BILE ACID SYNTHESIS AND METABOLISM DEFECTS
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 14 enzymatic steps. A failure to perform any of these reactions will block bile acid production with failure to produce "normal bile acids" and instead, the accumulation of unusual bile acids and intermediary metabolites. These unusual metabolites are presumed to cause liver disease. Because each of the enzymes in the pathway is regulated by a gene, it is believed that abnormalities in any of the steps of the pathway are inherited. Inborn errors of bile acid metabolism cause liver disease, or may be manifestations of more generalized diseases which may include neurologic involvement.
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The 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 production pathway. These genes code for the enzymes in the pathway in specified amounts that allow normal production of bile acids. Currently there are potentially 14 known enzyme steps that may be affected by inborn errors in the pathway of which 7 defects have been identified to date. Below is the pathway with highlighting of currently recognized defects:
Figure 1: Recognized (red) defects in the bile acid biosynthetic pathway.
For all of the defects for which the genes have been identified, the inheritance of the bile acid defect is believed to be autosomal recessive. If someone inherits one abnormal gene with the same mutation from each parent, the patient will have a block in the bile acid production pathway with accumulation of compounds in the pathway proximal to the block combined with low production of normal bile acids. This may result in mild to severe liver disease depending upon which of the enzymes 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-5 ß-reductase deficiency, 3ß-hydroxy-C27-steroid dehydrogenase/isomerase deficiency, or now named 3β -hydroxy-C27-steroid oxidoreductase deficiency [3-HSD], conjugation defects). In some conditions there is liver disease associated with neurologic dysfunction (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 mental retardation, seizures, deafness, blindness, and muscular weakness.
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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 because of the failure of the liver to produce normal bile acids due to the absence of one of the enzymes 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.
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Symptoms of inborn errors of bile acid metabolism can include jaundice, poor growth, liver or spleen enlargement, bleeding, rickets (vitamin D deficiency), or liver disease of unknown cause. Liver chemistries measured in the blood are abnormal and serum fat-soluble vitamin 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 and serum 25-OH vitamin D, retinol and tocopherol levels. 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 bilirubin, alkaline phosphatase or AST/ALT.
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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 the diagnosis. 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). 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 and bile and evaluation of the microscopic appearance of the liver) would be necessary in order 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 few exceptions, BAD cause 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. Liver disease may be transient, delayed in onset and mild. 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, perhaps in S-L-O 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 neocholangiolar proliferation, and where fibrosis typically develops. Interlobular bile ducts are usually spared. Ultrastructure of liver reveals nonspecific changes with the possible exception of 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 all symptomatic 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.
Finally, detection of disease-causing mutations in specific enzymes in the bile acid synthesis pathway is available on a research basis by DNA sequencing of the respective genes encoding the suspected enzyme deficiency.
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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 an investigational drug approved by the U.S. Food and Drug Administration. 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 malabsorb fat and fat-soluble vitamins. 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.
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Patients treated with bile acids (cholic acid and ursodeoxycholic acid) 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 bile acids have progressive worsening until cirrhosis develops. 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, portosystemic 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.
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- Setchell KDR, Heubi JE. Defects in Bile Acid Biosynthesis-Diagnosis and Treatment. J Pediatr Gastroent Nutr 2006; 43 (Suppl 1):S17-S22.
- Heubi JE, Setchell KDR, Bove KE. Inborn errors of bile acid metabolism. Seminars in Liver Disease 2007; 27:282-294.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis, 2011 Jan (Epub ahead of print).
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