At the last follow-up in July 2018 (nearly 2 years after the initial admission and diagnosis), the patient had no jaundice, and liver function was normal. Tumor biomarker examinations, MRI, and enteroscopy provided no evidence of tumor recurrence. In the period between the initial admission and last follow-up, the patient's height had increased from 174 to 177 cm, and the patient's body weight had increased from 35 to 38 kg.
Cholestasis generally needs early diagnosis and intervention. The differential diagnosis of cholestasis in pediatric patients includes various causes and depends on the age of the patient and the type of cholestasis. In the present case, the initial differential diagnosis included bacterial or viral infection, DILI, hereditary metabolic disease, and autoimmune liver disease.
Blood cultures demonstrated no bacterial growth, and tests for various viral infections, including hepatotropic viruses, Epstein–Barr virus, cytomegalovirus virus, parvovirus B19, and herpes simplex virus, were negative. Therefore, infection was excluded as a likely cause of cholestasis in the present case.
The DILI presents with acute or chronic cholestasis and abnormally high levels of transaminases. Specific diagnostic markers for DILI are lacking, and the disorder may mimic other intrahepatic and extrahepatic cholestatic diseases. The most common causes of DILI are antimicrobial agents and drugs used to treat disorders of the central nervous system.[3,4] The patient described in this case report had been taking 2 antiepileptic medications for approximately 4 years and was therefore at risk of DILI. Although we suggested percutaneous liver biopsy to facilitate diagnosis, the patient's parents declined this procedure. However, the concentrations of the antiepileptic drugs in the blood were within the normal ranges, and liver function tests did not improve after withdrawal of the medication. These observations reduced the likelihood of DILI being the cause of cholestasis in our patient.
Autoimmune liver diseases are progressive disorders characterized by elevated serum levels of immunoglobulin G and transaminases, the presence of autoantibodies, and the detection of interface hepatitis by histologic analysis of the liver.[5,6] Autoimmune liver disease can affect both intrahepatic and extrahepatic bile ducts, and cholestasis may be the major presentation. Autoimmune liver disease should always be considered in the differential diagnosis of liver disorders in children because it will culminate in end-stage liver disease if not treated in a timely manner. In the present case, the levels of immunoglobulins A, M, and G were normal at admission, and tests for a variety of autoantibodies (including smooth muscle actin antibody, antinuclear antibodies, antimitochondrial antibodies, and liver-kidney microsomal antibodies) were negative. Thus, the results of these investigations did not support the diagnosis of autoimmune liver disease.
Hereditary metabolic diseases that can cause cholestasis include Wilson disease, Alagille syndrome, PFIC3, and benign recurrent intrahepatic cholestasis. Alagille syndrome is a multisystem disorder caused by defects in the JAG1 and NOTCH2 genes. The patients often present with chronic cholestasis and pruritus, with other clinical manifestations including a characteristic facial appearance, cardiovascular anomalies, posterior embryotoxon, abnormal vertebrae, vascular accidents, renal anomalies, growth failure, and learning difficulties.[8–12] Chronic cholestasis and elevated γ-glutamyltransferase occur in a very high proportion of patients with Alagille syndrome. Another hereditary disease considered in the differential diagnosis was PFIC3, a rare disorder due to ABCB4 gene mutation. Children with PFIC3 develop cholestasis between late infancy and adolescence and can present with abnormal liver tests (including elevated γ-glutamyltransferase), drug-induced cholestasis, cholesterol gallstone disease, adult idiopathic cirrhosis, and transient cholestasis in infancy. Some patients with PFIC3 may progress to biliary cirrhosis and liver failure. Alagille syndrome and PFIC3 were considered as possible causes of cholestasis in the present case because of the increased γ-glutamyltransferase at admission and age of onset. However, these and other hereditary metabolic diseases were excluded by a combination of detailed physical examination and genetic testing for mutations in 244 genes, including JAG1 and NOTCH2 (Alagille syndrome), ABCB4 (PFIC3), ABCB11 (recurrent benign cholestasis), ATP7B (Wilson disease), and ABCC2 (Dubin–Johnson syndrome).
Since the biochemical markers did not improve after 10 days of supportive therapy with ursodeoxycholic acid and lipid-soluble vitamins (A, D, and K1), we arranged for additional imaging examinations that subsequently identified a mass in the ampulla of Vater. Because we had no ERCP facilities, ERCP and surgical resection of the tumor were carried out in other hospitals. Postoperative pathology confirmed a diagnosis of poorly differentiated adenocarcinoma of the duodenal papilla. Duodenal papillary carcinoma represents 5% of all gastrointestinal tract malignancies, and although the average age of onset is in the seventh decade of life, rare cases of this malignancy occurring during adolescence have been reported.[13,14] Our patient presented with early onset of a highly aggressive carcinoma. Since no mass was identified at admission by abdominal ultrasound or CT, we initially focused on medical causes of cholestasis. However, after numerous examinations had excluded medical causes, we reevaluated the patient and detected the tumor. This highlights the importance of not definitively excluding malignancy as a cause of cholestasis in adolescents on the basis of initial imaging with abdominal ultrasonography or CT.
Although neoplastic disease is a rare underlying cause of cholestasis in pediatric patients, it should not be ignored even in the absence of positive findings in imaging examinations. Early and accurate diagnosis is important for patients with carcinoma as delayed diagnosis and treatment can lead to a poorer prognosis.
The authors thank the patient and his parents for agreeing to participate in this study.
Conceptualization: Haiyan Fu, Rongpin Li, Ruiqin Zhao.
Data curation: Haiyan Fu, Yingchao Li, Gelan Bai, Runkai Yin, Weina Shi, Lili Zhang.
Formal analysis: Haiyan Fu, Yingchao Li, Gelan Bai, Runkai Yin, Weina Shi, Lili Zhang.
Funding acquisition: Weina Shi.
Investigation: Yingchao Li, Runkai Yin, Rongpin Li.
Methodology: Haiyan Fu, Yingchao Li, Gelan Bai, Chunlan Yin.
Project administration: Chunlan Yin, Ruiqin Zhao.
Resources: Chunlan Yin, Lili Zhang, Rongpin Li.
Software: Haiyan Fu, Chunlan Yin, Lili Zhang, Rongpin Li.
Writing – original draft: Haiyan Fu.
Writing – review & editing: Haiyan Fu, Yingchao Li, Gelan Bai, Runkai Yin, Chunlan Yin, Weina Shi, Lili Zhang, Rongpin Li, Ruiqin Zhao.
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. Andiran F, Tanyel FC, Kale G, et al. Obstructive jaundice resulting from adenocarcinoma of the ampulla of Vater in an 11-year-old boy. J Pediatr Surg 1997;32:636–7.
Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
cholestasis; differential diagnosis; duodenal papillary carcinoma; pediatric patient