Efficacy of Oral Sildenafil in a Beraprost-Treated Patient With Severe Pulmonary Hypertension Secondary to Type I Glycogen Storage Disease

Abstract

ype Ia glycogen storage disease (GSD) is an autosomal recessive disorder caused by glucose-6-phosphatase deficiency and it is the best-known form of glycogenosis. In type Ia GSD, the liver, kidney, and intestinal mucosa are damaged by storage of excessive amounts of glycogen, 1 and pulmonary arterial hypertension (PAH) is a rare and severe complication. Several cases complicated by PAH have been reported, and the outcomes were poor. [2][3][4][5] Histological examination of the lung demonstrated pulmonary hypertensive arteriopathy indistinguishable from classical primary pulmonary hypertension. 2,3 PAH is a disease with a poor prognosis and is characterized by progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. 6 Since the 1990 s continuous intravenous infusion of prostacyclin (PGI2) has been administered to improve PAH. 7,8 The oral PGI2 analog, beraprost sodium (BPS), has been reported as effective against PAH in animal models 9 and human patients. 10 Another new treatment for PAH is oral sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor approved for erectile dysfunction. Cyclic guanosine monophosphate (cGMP) has a vasodilating action, but a short life because of rapid degradation by PDE-5, which is abundantly expressed in lung tissue. Sildenafil inhibits PDE-5 and causes nitric oxide-mediated pulmonary vasodilation by promoting an increased and sustained level of cGMP. 11 Recent studies suggest that sildenafil is effective against PAH. 12 We report a patient with PAH secondary to type Ia GSD who was treated with BPS and sildenafil in whom the combination therapy was effective in ameliorating pulmonary hypertension. Case ReportA 17-year-old Japanese boy diagnosed with type Ia GSD was admitted to our institution because of shortness of breath and easy fatigability. His sister had also been diagnosed with type Ia GSD. The patient was found to have hepatomegaly at 1 year of age and was diagnosed based on the results of glucagon challenge tests. Because of poor compliance with cornstarch therapy, the manifestations of GSD (ie, short stature, hypercholesterolemia, liver dysfunction) did not improve much. Although electrocardiography (ECG) and echocardiography at 15 years of age showed normal findings, the patient complained of chest pain when he was admitted. ECG showed right ventricular hypertrophy, his cardiac condition was New York Heart Association (NYHA) IV and the B-type natriuretic peptide (BNP) concentration was 391.0 pg/ml. Echocardiographic examination showed significant elevation of the right ventricular pressure (RVp) and decreased cardiac output. The pressure gradient between the right ventricle (RV) and right atrium (RA) calculated from the tricuspid regurgitation velocity using the simplified Bernoulli equation was 92 mmHg, and the cardiac index (CI) calculated as the area of the left ventricular outflow × Doppler time-velocity integral 13 was 2.2 L · min -1 · m -2 . Based on these findings, he was diagnosed with PAH secondary to GSD. Be...

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics

“…To date, nine GSD I patients with PAH have been reported. 49,50,[157][158][159][160][161][162][163] Of these, five had concomitant conditions that were also associated with the development of PAH, including three patients with portocaval shunts, one patient with an atrial septal defect, and one patient with hereditary hemorrhagic telangiectasia. 33,49,84,[157][158][159]161 It has been suggested that abnormal handling of serotonin might be one event in a multistep process leading to PAH in GSD I patients.…”

“…33,49,84,[157][158][159][160][161] There is one recent case report of a patient with significant PAH with systemic rightventricular pressure who responded well to medical management with prostacyclin and sildenafil (Viagra) to reduce the pulmonary artery pressure. 162 Historically, there have been few effective…”

Pulmonary Arterial Hypertension in Glycogen Storage Disease Type I

“…In the previous reports, 1 patient was treated with exercise limitation, warfarin, and diuretics, 8 and 1 was treated with the prostacyclin analog beraprost sodium, with subsequent transition to sildenafil. 9 In our case report, the patient was managed transiently on inhaled nitric oxide and sildenafil. Inhaled nitric oxide was weaned off within the first week of admission, and sildenafil was weaned off within 3 weeks of his admission, suggesting a transient pulmonary hypertensive crisis.…”

Respiratory manifestations in patients with inherited metabolic diseases

“…Respiratory manifestations were observed primarily in glycogenosis type I and type II [87]. Pulmonary hypertension is a rare and severe complication of type Ia (due to glucose-6-phosphatase deficiency) and type Ib (due to glucose-6-phosphate translocase deficiency) [5,6], the mechanism of which is unclear [88]. It has been postulated that vasoconstrictive amines such as serotonin, a pulmonary vasoconstrictor and growth factor for vascular smooth muscle cells that is stored in platelets, could favour the development of pulmonary hypertension in type Ia glycogenosis [88].…”

“…Interstitial lung disease (ILD) and pulmonary hypertension are by far the most frequently described complications in lysosomal storage disorders. Pulmonary hypertension may be seen in non-ketotic hyperglycaemia [4], and was described in glycogenoses type I [5,6], inborn errors of intracellular cobalamin metabolism [7], HUPRA (hyperuricaemia, pulmonary hypertension, renal failure and alkalosis) syndrome and in Wolman disease [8,9]. Several inherited metabolic diseases involve nervous or neuromuscular systems, are usually progressive, and often cause chronic airway aspiration and respiratory infections.…”