• benign recurrent intrahepatic cholestasis;
  • bile acids;
  • bile acid synthesis;
  • bile salt export pump;
  • farnesoid X-receptor;
  • hepatobiliary transport;
  • intrahepatic cholestasis of pregnancy;
  • progressive familial intrahepatic cholestasis


  1. Top of page
  2. Abstract
  3. Physiology
  4. Pathophysiology
  5. Acknowledgements
  6. References

Abstract: Bile salts take part in an efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver, the sodium-dependent taurocholate transporter at the basolateral (sinusoidal) membrane and the bile salt export pump at the canalicular membrane mediate hepatic uptake and hepatobiliary secretion of bile salts. Canalicular secretion is the driving force for the enterohepatic cycling of bile salts and most genetic diseases are caused by defects of canalicular secretion. Impairment of bile flow leads to adaptive changes in the expression of transporter proteins and enzymes of the cytochrome P-450 system involved in the metabolism of cholesterol and bile acids. Bile salts act as ligands for transcription factors. As such, they stimulate or inhibit the transcription of genes encoding transporters and enzymes involved in their own metabolism. Together these changes appear to serve mainly a hepatoprotective function. Progressive familial intrahepatic cholestasis (PFIC) results from mutations in various genes encoding hepatobiliary transport proteins. Mutations in the FIC1 gene cause relapsing or permanent cholestasis. The relapsing type of cholestasis is called benign recurrent intrahepatic cholestasis, the permanent type of cholestasis PFIC type 1. PFIC type 2 results from mutations in the bile salt export pump (BSEP) gene. This is associated with permanent cholestasis since birth. Serum gamma-glutamyltransferase (gamma-GT) activity is low to normal in PFIC types 1 and 2. Bile diversion procedures, causing a decreased bile salt pool, have a beneficial effect in a number of patients with these diseases. However, liver transplantation is often necessary. PFIC type 3 is caused by mutations in the MDR3 gene. MDR3 is a phospholipid translocator in the canalicular membrane. Because of the inability to secrete phospholipids, patients with PFIC type 3 produce bile acid-rich toxic bile that damages the intrahepatic bile ducts. Serum gamma-GT activity is elevated in these patients. Ursodeoxycholic acid therapy is useful for patients with a partial defect. Liver transplantation is a more definitive therapy for these patients.


progressive familial intrahepatic cholestasis


benign recurrent intrahepatic cholestasis


intrahepatic cholestasis of pregnancy


bile salt export pump


organic anion transporting polypeptide


multidrug resistance-related protein


apical sodium-dependent bile acid transporter


farnesoid X-receptor


small heterodimer partner


c-jun N-terminal kinase

Bile salts are the main organic solutes in bile, and their vectorial secretion from blood to bile represents the major driving force for bile formation. Although bile is iso-osmotic in relation to plasma, bile salts are 100–1000-fold concentrated in bile, necessitating active transport of bile salts by hepatocytes against a concentration gradient. The total bile salt pool size in adult humans amounts to 50–60 mmol/kg body weight, corresponding to 3–4 g, and is largely stored in the gallbladder during the fasting state. The human bile salt pool circulates 6–10 times per 24 h, resulting in a daily bile salt secretion of 20–40 g. Despite a high degree of intestinal bile salt conservation, about 0.5 g of bile salts is lost through fecal excretion. This loss is compensated for by de novo hepatic bile salt synthesis, which contributes less than 3% of bile salts secreted with hepatic bile. The intrinsic link between intestinal bile salt absorption and hepatic synthesis has recently been delineated by the discovery that bile salts are ligands for transcription factors that affect the expression of a number of genes involved in bile salt synthesis and transport. Disturbances of bile salt transport are important causes of acquired and genetic forms of cholestatic liver disease in humans.


  1. Top of page
  2. Abstract
  3. Physiology
  4. Pathophysiology
  5. Acknowledgements
  6. References

Hepatic transport proteins

Hepatic uptake

The Na+/taurocholate co-transporting polypeptide (NTCP; SLC10A1) is the major bile salt uptake system of hepatocytes (1) (Fig. 1). It is localized in the basolateral membrane of hepatocytes (2). Ntcp in rats preferentially mediates sodium-dependent transport of conjugated bile salts, such as taurocholate (capital letters, NTCP, are used to denote the human transporter and lowercase letters, Ntcp, the rodent protein). This transport comprises the major fraction of hepatic bile salt uptake. NTCP is not the only hepatic uptake transporter for bile salts. OATP-C (SLC21A6) transports a number of organic anions, including bilirubin and bile salts, in a sodium-independent manner. OATP-B, OATP-C and OATP8 exhibit broad overlapping substrate specificities and together account for drug clearance by human liver (3).


Figure 1.  Human hepatobiliary transport proteins involved in bile formation, secretion and reabsorption. Transporter proteins located in the basolateral membrane are responsible for hepatic uptake of bile salts (NTCP, OATPs), bulky organic anions, uncharged compounds (OATPs) and cations (OATPs, OCT1). Transporter proteins located in the canalicular membrane are responsible for the biliary secretion of bile salts, phosphatidylcholine, cholesterol and glutathione and the excretion of drugs and toxins. These are the bile salt export pump BSEP (ABCB11), the phosphatidylcholine translocator MDR3 (ABCB4), the multispecific organic anion transporter MRP2 (ABCC2) and the multidrug transporter MDR1 (ABCB1). The organic anion transporters MRP3 (ABCC3), MRP4 (ABCC4) and MRP1 (ABCC1) are present at very low levels in normal human liver but their expression is strongly increased during cholestasis. Both MRP3 and MRP4 are able to transport bile acid conjugates out of the hepatocyte. FIC1 (ATP8B1) has been characterized as an aminophospholipid translocase. In the terminal ileum, the apical sodium-dependent bile acid transporter (ASBT) is responsible for bile acid reabsorption. Genetic defects have been described for FIC1 (PFIC type 1, BRIC), BSEP (PFIC type 2), MDR3 (PFIC type 3, ICP), MRP2 (Dubin–Johnson syndrome) and ASBT (bile acid malabsorption).

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Canalicular bile salt transport

The human bile salt export pump (BSEP, ABCB11) is critical for ATP-dependent transport of bile acids across the hepatocyte canalicular membrane and for the generation of bile acid-dependent bile secretion (4). Murine Bsep was shown to transport taurocholate, taurocheno-deoxycholate and glycocholate (5, 6). Bsep (−/−) knockout mice are cholestatic in the sense that taurocholate accumulates in their plasma because its secretion into bile is strongly impaired (italics denote the gene, non-italics the protein) (7). However, in contrast to patients, the mice excrete substantial amounts of tauromuricholate as well as tetrahydroxy bile salts via hitherto undefined canalicular transporters. Humans are not capable of converting bile salts into muricholate or tetrahydroxy bile salts to any significant extent; therefore, this escape route is not available to man.

Basolateral escape routes

MRP3 (ABCC3), MRP4 (ABCC4) and MRP1 (ABCC1) are transporter proteins that support the basolateral export of organic anions, including that of bile acid conjugates (8, 9). In normal liver their expression is low, but in cholestasis these proteins are highly expressed (10, 11). It is postulated that these proteins play a role as basolateral escape transporters when canalicular Bsep function is impaired as during sepsis, drug-induced cholestasis or bile duct obstruction.

Intestinal reabsorption

In the ileum, bile salts are reabsorbed. A sodium-dependent apical bile salt transporting protein ASBT (SLC10A2) and an intracellular bile salt binding protein play an important role in reclaiming bile salts from the intestinal lumen, but other mechanisms for bile salt reabsorption probably co-exist (12, 13). About 90% of the total biliary bile salts are reabsorbed in the ileum.

Mechanisms of adaptation

Hepatocytes are strictly polarized cells. They absorb substrates from the blood and secrete metabolites into the bile. The supply of bile acids is highly variable. Absorption of bile salts by the liver from the portal venous blood is nearly complete and, in the fasting state, mainly occurs in periportal hepatocytes. Thus, periportal hepatocytes are continuously exposed to high bile salt concentrations. Hepatocytes more downstream into the hepatic acinus are exposed to varying concentrations of bile salts: low in the fasting state, high after a meal. Bile salts are cytotoxic and cellular homeostasis demands maintenance of intracellular bile salt concentrations within certain limits. Post-translational regulations with recruitment of BSEP from intracellular stores to the canalicular membrane may be operational for this purpose (14). Obstruction of bile efflux by gallstones or tumors will lead to a more chronic exposure of liver cells to bile salts. Transcriptional regulation enables alterations of BSEP expression in order to maintain cellular homeostasis. Cytokines also play a role here. Bile salts stimulate Kupffer cells to produce TNF-α and interleukin-1β. These act upon hepatocyte receptors that affect the c-jun N-terminal kinase signal transduction pathway.

Regulation of gene expression

Nuclear hormone receptors have been identified as important transcription factors in lipid and bile salt metabolism. The BSEP gene is under the transcriptional control of FXR (farnesoid X-receptor) (Fig. 2) (15). FXR is a ligand-activated transcription factor. Chenodeoxycholic acid and cholic acid bind and activate FXR (Fig. 2 (1)). Subsequently, FXR forms a heterodimer with RXR (retinoid X-receptor) and translocates to the nucleus (2). Here the FXR:RXR heterodimer acts as a transcription factor of e.g. the BSEP and SHP-1 (small heterodimer protein-1) genes. SHP-1 antagonizes the transcription of CYP7A1, CYP8B and NTCP (16, 17). Thus, FXR controls several key steps in bile salt metabolism. Studies in mice with a genetic disruption of Fxr showed that the Fxr-mediated response is particularly important in dealing with a bile salt load as occurs when mice are fed a high cholesterol- or cholate-containing diet. In Fxr null mice, the expression of the Ntcp, Cyp7a1 and Cyp8b genes fails to be downregulated and the expression of the Bsep and Shp-1 genes is not increased (18). Severe hepatic damage is the consequence of this failure of regulation.


Figure 2.  Gene regulation by bile salts. Bile salts are taken up in the liver by NTCP and secreted into bile by canalicular BSEP. In cholestasis BSEP activity is reduced the intracellular bile salt concentration increases (1). Bile salts serve as ligands for FXR, which forms a heterodimer with RXR and translocates to the nucleus (2). The heterodimer activates the transcription of the BSEP and SHP-1 genes. SHP-1 antagonizes the expression of the bile acid biosynthetic enzymes CYP7A1 and CYP8B1 and the transporter NTCP. In addition, Kupffer cells produce TNF-α and interleukin-1β during cholestasis and, via the c-Jun N-terminal kinase-dependent (JNK) pathway, they reduce the expression of NTCP and CYP7A1 (3). Recent evidence indicates that Lrh-1 (liver receptor homolog-1)-mediated Mrp3 transcription is enhanced via a TNF-α signalling pathway (25). Thus, at increasing bile salt concentrations, de novo synthesis is reduced, uptake is impaired and secretion, either across the canalicular or basolateral membrane, is stimulated. As a consequence, the intracellular bile salt concentration remains controlled and limited.

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Cholestasis in rats is associated with a decreased expression of Ntcp (19). This in part results from enhanced expression of Shp-1 through activation of Fxr by retained bile salts (17), but also Shp-1-independent pathways exist to suppress transcription of the Ntcp and Cyp7a1 genes (20, 21). In some of these, cytokines play an important role, but a recent study indicates that FXR can also suppress the Cyp7a1 gene in an Shp-1-independent way (21). This again indicates the key role of bile acids in these adaptations. Also in humans, NTCP expression in cholestatic liver disease is decreased (22). Downregulation of the NTCP and CYP7A1 genes, and the consquent decreased expression of NTCP and CYP7A1, in cholestatic liver disease reduces the entry and the synthesis of bile acids. This regulation most probably serves a cytoprotective function. This is particularly important in the case of bile duct obstruction when BSEP, via FXR-stimulated expression of its gene, remains active and keeps transporting bile acids into the bile canaliculus despite the downstream obstruction. This leads to disruption of tight junctions and bile infarcts (23). Up-regulation of MRP1, 3 and 4 in the basolateral membranes of hepatocytes probably constitutes an important escape route for the cellular release of cholestatic products. Bile salts, bilirubin and cytokines are involved in the transcriptional activation of their respective genes (11, 24, 25).


  1. Top of page
  2. Abstract
  3. Physiology
  4. Pathophysiology
  5. Acknowledgements
  6. References

Genetic transport defects

The spectrum of diseases caused by defects of ABC transporter proteins is diverse and includes the liver diseases: progressive familial intrahepatic cholestasis (PFIC) (26) (Table 1), benign recurrent intrahepatic cholestasis (BRIC) (27), intrahepatic cholestasis of pregnancy (28, 29), intrahepatic gallstone formation (30), cystic fibrosis (31), adrenoleukodystrophy (32) and Dubin–Johnson syndrome (33, 34).

Table 1.   Genetic cholestasis
  1. gamma-GT=gamma glutamyl tranferase.

PFIC type 118q21FIC 1 (ATP8B1) P-type ATPase, acts as an aminophospholipid translocatorFirst recurrent, later permanent cholestasis, bile duct proliferation is a late phenomenon. Diarrhea, pancreatitis, pruritus, short stature. Coarse granular bile on EM. Normal gamma-GTUrsodeoxycholic acid, bile diversion, liver transplantation
Benign recurrent intrahepatic cholestasis18q21FIC1 (ATP8B1)Recurrent episodes of cholestasis with severe pruritus, steatorrhea and weight loss. Normal gamma-GTCholestyramine and/or rifampicine as symptomatic antipruritus therapy
PFIC type 22q24BSEP (ABCB11), bile salt export pumpNeonatal hepatitis, progressive cholestasis, pruritus, short stature, bile duct proliferation is a late phenomenon, lobular and portal fibrosis. BSEP protein absent. Amorphous bile on EM. Normal gamma-GTUrsodeoxycholic acid bile diversion, liver transplantation
PFIC type 37q21PGY3 (ABCB4, MDR 3), P-glycoprotein 3Cholestasis, portal hypertension, extensive bile duct proliferation and periportal fibrosis. MDR3 is not expressed. Elevated gamma-GTUrsodeoxycholic acid, liver transplantation
Intrahepatic cholestasis of pregnancye.g. 7q21e.g. MDR3Cholestasis in third trimester of pregnancy. High gamma-GT in case of MDR3 defect; low gamma-GT cases may be caused by genetic defects of other transporter proteins. High incidence of fetal lossUrsodeoxycholic acid causes symptomatic relief in the mother and decreases fetal loss
Aagenaes syndrome15qLCS1, LCS2Episodic cholestasis, lymphedema, normal gamma-GTLiver transplantation but persistence of lymphedema
Familial Hypercholanemia9q12–q13 9q22–q32TJP2/ZO-2 BAATElevated bile acids, severe pruritus, fat malabsorption, failure to thrive, rickets, vitamin K coagulopathyLiver transplantation
Bile acid synthesis defectse.g. 8q2.33β-Δ5-C27-hydroxysteroid oxidoreductase; Δ4-3-oxosteroid-5β reductase; 3β-hydroxy C27 steroid dehydrogenase/isomerase; oxysterol 7α-hydroxylase; 24,25-dihydroxy-cholanoic cleavage enzyme.Intrahepatic cholestasis, neonatal giant cell hepatitis. Normal or elevated gamma-GT, low or elevated serum total bile acidsUrsodeoxycholic acid, chenodeoxycholic acid or cholic acid alone or in combination, depending on subtype

PFIC constitutes a group of autosomal recessive diseases characterized by cholestasis starting in infancy. For a first differentiation of various PFIC subtypes, measurement of the serum gamma-glutamyltransferase (gamma-GT) activity is useful. Diseases associated with a low bile salt concentration in bile have a low serum gamma-GT activity. These diseases have an intrahepatocellular blockade of bile salt secretion in common. Gamma-GT in human liver is mainly located in the membranes lining the biliary tree. Elevation of serum gamma-GT results from a detergent, membranolytic effect of bile salts on these membranes. Thus an intra- or extrahepatic obstruction of bile flow, or bile devoid of phosphatidylcholine (as in PFIC type 3, see below), causes gamma-GT to be released in the circulation.

PFIC type 1

PFIC type 1 or Byler disease often begins with cholestatic episodes progressing to permanent cholestasis with fibrosis, cirrhosis and liver failure in the first two decades of life (35). Children with PFIC type 1 are small for their age and, in addition to cholestasis and pruritus, they often have diarrhea and occasionally pancreatitis. The larger bile ducts are anatomically normal and liver histology shows bland canalicular cholestasis without much bile duct proliferation, inflammation, fibrosis or cirrhosis (35, 36). On electron microscopy, there is a paucity of canalicular microvilli and a thickened pericanalicular network of microfilaments. The coarse granular bile in the canaliculi is called ‘Byler bile’. Characteristically, the serum gamma-GT activity is not elevated while primary bile salt levels, in particular chenodeoxycholic acid, are increased. Serum cholesterol is usually normal. Patients belonging to the Byler kindred are descendants of Jacob and Nancy Byler, who emigrated in the late 18th century from Germany to the United States. The PFIC syndrome has also been described in families in the Netherlands, Sweden, Greenland and an Arab population (35, 37–40).


Recurrent familial intrahepatic cholestasis is also known under the name BRIC or Summerskil syndrome. Despite recurrent attacks of cholestasis, there is no progression to chronic liver disease in a majority of patients. During the attacks, the patients are severely jaundiced and have pruritus, steatorrhoea and weight loss. As in PFIC 1 the serum gamma-GT is not elevated. Some patients also have renal stones, pancreatitis and diabetes. The gene involved in recurrent familial intrahepatic cholestasis has been mapped to the FIC1 locus (27). This suggests that recurrent familial intrahepatic cholestasis and PFIC type I are genetically related. However, in not all BRIC patients could the defect be traced to chromosome 18 mutations (41). Ursodeoxycholic acid is of no benefit in BRIC (42). Case reports indicate that rifampicine may reduce the number of cholestatic episodes (43, 44).

PFIC type 2

Genetic studies revealed a number of PFIC patients in whom the FIC1 locus does not seem to be involved. In a large number of non-Amish patients, the disease was mapped to a locus on chromosome 2q24, which later proved to be the ABCB11 (BSEP) gene (45). Antibodies directed against BSEP showed that the protein is located in the canalicular domain of the hepatocyte plasma membrane. Liver specimens of patients with PFIC type 2 stain negative for canalicular BSEP on immunohistochemistry using BSEP antibodies (46). As in PFIC type 1, the serum gamma-GT activity in these patients is not elevated and bile duct proliferation is absent. However, there are also some differences with PFIC type 1: in PFIC2 the disease often starts as nonspecific giant cell hepatitis, which is indistinguishable from idiopathic neonatal giant cell hepatitis; patients are frequently jaundiced and the disease rapidly progresses to persistent and progressive cholestasis requiring liver transplantation within the first decade. The liver histology shows more inflammation than in PFIC type 1, with giant cell transformation, lobular and portal fibrosis (35). The bile of PFIC type 2 patients is amorphous or filamentous on transmission electron microscopy. This contrasts with the coarsely granular bile of PFIC type 1 patients. Extrahepatic manifestations are uncommon.

PFIC type 3

The third PFIC subtype, PFIC type 3, is quite different from the other PFIC subtypes. In patients with PFIC type 3, symptoms present somewhat later in life than in PFIC types 1 and 2, and liver failure also occurs at a later age. Jaundice may be less apparent during the early stages of disease. The serum gamma-GT activity is usually markedly elevated in these patients and the liver histology shows extensive bile duct proliferation, portal and periportal fibrosis (47, 48). In humans, the MDR3 gene is mutated in this disease (28, 29, 47, 48). Patients with a partial MDR3 defect often respond to ursodeoxycholic acid therapy (49). The majority of patients, particularly those with a complete defect, have to be transplanted.


Subgroups of PFIC types 1–3 may respond to ursodeoxycholic acid (50). However, progression of disease and insufficient control of symptoms may necessitate further intervention such as liver transplantation. Ursodeoxycholic may also lead to acceleration of disease (50) or to very high serum bile acid levels (>1 mmol/l) without any increase of bile salt secretion (46). PFIC 3 patients are more likely to respond to ursodeoxycholic acid therapy if they carry mild mutations of the MDR3 gene (48, 49).

For PFIC types 1 and 2, partial external biliary diversion is an accepted mode of therapy (51, 52). The majority of patients respond with a significant improvement of symptoms (52–54). When performed early, ongoing hepatic injury may be interrupted with resolution of histological abnormalities including reversal of fibrosis (54). Clinically, the patients may experience long-term amelioration of pruritus and induction of catch-up growth (52).

Liver transplantation has been performed for patients with PFIC types 1–3. In general, these patients have a good prognosis after successful transplantation (55). Since PFIC type 1 is a multiorgan disease, diarrhea may persist and pancreatitis may occur after transplantation. Diarrhea in these patients is associated with malabsorption; therefore, catch-up growth after transplantation may be disappointing.

Intrahepatic cholestasis of pregnancy (ICP)

Jacquemin et al. (29) reported a high incidence of ICP in families with PFIC type 3. This suggests that in persons carrying one mutated MDR3 gene, cholestasis may occur during pregnancy. Mutations leading to single amino acid substitutions of the MDR3 protein may cause intracellular traffic mutants, i.e. the protein is synthesized but does not reach its destination in the canalicular membrane (56). ICP has also been described in families with other PFIC subtypes (57). Thus, ICP may be associated either with elevated serum gamma-GT or with a normal enzyme activity. Ursodeoxycholic acid has been shown to be of benefit in these patients, with also a decrease of fetal loss (58, 59).

Other forms of intrahepatic cholestasis

Aageneas syndrome is a combination of severe progressive lymphedema and episodic intrahepatic cholestasis (60). The locus for this disease has been mapped to one locus, or perhaps two loci, on chromosome 15q (61, 62). Recently, Carlton et al. (63) described patients with familial hypercholanemia characterized by elevated serum bile acids, pruritus, fat malabsorption, failure to thrive, rickets and vitamin K coagulopathy. This disease is associated with a mutation of the tight-junction protein 2 gene (TJP2 or ZO-2) with or without additional mutations in a gene encoding the bile acid coenzyme A:amino acid N-acyltransferase gene (BAAT). Patients with TJP2 mutations had higher gamma-GT serum levels than patients with BAAT gene mutations only. The serum of patients with BAAT mutations did not contain bile acid amino acid conjugates.


  1. Top of page
  2. Abstract
  3. Physiology
  4. Pathophysiology
  5. Acknowledgements
  6. References

This research was supported by the Netherlands Organization for Scientific Research, NWO program grant 902-23-191 and NWO project grants 902-23-253, 902-23-257 and 903-39-188.


  1. Top of page
  2. Abstract
  3. Physiology
  4. Pathophysiology
  5. Acknowledgements
  6. References
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