Hypophosphatasia: What is it?

October 30th is Hypophosphatasia Awareness Day and because I was recently diagnosed with this ultra-rare genetic disease I wanted to write two posts. One to go into detail about the disease using current research, and the second post about my own journey with the disease and diagnosis.

Hypophosphatasia:

Hypophosphatasia=HPP

Alkaline Phosphatase= ALP

Hypophosphatasia (HPP) is a rare progressive inherited (genetic) disease that is devastating to a lot of patients with debilitating systemic complications that can be life-threatening. It is an inborn error of metabolism with the hallmark biochemical feature of low serum alkaline phosphatase (ALP) activity (3). It occurs from what’s known in genetics as a loss of function mutation in the gene that encodes tissue-non-specific alkaline phosphatase. Which is just as it sounds, there’s a genetic mutation in the gene that encodes alkaline phosphatase making it nonfunctional in the body, which leads to very low ALP levels. With the low ALP levels, there is an increase in vitamin B6, calcium and other substrates that contribute to the disease presentation. The severity of the disease presentation is different for every patient.

There are two types of inheritance patterns in HPP: Autosomal Recessive and Autosomal Dominant. With HPP the autosomal recessive inheritance are the ones that tend to be lethal and most severe.

Autosomal Recessive: Have to inherit two mutated genes, usually one from each parent. Autosomal recessive gives a 25% chance of having a child who is unaffected and does not have the mutation, a 50% chance of having a child who carries the mutation, and a 25% chance of having a child who is affected and has the two mutated genes.

Autosomal Dominant: Only have to inherit one mutated gene. In autosomal dominant HPP each child has a 50% chance of inheriting the mutation.

Prevalence:

HPP is not just a rare disease; it’s classified as Ultra-Rare. The estimation of HPP prevalence is about 1 of 100,000 people, which varies in some populations. It can be 1 out of 300,000 people and so on. In the UK the current estimate for severe HPP is about 7-8 new patients diagnosed per year.

Symptoms & Types of HPP:

People with HPP can experience many signs and symptoms: in bones like bowed legs, rachitic chest, bad joints; severely weakened muscles, teeth, and lungs; neurological issues like seizures; and kidney disease due to calcium build up on the kidneys. The symptoms occur due to the low level of ALP in the body allowing things like calcium, phosphate, & vitamin B6 to accumulate throughout the skeleton and organs.

A list I received from the company Alexion pharmaceuticals (hypophosphatasia.com) who developed strensiq to help track Hypophosphatasia symptoms, showing how it can affect the entire body.

Generally, you will hear of perinatal, infantile, childhood or adult Hypophosphatasia but there are a couple of more listed in the literature which i’ll break down here and the inheritance pattern.

Perinatal Hypophosphatasia is almost always fatal as they often fail to even form a skeleton in utero. (autosomal recessive).

Infantile Hypophosphatasia presents after birth but before 6-months and if fatal in about 50% of the infants (autosomal recessive).

Childhood or Juvenile Hypophosphatasia presents after 6months but before adult and is moderate to severe leading to skeletal abnormalities, unmineralized bones, lung problems and more. (autosomal dominant or recessive).

Benign Prenatal Hypophosphatasia is in between perinatal, infantile and childhood. Often can see skeletal abnormalities in utero then symptoms improve post birth that can be similar to infantile/childhood, adult or the mildest form odonto HPP.

Adult Hypophosphatasia typically presents during middle age and includes osteomalacia or osteoporosis and metatarsal fractures. It can progress to be very debilitating (autosomal dominant).

Odonto hypophosphatasia is the mildest form of the disease that has dental complications with premature teeth loss. Sometimes they do have evidence of osteomalacia or rickets and sometimes they do not. (autosomal dominant).

Why is Alkaline Phosphatase (ALP) important?

 Alkaline Phosphatase is an enzyme that plays a very important role in bone formation. It is expressed abundantly in the skeleton, liver, and kidneys. When levels of ALP are normal it allows calcium and phosphate to work together and help form healthy mineralized bones.

Due to the genetic mutation in people with HPP that causes ALP to be extremely low and not really functional the calcium and phosphate cannot work together to build healthy bones and instead of them working together they start to build up in other places of the body leading to damage of the bones and organs. There are also specific substrates that build up in the body that ALP helps regulate and also accumulate in the body, which can be in the blood, urine, and organs.

Those substrates are inorganic pyrophosphate (PPi), pyridoxal 5′-phosphate (PLP) and phosphoethanolamine (PEA). These all contribute to the devastating effects of the disease.

Pyridoxal 5′-phosphate is the circulating form of vitamin B6 and in patients with HPP vitamin B6 is elevated because there is not enough alkaline phosphatase to keep the vitamin B6 regulated. This marker is also very sensitive and specific biochemical marker for HPP, given it’s elevated in the absence of any known vitamin B6 supplements and in conjunction with low ALP. If vitamin B6 is too high in the body it can cause its own set of symptoms, the most common in HPP being vitamin B6 dependent seizures.

Treatment and Outlook:

Treatment for HPP is complicated. Due to the underlying genetic cause of the disease and the way it affects the bones traditional osteoporosis medications cannot be used and have very little effect on bone strength in HPP patients and they can also make the disease worse. It was mostly aimed at managing the symptoms using pain management and surgical methods. In 2015 there was finally the first ever approved therapy for HPP. It’s an enzyme replacement drug called Strensiq. This therapy replaces the ALP in the body, which can help strengthen the bones and ease the symptoms of the disease. It is only approved for perinatal, infantile and childhood/juvenile forms of the disease and is highly regulated. Adults who are diagnosed later in life but who clearly showed symptoms as a child can get on it if you can prove they have always had symptoms before an adult. It’s not a one-drug fix all but it is improving the outlook of the disease for many patients.

Hypophosphatasia is much more than just a bone disease. It can be life-threatening and carries a lifelong impact on affected patients. Thankfully, with the treatment and early diagnosis, the outlook has gotten better.

 
 
 

References:

The papers from Dr. Michael Whyte and the websites used for reference. Also, thank you to my friend Shelly Idziak, MD for her help.

http://www.hypophosphatasia.com/index.php/about-hpp/what-causes-hpp

 

https://www.magicfoundation.org/Growth-Disorders/Hypophosphatasia/

 

Whyte, M. P. (2017). Hypophosphatasia: An overview For 2017. Bone,102, 15-25. doi:10.1016/j.bone.2017.02.011

 

Whyte, M. P., Zhang, F., Wenkert, D., Mcalister, W. H., Mack, K. E., Benigno, M. C., . . . Mumm, S. (2015). Hypophosphatasia: Validation and expansion of the clinical nosology for children from 25years experience with 173 pediatric patients. Bone,75, 229-239. doi:10.1016/j.bone.2015.02.022

 

 

World IBD Day 2017: Why I am thankful for my IBD

Every year May 19th is World (Inflammatory Bowel Disease) day, a day to recognize and raise awareness for Crohn’s Disease, Ulcerative Colitis, and Indeterminate Colitis which are all inflammatory bowel diseases. For the more than 1.6 million Americans and over 5 million worldwide, every day is world IBD day. Every day we wake up and do our best to push on despite our illness and trust me it is not easy. Even the simplest tasks such as getting out of bed, showering and putting clothes on can be extremely challenging and some days we just can’t do it. One of the hardest parts of living with IBD is the uncertainty that comes with it. Will I be able to go to work, take care of myself or my family? Will I be able to make it to school and if I do will I be able to stay the entire day? We never know when that next big flare is going to hit us or how long it will last. We don’t know how long our medications will continue to work, hell sometimes we don’t even know if we can even afford the medication we desperately need. Living with a chronic disease is insanely hard, and living with IBD is no walk in the park.

One thing that is important to know is that every person’s disease is different and specific to them because IBD is extremely complicated. What may work for one person might not work for the next. When people ask me what it’s like to live with Crohn’s I often have no good answer because it’s so hard to describe. I try to make it relatable to them so I usually say have you ever had food poisoning or any type of stomach illness where you were nauseous, vomiting, diarrhea? I then say try living with that almost every day of your life but add in anemia, arthritis and bone problems, skin problems, eye problems etc. It’s way more complicated than your everyday “stomach bug” and it just doesn’t go away. Unfortunately, it can’t be cured but thankfully most often it can be managed.

Despite all of the hospitalizations, surgeries, secondary diseases, and the medical debt I am thankful for my Crohn’s.  Why? I tell people this all the time but when I was diagnosed someone very close to me said “you can let this situation make you bitter, or you can let it make you better” and I chose to be better. I became an advocate for the disease to help other patients and that has been the most rewarding thing I have ever done. I have been able to travel across the country and use my voice to help all IBD patients, I have made lifelong friends because of this disease, friends who have the illness and just get it that I can text or call anytime to vent. My disease has also pushed me harder than anything to be a better person and to learn as much I can about science. It hasn’t been easy but after 8 years I graduated with a Bachelor of Science in Biology and a Master of Science in Biology with a lot of research experience. There were plenty of days where I truly did not know if I could finish or would make it but people encouraged me to keep going. There were days that were filled with crying and self-pity. There are days I feel like I just can’t go on, then I think of the people who count on me such as my wife or other patients who need to see someone succeeding because maybe they feel like they can’t go on.

 

Why do I do what I do? Because of you, and me and everyone who feels like they just can’t get through another day with IBD. You can do it. One day, one minute, one second at a time you can do it. There will be days where you may not be able to get out of bed and that is okay. There may be days you make it out of bed but not out of the house and that is also okay. There will be days where you are frustrated and mad because of your disease and that is still okay, take a day and be mad and cry and yell if you must and trust me it helps. Just don’t forget that you are stronger than IBD and you can beat it.

So this World IBD Day I challenge you to think about what your disease has made you thankful for and share that with everyone. If you don’t have IBD but know someone who does maybe send them some encouragement because that goes a long way or even ask them to share their story about living with IBD with you. Whether it has allowed you to meet people you would never have met, showing you truly how strong of a person you are or even just made you more empathetic towards others. World IBD Day is a day to raise awareness for the disease. Awareness is so important because it makes our disease known to the world and the more people know about it, the more funding that can go into research to find better treatments and hopefully a cure. One of my favorite thing I heard someone say was: “Won’t it be great when we come together, not to work towards a cure but to celebrate its discovery?!” IBD takes a lot from us, but if you look around you may just see it has given you some pretty awesome things.

2016: A year in review.

I can’t believe that 2016 is over. This year has had a lot of ups and downs in regards to my health, schooling, and personal life. It has been one of those years that I try to grow from and instead of thinking about how bad it has been I like to think of the good things and learn from the bad. When the year started out back in January I was thinking this year was gonna be really great health wise. I finally found a GI doctor that I like and after being off a steady treatment for my Crohn’s for about 2 years, my new GI listened to me and I started Humira. After the first few rounds of Humira injections, I really felt a difference in my health. My GI symptoms were getting better and overall I was feeling well.

Then comes February.

February 8th is when I dislocated my left hip and I would begin one of the hardest health journeys I have had in a long time. When I dislocated my hip I didn’t realize what that meant because I was only 3 years post hip-replacements and I shouldn’t be having issues. After about a month of being in a leg brace and on crutches, I met with a new orthopedic surgeon, as my original hip surgeon moved unexpectedly (which was another big ordeal) and I found out that my hip prosthetics had failed only after 3 years and at 24 years old I was needing more hip replacements. I have blogged about this before so won’t go into too many details but this is how 2016 started. I was devastated. I cried for a couple of days, I had to meet with all of my teachers at school and drop some classes so I could have surgery in March. It was stressful. Not only because I had to drop everything for surgery, but I knew that I would have to have another surgery later in the year so the anxiety was pretty horrible.

March & April: Surgery, Recovery and Research.

On March 8th, exactly a month after dislocating my hip I had my 3rd hip replacement surgery and after a few days in the hospital and 5 weeks of physical therapy I returned to school, which was about the end of April. I had some minor Crohn’s flares during all of this because I had to adjust my Humira schedule but nothing major thankfully. Back in January before hip dislocation, I had submitted a research abstract to a big research conference in Boston and I found out that they had accepted my abstract as a poster presentation. I was stoked! In the midst of all the health issues, this was a much-needed win. I went back to school in April to focus on research and get everything I needed to be done for the conference that was in June. Also, in April I had the opportunity to attend a patient advocacy conference in Chicago where I got to meet a lot of the online advocates I had connected with over the years. It was really awesome and something that helped me cope in between hip replacement surgeries.

May & June: Summer School and ASM Microbe Conference

In May I started summer school to try to catch up on what I had missed in the spring semester and continued some research stuff in preparation for the conference. In between the end of May school term and beginning of June, I had the opportunity to attend Digestive Disease Week in San Diego with some other patient advocates. This trip again was another highlight in between hip surgeries. I had never been to California and San Diego was gorgeous. I was able to hear the latest research going into IBD and meet some of the scientists and physicians. Just a great experience overall that once again helped me in the midst of my health issues. In June, I was still in summer school, but June 16-20 I attended the research conference in Boston. It was amazing. This was my first big conference to attend and present at as a graduate student! There were over 10,000 people there, Bill Gates was the opening keynote speaker and it was just awesome. My research mentor who went with me did her undergraduate degree in Boston so she took me all over the town. It was a lot of fun as I got to see all the histories that are in Boston, eat amazing food and even go to a Red Sox game. It was also more than just a trip to Boston. I had a lot going on health wise as I have said and this trip helped me feel normal and cope with what was going on with me. I was less than a month away from having my 4th hip replacement and had a lot of emotions running through my mind and this trip helped tremendously. It was more than just me presenting research at a big conference for the first time (which by the way I seriously will never forget) but it helped me cope and I can’t thank my mentor enough for helping me go and going with me.

July-December: More Surgery, Conferences & School.

On July 11th I had my 4th hip replacement. I did 10 weeks of physical therapy for this surgery which was rough but necessary. By the end of August, I had started back school and had to get back into a set schedule. Being out for surgery for so long was tough because now I had to get back to school and get into a normal routine of studying and doing my work as a graduate teaching assistant. The semester was hard. I found out I had Osteoporosis (yay), I found out I might have another rare disease that half the doctors I have seen have never heard of and I had issues with my Crohn’s again because I had to stop my Humira for a bit for surgery. This took a lot out of me mentally and emotionally. I had to drop some research stuff at school to focus on my health and grades which I hated doing. I hate giving up on something because of my health but sometimes it is necessary so that I can get better. I focused on my health, my school work, my TA’ing labs and trying to just get through the semester.

The end of December I had the opportunity to attend two IBD advocacy events. One was in Chicago where I spoke about my journey with Crohn’s from diagnosis to where I am at today which was amazing. One of the highlights of the year. Then I went to Orlando to attend the Advances in IBD Conference with 16 other IBD health advocates. It was pretty amazing as well as I was able to learn more about new IBD research and science and hang out with pretty amazing advocates and do some advocacy work. I also won an award for Best In Show Facebook in the WeGo health Health activist awards in December which I was pretty stoked about! 2016 has been hard but it has had some GREAT moments and memories that I will never forget.

In the first few weeks of 2017, I have a few doctors appointments, one where they are trying to decide if I have a rare metabolic disease and then another for my Osteoporosis. My hope is that 2017 my health continues to get better and I do not face any more surgeries. In May I will have my Masters Degree in Biology Research and will have a little time off. I’m the worst at setting and keeping New Year’s goals, but I want to focus on my health, eat healthier and be more active for my bone health and to work on my science communication skills. I also am trying to get some IBD advocacy work up and running in my local community as the IBD patients here really need support. I am looking forward to the new year and continuing my IBD advocacy work and honing my science communication skills. Here’s to a healthy, happy new year!

Making IBD Visible: IBD Looks Like Me.

The main theme of Inflammatory Bowel Disease (IBD) Awareness week (December 1st-7th) this year is making IBD visible. What does this mean? IBD is considered an “Invisible Illness” which means that even though we don’t look sick on the outside, our insides show a whole different story. I can’t tell you how many times I have heard “but you don’t look sick.” This happens to IBD patients more often than not which is not okay. While I appreciate you saying I don’t look sick, that’s not helpful when we are trying to show that IBD can be very debilitating and is so much more than just a bathroom disease.

Why we need to make IBD Visible.

Why do we need to make IBD visible? People need to see the face of IBD, that just because we don’t “look sick” does not mean we aren’t. I have always wondered what sick actually looked like. We need to clear up misconceptions, raise awareness which leads to funding for research and so much more!

Clearing up misconceptions.

Making IBD visible also helps clear up the misconceptions that come along with the disease like IBD is NOT IBS, IBD is more than just a bathroom disease, it is not just a stomach ache. IBD is so much more than that. It’s fatigue, embarrassment, depressing, painful, it’s incurable, it causes other problems outside of the GI tract such as eye inflammation and joint pain, surgery. We deal with a thousand obstacles a day yet most people have no clue what we go through. I personally have had 4 total hip replacements due to a complication from prednisone. Nobody would ever know that I have had hip replacements, and would not relate it back to IBD but that’s where it came from.

Raising Awareness.

Making IBD visible also raises awareness for the disease. Awareness leads to better education of patients and those affected by IBD. More awareness also means more funding for research which in turn leads to better treatments and possibly a cure. Making IBD Visible is so much more than just telling people about IBD, it’s about showing them what IBD is truly like and that even though we don’t look sick on the outside, we are fighting a war on the inside.

I would love for you guys to send any pictures to me of you raising awareness and making IBD Visible that I can share with the community. Let’s make IBD visible and show others the real side of our disease.

IBD looks like me.

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