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3Beta-Hydroxy-Delta5-C27-Steroid Oxidoreductase Deficiency

Bile Acid Synthesis Defect Congenital 1

3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency (3β-HSD) is an uncommon autosomal recessive disorder, characterized by defects in the synthesis of bile acids. It is also known as congenital bile acid synthesis defect type 1 (BAS defect type 1).

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Presentation

Due to the incomplete bile acid biosynthetic process, the bile that is produced in patients affected by 3βHSD cannot regulate the digestive procedure normally; as a result, digestion of lipids and lipid-soluble vitamins is incomplete. Patients are expected to manifest symptoms of the disease within the first days or months of their lives and the primary alarming symptom is usually cholestatic jaundice [10] [11] [12] [13] [14] [15]. Hepatomegaly, splenomegaly, and steatorrhea are also common symptoms that complete the clinical picture, alongside vitamin deficiencies [16]. The inability of the gastrointestinal tract to absorb adequate amounts of vitamin D results in rickets, while other symptoms, such as a hemorrhagic tendency due to vitamin K deficiency have also been described. Although rarely seen, pruritus may arise as well and a single case of 3βHSD, manifesting with chronic hepatitis in the patient's 20s has been documented [17].

Splenomegaly
  • 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]
  • Hepatomegaly and/or splenomegaly are also commonly observed and pruritus is a rare observation.[symptoma.com]
  • Attention to hepatomegaly, splenomegaly, and ill appearance warrants special considerations [a] a. Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16.[slideplayer.com]
  • Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs.[rarediseases.org]
  • Splenomegaly was absent. There was no neurological deficit. Laboratory values at discharge were ALT 37U/L, conjugated bilirubin 0.4 mg/dl, alkaline phosphatase 354 IU, albumin 3.5gm/dl.[knowledgehub.uscap.org]
Steatorrhea
  • Hepatomegaly, splenomegaly, and steatorrhea are also common symptoms that complete the clinical picture, alongside vitamin deficiencies.[symptoma.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]
  • The clinical presentation resembles that of congenital BAS defect type 1 (see this term) with hepatosplenomegaly, jaundice, fat-soluble vitamin malabsorption, and steatorrhea.[orpha.net]
  • Peroxisomal disorder (PD) The member has a documented diagnosis of a peroxisomal disorder (see Appendix 2 ); and The member exhibits manifestations of liver disease (e.g. jaundice, enlarged liver, abnormal liver enzyme tests), steatorrhea, or complications[aetna.com]
  • Affected individuals may also exhibit diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools due to the suppression of bile flow (acholic stools).[rarediseases.org]
Failure to Thrive
  • Affected infants show failure to thrive and secondary coagulopathy.[malacards.org]
  • Additional symptoms may include failure to thrive, jaundice, fat malabsorption and rickets.[cincinnatichildrens.org]
  • Features of cholestasis may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, and growth deficiency. Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur.[rarediseases.org]
  • […] to thrive, vomiting and diarrhea • Predisposition to overwhelming E. coli septicemia • Hemolytic anemia • Jaundice • Long-term neurodevelopmental complications: ataxia dyspraxic speech developmental delay • Diagnosis made by demonstrating a deficiency[clinicalgate.com]
  • […] to thrive –Poor feeding –Lethargy –Hepatomegaly –Splenomegaly –Laboratory tests  Hyperbilirubinemia (direct)  Elevated liver function tests  Hypoglycemia, especially with absent urinary ketones  Hyperammonemia 22 Differential Diagnosis of Treatable[slideplayer.com]
Diarrhea
  • MalaCards based summary : Bile Acid Synthesis Defect, Congenital, 1, also known as cbas1 , is related to cholestasis, progressive familial intrahepatic, 4 and congenital bile acid synthesis defect , and has symptoms including diarrhea and icterus .[malacards.org]
  • Affected individuals may also exhibit diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools due to the suppression of bile flow (acholic stools).[rarediseases.org]
  • […] of stool indication 249515001 Calculus in biliary tract indication 266474003 Hypercholesterolemia contraindication 13644009 Obstruction of bile duct contraindication 30144000 DOID:13580 Primary biliary cirrhosis contraindication 31712002 DOID:12236 Diarrhea[drugcentral.org]
  • Inherited defect in fumarylacetoacetate hydrolase (type I) Genetics • Autosomal recessive mutation in the fumaryl acetoacetate hydrolase (FAH) gene chromosome 15q22-25 particularly common in the Canadian province of Quebec Clinical features • Vomiting • Diarrhea[clinicalgate.com]
Clay-Colored Stool
  • Affected individuals may also exhibit diarrhea, excess fats in the stools (steatorrhea), and pale or clay-colored stools due to the suppression of bile flow (acholic stools).[rarediseases.org]
Hematochezia
  • In such patients, liver disease is not always evident and patients may have fat-soluble vitamin malabsorption with rickets, corrected by vitamin supplementation, and/or other complications including bleeding diathesis (hematochezia or intracranial bleeding[malacards.org]
Jaundice
  • Jaundice is usually the first symptom: jaundice is the yellow coloring of the skin and whites of the eye, due to an abnormally high level of bilirubin.[symptoma.com]
  • Clinical features include neonatal jaundice, severe intrahepatic cholestasis, cirrhosis.[malacards.org]
  • Subjects with autosomal recessive mutations in the encoding gene, HSD3B7, on chromosome 16p11.2-12 fail to synthesize bile acids and develop a form of progressive liver disease characterized by cholestatic jaundice and malabsorption of lipids and lipid-soluble[ncbi.nlm.nih.gov]
  • 8 Prolonged Neonatal Jaundice Breast Milk-Related Jaundice Persists in otherwise healthy, full-term, breast-fed babies ( 0.5% to 2.4% of all newborns [a] ) after physiologic jaundice subsides a.[slideplayer.com]
  • Additional symptoms may include failure to thrive, jaundice, fat malabsorption and rickets.[cincinnatichildrens.org]
Hepatomegaly
  • Hepatomegaly and/or splenomegaly are also commonly observed and pruritus is a rare observation.[symptoma.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]
  • Attention to hepatomegaly, splenomegaly, and ill appearance warrants special considerations [a] a. Fawaz R, et al. J Pediatr Gastroenterol Nut. 2016 Jul 16.[slideplayer.com]
  • […] poliodystrophy) Peroxisomal disorders Paucity of intrahepatic bile ducts Primary sclerosing cholangitis Sepsis and total parenteral nutrition-associated liver disease North american indian childhood cirrhosis (NAIC) Neonatal iron overload Investigation of hepatomegaly[clinicalgate.com]
  • Enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly) may also occur. Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs.[rarediseases.org]
Scleral Icterus
  • icterus can be missed –Level of bilirubin required for jaundice to be visually apparent is unknown, but thought to be 5 mg/dL –Cannot determine whether jaundice is due to indirect (cause is physiologic) or direct (cause is liver disease) hyperbilirubinemia[slideplayer.com]
Pruritus
  • Hepatomegaly and/or splenomegaly are also commonly observed and pruritus is a rare observation.[symptoma.com]
  • In most cases, pruritus is absent. Liver function tests present elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT.[malacards.org]
  • Persistent, severe itchiness (pruritus) is common to other disorders that cause cholestasis, but rarely occurs in individuals with BASDs.[rarediseases.org]
  • Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal γ-glutamyl transpeptidase concentrations and the absence of pruritus.[humpath.com]
  • Clinical features • Severe pruritus • Conjugated hyperbilirubinemia • Low or normal levels of gamma glutamyl transpeptidase in types 1 and 2 • Serum bile acid concentrations are usually high decreased bile acids have also been reported in some cases •[clinicalgate.com]

Workup

Laboratory testing findings vary, depending on the patient's age and the degree to which the condition has progressed at the time of diagnosis. Liver function tests reveal a normal profile at the initial stages of the condition; as it progresses, elevated transaminases in the blood, normal or decreased γ-GT levels, minimal concentrations of various lipid-soluble vitamins and direct hyperbilirubinemia are the typical findings. For an accurate diagnosis to be made, mass spectrometry of biological fluids, usually urine, is mandatory: the method of LSIMS can be employed to detect sulfate or glycosulfate conjugates of the bile acids, that are pathognomonic for this type of disorder [18] [19] [20] [21] [22] [23].

The degree to which the enzyme retains its activity and functional ability can actually be measured by using a substrate of 7α-hydroxycholesterol and cultured skin fibroblasts. The enzyme of patients with 3βHSD is expected to be completely inactive. Further, genetic testing will detect genetic mutations of the HSD3B7 gene, which is consistent with 3b-hydroxy-D5-C27-steroid oxidoreductase deficiency [24] [25]. A histopathological examination of a neonate or infant liver specimen will reveal findings corresponding to fibrosis, as well as giant cell hepatitis, cholestasis and canalicular bile plugs [26] [27].

Liver Function Tests Abnormal
  • function tests abnormal contraindication 166603001 Disease of liver contraindication 235856003 DOID:409 Sclerosing cholangitis contraindication 235917005 DOID:14268 Pregnancy, function contraindication 289908002 Gallstone Complications contraindication[drugcentral.org]

Treatment

The treatment options for 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency aim at the stimulation of biliary flow and the reduction of the hepatotoxic type of bile acids. There have been studies that viewed bile acid supplementation therapy (per os) as an effective agent that significantly decreases the concentrations of hepatotoxic bile products; cholic acid is believed to generally improve symptoms and eliminate jaundice. The secretion of bile from the liver is re-induced with ursodeoxycholic acid (UDCA), an agent that is thought to help attain short-term beneficial results but is viewed in a negative light concerning its ability to maintain the same effects on a long-term scale [28] [29] [30]. Concerning the other symptoms caused by the condition, such as vitamin deficiencies or hepatitis, they are also treated in a supportive manner.

Prognosis

If the condition is not therapeutically addressed, end-stage liver disease (ESLD) and death are expected within the first five years of the young patient's life, according to a study published in 1991 [2]. According to the same study, the delayed administration of treatment in one of the affected children of the family at the age of 4 years old markedly improved symptoms and bile biosynthesis [8] [9]. Studies conducted later confirmed that bile acid supplementation, including chenodeoxycholic acid and cholic acid, achieved positive results and lead to restored levels of vitamin A and D, as well as minimized liver injury.

Etiology

The 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency is the most frequently diagnosed bile acid production defect [2] [3] [4]. 3b-hydroxy-D5-C27-steroid oxidoreductase is an enzyme that mediates the catalyzation of the initial steps in bile acid production. The exact genetic locus of the genes that encodes for the enzyme is 16p11.2-12 and various alterations to its sequence lead to an inactive enzyme [5]. However, the remaining stages of bile acid synthesis are performed normally; as a result, bile contains an increased concentration of abnormal bile products, such as 3b-hydroxy-D5-cholenoic acids 1 and 2.

Epidemiology

Congenital defects in the synthesis of bile acid are a rare disease, that is passed down from parents to offspring via the autosomal recessive pattern of inheritance. Up to this day, nine such conditions have been classified and 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency is the most common of all nine. Patients are primarily diagnosed during infancy but it is possible for the disease to remain dormant until adolescence. The condition accounts for 1% to 2% of all occurrences of conjugated hyperbilirubinemia during infancy.

Sex distribution
Age distribution

Pathophysiology

In general, up to 2% of all cases of cholestasis in childhood are attributed to anomalies in the production of bile acid. These anomalies are rarely diagnosed and are inherited through the autosomal recessive pattern.

All nine of the disorders induce direct hyperbilirubinemia and liver disease with a varying degree of severity. The clinical picture can be extremely severe under some circumstances when neonatal hepatitis or advanced liver disease open link develop as soon as within the first months of life. The aggressive disease is also associated with the buildup of products such as mono-hydroxylated or unsaturated oxo-bile acids [6]; some cases of adult liver conditions that involve cholestatic alterations are also a result of inborn defects in the production of bile [7].

The 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency particularly affects one of the initial steps of bile acid production and specifically catalyzes the oxidoreduction of the 3β-hydroxyl group of 7α-hydroxycholesterol. Genetic irregularities in the gene responsible for the regulating enzyme, HSD3B7, leads to an incomplete catalyzation and defective bile, which, in turn, induces liver disease, jaundice due to cholestasis and a defective lipid digestive process.

Prevention

The bile acid synthesis defect known as 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency cannot be prevented, as it is an genetically inherited abnormality.

Summary

The 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency is a disease that is usually diagnosed within the first months of a person's life, although it can be delayed until early adolescence [1]. It is one of the nine inherited defects in the biosynthesis of bile acid that have been classified as of yet and is otherwise referred to as congenital bile acid synthesis defect type or BAS defect type 1.

Bile acid is a fluid that is mandatory for the process of digestion, as it regulates the absorption of fats and fat-soluble vitamins, together with the pancreatic secretions; additionally, it provides the medium through which bilirubin can be excreted. 3β-HSD leads to an abnormal composition of bile acid, as it is responsible for one of the initial steps in the procedure of bile acid synthesis. The irregular composition greatly impairs the functionality of bile.

All congenital defects of bile acid production are rare disorders and the exact prevalence in unknown. Clinically, the initial symptom is cholestatic jaundice, caused by the blockage of bilirubin flow. Fat and lipid-soluble vitamins malabsorption lead to steatorrhea and vitamin deficiencies, particularly regarding vitamins K, A and D. End-stage liver disease can be reached as soon as the age of 5 years old and hepatic fibrosis occurs as a result; there has been a case where the patient presented with chronic hepatitis as the initial symptom. Hepatomegaly and/or splenomegaly are also commonly observed and pruritus is a rare observation. Laboratory testing reveals findings that correspond to the degree of hepatic disease at the time that the procedure is carried out; transaminases are usually high, γ-GT is either normal or decreased and direct hyperbilirubinemia is a frequent finding. A liver biopsy will reveal fibrosis, cholestasis, and inflammation.

The condition is diagnosed via mass spectrometry, which helps to detect sulfate and glycosulfate conjugates of 3-beta-hydroxy-delta-5 bile acids; the exact method used is the liquid secondary ionization mass spectrometry (LSIMS) analysis, usually performed on urine. The deficiency of 3beta-hydroxy-delta5-c27-steroid oxidoreductase has clinical similarities with various other disorders that manifest with neonatal icterus, including biliary atresia, cystic fibrosis, galactosemia, alpha-1-antitrypsin deficiency of ZZ phenotype, hereditary fructose intolerance and a multitude of other conditions. It is treated with oral supplementation with cholic acid, which can achieve therapeutic results even in progressed disease stages.

Patient Information

The liver is a unique organ that is responsible, amongst others, for the secretion of bile acid, which circulates from its production site through the biliary tree to the gallbladder for storage purposes, and then to the small intestine, where it plays a significant role in the digestive process. Bile is required, in order for the metabolism of fats to be carried out; it also regulates the absorption of nutrients from the intestine such as vitamins. Other than this function, bile also acts as a medium through which bilirubin, a by-product of the recycling process of the red blood cells after their death, is excreted from the body.

Given its vital function for the organism, bile has a specific composition and is produced according to a procedure that is mediated by various enzymes and other substances. Bile acid synthesis disorders are a group of conditions that lead to a faulty bile production process, which, as a result, affects its functionality.

Up to this day, 9 distinct inborn defects of the production of bile acid have been identified. 3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency, also known as bile acid synthesis type 1, is the most common of all nine and remains a rare disorder. It is caused by a genetic mutation in the gene that encodes for 3β-hydroxy-Δ5-C27-steroid dehydrogenase, which is an enzyme that plays an important role in the first stages of bile acid production. With this enzyme being inactive, the composition of bile is defective and its functions are greatly impaired. The disease is inherited via the autosomal recessive pattern of inheritance. The disease is mainly diagnosed within the first months of a child's life, even though a case has been diagnosed as late as 20 years after a person's birth.

Due to the fact that normal bile acids regulate digestion and more specifically the absorption of fats and lipid-soluble vitamins, but also helps to excrete bilirubin, the symptoms caused by this deficiency are corresponding. Jaundice is usually the first symptom: jaundice is the yellow coloring of the skin and whites of the eye, due to an abnormally high level of bilirubin. Other than that, the spleen and liver are enlarged, fat is accumulated in the stool and vitamin deficiencies cause various other symptoms. The condition is diagnosed with laboratory testing and findings correspond to the stage and severity. Liver enzymes called transaminases are indicators of liver damage and are usually increased, γ-GT another indicator of cholestasis is found mainly normal and bilirubin circulates in increased concentrations. Laboratory testing will also reveal vitamin deficiencies. A liver biopsy is required in order to determine the extent of fibrosis and hepatic damage in general and genetic testing is also mandatory, so as to detect mutations in the corresponding gene.

3beta-hydroxy-delta5-c27-steroid oxidoreductase deficiency is treated with cholic acid replacement therapy, which involves the oral supplementation of cholic acid. It can be used to treat both children and adults and has proved effective, as far as the improvement of symptoms and the correction of hepatic function are concerned, even though its efficacy does not last particularly long. Ursodeoxycholic acid is another agent that is known to enhance the clinical picture and biochemical markers in individuals affected by the condition but its effectiveness remains short-term.

References

Article

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  2. Clayton PT, Leonard JV, Lawson AM, et al. Familial giant cell hepatitis associated with synthesis of 3-beta, 7-alpha-dihydroxy-and 3-beta, 7-alpha, 12-alpha-trihydroxy-5-cholenoic acids. J Clin Invest 1987; 79:1031–1038.
  3. Subramaniam P, Clayton PT, Portmann BC, et al. Variable clinical spectrum of the most common inborn error of bile acid metabolism-3beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency, J Pediatr Gastroenterol Nutr. 2010; 50:61–66.
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Last updated: 2018-06-21 16:38