Neonatal cholestasis: a red alert for the jaundiced newborn.

Neonatal jaundice may indicate cholestasis rather than a benign, physiological condition. Any four-week-old newborn with persistent jaundice should have a fractionated bilirubin screen to determine whether the hyperbilirubinemia is unconjugated. Conjugated hyperbilirubinemia, a hallmark of neonatal cholestasis, is pathological and requires further investigation. These infants need prompt diagnosis, early intervention and careful follow-up to ensure continued growth and development. Recent progress in the physiology of bile flow is reviewed, and the evaluation and management of neonatal cholestasis are summarized. Further advances in delineating the cellular and molecular processes that regulate bile acid metabolism in both health and disease will lead to a greater understanding of the conditions causing neonatal cholestasis. Unravelling the etiopathogenesis of these neonatal cholestatic disorders will allow the development of novel diagnostic and therapeutic interventions that ultimately will effectuate the prognosis for these young patients.

Life-threatening gastrointestinal hemorrhage due to juvenile polyposis.

A 14-yr-old, previously healthy boy presented with massive lower GI hemorrhage. After the routine endoscopic and radiological evaluation, laparotomy and intraoperative colonoscopy revealed multiple polyps in the colon. A hemicolectomy was performed because of the severity of hemorrhage. A diagnosis of juvenile polyposis was made based upon histological findings and the family history. This is an extremely unusual presentation of juvenile polyposis and has been reported only once before. The clinical features, diagnosis, and therapeutic options for juvenile polyposis are discussed. Juvenile polyposis, although a rare condition in the pediatric population, should be considered in the differential diagnosis of life-threatening GI hemorrhage.

Vascular abnormalities in Adams-Oliver syndrome: cause or effect?

We describe a young girl diagnosed with the Adams-Oliver syndrome (AOS) associated with double outlet right ventricle, portal hypertension, and pulmonary hypertension. We hypothesize that a congenital vascular abnormality is the underlying pathogenesis and that the cutaneous defects characteristically seen in AOS represent the most common manifestation of this. We suggest that AOS should not merely be considered a syndrome consisting of aplasia cutis congenita and terminal transverse limb defects but rather a constellation of clinical findings resulting from an early embryonic vascular abnormality.

Rejection of murine congenic bile ducts: a model for immune-mediated bile duct disease.

Immune-mediated injury of prenatal and postnatal extrahepatic bile duct epithelium has been poorly characterized. In a transplantation model of bile duct allografts, segments of the common bile duct from fetal day 18, postnatal day 7 and day 21, and adult (greater than 6-weeks) mice were grafted under the renal capsule of adult congenic mice. The progression of rejection injury in these bile duct allografts was then followed by histological evaluation at 1-week intervals. After 3 weeks there was a significant difference in the number of fetal congenic bile duct grafts that had maintained their luminal architecture compared with the more mature adult congenic grafts that had fibrosclerosed. The onset and progression of the rejection injury in the adult congenic bile duct grafts was associated with an induction of class I and class II histocompatibility antigen expression in the adult bile duct epithelium; the severity of this injury could be attenuated by treatment of the recipient mice with cyclosporin A. Thus, the fibrosclerosing lesion of extrahepatic ducts observed in this model of rejection injury is similar to the histopathology of neonatal biliary atresia or primary sclerosing cholangitis, and susceptibility to this injury is dependent on the age of the donor tissue. The immune nature of the injury and the ontogeny of expression of histocompatibility antigen in bile duct tissue indicate that the above factors may be important to the pathogenesis of these extrahepatic bile duct diseases. This experimental model may be used to test for novel factors that may modulate immune responses directed against extrahepatic bile duct epithelium.

Food allergy: facts and fiction.

Hypersensitivity reactions to dietary products are especially common in the pediatric population, yet food allergy as a distinct clinical entity remains poorly defined. The clinicopathologic features of this syndrome can vary considerably from patient to patient; no reliable diagnostic laboratory tests are available, and some of the treatment regimens are controversial. The pathogenesis of this condition is not well understood. An important factor is the role of the intestinal mucosal barrier in the regulation of uptake of dietary antigen from the intestinal tract. Recently, significant differences have been observed between the features of the immature newborn and the mature adult intestinal mucosal barriers. These findings may be of fundamental importance to the pathogenesis of food allergy and are currently an area of intense research.

Temporal changes in plasma levels and metabolism of ketone bodies by liver and brain after ethanol and/or starvation in C57BL/6J mice.

The effects of ethanol and starvation on ketone body production and utilization were investigated. In the first experiment, adult C57BL/6J mice were divided into four groups: (i) control (fed); (ii) starvation (up to 31 h); (iii) ethanol (acute 5 g/kg i.p.); (iv) ethanol (ETOH) + starvation. Plasma ketone body (KB) concentrations in control mice remained constant at approx. 0.37 mM. The levels of KBs in starved mice began to increase at about 7 h and rose to a peak of 2.5 mM at about 24 h, then fell to 1.8 mM at 31 h. The levels in mice treated with ETOH began to rise soon after injection, reached 1.5 mM at 10 h, and returned to control levels by 15 h. Although there was no difference in elevated levels of KBs between two groups of mice treated with ETOH plus starvation and ETOH alone at 7-10 h, the level continued to rise steadily to 2.0 mM through 31 h in the former group. At 10 h post ETOH, mice either fed ad lib. or fasted had increased hepatic capacity to synthesize acetoacetate (AcAc) from palmitate; this effect was prolonged and enhanced by continued fasting for 24 h. In the brain, the rate of AcAc oxidation was twice that for beta-hydroxybutyrate (beta OHB) and glucose. Neither ETOH nor starvation affected energy production from KB and glucose. AcAc was also utilized for fatty acid synthesis and the rate of synthesis was stimulated by ETOH at 10 h after injection. The rate of lipogenesis from beta OHB accounted for less than 10% of that from AcAc. Together these experiments demonstrate that ETOH increases both hepatic ketone production and plasma KB levels for at least 10 h. ETOH alone led to elevated KB levels long before the rise due to starvation. In brain, at 10 h, an increased capacity to utilize AcAc for lipogenesis was found. The results indicate that ETOH through the production of KBs could provide an important source of energy and lipid precursors for the brain of mice.

Temporal changes in liver, blood, and brain glucose, glycogen, and beta-hydroxybutyrate after ethanol in C57BL/6J mice.

The time courses of changes in levels of beta-hydroxybutyrate (BOHB), glucose (GLC), and glycogen (GLY) were measured hourly for 7 h after i.p. 2 g/kg ethanol (ETOH) in samples of liver, blood, and brain in 21 day old C57BL/6J mice. After acute ETOH, brain GLC remained at 2.1 mmol/kg for 2 h, fell to a low of 1.5 mmol/kg at 5 h, then rose slightly. Blood GLC remained near 8 mmol/kg until 3 h, then fell. Liver GLC fell steadily from 10.2 to 7.2 mmol/kg at 7 h. Brain GLY rose from 1.7 to 2.9 mmol/kg at 3 h, then fell steadily. Blood GLY increased from 2.7 to 4.6 mmol/kg at 2 h, then fell to 1.7 mmol/kg. Liver GLY decreased from 70 to 30 mmol/kg. BOHB changes were similar in all samples. BOHB in brain fell from 0.12 to 0.08 mmol/kg at 2 to 3 h; then rose steadily to 0.27 mmol/kg at 7 h. Blood and liver BOHB fell from 0.40 to 0.25 mmol/kg, then rose to 1.0 mmol/kg. In a previous study, susceptibility to audiogenic seizures after 2 g/kg ETOH was completely suppressed for up to 1 h, then susceptibility increased to a maximum at 5 1/2 h, when a period of potentiation was observed. In this study, brain GLY levels were increased during the period of protection, and brain GLC levels were decreased during the period of potentiation. Together, these data may lend support to an hypothesis of an indirect effect of ETOH on the brain, leading to changes in susceptibility to audiogenic seizures via changes in metabolite availability.

Glucose protects DBA/2J mice from audiogenic seizures: correlation with brain glycogen levels.

The time courses of changes in liver, blood, and brain cortical glucose and glycogen levels were measured in 21-day-old DBA/2J mice after an IP injection of 10 g/kg glucose. Other mice were injected with glucose and tested for susceptibility to audiogenic seizures (AGS). Susceptibility to AGS fell from maximal levels to complete protection by 4 h, remained low through 6 h, then began to return to control levels by 8 h. Liver, blood, and brain glucose levels all rose to a peak soon after the injection, then fell linearly and returned to control levels by 6-8 h. Changes in brain glycogen levels reflected changes in AGS susceptibility.

Ethanol induces a transient susceptibility to audiogenic seizures in weanling C57BL/6J mice.

An acute dose of 5 g/kg ethanol led to a transient few days of a low incidence of susceptibility to audiogenic seizures in C57BL/6J mice (normally not susceptible) if the ethanol was administered during the transition from suckling to dietary self-sufficiency. This demonstrates a critical period of responsiveness to ethanol, shows ethanol-induced audiogenic priming, and may provide evidence for an indirect effect of ethanol on the brain.

Effect of ethanol on audiogenic seizures in C57BL/6J and DBA/2J mice.

DBA/2J mice, 30 or 60 days of age, representing low and no susceptibility to audiogenic seizures (AGS), were injected with 5 g/kg ethanol (ETOH) i.p. and tested for AGS from 5 to 10 1/2 h later. No responsiveness was seen to 6 h in either group. A rapid linear rise in AGS scores to a peak at 9 1/2 to 10 1/2 h was seen in the 30 day-old mice. In the 60 day-old mice, a period of reinduction of susceptibility was found, peaking at 10 h, in mice nominally presumed near-deaf at this age. In a second experiment, C57BL/6J mice were audiogenic-primed at 16 days of age and injected at 21 days. These ages were chosen to represent an intermediate level of AGS in controls. Mice received 4 g/kg of ETOH and were found to be completely protected from AGS through 4 1/2 h, followed by a transient overshoot at 9 h. Data with 4 g/kg show the same time course of suppression of seizures, followed by a brief period of potentiation as has been observed for other seizure-inducing methods. A more complete time course study was then performed using 2 g/kg, the approximate maximal dose tolerated with minimal overt behavioral changes in these mice. At this dose, mice were maximally protected for 2 to 3 h, and the overshoot in AGS scores was found at 5 to 5 1/2 h. The reported studies demonstrate a controlled experimental approach to investigate the biochemical events associated with nervous system function during seizure activity.

A proposed mechanism for the anticonvulsant action of valproate.

Valproate (n-dipropylacetate), the most recent major anticonvulsant drug, is unique in that it is a short-chained branched fatty acid with no cyclic components. It is proposed that its anticonvulsant action may be due to its stimulation of the beta-oxidation pathway, with a concomitant whole-body system shift toward metabolic acidosis. The circulating ketone bodies may then be utilized by brain, allowing an increased brain energy reserve and a greater tolerance to a transient stimulation which would have, without Valproate, triggered an epileptic seizure.