Liver disease in infancy is an important cause of disability or death in childhood. Most neonatal or infantile liver disorders present as cholestasis with similar clinical and laboratory features and have a variety of etiologies. Most patients with BASD can be treated well with oral bile acid supplementation and fat-soluble vitamins, but early treatment is needed, so early diagnosis is important. The conversion of cholesterol to bile acids involves a 17-step reaction catalyzed by 16 enzymes.2 Eleven enzyme defects have been identified that can cause related diseases, ranging from childhood to adulthood, with a spectrum of disorders such as neonatal liver failure, intrahepatic cholestasis in childhood, hypercholesterolemia, cerebral tendon xanthomatosis, and progressive neurological lesions. Among them, most of the enzyme defects in steroid nucleus ring structure modification are manifested as progressive cholestatic liver disease with elevated serum liver enzymes, hyperconjugated bilirubinemia and fat-soluble vitamin malabsorption; while the enzyme defects in side chain modification are often manifested as neurological disorders such as sensory neurological disorders, dementia, cataracts, etc., without or with mild clinical manifestations of liver disease, such as only mild hepatic transaminase In other patients, the defective acylation in bile acid synthesis can also be manifested as cholestasis, but its main clinical manifestation is severe malabsorption of fat-soluble vitamins. Several enzyme defects associated with cholestatic liver disease in children are described in detail below. (1) 3β-Hydroxy-C27-Steroid Dehydrogenase/Isomerase Deficiency (3β-Hydroxy-C27-Steroid Dehydrogenase/Isomerase Deficiency) 3β-Hydroxy-C27-Steroid Dehydrogenase Deficiency is the most common bile acid synthesis enzyme defect in late-onset chronic cholestasis, causing a The clinical phenotype is called Bile acid synthesis defect, congenital, type 1 (BASD-1), also known as Progressive familial interhepatic cholestasis type 4 (PFIC4). It was first identified in Saudi Arabia by Clayton et al.3 in 1987. To date, approximately 40-50 cases have been reported3-6 with varying ages of onset, ranging from as young as 3 months to as old as 26 years. Clinically, it presents with progressive jaundice, elevated serum transaminases, hyperconjugated bilirubinemia, but normal serum γ-GT; physical examination may reveal hepatomegaly or hepatosplenomegaly, lipid/fat-soluble vitamin malabsorption, and mild steatorrhea, mostly without pruritus. It is often detected by normal serum total bile acids that are not consistent with the severity of cholestasis. PAB-MS and GC-MS of the patient’s urine reveal large amounts of abnormal bile acids such as 3β,7α-dihydroxy or 3β,7α,12α-trihydroxycholanic acid. Liver pathology may show hepatic giant cell-like and inflammatory changes, cholestasis, partial bile duct disorder or small amount of bile duct hyperplasia, and liver fibrosis. (2) δ-4-3-Oxosteroid-5β-Reductase Deficiency The clinical phenotype caused by δ-4-3-Oxosteroid-5β-Reductase Deficiency is called congenital bile acid synthesis defect type 2 (Bile acid synthesis defect, congenital, 2; BASD-2) and is an important cause of severe progressive cholestasis of the newborn. δ-4-3-oxysterol-5β-reductase defect was first identified in monozygotic twin boys by Setchell et al7 in 1988. About 10 cases have been reported7-10 , mostly in the neonatal period with severe cholestasis and liver failure. Clinical manifestations include marked jaundice, dark urine, white clay or light yellow stools with steatorrhea, and may present with impaired growth, hepatosplenomegaly and coagulation dysfunction. Liver function tests showed marked hyperbilirubinemia with predominantly elevated conjugated bilirubin without pruritus, markedly elevated serum transaminases but normal gamma-GT, and normal total blood cholesterol. Mass spectrometry of the urine revealed large amounts of 7α-hydroxy-3-oxo-4-cholanic acid and 7α,12α-dihydroxy-3-oxo-4-cholanic acid. Liver biopsies showed disorganized bile ducts with giant cell-like hepatocytes and marked intrahepatocellular cholestasis, and occasionally single hepatocyte necrosis with or without extramedullary hematopoiesis. Most of these children die in the neonatal period due to fulminant liver failure or multi-organ failure. (3) Oxysterol 7α-Hydroxylase Deficiency The clinical phenotype caused by oxysterol 7α-hydroxylase is called Bile acid synthesis defect, congenital, 3 (BASD-3). Only two cases of congenital bile acid synthesis disorder clearly caused by defective oxysterol 7α-hydroxylase have been reported. In 1998 and 2008, reported by Setchell et al11 and Ueki et al12 respectively, both presented with marked cholestasis in the neonatal period with progressive worsening, with hepatosplenomegaly and no pruritus. Laboratory tests revealed hyperbilirubinemia, markedly elevated serum transaminases but normal γ-GT, and normal serum total cholesterol concentration with decreased total bile acids. Urine FAB-MS showed primary bile acid deficiency with large amounts of unsaturated monohydroxycholanic acids (3β-hydroxy-5 bile acids and 3β-hydroxy-5 bile acids). Liver biopsy showed cholestasis, marked hepatic giant cell-like changes, extensive fibrosis, disturbed bile duct arrangement and small bile duct hyperplasia. Drug treatment did not show significant results and both children died of liver failure within one year of age. (4) 2-Methylacyl-CoA Racemase Ddficiency The clinical phenotype caused by 2-formyl-CoA racemase defect is called congenital bile acid synthesis defect, congenital, 4 (BASD-4). In 2000, Ferdinandusse et al13 reported 3 adult cases with progressive sensory neuropathy presenting with elevated blood drop phytanic acid and poly(isoprenoid) fatty acids, and these branched-chain fatty acid accumulations were consistent with the biochemical manifestations of 2-formyl CoA racemase deficiency, but without manifestations of fat-soluble vitamin malabsorption or liver disease. Testing of the AMACR gene in these three patients revealed mutations in exons, and fibroblast cultures confirmed impairment of the synthetic pathway involved in 2-formyl CoA racemase [32].In 2003, Setchell et al.14 reported a case of childhood 2-formyl CoA racemase deficiency in a child with fat-soluble vitamin deficiency, hematochezia, and mild cholestatic liver disease in the neonatal period. Analysis of the patient’s blood and urine showed an elevated 25R isomer of cholestyramine (25R-THCA). Genetic testing confirmed a mutation in the AMACR gene. (5) Sterol 27-hydroxylase deficiency Sterol 27-hydroxylase deficiency was the first enzyme defect identified in bile acid synthesis disorder15 and causes a rare lipid storage disease called Cerebrotendinous xanthomatosis (CTX) In the early years, steroid 27 hydroxylase defects were mostly detected in adulthood when symptoms appeared, with clinical manifestations including symptoms of progressive neurological disorders, dementia, ataxia, cataracts, and xanthomatous changes of the brain and tendons.16 Steroid 27 hydroxylase defects were later found in some pediatric patients, manifesting as mild cholestasis within the first few months of life 17, which may undergo spontaneous remission; it may also manifest as juvenile cataracts and chronic diarrhea.18 Therefore, it is thought that these childhood symptoms may be early clinical manifestations of sterol 27 hydroxylase deficiency. The main characteristic manifestations of patients with sterol 27 hydroxylase deficiency are the presence of abnormal cholestrol in blood and tissues, decreased normal bile acids, accumulation of cholestrol and 5α-reduced derivatives of dihydroxycholestrol, which appear in the myelin sheaths of the brain and peripheral nerves and disrupt the normal function of these structures, causing progressive neurological dysfunction and eventually death. Laboratory tests show elevated blood cholestanol/cholesterol ratio and/or increased secretion of bile alcohols in the urine, and mass spectrometry of the urine mainly shows elevated cholestanol glucuronide.19 Chronic irreversible accumulation of cholestanol and dihydroxycholestanol in tissues is the cause of Neurological and cardiovascular complications are the main basis for early diagnosis of CTX, which can be made in combination with mass spectrometry, but definitive diagnosis still relies on genetic testing analysis. (6) Cholesterol 25-Hydroxylase Deficiency So far, only one case of sterol 25-hydroxylase deficiency has been reported.20 The child presented with severe intrahepatic cholestasis at 9 weeks of age. Laboratory tests revealed decreased blood concentrations of bile acids and goose deoxycholic acid and elevated glucuronide-conjugated cholestrol, particularly 5β-cholestane-3β,7α,12α,24-tetraol, 5β-chol-24-ene-3β,7α,12α,24-tetraol, and 5β-cholestane-3β,7α,12α,25-tetraol, and these abnormal cholestrol was also present in the urine. It is therefore speculated that this may be related to a congenital defect in cholesterol 25 hydroxylase, but genetic testing of DNA from this patient has not been performed. (7) Defective bile acid binding The final step in bile acid synthesis is the combination of glycine and taurine with primary bile acids to form conjugated bile acids. Two enzymes catalyze the binding of bile acids and cause the acylation of bile acids21: one is bile acid-CoA ligase (bile acid-CoA ligase), which catalyzes the formation of CoA thioester and is the rate-limiting enzyme in bile acid binding; the other enzyme is bile acid-CoA: amino acid N -acyltransferase (bile acid-CoA: amino acid N The other enzyme is bile acid-CoA: amino acid N -acyltransferase, which catalyzes the binding of sapogenins and taurine to bile acid-CoA in the cytoplasm.22 Setchell et al. first reported three cases of defective acylation of bile acid synthesis, one in a 14-year-old boy who presented with malabsorption of fat-soluble vitamins, hyperconjugated bilirubinemia, and elevated blood transaminases but normal γ-GT; the other two cases were in 5-year-old boys born to closely married parents. The other two cases were 5-year-old boys born to consanguineous parents, who presented with severe fat-soluble vitamin malabsorption and rickets, but normal or mildly elevated liver function. The clinical manifestations and biochemical features were consistent with the acylation deficiency postulated by Hofmann et al23; in addition, a similar phenotype was observed in bile acid-CoA ligase deficient mice24 and therefore it was postulated that bile acid-CoA ligase deficiency exists in humans. In addition, mutations in the BAAT gene encoding bile acid-CoA:amino acid N-acyltransferase have been found in some Amish families25, causing familial hypercholanemia (FHC), characterized by elevated blood bile acid concentrations, pruritus, and lipid malabsorption, which can manifest as impaired growth and development and VitK deficiency induced coagulation disorders. FHC is an atypical liver disease with often normal indicators of hepatic impairment, and its most prominent clinical manifestation is severe lipid-soluble vitamin malabsorption.23 Urinalysis shows markedly elevated bile acids, mainly unconjugated bile acids such as bile acids and deoxycholic acid, and a complete deficiency of glycine and glucuronide-conjugated bile acids. Diagnosis, treatment, and prognosis In congenital bile acid synthesis disorders, liver disease occurs as a result of a combination of hepatotoxicity of intermediate metabolites of bile acid synthesis and/or secondary damage due to primary bile acid deficiency (e.g., cholestasis and lipid/fat-soluble vitamin malabsorption). Because of the similar clinical and biochemical presentation of BASD, clarification of the enzyme deficiency requires genetic testing in conjunction with blood and urine bile acid analysis. Most of BASD can be treated with oral primary unconjugated bile acids, such as bile acid (CA), goose deoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), and their clinical symptoms and biochemical indices can be significantly improved, but oral bile acid therapy needs to be given before severe liver dysfunction, and liver transplantation can be avoided. The treatment principles are: 1) to provide essential primary bile acids; 2) to down-regulate the synthesis of abnormal bile acids through negative feedback effects, thus reducing the production of abnormal toxic intermediate metabolites in defective hepatocytes. The therapeutic dose is mostly empirical and is regulated according to the amount of abnormal metabolites analyzed by urine mass spectrometry. Oral primary bile acid treatment is ineffective in patients with defective oxysteroid 7α hydroxylase and defective acylation. Oxysteroid 7α hydroxylase deficiency is particularly severe, which may be related to the importance of the alternative pathway of bile acid synthesis in early infancy, for which the main treatment is currently liver transplantation. Patients with acylation deficiency do not lack unconjugated bile acids, so treatment with CA, CDCA, and UDCA is ineffective and treatment requires oral primary conjugated bile acids, but further studies are needed to confirm this. In addition, liver disease caused by 2-formyl CoA racemase deficiency can be remitted by primary bile acid therapy, but with progressive aggregation of hypophyllothenic acid, neurological lesions can develop in adulthood, so it is clear that the intake of branched-chain fatty acids in the diet of patients with 2-formyl CoA racemase deficiency must be restricted. Studies in AMACR knockout mice have found that limiting intake of branched-chain fatty acids such as phytanic acid is important in protecting the nervous system and liver.26 In patients with CTX caused by sterol 27 hydroxylase deficiency, UDCA treatment is ineffective because it does not inhibit cholesterol 7α-hydroxylase, and better results may be achieved with the combination of HMG-CoA reductase inhibitors, because HMGCoA reductase inhibitors inhibit cholesterol synthesis. Most diseases caused by congenital disorders of bile acid synthesis have a better prognosis if the diagnosis of the enzyme defect is clarified early in life and appropriate treatment is given. If severe hepatic impairment has occurred at the time of diagnosis, liver transplantation is often required, and death may even result from liver failure. In addition, several peroxidase deficiency disorders including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease can occur secondary to impaired bile acid synthesis. These disorders are not described here because they are not caused by mutations in genes encoding enzymes related to bile acid biosynthesis.