Bile Acid Synthetic Disorders

Bile acid synthetic defects (BASD) are uncommon genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants. The associated liver diseases may be life threatening and are treatable, usually with replacement of deficient primary bile acids. Specific diagnosis is made by analysis of body fluids (bile, blood and urine) using fast atom bombardment-mass spectroscopy (FAB-MS) and gas chromatography-mass spectroscopy(GC-MS. Inborn errors have been demonstrated in four enzymes involved in modification of the sterol nucleus and in five steps in modification of the sterol side-chain that lead to formation of cholic and chenodeoxycholic acids, the primary bile acids (see Figure 1 below).

Liver diseases due to BASD are characterized by progressive destruction of the liver with impairment of essential liver function resulting in either acute or chronic liver failure. Clinical severity is highly variable depending on the defect. Generally in BASD, clinical testing reveals deficiency of normal serum bile acids, atypical bile acids in serum, urine and bile, elevated serum aminotransferases, indicators of hepatocellular injury, and normal serum GGT, an indicator, when elevated, of bile duct epithelial injury. In three of four known defects of sterol nucleus modification (yellow boxes in Figure 1), liver disease is rapidly progressive in infancy. However, in defects in bile acid side chain synthesis (blue boxes in Figure 1), liver disease may be transient in infancy or mild or delayed in onset, slowly progressive through childhood, or mysteriously bimodal, affecting infants and adults quite differently in ways that are not yet understood. Progression of liver disease is most rapid in those defects in sterol nuclear modification that result in accumulation of toxic monohydroxy or unsaturated oxo-bile acids. Reduced bile flow caused by atypical bile acids in combination with reduced primary bile acids produces cholestasis in 3-beta-OH steroid dehydrogenase deficiency, defects of side-chain synthesis, peroxisomal abiogenesis and S-L-O syndrome.

Pathological findings may include intralobular cholestasis with giant cell transformation, prevalence of necrotic hepatocytes including giant cell forms, and hepatitic injury concentrated at the portal limiting plate where the smallest bile ductules are injured (cholangiolitis). Fibrosis is typically progressive and periportal. Interestingly, pericellular (intralobular) fibrosis, a pattern that is common in other metabolic liver disorders, is minimal to absent. Larger interlobular bile ducts and major bile ducts are spared, an important correlate of the low serum GGT levels that typify BASD.

Ultrastructure of liver in BASD has thus far revealed nonspecific changes in structure and in appearance of trapped bile residue in canaliculi with the possible exception of unusual canalicular morphology in infants with liver failure due to 3-beta-OH steroid dehydrogenase deficiency.

Clinical experience to date indicates that in most patients, progressive liver disease and the clinical course of BASD may be modified by replacement of deficient primary bile acids with oral cholic acid. This treatment is capable of reversing the course of liver disease, except in patients who already have irreversible liver damage. The beneficial effect of bile acid replacement therapy is ascribed to feedback inhibition of production of toxic bile acid intermediary metabolites and to enhancement of bile flow (choluresis), a function of normal hydrophillic bile acids such as cholic acid.

References (for this section):

Setchell K. Disorders of bile acid synthesis. In: Waler W, Durie P, Hamilton J, Walker-Smith J, Watkins J, al e, eds. Pediatric Gastrointestinal Disease. Philadelphia: B.C. Decker Publishing; 1990:992-1013.

Balistreri W. Liver disease in infancy and childhood. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff's diseases of the liver. Philadelphia: Lippencott-Raven; 1999:1415-18.

Frederick J Suchy, Ronald J Sokol and William Balistreri. Eds., Liver Diseases in Children: Second edition. Lippencott Williams and Wilkins, 2001

Bove KE, Heubi JE, Balistreri WF and Setchell KDR. Bile Acid Synthetic Defects and liver Disease: a Comprehensive Review. Pediatr and Devel Pathol 2004:7;315-334

Disease is adult onset with LDL (low density lipoprotein) hypercholesterolemia, increased cholesterol in bile and a tendency to develop cholesterol gallstones. No liver disease is reported in adults or children. Bile acids should be qualitatively and quantitatively normal presumably because alternate acidic synthetic pathway (see Figure 1) is intact.

Reference (for this section):

Pallinger CR, Eng C, Salen G, et al. Human cholesterol 7-alpha-hydroxylase deficiency has a hypercholesterolemic phenotype. J Clin Invest 2002;110:109-17