Title
IMPACT OF ORTHOTOPIC LIVER TRANSPLANTATION ON DIAPHRAGMATICTROPHISM AND FUNCTION IN A PATIENT WITH MITOCHONDRIALNEUROGASTROINTESTINAL ENCEPHALOMYOPATHY
Authors
A. Sanchioni¹, A. Adamo¹, E. Prosperi², S. Tigano³, A. Bianchini³
1Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126 Bologna, Italy.
2Department of Digestive, Hepatic and Endocrine-Metabolic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
3Post-Surgical and Transplant Intensive Care Unit, Department of Digestive, Hepatic and Endocrine-Metabolic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
Background
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by TYMP mutations leading to thymidine phosphorylase deficiency, systemic nucleoside accumulation, mitochondrial DNA instability, and dysfunction. Clinically, it presents with severe gastrointestinal dysmotility, progressive cachexia, and neurological features including ptosis, external ophthalmoplegia, and demyelinating sensorimotor polyneuropathy, with mean mortality in the late 30s. Respiratory muscle involvement is uncommon; when present, it is typically secondary to cachexia or systemic decline rather than primary myopathic or neuropathic effect on the diaphragm. Current therapeutic approaches for MNGIE include allogeneic hematopoietic stem cell transplantation (HSCT), orthotopic liver transplantation (OLT) and enzyme replacement therapy (ERT). OLT shows lower perioperative mortality and superior safety compared to HSCT. OLT acts as enzyme replacement therapy in MNGIE by leveraging hepatic thymidine phosphorylase expression to restore enzymatic activity, thereby normalizing plasma thymidine and deoxyuridine levels. Clinical evidence indicates rapid, sustained biochemical correction with stabilization or partial improvement of features such as peripheral neuropathy and ambulation, while gastrointestinal dysmotility, low body weight, ophthalmoparesis, and leukoencephalopathy often persist due to irreversible pre-existing damage. [1,2]
Material, Methods and Results
A 34-year-old patient affected by MNGIE, presenting with a predominantly neurological phenotype, severe cachexia, and marked weight loss, was admitted to the Transplant Intensive Care Unit of S. Orsola-Malpighi University Hospital in Bologna in 2018. The patient underwent OLT. The postoperative course was complicated by difficult respiratory weaning requiring tracheostomy, prolonged mechanical ventilation (>1 month), and extended hospitalization. A diaphragmatic ultrasound assessment was performed prior to OLT and again seven years after transplantation, during hospitalization for septic shock secondary to Enterococcus faecium bacteremia. Preoperatively, ultrasound revealed severe diaphragmatic atrophy with a thickness of 1 mm, cranio-caudal excursion of about 5 mm, and a thickening fraction <10% during a spontaneous breathing trial (see Figure 1; video available upon request from amedeo.bianchini@aosp.bo.it). These findings, consistent with severe neuromuscular impairment, necessitated prolonged mechanical ventilation. Seven years after transplantation, diaphragmatic thickness had normalized (2.3 mm) with a normal thickening fraction (31%) and excursion (1.5 cm).
Discussion and Conclusions
Diaphragmatic ultrasound monitoring represents a valuable and noninvasive tool in the intensive care setting, allowing optimization of mechanical ventilation strategies and individualized weaning management.[3] In the present case, this technique proved useful in 1) assessing the progressive impact of MNGIE on respiratory muscle function, and 2) evaluating the therapeutic effect of OLT on both muscular and systemic recovery, as well as the restoration of respiratory autonomy. OLT resulted in complete normalization of diaphragmatic trophism and contractile performance, which in turn facilitated recovery during a subsequent episode of septic shock. These findings support the role of OLT as a potential disease-modifying treatment in MNGIE and highlight the utility of serial diaphragmatic ultrasound for long-term functional monitoring in complex critical care patients
