Acute Upper Gastrointestinal Bleeding Associated With Epstein–Barr Virus Reactivation in an Immunocompetent Patient

Acute Upper Gastrointestinal Bleeding Associated With Epstein–Barr Virus Reactivation in an Immunocompetent Patient

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  © 2009 by the American College of Gastroenterology The  American Journal of    GASTROENTEROLOGY 253 Letters to the Editor Acute Upper Gastrointestinal Bleeding Associated With Epstein – Barr Virus Reactivation in an Immunocompetent Patient Antonio Cuadrado Lav í n , MD , PhD 1  , Javier G ó mez Rom á n , MD 2  , Santiago Aresti Z á rate , MD 1  , Miguel Carrascosa Porras , MD 3  and J. Ram ó n Salcines Caviedes , MD 1   doi: 10.1038/ajg.2008.25 Presence of Epstein – Barr virus (EBV) DNA was demonstrated in the duode-nal biopsy samples by PCR technique. Additionally, an in situ  hybridization test revealed the presence of EBV-encoded RNAs (EBER)-1 and 2 in the cytoplasm as well as in the nucleus of the infected epithelial cells, but only in areas near to ulcerated lesions ( Figure 2  ). Serum anti-EBV IgG was positive whereas anti-EBV immunoglobulin M was negative. Sero-logy for HIV infection was negative. No other immunosuppressive status could be demonstrated. At 2 months aer dis-charge, the patient was asymptomatic and a new upper gastrointestinal endo-scopy was completely normal. We per-formed again the same molecular bio-  Figure 1.   Endoscopic appearance of the second duodenal portion. Upper gastrointestinal endo-scopy shows one of the multiple duodenal ulcers, with signs of recent hemostasis (arrow), and multiple white-yellow pseudomembranes.  Figure 2.   Pathological findings. In situ   hybridiza-tion for Epstein–Barr virus (EBV)-encoded RNAs (EBER) 1 and 2 of a duodenal tissue specimen. Note dark violet-blue precipitate in the cyto-plasm as well as in the nucleus of the epithelial infected cells near to ulcerated lesion (srcinal magnification, ×250).  To the Editor :  A previously healthy 49-year-old man was admitted to the emergency department with a 16-day history of worsening epigastric pain, melena, and lightheadedness. e patient attributed his symptomatology to deep psychological stress and depression aer having being recently dismissed from his company. On admission, the blood pres-sure was 100 / 60 mm Hg and the pulse rate 90 per min. Physical examination disclosed no abnormalities. Initial hema-tocrit and hemoglobin concentration were 29 % (reference range, 37 – 52 % ) and 10 g / dl (12 – 18 g / dl), respectively. Upper gastrointestinal endoscopy revealed multiple ulcerated lesions — some of them with signs of recent hemostasis—erosions, and white-yellow pseudomem-branes in the second duodenal portion ( Figure 1  ). Biopsies of the ulcerated lesions were taken and therapy with ome-prazol (40 mg daily) and ferrous sulfate was given. Blood biochemistry, leukocyte count, coagulation tests, and erythrocyte sedimentation rate were within normal limits. Serum concentrations of immuno-globulins and gastrin were normal. Anti-tissue transglutaminase antibodies as well as the urease test for Helicobacter pylori  were negatives. Colonoscopy and barium study of the small intestine revealed no abnormalities. Cultures of the lesions yielded no pathogens and the pathologi-cal study showed ulcerated lesions with a lymphocytic and polymorphonuclear inflammatory infiltrate. logy studies in duodenal biopsy samples that showed negative results. e patient has remained under intensive psychologi-cal support since hospital admission, with successful results. Epstein – Barr virus is recognized as one of the most successful viruses, infect-ing over 90 % of humans and persisting for the lifetime of the person (1) . Human EBV infection results in humoral and cel-lular immunity to the virus, the cellular response being more important for the control of infection. e diagnosis of an organ-specific EBV disease requires the demonstration of EBV DNA, RNA, or proteins in biopsy tissue. Herein, we have demonstrated the presence of EBV DNA and EBV-encoded RNA in epithelial cells from morphologically altered duodenal regions. Although some authors suggest herpesviruses may not play a role in the pathogenesis of duodenal ulcer (2) , it seems there is evidence to support such a role for EBV in the present case. e epidemiological, clinical and serologic profile of our patient suggest an EBV reactivation instead of a pri-moinfection. Although reactivation is not a relevant phenomenon with EBV, it can complicate the clinical course of some immunosuppressed patients such as transplant recipients (3) . We hypo-thesize that stress and depression caused by work dismissal could have impaired the immune response in our patient, pre-disposing him to EBV reactivation. In this regard, psychological and physical stress-induced immune dysregulation has been shown to be significant enough to result in health consequences, including reactivation of latent herpesviruses, such as EBV, and enhancing the risk for more severe infectious disease (4,5) . On the other hand, it has been recognized that depression can decrease the cell-mediated immunity by impairments in T-cell-mediated functions and reduced natural-killer cell counts and cytotoxicity (6) . e present case serves to illustrate that the clinical spectrum of symptomatic EBV reactivation is growing. We believe EBV reactivation should be regarded as a new additional cause of duodenal ulcer disease in seemingly immunocompetent patients.  The  American Journal of    GASTROENTEROLOGY VOLUME 104 |  JANUARY 2009 254  Letters to the Editor REFERENCES 1 . Cohen JI . Epstein-Barr virus infection . N Engl J Med 2000 ; 343 : 481 – 92 . 2 . Kottaridis SD , Mihas TA , Goula I et al.  Herpes  viruses and duodenal ulcer disease . J Med Virol 1989 ; 29 : 224 – 6 . 3 . Aoyama Y , Nakao Y , Ohta K et al.  Pericarditis associated with Epstein-Barr virus reacti- vation in a patient following allogeneic peripheral blood stem cell transplantation from an HLA genotypic 1-locus mismatched sibling donor . Leuk Lymphoma 2004 ; 45 : 393 – 5 . 4 . Godbout JP, Glaser R . Stress-induced immune dysregulation: implications for wound healing, infectious disease and cancer . J Neuroimmune Pharmacol 2006 ; 1 : 421 – 7 . 5 . Mehta SK , Pierson DL , Cooley H et al.  Epstein-Barr virus reactivation associated with disminished cell-mediated immu-nity in antarctic expeditioners . J Med Virol 2000 ; 61 : 235 – 40 . 6 . Prince M , Patel V, Saxena S et al.  No health without mental health . Lancet 2007 ; 370 : 859 – 77 . 1  Gastroenterology Section, Internal Medicine Department, Hospital of Laredo , Laredo, Cantabria , Spain ; 2  Molecular Biology Laboratory, Pathology Service, University Hospital Marqu é s de Valdecilla, Faculty of Medicine , Santander, Cantabria , Spain ; 3  Internal Medicine Section, Internal Medicine Department, Hospital of Laredo , Laredo, Cantabria , Spain . Correspondence:   Miguel Carrascosa Porras, MD, Internal Medicine Section, Internal Medicine Department, Hospital of Laredo, Avenida Derechos Humanos s/n, 39770 Laredo, Cantabria, Spain. E-mail: Sildenafil-Induced Severe Cholestatic Hepatotoxicity Masaru Enomoto , MD 1  , Hiroki Sakaguchi , MD 1  , Masaki Ominami , MD 1  , Shuji Iwai , MD 1  , Hiroyasu Morikawa , MD 1  , Akihiro Tamori , MD 1  and Norifumi Kawada , MD 1  doi:10.1038/ajg.2008.18 To the Editor:  Sildenafil citrate (Viagra) is a potent, orally active, cyclic guanosine monophosphate-specific phosphodieste-rase type 5 inhibitor, used globally for the treatment of penile erectile dysfunction. e most common adverse effects are headache, flushing, dyspepsia, and car-diovascular events. Liver toxicity attrib-uted to sildenafil appears to be very rare. In the English-language literature, only one case of mild hepatotoxicity induced by sildenafil has been reported earlier (1) . We describe a case of severe cholestatic hepatotoxicity induced by sildenafil. A previously healthy 58-year-old man was referred to us because of jaundice, pruritus, and malaise. e laboratory  values were as follows: aspartate amino-transferase 42 IU / l, alanine aminotrans-ferase 64 IU / l, alkaline phosphatase 476 IU / l, total bilirubin 8.5 mg / dl, direct bilirubin 6.3 mg / dl, albumin 3.6 g / dl, white blood cell count 4,300 / mm 3  (with 2.8 % eosinophils), hemoglobin concentration 13.3 g / dl, platelet count 239,000 / mm 3  , and prothrombin time 95 % . Tests for immunoglobulin M anti-hepatitis A virus, hepatitis B surface anti-gen, immunoglobulin M anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, immunoglobulin M anti-viral capsid antigen of Epstein-Barr virus, and immunoglobulin M anti-cytomegalovi-rus were all negative. C-reactive protein and anti-nuclear, anti-mitochondrial, and anti-neutrophil cytoplasmic anti-bodies were also negative. No history of recent drug use or excessive alcohol intake was reported. Abdominal ultra-sound, computed tomography, and magnetic resonance cholangiopancrea-tography showed no signs of bile duct obstruction. Macroscopically, the liver was green, enlarged, and had a smooth surface without nodularity on laparo-scopic examination ( Figure 1  ). A liver biopsy specimen revealed features of int-rahepatic cholestasis; marked bile stasis was seen in canaliculi around the peri-central area, and cellular necroinflam-mation in the portal area was minimal ( Figure 2  ). On carefully obtaining his history again, the patient admitted that he had taken sildenafil 50 mg 1 month before symptom onset. No other medications, including nonsteroidal anti-inflamma-tory drugs, were used. On the basis of criteria for drug-induced liver disorders (2) and the Naranjo adverse drug reac-tion probability scale, (3) we diagnosed probable sildenafil-induced cholestatic hepatotoxicity. e laboratory data steadily improved thereaer without any medical treatment and returned to nor-mal 4 months aer symptom onset. Daghfous et al   . (1) reported a case of acute hepatotoxicity attributed to sildenafil. However, the causal relation between sildenafil use and subsequent liver damage was uncertain. e alanine aminotransferase level increased to only 1.2 times the upper limit of normal, and the biluribin and alkaline phosphatase levels were normal. A liver biopsy was not undertaken. Liver injury did not recur aer rechallenge with sildenafil. Figure 2.   Liver biopsy specimen showing intrahepatic cholestasis (hematoxylin and eosin; srcinal magnification, ×200).  Figure 1.   Laparoscopic image showing a green and enlarged liver without nodularity. 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