Detailed guidelines for patient's management based on the data of the European Study on Glycogen Storage Disease type I have been provided .
Treatment aims at preventing hypoglycemia in order to avoid neurological involvement and long-term complications (hepatic, renal, etc.) and to assure normal growth.
Treatment is essentially dietary and consists of frequent meals, continuous nocturnal nasogastric drip feeding, ingestion of slow-absorption carbohydrates (uncooked starch: ), and restricted intakes of both fructose and galactose which can aggravate hyperlactacidemia.
Daily caloric intake must be monitored: insufficient intake does not correct the metabolic disorder (hypoglycemia, hyperlactacidemia and hyperuricemia) and leads to retarded growth, whereas excessive intake increases the glycogen overload, hepatomegaly and hyperlipidemia, and causes obesity. The diet must provide 60-65% of total caloric intake from carbohydrates, 10-15% from proteins and the reminder from fat.
Until 12 months, frequent meals (5 meals per day) and continuous nocturnal feeding via a nasogastric tube, providing 6-8 mg of glucose/kg/min, are recommended. However, continuous nocturnal feeding may be, in some cases replaced by nocturnal meals.
After 1 year, uncooked cornstarch (which may be introduced from 9 to 12 months of age, with progressive increase of doses) can, in some patients, replace the continuous nocturnal feeding at the initial dose of 0.5 g/kg then slowly increased to 1 g/kg every 4 hours. As the child grows older, the cornstarch regimen can be changed to the dose of 1.5-2.0 g/kg every 6 hours.
Another therapeutic regimen may be proposed and discussed for cornstarch which can be started during infancy, and given between meals or before bed so as not to interfere with appetite at meal time (94). Recommendations for dosing are: 1.6 g/kg body weight every 4 hours for infants, 1.7-2.5 g/kg body weight every 6 hours for young children through puberty, and 1.7-2.5 g/kg body weight given before bed time for adults. A novel and modified starch is being tested in GSD patients. To date, it seems that this new starch might allow, in some patients, longer duration of euglycemia and better short-term metabolic control [97, 98]. This starch is allowed in several countries (United Kingdom, Netherlands, Germany).
In adults, the cornstarch dose and the intake interval can be increased. However, several adults stop taking cornstarch, even though they are encouraged to continue.
Treatment efficacy is evaluated by monitoring clinical (growth curve, body mass index, importance of hepatomegaly, blood pressure) and biological parameters. The preprandial glycemia must be above 3.5 mmol/L and adjusted to the actual urinary lactate excretion, which must be below 0.06 mmol/mmol creatinine in 12 hours urine samples (night and day). Blood lactate monitoring, when available, may be useful for supplementing glucose monitoring . Hyperlactatemia causes acute clinical deterioration whereas chronic hyperlactatemia has been associated with long-term complications of GSDI. The main use of lactate monitoring is during intercurrent illness, when the rapid development of lactic acidosis is very likely. In such situations, the use of a portable lactate meter seems to be a valuable tool . Triglyceridemia, cholesterolemia, uricemia, blood gazes, proteinuria and complete blood cell count should be measured at each outpatient visit.
Portocaval shunts were recommended in the past but accorded very limited clinical benefit and have been abandoned, since 1984 .
Surgery requires special care  in these patients at increased risk of hemorrhages and metabolic imbalances (hypoglycemia and hyperlactacidemia): glycemia must be maintained (perfusions of 10% glucose before, during and after the intervention) and solutions containing lactate should be avoided (Ringer's, for example). Corticosteroids may be discussed for a short period even though their use is usually contraindicated., and careful follow-up and correction of hemostasis abnormalities are mandatory.
Therapeutic adjuvants include vitamin supplements (vitamins D and B1, etc.), calcium (considering limited milk intake), iron in case of anemia (after excluding other causes) and allopurinol when hyperuricemia is present. If permanent microalbuminuria is present, treatment with angiotensin-converting enzyme (ACE) inhibitor is started with the aim of preventing renal complications , and additional blood pressure lowering drugs may be added if blood pressure remains elevated. Should the patient become pregnant, ACE inhibitors must be stopped at once. Hyperlipemia only responds partially to dietary treatment, but triglyceride lowering drugs are not indicated if the level remains below 10 mmol/L. Cholesterol lowering drugs are not indicated in young patients because of the low risk of atherogenicity.
For GSD type Ib, granulocyte colony-stimulating factor (G-CSF) is able to correct the neutropenia, reduces the severity of bacterial infections and attenuates inflammatory intestinal disease [33, 100]. Chronic G-CSF therapy may consist in two to three weekly injections, the average dose per injection being about 5 μg/kg body weight. G-CSF therapy must be carefully monitored and untoward effects may develop such as splenomegaly, thrombocytopenia, renal carcinoma . Should pegylated G-CSF be used, other side effects must be known such as the occurrence of Sweet syndrome in one patient , respiratory distress and sudden death in another patient . Careful monitoring of the patient's spleen size, total blood cell counts and bone density is recommended in GSD Ib patients receiving G-CSF [35, 100].
Colitis is often treated with success using a combination of G-CSF and 5-aminosalicylic acid derivatives [36, 100]. However, in a few cases, this treatment fails and other therapeutic approaches must be discussed. Corticosteroids are generally avoided in such situations, owing to steroid-induced glycogenolysis and the possibility of lactic acidosis and hyperlipidemia., Immunosuppressive drugs such as methotrexate, azathioprine and 6-mercaptopurine carry the risk of excessive immunosuppression and worsening neutropenia in GSD Ib patients. Adalimumab, a fully humanized monoclonal anti-TNF has been reported to be successful in one GS Ib patient with inflammatory bowel disease who was refractory to usual medical treatment . Fecal alpha-1 antitrypsin must be monitored for evaluation of inflammatory bowel disease in GSDIb .
Detection and follow-up of complications
Even though the risk of malignant transformation of adenomas into hepatocellular carcinomas appeared to be low [2, 16, 17], ie no malignant transformation had been reported in the European retrospective study, some recent reports suggested that the older the patients get, the more important the risk of transformation becomes . The management of adenomas remains empirical; it may be expectant or surgical. Clinically, should abdominal pains occur and require major painkillers to be controlled, malignant transformation must be suspected, even though these manifestations are not specific. Biological markers (serum α fetoprotein and ACE) are not predictive of malignant transformation. Liver CT scan and MRI may be useful in such cases, even though further evaluations are needed. Surgical resection of hepatic adenomas is feasible. Previous reports have noted frequent haemorragic problems , but such complications may be avoided, provided meticulous metabolic control is obtained before surgery (personal data).
If dietary control fails or hepatic adenomas undergo malignant transformation, treatment of complications consists of liver transplantation . Liver grafting corrects the hypoglycemia and the other biochemical anomalies but the correction of neutropenia is not constant [106, 107]. It has not been proven that it can prevent renal involvement, which may even be worsened by the immunosuppressive therapy. However, there is limited experience of liver transplantation for GSDI given the rarity of the disease. Chronic allograft rejection, post-transfusion hepatitis C infection, renal failure, gouty arthritis, and portal vein thrombosis requiring re-transplantation have been reported . The current literature shows that satisfactory medium-term outcomes can be achieved in GSD I patients (review in ). Similar data have been reported regarding living donor liver transplantation in such patients . As pointed out by Davis and Weinstein (2008), the risks and benefits of liver transplantation should be carefully evaluated and the latter should only be performed when there risk for hepatocellular carcinoma or liver dysfunction is high . Liver cell transplantation could provide a less invasive approach in the future . It has been reported in a GSDIb patient with marked improvement up to 250 days following transplantation; however, long-term results are still unknown and the use of immunosuppressive agents is mandatory .
Bone marrow transplantation has been reported in one GSDIb patient who had life-threatening complications related to neutropenia and thrombocytopenia. It resulted in improved metabolic control and reduction of inflammatory bowel disease-related symptoms .
Kidney transplantation, performed in case of severe renal failure, does not correct hypoglycemia . Should grafting be indicated, combined liver-kidney graft has been discussed when renal function is already compromised and successfully performed in a few cases [113, 114].