Finding New Treatments for These Rare, Often Misdiagnosed, Disorders
About 30 years ago, Michael Linenberger, MD, then a junior faculty hematologist, and his colleagues at the Hematology Clinic at the University of Washington Medical Center saw a cluster of patients who were thought to have porphyria, a rare metabolic disorder caused by a genetic defect within the heme biosynthetic pathway. These patients were referred to the University of Washington for a second opinion and treatment.
- Prevalence (U.S.): <200,000 people (all forms of porphyria combined)
- Number of FDA-approved treatments: 3 (hemin for acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria; givosiran for acute hepatic porphyria; afamelanotide for erythropoietic protoporphyria)
- Social media hashtag: #porphyria
- American Porphyria Foundation (org): APF is dedicated to improving the health and well-being of individuals and families affected by porphyria. The organization’s goals are to enhance public awareness about porphyria, develop educational programs, distribute educational materials, and support porphyria research.
Dr. Linenberger, now the Medical Director of the Apheresis and Cellular Therapy at the Seattle Cancer Care Alliance and a professor of hematology at the University of Washington School of Medicine, had seen enough of these patients to realize that most had been initially misdiagnosed. Patients with an accurate diagnosis of porphyria lacked medical resources in their local communities to manage their disease successfully. Over time, the University of Washington clinic became a referral center that offered reliable workup and management for patients with hepatic and erythropoietic porphyrias.
Dr. Linenberger's experience is not unique. Porphyrias are a group of rare and often misdiagnosed disorders – even among hematologists. ASH Clinical News spoke with Dr. Linenberger and other clinical experts who diagnose and treat patients with porphyrias about the disorder subtypes, patient presentation, treatment, and management of this rare group of hematologic disorders.
The Pathogenesis of Porphyrias
The porphyrias have different genetic etiologies, biochemical derangements, and clinical features, but share the commonality of either a genetic or acquired defect in one of the eight enzymes required to form the heme molecule.1 The biosynthetic pathway starts with glycine and succinyl-coenzyme A and results in the production of the heme molecule, requiring eight enzymatic steps and seven intermediate porphyrin precursors of porphyrins or their reduced forms, called porphyrinogens. The enzymes are encoded by nine genes, with two isoforms of ALA synthase, the first enzyme in the pathway, encoded by two genes: ALAS1, which encodes the dominant isoform in the liver, and ALAS2, which encodes the major erythroid-specific version.
A mutation in one of these enzymes is either inherited as an autosomal dominant, autosomal recessive, or X-linked trait. The most common porphyria, porphyria cutanea tarda (PCT), is acquired in about 80% of cases. Because the penetrance of porphyria disorders varies among affected individuals, the clinical manifestation and severity are also influenced by physiological and environmental factors.
The excessive buildup of porphyrin precursors in liver or erythroid cells results in their distribution in systemic circulation and into tissues followed by excretion into the urine and/or bile. Certain subtypes of porphyrias can result in urinary excretion of photoactive porphyrin molecules that generate a red or purple color following exposure to light. Other types of porphyrias – namely PCT, congenital erythropoietic porphyria, and hepatoerythropoietic porphyria – result in freshly passed urine that is already colored. This is where the term porphyria comes from – the Greek word porphyrus means purple.2
How Are Porphyrias Diagnosed?
When porphyria is suspected, the standard approach to the initial diagnosis is a biochemical profile of multiple porphyrins and their precursors, ALA (5-aminolevulinic acid) and PBG (porphobilinogen), in the urine or blood.
To confirm a diagnosis, clinicians then order DNA sequencing of the heme biosynthetic pathway enzyme genes. "The gene analysis to identify a mutation is not only to confirm the diagnosis, but also for family screening purposes," said Dr. Linenberger.
However, he cautioned that a genetic test should only be performed after a positive urine or blood biochemical test. "We have met patients in our clinic who self-referred because they had atypical signs or symptoms and they were led to believe by a report from direct-to-consumer testing that they have a mutation consistent with a porphyria," Dr. Linenberger explained, "but the vast majority of these are misinterpretations and the individual actually has a non-pathological variant." He added that the Porphyrias Consortium of the National Institutes of Health's Rare Diseases Clinical Research Network provides up-to-date, accurate information and resources on genetic testing and a curated database of mutations to distinguish pathogenic from non-pathogenic variants.3
Porphyrias can be grouped into overproduction and accumulation of heme precursors either in the liver or bone marrow erythroid cells. The eight major porphyrias are further grouped into two categories based on their primary symptoms:
- acute porphyrias: acute intermittent porphyria (AIP), hereditary coproporphyria (HC), variegate porphyria (VP), and ALA-dehydratase deficiency (ALAD) porphyria
- cutaneous porphyrias: PCT, hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP)4
Patients with symptomatic acute hepatic porphyrias, which result from an overproduction of porphyrin precursors in hepatocytes, sometimes experience acute abdominal pain as young adults – although most remain asymptomatic.
Skin rashes are the main features of the photocutaneous porphyrias, as the porphyrin intermediate molecules that accumulate in the skin are photoactivated, resulting in painful blisters and sunburn-like rashes. In the case of erythropoietic porphyrias, skin signs and symptoms can present in early childhood and are caused by the overproduction of porphyrin intermediates in red blood cell precursors.
Clinical features can overlap, as patients with two of the acute porphyrias can have cutaneous lesions, and those with erythroid-based porphyrias may develop liver complications.
The hepatic porphyrias result in high levels of ALA, and in most subtypes, high systemic levels of PBG. Acute and symptomatic attacks in patients can be triggered by upregulation of ALAS1 which floods the system with ALA and PBG.5 "These early porphyrin intermediates, ALA and PBG, are toxic to nerve cells and cause abdominal pain because they affect the autonomic nerves in the abdomen and in the gastrointestinal tract, decreasing motility of the gut," Dr. Linenberger explained.
AIP is the most common acute subtype, occurring in about one in 2,000 individuals of Western European descent. The penetrance of symptomatic AIP is low, though, on the order of 1% to 10%.
Typically, acute attacks begin with a few hours or days of progressing symptoms, leading to severe abdominal pain, vomiting, and nausea, as well as weakness, musculoskeletal aches and pains, and dysesthesia. Hyponatremia is sometimes associated with these symptoms.6
About half of patients with symptoms develop kidney disease over time and have a higher risk of developing hepatocellular carcinoma and cholangiocarcinoma.7 Triggers include alcohol, smoking, and certain medications. Women are more likely than men to have earlier onset of attacks, as well as more frequent, cyclical attacks that occur following ovulation, as progesterone is a known trigger.
The less common acute porphyrias cause neurovisceral signs and symptoms similar to those associated with AIP.
EPP is the most common hereditary cutaneous porphyria, occurring in about one to two in 100,000 white children. "Children with this type of porphyria often cry and scream when taken outside because they are experiencing pain from the effect of sunlight on their skin, but the disorder is often attributed to behavioral issues or sun allergy," Herbert Bonkovsky, MD, a gastroenterologist at Wake Forest Baptist Health in North Carolina with special expertise in the diagnosis and treatment of porphyrias, told ASH Clinical News.
Novel Therapies for Porphyrias
For severe, acute attacks in AIP, narcotic analgesics are usually given to treat abdominal pain. Phenothiazines or anxiolytics can be effective to curb nausea, vomiting, anxiety, and restlessness. Intravenous glucose is used for milder acute attacks that do not involve paresis or hyponatremia. Avoidance of specific triggers, such as extreme dieting or certain medications, also can help prevent attacks.
Hemin, an intravenous form of heme, is approved to treat moderate to severe attacks. Its administration inhibits ALAS1 production in hepatocytes. According to Dr. Linenberger, some women with monthly attacks related to their menstrual cycle can be managed with mid-cycle prophylactic hemin infusions.
The treatment has its drawbacks, however. It is administrated only through a central line or large peripheral vein, can cause platelet aggregation and prolongation of the prothrombin time, and frequent use can cause hepatic iron buildup and injury. Reconstituting hemin in 25% albumin can reduce these adverse effects.
The U.S. Food and Drug Administration approved the small interfering RNA (siRNA) therapeutic givosiran in November 2019 for adults with acute hepatic porphyria. Delivered as a subcutaneous injection every 28 days, givosiran decreased the rate of attacks over a six-month period by 70%, compared with placebo, in the ENVISION phase III clinical trial. Adverse reactions that occurred in at least 20% of patients included nausea and injection site reactions. One patient experienced an anaphylactic reaction, hepatic toxicity in the form of transaminase elevation, and renal toxicity.
Givosiran prevents the acute buildup of ALA and PBG by homing to hepatocytes where the siRNA specifically binds the ALAS1 mRNA and decreases ALAS1 translation. The drug is still relatively new, but "it is probably the most impressive drug I’ve seen in terms of changing the life of a patient who has been severely disabled by the disease," said David Rees, MBBS, FRCP, FRCPath, FRCPCH, a hematologist at King's College Hospital in London who specializes in porphyrias. "A patient can go from being basically house- or hospital-bound to leading a relatively normal life."
Dr. Linenberger agreed that the drug effectively and significantly reduces the number of porphyria attacks, visits to the emergency department, and need for hemin infusions. Still, he noted that patients can continue to suffer from chronic sleep problems, pain, constipation, and other long-term complications due to nerve damage.
It also is unclear whether givosiran therapy could reverse some of the chronic manifestations of the disease, particularly in older adults with more severe AIP. Cost is a consideration as well. Givosiran costs an average of $442,000 per year, and clinicians should likely save this therapy for the most severely affected patients.
Afamelanotide, a subcutaneous implant that is worn for one month, was approved by the FDA in October 2019 for adults with EPP who have a history of phototoxic reactions. This melanocortin-1 receptor (MC1-R) agonist increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources – thus enabling pain-free exposure to the sun.
In two randomized, placebo-controlled trials, participants who received afamelanotide reported significantly longer pain-free time outside the house, reduced phototoxic reactions, and improved quality of life compared with those who received placebo.
Who Should Care for Patients With Porphyria?
At some academic centers, hematologists are the go-to clinicians for patients diagnosed with or suspected of having porphyria, given the connection of all porphyrias to hemoglobin.
"Our center has a strong nonmalignant hematology focus with active research in hematopoiesis and erythropoiesis," Dr. Linenberger said. "Our activities as a porphyria clinic are aligned with our clinical and investigative interests. I think if you are a hematologist-oncologist or general hematologist, you should have at least a working knowledge of porphyrias."
"Porphyrias fall under the umbrella of various medical specialties," explained Dr. Rees. "Different clinicians at different institutions care for these patients, including metabolic hepatologists." For Dr. Rees, caring for patients with porphyrias is more a matter of disposition and interest, rather than specialty. "You need to be able to establish good venous access and be familiar with caring for patients who are often in pain and quite ill – that describes many hematologists. But I don’t think the subspecialty matters as much as a specific interest in porphyrias."
The porphyria clinical experts who spoke with ASH Clinical News all outlined several remaining challenges in porphyria. One is the 10% of those with severe acute hepatic porphyria attacks who will likely not respond to givosiran, for whom new therapies are needed.
Another, according to Drs. Bonkovsky and Linenberger, remains the correct and timely diagnosis of the disorders. Direct-to-consumer genetic testing aside, clinicians still misdiagnose patients who have nonspecific or isolated increases in urine porphyrin precursor levels.
"There are pitfalls to properly collecting, assaying, and interpreting blood and urine porphyrin levels," Dr. Linenberger noted. Clinicians must understand that, for patients with symptomatic acute hepatic porphyria, the buildup of the porphyrin precursors in the blood or urine is "not subtle" in the midst of an acute attack. "A mild elevation of less than three times above the upper limit of normal and elevation in only one porphyrin precursor, while other precursor intermediate levels are normal, is not diagnostic of an acute hepatic porphyria disorder."
â€”By Anna Azvolinsky
- Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. 2012;120(23):4496-4504.
- American Porphyria Foundation. About Porphyria. Accessed January 12, 2021, from https://porphyriafoundation.org/for-patients/about-porphyria/.
- Rare Diseases Clinical Research Network. The Porphyrias Consortium. Accessed January 12, 2021, from https://www.rarediseasesnetwork.org/cms/porphyrias/.
- American Porphyria Foundation. Types of Porphyria. Accessed January 12, 2021, from https://porphyriafoundation.org/for-patients/types-of-porphyria/.
- Stolzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019;157(2):365-381.e4.
- Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017;377(9):862-872.
- Pallet N, Karras A, Thervet E, et al. Porphyria and kidney diseases. Clin Kidney J. 2018;11(2):191-197.