Philippe Labrune

Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature.

BACKGROUND Hepatocellular adenomas may develop in patients with glycogen storage disease types I and III, and the malignant degeneration of adenomas in hepatocellular carcinoma has been reported in ten cases. The aim of this work was to study the characteristics of hepatic adenomas in a large series of 43 patients with glycogen storage disease types I and III and to determine the optimal means of follow-up. METHODS The charts of 43 patients with glycogen storage disease type I and III were studied. In all these patients, abdominal ultrasonography and the determination of serum alpha-fetoprotein had been performed yearly and serum concentrations of several proteins were determined once. RESULTS 51.8% of patients with type I and 25% of patients with type III glycogen storage disease had hepatic adenomas at the time of the study. The male to female ratio was 2 to 1 in type I, and no female had adenomas in type III. No evidence of malignant transformation was observed during the follow-up period. Serum concentrations of several proteins were significantly higher in patients with hepatic adenomas than in patients without such lesions. CONCLUSIONS In patients with glycogen storage disease type I and III, the determination of alpha-fetoprotein serum concentration has to be combined with yearly hepatic ultrasound examinations. Other investigations such as CT scan should be considered when the size of any adenoma increases. The malignant transformation of hepatocellular adenoma into hepatocellular carcinoma remains a rare event.

Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I (ESGSD I)

Abstract. Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease and therefore, no metabolic centre has experience of large numbers of patients. To document outcome, to develop guidelines about (long-term) management and follow-up, and to develop therapeutic strategies, the collaborative European Study on GSD I (ESGSD I) was initiated. This paper is an descriptive analysis of data obtained from the retrospective part of the ESGSD I. Included were 231 GSD Ia and 57 GSD Ib patients. Median age of data collection was 10.4 years (range 0.4–45.4 years) for Ia and 7.1 years (0.4–30.6 years) for Ib patients. Data on dietary treatment, pharmacological treatment, and outcome including mental development, hyperlipidaemia and its complications, hyperuricaemia and its complications, bleeding tendency, anaemia, osteopenia, hepatomegaly, liver adenomas and carcinomas, progressive renal disease, height and adult height, pubertal development and bone maturation, school type, employment, and pregnancies are presented. Data on neutropenia, neutrophil dysfunction, infections, inflammatory bowel disease, and the use of granulocyte colony-stimulating factor are presented elsewhere (Visser et al. 2000, J Pediatr 137:187–191; Visser et al. 2002, Eur J Pediatr DOI 10.1007/s00431-002-1010-0). Conclusion: there is still wide variation in methods of dietary and pharmacological treatment of glycogen storage disease type I. Intensive dietary treatment will improve, but not correct completely, clinical and biochemical status and fewer patients will die as a direct consequence of acute metabolic derangement. With ageing, more and more complications will develop of which progressive renal disease and the complications related to liver adenomas are likely to be two major causes of morbidity and mortality.

Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I

BACKGROUND & AIMS Hepatocellular adenomas (HCA) are benign liver tumors mainly related to oral contraception and classified into 4 molecular subgroups: inflammatory (IHCA), HNF1A-inactivated (H-HCA), β-catenin-activated (bHCA) or unclassified (UHCA). Glycogen storage disease type I (GSD) is a rare hereditary metabolic disease that predisposes to HCA development. The aim of our study was to characterize the molecular profile of GSD-associated HCA. METHODS We characterized a series of 25 HCAs developed in 15 patients with GSD by gene expression and DNA sequence of HNF1A, CTNNB1, IL6ST, GNAS, and STAT3 genes. Moreover, we searched for glycolysis, gluconeogenesis, and fatty acid synthesis alterations in GSD non-tumor livers and compared our results to those observed in a series of sporadic H-HCA and various non-GSD liver samples. RESULTS GSD adenomas were classified as IHCA (52%) mutated for IL6ST or GNAS, bHCA (28%) or UHCA (20%). In contrast, no HNF1A inactivation was observed, showing a different molecular subtype distribution in GSD-associated HCA from that observed in sporadic HCA (p = 0.0008). In non-tumor GSD liver samples, we identified glycolysis and fatty acid synthesis activation with gluconeogenesis repression. Interestingly, this gene expression profile was similar to that observed in sporadic H-HCA. CONCLUSIONS Our study showed a particular molecular profile in GSD-related HCA characterized by a lack of HNF1A inactivation. This exclusion could be explained by similar metabolic defects observed with HNF1A inactivation and glucose-6-phosphatase deficiency. Inversely, the high frequency of β-catenin mutations could be related to the increased frequency of malignant transformation in hepatocellular carcinoma.

Glucose-6-phosphatase deficiency

Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span.Disease name and synonymsGlucose-6-phosphatase deficiency or G6P deficiency or glycogen storage disease type I or GSDI or type I glycogenosis or Von Gierke disease or Hepatorenal glycogenosis.

Extensive brain calcifications, leukodystrophy, and formation of parenchymal cysts A new progressive disorder due to diffuse cerebral microangiopathy

A new cerebral disorder, described in three unrelated children, has recognizable clinical, radiologic, and neuropathologic findings. The onset occurs from early infancy to adolescence with slowing of cognitive performance, rare convulsive seizures, and a mixture of extrapyramidal, cerebellar, and pyramidal signs. CT shows progressive calcifications in the basal and cerebellar gray nuclei and the central white matter. MRI reveals diffuse abnormal signals of the white matter on T,-weighted sequences. A special feature is the development of parenchymal cysts in the cerebellum and the supratentorial compartment, leading to compressive complications and surgical considerations. Neuropathologic examination of surgically removed pericystic samples reveals angiomatous-like rearrangements of the microvessels, together with degenerative secondary changes of other cellular elements. Both the anatomic findings and the course of the disease suggest a constitutional, diffuse cerebral microangiopathy resulting in microcystic, then macrocystic, parenchymal degeneration.

GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation

BACKGROUND & AIMS Mosaic G-protein alpha-subunit (GNAS)-activating mutations are responsible for the McCune-Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. METHODS GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. RESULTS A somatic GNAS-activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A, CTNNB1, and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS-mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS-mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. CONCLUSIONS We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS-activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.

Effectiveness of chest physiotherapy in infants hospitalized with acute bronchiolitis: a multicenter, randomized, controlled trial.

Vincent Gajdos and colleagues report results of a randomized trial conducted among hospitalized infants with bronchiolitis. They show that a physiotherapy technique (increased exhalation and assisted cough) commonly used in France does not reduce time to recovery in this population.

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

Abstract. 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 long-term 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 long-term complications may still develop.

Successful Treatment of Severe Cardiomyopathy in Glycogen Storage Disease Type III With D,L-3-Hydroxybutyrate, Ketogenic and High-Protein Diet

Glycogen storage disease type III (GSD III) due to debranching enzyme deficiency presenting usually with hepatomegaly and hypoglycemia may be responsible for severe cardiomyopathy which is often fatal. Current treatment of GSD III is based on frequent high-carbohydrate meals that have no effect on the cardiomyopathy. We describe a 2-mo-old infant presenting with a familial form of GSD III complicated with cardiomyopathy. As conventional treatment was unable to improve his sisters cardiomyopathy who was deceased at age 11 mo, we proposed an experimental treatment combining the use of synthetic ketone bodies (d,l-3-OH butyrate) as an alternative energy source, 2:1 ketogenic diet to reduce glucose intake and high-protein diet to enhance gluconeogenesis. Twenty-four months after the onset of this treatment, echocardiography showed an improvement of cardiomyopathy. Growth and liver size remained normal, and no side effects were observed. Blood glucose levels remained within the normal range and insulin levels decreased. These findings show that synthetic ketone bodies as well as low-carbohydrate, high-lipid, and high-protein diet may be a more beneficial therapeutic choice therapeutic choice for GSD III patients with cardiomyopathy. These encouraging data need to be confirmed in more GSD III patients presenting with cardiac or muscular symptoms.

Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency.

Abstract An 18-month-old girl presented with macrocytic megaloblastic anaemia followed by haemolytic uraemic syndrome. Metabolic investigations led to the identification of an inborn error of cobalamin metabolism consisting of defective methylcobalamin biosynthesis, probably cobalamin G, since methionine synthase activity was decreased under standard reducing conditions. Despite treatment, pulmonary hypertension progressively developed and responded to oxygen therapy. Renal involvement evolved to terminal failure and haemodialysis, while pulmonary hypertension was controlled by oxygen therapy. Such clinical manifestations have never been reported in association with a defect of methylcobalamin and thus of methionine biosynthesis. Conclusion A congenital abnormality of cobalamin metabolism was suspected then confirmed in the presence of typical haematological features associated with unusual clinical manifestations such as progressive renal failure and pulmonary hypertension.