Case 1 -
Childhood Leukemia Presenting with Acute Hepatic Failure
Milton J. Finegold
Texas Children's Hospital
Click on each slide thumbnail image for an enlarged view
Three weeks prior to admission a 13 year old boy with cystic acne presented to his dermatologist to
begin Accutane and had blood drawn per protocol. The acne was originally treated two months earlier with
oral minocycline for one month. His liver functions at that time included total bilirubin 0.8 mg/dl, AST
22 U/L, ALT 17 U/L, and alkaline phosphatase 202 U/L. A complete blood count revealed an "increased
white blood cell count". He proceeded to take two one-half doses of Accutane as prescribed. Five days
prior to admission he had four days of nausea and vomiting. He was hospitalized, rehydrated, given
vitamin K and his nausea and vomiting improved. He was transferred to Texas Children's Hospital due to
the findings of lymphoblasts on a peripheral smear as well as abnormal liver chemistries. At the time of
admission, he complained of increased fatigue, easy bruising, intermittent chills and fevers for over the
past one and one-half weeks, and jaundice for the prior three days. There was a 10 pound weight loss in
About two years ago, he had iron deficiency anemia, which was treated briefly with oral iron sulfate.
His immunizations were up to date and he had completed his Hepatitis B series. His food allergies
included strawberries but he did not have any known allergies to medications. Nutritional
supplementation consisted of Brewer's yeast pills from GNC and Wal-Mart brand Vitamin E 400 IU daily.
At TCH he had hemoglobin 9.8 g/dl, hematocrit 28.8%, platelets 22 x 103/UL
and white blood cells 3.41 x 103/UL. The differential
showed 10% neutrophils, 8% bands, and 77% lymphocytes. Peripheral smear revealed "relative lymphocytosis
with atypical blast like cells". Liver tests revealed elevated AST 3095 U/L, ALT 3872 U/L and GGT 124
U/L with alkaline phosphatase 192 U/L. Conjugated bilirubin was 9 mg/dl and uric acid was 6.6 mg/dl.
Viral serology for Hepatitis A, B, and C were negative except for the hepatitis B surface antibody.
Pro-time was 25.4 seconds with an INR of 2.3. His PTT was within normal limits at 32.6 seconds and
D-dimer was negative.
Negative serological viral studies included cytomegalovirus IgM and IgG, Human Immunodeficiency Virus,
Herpes virus IgM and IgG, Parvovirus B19 IgM and IgG. Epstein Barr virus IgG was elevated at 640. A
rapid toxicology screen was negative except for benzodiazepines. Serology for antinuclear antibody and
smooth muscle IgG were negative. Alpha-1 antitrypsin and factor V Leiden were normal. Blood copper
level within normal limits. Ammonia was slightly elevated at 50 μmol/L.
The marrow biopsy contained 98% blasts, which marked as early B-lineage ALL (CD10, 19, 20, 22 and
HLA-DR+). Karyotyping and FISH revealed t (5q; 9p) (12;22) and t (9p;16q) (22;24). There were no
chromosome 4 or 10 abnormalities and probes specific for BCR/ABL and TEL/AML1 were negative. The next
day Allopurinol and prednisone (40mg/m2 /day) were initiated in preparation for chemotherapy.
Other medications included Ceptaz, Zofran and Zantac. The Ceptaz was initiated as a precaution due to
low grade fevers, even though blood cultures remained negative. The next day he underwent a liver needle
biopsy at the same time that a left subclavian catheter was placed.
The pathologic findings in this biopsy are most consistent with:
(a) Viral hepatitis.
(b) Autoimmune hepatitis.
(c) Lymphoblastic leukemia.
(d) Accutane-induced hepatic necrosis.
(e) Minocycline toxicity.
Post Biopsy Course
The liver biopsy revealed widespread and intense portal and periportal infiltration of leukemic
cells. There was generalized hydropic swelling of hepatocytes with scattered single cell necrosis and
debris. Predicting the viability of the still intact hepatocytes was impossible.
The patient responded well to the pre-chemotherapy medications and had mild laboratory evidence of
tumor lysis with mild elevation of his uric acid in his serum and reduction of lymphocytes by cell count,
though the atypical lymphocytes remained detectable in his peripheral blood smear. During this time, he
was provided red blood cells, platelets, fresh frozen plasma and cryoprecipitate in response to needs.
The night of the biopsy, the patient had altered mental status with agitation and difficulty answering
questions. Ammonia level was 122 μmol/L. Lactulose was initiated and he was given Ativan and
later, fentanyl for the combative behavior. CT scan did not reveal acute intracranial hemorrhage.
Cerebral edema could not be detected. Prednisone and allopurinol were discontinued. Transaminases
continued to fall. The next day coagulation studies revealed pro-time 23.9 sec, INR 2.2, prothrombin
time 30.3 seconds, fibrinogen 202 mg/dl, D-dimer>4 ug/ml, and platelet count of 33 x
103/ul. Glasgow coma scale was determined to be 10-13. Later that day, due to increased work
on breathing and decreased level of consciousness he was intubated. A repeat CAT scan suggested cerebral
edema. Methylpredisone 30 mg IV every 8 hours was reinstituted with the thought that a component of his
encephalopathy might be related to leukemic infiltration into the central nervous system.
The next morning the patient had "head jerks", described as a '20 second episode of head jerking to
the left side' with posturing of the left arm which was suggestive of a seizure. Fosphenytoin loading
dose was started. A nasogastric tube was placed to begin enteral feeds and to continue oral
medications. BUN rose from 12 mg/dl to 19 mg/dl and his creatinine from 1 mg/dl to 1.1 mg/dl. He began
to have progressive hemodynamic instability, which required initiation and increased inotropic support.
The next day the pupils were fixed and dilated. Gag reflex, which was present at the time the
nasogastric tube was placed, was absent. A repeat CAT scan revealed "worsening of the brain edema".
After a discussion with the family all life support measures were stopped. Complete autopsy was
Diagnosis: Childhood Leukemia Presenting with Acute Hepatic Failure
The liver at autopsy weighed 1.4 times expected for age but the boy's measurements all exceeded the
99%. It displayed diffusely necrotic hepatocytes with scattered microsteatosis and extensive
portal-portal bands of collapse with loss of parenchyma. What remained were reticulin fibers and
perilobular collapse corresponding to the distribution of the previously intense leukemic infiltrate.
The other findings at autopsy included eradication of blasts from the bone marrow, with persistence in
spleen and GI tract. There was diffuse hypoxic – ischemic encephalopathy and cerebral edema with
In summary, the patient was a previously healthy 13 year old with cystic acne with the sudden onset of
liver failure. As best we could determine, he received minocycline for about one month beginning two
months before. This treatment has been reported once to produce hepatic necrosis.  A
hypersensitivity syndrome with rash and eosinophilia that may be accompanied by hepatic dysfunction and
auto-immune hepatitis are more common.  His only over the counter medications were Baker's
yeast pills and vitamin E. Upon initiation of Accutane, an elevated white blood cell count was
discovered. In 3 weeks, this young man was diagnosed with B-lineage acute lymphoblastic leukemia (ALL)
and hepatic failure of unknown etiology. While Accutane is associated with mild elevation of liver
enzymes, it is not known to progress to liver failure.  Acute liver failure as an initial
presentation for leukemia is an exceptionally uncommon but documented occurrence in adults
Acute tumor lysis becomes a concern after the administration of chemotherapeutic medications for
leukemia and some solid tumors. Spontaneous tumor lysis is the occurrence of tumor lysis without
associated chemotherapy induction. On extremely rare occasions spontaneous tumor lysis has been
associated with leukemias having a high proliferation index. The boy presented with acute liver failure
at the time of diagnosis for pre-B-cell ALL, at which time his WBC was only 3400. The clinicians at
Texas Children's Hospital were aware of liver dysfunction and avoided hepatotoxic medications. He was
given allopurinol and methylprednisolone in preparation for chemotherapy. There was mild elevation of
uric acid. Allopurinol works to decrease production of uric acid and inhibits microsomal enzyme activity
in hepatocytes.  Evidence of tumor lysis was also evident at time of autopsy with absence of
lymphocytes in the portal tracts of the liver as compared with his liver biopsy obtained 3 days earlier.
Methylprednisolone, like other corticosteroids, is metabolized primarily by hepatocytes. The only known
toxicity is steatosis.  The patient was also given pain medications, including Tylenol with
codeine, Morphine, and Codeine, for procedures. Tylenol as needed was used sparingly. All of these pain
medications are potentially hepatotoxic due to route of excretion and vasodilatory effect. However,
progression to fulminant liver failure preceded the use of these medications.
Viral and autoimmune causes for liver failure were excluded, as was Wilson's disease. The possible
role of antibiotics prescribed for acne was considered. With one exception  only pregnant
women and patients receiving very large doses of tetracycline are reported to develop liver failure. We
conclude that the massive leukemic infiltrate, localized to the portal tracts and interface with the
parenchyma likely compromised perfusion of the parenchyma and rendered it highly susceptible to any
further reduction in blood flow, as might have occurred with blood loss. The postulated process also
appears to explain all the cases reported by others as listed in the Table. It is interesting that the
peripheral blood white count has been low in all of these patients and coagulopathy has been a major
presenting feature. Of great importance are the reports of Belgaumi  and Kelleher 
of patient recovery with standard ALL therapy. The hesitancy regarding hepatotoxicity may not
- Min, DI., et al. Acute hepatic failure associated with oral minocycline. Pharmaco therapy 1992; 12:68-71.
- Teitelbaum, JE., el al. Minocycline-related autoimmune hepatitis. Arch Pediatr. Adoles. Med 1998; 152:1132-6.
- Roenigh, HH., Jr. Liver toxicity of retinoid therapy. J Amer Acad Derm 1988; 19:199-208.
- Souto, P., et.al. Severe acute liver failure as the initial manifestation of hematological malignancy. Eur. J. Gastroenterol Hepatol 1997, 9:1113-1115.
- Anderson, SHC., Richardson, P. Wendon, J., Pagliuca, A., Portmann, B. Acute liver failure as the initial manifestation of acute leukemia. Liver 2001; 21:287-292.
- Zafrani, ES., et al. Massive blastic infiltration of the liver: a cause of fulminant hepatic failure. Hepatol 1983; 3:428-432.
- McCord, RG., et.al. Acute leukemia presenting as jaundice with acute liver failure. Clin Pediatr 1973; 12:17-20.
- Conway, EE., Jr. Fulminant hepatic failure in a child with acute lymphoblastic leukemia. J. Pediatr Gastroenterol Nutr 1992; 15:194-197.
- Devictor D., et.al. Early Pre b acute lymphoblastic leukemia presenting as fulminant liver failure. J Pediatr Gastroenterol Nutr 1996; 22:103-6.
- Mori, T., et al. Histophathologic features of the biopsied liver at the onset of childhood B-precursor acute lymphoblastic leukemia presenting as severe jaundice. J. Pediatr Gastroent Nutr 1997; 25:354-7.
- Felice, MS., et al. Acute lymphoblastic leukemia presenting as acute hepatic failure in childhood. Leukemia Lymphoma 2000; 38:633-7.
- Kelleher, JF., et al. Hepatic dysfunction as the presenting feature of acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2001; 23:117-121.
- Belgaumi, AF., Hudson, NM. Childhood acute lymphoblastic leukemia presenting with sever hepatic dysfunction. Med Pediatr Oncol 2001; 37:142-144.
- Lazure, T., et al. Congenital anerythremic erythroleukemia presenting as hepatic failure. Arch Pathol Lab Med 2003; 127:1362-5.
- Pizzo PA., et.al. editor Principles and Practices of Pediatric Oncology, 4th edition. Lippincott Williams & Wilkins, Philadelphia, 2002, page 280-1.