Purple Canaries

Joyce Gould with Jill Gould

STILL FEAR-RIDDEN, FRUSTRATED, FORGOTTEN and FED-UP: Patients with Atypical Acute Porphyria STILL Stuck in Urinary Diagnostic Quagmire


Patients with Atypical Acute Porphyria STILL Stuck in Urinary Diagnostic Quagmire


Caregiver/patient perspective/opinion by parent/advocate/author of Purple Canary


© J. Gould, 1st Quarter, 2018


“If you’re not outraged, you’re not paying attention.”

– J. Milstein



I am a former business executive turned Mom—neither a certified medical doctor nor scientist. For that matter, I have no formal medical training whatsoever. Heck, I’m not the greatest baker either—but even I know that baking powder is key to making breads, muffins, cakes and other baked products rise. Without this essential ingredient, the end product just doesn’t “cut it.” Please keep that thought in mind—it’ll take a while but I will get back to it. That being said, the following opinions are my own and are based on years of intense observation, experience and lots of primary (reports and communications with actual patients and caregivers) and secondary (medical articles, books, etc.) research. As always, I do my best to credit references and this piece will reflect that.

So who am I? An individual who’d had a lifetime of odd, unexplainable, sometimes sidelining medical symptoms but soldiered on like so many others do. Until I was felled by a series of strokes, each progressively worse than the one before—all because of an undiagnosed, genetic condition. Even as miserable as I sometimes felt Before Stroke, I didn’t have porphyria; never even heard the word before September, 2008. But my daughter, an adoptee, does have porphyria. To be precise, she has acute intermittent porphyria (AIP). And that really stinks because I’ve seen firsthand that porphyria is genuine medical misery.

The matter I’m submitting commentary on is something that has caused (and continues to cause) a significant number of patients to suffer without acknowledgement or expert-sanctioned treatment. I’m addressing the acute hepatic porphyrias; more particularly, an atypical acute porphyria presentation from which patients languish in a sort of undiagnosed hell because they don’t produce the dogmatic diagnostic urinary biochemical proof. Patient numbers continue to increase across the globe yet too many US (and other countries’) porphyria experts turn backs, shrug shoulders, walk away. Some even shoot insinuations that my daughter and those like her are “misguided” (or worse). Some scoff outright that such patients just “want to have porphyria.” Like it’s a choice. Sorry. All these people want is a truthful diagnosis for what ails them. If it turns out be porphyria, then at least they (and the doctors who try to help them) know—although knowing does not mean they will receive adequate treatment. Evidentially, that part still eludes porphyria medical science, even for those patients whose acute porphyria has been granted and/or confirmed by experts.

I can only relate to and comment about US acute porphyria conditions, particularly atypical AIP presentation because I’ve witnessed it for over ten years now. However, contact with so many atypical and “typical” porphyria patients, caregivers and experts through online FB forums (closed and open), email, snail mail and/or telephone confirms that undiagnosed and/or atypical porphyria problems don’t stop at US borders. Thankfully, this enigma appears to have finally earned a bit of expert recognition. As well it should because it isn’t a new phenomenon. There are numerous references found in medical literature of darkened urine not appearing during AIP attacks—from early beginnings to recent times. To wit, in 1936 Sweden, Waldenstrom reported witnessing an AIP attack without urinary biochemical excretion in one of three brothers (the other two did excrete biochemical “proof”). In 1958, Shaper reported and posited, “To complicate matters, in a recent survey of 80 cases seen at the Mayo Clinic it was noted that no porphobilinogen was found in nine cases with severe CNS involvement and in six cases with abdominal crisis…It should be emphasized that porphyrin excretions may be intermittent.” [Shaper; Porphyria in Africa; The Central African Journal of Medicine, Oct 1958; https://opendocs.ids.ac.uk/opendocs/bitstream/handle/123456789/6524/Sharper, %20A.G.%20%20CAJM%20%20vol.%204,no.10.pdf?sequence=1].

As the American Porphyria Foundation (APF) holds itself as leader of all things porphyria in this country, I refer to the March 1, 2017 FDA/APF Patient Focused Drug Meeting for the Acute Porphyrias video (www.porphyriafoundation.com) as a relatively recent sample to further challenge its urinary biochemical excretion position. At ~22:26 on that video timeline, APF scientific advisory board (SAB) member Dr. Herbert Bonkovsky presents a chart titled Acute Porphryias: Symptoms in Patients Requiring Hospitalization. Of the seven symptoms depicted, abdominal pain ranks at the top—but doesn’t reach 100% which means in some cases abdominal pain does not present. Immediately following that slide, Dr. Bonkovsky exhibits the next, Acute Porphyrias: Signs in Patients Requiring Hospitalization (~22:41on the video timeframe). Of the thirteen signs listed, tachycardia ranked the highest—at or very near the 80% mark. Darkened urine is second—at perhaps75-78%. (Darkened urine, specifically a port-wine colored urine is more likely to yield high levels of PBG.) Which means at least 20+% of patients didn’t produce darkened urine. THAT IS the essence of what this is all about. What about those 20+% patients? 20+% is a fairly significant number. What’s going on regarding the 20+% patient pools’ urinary biochemical production? Did they not excrete urinary biochemicals because as Shaper postulated, porphyrin excretions may only be intermittent and the patients did not excrete within the research study’s timeframe?

Thankfully, around the world, some physicians appear to “get” that excreted PBG and/or ALA may not be the be-all-to-end-all of the acute hepatic porphyria diagnostic protocol. For the most part, these insightful medical professionals adhere to the Hippocratic Oath, keep their own counsel, do plenty of research—and treat patients.

Interestingly, in speaking about the acute porphyrias during the September 7, 2017 Alnylam Pharmaceutical’s RNAi Roundtable Givosiran session, highly respected porphyria expert Dr. Eliane Sardh of Karolinska Institute, Stockholm noted, “We still have very limited knowledge of the pathophysiology of the disorder as well as the natural history. And international collaborations are needed to answer this question. We need better biomarkers for the disease since ALA and PBG are probably just surrogate markers, and the specific levels of porphyrin precursors do not correlate to the disease severity nor the risk for the patient to become recurrent.” [http://www.alnylam.com/wp-content/uploads/2017/09/Givosiran_Roundtable_Transcript_09072017-1.pdf;p.4]

In a recent attempt to clear up some muddy waters, I was inspired to re-read American Porphyria Foundation executive vice president Desiree Lyon Howe’s 2004 memoir, Porphyria, A Lyon’s Share of Trouble. When I first read the tome years ago, I noted several passages that validated the erraticism and severity of AIP symptoms my daughter experienced. But this time, having accumulated years of clues, my reading was laser focused. At long last, dots connected. And they linked the index case (Ms. Howe) upon which APF had been established, cultivated and expanded to something deeply troubling for me, my daughter and countless others—acute porphyria attacks sans urinary biochemical excretion. The following recaps the story directly from the “horse’s mouth:”

Ms. Howe opened her book with a statement about suffering her first attack of Porphyria at the age of seventeen. She acknowledged that in spite of abdominal pain (akin to being “pierced with a thousand flaming swords”), breathing difficulty, arm and leg weakness her tests results “were normal in every category.” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p 2-5]. As the terrifyingly painful bouts of illness continued to appear and disappear in mysterious fashion, standard lab tests continued to yield no clues. In fact for years, even though she occasionally noticed “strange colored” urine which was attributed to menses by patient and doctors; regarding blood or urine, she reported nothing was remarkable about any of her test results.

She told of visiting multiple doctors who, when unable to find biochemical explanations for her condition, time and again viewed her symptomology with an air of disbelief. She was also given misdiagnoses—and labels: over-anxious, hypochondriac, postpartum depression, possible manic depression—about which she was terribly insulted.

She explained how a friend’s father who happened to be a physician took special interest in her litany of troubling symptoms and ordered an EEG. When the EEG results indicated minor seizure activity, he prescribed Dilantin. One dose put the future EVP of the APF in dire straits. She experienced excruciating abdominal pains, was unable to respond intelligibly or to follow simple commands like getting herself onto an examination table and freakish hallucinations developed as the situation rapidly morphed into a life-threating crisis.

Amid the overwhelming cacophony exploding inside and outside her body, Ms. Howe remembered praying to the Lord to take her from the torment. He ultimately did—after dark, purple-red colored urine began flowing into the urine bag—and returned her to life. Samples of blood and the dark, purple-red urine were taken, followed by a 24-hour urine sample the next day. Acute intermittent porphyria was diagnosed. The physician later confirmed that Dilantin had “caused [her] life-threatening attack of Porphyria.” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 23]

When I finished reading it this time, the book was studded with sticky note pad papers—and I was incensed. So many incongruities exploded in my mind; so much to sort out. But sort out I was determined to do. That Ms. Howe and APF doctor scientists would summarily discount and dismiss the suffering of my daughter and a multitude of other patients having DNA confirmation or documented familial porphyria as not suffering porphyria activity or attacks was incomprehensible to me. Especially because prior to swallowing that Dilantin capsule at about the age of 27, Ms. Howe had been in the same boat herself—for about ten years. Yet, according to some patients and/or caregivers who’ve had interaction with APF for decades, that’s what’s been happening for decades. It’d happened to my daughter; I had no reason to doubt them.

To reiterate, the book, Porphyria, A Lyon’s Share of Trouble opened with Ms. Howe’s stating, “I was only seventeen when I suffered my first attack of Porphyria.” [p.2]. Yet the APF EVP blithely told my daughter in January 2015 written correspondence, “We have several patients in the same situation with DNA but no attacks.” So it is acceptable for Ms. Howe to describe her pre-Dilantin abdominal pain (like a thousand burning swords), weakness so that it was difficult to breathe or lift arms and legs [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 2], without urinary biochemical proof situation as an attack, but not to acknowledge that my daughter or others who suffer similarly—and have for years (some for decades)—have Porphyria attacks?

My daughter’s first porphyria attack happened at age eleven. It took a few months for the abdominal pains to escalate from prodome “stomach hurts” to full blown devastatingly brutal liver attack pain symptom accompanied by a litany of distressing porphyria activity—all usually involving seizure/convulsive episodes—accompanied by normal lab tests.

Fourteen months later, with little or no break in the horrific attacks, I’d insisted that her DNA be tested. The results were positive for AIP. But those results were essentially discounted by Mount Sinai’s Porphyria Center (2009) doctors then routinely ignored and/or dismissed by Dr. Herbert Bonkovsky (2009), Dr. Robert Desnick (2014) and Dr. Peter Tishler (2016)—each one a member of APF’s scientific advisory board.


Natural biomarker production vs drug-induced biomarker production

Re-reading Ms. Howe’s book caused me to wonder how many acute hepatic porphyria diagnoses were based on “natural” production of urinary biochemical markers versus those made based on drug-induced biochemical “proof” so I analyzed 129 confirmed AIP, VP and HCP cases. The results:

* urinary biochemical testing following “natural” excretion:                             60%

* urinary biochemical testing due to drug induction:                                         5%

* DNA, blood, urine or spinal fluid samples:                                                     4%

* received diagnosis prior to advent of biochemical testing:                           31%                                                                                                                                                                                    100%

Of course, the levels of “biochemical proof” corresponding to diagnoses were not available, so I was not able to compare levels of natural- versus drug-induced precursor excretions.

While on the subject of urinary biochemical measurement, it is important to note that many “undiagnosed” patients report repeated attempts to achieve diagnostic levels of urinary biochemicals during much of time period that APF has been in existence. For many years I’ve been involved with Jill’s AIP, my attention has always first been on her PBGD level—I honestly never even asked what urinary biochemical levels were expected versus what Jill’s actually were. That was largely because an angel in the guise of a Swedish born, bred and medically trained/US transplanted pediatric hematologist/AIP specialist had determined that Jill’s AIP was indeed active and early on set her up with life-saving D10/Panhematin® treatments so it was of little concern to me for sustained periods of time.

Nonetheless, a significant number of patients and/or caregivers most certainly did pay attention to the minimum “requisite” level and type of biochemicals required by experts to achieve a diagnosis of acute porphyria. Those were/are the patients whose urine was/is repeatedly tested with each attack. The dreadful attacks are made even more horrific by the hopeful anticipation that the patient will be able to produce urine during the episode, that the sample will collected “at the height” of the attack, properly handled and shipped and accompanied with the appropriate instructions—not to mention the agonizing wait to find out if indeed the sample “made the grade.”

Based on their own experiences and research, a number of “undiagnosed/misdiagnoed” patients reported inconsistencies in cited expectations for minimum ALA and PBG levels required to achieve an acute porphyria diagnosis and became alarmed by the trend of incremental increases in that “bar” over the years. While I could not readily verify or refute those claims, I was able to identify an odd disparity within APF concerning diagnostic biochemical expectations:

  • “For AIP- a urine porphobilinogen (PBG) test during an acute attack—the urine PBG level will be very high if the symptoms are caused by an acute porphyria (greater than 5 times the normal value).” [2/14/2018 APF>Home>Testing for Porphyria? Diagnostic Testing for the Acute Porphyrias – Clarification of Testing Results>Diagnosing Acute Porphyria]
  • “To indicate whether a person has Porphyria, the ALA and/or PBG should be approximately ten times the normal level.” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 195]


I know I’m not alone in thinking it highly inappropriate that U.S. porphyria experts have dismissed (and continue to dismiss) case after case of patients presenting with similar symptomology (clinical neurological debilitation but no urinary biochemical proof) endured by Ms. Howe for the years prior to her AIP diagnosis being made. In those days, few doctors had heard of AIP, never mind seen or treated it. As Ms. Howe remembers, “this disease had so intrigued Dr. P… since he first studied it in medical school that he had watched for a case of Porphyria for years and had never encountered one until mine.” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 22]

It appears that medical excitement was so high about this particular case that this probably marked the beginning of identifying urinary biochemicals (at the time, ALA and PBG) when AIP was suspected. But according to her book, her urine tests had been normal for ten years—likely just the day or two before, even.

Throughout the rest of her story, Ms. Howe told about suffering continued, albeit intermittent AIP attacks but no further information concerning urinary excretion during the post-Dilantin era was offered. Therefore, it is unknown if following her Dilantin-induced attack Ms. Howe excreted “requisite” levels of urinary biochemicals during successive attacks, or if she resumed generating “normal” urine, or “slight” levels of porphyrin/precursors.

Of course, times have changed over the past 36+ years. Patients have become more sophisticated about their own (and their family member’s) health issues, particularly those with bio-family knowledge of porphyria. The Internet has been behind that emerging sophistication, and of course, APF maintains a web site on that 24/7/365 medium. APF zealously encourages patients and doctors alike to pursue urinary biochemical testing when/if acute porphyria ends up on a differential diagnosis list. Many, if not most of the patients who languish in the “undiagnosed” category beg medical professionals to take samples of excreted urine during every attack to be sent for porph testing, hoping to grab that brass ring. However, it is more than likely that, as with Ms. Howe’s situation during the pre-Dilantin era, they either have “normal” urinary excretions or sometimes minimal (though not “requisite”) amounts of biochemical levels. I wonder, how many of these “latent” patients, if given an unsafe for porphyria medication, would join the AIP-confirmed club?

It doesn’t appear to matter because APF seems set up to maintain AIP’s status as a rare disease and encourages wondering patients and doctors to take urine samples during attacks and submit them for porphyria testing—preferably by APF-associated labs. They’ve played the same, tired record for years:

  • “If urine ALA, PBG and total porphyrins are normal, it is quite certain that any recent symptoms are not due to an acute Porphyria.” [2/14/2018 APF>Home>Testing for Porphyria>First-line test]
  • If the urine PBG level is normal then there is likely another cause to this person’s symptoms.” [2/11/2018 APF>Home>Testing for Porphyria>Diagnostic Testing for the Acute Porphyrias – Clarification of Testing Results]


  • “If Panhematin® is administered and subsequently the diagnosis of acute porphyria cannot be confirmed by elevated urine PBG values or DNA testing, then it would be concluded that the “attack” is not caused by an acute porphyria.” [2/11/2018 APF>Home>Testing for Porphyria>Diagnostic Testing for the Acute Porphyrias – Clarification of Testing Results]


  • All leading to promulgation of a potentially deadly assumption: “many patients have not had an acute attack or are not symptomatic at present, so biochemical testing may be inconclusive.” [APF>Home>Testing for Porphyria>DNA Testing for Porphyria]



Getting back to the baking analogy, it is a stretch to attempt to relate baking to the complicated mechanism of blood building, especially when it involves the complex hepatic biosynthetic pathway, but here goes. The protein PBGD is the central ingredient of AIP; it is produced at the third step of blood building in the liver. But for individuals with an inherited mutant HMBS gene (aka the PBGD gene) the enzyme’s power is effectively reduced and this may cause real problems (for some, but not all patients). Much is known and has been published about PBGD; articles are available to anyone who looks for them. One example:

“PBGD is a monomeric protein containing a unique dipyrromethane cofactor. This cofactor consists of two molecules of the substrate PBG and remains covalently attached to the protein via a thioether linkage to a conserved cysteine residue during the protein’s lifetime…The dipyrromethane cofactor is positioned at the opening of the active site cleft between domains I and II (Figure 9(a)). At the beginning of the PBGD catalytic cycle the dipyrromethane cofactor serves as a primer for the sequential polymerization of the four following PBG molecules (Figure 9(b)). It has been shown that the pyrrole forming ring A of the final cyclic tetrapyrrole arrives first at the enzyme followed by rings B, C, and D. A conserved aspartate residue is involved in catalysis putatively by deaminating PBG. At present, it is not clear how the enzyme exactly deals with the growing reaction intermediates in order to position them correctly in the active site for the new incoming PBG molecules to be attached. It has been observed that PBGD undergoes conformational changes during the tetramerization of PBG, which could be either due to the enzyme ‘pulling’ the growing chain of pyrroles through the active site or to a reorganization of the oligopyrrole as it is assembled. The catalytic cycle of PBGD ends with the cleavage of the linear tetrapyrrole preuroporphyrinogen from the cofactor dipyrromethane.” [Gunhild Layer et al; Cofactors chapter of Comprehensive Natural Products II; 2010; https://www.sciencedirect.com/topics/neuroscience/porphobilinogen]

Obviously, APF-connected doctor scientists are familiar with HMBS/PBGD. However, on the APF web site, while they dwell on the substrate PBG, the cofactor PBGD is never identified nor discussed in that context; “Each porphyria is due to a deficiency but not a complete absence of one of the enzymes. (Table 1 shows the enzyme that is deficient in each of the porphyrias.) As in other pathways in the body, each enzyme acts by making a specific change in a chemical called its substrate, to form a product. The product of one enzyme is the substrate for the next. The substrates and products are also known as intermediates in the pathway. When an enzyme is deficient, the substrate for that enzyme may accumulate. (Table 1 also shows the substrates and products of the heme pathway with the sequence indicated by arrows.)” [2/11/2018 APF Home>Testing for Porphyria>Porphyrins & Porphyria Diagnosis]

In fact, cofactor PBGD plays a critical role in the AIP “baking” scenario. Without a full ration of PBGD, the final blood product just doesn’t “cut it.” APF’s literature describes how the heme biosynthetic pathway process of attempting to build red blood cells with deficient PBGD may result in excreting pieces of those cells (called porphyrins or precursors) in excess—the Holy Grail of US and European porphyria expert AIP diagnosis. These porphyria experts specifically look for excessive amounts of substrate PBG in a patient’s excreted urine to diagnose AIP.

I mentioned earlier that Dr. Eliane Sardh commented that better biomarkers are needed for the disease since ALA and PBG are probably just surrogate markers. She also noted that the specific levels of porphyrin precursors do not correlate to the disease severity nor the risk for the patient to become recurrent. By scrutinizing my daughter’s lab reports over the years, I realized that PBGD is a reliable biomarker/indicator of my daughter’s AIP activity. The Japanese have been using PBGD to do the same for years. I mentioned this in last year’s white paper and will do so again—because it is so important. Authors of Long-term Follow-up of Erythrocyte Porphobilinogen Deaminase Activity in a Patient with Acute Intermittent Porphyria: The Relationship between the Enzyme Activity and Abdominal Pain Attacks validated “that AIP patients show an abnormal urinary profile of ALA, PBG, UP and PBGD and that profile shows wide variations from status to status within the same subject.” (Tanaka, et al; www.osaka-med.ac.jp/deps/b-omc/articles/533/533tanaka.pdf; p. 156) and “propose monthly range PBG-D monitoring is crucial for prediction of the acute phase in AIP patients….” [Tanaka, et al; www.osaka-med.ac.jp/deps/b-omc/articles/533/533tanaka.pdf; pg 159]. APF dismissed this more than once. When I posted this information on a FB forum, APF’s EVP scoffed, “are you saying we should follow the Japanese?” My response, “Well, if it could help someone manage AIP better…of course!” I removed myself from that particular FB porphyria forum where discussion of research papers other than APF’s is not encouraged. My intent has always been to get to the truth of my daughter’s (and others like her) porphyria problem(s).

I eventually connected my daughter’s PBGD biomarker reliably indicating AIP activity to a couple of AIP sub-types, but not being a biochemist and having been rebuffed by a couple of hematologists when I asked for help, I let the issue rest. At least three APF SAB members (KE Anderson, RJ Desnick, PA Tishler) have authored medical articles about AIP sub-types, which are determined via the enzyme involving what is known as CRIM (cross-reacting immunological material). So, it’s obvious that they have long been familiar with the concept. Porphyria sage Dr. Shigeru Sassa (deceased, formerly of Rockefeller University and an original APF SAB member) continued to generate articles that included information about the AIP sub-types during the 2000s. However, in the US, it appears excitement about the potential of achieving DNA diagnostics for the acute porphyrias hastened the demise of CRIM identification of the AIP sub-types.

I’ve been communicating with patients, doctors and specialists from around the world since 2009. I very recently was presented with game-changing information that I am ecstatic to share with FFFF readers—particularly those patients with atypical acute porphyria presentation, their caregivers and loved ones and the physicians who to try to treat them. It all started with my determinedness to get to the bottom of my daughter’s AIP DNA diagnosis conundrum, awarded in 2008 then revoked in 2014 by Dr. Desnick of Mount Sinai. No reason for why this geneticist felt it necessary to “revisit” her diagnosis has ever been disclosed. The revocation caused enormous distress for our family, not the least of which, of course, was Jill. Following a telephone conversation her then-treating hematologist had with Dr. Desnick, after five and half years of successful AIP management with D10/Panhematin®, Jill’s treatments were immediately cut off, not to be reinstated until/unless urinary biochemical “proof” is excreted during a potentially life-threatening attack. Jill’s world collapsed. It wasn’t too long before her AIP symptoms began to intensify, her PBGD levels began to correspondingly diminish, and I resumed intense attempts to once again save my daughter—and to get to the bottom of what I felt in my gut were nefarious undertakings.


Pardon the interruption: Breaking News!

I eventually connected with a team of Venezuelan porphyria experts. Long story short, the stars aligned and based on my input (including Dr. Desnick’s revocation letter/report and 23andMe incontrovertible proof that his 2014 “revised diagnosis” lacked some teeth), porphyria experts from the Instituto Venezulano de Investigacions Cientificas (IVIC) in Venezuela offered a medical opinion that, at long last, makes logical sense. Instead of relying on excreted bodily fluids that may or may not appear, the opinion is based on blood components, specifically cofactor PBGD. Along with their medical view, Genetic Counselor Dr. Sergio Arias C., MD and Dra. Irene Paradisi, PhD offered to contribute to “probe it right.” As I know that it will give many, perhaps hundreds of patients at least a measure of relief (and restore hope) in knowing that there are experts who are not 100% in line with the US/European AIP diagnostic model, following is the Venezuelan experts’ opinion summation of Jill’s case:

“In summary, we believe that there are enough and clear evidences: enzymatic and clinical ones to sustain a medical diagnosis of AIP regardless of the mutation identification failure, which is a known obstacle found in ~40% of populations worldwide and that the symptoms she presents and her enzyme levels are evidences of acute porphyria crises which should be treated every time, if possible with hemarginate or in its defect with hemin…Plasma PB must be performed during any acute crisis and its level should be found above any value encountered in controls if our diagnostic conclusion is right. Enzyme levels should stay abnormally low.”

As it is so very important to what this paper is all about the final paragraph is presented just as it was received—in all caps:


It’s truly unfortunate (though not surprising) that help had to come from outside our own country. And yes, I do intend to pursue the IVIC porphyria experts’ offer to “probe it right.” Because doing so will not only help Jill, but will re-light the candle of hope for so many other patients, caregivers and their families who’ve been left far too long in the dark.

There is no a doubt that the opinion presented by the Venezuelan team will challenge the US/European porphyria model. Since its beginning, APF has insisted that unless excessive levels of urinary biochemicals (until recently ALA and PBG; more recently, the focus has turned to PBG) excretion during extreme porphyria-type activity, the attack cannot be attributed to porphyria. In my opinion, publishing the statement, “I was only seventeen when I suffered my first attack of Porphyria” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, pg.2], twenty two years after APF was established was disingenuous to say the least. Because since that time, plenty of patients with DNA and/or bio-family members with porphyria but without biochemical proof were (and continue to be) routinely denied acknowledgement that the attacks they suffer are porphyria-related. And they aren’t warned to avoid triggering agents like certain medications or chemicals. All because their bodies did not generate excessive levels of biochemical “proof” in voided urine while in porphyria attacks.



It is well known in porphyria circles that Ms. Howe was among the first patients treated with the not-yet-then-FDA-approved orphan medication Panhematin® which she credits with saving her life. Thankfully, she made a desperate yet fortuitous decision to try it because decades later when my daughter in the crosshairs of life-threatening AIP activity at age 12, I was grateful that she and other US individuals had been compassionate human “guinea pigs” years before. Since then, Panhematin® has saved my daughter’s sanity (and life) many times.


Heme Deficiency

APF neatly sidesteps referring to AIP (or other acute porphyrias) as resulting from heme deficiency, instead choosing to focus on enzyme deficiency. “Blood 101” teaches that heme is the iron-containing molecule in blood, blood is comprised of enzymes and that blood is essential to life (www.oneblood.org). APF agrees with the latter, though uses blood and heme terms interchangeably, “Heme is essential for life, and each enzyme is also essential, because it is responsible for one of the eight steps in making heme. Each porphyria is due to a deficiency but not a complete absence of one of the enzymes.” [2/11/2018 APF>Home>Testing for Porphyria]; and “Many of the triggers of an acute attack act by increasing the demand for heme, which makes the CPO deficiency more significant.” [2/11/2018 APF>Home>About Porphyria>Hereditary Coproporphyria (HCP)>Additional reading about HCP>Causes]

“Blood 101” also teaches that blood is comprised of enzymes. So, knowing that porphyria symptoms are due to deficiency of enzymes, wouldn’t it stand to reason that enzyme deficiency=heme deficiency? In fact, APF web site says, “Doctors administer Panhematin® to correct heme deficiency in the liver and repress production of porphyrin precursors.” [2/11/2018 APF>Home>Treatment Options>Panhematin® for acute porphyria]

And Ms. Howe made the same statement in her book, “the rationale for administering heme therapy (Panhematin®) is to correct a heme deficiency in the liver and repress production of porphyrin precursors.” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 33]. This makes sense because Panhematin® replenishes the putative heme pool with complete red blood cells (question: do precursors ever end up in the heme pool?) which quickly reduces or eliminates, at least temporarily, the need for the heme biosynthetic process to crank out new blood cells which, because of the patient’s mutant porphyria gene, may be defective—at least until porphyria is triggered again.

Like a firework storage bunker, acute porphyria can be potentially dangerous and life threatening. For that reason, a great number of published medical papers about porphyria warn “if a diagnosis of Porphyria is not made promptly, serious consequences to the patient may follow.” [2/11/2018 APF>Home>Testing for Porphyria>Sensitivity & specificity of tests for Porphyria)]. Yet plenty of patients remain undiagnosed. What is terrifying about undiagnosed porphyria is the potential of being triggered by the administration of) harmful (unsafe for porphyria) drug, as Ms. Howe and her doctors found out. If it was so evident to Ms. Howe by the time she’d written her first book in 2004 that she had been suffering with porphyria from the age of seventeen through her early adulthood until about age 27 when the infamous Dilantin-effect caused her urine to change which led to the AIP diagnosis why in heaven’s name didn’t she (and still won’t) consider that Porphyria attacks without U-biochemical proof has happened to others since APF was launched?


Undiagnosed Acute Porphyria Patients Not Told About Medications

In the US, patients who meet diagnostic biochemical criteria are always counseled to be extremely careful about medications and encouraged to refer to the drug list maintained by the organization. Perhaps because APF’s index case (Ms. Howe)’s life-threatening episode had been triggered by Dilantin, APF literature has been rife with warnings for years:

  • “Harmful drugs should be stopped. These include barbiturates, sulfonamides, and many others.” [2/11/2018 APF>Home>About Porphyria>Acute Intermittent Porphyria]
  • “A deficiency of PBGD is not sufficient by itself to produce AIP, and other activating factors must also be present. These include hormones, drugs and dietary changes.” [2/11/2018 APF>Home>About Porphyria>Acute Intermittent Porphyria>Treatment and Prognosis]
  • “Most of these triggers are believed to stimulate increased heme production (synthesis) in the liver and include certain drugs,” [2/11/2018 APF>Home>About Porphyria>Acute Intermittent Porphyria>Additional reading on AIP>Causes]
  • “factors such as endocrine factors (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms.” [2/11/2018 APF>Home>About Porphyria>Acute Intermittent Porphyria>Additional reading on AIP>Summary]
  • “Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible…If a proper diagnosis has not been made, AIP can be particularly dangerous, especially if drugs which aggravate the disorder are administered.” [2/11/2018 APF>Home>About Porphyria>Acute Intermittent Porphyria>Additional reading on AIP>Treatment]
  • “Harmful drugs should be stopped. Attacks are treated with either glucose loading or intravenous administration of hemin (Panhematin®).” [2/11/2018 APF>Home>About Porphyria>ALAD-Deficiency Porphyria (ADP)> What are treatments for δ-Aminolevulinic Acid Dehydratase Porphyria?]
  • Attacks can be prevented in many cases by avoiding harmful drugs and adverse dietary practices. “Lists are available of drugs that are risky for HCP genetic carriers as well as drugs that are safe. The worst offenders are barbiturates, sulfonamide antibiotics, anti-seizure drugs, rifampin, and oral contraceptives (progesterone, in particular)” [2/11/2018 APF>Home>About Porphyria>Hereditary Coproporphyria (HCP)>Who Gets Hereditary Coproporphyria?]
  • “Yes, particularly with regard to drugs and diet. Genetic HCP carriers should become informed on drugs and other factors that can lead to symptoms…They should be prepared to point their healthcare providers to drugs and medications to avoid.” [2/11/2018 APF>Home>About Porphyria>Hereditary Coproporphyria (HCP)>Can attacks be prevented?]
  • “Harmful drugs should be stopped.” [2/11/2018 APF>Home>About Porphyria>Hereditary Coproporphyria (HCP)>What are treatments for Hereditary Coproporphyria?]
  • “Additional factors such as endocrine factors (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms.” [2/11/2018 APF>Home>About Porphyria>Hereditary Coproporphyria (HCP)>Additional reading about HCP>General Discussion>Summary]


  • “Although many types of drugs are believed to be safe in individuals with HCP, recommendations about drugs for treating HCP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted.” [2/11/2018 APF>Home>About Porphyria>Hereditary Coproporphyria (HCP)>Additional reading about HCP>Treatment]


  • “A variety of triggers are known to set off an acute attack. These include a variety of drugs, steroid hormones alcohol, decreased intake of calories or carbohydrates, and metabolic or possibly psychological stress.” [2/11/2018 APF>Home>About Porphyria>Variegate Porphyria> Additional reading on AIP>Signs & Symptoms]
  • These preventive measures include avoidance of certain drugs and alcohol for some types of porphyria…Some of the drugs that affected individuals may need to avoid include barbiturates, tranquilizers, birth control pills, sedatives, and alcohol. [2/11/2018 APF>Home>About Porphyria>Standard Therapies]


By ignoring the acute porphyria potential that lurks in every patient with DNA confirmation (or even suspected) of an acute porphyria mutated gene, or presence of low enzymatic activity or bio-family members with known porphyria, people’s lives are at stake. Every single day.

Getting excessive amounts of precursors to “kick in” by administering unsafe medications is a standard practice used by scientists in studying the acute porphyrias. On animals. And yes, it worked for Ms. Howe, though it sure wasn’t a planned experiment. In my opinion every single patient where acute porphyria appears on his/her differential diagnosis list (especially if s/he has DNA confirmation—even “inconclusive” results and/or bio-family members with porphyria) should be warned to stay on the safe side of chemicals, including medications. That is—awareness and avoidance.

Given what my daughter has gone through since the summer of 2014, it is quite evident that the worldwide porphyria expert community currently has no qualms (nor moral fibers, it seems).



Now comes time to discuss the point where everything starts in the porphyrias—the basic physical and functional unit of heredity known as the gene. Genes are made up of DNA, and act as instructions to make molecules called proteins. (https://ghr.nlm.nih.gov/primer/basics/gene) Wikipedia reports, “There are an estimated 19,000-20,000 human protein-coding genes.” That estimate is a reduction of the initial 100,000 or more genes; genome sequence quality and gene finding methods continue to improve, the 19,000-20,000 could continue to drop. [https://www.google.com/search?source=hp&ei=Kc-FWuTCC8jwsQXr94y4BA&q=how+many+genes+are+present+in+the+human+genome&oq=…]

Clearly, APF experts became enamored with DNA’s potential to identify porphyria types early on. For the longest time, the organization’s web site proclaimed, “DNA …is now the gold standard of diagnosis and is available through specialty labs.” [2/11/2018 APF>Home>Testing for Porphyria: Acute Intermittent Porphyria (AIP)]. Mount Sinai’s Genetic Laboratory had long been regarded as APF’s preferred provider for DNA testing services. Desperate people, like me, turned to Mount Sinai to have patients’ (like my daughter) DNA analyzed. They still do.

So much so that in January (2018) APF introduced free genetic testing for acute porphyria offered by a start-up genetic testing service called Invitae. This testing is available through APF for patients who meet certain criteria: patients must be between age 16 – 55 and have one at least one of the following: elevated U-PBG; severe abdominal pain; red to brownish urine; known/suspected family history of acute porphyria; skin lesions on sun-exposed areas; and/or CNS/ANS manifestations around the time of abdominal pain. [https://porphyriafoundation.blogspot.com/2018/01/exciting-announcement-free-genetic.html]

Apparently, the success of genetic testing companies like 23andMe (which in its early days was soundly bashed by APF and just about the entire medical community) was the inspiration for Invitae’s development. One major difference, however, is that unlike 23andme, Invitae insists on receiving a patient’s request from the patient’s doctor and results are returned to the patient’s doctor. 23andMe eventually won its battle with FDA to be allowed to provide information directly to the consumer. Granted, 23andMe’s information comes in the form of raw data generated by genetic sequencing, but the consumer is able to choose for him- or herself which gene sequencing program to use and which health care provider and others (if others) will the see this very private health information. Also, some patients feel Invitae/APF’s age-range criteria are oddly restrictive. The Invitae/APF connection involves an interesting trail: Invitae and Alylam Pharmaceuticals are in partnership in this endeavor. Alnylam Pharmaceuticals and APF have partnered to run clinical trials for Givosiran, Alylam’s new “wonder drug” currently in development, is intended to treat acute hepatic porphyria. Doctor Desnick, APF SAB member of Mount Sinai conducted testing for ALN.AS1, now Givosiran. Dr. Desnick is a stock shareholder of Alynlam Pharmaceutical and applied for patent holder for Givosiran.

Reports from one of the earliest individuals to take advantage of Invitae’s free genetic service was that this person was not impressed to have received “inconclusive” results. In fact, the individual had earlier received confirmation of one of the genes from a different DNA service so was particularly frustrated to receive uncertainty from the newest scientifically-based endeavor.

This news only added flame to the rumor mill. Why, during the last few years, have increasing numbers of DNA test results been returned to patients as “inconclusive,” “unknown,” “possibly” and similar wiggle room replies? DNA doesn’t lie. One either has the mutant gene or one doesn’t, but even so, apparently the gene may not be entirely responsible for determining whether or not acute porphyria will become active. In the end, proteins play an active part in gene expression. Yet another argument to add enzyme analysis and DNA testing by unbiased entities to the acute porphyria diagnostic algorithm—even for those who pass the “first-line” test of urinary biomarker excretion with flying colors.

APF recently made an alarming volte-face regarding the “gold standard” of diagnosing acute hepatic porphyrias. The number of queries from desperate patients and caregivers regarding the handling of urine samples appearing on Facebook forums has always been substantial. At times, even APF FB discussion threads reflect patient frustration with the lack of knowledge, care and interest shown by medical personnel when collecting and submitting urine samples to be tested for acute porphyria. One such thread appeared on the APF’s open Facebook forum following the March 1, 2017 FDA/APF Drug Development Meeting. I’d already viewed the meeting video so wondered what the communication threads might reveal. As it happened, none of the FB thread participants indicated an awareness of that meeting or of having viewed the video. Too bad, because they would have seen/heard that after being asked by a member of the FDA/APF meeting audience (likely a plant) to address why some people’s diagnoses had been ‘taken away’ former DNA advocate Dr. Desnick made it abundantly clear that urinary biochemical proof is the end-all-to-be-all for diagnosing acute porphyrias (~3:13/48 timeline on video). He responded, “There are patients that don’t have ALA and PBG diagnoses…That’s. The. Gold. Standard…and you know, to do a genetic diagnosis is another level but if you are symptomatic and if you’re having problems and your doctor thinks you have it, ALA and PBG in the urine is a simple, not expensive test—and it’s not influenced by a lot. A lot of people are thinking, well, light influences it and how long it sits and so forth…you know, if you have a high level, you have a high level and you’re not going to change that very much.” [Desnick, RJ; FDA/APF Patient Focused Drug Development (PFDD) Meeting for the Acute Porphyrias, March 1, 2017]

Nonetheless, oddly enough, Ms. Howe recently posted on APF Facebook open forum, “dna tests are gold standard. At Mount Sinai they have 3% and the free test is like 99.9 as it has insertion deletion info too.” I have no idea what the numbers she used refer to, but nearly a year after the FDA/APF Patient Focused Drug Development Meeting was held one would think Ms. Howe and Dr. Desnick could have had time to get on the same page. [APF Facebook Page, Open Forum; February 17, 2018 9:16 a.m]



So there it is. Urinary biochemical output vs DNA testing vs enzyme assays. Africa, Argentina, Australia, Canada, United Kingdom, United States, New Zealand…just some of the countries where patients report suffering with atypical acute porphyria. Outside of a few individual, self-thinking doctors willing to take a chance and discerning, compassionate and dedicated porphyria experts like the IVIC team, it seems the US/European acute porphyria diagnostic body can’t or won’t see the forest for the trees. Doctors in Sweden and adjoining countries rarely look for enzyme activity because they don’t have to. Homogeneous gene pooling in those countries nearly insures that the majority of AIP patients will have traditional Swedish porphyria. However, as I learned from Waldenstrom’s and Hultin, et al’s writings, not all AIP patients in Sweden generate urinary biochemical proof.

While this paper might appear to be merely a US porphyria expert/APF bashing tool, in reality it is intended to remind the world that a significant group of demoralized, desperate and often destitute patients are still being victimized by porphyria over and over again. Before it can be treated, an illness has to be recognized. The majority of these patients feel that no one is willing to recognize that they suffer from acute porphyria. Last fall, “someone” (presumably me) was “called out” on an APF Facebook thread for allegedly accusing APF’s experts with decades’ worth of porphyria knowledge under their belts of not understanding porphyria. To that, a savvy porphyria patient responded (in a private message), “It’s not that they don’t understand porphyria or the research they do. It’s in giving conflicting information to patients as well as silencing those who point out those inconsistencies.”

Ms. Howe’s book offers a precedent that seems to have been forgotten or buried (or both) by APF and its connections all these years. Had she not swallowed that Dilantin pill, it’s possible the APF might not even exist and Ms. Howe, had she survived, might well have found herself in very different circumstances. Perhaps she would have ended up like so many others—undiagnosed. Still seeking answers. Still praying. Still receiving one misdiagnosis after another. Still suffering painful “mystery” symptoms that no one has time to fully look into, left to deal with effects of years of escalating neurological damage. Still being labeled (worse after all these years) as a complainer, hypochondriac, drug seeker, malingerer, and whatever else society proffers. Still receiving suggestions to consider seeing (and referrals to) mental health professionals. Still risking consignment to psych wards as happened to Jill—because she refused to ingest “mandatory” medications which were unsafe for AIP. She is not alone; it happens daily. Still fear-ridden, frustrated, forgotten and fed-up. Thanks to Dilantin, Ms. Howe escaped such routine demoralization all of these years.

There are many similarities between Ms. Howe’s pre-Dilantin episode and a majority of “undiagnosed” patients. Many, if not most, describe themselves has having had pride in their “sense if independence, responsibility and stability” [(Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 10-11] and for maintaining strong faith, and for being able to “handle” the painful, debilitating attacks. They, too, had goals in life—goals that have been left hanging because left without a diagnosis they are medically, financially, physically and emotionally burdened—beat down by a physical health problem, cast out of a society they can no longer successfully participant in. A large percentage are destitute—no diagnosis denotes no means of income, certainly no housekeeper to help with mundane daily needs and no lake or beach houses to offer respite. Where once there was self-esteem and pride in handling the punishing attacks, eagerly looking forward to what the urine test results say this time, many just hope against hope that each time will be the last. Most disturbing, too many pray to the Lord, as Ms. Howe did, to take them from the hell they are enmeshed in.

When the Dilantin-induced recovery period ended, Ms. Howe described a lengthy and difficult recovery period but eventually was able to enjoy healthy times—sometimes years’ worth (“I was surprised that I could live a normal life”). [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p.49]. That likely came about because over the years Ms. Howe has been able to benefit from participation in various clinical trials made available to her. Whenever AIP activity resurrected, she was able to receive hemin infusions and had an advantage of “frequent returns to NIH when doctors had a new treatment they thought might be helpful and for periodic checkups.” [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 52]. A week (or even consecutive days) of not having porph activity is considered a vacation for many undiagnosed patients. They are not offered Panhematin® or D10 and certainly are not even considered for any “new treatments thought might be helpful” or for periodic checkups. [Howe, D.L.; Porphyria, A Lyon’s Share of Trouble, p. 52]

While I would never wish porphyria on anyone, it is too bad that no one in the APF/SAB/Porphyrias Consortium suffers with atypical acute porphyria. Because one has to believe that would make a vast difference in the organization’s clinical approach to everything regarding the porphyrias.

In my mom opinion, how APF and its SAB members has compared (and continues to compare) its index case to other acute porphyria cases is unbalanced. There is no comparison to what happens following obtaining an acute porphyria diagnosis versus being left diagnosed. With perhaps the exception of how many atypical acute porphyria patients’ symptoms mimic Ms. Howe’s ten year stint Before Dilantin (some are much worse), not all AIP patients (typical or atypical) will respond as Ms. Howe does or did. That would work in a perfect world. As we all know, this is not a perfect world.



In closing, I offer this: the life of every single patient who suffers with porphyria symptoms—traditional or atypical—has meaning and worth. Withholding treatment from porph patients because they don’t have a “real” diagnosis as Ms. Howe stated in the FDA/APF meeting (video timeline ~3:17:19) meaning APF-accepted, is not Hippocratic medicine. In fact, attempting to play God by leaving such patients to fend for themselves, essentially turning them into unmonitored human lab rats is not patient support, it’s diabolical.

It is so very hard for those who’ve been kicked in the teeth time and again by a group “established to support porphyria patients.” But thanks to genetic counselor Dr. Sergio Arias C., MD and Dra. Irene Paradisi, PhD, they now have hope. It appears that deficient PBGD (enzyme) is indeed the missing ingredient in Jill’s AIP diagnosis as I’ve said for so many years. As Bob Dylan sang, “the times they are a-changin.’” Thank God. It’s fairly obvious that we have survived German philosopher Arthur Schnopenhaur’s first stages of truth and are bridging the second and third stages:

Truth goes through three stages.

First, it is ridiculed,

Second it is violently opposed.

Finally it is accepted as self-evident.


I have no doubt that what is to come is not going to be pretty or without stress. Still, there is no intention of acquiescing. My “mom” agenda is to insure that my daughter and others like her each achieve an acceptable quality of life.