EXPERIENCE AND REASON-BRIEFLY RECORDED 681
Aplastic
Anemia
Following
Hepatitis
The occurrence of hepatitis followed by
aplastic anemia is uncommon. Eleven such cases have been reported since 1955;’’ all ended in death from complications of aplastic anemia. The present report describes three
more children with pancytopenia following an
attack of hepatitis. Two of these patients were
treated with testosterone and prednisone and
are still alive in hematological remission.
CASE REPORTS
CASE 1: An 8-year-old Caucasian boy was ad-mitted to the Children’s Hospital for evaluation of jaundice of 3-weeks duration. Infectious hepatitis
was endemic in the local area, and the boy had
been exposed to a child with jaundice diagnosed as due tc hepatitis. There had been no known exposure to drugs or toxins. Physical examination
and laboratory studies, including liver function tests, were compatible with moderately severe hep-atitis. The peripheral blood count was normal. The boy was placed on prednisone and discharged. His jaundice cleared during the next 2 weeks, and the medication was discontinued. Six weeks after
dis-charge he was noted to have many bruises and was
readmitted. Laboratory studies showed a
pancy-topenia. A bone marrow examination revealed marked hypocellulanity of all elements. Liver
func-tion studies were normal. The patient was treated with blood and platelet transfusions and
predni-sone. There was no improvement in the
pancyto-penia, and he died 12 weeks later with E. coli
septicemia. No autopsy was performed.
CASE 2: A 33-year-old Caucasian boy was seen
at Children’s Hospital Medical Center for
evalu-ation of pancytopenia of more than 1 month’s duration. Five months earlier he had been admitted
to another hospital for evaluation of jaundice and
easy bruising of sudden onset. There had been no
known exposure to infectious hepatitis, drugs, or
toxins. Physical examination and laboratory studies, including liver function tests, were compatible with
moderately severe hepatitis. Hemoglobin concen-tration and leukocyte count were mildly depressed.
Platelet count was 10,000/mm’. A bone marrow examination revealed a normal marrow, except for a reduced number of megakaryocytes. During the
next 3 months he received two courses of predni-sone therapy of 2 weeks each. There was no fur-then evidence of liver disease, but moderate
pan-cytopenia was present. When first seen here, 4 months after the onset of his illness, moderate
pancytopenia was present. Bone marrow
examina-tion showed a markedly hypocellular marrow. The
boy was placed on testosterone propionate, 60 mg/day, and prednisone, 15 mg/day. After 3
months a definite response to therapy with a reti-culocyte level of 11% and a rising hemoglobin value was found.
CASE 3: A 3-year-old Negro boy was admitted
to the Children’s Hospital for evaluation of pallor and melena of one week’s duration. Four months
before admission he was seen by his physician for
jaundice and hepatomegaly. These symptoms sub-sided in 2 months. There had been no known
exposure to infectious hepatitis, drugs, or toxins.
On admission here severe pancytopenia was
present. Bone marrow examination revealed marked depression of all elements. Minimal liver
dysfunc-tion was evident from laboratory studies. He was placed on testosterone propionate, 40 mg/day, and prednisone, 10 mg/day. Two months later hemo-giobin concentration and leukocyte counts were nor-mal. Platelet count had improved to 25,000/mm’.
Liver chemistry tests were still slightly abnormal.
COMMENT
These three patients and the cases reported
in the literature have a history consistent with
infectious hepatitis. In most cases this was clearing and the liver function tests were
re-turning to normal at the time that aplastic
anemia became fully apparent. The autopsy
findings reported in the literature were
com-patible with subsiding hepatitis. No drugs,
toxins, nor recent injections could be impli-cated. Both children and adults were affected. Ten of the 14 patients were males. Aplastic anemia was diagnosed from 1 to 6 weeks fol-lowing the onset of clinical hepatitis in all
cases except that reported by Simpson,6 in
which the latent period was 6 months. Bone
marrow aspiration in our cases and in those in
which it is mentioned in the literature showed
marked hypocellularity involving all three hematopoietic elements. Thrombocytopenia and leukopenia were noted in some patients during the acute stage of the hepatitis.
Prognosis seems to have been poor. All the
cases in the literature and our Case 1 died within 5 months of the onset of aplastic
ane-mia. The majority of these patients received
corticosteroid therapy without response. One
patient was treated with androgen and steroids but died soon after the onset of therapy.’ Our Case 2 has been receiving testosterone pro-pionate and prednisone for 3 months with a definite response just beginning. A response
682 APLASTIC ANEMIA
values except for the platelet count, which has
been slowly rising. Shahidi and Diamond’
noted that the platelet response is the slowest
of all.
On the basis of the favorable response of
our last two cases and the fatal course in all
the other patients, a trial of androgen and
steroid therapy would seem to be indicated in
any new cases of this disorder. Thrombocyto-penia and fatty replacement of the bone
mar-row occasionally occur in the course of
sus-tamed high dosage corticosteroid therapy.’
Administration of corticosteroids should be
dis-continued for a trial period when an initial
re-sponse to therapy is followed by a relapse.
The relationship between infectious hepatitis
and progressive bone marrow depression is not clear. The pancytopenia may be due to in-vasion of tile marrow by virus causing a
dis-turbance of cellular proliferation. It might also result from the action of toxins circulating
secondary to depression of the detoxification in the liver during the acute phase of hepatitis.
In either of these instances the patient must
have an unusual sensitivity to the offending
agent with an inability to develop metabolic resistance to the stress. It has been suggested’#{176} that during the course of acute hepatitis there
may be a depression of production in the liver
of factors essential for normal hematopoietic
activity. There is as yet no experimental
evi-dence supporting this hypothesis.
Transient hematological aberrations during
acute hepatitis are common. A depression in
the absolute number of both granulocytes and
lymphocytes in the circulating blood is
char-actenistically seen in the febrile, preicteric phase of the disease. A relative lymphocytosis, with atypical lymphocytes, may then develop.
The leukocyte and differential counts usually
return to normal by tile end of the second
week after the onset of fever.” The platelet
count may be somewhat low during the acute phase of the disease. A mild anemia frequently
develops during the second to third week after
the onset of jaundice.” Reticulocytes are
in-creased in the second week, with a maximal elevation during the third and fourth weeks. Cr”-survival studies of autologous erythrocytes
show a mild shortening of life span of the cells.
The Coombs’ test is negative. This degree of
decrease in survival is not sufficient to explain
the anemia, and it seems likely that there is a
findings of increased total urinary
coproporphy-rn’3 and elevated serum iron levels’4 during
acute infectious hepatitis suggest a defect of
heme synthesis. A persistance of mild
hemo-lysis for as long as 1 year may occur. “ Tile
indirect-reacting bilirubin may remain slightly
elevated, and the Cr”-survival of red cells is
shortened. Other causes of persistent jaundice,
such as cirrhosis, chronic hepatitis, hereditary
hemolytic anemia, and Co:mbs’-positive
hema-lytic anemia should be investigated. Our Case 3 may have mild hemolysis, but we ilave not had the opportunity to evaluate tilis possibility.
Infection of mice VitIl tile IH\-3 virus
re-suits in histological changes in the liver that
are quite similar to those seen in viral
hepa-titis in man. Recent studies of tile extraliepatic
effects of the MHV-3 virus” have shown that
pancytopenia develops during tile course of tile
infection. Tile bone marrow shows erytilroid
hypoplasia, an arrest of development past the myelocyte stage in the white cell series, and
degenerative changes in all elements. Lymph
nodes and spleen show a marked degree of
cel-lular damage. High concentrations of virus are
grown from the bone marrow and
lympho-poietic tissue. Another pantropic virus that
causes damage to tile bone marrow and lymphopoietic systems in the mouse is the
Trinidad strain of Venezuelan equine
enceplla-litis (VEE).” Cuinea pigs, Illonkeys, burros,
and man show similar effects of the virus,
dif-fering only in degree of involvement. In man, depression of reticulocyte, lymphocytes, granu-locytes and platelets are seen at the end of the first week of infection.ls At the time of
maxi-mum peripheral blood changes there is
hypo-plasia of all marrow elements. Complete
re-covery follows in 3 to 14 days. The VEE virus
may be successfully grown from bone marrow
cultures at a time when the virus is no longer
demonstrable in the blood stream.’
The virus of infectious hepatitis can be
re-covered from blood, urine, and feces in the
infectious state. Depression of production of
erythrocytes, granulocytes, lymphocytes, and platelets during the acute stages of the disease
may be due to infection of lymph nodes i.Ild
bone marrow by the hepatitis virus. As in the
bone marrow toxicity associated with
cilloram-phenicol, the reason for progressive changes in
in-EXPERIENCE AND REASON-BRIEFLY RECORDED 683
caused by several different viral agents,” and
these may exilibit varying degrees of
hemato-poietic depression.
All the evidence accumulated here strongly suggests that aplastic anemia following
hepa-titis may be the more severe manifestation of a viral effect on hematopoiesis which occurs to a mild degree in many cases of viral hepatitis
or viremia and is so transient as to be over-looked or ignored.
SUMMARY
Three cases of aplastic anemia following
hepatitis are described, and the possible
rela-tionship of these two disorders is discussed. A
beneficial effect of testosterone and prednisone
treatment occurred in two of the patients.
ELIAS SCHWARZ, M.D.
ROBERT L. BAEHNER, M.D.
Louis K. DIAMOND, M.D. Department of Pediatrics,
Harvard Medical School, and the
Division of Hematology, Medical Service
Children’s Hospital Medical Center
300 Longwood Avenue
Boston, Massachusetts
Supported in part by grants from the John A.
Hartford Foundation and from the National !nsti-tutes of Health (National Heart Institute #HTS 5255).
REFERENCES
1. Lorenz, E., and Quaiser, K.: Panmyeio-patilie nach Hepatitis epidemica. Wien. Med. Wschr., 105: 19, 1955.
2. Kosan, N. : Pancytopenie als Komplikation eincr hepatitis und Ursache einer
Leber-dystrophie. Med. Mschr., 10:794, 1956.
3. Beickert, A., and Siering, H. :
Immunpan-cytopenie mit Auftreten heterophiler Anti-korper bei akuter Hepatitis epidemica komp-iiziert durch eine schwere Mvocarditis. Acta Flaemat. (Basei), 19:51, 1958.
4. Deller, J. J., Jr., Cirksena, W. J., and Mar-carelli, J.: Fatal pancytopenia associated
with viral hepatitis. New Eng. J. Med., 266:297, 1962.
5. Pitcher, C. S., and Spence, E. M.: Fatal mar-row apiasia complicating infectious hepatitis. Bnit. Med. J., 1:171, 1963.
6. Simpson, K.: Infective hepatitis and marrow
apiasia. Bnit. Med.
J.,
1:473, 1963.7. Levy, R. N., Sawitsky, A., Florman, A. L., and
Rubin, E. : Fatal aplastic anemia after hepa-titis. New Eng. J. Med., 273: 1 118, 1965. 8. Shahidi, N. T., and Diamond, L. K. :
Testo-sterone-induced remission in aplastic anemia
of both acquired and congenital types. New
Eng. J. Med., 264:953, 1961.
9. Cohen, P., and Cardner, F. H.: The
thrombo-cytopenic effect of sustained high-dosage prednisone therapy in thrombocytopenic
purpura. New Eng. J. Med., 265:611, 1961. 10. Editorial: Aplastic anemia after hepatitis. New
Eng. J. Med., 273:1165, 1965.
11. Havens, W. P., Jr., and Marck, R. E.: The leukocyte response of patients with
experi-mentally induced infectious hepatitis. Amer.
J. Med. Sci., 212:129, 1946.
12. Conrad, N!. E., Schwartz, F. D., and Young, A. A: !nfectious hepatitis-a generalized
disease. Amer. J. Med., 37:789, 1964. 13. Aziz, M. A., Schwartz, S., and Watson, C. J.:
Studies of coproporphynin VII. Reinvestiga-tion of the isomer distribution in jaundice
and liver diseases. J. Lab. Clin. Med., 63:
596, 1964.
14. Zhernakova, T. V. : Iron/copper ratio and fac-tons affecting the level of trace elements in blood serum in infectious hepatitis. Ten.
Arkh., 34:68, 1962.
15. Kalk, H., and Wildhirt, E.: Die posthepa-titische Hyperbilirubinamie. Klin. Med.,
153:354, 1955.
16. Piazza, M., Piccinino, F., and Matano, F.: Studio su alcuni aspetti ematologici e
viro-logici durante il decorso della epatite speri-mentaie da virus MHV-3. Riv. 1st. Sieroter.
!tai., 39:293, 1964.
17. Cleiser, C. A., Cochenour, W. S., Jr., Berge, T. 0., and Tigertt, W. D.: The
compara-tive pathology of experimental Venezuelan equine encephalomyelitis infection in
dif-ferent animal hosts. J. Infect. Dis., 110:80, 1962.
18. Howie, D. S., and Crosby, W. H.: Bone mar-row panhypoplasia in humans experimentally induced by viral infection. (Abst.) Blood,
18:800, 1961.
19. Smith, T. J., McKinney, R. W., and Sawyer,
W. D. : Isolation of Venezuelan equine
en-chephalomyelitis virus by bone marrow
cul-tune. Proc. Soc. Exp. Biol. Med., 117:271,
1964.
20. Conrad, M. D.: Infectious hepatitis Miit.
