How You Can Help Barbara Flanigan and Her Search For the Cause of IC
(Editors Note – I’ve wanted to share Barbara Flanigan’s story and theory about IC for many years. Barbara was the founder the first Interstitial Cystitis Association here in California in 1983. She has always had one key goal in her volunteer work, to discover the cause of IC. She believes that IC may be related to porphyria due to a hepatic Vitamin B-12 deficiency. For the past thirty years, she has worked with researchers in the IC and porphyria movement to explore this information but conducting the necessary studies has been difficult. As she says at the end of this article, this is her theory. It has not been conclusively proven but it is worthy of our consideration, especially given the role she played in launching the IC movement in the USA.
Thank You Barbara for advocating for IC when no one else was doing so. Thank you for working with patients, for beginning the IC Association of America, for approaching and working with the National Institutes of Health, for wading into a research community that was resistant to exploring new ideas and for not abandoning for your efforts. You are a hero to the IC community. I wish I could have said this publically years ago! – Jill Osborne, President & Founder – Interstitial Cystitis Network)
By Barbara Flanigan
First let me introduce myself ( to those who do not already know me ) and also provide you with a little bit of ICA history. Thirty two years ago, I established the Interstitial Cystitis Association in San Diego with the help of Dr. Parsons, Chairman of the Urology Department at UCSD. I was diagnosed with IC in my thirties and was simply amazed that in spite of the severity of symptoms, not a penny was spent by our Government on our disease. Luckily, I got sick at the right place. I told Dr. Parsons that I wanted to establish an organization to promote research and ask him to send like minded patients my way. Dr. Parsons responded: “How noble of you. Do you plan to have garage sales?” No, was the answer, and although he remained puzzled, I was contacted by a steady stream of patients, including, Lana and Paula, who joined the Board. Together we incorporated in 1983 as the Interstitial Cystitis Association of America.
Our goal was a simple one: Obtain research funding for our disease! We could not understand why there was no NIH funding for IC. We assumed that it must be due to being part of Urology, and the general perception that this was a discipline dedicated to the male uro-genital tract. Little did we know at the time that we were not alone. Most other female disorders were not being funded either.
We contacted the press and got excellent news coverage. Almost immediately Lana landed up on the evening news with a special titled: “In the Bladder, not in the Head”. Patients responded to this and other media events. We in turn organized them into a letter writing campaign directed at NIH via our elected officials. It was an exhausting and arduous process because women at the time were still relatively unassertive. Paula, who was an excellent public speaker, organized support group meetings and soon afterwards we were joined by a couple of volunteers from Los Angeles. We met with members of Congress and it was heartening to see that the political process actually works. Back then, NIH fought us tooth and nail. Their response was always the same: “We believe that research works best if it is researcher initiated. Unfortunately, no one is interested in your disease.”
The answer of course was to get some of our doctors to submit proposals. We started with Dr. Parsons and soon thereafter I contacted Dr. Tan at Scripps. He had already read about us in the paper and was willing to help. In the meantime we were joined by Dr. Vicki Ratner, who also suffered from IC and was finishing here residency. In 1984, we asked Vicki to incorporate under our name in New York, in order to limit liability. This was the brainchild of our attorney, because of the inability of small non-profits to obtain liability insurance. By incorporating separately, each organizational entity would be legally responsible for its own actions and there would be no way to sue us on the west coast for actions of another organization on the east coast, and vice versa.
Our two organizations worked together harmoniously for several years, but we differed on research priorities. Vicki’s priority was occult bacteria because she came down with IC after chronic urinary tract infections. We on the other hand felt that the autoimmune project held much more promise, although we were open to everything. Early on, Vicki and Dr. Hanno at the University of Pennsylvania established a working relationship and they eliminated two potential causes of IC: 1. Eosinophil Cationic Protein, and 2. Acute Porphyria. The bladder symptoms of acute porphyria are identical with those of IC. One paper described them as pain, frequency and nocturia. We poured over the scientific papers relating to both disorders and when Dr. Hanno conducted the necessary tests and the results were negative, we were confident that both could be eliminated. What we never suspected, however, was that the porphyria enzyme theory, on which the tests are based, was only partially correct. So stay tuned.
In the meantime, we were invited to witness the NIH peer review process for Dr. Tan’s IC research project, conducted at Scripps Research Institute in La Jolla. One of our volunteers gave a very moving speech to this panel on the social and economic costs of IC. The process itself was an eye opener. What surprised us the most were the conflicts of interest inherent in this process. A more accurate term for peer review would be: “Committee to keep the money within the discipline”. Although we had to protest the outcome of this process, we eventually prevailed and the immunology project at Scripps became the first IC project to be funded, followed by Dr. Parsons’ project at UCSD and Dr. Hanno’s at the University of Pennsylvania.
At just about this time, the divisions between the two independent ICAs came to a head. We did not agree on many issues, one of them being the Scripps project, and we simply could not generate enough money to support our operations, being located in the backwater of San Diego. It was tragic that we could not keep it together any longer, because we would have supported the Scripps project until the work was completed and there were no more loose ends. Dr. Tan’s findings were significant. He found auto-antibodies which were common in scleroderma and wondered if there could be a connection between the two disorders. Little did we know back then that had he been allowed to finish his work, we might have found the cause of IC a generation ago. Today, there is considerable evidence that IC is closely related to scleroderma. I think that I can connect the dots between IC and scleroderma, via a third disease which was also abandoned prematurely in the rush to focus on occult bacteria. I am talking here about none other than acute porphyria.
In 1995, I came down with a severe peripheral neuropathy, which no one could explain. As I was reviewing neurologic textbooks, I was startled to find the reason why the NIH sponsored Correlation Study was never published. Prior to the first Interstitial Cystitis Workshop, NIH contracted with an epidemiologist to determine the incidence of IC. Dr. Ratner was our liaison to this project, along with Dr. Hanno. We, ICA West, our East Coast counterpart as well as researchers and potential researchers were invited to submit questions. By this time, I had spoken with thousands of IC patients over the telephone and at Support Group meetings. I asked them all what they associated with the onset of symptoms. Many women made a connection between IC and prescription drugs and alcohol. Then I kept on hearing from others about an association with dieting. Sounded somewhat strange, but I kept on getting reports such as: “I lost 50 lbs. and then I got IC.” I submitted this question on weight loss and dieting to the NIH contractor for inclusion on the questionnaire, along with the rest of the queries from the ICA. I was happy to see that this odd question was included on the finalized questionnaire. However, when the results were presented at the first NIH – IC Workshop, this question on dieting had been removed in violation of protocol. No other question had been removed. I smelled a skunk, but at the time, I could not figure out the rationale for this act of academic dishonesty. However, I figured it out eventually, about ten years too late. One of the risk factors of porphyria, the disease that we had already eliminated based on negative test results, was: “A reduction in caloric intake and starvation”. In addition, all the other risk factors associated with IC, were also the risk factors of porphyria. This included the worsening of symptoms during the progesterone phase of the menstrual cycle, as well as the association with drugs used to treat urinary tract infections, and the list goes on.
Although I was no longer with the ICA, I tried my best to redirect the research back to where it might have gone if the Correlation Study had not been sabotaged. I wrote up a detailed list of overlapping symptoms and demographics between IC and porphyria. Dr. Messing responded positively, as did Dr. Parsons and Dr. Sant. I also called the NIH Urology Director, Dr. Nyberg, in an effort to enlist his help. He himself lamented among other things that Dr. Tan’s research was cut short and he always ended our conversations with: “I’ll talk with Dr. Briggs. Let me see what I can do.” He also made the observation that once research takes off in a certain direction, it becomes very hard to redirect. Yes, that remains the number one problem!
I gave up on NIH. Instead, I tried to engage the porphyria researchers directly, and was more successful on that front. To make a long story short, I made contact with the worlds’ foremost porphyria researcher, Dr. Yves Nordmann and he agreed to run the definitive enzyme tests. I met Dr. Nordmann in 1997 in Paris. Although I tested negative on all 4 enzymes involved in acute porphyria, this gracious doctor agreed to see me. As I described my symptoms, he began to ask questions, and then he interrupted me and stated: “You have porphyria”. However, he could not understand why I had it. I pointed to the very beginning of the heme equation and he responded : “Succinyl and glycine, they are like air and water.” For a while the entire French team worked on this conundrum, but they could not figure it out. However, today, I can tell you without reservation that IC is indeed porphyria, as are half a dozen additional syndromes. The problem was that a generation earlier, the porphyria research took a wrong turn, just as IC did with occult bacteria. Drs. Ridley and Cavanaugh were on the right path when one picked up on abnormal pyruvate metabolism and the other on a vitamin B-6 deficiency.
Understanding Acute Porphyria
Now, for some background information on the science of acute porphyria. I had to work my way through it and you can master it too. Thankfully, we now have the internet. So, you should be able to navigate this after a very basic primer:
You cannot live without heme. Even a partial deficiency of this substance causes porphyria. The functions of these substances are too long to list here, but you can look them up. There are two major heme pathways: The first is called the erythroid heme pathway. The synthesis of this product, heme, takes place in the bone marrow, and you probably know it best as the oxygen transport protein, hemoglobin. The second heme pathway, and the only one of interest to us is the hepatic heme pathway. The synthesis of this product, heme, takes place entirely inside liver cells. Both erythroid heme and hepatic heme share the same chemical equation, although the two hemes have different functions. They are also encoded by different genes. The functions of hepatic heme are listed on the internet. A good review of basics can also be found in the Merck Manual.
A major difference between the 2 pathways has to do with ease of testing. There is easy access to the erythroid heme pathway. All you need is a blood sample. That is not the case with the hepatic heme pathway. Although some abnormalities on the hepatic heme pathway can be picked up via blood and serum, the most important tests are out of reach. Fluctuations of hepatic heme levels can only be measured via a liver biopsy. This is risky. Therefore, the porphyria researchers improvised. They made the assumption that acute porphyria is limited to 4 enzymes. In other words, although the underlying problem is most likely the heme deficiency itself, they insisted that all you had to do was check for 4 enzyme deficiencies. (You substitute enzyme deficiency for heme. Never mind that one does not necessarily equal the other. ) But again, they insisted that this was not a problem, because one can double check the results via a second test that measures the heme feedback system.
Whenever there is a need for more heme, delta aminoluvilinic acid ( produced by the first enzyme of the heme pathway ) increases in a feedback mode. It increases astronomically in patients with the 4 enzyme glitches mentioned above. It also increases in normal controls, but at much lower levels. What to do about any glitches that may occur on the hepatic heme equation before the synthesis of ALA? The porphyria researchers ignored these potential problems, at least until I came along. At that point, Dr. Nordmann did reconsider, but checking for abnormalities at and above the first enzyme ALA – synthase, turned out not to be easy.
I was referred to a first enzyme specialist and it would take many years to rule out even the most common sites that could cause a deficiency of this enzyme, ALA – S. The reason was that there were no reliable chemical assays available. One needed to run DNA tests. Unfortunately, this was before the technology improved. The tests were very time consuming and expensive. Then, eventually this super researcher was able to tell me that the most common sites for DNA abnormalities were normal. However, 10% of the abnormalities are contained in the regulatory genes and these have not been analyzed to this day. At about this time this professor lost his grant, and his research remains unfinished. I did, however, get two additional DNA tests, CPOX and PPOX and they were also negative. I used this time wisely and asked questions whenever I could.
Throughout this lengthy investigation, I tried to interest various IC researchers in porphyria but not one IC researcher would bite. I finally realized the sad truth: I would have to do the work myself. This was not completely unrealistic, because there were a limited number of possibilities left to explore. I was pretty certain that the missing patients would most likely be at the beginning of the heme equation, even before ALA- S. I discussed this with my first enzyme researcher before he retired and he thought this was impossible. As mentioned previously, I had asked Dr. Nordmann about the very beginning of the heme equation in Paris many years earlier. He stated: “Succinyl and glycine, they are like air and water.” Yes, they are, but there is something else at the very beginning of this equation. There is vitamin B-12. Vitamin B-12 is needed for DNA and RNA transcription and it is also the cofactor necessary for the synthesis of Succinyl CoA, which sits at the very top of the heme equation. There actually are several additional sites where low levels of vitamin B-12 could potentially wreak havoc at the beginning of the heme pathway. My mentor assured me that this would result in giant cells and anemia. However, I already had my doubts.
My good fortune was actually a medical mistake. Some years earlier, a lab put down the wrong code for what was supposed be a regular vitamin B-12 test in serum. They tested for vitamin B-12 unsaturated binding capacity (UBBC) instead and it was abnormally low. The test is used to pick up elevated UBBC levels associated with two other disorders. No one could tell me what low levels meant. I was given the royal runaround. A couple of years later, when I had more stamina, I had the test repeated and the levels were substantially lower than on the first test. This time I managed to get in touch with the lab director who explained that low levels could mean, among other things, that I do not make enough vitamin B-12 transport proteins.
Unfortunately, the tests to determine which are low, were no longer commercially available. This unusually helpful man also provided some references to make this more understandable. A paper by vitamin B-12 researcher Ulf Hakan Stenman explained that: “TC II delivers vitamin B-12 to both the liver and to other tissues, but the relative magnitudes of these pathways are not known.” In times of plenty, the liver is stocked with large reserves of B-12. However, in times of starvation, when B-12 is in limited supply, the peripheral tissue may get priority, with the larder in the liver only being restocked intermittently whenever the supply of B-12 is greater than the demand.
In light of the Stenman paper and the fact that the two heme pathways, erythroid and liver, are substantially different, a vitamin B-12 deficiency limited to liver became more plausible. Then one day, it all fell into place. I plugged vitamin B-12 UBBC into the computer again. Up popped a paper by Teplinsky, V. et al. titled: Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults. Apparently, no one paid much attention when this paper was published in 2003, but I knew exactly what to do with the result. The authors traced 24 relatives of a couple with a hereditary deficiency of the vitamin B-12 transport protein TC II and found that they had substantial neurologic morbidity in spite of normal B-12 levels in serum and as well as an absence of giant cells and anemia. If you will recall, TC II is one of three vitamin B-12 transport proteins which could have caused the low levels of my UBBC test ( the one that was run by mistake ). Dr. Teplinsky also theorized that the underlying problem here was a deficiency of vitamin B-12 in storage in the liver. I quickly had myself tested for folate, methylmalonic acid and homocysteine. My folate and MMA were normal and my homocysteine was elevated. These tests are needed to eliminate other potential causes and narrow down the list of suspects. As a result, TC II deficiency becomes much more likely, and I am now awaiting DNA testing. This is also where the strange risk factor for IC fits in. I had mentioned before that dieting and weight loss was associated with the onset of IC. Yes, it makes perfect sense. TC II reduces the amount of B-12 that reaches the liver. Severe diets reduce B-12 levels even further.
So, what next? I contacted everybody, including the porphyria researchers. They got it. I was told by one porphyria researcher that they are all doing DNA tests now. He seemed somewhat too delighted that I could not do the chemistry. Yes, I do need help with the chemistry, but I am getting better at it every day. I did manage to figure out that only a partial TC II deficiency can explain the abnormalities on the pyruvate pathway which Dr. Alan Ridley found in all active cases of porphyria more than 40 years ago. It is certainly possible that some cases of porphyria are caused by four enzymes, but it is also conceivable, that these enzyme deficiencies only manifest themselves when an attack is already in progress and the entire heme pathway is put on overdrive. The enzyme deficiencies will certainly increase the magnitude of the total heme deficiency, but they may also be a secondary effect of the primary vitamin B-12 heme deficiency, which is already underway. So, the good thing is that at least one group got it and that is a giant step forward. What’s bad is that every research study tends to take 5 years. I am not willing to wait. I am actually shopping for a chemist. I know how everything fits together, but we still need someone to work out the formula from beginning to end at the molecular level. Any volunteer bio-chemists out there who would like to lend a hand?
In the meantime, perhaps some of you patients may wish to ask your doctor to test you for homocysteine and UBBC. Homocysteine should be elevated and UBBC should be below normal. If both tests are normal, then you have Painful Bladder Syndrome. As you know, IC is a syndrome. There is no one size fits all, but perhaps these tests may serve to separate some of the apples from the oranges.
Now, back to porphyria / IC. The reason that one comes down with the very painful neurologic symptoms, which includes bladder symptoms, is actually quite simple. Basically, the supply of hepatic heme cannot keep up with the demand for heme, because our supply line into the liver is defective. Our livers use up different quantities of heme for various functions. Large amounts of heme are needed to metabolize drugs via cytochrome P-450 and that is why the drugs that are used to treat urinary tract infections put us at high risk. A good analogy would be to imagine different size hoses going into a pool of water. In men and most women, the supply hoses are the size of fire hoses, but we instead have tiny garden hoses. In times of high water consumption, the larger hoses will resupply the pools and keep them from draining out completely. With us however, during periods of sudden high demand, the pools do drain out completely, before the tiny hoses manage to replenish the water level. This generally happens after the demand has normalized. In other words, due to our low levels of transport proteins, the liver runs out of vitamin B-12 repeatedly. That is why our disease is an endless cycle of painful flare and remission.( I am using B-12 and heme here interchangeably. The level of heme is dependent on the availability of B-12 in the liver, and only TC II can take it there.)
Lastly, there is scleroderma. Remember the abundance of antinucleolar antibodies found by Dr. Tan which made him wonder if IC may be related to scleroderma. That connection may not be farfetched. Both porphyria and scleroderma share the identical abnormality of tryptophan metabolism. Given a tryptophan load test of 2gs, both disorders excrete the same abnormal amounts of kynurenic acid, 5HIAA and xanthuric acid into the urine. What led me to consider vitamin B-12 deficiency as the primary cause of porphyria was among other things, the similarities in symptoms between B-12 deficiency in blood and liver. The giveaway, which could not be ignored, was the labile hypertension of pernicious anemia, which is identical with the labile hypertension in some cases of porphyria.
The same can be said about the symptoms of pellagra and scleroderma. Pellagra is caused by a dietary deficiency of tryptophan which results in a vitamin B-3 deficiency, and on occasion, skin lesions resembling those of scleroderma. I have been thinking about this not only because of Dr. Tan’s finding of scleroderma auto-antibodies in IC, but also because I have come across some cases of scleroderma in the IC population. Could a B-12 deficiency in the liver, also cause a deficiency of vitamin B-3 or B-6 within the liver indirectly through localized chemical interactions between these vitamins? For example, when there is insufficient heme as a result of the vitamin B-12 deficiency, then ultimately it would affect the hemoprotein tryptophan pyrrolase. This deficient hemoprotein is no longer able to adequately split tryptophan, with the result that both tryptophan as well as serotonin increase abnormally.
On the flip side of this very same equation, there should be a commensurate decrease on the kynurenine pathway. There are two hemoproteins on the kynurenine pathway. Besides the dysfunctional tryptophan pyrrolase, there is also tryptophan oxygenase which should also be a dud due to the heme deficit. As far as I can tell, if you follow the kynurenine pathway downward, you land up with NAD, which is niacin (vitamin B-3). Can the two deficient hemoproteins here cause defective niacin as a secondary effect of the B-12 heme deficiency in one direction, and a buildup of tryptophan going in the opposite direction? Also, I understand that vitamin B-12 and B-6 are chemically intertwined. ( Don’t ask me how. All I know is that the B vitamins are coenzymes of each other.) Can low B-12 result in low vitamin B-6? * Vitamin B-6 is also required for the conversion of tryptophan to niacin and low vitamin B-6 status will impair this conversion. Because these interactions all take place within the liver, one may not be able to pick up this B-6 deficiency with regular vitamin tests designed to pick up a dietary deficiency in the peripheral blood stream. Right here, again, we need the help of a competent chemist. If you know someone who is willing to do some volunteer work, please send them my way!
Lastly, I will keep you informed as I work my way through the vitamin B-12 / TC II testing process. I am scheduled to obtain some DNA tests next. You may wonder why I have contacted you, our patients directly. The reason is a simple one. I have spent more than 30 years on this, and progress has been very, very slow. I hope to speed it up. I have found in years past that the best resources can be found within ourselves and in our patient base. No one is more interested in a cure than you. Some of you may know chemists or doctors, who might want to organize a TC II screening program, or work on the chemistry. I have done just about all that I can. The rest is up to you! You can ask your doctor to screen you for a TC II deficiency utilizing the above mentioned tests. Please keep the IC Network and the ICA informed of your test results. That’s all for now. Best wishes and good health!
* Note to porphyria researchers – Forty some years ago, Drs. Ridley and Cavanaugh picked up a vitamin B-6 deficiency in many porphyria patients with standard tests. I eat a wholesome, mostly organic diet, and I too share very low levels of vitamin B-6, which at times have dipped below normal. I suspect that this B-6 deficiency is still present today, but can no longer be picked up routinely, because it is obscured by the ubiquitous use of artificial vitamins in processed foods. I surmise that this B-6 anomaly is not a dietary deficiency, but perhaps a secondary effect of the TC II, B-12 deficiency?
How You Can Be Involved:
Have your self-tested for Vitamin B-12 unsaturated binding capacity (UBBC)? If Barbara’s theory is correct, your UBBC levels would be below normal.
Have your self-tested for homocysteine. If her theory is correct, your homocysteine level would be higher than normal.
You can send your test results to the IC Network. We will collate them and share with Barbara.
1. Hereditary Partial Transcobalamin II deficiency with Neurologic, Mental and Hematologic Abnormalities in Children and Adults: Teplinsky, V. et al. 2003.
2. Motor neuropathy in porphobilinogen deaminase deficient mice imitates the peripheral neuropathy of human acute porphyria: Urs A. Meyer et al. 1999. Here the researchers mention bladder dysfunction as one of the symptoms of porphyria. Although the symptoms of porphyria can be highly diverse, most patients tend to get the same symptoms repeatedly. Some of the “other” IC symptoms were picked up on the NIH sponsored Correlation Study and subsequently, unearthed again by Dr. Theoharides.
3. Pathogenesis of Acute Porphyria: Liawah, Moore and Goldberg, 1987. Good review of current porphyria theories;
4. The Neuropathy of Acute Intermittent Porphyria: Alan Ridley, 1969; Refer to pages 319 and 320, pertaining to abnormal pyruvate metabolism. ( My note: Partial TC II deficiency can explain the temporary abnormality of pyruvate metabolism found by Dr. Ridley. I suspect that during an attack, MMA may be temporarily abnormal too, but this remains to be seen. To understand this better, you need to look at the TC II pathway ( copy enclosed ). Furthermore, we are the Joiner, McArdle and Thompson patients referenced in this paper ).
5. Decreased Nocturnal Plasma Melatonin Levels in Patients with Recurrent Acute Intermittent Porphyria Attacks: Yves Nordmann et al. 1993; This paper is very important, not only because it explains the abnormal chemistry at the level of tryptophan pyrrolase, but also because he found abnormally low levels of melatonin. These low levels cannot be explained by enzyme abnormalities, but I wonder if they can be explained by TC II deficiency? My own melatonin values are also half of the age adjusted normal values. All IC patients should be tested for this abnormality too!
6. Sequential Induction of Heme Pathway Enzymes: Shigeru Sassa 1975; This paper explains that DMSO is a heme stimulant. For those not familiar with IC, DMSO is the only drug that passed rigorous FDA drug testing ( even before the advent of the Orphan Drug Act ) and was approved for one use only: The treatment of IC. No one understood how it works before, but it fits perfectly, right here, with a TC II deficiency!
This material is theory and is provided for information purposes only. Nothing in here should be construed as medical advice. The author is not a medical professional. Your medical decisions need to be made in consultation with qualified medical personnel. Only your doctor can and should give you medical advice!
Reprinted from the Spring 2015 IC Optimist Magazine!