Inherited Cholestatic Diseases in the Era of Personalized Medicine

Abstract

Watch a video presentation of this article Neonatal cholestasis includes a wide variety of disorders characterized by impaired bile excretion caused by hepatobiliary or metabolic disorders. Hepatic accumulation of bile acids (BAs) results in pruritus, hepatocyte toxicity, and cirrhosis. The incidence of neonatal cholestasis is ~1:2500 live births worldwide, and 25% to 50% of cases are considered inherited based on known genetic mutations.1 Next-generation DNA sequencing has afforded the ability to rapidly screen for mutations with gene array panels (Table 1) and to perform whole exome sequencing and whole genome sequencing for enigmatic cases. In a current study using a targeted gene panel for infants with cholestasis after exclusion of biliary atresia, 86% of infants received a diagnosis of a monogenic etiology for their cholestatic disease.2 In the past decade, new genetic associations of cholestatic diseases have been discovered at a rapid rate. Earlier diagnoses, accurate risk assessments, and optimal treatments based on genetic mutation associations are examples of personalized medicine that holds promise for significant improvement in patient care. In this review, we focus on two inherited intrahepatic cholestatic diseases, progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (ALGS), that have recent discoveries related to genetic diagnoses and personalized management. PFIC is a group of cholestatic disorders defined by a genetic defect in BA transport or tight junction structure at the level of the hepatocyte.3 The inheritance is autosomal recessive in nature; however, in up to 30% of patients with a clinical phenotype of PFIC, a known PFIC mutation is not identified. Currently, six PFIC types have been described, each identified by unique gene mutations and clinical manifestations3 (Table 2 and Fig. 1). Due to advances in genomics, mutations in tight junction protein 2 (TJP2) (PFIC4), NR1H4 (PFIC5), and myosin 5b (MYO5B) (PFIC6) were all discovered in the last 5 years. Recently, seven families with cholestatic liver diseases who were negative for known PFIC mutations underwent whole exome sequencing, leading to the discovery of three new pathogenic variants associated with PFIC-like presentations. These included USP53 (encodes for a protein that interacts with TJP2), LSR (regulator of liver development), and WDR83OS (interacts with bile salt export pump [BSEP]).4 The management of PFIC disease in infancy and childhood focuses on ensuring adequate nutrition in the setting of fat and fat-soluble vitamin malabsorption, controlling the severe pruritus with medications or surgery, and monitoring for cirrhosis and portal hypertension. One option for treating pruritus is the surgical partial external biliary diversion (PEBD), whereby the bile from the gallbladder is diverted to the skin via a loop of jejunum, thus decreasing the systemic pool of bile salts. This has resulted in not only improvement in pruritus, but also prevention of progression to cirrhosis in some cases. A recent analysis of patients with PFIC1 and PFIC2 led to the discovery that certain genotypes predict response to PEBD.5 Complete resolution of pruritus after PEBD was observed in 19% of patients with PFIC1, 55% of patients with PFIC2 genotype D482G, 21% of patients with PFIC2 genotype E297G, and 22% of patients with PFIC2 “other” genotypes. A poor outcome defined as cirrhosis, liver transplant, or death was observed in 27% of patients with PFIC1, 18% of patients with PFIC2 genotype D482G, 36% of patients with PFIC2 genotype E297G, and 70% of patients with PFIC2 “other” genotypes. The high rates of complete resolution of pruritus for patients with PFIC2 genotype D482G and poor outcomes in PFIC2 “other” genotypes are examples of how the specific genotype can guide personalized management. A “medication equivalent” to the PEBD involves the inhibition of the ileal apical sodium-dependent bile acid transporter (ASBTi), thus blocking BA enterohepatic recirculation (Fig. 1). A case series on the use of an ASBTi for PFIC2 showed promising results, and placebo-controlled trials are presently ongoing (ClinicalTrials.gov; NCT03905330, NCT03566238).6 The majority of patients will progress to cirrhosis and require liver transplantation. Liver transplantation has excellent overall outcomes; however, in PFIC1, the extraintestinal manifestations of severe diarrhea and pancreatic insufficiency persist posttransplant, impacting health and quality of life. Furthermore, there is a well-described phenomenon of “recurrent PFIC2 after liver transplant” due to autoantibody-mediated damage of BSEP that occurs in ~10% of children. ALGS is a multisystem disease that includes the hepatic manifestation of paucity of interlobular bile ducts. ALGS is an autosomal dominant disease, with gene mutations within the Notch signaling pathway; JAGGED1 (JAG1) accounts for 95% of cases and NOTCH2 for 2% to 3%. JAG1 is expressed early in the development of the cardiopulmonary system, biliary system, kidney, and brain. The extrahepatic manifestations are summarized in Fig. 2 and include vascular, facial, ocular, cardiac, vertebral, and renal anomalies.7, 8 There is great variability in penetrance of disease. Traditionally the diagnosis of ALGS was based on having three of the following five criteria: cholestasis, abnormal facies, posterior embryotoxon, cardiac defects, and vertebral anomalies. It has recently been proposed that the number of phenotypic criteria should be expanded to seven, to include renal and vascular anomalies.7 To date, there are no genotype-phenotype correlations in ALGS. However, patients with NOTCH2 mutations have a markedly lower incidence rate of cardiac disease (60% versus 100% in JAG1), abnormal facies (20% versus 100%), and skeletal anomalies (10% versus 64%).7 The management of patients with ALGS involves a multidisciplinary team consisting of hepatology, cardiology, nephrology, ophthalmology, and neurology. One of the life-threatening complications of ALGS is related to vascular anomalies. Moyamoya can lead to strokes, and intracranial or internal carotid artery aneurysms can result in catastrophic bleeding. Recently, visceral artery anomalies, including superior mesenteric artery aneurysms and visceral artery stenoses, have been described in ALGS.9 The potential for vascular anomalies is particularly concerning in the setting of liver transplantation, and it is recommended that children with ALGS who are being evaluated for transplant have magnetic resonance imaging with angiogram to screen for intracranial and intra-abdominal vascular anomalies. The future for managing ALGS liver disease will likely include therapies that target the enterohepatic circulation of bile (i.e., ASBTi), aimed at controlling the symptom of pruritus, as detailed earlier for PFIC disease. A placebo-controlled trial of an ASBTi for pruritus in ALGS revealed decreases in caregiver and clinician “itch scores” in the ASBTi group.10 The drug was well tolerated; however, it did not result in a reduction in serum bilirubin or BAs compared with placebo; the reason for this is not clear. In summary, the field of inherited cholestatic diseases is evolving rapidly based on next-generation DNA sequencing technology that allows for rapid diagnoses of known mutations and discoveries of novel genetic mutations associated with bile transport. Future medical therapies will include targeting various proteins involved in hepatocyte regulation and export or intestinal reuptake of BAs. Novel approaches to replacing the gene defect include hepatocyte transplantation of induced pluripotent stem cells and gene therapy.11 Another intriguing intervention that is currently being studied in animal models, and that could highly impact ALGS outcomes if successful, entails hepatocyte transdifferentiation into cholangiocytes, resulting in growth of functional intrahepatic bile ducts.12 The current revolution of genomics, organoid development, and personalized medicine signifies a bright future for inherited cholestatic diseases.

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