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

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.     

Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure

Abstract:  GSD-I, III, and IV are congenital disorders of glycogen metabolism that are commonly associated with severe liver disease. Liver transplantation has been proposed as a therapy for these disorders. While liver transplantation corrects the primary hepatic enzyme defect, the extrahepatic manifestations of GSD often complicate post-transplantation management. Upon review of the English-language literature, 42 children <19 yr of age were discovered to have undergone liver transplantation for complications associated with GSD (18 patients with GSD-Ia, six with GSD-Ib, one with GSD-III, 17 with GSD-IV). An additional two children followed at our institution have undergone liver transplantation for GSD complications (one with GSD-Ia and one with GSD-III) and are included in this review. The risks and benefits of liver transplantation should be considered prior to performing liver transplantation in these metabolic disorders, particularly in GSD-Ia. As liver pathology is not the major source of morbidity in GSD-Ib and GSD-IIIa, liver transplantation should only be performed when there is high risk for HCC or evidence of substantial cirrhosis or liver dysfunction. Liver transplantation remains the best option for treatment of GSD-IV.     

Glycogen storage disease type I: indications for liver and/or kidney transplantation

Even though significant progress has been achieved in the management of patients with glycogen storage disease type I, hepatic (mainly adenomas) and renal (proteinuria, renal failure) complications may still develop. Orthotopic liver transplantation has been reported in less than 20 patients, and, in most cases, its indications were multiple hepatic adenomas, sometimes combined with poor metabolic control and/or growth retardation. Even though short-term outcome seems to be favourable, long-term complications have been reported in several cases. Thus it appears that improved metabolic control has to be attempted before performing liver transplantation in such patients. As for renal transplantation, it has been performed in patients with terminal renal failure. It is hoped that improving longterm metabolic control will prevent renal involvement from evolving to terminal renal failure. Finally, combined liver and kidney transplantation may be indicated in a few patients.Conclusion: organ (liver/kidney) transplantation in glycogen storage disease type I may be advantageous when long-term metabolic control has been attempted. Nevertheless, post-transplantat longterm complications may still develop. Published online: 19 July 2002     

糖原累积病Ⅵ型和Ⅸa型7例病例报告并文献复习

目的总结糖原累积病(GSD)Ⅵ、Ⅸa型的临床、病理和基因突变情况,提高临床对这两型GSD的认识。方法回顾性收集GSD3例Ⅵ型和4例Ⅸa型患儿的临床资料。结果 (1)7例患儿均为男性,确诊年龄2岁3月至5岁。7例均有肝脏肿大和转氨酶升高,身材矮小1例,空腹低血糖、高乳酸血症和高甘油三酯血症各2例,血酮体增高3例,尿有机酸分析结果阳性2例。7例患儿均有肝细胞弥漫性肿大变形和糖原凝聚,4例有肝脏脂肪变性;3例GSDⅥ型有门管区纤维化、肝硬化表现。3例GSDⅥ型检测到6种PYGL基因突变,c.772+1GA、c.244-1GA、c.730CT(p.L244F)、c.2417_2418del TA(p.I806Sfs X9)为新突变,4例GSDⅨa型检测到4种PHKA2基因突变,c.3529CT(p.Q1177X)、c.3574CT(p.Q1196X)为新突变。(2)复习文献共检索到13篇文献,与本文病例合并后共22例Ⅵ型、99例Ⅸa型GSD。肝脏转氨酶增高和肝脏肿大91.9%~100%,有身材矮小18%~23%、空腹低血糖44%~48%、高甘油三酯血症37%~44%、高乳酸血症35%~72%和血酮体增高50%~56%。肝脏活检均可见肝细胞内糖原凝聚,17%有脂肪变性,Ⅵ型25%、Ⅸa型33%检出肝硬化。报道19种PYGL基因突变,多为点突变,剪切位点突变亦较常见,插入突变少见;43种PHKA2基因突变,突变类型多样。结论肝大伴转氨酶升高的患儿需警惕Ⅵ、Ⅸa型GSD;Ⅵ型患儿可早期存在肝硬化,需要进一步随访。     

Improved neutrophil function in a glycogen storage disease type 1b patient after liver transplantation

Patients with glycogen storage disease type 1b (GSD1b) not only show hepatomegaly, hypoglycaemia and lactic acidosis, but also neutropenia and neutrophil dysfunction. Here, we report improvement of neutropenia and neutrophil function in a 22-year-old male GSD1b patient who had undergone living-related partial liver transplantation (LT) at 18 years of age. After LT, the patients infectious episodes decreased, gastrointestinal symptoms ameliorated, neutrophil counts increased, and neutrophil function tests normalised. Conclusion:although it is not known whether this improvement was causally related to liver transplantation, this may be the first recorded case of restoration of neutrophil dysfunction in a glycogen storage disease type 1b patient.Abbreviations G6PT glucose-6-phosphate translocase - GSD glycogen storage disease - GSD1b glycogen storage disease type 1b - LT liver transplantation - PMA phorbol-12-myristate-13-acetate - rhGCSF recombinant human granulocyte colony stimulating factor     

Reliability of Histological Criteria in Glycogen Storage Disease of the Liver

The histological criteria for the diagnosis of the hepatic glycogen storage diseases (GSDs) are well recognized. However, some biopsies do not have the characteristic features peculiar to their type and not all biopsies with GSD changes are confirmed by enzyme analysis. We reviewed the liver biopsies of 59 patients with clinically suspected GSD. The enzyme defects in 31 of 40 patients with GSD morphology were demonstrated by enzyme analysis. We describe the history and histology of the 9 patients with GSD morphology not confirmed by enzyme analysis, present the diagnoses of the 19 patients shown not to have a GSD, and evaluate the reliability of the morphological criteria used to distinguish the types of hepatic GSD.

In this study the predictive value of a biopsy with GSD changes was 90%. Mosaicism, the most sensitive criterion in the diagnosis of GSD, is not type-specific. Fibrosis does not reliably distinguish between the GSD types and although nuclear hyperglycogenation and lipid are characteristic of type I GSD, these features are not diagnostic of any particular enzyme deficiency. The lack of morphological specificity implies that a complete enzyme analysis be performed on each biopsy. A normal enzyme analysis does not exclude a GSD and careful long-term follow-up may be necessary.     

Glycogen storage disease type I: diagnosis and phenotype/genotype correlation

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in theG6PC gene encoding the phosphatase of the microsomal glucose-6-phosphatase system. GSD Ia is characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia and short stature. Other forms of GSD I (GSD I non-a) are characterized by the additional symptom of frequent infections caused by neutropenia and neutrophil dysfunction. GSD I non-a is caused by mutations in a gene encoding glucose-6-phosphatase translocase (G6PT1). We report on the molecular genetic analyses of G6PC and G6PT 1 in 130 GSD Ia patients and 15 GSD I non-a patients, respectively, and provide an overview of the current literature pertaining to the molecular genetics of GSD I. Among the GSD Ia patients, 34 different mutations were identified, two of which have not been described before (A65P; F117C). Seventeen different mutations were detected in the GSD I non-a patients. True common mutations were identified neither in GSD Ia nor in GSD I non-a patients,Conclusion: Glycogen storage disease type Ia and and type I non-a are genetically heterogenous disorders. For the diagnosis of the various forms of glycogen storage disease type I, molecular genetic analyses are reliable and convenient alternatives to the enzyme assays in liver biopsy specimens. Some genotype-phenotype correlations exist, for example, homozygosity for oneG6PC mutation, G188R, seems to be associated with a glycogen storage disease type I non-a phenotype and homozygosity for the 727G>T mutation may be associated with a milder phenotype but an increased risk for hepatocellular carcinoma. Published online: 27 July 2002     

Glycogenosis type IV: liver transplant at 12 years.

Hepatomegaly, the presenting feature of type IV glycogen storage disease at 20 months of age, regressed during childhood. The patient remained asymptomatic until 12 years of age when, after an episode of shock, septicaemia, and spontaneous peritonitis, liver transplantation was successfully performed.     

Glycogen storage disease type Ib without neutropenia

We report 2 patients with atypical glycogen storage disease type Ib without neutropenia or infectious complications. Neither patient was deficient in hepatic glucose-6-phosphatase activities in microsome-disrupted homogenates; both had mutations in the glucose-6-phosphate transporter gene, suggesting an allelic variant of glycogen storage disease type Ib.     

Glycogen storage disease type Ib: familial bleeding tendency

A mild bleeding tendency with characteristics of the von Willebrand disease was documented in family members of a girl with glycogen storage disease type Ib (GSD) Ib). It was assumed that a defective glucose-6-phosphate dependent microsomal glycoprotein synthesis was involved in the bleeding disorder of the patient and the GSD Ib heterozygotes.Abbreviations GSD Ia glycogen storage disease type Ia - GSD Ib glycogen storage disease type Ib - G6P glucose-6-phosphate - G6P-ase glucose-6-phosphatase     

Phenylketonuria and glycogen storage disease type III in sibs of one family

Hyperphenylalaninemia result from a block in the conversion of phenylalanine into tyrosine due to a defect in either the enzyme phenylalanine hydroxylase (98% of subjects) or in the metabolism of the cofactor tetrahydrobiopterin. Phenylalanine hydroxylase deficiency is the most common form of inherited hyperphenylalaninemia disorders, with a prevalence between 1/4,000-1/40,000. Glycogen storage disease (GSD) type III is caused by debranching enzyme deficiency of glycogen degradation. The clinical features vary in relation to the localization of the enzyme defect. Two clinical entities exist: a combined hepatic myogenic form (GSD IIIa) and a purely hepatic form (GSD IIIb). The inheritance is autosomal recessive. We describe a Turkish family in which two girls were found to have phenylketonuria, while in two other sisters glycogen storage disease type III was diagnosed. The parents of these children are cousins and they have had 12 children.     

Focal nodular hyperplasia in an adolescent with glycogen storage disease type I with mesocaval shunt operation in childhood: a case report and review of the literature

As patients with glycogen storage disease type I survive longer, cases with hepatic tumor have been increasingly documented. A 16 year old boy with glycogen storage disease type I was evaluated for multiple liver tumors. He was diagnosed on clinical features at 9 months of age and underwent a mesocaval shunt operation at 5 years of age. The biopsy of one of the masses showed focal nodular hyperplasia. This is uncommon in patients with glycogen storage disease type I, compared to those with adenoma or malignant hepatic tumor. The association of a portacaval shunt with focal nodular hyperplasia is significant compared to other tumors. An environment of high estrogen concentration or sex hormone binding globulin accompanied by shunt operation may cause focal nodular hyperplasia to develop in the liver of patients with glycogen storage disease type I.     

Glycogen storage disease type I: pathophysiology of liver adenomas

Of the many complications associated with glycogen storage disease type I, hepatic tumours cause great concern because of their malignant potential and the current difficulties in monitoring them. Hepatic adenomas occur in 22%–75% of affected adults, according to the population studied, and from those reported in the literature are thought to have an approximately 10% risk of undergoing malignant transformation. Their aetiology is unclear, but they occur generally in postpubertal patients, and can be either single or multiple. This article discusses theories of their aetiology, methods of detection and monitoring, and treatment options.Conclusion: the incidence of liver tumours in younger adults seems less than in older ones, suggesting that better dietary treatment, and thus improved metabolic control, may be protective. Surgery (partial hepatectomy or orthotopic liver transplantation) is the definitive therapy for these tumours, but the timing of this intervention is difficult to determine and it is not without its own hazards. Published online: 12 July 2002     

Orthotopic liver transplantation in liver-based metabolic disorders

The efficacy of orthotopic liver transplantation (OLT) in the management of more common liver-based metabolic disorders associated with severe liver damage, alpha-1-antitrypsin deficiency (PIZZ), Wilson disease and tyrosinaemia has been demonstrated and indications defined. An early mortality in excess of 15% and finite resources limit its use. Phenotypic heterogeneity make the precise indication in other disorders less certain. In disorders in which endstage liver disease is less frequent such as cystic fibrosis, haemochromatosis and galacosaemia it has been a very effective therapy. It has been used with encouraging results in disorders in which the liver is structurally normal such as Crigler-Najjar type I, primary hyperoxaluria type I and primary hypercholesterolaemia. In these it should be performed before there is permanent damage to brain, kidneys or heart. OLT in the short term prevents hyperammonaemic coma in urea cycle defects and may prevent extrahepatic disease in glycogen storage disease type IV. Its limitation in reversing all metabolic effects in these and other disorders is discussed. It is ineffective in protoporphyria or Niemann Pick disease type II (Sea Blue Histiocyte syndrome) in which the transplanted liver acquires the lesions of the initial disorder and extrahepatic features progress. Early referral provides optimum circumstances to assess the benefits of OLT as compared with those of other forms of management and to achieve transplantation at the ideal time. The place of OLT in management will require constant review as metabolic disorders are better defined, new forms of therapy evolve and as techniques of liver transplantation and modes of immunosuppression improve.     

Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis

Orthotopic liver transplantation (OLT) has been proposed to treat patients with type IV glycogenosis because of early progressive cirrhosis. Reports have shown absence of disease progression in other organs after OLT and even regression of cardiac amylopectin infiltration in one case. We describe a 15-month-old child in whom a liver transplant was performed for type IV glycogenosis. There were no clinical signs of extrahepatic disease before OLT. Nine months later, the patient developed progressive cardiac insufficiency and died from cardiac failure. Because of massive amylopectin deposits, decreased myofibrils in cardiac cells, and exclusion of other causes of cardiac failure, death was attributed to amylopectinosis. Our observation contrasts with the Pittsburgh experience and suggests that cardiac amylopectionosis may progress after OLT.     

Studies on a patient with in vivo evidence of type I glycogenosis and normal enzyme activities in vitro.

Biochemical and clinical studies on a patient with hepatic glycogen storage disease are reported. The patient showed many of the clinical and biochemical features of type I glycogenosis (glucose-6-phosphatase deficiency), but had normal activities of the following enzymes in liver tissue: glucose-6-phosphatase (EC3.1.3.9); amylo-1,6-glucosidase (EC3.2.1.33); glycogen phosphorylase (EC2.4.1.1); fructose-1,6-diphosphatase (EC3.1.3.11). The urinary excretion of 2-oxoglutaric acid was greatly increased in this patient and in a case of enzymologically proven type I glycogenosis. Abnormal 2-oxoglutaric aciduria has not been previously reported in the glycogen storage diseases. The results are discussed in relation to the possible nature of the underlying biochemical defect in patients of this type.     

Neuromuscular involvement in glycogen storage disease type III

Sixteen patients with glycogen storage disease type III (GSD III) aged 3 to 22 years underwent a detailed neuromuscular evaluation. A minimal impairment of skeletal muscle function was presented in eight patients, slight impairment in four and severe impairment in one patient. Serum creatinine phosphokinase (CPK) was elevated in all patients studied. In the nine patients, in whom electromyography (EMG) was performed; six exhibited a myopathic pattern while a "mixed" (neurogenic-myopathic) pattern was present in three. Muscle biopsies performed in 12 patients, revealed in all cases amylo-1,6,-glucosidase deficiency and biochemical as well as morphological evidence of glycogen accumulation. Two brothers suffered from late onset myopathy, which in the older sibling was associated with clinical, EMG and EM findings of a peripheral neuropathy. Fifteen patients had either electrocardiographic and or echographic evidence of cardiomyopathy. Observations based on this patient material suggest a widespread myopathy in GSD III patients with heterogeneous expression, while peripheral nerve involvement is rarely encountered.     

Pulmonary hypertension in type I glycogen storage disease

Summary Two cases of pulmonary hypertension associated with type I glycogen storage disease (type I GSD) are reported. Before the development of pulmonary hypertension, patient 1 had been treated with dietary therapy with nocturnal gastric-drip infusion and zyloric therapy. Patient 2 had received a shunt operation between the intestinal vein and inferior vena cava, as well as dietary therapy. Both patients died of progressive heart failure due to pulmonary hypertension despite many attempts at drug therapy. There was no evidence in either case of a disorder that could have been the cause of the pulmonary hypertension. In case 1, the autopsy revealed a vascoconstrictive type of pulmonary hypertension with plexiform vascular lesions.     

Hepatocellular carcinoma in glycogen storage disease type IV

A 13 year old patient with juvenile type IV glycogen storage disease died of the complications of hepatocellular carcinoma. To our knowledge this is the first reported case of hepatocellular carcinoma in association with type IV glycogen storage disease.