Onset of Hemophagocytic Lymphohistiocytosis during Piperacillin-Tazobactam Therapy in Three Children with Acute Focal Bacterial Nephritis.

Hemophagoytic lymphohistiocytosis (HLH) is a rare life-threatening disorder caused by overactivation of the immune system, associated with infections, autoimmune disorders, and malignancies. The pathological hallmark of HLH is phagocytosis of blood cells and platelets by activated macrophages and histiocytes. In this report, we describe the onset of HLH in three children, aged 2, 5 and 7 years old, during the treatment of acute focal bacterial nephritis (AFBN) with an antibiotic, piperacillin-tazobactam (PIPC-TAZ). AFBN is acute localized bacterial infection of the kidney without abscess formation. PIPC-TAZ was chosen for the treatment of AFBN, because it not only has indications for complicated urinary tract infections, but also covers most of the causative bacteria of urinary tract infections, including ß-lactamase-producing Escherichia coli. The clinical courses of the three patients were similar, and they were treated with PIPC-TAZ and amikacin (AMK) for AFBN. Fever went down 2 to 5 days later, and AMK was discontinued by day 6. However, fever recurred on 13 to 15 days after introduction of PIPC-TAZ therapy, even though all of the patients had no signs of recurrence of AFBN. The clinical features and laboratory tests of two patients fulfilled the criteria of HLH, whereas the other patient had initiated therapy before fulfilling the criteria. Cessation of PIPC-TAZ combined with corticosteroid therapy improved clinical symptoms. HLH of our patients was probably induced by PIPC-TAZ, as judged by the timing of the onset of HLH and the positivity of the drug-lymphocyte stimulation test. In conclusion, prolonged antibiotic therapy with PIPC-TAZ could be a cause of HLH.

Histological findings in the livers of patients with neonatal intrahepatic cholestasis caused by citrin deficiency.

AIM: To characterize the histological features of the livers of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), we studied specimens from 30 patients diagnosed with NICCD by genetically analyzing the SLC25A13 gene. METHODS: Liver biopsy specimens were subjected to hematoxylin-eosin, Azan, and Berlin-blue staining. RESULTS: Most specimens showed varying degrees of fibrosis. The degree of inflammation varied among the specimens, with half showing moderate or severe inflammatory changes. Fat deposition in hepatocytes was observed in almost all of the specimens, and severe fatty liver was noted in 20 (67%) of them. There was a mixture of two types of hepatocytes with macrovesicular or microvesicular fat droplets, and cholestasis was observed at a rate of 77%. Hemosiderin deposition, mostly mild and localized in periportal hepatocytes and macrophages in portal areas, was observed in 57% of the specimens. CONCLUSION: A combination of mixed macrovesicular and microvesicular fatty hepatocytes and the above-described findings, such as fatty liver, cholestasis, necroinflammatory reaction and iron deposition, are almost never observed in other liver diseases in infants and adults. We believe that NICCD is a disease with characteristic hepatopathological features.

A possible mechanism of neonatal intrahepatic cholestasis caused by citrin deficiency.

For this study, we investigated why cholestasis develops into neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and concluded that primary mitochondrial impairment associated with the delayed maturity of bile acid metabolism may contribute to the occurrence of NICCD.

Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients.

A deficiency of citrin, which is encoded by the SLC25A13 gene, causes both adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). We analyzed 16 patients with NICCD to clarify the clinical features of the disease. Severe intrahepatic cholestasis with fatty liver was the most common symptom, but the accompanying clinical features were variable, namely; suspected cases of neonatal hepatitis or biliary atresia, positive results from newborn screening, tyrosinemia, failure to thrive, hemolytic anemia, bleeding tendencies and ketotic hypoglycemia. Laboratory data showed elevated serum bile acid levels, hypoproteinemia, low levels of vitamin K-dependent coagulation factors, and hypergalactosemia. Hypercitrullinemia was detected in 11 out of 15 patients examined. Most of the patients were given a lactose-free and/or medium chain triglycerides-enriched formula and lipid-soluble vitamins. The prognosis of the 16 patients is going fairy well at present, but we should observe these patients carefully to see if they manifest any symptom of CTLN2 in the future.

A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency.

UNLABELLED: Adult-onset type II citrullinaemia, caused by deficiency of the citrin protein encoded by the SLC25A13 gene, is characterised by a liver-specific argininosuccinate synthetase deficiency. DNA analysis for citrin deficiency revealed that SLC25A13 mutations are the cause of a particular type of neonatal intrahepatic cholestasis. We retrospectively investigated nine infants with cholestatic jaundice of unknown origin, detected by newborn screening over a period of 17 years, to determine the role of SLC25A13 defects in children. The results of the newborn screening were varied; four neonates were positive for hypermethioninaemia, two for hyperphenylalaninaemia, one for hypergalactosaemia and two for both hypermethioninaemia and hypergalactosaemia. Clinical characteristics of the patients were severe intrahepatic cholestasis, hypercitrullinaemia, and fatty liver. The symptoms resolved in all patients by 12 months of age without special treatment other than nutritional management. Although five patients were lost to follow-up, we detected SLC25A13 mutations in the remaining four patients examined. CONCLUSION: the differential diagnosis of cholestatic jaundice of unknown origin in infants should therefore include citrin deficiency. In this paper, we stress the importance of newborn screening to detect infants with neonatal intrahepatic cholestasis caused by citrin deficiency.

Response of anti-oxidant enzymes mRNA in the neonatal rat liver exposed to 1,2,3,4-tetrachlorodibenzo-p-dioxin via lactation.

BACKGROUND: The aim of this study was to assess the response to dioxin-induced oxidative stress in neonates via lactation in the model we have described previously. METHODS: Maternal rats were treated with a single dose of 50 or 100 micro mol/kg 1,2,3,4-tetrachlorodibenzo-p-dioxin (TCDD) on the first day postpartum (day 1). Messenger RNA levels of the key anti-oxidant enzymes (AOE), phospholipid hydroperoxide-glutathione peroxidase (PH-GPx), cellular-glutathione peroxidase (cell-GPx), copper-zinc superoxide dismutase (CuZn SOD), manganese superoxide dismutase (Mn SOD) and catalase (CAT) in the neonatal and maternal livers were determined by a competitive reverse transcription- polymerase chain reaction method. RESULTS: Lactational transfer of 1,2,3,4-TCDD induced an inhibition of PH-GPx and cell-GPx mRNA in the neonatal liver on day 2 to 68 (P < 0.01) and 62% (P < 0.05) of the control at 100 micro mol/kg, respectively. Both GPx mRNA returned to control levels on day 6 and thereafter increased to levels higher than the controls on day 10. In the dam rat, 10 days after the treatment, no remarkable change of PH-GPx or cell-GPx mRNA was observed. Copper-zinc superoxide dismutase and CAT mRNA of neonates on day 2 were also suppressed at 100 micro mol/kg and then slightly increased on day 10. However, Mn SOD mRNA was not suppressed, but increased to a 2.1-fold level of the control (P < 0.05) on day 10 with 100 micro mol/kg 1,2,3,4-TCDD. CONCLUSION: Quantitative analysis of AOE mRNA showed that PH-GPx and cell-GPx mRNA, as well as CuZn SOD and CAT mRNA in the neonatal liver were suppressed for a short period of time by 1,2,3,4-TCDD exposure via lactation. Dioxin induced oxidative stress by lactational transfer may alter pretranslation regulation of protective AOE in neonates.