural heart disease, posterior embryotoxic, and vertebral arch defects. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), and poor weight gain and growth, and severe itching (pruritis). Additional symptoms include heart murmurs, congenital heart defects, vertebral (backbone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxic), and distinctive facial features. Most people with Alagille syndrome have changes (mutations) in one copy of the JAG1 gene. A small percentage (2 percent) of patients have mutations of the NOTCH2 gene. These mutations can be inherited in an autosomal dominant pattern, but in about half of the cases, the mutation occurs as a new change (“de novo”) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is approximately 1/30,000 –1/45,000.
Causes
Alagille syndrome is caused by mutations in one of two genes – the JAG1 gene or the NOTCH2 gene. Mutations of the JAG1 gene have been identified in more than 88 percent of cases. Mutations in the NOTCH2 gene account for less than 1 percent of cases. These mutations are inherited in an autosomal dominant pattern. In some cases, the mutations occur randomly due to a spontaneous genetic change (i.e., a new mutation).
Dominant genetic disorders occur when only a single copy of a gene with a mutation is necessary for the appearance of the disorder. The gene with the mutation can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. If carried by a parent, the risk of passing the gene with the mutation from the affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
Almost 90% of cases are due to mutations in JAG1 (20p12), an additional 5–7% are due to deletions incorporating JAG1, and about 1% is due to mutations in NOTCH2 (1p13). ALGS may be referred to as type 1 (JAG1-associated) or type 2 (NOTCH2-associated).
Diagnosis
A diagnosis of Alagille syndrome is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because the symptoms of Alagille syndrome are highly variable, obtaining a diagnosis can be difficult. Surgical removal and microscopic study of liver tissue (liver biopsy) can reveal bile duct paucity. Although bile duct paucity is considered a key characteristic of Alagille syndrome, this finding is not always present in infants with the disorder.
A physician may suspect Alagille syndrome if an individual has three of the following five clinical findings in addition to bile duct paucity: symptoms of liver disease or cholestasis, heart defect, skeletal abnormality, eye (ophthalmologic) abnormality, and/or distinctive facial features.
The biochemical profile of patients with ALGS reflects biliary damage and cholestasis. Markers of cholestasis (serum bile acids, bilirubin, cholesterol, γ-glutamyltransferase (GGT), and alkaline phosphatase) are often strikingly elevated and almost always exceed that of hepatocellular injury (alanine and aspartate aminotransferase) [rx]. GGT may, however, be normal, and therefore should not defer further testing if there is a high index of suspicion for ALGS [rx]. Cholestasis often spontaneously improves in patients during childhood and is accompanied by a reduction in pruritus and xanthomas [rx].
Due to biliary tree hypoplasia, liver ultrasonography may show a small or absent gallbladder in 28% of patients [rx]. Hepatic regenerative nodules have been reported in 30% of patients and can be confused with hepatocellular carcinoma. They are distinguishable biochemically by normal alpha-fetoprotein, and radiologically by their central location, isoechoic texture to the surrounding liver, and absence of invasion of portal venous structures on MRI [rx, Rx,rx].
Lastly, in any patient where ALGS is suspected, formal echocardiography, dedicated vertebral radiography, slit-lamp examination of the eyes, and renal ultrasonography with a doppler should be performed. Brain MRI/MRA is recommended in patients with ALGS with neurologic symptoms or for screening later in childhood.
Liver Histopathology
With advancements in molecular diagnostics, a liver biopsy is no longer required to diagnose ALGS but remains an integral part of clinical diagnosis if molecular testing is not available in a timely fashion, and to differentiate between ALGS and BA [rx]. Bile duct paucity remains the hallmark of ALGS and was once an absolute requirement for diagnosis. It is assessed by calculating the interlobular ducts to portal tracts ratio, with normal being 0.9–1.8 [rx], and is diagnosed if <0.9 in full-term infants. As the number of ducts to portal tracts decreases over time, the ratio is typically < 0.5–0.75 in older infants [rx,rx]. Bile ductules that are usually peripherally located are not included in this ratio. It is important to have an adequate number of evaluated portal tracts to arrive at a precise ratio. When wedge biopsies were historically used, Alagille et al. suggested that 20 portal tracts should be evaluated [rx]. However, 6–10 portal tracts are usually sufficient at present with needle biopsies [rx,rx,rx].
To date, bile duct paucity has been reported in approximately 89% of patients with ALGS [rx,RX,rx,rx]. It is more commonly found in children > 6 months of age as reported by Emerick et al. where paucity was found in only 60% of children < 6 months compared to 95% in > 6 months [rx]. Factors leading to the paucity progression (which mirrors the severity of clinical hepatic phenotype) are unknown, but hypotheses include postnatal ductal destruction, lack of development of terminal branches of the bile ducts, and/or differential maturation of portal tracts [rx,rx].
Other reported histological features include occasional ductular proliferation that is typically associated with portal inflammation, and giant cell hepatitis due to cholestasis (which may mimic BA). Regenerative liver nodules if found, show preserved ductal architecture, lesser degrees of fibrosis, and relative preservation of interlobular bile ducts compared to the background cirrhotic liver [rx,rx,rx].
Genetic Testing
Genetic testing in clinically defined patients with ALGS reveals a disease-causing mutation in almost 95%. Since most ALGS-associated mutations are found in JAG1, Sanger sequencing of all 26 exons and adjacent intronic regions will identify 85% of JAG1 pathogenic variants. If no mutation is found, large deletion duplication analysis using multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray (CMA), or fluorescence in situ hybridization (FISH) will successfully identify an additional 9% of mutations [rx,rx]. If no JAG1 mutation is found, sequencing of the 34 exons encoding for the NOTCH2 gene should be carried out, which identifies 2–3% of additional mutations. MLPA, FISH, and CMA are typically not carried out since no large deletions of NOTCH2 have been reported. [rx,rx]. For practical reasons and cost-effectiveness, simultaneous testing of both genes is now carried out by commercially available next-generation sequencing (NGS) panels.
In addition to a liver biopsy, physicians may conduct other tests to aid in the diagnosis of Alagille syndrome. Such tests may include blood tests to determine the liver function and detect fat-soluble vitamin deficiencies, an eye examination, x-rays of the spine to detect characteristic changes such as butterfly vertebrae, an abdominal ultrasound of the hepatobiliary tree (e.g., liver, pancreas, gall bladder and spleen) to detect abnormalities or rule out other conditions, and an examination of heart structure and function to detect potential heart abnormalities.
The diagnosis of Alagille syndrome can be confirmed in many cases by molecular genetic testing, which reveals the presence of a JAG1 or NOTCH2 gene mutation. However, in some people with Alagille syndrome, genetic testing may not reveal a JAG1 or NOTCH2 mutation.
Treatment
The treatment of Alagille syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, gastroenterologists, cardiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Individuals with Alagille syndrome should have a baseline echocardiogram (ultrasound of the heart) to screen for heart involvement, an ultrasound of the abdomen to screen for liver and kidney anomalies, and a screening eye (ophthalmology) exam, In addition, if not previously obtained for specific symptoms, a screening imaging study of the blood vessels of the head (MRI/MRA) is recommended for children who are old enough to sit through the study without the need for anesthesia or sedation. Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E and K. Young children may be given formula with medium-chain triglycerides because this form of fat is better absorbed by individuals with Alagille syndrome who have cholestasis. Some affected children may need to receive extra calories through a tube that runs from the nose to the stomach (nasogastric tube) or through a tube placed directly into the stomach through a small incision in the abdominal wall and stomach (gastrostomy tube).
Pharmacological step-up therapy of cholestatic pruritus in Alagille syndrome.
| Medication Class | Medication | Side Effect Profile |
|---|---|---|
| 1st line: Choleretics |
Ursodeoxycholic acid | Generally safe; Diarrhea, abdominal pain, vomiting |
| Bile salt-binding agents | Cholestyramine | Constipation, abdominal pain, worsening FSVD, poor palatability |
| 2nd line: Bile acid hydroxylation | Rifampin | Red discoloration of bodily fluids (sweat, tears), vomiting, hepatitis, idiosyncratic hypersensitivity reaction |
| 3rd line: Opioid antagonists | Naltrexone | Limited data; abdominal pain, nausea, irritability, diarrhea |
| 4th line (not yet approved by regulators): Intestinal bile acid transport (IBAT) inhibitors |
Maralixibat Odevixibat |
Limited data; vomiting, diarrhea, abdominal pain, rash, hepatitis, FSV deficiencies |
| Adjunctive therapy: | ||
| Antihistamines | Diphenhydramine | Drowsiness |
| SSRI | Sertraline | Limited data; agitation, alopecia and drug eruption, vomiting, hypertension |
Treatment for patients with ALGS is supportive and aimed at optimizing nutrition and managing complications related to cholestasis, such as DVD and pruritus.
Nutrition and DVD
The etiology of growth failure in ALGS is multifactorial and includes inadequate intake, fat malabsorption due to cholestasis, and cardiac disease [rx]. Although children with ALGS, have normal resting energy expenditure [rx], they require 25% additional recommended daily allowance due to cholestasis [rx], and may even require more for a catch-up growth if malnutrition is severe [rx]. Patients should be encouraged to consume calorie-dense food, especially medium-chain triglycerides-rich foods or formula since they do not require micellar formation for absorption. Nasogastric or gastrostomy tube feeding should be considered in children unable to meet their caloric needs and is often necessary for cholestatic children.
Cholestasis-specific formulations exist for fat-soluble vitamin (FSV) supplementation (e.g., DEKA’s), which may help with medication compliance and cost, especially in patients with multiple DVD. If only generic multivitamin preparations are available, then individual supplementation of FSV is preferred.
Medical Management of Pruritus
Therapies aiming at decreasing total body bile acid load are typically effective for pruritus. However, there are likely other mechanisms underlying pruritus, as serum bile acid levels do not always correlate with itching severity [rx]. Pruritus treatment in ALGS follows a step-by-step approach, as outlined. Antihistamines are used for mild cases. They are rarely used as single agents due to their short-lived effect [rx]. Ursodeoxycholic acid (UDCA) promotes bile excretion and makes it more hydrophilic and is used in most cholestatic children with ALGS. Other available therapies include rifampin, bile salt-binding agents (cholestyramine), opioid antagonists, and selective serotonin reuptake inhibitors (SSRI) such as Sertraline [rx,rx]. Cholestyramine disrupts the enterohepatic circulation and reduces total body bile acids by preventing re-uptake in the terminal ileum. Due to its poor taste, and interference with the absorption of food, medications, and FSV, it is of limited use in clinical practice [rx]. Rifampin is thought to be 6-hydroxylase bile acids making them less pruritogenic [rx] and excretable by the kidneys [rx]. Almost 50% of patients treated with Rifampin report good improvement in pruritus [rx]. Naltrexone, an opioid antagonist that blocks mu receptors, which are upregulated in cholestasis [rx], has been associated with at least minimal improvement in most children with ALGS [rx]. However, symptoms of opioid withdrawal syndrome, such as diarrhea and irritability, occur in almost 30% of patients. Although sertraline, a selective serotonin reuptake inhibitor (SSRI) has been effective in treating adults with cholestatic pruritus [rx], its mechanism of action is unknown. Limited pediatric data are available supporting its use as an additional therapy for pruritus [rx].
Surgical Management of Pruritus
In ALGS patients with pruritus refractory to medical therapy, surgical procedures targeted at interrupting the enterohepatic circulation should be considered. Since bile duct hypoplasia associated with ALGS can result in less bile reaching the bowel, these procedures are generally less effective than in other causes of cholestasis (such as progressive familial intrahepatic cholestasis). Partial external biliary diversion (PEBD), where the gallbladder is drained externally via a jejunal conduit, is the most commonly performed procedure [rx]. Wang et al. reported improvement in total serum cholesterol, pruritus severity, and xanthomas in 20 ALGS patients who have undergone PEBD [rx]. Other less commonly performed procedures include ileal exclusion and internal biliary diversion.
Liver Transplantation
The indications of LT in ALGS are typically multifactorial but can be broadly classified as an end-stage liver disease due to progressive cholestasis (malnutrition refractory to nutritional therapy, intractable pruritus, and bone fractures) and/or end-stage liver disease with portal hypertension and complications, such as ascites and variceal bleeding [rx]. When assessing candidacy, careful consideration should be sought for the multisystemic involvement; cardiac, renal, and vascular disease. As mentioned previously, patients should undergo MRI/MRA of the brain and computed tomography (CT) imaging of the abdomen, and echocardiogram when being assessed for transplant. Renal-sparing immunosuppression protocols should be used.
When considering living-related transplantation, it is important to emphasize that donors with JAG1 and/or NOTCH2 mutations should be avoided as they may have unrecognized liver disease. Therefore, all potential related donors should have a comprehensive clinical assessment, genetic screening for the known mutation in the proband, abdominal imaging for vascular anomalies, and potentially liver biopsy [rx,rx].
IBAT Inhibitors
The concept of molecular therapy with IBAT inhibitors is similar to that of biliary diversion procedures; reduction of the total bile acid pool size via inhibition of enterohepatic circulation results in mitigating the toxic effects of bile acids on the liver and improvement of cholestasis [rx,rx]. Located on the apical membrane of ileal enterocytes, IBATs actively transport conjugated bile acids from enterocytes, which are then exported into the portal system via different mechanisms, facilitating return to the liver [rx]. As a result, more than 90% of intestinal bile acids are reabsorbed in healthy individuals [rx,rx]. Currently, two drugs in this class are under study for pruritus in children with cholestasis—Maralixibat and Odevixibat—though at this time there are more available data for the former in the study of ALGS.
The efficacy of Maralixibat, an IBAT inhibitor, has been evaluated in phase 2 trials in patients with ALGS. The ITCH trial evaluated 37 patients with ALGS in a placebo-controlled randomized trial [rx]. Although the pre-specified primary endpoints were not met in this study, a reduction in pruritus, as measured by caregiver observation a validated scale (ItchRO), was more common in the Maralixibat treated group as compared to the placebo group. Maralixibat was safe with comparable adverse events between groups. The ICONIC trial evaluated 31 patients with ALGS in a multicentered trial using a randomized drug-withdrawal study design (though these data have only been presented in abstract form, to date) [rx]. Serum bile acid levels fell, as expected, on Maralixibat treatment; however, during the randomized drug withdrawal period, bile acid levels in the placebo group returned to baseline, and subjects had significantly higher ItchRO scores. [rx].
These preliminary studies show that IBAT inhibitors hold promise as future treatments for pruritus that may potentially also prove to be hepatoprotective. Continued investigations are warranted to explore their therapeutic effect on the natural history of cholestatic disease in ALGS.
Cholangiocyte Regeneration
The cholangiopathy of ALGS involves defects in cholangiocyte specification, differentiation, and morphogenesis, making this pathobiological process subject to investigational cell rescue and/or tissue regeneration. Similar to stem cell-mediated organ regeneration, cellular transdifferentiation is a process of complete and stable change in cell identity. This makes it an attractive system to utilize in repairing the defective biliary system in ALGS [rx], by potentially harnessing the ability of hepatocytes to transdifferentiate into cholangiocytes.
In a recent important study, transdifferentiation was explored in an ALGS mouse model made by NOTCH deletion, showing severe cholestasis and lacking peripheral bile ducts [rx]. At postnatal day 120, newly formed peripheral bile ducts were detected, with cholangiocytes harboring markers indicative of hepatocyte origin. Hepatocyte-derived peripheral bile ducts (HpBDs) were found to be contiguous with the extrahepatic biliary system and were effective in draining bile, evidenced by the normalization of total bilirubin [rx]. HpBDs showed signs of cholangiocyte maturity and authenticity and expressed markers of biliary differentiation, indicating that they were not merely hepatocyte-derived metaplastic biliary cells. This transdifferentiation was not only limited to immature hepatocytes but also seen in murine adult and transplanted hepatocytes [rx]. This signifies that hepatocytes can form peripheral bile ducts de novo and can provide normal and stable biliary function. Further investigations in this report led to the discovery that TGFβ is responsible for hepatocyte transdifferentiation and morphogenesis in HpBD formation [rx]. This was also identified in regenerative nodules in adult ALGS patients that stained positive for cytokeratin-7 and contained peripheral bile ducts, suggesting that this mechanism is active in humans with ALGS. This study not only highlights the significance of hepatic plasticity and cellular transdifferentiation, but also emphasizes the utility of therapeutic hepatocyte transplantation, and targeting TGFβ induction as future treatment strategies in ALGS-related cholestasis.
Stem Cell Applications in ALGS
The rationale for using stem cell technology to model and perhaps treat biliary diseases is powerful and includes reasons, such as limited access to human biliary tissue, lack of physiological responses in cultured cholangiocytes, and the inability of murine models to fully recapitulate human biliary disease [rx]. Induced pluripotent stem cells (iPSCs) are generated through reprogramming mature human somatic cells to a pluripotent state [rx]. iPSCs have the potential to differentiate into any germ layer in vitro, which when utilizing unique protocols can be directly differentiated into almost any cell type, including cholangiocytes. Cholangiocytes that express mature biliary markers and demonstrate biliary functions have been successfully differentiated by a number of groups [rx]. Furthermore, iPSC-derived cholangiocytes have been shown to recapitulate disease features of cystic fibrosis-related cholangiopathy [rx].
In severe cases of Alagille syndrome (i.e., cases that have progressed to cirrhosis or liver failure or in which other therapies were unsuccessful), liver transplantation may be required.
Additional complications that can be associated with Alagille syndrome including heart, blood vessel, and kidney abnormalities are treated in the standard manner. In some cases, this may include surgery.
Genetic counseling is recommended for affected individuals and their families. Another treatment is symptomatic and supportive.
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