Adenovirus Infection As Possible Cause of Acute Liver Failure in A

Turk J Gastroenterol 2008; 19 (4): 281-283

Adenovirus infection as possible cause of acute liver failure in a healthy child: A case report Adenovirus infeksiyonu: Sa¤l›kl› bir çocukta akut karaci¤er yetmezli¤inin muhtemel bir nedeni olabilir: Olgu sunumu

Ferda ÖZBAY HOﬁNUT1, O¤uz CANAN1, Figen ÖZÇAY1, Banu B‹LEZ‹KÇ‹2 Departments of 1Pediatric Gastroenterology, Hepatology and Nutrition and 2Pathology, Baﬂkent University Faculty of Medicine, Ankara

Adenoviruses are common viral pathogens in childhood; howe- Adenoviruslar çocukluk ça¤›nda yayg›n olarak görülen viral in- ver, they can cause serious disease in an immunocompromised feksiyonlard›r. Fakat, immunsupresif kiflilerde ciddi hastal›k- host. Fulminant hepatitis is a rare complication of adenoviral lara neden olabilirler. Fulminan hepatit, adenoviral infeksiyo- infection. We report herein a case of fatal fulminant hepatitis nun nadir bir komlikasyonudur. Bu yaz›da adenovirus infeksi- possibly caused by adenovirus infection. Although rare, adeno- yonuna ba¤l› olabilece¤i düflünülen fatal seyreden fulminan he- virus infection should be considered in the differential diagno- patitli bir olgu sunulmufltur. Nadir olmas›na ra¤men immun- sis of acute liver failure in immunocompetent children. supresif olmayan çocuklarda akut karaci¤er yetmezli¤inde adenovirus infeksiyonlar› ay›r›c› tan›da düflünülmelidir.

Key words: Adenovirus, acute liver failure, polymerase chain Anahtar kelimeler: Adenovirus, akut karaci¤er yetmezli¤i, reaction PCR

INTRODUCTION Any virus that can cause acute hepatitis may po- nation. The pathogenesis of invagination was at- tentially give rise to acute liver failure. Such viru- tributed to enlarged intra-abdominal lymph no- ses can be categorized as those that primarily af- des. Adenoviruses were recovered from mesenteric fect the liver, such as hepatitis A to E viruses, and lymph nodes (3). Rarely, more virulent types (par- those in which liver involvement may occur as ticularly type 7) can cause respiratory failure, part of disseminated infection, such as Epstein- shock and hepatitis in immunocompetent children Barr virus (EBV), cytomegalovirus (CMV), varicel- (3). However, in immunocompromised patients, la zoster virus, herpes simplex virus, and adenovi- adenovirus can cause fulminant or disseminated rus (1). disease such as colitis, pneumonitis, pancreatitis, Adenoviruses, which have been suggested as one nephritis, meningoencephalitis and hepatitis (4). of the causes of acute viral hepatitis, are DNA vi- Acute liver failure due to adenovirus is rare, and ruses that include 47 distinct serotypes that cause is described especially in immunocompromised patients, in whom it is usually fatal. (4). Herein, we disease in humans (2). They are endemic in chil- present a previously healthy child who died due to dren, with 80% of 1-to-5-year-olds having antibody adenoviral acute liver failure. to at least one of the many serotypes. In healthy children, adenoviral infection causes a benign, self-limited illness (2). Symptomatology includes CASE REPORT pharyngoconjunctival fever, follicular conjunctivi- An 18-month-old boy was admitted to a local hos- tis, epidemic keratoconjunctivitis, myocarditis, he- pital with watery diarrhea, vomiting and jaundice morrhagic cystitis and acute diarrhea and invagi- for the last three days. After admission, his cons-

Address for correspondence: Ferda ÖZBAY HOfiNUT Manuscript received: 29.06.2007 Accepted: 22.11.2007 Baflkent Üniversitesi Ankara Hastanesi Fevzi Çakmak Cad. 10. Sok. No: 45 06490 Bahçelievler, Ankara, Turkey Phone: + 90 312 212 68 68 / 1314 • Fax: + 90 312 215 75 97 E-mail: [email protected] 282 HOfiNUT et al. ciousness level gradually deteriorated, and he and anti-smooth muscle antibody tests were all eventually fell into a grade III coma with abnor- negative. His urine organic acid analysis and tan- mal findings in blood coagulation tests, and prog- dem mass screening for metabolic diseases did not ressive increase in bilirubin levels. He was diagno- indicate any disease of inborn errors of metabo- sed with acute liver failure and transferred to Bafl- lism. The abdominal ultrasonography showed pro- kent University Ankara Hospital for liver trans- ximal jejunal invagination. Supportive therapy plantation. He had previously been healthy, with including plasmapheresis was given for acute liver normal development, and was the first child of un- failure. However, no liver donor was available and related, healthy parents. There was no history of the patient died due to multiple organ failure a previous liver disease, exposure to a toxic agent or few days later. administration of medications. Postmortem histological examination of his liver On physical examination, his weight was 13 kg (50 specimen revealed massive hepatic necrosis. The percentile) and height 80 cm (50 percentile). He liver had lost all hepatocytes; the lobule was popu- was jaundiced and in grade III hepatic encephalo- lated only by macrophages. Slight condensation of pathy. His abdomen was soft and there was no he- reticulin was present, without fibrosis. On immu- patosplenomegaly or ascites. The remainder of his nostaining, adenovirus antigens were not identifi- physical examination was normal. ed and the cells within the lobule were confirmed Laboratory tests on admission were as follows (nor- as macrophages. mal range in parentheses): White blood cell count Adenovirus PCR was negative in the paraffin 23.2x109/L, hemoglobin 7.01 g/dl and platelet count blocks of postmortem-obtained liver tissue. 117 x109/L. His glucose level was 9 mg/dl, asparta- te aminotransferase (AST) 149 U/L (0-40), alanine DISCUSSION aminotransferase (ALT) 193 U/L (0-41), GGT 27 We report the case of a healthy 18-month-old boy U/L (18-61), ALP 258 U/L (100-250), total bilirubin who developed acute liver failure possibly due to 49.99 mg/dl (0-1.2), direct bilirubin 26.71 mg/dl (0- adenovirus infection. Although most adenovirus 0.3), LDH 1234 U/L (180-430), ammonia 120 infections are self-limited, the virus can be asso- µmol/L (14.7-55.3), ferritin 4393 ng/dl (20-200), lac- ciated with lethal infection in both immunocom- tate 5.4 mmol/L (0.7-2.1), PT 36.6 sec (11-15), aPTT promised and healthy children (5). A retrospective 46.5 sec (24-40), INR 3.84 (1-1.2), factor V 20% (60- review of pediatric adenovirus infections disclosed 150), fibrinogen 112 mg/dl (200-400), fibrin degra- that 11 (2.5%) out of 440 adenovirus infections we- dation products 40 ug/ml (0-5), and D-dimer 9.5 re classified as disseminated infections (6). Five of ug/ml (0-0.5). Serum quantitative immunoglobulin these 11 patients were immunocompetent and the levels were all within normal limits. Lymphocyte mortality rate in this group was 60%, while it was subset analysis was not compatible with immuno- 83% in immunodeficient cases. Rocholl et al. (5) deficiency. The ratio of CD4/CD8 was 4.47. reported that disseminated adenoviral disease oc- In order to identify an etiologic agent for his disea- curred at a younger age in immunocompetent chil- se, serological examinations were carried out on dren. They also described a case with fulminant serum samples obtained at the time of admission. hepatic failure, pancreatitis, encephalopathy and Hepatitis A, B, C, E viruses, CMV, EBV, human basilar pneumonia due to adenovirus infection. An immunodeficiency virus (HIV), parvovirus B-19, evaluation for liver transplantation was initiated herpes simplex virus types I-II, toxoplasma and for their patient; fortunately, the patient respon- rubella infections were ruled out by the serological ded to the cidofovir treatment and recovered wit- assays, while serum adenovirus IgM and IgG an- hout liver transplantation (5). tibodies were positive. Blood, stool, and urine cul- Several methods are used to detect adenovirus in- tures were negative for bacterial and fungal pat- fection depending on the site and severity of infec- hogens. Widal test for salmonellosis was negative. tion. Adenovirus can be shown by immunohisto- Stool enteric adenovirus antigen test was positive. logy or characteristic pathologic changes including Peripheral blood adenovirus polymerase chain re- intranuclear inclusion bodies in biopsy material, action (PCR) was positive. isolation of virus by culture or PCR, or demonstra- His ceruloplasmin, alpha-1 antitrypsin, antinucle- tion of an increase in antibody titers (3). Isolation ar antibody, liver-kidney microsomal antibody, of adenovirus from possible infectious sites (urine, Acute liver failure due to adenovirus infection 283 stool, respiratory secretion, and cerebrospinal flu- adenovirus. However, several authors have com- id) is not always successful and because of the li- mented on the difficulty of confirming the adenovi- mited sensitivity, negative cultures for adenovirus ral infection by histopathology. Flomenberg et al. from body fluids do not exclude adenovirus infecti- (8) reported that only three of eight bone marrow on. On the other hand, positive viral cultures do patients with positive adenoviral stool cultures not provide evidence of invasive or disseminated had diagnostic viral histopathology. Similarly, Pa- disease due to shedding of epithelial cells harbo- rizhkaya et al. (9) reported only three of 70 small ring adenovirus (7). bowel transplant recipients diagnosed with adeno- Onset of hepatic injury in the present case appea- virus enteritis had characteristic epithelial chan- red to occur concomitantly or just after the watery ges in small bowel biopsy. PCR is a very useful diarrhea. Therefore, an infectious disease causing method in the detection of adenovirus in biopsy acute liver failure was highly possible. Lack of se- tissues. However, adenovirus PCR tested in the li- rologic evidence of other etiologic factors causing ver tissue was found negative in our patient. This viral hepatitis, diarrhea and intestinal invaginati- could be secondary to massive hepatic necrosis in on led us to search adenovirus in the stool and blo- our patient and clearance of adenovirus from his od (adenovirus serology and PCR). It is known necrotic liver. Acute liver failure arises from an that the presence of the virus in the stool does not imbalance between liver cell death and regenerati- indicate clinical adenovirus infection because the- on. Liver cell death occurs through complex cellu- se viruses may be excreted chronically and asym- lar interactions and is mediated by immunological, ptomatically. But, in these instances, discovery of inflammatory and chemical components. Whether a coincident increase in antibody is helpful in the adenovirus infection can trigger immune-media- diagnosis (3). Since there was positive adenovirus ted acute liver failure must be considered. IgM and IgG antibody, and positive blood PCR, it In conclusion, we recommend that adenovirus in- was conceivable that our patient had primary ade- fection should be included in the differential diag- novirus infection. nosis of fulminant hepatic failure seen in childho- The histological examination of his postmortem li- od. Blood PCR test may be more sensitive than liver biopsy specimen was reported as massive he- ver PCR test in the case of acute liver failure with patic necrosis without specific inclusion bodies for massive hepatic necrosis.

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