Unusual Cystic Fibrosis Transmembrane Conductance Regulator Mutations and Liver Disease: A Case Series and Review of the Literature.

Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene, deranging the activity of chloride channels on the epithelial cell surface. Herein we describe end-stage liver disease in 3 infants with rare CFTR gene mutations; 2 of them were heterozygous. Case 1 was a premature male infant with negative CF screening at birth who developed a small bowel obstruction in the neonatal period requiring an ileostomy, with subsequent cholestatic liver disease and portal hypertension. In addition, he was noted to have frequent respiratory infections prompting a sweat test, which was positive. Genetic testing revealed that he was heterozygous for P.1177F. He then underwent a successful liver transplant. Case 2 was a female infant who developed progressive cholestasis with poor weight gain and was found to have neonatal hepatitis on liver biopsy. A sweat test was negative and genetic testing revealed she was heterozygous for CFTR and PEX26 gene mutations. She subsequently developed pneumatosis involving the cecum that was treated conservatively, followed by a successful liver transplant. Case 3 was a male infant who developed progressive liver disease, with liver biopsy showing neonatal hepatitis. He was extensively investigated but had a negative sweat test on repeated studies. Genetic testing revealed that the patient was heterozygous P.K186N-variant in the AKRID1 gene and homozygous P.R75Q-variant in the CFTR gene. Unfortunately, he succumbed to an acute upper gastrointestinal hemorrhage. Rare and unusual CFTR mutations, even in the heterozygous form, may be a feature in otherwise undiagnosed end-stage liver disease of infancy.

Clinicopathologic features of post-transplant lymphoproliferative disorders arising after pediatric small bowel transplant.

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT--isolated or in combination with other organs--showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.

Expansion of transplanted hepatocytes during liver regeneration.

BACKGROUND: Successful clinical application of hepatocyte transplantation has been limited by poor engraftment of the recipient liver by transplanted hepatocytes. METHODS: To address the hypothesis that liver regeneration induced by an acute hepatotoxic injury promotes expansion of transplanted hepatocytes, we injected beta-galactosidase-labeled hepatocytes intrasplenically into mice 24 hr after treatment with carbon tetrachloride (CCl4) and into untreated controls. RESULTS: Macroscopic examination of whole liver segments identified clusters of transplanted hepatocytes uniformly spread on the capsular surface of the recipient liver and in the liver core following the distribution pattern of portal vein branches. Frozen sections showed that although the degree of initial engraftment of transplanted hepatocytes was similar in CCl4-treated and control livers, there was a fourfold increase of engrafted hepatocytes in CCl4-treated livers 10 days after transplantation which persisted to 28 days. CONCLUSIONS: We conclude that the number of transplanted hepatocytes increases in response to regeneration signal triggered by an acute hepatocyte-specific liver injury.

Mitochondrial enlargement and crystalloid matrix arrays: distinctive finding in childhood portal hypertension due to cavernous transformation of the portal vein.

Elongated, enlarged mitochondria with crystalloid matrix arrays were discovered in periportal hepatocytes in 11 of 12 children (age 6 to 15 years) with portal hypertension, minimal alterations on light microscopy, and cavernous transformation of the portal vein. Eleven of the children were clinically well before onset of symptoms, one was anemic with megaloblastic bone marrow, and a second had undergone renal transplantation. Minimal findings by light microscopy included slight portal fibrosis (six cases), pericentral venular fibrosis (one case), mild, patchy sinusoidal sclerosis (one case), central venular and sinusoidal dilatation (two cases), and mild hepatocellular lipid accumulation (one case). Four were judged normal by routine histologic examination. Subtle depletion of periportal hepatocellular glycogen was present in six. In 10, subtle striation or granularity of periportal hepatocyte cytoplasm was visible with high-magnification light microscopy. Although similar mitochondria are seen sporadically in hepatocytes in diverse settings, enlarged mitochondria with crystalloid matrix inclusions have not been previously reported as a uniform feature in children with portal hypertension due to cavernous transformation of the portal vein and minimal other hepatic alteration. It is postulated that the mitochondria are adapting in response to an abnormal metabolic milieu created by hemodynamic alterations.

Polymerase chain reaction assay for the detection of Helicobacter pylori in gastric biopsy specimens: comparison with culture, rapid urease test, and histopathological tests.

Ulcer recurrence is probably related to residual Helicobacter pylori (H pylori). Histological examination and culture are considered to be the most specific tests. CLO test is a rapid but less specific test, which is usually used as an alternative test to culture. The aim of this study was to investigate the efficiency of a simplified polymerase chain reaction (PCR) assay as a procedure for the diagnosis of gastric H pylori infection of patients. Biopsy specimens were obtained from antral mucosa of 58 patients at endoscopy and submitted to four tests for detection of H pylori. The bacteria were found in 53%, 43%, 48%, and 50% of patients according to the results of PCR, CLO test, culture, and histological examination. Twenty three patients had both negative histology and negative culture and PCR was negative in all of these. Thirteen patients were not classified because only histology or culture was positive and 10 of these had a positive PCR test. When the diagnosis of H pylori was established by agreement with both histology and culture or three positive tests out of four, 29 patients were H pylori positive (28 having had three positive tests and one displaying positive histology and culture), and 26 were negative, and three undetermined. PCR proved the most sensitive and specific test. These results suggest the simplified PCR assay may be a valuable test for the detection of H pylori.

Secrecao basal pulsatil de hormonio luteinizante e de testosterona no homem adulto normal. / Pulsatile basal secretion of luteinizing hormone and testosterone in normal adult men

Em 10 homens adultos normais estudou-se atraves de colheitas seriadas durante 3 horas, a secrecao basal pulsatil de hormonio luteinizante (LH), procurando correlaciona-la com a da testosterona. Os resultados obtidos demonstram uma importante e significativa correlacao dos censores superiores e inferiores dos pulsos de LH entre si, sendo,em media, os primeiros 2 vezes maiores que os ultimos.Alem disso, ambos se correlacionam positivamente com a media dos niveis plasmaticos de 3 horas. Semelhante padrao de correlacao e encontrado quando se analisa a secrecao de testosterona. Estas relacoes limitariam a oscilacao dos valores individuais, de cada paciente, a um determinado intervalo de niveis hormonais, naquele periodo de estudo. No conjunto, as observacoes obtidas favorecem a ideia de que no homem adulto, em condicoes basais, a secrecao pulsatil de LH, decorrente de um ritmo ultradiano inerente ao sistema nervoso central, poderia ter alguns dos seus parametros quantitativos refletidos na secrecao de testosterona pelos testiculos