Outcomes of Pediatric Liver Transplantation in Glycogen Storage Disease Type 1b-A Single-Center Experience.

BACKGROUND: Liver transplantation (LT) normalizes fasting tolerance in glycogen storage disease type (GSD) 1b. However, reported outcomes post-LT with respect to correction of neutropenia, infection risk and growth are varied. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently shown to improve neutropenia in GSD1b patients. METHODS: In this single-center retrospective study, we reviewed all children who underwent LT for GSD1b. Neutropenia, dose of granulocyte colony-stimulating factor (G-CSF), unplanned hospital attendance, anthropometrics, graft rejection, survival, and the effects of dapagliflozin were analyzed. Data from protocol biopsies obtained at 1, 5, and 10 years post-LT and immunosuppression levels were collected. RESULTS: Eight children (6 female), all on G-CSF pre-transplant, underwent cadaveric LT for GSD1b at median age 3.6 years (IQR 3.3-5.1) with mean follow-up time of 10.3 years (95% CI 7.5-13.1). Neutrophil count and G-CSF requirement did not improve post-LT. Although a reduction in unplanned hospital attendance due to infection (0.98 [95% CI 0.76-1.26] vs. 0.49 [95% CI 0.41 to 0.57] per person-year, p < 0.01) was observed, gastrointestinal complaints and graft dysfunction accounted for a similar hospitalization burden pre- versus post-LT. Body mass index (BMI) reduced post-LT (Z-score 1.47 [95%CI 0.39-2.23] vs. 0.56 [95% CI -0.74 to 1.45], p = 0.02), with no significant change in height. Although all children and grafts have survived, 75% of recipients developed rejection, despite adequate immunosuppression levels, with two children having been found to have developed significant fibrosis on their 5-year protocol biopsy. Although dapagliflozin allowed cessation of G-CSF, no improvement in neutrophil count was observed. Despite this, a reduction in gastrointestinal and infection-related morbidity was noted following dapagliflozin. CONCLUSION: Although LT normalizes fasting tolerance in GSD1b and reduces hospital attendance due to infection, morbidity from infection and gastrointestinal manifestations persist. Children in our cohort experienced high rates of rejection necessitating titration of immunosuppression to balance risk of infection against organ rejection. Future studies should investigate whether early introduction of SGLT2 inhibitors post-LT impact morbidity in this group.

Long-term outcome after liver transplantation in children with type 1 glycogen storage disease.

Patients with GSD type 1 (von Gierke disease) are initially managed medically to maintain normoglycemia. However, if they do not achieve good metabolic control, LT is then considered. We describe the long-term outcome of 6 children with GSD type 1 who underwent LT. Retrospective chart review of the data of 6 children with GSD type 1 who underwent LT at National University Hospital, Singapore, from May 1998 to October 2018, was performed. The median (IQR) age at diagnosis of the GSD was 1 year (0.92-5.50) and at transplant was 13.88 years (11.46-16.38). All of the patients had elevated liver enzymes, hypercholesterolemia, hypertriglyceridemia, and hyperlactatemia prior to transplant. All of the patients are alive at the time of analysis and follow-up. None of them required a re-transplant. For the three patients who had hypoglycemia pretransplant, there was no recurrence post-transplant. All of the patients had normalization of liver enzymes by 1 year post-transplant. Long-term outcome of patients with GSD who underwent LT has been positive with improvement in metabolic control for most patients. We report the unusual finding of two siblings with persistent hyperuricemia post-transplant requiring allopurinol.

Immunological features and complications in patients with glycogen storage disease 1b after living donor liver transplantation.

BACKGROUND: LT is an elective treatment choice for children diagnosed with GSD1b that can improve their quality of life and stabilize their glucose intolerance. However, careful attention should be paid to immunosuppression after LT due to the susceptibility to infection because of neutropenia and neutrophil dysfunction in GSD1b patients. This study revealed the immunological features and complications in the early post-LT period. METHODS: We compared findings between 11 (1.9%) children with GSD1b and 273 children with BA. Analyses using the PSM were performed to overcome selection bias. RESULTS: Despite persistent low tacrolimus trough levels in GSD1b patients, none of these children developed TCMR within 1 month after LDLT (GSD1b: 0/11 [0%] vs. BA: 86/273 [31.5%], p = .038). This result was also confirmed in PSM. The incidence of bloodstream infections was higher in GSD1b patients than in BA patients in the early phase of the post-transplant period (GSD1b: 4/11 [36.4%] vs. BA: 33/273 [12.1%], p = .041), but not reach statistical significance in PSM. In a phenotypic analysis, the ratio of CD8+ T cells in GSD1b recipients' peripheral blood mononuclear cell samples was lower than in recipients with BA through the first month after LDLT. CONCLUSIONS: We found that GSD1b recipients were more likely to develop postoperative bloodstream infection than recipients with BA but did not experience TCMR despite low tacrolimus levels in the early post-LDLT period. A tailored immunosuppression protocol should be prepared for GSD1b recipients after LDLT.

Longterm Outcomes of Living Donor Liver Transplantation for Glycogen Storage Disease Type 1b.

Glycogen storage disease (GSD) type 1b (Online Mendelian Inheritance in Man [OMIM] 232220) is an autosomal recessive inborn error of carbohydrate metabolism caused by defects in glucose-6-phosphate translocase. GSD1b patients have severe hypoglycemia with several clinical manifestations of hepatomegaly, obesity, a doll-like face, and neutropenia. Liver transplantation (LT) has been indicated for severe glucose intolerance, poor metabolic control (PMC), and poor growth (PG). We retrospectively reviewed 11 children with GSD1b who underwent living donor liver transplantation (LDLT) at the National Center for Child Health and Development in Tokyo, Japan. Between November 2005 and December 2018, 495 children underwent LDLT with an overall 10-year patient and graft survival of 90.6% and 88.9%, respectively. Of these, LT was indicated for 11 patients with GSD1b. All patients are doing well with the stabilization of glucose intolerance and decreased hospitalization for infectious complications. Demand for granulocyte colony-stimulating factor significantly decreased. However, although LT stabilized the blood glucose level, the platelet function was not improved. The posttransplant developmental quotient (DQ) remained similar to the pretransplant DQ without deterioration. LDLT is a feasible procedure for GSD1b patients with regard to the longterm prognosis. LT should be considered for patients with severe glucose intolerance to protect the cognitive function against hypoglycemic encephalopathy and to ameliorate PMC and PG.

Liver transplantation for adenomatosis: European experience.

The aim of this study was to collect data from patients who underwent liver transplantation (LT) for adenomatosis; to analyze the symptoms, the characteristics of the disease, and the recipient outcomes; and to better define the role of LT in this rare indication. This retrospective multicenter study, based on data from the European Liver Transplant Registry, encompassed patients who underwent LT for adenomatosis between January 1, 1986, and July 15, 2013, in Europe. Patients with glycogen storage disease (GSD) type IA were not excluded. This study included 49 patients. Sixteen patients had GSD, and 7 had liver vascular abnormalities. The main indications for transplantation were either a suspicion of hepatocellular carcinoma (HCC; 15 patients) or a histologically proven HCC (16 patients), but only 17 had actual malignant transformation (MT) of adenomas. GSD status was similar for the 2 groups, except for age and the presence of HCC on explants (P = 0.030). Three patients with HCC on explant developed recurrence after transplantation. We obtained and studied the pathomolecular characteristics for 23 patients. In conclusion, LT should remain an extremely rare treatment for adenomatosis. Indications for transplantation primarily concern the MT of adenomas. The decision should rely on morphological data and histological evidence of MT. Additional indications should be discussed on a case-by-case basis. In this report, we propose a simplified approach to this decision-making process.

Successful Anesthetic Management of an Adult Patient With Glycogen Storage Disease Type 1 During Liver Transplant: A Case Report.

Glycogen storage disease type 1 is a congenital abnormality of metabolism caused by the deficiency of the glucose-6-phosphatase enzyme, essential in glucose homeostasis. Patients with this disease are at high risk of developing hypoglycemia, hyperlipidemia, lactic acidemia, growth retardation, neutropenia, inflammatory bowel disease, and many other severe complications, such as hepatic adenomas converting into hepatocellular carcinomas. To prevent these complications, a liver transplant is the ultimate method of treatment. We present the successful anesthesia management for a 21-year-old man who had gross hepatomegaly, severe hypoglycemia, and hyperlactatemia and who received a liver transplant from his mother, which is a substantial challenge for anesthesiologists. Anesthesiologists should know the underlying pathophysiological condition and perform a comprehensive preoperative evaluation to determine the correct anesthesia plan in patients with glycogen storage disease type 1 who will undergo an orthotopic liver transplant due to multiple system disorders. Successful perioperative management of patients with glycogen storage disease type 1 relies on effective communication and collaboration between specialists through a multidisciplinary team approach.

Glycemic management in living donor liver transplantation for patients with glycogen storage disease type 1b.

GSD type 1b is an autosomal recessive inborn error of carbohydrate metabolism caused by defects of the G6Pase translocase (G6PT). Patients with GSD1b have severe hypoglycemia with several clinical manifestations of hepatomegaly, obesity, a doll-like face, and neutropenia. LT has been indicated for severe glucose intolerance. This study retrospectively reviewed glycemic management of eight children with a diagnosis of GSD1b who underwent liver transplantation (LDLT). Between November 2005 and September 2011, 172 children underwent LDLT, of which eight (4.7%) were indicated for GSD1b. Glucose-rich solution was placed in all children when preoperative fasting started to prevent preoperative hypoglycemia. During the reperfusion of graft, the glucose administration could significantly be reduced to maintain the proper blood glucose level, while the dosage of glucose administration prior to reperfusion of graft was significantly higher in the patients with GSD1b in comparison with patients with BA. The current series also showed significantly high incidence of infectious complications in the patients with GSD1b owing to persistent neutropenia after LDLT. All patients are doing well with an excellent quality of life owing to the stabilization of glucose intolerance. This current study clearly documented drastic change in glycemic management in LDLT. Cautious perioperative management to prevent hypoglycemia and infection is crucial for successful LT.

Liver transplantation in glycogen storage disease: a single-center experience.

BACKGROUND: Glycogen storage diseases (GSDs) are inherited glycogen metabolic disorders which have various subtypes. GSDs of type I, III, IV, VI, and IX show liver involvement and are considered as hepatic types of GSDs. Thus, liver transplantation (LT) has been proposed as a final therapy for these types of GSD. LT corrects the primary hepatic enzyme defect; however, the long-term outcomes of LT in these patients have not been extensively evaluated so far. There are few reports in the English literature about the outcome of GSD patients after LT. There has been no report from Iran. The present retrospective study aimed to evaluate the long-term outcomes of eight patients with GSD types I, III, and IV who underwent LT in the affiliated hospitals of Shiraz University of Medical Sciences, from March 2013 to June 2021. During this period, there were no patients with GSD VI and IX identified in this center. RESULTS: The median time of diagnosis of the GSDs and at transplant was 1 year and 11 years, respectively. All eight transplanted patients were alive at the time of follow-up in this study. None of them required a re-transplant. All of the patients showed normalized liver enzymes after LT with no sign of hypoglycemia. CONCLUSIONS: LT is an achievable treatment for end-stage hepatic involvement of GSDs with a cure for metabolic deficiency. Our experience in these eight patients shows a favorable outcome with no mortality and no major complication.

[Angiographic moyamoya in a female with glycogenosis type IA - a case report focusing therapeutic management: bilateral encephalo-duro-arterio-myo-synangiosis (EDAMS)]. / Angiografisches Moyamoya bei Glykogenose Typ IA - Management bei einer erwachsenen Patientin: Fallbericht mit Schwerpunkt auf der Behandlung: beidseitige Encephalo-Duro-Arterio-Myo-Synangiose (EDAMS).

Angiographic Moyamoya is a rare cerebrovascular disease most frequent in asia. Its characateristics are recurrent ischemic attacks due to progressive occlusion of ICA branches. Angiography reveals fine arterial collateralisation reminding of ascending smoke ("moyamoya" in japanese). Neurosurgical treatment strategies include direct and indirect reanastomosation procedures. Randomised trials for comparison of clinical outcome and long term survival remain missing. A 23 years old female with glycogenosis type IA was first diagnosed bilateral angiographic moyamoya with bilateral proximal stenosis of ICA after transient ischemic attack (TIA). Coincidence of both rare diseases moyamoya and glycogenosis has previously been reported in three cases, so that this metabolic dysfunction presumably is a true risk factor for moyamoya. In our case, excellent angiographic and functional results were achieved by bilateral, consecutive Enzephalo-Duro-Arterio-Myo-Synangiosis (EDAMS).

Liver transplantation for glycogen storage disease type Ia.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) most often occurs within hepatocellular adenomas (HCAs) in glycogen storage disease Ia (GSD Ia) patients. The objective of this retrospective study is to assess outcomes after liver transplantation (LT) for GSD Ia where the principal indication for transplantation was prevention of HCC. METHODS: Petitions to the United Network for Organ Sharing region 11 review board for additional model for end-stage liver disease listing points were made on behalf of GSD Ia patients. Demographics, pre-operative comorbidity, and outcomes for GSD Ia patients who underwent LT were reviewed. RESULTS: Between 2004 and 2006, five GSD Ia patients underwent LT. Multiple HCAs with focal hemorrhage and/or necrosis but without histological evidence of malignancy were identified in all explanted specimens. Four of five patients had complications after LT, including cytomegalovirus (CMV) infections and steroid responsive allograft rejection. Hemoglobin levels and serum triglyceride, total cholesterol, blood glucose, and lactic acid concentrations improved in all patients after LT. Corn starch feeding was not required in any patient after LT. Renal function worsened in three patients despite modifications to primary immunosuppressive medications. All patients are alive at last follow-up (range 25-48 months) and all post-transplant complications have resolved. CONCLUSIONS: By removing all possible adenomatous tissue and reversing the underlying hepatic enzymatic deficiency, LT provides definitive prevention against HCC and correction of most metabolic derangements in GSD Ia patients. Renal dysfunction secondary to GSD Ia persists--underscoring the need for further studies to better understand the mechanisms of renal dysfunction in these patients.

Living donor liver transplantation for glycogen storage disease type Ib.

Glycogen storage disease type 1b (GSD-1b) is due to an autosomal recessive inborn error of carbohydrate metabolism caused by defects in glucose-6-phosphatase translocase. Patients with GSD-1b have severe hypoglycemia with several clinical manifestations of hepatomegaly, obesity, a doll-like face, and neutropenia. Liver transplantation has been indicated for severe glucose intolerance. This study retrospectively reviewed 4 children with a diagnosis of GSD-1b who underwent living-donor liver transplantation (LDLT). Between November 2005 and June 2008, 96 children underwent LDLT with overall patient and graft survival of 92.3%. Of these, 4 (4.2%) were indicated for GSD-1b. All patients are doing well with an excellent quality of life because of the stabilization of glucose intolerance, decreased hospital admission, and normalized neutrophil count. LDLT appears to be a feasible option and is associated with a better quality of life for patients with GSD-1b. Long-term observation may be necessary to collect sufficient data to confirm the efficacy of this treatment modality.

Arterial anastomosis in a pediatric patient receiving a right extended split liver transplant: a case report.

We report a case of a pediatric patient who received a right-extended liver transplant. The size of the recipient hepatic artery did not match with the donor right hepatic arterial stump. Moreover, recipient arterial anatomy made the direct anastomosis difficult or at increased risk for complications. The recipient's splenic artery was then mobilized, divided and anastomosed to the donor's right hepatic artery. The spleen was preserved and revascularization through collaterals is demonstrated by Angio CT Scan. Doppler US of the transplanted liver demonstrated good flow through the liver and the patient was discharged with perfect liver function. Splenic artery is perfectly suited for hepatic artery anastomosis. The use of splenic artery is favored in particular situations as in the case of a pediatric recipient receiving a right-extended liver graft with small caliber artery.

Reduced-size liver transplantation for glycogen storage disease.

BACKGROUND: Glycogen storage disease (GSD) is an inherited metabolic disorder in which the concentration and/or structure of glycogen in tissues is abnormal. Essentially, abnormalities in all known enzymes involved in the synthesis or degradation of glycogen and glucose have been found to cause some type of GSD. Liver and muscle have abundant quantities of glycogen and are the most common and seriously affected tissues. This study was to assess reduced-size liver transplantation for the treatment of GSD. METHODS: The clinical data from one case of GSD type I with hepatic adenoma was retrospectively analyzed. The clinical manifestations were hepatomegaly, delayed puberty, growth retardation, sexual immaturity, hypoglycemia, and lactic acidosis, which made the young female patient eligible for reduced-size liver transplantation. RESULTS: The patient recovered uneventfully with satisfactory outcome, including 12 cm growth in height and 5 kg increase in weight during 16 months after successful reduced-size liver transplantation. She has been living a normal life for 4 years so far. CONCLUSIONS: Reduced-size liver transplantation is an effective treatment for GSD with hepatomegaly and hepatic adenoma. Delayed puberty, growth retardation, hypoglycemia and lactic acidosis can be cured by surgery.

PRE AND POST-OPERATIVE OTORHINOLARYNGOLOGY SURGERY CARE IN PATIENTS WITH GLYCOGEN STORAGE DISEASE TYPE 1.

OBJECTIVE: To discuss aspects of pre and post-operative otorhinolaryngology surgery in patients with glycogen storage disease type 1b. CASE DESCRIPTION: Description of three clinical cases with probable glycogen storage disease type 1b who underwent otorhinolaryngology surgery, showing the importance of multidisciplinary interaction to avoid episodes of hypoglycemia. COMMENTS: Patients with glycogen storage disease type 1b present recurrent infections, including the otorhinolaryngology affections. When there is an indication for surgical treatment, the caloric intake should be carefully followed in order to prevent hypoglycemia. The way to ensure this is to perform the pre and postoperative period in the hospital ward. In the postoperative period, it is important to make a slow transition between the intravenous and oral routes and not suspend the infusion of glucose during the surgical procedure. The cases illustrate the need for the interaction of the otorhinolaryngologic surgeon with the anesthesiologist, the pediatrician and the gastro-pediatrician in the management of these patients, avoiding hypoglycemic episodes.

Preemptive living donor liver transplantation in glycogen storage disease Ia: case report.

UNLABELLED: Even with substantial progress in the management of patients with glycogen storage disease type Ia (GSD-Ia), hepatic and renal complications may still develop during long-term follow-up. Herein, we report a case of preemptive living donor liver transplantation in a patient with GSD-Ia. PATIENT: The patient was a 5-year-old boy in whom GSD-Ia was diagnosed at age 10 months. Clinical symptoms included frequent hypoglycemic episodes, hyperlipidemia, hyperuricemia, and growth retardation, which were poorly controlled using conventional treatments. At age 5 years, frequent massive nasal bleeds developed, which led to severe anemia. The patient was brought to our institute for living donor liver transplantation (LDLT). Because GSD-Ia usually responds to dietary and medical treatments, we had a long discussion to determine whether preemptive LDLT was indicated. Transplantation was performed using the left lateral liver segment from the patients mother. The weight of his native liver was almost 2 kg. After reperfusion of the graft, the blood glucose concentration rapidly increased, and regular glucose was administered throughout the operation. The posttransplantation course was uneventful. The patient had no episodes of hypoglycemia with a regular diet. Total cholesterol, triglyceride, and uric acid concentrations also reverted to normal without medication. The patient had a few episodes of nasal bleeding after transplantation, which stopped spontaneously. He was discharged from our hospital with normal liver function. CONCLUSION: Patients with GSD-Ia should be considered for preemptive LDLT to improve their quality of life when clinical symptoms do not respond to appropriate treatment.

Glycogen storage disease types I and II: treatment updates.

Prior to 2006 therapy for glycogen storage diseases consisted primarily of dietary interventions, which in the case of glycogen storage disease (GSD) type II (GSD II; Pompe disease) remained essentially palliative. Despite improved survival and growth, long-term complications of GSD type I (GSD I) have not responded to dietary therapy with uncooked cornstarch or continuous gastric feeding. The recognized significant risk of renal disease and liver malignancy in GSD I has prompted efforts towards curative therapy, including organ transplantation, in those deemed at risk. Results of clinical trials in infantile Pompe disease with alglucosidase alfa (Myozyme) showed prolonged survival reversal of cardiomyopathy, and motor gains. This resulted in broad label approval of Myozyme for Pompe disease in 2006. Furthermore, the development of experimental therapies, such as adeno-associated virus (AAV) vector-mediated gene therapy, holds promise for the availability of curative therapy in GSD I and GSD II/Pompe disease in the future.

Successful staged kidney and liver transplantation for glycogen storage disease type Ib: A case report.

Glycogen storage disease type Ib is a rare metabolic disease caused by a defect of the G6P transporter. Patients suffer from hypoglycemic episodes; growth and developmental delay; osteoporosis; neutropenia; and tendency to infections, ovarian cysts, and liver adenomas. Terminal kidney disease is a rare complication. Liver transplantation has been performed to prevent malignant transformation of hepatic adenomas. We present the case of a female patient with glycogenosis type Ib who had severe hypoglycemic episodes and recurrent infections since early childhood. She became dialysis dependent at the age of 24 years. Kidney transplantation was performed at age 30, and liver transplantation 2 years later. The main indication for liver transplantation were the persistent, therapy-refractory hypoglycemic episodes. The transplanted kidney function is stable. The liver transplantation resulted in the disappearance of hypoglycemic episodes, with the patient leading a normal life and eating a normal diet. The neutropenia did not recover, but there were no more significant infectious episodes after liver transplantation. This is, to the best of our knowledge, the first communication of a dual kidney and liver transplant performed in a patient with glycogenosis type Ib. It confirmed the beneficial effect of liver transplantation on the quality of life of patients with severe hypoglycemia. The transplantation should be attempted earlier in the course of the disease to reduce complications and allow catch-up growth. Hepatocyte transplantation may be considered; however, long-term results seem to be rather poor in the few documented cases.

Reappraisal of the Role of Portacaval Shunting in the Growth of Patients With Glycogen Storage Disease Type I in the Era of Liver Transplantation.

BACKGROUND: Instead of dietary modification, surgical management is considered for correcting growth retardation, poor metabolic control, and hepatocellular adenoma (HCA) in glycogen storage disease (GSD) type I. METHODS: The records of 55 GSD type I patients were retrospectively reviewed. Thirty-two patients underwent only dietary management (group D) and 23 underwent surgical management (group S). In group S, 17 underwent portacaval shunting (PCS), 13 underwent liver transplantation (LT; 7 underwent both PCS and LT). Height-for-age and body mass index-for-age Z-scores based on World Health Organization data were used to compare growth patterns before and after surgery. Changes in metabolic abnormalities and HCA after operation were also investigated. RESULTS: Height-for-age Z-scores for group S were higher by an average of 0.377 compared to that for group D. Metabolic abnormalities often disappeared after LT but improved partially after PCS. De novo HCA was detected in 4 patients (13%) from group D, 12 (100%) who underwent PCS, and none who underwent LT. One case of hepatocellular carcinoma and one of hemorrhage from a HCA were noted in group D. Two cases of hepatocellular carcinoma, 2 of hemorrhage, and 1 of necrosis were noted after PCS. CONCLUSIONS: Surgery yielded greater growth improvement than dietary management. However, after PCS, metabolic abnormalities remained unresolved, and the de novo HCA rate was high. Portacaval shunting can be used to improve growth in GSD type I patients when LT is not possible, but close observation for metabolic abnormalities and HCA is essential.

Effect of liver transplantation on hepatic glucose metabolism in a patient with type I glycogen storage disease.

BACKGROUND: In type I glycogenosis, mutation of the glucose-6-phosphatase gene results in absent glucose-6-phosphatase activity in liver cells leading to fasting hypoglycemia. Liver transplantation is expected to normalize glucose homeostasis. METHODS: Endogenous glucose production (6,6 2H2 glucose) was measured after an overnight fast and during exogenous 13C-labeled glycerol infusion in a patient with glycogenosis type I 24 months after liver transplantation and in a group of healthy subjects. RESULTS: Compared with healthy subjects, the glycogenosis patient had normal fasting glucose production and glucose and insulin concentrations after liver transplantation, but mildly elevated plasma glucagon concentrations. Gluconeogenesis from exogenous glycerol (13C glucose synthesis) was similar and did not lead to enhancement of glucose production in both healthy controls and the patient. CONCLUSIONS: Liver glucoregulatory function is restored by orthotopic liver transplantation in type I glycogenosis.