A history of research into the physiology of bile, from Hippocrates to molecular medicine.

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Obeticholic acid in primary biliary cholangitis.

In a double-blind, randomized, placebo-controlled study including 217 patients with primary biliary cholangitis, the authors show that obeticholic acid (a potent farnesoid X agonist) administered with ursodeoxycholic acid or as monotherapy significantly decreases serum alkaline phosphatase and bilirubin when compared to placebo. Pruritus (and serious adverse effects) was observed more frequently in obeticholic acid-treated patients than in controls, in spite of a decrease in serum bile acid concentration. These results are encouraging, but more studies are needed on clinical efficacy and safety before obeticholic acid can be widely recommended.

A microbial peptide to rescue severe and fulminant Wilson disease?

Wilson disease is characterized by massive copper overload caused by a mutation of the liver-specific copper-transporting ATPase, ATP7B. Presently, liver transplantation is the only treatment available to patients with advanced or acute liver disease. In this paper, the authors describe the therapeutic effect of methanobactin, a potent bacterial copper-binding protein, in a rat model of Wilson disease, the Atp7b-/- rat. Their results show a marked improvement of clinical, biochemical and ultrastructural abnormalities. They propose that methanobactin is a candidate drug for Wilson disease patients with severe liver disease.

Intrahepatic cholestasis of pregnancy: A risk factor for cancer, autoimmune and cardiovascular diseases?

The authors show, in an elegant population-based study, a significant association between intrahepatic cholestasis of pregnancy and liver and biliary cancer. This association is most probably related to the high frequency of hepatitis C and gallstone disease in women with intrahepatic cholestasis of pregnancy, both being risk factors for liver and biliary cancer. In addition, the study clearly shows an increased risk of diabetes mellitus and autoimmune diseases, such as thyroid diseases, psoriasis, autoimmune arthropathies and Crohn's disease, and a small increase in cardiovascular diseases. In practice, a follow-up of liver function tests 6-12 weeks after delivery is strongly recommended to detect a possible associated liver disease.

NTCP deficiency: a new inherited disease of bile acid transport.

The authors report the case of a child with extreme elevation of serum bile acid concentration, without pruritus, symptomatic cholestasis, liver disease, or abnormalities of liver function tests. Sequencing of the SLC10A1 gene, encoding NTCP (the sinusoidal uptake transporter of conjugated bile acids) revealed a single homozygous point mutation in the coding sequence of the gene resulting in an arginine to histidine substitution at position 252. This mutation resulted in a markedly reduced uptake activity of taurocholic acid. This is the first report of a new inborn error of bile acid transport, due to a mutation of NTCP.

Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences.

Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler-Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin-Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.

Bile acids in cholestasis: bad for the liver, not so good for the kidney.

The elegant paper by Fickert et al. on bile duct ligated mice provides convincing evidence for the hypothesis that bile acids retained in the serum during cholestasis and excreted through the kidneys are toxic to collecting duct cells. The authors propose that bile acids initiate a chain of reactions leading to tubulointerstitial nephritis and fibrosis. Mice with cholestasis were protected by prefeeding with the hydrophilic bile acid norursodeoxycholic acid, an observation which suggests a potential therapeutic option for cholemic nephropathy.

Hereditary conjugated hyperbilirubinaemia: 37 years later.

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.

Low phospholipid-associated cholestasis and cholelithiasis.

Low phospholipid-associated cholestasis and cholelithiasis (LPAC) is a genetic disorder characterized by cholesterol gallbladder and intrahepatic stones. It is caused by a mutation of the gene ABCB4, which encodes the canalicular protein ABCB4/MDR3, a flippase that plays an essential role in the secretion of phosphatidylcholine into bile. Failure of this protein leads to secretion of bile that is poor in phospholipids and, hence, highly lithogenic, with potent detergent properties. This, in turn, leads to cholangiocyte luminal membrane injury and biliary lesions causing cholestasis. The diagnosis should be suspected when at least two of the following criteria are present: onset of symptoms before the age of 40 years; recurrence of biliary symptoms (biliary colic, jaundice, cholangitis, acute pancreatitis) after cholecystectomy; presence of echogenic foci within the liver indicative of intrahepatic stones or biliary sludge; previous episode(s) of intrahepatic cholestasis of pregnancy; and family history of gallstones in first-degree relatives. Intrahepatic stones can be demonstrated by ultrasonography with color Doppler examination, computed tomography and magnetic resonance imaging with magnetic resonance cholangiography, and the diagnosis confirmed by ABCB4 genotyping. Therapy with ursodeoxycholic acid offers prompt relief of symptoms and usually prevents complications. In some cases, however, surgery may be necessary.

Chronic fibrosing cholangiopathies: a consequence of a defective HCO3⁻ "umbrella"?

The pathogenesis of chronic cholangiopathies, in particular primary biliary cirrhosis and primary sclerosing cholangitis, is still obscure. A stimulating hypothesis is proposed by Beuers et al. They reason that, since cholangiocytes are exposed to high concentrations of hydrophobic bile salts that are toxic at µM concentrations, these cells had to develop protective mechanisms. Apart from micelle formation, the authors argue that biliary HCO3⁻ secretion serves to maintain an alkaline pH near the apical surface of cholangiocytes by forming a HCO3⁻ "umbrella". In this alkaline environment, glycine conjugated bile salts (which are predominant in man), with a pKa of ~4, remain deprotonated and are unable to permeate the apical membrane and cause cell damage. Functional impairment of biliary HCO3⁻ secretion leads to enhanced vulnerability of cholangiocytes toward the attack of hydrophobic bile salts, causing cell damage and cholangitis. Such an impairment could be due to genetic factors, like mutations of the anion exchanger 2 (a variant of the Cl⁻/HCO3⁻ exchanger) in primary biliary cirrhosis or of TGR5 (a bile salt receptor implicated in the regulation of HCO3⁻ secretion) in primary sclerosing cholangitis. This stimulating hypothesis is amenable to experimental testing and has potential pathophysiological and therapeutic implications.