Gut 1996; 38: 623-628 623 A4-3-Oxosteroid 51-reductase deficiency: failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid Gut: first published as 10.1136/gut.38.4.623 on 1 April 1996. Downloaded from P T Clayton, K A Mills, A W Johnson, A Barabino, M G Marazzi Abstract mass spectrometry (FAB-MS) or liquid sec- Background-In some infants with liver ondary ion mass spectrometry (LSI-MS). disease, 3-oxo-A4 bile acids are the major These techniques can be used to analyse the bile acids in urine, a phenomenon cholanoids (bile acids and bile alcohols) in a attributed to reduced activity of the A4-3- urine sample.2-6 Most children with cholesta- oxosteroid 5p-reductase required for syn- tic liver disease excrete increased amounts of thesis ofchenodeoxycholic acid and cholic normal bile acids (principally the taurine and acid. These patients form a heterogeneous glycine conjugates of cholic acid and chen- group. Many have a known cause of odeoxycholic acid) but in a few, one of four hepatic dysfunction and plasma concen- unusual patterns of cholanoid excretion can trations of chenodeoxycholic acid and be recognised.6 One of these is characterised cholic acid that are actually greater than by the presence of ions attributable to the those of the 3-oxo-A4 bile acids. It is glycine and taurine conjugates of 7ot- unlikely that these patients have a hydroxy-3-oxo-4-cholenoic acid and 7oa,122o- primary genetic deficiency of the 51- dihydroxy-3-oxo-4-cholenoic acid.5-10 It is reductase enzyme. generally accepted that this pattern arises as a Aims-To document the bile acid profile, result of reduced activity of the enzyme clinical phenotype, and response to treat- that converts 7ot-hydroxy-cholest-4-en-3-one ment of an infant with cholestasis, to 7ot-hydroxy-5,B-cholestan-3-one and 7a., increased plasma concentrations of 3- 1 2a-dihydroxy-cholest-4-en-3-one to 7, 1 2aL- oxo-A4 bile acids, low plasma concentra- hydroxy-5,B-cholestan-3-one (Fig 1). As a tions of chenodeoxycholic acid and cholic result of the &4-3-oxosteroid 5 -reductase http://gut.bmj.com/ acid, and no other identifiable cause of deficiency, 3-oxo-A4 intermediates undergo liver disease. side chain oxidation to produce the corres- Patients-This infant was compared with ponding 3-oxo-A4 bile acids, which are con- normal infants and infants with cholesta- jugated with glycine and taurine but cannot sis ofknown cause. be secreted into the bile and appear in the Methods-Analysis of bile acids by liquid urine.6 The activity of A4-3-oxosteroid 5ot- secondary ionisation mass spectrometry reductase is preserved, leading to the appear- on September 30, 2021 by guest. Protected copyright. and gas chromatography - mass spec- ance of increased amounts of 5ot [H] -or trometry, allo-bile acids in plasma. The difficulty Results-The plasma bile acid profile of in an individual patient is deciding whether the patient was unique. She had chronic the 51-reductase deficiency is the primary cholestatic liver disease associated with cause of the liver disease or whether malabsorption of vitamins D and E and a reduced activity of the enzyme is a conse- normal y-glutamyltranspeptidase when quence of hepatocyte damage. This has also the transaminases were increased. The made it difficult to define the phenotype, liver disease failed to improve with natural history, and response to treatment ursodeoxycholic acid but responded to a of primary A4-3-oxosteroid 5,B-reductase combination of chenodeoxycholic acid deficiency. Institute of Child and cholic acid. Patients with deficiency have Health and Great 5p-reductase Ormond Street Conclusion-Treatment of primary 513- been treated with various combinations of Hospital for Children, reductase deficiency requires the use of bile acids."1 There is little information on the London bile acids that inhibit cholesterol 7a- use of ursodeoxycholic acid alone. This is P T Clayton K A Mills hydroxylase. important because this is the bile acid that A W Johnson (Gut 1996; 38: 623-628) is most widely used in the treatment of cholestatic disorders of childhood. In this Istituto G Gaslini, Keywords: inborn error, bile acid synthesis, giant cell paper we present a child with chronic Universita di Genova, hepatitis, cholestasis. Italy cholestatic liver disease who failed to respond A Barabino to ursodeoxycholic acid treatment but M G Marazzi improved rapidly with a combination of Correspondence to: Diagnosis of inborn errors of bile acid synthe- chenodeoxycholic acid and cholic acid. The Dr P T Clayton, Division of Biochemistry and Genetics, sis is important because specific treatment is low concentrations of primary bile acids in Institute of Child Health, 30 available in the form of oral supplements of the patient's plasma, urine, and duodenal Guilford Street, London bile acids and such treatment is often dra- juice before treatment suggested that this WC1N 1EH. 2 Accepted for publication matically effective.1 Rapid diagnosis is made patient probably had primary A4-3-oxosteroid 31 October 1995 possible by the use of fast atom bombardment 5,B-reductase deficiency. 624 Clayton, Mills, J7ohnson, Barabino, Marazzi (OH) (OH) cholestasis with steatorrhoea, failure to thrive, Sidechain oxidation - COOH and clinical rickets. At the age of 3 months, COOH investigations in the Gaslini Institute of Genoa showed a normal serumalantitrypsin concen- tration, red cell galactose-l-phosphate uridyl Gut: first published as 10.1136/gut.38.4.623 on 1 April 1996. Downloaded from "'OH I J,,,J "OH transferase, and UDP-galactose-4-epimerase. bile acids .ductase 5a-Reductase 3-oxo-A4 Plasma tyrosine was pu (normal Sidechain oxidation 40-130), plasma threonine 450F M (normal (OH) (OH) 65-185), and plasma methionine 10pu M 15-31). The urine organic acid analy- COOH sis(normalshowed increased excretion of 4-hydrox- yphenyl-pyruvic and -lactic acids but no a H ,H succinyl acetone. Plasma analysis showed "'OH HO H H low vitamin E concentration (1.4,u M; normal Allo-chenodeoxycholi acid 11.5-35) but a normal vitamin A concentra- allo-cholic acid tion. Serum ferritin was increased. Ultrasound (OH) A11°acand bladder and no dilatation J-(OH) showed a normal gall COOH of extrahepatic bile ducts. A liver biopsy at 4 1 1 months showed lobular disarray resulting from Chenodeoxycholic acid extensive giant cell transformation and H "OH'CheOHand cholic acid Thenecroticportalfocispaceswith granulocytewere of normalaccumulation.size and Figure 1: The effect of reduced activityof A4-3-oxosteroid5,8-reductase: reduced synthesis shape and the interlobular bile duct could of conjugcates of chenodeoxycholic acid and cholic acid and increased synthesis of (a) conjugate. of 7a-hydroxy-3-oxo-4-cholenoic acid and 7a,12a-dihydroxy-4-cholenoic acid, always be visualised. Some portal tracts were (b) allo-c:henodeoxycholic acid and allo-cholic acid. infiltrated by lymphocytes and some bile duct epithelial cells were vacuolated. The paren- Case report chyma showed considerable macrovesicular Our patient was the second child of unrelated steatosis and bile pigment accumulation. Sardinian parents. Her mother took carba- Granules of haemosiderin were localised mazepine throughout the pregnancy. The almost exclusively to Kupffer cells. infant was born at 37 weeks gestation and was Between the ages of 3 and 8 months our breast fed. She developed mild jaundice but patient had persistent jaundice with failure to remained well until the third week of life when thrive and steatorrhoea when fed a normal she developed fever, pronounced jaundice, and formula. She continued to fail to thrive when drowsiness. Investigations showed: bilirubin fed with Pregestemil, partly because of poor http://gut.bmj.com/ 316,uM (conjugated 145,uM), aspartate intake. Treatment with ursodeoxycholic acid aminotransferase (AST) 2279 IU/1 (normal at a dose of 12 mgfkg/d and then at a dose of 20-60), alanine aminotransferase (ALT) 1123 20 mgfkg/d did not lead to any clinical IU/1 (normal 5-45), y-glutamyltranspeptidase improvement or to significant improvement in (y-GT) 102IU/1 (normal 5-51), prothrombin liver function tests (Fig 2). The alkaline phos- time 15.4 seconds (control 12 seconds),ox feto- phatase fell in response to parenteral vitamin protein 680 000 ,ug/l. Screening tests for D. Vitamins A, E, and K were also given on September 30, 2021 by guest. Protected copyright. hepatitis viruses were negative. The plasma parenterally. The urine bile acids were first carbamazepine concentration was 1.4,ug/l and analysed when the patient was 0.3 years, the consequently breast feeding was stopped. The ursodeoxycholic acid treatment having been patient's liver function tests showed some stopped for two weeks. improvement but there was persistent At the age of 0.69 years the patient was seen at Great Ormond Street. She had been receiv- Chenodeoxycholic ing ursodeoxycholic acid treatment at a dose of Cholic 20 mglkg/d for 0.4 years. Examination showed a weight well below the third percentile, length Ursodec just below the third percentile, and head cir- )xycholic cumference just below the second percentile. - She was wasted and jaundiced but there were s0 no stigmata of chronic liver disease. The liver was cm from the costal ii )o _ \edge palpable 5-5 margin in the mid-clavicular line and 5 cm so- \ from the xiphisternum in the midline. m Investigations showed: haemoglobin 96 g/l 0 with normallindices, ferritin 245 gg/l (normal 100 0o 7-150), serum iron 13.7 jiM (normal 14-22), - 80)o A total iron binding capacity 54-9 ,uM (normal 60)o _ _ \42-66), copper 17.3 ,uM (normal 12.6-26.8), 1- 40 73-210).