ERJ
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Humbert, M.
Right arrow Articles by Simonneau, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Humbert, M.
Right arrow Articles by Simonneau, G.
Eur Respir J 2002; 20:59-65
Copyright ©ERS Journals Ltd 2002

Pulmonary arterial hypertension and type-I glycogen-storage disease: the serotonin hypothesis

M. Humbert1, P. Labrune2, O. Sitbon1, C. Le Gall1, J. Callebert3, P. Hervé1, D. Samuel4, R. Machado5, R. Trembath5, L. Drouet6, J-M. Launay3 and G. Simonneau1

1 Unité Propre de Recherche de l'Enseignement Supérieur (UPRES) 2705, Service de Pneumologie, Centre des Maladies Vasculaires Pulmonaires and 2 UPRES 2704, Service de Pédiatrie, Hôpital Antoine Béclère, Université Paris Sud, Clamart, 4 Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif and 6 Service d'Immuno-hématologie and 3 Service de Biochimie, Hôpital Lariboisière, Assistance Publique, Hôpitaux de Paris, Paris, France. 5 Division of Medical Genetics, Depts of Medicine and Genetics, University of Leicester, Leicester, UK

CORRESPONDENCE: M. Humbert, Service de Pneumologie, Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140, Clamart, France. Fax: 33 146303824. E-mail: humbert@ipsc.u-psud.fr

Keywords: pulmonary hypertension, serotonin, type-I glycogen-storage disease

Received: July 6, 2001
Accepted January 7, 2002

This study was supported by grants from Universite Paris-Sud, Institut National de la Santé et de la Médicale (INSERM) and Association Francaise contre les Myopathies (AFM).


   Abstract
TOP
 Abstract
Patients and methods
 Methods
 Results
 Discussion
 References
 
A case of pulmonary arterial hypertension in a patient with type-Ia glycogen-storage disease, a rare autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase is reported in this study. It has been suggested that the occurrence of pulmonary arterial hypertension in type-Ia glycogen-storage disease could be due to an abnormal production of vasoconstrictive amines such as serotonin.

To test this hypothesis, plasma serotonin concentrations were prospectively measured in 13 patients with type-Ia glycogen-storage disease, one patient with severe pulmonary hypertension and type-Ia glycogen-storage disease, 16 patients displaying severe pulmonary arterial hypertension, and 26 normal healthy controls.

Elevated plasma serotonin concentrations were found in patients with either severe pulmonary arterial hypertension (38.8±7.3 nmol·L–1) or type-Ia glycogen-storage disease (36.8±11.5 nmol·L–1), as compared with controls (8.8±0.6 nmol·L–1, p<0.001). Plasma serotonin was dramatically elevated in the patient with type-Ia glycogen-storage disease and pulmonary arterial hypertension (113.4 nmol·L–1).

It is concluded that type-Ia glycogen-storage disease may be another condition in which abnormal handling of serotonin is one event in a multistep process leading to severe pulmonary arterial hypertension.

Pulmonary arterial hypertension is characterised by the presence of pulmonary hypertension (mean pulmonary artery pressure >3.33 kPa (>25 mmHg) at rest or >3.99 kPa (>30 mmHg) during exercise) and normal pulmonary wedge pressure 1. In the absence of any factor or condition suspected of playing a causal or facilitating role in the process, pulmonary arterial hypertension is unexplained (primary pulmonary hypertension) 2. Type-I glycogen-storage disease is an autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase (type-Ia, von Gierke's disease) or glucose-6-phosphate translocase (type Ib) 3. Its estimated incidence is 1·100,000–1 4. Since the pioneering description by Pizzo 5 in 1980, six cases of severe pulmonary hypertension have been described in patients with type-Ia glycogen-storage disease 6–10. In all cases this condition was very severe leading to the patients' death within a few months of cardiopulmonary arrest and/or untractable congestive right heart failure 5–10. When available, post mortem examination of the lungs demonstrated pulmonary hypertensive arteriopathy, as described previously in primary pulmonary hypertension 5–8.

Pulmonary arterial hypertension, occurring in patients with rare diseases, provides valuable information for evaluating possible pathobiological hypotheses in pulmonary vascular disorders 2. For instance, development of severe pulmonary arterial hypertension without any identifiable cause in a patient with a rare familial platelet storage deficiency allowed the authors to hypothesise that serotonin, a pulmonary vasoconstrictor and growth factor for vascular smooth-muscle cells stored in platelets, could play a role in pulmonary arterial hypertension 11–14. In the initial report by Pizzo 5, it was suggested that the occurrence of pulmonary arterial hypertension in type-I glycogen-storage disease could be due to an abnormal production of vasoconstrictive amines such as serotonin. As a first step in studying handling of serotonin in this rare condition, plasma serotonin concentrations in patients with type-Ia glycogen-storage disease were prospectively measured.


   Patients and methods
TOP
 Abstract
 Patients and methods
Methods
 Results
 Discussion
 References
 
In September 1997, a patient with type-Ia glycogen-storage disease was referred to the authors' hospital (Hôpital Antoire Béclère) because of severe pulmonary arterial hypertension. Three groups of patients were subsequently analysed in a prospective study designed to measure plasma serotonin in severe pulmonary arterial hypertension, type-Ia glycogen-storage disease without pulmonary hypertension, and normal healthy controls. All patients and controls were tested after appropriate consent was gained in accordance with the declaration of Helsinki.

Patient with type-Ia glycogen-storage disease and severe pulmonary arterial hypertension
A 25-yr-old male was referred to the authors' centre so that severe pulmonary hypertension could be investigated. As a child, the patient demonstrated growth retardation, hepatomegaly and fasting hypoglycaemia. A diagnosis of type-Ia glycogen-storage disease was established on a liver biopsy (hepatic glucose-6-phosphatase deficiency). Despite dietary treatment, the patient's condition did not improve significantly. At the age of 8 yrs a porto-caval shunt was performed as indicated at that time to try to improve the growth status. After surgery, growth was satisfactory (adult height: 1.73 m), and clinical stability was maintained for several years. At the age of 25 yrs the patient complained of dyspnoea on exertion (functional class II of the classification of the New York Heart Association). Physical examination showed marked smooth hepatomegaly and a loud pulmonic component of the second heart sound. Chest radiography revealed cardiomegaly and a convex main pulmonary artery. An electrocardiogram demonstrated a pattern of right ventricular hypertrophy. Echocardiography showed evidence of right ventricular hypertrophy and dilatation with an elevated systolic pulmonary artery pressure estimated at 10.64 kPa (80 mmHg). There was no evidence of congenital heart disease. Pulmonary embolism was excluded with a negative perfusion scan. Lung function was within the normal range. Right-heart catheterisation confirmed severe pulmonary arterial hypertension (table 1Go). The patient could walk 450 m in 6 min with a mild desaturation on exercise (decreasing from 98% to 94%). Echography and computed tomodensitometry of the liver demonstrated a patent porto-caval shunt and multiple adenomas of the liver. The patient was treated with conventional therapy, including exercise limitation, warfarin at sufficient doses to increase the international normalised ratio to ~2.0, and diuretics. The patient has subsequently been followed-up in the authors' centre without significant modifications of the clinical and haemodynamical status (table 1Go).


View this table:
[in this window]
[in a new window]
  		Table 1 A 4-y follow-up of a patient with severe pulmonary hypertension and type-Ia glycogen-torage disease

 
Patients with type-Ia glycogen-storage disease and no pulmonary hypertension
Of the 30 patients with type-Ia glycogen-storage disease regularly followed-up between 1997–1999, 13 (12±10-yr-olds) were randomly analysed in this study. Pulmonary hypertension was ruled out by clinical examination and a normal transthoracic echography with Doppler.

Patients with severe pulmonary arterial hypertension in the absence of glycogen-storage disease type Ia
During the same period (1997–1999), 16 patients referred to the hospital for initiation of continuous intravenous epoprostenol therapy were included in the present study (six with pulmonary arterial hypertension associated with a past history of appetite suppressant exposure, nine with sporadic and one with familial primary pulmonary hypertension). Clinical and haemodynamical information, before initiation of epoprostenol therapy, are listed in table 2Go. Plasma serotonin was measured in all patients before epoprostenol therapy. In patients with a history of fenfluramine intake, fenfluramines exposure was stopped several years before analysis.


View this table:
[in this window]
[in a new window]
  		Table 2 Patients with primary pulmonary hypertension

 
Controls
Twenty-six normal, age-matched healthy controls were included in parallel, corresponding to 10 individuals aged <18 yrs and 16 adults (>18 yrs).


   Methods
TOP
 Abstract
 Patients and methods
 Methods
Results
 Discussion
 References
 
In all patients and controls, 4.5 mL of blood was drawn by venipuncture from a peripheral vein in 0.5 mL of 0.129 M trisodium citrate. Platelet-rich plasma was prepared by centrifugation of citrated blood at 120xg for 10 min. Platelets were counted and platelet-rich plasma was further centrifuged at 2,000xg for 10 min in order to harvest separately the platelet pellets and the platelet-poor plasma. Serotonin levels were measured by radioenzymology and high-performance liquid chromatography in citrated whole blood, platelet-poor plasma (also referred to as plasma) and platelet pellet, as described previously 15.

Statistical analysis
Data were analysed with a Macintosh computer (Apple Company, New York, NY, USA) using the Stalview® 4.5 Software (Abacus Concepts Inc., Berkeley, CA, USA). The two-tailed Mann-Whitney U-test and the Spearman's test were used for between-group comparison and correlations, respectively. Data are presented as mean±sem. A p-value of <0.05 was statistically significant.


   Results
TOP
 Abstract
 Patients and methods
 Methods
 Results
Discussion
 References
 
Serotonin measurements
In patients and controls, whole-blood serotonin concentrations were within the normal range, as reported previously by the authors' group (data not shown) 11–13 and others 14. In contrast, elevated plasma-serotonin concentrations were measured in patients with either severe pulmonary arterial hypertension (38.8±7.3 nmol·L–1) or type-Ia glycogen-storage disease (36.8±11.5 nmol·L–1), as compared to controls (8.8±0.6 nmol·L–1, p<0.001) (fig. 1Go). Elevated plasma serotonin levels were similar in patients with a past history of fenfluramine intake and patients displaying primary pulmonary hypertension. Similarly, plasma serotonin concentrations were dramatically elevated in the patient with glycogen-storage disease type Ia and severe pulmonary hypertension (113.4 nmol·L–1). Repeated measures in the same individuals did not show significant modifications. In patients and controls, plasma serotonin concentrations were not influenced by age or sex (data not shown), as reported previously 15, 16. Plasma serotonin did not correlate with any clinical or haemodynamical parameters, such as the 6-min walk test, mean pulmonary artery pressure, the cardiac index, and total pulmonary resistance (data not shown). Platelet serotonin was within the normal range (0.50–5.0 amol·platelet–1) in glycogen-storage disease type Ia (2.41±0.25 amol·platelet–1) and severe pulmonary arterial hypertension (4.36±3.60 amol·platelet–1). There was a trend for lower platelet counts in pulmonary arterial hypertension (140±63x109 L–1) as compared to glycogen-storage disease (357±51x109 L–1) or controls (332±51x109 L–1).



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1.— Plasma serotonin concentrations in primary pulmonary hypertension, type-I glycogen- storage disease and normal healthy controls. The horizontal bar represents mean values. **: p<0.01.

 

   Discussion
TOP
 Abstract
 Patients and methods
 Methods
 Results
 Discussion
References
 
A case of severe pulmonary hypertension in a patient with type-Ia glycogen-storage disease is reported. Interestingly, the patient with severe pulmonary arterial hypertension and type-Ia glycogen-storage disease had elevated plasma serotonin concentrations, suggesting that this mediator may play some role in the occurrence of pulmonary arterial hypertension. In order to evaluate whether abnormal serotonin-plasma levels are a common feature in type-Ia glycogen-storage disease and without overt pulmonary hypertension, this parameter was prospectively measured in 13 consecutive patients referred to the authors' hospital for this condition. Demonstration of elevated plasma serotonin in these individuals, in the absence of pulmonary arterial hypertension, suggested that elevated plasma serotonin is a characteristic of type-Ia glycogen-storage disease. However, most patients will not develop severe pulmonary vascular disorders, emphasising the argument that additional factors of individual susceptibility may be required to lead to pulmonary vascular involvement. Indeed, it has been previously suggested that individual susceptibility to serotonin explains the occurrence of pulmonary arterial hypertension in a minority of patients exposed to an established risk factor 2. For instance, only a minority of patients using fenfluramine derivatives, appetite suppressant drugs that impair platelet storage of serotonin and elevate its plasma levels, developed pulmonary arterial hypertension, indicating that drug-induced abnormal serotonin handling was one event in a multistep process leading to severe pulmonary arterial hypertension in susceptible individuals 2, 17. Recent studies have shown that patients with a predisposition for developing primary pulmonary hypertension may manifest early changes in pulmonary hypertension when studied by stress echocardiography 18. Further studies are needed to evaluate whether patients with type-I glycogen-storage disease and pulmonary hypertension may have abnormal stress echocardiography.

Current results concerning the possible role of serotonin in the setting of pulmonary hypertension complicating the course of type-I glycogen-storage disease are purely descriptive and direct evidence that serotonin is causally related to pulmonary hypertension cannot be provided. Moreover, the exact mechanisms leading to the increase in plasma serotonin in type-I glycogen-storage disease remain unclear. Blood serotonin is produced by the enterochromoffin cells of the intestine. Virtually all blood serotonin is stored in the platelets and free serotonin is rapidly metabolised by the endothelial monoamine oxidase in the liver and the lung. Increased plasma concentrations of free serotonin in type-Ia glycogen-storage disease might be the result of excessive production by the gut and/or decreased endothelial metabolism and/or impaired ability of the platelets to store large amounts of serotonin 11. The authors also confirm that severe pulmonary arterial hypertension is associated with elevated serotonin plasma levels. As was shown previously, these raised plasma concentrations were not the mere consequence of pulmonary arterial hypertension, as they remained elevated after successful lung transplantation 11. To the best of the authors' knowledge, no recurrence of pulmonary arterial hypertension has been described after lung transplantation, suggesting that elevated plasma serotonin is not sufficient to induce a relapse of the disease in the years following surgery 11. Nevertheless, further long-term studies are needed to firmly establish this point. In addition to chronic serotonin exposure, abnormal native pulmonary endothelial cells (increased endothelin-1, decreased prostaglandin synthase or nitric oxide synthase) or smooth muscle cells (abnormal potassium channels, abnormal serotonin transporter) may be critical in the development of pulmonary arterial hypertension 19.

Table 3Go shows that six out of the seven reported cases of severe pulmonary arterial hypertension complicating the course of type-I glycogen-storage disease occurred in the second or third decade of life, suggesting that long-term metabolic abnormalities may be necessary to lead to pulmonary hypertension. The only case occurring before the age of 10 yrs was in a young female with atrial-septal defect of the secundum type and type-Ia glycogen-storage disease 8. Interestingly, neither atrial-septal defect nor type-Ia glycogen-storage disease usually lead to severe pulmonary hypertension in the first decade of life. Therefore, these conditions could have cumulative negative effects with a faster progression of the pulmonary vascular disease 8, 20.


View this table:
[in this window]
[in a new window]
  		Table 3 Pulmonary hypertension (PH) and type-Ia glycogen-storage disease: review of the litterature

 
The patient in the present study had a history of porto-caval shunt without portal hypertension. Indeed, until ~1984, some authors proposed porto-caval shunts in type-I glycogen-storage disease to improve the patient's growth status 21. Table 3Go shows that three out of the seven published cases of type-I glycogen-storage disease with pulmonary arterial hypertension had a history of shunt operation, suggesting that substances of intestinal origin normally metabolised in the liver had significantly influenced the course of the disease 5, 7. Serotonin, a product of the enterochromoffin cells of the gut, is one of these substances. Under normal conditions, the pulmonary vascular bed is not exposed to excessive serotonin levels, because of its position as a second filter located downstream of the liver, and because of the ability of platelets to store large amounts of serotonin 11. Since vasoconstrictive pulmonary hypertension is uncommon in patients with portosystemic shunts 22, one or more additional factor(s) of individual susceptiblity is (are) believed to be necessary to develop severe pulmonary hypertension after a shunt operation. In order to evaluate whether a simple porto-caval shunt may induce detectable elevation in circulating serotonin concentrations, whole blood and plasma serotonin concentrations were measured in a group of nine patients with porto-caval shunts. In this population, whole blood and plasma serotonin concentrations were within the normal range (unpublished data). Therefore, elevated plasma serotonin concentrations detected in the patient with a patent porto-caval shunt, described in the present report, could not be explained by the presence of a porto-caval shunt.

The patient presented with multiple adenomas of the liver. With longer survival of patients with type-Ia glycogen-storage disease, cases with hepatic tumours (mostly adenomas) have been increasingly demonstrated 23. Adenomas are also known to be associated with the use of oral contraceptives, a condition known to increase oestrogen in the systemic circulation 24. Interestingly, sex is regarded as a definite risk factor of primary pulmonary hypertension with a female:male ratio exceeding 1:1.7 in large cohorts, indicating that hormonal influences play a part in these pulmonary vascular diseases 25. Similarly five out of the seven cases of severe pulmonary hypertension, complicating the course of type-Ia glycogen-storage disease, occurred in females (table 3Go).

The occurrence of severe pulmonary arterial hypertension in patients with type-I glycogen-storage disease could be due, at least in part, to endothelial cell dysfunction secondary to the metabolic disturbances characteristic of this condition, such as marked hyperlipidaemia 26. It must be stressed, however, that hyperlipidaemia is not a recognised cause of pulmonary vascular diseases 2 and that patients with type-I glycogen-storage disease appear to be less susceptible to the damaging effects of hyperlipidaemia than the general population 26. Thrombosis may also play a role in the development or progression of pulmonary arterial hypertension in patients with type-I glycogen-storage disease, as previously suggested with regard to primary pulmonary hypertension 27. Indeed, Taki et al. 28 have shown that thrombus formation may be a result of abnormal platelet adhesion to subendothelium in type-I glycogen-storage disease 28. However, when available, pulmonary histology did not show marked pulmonary thrombosis in patients displaying severe pulmonary arterial hypertension and type-I glycogen-storage disease (table 3Go). Moreover, there was no evidence of thromboembolic disease in the patient reported in the present study.

Familial and sporadic primary pulmonary hypertension can be caused by mutations in receptor members of the transforming growth factor-ß family (BMPR2 and ALK1) suggesting that dysfunctional transforming growth factor-ß signalling could lead to abnormal proliferation of pulmonary vascular cells 29, 30. The patient with type-Ia glycogen-storage disease and pulmonary arterial hypertension was sequenced for all BMPR2 and ALK1 exons. No sequence variants were found. The gene responsible for type-Ia glycogen-storage disease (glucose-6-phosphatase deficiency) has been cloned on the long arm of chromosome 17r (17q21) 31. Several mutations have been detected in the coding sequence of the gene in type-Ia glycogen-storage disease, thus illustrating the genetic heterogeneity of this condition 31. Further studies are needed to investigate a possible gene linked to pulmonary hypertension in the same chromosomic region.


   References
TOP
 Abstract
 Patients and methods
 Methods
 Results
 Discussion
 References
 

  1. Rubin LJ. Primary pulmonary hypertension. Chest 1993;104:236–250.[Free Full Text]
  2. Humbert M, Nunes H, Sitbon O, Parent F, Hervé P, Simonneau G. Risk factors for pulmonary arterial hypertension. Clin Chest Med 2001;22:459–475.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  3. Chen YT, Burchell A. Glycogen storage disease In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th EdnNew York, Mc Graw Hill, 1995; pp. 935–965.
  4. Moses SW. Pathophysiology and dietary treatment of the glycogen storage diseases. J Pediatr Gastroenterol Nutr 1990;11:155–174.[ISI][Medline] [Order article via Infotrieve]
  5. Pizzo CJ. Type I glycogen storage disease with focal nodular hyperplasia of the liver and vasoconstrictive pulmonary hypertension. Pediatrics 1980;65:341–343.[Abstract/Free Full Text]
  6. Furukawa N, Kinugasa A, Inoue F, Imashuku S, Takamatsu T, Sawada T. Type I glycogen storage disease with vasoconstrictive pulmonary hypertension. J Inher Metab Dis 1990;13:102–107.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  7. Hamaoka K, Nakagawa M, Furukawa N, Sawada T. Pulmonary hypertension in type glycogen storage disease. Pediatr Cardiol 1990;11:54–56.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  8. Bolz D, Stocker F, Zimmermann A. Pulmonary vascular disease in a child with atrial septal defect of the secundum type and type I glycogen storage disease. Pediatr Cardhl 1996;17:265–267.
  9. Ohura T, Inoue CN, Abukawa O, et al. Progressive pulmonary hypertension: a fatal complication of type I glycogen storage disease. J Inher Metab Dis 1995;18:361–362.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  10. Kishnani P, Bengur AR, Chen YT. Pulmonary hypertension in glycogen storage disease type I. J Inher Metab Dis 1996;19:213–216.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  11. Hervé P, Drouet L, Dosquet C, et al. Primary pulmonary hypertension in a patient with a familial platelet storage pool. Am J Med l990 89:117–120.
  12. Hervé P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995;99:249–254.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  13. Kereveur A, Callebert J, Humbert M, et al. High plasma serotonin levels in primary pulmonary hypertension: effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler Thromb Vasc Biol 2000;20:2233–2239.[Abstract/Free Full Text]
  14. Egermayer P, Town GI, Peacock AJ. Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension. Thorax 1999;54:161–168.[Free Full Text]
  15. Beck D, Wallen NH, Bröijersen A, Larsson PT, Hjemdahl P. On the accurate determination of serotonin in human plasma. Biochem Biophys Res Comm 1993;196:260–266.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  16. Lee MS, Chang FC, Yeh HZ, Liou TY, Liu JH. Determination of plasma serotonin and 5-hydroxyindoleacetic acid in healthy subjects and cancer patients. Clin Chem 2000;46:422–423.[Free Full Text]
  17. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996;335:609–616.[Abstract/Free Full Text]
  18. Grunig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000;102:1145–1150.[Abstract/Free Full Text]
  19. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research "Work in progress". Circulation 2000;102:2781–2791.[Abstract/Free Full Text]
  20. Vongpatanasin W, Brickner E, Hillis D, Lange RA. The Eisenmenger syndrome in adults. Ann Int Med 1998;128:745–755.[Abstract/Free Full Text]
  21. Borowitz SM, Greene HL, Gay JC, Neblett WW. Comparison of dietary therapy and portocaval shunt in the management of a patient with type Ib glycogen storage disease. J Pediatr Gastroenterol Nutr 1987;6:635–639.[ISI][Medline] [Order article via Infotrieve]
  22. Hervé P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in liver disease. Eur Respir J 1998;11:1153–1166.[Abstract]
  23. Labrune P, Trioche P, Duvaltier I, Chevalier P, Odièvre M. Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature. J Pediatr Gastroenterol Nutr 1997;24:276–279.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  24. Sakatoku H, Hirokawa Y, Inoue M, Kojima M, Yabana T, Sakurai M. 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. Acta Pediatr Jpn 1996;38:172–175.
  25. Brenot F. Primary pulmonary hypertension: case series from France. Chest 1994;105:33s–36s.
  26. Lee PJ, Celermajer DS, Robinson J, McCarthy SN, Betteridge DJ, Leonard JV. Hyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type Ia. Atherosclerosis 1994;110:95–100.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  27. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984;70:580–587.[Abstract/Free Full Text]
  28. Taki M, Inagaki M, Tomita Y, Meguro T, Yamada K. Abnormal platelet adhesion to subendothelium and thrombus formation in glycogen storage disease, type I. Rinsho Ketsueki 1981;22:1875–1879.[Medline] [Order article via Infotrieve]
  29. Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001;68:92–102.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  30. Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001;345:325–334.[Abstract/Free Full Text]
  31. Lei KJ, Chen YT, Chen H. Genetic basis of glycogen storage disease type Ia: prevalent mutations at the glucose-6-phosphatase locus. Am J Hum Genet 1995;57:766–771.[ISI][Medline] [Order article via Infotrieve]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (7)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Humbert, M.
Right arrow Articles by Simonneau, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Humbert, M.
Right arrow Articles by Simonneau, G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS