Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature.

Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases caused by defects in glycosylation. Nearly 100 CDG types are known so far. Patients present a great phenotypic diversity ranging from poly- to mono-organ/system involvement and from very mild to extremely severe presentation. In this literature review, we summarize the liver involvement reported in CDG patients. Although liver involvement is present in only a minority of the reported CDG types (22 %), it can be debilitating or even life-threatening. Sixteen of the patients we collated here developed cirrhosis, 10 had liver failure. We distinguish two main groups: on the one hand, the CDG types with predominant or isolated liver involvement including MPI-CDG, TMEM199-CDG, CCDC115-CDG, and ATP6AP1-CDG, and on the other hand, the CDG types associated with liver disease but not as a striking, unique or predominant feature, including PMM2-CDG, ALG1-CDG, ALG3-CDG, ALG6-CDG, ALG8-CDG, ALG9-CDG, PGM1-CDG, and COG-CDG. This review aims to facilitate CDG patient identification and to understand CDG liver involvement, hopefully leading to earlier diagnosis, and better management and treatment.

Liver abscesses in the Western pediatric population.

Background and study aims: Liver abscesses are rare in the Western pediatric population and data on predisposing factors and etiology are scarce. We aimed to describe predisposing factors, microbiological characteristics, and treatment. Patients and methods: Retrospective analysis of children admitted to two tertiary care hospitals in Belgium from 1 January 1996 to 31 December 2019. We analyzed clinical features, predisposing factors, imaging characteristics, microbiological data, treatment, and outcome in children with a liver abscess and compared these data with the literature. Results: We collected 24 cases with a male to female ratio of 1.4 and a median age of 3.2 years at time of diagnosis. Survival was 95.8%. Invasive culture specimens were obtained in 83.3% and showed growth of bacteria in 55%. Parenteral antibiotics were administered before invasive culture sampling in 80%. Liver abscesses were cryptogenic in four (16.7%) patients. Hepatobiliary disease was the most prevalent predisposing factor (n = 6; 25%), followed by recent antineoplastic therapy for malignancies (n = 5; 20.8%), intra-abdominal surgical pathology (n = 4; 16.7%) and umbilical venous catheters (n = 2; 8.3%). In two patients there was a parasitic origin (n = 2; 8.3%) and in one it was caused by Bartonellosis. There was no diagnosis of chronic granulomatous disease (CGD) in our cohort. Conclusions: Pediatric liver abscesses have a favorable outcome in the developed world. Whenever feasible, invasive abscess culture specimens should be obtained. In patients presenting with a cryptogenic liver abscess or atypical disease course, immunological workup should be ensured.

Use of a mobile application for self-management of pancreatic enzyme replacement therapy is associated with improved gastro-intestinal related quality of life in children with Cystic Fibrosis.

BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient's data and provide feedback. METHODS: A 6-month open label prospective multicenter interventional clinical trial was performed to assess effects of using the app on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module). RESULTS: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p< 0.0001). Similar improvements were reported by parents. Lower baseline CF-PedsQL-GI was associated with a greater improvement at M6 (p < 0.001). CONCLUSIONS: The results suggest that the MyCyFAPP may improve GI QOL for children with CF. This tool may help patients to improve self-management of PERT, especially those with considerable GI symptoms.

The role of endothelial cells in cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein which primarily acts as a chloride channel. CFTR has mainly been studied in epithelial cells although it is also functional and expressed in other cell types including endothelial cells. The present review summarizes current knowledge on the role of the endothelium in CF. More specifically, this review highlights the role of endothelial cells in CF in acting as a semipermeable barrier, as a key regulator of angiogenesis, coagulation, the vascular tone and the inflammatory responses. It could contribute to different aspects of the disease including cardiovascular symptoms, excessive blood vessel formation, pulmonary and portal hypertension and CF-related diabetes. Despite the important role of vascular endothelium in many biological processes, it has largely been under investigated in CF.

An Electronic Questionnaire for Liver Assessment in Congenital Disorders of Glycosylation (LeQCDG): A Patient-Centered Study.

Congenital disorders of glycosylation (CDG) are ultra-rare diseases showing a great phenotypic diversity ranging from mono- to multi-organ/multisystem involvement. Liver involvement, mostly nonprogressive, is often reported in CDG patients. The main objectives of this work were (1) to better understand liver involvement in CDG patients through a liver electronic questionnaire targeting CDG families (LeQCDG) and (2) to compare responses from LeQCDG participants with literature review regarding the prevalence of liver disease and the occurrence of liver symptoms in CDG patients. The network of patient advocacy groups, families and professionals (CDG & Allies - PPAIN) developed the LeQCDG by adapting validated published questionnaires. The LeQCDG was approved by an ethics committee, and the recruitment of patients and caregivers proceeded through social media platforms. Participants were asked to report past or present liver-related symptoms (e.g. hepatomegaly, liver fibrosis and cirrhosis) and laboratory results (e.g. biochemical and/or radiological). From 11 December 2016 to 22 January 2017, 155 questionnaires were completed. Liver disease was present in 29.9% of CDG patients. Main symptoms reported included hepatomegaly, increased levels of serum transaminases, fibrosis, steatosis and cirrhosis. The data obtained in this online survey confirm findings from a recent literature review of 25 years of published evidence (r = 0.927, P = 0.02). Our questionnaire collected large amounts of meaningful, clinical and patient-oriented data in a short period of time without geographic limitations. Internet-based approaches are especially relevant in the context of ultra-rare diseases such as CDG.

ADP-degrading enzymes inhibit platelet activation in bile duct-ligated rats.

BACKGROUND: The effect of cholestatic liver disease on primary hemostasis function remains ill-defined. OBJECTIVES: To determine platelet function and identify the mechanisms involved in the observed platelet function in cholestatic rats. METHODS: Platelet function was studied in a model of 2-week bile duct ligation and compared to that in sham-operated rats with and without a storage pool defect. RESULTS: ADP-induced and collagen-induced platelet aggregation were clearly impaired following bile duct ligation (P<0.01 for areas under the curve). Crossover experiments, with sham platelets in bile duct-ligated plasma and vice versa, demonstrated that this is due to inhibition by a plasmatic factor, as sham platelets aggregated less in cholestatic plasma (P<0.03) and to an equal extent as platelets from bile duct-ligated rats when they were in the same sham or cholestatic plasma. Moreover, in bile duct-ligated rats, platelet ultrastructure was unaffected and platelet aggregation was similar to that of sham platelets when resuspended in the same plasma (P-value not significant). Additionally, studies in storage pool-deficient rats showed no role of platelet exhaustion. The plasmatic factor causing impaired aggregation was shown to be increased total activity of ADP-degrading enzymes upon bile duct ligation (P<0.01), as there was no decreased aggregation with a stable ADP analog in bile duct-ligated rats (P-value not significant vs. sham-operated rats). Furthermore, preincubation of plasma from bile duct-ligated rats with ADP decreased aggregation more than was seen with sham plasma (P<0.01). CONCLUSIONS: Bile duct ligation does not affect intrinsic platelet function, but impairs platelet activation via release of ADP-degrading enzymes in the circulation.

Review article: blood platelet number and function in chronic liver disease and cirrhosis.

BACKGROUND: The liver plays a central role in coagulation and fibrinolysis but is also closely intertwined with the function and number of blood platelets. AIM: To describe and integrate all literature concerning blood platelets and liver disease by performing a thorough literature research. METHODS: A thorough literature research on 'blood platelets' and 'liver disease' was performed. RESULTS: Thrombocytopenia is a marked feature of chronic liver disease and cirrhosis. Traditionally, this thrombocytopenia was attributed to passive platelet sequestration in the spleen. More recent insights suggest an increased platelet breakdown and to a lesser extent decreased platelet production plays a more important role. Besides the reduction in number, other studies suggest functional platelet defects. This platelet dysfunction is probably both intrinsic to the platelets and secondary to soluble plasma factors. It reflects not only a decrease in aggregability, but also an activation of the intrinsic inhibitory pathways. The net effect, finally, is a decreased platelet function in the various types of chronic liver diseases and cirrhosis. Finally, recent data suggest that platelets are not only affected by but can also contribute to the liver disease process, as for instance, in viral hepatitis and cholestatic liver disease. CONCLUSION: Platelet research in liver disease is a growing area of investigation and could provide new pathophysiological insights.

Characterization of metabolites in domestic sow urine after intravenous administration of radioactive estrogen and corticosteroids.

We measured distribution of radioactivity among urinary metabolites excreted in nonpregnant and ovariectomized sows after intravenous injection of radionuclides (14carbon) labeled estrone, estradiol-17beta, cortisol, and corticosterone. Treatment with an enzyme preparation (Glusulase) containing both beta-glucuronidase and sulfatase activity, rendered extractable over 95% of the radioactivity recovered from urine with diethyl ether (estrogens) and ethyl acetate (corticoids). Only an additional 1 to 4% of the radioactivity was extracted following solvolysis of the aqueous residue remaining after enzyme hydrolysis and extraction. Radioactivity in nonpregnant sow urine was predominantly in the estrone fraction following injection of either estrone or estradiol-17beta. Moreover, the principal metabolite was estrone monoglucuronide. Only traces of estradiol-17beta and an estriol-like compound were detected. Two other isolates contained radioactivity. One compound probably was 2-methoxyestrone, but structure of the other compound (X1) could not be established. The principal urinary metabolites from injection of cortisol corresponded to chromatographic properties of tetrahydrocortisol and tetrahydrocortisone. Both metabolites were low in urine following injection of corticosterone. The major urinary metabolites from corticosterone injection corresponded to chromatographic properties of tetrahydrocorticosterone and corticosterone. Considerable radioactivity from injection of both corticoids was isolated in the cortol, cortolone, and 11-ketoetiocholanolone - 11beta-hydroxyetiocholanolone areas of chromatograms. The data for corticoids agree with similar data for the human being and cow.