Letter to the Editor
Atypical presentation and delayed diagnosis in a case of primary bile acid synthesis disorder
Presentación atípica y diagnóstico tardío en un caso de déficit primario de ácidos biliares
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Teresa García Silva" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Cristina" "apellidos" => "Garfia Castillo" "email" => array:1 [ 0 => "cgarfia@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Javier" "apellidos" => "Manzanares López-Manzanares" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M. Teresa" "apellidos" => "García Silva" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina de Aparato Digestivo, Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Pediatría, Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Presentación atípica y diagnóstico tardío en un caso de déficit primario de ácidos biliares" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Inborn errors of bile acid metabolism are rare genetic diseases. The most common error is the 3beta-hydroxy-delta-5-C27 steroid dehydrogenase (3beta-HSDH) deficiency. It usually occurs in childhood as a progressive cholestasis with severe chronic liver disease, steatorrhea and fat-soluble vitamin deficiency. We report the case of a patient without liver disease but with intense steatorrhea and severe malabsorption of fat-soluble vitamins difficult to control until he was diagnosed with 3beta-HSDH deficiency at the age of 20 and he initiated treatment with bile acids.</p><p id="par0010" class="elsevierStylePara elsevierViewall">This is a male monitored for diarrhea since the age of 2 months old. At the age of 3 years, he required hospitalization from severe coagulopathy due to vitamin K deficiency, very pathological steatorrhea (135<span class="elsevierStyleHsp" style=""></span>g fat/day) and fat-soluble vitamin deficiency (A, D, E). Clinicians were unable to establish its etiology. Blood test: GPT 61, total bilirubin 1.8, (BD 1.2), cholesterol 94; the remaining parameters were normal. The antibodies of celiac disease, apolipoproteins A and B, bile acids, <span class="elsevierStyleSmallCaps">d</span>-xylose, fecal chymotrypsin, sweat test, intestinal biopsy and colonoscopy with biopsies were normal. Liver biopsy showed small areas of fibrosis, with no other findings. He received empirical treatment with pancreatic enzymes, ursodeoxycholic acid and vitamins A, D, E and K, with partial improvement of steatorrhea (50<span class="elsevierStyleHsp" style=""></span>g/day), but failing to correct vitamin deficiencies despite replacement with high doses. At the age of 10 he presented xerophthalmia due to vitamin A deficiency, and since the age of 9, walking difficulty, being diagnosed with symptomatology similar to Friedreich's ataxia due to involvement of the spinal posterior roots caused by deficiency of vitamin E. During adolescence, intestinal biopsy, liver biopsy, elastase and fecal chymotrypsin, were repeated, being normal. At the age of 20, the patient underwent bile acid blood test performed by HPLC/Q-TRAP<span class="elsevierStyleSup">®</span> blood method, detecting highly increased excretion of di and trihydroxy cholanoic acid and glycoconjugates; in urine it allowed to see the presence of abnormal bile acid metabolites (di and trihydroxy cholanoic acids with glycine and sulfate conjugates) in large quantity and very low excretion of primary bile acids. The determination of 7-dehydrocholesterol by quantification with GC/SIM/MS showed highly increased levels (6.98<span class="elsevierStyleHsp" style=""></span>μmol/l; vn 0.74–1.30). This allowed to diagnose the patient with 3beta-HSDH deficiency. The study of HSD3B7 gene mutations showed the patient was homozygous for the switch from glutamic acid to lysine at position 167 in exon 4 (E167K). Treatment was initiated with bile acids, initially with chenodeoxycholic acid, and when available, with cholic acid, normalizing steatorrhea and controlling plasma levels of fat-soluble vitamins.</p><p id="par0015" class="elsevierStylePara elsevierViewall">3beta-HSDH deficiency is a rare disease.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> In 1987, Clayton et al.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> reported the first case of 3beta-HSDH deficiency. Although a wide phenotypic variability in 3beta-HSDH deficiency has been observed,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,3</span></a> most often it occurs as a severe neonatal cholestasis very similar to progressive familial intrahepatic cholestasis symptoms but without pruritus and with fat-soluble vitamin deficiencies. Akobeng et al.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> reported 2 cases in which steatorrhea and fat-soluble vitamin deficiency were the initial presentation of the disease. One of them subsequently developed jaundice. Isolated cases with signs of chronic hepatitis have also been reported in the second decade of life.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</span></a> However, our patient did not show hepatic involvement.</p><p id="par0020" class="elsevierStylePara elsevierViewall">This entity is inherited in an autosomal recessive inheritance pattern.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> It is caused by mutations in the HSD3B7 gene, located on chromosome 16 (16p 11.2).<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> In this patient the E167K mutation was detected in homozygosis in exon 4, not reported in other individuals with 3beta-HSDH deficiency.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The definitive diagnosis is usually provided after demonstrating abnormal bile acids in urine and plasma through mass spectrometry,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> being a key factor for diagnosis, as in this case. Most patients with 3beta-HSDH deficiency have abnormal urine bile acids, preferably consisting of 3beta-hydroxy group sulfate and glycine conjugates and absence of primary bile acids.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">It is essential to provide a diagnosis because it is a treatable disease. It responds extremely well to bile acid replacement treatment, normalizing liver function and correcting malabsorption of fat-soluble vitamins. This has been achieved with chenodeoxycholic acid alone, with chenodeoxycholic acid and cholic acid, with chenodeoxycholic acid and ursodeoxycholic and with cholic acid alone. The drug of choice is cholic acid because it is not hepatotoxic, and it has been proven safe and effective.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> After initiation of therapy, steatorrhea and fat-soluble vitamin deficiency disappeared in this patient.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In cases of steatorrhea of unknown etiology, inborn errors of bile acid metabolism should be considered for providing a diagnosis and early initiation of therapy, preventing from irreparable damage.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Garfia Castillo C, Manzanares López-Manzanares J, García Silva MT. Presentación atípica y diagnóstico tardío en un caso de déficit primario de ácidos biliares. 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