An unexpected case of acute intermittent porphyria.

Acute Intermittent Porphyria (AIP) can be a challenging diagnosis to make, due to its rarity in actual practice and presenting symptoms often being attributed to more common conditions. This is particularly the case, since many patients will likely present to acute and general hospitals where the diagnosis may often not be considered. However, it remains pivotal to diagnose the condition as early as possible to prevent significant morbidity and even death. Here we present an unexpected case of AIP, illustrating the diagnostic delay that is commonly seen with the condition and yet emphasise the importance of its detection to commence urgent treatment.

Portuguese Consensus on Acute Porphyrias: Diagnosis, Treatment, Monitoring and Patient Referral.

Acute porphyrias are a group of rare genetic metabolic disorders, caused by a defect in one of the enzymes involved in the heme biosynthesis, which results in an abnormally high accumulation of toxic intermediates. Acute porphyrias are characterized by potentially life-threatening attacks and, for some patients, by chronic manifestations that negatively impact daily functioning and quality of life. Clinical manifestations include a nonspecific set of gastrointestinal, neuropsychiatric, and/or cutaneous symptoms. Effective diagnostic methods are widely available, but due to their clinical heterogeneity and non-specificity, many years often elapse from symptom onset to diagnosis of acute porphyrias, delaying the treatment and increasing morbidity. Therefore, increased awareness of acute porphyrias among healthcare professionals is paramount to reducing disease burden. Treatment of acute porphyrias is centered on eliminating the potential precipitants, symptomatic treatment, and suppressing the hepatic heme pathway, through the administration of hemin or givosiran. Moreover, properly monitoring patients with acute porphyrias and their relatives is fundamental to preventing acute attacks, hospitalization, and long-term complications. Considering this, a multidisciplinary panel elaborated a consensus paper, aiming to provide guidance for an efficient and timely diagnosis of acute porphyrias, and evidence-based recommendations for treating and monitoring patients and their families in Portugal. To this end, all authors exhaustively reviewed and discussed the current scientific evidence on acute porphyrias available in the literature, between November 2022 and May 2023.

Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria.

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.

[Abdominal pain with neuropsychiatric symptoms and ventilatory failure as a presentation of acute porphyria]. / Abdomen agudo con compromiso neuropsiquiátrico y ventilatoria como presentación de porfiria agudac.

Background: Acute intermittent porphyria (AIP) is an uncommon metabolic disease, being the most common of the acute porphyrias. The most frequent symptom is acute abdominal pain, although can be accompanied by seizures, neuro-psychiatric alterations or symmetrical motor neuropathies, which in some patients can progress to respiratory musculature paralysis. Objective: To describe an atypical presentation of acute porphyria to be considered as differential diagnoses in abdominal pain. Clinical case: We present a case of a patient with AIP, presenting acute abdomen, seizures, later developed neuropsychiatric compromise and symmetrical motor neuropathy, and was admitted to mechanical ventilation. Due to the severity of the neurological involvement, he received hemin arginate, presenting with transient hypertransaminemia, an adverse event not previously reported. The evolution was favorable, with mechanical ventilation and hospital discharge withdrawn. Conclusions: The diagnosis of AIP should be considered in cases of acute abdominal pain associated with neurological and/or psychiatric symptoms, particularly young women. The administration of hemin is considered the standard of treatment, and even late could have beneficial effects.

Introducción: la porfiria aguda intermitente (PAI) es una enfermedad metabólica infrecuente, siendo la más común de las porfirias agudas. El síntoma más frecuente es el dolor abdominal agudo, aunque también pueden acompañarse de convulsiones, alteraciones neuro-psiquiátricas o neuropatías motoras simétricas, y que en algunos pacientes puede progresar a la parálisis de la musculatura respiratoria. El objetivo de este trabajo es describir una forma atípica de presentación de una porfiria aguda, a fin de considerar como diagnósticos diferenciales en dolor abdominal. Caso clínico: paciente con PAI, que presenta abdomen agudo, convulsiones, posteriormente compromiso neuro-psiquiátrico y neuropatía motora simétrica, ingresando a ventilación mecánica. Por la gravedad del compromiso neurológico recibió arginato de hemina, cursando con hipertransaminemia transitoria, evento adverso no reportado previamente. La evolución fue favorable, retirándosele la ventilación mecánica y el alta hospitalaria. Conclusiones: se debe considerar el diagnóstico de PAI en casos de dolor abdominal agudo asociado a síntomas neurológicos y/o psiquiátricos, particularmente en mujeres jóvenes. La administración de hemina es considerada el estándar de tratamiento, y aun en forma tardía podría tener efectos beneficiosos.

Key terms and definitions in acute porphyrias: Results of an international Delphi consensus led by the European porphyria network.

Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by two Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. A total of 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of nine terms and definitions. A total of 34 experts were invited to take part in the Delphi rounds. Seven of the initial nine terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all nine definitions achieved agreement. Agreement on the definitions for nine important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence-based clinical guidelines.

[Acute hepatic porphyrias]. / Akute hepatische Porphyrien.

Acute porphyrias are caused by rare hereditary disorders of hepatic heme biosynthesis. Episodes of accumulating neurotoxic metabolites lead to multisystemic symptoms such as visceral pain, autonomic dysregulation, neurocognitive impairment, hyponatremia, and occasionally motor paralysis. In addition to protracted non-emergency courses, acute life-threatening crises can occur, often triggered by infection, medication, fasting, or hormonal stimuli. Since the clinical presentation is nonspecific and multifaceted, many patients have gone through a long odyssey until they receive a diagnosis. Acute attacks often lead to presenting initially to the emergency department, where acute hepatic porphyria (AHP) is easily overlooked in the differential diagnosis. Establishing the diagnosis requires a high level of genuine suspicion (e.g., cluster of signs and symptoms along with certain patterns of health care resource utilization). The initial diagnostic work-up requires the measurement of metabolites in the urine. Emergency management consists of infusions of glucose and heme arginate along with symptomatic therapy. However, porphyrinogenic agents must be strictly avoided ( www.drugs-porphyria.org ). After initial diagnosis, a thorough work-up should be done at a porphyria center (confirming the diagnosis, education, genetic counselling) and issuance of an emergency identification card is mandatory. If the frequency of relapses is high, new targeted prophylactic therapies have proven effective. Patients with known porphyria require special attention in any acute medical condition in order to avoid porphyrinogenic triggers and to exclude threatening differential diagnosis (e.g., sepsis) by consistent basic diagnostics.

Porphyria: a case report.

BACKGROUND: Prompt diagnosis of metabolic disorders in a resource-limited country like Nepal is daunting. Acute intermittent porphyria is a rare but common hepatic porphyria mostly seen in females of the reproductive age group. As its incidence is quite uncommon, conjectures about porphyria diagnosis are often duped into a diagnostic conundrum. CASE PRESENTATION: Here we unravel a case of a 15-year-old Hindu Nepalese girl distraught by the myriad of symptoms in the setting of severe abdominal pain accompanied by constipation and limb pain as the chief complaints. She presented with acute severe hypertension with marked persistent hyponatremia (up to 109 mEq/L). Despite conservative management of hypertension and electrolytes, unresolved electrolyte imbalance led us to the speculation of disturbance in the renin-angiotensin-aldosterone system. Due to her exacerbating neurovisceral status, she also required intensive care during the disease course. After thorough investigations and exemption of presumed provisional diagnoses, based on sustained symptomatic presentation, the clinical suspicion was driven towards a diagnosis of porphyria-related disorders. Positive Watson-Schwartz test substantiated the diagnosis of acute intermittent porphyria. Her symptoms gradually abated after the consumption of high carbohydrate diets. CONCLUSION: This case highlights the baffling amalgamation of symptoms that simulate common diseases of concern yet are buried in the realm of porphyric disorders. Porphyria can be diagnosed using simple screening tools and timely treatment can diminish serious consequences.

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives.

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, [Formula: see text]-aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

[Anesthesia in patients with acute porphyria]. / Anästhesie bei Patienten mit akuter Porphyrie.

Porphyrias are a group of rare, mostly inherited metabolic disorders of heme biosynthesis. Each type of porphyria results from a specific deficiency of one of the pathway enzymes, causing a characteristic accumulation and excretion of heme precursors. Diagnosis is confirmed by the biochemical detection of these porphyrins and the precursors in urine, feces and blood. Porphyrias can be classified into acute and non-acute forms. The clinical presentation is unspecific and includes acute neurovisceral and/or cutaneous symptoms. The latent phase can evolve into a potentially life-threatening acute crisis, which is often misdiagnosed. The four acute hepatic porphyrias are relevant for anesthesiologists as precipitating factors are commonly found in the perioperative setting. Safe anesthetic management in cases of known porphyria is possible by adherence to current recommendations. The immediate administration of heme arginate as specific treatment for acute attacks is decisive for the outcome.

RNAi therapy with givosiran significantly reduces attack rates in acute intermittent porphyria.

Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life. Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed small interfering RNA targeting ALAS1. The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during acute porphyria attacks. Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.

Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria.

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.

Porphyria: awareness is the key to diagnosis!

Porphyrias are disorders of the haem biosynthesis which are encountered infrequently and which often present themselves atypically as a combination of gastrointestinal, neurologic and/or dermatologic symptoms. Although they are primarily caused by enzyme defects, inheritance patterns are mostly not evident. Considering all of these characteristics, it is not surprising that there is a long delay between the onset of symptoms and the diagnosis of the disease, with as possible consequences impaired quality of life, irreversible neurologic damage and even death. This review aims to increase the clinical suspicion of the three most common porphyrias in adults: acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT) and protoporphyria. Their relevant pathophysiology, clinical manifestations, diagnosis and treatment are discussed aiming at increasing the awareness of these diseases among physicians.

Peritoneal dialysis resulting in discontinuance of recurring attacks of acute intermittent porphyria: A case report.

Acute intermittent porphyria is one of eight disorders arising from disturbances in heme biosynthesis where the precursors, 5-aminolevulinate and porphobilinogen, are elevated in plasma and urine. Attacks are characterized by severe abdominal pain, vomiting and/or obstipation, neurological manifestations, and psychological disturbances. The mainstay of treatment is hemin infusion to induce the negative feedback of heme synthesis. Hemodialysis is casuistically suggested as an alternative treatment. We present a case report of a 78-year-old male with acute intermittent porphyria and renal failure treated with peritoneal dialysis resulting in complete discontinuance of longstanding painful and disabling porphyria attacks.

Neurology of the acute hepatic porphyrias.

Porphyrias are a set of rare inherited metabolic disorders, each of them representing a defect in one of the eight enzymes in the haem biosynthetic pathway resulting in the accumulation of organic compounds called porphyrins. Acute hepatic porphyrias (AHP) are those in which the enzyme deficiency occurs in the liver, of which acute intermittent porphyria is by far the most common subtype. Neurology of the AHP is still challenging in practice, and patients rarely receive the correct diagnosis early in the disease course. For AHP, which primarily affects the central and peripheral nervous system, the cause of symptoms seems to be the increased production of neurotoxic precursors, in particular delta-aminolaevulinic acid and porphobilinogen. Neurological complications usually result from severe episodes of acute attacks. The neurologic hallmark of porphyrias is an acute predominantly motor axonal neuropathy resembling a Guillain-Barré syndrome that generally occurs after the onset of other clinical features such as abdominal pain and central nervous system manifestations. Neuropsychiatric syndromes, seizures, encephalopathy, and cerebrovascular disorders are among the possible central nervous system presentations. Therapeutic approach to AHP is divided into management and prophylaxis of an acute attack, including long standing options such as intravenous hematin and new therapeutic agents such as givosiran.

Acute hepatic porphyrias for the neurologist: current concepts and perspectives.

BACKGROUND: Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. OBJECTIVE: We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. METHODS: The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. RESULTS: Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. CONCLUSIONS: This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators.

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, and, in the long-term setting, the development of primary liver cancer, hypertension and kidney failure. Treatment options are few, and therapies preventing the development of symptomatic disease and long-term complications are non-existent. Here, we provide an overview of the disorder and treatments already in use in clinical practice, in addition to other therapies under development or in the pipeline. We also introduce the pathomechanistic effects of HMBS mutations, and present and discuss emerging therapeutic options based on HMBS stabilisation and the regulation of proteostasis. These are novel mechanistic therapeutic approaches with the potential of prophylactic correction of the disease by totally or partially recovering the enzyme functionality. The present scenario appears promising for upcoming patient-tailored interventions in AIP.

Acute hepatic porphyrias for the neurologist: current concepts and perspectives / Porfirias hepáticas agudas para o neurologista: conceitos atuais e perspectivas

ABSTRACT Background: Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. Objective: We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. Methods: The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. Results: Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. Conclusions: This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

RESUMO Introdução: As porfirias hepáticas agudas representam um grupo de doenças metabólicas hereditárias complexas em expansão, decorrentes de erros inatos do metabolismo, envolvendo a via de biossíntese do grupamento heme. Objetivo: realizar revisão dos principais aspectos clínicos e terapêuticos associados com as porfirias hepáticas agudas. Métodos: Os autores realizaram ampla revisão não-sistemática sobre conceitos atuais e conhecimentos recentemente adquiridos. Resultados: Ataques neuroviscerais agudos representam a apresentação clínica mais comum e de maior risco, e são comumente considerados como principal manifestação na prática clínica durante o diagnóstico diferencial e início apropriado da investigação diagnóstica para porfirias agudas. Entretanto, apresentações atípicas com envolvimento do sistema nervoso central, alterações neuropsiquiátricas e alguns subtipos com fotossensibilidade fazem com que o diagnóstico definitivo seja comumente difícil e tardio. As intervenções terapêuticas precoces são essenciais durante o tratamento emergencial e em período intercrítico evitando formas recorrentes graves. A disponibilidade de novas propostas terapêuticas modificadoras de doença baseadas em terapias com pequenas moléculas de RNA de interferência (siRNA) complementares aos clássicos tratamentos com infusão de glicose intravenosa e à base de hemina enfatiza a importância do diagnóstico precoce de tais pacientes e do aconselhamento genético. Conclusões: Este artigo de revisão destaca os principais aspectos bioquímicos, fisiopatológicos, clínicos e terapêuticos das porfirias hepáticas agudas na prática clínica.

Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP.

The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.