This 2-day-old girl was transferred to Children's Memorial Hospital for evaluation of liver failure. She was the appropriate weight of 3.1 kg for gestational age, the product of a full-term pregnancy to a 26-yearold G7P7 female. The mother had not received any prenatal care. Her membranes were artificially ruptured 2 hours prior to delivery. It was a spontaneous vaginal delivery. There were variable decelerations prior to delivery; thick meconium was present in the amniotic fluid. Apgar scores were 7 at 1 minute and 9 at 5 minutes. Several hours after delivery, the infant developed respiratory distress requiring supplemental oxygen therapy. She was noted to have a serum blood sugar of 14 mg/dL.
Physical examination revealed a mildly tachypneic infant who was afebrile. Her growth parameters were all in the 25th percentile. HEENT exam was unremarkable save for scleral icterus. The lungs were clear. Sl was normal; S2 was physiologically split. There were no murmurs, rubs, or gallops. The liver was firm and was palpable 5 cm below the right costal margin. The spleen was palpable 3 cm below the left costal margin. The remainder of the examination was unremarkable.
Complete blood count revealed hemoglobin 17 g/dL, white blood cell count 17,500/mm3 with 33% polymorphonuclear cells, 12% immature neutrophils, and 55% lymphocytes. The platelet count was 40,000/mm3. Other abnormalities included AST 3,725 IU, ALT 1,413 IU, total bilirubin 6 mg/dL, direct bilirubin 3.4 mg/dL, and ammonia 126 pmol/L. The prothrombin time was modestly elevated and partial thromboplastin time was just above the upper limit of normal. D-dimer levels were elevated.
Ben Katz, MD, moderator: What is going through the neonatologist's mind at this point?
Dan Polk, MD, neonatologist: The obvious answer is that this child has a form of sepsis syndrome with multisystem involvement. The severe liver involvement suggests that it's not a bacterial process. More likely, this might be viral sepsis caused by either herpes simplex or an enterovirus. In addition, the lack of prenatal care raises the possibility of a congenital infection.
Dr. Katz: Is this child in liver failure?
Peter Whitington, MD, pediatric hepatologist: The question is more than academic. It goes to the heart of how one approaches this child diagnostically and therapeutically. There is significant hepatic necrosis, as the transaminases are greatly elevated. Although the serum ammonia is elevated, it is not a very good test of liver function; in addition, the upper limit of normal in the newborn is significantly higher than that of older children. An abnormal coagulation profile might indicate liver failure.
As in this child, one needs to distinguish between abnormal coagulation times caused by disseminated intravascular coagulation (DIC) and those caused by liver failure. Factor VIII is made in the endothelium exclusively; factor VII, which has a very short half-life, is made in the liver. If both factor levels are low, the child has DIC. If the Factor Vffl level is normal and VII is low, the child has liver synthetic failure. Ddimer levels are elevated in both sepsis and liver failure; they are elevated in the latter condition because the liver clears D-dimers. A diseased liver doesn't clear them effectively. Finally, this child's hypoglycemia may be indicative of synthetic liver failure, although we don't have enough information to prove this.
Dr. Katz: How should we approach the differential diagnosis?
Dr. Whitington: There are several factors that we should consider before creating a differential diagnosis. First, this baby was appropriate for gestational age, suggesting that whatever insult that has occurred, started very late in gestation. Next, in my experience, inborn errors of metabolism generally don't present on the first day of life. Severe liver dysfunction on the first day of life could be caused by neonatal hemochromatosis or hemophagocytic syndrome.
Dr. Katz: What is neonatal hemochromatosis?
Dr. Whitington: Neonatal hemochromatosis is often undiagnosed. The exact cause or causes are unknown. It results from iron deposition in the liver, pancreas, and heart. Iron deposition in the submucosal gland epithelium allows us to make the diagnosis easily by oral mucosal biopsy. Infants with this syndrome present with fulminant liver failure on the first day of life. The average life expectancy is less than 2 days. The disease may recur in as many as 80% of subsequent gestations.
Dr. Katz: Any clues as to its pathogenesis?
Dr. Whitington: We believe that this is an alloimmune disease similar to Rh disease or alloimmune thrombocytopenia. We rarely see this in first-born infants. We have treated 15 women who had had infants with this disease with intravenous immunoglobulin during subsequent pregnancies and have had remarkable success preventing recurrences. So far, we have been unable to identify the inciting antigen.
Dr. Katz: Are there any other inborn errors of metabolism that we should consider?
Joel Charrow, MD, geneticist: Assuming the hypoglycemia was real, there are three inborn errors of metabolism that should come to mind in an infant with severe liver disease and hypoglycemia-galactosemia, hereditary fructose intolerance, and type I tyrosinemia. None of them is particularly likely in this child given the rapidity of onset. The first two diseases occur as a result of exposure to the offending sugar - either galactose or fructose. This child hadn't receive any fructose and had had only one feeding of a galactose-containing formula, making a diagnosis of galactosemia exceedingly unlikely and hereditary fructose intolerance essentially impossible.
Tyrosinemia type I is caused by a defect in the tyrosine metabolic pathway and may present with neonatal liver failure, but generally not this early. The liver disease develops as the toxic metabolites accumulate; in utero, these metabolites are removed by the placenta, preventing disease. More often, these patients have a more insidious course, presenting later in infancy with cirrhosis and rickets secondary to renal phosphaturia.
I'd also like to point out that hyperammonemia within the first 24 hours of life is rarely the result of an inborn error of metabolism. If significantly elevated, it is generally the result of a condition termed transient hyperammonemia of the newborn, which is characterized by lung disease and severe hyperammonemia. These patients have no other evidence of hepatic dysfunction.
Dr. Katz: Don't we have newborn screening for these diseases?
Dr. Charrow: Obviously, this child presented much too rapidly for newborn screening to have been effective, even if she had one of these diseases. Illinois has screened for galactosemia using blood galactose levels since 1984. Screening for a number of aminoacidurias, including tyrosinemia, and organic acid disorders, was introduced in 2003.
Stan Shulman, MD, pediatric infectious disease specialist: It should be mentioned that asphyxia can cause severe multiorgan dysfunction, including liver failure and disseminated intravascular coagulation. However, this child's Apgar scores were not consistent with severe asphyxia.
Dr. Katz: Are there other conditions that should be on our differential diagnosis?
Dr. Whitington: Other things to consider would include congenital infections, congenital leukemia, and hemophagocytic syndrome.
Dr. Katz: Can you explain hemophagocytic syndrome?
Dr. Shulman: Hemophagocytic syndrome, also termed hemophagocytic lymphohistiocytosis, is a macrophage proliferative disorder. It leads to hemophagocytosis and a barrage of cytokine release which causes fever, rash, pancytopenia, and hepatosplenomegaly. These infants may have severe liver dysfunction. It may be a primary autosomal recessive disorder that leads to defective natural killer cell function. Alternately, it may be secondary to a number of bacterial and viral infections (commonly Epstein-Barr virus), malignancies, and immune mediated conditions such as lupus or Kawasaki disease. Common laboratory findings besides pancytopenia and liver dysfunction include hyperferritinemia, hypofibrinogenemia, and elevated lactic dehydrogenase.
Dr. Katz: Ashamedly, I have to admit that I purposely left out one piece of information. After the infant was born, the outside hospital discovered that the mother's serology was abnormal. The mother's rapid plasma reagin (RPR) was 1:128, the baby's RPR was 1:32, and the mother's test for antibody to the human immunodeficiency virus (HIV) was negative. How should we interpret these results?
Dr. Shulman: The mother has a very high titer RPR, which suggests the presence of active, untreated syphilis. However, the RPR is not a specific test and may be falsely positive in other maternal conditions, such as lupus. The child's RPR may represent passive transfer of maternal antibody or it may be the result of active infection in the infant. In order to distinguish between these two possibilities, we need to look at the child's clinical symptoms as well as the results of more specific treponemal antibody testing.
Dr. Katz: What is the clinical picture of congenital syphilis?
Dr. Shulman: Most infants born to infected mothers are infected themselves. Early manifestations may include hepatosplenomegaly and hepatic dysfunction, diffuse lymphadenopathy, rash, anemia, and thrombocytopenia. They may have "snuffles" (a continuous purulent rhinitis that is teeming with spirochetes), a diffuse painful periostitis of the long bones, chorioretinitis, and nephrotic syndrome. Late manifestations if untreated may include destructive bony lesions, abnormal dentition (Hutchinson's peg-shaped teeth), a saddle nose as a result of a perforated nasal septum, and central nervous system involvement.
Anthony Mancini, MD, pediatric dermatologist: All the skin lesions of syphilis are highly contagious. The classic rash consists of erythematous, scaly macules, papules, and plaques over the entire body including the palms and soles. It is generally scaling with linear fissures. On occasion, the rash may even be vesicular or bullous.
Dr. Katz: How do we confirm the diagnosis of congenital syphilis?
Dr. Shulman: The baby's fluorescent treponemal antibody absorbed test was positive; her cerebrospinal fluid VDRL was negative.
Dr. Katz: How was she treated?
Dr. Shulman: She received 14 days of intravenous penicillin and did well. Her liver dysfunction improved rapidly. When treating any form of syphilis, the physician should be aware of the possibility of a Jarisch-Herxheimer reaction. This is a systemic reaction that occurs within hours of the institution of treatment consisting of fever, chills, myalgias, and hypotension. It is the result of the massive killing of spirochetes with release of a pyrogen. Prednisone may be used to treat this reaction.
Robert Listernick, MD, general academic pediatrician: Here's the literary trivia question for the day. What classic play dealt with congenital syphilis as a metaphor visited upon children as punishment for the sins of their fathers?
Dr. Katz: I don't think that that answer will be on Medline@ Thanks, everybody.