Acute liver failure in a renal transplant patient caused by adenoviral hepatitis superimposed on a fibrosing cholestatic hepatitis B

HUMAN PATHOLOGY

Volume 35, No. 7 (July 2004)

TABLE 1. Shared and Different Clinical and Histopathologic Findings Findings Clinical Maculopapular rash Papules and plaques Palpable cords Ulceration Nodules Histopathologic Mononuclear cell infiltration Neutrophilic infiltration Collagen degeneration Mucin deposition Vasculitis Leukocytoclasia Vacuolar interphase changes

IGDA

Granulomatous Drug Reactions

Interstitial GA

RND

PNGD

⫺ ⫹ ⫾ ⫺ ⫺

⫹ ⫹ ⫺ ⫺ ⫺

⫺ ⫹ ⫺ ⫺ ⫺

⫺ ⫹ ⫺ ⫺ ⫹

⫺ ⫹ ⫺ ⫹ ⫺

⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺

⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹

⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺

⫺ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺

⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺

Abbreviations: IGDA, interstitial granulomatous dermatitis with arthritis; GA, granuloma annulare; RND, rheumatoid neutrophilic dermatitis; PNGD, palisased neutrophilic and granulomatous dermatitis.

legs, rather than linear bands on the trunk or axilla. Therefore it appears that the clinical appearance of IGDA may be variable and is not restricted to linear bands of the trunk. Although histopathologic differential diagnosis of this entity is extensive, the described features enable a distinction to be made from granulomatous dermatitis. REFERENCES 1. Ackerman AB, Guo Y, Vitale P, et al: Clues to Diagnosis in Dermatopathology. Chicago, IL, ASCB Press, 1993, pp 309-312 2. Long D, Thiboutut DM, Majeski JT, et al: Interstitial granulomatous dermatitis with arthritis. J Am Acad Dermatol 34:957-961, 1996 3. Tomasini C, Pippione M: Interstitial granulomatous dermatitis with plaques. J Am Acad Dermatol 46:892-899, 2002

4. Aloi F, Tomasini C, Pippione M: Interstitial granulomatous dermatitis with plaques. Am J Dermatopathol 21:320-323, 1999 5. Verneuil L, Dompmartin A, Comoz F, et al: Interstitial granulomatous dermatitis with cutaneous cords and arthritis: A disorder associated with autoantibodies. J Am Acad Dermatol 45:286-291, 2001 6. Sangueza OP, Caudell MD, Mengesha YM, et al: Palisaded neutrophilic granulomatous dermatitis in rheumatoid arthritis. J Am Acad Dermatol 47:251257, 2000 7. Chu P, Connally MK, LeBoit PE: The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular diseases. Arch Dermatol 130:1278-1283, 1994 8. Magro CM, Crowson AN, Schapiro BL: The interstitial granulomatous drug reactions: A distinctive clinical and pathological entity. J Cutan Pathol 25:72-78, 1998 9. Mashek HA, Pham CT, Helm TN, et al: Rheumatoid neutrophilic dermatitis. Arch Dermatol 113:757-760, 1997

ACUTE LIVER FAILURE IN A RENAL TRANSPLANT PATIENT CAUSED BY ADENOVIRAL HEPATITIS SUPERIMPOSED ON A FIBROSING CHOLESTATIC HEPATITIS B T. LONGERICH, MD, K. HAFERKAMP, MD, U. TO¨ X, MD,

AND

PETER SCHIRMACHER, MD

We report the first case of fulminant liver failure due to necrotizing adenovirus hepatitis superimposed on a fibrosing cholestatic hepatitis B in an immunosuppressed patient after renal transplantation. Diagnosis was made in vivo by liver biopsy and confirmed at autopsy. HUM PATHOL 35:894-897. © 2004 Elsevier Inc. All rights reserved.

Key words: hepatitis, transplantation, hepatitis B virus, adenovirus, liver failure. Abbreviations: CMV, cytomegalovirus; FCH, fibrosing cholestatic hepatitis; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; PCR, polymerase chain reaction; RT-PCR, reversetranscriptase polymerase chain reaction; VZV, varicella-zoster virus.

Fibrosing cholestatic hepatitis (FCH) is a unique, but infrequent form of hepatitis B virus (HBV) or hepatitis C virus

(HCV) infection in immunosuppressed patients.1 Typical histological changes include prominent ductular proliferation, prominent perisinusoidal fibrosis, and intense positivity of hepatocytes for HBs and HBc antigens. FCH is clinically characterized by progressive deterioration of liver function. It has been described mostly in patients after liver transplantation; some cases have also occurred in kidney and bone marrow transplant recipients.2-5 Adenovirus infections in general may typically cause upper respiratory tract infections, and, less frequently, lower respiratory infections, gastroenteritis, hemorrhagic cystitis, myocarditis, and keratoconjunctivitis.6,7 In addition, adenovirus may cause acute hepatitis.8-10

From the Institute of Pathology, IV Medical Clinic, and Center for Molecular Medicine, University of Cologne, Cologne, Germany. Accepted for publication March 30, 2004. Address correspondence and reprint requests to Peter Schirmacher, MD, Institute of Pathology, University of Cologne, JosephStelzmann-Str. 9, Cologne D-50931, Germany. 0046-8177/$—see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2004.04.004

894

CASE STUDIES

Adenovirus infections causing acute necrotizing hepatitis and acute liver failure have been described in immunosuppressed patients, most frequently those who have undergone bone marrow transplantation. In adult patients who have undergone kidney transplantation, adenovirus infections are generally of subgenus B. Adenoviral infections after transplantation for solid tumors or nonmalignant conditions are very rare.8 Here we present a case of acute liver failure due to adenovirus hepatitis superimposed on FCH caused by HBV in an adult patient after renal transplantation. CASE REPORT

exhibited moderate steatosis, but did not exhibit Cowdry type A or B viral inclusions, although a few enlarged, hyperchromatic hepatocyte nuclei, resembling so-called “smudge cells” (Fig 2, insert), were present. These changes were already clearly detectable in premortem liver biopsy and allowed the intravitam diagnosis of a severe combined liver damage resulting from FCH B and acute, focal necrotizing hepatitis most likely due to adenoviral infection. Autopsy confirmed the biopsy findings and revealed further progression of the liver lesions, as well as severe hemorrhagic necrotizing enteritis and nonspecific signs of multiorgan failure. Virology

Clinical Course A 42-year-old, male caucasian patient was admitted to the hospital with progressive deterioration, jaundice, and diarrhea. He had undergone renal transplantation for unknown reason with a cytomegalovirus (CMV)-positive transplant 2.5 years earlier, himself being CMV-negative. Immunosuppressive therapy after transplantation included ciclosporin (175 mg/day), mycophenolate mofetil (1 g/day), and prednisone (2.5 mg/day). Three months after transplantation, he had developed a CMV pneumonia, which was successfully treated with anti-CMV immunoglobulin and ganciclovir. The patient’s medical history included chronic hepatitis B infection detected during screening before initiation of dialysis 9 years earlier. Ten days after admission, the patient’s condition deteriorated further. He developed fever along with serologic signs of acute liver and renal failure. Hepatorenal syndrome was suspected, and liver biopsy was performed. The patient developed signs of multiorgan failure, including hypoglycemia, hypothermia, and somnolence. Serology studies at day 14 revealed the following results: C-reactive protein, 23 mg/L (reference value, ⬍8); aspartate aminotransferase, 7765 U/L (⬍20); alanine aminotransferase, 275 U/L (⬍24); ␥-glutamyltransferase, 39 U/L (⬍29); alkaline phosphatase, 248 U/L (60 to 175); total bilirubin, 10.4 mg/dL (⬍1.1); cholinesterase, 3.2 kU/L (3.5 to 8.5); creatinine, 3.02 mg/dL (0.5 to 1.1); erythrocyte count, 2.8 ⫻ 1012/L (4.5 to 5.9); hemoglobin, 8.6 g/dL (13.5 to 18); leukocyte count, 18.7 ⫻ 109/L (4.4 to 11.3); thrombocyte count, 34 ⫻ 109/L (150 to 400); international normalized ratio (INR), 2.1; antithrombin III (ATIII), 26% (70 to 120); fibrinogen, 0.6 g/L (1.8 to 3.5); and D-dimer, 2.05 mg/L (⬍0.19). Serology was positive for HBs antigen and negative for anti-HBs antigen; HCV-RNA in the serum was negative. Anti-CMV IgM was positive, and anti-CMV IgG was 197 U/mL. Serology results were negative for herpes simplex virus (HSV)-IgM and varicella-zoster virus (VZV)-IgM. Despite intensive care, the patient died with multiorgan failure at day 14. An autopsy was performed. No antiviral agents (eg, aciclovir) were administered during hospitalization. Pathological Findings Liver histology obtained by biopsy 4 days before death showed typical lesions of FCH B (Fig 1). There was intense ductular proliferation as demonstrated by immunohistology results showing CK7, cholestasis, and excessive pericellular fibrosis. Furthermore, most of the hepatocytes were strongly positive for HBs and HBc antigens (nuclear and cytoplasmic). In addition, the parenchyma exhibited large, hemorrhagic, partly confluent necroses without zonal restriction (Fig 2). Surrounding hepatocytes were partly necrobiotic and

A liver smear directly taken at autopsy was positive for adenoviral DNA on polymerase chain reaction (PCR), whereas PCR with DNA extracts obtained from autopsy liver tissue failed to detect adenoviral DNA; this discrepancy may be explained by further autolysis. Enteroviral RNA was detected by reverse transcriptase PCR (RT-PCR) in ascites fluid, whereas it was constantly negative in serum and liver biopsy tissue. Serum was negative for VZV-IgM and positive for CMVIgM and CMV-DNA, whereas the liver biopsy tissue was negative for CMV by immunohistology and PCR. In addition, the liver biopsy was negative for HSV by immunohistology and PCR. DISCUSSION Here we describe a case of acute adenoviral hepatitis superimposing FCH B in an immunocompromised patient. The diagnosis of FCH B was based on the full-blown typical histological picture with pericellular fibrosis, ductular proliferation, cholestasis, and intense positivity for HBs and HBc antigens in an immunocompromised setting. In contrast, focal necrotizing hepatitis is not a manifestation of FCH B and must be due to an independent etiology. In general, in adults it may be caused by HSV, VZV, or adenoviral infection. Liver tissue surrounding the necroses did not exhibit the characteristic viral inclusion (Cowdry type A or B) of HSV hepatitis, and examination of liver tissue by PCR analyses, and immunohistology (for HSV) as well as serology failed to show any evidence for HSV or VZV infection. In contrast, liver smears obtained at autopsy were positive for adenoviral DNA by PCR. Interestingly, the patient also had necrotizing enteritis and enteroviral RNA in ascites as detected by RT-PCR. Because liver tissue was constantly negative for enteroviral RNA and enterovirus is known to cause focal necrotizing hepatitis only in children but not adults,11,12 we concluded that enteroviral infection was responsible for the necrotizing enteritis but not for the focal necrotizing hepatitis. In conclusion, all serologic and liver tissue analyses support the hypothesis that in this patient, focal necrotizing hepatitis superimposing FCH B was due to adenoviral infection.6,8,13,14 To our knowledge, this is the first report of such a combined liver disease, and due to the presence of characteristic histological changes, the diagnosis was already made intravitam by liver biopsy. Clearly, immunosuppression was a predisposing factor for FCH B and also for adenoviral hepatitis, as has been reported previously.2,4,6,8,15 However, it is not known whether FCH B itself may have further increased the likelihood of adenoviral hepatitis in this case. Our case is also unusual in that FCH B is significantly more common in patients undergoing liver transplantation and adenoviral hepatitis is less common in patients undergoing solid organ transplantation

895

HUMAN PATHOLOGY

Volume 35, No. 7 (July 2004)

FIGURE 1. Typical changes of fibrosing cholestatic hepatitis B. (A) Intense ductular proliferation (CK7-immunohistology), (B) severe pericellular fibrosis (modified Gomori's stain), (C) intense cytoplasmic positivity for HBsAg, and (D) nuclear and cytoplasmic positivity for HBcAg. (Original magnification ⫻ 250.)

FIGURE 2. Focal necrotizing hepatitis. (A) Acute, coagulative, poorly demarcated necroses. (Original magnification ⫻ 250.) (B) The perinecrotic parenchyma with steatosis, but absence of hepatocellular viral inclusions. (Hematoxylin and eosin; original magnification ⫻ 400.) (Insert) Hepatocyte with an enlarged, hyperchromatic nucleus, resembling a smudge cell. (Original magnification ⫻ 400.)

896

CASE STUDIES

(compared with bone marrow transplantation). Typically, FCH represents a unique course of HBV or HCV infection (re)occurring after (liver) engrafting. In contrast, in this patient chronic HBV infection was documented long before renal transplantation and must have permutated into a FCH due to immunosuppression. Because our patient succumbed to 3 different severe and potentially fatal viral infections (FCH B, focal necrotizing adenoviral hepatitis, and necrotizing enteroviral enteritis), we suggest that he suffered from a severe breakdown of resistance to viral infections. This is unlikely to be due to the standard immunosuppression for kidney transplant patients alone, and may further reside on an additional preexisting or acquired immune insufficiency. REFERENCES 1. Lee HK, Yoon GS, Min KS, et al: Fibrosing cholestatic hepatitis: A report of three cases. J Korean Med Sci 15:111-114, 2000 2. Lam PW, Wachs ME, Somberg KA, et al: Fibrosing cholestatic hepatitis in renal transplant recipients. Transplantation 61:378-381, 1996 3. Munoz de Bustillo E, Ibarrola C, Andres A, et al: Hepatitis B virus– related fibrosing cholestatic hepatitis after renal transplantation with acute graft failure following interferon-alpha therapy. Nephrol Dial Transplant 13: 1574-1576, 1998 4. Chen CH, Chen PJ, Chu JS, et al: Fibrosing cholestatic hepatitis in a

hepatitis B surface antigen carrier after renal transplantation. Gastroenterology 107:1514-1518, 1994 5. Davies SE, Portmann BC, O’Grady JG, et al: Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 13:150-157, 1991 6. Hale GA, Heslop HE, Krance RA, et al: Adenovirus infection after pediatric bone marrow transplantation. Bone Marrow Transplant 23:277-282, 1999 7. Piedra PA, Kasel JA, Norton HJ, et al: Description of an adenovirus type 8 outbreak in hospitalized neonates born prematurely. Pediatr Infect Dis J 11:460-465, 1992 8. Hierholzer JC: Adenoviruses in the immunocompromised host. Clin Microbiol Rev 5:262-274, 1992 9. Johnson PR, Yin JA, Morris DJ, et al: Fulminant hepatic necrosis caused by adenovirus type 5 following bone marrow transplantation. Bone Marrow Transplant 5:345-347, 1990 10. Krilov LR, Rubin LG, Frogel M, et al: Disseminated adenovirus infection with hepatic necrosis in patients with human immunodeficiency virus infection and other immunodeficiency states. Rev Infect Dis 12:303-307, 1990 11. Abzug MJ: Prognosis for neonates with enterovirus hepatitis and coagulopathy. Pediatr Infect Dis J 20:758-763, 2001 12. Chen CA, Tsao PN, Chou HC, et al: Severe echovirus 30 infection in twin neonates. J Formos Med Assoc 102:59-61, 2003 13. Carmichael GP Jr, Zahradnik JM, Moyer GH, et al: Adenovirus hepatitis in an immunosuppressed adult patient. Am J Clin Pathol 71:352-355, 1979 14. Saad RS, Demetris AJ, Lee RG, et al: Adenovirus hepatitis in the adult allograft liver. Transplantation 64:1483-1485, 1997 15. Chakrabarti S, Collingham KE, Fegan CD, et al: Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: Failure of intravenous ribavirin therapy. Bone Marrow Transplant 231:1209-1211, 1999

INTESTINAL PSEUDOTUMOROUS GOUTY NODULOSIS: A COLONIC TOPHUS WITHOUT MANIFESTATION OF GOUTY ARTHRITIS HUIQING WU, MD, MICHAEL J. KLEIN, MD, ROSALYN E. STAHL, MD,

AND

A 37-year-old black woman with nephritis secondary to systemic lupus erythematosus, steroid-induced diabetes mellitus, and hypertension presented with fever, nausea, vomiting, and right upper quadrant abdominal pain with distension. Abdominal computed tomography (CT) scan revealed a colonic mass, and CT- guided fineneedle aspiration demonstrated birefringent crystalline material. After several weeks of antibiotic therapy, the patient underwent laparoscopic examination followed by extended right hemicolectomy for a large mass in the subserosa of the transverse colon. Pathological

examination of this mass revealed it to be a gouty tophus. To our knowledge, no case of tophaceous gout presenting as an intestinal mass has previously been reported. HUM PATHOL 35:897-899. © 2004 Elsevier Inc. All rights reserved. Key words: gout, gouty nodulosis, intestinal tophus, colonic tophus, uric acid crystals. Abbreviations: BUN, blood urea nitrogen; CT, computed tomography; SLE, systemic lupus erythematosus.

Gout is a clinical syndrome resulting from the tissue deposition of monosodium urate monohydrate.1 It encompasses a group of disorders including hyperuricemia, gouty arthritis, tophaceous deposition, uric acid urolithiasis, and

gouty nephropathy. Although the typical sequence involves progression through asymptomatic hyperuricemia, acute gouty arthritis, interval or intercritical gout, and chronic or tophaceous gout, the manifestations can occur in any combination or alone.1,2 Extra-articular uric acid deposits, also called tophi, can occur in the absence of gouty arthritis in the connective tissue of ears, breast, kidney, elbows, wrists, fingers, finger pulp, legs, knees, ankles, feet, and toes.3-7 We report the case of 36-year-old woman with a large urate tophus in the colonic wall resembling a tumor in the absence of gouty arthritis.

From the Department of Pathology, Mount Sinai School of Medicine, New York, NY and Department of Pathology and Laboratory Medicine, Englewood Hospital and Medical Center, Englewood, NJ. Accepted for publication March 25, 2004. Huiqing Wu is currently at the Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Michael J. Klein is currently at the Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, AL. Address correspondence and reprint requests to Dr. Miguel A. Sanchez, Department of Pathology and Laboratory Medicine, Englewood Hospital and Medical Center, 350 Engle St., Englewood, NJ 07631. 0046-8177/$—see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2004.04.003

MIGUEL A. SANCHEZ, MD

CASE REPORT The patient is a 36-year-old black woman with a past medical history significant for systemic lupus erythematosus (SLE) diagnosed 6 years ago, nephritis secondary to lupus vasculitis, steroid-induced diabetes mellitus, hypertension, pancreatitis, and nongouty arthritis. On February 12, 2001, she presented to the Englewood Hospital and Medical Center with a 2-day history of nausea, vomiting, diffuse right upperquadrant pain precipitated by food intake, and shortness of

897