Congenital bile acid synthesis defect type 2 (CBAS2) is a hereditary disorder associated with severe intrahepatic cholestasis of neonatal or infantile onset. Diagnosis rests on bile acid profiles in plasma and urine and sequencing of the AKR1D1 gene. This gene encodes for the enzyme delta(4)-3-oxosteroid-5-beta-reductase, which catalyzes essential reactions in bile acid synthesis. Mutations in this gene have been identified as the cause of CBAS2. Therapy is based on primary bile acid replacement and aims at preventing disease progression and liver failure, the usual outcome of the disease if left untreated. So far, this treatment has been proven effective and safe.
Congenital bile acid synthesis defects have been associated with variable phenotypes. In detail, they may cause cholestatic liver disease of neonatal or infantile onset, or may not cause any complaints until adulthood. The hallmark of late-onset forms of the disease is a sensorimotor neuropathy. However, those bile acid synthesis defects resulting in the accumulation of toxic intermediates are usually of the early-onset type and follow a severe progressive form. This is the case with CBAS2, a condition that causes the accumulation of toxic unsaturated oxo-bile acids .
Few patients have been described to date, with all of them presenting with severe intrahepatic cholestasis in the neonatal period or infancy   . Progressive jaundice with dark urine and acholic stools are commonly reported. Jaundice may be accompanied by pruritus , but has been described as atypical elsewhere . During clinical examination, hepatomegaly may be palpated.
The lack of primary bile acids interferes with the digestion and subsequent absorption of lipophilic food components. Thus, CBAS2 patients may additionally present symptoms of fat-soluble vitamin deficiency  . The latter comprise nyctalopia and xerophthalmia due to vitamin A deficiency, bone pain and and skeletal deformities because of vitamin D deficiency, and a propensity to bleed due to vitamin K deficiency. Vitamin E deficiency may cause neurological symptoms like areflexia.
Entire Body System
- Death in Infancy
Clinical description Patients present with neonatal cholestasis and rapid progression to cirrhosis and death in infancy without intervention. [rarediseases.info.nih.gov]
- Death in Childhood
If left untreated, congenital bile acid synthesis defect type 2 typically leads to cirrhosis and death in childhood. The prevalence of congenital bile acid synthesis defect type 2 is unknown. [ghr.nlm.nih.gov]
If left untreated, this disease can lead to cirrhosis and death in childhood. The congenital defect of the bile acid synthesis is due to mutations in genes HSD3B7 and AKR1D1. [ivami.com]
If left untreated, congenital bile acid synthesis defect type 1 often leads to cirrhosis and death in childhood. [malacards.org]
Clinical features include failure to thrive, jaundice, steatorrhea, hepatomegaly, cirrhosis, rickets and splenomegaly. [preventiongenetics.com]
Other signs and symptoms may include splenomegaly and inability to absorb certain fat - soluble vitamins, vitamin D, in particular, which can lead to rickets in some individuals. [ivami.com]
Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. In most cases, pruritus is absent. [malacards.org]
Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. [dovemed.com]
Short stature Growth delay Failure to thrive Cataract SOURCES: OMIM ORPHANET MENDELIAN More info about GLYCOGEN STORAGE DISEASE DUE TO GLUT2 DEFICIENCY Top 5 symptoms//phenotypes associated to Hepatomegaly and Osteoporosis Symptoms // Phenotype % cases Splenomegaly [mendelian.co]
The clinical presentation resembles that of congenital BAS defect type 1 (see this term) with hepatosplenomegaly, jaundice, fat-soluble vitamin malabsorption, and steatorrhea. [rarediseases.info.nih.gov]
- Failure to Thrive
Clinical features include failure to thrive, jaundice, steatorrhea, hepatomegaly, cirrhosis, rickets and splenomegaly. [preventiongenetics.com]
Affected infants usually have a failure to gain weight and grow at the expected rate (failure to thrive) and yellowing of the skin and eyes (jaundice) due to impaired bile flow and a buildup of partially formed bile. [ghr.nlm.nih.gov]
Related symptoms: Growth delay Failure to thrive Muscle weakness Anemia Feeding difficulties SOURCES: OMIM ORPHANET MENDELIAN More info about BETA-THALASSEMIA Medium match SYMPTOMATIC FORM OF HEMOCHROMATOSIS TYPE 1 Symptomatic form of hemochromatosis [mendelian.co]
Affected infants show failure to thrive and secondary coagulopathy. [malacards.org]
The majority of the cases present intrauterine growth retardation (IUGR), failure to thrive, decreased subcutaneous fat, and low or undetectable C-peptide levels (4). [ncbi.nlm.nih.gov]
- Abdominal Pain
pain, weakness, lethargy, weight loss, elevated serum aminotransferase levels, increase in skin pigmentation, and/or arthropathy in the metacarpophalangeal joints. [mendelian.co]
Unfortunately, many patients find them difficult to tolerate; although the diarrhea may improve, other symptoms such as abdominal pain and bloating may worsen. [en.wikipedia.org]
- Long Arm
The AKR1D1 gene, located on the long arm of chromosome 7 (7q32-q33), encoding an enzyme called 4-3-oxo-5-? steroid dehydrogenase, found in liver cells. [ivami.com]
Amino acid n-acyltransferase deficiency is caused by mutations in the BAAT gene located on the long arm of chromosome 9 (9q31.1). [rarediseases.org]
- Short Arm
The HSD3B7 gene, located on the short arm of chromosome 16 (16p11.2), encoding the enzyme beta-hydroxysteroid dehydrogenase type-7-3 (3?-hsD7), found in liver cells. [ivami.com]
Alpha-methylacyl-CoA racemase deficiency is caused by mutations in the AMACR gene located on the short arm of chromosome 5 (5p13.2). [rarediseases.org]
Heritability: Autosomal recessive inheritance Clinical Modifiers: Neonatal onset AKA: BASD2, congenital bile acid synthesis defect type 2, AKR1D1 congenital bile acid synthesis defect, congenital bile acid synthesis defect, type 2, bile acid synthesis [monarchinitiative.org]
Clinical Features Congenital bile acid synthesis defect type 2 (CBAS2) is a progressive liver disease of neonatal onset characterized by cholestasis (Lemonde et al. 2003; Ueki et al. 2009). [preventiongenetics.com]
OMIM : 56 Congenital defects of bile acid synthesis are autosomal recessive disorders characterized by neonatal onset of progressive liver disease with cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal [malacards.org]
The clinical presentation of CBAS2 does not allow for its distinction from other types of congenital bile acid synthesis defects, or even from cholestatic liver disease due to any other pathological condition. In this regard, laboratory results of blood sample analyses often provide valuable first indications as to the underlying disease. In detail, hepatic transaminases and conjugated bilirubin concentrations are usually increased in samples obtained from those suffering from congenital bile acid synthesis defects, while γ-glutamyltransferase levels typically remain within reference ranges or are found to be mildly elevated  . Analytical techniques must then be applied to assess the patient's bile acid profiles in plasma and urine. Fast atom bombardment ionization-mass spectrometry, electrospray ionization-tandem mass spectrometry, and gas chromatography-mass spectrometry, and liquid chromatography-tandem mass spectrometry have been used to this end  . CBAS2 is associated with an increase of levels of the glycine and taurine conjugates of 7α-hydroxy-3-oxo-4-cholenoic acid and 7α,12α-dihydroxy-3-oxo-4-cholenoic acid, while primary bile acid concentrations are pathologically reduced   . Finally, the sequencing of the AKR1D1 gene allows for the identification of the causal mutation and the confirmation of the diagnosis. It is highly recommended to not skip this step, because liver diseases other than CBAS2 may be associated with bile acid profiles very similar to those obtained in case of CBAS2 may be caused by other liver diseases   . In fact, distinct hepatopathies may entail a reduced activity of enzymes like delta(4)-3-oxosteroid-5-beta-reductase, thereby provoking symptoms and findings that may be falsely attributed to CBAS2 . Some authors have stated that the ratio of abnormal to normal bile acids in urine samples may serve as an index to distinguish CBAS2 from other liver diseases affecting bile acid synthesis in a similar manner: If the ratio of 3-oxo-delta(4) bile acids is >75 or even 90%, the patient is likely to suffer from CBAS2 .
High-throughput sequencing technologies allow for a different approach to diagnosing hereditary liver disease and neuropathies accompanied by non-specific symptoms. Indeed, CBAS2 has been diagnosed based on the results of whole exome sequencing that, in turn, have been confirmed by means of bile acid profiling .
Upon histopathological examination, intralobular cholestasis with giant cell transformation, hepatocytes containing few peroxisomes and undergoing necrosis may be observed. Giant cell transformation has been reported to be discernible in all symptomatic infants with congenital bile acid synthesis defects and has been proposed as a marker of such diseases. An extensive list of morphological features in a cholestatic liver that suggest a bile acid synthetic defect has been published elsewhere .
An early diagnosis and timely initiation of treatment is important to prevent disease progression and liver failure. Therapy relies on the replacement of primary bile acids, namely chenodeoxycholic and cholic acid. Distinct treatment regimens based on the application of either one of those bile acids, or even ursodeoxycholic acid, have been followed in the past . Cholic acid is now recognized as the bile acid of choice because it is not hepatotoxic and has been proven effective in normalizing liver function tests and urine composition, and preventing disease progression to liver failure . If applied, ursodeoxycholic acid needs to be combined with chenodeoxycholic or cholic acid in order to guarantee negative feedback on bile acid synthesis.
In case of persisting fat-soluble vitamin deficiency, the respective vitamins should be supplemented.
If left untreated, CBAS2 inevitably leads to liver failure. The disease is therefore potentially life-threatening. However, patients usually respond well to primary bile acid therapy. In 2009, Gonzalez et al. published their results of long-term follow-ups of patients who had received daily doses of cholic acid for a median of 12 years. They found this therapy to be well tolerated, safe and effective. Some patients did present residual symptoms at the time of their last examination, though .
CBAS2 is related to a reduced activity of the enzyme delta(4)-3-oxosteroid-5-beta-reductase, which catalyzes an essential step in bile acid synthesis. This enzyme is encoded by the AKR1D1 gene, located on the long arm of chromosome 7. Distinct types of mutations have been described in CBAS2 patients, e.g., missense and nonsense mutations, deletions, and frame shift mutations . Data is too scarce, though, to derive genotype-phenotype relations.
CBAS2 is inherited in an autosomal recessive manner, i.e., only those with mutations in both alleles of the AKR1D1 gene will develop the disease. Homozygosity and compound heterozygosity have been described in CBAS2 patients  .
Bile acid synthesis defects are rare disorders. It has been estimated that they account for about 2% of persistent cholestasis in infants . Congenital bile acid synthesis defect type 1 and CBAS2 are supposed to be the most common congenital bile acid synthesis defects , but this assumption disregards the fact that milder forms are largely underdiagnosed. In sum, less than two dozen cases of CBAS2 have been reported .
The synthesis of bile acids comprises several reactions that take place in distinct cell organelles. An essential step of bile acid synthesis is the reduction of 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one to 7α-hydroxy-5β-cholestan-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one, respectively. This reaction is catalyzed by delta(4)-3-oxosteroid-5-beta-reductase, a cytosolic enzyme  . Under physiological conditions, 7α-hydroxy-5β-cholestan-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one undergo further conversions to produce the corresponding C24 bile acids chenodeoxycholic and cholic acid. However, CBAS2 patients are unable to continue bile acid synthesis at this point and thus, the aforementioned intermediates are converted into 3-oxo-delta(4) bile acids by means of side-chain oxidation and are then conjugated to glycine and taurine. The resultant intermediates cannot be secreted into the bile and thus appear in blood and urine .
The abnormal intermediates accumulating in CBAS2 patients have been postulated to exert hepatotoxic effects. Furthermore, there is no regulatory feedback inhibition of bile acid production because the necessary threshold of primary bile acids is never reached. This condition enhances those reactions taking place in early bile acid synthesis, leading to the formation of even more potentially toxic compounds. The modified composition of bile in CBAS2 patients interferes with biliary secretion causing cholestasis and malabsorption of lipophilic food components like fat-soluble vitamins .
Of note, lack of delta(4)-3-oxosteroid-5-beta-reductase has also been postulated to interfere with steroid hormone synthesis. This hypothesis is based on abnormalities of urinary steroid profiles that have been observed in CBAS2 patients. However, such disturbance of steroid hormone synthesis doesn't seem to cause any clinical symptoms .
Affected families may benefit from genetic counseling. The latter does, however, require precise knowledge regarding the underlying mutation. In some cases of CBAS2, familial anamnesis revealed a history of early-onset liver disease and/or fat-soluble vitamin deficiency in living or deceased relatives  , but the identification of carriers and the prenatal diagnosis of the disease is not feasible without targeted genetic analyses.
Congenital bile acid synthesis defects are rare genetic disorders resulting from mutations in distinct genes that cause enzyme deficiencies. The respective enzymes are required for bile acid synthesis and any reduction of their activity interferes with the production and release of bile from hepatocytes. Accordingly, intrahepatic cholestasis is a clinical hallmark of bile acid synthesis defects.
In detail, the following congenital bile acid synthesis defects are distinguished:
- Congenital bile acid synthesis defect type 1 or 3beta-hydroxy-delta5-C27-steroid oxidoreductase deficiency due to mutations in the HSD3B7 gene
- CBAS2, which will be discussed in this article
- Congenital bile acid synthesis defect type 3, which has been related to CYP7B1 mutations
- Congenital bile acid synthesis defect type 4 or intrahepatic cholestasis with defective conversion of trihydroxycoprostanic acid to cholic acid, resulting from mutations in the AMACR gene
- Congenital bile acid synthesis defect type 5, a disease that is caused by mutations of the ABCD3 gene
- Congenital bile acid synthesis defect type 6, which is triggered by ACOX2 mutations
CBAS2 is also called "cholestasis with delta(4)-3-oxosteroid-5-beta-reductase deficiency" and is caused by mutations in the AKR1D1 gene. In healthy people, delta(4)-3-oxosteroid-5-beta-reductase catalyzes the conversion of certain bile acid intermediates so that the following steps of bile acid synthesis can take place. Any reduction of its activity leads to the formation of abnormal intermediates that can be detected in blood and urine samples. At the same time, primary bile acids chenodeoxycholic and cholic acid are hardly produced at all. As a consequence, bile secretion is largely disturbed and affected individuals develop severe intrahepatic cholestasis at a very early age. They also suffer the consequences of lack of primary bile acids, namely maldigestion and malabsorption of lipophilic food components.
Bile acids are synthesized in the liver and are the secreted into the small intestine. They facilitate the digestion and subsequent absorption of lipids ingested with foods. Bile acid synthesis itself is a complex process involving several reactions, with each of them being catalyzed by a specific enzyme. Due to mutations in the respective genes, some people suffer from congenital enzyme deficiencies and bile acid synthesis defects. In detail, congenital bile acid synthesis defect type 2 (CBAS2) is caused by a mutation in the AKR1D1 gene.
First symptoms become apparent in the neonatal period or in infancy: CBAS2 patients typically develop cholestatic liver disease within their first year of life. It manifests in form of jaundice, dark urine and pale or clay-colored stools. Some patients suffer from pruritus. Because bile acids are required for the absorption of fat-soluble vitamins, namely vitamins A, D, E, and K, affected infants may also present symptoms of vitamin deficiency. For instance, they may develop rickets, neurological symptoms and be prone to bleed. The disease follows a progressive course and if left untreated, leads to life-threatening liver failure.
In order to diagnose the disease, blood and urine samples have to be obtained and analyzed. In CBAS2 patients, plasma and urine contain specific intermediates of bile acid synthesis that cannot be metabolized due to the deficiency of delta(4)-3-oxosteroid-5-beta-reductase, the enzyme encoded by the AKR1D1 gene. The diagnosis must be confirmed by sequencing of the AKR1D1 gene and identifying the causal mutation. Treatment is based on the replacement of those primary bile acids that cannot be produced by the patient due to their enzyme deficiency. Cholic acid is most commonly used to this end and must be applied daily throughout life. Such a therapy is well tolerated and safe. It prevents disease progression to liver failure and is thus life-saving.
- Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004; 7(4):315-334.
- Gonzales E, Cresteil D, Baussan C, Dabadie A, Gerhardt MF, Jacquemin E. SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect. J Hepatol. 2004; 40(4):716-718.
- Lemonde HA, Custard EJ, Bouquet J, et al. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003; 52(10):1494-1499.
- Zhao J, Fang LJ, Setchell KD, Chen R, Li LT, Wang JS. Primary Δ4-3-oxosteroid 5β-reductase deficiency: two cases in China. World J Gastroenterol. 2012; 18(47):7113-7117.
- Gonzales E, Gerhardt MF, Fabre M, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009; 137(4):1310-1320.e1311-1313.
- Clayton PT, Mills KA, Johnson AW, Barabino A, Marazzi MG. Delta 4-3-oxosteroid 5 beta-reductase deficiency: failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid. Gut. 1996; 38(4):623-628.
- Haas D, Gan-Schreier H, Langhans CD, et al. Differential diagnosis in patients with suspected bile acid synthesis defects. World J Gastroenterol. 2012; 18(10):1067-1076.
- Sumazaki R, Nakamura N, Shoda J, Kurosawa T, Tohma M. Gene analysis in delta 4-3-oxosteroid 5 beta-reductase deficiency. Lancet. 1997; 349(9048):329.
- Setchell KD, Suchy FJ, Welsh MB, Zimmer-Nechemias L, Heubi J, Balistreri WF. Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis. J Clin Invest. 1988; 82(6):2148-2157.
- Morgan NV, Hartley JL, Setchell KD, et al. A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease. Orphanet J Rare Dis. 2013; 8:74.
- Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003; 72:137-174.
- Palermo M, Marazzi MG, Hughes BA, Stewart PM, Clayton PT, Shackleton CH. Human Delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency and steroid metabolism. Steroids. 2008; 73(4):417-423.