Dennis D. Black

Esophagitis in infants. Morphometric histological diagnosis and correlation with measures of gastroesophageal reflux

To assess the incidence of histological esophagitis in infants less than 2 yr old with symptoms of gastroesophageal reflux, 35 infants were studied with esophageal suction biopsy and pH probe monitoring. Intraepithelial and lamina propria inflammatory cells, basal cell layer thickness, and papillary height were quantitated. Distal esophageal sections from infant sudden death trauma victims were used to provide normal morphometric control values. The upper limit of normal for each of the four histological parameters of esophagitis was defined as the mean plus three standard deviations. The values thus derived were similar to established adult normal values. Seventy-seven percent of the patients had at least one abnormal histological parameter (intraepithelial eosinophils or neutrophils, thickened basal cell layer, or increased papillary height) and were thus considered to have esophagitis. These measures of esophagitis all correlated well with each other, providing an internal consistency to the histological interpretation. Lamina propria eosinophilia correlated highly with intraepithelial eosinophils (r = 0.98) and was found to have a sensitivity of 41% and specificity of 89% for diagnosing histological esophagitis, defined as abnormality of any of the four histological parameters. Ninety-three percent of the patients with histological esophagitis had significant reflux as determined by pH probe monitoring. However, there was generally poor correlation between the severity of the esophagitis as quantitated by morphometric parameters and severity of the reflux as measured by pH monitoring. Esophageal suction biopsies, which provide adequate specimens for morphometric interpretation, are appropriate for diagnosing reflux esophagitis in infants.

Improved results of living-related liver transplantation with routine application in a pediatric program

Living related liver transplantation (LRT) was introduced as a response to the shortage of donor organs that has existed for small children. Results were promising in the initial experience, with a one-year patient survival of 80% and a graft survival of 75%. Since the completion of the protocol, LRT has been considered routinely in the management of children in our center. We present here our experience with 45 consecutive transplants in which LRT accounts for 40% of grafts with an overall patient survival of 90%. Between 4/91 and 4/92, 45 OLT were performed in 41 children. Median age was 2.7 years (3 months to 13 years) and weight was 10.4 kg (3.5-60 kg). Thirty-five were primary grafts, 10 were retransplants. One patient received 2 grafts in the orthotopic auxiliary position. Cholestatic disorders including biliary atresia accounted for 60%, metabolic diseases for 15%. Grafts were obtained from cadaver donors in 27/45 (60%) cases; reduction was required in 12/27 (44%). LRT was performed in 18 cases. Fifty-two percent of recipients of cadaver grafts were UNOS status 4, while 16% of LRT recipients met these criteria. Actual patient survival for cadaver grafts is 21/24 (88%) and graft survival is 20/27 (74%). Patient survival in 18 LRT was 94%. Two grafts were lost to arterial thrombosis for a graft survival of 83%. All donors have been discharged and are well. One patient, a teenager with fulminant hepatitis, was successfully transplanted with a left lobe from his father. This experience demonstrates the programmatic flexibility accorded by use of LRT. Since 40% of grafts were LRT, more livers were available for urgent use for patients who did not have a donor available, as reflected in the 73% incidence of cadaver recipients on status 3 or 4. Therefore, patients are more likely to receive a transplant at the optimal time. We are now prepared to offer LRT for fulminant hepatic failure since the benefit of graft availability appears to outweigh concerns about coerced donation. The successful treatment of a teenaged patient may herald extension of LRT to adults. We conclude that the use of LRT should be expanded.

Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia

A 20-year-old woman with abetalipoproteinemia underwent orthotopic liver transplantation for cirrhosis, affording access to her liver and small intestine for study. Before transplantation, her plasma apolipoprotein B concentration was less than 1 mg/dL according to enzyme-linked immunosorbent assay, whereas after transplantation her plasma apolipoprotein B concentration was 76 mg/dL (all apolipoprotein B-100). Apolipoprotein B content was reduced in her intestine and liver compared with normal and cirrhotic controls. Cultured hepatocytes from the patients explanted liver secreted a 1.006 g/mL less than or equal to d less than or equal to 1.063 g/mL lipoprotein rich in apolipoprotein E and a 1.063 g/mL less than or equal to d less than or equal to 1.21 g/mL lipoprotein containing apolipoproteins E and A-I with no immunodetectable apolipoprotein B in the culture medium. Normal hepatocytes secreted very low-density lipoprotein and low-density lipoprotein containing apolipoprotein B-100. Abetalipoproteinemic intestinal apolipoprotein B messenger RNA concentration was 4-5-fold higher than control values. However, the patients liver apolipoprotein B messenger RNA level was one fifth that of control normal and cirrhotic liver. Analysis of the patients intestinal and hepatic apolipoprotein B messenger RNA for posttranscriptional stop-codon insertion revealed normally edited transcripts. These results suggest that apolipoprotein B is synthesized as the product of a normally edited messenger RNA transcript, but not secreted, in abetalipoproteinemia.

Apolipoprotein B messenger RNA editing is developmentally regulated in pig small intestine: Nucleotide comparison of apolipoprotein B editing regions in five species

Apolipoprotein B (apo B) mRNA undergoes a posttranscriptional tissue-specific editing reaction which changes codon 2153 from glutamine (CAA) in apoB-100 mRNA to an in-frame stop codon (UAA) in apoB-48 mRNA. Small intestinal apo B mRNA was found to be predominantly (greater than 90%) unedited in fetal (40-day gestational age) piglets but greater than 95% edited in neonatal, suckling and adult animals. By contrast, both fetal, neonatal and adult pig liver contained greater than 99% unedited, apo B-100 mRNA. The nucleotide sequence spanning the edited region in apo B mRNA was found to be highly conserved. We speculate that the regulation of apo B mRNA editing may be developmentally modulated in pig small intestine.

Outpatient percutaneous liver biopsy in children.

Summary We reviewed data from 184 percutaneous liver biopsies performed as an outpatient procedure in 104 patients (5 weeks to 22 years of age) over a 4-year period. Hepatic allograft rejection was the indication for 130 of the biopsy procedures, while 54 were performed for a variety of indications in patients who had not undergone transplant. Abnormalities of coagulation that necessitated correction were present in 19 patients at the time of biopsy. Patients tolerated the procedure well. There were no major complications. None of the patients required blood product transfusion or hospitalization as a result of the procedure. Two patients suffered respiratory depression as a complication of sedation, which was easily reversed with administration of intravenous naloxone. Two specimens were insufficient for interpretation. We conclude that percutaneous liver biopsy in the proper outpatient setting can reduce the need for hospitalization solely for the purpose of the procedure.

OKT3 therapy for hepatic allograft rejection: Differential response in adults and children

The clinical courses following OKT3 therapy for hepatic allograft rejection (HAR) in adults and children have not been individually defined. We have reviewed our experience with OKT3 therapy for HAR in adults and children to compare: (1) the initial response to OKT3 therapy, (2) the clinical course following OKT3 therapy, and (3) the antimurine antibody response and immunologic monitoring results. Children required OKT3 therapy more frequently than adults: fourteen courses of OKT3 therapy were required in 130 orthotopic liver transplants (OLT) in 108 adult patients, whereas nineteen courses of OKT3 therapy were required in 94 OLT in 78 children (P<0.02). Repeat OKT3 therapy was not required in adults—however, four of nineteen courses of OKT3 therapy in children were repeat OKT3 therapy for rejection. No differences existed between adult and pediatric treatment groups with respect to number of prior OLT procedures, previous graft loss to rejection, percentage of ABO-incompatible grafts, frequency of positive donor-recipient lymphocyte crossmatches, or time to first rejection. The initial response to OKT3 therapy (rapid reversal, delayed reversal, and failure) was remarkably similar in adults and children. However, nine of 13 (70%) children with clear evidence of response to OKT3 treatment experienced breakthrough rejection or early recurrent rejection, whereas none of 12 adults suffered breakthrough rejection or early recurrent rejection (P<0.01). Early recurrent rejection did not correlate with delayed reversal of rejection, early return of CD3+ cells by peripheral blood monitoring, or development of anti-OKT3 antibodies. All 4 courses of OKT3 retreatment in children were successful in reversing rejection, and breakthrough rejection and early recurrent rejection did not occur. Overall graft and patient survival in pediatric patients requiring OKT3 therapy (67% and 73%) was not different from that in adults (71% and 79%). Results obtained in one patient provide the first evidence that successful OKT3 retreatment of HAR can be achieved in the presence of preexisting idiotypic anti-OKT3 antibody. In conclusion, OKT3 therapy for HAR was required more frequently in children than in adults. The clinical outcome following OKT3 therapy for HAR also differs markedly, with early recurrent rejection and breakthrough rejection occuring more frequently in children.

Isolated granulomatous gastritis in an adolescent

SummaryThis is a case of a 14 1/2-year-old black male with isolated granulomatous gastritis. The case is unusual in several aspects. For the first time this disorder has been seen in the pediatric age group. The symptoms and signs were more acute and severe than previously reported, and the inflammatory process involved the entire gastric mucosa. Several findings suggested an (auto)immune pathogenesis. The patient had a good clinical and histologic response to prednisone therapy, but the disease recurred after two years when therapy was discontinued.

Sequences and expression of the porcine apolipoprotein A-I and C-III mRNAs

Apolipoprotein A-I (ApoA-I) is the principal protein component of plasma high-density lipoprotein (HDL) and an activator of lecithin:cholesterol acyltransferase. Apolipoprotein C-III (ApoC-III) exchanges between triglyceride-rich lipoproteins and HDL and inhibits the lipolysis and uptake of triglyceride-rich lipoproteins. To study the expression of these Apo-encoding genes in the developing swine, apoA-I and apoC-III cDNAs from a lambda gt11 porcine liver cDNA library and apoC-III from a porcine genomic DNA library were isolated and sequenced. The predicted amino acid (aa) sequence and composition for ApoC-III matched the N-terminal aa sequence and composition of purified swine ApoC-III. Comparison among known ApoA-I and C-III aa sequences from various species revealed strict conservation of amphipathic helices. In adult pigs, the apoA-I mRNA was found predominantly in the intestine and liver, with a small amount detected in the testes. In contrast, apoC-III mRNA was found predominantly in adult liver. Developmentally, hepatic apoA-I and apoC-III mRNAs were expressed in livers of fetal, newborn, and suckling animals. Intestinal apoA-I and apoC-III mRNAs, however, were detected only in postpartum animals. Although intestinal apoA-I mRNA expression continued into the adult, intestinal apoC-III mRNA expression declined sharply after the newborn period.

Acute Liver Injury after Protracted Seizures in Children

Three children were observed to have extensive liver injury following protracted seizures. Two recovered with supportive care and one died from central nervous system complications. When first measured, the levels of aminotransferases were minimally elevated, but they increased to 250 to 8,000 times normal within 12 to 24 h after the seizure episode. They fell to near normal over the next 8 to 11 days in the survivors, and to one sixth of the peak level by 4 days in the patient who died. A percutaneous liver biopsy from one child demonstrated centrolobular necrosis consistent with severe ischemic injury. Common causes for liver dysfunction, including viral hepatitis, drug hepatitis, and Reye syndrome, were excluded on clinical, serologic, and histologic grounds. We reason that hepatic injury resulted from ischemia. We speculate that prior treatment with anticonvulsants, which are capable of inducing mixed-function oxidases in the liver, aggravated the ischemia-reperfusion injury by increasing the production of reactive oxygen intermediates and reducing cytoprotective mechanisms. Prevention of such injury should be directed toward control of seizures and early respiratory support when seizures occur, not restructuring medication regimens.

Sequence of the porcine apoA-I gene

The nucleotide sequence of the swine apoA-I gene (encoding apolipoprotein) has been determined. The structure of the gene is similar to that of the human gene, and the exons exhibit a high degree of homology with those of the human gene. The porcine apoA-I gene is located adjacent to the apoC-III gene, as in humans.