Carbamazepine mitigates parenteral nutrition–associated liver disease in a novel ambulatory piglet model

Abstract

Background Parenteral nutrition (PN) remains a critical therapeutic option in patients who cannot tolerate enteral feeding. However, although lifesaving, PN is associated with significant side effects, including liver injury, the etiology of which is multifactorial. Carbamazepine (CBZ), an antiepileptic medication, is known to modulate hepatic fibrosis and hepatocellular injury in a variety of liver diseases. We hypothesized that CBZ could prevent PN‐associated liver disease (PNALD), which we tested by using our novel ambulatory PN piglet model. Methods Piglets were fitted with jugular catheters and infusion pumps for PN and randomized to enteral nutrition (n = 7), PN (n = 6), or PN with parenteral CBZ (n = 6) for 2 weeks. Serum and liver tissue were analyzed via light microscopy, quantification of serum liver injury markers, Ki67 and cytokeratin‐7 indexing, and real‐time quantitative polymerase chain reaction. Results PN‐fed piglets in our model developed manifestations of PNALD—particularly, increased serum bilirubin, gamma‐glutamyltransferase, liver cholestasis, and Ki67 expression compared with that of EN‐fed animals (P < 0.03). CBZ therapy in PN‐fed animals led to a significant reduction in these markers of injury (P < 0.05). Investigation into the mechanism of these therapeutic effects revealed increased expression of sterol regulatory element‐binding protein 1 (SREBP‐1), peroxisome proliferator‐activated receptor alpha (PPAR‐α), and fatty acid binding protein (FABP) in PN‐fed animals receiving CBZ (P < 0.03). Further investigation revealed increased LC3 expression and decreased lysosomal‐associated membrane protein (LAMP1) expression with CBZ (P < 0.03). Conclusion CBZ administration mitigates PNALD severity, suggesting a novel therapeutic strategy targeting PN‐associated side effects, and may present a paradigm change to current treatment options.

Intestinal failure-associated liver disease in the neonatal ICU: what we know and where we’re going

“…Song et al investigated the effect of carbamazepine on a TPN piglet model. This antiepileptic and autophagy enhancer when combined with TPN vs. TPN alone led to a significant decrease in mean serum bilirubin, GGT, and cholestasis, as well as Ki67 expression ( P = 0.01), indicating that carbamazepine can potentially mitigate the severity of PNALD [22 ▪ ]. These studies show that FXR and autophagy regulators may be future therapeutic strategies for ameliorating the progression of IFALD.…”

Liver complications of total parenteral nutrition: the latest therapeutic strategies

“…Song et al hypothesized that this drug could also prevent the development of PNALD. A study on piglets was conducted and it was found that the administration of CBZ alleviated the severity of PNALD [48].…”

Novel Therapeutic Approaches for Mitigating Complications in Short Bowel Syndrome

“…Song et al (2022) introduced supplementary oral carbamazepine (30 mg/kg/day) to piglets given TPN and observed a decrease in hepatic cholestatic deposits with CBZ treatment (12.5 ± 2.4, p = 0.038) vs. TPN animals (TPN 15.7 ± 2.2, p < 0.001). Additionally, elevated GGT levels in TPN (26.3 ± 6.9 IU/L) decreased when CBZ was introduced (19.8 ± 2.7 IU/L, p = 0.047) [ 117 ] ( Table 1 ).…”