Treatments and Disease Management

No Cure, Only Treatment

Since GSD-I is the result deficient proteins due to genetics, there is no way to cure the patient of GSD-I. Since the genetics of a patient are unable to be altered, the patient will have GSD-I for the rest of their life. Thus, doctors and health professionals can only treat the symptoms of GSD-I, but not the condition itself.

Proper Diet and Supplements

One aspect of treating GSD-I revolves around addressing the metabolite imbalances the patient is suffering from while also promoting growth and development. Due to the fact that glucose is not being synthesized during fasting periods, it has been recommended that the patient eats small, frequent meals of carbohydrates throughout the day instead of a few, big meals (Rake et al., 2002). This will reduce the need for gluconeogenesis pathway being activated and utilized. Since the gluconeogenesis pathway is not being utilized as much, there will not be an accumulation of G6P which is being fluxed in the uric acid, glycerides, and lactate (Rake et al., 2002). It has been well understood that fructose and galactose are to be avoided along with anything high in sugar content (fruits, syrup, honey, candy, etc) (Fernandes, 1974). The addition of calcium, vitamin D and iron supplements may be recommended for GSD-I patients in order to support bone growth, mineralization, and strengthen the immune system of the patient (Minarich, 2012). This strict diet in addition to the supplements has been successfully used in GSD-I patients in order to maintain normal glucose levels, prevent hypoglycemia and maximize growth and development.

Allopurinol

In order to address the hyperuricemia and gout a GSD-I patient may encounter, the pharmaceutical drug Allopurinol is often prescribed. Allopurinol (1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) is a 1966 synthesized structural isomer of hypoxanthine which binds and inhibits xanthine oxidase (Kishnani, 2014). Xanthine oxidase is an enzyme involved in converting nucleic acids into uric acid by oxidizing xanthine and hypoxanthine into uric acid (Kishnani, 2014). As a result of inhibiting xanthine oxidase, the production of a uric acid is reduced. Thus, Allopurinol is a drug capable of reducing the level of uric acid in the blood and reduces the possibility of a GSD-I patient suffering from gout-like symptoms.

Figure 1: The structure of Allopurinol is very similar to Hypoxanthine (rearrangement of adjacent carbon and nitrogen). Allopurinol inhibits Xanthine Oxidase and prevents the formation of uric acid, thus preventing gout. Source: Google Image
Figure 1: The structure of Allopurinol is very similar to Hypoxanthine (rearrangement of adjacent carbon and nitrogen). Allopurinol inhibits Xanthine Oxidase and prevents the formation of uric acid, thus preventing gout.
Source: Google Image

Liver Surgery and RFA

A problematic area surrounding GSD-I is how to address the complications surrounding the liver. With the accumulation of glycogen in the liver resulting in tumors being generated, it is important to address them immediately. A majority of the tumors produced this way are benign which means they can be surgically removed. GSD-I patients that have malignant tumors require more invasive measures such as surgery or a procedure known as radiofrequency ablation (RFA) (Ahn et al., 2013). Radiofrequency ablation is a procedure where the doctor uses X-Ray guidance (fluoroscopy) with needle electrodes in order to direct electrical current to the tumor site. The electrical currents produce heat which destroys the tumor cells. If RFA and surgery are not viable options, then liver transplantation may be required (Ahn et al., 2013). In order to reduce the risk of liver and kidney tumors being problematic, GSD-I patients are suggested to be monitored annually with liver and kidney ultrasounds and blood work (Koeberl, 2009).

Figure 2: Radiofrequency Ablation is a cancer treatmeent method of applying heat to tumor cells in the form of electrical currents in order to destroy the cells. Source: Google Image
Figure 2: Radiofrequency Ablation is a cancer treatmeent method of applying heat to tumor cells in the form of electrical currents in order to destroy the cells.
Source: Google Image

Cornstarch Diet

One of the most intriguing treatments available to GSD-I is the use of uncooked cornstarch. Uncooked cornstarch is a continuous nasogastric glucose polymer which is digested slowly and helps maintain blood glucose levels (Bhattacharya et al., 2007). Upon further review of these uncooked cornstarches, although it did help the GSD-I patients, administering it was difficult because many found it unpalatable and resulted in stomach pains and diarrhea. Why seeking an alternative, Bhattacharya et al. synthesized a new uncooked physically modified cornstarch (WMHM20). When comparing the results of uncooked cornstarch and WMHM20, they discovered that not only was administering the cornstarch easier, but WMHM20 resulted in blood glucose concentrations decreasing more slowly and lactate concentrations decreased more rapidly (Bhattacharya, 2007). In addition to this new discovery, Beegle et al. discovered that while administering cornstarch and stabilizing metabolic conditions, livers and liver tumors in GSD-I patients decreased in size up to 10% (Beegle et al., 2015). This finding is incredible because if researcher can begin to investigate and synthesize new cornstarches which will reduce liver and liver tumor size, then invasive techniques such as RFA and surgery will no longer be necessary.

8 Replies to “Treatments and Disease Management”

  1. This is a really helpful and fascinating explanation of GSD-I! I am really interested in the buildup of G6P and glycogen in the liver leading to tumor formation- it almost seems counter-intuitive as one would think the metabolite buildup would be toxic to the hepatocytes and cause apoptosis rather than cell proliferation. I’m wondering if you were able to find anything in the literature about the molecular basis for tumorigenesis in GSD-I? It might turn out that the key to tumor prevention lies in targeting one of the downstream consequences of the buildup rather than the buildup itself.

    1. Hello Rebecca! Thank you very much for reading about my disease and for your feedback. Your question is an interesting one. A 1987 paper by Coire et al. demonstrated that the result of malignant liver cancer (hepatocellular carcinoma) in GSD-Ia patients was metabolic instead of hormonal. It has been observed that the build-up of glycogen and other metabolites results in enlarged livers (hepatomegaly) and benign liver tumors (hepatocellular adenomas). Although the exact mechanism has yet to be determined which results in the formation of hepatocellular carcinoma, it has been implicated that an excessive amount of glycogen is involved (Kishnani et al., 2004). Similarly, the build-up of lactate would demonstrate also assist in the transition of hepatocellular adenomas and healthy cells into mass proliferating cells uncontrollably dividing (Ozen et al., 2007). The build-up itself is problematic and can lead to tumorigenesis, but potentially developing inhibitors for lactate dehydrogenase to halt production of key metabolite implicated in tumorigenisis. However, such an inhibitor would have a negative impact on the entire metabolic system and would generate a host of other side effects. You question does raise an interesting question regarding where research should head and if more research into inhibitors for downstream metabolites is a viable solution. At the moment, the literature has not investigated inhibiting downstream metabolites with exception to uric acid. Thank you for reading about my disease and for a very insightful question!
      Tyler Florio

  2. Hello!
    I found GSD-I to be very interesting, and your explanation of the molecular basis and treatment were very thorough. Well done! The role of glycogen and G6P in liver tumor formation actually peaked my curiosity as well, and I was wondering, have you read anything about administering synthetic glucagon or cortisol (since they do participate in glycogenolysis in the liver) as a means to prevent this? Or do you think that is a pathway that could potentially be implemented? I’d love to hear your thoughts. Thanks 🙂

    1. Hello Radhika! Thank you for reading about my disease and for commenting. I appreciate your feedback and I am glad to hear that you enjoyed reading it. Your question is a complex one and has very interesting implications for GSD-I patients. What you are proposing is administering either glucagon or cortisol in order to breakdown glycogen which effectively would result in less glycogen being stored in the liver and kidneys. This ordinarily would be a great idea and may result in a decrease in hepatomelagy; However, there is a problem with this proposal and that lies with the fact that GSD-I patients lack the ability to convert G6P to glucose. This is a serious problem because the inability to convert G6P to glucose will result in increased flux into other metabolites such as triglycerides, uric acid, and lactate. This increased flux into these metabolites would have a serious affect on the body; in fact, I believe that the increase in lactate could potentially result in tumorigenesis since lactate has been implicated in uncontrolled mass cell division. The addition of cortisol or glucagon in order to promote gluconeogenesis would have a negative impact on the body overall since more lactate, uric acid, and triglycerides are being produced which would cause the GSD-I patient to then experience symptoms associated with lactic acidosis, hyperuricemia, and hypertriglyceridemia, respectively. What is your opinion on this analysis?

  3. Hey Tyler! You presented the disease in a very informative, clear and concise manner that made reading through your pages very helpful. I am interested in treatment of the disease through the use of uncooked corn starch. I found this idea very intriguing because of the amount of ways we have examined diet as a treatment for diseases this year in class. I was wondering how the synthetically modified cornstarch was actually created and how the results showed that this treatment produced different effects than normal uncooked corn starch? Additionally, I also wanted to know why the uncooked corn starch resulted in some adverse side effects like stomach pains and diarrhea because I would think that the slow digestion might actually aid with those symptoms? Also, has there been any discussion of treatment through a drug that would maintain glucose levels to this extent due to the unpalatability of the uncooked corn starch?

    1. Hello Tyler! Thank you for reading about my disease and I appreciate the positive feedback. II agree that it is fascinating how our diet impacts so much of our bodily function and can either help or harm us. In Bhattacharya et al. study in 2007, the modified cornstarch (WMHM20) differed in a few percentages of its composition and is synthesized in a laboratory using organic chemistry and modifications. Ordinary uncooked cornstarch contains a moisture content, amylopectin content, total carbohydrate, and resistant starch of 10.9%, 72.8%, 84.6%, and 60.5% respectively. The WMHM20 composition consisted of 11.9%, 99.5%, 84.2%, and 67.7%, respectively. The authors tested the blood of patients taking ordinary cornstarch and WMHM20 for blood glucose and lactate levels were recorded at various time points. Similarly, CO2 breathe tests were also conducted in order to respiration rates. The tests showed that blood glucose levels were maintained for longer, lactate concentration in the blood decreased significantly, and respiration rates significantly decreased compared to ordinary uncooked cornstarch. It has been noted that these adverse side effects occur because the slow digestion could result in alpha-amylase activity being impaired or slowed down which generates the associated stomach pains. Similarly, the structure of the uncooked cornstarch is such that it is difficult to digest and requires the production of more digestive enzymes which can also result in the creation of stomach pain. The continual treatment of the uncooked cornstarch would then result in continual stomach pains, diarrhea, and IBS. Your question regarding the development of a drug to maintain glucose levels is interesting, but given the context of GSD-I it is not a possibility. Glucose is used by our body every second to power cellular function, organs, and tissues. This continual use of glucose by our body depletes the naturally circulating glucose in our bloodstream. A drug designed to maintain blood glucose would deprive these cells, organs, and tissues of glucose. If there was a drug designed to promote gluconeogenesis, there would still be the problem of the final step where GSD-I patients cannot convert G6P into glucose. This inability to convert G6P into glucose prevents the production of glucose and thus resulting in hypoglycemia. A drug would not be able to impact this cycle because glucose is continuously being used by the body and the main way to produce glucose is impaired at the final step. Thus, the only way to treat hypoglycemia for GSD-I patients is through diet. I hope I addressed all of your questions and comment back if you still have more questions.

  4. Great Review! Your analysis of the metabolic changes caused by GSD-1 were very well done. I found you ideas about future work into the potential treatments of GSD-1 using gene therapy and new cornstarch to be very interesting. When you discussed the build up of lactate as a symptom of GSD-1, I immediately started thinking of the Warburg effect. Did you find anything that linked the lactate build up from GSD-1 to increased proliferation that leads to the growth of tumors?

    1. Hello Zach! Thank you for reading about my disease and for those your positive feedback! I too found the treatment with cornstarch to be interesting and it goes to show how diet impacts our bodily function. I enjoyed to see you drawing connections to previous topics discussed in class. Although there is nothing definitive in this realm of research despite the presence of lactic acidosis, I would argue that this would be a factor. There was a 1987 paper by Coire et al. which demonstrated that malignant liver cancer (hepatocellular carcinoma) in GSD-Ia patients was caused by metabolic byproduct instead of hormonal. Since lactate is a metabolic byproduct, would be interesting to see a parallel drawn between the two concepts. I personally see the link between lactic acidosis and hepatocellular carcinoma as entirely plausible and worth investigation. Orzen et al, 2007 believed that this was entirely plausible as well although he did not investigate.

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