Hepatosplenomegaly and Periventricular Cyst in a Neonate with Direct Hyperbilirubinemia

Abstract

An infant is born at 36 weeks to a 27-year-old gravida 4, para 3 woman via precipitous vaginal delivery through meconium-stained amniotic fluid. The pregnancy had been complicated by diet-controlled gestational diabetes. The mother works as a daycare teacher and had traveled to Europe 12 weeks before delivery. She had clinical symptoms of an acute upper respiratory illness 3 weeks before delivery. The neonate’s physical parameters include weight of 2.085 kg (13th percentile), length of 43 cm (38th percentile), and head circumference of 31 cm (16th percentile).Initial blood glucose level is 23 mg/dL (1.28 mmol/L), and the neonate is given a D10 bolus and maintenance intravenous fluids are started. The neonate’s initial platelet count is 37 × 103/μL (37 × 109/L) with no active bleeding or oozing. He is noticed to be thrombocytopenic on subsequent complete blood cell counts. A sepsis evaluation is done, blood specimens for culture are drawn, and ampicillin and gentamicin are started. Initial C-reactive protein is 6 mg/dL (60 mg/L) and white blood cell count is 15,000/μL (15 × 109/L). An initial total bilirubin is 18.8 mg/dL (321.5 μmol/L) and direct bilirubin is 10 mg/dL (171 μmol/L). Results of a liver function panel are as follows: alanine aminotransferase (ALT) 117 U/L (1.9 μkat/L), aspartate aminotransferase (AST) hemolyzed, albumin 2.7 g/dL (27 g/L). Abdominal ultrasonography reveals hepatosplenomegaly. Result of urine cytomegalovirus (CMV) test is pending at the time of transport.The infant is transferred to our tertiary NICU for multidisciplinary management of neonatal direct hyperbilirubinemia and transaminitis. Physical examination findings are notable for hepatomegaly, splenomegaly, and petechiae on the abdomen and back. Admission laboratory findings are significant for calcium less than 5 mg/dL (1.25 mmol/L), magnesium 0.6 mg/dL (0.25 mmol/L), albumin 2 g/dL (20 g/L), total bilirubin 23 mg/dL (393 μmol/L), direct bilirubin greater than 16 mg/dL (273.6 μmol/L), ALT 106 U/L (1.7 μkat/L), AST <5 U/L (0.08 μkat/L), alkaline phosphatase 290 U/L (4.8 μkat/L), ammonia less than 10 μg/dL (7.1 μkat/L), and platelet count 82 × 103/μL (82 × 109/L). Coagulation profile shows an international normalized ratio of 1.6 and PTT of 37 seconds. A hepatitis panel is negative. Abdominal ultrasonography reveals hepatosplenomegaly and patent ductus venosus. Echocardiography findings are normal. Central access is established.Hepatology and infectious disease specialists are consulted on admission. For hepatology evaluation, α1-antitrypsin and cholestasis panel are negative. Serum ferritin is 1,951 ng/mL (1,951 μg/L). Because the direct reacting (or conjugated) bilirubin level is greater than 50% of the total bilirubin and there are no good data to guide therapy, phototherapy is started. Double volume exchange and intravenous immunoglobulin are not given at the time. Evaluation for infections includes repeat CMV, herpes simplex virus (HSV), toxoplasma immunoglobulin M, Epstein-Barr virus (EBV), adenovirus, and coxsackie virus. A lumbar puncture is deferred due to coagulopathy. No placental pathology is available.Genetics consultation on admission recommends the following: urine organic acids to assess for mevalonic acid and succinyl acetone, oxysterol to assess for Niemann-Pick disease, galactose-1-phosphate uridylyltransferase enzyme testing and galactose-1-phosphate red blood cells, transferrin isoelectric focusing, acylcarnitine profile, and plasma amino acids.The neonate is started on enteral feeds on day 4 and advanced to full volume feeds. The liver function test trends are studied (Fig 1) and the infant is started on ursodiol and fat-soluble vitamins. Feedings are fortified to 24 kcal with medium-chain triglycerides for poor weight gain. Head ultrasonography shows right grade 1 intraventricular hemorrhage and bilateral periventricular temporal lobe cyst without calcification. Magnetic resonance imaging of the brain shows medial temporal horn cysts, banding of the interventricular regions, immature white matter, and cerebellar vermis hypoplasia (Fig 2).The fetal-neonatal continuum of liver diseases allows the occurrence of cirrhosis in cases defined as neonatal acute liver failure (NALF). All neonatal liver failure is “acute” by definition. The common differential diagnostic considerations include viral infections (20%–30%), hemophagocytic lymphohistiocytosis, mitochondrial cytopathy, and gestational alloimmune liver disease, which is the most common cause. HSV is the most common viral agent associated with NALF. Neonates with HSV-associated NALF may have disseminated HSV with or without central nervous system infection. In either of those cases, neonates often lack cutaneous manifestations; therefore, a high index of suspicion is required. CMV is very rarely associated with NALF, but more often with less fulminant hepatitis and prominent cholestasis. Enterovirus should be a consideration in evaluating any neonate with a combination of necrotizing enterocolitis and NALF.In our case, the urine CMV result from the birth hospital was positive, consistent with a diagnosis of congenital CMV (CMV) and the neonate was subsequently started on ganciclovir. The repeat blood and urine samples tested for CMV at our NICU confirmed the diagnosis, and EBV polymerase chain reaction (PCR) (initially 350 copies/mL and then 1,500 copies/mL) was positive as well. Ganciclovir was switched to oral valganciclovir on postnatal day 6. The neonate failed the otoacoustic emissions test bilaterally. The eye examination performed as part of the evaluation for toxoplasmosis, other infections, rubella, CMV, and HSV (TORCH) syndrome showed posterior embryotoxon. Re-examination after the diagnosis of CMV was made showed no chorioretinitis.Human CMV is a human-specific DNA virus of the Herpesviridae family. In the developed world, congenital CMV is the leading nongenetic cause of sensorineural hearing loss (SNHL) in children and accounts for 21% and 24% of cases of hearing loss at birth and 4 years of age, respectively. (1) In addition, congenital CMV is the leading viral cause of neurodevelopmental delay.The clinical spectrum of congenital CMV varies widely, from asymptomatic infection to potentially life-threatening disseminated disease. Presentation can be with intrauterine growth restriction, preterm labor, petechiae, jaundice, hepatomegaly, splenomegaly, and microcephaly. Laboratory and imaging findings include thrombocytopenia, transaminitis, direct hyperbilirubinemia, SNHL, periventricular calcifications, and rarely, chorioretinitis. Radiographic findings are abnormal in 50% to 70% of children with symptomatic infections at birth and include intracranial calcifications, ventricular dilation, cysts, lenticulostriate vasculopathy, choroid plexus cyst, and echogenic bowel.Because infants with congenital CMV shed large amounts of virus in saliva and urine, saliva (at least 1 hour after breast feeding) or urine PCR is used for diagnosis. The treatment of symptomatic congenital CMV disease is with intravenous ganciclovir or the oral prodrug valganciclovir. Neonates receiving valganciclovir for 6 months had a 2.6-times higher likelihood of improved total hearing at 12 and 24 months than those who received only 6 weeks of valganciclovir treatment. (2) Neurodevelopmental outcomes on the language composite of the Bayley Scale III were improved with longer duration of therapy.Whether the infection with EBV in our case was a coincidence or contributed to the disease severity remains uncertain. EBV is a γ herpes virus associated with infectious mononucleosis, nasopharyngeal carcinoma, Burkitt lymphoma, B-cell lymphoma, and posttransplant lymphomas. Infection with EBV is extremely common and 90% of adults in the United States are seropositive before the age of 30 years. Purtilo and Sakamoto (3) reported that EBV reactivation in pregnancy is a much more common occurrence than primary infection due to the high rates of seroprevalence.Transmission of EBV is usually horizontal, requiring close contact with the saliva of an infected person; vertical transmission is felt to be rare. Several case reports of fetal outcomes of EBV infection during pregnancy have been published, but there is no specific syndrome that can be described as an outcome of EBV infection during pregnancy.In a cohort of 500 women whose serum samples were studied for EBV nuclear antigen early in pregnancy, 28 neonates had anomalies. Of these, 16 had minor anomalies and 12 had major anomalies including congenital heart disease, microcephaly, anencephaly, meningomyelocele, and achondroplasia. (4) In a case report by Brown and Stenchever, (5) severe congenital anomalies were described in an infant exposed to EBV infection from conception to delivery. Another case report described congenital anomalies such as cryptorchidism, micrognathia, cataract, and hypotonia in a male infant exposed to EBV during pregnancy. Two other reports described liver and bile duct anomalies in infants exposed to EBV during pregnancy. A case control study of 403 infants born to mothers with EBV infection at 12 to 14 weeks of gestation suggested an increased risk for leukemia.To our knowledge, this is the third case in literature to report coinfection with CMV and EBV in neonates. Two previous cases were reported by Joncas et al (Table). (6) Although congenital CMV could explain all of this infant’s findings, the severity may have been due to concurrent in utero infection with CMV and EBV.Our patient was discharged on postnatal day 17, with infectious disease, hepatology, ophthalmology, and audiology follow-up. Currently, at 2 years of age, he has not undergone brainstem auditory evoked response testing but has speech delay.