Biliary atresia (BA) is a progressive idiopathic inflammatory process that results in obliteration and fibrosis of the extrahepatic biliary tract and presents in the first few weeks of infancy with jaundice leading to cirrhosis before 2 years of age [1]. The overall incidence is 1:10,000. The most common form is BA without any other anomalies or malformations, also named perinatal BA. These patients are born anicteric and develop progressive jaundice and acholic stools within the first weeks of life. In approximately 15 % of cases, BA is associated with other malformations such as asplenia, polysplenia, situs inversus, malrotation, interrupted inferior vena cava, and cardiac anomalies and is also named BASM (biliary atresia splenic malformation) or embryonic BA [2]. In a smaller percentage BA may be associated with other congenital malformations, such as intestinal atresia, imperforate anus, kidney anomalies, and/or heart malformations [3].

The etiology remains idiopathic and is likely multifactorial: genetic, immunologic, viral and toxic [4]. Most infants are born full term and develop progressive jaundice and pale/acholic stools over the first weeks of life. Laboratory studies reveal elevated direct bilirubin and GGT with moderate increase in transaminases. Coagulopathy is likely the consequence of vitamin K deficiency [5]. Alpha 1 antitrypsin deficiency and Alagille may mimic BA. Ultrasonography may reveal absent or irregular gallbladder, absent common bile duct and occasionally the triangular cord sign (echogenicity of the portal hepatis remnant of the common bile duct) [6]. Hepatobiliary scintigraphy, usually primed with phenobarbital, does not reveal intestinal secretion. Liver biopsy is important to exclude other causes of cholestasis and is significant for expanded portal tracts with edema, inflammation and fibrosis with ductular proliferation, canalicular and bile duct biliary plugs. An intraoperative cholangiogram is considered the gold standard and reveals biliary obstruction. Alternatively, ERCP or percutaneous cholangiography may be performed [7].

Hepatoportoenterostomy (HPE, also known as the Kasai procedure) is resection of the fibrotic biliary remnant in the hilum with reconstruction of a Roux-en-Y loop of intestine to the liver hilum. HPE performed before 60 days of life have a better prognosis [8]. Postoperative management of patients after Kasai may include administration of ursodeoxycholic acid, nutritional support (calories and fat-soluble vitamins) [9], and prevention of cholangitis with prophylactic antibiotics [10]. There is controversy around the utility of corticosteroids with some studies showing efficacy short term without reducing the need for liver transplantation [11]. If jaundice persists beyond 3 months after the Kasai, the patient should be referred for liver transplant evaluation. Long-term complications include recurrent cholangitis, portal hypertension and liver tumors [12, 13]. Despite successful HPE and restoration of bile flow, 70–80 % of children require liver transplantation before adulthood and biliary atresia continues to be the most common indication for liver transplantation in children. However, with improvement in surgical technique and postoperative care, a percentage of patients are now reaching adulthood before transplantation.

AGS is an autosomal dominant inherited, highly variable, multi-systemic condition with an estimated prevalence of approximately 1 per 70,000 live births [14] with both genders being equally affected. The majority of cases are due to mutation in JAG1 in the Notch signaling pathway, and a small portion of cases are due to mutation in NOTCH2 [15, 16]. Reduced penetrance and variable expression are common in this disorder, and somatic/germ line mosaicism may also be relatively frequent. Main clinical and pathological features are intrahepatic bile duct paucity which results in chronic cholestasis, peripheral pulmonary artery stenosis, vertebral anomalies, characteristic facies, posterior embryotoxon, pigmentary retinopathy, dysplastic kidneys, and vascular abnormalities [17–19].

The multiple manifestations of AGS in humans suggest that JAG1 and Notch interactions are critical for normal embryogenesis of the heart, kidney, eye, face, skeleton, and other organs affected in this syndrome [20, 21]. Multiple mutations within the coding region of JAG1 have been documented in patients with AGS. The majority of JAGI mutations in patients are new and not found in either parent [22, 23]. Nonetheless, mutations can be present in 70 % of patients who meet clinical criteria for AGS [24]. Nearly half of these mutations are frameshift or nonsense mutations leading to premature truncation of the protein. The remaining mutations include gene deletions and missense mutations [25].

It is unclear as to whether missense mutations may cause milder variants of AGS or perhaps even single-organ abnormalities, though phenotypic differences between whole gene deletions and isolated point mutations have not been reported. Both copies of JAG1 are necessary for normal embryogenesis in humans [20, 21, 26]. However, the mechanism by which mutated JAG1 results in AGS remains unclear.

The clinical presentation of AGS is variable. Even within families, there is extreme variability in the severity of the disease, likely to be a result of other genetic and environmental modifying factors. Given the clinical variability and incomplete penetrance of the disorder, AGS often goes undiagnosed. Patients may present with progressive pruritus, cirrhosis, or liver failure. Still other individuals may lack or have few symptoms. Importantly, AGS is one of the more common etiologies of cholestasis in the neonatal period and must be differentiated from biliary atresia, which requires prompt surgical intervention. This is important, because the Kasai portoenterostomy is not beneficial in AGS [27].

Conjugated hyperbilirubinemia within the first 3 months of life is often the first presenting symptoms in the majority of patients with AGS. Progressive liver disease, eventually causing cirrhosis and failure, and requiring liver transplantation, occurs in approximately 15 % of cases [19]. Characteristic liver histology shows bile duct paucity in addition to major extrahepatic findings including characteristic facies, cardiac murmur, vertebral anomalies, and posterior embryotoxon. Cardiovascular anomalies can occur in close to 90 % of individuals with AGS [28]. Involvement of the pulmonary outflow tract is the most common type of congenital heart disease, with peripheral pulmonary stenosis (PPS) affecting at least two-thirds of cases. Tetralogy of Fallot (TOF) is the most common complex structural anomaly, occurring in up to 16 % of cases [19, 28]. Posterior embryotoxon has been reported in up to 90 % of ALG patients [29], however can also be found in up to 15 % of the normal population. Vascular accidents have been reported to occur in up to 15 % of cases, and were a cause of death in 34 % in one series [19, 30]. Intracranial bleeding may occur as a consequence of relatively minor head trauma.

There are currently no effective medical therapies for AGS. Supportive measures can be offered for nonspecific complications including pruritus. Medical therapies to improve pruritus include ursodeoxycholic acid, rifampin, cholestyramine, naltrexone, alimemazine, non-sedating antihistamine agents, and phenobarbitone or antihistamines; if these fail, biliary diversion may be required [31, 32]. The management of cholestatic pruritus in AGS is difficult and often suboptimal. Pruritus may remain intractable even with combination medical treatment, and at this stage, surgery or liver transplantation is indicated [32]. The survival post-liver transplantation for AGS patients is reduced compared to biliary atresia patients; the 1-year patient survival in patients with AGS is approx. 87 % compared to 96 % for biliary atresia patients. Deaths in AGS patients mostly occur within the first month post transplantation. Biliary, vascular, central nervous system, and renal complications after liver transplantation are associated with death in AGS patients; and renal insufficiency in the AGS patients usually worsens after liver transplantation [33].

PFIC represents a heterogeneous group of autosomal recessive disorders of bile formation disruption. PFIC is the cause of cholestasis in approximately 10–15 % of children with an estimated incidence of 1/50,000–1/100,000 births [34]. PFIC is noted by the onset of cholestasis in infancy or early childhood that persists throughout life and often leads to liver cirrhosis within the first decade unless treated. There are three types of PFIC related to mutations in genes controlling the hepatocellular formation and transport of bile. Patients with PFIC-1 and PFIC-2 present with low serum GGT; patients with PFIC-3 have high serum GGT.

PFIC-1, also known as Byler’s disease, was first described in Amish descendants of Jacob Byler [35], in the Inuit population in Greenland and Canada and other populations [36]. PFIC-1 is autosomal recessive caused by mutation for PFIC-1 to mutation of the FIC1 gene, on chromosome 18q21-22 [37, 38]. FIC1 encodes a P-type ATPase (ATP8Bl) involved in aminophospholipid flippase from the outer to the inner leaflet of plasma membranes, which is important in protection against the high bile salt concentration in the canalicular lumen and maintaining canalicular membrane integrity [38]. Expression of FIC1 has been found in a number of tissues including the intestine (highly expressed), liver, biliary tract, pancreas, and kidney [34]. The mechanism by which ATP8Bl defects lead to PFIC-1 remains unknown. Impaired ATP8Bl function results in downregulation of farnesoid X receptor (FXR) and subsequent Bile Salt Export Pump (BSEP) down regulation which leads to upregulation of the ASBP Apical Sodium Bile salt Transporter (ASBP) in the intestine [39]. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) downregulation has been reported in PFIC-1 that may explain some of the extrahepatic features [34].

Patients with PFIC- 1 usually present in the first weeks of life with severe pruritus disproportionate to the degree of jaundice [40]. Cholestasis can be initially episodic but becomes progressive. Progression to cirrhosis and end-stage liver disease occurs at a variable rate. Extrahepatic manifestation includes chronic diarrhea, short stature, failure to thrive, deafness, pancreatitis, biliary stones, and respiratory symptoms [40]. PFIC-1 is characterized by low serum GGT, high primary serum bile salts (chenodeoxycholic acid and cholic acid) and direct bilirubin, moderately elevated transaminase activities, normal serum cholesterol, and low biliary chenodeoxycholic concentrations. Liver imaging is normal [34, 40]. Liver histology reveals a “bland” picture of cholestasis and electron microscopy may show coarse granular bile [41, 42]. Mutational analysis of the ATP8B1 gene is the cornerstone of the diagnosis [43]; however, many patients are compound heterozygous.

Medical management is mostly supportive, assuring adequate nutrition and preventing fat soluble vitamins deficiency. Treatment with UDCA may be effective in some patients [34]. Treating pruritus is very challenging and children with PFIC-1 and PFIC-2 may benefit from surgical partial biliary diversion: external or internal before progression to cirrhosis [44, 45]. In partial external biliary diversion (PEBD) the gallbladder is connected to a cutaneous stoma by a loop of small bowel leading to reduction of the bile salt pool and inducing a shift to less toxic hydrophilic bile salts [46]. Internal biliary diversions are intestinal conduits between the gallbladder and the cecum, bypassing the terminal ileum, without external stoma [47]. However, recurrence of cholestasis has been reported in a few cases [48]. In ileal bypass (IB) the terminal ileum is skipped by an ileocolonic anastomosis [45]. Nasobiliary drainage may help selecting potential responders to biliary diversion [34]. Liver transplantation is performed in cirrhosis, portal hypertension and refractory pruritus [49]. Patients with PFIC-1 may experience worsening watery diarrhea (responsive to bile salt sequestrants) and liver graft steatosis which may progress to steatohepatitis [34, 40, 50].

PFIC-2 is an autosomal recessive disease caused by a mutation ABCB11 gene on chromosome 2q24 encoding the bile salt export pump (BSEP). Inhibition of BSEP leads to reduced bile salt secretion, reduced bile flow, and cholestasis. The spectrum of PFIC-2 is associated with the BSEP mutation. Jaundice, pruritus, failure to thrive, hepatomegaly, and splenomegaly present within the first months of life and cirrhosis has been noted as early as in the neonatal period [34, 40]. PFIC-2 patients manifest with a more severe hepatobiliary disease in comparison to PFIC-1 [51]. Significant coagulopathy with bleeding and hypocalcaemia due to vitamin D deficiency may be the presenting symptoms. Patients are a high risk of developing hepatocellular carcinoma at a young age and surveillance is warranted [52]. Hepatoblastoma and cholangiocarcinoma were also described at a young age [40]. There are no extrahepatic manifestations in PFIC-2 [51].

Laboratory findings include direct hyperbilirubinemia, elevated aminotransferase and Alpha fetoprotein (higher than PFIC-1), normal GGT, elevated serum bile acids, and decreased biliary bile salts [51]. Imaging studies show a normal biliary tree. Liver biopsy reveals giant cell transformation with canalicular cholestasis. Immunostaining for BSEP protein is negative. Electron microscopy reveals amorphous or finely filamentous bile [34]. Medical management is mostly supportive and often unsatisfactory. Surgical diversions may be effective, especially in those with functionally milder mutations [34]. Diversion should be offered early in the course of PFIC-2 as they it may slow progression of disease [53]. Treatment of a child with PFIC-2 with a mutation specific chaperone with 4-phenylbutyrate resulted in improved cholestasis and liver function [54]. Liver transplantation is indicated in cirrhosis, failed medical and surgical approaches, intractable pruritus, or HCC. Allo-immune mediated BSEP dysfunction may occur after liver transplantation in PFIC-2 patients leading to a PFIC-2 like phenotype recurrence [55].

PFIC-3 disease is caused by mutation of the multidrug-resistance-3, MDR3 glycoprotein, which is coded by the ABCB4 gene on chromosome 7q21 [34, 56]. MDR3 protein is an ATP dependent phosphatidylcholine flippase and expressed primarily within hepatocytes, though detected in other tissues. Consequently, PFIC-3 patients lack MDR-3 on the canalicular domain of the hepatocyte and have a significant decrease (<15 % of normal) in biliary phospholipid concentrations despite normal canalicular excretion of bile salts, promoting lithogenic hydrophobic bile with crystallized cholesterol. Disease-causing mutations on both alleles were found to be associated with reduced liver expression of ABCB4 protein, lack of response to ursodeoxycholic acid therapy, and progression to cirrhosis and end-stage liver disease, whereas mild genotypes, including single heterozygous mutations, were generally associated with less severe disease and, often, absence of symptoms [57]. MDR3 deficiency has been documented in several disease phenotypes, including intrahepatic and gallbladder cholesterol lithiasis, intrahepatic cholestasis of pregnancy, and progressive familial intrahepatic cholestasis type 3 (PFIC3).

PFIC-3 may present in infancy in half of the cases or later in life with jaundice, pale stools, pruritus, hepatomegaly, and splenomegaly (as a manifestation of portal hypertension) [58]. Children with PFIC3 are also at risk to develop intrahepatic and gallbladder cholesterol cholelithiasis and drug-induced cholestasis (DIC) [59]. Liver function tests showed elevated aminotransferases, AlkPhos, GGT, total serum bile acid and conjugated hyperbilirubinemia and absent serum lipoprotein X. Bile analysis revealed low concentrations of phospholipids and elevated ratios of bile salt to phospholipid and cholesterol to phospholipid. Liver imaging is typically normal, but may show a large gallbladder or biliary stones. Liver biopsy reveals ductular proliferation, biliary fibrosis, and immunohistochemical staining for MDR3 shows complete absence of canalicular staining. UDCA has variable results depending on the severity of the mutation: complete normalization of liver function test in 41 %, negative response in 37 %, and partial improvement in 20 % the rest [58]. UDCA benefit may be related to the modulation of biliary bile acid composition in favor of hydrophilic bile acids. Refractory progressive cases may require a liver transplantation [59].

BRIC is characterized by intermittent attacks of jaundice and pruritus separated by symptom-free intervals usually manifesting at adolescence [60] and was first described in 1959 [61]. There are two types of BRIC, affecting the ATP8B1 (BRIC 1) or ABCB11 (BRIC 2) gene, respectively [34]. It is postulated that in BRIC the protein is only partially impaired. Unlike PFIC, there is no permanent liver damage, no progression to cirrhosis, and no long-term complications of chronic liver disease [34]. Attacks consist of 2- to 4-weeks pre-icteric phase of malaise, anorexia, and pruritus, and an icteric phase lasting from usually 2–3 months. The number of discrete cholestatic episodes varies from a few episodes per year to one episode per decade and later in life, the cholestatic episodes become less frequent. Flares may have seasonal variation and exacerbation with infection, pregnancy, or contraception [62]. Patients with BRIC-1 may have significant weight loss, pancreatitis, and steatorrhea [62]. Patients with BRIC-2 have a higher incidence of cholelithiasis [63]. Attacks result in a characteristic cholestatic liver enzyme panel except that serum GGT remains low. Liver biopsy shows no pathologic characteristics even during episodes. Clinical, laboratory, and histologic features of BRIC remain normal during the asymptomatic phase [34]. Some patients present in childhood with recurrent attacks of cholestasis (BRIC) and cholestasis may gradually become permanent [64].

Medical therapies during the BRIC pruritic flare include UDCA and bile salt sequestrates with conflicting results [34]. Nasobiliary drain [65], extracorporeal albumin dialysis (MARS) [66], and the extracorporeal artificial liver support (Prometheus) have been shown to alleviate pruritus in refractory cases [67]. There is no proven effective therapy to avoid prevent or to shorten the cholestatic episodes in BRIC.

Dubin–Johnson syndrome (DJS) is a rare autosomal recessive liver disorder characterized by elevation of both conjugated and unconjugated bilirubin, with more than 50 % of the total bilirubin being conjugated [68]. Hepatomegaly can sometimes be seen but transaminases, GGT and bile acids are within normal limits [69]. Total urine excretion of coproporphyrin isomer I is >80 % (normal 25 %) excretion and excretion of coproporphyrin isomer III is concomitantly decreased [70, 71]. Jaundice can worsen with use of oral contraceptives and pregnancy [72, 73].

Liver biopsy shows characteristic brown to black discoloration of the liver with otherwise normal histology. DJS is linked to a deficient hepatic excretion of non-bile salt organic anions at the apical canalicular membrane, by the ABC transport system known as canalicular multispecific organic anion transporter (cMOAT) encoded by the human gene MRP2 (ABCC2) located on chromosome 10q24 [74, 75].

This protein mediates ATPdependent transport of a broad range of endogenous and xenobiotic compounds across the canalicular membrane of the hepatocyte. Defects in cMOAT may account for the impaired hepatobiliary transport of non-bile salt organic anions seen in patients with DJS. Although jaundice is a lifelong finding in patients with DJS, no specific therapy is required. It is not associated with morbidity or mortality [76].

Rotor syndrome (RS) is an autosomal recessive inherited disorder with chronic elevation of conjugated and unconjugated serum bilirubin and can present in early childhood [77]. Liver functions tests and liver histology are normal. In RS there is a marked increase in urinary coproporphyrins with <80 % being coproporphyrin isomer I.

The SLCO1B1 and SLCO1B3 genes are involved in Rotor syndrome. Mutations in both genes are required for the condition to occur. The SLCO1B1 and SLCO1B3 genes provide instructions for making similar proteins, called organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), respectively. Both proteins are found in liver cells; they transport bilirubin and other compounds from the blood into the liver so that they can be cleared from the body. In the liver, bilirubin is dissolved in digestive fluid called bile and then excreted from the body.

The SLCO1B1 and SLCO1B3 gene mutations that cause Rotor syndrome lead to abnormally short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins. Without the function of either transport protein, bilirubin is less efficiently taken up by the liver and removed from the body. The buildup of this substance leads to jaundice in people with Rotor syndrome.

Crigler–Najjar syndrome (CNS) is another rare genetic disorder resulting in chronic hyperbilirubinemia. Two types of CNS have been identified and recognized to be clinically distinct. Both are caused by an autosomal recessive defect in the UGTJA1 gene complex [78]. This gene encodes for the enzyme uridine diphosphate (UDP) glycosyltransferase 1 family, polypeptide AI, known to conjugate bilirubin.

In CNS type I, there is complete absence of functional UGTIAI. The unconjugated hyperbilirubinemia is severe and can lead to significant neurologic impairment due to bilirubin encephalopathy and permanent sequelae (kernicterus). The syndrome occurs in all races and has been associated with consanguinity in some patients. CNS 1 presents in the first days of life with elevated unconjugated bilirubin in the range of 20–25 mg/dL but can be as high as 50 mg/dL, normal transaminases, serum bile acids and no evidence of hemolysis. Stool is pigmented with low fecal urobilinogen excretion. The liver histology is normal.

In contrast, some functional UGT1Al activity is preserved in CNS type 2 (also known as Arias syndrome). Serum bilirubin is usually lower and jaundice may develop later in life and neurologic sequelae are less common. Jaundice may increase during fasting or intercurrent illness. CNS type 1 and type 2 are further differentiated by their response to phenobarbitol. (60–120 mg for 14 days) can significantly decrease serum bilirubin levels in CNS type 2 but have no effect on type I. Chromatographic analysis of bile collected from the duodenum reveals absence of conjugated bilirubin in CNS 1 and significant amount in CNS 2. DNA testing and prenatal diagnosis is available.

Treatment includes phototherapy (8–16 h per day) acting by converting a portion of bilirubin into a structural isomer that can be excreted in the bile without conjugation. This becomes less effective at puberty due to skin thickening and pigmentation, and decreased surface area in relation to body mass [79]. Late onset kernicterus may develop with treatment failure. Plasmapheresis is used to reduce bilirubin rapidly during a crisis to remove albumin bound bilirubin. Calcium carbonate and orlistat [80] can result in a modest reduction in bilirubin in patients with CNS1 on phototherapy by trapping intestinal bilirubin. Tin-protoporphyrin or tin-mesoporphyrin results in reduced bilirubin production [81]. Liver transplantation is considered the only definitive treatment for CNS 1 to prevent the risk of kernicterus [79]. Hepatocyte transplantation in a patient with CNS1 resulted in reduction of serum bilirubin levels that may be transient [82]. Gene therapy is being studied. Patients with CNS 2 affecting quality of life can be treated with phenobarbital or clofibrate [83].