Riccardo A. Superina

Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium

OBJECTIVE To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era. STUDY DESIGN The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%). RESULTS 272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry. CONCLUSIONS Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features

BACKGROUND AND METHODS We describe a new form of hepatitis, occurring in 10 patients over a period of six years, characterized clinically by manifestations of severe hepatitis, histologically by large syncytial giant hepatocytes, and ultrastructurally by intracytoplasmic structures consistent with paramyxoviral nucleocapsids. RESULTS The patients ranged in age from 5 months to 41 years. The tentative clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients underwent liver transplantation; the others died. The diagnosis of syncytial giant-cell hepatitis was established pathologically. The liver cords were replaced in all 10 patients by syncytial giant cells with up to 30 nuclei. In 8 of the 10 the cytoplasm contained pleomorphic particles of 150 to 250 microns, filamentous strands, and particles of 14 to 17 nm with peripherally disposed spikes resembling paramyxoviral nucleocapsids. Structures resembling degenerated forms were found in the other two patients. One of two chimpanzees injected with a liver homogenate from the index patient had an increase in the titer of paramyxoviral antibodies, probably an anamnestic reaction to previous paramyxoviral infection, suggesting that a paramyxoviral antigen but not viable virus was present in the liver homogenate. CONCLUSIONS Although further virologic studies will be required for precise classification, we believe that paramyxoviruses should be considered in patients with severe sporadic hepatitis.

Screening and outcomes in biliary atresia: Summary of a National Institutes of Health workshop

Biliary atresia is the most common cause of end‐stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30‐45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune‐mediated fibro‐obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the centers experience, the presence of associated congenital anomalies, and the postoperative occurrence of cholangitis. A number of screening strategies in infants have been studied. The most promising are early measurements of serum conjugated bilirubin and a stool color card given to new parents that alerts them and their primary care provider to acholic stools. This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006, in Bethesda, MD, that addressed the issues of outcomes, screening, and pathogenesis of biliary atresia. (HEPATOLOGY 2007;46:566–581.)

Timing of surgery for congenital diaphragmatic hernia: Is emergency operation necessary?

Congenital diaphragmatic hernia (CDH) is considered by most researchers to be a surgical emergency. However, early repair does not necessarily improve respiratory function or reverse fetal circulation, and many patients deteriorate postoperatively. As a result, in 1985, we began to employ a protocol in which surgery was delayed until the PCO2 was maintained below 40 and the child was hemodynamically stable; children in whom these criteria could not be achieved died without surgical repair. Sixty-one consecutive infants with CDH were managed over 4 years; 31 from 1983 to 1984 (group 1) and 30 from 1985 to 1986 (group 2). The groups were similar with respect to sex, side of the defect, birth weight, gestational age, incidence of pneumothorax, and blood gases. High frequency oscillation was used with increasing frequency during the study period, for patients with refractory hypercarbia (13% in group 1, 30% in group 2). All patients were initially paralyzed and ventilated. Mean time from admission to surgery was 4.1 hours in group 1 and 24.4 hours in group 2 (P less than .05). In group 1, 87% of patients had surgical repair (77% within eight hours of admission, 10% after eight hours), and in group 2 only 70% of patients had surgery (10% within eight hours, 60% after eight hours). All patients who were not operated on died. Overall mortality was 58% in group 1 and 50% in group 2; this difference was not statistically significant. These data indicate that our current approach has not increased overall mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience With the Rex Shunt (Mesenterico-Left Portal Bypass) in Children With Extrahepatic Portal Hypertension

BACKGROUND/PURPOSE Extrahepatic portal vein thrombosis (EPVT) in children can lead to severe bleeding from gastrointestinal varices, ascites, thrombocytopenia from hypersplenism, and other coagulation disorders. The authors have used the superior mesenteric vein to intrahepatic left portal vein (Rex) shunt in 5 children with symptomatic EPVT and report their results with this novel technique. METHODS Children with symptomatic portal hypertension were screened for the underlying cause. All children with essentially normal livers and obstruction of the extrahepatic portal vein were considered for the Rex shunt. Evaluation included liver function tests, liver biopsy, and radiological evaluation of the intrahepatic vascular anatomy. RESULTS Five patients between the ages of 2.8 and 10.5 years underwent evaluation for portal hypertension secondary to extrahepatic portal vein obstruction. Three patients had idiopathic extra hepatic portal vein thrombosis with cavernous transformation, 1 had thrombosis after a living-related liver transplant, and 1 had compression and obstruction of the main portal vein from enlarged lymph nodes after treatment of systemic histoplasmosis. All patients were symptomatic. Three patients had intermittent bleeding from esophageal and gastric varices, and all 5 had relative degrees of hypersplenism with enlarged spleens and thrombocytopenia (11,000 to 77,000). Three patients had significant leukopenia. Results of imaging studies suggested that 3 patients had inadequate intrahepatic portal veins for shunting, but all patients at exploration underwent successful shunting. There were no serious intraoperative complications. Postoperative complications included ascites in 2 patients that resolved within 1 month. There were no early shunt thromboses. The median postoperative length of stay was 7 days. Clinical follow-up ranged from 7 to 21 months. Gastrointestinal bleeding did not recur in any patient, and ascites resolved in all. Spleen size decreased significantly (P < .01) from 9.4 +/- 4.0 cm to 5.0 +/- 3.7 cm below the left costal margin. Mean platelet count and white blood cell count rose after shunting from 79 +/- 42 to 176 +/- 73 (P < .02) and 5.4 +/- 2.3 to 7.5 +/- 3.9 (P = .06), respectively. All shunts were studied at 1 and 7 days, and 3 and 6 months after the procedure. Shunt patency was documented in all cases. Subsequently, shunt blockage occurred in 2 patients. CONCLUSIONS The Rex shunt has proven to be an effective method of resolving portal hypertension caused by EPVT including thrombosis after living donor transplantation. This shunt is preferable to other surgical procedures because it eliminates portal hypertension and its sequelae by restoring normal portal flow to the liver.

Surgical guidelines for the management of extra-hepatic portal vein obstruction

Abstract:  The recent introduction of the meso Rex bypass raises a possible paradigm shift in the therapeutic approach to extra‐hepatic portal vein obstruction (EHPVO). Long‐term follow‐up of patients with EHPVO has revealed a variety of complications including variceal hemorrhage, hypersplenism, biliopathy, growth/development retardation and neuropsychiatric disease. The meso Rex bypass restores physiologic blood flow to the liver. Thus, when feasible, the meso Rex bypass should be considered in patients with clinically significant manifestations of EHPVO. The opinions of a panel of experts regarding the surgical approach to the management of EHPVO are presented.

Portal Hypertension in Children: Expert Pediatric Opinion on the Report of the Baveno V Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension

Shneider BL, Bosch J, de Franchis R, Emre SH, Groszmann RJ, Ling SC, Lorenz JM, Squires RH, Superina RA, Thompson AE, Mazariegos GV. Portal Hypertension in Children: Expert Pediatric Opinion on the Report of the Baveno V Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.

Correction of Extrahepatic Portal Vein Thrombosis by the Mesenteric to Left Portal Vein Bypass

Objective:The goal of this study was to determine the effectiveness of mesenteric vein to left portal vein bypass operation (MLPVB) in correcting extrahepatic portal vein thrombosis (EHPVT) in children. The treatment of idiopathic EHPVT has been primarily palliative, whereas MLPVB restores hepatic portal flow in patients with EHPVT. Methods:Thirty-four children with symptomatic EHPVT underwent surgery with intent to perform MLPVB and were followed for up to 7 years. MLPVB was successful in 31 patients (91%), all of whom maintain patent vein grafts and have symptomatic relief of EHPVT in follow-up. All patients had complete relief from gastrointestinal bleeding. Patients with hypersplenism had significant increases in platelet and leukocyte counts and reduction in spleen size. Superior mesenteric vein flow increased from 119 ± 66 mL/min before bypass to 447 ± 225 mL/min (P < 0.0001) after surgery. Postoperative blood flow in the bypass graft expressed as a fraction of calculated ideal portal flow for size correlated inversely with age (P < 0.001). Left-portal vein diameter increased from 2.6 ± 1.6 mm to 7.3 ± 2.4 mm 2 years after surgery (P < 0.002). Liver volume increased from 703 ± 349 cm3 to 799 ± 351 cm3 1 week after surgery (P < 0.001). Prothrombin time improved to normal in all patients 1 year after surgery. Conclusions:MLPVB provides excellent relief of symptoms in children with idiopathic EHPVT and results in liver growth and normalization of coagulation parameters. This surgery is corrective and should be done at as early an age as possible.

Resting energy expenditure is increased in infants and children with extrahepatic biliary atresia

To determine if liver dysfunction in children affects energy and macronutrient homeostasis, we performed 13 metabolic studies in 11 patients (age, 17.8 +/- 5.9 months [mean +/- SEM]) with extrahepatic biliary atresia (EHBA). Nutritional balance, indirect calorimetry, anthropometry, and biochemical liver function tests were utilised. Sixty-four percent of the energy losses were in the form of stool fat. Energy expenditure (68 kcal/kg/d) was 29% higher than normal (P less than 0.0025). Only one third of the metabolisable energy intake (37 kcal/kg/d) was stored in the body for new tissue synthesis. In spite of the bountiful protein intake for age, the increased protein oxidation (2g/kg/d) resulted in a virtually zero mean nitrogen balance. In addition, four patients oxidised endogenous protein as well. The respiratory quotient was 0.96, and did not change significantly between pre- and post-meal measurements, suggesting a predominant utilisation of carbohydrate for energy metabolism. Net lipid oxidation was severely diminished. We found that the higher the serum aspartate aminotransferase level (previously named SGOT), the lower the net fat oxidation, and the higher the conversion of glucose to fat. These data suggest that markedly increased energy expenditure contributes to the malnutrition of patients with EHBA. We characterised for the first time how severe liver disease in infants and children affects carbohydrate, fat, and protein metabolism, thus inducing protein-energy malnutrition.

Liver repopulation after cell transplantation in mice treated with retrorsine and carbon tetrachloride.

Background. Efficiency of engraftment after liver cell transplantation is less than 1% under conventional conditions. Our aim was to develop a high-efficiency, nonsurgical, no-genetic-advantage mouse model of liver repopulation with transplanted cells. Methods. Mice were conditioned with nonlethal doses of a cell cycle inhibitor, retrorsine, 70 mg/kg, to irreversibly block proliferation of native hepatocytes. After the drug was eliminated, 2 million freshly isolated &bgr;-galactosidase–labeled liver cells were transplanted into the spleens of C57BL/6J recipient mice. To stimulate donor cell proliferation, three doses of carbon tetrachloride (CCl4), 0.5 ml/kg, were given. Several control groups were studied to evaluate the contribution of each treatment to liver repopulation. Results. Repopulation, as measured by cell isolation from recipient livers 1–7 months after transplantation, was on average 20%. Repopulation was 10% if CCl4 was given only once, between 0.5% and 1% if only retrorsine or CCl4 were used, and 0.05% if no conditioning was used. Phenotypically, whole livers turned blue on exposure to X-gal staining, whereas negative (control) livers remained pale brown. More than 55% of liver repopulation resulted from clusters containing 21 or more cells, some of which contained more than 200 cells, suggesting seven or more rounds of cell division in a subset of transplanted cells. Conclusion. This murine study demonstrates high levels of repopulation after liver cell transplantation into nongenetically modified livers, using a cell cycle inhibitor and chemical liver injury to provide transplanted cells a proliferative advantage. Liver repop-ulation was effected mostly by a small fraction of transplanted cells. Analogous nonsurgical liver cell transplantation strategies, but with clinically applicable drugs, could be devised for the treatment of liver-based metabolic diseases.