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Adult herpes simplex hepatitis
Medical Intelligence
ADULT HERPES SIMPLEX HEPATITIS* j. C. Lee, M.D., Ph.D.,t and Ignacio E. Fortun», MD.:j:
Abstract The development of hepatitis in adult patients with generalized herpes simplex infections , although rare, is fatal if complicated by hepatic and ad ren a l necrosis and intravascular coagulation. The presumptive diagnosis is made possible by the demonstration of intranuclear inclusions in material obtained from scrapings of mucosal lesions and liver biopsy material. The infection can be effectively treated with cytosine arabinoside , a pyrimidine nucleoside that inhibits deoxyribonucleic acid synthesis and that is a potent antiviral agent particularl y against the herpes vir us group. Without a specifi c agent to control the infection , herpes virus hepatitis leads to disseminated intravascular coagu la tion, which cannot be controlled by heparin.
Herpes simplex virus as an etiologic agent of hepatitis has been described in newborn infants and youn g children with disseminated infection.t -" but in the adult with generalized in fection hepatitis appears to be rare , with only three previously reported instances in the literature.s" The clinical recognition of hepatitis in generalized herpes simplex infections in adult patients treated with corticostero ids, antimetabolite s, or alkylating agen ts
is of importance because cure of this infecti on can be achieved with cytosine arabinoside.v " Although a definite diagnosis rests upon the identification of the virus by antiserum neutralization tests,' : 8 . 9, a presumptive diagnosis is possible by the demonstration of intranuclear inclusions in Giemsa stained tissue obtained from scrapings of mucosal lesions or liver biopsy. T he clinical course and pathologic findin gs in a youn g adult male with
*Su ppor ted by grants CA-08832 , CA-05 158. an d CA-08 101 from the Nation al Cance r Institute, U.S. Public Health Service. t Medical Fellow, Depa r tme nt of Laboratory Medicine, Un iversity o f Minnesota Hospitals , Min neapolis , Minnesot a. *Associate Professor, Medical Oncology Section, Departm ent of Medicine, University of Minnesota School of Medicine, University of Minnesota Hos pitals, Minneapolis, Minnesota.
277
HUMAN PATHOLOGY-VOLUME 3, NUMBER 2 [une 1972
Hodgkin's disease who developed generalized herpes simplex infection, complicated by hepatitis and disseminated intravascular coagulation, are described.
REPORT OF A CASE The diagnosis of Hodgkin's disease (mixed cellularity, clinical stage IIA) was established from a cervical node biopsy in a 17 year old Caucasian male. The initial treatment consisted of widefield irradiation above the diaphragm over involved and contiguous lymphatic chains. Seventeen months later right inguinal adenopathy developed and biopsy disclosed Hodgkin's disease with a mixed cellularity pattern. By lymphangiography the para-aortic lymph nodes were seen to be involved. Wide field irradiation below the diaphragm over involved and contiguous lymphatic chains was the treatment given. The patient noted the onset of shortness of breath followed by fever and cough productive of abundant sputum 32 months after the diagnosis was made. A chest roentgenogram disclosed bilateral soft infiltrates and hilar adenopathy. Sputum cultures grew streptococci and Neisseria but were negative for acid fast bacteria as well as for aerobic and anaerobic fungi. Histologic examination of the sputum sediment failed on several occasions to demonstrate cytomegalovirus or Pneumacystis carinii. Treatment consisted of the administration of 150 mg. ofcyclophosphamide daily by mouth and I mg. of vincristine given intravenously once a week. The fever disappeared and at the end of two months of this regimen the lung infiltrates and enlargement of hilar nodes had disappeared. Remission was maintained
TABLE 2. Controls
278
Prothrombin time (seconds) PTT (seconds) T. T. (seconds) Fibrinogen (gm. per 100 ml.) Fi test (titer) Factor V (%) Platelets (per cu. m m.)
12-14 29-32 14-15.5
TABLE 1.
LIVER FUNCTION* 12/5
12/10
0.8
0.9
1.2
1.4
0.3
0.4
0.6
0.8
20
26
456 375 14
4793 3450 14
6525 41550 25
8700 5935 '14
1.1
1.1
1.6
2.5
Bilirubin, total (mg. per 100 ml.) Bilirubin, direct (mg. per 100 ml.) Alkaline phosphatase (K-A units) SGOT (MI units) OCT (D units) BUN (mg. per 100 ml.) Creatinine (mg. per 100 rnl.) Ammonia (mg. per 100 ml.)
60
12/15
52
141
*Bleeding and fever began on 12/3 and the patient was hospitalized.
with cyclophosphamide. After seven months of this regimen stomatitis developed; the oral mucosa and tongue were covered with a vesicular eruption adjacent to superficial ulcerations covered with a pseudomembranous exudate. Cultures grew out Monilia albicans and oral treatment with Mycostatin was begun. Within four days the temperature rose to J 02° F. and the process extended to involve the nasal mucosa, middle ear, pharynx, larynx, and esophagus. Purpura, epistaxis, oral bleeding, and melena developed, and laboratory evidence of abnormal liver function and intravascular coagulation was obtained (Tables I and 2). The blood cultures remained negative and treatment consisted of heparin, Keflin, and gentamycin. Bleeding continued, shock and stupor progressed, and the patient died. The total course from the beginning of the stomatitis to death was three weeks and ten days after the first laboratory evidence of liver damage.
COAGULATION STUDIES* 12/5
13 31 14.9 0.48 100 170,000
12/10
12/12
12/13
12/15
21 38.4 24.4 0.'16 1:256 100 80,000
15.7 45 30.7
19 56 95
20 57.7 36 0.33 1:256 50 40,000
0.:~3
1:285 73 49,000
ADULT HERPES SIMPLEX HEPATITIS- LEE,
FORTUNY
Figure 1. Lo w power view of live r sec tion showi ng di ffu se necros is and he morrhage. (H e matoxylin an d eos in stai n. X 100.)
Pathologic Findings On gross e xa mi n ation the liver weighed 2650 g m. The su r face was dark brown and studded with punctate, pale yellow lesions su rrounded by a hemorrhagic halo and meas u ring' I to 2 mm. in diameter. The ri gh t adren al gland was hemorrhagic a nd containe d innumerable punctate lesions similar to th ose found in the liver surface. Histologic sections of the liver showed necrosis, hem orrhage , and a m inimal inflammatory re actio n aro u nd liver cell co rds (Fig. I). H e pat ic cells were enlarged and con tained intranucl ear inclusion bodies (Fig. 2). Inclusion s were no t identified in eithe r po rtal areas or bile duct e p itheliu m. Inclusion bodi es were also fo u n d in th e ne crot ic ad renal gland. Histologic evid ence o f Hod gkin's disea se, mixed cellu larity pa ttern , was pres en t in liver , splee n , pe r iaortic lymph no d es, and lu ng.
Viral Studies Homogenates o f liver and adrenal tissue for virus isolati on were inoculated
into human a m niotic cell cultu r es , p rod ucing cyto pat hic changes char acteristic of herpes simplex virus wit hin fo ur d ays . The isolate was typed by neutral ization with antiser um to a known strain of herpes simplex virus (strain £263).
DISCUSSION Th e clinical manifestat ions of a vesicular e r uptio n o f th e mucous m embranes , increasing fev er, progr essive leth argy, bleedi ng, j a un d ice, and hep ato meg al y ar e indi cati ve of gene ra lized herpes sim plex infection with liver in vol vement. 3 - 5 , 1 The diagnosis can be p r esu m ptively esta blished by the demonstr ation of in tranu clear inclusion bodies in Gie msa staine d scra pings from the m ucosal les ions and from a liver biops y specime nv s - II an d by the rising se r u m titers of complement fixin g o r neutrali zing an tibod ies to herpes sim plex." Live r biopsy homo genates in ocu lated into human amniotic cell cu lture s may, as early as five d ays, produce cytopathic changes. characteristic o f herpes simplex virus.": s, fl As early as ten days
279
HUlvfAN PATHOLOGY-VOLUME
Figure 2.
280
s,
NUMBER 2 [une 1972
Enlarged hepatocytes containing intranuclear inclusions. (Hematoxylin and eosin stain. x 100,)
after inoculation further identification can be obtained by neutralization of the isolate with antiserum to a known strain of herpes simplex virus. Cytosine arabinoside, a pyrimidine nucleoside that inhibits deoxyribonucleic acid synthesis, has antiviral activity against the herpes virus group." Clinical experience with this agent has been limited to the treatment of acute leukemia because of the toxicity of recommended doses. However, Chow" has demonstrated that the administration of cytosine arabinoside at one-fifth the usual antileukemia dose for two to three days (one-third of the usual time) is antiviral without producing bone marrow suppression or further depression of the patient's natural immunity. The recommended dosage of cytosine arabinoside in herpetic infection is 20 mg. per square meter administered intravenously every 24 hours for three to five days.' Bleeding is a common complication of hepatic necrosis due to halothane anesthesia, viral hepatitis,'? as well as disseminated herpes simplex infection.': 2. 11 Measuring the intravascular survival of p25 labeled human librinogen in pa-
tients with acute liver necrosis, Rake'" demonstrated increased rates of catabolism of fibrinogen. These findings suggest that. decreased synthesis of clotting factors by a necrotic liver compounded by acceleration in their utilization leads to severe hemorrhage. He further postulates that the stimulus to intravascular coagulation arises from the necrotic liver cells, since the circulating activator of fibrinolysis was not increased in these patients. Liver necrosis leads to deficiency in clearing activated coagulation factors and fibrin, resulting in damage to the microcirculation, thus explaining the presence of focal hemorrhages found in the liver, adrenals, kidney, brain, lung, and gastrointestinal tract.': 2,10 The use of heparin has been shown to increase the survival of the p25 labeled fibrinogen but proved ineffective by itself because adequate treatment to reverse the on-going hepatic necrosis was not available. to The diagnosis of generalized herpes simplex infection may be suspected in immunosuppressed patients with malignant disease. The demonstration of intranuclear inclusions in Giemsa stained
ADULT HERPES SIMPLEX HEPATITIS-LEE,
scrapings of the oral mucosa as well as in liver biopsy specimens should be presumptive reason for the initiation of treatment with cytosine arabinoside, which at the recommended antiviral dosage does not have significan t toxicity. The case presented demonstrates that the infection was disseminated over a three week period and that the ensuing hepatitis progressed over a ten day period, suggesting that it may be possible to establish a presum ptive diagnosis and begin treatment before the intravascular coagulation becomes irreversible.
REFERENCES I. Hathaway, W. E., Mull, M. M., and Pechet, G. S.:
Disseminated intravascular coagulation in the newborn. Pediatrics, 43:233, 1969. 2. Miller, D. R., Hanshaw, JR., O'Leary. D. S.. and Hnilicka, .J. Y.: Fatal disseminated herpes simplex virus infection and hemorrhage in the neonate. .J. Pediat., 76:409, 1970.
FORTUNY
,I. Diderholm, Y., Stemam, U., Tegner, K. B., and Willen, R.: Herpes simplex hepatitis in an adult. Acta Med. Scand., /86:151,1969. 4. Flewett, T. A., Parker, R. G., and Philip, W. M.: Acute hepatitis due to herpes simplex virus in an adult. J. Clin. Path., 22:60, 1969. 5. Juel-Jensen, H. E.: Severe generalized primary herpes treated with cytarabine. Brit, Med. J., 2:154,1970. 6. Buthala, D. A.: Cell culture studies on antiviral agents. I. Action of Ara-C and some comparisons with 5-iodo-2-desoxyuridine. Proc, Soc. Exp, BioI. !'vIee!., 115:69, 1964. 7. Chow, A. W., Foerster, J., and Hrynfuk, W.: Cytosine arabinoside therapy for herpes virlls infections. Antimicrob. Agents Chemother., 1970, p. 2l4. 8. Scott, T. F. M.: Infection with the virus of herpes simplex. New Eng.J. Med., 250:183, 1954. 9. Tucker, E. S., and Scofield, G. F.: Hepato-adrenal necrosis. Arch. Path., 71 :538, 1961. 10. Rake, M. 0., Flute. P. T., Pannell, Goo and Williams, R.: Intravascular coagulation in acute hepatic necrosis. Lancet, i:5:13, 1970. II. Robinson, M. G., and Kaufman, S.: Disseminated herpes simplex, a cause of consumption coagulopathy, Soc. Ped. Res. Abst., 103, 1969. Box 325 Mayo University of Minnesota Hospitals Minneapolis, Minnesota 55455 (Dr. Fortuny)
281
ADULT HERPES SIMPLEX HEPATITIS* j. C. Lee, M.D., Ph.D.,t and Ignacio E. Fortun», MD.:j:
Abstract The development of hepatitis in adult patients with generalized herpes simplex infections , although rare, is fatal if complicated by hepatic and ad ren a l necrosis and intravascular coagulation. The presumptive diagnosis is made possible by the demonstration of intranuclear inclusions in material obtained from scrapings of mucosal lesions and liver biopsy material. The infection can be effectively treated with cytosine arabinoside , a pyrimidine nucleoside that inhibits deoxyribonucleic acid synthesis and that is a potent antiviral agent particularl y against the herpes vir us group. Without a specifi c agent to control the infection , herpes virus hepatitis leads to disseminated intravascular coagu la tion, which cannot be controlled by heparin.
Herpes simplex virus as an etiologic agent of hepatitis has been described in newborn infants and youn g children with disseminated infection.t -" but in the adult with generalized in fection hepatitis appears to be rare , with only three previously reported instances in the literature.s" The clinical recognition of hepatitis in generalized herpes simplex infections in adult patients treated with corticostero ids, antimetabolite s, or alkylating agen ts
is of importance because cure of this infecti on can be achieved with cytosine arabinoside.v " Although a definite diagnosis rests upon the identification of the virus by antiserum neutralization tests,' : 8 . 9, a presumptive diagnosis is possible by the demonstration of intranuclear inclusions in Giemsa stained tissue obtained from scrapings of mucosal lesions or liver biopsy. T he clinical course and pathologic findin gs in a youn g adult male with
*Su ppor ted by grants CA-08832 , CA-05 158. an d CA-08 101 from the Nation al Cance r Institute, U.S. Public Health Service. t Medical Fellow, Depa r tme nt of Laboratory Medicine, Un iversity o f Minnesota Hospitals , Min neapolis , Minnesot a. *Associate Professor, Medical Oncology Section, Departm ent of Medicine, University of Minnesota School of Medicine, University of Minnesota Hos pitals, Minneapolis, Minnesota.
277
HUMAN PATHOLOGY-VOLUME 3, NUMBER 2 [une 1972
Hodgkin's disease who developed generalized herpes simplex infection, complicated by hepatitis and disseminated intravascular coagulation, are described.
REPORT OF A CASE The diagnosis of Hodgkin's disease (mixed cellularity, clinical stage IIA) was established from a cervical node biopsy in a 17 year old Caucasian male. The initial treatment consisted of widefield irradiation above the diaphragm over involved and contiguous lymphatic chains. Seventeen months later right inguinal adenopathy developed and biopsy disclosed Hodgkin's disease with a mixed cellularity pattern. By lymphangiography the para-aortic lymph nodes were seen to be involved. Wide field irradiation below the diaphragm over involved and contiguous lymphatic chains was the treatment given. The patient noted the onset of shortness of breath followed by fever and cough productive of abundant sputum 32 months after the diagnosis was made. A chest roentgenogram disclosed bilateral soft infiltrates and hilar adenopathy. Sputum cultures grew streptococci and Neisseria but were negative for acid fast bacteria as well as for aerobic and anaerobic fungi. Histologic examination of the sputum sediment failed on several occasions to demonstrate cytomegalovirus or Pneumacystis carinii. Treatment consisted of the administration of 150 mg. ofcyclophosphamide daily by mouth and I mg. of vincristine given intravenously once a week. The fever disappeared and at the end of two months of this regimen the lung infiltrates and enlargement of hilar nodes had disappeared. Remission was maintained
TABLE 2. Controls
278
Prothrombin time (seconds) PTT (seconds) T. T. (seconds) Fibrinogen (gm. per 100 ml.) Fi test (titer) Factor V (%) Platelets (per cu. m m.)
12-14 29-32 14-15.5
TABLE 1.
LIVER FUNCTION* 12/5
12/10
0.8
0.9
1.2
1.4
0.3
0.4
0.6
0.8
20
26
456 375 14
4793 3450 14
6525 41550 25
8700 5935 '14
1.1
1.1
1.6
2.5
Bilirubin, total (mg. per 100 ml.) Bilirubin, direct (mg. per 100 ml.) Alkaline phosphatase (K-A units) SGOT (MI units) OCT (D units) BUN (mg. per 100 ml.) Creatinine (mg. per 100 rnl.) Ammonia (mg. per 100 ml.)
60
12/15
52
141
*Bleeding and fever began on 12/3 and the patient was hospitalized.
with cyclophosphamide. After seven months of this regimen stomatitis developed; the oral mucosa and tongue were covered with a vesicular eruption adjacent to superficial ulcerations covered with a pseudomembranous exudate. Cultures grew out Monilia albicans and oral treatment with Mycostatin was begun. Within four days the temperature rose to J 02° F. and the process extended to involve the nasal mucosa, middle ear, pharynx, larynx, and esophagus. Purpura, epistaxis, oral bleeding, and melena developed, and laboratory evidence of abnormal liver function and intravascular coagulation was obtained (Tables I and 2). The blood cultures remained negative and treatment consisted of heparin, Keflin, and gentamycin. Bleeding continued, shock and stupor progressed, and the patient died. The total course from the beginning of the stomatitis to death was three weeks and ten days after the first laboratory evidence of liver damage.
COAGULATION STUDIES* 12/5
13 31 14.9 0.48 100 170,000
12/10
12/12
12/13
12/15
21 38.4 24.4 0.'16 1:256 100 80,000
15.7 45 30.7
19 56 95
20 57.7 36 0.33 1:256 50 40,000
0.:~3
1:285 73 49,000
ADULT HERPES SIMPLEX HEPATITIS- LEE,
FORTUNY
Figure 1. Lo w power view of live r sec tion showi ng di ffu se necros is and he morrhage. (H e matoxylin an d eos in stai n. X 100.)
Pathologic Findings On gross e xa mi n ation the liver weighed 2650 g m. The su r face was dark brown and studded with punctate, pale yellow lesions su rrounded by a hemorrhagic halo and meas u ring' I to 2 mm. in diameter. The ri gh t adren al gland was hemorrhagic a nd containe d innumerable punctate lesions similar to th ose found in the liver surface. Histologic sections of the liver showed necrosis, hem orrhage , and a m inimal inflammatory re actio n aro u nd liver cell co rds (Fig. I). H e pat ic cells were enlarged and con tained intranucl ear inclusion bodies (Fig. 2). Inclusion s were no t identified in eithe r po rtal areas or bile duct e p itheliu m. Inclusion bodi es were also fo u n d in th e ne crot ic ad renal gland. Histologic evid ence o f Hod gkin's disea se, mixed cellu larity pa ttern , was pres en t in liver , splee n , pe r iaortic lymph no d es, and lu ng.
Viral Studies Homogenates o f liver and adrenal tissue for virus isolati on were inoculated
into human a m niotic cell cultu r es , p rod ucing cyto pat hic changes char acteristic of herpes simplex virus wit hin fo ur d ays . The isolate was typed by neutral ization with antiser um to a known strain of herpes simplex virus (strain £263).
DISCUSSION Th e clinical manifestat ions of a vesicular e r uptio n o f th e mucous m embranes , increasing fev er, progr essive leth argy, bleedi ng, j a un d ice, and hep ato meg al y ar e indi cati ve of gene ra lized herpes sim plex infection with liver in vol vement. 3 - 5 , 1 The diagnosis can be p r esu m ptively esta blished by the demonstr ation of in tranu clear inclusion bodies in Gie msa staine d scra pings from the m ucosal les ions and from a liver biops y specime nv s - II an d by the rising se r u m titers of complement fixin g o r neutrali zing an tibod ies to herpes sim plex." Live r biopsy homo genates in ocu lated into human amniotic cell cu lture s may, as early as five d ays, produce cytopathic changes. characteristic o f herpes simplex virus.": s, fl As early as ten days
279
HUlvfAN PATHOLOGY-VOLUME
Figure 2.
280
s,
NUMBER 2 [une 1972
Enlarged hepatocytes containing intranuclear inclusions. (Hematoxylin and eosin stain. x 100,)
after inoculation further identification can be obtained by neutralization of the isolate with antiserum to a known strain of herpes simplex virus. Cytosine arabinoside, a pyrimidine nucleoside that inhibits deoxyribonucleic acid synthesis, has antiviral activity against the herpes virus group." Clinical experience with this agent has been limited to the treatment of acute leukemia because of the toxicity of recommended doses. However, Chow" has demonstrated that the administration of cytosine arabinoside at one-fifth the usual antileukemia dose for two to three days (one-third of the usual time) is antiviral without producing bone marrow suppression or further depression of the patient's natural immunity. The recommended dosage of cytosine arabinoside in herpetic infection is 20 mg. per square meter administered intravenously every 24 hours for three to five days.' Bleeding is a common complication of hepatic necrosis due to halothane anesthesia, viral hepatitis,'? as well as disseminated herpes simplex infection.': 2. 11 Measuring the intravascular survival of p25 labeled human librinogen in pa-
tients with acute liver necrosis, Rake'" demonstrated increased rates of catabolism of fibrinogen. These findings suggest that. decreased synthesis of clotting factors by a necrotic liver compounded by acceleration in their utilization leads to severe hemorrhage. He further postulates that the stimulus to intravascular coagulation arises from the necrotic liver cells, since the circulating activator of fibrinolysis was not increased in these patients. Liver necrosis leads to deficiency in clearing activated coagulation factors and fibrin, resulting in damage to the microcirculation, thus explaining the presence of focal hemorrhages found in the liver, adrenals, kidney, brain, lung, and gastrointestinal tract.': 2,10 The use of heparin has been shown to increase the survival of the p25 labeled fibrinogen but proved ineffective by itself because adequate treatment to reverse the on-going hepatic necrosis was not available. to The diagnosis of generalized herpes simplex infection may be suspected in immunosuppressed patients with malignant disease. The demonstration of intranuclear inclusions in Giemsa stained
ADULT HERPES SIMPLEX HEPATITIS-LEE,
scrapings of the oral mucosa as well as in liver biopsy specimens should be presumptive reason for the initiation of treatment with cytosine arabinoside, which at the recommended antiviral dosage does not have significan t toxicity. The case presented demonstrates that the infection was disseminated over a three week period and that the ensuing hepatitis progressed over a ten day period, suggesting that it may be possible to establish a presum ptive diagnosis and begin treatment before the intravascular coagulation becomes irreversible.
REFERENCES I. Hathaway, W. E., Mull, M. M., and Pechet, G. S.:
Disseminated intravascular coagulation in the newborn. Pediatrics, 43:233, 1969. 2. Miller, D. R., Hanshaw, JR., O'Leary. D. S.. and Hnilicka, .J. Y.: Fatal disseminated herpes simplex virus infection and hemorrhage in the neonate. .J. Pediat., 76:409, 1970.
FORTUNY
,I. Diderholm, Y., Stemam, U., Tegner, K. B., and Willen, R.: Herpes simplex hepatitis in an adult. Acta Med. Scand., /86:151,1969. 4. Flewett, T. A., Parker, R. G., and Philip, W. M.: Acute hepatitis due to herpes simplex virus in an adult. J. Clin. Path., 22:60, 1969. 5. Juel-Jensen, H. E.: Severe generalized primary herpes treated with cytarabine. Brit, Med. J., 2:154,1970. 6. Buthala, D. A.: Cell culture studies on antiviral agents. I. Action of Ara-C and some comparisons with 5-iodo-2-desoxyuridine. Proc, Soc. Exp, BioI. !'vIee!., 115:69, 1964. 7. Chow, A. W., Foerster, J., and Hrynfuk, W.: Cytosine arabinoside therapy for herpes virlls infections. Antimicrob. Agents Chemother., 1970, p. 2l4. 8. Scott, T. F. M.: Infection with the virus of herpes simplex. New Eng.J. Med., 250:183, 1954. 9. Tucker, E. S., and Scofield, G. F.: Hepato-adrenal necrosis. Arch. Path., 71 :538, 1961. 10. Rake, M. 0., Flute. P. T., Pannell, Goo and Williams, R.: Intravascular coagulation in acute hepatic necrosis. Lancet, i:5:13, 1970. II. Robinson, M. G., and Kaufman, S.: Disseminated herpes simplex, a cause of consumption coagulopathy, Soc. Ped. Res. Abst., 103, 1969. Box 325 Mayo University of Minnesota Hospitals Minneapolis, Minnesota 55455 (Dr. Fortuny)
281