Genetic Disorders of Bile Acid Transport.

Abstract

Content available: Audio Recording Answer questions and earn CME Cholestasis, the slowing or stoppage of bile flow, causes toxic bile acids to accumulate in the liver resulting in liver injury. Impaired bile flow can result from a variety of conditions, the most common of which are obstruction of the extrahepatic bile ducts (e.g., gallstones, tumors, or strictures related to primary sclerosing cholangitis), drug toxicity, or primary biliary cholangitis. Although these conditions have clear genetic influence, they are multifactorial in etiology. In addition, there is a collection of relatively rare conditions with monogenic causes manifesting as intrahepatic cholestasis. This review focuses on these genetic disorders of bile acid transport. Under normal physiological conditions, bile acids are shuttled between the liver and small intestine through a process termed the enterohepatic circulation (Fig. 1). Although the kinetics of the enterohepatic circulation have been known for nearly a century, the molecular mechanisms facilitating the proper flow of bile acids have been elucidated largely over the past three decades.1 Bile acids are synthesized in hepatocytes and actively secreted across the canalicular membrane into small terminal bile ducts, termed bile canaliculi. The major canalicular bile acid transporter is the bile salt export pump (BSEP) encoded by ABCB11 (Fig. 2). Other components of bile, including phospholipids and cholesterol, are exported with bile acids across the canalicular membrane via specific transporters as shown in Fig. 2. Proper bile flow requires the coordinated action of all of the canalicular membrane transporters, and disruption of any one transporter can lead to cholestasis. After bile acids reach the small intestine and have performed their critical function in lipid solubilization, they are actively taken up in the ileum and returned to the liver via the portal circulation (Figs. 1 and 2). In each cycle of the enterohepatic circulation, about 5% of bile acids escape reabsorption in the ileum, and the liver must synthesize new bile acids to replace those that are lost. Bile acids are synthesized from cholesterol through a series of enzymatic steps, many of which are subject to genetic disruption1 (Table 1). Bile acids regulate their own synthesis through a feedback loop involving activation of the endogenous bile acid receptor, the farnesoid X receptor (FXR), encoded by NR1H4.2 In addition to regulating bile acid synthesis, FXR regulates several other transporters that are critical to the normal flux of bile acids through the hepatocyte (Fig. 2). In summary, bile acid synthesis and transport are tightly regulated processes with multiple steps that are prone to disruption. Genetic mutations have been identified in key regulators of bile acid flow resulting in a range of cholestatic phenotypes. Cholestasis is a feature of a myriad of genetic disorders as summarized in Table 1. Many inborn errors of metabolism, for example, have been identified as causes of cholestasis in infancy, particularly those affecting genes encoding bile acid synthetic enzymes. In addition, several multisystem genetic diseases, such as Alagille syndrome (ALGS) and cystic fibrosis, exhibit cholestasis as one of many diverse manifestations. There is a range of pathophysiological disturbances that lead to cholestasis in these diverse genetic diseases. For example, the cholangiopathy in ALGS results from aberrant bile duct development. The remainder of this review focuses on progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), and intrahepatic cholestasis of pregnancy (ICP), a spectrum of diseases arising from defects in hepatocellular bile formation and flow. Complete or near-complete disruption of the affected genes results in PFIC, a severe form of intrahepatic cholestasis that presents in early childhood and progresses to end-stage liver disease. In contrast, mutations resulting in partial deficiency of select PFIC-associated genes predispose to BRIC or ICP, milder forms of the disease that present later in life. Traditionally, there have been three main subtypes of PFIC resulting from mutations in ATP8B1 (FIC), ABCB11 (BSEP), and ABCB4 (MDR3) (Table 2 and Fig. 2). Because of the expanding use of next-generation sequencing technology, mutations causing three additional subtypes of PFIC have been identified in the last decade. Specifically, mutations in tight junction protein 2 (TJP2), FXR (NR1H4), and myosin Vb (MYO5B) have been identified as novel causes of genetic cholestasis.3-6 A recent analysis of families with cholestatic diseases resembling PFIC has led to the identification of other novel mutations associated with cholestasis (KIF12, PPM1F, USP53, LSR, and WDR83OS), thereby expanding our understanding of the mechanistic underpinnings of intrahepatic genetic cholestasis.7 The PFIC subtypes resulting from defects in FIC, BSEP, and MDR3 have been historically identified numerically as PFIC 1 through 3, respectively. With the rapidly increasing number of genes linked to PFIC, this numerical classification is no longer preferred. Instead, molecular classification, in which the subtype is identified by the genetic defect, is increasingly favored. The pathophysiology underlying “classic” PFIC (i.e., FIC, BSEP, and MDR3 deficiency) is fundamentally similar in that these subtypes result from defects in the major canalicular membrane transporters (Fig. 2). The discovery of mutations in TJP2, NR1H4, and MYO5B has broadened our understanding of the range of pathophysiological disturbances that lead to intrahepatic cholestasis. TJP2, for example, encodes a TJP, the loss of which allows leakage of biliary components from the canaliculi into hepatocytes. Disruption of NR1H4 (FXR) leads to severe cholestasis through multiple mechanisms, chief of which are the loss of feedback inhibition of bile acid synthesis and impaired induction of canalicular membrane transporters. MYO5B is involved in the trafficking of BSEP to the canalicular membrane, the dysfunction of which impairs canalicular bile acid secretion. Clinically, PFIC typically presents in infancy with jaundice and pruritus and, if left untreated, progresses to cirrhosis. The pruritus is often intense and intractable. The subtypes of PFIC can be differentiated to some degree clinically based on the age of onset and rapidity of progression, as well as other distinct clinical features (Table 2). Although PFIC is classically associated with low/normal serum gamma glutamyl transferase (GGT), the exception is MDR3 deficiency, which exhibits high GGT. Interestingly, mutations in MYO5B were first identified as the cause of microvillus inclusion disease (MVID), and the association with low-GGT cholestasis is a relatively recent discovery. Certain PFIC subtypes confer an increased risk for hepatocellular carcinoma in childhood, most notably BSEP deficiency. Additional differentiating features of the PFIC subtypes are summarized in Table 2. BRIC represents a less severe form of PFIC typically characterized by recurrent episodes of cholestasis triggered by infections or medications. There are two subtypes of BRIC (BRIC 1 and BRIC2) caused by mutations in ATP8B1 and ABCB11, respectively8, 9 (Table 2). In contrast with PFIC, BRIC typically manifests in late childhood or early adulthood with mild cholestatic symptoms, classically pruritus. Liver histology is typically normal between episodes of cholestasis, and progression to advanced liver disease is rare. ICP is characterized by the onset of cholestatic symptoms during pregnancy. Mutations in several genes, including ABCB4, ABCB11, ABCC2, ATP8B1, TJP2, and NR1H4, have been linked to ICP, with mutations in ABCB4 being most common10-12 (Table 2). The classic presentation is pruritus beginning in the third trimester. Typical laboratory findings include elevated aminotransferases and high levels of serum bile acids. The management centers on controlling symptoms, typically using ursodeoxycholic acid for pruritus. The definitive treatment is delivery, with most cases of ICP resolving completely in the postpartum period. Although the condition is thought to have little impact on the long-term health of the mother, ICP is associated with an increased risk for serious pregnancy complications, including fetal distress or intrauterine death. Due to advances in next-generation sequencing, tremendous progress has been made in recent years toward discovering all of the genes responsible for various forms of genetic cholestasis. Still, nearly a third of patients with PFIC-like syndromes do not harbor mutations in any of the known PFIC-associated genes. As such, there is considerably more work to be done to fully characterize this family of disorders at a genetic level.