Acute hepatic porphyrias for the neurologist: current concepts and perspectives

Porfirias hepáticas agudas para o neurologista: conceitos atuais e perspectivas

Paulo Victor Sgobbi de Souza Bruno de Mattos Lombardi Badia Igor Braga Farias Eduardo Augusto Gonçalves Wladimir Bocca Vieira de Rezende Pinto Acary Souza Bulle Oliveira About the authors

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.

Keywords:
Neuromuscular Diseases; Porphyria; Inborn Errors of Metabolism; Acute Intermittent Porphyria; Hepatic Porphyrias

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.

Palavras-chave:
Doenças Neuromusculares; Porfirias; Erros Inatos do Metabolismo; Porfiria Aguda Intermitente; Porfirias Hepáticas

INTRODUCTION

Porphyrias (from the Greek Porphyrus, purple) are rare inherited metabolic disorders of the heme biosynthesis pathway, leading to the pathogenic accumulation of heme precursors (i.e., porphobilinogen and delta-aminolevulinic acid) and porphyrins. Skin and peripheral nervous system involvement arise from the toxic effects of such precursors. Porphyrias are divided according to two main categories: (i) the site of main overproduction of porphyrin precursors, including hepatic and erythropoietic porphyrias; and (ii) type of clinical presentation, including acute and chronic porphyrias11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
.

Acute hepatic porphyrias (AHPs) represent a complex group of inborn errors of metabolism that cause acute episodic neurovisceral attacks and include four life-threatening disorders — acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and delta- or 5-aminolevulinic acid (ALA) dehydratase deficiency (or Doss porphyria) (ALADP)11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,55. Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 2018 Dec;3(2):193-206. https://doi.org/10.1002/hep4.1297
https://doi.org/10.1002/hep4.1297...
,66. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-22. https://doi.org/10.1002/hep.29313
https://doi.org/10.1002/hep.29313...
.

AHPs have a global and pan-ethnic distribution and affect all age groups, with higher prevalence rates among young women. AIP represents the most common form of AHP, with an estimated prevalence of 5 cases per 100,000 inhabitants in the United States (US). VP is the second (up to 1:30,000 inhabitants) and HCP the third (2:1,000,000 inhabitants in Denmark) most common form AHP. Higher prevalence rates of VP have been identified in the Afrikaner population of Dutch descent in South Africa and Finland and associated with a founder effect. ALADP is an extremely rare presentation, with little more than a dozen cases identified11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,55. Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 2018 Dec;3(2):193-206. https://doi.org/10.1002/hep4.1297
https://doi.org/10.1002/hep4.1297...
,66. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-22. https://doi.org/10.1002/hep.29313
https://doi.org/10.1002/hep.29313...
. In Brazil, epidemiological data result from information published by the Brazilian Porphyria Association (Associação Brasileira de Porfíria — ABRAPO) and reveal a similar prevalence of AHPs, except for the low occurrence of VP in the country77. Dorr AM, Picharski GL, Osternack BR. Porphyria: analysis of register from Brazilian association of porphyria (ABRAPO). Hematol Transfus Int J. 2016 Oct;2(6):112-4. https://doi.org/10.15406/htij.2016.02.00052
https://doi.org/10.15406/htij.2016.02.00...
.

Furthermore, AHPs are associated with medical and financial burden in Europe and the US due to recurrent and extended hospitalizations, chronic and severe clinical comorbidities, and the high costs of disease-modifying therapies and medical health related to chronic complications88. Neeleman RA, Wagenmakers MA, Koole-Lesuis RH, Mijnhout GS, Wilson JHP, Friesema EC, et al. Medical and financial burden of acute intermittent porphyria. J Inherit Metab Dis. 2018 Sep;41(5):809-17. https://doi.org/10.1007/s10545-018-0178-z
https://doi.org/10.1007/s10545-018-0178-...
. Currently, the study of acute porphyria is crucial for the early diagnosis of debilitating disorders, proper distribution of financial resources in the health care system, and the early availability of new genetic therapies for the treatment of AHPs.

BIOCHEMISTRY AND PATHOPHYSIOLOGY

AHPs result from the deficiency of enzymes involved in the heme biosynthesis pathway, leading to the pathological accumulation of porphyrins and their intermediates. Heme is a key cofactor related to several homeostatic proteins, such as hemoglobin, myoglobin, hepatic cytochrome P450, mitochondrial respiratory chain cytochromes, microsomal cytochrome b5, and some catalases and peroxidases. Its biosynthesis results from a multistep pathway involving eight enzymes and two cell compartments in mitochondrion and cytoplasm (Figure 1). Heme synthesis pathway occurs both in bone marrow erythroblasts (80% of total heme) and hepatocytes (20% of total heme). The rate-limiting step is represented by ALA synthase 1 (ALAS1) in the liver and ALAS2 in the erythrocyte. There is also a dependence on individual genetic factors of high susceptibility related to polymorphisms in genes associated with cytochrome P45022. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
https://doi.org/10.1016/j.ymgme.2019.03....
,1010. Barreda-Sánchez M, Buendía-Martínez J, Glover-López G, Carazo-Díaz C, Ballesta-Martínez MJ, López-González V, et al. High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor. Orphanet J Rare Dis. 2019 Feb;14(1):59. https://doi.org/10.1186/s13023-019-1031-7
https://doi.org/10.1186/s13023-019-1031-...
,1111. Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2019 Nov;128(3):320-31. https://doi.org/10.1016/j.ymgme.2018.11.012
https://doi.org/10.1016/j.ymgme.2018.11....
.

Figure 1
Metabolic heme biosynthesis pathways and pathogenesis of acute hepatic porphyrias. delta-aminolevulinic acid and porphobilinogen are involved in the most important neurotoxic effects of acute hepatic porphyrias. Precipitating and susceptibility factors are also represented and modulate the synthesis, function, or amount of delta-aminolevulinic acid synthase 1 expressed in the liver. Porphyrins and their intermediate metabolites are also represented and indicate the main excretion routes in each case (feces, urine).

Several pathophysiological mechanisms connected to porphobilinogen (PBG), ALA, and heme depletion in different tissues have been associated with AHPs, including complex mechanisms: (i) dysfunction of gamma-aminobutyric acid (GABA) and benzodiazepine receptors mediated by ALA; (ii) abnormal neurotransmitter and aminoacid metabolism due to ALA and PBG effects: tryptophan, glycine, acetylcholine, noradrenaline; (iii) low degree of systemic and neuronal mitochondrial oxidative capacity due to dysfunction of respiratory chain complexes; (iv) liver and neuronal dysfunction of mitochondrial cytochrome P450 related to abnormal intermediate metabolites and susceptibility gene polymorphisms; (v) persistent and prolonged ALA levels associated with chronic neurovisceral symptoms due to oxidative stress; (vi) during acute neurovisceral attacks, there is high hepatic oxidative activity of ALAS1 with secondary depletion of pyridoxal-phosphate and, thus, secondary axonal neuropathy; (vii) neurotoxic effects to axonal membrane with dysfunction of Na-K ATPase pump; (viii) protein oxidation and aggregation induced by porphyrins; (ix) nitric oxide synthase dysfunction leading to cerebral and intestinal vasospasm and abdominal pain22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
https://doi.org/10.1016/j.ymgme.2019.03....
,1111. Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2019 Nov;128(3):320-31. https://doi.org/10.1016/j.ymgme.2018.11.012
https://doi.org/10.1016/j.ymgme.2018.11....
,1212. Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015 Mar;128(3):313-7. https://doi.org/10.1016/j.amjmed.2014.10.026
https://doi.org/10.1016/j.amjmed.2014.10...
,1313. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011 Dec;122(12):2336-44. https://doi.org/10.1016/j.clinph.2011.07.036
https://doi.org/10.1016/j.clinph.2011.07...
,1414. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-77. https://doi.org/10.1016/j.ymgme.2019.04.008
https://doi.org/10.1016/j.ymgme.2019.04....
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,1616. Maitra D, Bragazzi Cunha J, Elenbaas JS, Bonkovsky HL, Shavit JA, Omary MB. Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury. Cell Cell Mol Gastroenterol Hepatol. 2019 Jan;8(4):535-48. https://doi.org/10.1016/j.jcmgh.2019.06.006
https://doi.org/10.1016/j.jcmgh.2019.06....
,1717. Kakoullis L, Louppides S, Papachristodoulou E, Panos G. Porphyrias and photosensitivity: pathophysiology for the clinician. Postgrad Med. 2018 Nov;130(8):673-86. https://doi.org/10.1080/00325481.2018.1533380
https://doi.org/10.1080/00325481.2018.15...
.

CLINICAL FEATURES OF ACUTE HEPATIC PORPHYRIAS

AHPs are often misdiagnosed, and diagnostic delays of up to 15 years are sometimes observed, especially in atypical presentations and early or late-onset cases. Natural history studies have been performed, notably the EXPLORE study (NCT02240784). In this study, within a group of 112 AHP patients, 89% were female, 85% were Caucasian, the mean age at diagnosis was 39 years, and all cases emerged after puberty. Among the participants, 93% had AIP, 4% had VP, and 3% had HCP44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,1818. Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stötzel U, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020 May;71(5):1546-58. https://doi.org/10.1002/hep.30936
https://doi.org/10.1002/hep.30936...
. In Brazilian patients, AIP represents 59% of cases, HCP 4%, VP 2.5%, and Doss porphyria less than 1%. Compared to the EXPLORE study, a similar profile of age at onset is identified in AHP subtypes: 40 years in AIP, 38 years in HCP, 39 years in VP, and 36 years in Doss porphyria77. Dorr AM, Picharski GL, Osternack BR. Porphyria: analysis of register from Brazilian association of porphyria (ABRAPO). Hematol Transfus Int J. 2016 Oct;2(6):112-4. https://doi.org/10.15406/htij.2016.02.00052
https://doi.org/10.15406/htij.2016.02.00...
.

AHPs are typically recognized by acute neurovisceral attacks (Figure 2) with systemic and neuropsychiatric signs and symptoms (Table 1), including: (i) autonomic disturbances (i.e. gastrointestinal dysmotility, acute abdominal pain, fever, sweating disorders, tachycardia, cardiac arrhythmia, postural hypotension, or arterial hypertension); (ii) acute neuropathic involvement (i.e., acute motor axonal neuropathy; cranial neuropathy with involvement mainly of the third, sixth, ninth, and tenth cranial nerves; neuropathic pain and acute respiratory failure with diaphragmatic paresis); (iii) metabolic disturbances (i.e., mildly abnormal liver tests and hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion); and (iv) acute neuropsychiatric disturbances or other central nervous system (CNS) involvement (i.e., acute encephalopathy, posterior reversible encephalopathy syndrome, seizures, status epilepticus, cerebral vasospasm and vasoconstriction, acute psychosis, and abnormal circadian rhythm with insomnia)11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
https://doi.org/10.1016/j.ymgme.2019.03....
,1313. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011 Dec;122(12):2336-44. https://doi.org/10.1016/j.clinph.2011.07.036
https://doi.org/10.1016/j.clinph.2011.07...
,1414. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-77. https://doi.org/10.1016/j.ymgme.2019.04.008
https://doi.org/10.1016/j.ymgme.2019.04....
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,1919. Suh Y, Gandhi J, Seyam O, Jiang W, Joshi G, Smith NL, et al. Neurological and neuropsychiatric manifestations of porphyria. Int J Neurosci. 2019 Dec;129(12):1226-33. https://doi.org/10.1080/00207454.2019.1655014
https://doi.org/10.1080/00207454.2019.16...
,2020. Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL. Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab. 2019 Nov;128(3):242-53. https://doi.org/10.1016/j.ymgme.2019.10.011
https://doi.org/10.1016/j.ymgme.2019.10....
,2121. Souza Júnior VR, Lemons VMV, Feitosa IML, Florencio R, Correia CWB, Fontes LBC, et al. Effect of menstrual cycle on acute intermittent porphyria. Child Neurol Open. 2017 Jan-Dec;4:2329048X17736170. https://doi.org/10.1177/2329048X17736170
https://doi.org/10.1177/2329048X17736170...
.

Figure 2
Clinical progression and neurovisceral and laboratory findings during acute neurovisceral attacks in acute hepatic porphyrias, according to the time after onset and the use of glucose overload or hemin during the clinical course. The course of neurovisceral symptoms is represented by continuous black arrows in mild or moderate/severe clinical presentations. Delta-aminolevulinic acid levels are represented by thin dashed lines. Porphobilinogen levels are represented by thick dashed lines.
Table 1
Summary of the main clinical, laboratory, neurophysiological, and neuroimaging findings of each acute hepatic porphyrias.

Before a neurovisceral attack, the patient frequently experiences prodromal gastrointestinal symptoms, mainly starting with intestinal constipation and gastroparesis. Diffuse abdominal pain and abdominal distension may also occur and can be associated with urinary bladder dysfunction. According to the EXPLORE study, 69% of recurrent attacks require hospitalization, with each patient having five attacks per year with a median duration of seven days per attack (varying from 1.3 to 33.2 days). In AHPs, skin lesions in sun-exposed (photosensitive) regions are more common in the HCP and VP types and absent in AIP; they may be found from early stages of the acute attack and eventually progressing throughout the episode or only in chronic intercritical periods11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
https://doi.org/10.1016/j.ymgme.2019.03....
,1313. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011 Dec;122(12):2336-44. https://doi.org/10.1016/j.clinph.2011.07.036
https://doi.org/10.1016/j.clinph.2011.07...
,1414. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-77. https://doi.org/10.1016/j.ymgme.2019.04.008
https://doi.org/10.1016/j.ymgme.2019.04....
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,1919. Suh Y, Gandhi J, Seyam O, Jiang W, Joshi G, Smith NL, et al. Neurological and neuropsychiatric manifestations of porphyria. Int J Neurosci. 2019 Dec;129(12):1226-33. https://doi.org/10.1080/00207454.2019.1655014
https://doi.org/10.1080/00207454.2019.16...
.

Other clinical presentations include acute dysautonomia or acute flaccid paralysis in the intensive care unit as a differential diagnosis in patients with suspected critical illness polyneuropathy. Atypical presentations include pure dysautonomia, CNS involvement, and late-onset pure neuropsychiatric disturbances. Other psychiatric contexts may also be found, including catatonia, delusions, mood and behavioral changes, visual and auditory hallucinations, paranoid psychosis, or late-onset personality disorders11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
https://doi.org/10.1016/j.ymgme.2019.03....
,1313. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the pathophysiology of acute porphyric neuropathy. Clin Neurophysiol. 2011 Dec;122(12):2336-44. https://doi.org/10.1016/j.clinph.2011.07.036
https://doi.org/10.1016/j.clinph.2011.07...
,1414. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-77. https://doi.org/10.1016/j.ymgme.2019.04.008
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,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
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,1919. Suh Y, Gandhi J, Seyam O, Jiang W, Joshi G, Smith NL, et al. Neurological and neuropsychiatric manifestations of porphyria. Int J Neurosci. 2019 Dec;129(12):1226-33. https://doi.org/10.1080/00207454.2019.1655014
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,2020. Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL. Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab. 2019 Nov;128(3):242-53. https://doi.org/10.1016/j.ymgme.2019.10.011
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,2121. Souza Júnior VR, Lemons VMV, Feitosa IML, Florencio R, Correia CWB, Fontes LBC, et al. Effect of menstrual cycle on acute intermittent porphyria. Child Neurol Open. 2017 Jan-Dec;4:2329048X17736170. https://doi.org/10.1177/2329048X17736170
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In the EXPLORE study, besides neuropsychiatric disorders (up to 30% of cases), long-term disease complications include chronic kidney disease (up to 8% of cases), hepatocellular carcinoma2222. Onuki J, Teixeira PC, Medeiros MH, Dörnemann D, Douki T, Cadet J, et al. Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria? Cell Mol Biol (Noisy-le-grand). 2002 Feb;48(1):17-26., and chronic systemic arterial hypertension (up to 23% of cases)1818. Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stötzel U, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020 May;71(5):1546-58. https://doi.org/10.1002/hep.30936
https://doi.org/10.1002/hep.30936...
. They occur more often in patients with a recurrent disease course. Iron overload with liver fibrosis and cirrhosis is also observed after chronic treatment with heme therapy2323. Willandt B, Langendonk JG, Biermann K, Meersseman W, D’Heygere F, George C, et al. Liver fibrosis associated with iron accumulation due to long-term heme-arginate treatment in acute intermittent porphyria: a case series JIMD Rep. 2016 Jun;25:77-81. https://doi.org/10.1007/8904_2015_458
https://doi.org/10.1007/8904_2015_458...
. Moreover, AHPs cause severe impairment of quality of life: 46% of patients have chronic daily symptoms, such as gastrointestinal dysmotility in 30% of cases, chronic pain in 20%, and chronic fatigue and sleep disorders in 15%1818. Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stötzel U, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. 2020 May;71(5):1546-58. https://doi.org/10.1002/hep.30936
https://doi.org/10.1002/hep.30936...
.

Acute intermittent porphyria

AIP (Online Mendelian Inheritance in Man — OMIM #176000), formerly known as Swedish type porphyria, is an autosomal dominant inherited metabolic disorder resulting from heterozygous pathogenic variants in the HMBS gene (11q23.3), encoding cytoplasmic hydroxymethylbilane synthase (porphobilinogen deaminase), leading to the abnormal conversion of porphobilinogen into hydroxymethylbilane. AIP is the most common form of AHP. Despite its global and pan-ethnic distribution, it has been widely described in northern Sweden with a founder effect with the pathogenic variant c.593G>A (p.Trp198Ter). Other familial aggregations were described in Murcia (Spain) and in the UK33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
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,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
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,2424. Chen B, Solis-Villa C, Erwin AL, Balwani M, Nazarenko I, Phillips JD, et al. Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria. J Inherit Metab Dis. 2019 Jan;42(1):186-94. https://doi.org/10.1002/jimd.12040
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,2525. Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and delta-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol. 2014 Jan;67(1):60-5. https://doi.org/10.1136/jclinpath-2012-201367
https://doi.org/10.1136/jclinpath-2012-2...
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AIP presents with the typical clinical features observed in most AHPs. Most cases are associated with a classic acute neurovisceral presentation without skin lesions. However, only 10 to 20% of AIP gene mutation carriers become symptomatic during their lifetime. Furthermore, the classic form (95% of cases) results from erythroid isoform deficiency, while only 5% of cases may be caused by a variant with ubiquitous nonerythroid isoform deficiency, both with similar clinical features33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
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,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,2424. Chen B, Solis-Villa C, Erwin AL, Balwani M, Nazarenko I, Phillips JD, et al. Identification and characterization of 40 novel hydroxymethylbilane synthase mutations that cause acute intermittent porphyria. J Inherit Metab Dis. 2019 Jan;42(1):186-94. https://doi.org/10.1002/jimd.12040
https://doi.org/10.1002/jimd.12040...
,2525. Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and delta-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol. 2014 Jan;67(1):60-5. https://doi.org/10.1136/jclinpath-2012-201367
https://doi.org/10.1136/jclinpath-2012-2...
. Peripheral, autonomic, and CNS involvement are common in AIP. CNS involvement is observed in different contexts, including: (i) unexplained cerebral vasospasm with ischemic brain areas2626. Olivier P, Van Melkebeke D, Honoré PJ, Defreyne L, Hemelsoet D. Cerebral vasospasm in acute porphyria. Eur J Neurol. 2017 Sep;24(9):1183-7. https://doi.org/10.1111/ene.13347
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; (ii) posterior reversible encephalopathy syndrome (PRES); (iii) hemorrhagic stroke and cerebral vasospasm; (iv) reversible cerebral vasoconstriction syndrome; (v) severe hyponatremia complicating central pontine and extrapontine myelinolysis2020. Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL. Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab. 2019 Nov;128(3):242-53. https://doi.org/10.1016/j.ymgme.2019.10.011
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,2626. Olivier P, Van Melkebeke D, Honoré PJ, Defreyne L, Hemelsoet D. Cerebral vasospasm in acute porphyria. Eur J Neurol. 2017 Sep;24(9):1183-7. https://doi.org/10.1111/ene.13347
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,2727. Balwani M, Singh P, Seth A, Debnath EM, Naik H, Doheny D, et al. Acute intermittent porphyria in children: a case report and review of the literature. Mol Genet Metab. 2016 Dec;119(4):295-9. https://doi.org/10.1016/j.ymgme.2016.10.005
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. Regarding peripheral nervous system involvement, acute neuropathic pain due to small-fiber neuropathy is classically recognized, sometimes as a presenting feature, and can precede motor and autonomic involvement from several days to weeks2828. Cardenas JL, Guerrero C. Acute intermittent porphyria: general aspects with focus on pain. Curr Med Res Opin. 2018 Jul;34(7):1309-15. https://doi.org/10.1080/03007995.2018.1435521
https://doi.org/10.1080/03007995.2018.14...
. During acute attacks, most patients progress to acute axonal polyneuropathy and asymmetrical motor involvement, starting in proximal regions of the upper limbs. Diaphragmatic and cranial nerve involvement may occur2929. Wu CL, Ro LS, Jung SM, Tsai TC, Chu CC, Lyu RK, et al. Clinical presentation and electrophysiological findings of porphyric neuropathies: a follow-up study. Muscle Nerve. 2015 Mar;51(3):363-9. https://doi.org/10.1002/mus.24327
https://doi.org/10.1002/mus.24327...
. AIP is currently considered a key differential diagnosis of recurrent or refractory Guillain-Barré syndrome (GBS). Acute episodes in AIP tend to present with severe bulbar involvement and early and more prominent acute respiratory failure than in other AHPs. Rhabdomyolysis and cortical blindness have also been described in AIP11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
https://doi.org/10.1053/j.gastro.2019.04...
,2222. Onuki J, Teixeira PC, Medeiros MH, Dörnemann D, Douki T, Cadet J, et al. Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria? Cell Mol Biol (Noisy-le-grand). 2002 Feb;48(1):17-26.. Only 5% of patients have recurrent acute attacks, defined as four or more attacks per year, more commonly found in women and precipitated in the perimenstrual period, pregnancy, puerperium, and by porphyrinogenic drugs2828. Cardenas JL, Guerrero C. Acute intermittent porphyria: general aspects with focus on pain. Curr Med Res Opin. 2018 Jul;34(7):1309-15. https://doi.org/10.1080/03007995.2018.1435521
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,3030. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). 2005 Jan;84(1):48-60. https://doi.org/10.1097/01.md.0000152454.56435.f3
https://doi.org/10.1097/01.md.0000152454...
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Regarding women of childbearing age with AIP, pregnancy means a high-risk period for maternal and fetal health. It represents a high risk of intrauterine growth retardation in fetuses, low birth weight in newborns, premature delivery, and higher rates of perinatal mortality. Women with AIP are at high risk during pregnancy or after delivery for pre-eclampsia, PRES, neuropsychiatric disturbances, and other CNS vascular complications, including cerebral vasospasm and ischemic stroke3131. Tollånes MC, Aarsand AK, Sandberg S. Excess risk of adverse pregnancy outcomes in women with porphyria: a population-based cohort study. J Inherit Metab Dis. 2011 Feb;34(1):217-23. https://doi.org/10.1007/s10545-010-9231-2
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Long-term follow-up reveals three possible clinical outcomes: (i) asymptomatic latent AIP; (ii) active phase (1–2 years) with acute attacks and long-lasting clinical remission or few sporadic minor attacks; (iii) recurrent attacks since the first episodes and no long-term biochemical remission, requiring chronic administration of hemin3232. Herrero C, Badenas C, Aguilera P, To-Figueras J. Acute intermittent porphyria: long-term follow-up of 35 patients. Med Clin (Barc). 2015 Oct;145(8):332-7. https://doi.org/10.1016/j.medcli.2014.06.012
https://doi.org/10.1016/j.medcli.2014.06...
. However, chronic systemic complications may arise in AIP, similar to other AHPs, with high risk for early-onset chronic kidney disease secondary to tubulointerstitial nephropathy, hepatocellular carcinoma, and porphyria-induced hypertension11. Stötzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-81. https://doi.org/10.1053/j.gastro.2019.04.050
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,2222. Onuki J, Teixeira PC, Medeiros MH, Dörnemann D, Douki T, Cadet J, et al. Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria? Cell Mol Biol (Noisy-le-grand). 2002 Feb;48(1):17-26..

Biochemical evaluation gives important clues about AIP suspicion during acute episodes; nevertheless, metabolic work-up during asymptomatic or intercritical periods is commonly unremarkable. Urinary samples are critical during AIP evaluation, with markedly elevated urinary porphyrin levels, mostly with high uroporphyrin and PBG levels. Qualitative tests (Watson-Schwartz or Hoesch tests) are often used to characterize positive (elevated amount of PBG) or negative results based on spot urine samples with low diagnostic sensitivity and specificity. Measuring PBG in a 24-hour specimen by quantitative methods offers better results. Urinary PBG levels in AIP remain high between acute attacks for longer periods than other AHPs. In addition, urinary PBG is almost always normal in asymptomatic individuals with genetically proven AIP. Fecal porphyrin levels are normal in AIP or, in rare cases, slightly increased. During acute episodes, plasma porphyrin levels are normal or slightly increased and do not correlate with clinical severity. Enzyme profile in liver and erythrocytes and gene mutations in AIP present distinct patterns: (i) 10% with normal enzyme activity in erythrocytes, but defective expression in other tissues; (ii) about 10% have enzyme reduction to a minimal extension in erythrocytes (indeterminate zone); (iii) all other cases have enzyme reduction in liver, erythrocytes, and other tissues. Almost 96% of cases present pathogenic variants in the HMBS gene, detected by sequence analysis33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
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,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
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,3333. Floderus Y, Sardh E, Möller C, Andersson C, Rejkjaer L, Andersson DE, et al. Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion. Clin Chem. 2006 Apr;52(4):701-7. https://doi.org/10.1373/clinchem.2005.058198
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Autosomal recessive presentations are associated with distinct phenotypes and typical biochemical findings observed in AIP. Autosomal recessive childhood-onset cases result from compound heterozygous gene mutations in the HMBS gene with complex clinical findings, including: (i) porencephaly, neuropsychomotor developmental delay, and excessive urinary ALA, PBG, and uroporphyrin3434. Beukeveld GJ, Wolthers BG, Nordmann Y, Deybach JC, Grandchamp B, Wadman SK. A retrospective study of a patient with homozygous form of acute intermittent porphyria. J Inherit Metab Dis. 1990 Sep;13(5):673-83. https://doi.org/10.1007/BF01799566
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; (ii) childhood-onset mild chronic anemia, hepatosplenomegaly, mild intellectual disability, yellow-brown teeth, dark urine with highly elevated levels of urinary uroporphyrin, ALA, PBG, and raised urinary levels of hepta-, penta-, hexa- and coproporphyrins3535. Hessels J, Voortman G, van der Wagen A, van der Elzen C, Scheffer H, Zuijderhoudt FM. Homozygous acute intermittent porphyria in a 7-year-old boy with massive excretions of porphyrins and porphyrin precursors. J Inherit Metab Dis. 2004 Mar;27(1):19-27. https://doi.org/10.1023/B:BOLI.0000016613.75677.05
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; and (iii) severe encephalopathy due to R167W homozygous pathogenic variant, with early childhood lethality, severe psychomotor delay, axonal neuropathy, diffuse leukoencephalopathy, and high urinary levels of porphyrins3636. Solis C, Martinez-Bermejo A, Naidich TP, Kaufmann WE, Astrin KH, Bishop DF, et al. Acute intermittent porphyria: studies of the severe homozygous dominant disease provide insights into the neurologic attacks in acute porphyrias. Arch Neurol. 2004 Nov;61(11):1764-70. https://doi.org/10.1001/archneur.61.11.1764
https://doi.org/10.1001/archneur.61.11.1...
. Bi-allelic HMBS missense compound heterozygous pathogenic variants have also been associated with complex neurological phenotypes, including childhood-onset progressive spastic ataxia, neuropathy, optic atrophy, nystagmus, vertical gaze palsy, and diffuse leukoencephalopathy, besides moderate rise in urinary PBG and plasma ALA3737. Kevelam SH, Neeleman RA, Waisfisz Q, Friesema EC, Langendonk JG, van der Knaap MS. Acute intermittent porphyria-related leukoencephalopathy. Neurology. 2016 Sep;87(12):1258-65. https://doi.org/10.1212/WNL.0000000000003129
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,3838. Pinto WB, Sgobbi de Souza PV, Bortholin T, Troccoli Chieia MA, Oliveira AS. Letter re: Acute intermittent porphyria-related leukoencephalopathy. Neurology. 2017 Feb;88(7):718. https://doi.org/10.1212/WNL.0000000000003624
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Hereditary coproporphyria

HCP (OMIM #121300) is an autosomal dominant inherited metabolic disorder caused by heterozygous pathogenic variants in the CPOX gene (3q11.2), which codes for mitochondrial coproporphyrinogen III oxidase (CPOX), leading to deficiency in the conversion of coproporphyrinogen III into protoporphyrinogen IX. Symptomatic patients have markedly decreased CPOX activity to less than 5% in lymphocytes. Typical acute neurovisceral attacks in HCP usually start after the third decade of life. Most individuals present with lower back pain and recurrent abdominal pain, besides skin photosensitivity in 15% of cases. Skin involvement is observed in sun-exposed areas with bullae, hypertrichosis, and hyperpigmented scars. Pure acute neurovisceral attacks are seen in 72% of cases, while 7% present with pure dermatological signs, and only 21% have both dermatological and neurovisceral symptoms. CNS involvement is also reported, including PRES episodes2020. Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL. Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab. 2019 Nov;128(3):242-53. https://doi.org/10.1016/j.ymgme.2019.10.011
https://doi.org/10.1016/j.ymgme.2019.10....
, cerebral vasospasm with ischemic stroke, refractory epilepsia partialis continua, and status epilepticus. Screening for chronic complications is mandatory and involves evaluation of liver fibrosis and annual screening for hepatocellular carcinoma with serum alpha-fetoprotein and abdominal imaging studies in patients older than 50 years1414. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-77. https://doi.org/10.1016/j.ymgme.2019.04.008
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,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
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,1717. Kakoullis L, Louppides S, Papachristodoulou E, Panos G. Porphyrias and photosensitivity: pathophysiology for the clinician. Postgrad Med. 2018 Nov;130(8):673-86. https://doi.org/10.1080/00325481.2018.1533380
https://doi.org/10.1080/00325481.2018.15...
.

Biochemical evaluation indicates a suggestive metabolic profile in most cases: (i) elevated fecal porphyrin levels, mainly with fecal coproporphyrin isomer III (without significant fecal protoporphyrin elevation); (ii) markedly elevated urinary porphyrin levels, mostly coproporphyrin III/I isomer ratio >1.5 with mildly to moderately elevated PBG levels; (iii) normal plasma porphyrin levels are common, despite a slight increase in some patients with skin involvement; (iv) plasma fluorescence emission spectroscopy with a peak wavelength at 615–620 nm. Gene sequencing analysis is the gold-standard definitive method for diagnosis and identifies pathogenic variants in more than 95% of patients with HCP33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
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,99. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). Mol Genet Metab. 2019 Nov;128(3):213-8. https://doi.org/10.1016/j.ymgme.2019.03.002
https://doi.org/10.1016/j.ymgme.2019.03....
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
.

Harderoporphyria is an autosomal recessive erythropoietic variant of HCP caused by compound heterozygous or homozygous pathogenic variants in the CPOX gene, affecting the conversion of harderoporphyrinogen into protoporphyrinogen IX. Its clinical presentation is distinct from that of classic HCP and includes neonatal hemolytic anemia, neonatal jaundice, and mild chronic anemia during childhood and adulthood. Hepatosplenomegaly and dark-reddish urine may also be observed. Blistering lesions with photosensitivity occur in 20% of cases. Acute neurovisceral attacks are rare during adulthood. Elevated liver enzymes and mild metabolic acidosis can be detected at early stages. Massive excretion of harderoporphyrin in feces is a hallmark of the disorder3939. Hasanoglu A, Balwani M, Kasapkara CS, Ezgü FS, Okur I, Tümer L, et al. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. J Inherit Metab Dis. 2011 Feb;34(1):225-31. https://doi.org/10.1007/s10545-010-9237-9
https://doi.org/10.1007/s10545-010-9237-...
.

Variegate porphyria

VP (OMIM #176200), formerly called South African type porphyria, is an autosomal dominant inherited metabolic disorder resulting from heterozygous pathogenic variants in the PPOX gene (1q23.3), leading to protoporphyrinogen oxidase (PPOX) deficiency and reduced conversion of protoporphyrinogen IX into protoporphyrin IX. VP has a regional founder effect in South Africa among the Afrikaner population of Dutch descent, showing the pathogenic variant c.175C>T(p.Arg59Trp). Almost 59% of cases present with pure dermatological signs, 20% with pure acute neurovisceral attacks, and only 21% with both skin and neurological involvement. Postinflammatory facial and limb hyperpigmentation, hypopigmented skin patches, hypertrichosis, skin fragility, chronic blistering lesions, subepidermal vesicles, and bullae are common dermatological complaints1717. Kakoullis L, Louppides S, Papachristodoulou E, Panos G. Porphyrias and photosensitivity: pathophysiology for the clinician. Postgrad Med. 2018 Nov;130(8):673-86. https://doi.org/10.1080/00325481.2018.1533380
https://doi.org/10.1080/00325481.2018.15...
. Motor axonal neuropathy and dysautonomia during acute attacks are similar to other AHPs. Acute encephalopathy, PRES, and behavioral changes are rare neurological presentations. The risk for chronic kidney disease and hepatocellular carcinoma is also high, making routine diagnostic screening necessary33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
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,2020. Jaramillo-Calle DA, Solano JM, Rabinstein AA, Bonkovsky HL. Porphyria-induced posterior reversible encephalopathy syndrome and central nervous system dysfunction. Mol Genet Metab. 2019 Nov;128(3):242-53. https://doi.org/10.1016/j.ymgme.2019.10.011
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,4040. Frank J, Jugert FK, Breitkopf C, Goerz G, Merk HF, Christiano AM. Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria. Am J Med Genet. 1998 Aug;79(1):22-6. https://doi.org/10.1002/(SICI)1096-8628(19980827)79:1<22::AID-AJMG6>3.0.CO;2-K
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.

Metabolic profile may give important diagnostic clues. Increase in urinary ALA, PBG (rarely with normal PBG levels), and porphyrins during acute attacks is common, and, in most cases, urinary porphyrins (coproporphyrin) remain elevated even when urinary PBG levels return to normal. Urinary PBG and ALA levels become normal earlier in VP than in AIP after acute attacks. During intercritical periods or in asymptomatic patients, the urinary metabolic profile may be almost normal. Elevated fecal levels of protoporphyrin and coproporphyrin isomer III may be observed during or after acute attacks. Markedly elevated plasma porphyrin levels are common during acute attacks and present a distinctive fluorescence peak wavelength at 626 nm (624–627) on fluorescence scanning of diluted plasma at neutral pH33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
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,1414. Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-77. https://doi.org/10.1016/j.ymgme.2019.04.008
https://doi.org/10.1016/j.ymgme.2019.04....
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,3030. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). 2005 Jan;84(1):48-60. https://doi.org/10.1097/01.md.0000152454.56435.f3
https://doi.org/10.1097/01.md.0000152454...
.

Homozygous variants with atypical presentations have been associated with complex neurological and systemic contexts due to severe PPOX deficiency, including early childhood- or neonatal-onset photosensitization, bullous lesions, skin fragility, keloid scarring, short stature, skeletal abnormalities, intellectual disability, epileptic encephalopathy, and sometimes IgA nephropathy. Acute neurovisceral attacks are not observed in such cases. The analysis of PPOX enzyme activity in lymphocytes reveals very low levels, and the concentration of protoporphyrins in erythrocytes is high4141. Roberts AG, Puy H, Dailey TA, Morgan RR, Whatley SD, Dailey HA, et al. Molecular characterization of homozygous variegate porphyria. Hum Mol Genet. 1998 Nov;7(12):1921-5. https://doi.org/10.1093/hmg/7.12.1921
https://doi.org/10.1093/hmg/7.12.1921...
,4242. Coakley J, Hawkins R, Crinis N, McManus J, Blake D, Nordmann Y, et al. An unusual case of variegate porphyria with possible homozygous inheritance. Aust N Z J Med. 1990 Aug;20(4):587-9. https://doi.org/10.1111/j.1445-5994.1990.tb01320.x
https://doi.org/10.1111/j.1445-5994.1990...
.

Doss porphyria (5-aminolevulinic acid dehydratase deficiency)

Doss porphyria (OMIM #612740) is an extremely rare autosomal recessive inherited metabolic disorder caused by compound heterozygous or homozygous pathogenic variants in the ALAD (9q32) gene, coding the cytoplasmic ALA dehydratase (ALAD, porphobilinogen synthase), resulting in the abnormal conversion of ALA into porphobilinogen. Cases have been mainly described in male patients from Sweden and Germany without skin lesions; however, two Brazilian women have also been identified. Most cases have a childhood or juvenile onset. Its clinical course is similar to but more severe than that of other AHPs due to almost complete enzymatic deficiency (less than 3% of normal enzyme activity). Biochemical work-up shows ALA increases in plasma and urine, elevated urinary coproporphyrin, and erythrocyte protoporphyrin77. Dorr AM, Picharski GL, Osternack BR. Porphyria: analysis of register from Brazilian association of porphyria (ABRAPO). Hematol Transfus Int J. 2016 Oct;2(6):112-4. https://doi.org/10.15406/htij.2016.02.00052
https://doi.org/10.15406/htij.2016.02.00...
,1515. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Dec;4(4):977-1006. https://doi.org/10.3390/metabo4040977
https://doi.org/10.3390/metabo4040977...
,4343. Doss M, Schneider J, Von Tiepermann R, Brandt A. New type of acute porphyria with porphobilinogen synthase (delta-aminolevulinic acid dehydratase) defect in the homozygous state. Clin Biochem. 1982 Feb;15(1):52-5. https://doi.org/10.1016/s0009-9120(82)90493-3
https://doi.org/10.1016/s0009-9120(82)90...
,4444. Jaffe EK, Stith L. ALAD porphyria is a conformational disease. Am J Hum Genet. 2007 Feb;80(2):329-37. https://doi.org/10.1086/511444
https://doi.org/10.1086/511444...
.

DIAGNOSTIC APPROACH TO HEPATIC PORPHYRIAS

AHPs must be included in the differential diagnosis of cases with motor-predominant (or pure) axonal neuropathy associated with neuropsychiatric manifestations and gastrointestinal or abdominal involvement (neurovisceral involvement). Any patient with this clinical picture should be carefully considered for AHP diagnostic work-up (Table 2)33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
,2525. Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and delta-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol. 2014 Jan;67(1):60-5. https://doi.org/10.1136/jclinpath-2012-201367
https://doi.org/10.1136/jclinpath-2012-2...
,3333. Floderus Y, Sardh E, Möller C, Andersson C, Rejkjaer L, Andersson DE, et al. Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion. Clin Chem. 2006 Apr;52(4):701-7. https://doi.org/10.1373/clinchem.2005.058198
https://doi.org/10.1373/clinchem.2005.05...
,4545. Sardh E, Harper P, Andersson DE, Floderus Y. Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks. Eur J Intern Med. 2009 Mar;20(2):201-7. https://doi.org/10.1016/j.ejim.2008.06.012
https://doi.org/10.1016/j.ejim.2008.06.0...
. Several different diagnostic methods are currently available for AHP evaluation. Specific genetic testing using Sanger sequencing or next-generation sequencing (NGS) strategies (including HMBS, CPOX, and PPOX genes) or the analysis of specific familial pathogenic variants are gold-standard diagnostic methods for AHPs. DNA testing is usually requested after initial biochemical screening tests (urinary, stool, and plasma porphyrins and porphyrin precursors or specific enzyme assays) (Figure 3). If genetic testing is not available and patients are in the intercritical period, full biochemical testing is indicated, including fecal porphyrins, plasma porphyrins, and urinary ALA, PBG, and porphyrins. Since biochemical profile results can be frequently inconclusive, urinary PBG and ALA (24-hour sample), plasma porphyrins, and fecal porphyrins should be ideally evaluated at the same time. If urinary PBG is normal, total porphyrins and ALA from the same sample should be evaluated in highly suspicious cases. Normal PBG levels do not rule out AHPs, such as ALA dehydratase deficiency. Enzyme activity assays in erythrocytes (i.e., PBG deaminase) or lymphocytes can also be used during diagnostic work-up. Qualitative testing (i.e., calorimetric methods like Watson-Schwartz and Hoesch tests for PBG) must be confirmed by quantitative techniques or genetic testing. Currently, plasma PBG evaluation by liquid chromatography-mass spectrometry (LC-MS) represents the most sensitive biomarker available to monitor clinical and therapeutic responses after acute episodes, if compared to urinary PBG and ALA by ion-exchange chromatography33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,66. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-22. https://doi.org/10.1002/hep.29313
https://doi.org/10.1002/hep.29313...
,2525. Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and delta-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol. 2014 Jan;67(1):60-5. https://doi.org/10.1136/jclinpath-2012-201367
https://doi.org/10.1136/jclinpath-2012-2...
,3333. Floderus Y, Sardh E, Möller C, Andersson C, Rejkjaer L, Andersson DE, et al. Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion. Clin Chem. 2006 Apr;52(4):701-7. https://doi.org/10.1373/clinchem.2005.058198
https://doi.org/10.1373/clinchem.2005.05...
,4545. Sardh E, Harper P, Andersson DE, Floderus Y. Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks. Eur J Intern Med. 2009 Mar;20(2):201-7. https://doi.org/10.1016/j.ejim.2008.06.012
https://doi.org/10.1016/j.ejim.2008.06.0...
.

Table 2
Clinical (neurological and systemic), laboratory, neurophysiological, and neuroimaging findings of high suspicion for a possible acute hepatic porphyrias.
Figure 3
Diagnostic flowchart for the clinical, metabolic, and genetic evaluation of suspected acute hepatic porphyrias.

DIFFERENTIAL DIAGNOSIS

The group of clinical conditions that make a differential diagnosis with AHPs is broad and can be best evaluated based on the main clinical and neuromuscular signs involved (Table 3). Clues for considering AHPs include: (i) acute flaccid paralysis mainly with acute motor axonal involvement; (ii) severe dysautonomia; (iii) hyponatremia; (iv) CNS involvement, including PRES, neuropsychiatric disturbances, and acute epileptic encephalopathy; and (v) dark-reddish urine. Pure severe dysautonomic presentations with associated complex cardiac arrhythmia must also be considered. Cases without skin involvement must refer to AIP and rarely to Doss porphyria, but VP and HCP presentations limited to neurological involvement must also be considered22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
.

Table 3
Main differential diagnosis of acute hepatic porphyrias during acute neurovisceral attacks and chronic presentation.

THERAPEUTIC APPROACHES

The management of acute and chronic complications involve several different approaches, including: (i) treatment of acute neurovisceral attacks; (ii) treatment during the intercritical period or after acute attacks; and (iii) prevention of recurrent attacks and chronic long-term complications22. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug;377(9):862-72. https://doi.org/10.1056/NEJMra1608634
https://doi.org/10.1056/NEJMra1608634...
,33. O’Malley R, Rao G, Stein P, Bandmann O. Porphyria: often discussed but too often missed. Pract Neurol. 2018 Sep;18(5):352-8. http://dx.doi.org/10.1136/practneurol-2017-001878
http://dx.doi.org/10.1136/practneurol-20...
,44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,66. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-22. https://doi.org/10.1002/hep.29313
https://doi.org/10.1002/hep.29313...
,4646. Fontanellas A, Ávila MA, Anderson KE, Deybach JC. Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol. 2019 Aug;71(2):422-33. https://doi.org/10.1016/j.jhep.2019.05.003
https://doi.org/10.1016/j.jhep.2019.05.0...
,4747. Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015 Sep;8:201-14. https://doi.org/10.2147/TACG.S48605
https://doi.org/10.2147/TACG.S48605...
. During an acute AHP presentation, evaluating its severity with a specific score is essential and can aid clinicians to predict overall outcomes and prognosis, including five different domain:

  1. assessment of muscle strength by the Medical Research Council (MRC) sum-score (0: MRC 55–60; 1: MRC 45–54; 2: MRC 35–44; 3: MRC 25–34; 4: MRC 15–24; 5: MRC 5–14; 6: MRC 0–4);

  2. mechanical ventilation (0: no; <2 weeks: 2; 2–4 weeks: 4; >4 weeks: 6);

  3. bulbar involvement with dysarthria, dysphonia, or dysphagia (0: absent; 6: present);

  4. consciousness (0: normal; 2: lethargy; 4: stupor; 6: coma);

  5. hyponatremia (0: >132 mmol/L; 3: >120 mmol/L; 6: <120 mmol/L)4848. Pischik E, Bulyanitsa A, Kazakov V, Kauppinen R. Clinical features predictive of a poor prognosis in acute porphyria. J Neurol. 2004 Dec;251(12):1538-41. https://doi.org/10.1007/s00415-004-0584-z
    https://doi.org/10.1007/s00415-004-0584-...
    .

According to the total score, during the nadir of an acute attack, clinical manifestations are classified as:

  1. score 0: mild episode, only mild dysautonomia;

  2. score 1-4: moderate episode, with dysautonomia and hyponatremia, lethargy, seizures, or flaccid paralysis, without mechanical ventilation;

  3. score 5–25: severe episode, with severe dysautonomia and flaccid paralysis, bulbar palsy, mechanical ventilation, severe hyponatremia, and stupor/coma;

  4. score 26–30: critical episode, with severe dysautonomia, severe motor involvement, coma, long-lasting mechanical ventilation, and high risk of death4848. Pischik E, Bulyanitsa A, Kazakov V, Kauppinen R. Clinical features predictive of a poor prognosis in acute porphyria. J Neurol. 2004 Dec;251(12):1538-41. https://doi.org/10.1007/s00415-004-0584-z
    https://doi.org/10.1007/s00415-004-0584-...
    .

The treatment of acute attacks involves different therapeutic measures, such as hemin-based therapies; infusion of high doses of glucose; screening, identification, and treatment of triggering factors; review of harmful drugs; supportive treatment (fluid and electrolyte therapy and dietary support); and education about AHPs and their red-flag signs4747. Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015 Sep;8:201-14. https://doi.org/10.2147/TACG.S48605
https://doi.org/10.2147/TACG.S48605...
. During acute attacks, the first steps are:

  1. detailed evaluation of medical prescription (searching for porphyrinogenic drugs) (Table 4);

  2. general supportive treatment (i.e., correction of electrolyte disturbances, mainly hyponatremia and hypomagnesemia, stabilization of dysautonomia);

  3. removal of precipitating factors (i.e., alcoholic beverages, prolonged fasting, restrictive low-carbohydrate diets, Atkins diet, smoking, anesthetic agents, strenuous physical exercise, emotional stress, pregnancy, puerperium);

  4. treatment of seizures and status epilepticus with safe drugs (including propofol, benzodiazepines, gabapentin, and vigabatrin); and

  5. start of glucose overload therapy. Refractory seizures in acute episodes, progressive acute motor neuropathy, severe hyponatremia, and early autonomic disturbances represent red-flags, indicating a life-threatening episode and the need for management in an intensive care unit. Important variations can be found in safe drug list criteria among specialized centers. In this context, we present data from the Drug Database for Acute Porphyria, which is annually updated by the UK Porphyria Medicines Information Service (UKPMIS), the Cardiff Porphyria Service, and the National Acute Porphyria Service (NAPS) (Table 4)66. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-22. https://doi.org/10.1002/hep.29313
    https://doi.org/10.1002/hep.29313...
    ,2222. Onuki J, Teixeira PC, Medeiros MH, Dörnemann D, Douki T, Cadet J, et al. Is 5-aminolevulinic acid involved in the hepatocellular carcinogenesis of acute intermittent porphyria? Cell Mol Biol (Noisy-le-grand). 2002 Feb;48(1):17-26..

Table 4
Current list of some of the drugs that are considered safe for acute hepatic porphyria patients*. In the context of drugs with uncertain or doubtful safety profiles, the recommendation is to choose alternate safe drugs.

Intravenous dextrose (or glucose) infusion and high oral carbohydrate intake are key therapeutic approaches during mild to moderate acute episodes. A glucose loading of 300–500 g daily by intravenous infusion for 2–3 days is the most common therapy. Hyperglycemia promotes downregulation of ALAS1 expression by intracellular pathways related to peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,66. Balwani M, Wang B, Anderson KE, Bloomer JR, Bissell DM, Bonkovsky HL, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017 Oct;66(4):1314-22. https://doi.org/10.1002/hep.29313
https://doi.org/10.1002/hep.29313...
,4646. Fontanellas A, Ávila MA, Anderson KE, Deybach JC. Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol. 2019 Aug;71(2):422-33. https://doi.org/10.1016/j.jhep.2019.05.003
https://doi.org/10.1016/j.jhep.2019.05.0...
. Hemodialysis and hemoperfusion are also alternative therapies in moderate to severe acute attacks in patients without access to hemin-based therapies (further discussed) and without marked response to glucose infusion4949. Prabahar MR, Manorajan R, Sathiyakumar D, Soundararajan P, Jayakumar M. Hemodialysis: a therapeutic option for severe attacks of acute intermittent porphyria in developing countries. Hemodial Int. 2008 Jan;12(1):34-8. https://doi.org/10.1111/j.1542-4758.2008.00237.x
https://doi.org/10.1111/j.1542-4758.2008...
.

Hemin is an oxidized form of human iron protoporphyrin IX from blood donors. Hemin-based therapies are well-known options for the treatment of moderate to severe neurovisceral attacks, refractory attacks to high carbohydrate overload, and recurrent attacks as prophylactic therapy. After intravenous infusion, heme circulates as heme-albumin and is taken by hepatocytes, promoting downregulation of hepatic ALAS1 biosynthesis. Several protocols are used for intravenous infusion of hemin as heme arginate (Normosang®, from Orphan Drug Europe) or hematin (Panhematin®, from Recordati Rare Diseases Inc and Ovation Pharmaceuticals). Panhematin®, a product of the reaction of hemin with sodium carbonate, is a lyophilized preparation of hydroxyheme (350 mg hemin per vial) used with the standard dosage of 3–4 mg per kg, once daily, for 4–5 days. Weekly or biweekly infusions are used for chronic prophylactic purposes. Clinical evidence of Panhematin use has emerged from five open-label multicenter compassionate-use studies, including 229 AHP patients, most of them with AIP5050. Anderson KE, Collins S. Open-label study of hemin for acute porphyria: clinical practice implications. Am J Med. 2006 Sep;119(9):801.e19-24. https://doi.org/10.1016/j.amjmed.2006.05.026
https://doi.org/10.1016/j.amjmed.2006.05...
. Panhematin reduces motor weakness and acute pain (especially abdominal pain) by 85.5% and completely improves biochemical markers during acute attacks. It is the only US Food and Drug Administration (FDA)-approved therapy during acute attacks in women with recurrent attacks related to the menstrual cycle and refractory attacks after carbohydrate therapy. Adverse events can occur after reconstitution with sterile water with mild transient anticoagulant effects and local phlebitis. Acute tubular necrosis has been associated with a single intravenous infusion of high doses (up to 12.2 mg/kg). Recurrent use of hemin is associated with chronic inflammatory liver disease. Thus, restricting hemin infusions to moderate or severe neurovisceral attacks and recurrent life-threatening attacks is reasonable44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,55. Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 2018 Dec;3(2):193-206. https://doi.org/10.1002/hep4.1297
https://doi.org/10.1002/hep4.1297...
,3030. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). 2005 Jan;84(1):48-60. https://doi.org/10.1097/01.md.0000152454.56435.f3
https://doi.org/10.1097/01.md.0000152454...
,5050. Anderson KE, Collins S. Open-label study of hemin for acute porphyria: clinical practice implications. Am J Med. 2006 Sep;119(9):801.e19-24. https://doi.org/10.1016/j.amjmed.2006.05.026
https://doi.org/10.1016/j.amjmed.2006.05...
,5151. Schmitt C, Lenglet H, Yu A, Delaby C, Benecke A, Lefebvre T, et al. Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver. J Intern Med. 2018 Jul;284(1):78-91. https://doi.org/10.1111/joim.12750
https://doi.org/10.1111/joim.12750...
,5252. Yarra P, Faust D, Bennett M, Rudnick S, Bonkovsky HL. Benefits of prophylactic heme therapy in severe acute intermittent porphyria Mol Genet Metab Rep. 2019 Jun;19:100450. https://doi.org/10.1016/j.ymgmr.2019.01.002
https://doi.org/10.1016/j.ymgmr.2019.01....
.

Human hemin presentation as heme arginate (Normosang® 25 mg/mL) has been approved for clinical use in all AHPs with a daily dose of 3 mg per kg for 4 consecutive days. A total daily dose of up to 250 mg is allowed, under careful monitoring. Weekly use of heme arginate may be considered in chronic or refractory presentations and can be extended in each course for up to 14 days. Heme arginate presentations are used in most countries in Europe, Latin America, and South Africa. Despite the well-established use of heme arginate for more than 35 years, it has limited experience in pediatric cases. Clinical efficacy and safety results were obtained after evaluation of more than 100 attacks in South Africa, Sweden, and an open-label phase III study, which revealed marked clinical and biochemical responses the earlier the treatment started during acute attacks2323. Willandt B, Langendonk JG, Biermann K, Meersseman W, D’Heygere F, George C, et al. Liver fibrosis associated with iron accumulation due to long-term heme-arginate treatment in acute intermittent porphyria: a case series JIMD Rep. 2016 Jun;25:77-81. https://doi.org/10.1007/8904_2015_458
https://doi.org/10.1007/8904_2015_458...
,3030. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). 2005 Jan;84(1):48-60. https://doi.org/10.1097/01.md.0000152454.56435.f3
https://doi.org/10.1097/01.md.0000152454...
,4545. Sardh E, Harper P, Andersson DE, Floderus Y. Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks. Eur J Intern Med. 2009 Mar;20(2):201-7. https://doi.org/10.1016/j.ejim.2008.06.012
https://doi.org/10.1016/j.ejim.2008.06.0...
,5252. Yarra P, Faust D, Bennett M, Rudnick S, Bonkovsky HL. Benefits of prophylactic heme therapy in severe acute intermittent porphyria Mol Genet Metab Rep. 2019 Jun;19:100450. https://doi.org/10.1016/j.ymgmr.2019.01.002
https://doi.org/10.1016/j.ymgmr.2019.01....
.

An important evaluation issue during acute episodes in recurrent attacks is the presence of perimenstrual symptoms in women of childbearing age. In women with recurrent attacks related to the perimenstrual period, long-acting agonists of luteinizing hormone-releasing hormone (LH-RH) or gonadotropin-releasing hormone (GnRH, gonadorelin analogs) receptors are indicated and can suppress the estrogen effects in heme biosynthesis44. Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab. 2019 Nov;128(3):219-27. https://doi.org/10.1016/j.ymgme.2019.07.002
https://doi.org/10.1016/j.ymgme.2019.07....
,2121. Souza Júnior VR, Lemons VMV, Feitosa IML, Florencio R, Correia CWB, Fontes LBC, et al. Effect of menstrual cycle on acute intermittent porphyria. Child Neurol Open. 2017 Jan-Dec;4:2329048X17736170. https://doi.org/10.1177/2329048X17736170
https://doi.org/10.1177/2329048X17736170...
,5353. Schulenburg-Brand D, Gardiner T, Guppy S, Rees DC, Stein P, Barth J, et al. An audit of the use of gonadorelin analogues to prevent recurrent acute symptoms in patients with Acute Porphyria in the United Kingdom. JIMD Rep. 2017 Feb;36:99-107. https://doi.org/10.1007/8904_2017_2
https://doi.org/10.1007/8904_2017_2...
. Liver transplantation in AHPs has been studied by different metabolic centers. Most procedures have been performed in patients with recurrent and severe acute attacks or recurrent attacks without early availability of intravenous heme therapy. Liver transplantation may also be considered a therapeutic option in patients with chronic liver disease associated with AHPs4747. Pischik E, Kauppinen R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015 Sep;8:201-14. https://doi.org/10.2147/TACG.S48605
https://doi.org/10.2147/TACG.S48605...
,5454. Singal AK, Parker C, Bowden C, Thapar M, Liu L, McGuire BM. Liver transplantation in the management of porphyria. Hepatology. 2014 Sep;60(3):1082-9. https://doi.org/10.1002/hep.27086
https://doi.org/10.1002/hep.27086...
.

New therapeutic options have been studied, bringing more sustained clinical responses for patients with AHP. N-Acetyl-D-Galactosamine (GalNAc)-conjugated small interfering RNA (siRNA)-based therapies have been developed for several inherited disorders, including AHPs, primary hyperoxaluria type 1, hereditary TTR-related amyloidosis, and familial hypercholesterolemia4646. Fontanellas A, Ávila MA, Anderson KE, Deybach JC. Current and innovative emerging therapies for porphyrias with hepatic involvement. J Hepatol. 2019 Aug;71(2):422-33. https://doi.org/10.1016/j.jhep.2019.05.003
https://doi.org/10.1016/j.jhep.2019.05.0...
,5555. Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, et al. Phase 1 trial of an RNA interference therapy for Acute Intermittent Porphyria. N Engl J Med. 2019 Feb;380(6):549-58. https://doi.org/10.1056/NEJMoa1807838
https://doi.org/10.1056/NEJMoa1807838...
,5656. Springer AD, Dowdy SF. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 2018 Jun;28(3):109-18. https://doi.org/10.1089/nat.2018.0736
https://doi.org/10.1089/nat.2018.0736...
,5757. Dong Y, Siegwart DJ, Anderson DG. Strategies, design, and chemistry in siRNA delivery systems. Adv Drug Deliv Rev. 2019 Apr;144:133-47. https://doi.org/10.1016/j.addr.2019.05.004
https://doi.org/10.1016/j.addr.2019.05.0...
. Givosiran (ALN-AS1; Givlaari, Alnylam Pharmaceuticals, US) 189 mg/mL has been recently approved by the FDA and the European Medicines Agency (EMA) for the treatment of AHPs. Once-monthly subcutaneous administration of givosiran 2.5 mg/kg promotes a sustained reduction of liver ALAS1 levels by degradation of its mRNA in hepatocytes. Thus, it decreases the production of neurotoxic intermediates ALA and PBG and prevents recurrent attacks and chronic and acute symptoms of AIP. Hepatocytes express a galactose receptor in their surface that enables the recognition of trivalent GalNAc and endocytosis of synthetic siRNA carrying ALAS1 sequence, allowing interaction of siRNA with original mRNA in the RNA-induced silencing complex (RISC) and promoting degradation of this mRNA and inhibition of ALAS1 synthesis by gene silencing55. Wang B, Rudnick S, Cengia B, Bonkovsky HL. Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 2018 Dec;3(2):193-206. https://doi.org/10.1002/hep4.1297
https://doi.org/10.1002/hep4.1297...
,5858. Nair JK, Willoughby JL, Chan A, Charisse K, Alam MR, Wang Q, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014 Dec;136(49):16958-61. https://doi.org/10.1021/ja505986a
https://doi.org/10.1021/ja505986a...
,5959. De Paula Brandão PR, Titze-de-Almeida SS, Titze-de-Almeida R. Leading RNA interference therapeutics Part 2: silencing delta-aminolevulinic acid synthase 1, with a focus on Givosiran. Mol Diagn Ther. 2020 Feb;24(1):61-8. https://doi.org/10.1007/s40291-019-00438-6
https://doi.org/10.1007/s40291-019-00438...
. A randomized, double-blind, placebo-controlled, global, and multicenter study was performed in three clinical phases, initially enrolling patients in a 3:1 givosiran: placebo ratio. Only genetically confirmed AIP patients were included in the initial 6 months of the phase I study. Part A was characterized by a single injection of ascending doses, and Part B involved multiple injections of ascending doses in 23 patients without attacks in the prior 6 months. Part C, with multiple injections, included 17 patients with recurrent attacks, defined as two or more recurrent attacks in the prior 6 months or in hemin prophylaxis over the 6 months before the study start. All 6 patients who received once-monthly intravenous injections of givosiran had sustained reductions in ALAS1 mRNA, ALA, and PBG to normal levels with a 79% decrease in annualized recurrent attack rate at that stage. Four groups receiving monthly or quarterly infusions of givosiran at 2.5 or 5.0 mg/kg were compared regarding safety and tolerability. Patients who completed the 6-month investigation were enrolled in an open-label phase I/II extension study (NCT02949830) for up to 42 months, which evaluated the long-term safety and tolerability of givosiran in adults with AIP4545. Sardh E, Harper P, Andersson DE, Floderus Y. Plasma porphobilinogen as a sensitive biomarker to monitor the clinical and therapeutic course of acute intermittent porphyria attacks. Eur J Intern Med. 2009 Mar;20(2):201-7. https://doi.org/10.1016/j.ejim.2008.06.012
https://doi.org/10.1016/j.ejim.2008.06.0...
,5959. De Paula Brandão PR, Titze-de-Almeida SS, Titze-de-Almeida R. Leading RNA interference therapeutics Part 2: silencing delta-aminolevulinic acid synthase 1, with a focus on Givosiran. Mol Diagn Ther. 2020 Feb;24(1):61-8. https://doi.org/10.1007/s40291-019-00438-6
https://doi.org/10.1007/s40291-019-00438...
,6060. Chan A, Liebow A, Yasuda M, Gan L, Racie T, Maier M, et al. Preclinical development of a subcutaneous ALAS1 RNAi therapeutic for treatment of hepatic porphyrias using circulating RNA quantification. Mol Ther Nucleic Acids. 2015 Jan;4:e263. https://doi.org/10.1038/mtna.2015.36
https://doi.org/10.1038/mtna.2015.36...
. New data on givosiran safety and efficacy for AHPs will be available in the ENVISION study (NCT03338816), including patients with AIP, VP, and HCP. Current data, thereby, suggests that givosiran is a key therapeutic option for refractory or recurrent AIP, refractory individuals, or cases without access to hemin therapies as a prophylactic alternative.

CONCLUSIONS

AHPs are inherited metabolic diseases related to heme biosynthesis and associated with broad and heterogeneous clinical presentations, particularly classic acute neurovisceral attacks and, more rarely, chronic skin lesions with photosensitivity. Knowledge of specific clinical, laboratory, and neuroimaging diagnostic clues is critical to the proper and early recognition of AHPs and screening of other family members. Therapies related to the treatment of acute neurovisceral attacks and prophylactic approaches for recurrent episodes have been used in clinical practice with significant success in modifying the natural history of this life-threatening condition. More recently, the approval of a new siRNA-based therapy by the FDA and its clinical impact on the disease course became a key milestone in the history of AHPs. Current data, thereby, suggests that givosiran is a key therapeutic option for recurrent AHPs, refractory individuals, or those without access to hemin therapies as a safe and more effective prophylactic treatment.

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Publication Dates

  • Publication in this collection
    06 Jan 2021
  • Date of issue
    Jan 2021

History

  • Received
    31 Mar 2020
  • Reviewed
    22 May 2020
  • Accepted
    07 June 2020
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