A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction.

SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane protein required for transporting glucose-6-phosphate (Glc-6P) into the ER. Once transported into the ER, Glc-6P is subsequently hydrolyzed by tissue-specific phosphatases to glucose and inorganic phosphate during times of glucose depletion. Pathogenic variants in SLC37A4 cause an established recessive disorder known as glycogen storage disorder 1b characterized by liver and kidney dysfunction with neutropenia. We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423∗), in SLC37A4; the affected individuals were from four unrelated families. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans, while N-glycans in fibroblasts and undifferentiated iPSC were normal. Due to the liver-specific nature of this disorder, we generated a CRISPR base-edited hepatoma cell line harboring the c.1267C>T (p.Arg423∗) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.

Effect of N-acetyl cysteine in children with metabolic dysfunction-associated steatotic liver disease-A pilot study.

BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and (LS) in children with obesity and biopsy-confirmed MASLD. METHODS: Thirteen children (n = 13; age: 13.6 ± 2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200 mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. HOMA-IR was calculated. RESULTS: Sixteen-week NAC treatment improved (baseline adjusted between-group p < .05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and insulin resistance (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes. CONCLUSIONS: Sixteen-week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.

Vaping Induced Severe Erosive Esophagitis.

Esophagitis can be attributed to several etiologies including gastroesophageal reflux disease, caustic ingestion, medication or pill induced, radiotherapy, infectious or eosinophilic disease. There are also new consumer items on the market which can cause harmful side effects, including erosive esophagitis. In this case, we present an otherwise healthy teenage male with a history of daily vape usage with a clinical presentation of odynophagia, who was subsequently diagnosed with vaping associated esophagitis. There is currently little to no data available on the occurrence of vaping-associated esophagitis, particularly in adolescents.

Foreign Body in the Bronchus Intermedius: Inadvertent Deployment of a Bravo Wireless pH Probe in the Airway.

The Bravo pH probe is a wireless capsule allowing remote quantification of gastroesophageal reflux. A 14-year-old male presented for Bravo probe placement. Following esophagogastroduodenoscopy, attachment of the Bravo probe was attempted. Immediately, the patient began coughing without oxygen desaturation. Repeat endoscopy did not reveal the probe within the esophagus or stomach. He was then intubated, and fluoroscopy demonstrated a foreign body within the bronchus intermedius. Rigid bronchoscopy was performed to retrieve the probe using optical forceps. This is the first case of pediatric inadvertent airway deployment requiring retrieval. We recommend endoscopic visualization of the delivery catheter entering the cricopharyngeus before Bravo probe deployment, then followed by repeat endoscopy to confirm position of the probe after attachment.

Energy- and protein-enriched formula improves weight gain in infants with malnutrition due to cardiac and noncardiac etiologies.

BACKGROUND: We aimed to assess safety, tolerability, and improvement in weight gain with an energy- and protein-enriched formula (EPEF) in infants with poor growth. METHODS: Infants aged 1-8 months with poor growth received EPEF for 16 weeks. Our primary objective was improvement in weight as measured by change in weight-for-age z-score (WAZ) and weight gain velocity (grams per day) ≥ median for age. Secondary objectives included improvement in other anthropometric z-scores, formula tolerance, and safety. RESULTS: Twenty-six patients with poor growth due to congenital heart disease (n = 15), other organic causes (n = 9), and nonorganic causes (n = 2) completed the study per protocol. Mean daily energy intake was 123 ± 32 kilocalories per kilogram of body weight, with >90% of energy coming from EPEF. Weight gain velocity exceeded the median for 83% (20 of 24) and 67% (16 of 24) of infants at ≥1 time point and for the overall study period, respectively. Mean ± SD WAZ improved from -2.92 ± 1.04 at baseline to -2.01 ± 1.12 at 16 weeks (P = 0.0001). Z-scores for weight-for-length and head circumference (P = 0.0001) and for length-for-age (P = 0.003) improved significantly at 16 weeks. Compared with baseline, stool consistency was different at 2, 4, and 16 weeks (P < 0.05). There were no significant differences in vomiting, fussiness, or daily number of stools while there was a decrease or no change in spit-up, flatulence, crying, or gassiness. CONCLUSION: EPEF is safe, well tolerated, and improves weight gain in infants with poor growth.

Herpes simplex virus hepatitis in infants: clinical outcomes and correlates of disease severity.

OBJECTIVE: To better characterize the clinical outcomes of infants with herpes simplex virus (HSV) infection and identify useful correlates of disease severity. STUDY DESIGN: Infants aged ≤6 months with HSV infection treated between 1999 and 2009 were identified. In patients with concurrent hepatitis, laboratory and clinical variables were examined to identify predictors of specific outcomes, including death or the need for liver transplantation and the need for intensive care. RESULTS: Of the 15 patients enrolled, 4 (27%) had fatal disease and 2 (13%) required liver transplantation. Infants who lacked skin lesions (P = .04), had a positive HSV polymerase chain reaction result (P = .01), had more severe thrombocytopenia (P = .001), or had other organ system dysfunction (P = .002) were more likely to require intensive care. A higher International Normalized Ratio value (P = .001) and peak total bilirubin level (P = .0002) were predictive of death or the need for liver transplantation. Peak direct bilirubin level was predictive of the need for intensive care and of death or the need for liver transplantation (P = .04 and .009, respectively). CONCLUSIONS: HSV hepatitis represents a broad spectrum of disease from mild aminotransferase elevation to fulminant liver failure and death. HSV DNA detected by polymerase chain reaction, a lack of skin lesions, and the degree of coagulopathy, thrombocytopenia, and cholestasis portend unfavorable outcomes.

Performance of the AST-to-platelet ratio index as a noninvasive marker of fibrosis in pediatric patients with chronic viral hepatitis.

We investigated the performance of aspartate aminotransferase to platelet ratio index (APRI) as a noninvasive marker of fibrosis and cirrhosis in children with chronic viral hepatitis. All of the patients 0 to 20 years old with chronic hepatitis B or C presenting at a tertiary medical center from 1992 to 2008 were identified. Thirty-six patients were evaluated with 48 biopsy results. The areas under the receiver operating characteristic curve were 0.71 for fibrosis and 0.52 for cirrhosis. When examining subgroups, the APRI performed better in older patients and in those with vertically transmitted hepatitis C virus. Further research into APRI and the other noninvasive markers of fibrosis in children with chronic viral hepatitis is warranted.

Neonatal gastric lactobezoar: management with N-acetylcysteine.

Gastric lactobezoars (GLBs) are the most common form of bezoars in neonates and consist of aggregations of undigested milk constituents. GLB can present with a variety of intra-abdominal clinical symptoms, and occasionally, extra-abdominal symptoms. Conservative management, with a period of bowel rest and intravenous fluids, is the most common treatment regimen for uncomplicated GLB. Surgical measures are reserved for the rare complications of obstruction and/or perforation. Although limited, utilization of the protein-cleaving enzyme N-acetylcysteine has been described for the disintegration of GLB in toddlers. In this paper, we discuss the first documented use of N-acetylcysteine for a neonatal GLB. Supporting literature, the infant's unusual presentation, and details of the treatment regimen are discussed.

High-efficiency transduction of liver cancer cells by recombinant adeno-associated virus serotype 3 vectors.

Recombinant vectors based on a non-pathogenic human parvovirus, the adeno-associated virus 2 (AAV2) have been developed, and are currently in use in a number of gene therapy clinical trials. More recently, a number of additional AAV serotypes have also been isolated, which have been shown to exhibit selective tissue-tropism in various small and large animal models. Of the 10 most commonly used AAV serotypes, AAV3 is by far the least efficient in transducing cells and tissues in vitro as well as in vivo. However, in our recently published studies, we have documented that AAV3 vectors transduce human liver cancer - hepatoblastoma (HB) and hepatocellular carcinoma (HCC) - cell lines extremely efficiently because AAV3 utilizes human hepatocyte growth factor receptor as a cellular co-receptor for binding and entry in these cells. In this article, we describe the steps required to achieve high-efficiency transduction of human liver cancer cells by recombinant AAV3 vectors carrying a reporter gene. The use of recombinant AAV3 vectors carrying a therapeutic gene may eventually lead to the potential gene therapy of liver cancers in humans.

Human hepatocyte growth factor receptor is a cellular coreceptor for adeno-associated virus serotype 3.

Adeno-associated viruses (AAVs) use a variety of cellular receptors/coreceptors to gain entry into cells. A number of AAV serotypes are now available, and the cognate receptors/coreceptors for only a handful of those have been identified thus far. Of the 10 commonly used AAV serotypes, AAV3 is by far the least efficient in transducing cells in general. However, in our more recent studies, we observed that AAV3 vectors transduced human liver cancer cells remarkably well, which led to the hypothesis that AAV3 uses hepatocyte growth factor receptor (HGFR) as a cellular coreceptor for viral entry. AAV3 infection of human liver cancer cell lines was strongly inhibited by hepatocyte growth factor, HGFR-specific small interfering RNA, and anti-HGFR antibody, which corroborated this hypothesis. However, AAV3 vectors failed to transduce murine hepatocytes, both in vitro and in vivo, suggesting that AAV3 specifically uses human HGFR, but not murine HGFR, as a cellular coreceptor for transduction. AAV3 may prove to be a useful vector for targeting human liver cancers for the potential gene therapy.