The significance of GDF15 for Hyperemesis Gravidarum
Sometimes in science, two separate discoveries happen at the same time and combine to make more than the sum of their parts. This is the case with a discovery published in late 2017, and another in March 2018, both of them in the Nature group of journals.
- Written by Dr Margaret O'Hara
These discoveries have huge implications and are extremely hopeful for women with Hyperemesis Gravidarum.
The first one was seemingly nothing to do with pregnancy, in a field of biology relevant for obesity and diabetes. It concerns a protein called GDF15, which has been the subject of research for several years and is known to be associated with various conditions – for example cardiovascular disease, tissue injury, chronic kidney disease and cancer. It is also known to be higher in people who have a condition called cancer cachexia, this causes loss of appetite which makes these people waste away as they are unable to eat. Pharmaceutical companies are interested in GDF15 as a possible target for anti-obesity drugs due to its ability to cause loss of appetite.
The breakthrough on GDF15 came in publications in Nature Medicine in October 2017. Finally, after years of searching, the receptor for this protein had been discovered. It is located in the brainstem in a part of the brain which is responsible for producing the sensation of nausea. This is where things get interesting for women with HG, because it is known that GDF15 is also higher in pregnancy. It increases in the blood of pregnant women early in pregnancy, increasing tenfold within a short space of time.
The cause of pregnancy sickness has never been identified. Partly because not a great deal of scientific attention has been paid to it, compared with other disorders. Various causes have been suggested, but none has ever really been tied to a very good reason why that would make you feel sick. Also none of them have ever been able to explain why hyperemesis gravidarum exists. For example, hormones have been implicated because they rise in early pregnancy, particularly human chorionic gonadotropin. But hCG peaks early and drops at the end of the first trimester. This may explain regular pregnancy sickness, but it can’t explain HG, which continues well into the second and, often, the third trimesters.
GDF15 on the other hand has a lot going for it as an explanation – it rises in early pregnancy, it causes loss of appetite in people with cancer who have cachexia; mice who are given drugs which cause GDF15 to rise in their blood eat less and lose weight; mice who are genetically engineered to not have the receptors for GDF15 suffer no such effects from this drug and carry on eating as normal; and the receptors for GDF15 are in a part of the brain that causes nausea.
This is already incredibly encouraging, but then in March 2018, a paper is published in Nature Communications which really seals the deal. Marlena Fejzo, a scientist at UCLA and USC and partly funded by the HER (Hyperemesis Education and Research) foundation in the USA has been working on the genetics of HG for some time. Marlena had HG herself, and the rationale for investigating genetics is that it has long been known that HG can run in families. You may not always see it in your family because, for example, it may be inherited from your father. She obtained genome data from women who had completed a questionnaire about pregnancy sickness from the genomics company 23andMe. This showed that two genes are associated with HG. One of these is GDF15. She then confirmed the link between GDF15 and HG in the DNA from her separate collection of 100s of HG patients, validating the genetic findings.
To explore whether the HG gene might result in higher GDF15 levels in the blood of women with HG, she then analysed GDF15 in patients hospitalized for HG. This work, presented in October 2017 at the ICGH (https://vimeo.com/260389622) revealed that women with HG did indeed have abnormally high levels of GDF15 compared to women with normal NVP. In addition to all this, Stephen O’Rahilly, a clinical academic at Cambridge University has done some recent work showing that GDF15 is higher in the blood of pregnant women who have taken antiemetics compared with pregnant women who haven’t. Generally speaking, the only women who take antiemetics in pregnancy are those who have HG or, at least, severe pregnancy sickness. So this is another way of saying that pregnant women with severe nausea and vomiting have more GDF15 in their blood than pregnant women who don’t.
Further work will have to be done before we can say definitively that GDF15 causes HG, but the evidence so far is compelling. It’s certainly the most promising theory yet.
If it does prove to be the case, then it opens up the possibility that a drug treatment could be developed that would treat the root cause of HG. This would be a huge improvement on current treatment with antiemetics that just attempt to treat the symptoms, often ineffectively. There are no guarantees, and in any case, it would take years for a drug to pass through all the stages of development. So not on a timescale to help all the women with HG now, but hopefully in time for our daughters.
Even if they can’t develop a treatment, then just the existence of a known biochemical pathway to explain HG will mean that healthcare professionals will have to stop telling women that it is all in their heads, or that it’s normal. For women who are dismissed by their doctors or told to go away and just get on with it, this will be the most immediate benefit of all of these developments.
This sort of research is incredibly expensive and there is very little interest worldwide from funding bodies, Most of this research to date has been funded through donations to the HER Foundation. If you would like to support the ongoing research by Marlena Fejzo please consider donating.
