Hepatic Lesion in Chickenpox

64:462-466, 1973 Copyright © 1973 by The Williams & Wilkins Co.

Vol. 64, No.3

GASTROENTEROLOGY

Printed in U.S.A.

HEPATIC LESION IN CHICKENPOX A case report J.

ESHCHAR,

L.

REIF,

M.

WARON, AND W.

J.

ALKAN

Gastroenterologic Service and Departments of Pathology and Medicine A, Asaf Harofe Government Hospital, Tel-Aviv University Medical School, Zrifin, Israel

An adult male, asthmatic since childhood and for many years on steroid medication, had chickenpox when he was a young boy and again at the age of 40. During this last episode he was found to have a granulomatous lesion with necrosis in the liver. After clinical and biochemical regression of the acute illness, a cholecystectomy was performed for the removal of biliary calculi. At this stage the liver was found to be normal. Chickenpox in adults is not common and recurrences are rare. Even less common is hepatic involvement in varicella. We had the opportunity to observe such a hepatic lesion in an adult. Case Report A 40-year-old man had had bronchial asthma since the age of 2 and had been treated with corticosteroids for many years, more recently with 5 mg of prednisone daily. He had had varicella as a child. He was hospitalized after 4 days of upper abdominal pain, nausea, and fever. On the evening prior to admission he had noticed a rash on his face, which, by the following morning, covered his whole body. On examination, the patient was very restless and had outbursts of screaming every few minutes. His temperature was 38.4 C. He had a generalized rash typical of varicella. The epigastrium and right hypochondrium were very tender on palpation. There was no other abnormality on physical examination. Fever Received August 23, 1972. Accepted November 7, 1972. This paper was presented in part to the First Meeting of the Israel Association for the Study of the Liver, held during the First Annual Meeting of the Israel Society of Internal Medicine, Tel-Aviv, November 8, 1972. 1 Address requests for reprints to: Dr. J. Eshchar, Asaf Harofe Government Hospital, P. O. Beer Ya'acov, Zrifin, Israel. 'The authors wish to thank Dr. P. J. Scheuer and Dr. H. J. Zimmerman for their help and criticism. 462

and pain abated 2 days later, but the nausea and vomiting continued. On the 9th day, he again developed a fever of 38 C which lasted until the 17th day. Results of laboratory tests are summarized in table 1. There was no clinical or laboratory evidence of hemolysis. Typhoid fever was ruled out by sterile cultures and negative serology. An oral cholecystography revealed calculi in the gallbladder. A percutaneous liver biopsy was performed on the 16th day of illness while the patient was maintained on prednisone and was given "asthmin" (containing papverine, and theophylline, caffeine, barbiturate, amidopyrine), 2.0 g of tetracycline, aminophylline suppositories, and an antihistaminic drug (Fenistil). The biopsy consisted of a few small fragments of liver tissue. It showed a small granuloma of epithelioid cells, without necrosis or giant cells. Some eosinophils and granulocytes were seen between the epithelioid cells (fig. 1). Another, larger granuloma (fig. 2) consisted of identical epithelioid cells but also showed central necrosis with many nuclear fragments. In the periphery of this lesion a giant cell was found with a few hyperchromatic nuclei (fig. 3). This giant cell was not of the Langhans' type. No surrounding lymphocytes were noted in either focus. The Kiipffer cells contained a small amount of hemosiderin. No Cowdry type A inclusion bodies were found. The adjacent liver tissue was without pathological changes. During the following months the patient felt well except for his asthma. Typical varicella scars which had remained disappeared

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VARICELLA HEPATITIS

March 1973

TABLE

1. Results of laboratory tests Days of illness

Test"

6

Hemoglobin (g/l00 mI). Leukocytes (fmm ") .. ' . Band (%) .. . . ......... Segments (%) . .... . .. . Eosinophils (%) .. . .. . . Basophils (%) Monocytes (%) .... . . . Lymphocytes (%) .. . . . . Plasma cells (%) .. . .. .. Thrombocytes (fmm") .. Prothrombin time (%) . . Total bilirubin (1 mg/100 ml) . ............... Direct bilirubin (mg/100 ml) ... .. ......... , Alkaline phosphatase (48 IV O) . . . . ........... SGOTc (20 IV) .... . ... SGPTd (16 IU) . . . . .. .. Cholesterol (280 mg/100 ml) .... .... ..... . Total protein (6.1-8.2 g/ 100ml) . . ... .. . ..... Albumin (3.5-5.1 g/l00 ml) .. . . . ....... . . . Thymol turbidity (5 MeL. U e) . . _,.......... o. Thymol flocculation (0) .. ",

••

,

.

o

9

18 7,500 6 73

11

12

13

15

42

2 months 4 months

14.3 6,200 9 56 3

16 . 7 8 , 600 1 50 4 1 6 38

.

6 10 5

17 15 160,000

528 , 000 60

0 .9

1.65

1.5

0.8

0.9

0.8

0.2

0.7

0.8

0.2

0.3

0.1

52 84

163

132 70 133

148 42

172 50 90

173

102 10

53 26 39

213

205

42

18 16

7.9

6.4

6 .7

7.5

7.6

6.9

7 .5

4.4

3.2

2.8

3.1

3.2

4. 5

5. 3

9 2

7 2

8 2

11 3

11 4

15 4

11 2

• Units and normal values are in parentheses. o IU, international units.

SGOT, serum glutamic oxaloacetie transaminase. SGPT, serum glutamic pyruvate transaminase. ' MeL. U, Maciagan units. C

d

very slowly. Values for liver function tests returned to normal (table 1). Four months after the acute illness, a cholecystectomy was performed. The liver appeared normal by inspection and palpation, as well as by histological examination of several surgical and needle biopsy specimens. The gallbladder, which contained two stones, was excised. The postoperative course was normal. One year after the second episode of chickenpox, the patient remains well except for his asthma. He is receiving oral steroids and asthmin regularly.

Discussion This patient showed some unusual features of chickenpox-the simultaneous occurrences of a second attack of varicella in an adult, and a curious hepatic lesion.

It seems quite certain that our patient indeed had a recurrence of chickenpox. The recurrence rate of this disease in adults who have had chickenpox in childhood is very low. 2 , 3 Such a rare second bout, particularly when complicated by a liver lesion, must be considered either a coincidence or to be due to specific factors such as unusual features of the infecting agent, abnormal immunological or other host reactions, or possible contributory effects of medications. 4 It has been suggested that the varicella virus might be hepatotropic. 5 We are more in favor of a theory that abnormal host reactions and, possibly, drugs caused such a peculiar response in a chronic asthmatic patient on prolonged steroid

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ESHCHAR ET AL.

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FIG. 1. Liver biopsy showing an epithelioid cell granuloma without necrosis (hematoxylin and eosin, x 130).

FIG. 2. Same biopsy showing an epithelioid cell granuloma with central necrosis. The giant cell could be recognized at the left upper border of the necrotic area (hematoxylin and eosin, x 50).

medication. A defective immunological status, as in Hodgkin's disease, 6, 7 or a prolonged intake of steroids 8 causes a more severe course of varicella 9 as well as of other viral infections. 8 One observer thought that this lesion

somewhat resembled the infiltration of the liver which is caused by Hodgkin's disease. It is interesting to note that postvaccinial lymphadenitis may simulate a histological picture of malignant lymphoma. 10 Although we describe a

March 1973

VARICELLA HEPA TITIS

465

FIG. 3. The foreign body type giant cell seen in figure 2 (hematoxylin and eosin x 320) .

hepatic and not a lymph node lesion, this correlation could serve as additional circumstantial evidence that the hepatic lesion we describe had indeed been caused by the chickenpox virus. A coincidence of varicella and a distinct liver lesion, each occurring and disappearing simultaneously, does not seem likely. There was no other overt cause for liver involvement. This lesion is unlikely to be a sequel to cholelithiasis. Hepatotoxic injury can be ruled out, since the lesion disappeared in spite of continuation of steroids and asthmin. Diseases causing necrotic and/or granulomatous foci in the liver, such as infectious mononucleosis, typhoid fever, brucellosis, Q fever, tuberculosis, sarcoidosis, leukemia, and Hodgkin's disease, can also be ruled out in this case. Varicella hepatitis in adults is frequently complicated by meningoencephalitis and a pulmonary lesion. 11 The restlessness and spells of screaming which occurred during the first 2 days of hospitalization might possibly have been caused by an encephalitic process. Our patient did not manifest any parenchymal lung pathology in spite of his long-standing bronchial disease. Involvement of the liver in chickenpox

was first described by Schleussing (cited by Johnson),12 who studied mainly necropsy material, in 1927. In another autopsy study of 2534 cases of chickenpox with 191 complications, no hepatic lesions were seen. 13 Siede 5 describes 7 cases of herpes zoster with liver damage, although the relation between this disease and the liver involvement is not clear. Focal liver cell necrosis in varicella is described more often, 11, 14-19 sometimes as periportal, 12 or in the periphery of the liver lobule. 11 Ishak 19 states that diffuse necrosis is seen in herpes simplex hepatitis, and not in that of herpes zoster. Another type of liver cell necrosis, the free hyaline bodies, has also been described in conjunction with chickenpox hepatitis. 11 Periportal 11, 18 or parenchymal 19 infiltration with leukocytes, monocytes, and plasma cells was noted. Johnson 12 believes that this infiltration is not the primary lesion, but rather is seondary to hepatic necrosis, which he considers to be directly due to viral action. Fatty infiltration of the liver as part of Reye's syndrome is also documented in varicella. 4, 11 We were unable to find, in the literature at our disposal, reports on extensive, granulomatous lesions with necrosis, like

466

ESHCHAR ET AL.

those we observed in this case. On the other hand, F. Schaffner and K. Ishak (personal communication) recognized this lesion as being consistent with a disseminated viral infection. Granulomas are found in 0.75 to 10% of all liver biopsies. 20 , 21 In 20 to 27% of these the etiology is unknown. 21 -23 Most granulomas are not found in acute conditions. 21, 22 Viral, rickettsial disorders such as lymphogranuloma venereum,22, 23 influenza B infections,22 psittacosis,24 Q fever,25 infectious mononucleosis,22 and related diseases 26 might occasionally be accompanied by liver granulomas. Nevertheless, hepatic granulomas are quite rare in viral diseases, 21 and have not been documented previously as occurring during the course of chickenpox. REFERENCES 1. Eshchar J, Reif L, Waron M, et al: Hepatic lesion in chickenpox (abstr). Isr J Med Sci 8:1851, 1972

2. Rhodes AJ, Van Rooyen, CE: Textbook of Virology, chap 13. Fifth edition. Baltimore, Williams & Wilkins Co, 1968, p 399. 3. Krugman S, Ward R: Infectious Diseases of Children. Third edition. St. Louis, C V Mosby, 1964, p 30 4. Glick TH, Ditchek NT, Salitsky S, et al: Acute encephalopathy and hepatic dysfunction associated with chickenpox in siblings. Am J Dis Child 119:68-71, 1970 5. Siede W: Herpes Zoster und Leberschadigung. Dtsch Med Wochenschr 81:1401-2, 1956 6. Schwarczmann P: Die Viszeralen Erscheinungsformen den Herpes Zoster. Munch Med Wochenschr 106:1033-37, 1964 7. Bichel J: Herpes Zoster in Hodgkin's disease. Acta Psychol Neurol Scand (supp\) 108:53-59, 1956 8. Diderholm H, Stenram U, Tegner KB, et al: Herpes Simplex hepatitis in an adult. Acta Med Scand 186:151-5, 1969 9. Johnson RWP, Nelson AM: Hemorrhagic chicken-pox. Br Med J 1:1183-4, 1960 10. Hartsock RJ: Postvaccinial lymphadenitis: hyperplasia of lymphoid tissue that simulates

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malignant lymphoma. Cancer 21:632-649, 1968 11. Castleman B, NcNeely BU: Case Records of the Massachusetts General Hospital. N Engl J Med 276:47-55, 1967 12. Johnson HN: Visceral lesions associated with varicella. Arch Pathol 30:292-307, 1940 13. Bullowa JGM, Wishik SM: Complications of varicella. Am J Dis Child 49:923-6, 1935 14. Rigdon RH, Shojai SA, Garba EP: Fatal chickenpox. Am Pract 13:292-302, 1960 15. Oppenheimer EH: Congenital chickenpox with disseminated visceral lesions. Bull Johns Hopkins Hosp 74:240-7, 1944 16. Krugman S, Goodrich CH, Ward R: Primary varicella pneumonia. N Engl J Med 257:843-848, 1957 17. Hayes JA, Been TE, Valentine EJ, et al: A case of fatal dissemination of varicella. J Pathol Bacteriol 90:328-333, 1965 18. Cheatham WJ, Weller TH, Dolan TF Jr, et al: Varicella: report of two fatal cases with necropsy, virus isolation and serologic studies. Am J Pathol 32:1015-1036, 1956 19. Ishak KG: The Liver Biopsy in the Diagnosis of Liver Disease in Infants and Children in Laboratory Diagnosis of Liver Diseases. Edited by FW Sunderman, FW Sunderman Jr. St. Louis, WH Green, 1968, p 442-468 20. Iversen K, Christoffersen P, Poulsen H: Epitheloid cell granulomas in liver biopsies. Scand J Gastroenterol (supp\) 7:61-67, 1970 21. Bunim JJ, Kimberg DV, Thomas LB, et al: The syndrome of sarcoidosis, psoriasis and gout. Ann Intern Med 57:1018-1040, 1962 22. Guckian JC, Perry JE: Granulomatous hepatitis. Ann Intern Med 65:1081-1100,1966 23. Wagoner GP, Anton AT, Gall EA, et al: Needle biopsy of the liver. VIII. Experiences with hepatic granulomas. Gastroenterology 25:487-494, 1953 24. Cornog JL, Hauson CW: Psittacosis as a cause of miliary infiltrates of the lung and hepatic granulomas. Am Rev Resp Dis 98:1033-1036, 1968 25. DuPont HL, Rapoport MI, Woodward TE: Granulomatous hepatitis associated with coxiella burneti. Clin Res 17:470,1969 26. Eliakim M, Levij IS, Eisenberg S, et al: Granulomatous hepatitis accompanying a self-limited febrile disease. Lancet 1:1348-1352, 1969