Liver transplantation in patients with type IIIa glycogen storage disease, cirrhosis and hepatocellular carcinoma.

Type III glycogen storage disease (GSD-III) is an autosomal recessive disorder due to the deficiency of the glycogen debrancher enzyme. 80% of the patients have hepatic and muscular involvement (IIIa), compared to 15% with only liver involvement (IIIb). As the life expectancy improves in these patients, the possible liver complications are better understood.

Distinct Clinical and Genetic Findings in Iranian Patients With Glycogen Storage Disease Type 3.

OBJECTIVES: Glycogen storage disease type 3 (GSD-III) is a rare inherited metabolic disorder caused by glycogen debranching enzyme deficiency. Various pathogenic mutations of the AGL gene lead to abnormal accumulation of glycogen in liver, skeletal, and cardiac muscles. Here, we report distinct clinical and genetic data of Iranian patients with GSD-III. METHODS: Clinical and laboratory data of 5 patients with GSD-III were recorded. Genetic investigation was performed to identify the causative mutations. RESULTS: Three patients had typical liver involvement in childhood and one was diagnosed 2 years after liver transplantation for cirrhosis of unknown etiology. Four patients had vacuolar myopathy with glycogen excess in muscle biopsy. All patients had novel homozygous mutations of the AGL gene namely c.378T>A, c.3295T>C, c.3777G>A, c.2002-2A>G, and c.1183C>T. CONCLUSIONS: This is the first comprehensive report of patients with GSD-III in Iran with 2 uncommon clinical presentations and 5 novel mutations in the AGL gene.

Hepatocellular Adenomas and Carcinoma in Asymptomatic, Non-Cirrhotic Type III Glycogen Storage Disease.

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders characterized by accumulation of abnormal glycogen in muscle or liver or both. Specific hepatic complications include liver adenomas and hepatocellular carcinoma (HCC). Hepatocellular carcinomas described in GSD type I are often due to the degeneration of liver adenomas. Hepatocellular carcinoma in GSD type III, however, is rare and is thought to be associated with underlying cirrhosis.We present the case of a 63-year old male who was admitted for assessment of suitability for liver transplantation because of development of recurrent HCC in the presence of multiple liver adenomas. A diagnosis of GSD type III was made in this patient without underlying cirrhosis or metabolic disturbances resembling GSD. This case report is the first documentation of HCC development in an asymptomatic, non-cirrhotic patient with GSD type III. This raises the possibility that in GSD type III, the adenoma - carcinoma sequence can occur as it is also seen in GSD type I. Physicians taking care of GSD patients should be aware of this and some form of surveillance for cirrhosis and HCC should be considered. Also male patients with adenomas should have a thorough workup to reveal any underlying disease such as GSD.

Long-term results of living donor liver transplantation for glycogen storage disorders in children.

Liver transplantation (LT) may be indicated in glycogen storage disorders (GSD) when medical treatment fails to control the metabolic problems or when hepatic adenomas develop. We present our institutional experience with living donor LT (LDLT) for children with GSD. A total of 244 patients underwent primary LDLT at our institution from June 1994 to December 2005. A total of 12 (5%) children (8 female and 4 male) were afflicted with GSD and were not responsive to medical treatment. Nine patients had GSD type I and 3 had GSD type III. The median age at the time of transplantation was 7.27 yr (range, 2.4-15.7). All patients presented with metabolic abnormalities, including hypoglycemia, and lactic acidosis. In addition, 4 patients presented with growth retardation. A total of 11 patients received left lobe grafts and 1 received a right lobe graft. The mean graft-to-recipient weight ratio was 1.25 (range, 0.89-1.61). Two patients had hepatic vein stenoses that were treated by balloon dilatation; 1 patient had bile leak, which settled spontaneously. The overall surgical morbidity rate was 25%. Three patients had hepatic adenomas in the explanted liver. There was a single mortality at 2 months posttransplantation due to acute pancreatitis and sepsis. The mean follow up was 47.45 months. The metabolic abnormalities were corrected and renal function remained normal. In patients with growth retardation, catch-up growth was achieved posttransplantation. In conclusion, LDLT is a viable option to restore normal metabolic balance in patients with GSD when medical treatment fails. Long-term follow-up after LT for GSD shows excellent graft and patient survival.

Nesiritide as bridge to multi-organ transplantation: a case report.

Nesiritide, an intravenous form of human B-type natriuretic peptide, has been approved as treatment for patients with acute decompensated heart failure. Due to its action on different receptors, nesiritide has many effects, including vasodilation and natriuresis. Cardiac preload and afterload decrease, leading to an increase in cardiac output through effects on smooth muscle and the kidneys. As a bridge to cardiac transplantation, nesiritide has been used to maintain vasodilation and diuresis without sacrificing kidney function. Our patient, prior to multi-organ transplantation, had a pulmonary capillary wedge pressure of 41 mm Hg on milrinone monotherapy, which decreased slightly with nitroprusside and further decreased to 4 mm Hg after the addition of nesiritide. The patient's measured creatinine clearance level was calculated to be 40 mL/min. When nesiritide therapy was begun, the renal function did not improve, but, as the hemodynamics improved, renal function did not decrease.

Liver transplantation for glycogen storage disease types I, III, and IV.

UNLABELLED: Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy have dramatically improved the outcome of GSD type I by reducing the incidence of liver adenoma and renal insufficiency. Nine type I and 3 type III patients have received liver transplants because of poor metabolic control, multiple liver adenomas, or progressive liver failure. Metabolic abnormalities were corrected in all GSD type I and type III patients, while catch-up growth was reported only in two patients. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in both GSDIb patients post liver transplantation necessitating continuous granulocyte colony stimulating factor treatment. Thirteen GSD type IV patients were liver transplanted because of progressive liver cirrhosis and failure. All but one patient have not had neuromuscular or cardiac complications during follow-up periods for as long as 13 years. Four have died within a week and 5 years after transplantation. Caution should be taken in selecting GSD type IV candidates for liver transplantation because of the variable phenotype, which may include life-limiting extrahepatic manifestations. It remains to be evaluated, whether a genotype-phenotype correlation exists for GSD type IV, which may aid in the decision making. CONCLUSION: Liver transplantation should be considered for patients with glycogen storage disease who have developed liver malignancy or hepatic failure, and for type IV patients with the classical and progressive hepatic form.

Type IIIb glycogen storage disease associated with end-stage cirrhosis and hepatocellular carcinoma. The Liver Transplant Group.

Type III glycogen storage disease (GSD) is a disorder of carbohydrate metabolism caused by a deficiency of debranching enzyme. Different subtypes with different clinical pictures have been recognized. During childhood and early adulthood, the symptoms generally regress, and normal adulthood appears possible in most patients without symptoms or signs of cirrhosis. We report on an adult patient with GSD who developed endstage cirrhosis and a small hepatocellular carcinoma. She had GSD subtype IIIb, i.e., there were no signs of cardiomyopathy, myopathy, or neuropathy. She underwent a successful transplantation, representing the first case treated this way for this indication to our knowledge, and she is doing well after 1 year. Debranching enzyme activity was absent both in the liver and in the leukocytes before transplantation. The debranching enzyme activity remained absent in the leukocytes after transplantation. We conclude that patients with GSD type III may develop end-stage cirrhosis and hepatocellular carcinoma and therefore need hepatological follow-up during adulthood.