A 51-year-old white woman with a history of recurrent cystitis went to her physician after 2 days of dysuria, chills, and reddish discoloration of urine. Treatment was empirically started with nitrofurantoin for suspected urinary tract infection. Two days later, she remained symptomatic, and the dose was doubled. Three days later, treatment was changed to double strength trimethoprim/sulfamethoxazole, 1 bid for persistent dysuria on the basis that her urinary tract infection was partially treated. One day later, after the onset of nausea, vomiting, and abdominal pain, the patient was hospitalized for presumed urosepsis. Throughout her illness, she took approximately 4 g of acetaminophen daily. Her medical history was notable only for irritable bowel disease. Her surgical history included an ectopic pregnancy in 1970, tubal ligation in 1981, laparoscopic cholecystectomy in 1990, hysterectomy in 1995, and rectocele repair in January 1995. The patient also had had urethral dilatation up to five times for stricture and recurrent cystitis. Medications before admission were estrogen, phenylephrine/phenylpropanolamine, hyoscyamine, calcium citrate, trazodone, and phenazopyridine (urinary local anesthetic). She was allergic to cefazolin. She drank alcohol rarely and had no known risk factors for hepatitis.
On physical examination, the patient was afebrile, anicteric, and mildly confused. Findings on head and neck examination were normal. No mucosal lesions were identified. Chest examination revealed diminished basilar breath sounds. Cardiac examination was unremarkable. Abdominal examination revealed right upper quadrant and bilateral flank tenderness without organomegaly. Urinalysis showed 5 to 10 white blood cells (WBC) per high-power field, a moderate number of bacteria, and occasional red blood cells. Intravenous ampicillin and gentamicin were given for possible urosepsis or ascending cholangitis.
Initial investigations revealed markedly elevated transaminases, hypoglycemia, leukopenia, thrombocytopenia, coagulopathy (Table), and a metabolic acidosis with mild hypoxemia. Further studies to evaluate the elevated transaminase values included both ultrasonography and computed tomography (CT) of the abdomen; neither showed any abnormalities other than mild ascites and diffuse areas of decreased attenuation more prominent in the left lobe. The patient was believed to have acute hepatic failure. Three days after admission, as her clinical condition continued to deteriorate (Table), she was transferred to Ohio State University Medical Center for possible orthotopic liver transplantation. After transfer, the patient was alert, oriented, and anxious. Her temperature was 100.7°F, pulse rate 104/min, respiratory rate 20/min, and blood pressure 90/54 mm Hg. Physical examination revealed anicteric sclerae. The oropharynx was without abnormality. There were diminished breath sounds bilaterally with crepitations in the right base. Cardiac examination was unremarkable. The abdomen was soft, with right upper quadrant tenderness. Liver span was 11 cm with a 4-cm palpable liver edge. Stool guaiac test was negative for occult blood. The genitalia showed no external lesions. Laboratory tests on the day of admission revealed leukopenia, with 65% segmented neutrophils, 12% band forms, 18% lymphocytes, and 4% eosinophils. A screen for disseminated intravascular coagulation revealed a negative protamine sulphate gelation. Fibrin degredation products were elevated at 1:8. Rare schistocytes were seen on blood smear. The serum fibrinogen level was low (133 mg/dL), the factor VIII level was 63% of predicted (normal 50% to 150%), and the factor V level was 15% of predicted. These abnormalities were considered most consistent with diminished hepatic synthetic function.
The patient required continuous intravenous glucose infusion and platelet and clotting factor replacement. The serum lactate level rose rapidly. Despite evidence of diminished synthetic function, the serum bilirubin was only mildly elevated at 2.0 mg/dL and peaked at 6.5 mg/dL. This is in contrast to the marked elevation in other liver function parameters. At this time, repeated CT of the abdomen showed a normal sized liver and diffuse areas of low attenuation more confluent in the left lobe (Fig 1). The initial clinical impression was of FHF possibly of drug, viral, or autoimmune etiology. All potential hepatotoxic medicines were discontinued. In view of the temporal relationship of symptoms with both antibiotic therapy and use of phenazopyridine and acetaminophen, the absence of viral mucosal lesions, and the apparent immunocompetent state, drug-induced hepatitis was thought the most likely cause. Empiric therapy with acyclovir was debated but witheld in view of the potential to exacerbate the leukopenia and its association with coma, seizures, somnolence, and elevated transaminase values, all of which could potentially interfere with assessment of neurologic status and progression of hepatic failure. Liver biopsy was not done because of the risk of bleeding due to coagulopathy. Acetylcysteine was given empirically until an acetaminophen level was found to be 1 mg/dL. Viral hepatitis serology was negative for HAV, HBV, HCV, EBV, and CMV. Autoimmune workup including antinuclear antibodies, anti-smooth muscle antibody, and liver-kidney-microsome antibody tests were negative. Human immunodeficiency virus 1 and 2 antibody tests were negative. The sedimentation rate was normal. Rapid viral blood cultures were obtained.
On day 3 after transfer, the patient required intubation because of respiratory distress and worsening hypoxia due to adult respiratory distress syndrome. She was classified stage 1 priority (highest priority) for liver transplantation. The serum lactate value rose to 7.7 mEq/L, and mental status deteriorated rapidly. Despite supportive measures, the patient died (6 days after transfer) of complications related to FHF. Two days after the patient's death, the test for HSV IgM antibody returned positive. The IgG titre was negative. Rapid viral blood cultures were also positive for HSV type 2.
Autopsy revealed diffuse liver necrosis with areas of interspersed hemorrhage. Histologically, there was extensive hepatocellular necrosis. A sparse inflammatory cell reaction consisting of lymphocytes and neutrophils was seen. Eosinophilic intranuclear inclusion bodies were identified in hepatocytes surrounding the necrotic foci, consistent with herpes-induced hepatitis (Fig 2). Liver cultures grew HSV type 2. This was confirmed by immunoperoxidase staining. No mucosal lesions were identified on the lips, mouth, vagina, or vulva.
