Definition

Bile acids are the natural detergents the liver makes to help with bile flow and efficient fat and fat-soluble vitamin absorption. Bile acids are synthesized by the liver from cholesterol through a complex series of reactions involving at least 15 enzymatic steps. A failure to perform any of these reactions will block bile acid production with failure to produce "normal bile acids" and instead, atypical bile acids and intermediary metabolites accumulate. These atypical metabolites are presumed to cause liver disease. Because each of the enzymes in the pathway is encoded by a gene, it is believed that disease causing mutations in any of these genes of the pathway can disrupt normal bile acid synthesis. Inborn errors of bile acid metabolism can cause liver-specific disease or may be manifestations of more generalized diseases which may include neurologic involvement.

Etiology

Enzyme defects in the bile acid synthesis pathway are genetic conditions.  Genes code for specific enzymes that are responsible for each of the steps in the bile acid synthesis pathway.  These genes code for the enzymes in the pathway that allow normal production of bile acids. Currently there are potentially 16 known enzymes that may be affected by inborn errors in the pathway of which 10 defects have been identified to date. Below is the pathway with highlighting of currently recognized gene defects:

Figure 1: Recognized (red) gene defects in the enzymes of the bile acid biosynthetic pathway (adapted from reference: Russell DW, JLR, 2009).

For all the identified gene defects in bile acid synthesis, the inheritance is autosomal recessive. If someone inherits or carries (through de novo mutation) two abnormal genes, the patient will have a block in bile acid production with accumulation of compounds in the pathway proximal to the block, and a low production of normal bile acids. This may result in mild to severe liver disease depending upon which of the enzyme is affected.  Some conditions are associated with jaundice and significantly impaired hepatic synthetic function while in others there may be mild elevations of liver enzymes with poor bile flow and associated malabsorption of fat and fat-soluble vitamins with its attendant complications (∆4-3-oxosteroid 5ß-reductase (AKR1D1) deficiency, 3ß-hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency, or now named 3β-hydroxy-5-C27-steroid oxidoreductase deficiency (HSD3β7), conjugation defects).  In some conditions there is liver disease associated with neurologic dysfunction (2-methylacyl-CoA racemase deficiency, cerebrotendinous xanthomatosis). Patients with conditions called peroxisomal diseases, including Zellweger Disease and Neonatal adrenoleukodystrophy, have abnormalities in bile acid production because part of the synthesis of bile acids require reactions that take place within the peroxisome.  These disorders affect many organ systems since peroxisomes are present in all cells except red blood cells.  Liver disease may be variable in severity and is accompanied by neurologic disease, which may include intellectual disability, seizures, deafness, blindness, and muscular weakness.

Pathogenesis of Liver Disease

There are two principal causes of liver injury associated with inborn errors of bile acid metabolism. The first relates to the failure to make "normal" bile acids, which are a major driving force of bile secretion. This leads to impaired bile flow with attendant reduction of biliary excretion of individual components including cholesterol and other lipids, proteins, drugs, and environmental toxins out of the liver. Secondly, the intermediary metabolites produced due to failure of the liver to produce normal bile acids may themselves lead to liver injury. The combination of poor bile flow coupled with the production of potential toxic bile acid metabolites is most likely responsible for the injury to the liver seen in these conditions.

Clinical Features

Symptoms of inborn errors of bile acid metabolism can include jaundice, poor growth, liver or spleen enlargement, bleeding, rickets (vitamin D deficiency). Liver chemistries measured in the blood are abnormal and serum fat-soluble vitamin levels (e.g. 25-hydroxy-vitamin D, retinol and tocopherol levels) may be reduced. For most inborn errors, there is elevation in the serum ALT and AST and often but not always a normal GGT concentration. There may be variable alterations in the prothrombin time. For most of the conditions, serum bile acids measured by standard clinical methods are either inappropriately normal or low in the presence of other abnormal liver chemistries such as the serum direct or conjugated bilirubin, alkaline phosphatase or aminotransferases.

Diagnosis

Diagnosis of these rare conditions requires a high index of suspicion by the treating physician. In the clinical setting in which an infant or child has jaundice, liver disease of unknown cause, or abnormalities of fat or fat-soluble vitamin absorption, the treating physician needs to consider bile acid synthesis defects (BASD). In the presence of obstructive jaundice, the elevated serum bile acid levels usually exclude the diagnosis. If the levels of bile acids in the blood are low or normal, urine must be sent for analysis to specialized laboratories for measurement of urinary bile acids by a method called fast atom bombardment-mass spectrometry (FAB-MS) or related mass spectrometric technique. This technique allows identification of the "profile" of the bile acids in urine that would determine the potential presence of an inborn error of bile acid metabolism. If the urine FAB-MS study suggests an abnormality, additional evaluation (including measurement of bile acids in blood, evaluation of the microscopic appearance of the liver and genetic testing) may be necessary to establish the diagnosis. Examples of FAB-MS spectra, highlighting this finger printing approach to diagnosis for 6 of the inborn errors in bile acid synthesis is shown below:

Figure 2: Reconstructed characteristic FAB-MS spectra typical of 6 different defects in bile acid synthesis highlighting the diagnostic ions for the conditions and structural features of the atypical bile acid metabolites produced in each defect. (Reproduced from; Setchell & Heubi, JPGN 2005)

With a few exceptions, BASD causes liver disease that varies from severe to mild depending on the defect. In three of four known defects of sterol nucleus modification, liver disease is progressive. Progression of liver disease is most rapid when the defect results in accumulation of toxic monohydroxy and unsaturated oxo-bile acids. Reduced bile flow caused by atypical bile acids contributes to cholestasis and may be the dominant factor in defects of side-chain synthesis, peroxisomal biogenesis and in SmithLemliOpitz (SLO) syndrome. Pathological findings may include intralobular cholestasis with giant cell transformation, prevalence of necrotic hepatocytes including giant cell forms, and injury confined to the portal limiting plate where the smallest bile ductules may be injured, resulting in neo-cholangiolar proliferation, and where fibrosis typically develops. Interlobular bile ducts are usually spared. Ultrastructure of liver reveals nonspecific changes except for unusual canalicular morphology in some defects. The course of BAD may be modified by replacement of deficient primary bile acids, which produces beneficial feedback inhibition of abnormal bile acid production and enhances choleresis. 

Giant cell transformation is present in infants with BAD and seems to have a more consistent association with BAD than with the many other liver diseases in infants where it occurs. It is possible that immature hepatocytes of infants may fuse to form multinucleate hepatocytes whenever atypical or toxic bile acids are present and the pool of normal bile acids is critically reduced. Examples of two of the most common defects are shown in Figures 3 and 4 below: