The following discussion paper/commentary about a very serious and devastating component of acute porphyria is based on solicited anecdotal patient input and research by Joyce Gould, caregiver/parent advocate/author of “Purple Canary.” Released 9/1/2018.
Acute Porphyria is not “all in your head.” It’s in your blood and liver…
…but it can affect what’s happening in your head. In his Textbook of Medical Biochemistry, Dinesh Puri, MD, PhD wrote, “[AIP i]s one of the most bizarre disorders a physician ever encounters.”(1) [Please note, in medical parlance, AIP is frequently used by professionals as an acute porphyria catch-all descriptive, perhaps because it was the first concentrated population of acute porphyria patients (Sweden) to be extensively studied. There is no intent herein to exclude other acute porphyria categories.]
It has been well documented that the acute porphyrias are neurologically based. In fact, acute porphyria was long referred to as neuroporphyria. Some experts still refer to it as such. As did a team of Israeli specialists that reported a case in which psychosis was the only clinical manifestation of AIP.(2) More recently, authors of a 2016 naturopathic medical book noted that “confusion to acute psychosis can be the first presentation” [of acute porphyria].(3) AIP—indeed any of the acute porphyrias, with outwardly imperceptible nuances, can present as a confounding constellation of physical, neurological and/or psychiatric symptoms that may manifest individually or in any combination or format. The acute porphyria-associated neuropsychiatic symptom list, derived from patient input and a multitude of professional articles and professional textbook chapters is long and varied. It includes aggression, agitation, anxiety, behavioral disturbances, cognitive decline, compulsivity, confusion, delirium, delusions, depression, disorientation, echolalia, emotional lability, fearfulness, hallucinations (auditory and visual), histrionics, hyperactivity, hypervigilance, hypomania, hysteria, impatience, impulsivity, insomnia, irritability, mania, muteness, negative attitude, neglect of self-care & hygiene, uncooperative, paranoia, phobias, psychosis, restlessness, self-harm, suicide ideation/attempt and altered states of consciousness ranging from vacant stare to catatonia to somnolence to coma.
No matter the form, intensity or frequency, all acute porphyria symptoms are neurologically based. However, that neurological base doesn’t start in an affected patient’s head. Very simplistically, the problems start in the blood with genetic information that defines blood enzyme development. This development is further aggravated as to-be-constructed blood products enter and work their way through the liver’s blood (heme)-building process. According to experts, excesses of porphyrins/precursors (aka metabolites ALA and PBG) are cast off and accumulate during this heme biosynthetic process, ending up in organ tissues or expelled in bodily waste products. The theory is that these cast-off metabolites affect multiple body systems—particularly the central nervous system (CNS) which includes the brain and ancillary nervous systems. Exactly how this results in neuropsychiatric disturbance is unclear. However, it is known that ALA, allegedly the most neurotoxic of the heme precursors, is able to cross the blood brain barrier.(4) Perhaps this accounts for acute porphyrias’ psychiatric presentations. When it comes to understanding the individualities of each acute porphyrias’ complex pathogenicity, much is still to be uncovered, substantiated and documented. The hardest hurdle will be for such information to be digested and publicly acknowledged by the experts.
For decades, the vast majority of US/EU experts have used urinary biochemical (U-BP) tests to diagnose the acute porphyrias. For a few years, this diagnostic method has received some pushback, especially from U.S. and Australian patients and parent-advocate caregivers who claim the method is fallible and therefore unreliable, and should not be the sole means of diagnosing such complex disorders. Some doctors agree with that assessment and eschew the method which appears to have been derived from a first-line screening method for “Swedish porphyria” (AIP). The position that U-BP testing is fallible/unreliable recently received corroboration by a team of Dutch scientists associated with the European Porphyria Network (EPNET). These experts developed an enzymatic assay for plasma ALA and PBG that is a more sensitive test for AIP than urine ALA and PBG analysis and plasma fluorescence scanning that is a more sensitive test for Variegate Porphyria (VP) than feaces analysis.(5) A chart reflecting the efficacy of plasma, fluorescence, HMBS erythrocytes and CPO[X], PPOX lymphocytes assays is presented within the article. Adding to the report’s remarkability are two additional points: “All patients who had previously had an acute porphyria attack, had abnormal plasma ALA, PBG or fluorescence results in the asymptomatic period” and “One family had combined HCP and VP mutations.”(5) Over many decades, each of these EPNET findings had been verbalized by various members of a porphyria patient group, comprised of individuals from around the world, yet unacknowledged by APF et al (APF and its scientific advisory board) and other porphyria experts. As long as this U.S. clique continues to stifle and silence the patient community dismissed by APF et al as “misdiagnosed,” the longer the EPNET experts’ critical findings will be ignored. However, it is my fervent hope that EPNET will rise to the occasion and promote this validating information.
To be medically correct, acute porphyrias belong to the disease category known as inborn errors of metabolism (IEM). I would be remiss if I didn’t acknowledge the brilliance of British physician/scientist Sir Archibald Garrod (1857-1936) who in 1902 suggested that unusual reactions to drugs might be caused by genetically-determined aberrations in the metabolic pathways. From these findings, he developed the concept of “chemical individuality,” and believed “no two individuals are exactly alike chemically any more than structurally,”(6) something porphyria patients know all too well. Based on Mendel’s law of inheritance, he described some diseases as resulting from missing or false steps in the body’s metabolic (aka chemical) pathway—and in 1908 coined the term “inborn errors of metabolism.”(7) Continuation of his work eventually led him to develop and identify the concept of “inborn factors in disease” (in those times, “factor” was a commonly used term for gene) and to write The Inborn Factors in Disease (1931).He was the first to draw a connection between genes and biochemistry in the human body.(8)
While Garrod was known to be more “scientist” than physician, his ability to recognize and respect human nature was strong. That was apparent when he made the insightful metaphoric connection, “[i]ndividual cases of any particular disease are not exactly alike; they resemble rather the drawing made from the same model by individual members of a drawing class.”(9) His ability to blend his scientist and physician personas was evident when he stated, “[i]t is in the ward rather than the laboratory that the importance of inborn factors is to be appreciated.” That was further underscored when he emphasized that the physician should remember: “each [patient] is an individual and not merely a member of the human race. The task of a practitioner is far more than to apply the knowledge supplied to him from the laboratories, he calls upon his experience to guide him as to how he may best help the particular patient [manage his/her disease] with the least possible damage.”(9) Declarations such as these are what many consider to be the first clear statements of the goals of precision medicine.(9) In fact, being that he was “the first person to appreciate the ubiquity of individual variation [aka chemical individuality] in both health and disease,” Sir Archibald Garrod was suitably dubbed the “intellectual father of precision medicine.”(9) Dr. Garrod passed away in 1936. His concepts were essentially ignored for a few years until a scientist duo showed that a defective gene leads to a defective enzyme, validating Garrod’s concepts. From that point forward, scientific interest in genetics marched ahead with reputable gains made almost annually, culminating in the sequencing of the human genome in 2003.(10)
Unfortunately, neither Garrod’s magnificent scientific decorum nor his brilliant physician principles have transcended to the contemporary IEM/acute porphyrias field—at least not in the U.S. where a recent Internet search for IEM specialists produced less than six sources. Yet a similar search for acute porphyria specialists yielded nearly double that number—eight of which are directly or indirectly connected to APF et al. So it should be a logical assumption to expect that APF would be the pivotal point not only to acute porphyria but IEM knowledge steeped in Sir Archibald’s legacy. Sadly, that is not the case.
An Australian neuropsychiatric team specializing in IEMs understands the IEM/psychiatric symptomatology quite well. In 2012, they described twelve IEM disorders that affect the central nervous system, of which AIP is one. In The neuropsychiatry of inborn errors of metabolism they stated, “metabolic disorders that result in neuropsychiatric illness alter CNS function…and can severely change excitatory/inhibitory neurotransmitter systems….” More plainly stated, “CNS [impact] can present with psychosis, depression, anxiety or mania.” Such presentation is identified as a “phenocopy” (basically, “indistinguishable from primary psychiatric disorder”) and the team cautioned that left undetected and untreated, metabolic disorders can lead to major psychiatric disorders.(11) Much as the Israeli team pointed out in 2006 about psychosis being the sole clinical indication of AIP, the Australian team likewise noted that neuropsychiatric symptoms may be the only clinical signs of an IEM.
Lest one think that the medical field is totally oblivious to such dilemmas, kudos go to the Aussie IEM team for sharing, “Metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood…[and]… may present as major psychiatric syndromes such as psychosis, depression, anxiety or mania. This is hypothetically due to oxidative stress, vascular change and demyelination, impaired release of GABA from synapses of GABAergic inhibitory neurons, reductions in heme dependent enzymes resulting in increased serotonin turnover and reduced nitric oxide activity.” They further “postulate that the causality of psychiatric illness is the result of…acute alteration of excitatory/inhibitory neurotransmitter systems.” Finally, a medical warning, “Failure to recognize the underlying illness whilst focusing on treatment for the secondary psychiatric syndrome alone can delay the institution of appropriate treatment and result in potentially irreversible CNS changes.”(11)
Regarding IEMs, the NIH offers, “In general, the earlier someone develops symptoms of an IEM, the more severe their disorder. The severity of symptoms is generally based [on] the position of the defective enzyme within the metabolic pathway and whether or not there is any functional enzyme or co-factor being produced. However, other environmental and genetic factors may play a role in determining the severity of symptoms for a given patient. IEM are multisystemic diseases and thus patients may present with a variety of symptoms, many of which depend on the specific metabolic pathway(s) involved. Some findings in patients with IEM may include elevated acid levels in the blood, low blood sugar, high blood ammonia, abnormal liver function tests, and blood cell abnormalities. Certain patients may also have neurologic abnormalities such as seizures and developmental delays.” (12)
When it comes to the acute porphyria/IEM connection and psychiatric symptoms, the Aussie IEM team “gets” it. As did the first committed-to-helping-us-AIP-specialist we met back in 2009, Dr. Perdahl. Jill had already been diagnosed with anxiety, depression and bipolar disorder (age 10) then conversion disorder (age 11) before being diagnosed with AIP via DNA (age 12). At the time, Dr. Perdahl told Ed, me and Jill that in her native Sweden when a patient in distress appears in hospital, one of the first things done for the individual (after vital signs) is a porphyria check and consultation of the national porphyria database. It’s that common. Looking at Jill, she continued, “IF she has a psychiatric condition it is secondary to her AIP.” She assured us that treating the AIP would resolve the psychiatric symptoms. And that’s what happened. After having been cut loose by APF et al with little help besides an ineffective Panhematin® treatment schedule, thanks to Dr. Perdahl’s consultation, Jill began an aggressive AIP treatment program and sure enough, regained “mental status stability.” However, whenever AIP comes a callin’, whether trigged exogenously (chemicals, medications) or endogenously (for Jill, PBGD reflects heme deficiency), mental status changes return—often even before the physical pains.
As said previously, neuropsychiatric symptoms associated with acute porphyria may present individually or in concert with physical and neurological symptoms. While most experts tend to refer to this symptom group as psychiatric or neuropsychiatric, I concede that APF’s sanitized version, “altered mental functioning” is a more palatable term for patients.(13) In my opinion, this descriptive stems from co-founder Desiree Lyon’s obvious pathological dread of being tagged with psychiatric labels beyond the hypochondriac tag she’d inherited before she’d ingested a dose of Dilantin which prompted the excretion of purplish-red urine all those years ago.[See 2018 FFFF @www.purplecanaries.com] Following that, a bevy of scientific porphyria experts attributed her AIP diagnosis to the porphyrinogenic Dilantin, thereby preserving the “solidity” of her mental status. It is fairly obvious that the Dilantin episode encouraged APF leaders and members of its scientific advisory board (SAB) to establish a safe/unsafe drug list to support “expert-confirmed” acute porphyria patients’ health safety and to build/enhance APF’s credibility of being a leading porphyria patient advocacy and physician education organization.
However, the Dilantin incident in effect deprived Ms. Lyon the reality of having been locked indefinitely into the frustratingly fear-filled phase she’d endured for ten years. Regarding that time period, she described in her memoir how, “sad it was to hear my name whispered” [by hospital staff] and [to endure] extended wait periods before being seen in emergency rooms only to be finally brought to an examining room where she “would be given a lecture about the benefit of psychological counseling.” This was followed by being told “there was nothing that could be done for me in light of the lack of biochemical indicators.”(14)
Yet that and more is exactly what APF et al has consigned an untold number of desperate patients “lacking in biochemical indicators” to. Without benefit of having endured decades more of that pre-Dilantin experience, it appears as though she and her APF SAB leaders came together in 1982, set an agenda—and for all these years, stuck to it. Sir Archibald Garrod made a point of saying no two diseases are entirely alike yet APF et al made it its mission to diagnose all types of acute porphyria in the same manner. Meaning only individuals who excrete first-line diagnostic excess amounts of the previous mentioned cast-off metabolites (ALA and PBF) in urine during attack(s) get the diagnosis. Although experts say that cast-off metabolites end up in body tissue or are excreted in urine, no scientific evidence has been released about what the ratio between tissue embedment and excretion may be. Quality of the “blood product” that makes it through the heme biosynthetic process is questionable, as are the genes involved that start and oversee the whole shooting match.
There have been rumors of late of a “PBG retention gene” having been identified and revealed. The probability of such a gene of course makes sense to those who “lack biochemical indicators” yet not surprisingly, APF et al is silent on the matter. The notion that a single gene could be responsible for any health condition—especially a complex one is going to be a hard one to hang onto. While APF et al-connected geneticists are running around testing porphyria genes—for fee or free, the DNA arena is steadily (and rapidly) getting more and more complicated—and crowded. Concepts like oligogentic (trait influenced by more than one gene) and omnigenic (all genes affect every complex trait) have entered the fray. Perhaps that’s why APF et al appears to have thrown in the towel on DNA and zealously embraced the embattled U-BP as the “gold standard” for diagnosing all the acute porphyrias? I don’t think so—just doesn’t “fit.” Remember that Dr. Garrod’s focus was on blood; even though urine was a sign of various IEM disorders, he found answers in the blood.
Still, darkened urine has been a recognized porphyria characteristic since Hippocrates noticed urinary discoloration among his sickest patients. However, fast forward a couple thousand years to 1939. That’s when Jan Waldenstrom, “Father of Acute Intermittent Porphyria,” reported “a case where porphyrins could be detected neither in urine nor bile” during AIP attacks.(15) This same “phenomenon” has been reported, at least anecdotally, by “expert-confirmed” acute porphyria patients for years.(16) Many of not most acute porphyria patients divulge that U-BP doesn’t always appear with every attack s/he endures, and particularly not when symptoms develop chronicity. This was essentially acknowledged by APF SAB member Karl Anderson during the 3/1/2017 FDA/APF Patient Focused Drug Development Meeting. At that time, he noted that some acute porphyria patients (“expert-confirmed”), when chronic acute porphyria symptoms are occurring don’t excrete U-BP.(17)
In typical APF discrepancy-laden fashion, a 2015 chart presented by its partner Alnylam Pharmaceutical revealed an interesting yet validating acute porphyria symptom story. Titled Patient-reported Attack Symptoms Screening Questionnaire, the chart presents thirty-one symptoms.(18) Not surprisingly, abdominal pain ranks highest (but notably behind the 100% mark—meaning not all patients experience this debilitating symptom). To round out the top five, this is followed by nausea, back pain, weakness and tiredness. Yet “change in urine color” (presumably indicative of requisite urinary biochemical indicators (U-BP)), ranks in sixth place.(18) This corroborates that not even “expert-confirmed” acute porphyria patients excrete changed urine color 100% of the time. If this chart is meant to be a screening method to identify the possible presence of acute porphyria, then it totally misses the mark. One need only review the more recent EPNET study referred to on page 2 to get a more complete picture.
Even in countries where AIP has been known to have higher prevalence of AIP than U.S., darkened urine during acute attack is essentially never recorded as being present in 100% of clinical cases. A Finnish report of fourteen symptoms/signs of acute attack puts darkened urine at 89% (and “mental symptoms” at 46%).(19)
Several years ago, some APF-rejected, “misdiagnosed” individuals established the first closed Facebook forum to support this pummeled patient population. Since then, as the number of rejected patients burgeoned, so has the number of closed Facebook forums multiplied. One insightful, intrepid “misdiagnosed” patient dubbed these “APF rejected” patients the “Misfit Porphs.” The vast majority of Misfit Porphs, out of necessity, have unknowingly followed Dr. Garrod’s path, albeit as patients. Many if not most are experts of their own body’s reactions to nutrients, supplements, environmental and other triggers. Some work with naturopathic practitioners. A few find MDs who, if they are not familiar with acute porphyria, are at least open to learn and willing to team with the patient to seek better health for him/her. And a very few (like me and my daughter) were extraordinarily lucky enough to find MDs familiar with porphyria who know how to treat patients with FDA-approved therapies. A great number of Misfit Porphs are blessed with incredible intelligence and thanks to the Internet, became porphyria research savants. Besides offering “safe places to fall,” the closed forums provide collaborative opportunities to share DIY tips and techniques for “living” with acute porphyria. While the number of expert-confirmed acute porphyria patients has remained within the parameters of the rare disease category since APF was established, the number of Misfit Porphs has burgeoned over the years. And no one questions why—because “everybody” know acute porphyria is “rare”—or since Alnylam came into to the APF picture, “ultra-rare.” But is it really either? It has been speculated for years by various experts (except the U.S., of course) that porphyria is under-diagnosed.
There are several unsettling aspects associated with being among the Misfit Porph community. One is witnessing the emotional pain associated with patient after patient submitting to test after test only to be told, “everything’s normal” when they know it’s not. It is wrenching to see the APF et al déjà vu pattern of rejection reenacted over and over. Because we all know that this rejection exacerbates the patient’s loss of credibility with the medical community, members of society and sadly, some (or all) family members. In fact, that medical experts rejected a patient’s claim emboldens some individuals to bully very sick patients with harsh, critical messages. Piling that on top of physical, neurological and altered mental functioning symptoms these patients have no way of escaping erodes the individual’s self-worth. Too, it is distressing to bear witness to the harrowing effects of ongoing chronicity and severity that acute porphyrias progress to. Finally, it is devastating to learn about yet another abusive episode brought to bear by trained, medical professionals (usually emergency department or psychiatric unit personnel) upon hapless Misfit Porph individuals. Ms. Lyon’s recollection of receiving “lecture[s] about the benefit of psychological counseling”(14) pales in comparison and in fact is laughable to what too many Misfit Porphs have been—and continue to be—subjected to. Perhaps the most heart-wrenching of all is learning of yet another APF et al involvement in the revocation of an acute porphyria diagnosis. This means blatant interference in a physician/patient relationship—something not even the FDA can do. It happened to my daughter and countless other patients including some Ms. Lyon acknowledged knowing about it at the FDA/APF Patient Focused Drug Development Meeting.(20)
Had I’d paid better attention to Chapter 26 of Ms. Lyon’s 2004 book, I never would have invited her to read my draft of Purple Canary nor to offer commentary about it. For it was in that chapter that she told the story about a woman who’d written her to say she was “taking Panhematin® monthly.”(21) Evidentially this woman had not been diagnosed by an APF-affiliated doctor. The woman explained she had been “taking Panhematin®” for “neuro problems (mental troubles)”and “some minor pain in her back and maintained that having monthly infusions of Panhematin® made her feel better.” [Note, it is not known if “mental troubles” or “minor” were the patient’s or Ms. Lyon’s words.] When asked about tests, the patient said her urine “copros were higher than normal.” Ms. Lyon suggested the woman’s tests be redone. When the results came back, urinary ALA and PBG levels, blood and stool tests were all within normal range. Ms. Lyon stated, “to indicate whether a person has Porphyria, the ALA and/or PBG should be approximately ten times the normal level.”(22) According to some Misfit Porphs, this acute porphyria indicator has varied over time. Ms. Lyon then explained, “Considering the biochemistry and the symptoms, it was clear that the woman did not have Porphyria” then defended the woman’s doctor’s inability to justify the treatments because the woman “clearly did not have porphyria.”(21) So the woman’s lifeline, Panhematin®, was discontinued and Ms. Lyon said she “showed up at different emergency rooms every weekend with years of old paperwork that had her Porphyria diagnosis attached. She would insist that she had Porphyria, despite the biochemistry that proved otherwise. I am not sure what happened in the end but I felt very sorry for her because she was hanging onto a misdiagnosis and would miss the true problem. Plus I felt sorry for the physicians who had tried to convince her of the truth and wanted to discover the source of her real medical problem.”(23) Ten years after that book was published, a similar revocation pattern happened—my daughter’s; after that—a Michigan mom’s—and on and on. Lives torn apart because of urine. But the medical field has answers—albeit misguided ones, because they target the head.
While the physical (i.e. severe abdominal, leg, back pain, etc.) and neurological (i.e. headache, seizure, etc.) symptoms are debilitating enough for patients to seek medical help, the altered mental functioning symptoms generally make diagnosing a conundrum. Nonetheless, this symptom category is what produces a diagnosis. GPs and psychiatrists unfamiliar with IEMS/acute porphyrias (and without time or interest in getting to the bottom of “complex” matters”) usually find a diagnosis in the American Psychiatric Association’s brainchild, the DSM-5 (Diagnostic and Statistical Manual for Mental Disorders).
None of the acute porphyrias are listed in the DSM and rightly so because given the blood/liver biological base, porphyrias are organic disorders (but not organic brain diseases). In fact, the DSM contains only a few organic disorders that present with psychiatric symptoms: epilepsy, Alzheimer’s and Huntington’s among them.(24) So, based on presentation of (or patient’s confiding) symptoms, psychiatric diagnoses are commonly assigned to acute porphyria symptomatology, albeit erroneously. Such diagnoses may include chronic fatigue syndrome, conduct disorder, conversion disorder, major depressive disorder, histrionic personality disorder (aka attention-seeking), illness anxiety disorder, personality disorder (often borderline or schizoaffective personality disorder), schizophrenia, substance use disorder (aka drug-seeking) and the all-encompassing somatic symptom disorder [SSD]. One such disorder is never discussed in the same breath as porphyria and that is PTSD (post-traumatic stress disorder). As I’ve said numerous times, I am not a doctor, but with foster parenting experience, a Vietnam War veteran for a husband, and years of three foster/adoptive kids’ psychotherapies under my belt, I am able to recognize PTSD when I see it. I found neurofeedback helped the kids improve so much better than chemical meds or talk therapies.
Being that acute porphyrias are based in blood/the liver, according to the Australian IEM specialists, the error comes in addressing and treating them as primary psychiatric illness rather than secondary psychiatric symptoms.
Sad to say, since the DSM’s debut in the 1950s, decades-worth of medical/societal changes ultimately evolved into the all-too-common abdication of solid, medical investigation to DSM-diagnostics. Unfortunately, this has had unsettling if not horrific consequences for entire populations of acute porphyria patients, of which my daughter is one.
During the time I was still of the naïve mindset that APF was going to help us, an insightful and articulate acute porphyria patient named Wendi Petit had already apprised and addressed the DSM-5/porphyria quicksand. She’d written an article titled, “DSM-5 and Somatic Symptom Disorder—Dire Consequences for Rare Disorders,” in which she aptly predicted and conveyed SSD/acute porphyria perils. She wrote, “This category [(SSD) is] targeted towards primary care doctors. Essentially, your doctor will give you a mental illness label if he or she thinks you can’t cope with your physical symptoms the way they think you should. Not only must you deal with your illness in a way that your doctor deems as “normal,” but you must do it in six months or less. While your doctor may think he or she is doing you a favor, the fact is, that label will remain on your record for life…The journey towards a root cause for our symptoms is neither a straight road nor one that’s without potholes, breakdowns or roadblocks. Both doctor and patient need to work together. This SSD category interrupts that process. It gives doctors permission to dump us on the side of the road, never to see us again.”(25)
She was right, but there is another obstacle—one with enigmatic intent that has been known to get between doctors and patients working together. That is APF et al’s diagnostic one-size-fits-all U-BP formula. In fact, it epitomizes the “potholes, breakdowns or roadblocks” that Ms. Petit mentions. Wielding the U-BP truncheon, APF has thrown tens, hundreds, perhaps thousands of patients to long-term DSM diagnostics. APF’s long-held custom of dismissing patients who “lack biochemical evidence” exponentially increases the odds that these patients will be subjected to DSM diagnosing, which means pharmaceutical “therapies.” Because when stymied, contemporary GPs and psychiatrists, ignorant (no negative connotation meant) of IEMs/acute porphyrias do what they’ve been trained to do when experts aren’t able to provide answers—they consult the DSM. Once a DSM diagnosis is determined, pharmacological therapy (aka “treatment”) is generally recommended. More often than not, this consists of pharmaceutical “cocktails,” essentially, combinations of chemical medications. The potential health ramifications of such actions handed out by a medically connected organization are mind-blowing.
Though obviously intended to support the “expert-confirmed” acute porphyria patient population, APF’s safe/unsafe list turned out to be low hanging fruit for Misfit Porphs. Knowing of the possibility (or probability) of acute porphyria lurking in one’s liver, Misfit Porphs generally quickly became familiar with the public-access med list.
This—and the fact that patients “lacking biochemical indicators” are dismissed without caution afforded the patient (better safe than sorry is thrown to the wind) is alarming. Or, perhaps there was a calculated, ulterior motive for APF et al in making the safe/unsafe list public? A sinister idea has been floated that seems inconceivable—but may not be. And that is, insuring the Misfit Porph population stays “misdiagnosed” (or undiagnosed) by virtue of them avoiding the “BAD!” drugs. It all started when that Dilantin triggered severe, life threatening symptoms in Ms. Lyon and resulted in U-BP—lots of it. Allowing “misdiagnosed” patients to access the safe/unsafe drug list almost guaranteed these individuals would avoid unsafe medications which turn would reduce the odds they’d suffer the severest of life threatening symptoms. More importantly, it also reduced the odds that they might generate U-BP, thus insuring the “expert-confirmed” acute porphyria population would stay within “rare” disease category parameters, which translates to maintaining orphan drug status for Alnylam’s Givosiran. I don’t know. Sounds too macabre to be true, but some insist…
That being said, I refer once again to Ms. Lyon’s memoir, this time to “words of wisdom” she passed along to readers of her book (presumably those who could become “expert-confirmed” acute porphyrics). She encouraged them with motivators like, “That’s why obtaining a correct diagnosis as soon as possible and not giving up until you have one is of ultimate importance,”(26) “those who know the most do the best;”(27)“make sure you clearly understand your diagnosis and continue to ask questions until you understand;” “a patient deserves a listening ear from a doctor and vice versa” (28) and others. I need say no more; the irony and duplicitous is palpable. Problem was, she was speaking from a platform of power—not from the netherworld of the pre-Dilantin era where she once subsisted and where and how Misfit Porphs continue to subsist.
The reality is that for the vast majority of Misfit Porphs, every new day is a personal science experiment—or on really bad days, a series of science experiments. I have no doubt Dr. Garrod would recognize this grotesque anomaly—and be disgusted by the conditions brought to bear for it all to have happened. But Dr. Garrod is not among us. And until sweeping changes are made, Misfit Porphs have to rely on the only tools they can grab onto. If nothing else, knowing which medications are rated unsafe, improves the chances of dodging potentially deadly situations. It should be noted, however, based on numerous adverse reactions over time to meds deemed safe on the APF list, NAPOS’ list (www.drugs-porphyria.org), developed for physicians, has become the Misfit Porphs’ preferred source for safe/unsafe medications.
In researching this “porph-psyche” topic, I came across an abstract sponsored by the American Psychiatric Association that works perfectly here. While the author obviously doesn’t understand the Misfit Porph position (few do), because the article touches on so many ideas relevant to this topic, I’m including it here:
“Porphyria—A Deceptive Syndrome.
“Most ‘organic brain syndromes’ are not difficult to diagnose. However some ‘organic’ states resemble schizophrenia, and this is particularly true of the acute intermittent type of porphyria. Here, the variable pain and paralysis and the prominent psychic changes can easily lead to errors in diagnosis—as recounted in the cases presented—unless this classical triad is kept in mind as being characteristic of porphyria
“Early diagnosis would prevent unnecessary surgery and psychotherapy, the administration of drugs which can precipitate an attack, and even commitment as a schizophrenic. It is likely that there are undiagnosed porphyrics in the present mental hospital population in this country; we should therefore routinely do a Watson test on any patient—especially the young female—who is troubled with unusual abdominal pain and any sort of psychic disorder, with or without any concomitant neurological symptoms being present.
“Little mention has been made of this disease in the past, because it has been thought to be very rare. However, an average of more than one case a year is seen at our 1,000-bed hospital, and it has often been shown in the past that when attention is focused on supposedly “rare” diseases, they are found to be much more common than previously supposed.”(29)
Following are some medications that have been/are prescribed to patients who’ve ended up on the “it could be porph trail” to address various symptoms. Note some are rated B=Bad, VB=Very Bad, W=warning; mixed reviews. What works for one may not work for others, and depending on a host of internal and external factors, what works for one patient one time may not work the same way every other time. This list (and rating) is based on patient report(s) and my research of various porphyria drug lists. The reader is advised to discuss with his/her medical advisor, every medication prior to ingesting it, to insure the medication is safe for acute porphyria.
alprazolam (Xanax, Niravam, and others)
clonazepam (Klonopin and others)W
clozapine (Clozaril, FazaClo, and others)
droperidol (Inapsine and others)
fluoxetine (Prozac and others) W
fluvoxamine (Luvox and others)
gabapentin (Neurontin and others)W
haloperidol (Haldol and others)
lidocaine – topical (skin surface only) W
lithium (Lithobid and others)
lorazepam (Ativan and others)W
metformin (w/various additives)
methylphenidate (Focalin, Daytrana, and others)
prochlorperazine (Compro and others)
rivastigmine (Exelon and others)
temazepam (Restoril and others)W
trazodone (Desyrel, Oleptrol)
zopiclone (non benzo for insomnia)
benztropine (Cogentin and others)W
bupropion (Wellbutrin, Aplenzin, and others)W
buspirone (BuSpar and others)B
butabital (Fiorinal) VB
carbamazepine (Carbatrol, Equetro, and others)VB
citalopram (Celexa and others)W,B
clomipramine (Anafranil and others)W
diazepam (Diastat, Valium, and others)B,W
donepezil (Aricept and others)W
escitalopram (Lexapro and others)W
fluconazole – (Diflucan)B
imipramine (Tofranil and others)B
lamotrigine (Lamictal and others)W
lidocaine – injectable or viscous mixture B, VB
mianserin – W
mirtazapine (Remeron and others)W
naltrexone (Vivitrol, ReVia, and others)W
nitrofurantoin (Macrobid and others)B
nortriptyline (Pamelor, Aventyl, and others)VB
oxcarbazepine (Trileptal and others)B
oxycondone (Endocet) W
paroxetine (Paxil, Pexeva, and others)B
phenytoin (Dilantin, Phenytek, and others)VB
progesterone – W
risperidone (Risperdal and others)B
sertraline (Zoloft and others)W
topiramate (Topamax and others)B
valproic acid (Valproate, Depakene, Stavzor, and others)VB
venlafaxine (Effexor and others)W
zaleplon (Sonata and others)W
zolpidem (Ambien and others)W
chlordiazepoxide (Librium and others)?
dextroamphetamine (Dexedrine and others)?
doxepin (Zonalon, Silenor, and others)?
flurazepam (Dalmane and others)
tranylcypromine (Parnate and others)?
As far as the above list of medications goes, the Aussie IEM team shares some that they, as professionals, noted have been safe and effective for their patients, “Psychopharmacological management of AIP involves judicious use of medication that will not worsen the biochemical deficit, which for psychosis includes chlorpromazine and droperiodol; fluoxetine or sertraline for depression; lithium for mania, and lorazepam, triazolam and temazepam for anxiolysis [level of sedation in which a person is very relaxed and may be awake] and sedation.(11)
Many patients (not just porphyria patients) have had experiences with various mediations that “don’t work” or exacerbate symptoms—or seem to generate other symptoms. Where psychopharmacological medications are concerned, the Australian IEM team explains that secondary psychiatric illnesses are less likely to respond to traditional treatment because the “underpinning neurobiology of secondary presentation differs from the primary psychiatric illness in which the particular treatment has been shown to be beneficial.” They add that ongoing treatment of the secondary psychiatric syndrome may result in the patient’s neurobiological system becoming treatment-resistant…” and warn, “To minimize motor and cognitive side effects that may worsen the concomitant neurological manifestations of the underlying metabolic disorder, careful consideration of [medication] choice is crucial in treating patients with secondary psychiatric syndromes.”(11)
So once again, the problem is not in the acute porphyric’s head but in the liver—specifically from that chemical individuality that Garrod spoke of. These warnings should behoove every medical professional faced with a child, adolescent or adult patient presenting with psychiatric symptomatology to earnestly address the potential for underlying medical disorders such as IEMs/an acute porphyria.
Given the potential for serious negative impact on neurodevelopment, medical professionals should be especially attentive to identifying acute porphyria in childhood. This in no way is meant to exclude the potential effects medications can have on adolescent or mature adult systems. Brain plasticity is a wonder of nature, but not a sure bet by any means. Metabolic disturbance is formidable and shouldn’t be left to unarmed medical opponents to try to wrestle it alone. In spite of more than three decades of APF’s physician/medical community education efforts, this critically-important audience base (and therefore society) remains largely ignorant of and misinformed about the acute porphyrias. Consequently, it is becoming increasingly clear that the acute porphyrias are significantly under-diagnosed. This has resulted in uncounted patients being shuffled off to mental health specialists to be readily slapped with erroneous psychiatric labels. Most are broken—physically, neurologically, emotionally, socially. Some become addicts and/or have had run-ins with the law. Others really have been misdiagnosed—with mental illness—and been confined to mental institutions. Such happenings are not far-fetched. Too many people suffer indignities better left to by-gone eras—all because their urine “lacks biochemical indicators.” Whatever the secondary condition may be, treating the porphyria FIRST is of utmost importance. Mind-altering drugs won’t cut it—and can make things worse. Who’s to say such medications aren’t adversely impacting the underlying IEM/acute porphyria? Ignoring that possibility is negligent and yet other reason for APF et al to insist (and use) its collective pseudo-scientific positioning to insure NOTHING but U-BP is acknowledged as definitive acute porphyria diagnostic methods. Hiding behind the acute porphyrias’ complexity for all these years is arrogant and cowardly behavior. Manslaughter and murder charges have long been potential outcomes—and could come to fruition yet.
In a perfect world, it would be well-known (and recognized) that acute porphyria can manifest with or without U-BP. In a perfect world all acute porphyria patients would be treated with respect, compassion, and genuine interest—there would be no differentiation or favoritism. Speaking of treatment, in a perfect world, it wouldn’t be up to patients or caregivers to figure this out; acute porphyria patients would receive diagnoses and healing therapies based not solely on the contents of their urine, but on concepts associated with true personal medicine practices. In a perfect world, non-profit porphyria patient advocacy organizations would truly be patient-centered; not able to partner with pharmaceutical companies—in any capacity and certainly not able to interfere with doctor/patient relationships, especially without knowledge and approval from the patient. In a perfect world physician/scientists in the ilk of Sir Archibald Garrod would eagerly embrace the Misfit Porph Challenge, conduct real research befitting the complexity of acute porphyrias to result in treatments that would respect and reflect chemical individuality associated with acute porphyrias. In a perfect world, comprehensive (not just surface) physician training programs would be made available to all medical disciplines. In a perfect world, every “major” medical facility would house porphyria specialists.
As we all know, this is not a perfect world—and never will be. After all, in a perfect world there would be no acute porphyria! But there is, and until and unless a cure is found—or humans stop procreating, porphyrias will be among us. As the current porphyria patient advocacy /physician education organization refuses to recognize porphyria patients “lacking in biochemical indicators”—indeed, there collusion against Misfit Porphs—it is up to the Misfit Porph community to strive to know the most and continue to do best, for themselves. And while former President O’Bama introduced the Precision Medicine Initiative (PMI) in 2015 as an ‘innovative concept …that will pioneer a new model of patient-powered research [DNA]…[and] …promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge and therapies to select which treatments will work best for which patients,”(30) the reality is the plight of Misfit Porphs is nowhere on that radar. Because (at least in the U.S.) because APF et al holds the porphyria diagnostic cards.
To that end, while the above list of chemical medications is long, over the years, some in the “Misfit Porph” community have found DIY “hacks” for managing acute porphyria symptoms. One of the more palatable (and effective), discovered and promulgated by a Misfit patient, is reliance on powdered dextrose mixed with patient-preferred beverage (depending on system tolerance—water, juice, sports drink for electrolytes). Taken at earliest prodome recognition and sipped until symptoms withdraw is becoming a favorite remedy among this patient population. A caution goes along with this, however and that is the need to balance the glucose loading with sodium intake. This caution is based first on the fact that hyponatremia (low blood serum) is a common complication in AIP and second, a report from U.K. porphyria experts about the death of patient following glucose infusion to treat an AIP attack.(31) The patient was a 17 year old schoolgirl who presented “with five-day history of general malaise, vomiting, constipation, abdominal pain and aching in her legs. She’d consumed several alcoholic drinks the evening prior. Provisional dx was a viral illness. Over the following days, she was anxious and confused and complained of increasing leg weakness. Six days after admission, her serum sodium had fallen to 129 mmol/l. One week after admission, dark-red urine was observed then tested; acute porphyria was identified. On day eight, intravenous glucose 5% was started but stopped when her serum sodium was found to be 116 mmol/l. Later that day, she had hallucinations. The next day her serum sodium was 115 mmol/l. Fluids were restricted and glucose 50% was infused. On day 10 she had respiratory arrest and died.”(31)
I am betting this report is what fueled experts’ decision in the not too distant past to veer away from recommending the use of glucose treatments to manage acute attacks.
Now of course I’m no doctor, but know that beginning with my daughter’s first glucose treatment (which “sandwiched” her Panhematin® treatments beginning in 2009) ½ Na (sodium) and 10 mEq KCL/l (potassium chloride) were always on the glucose treatment order (D10). There was no mention of electrolytes having been tested or supplemental sodium, potassium or oxygen being provided during any of these treatments in the report. It is concerning that it took more than a week after the patient’s admittance to use glucose—5% is understandable for a “first timer” as they’d had no history with the patient. But to jump to glucose 50% so rapidly is concerning to this layperson. And none of it with supplemental NA or KC? I am very sad for this young woman and her family about the outcome but those among the Misfit Porph community, due to their own brand of research (ongoing trial and error), may have valid information to impart to doctors, specialists and experts when it comes to porphyria activity, attacks and “standard” acute porphyria treatment protocols. The patient who brought powdered dextrose option to the Misfit Porph population also developed the Sip. Nibble. Nap. protocol. She has worked with various types of doctors throughout her porphyria years and has generously shared what she’s learned with others. The nature of using the amounts of DYI powdered glucose dissolved in drinks of one’s choosing is nowhere near the capacity or duration that in-hospital (or clinic) intravenous glucose would involve, but as with everything, it is highly recommended that you check with your professional medical advisor before implanting this or any other remedy.
Other ideas from the Misfit Porph community to help manage acute porphyria symptoms include cannabis (legal medical marijuana)—not “street”—free of pesticides/herbicides, and in the last few years, select essential oils and CBD (hemp) oil—with or without THC (CBD oil not legal yet by federal law; check state law). Cimetidine (otc Tagamet)—yes a chemical, but one that was proven effective in treating acute porphyria.(32) A young mother’s endorsement several years ago (her physician ordered it compounded for her and her young daughter) shared, “Cimetidine gave me my life back.” I was encouraged to investigate Cimetidine further and try it for my daughter. Thankfully, for Jill, 800 mg at first sign of prodome taken with 3 Tb of powdered dextrose in Gatorade and repeated as necessary has thwarted many attacks over the years. Unfortunately, Cimetidine doesn’t work for everyone, and actually exacerbates some Misfit Porph’s condition. Chemical individuality.
Supplemental oxygen has proven to be a game changer for many Misfit Porphs—especially when in medical crisis and/or during routine administration of IV glucose and/or Panhematin®–which the vast majority of Misfit Porphs has never had. The story of how I came to recognize how something so “simple” as supplemental oxygen could help can be read in Purple Canary. A few Misfit Porphs’ doctors have prescribed supplemental oxygen to patients to use as-needed. Not able to get such a prescription, some Misfit Porphs purchase canisters of supplemental oxygen (known as “recreational oxygen inhalers”) over the counter.
As said many times before, acute porphyria is a disease of individualities and every patient (and situation) is different. Such is the nature of “helpful hints” to be found on closed porphyria forums, several of which exist. Of course, disclaimers abound and participants (generally adults) are urged to contact his/her trained medical advisor prior to trying anything that works for another patient. For social stimulation, I encourage each of you to check the forums out and request to join those that appeal to you. Unlike APF’s forums, participants in these forums are encouraged to share DIY tips and techniques, provide information obtained from research, exchange theories and/or info learned from their own experiences about medications, foods, triggers, etc., and/or share physician information.
To “porph newbies,” a fair warning: unless you DO excrete observable, darkened urine (Coca-Cola or purplish-red) urine, be aware that APF’s and Porphyria Sucks’ open Facebook pages specifically cater to the “expert-confirmed” patient category. Neither welcomes posting of non-APF et al produced articles. APF and its followers have a long history of infiltrating (or attempting to infiltrate) other online forums. It started (and continues) as a means to further APF’s agenda; some APF followers have even created “fake” FB profiles to gain access to closed forums. Administrators of some closed forums allow APF followers to join. It is clearly evident that some of those APF followers’ mission for joining is to report back to APF about “goings on.” For that reason, in order to minimize APF interference, some of the closed forums scrutinize potential participants closely.
In closing, I will say that a determined cadre of Misfit Porph patients and caregivers (sometimes referred to as “Moms & Friends”) is working specifically for Misfit Porphs’ causes. In respectful memory of the most inspirational Rachel Carson, with dignity and deliberation, we intend to disturb and disrupt. This has obviously shaken APF et al, hence the sometimes rancorous communications on the closed forums, particularly when APF-followers decide to push the APF agenda on a community that has no love lost for the patient advocacy organization. I, for one, don’t suffer any medical or educational professionals’ gaslighting techniques well. Having born witness to the destruction that APF et al wrought on my daughter, my family and multitudes of other patients, I personally have no patience left for the lot and don’t apologize for it.
I extend my personal thanks to those who have established closed FB porph forums for providing Misfit Porphs “safe places to fall.” Your allowing participants to share DIY tips and techniques as well as information based on experience and/or research culled from the full worldwide range of porphyria experts is and always will be refreshing and very much appreciated.
Please remember, many in this group (including you or a loved one) may be broken by what has been done to you, but you surely aren’t the ones with loose screws or messed up morals.
Lives continue to be at stake. It’s well past time to make things right for all porphyria patients—particularly the unacknowledged “Misfit Porphs.” Nearly forty years of research, and what does the U.S. have to show for it:
- Repeated attempts to find the pharmaceutical “one” sacred treatment for “expert-confirmed” acute porphyria patients—while destroying others’ lives;
- An inability to produce audited prevalence and incident statistics—for every porphyria type. Instead, U.S. experts rely on numbers from other countries—hardly suitable for comparison sake, given the lack of diversity in such countries;
- An inability to provide U.S. patients with a safer form of heme treatment (Normosang®)—allegedly better than Panhematin® which is known to be harsh on patients’ veins (and ports);
- Patients left out to dry (and die), slowly, miserably because they lack biochemical indicators.
“Never doubt that a small group of thoughtful, committed citizens can change the world; indeed, it’s the only thing that ever has.” – Margaret Mead, American anthropologist
“Truth goes through three stages. First, it is ridiculed, second it is violently opposed. Finally it is accepted as self-evident.” – Arthur Schnopenhaur, German philosopher
“Kites rise highest against the wind, not with it.”– Sir Winston Churchill
- Puri, MD, PhD, Dinesh; Textbook of Medical Biochemistry; Elsevier; 2011; p.340.
- https://www.ncbi.nlm.nih.gov/pubmed/16910386; Acute intermittent porphyria: psychosis as the only clinical manifestation
- https://www.sciencedirect.com/book/9780702055140/the-clinicians-handbook-of-natural-medicine; Pizzorno, Murray, Joiner-Bey; The Clinicians Handbook of Natural Medicine; 2016, Elsevier Ltd.
- http://journals.sagepub.com/doi/pdf/10.1177/014107688307600512; Pathogenesis and treatment of acute intermittent porphyria: discussion paper
- http://porphyria.eu/he/content/diagnosis-acute-hepatic-porphyria-plasma-ala-pbg-fluorescence-scanning-and-enzyme-assays;The Diagnosis of Acute Hepatic Porphyria by Plasma ALA, PBG, Fluorescence Scanning and Enzyme Assays, Using DNA Analysis as Reference
- http://www.genonenewsnetwork.org.resources/timeline/1908_Garrod.php; Archibald E. Garrod (1857-1936) postulates that genetic defects cause many inherited diseases
- http://www.dnaftb.org/13/bio.html; Mendelian laws apply to human beings
- https://en.wikipedia.org/wiki/Onegene%E2%80%93one_enzyme_hypothesis; One gene—one enzyme hypothesis
- ;http://home.uchicago.edu/~rper/Selected_Publications/Garrod_and_Precision_Medicine_Genetics_in_Medicine_2016.pdf; Archibald E. Garrod: The Father of precision medicine
- https://en.wikipedia.org/wiki/Human_Genome_Project; http://www.genonenewsnetwork.org/resources/timeline/1908_Garrpd/php
- http://u2pea.free.fr/resources/NeuropsychiatryIEM-Walterfang-JIMD2013.pdf; The neuropsychiatry of inborn errors of metabolism
- https://www.genome.gov/27551373/the-nih-mini-study-general-information-about-inborn-errors-of-metabolism;The NIH MINI Study: Metabolism, Infection and Immunity in Inborn Errors of Metabolism
- Lyon Howe, Desiree; “Porphyria, A Lyon’s Share of Trouble,” 2004 Howewrite, Inc. p. 11.
- https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0447.1939.tb06652.x; Neurological Symptoms Caused by Socalled Acute Porphyria by Jan Waldenstrom, 1939
- https://www.porphyriafoundation.comtaped by and posted on APF website landing page (~3:15:36 on the video timeline); FDA/APF Drug Development Meeting, March 1, 2017
- http://www.alnylam.com/wp-content/uploads/2017/06/ICPP-2017-EXPLORE-Presentation-Capella.pdf; Patient-reported Attack Symptoms, Screening Questionnaire
- http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.335.9042&rep=rep1&type=pdf; Molecular Genetics of Acute Intermittent Porphyria in Finland, Mustajoki, 1999
- https://www.porphyriafoundation.comtaped by and posted on APF website landing page; (~3:17:25 on the video timeline); FDA/APF Drug Development Meeting, March 1, 2017
- Lyon Howe, Desiree; “Porphyria, A Lyon’s Share of Trouble,” 2004 Howewrite, Inc. p. 195
- Ibid, 196-197
- Davies, James (former NHS insider), ““Cracked, The Unhappy Truth About Psychiatry,” Pegasus Books, LLC, p. 15.
- https://socialjusticesisters.wordpress.com/2013/02/12/dsm-5-and-somatic-symptom-disorder-dire-consequence-for-rare-disorders/ Petit, Wendi; February 12, 2013; DSM-5 And Somatic Symptom Disorder – Dire Consequences For Rare Disorders
- Lyon Howe, Desiree; “Porphyria, A Lyon’s Share of Trouble,” 2004 Howewrite, Inc. p. 11
- Ibid, 91.
- https://ajp.psychiatryonline.org/doi/abs/10.1176/ajp.112.13.1919?journalCode=ajp; Porphyria—A Deceptive Syndrome
- https://obamawhitehouse.archives.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative; FACT SHEET: President Obama’s Precision Medicine Initiative
- http://www.clinmed.rcpjournal.org/content/12/3/293.long;Acute intermittent porphyria: fatal complications of treatment
- https://www.ncbi.nlm.nih.gov/pub,ed/9066947; Cimetidine in the treatment of acute intermittent porphyria