Bile Acid Synthesis and Metabolism Defects

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:

Figure 3. Liver, early onset 3 beta-OH-steroid dehydrogenase deficiency, age 6 months at biopsy. Panels A,B: Intralobular cholestasis with prominent giant cell transformation. Mild portal inflammation includes scattered polymorphonuclear leukocytes. Ductular profiles are increased slightly and have swollen epithelium (arrow). Panel C. Delicate periportal fibrosis accompanies regenerative ductule reaction (arrow). Trichrome stain. Panel D. Regenerative ductular reaction is highlighted by immunostain for mixed cytokeratins.

Figure 4. Findings in 5 oxysterol beta reductase deficiency in two infants, pretreatment. Panels A and B: Liver biopsy at age 5 days. Note mild intralobular cholestasis, necrotic giant hepatocyte, absence of portal inflammation and normal small bile ductule. - Liver biopsy, Panels C and D: Liver Biopsy at age 6 weeks. Note severe hepatocyte cytoplasmic ballooning with giant cell transformation, cytoplasmic bile stasis, scattered necrotic hepatocytes, focal sinusoidal erythropoesis, moderate portal inflammation and focal cholangitis.

Genetics

Finally, detection of disease-causing mutations in specific enzymes in the bile acid synthesis pathway is available by DNA sequencing of the respective genes encoding the suspected enzyme deficiency, or through specific gene disease panels.

Treatment

The treatment for inborn errors of bile acid metabolism focuses on restoring normal bile flow with concomitant reduction in the levels of the atypical and hepatotoxic bile acid metabolites. For all inborn errors of bile acid metabolism except conjugation defects, bile acid therapy with a specific bile acid, cholic acid, is available as Cholbam™ approved by the U.S. Food and Drug Administration on March 17, 2015. Another bile acid, ursodeoxycholic acid, is a drug approved by the FDA but not for this reason. It may be prescribed by physicians as an “off label” indication which means that a drug approved by the FDA for a specific disease may be used for other diseases at the discretion of the treating physician. For patients with conjugation defects, another bile acid, glycocholic acid, is available as an investigational drug approved by the U.S. Food and Drug Administration. When first diagnosed, most patients with inborn errors of metabolism have fat malabsorption and fat-soluble vitamin deficiencies. Fat-soluble vitamins (vitamins A, D, E and K) and infant formulas containing medium chain triglycerides (Alimentum®, Pregestimil®) may be prescribed to overcome initial deficits of these nutrients. Although most affected patients have a complete resolution of the jaundice and liver biochemistry abnormalities with bile acid treatment, the liver disease may progress to end-stage liver disease with cirrhosis and a liver transplant may be required.

Prognosis

Patients treated with bile acid (cholic acid) early enough usually correct all abnormalities of liver function including jaundice, growth failure, fat and vitamin malabsorption and blood liver chemistry abnormalities. This occurs over a period of several weeks to several months after starting therapy. Occasionally, patients have worsening of liver disease despite treatment with the development of cirrhosis and liver failure. Patients who are not treated with Cholbam™ have progressive worsening until cirrhosis develops. Ursodeoxycholic acid is not recommended for long term therapy because it does not prevent progression of liver disease. The development of cirrhosis leads to portal hypertension with appearance of esophageal and gastric varices with the potential for gastrointestinal bleeding. Ascites may accumulate with the potential for spontaneous bacterial peritonitis. With progressive liver failure, encephalopathy may develop. If cirrhosis develops, the only effective therapy is liver transplantation with the need for lifelong immunosuppression to allow tolerance of the liver graft. Liver transplant may not be indicated if there is evidence of severe extra-hepatic systemic involvement.

ChiLDReN Network studies that include patients with bile acid defects

The ChiLDReN Network currently has one study that includes patients with bile acid defects.

The LOGIC study is a natural history study that includes patients with bile acid defects and three other rare liver diseases.  A natural history study is aimed at acquiring information and data that will provide a better understanding of rare conditions. Participants will be asked to allow study personnel to obtain information from medical records and an interview, and to collect urine, and tissue samples when clinically indicated, in order to understand the causes of these diseases and to improve the diagnosis and treatment of children with these diseases. All of the information obtained in these studies is confidential and no names or identifying information are used in the study.

LOGIC: A longitudinal study of genetic causes of intrahepatic cholestasis.

Eligibility: Children and adults ages 6 months through 25 years diagnosed with Alagille Syndrome, alpha-1 antitrypsin deficiency, progressive familial intrahepatic cholestasis, or bile acid synthesis defects, both before and after liver transplantation.

ClinicalTrials.gov Study NCT00571272

Organizations or foundations that help families dealing with bile acid defects.

The ChiLDReN Network works with numerous groups that support patients and families who are dealing with rare liver diseases.  Please click here to go to that page on our website (Information for Families).  You will see the list of groups and information about them. 

https://childrennetwork.org/families.aspx

References

  1. Setchell KDR, Heubi JE.  Defects in Bile Acid Biosynthesis-Diagnosis and Treatment. J Pediatr Gastroent Nutr 2006; 43 (Suppl 1):S17-S22.
  2. Heubi JE, Setchell KDR, Bove KE.  Inborn errors of bile acid metabolism. Seminars in Liver Disease 2007; 27:282-294.
  3. Fischler B, Bodin K, Stjernman H, Olin M, Hansson M, Sjovall J, Bjorkhem I. Cholestatic liver disease in adults may be due to an inherited defect in bile acid synthesis.  J Internal Medicine 2007; 262:254-262.
  4. Ueki I, Kimura A, Nishiyori A, Chen H-L, Takei H, Nittonon H, Kurosawa T.  Neonatal cholestatic liver disease in an Asian patient with a homozygous mutation in the oxysterol 7α-hydroxylase gene. J Pediatr Gastroent Nutr 2008; 46:465-469.
  5. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid metabolism.  Nature Clin Pract Gastroenterol Heptaol 2008: 5:456-68.
  6. Ueki I, Kimura A, Chen H-L, Yorifuji T, Mori J, Itoh S et al.  SRD5B1 gene analysis needed for the accurate diagnosis of primary 3-oxo-Δ4-steroid 5β-reductase deficiency.  J Gastroenterology and Hepatology 2009; 24:776-785.
  7. Gonzales E, Gerhardt MF, Fabre M, Setchell KDR, Davit-Spraul A, Vincent I, Heubi JE, Bernard O, Jacquemin E. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroent 2009; 49:78-84.
  8. Nittono H, Takei H, Unno A, Kimura A, Shimizu T, Kurosawa, Tohma M, Une M.  Diagnostic determination system for high-risk screening for inborn errors of bile acid metabolism based on an analysis of urinary bile acids using gas chromatography-mass spectrometry: results for 10 years in Japan.  Pediatrics International 2009; 51:535-43.
  9. Subramaniam P, Clayton PT, Portman BC, Mieli-Vergani G, Hadzic N. Variable clinical spectrum of the most common inborn error of bile acid metabolism- 3β-hydroxy- Δ5-C27-steroid dehydrogenase deficiency.  J Peds Gastroent Nutr 2010; 50: 61-66.
  10. Riello L, D’Aniga L, Guido M, Alaggio R, Giordano G, Zancan L.  Titration of bile acid supplements in 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency.  J Pediatr Gastroent Nutr 2010; 50:655-660.
  11. Clayton PT.  Disorders of bile acid synthesis.  J Inherit Metab Dis, 2011; 34;593-604.Chong CP, Mills PB, McClean P, Gissen P, Bruce C, Stahlschmidt J, Knisely AS, Clayton PT.Bile acid-CoA ligase deficiency--a new inborn error of bile acid metabolism. J Inherited Disease 2012; 35:521-30.
  12. Setchell KDR, Heubi JE, Shah S, Lavine JE, Suskind D, Al-Edreesi M, Potter C, Russell DW, O’Connell NC, Wolfe B, Jha P, Zhang W, Bove KE, Knisely AS, Hofmann AF, Rosenthal P, Bull LN. Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology 2013;144:945-55 e6. Epub 2013/02/19.
  13. Dai D, Mills PB, Footitt E, Gissen P, McClean P, Stahlschmidt J, Coupry I, Lavie J, Mochel F, Goizet C, Mizuochi T, Kimura A, Nittono H, Schwarz K, Crick PJ, Wang Y, Griffiths WJ, Clayton PT. Liver disease in infancy caused by oxysterol 7 α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid. Inherit Metab Dis. 2014 Sep;37:851-61.
  14. Heubi JE, Setchell KD, Jha P, Buckley D, Zhang W, Rosenthal P, Potter C, Horslen S, Suskind D. Treatment of bile acid amidation defects with glycocholic acid. Hepatology2015 2015;61:268-74. Doi.10.1002/hep.27401 Epub 2014 Dec 23.
  15. Russell DW. Fifty years of advances in bile acid synthesis and metabolism. J Lipid Res. 2009 Apr;50 Suppl(Suppl):S120-5. doi: 10.1194/jlr.R800026-JLR200. Epub 2008 Sep 24. PMID: 18815433; PMCID: PMC2674696.

For information on studies about ChiLDREN diseases, click here.