Acute Porphyria Research Articles

Givosiran for the treatment of acute hepatic porphyria

Introduction Acute hepatic porphyrias (AHPs) are a family of rare inherited disorders characterized by enzyme dysfunctions in the hepatic pathway of heme biosynthesis. In AHPs, accumulation of the neurotoxic porphyrin precursors delta-aminolevulinic acid and porphobilinogen, caused by enhanced activity of hepatic aminolevulinate synthase 1 (ALAS1), is associated with acute, potentially life-threatening neurovisceral attacks. Symptoms during and between attacks dramatically reduce patients’ quality of life (QoL). Givosiran is the first mRNA-targeted treatment for AHPs, silencing ALAS1 expression. Areas covered For givosiran, this review summarizes its chemistry, mechanism of action, pharmacokinetics, pharmacodynamics, safety, preclinical and clinical data in AHP, postmarketing surveillance, and regulatory status. A literature search of public and internal databases was performed, bibliographies of retrieved articles were manually searched to identify additional studies of relevance, and information was also provided by Alnylam Pharmaceuticals. Expert opinion Givosiran is a small interfering RNA (siRNA) therapeutic that reduces hepatic activity of ALAS1 and decreases accumulation of neurotoxic porphyrin precursors in patients with AHPs, ultimately reducing the number of acute attacks and improving symptoms and QoL between attacks. As AHPs are lifelong diseases, long-term safety data are needed for givosiran as an siRNA-based therapy.

Anesthesia in patients with acute porphyria

Porphyrias are agroup of rare, mostly inherited metabolic disorders of heme biosynthesis. Each type of porphyria results from aspecific deficiency of one of the pathway enzymes, causing acharacteristic 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 apotentially 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.

Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals.

BackgroundThe acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register‐based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex.MethodsAll patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987‒2015 were included. This AHP cohort was compared with age‐, sex‐, and county‐matched reference individuals from the general population. National register‐based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U‐PBG). Incident PLC data were collected from national health registers.ResultsWe identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow‐up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP‐PLC was 38.0 (95% confidence interval: 24.3‒59.3). Previously elevated U‐PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U‐PBG (n = 157) had an annual PLC incidence of 1.8%.ConclusionThis study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.

Hypertensive Crisis in Patients with Acute Intermittent Porphyria

Abstract Introduction: Acute intermittent porphyria (AIP) is the most common and the most severe form of acute hepatic porphyria. Case report: Patient, 39 years old, was admitted to the Emergency Department because of abdominal pain. Abdominal pain started 5 days before the admission. The diagnostic research in his hospital showed presence of a stone in the right kidney, and the patient was transported to the other Clinical Centre, where a common urine test showed: high values of delta - aminolevulinic acid and porphobilinogen. The patient was transported to our Clinical Centre. At the admission, abdominal pain decreased, but the patient had a hypertensive crisis with a headache, tearing eyes, swelling, anxiety.Common laboratory tests were in reference range, except creatinine, CRP, arterial blood gas analysis, urine test. The hypertensive crisis was treated by beta blockers and diuretics in maximal doses, but without a positive effect, so we decided to try with Glyceryl trinitrate intravenously. Control blood pressure was 170/100mmHg….130/80mmHg. Discussion: Porphyria can be a diagnostic problem, because one of the manifestations can be abdominal pain. Conclusions: Comorbidities can be critical in the therapy of life threating conditions.

Les traitements par ARN interférents et par oligonucléotides antisens actuellement disponibles en France : une mise au point

L’arrivée des vaccins anti Covid-19 à ARN en 2020 ne doit pas occulter le fait que nous disposons déjà depuis plusieurs années de traitements à base d’ARN interférents ou d’oligonucléotides antisens dans un certain nombre de maladies rares de pronostic très sombre telles que l’amylose à transthyrétine, la porphyrie hépatique aiguë, l’hyperoxalurie primitive, l’amyotrophie spinale ou l’hyperchylomicronémie familiale. Si leurs performances, à l’inverse de celles des vaccins, ne sont pour l’instant qualifiées que de progrès thérapeutiques modérés dans les stratégies thérapeutiques opposées à ces maladies, il y a lieu de tenir compte du fait que leur évaluation initiale a été pénalisée par un certain nombre de facteurs défavorables : des essais de petits effectifs, des modalités thérapeutiques à affiner, le manque de recul, sur leurs effets à long terme mais surtout le choix du moment de l’instauration du traitement dans l’évolution naturelle de la maladie. Ce choix n’est pas anodin car l’on imagine mal que les produits utilisés puissent, au-delà d’une simple stabilisation de la maladie installée, permettre sa régression dès lors que certaines lésions constituées sont irréversibles. C’est pourquoi leur mise en œuvre très précoce, éventuellement fondée sur un dépistage génétique, est une piste à saisir dans l’intérêt des patients. Mais, dans le contexte concurrentiel des innovations dans le domaine, ARN interférents et oligonucléotides antisens devront compter avec les thérapies géniques et l’édition du génome par la technique CRISPR-Cas 9.

Long-term follow-up of acute porphyria in female patients: Update of clinical outcome and life expectancy

BackgroundAcute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include acute attacks, occurring mainly among female patients. This study describes the diversity of acute symptoms, changes in triggering factors and life expectancy among female patients during the past five decades. Methods107 Finnish female patients were enrolled into a retrospective, longitudinal study during 2015. Clinical, biochemical and genetic data was obtained from the medical reports, registry data and a questionnaire designed for the study. Causes of death were studied in additional 32 female patients. ResultsOf the 43 patients with hospitalization, 33% had non-complicated, 35% prolonged and 28% severe attacks with no correlation with the disease-causing mutation. Of the deceased patients, 31% died of an acute attack during 1957–1979. Thereafter the incidence and severity of acute attacks have decreased substantially. 55% of the subjects reported acute symptoms (dysautonomia and mental symptoms) without hospitalization, 29% had porphyria symptoms >10 times, and 23% within the last year. Despite 22% of the female patients had died of primary liver cancer, the life expectancy increased more than 10 years during the follow-up, and did not differ from the normal population at present. ConclusionsThe incidence of acute attacks requiring hospitalization has decreased, but more than half of the female patients reported acute symptoms affecting their well-being. Symptoms are currently triggered by hormonal changes and weight loss emphasizing the importance of early recognition and active management to avoid disease exacerbation. Death due to primary liver cancer is common and should be screened regularly.

Acute intermittent porphyria in adults: a clinical case

Background. Porphyria unites genetic pathologies related to abnormal haem (an intermediate product of haemoglobin metabolism) synthesis and its toxic products accumulation in human body. Symptoms can vary, from photosensitivity, skin rashes and chronic abdominal pain towards partial or complete paralysis and acute psychosis. This metabolic disorder is diagnosed with molecular genetic and laboratory biosample tests. Drug therapy aims at reducing toxic metabolites concentration in patient’s blood.Clinical Case Description. A 28-yo female patient had an acute atypical porphyria attack with a later onset of neurovisceral manifestations (acute abdominal pain, tachycardia) progressing post-drug-treatment into acute sensorimotor polyneuropathy with flaccid, predominantly proximal, hands-prevalent tetraparaesis. Biochemical urine tests at the National Research Center for Hematology (by 30.06.2020) revealed porphobilinogen 55.3 mg/L at norm <3. Vital indications required an urgent haem arginate pathogenetic therapy (Normosang) in a 4-day course of 3 mg/kg/day drop infusion. The recommended course was well tolerated. Drug therapy and rehabilitation entailed a positive dynamics of restoring limb muscle strength towards an almost easy getting-up from chair and bed, and skin lightening. The patient was discharged on day 20 with diagnosis: “Acute intermittent porphyria. Axonal-demyelinating sensorimotor polyneuropathy. Severe flaccid asymmetric predominantly proximal hands-prevalent tetraparaesis. Subacute course, stabilisation phase. Condition after one course of haem arginate pathogenetic therapy (Normosang) at 3 mg/kg/day”. A resident haematologist surveillance was recommended, with a routine referral for inpatient examination and treatment at the Department of Orphan Diseases of the National Research Center for Hematology, Ministry of Health of Russia.Conclusion. Porphyria is relatively rarely diagnosed, about 12 cases per 100,000 people. The symptoms variety and nonspecificity conduce to a low detection rate, and untimely diagnoses can entail severe clinical manifestations, including lethal outcomes.

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.

Acute hepatic porphyria attack following mini gastric bypass surgery

Acute Intermittent Porphyria, (AIP) is a rare disease caused by Hydroxymethylbilane Synthase (HMBS) deficiency. It is characterized by acute neurovisceral attacks, in which excessive heme production is induced following exposure to a trigger. One of the suggested triggers is low carbohydrate intake. We report a 32-year-old female who suffered from severe abdominal pain, nausea and general weakness following a bariatric mini gastric bypass surgery. There was a positive family history of AIP, but the patient had a normal Porphobilinogen urine test as a child, therefore diagnosis was not made. During current symptoms, urinary porphobilinogen was highly increased and AIP was diagnosed. Treatment with IV dextrose and Heme Arginate alleviated the patient’s symptoms. After discharge, Family genetic testing revealed a novel pathogenic mutation in the HMBS gene. Had genetic testing been performed earlier, diagnosis of AIP could have been established earlier. Early diagnosis may prevent attacks and reduce their severity. Since a bariatric surgery leads to low intake of carbohydrates, it might be an indirect trigger of an acute porphyria attack. Keywords: porphyria; bariatric surgery; porphobilinogen.

Prophylactic heme arginate therapy in acute intermittent hepatic porphyria: A case report

Introduction. Among the acute hepatic porphyrias, a small percentage of patients, predominantly female, present with recurrent cyclic attacks of acute intermittent porphyria that occur more than three times a year and sometimes at intervals of less than a month. In women, the attacks are typically related to the menstrual cycle, requiring several days of hospitalization and administration of heme arginate. For these patients, prophylactic heme arginate therapy may be the optimal treatment modality. Case report. We presented a 40-year-old female patient who has been suffering from porphyria for seventeen years. The first attack occurred in 2003, presenting with severe neurological symptoms, requiring the use of heme arginate (Normosang?, Orphan Europe), which resulted in a favorable therapeutic response. In 2004 and 2007, gonadorelin analogue goserelin (Zoladex?) was used, but without beneficial effects on the course of the disease. In 2008, a preventive administration of heme arginate was initiated. The patient received heme arginate in the early phase of symptoms, every month in the premenstrual phase of the cycle, which resulted in milder symptoms, full recovery within 24 hours, lower doses of Normosang? (1-2 ampoules), and fewer hospital days (1-2 days) per month. This regimen has significantly improved the patient's quality of life and reduced the risk of potential ad-verse effects. Conclusion. Preventive use of Normosang? is the optimal therapeutic modality in patients with frequent, recurrent severe attacks that are unresponsive to other therapeutic regimens. As a result, patients have a better quality of life due to an effective, short-term, targeted treatment regimen.

Inside Front Cover

The cover image is based on the Original Article Efficacy and safety of givosiran for acute hepatic porphyria: 24-month interim analysis of the randomized phase 3 ENVISION study by Paolo Ventura et al., https://doi.org/10.1111/liv.15090.

Verrüköz Karsinom ile Görülen Geç Teşhis Edilen Variegate Porfiri

Variegate porphyria (VP) is an autosomal dominant porphyria characterized by both cutaneous and neurovisceral symptoms. In this case we discuss a 65-year-old female patient with bullous lesions on hands, lethargy, increased facial hair and darkened facial skin. A form of acute porphyria, VP is caused by mutations in PPOX, a gene that carries instructions for making an enzyme called protoporphyrinogen oxidase. Here, we report a heterozygous mutation of the PPOX gene in a Turkish female VP patient who has been diagnosed with chronic renal failure secondary to porphyria. Porphyria is one of those disease needed to be kept in mind as differential diagnosis. Late diagnosis of this disease would lead to different chronic organ failures as a result of heme accumulation in different tissues and organs. This case, it is a clear reminder for the health care workers to remember the ''Primum non no nonocere'' rule and also remembering porphyria as a differential diagnosis in longterm attacks and symptoms.

Vincent Van Gogh and the elusive diagnosis of vestibular migraine

Vincent Van Gogh (1853–1890) was a creative genius and one of the greatest painters in history. He was a troubled soul plagued with an inner turmoil driven by his social, financial, personality and medical/psychiatric afflictions. His life has fascinated academic scholars of many disciplines who have researched extensively on his life and works. From his voluminous correspondences and contemporary medical records, his medical/psychiatric illnesses have been analysed in detail and several diagnostic formulations proposed. These include temporal lobe epilepsy, intermittent acute porphyria, Meniere’s disease, lead poisoning, sexually transmitted diseases, terpene/absinthe/alcohol abuse, ophthalmological disorders in addition to chronic bipolar disorder, schizophrenia, personality and anxiety disorder and narcissism/neuroticism. We hypothesized a new diagnosis in the form of vestibular migraine for Van Gogh which is a migraine variant but distinct from the classical migraine variety. Our hypothesis is unique as it also considers that this condition due to its recognised associations with Van Gogh’s proposed illnesses could have influenced his other conditions and thus offers a common unifying factor to explain his illness symptoms. We tested our hypothesis by individually analysing all of Van Gogh’s correspondences in the original French and Dutch as well as English translations. Further, we considered the existing literature on Van Gogh’s other illnesses and contemporary medical records. Van Gogh fulfilled all the criteria for vestibular migraine as formulated by Barany Society and International Classification of Headache Disorders (ICHD) 3 with episodic dizziness, present or past history of classical migraine, headache, photophobia, phonophobia and visual and position triggered vertigo with no other otologial cause to explain his symptoms (including Meniere’s disease). Furthermore, it appears that vestibular migraine could have interacted with most of his other proposed illnesses. We also observed that this condition influenced his art following onset for example, in his use of colours and depiction of his subject matter with a consistent vertical tilt on the left. It is anticipated that our hypothesis will add a new dimension to the understanding of his illnesses and increase the awareness of the complex condition of vestibular migraine that to this day has limited awareness amongst the medical and general fraternity.

Acute hepatic porphyria: when to perform liver transplantation?

Acute hepatic porphyrias (AHPs) are inborn errors of hemebiosynthesis and its most common and severe type is the acute intermittent porphyria (AIP). AIP is an hereditary autosomal dominant disease caused by accumulated porphobilinogen deaminase (PBG) and delta aminolevulin acid (ALA) products. The main symptoms are severe abdominal pain, neuromuscular and psychiatric disturbances, nausea, vomiting, encephalopathy, tachycardia, seizures, tremors and hypertension, that usually are manifested by acute crises. The treatment is based on clinical management and in cases which the patient’s quality of life is affected liver transplantation (LT) may be an alternative choice. We report the case of a patient with AHP presenting recurrent crisis leading to chronic symptoms occurrence and poor quality of life with progressive unresponsiveness to hemin treatment. Patient was submitted to LT as curative therapy proposal, but patient still presents some clinical manifestations that may indicate the possibility of a secondary cause to explain persistence of her symptoms despite of biochemical normalization of ALA and PBG.

Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications.

Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias.

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias.

Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs.

Givosiran (Givlaari)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses givosiran (Givlaari), 189 mg/mL, solution for subcutaneous injection.
 Indication: For the treatment of acute hepatic porphyria in adults.

ABCB6 polymorphisms are not overly represented in patients with porphyria

AbstractThe Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

Acute porphyrias - A neurological perspective.

Acute hepatic porphyrias (AHP) can cause severe neurological symptoms involving the central, autonomic, and peripheral nervous system. Due to their relative rarity and their chameleon‐like presentation, delayed diagnosis and misdiagnosis are common. AHPs are genetically inherited disorders that result from heme biosynthesis enzyme deficiencies and comprise four forms: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA‐dehydratase porphyria (ALADP). Depending on the clinical presentation, the main differential diagnoses are Guillain‐Barré syndrome and autoimmune encephalitis. Red flags that could raise the suspicion of acute porphyria are neurological symptoms starting after severe (abdominal) pain, in association with reddish urine, hyponatremia or photodermatitis, and the presence of encephalopathy and/or axonal neuropathy. We highlight the diagnostic difficulties by presenting three cases from our neurological intensive care unit and give a comprehensive overview about the diagnostic findings in imaging, electrophysiology, and neuropathology.

A novel mutation of porphyria variegate with predominant painful sensorimotor peripheral neuropathy disclosed by post gastric by-pass complications: A case report

Porphyrias are a group of rare genetic diseases due to various mostly autosomal dominant mutations causing enzymatic deficiency in heme biosynthesis. As a result, neuro-toxic porphyrin precursors and light-sensitizing porphyrins accumulate, while their targets determine the disease symptoms. Porphyria variegate (VP), one of the acute hepatic porphyrias, is caused by a PPOX mutation. During acute crisis triggered by drugs, stressors or fasting, an increase of porphobilinogen (PBG), aminolaevulinic acid (ALA) and porphyrins in urine and stool occur, damaging the autonomous, peripheral and central nervous system.