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

doi:10.1590/0004-282X20200096

Paulo Victor Sgobbi de Souza

Universidade Federal de São Paulo, Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, São Paulo SP, Brazil.

https://orcid.org/0000-0002-7416-7108

Bruno de Mattos Lombardi Badia

Universidade Federal de São Paulo, Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, São Paulo SP, Brazil.

https://orcid.org/0000-0001-7360-0494

Igor Braga Farias

Universidade Federal de São Paulo, Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, São Paulo SP, Brazil.

https://orcid.org/0000-0003-2187-6573

Eduardo Augusto Gonçalves

Universidade Federal de São Paulo, Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, São Paulo SP, Brazil.

https://orcid.org/0000-0002-9893-2468

Wladimir Bocca Vieira de Rezende Pinto Correspondence: Wladimir Bocca Vieira de Rezende Pinto; E-mail: wladimirbvrpinto@gmail.com

Universidade Federal de São Paulo, Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, São Paulo SP, Brazil.

https://orcid.org/0000-0002-0150-525X

Acary Souza Bulle Oliveira

Universidade Federal de São Paulo, Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, São Paulo SP, Brazil.

https://orcid.org/0000-0002-6986-4937

Correspondence: Wladimir Bocca Vieira de Rezende Pinto; E-mail: wladimirbvrpinto@gmail.com

Conflict of interest:

There is no conflict of interest to declare.

Authors’ contributions:

PVSS: manuscript project: conception, organization, execution (leading role in all steps); manuscript: writing of the first draft, review and critique (leading role for both). BMLB: manuscript project: conception, organization, execution (main participation in conception and organization steps); manuscript: writing of the first draft, review and critique (mild contribution in all steps). IBF: manuscript project: conception, organization, execution (leading role in conception and organization); manuscript: writing of the first draft, review and critique (main participation in writing step). EAG: manuscript project: conception, organization, execution (leading role in conception and organization); manuscript: writing of the first draft, review and critique (mild contribution for both). WBVRP: manuscript project: conception, organization, execution (leading role in all steps); manuscript: writing of the first draft, review and critique (leading role for both). ASBS: manuscript project: conception, organization, execution (leading role in all steps); manuscript: writing of the first draft, review and critique (leading role as reviewer).

Figuras (3)
Tabelas (4)

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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).

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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.

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Figure 3
Diagnostic flowchart for the clinical, metabolic, and genetic evaluation of suspected acute hepatic porphyrias.

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Table 1
Summary of the main clinical, laboratory, neurophysiological, and neuroimaging findings of each acute hepatic porphyrias.

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Table 2
Clinical (neurological and systemic), laboratory, neurophysiological, and neuroimaging findings of high suspicion for a possible acute hepatic porphyrias.

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

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Table 4
Current list of some of the drugs that are considered safe for acute hepatic porphyria patients^* * Adapted from sources: United Kingdom Porphyria Medicines Information Service (UKPMIS), Cardiff Porphyria Service, and National Acute Porphyria Service (NAPS); American Porphyria Foundation Drug Database. . In the context of drugs with uncertain or doubtful safety profiles, the recommendation is to choose alternate safe drugs.

Type of porphyria (OMIM)	Gene (locus)/Inheritance	Biochemical profile^* * During remission, intercritical periods, or in asymptomatic carriers, values and metabolic profiles may differ from the biochemical profile seen in symptomatic patients during acute attacks. Normal urinary, fecal, and blood levels of precursors and porphyrins may also be different among genetically distinct populations.				Skin lesions (blistering, scars…)	Neurovisceral attacks	Commentaries
Type of porphyria (OMIM)	Gene (locus)/Inheritance	Urine	Plasma	Stool (fecal)	RBC	Skin lesions (blistering, scars…)	Neurovisceral attacks	Commentaries
AIP (#176000)	HMBS (11q23.3)/AD	ALA, PBG, URO I	ALA, PBG, (URO I)	Normal, COPRO I, (URO I)	Low HMBS enzyme	Absent	⁺⁺⁺ +++ severe. motor axonal, dysautonomia	High risk for HCC; most severe neurological symptoms; atypical presentation in AR cases
HCP (#121300)	CPOX (3q11.2)/AD	ALA, PBG, COPRO III, URO I	COPRO	COPRO III ⁺⁺ ++ moderate; , PROTO, URO	Normal	⁺ + mild; /⁺⁺ ++ moderate; skin ≥ neuropathy	⁺ + mild; /⁺⁺ ++ moderate; motor axonal > dysautonomia	Plasma fluorescence emission peak wavelength at 620 nm; high risk for HCC; atypical presentation in AR cases
VP (#176200)	PPOX (1q23.3)/AD	ALA, PBG, COPRO III, URO I	Porphyrin conjugate, PROTO, COPRO III	PROTO⁺⁺ ++ moderate; , COPRO III, (URO)	Normal	⁺⁺ ++ moderate; /⁺⁺⁺ +++ severe. skin ≥ neuropathy	⁺ + mild; /⁺⁺ ++ moderate; motor axonal > dysautonomia	Plasma fluorescence emission peak wavelength at 624-628 nm; high risk for HCC; atypical presentation in AR cases
ALA dehydratase deficiency (#612740)	ALAD (9q32)/AR	ALA, (COPRO III)	ALA	Normal	Zn-PROTO; low ALAD activity	Absent	⁺ + mild;	Very rare; most cases in men; some cases associated with hemolytic anemia

Clinical, laboratory, neurophysiological, and neuroimaging findings indicating possible AHP
1. Acute or subacute-onset flaccid paralysis (proximal and upper limb-dominant weakness) in the ED/ICU, especially in case of: (i) prior chronic or subacute history of behavioral or neuropsychiatric changes (i.e., mood or psychotic changes); (ii) moderate to severe hyponatremia; (iii) severe dysautonomic changes (i.e., usually pandysautonomia in the ICU); (iv) severe abdominal pain with/without dark urine; (v) blistering skin changes involving hands or face; (vi) positive family history of AHP cases or possible diagnosis; (vii) normal CSF analysis; (viii) positive history of exposure to potentially porphyrinogenic precipitants (i.e., drugs, chronic lead poisoning, premenstrual period).
2. Recurrent episodes of GBS, especially if an axonal pattern of involvement is present (with/without skin lesions), normal CSF analysis or if associated with CNS complications (i.e., PRES, cerebral vasospasm).
3. Late-onset subacute or acute neuropsychiatric disturbances (i.e., psychosis) or refractory status epilepticus (i.e., acute encephalopathy) in the context of hyponatremia, catamenial (mainly premenstrual) or potential history of drug precipitated (evoked) episode
4. Recurrent episodes of abdominal pain without peritoneal signs (i.e., commonly with a prior history of acute abdomen with surgical procedures) but associated with: (i) dark-reddish or purple (port-wine) urine; (ii) recurrent hyponatremia; (iii) dysautonomic involvement; (iv) skin lesions in photosensitive areas (i.e., HCP, VP); (v) acute or chronic painful small-fiber neuropathy.
5. Painful small-fiber axonal neuropathy with associated gastrointestinal complaints and neuropsychiatric disturbances.

Differential diagnosis of AHPs during acute neurovisceral attacks and chronic presentation
1. Acute flaccid paralysis	GBS and variants; acute viral poliomyelitis (and polio-like virus); botulism; myasthenic crisis; periodic paralysis; HIV seroconversion; rhabdomyolysis; acute transverse myelitis; tick-paralysis; neuroparalytic snake envenomation.
2. Acute dysautonomia	GBS and variants; paraneoplastic disorders; idiopathic autoimmune postganglionic dysautonomia; systemic autoimmune disorders; toxic neuropathies.
3. Painful small-fiber neuropathy	Fabry disease; diabetes; hereditary TTR-related amyloidosis; toxic neuropathies; paraproteinemia; primary amyloidosis; paraneoplastic neuropathy; complex regional pain syndrome; vasculitis.
4. Neuropsychiatric disturbances	Primary psychiatric disorders; autoimmune encephalitis; brain tumor; other inherited neurometabolic disorders.
5. PRES	Hypertensive encephalopathy; neuroimmune disorders of the CNS; systemic inflammatory conditions; drug adverse/toxic event.
6. Dark-reddish urine	Drug-induced urine color; choluria; renal lithiasis; urinary tract infection; purple urine bag syndrome (urinary tract infection by Providencia sp., Klebsiella sp., Escherichia coli, Enterococcus sp., Pseudomonas sp.); macroscopic hematuria due to urinary tract neoplasia.
7. Abdominal pain with/without constipation	Deeply infiltrating endometriosis; pelvic congestion syndrome; chronic functional constipation; acute abdomen; inflammatory bowel disease; chronic lead poisoning.
8. Skin lesions	Cutaneous porphyrias; congenital epidermolysis bullosa; autoimmune bullous disorders; erythema multiforme; toxic epidermal necrolysis; paraneoplastic pemphigus; bullous pemphigoid; systemic vasculitis; staphylococcal scalded skin syndrome.

Safe drugs and therapeutic options for the treatment of acute hepatic porphyria patients^ Evidence-based drug safety assessment results vary among centers, foundations (e.g., ABRAPO), and expert opinions and are frequently updated according to new experimental and clinical evidence. All cited drugs and therapeutic options have their own risk of adverse events and their own porphyrinogenic-inducing potential. All illicit drugs of abuse and addiction (e.g., marijuana, lysergic acid diethylamide, heroin, amphetamines, ecstasy, crack cocaine, hashish, phencyclidine) and nicotine are considered unsafe and at high risk for acute decompensation in patients with acute hepatic porphyria.
Anesthetics	General anesthesia: Desflurane, Isoflurane, Propofol, Sevoflurane; Local use: Bupivacaine, Ethyl chloride, Prilocaine, Procaine, Tetracaine; Neuromuscular blockers: Pancuronium, Succinylcholine, Vecuronium.
Antineoplastic agents	Radioactive Iodine (I-131), Actinomycin D, Adriamycin, Amifostine, Asparaginase, Bleomycin, Carboplatin, Cisplatin, Cytarabine, Doxorubicin, Fludarabine, Thioguanine.
Antimicrobial agents	Aminoglycosides (Amikacin, Gentamicin, Streptomycin, Tobramycin); Antifungal agents (Amphotericin B, Caspofungin, Flucytosine, Nystatin); Antimalarials (Chloroquine, Atovaquone, Mefloquine, Primaquine, Proguanil, Pyrimethamine); Antimycobacterial agents (Ethambutol); Antiretroviral drugs (Abacavir, Zalcitabine); Antivirals (Acyclovir, Adefovir, Famciclovir, Foscarnet, Ganciclovir, Ribavirin, Valacyclovir, Valganciclovir, Zanamivir); Carbapenems (Doripenem, Imipenem, Meropenem); Cephalosporins (Cefaclor, Cefazolin, Cefepime, Cefotetan, Cefoxitin, Cefpodoxime, Ceftazidime, Ceftriaxone, Cefuroxime, Cephalexin); Fluoroquinolones (Ciprofloxacin); Penicillins (Amoxicillin, Amoxicillin/Clavulanate, Ampicillin, Penicillin, Piperacillin, Ticarcillin); Vancomycin.
Cardiovascular therapies	Antihypertensive drugs (Benazepril, Captopril, Enalapril, Lisinopril, Ramipril, Trandolapril; Candesartan, Losartan, Olmesartan, Valsartan, Eprosartan, Irbesartan, Telmisartan), Lipid-lowering drugs (Cholestyramine, Clofibrate, Colestipol, Ezetimibe, Rosuvastatin), Beta-blockers (Atenolol, Carvedilol, Esmolol, Labetalol, Metoprolol, Nadolol, Pindolol, Propranolol, Sotalol, Timolol), Diuretics (Acetazolamide, Amiloride, Bumetanide, Furosemide); Antiarrhythmic drugs (Adenosine, Digoxin, Flecainide, Procainamide), Isosorbide dinitrate, Diazoxide, Vasopressors (Dobutamine, Dopamine, Ephedrine).
Hematologic treatment	Anticoagulants (Unfractionated Heparin, Abciximab, Dabigatran, Dalteparin, Dipyridamole, Enoxaparin, Eptifibatide, Lepirudin, Protamine, Warfarin), Hemostatic agents (Aminocaproic acid, Aprotinin); Thrombolytic enzymes (Alteplase, Streptokinase, Tenecteplase); Tranexamic acid, Clopidogrel, Hydroxyethyl starch for plasma replacement, Filgrastim, Epoetin alfa, Cyanocobalamin.
Hormone therapy	Corticosteroids (Betamethasone, Cortisone, Fludrocortisone, Hydrocortisone, Prednisone, Triamcinolone), Conjugated estrogens, LHRH/GnRH agonists (Goserelin, Nafarelin), Ovulation stimulants (Clomid), Pituitary hormones (vasopressin/desmopressin, ergonovine, menotropin, methylergonovine, oxytocin, urofollitropin), chorionic gonadotropin, thyroid therapies (levothyroxine, liothyronine, propylthiouracil), octreotide, calcitonin.
Immunotherapy and vaccines	Abatacept, Adalimumab, Alemtuzumab, Anakinra, Belimumab, Certolizumab, Denosumab, Etanercept, Golimumab, Infliximab, Natalizumab, Rituximab; Interferon Alfa-2A or −2B, Interferon Gamma-1B; Antimicrobial vaccines: influenza, hepatitis B and A, Measles, Mumps & Rubella, Pneumococcal, Polio, Varicella; toxoids (Diphtheria, Tetanus, acellular Pertussis); Antivenoms^ Evidence-based drug safety assessment results vary among centers, foundations (e.g., ABRAPO), and expert opinions and are frequently updated according to new experimental and clinical evidence. All cited drugs and therapeutic options have their own risk of adverse events and their own porphyrinogenic-inducing potential. All illicit drugs of abuse and addiction (e.g., marijuana, lysergic acid diethylamide, heroin, amphetamines, ecstasy, crack cocaine, hashish, phencyclidine) and nicotine are considered unsafe and at high risk for acute decompensation in patients with acute hepatic porphyria. ; Azathioprine^ Evidence-based drug safety assessment results vary among centers, foundations (e.g., ABRAPO), and expert opinions and are frequently updated according to new experimental and clinical evidence. All cited drugs and therapeutic options have their own risk of adverse events and their own porphyrinogenic-inducing potential. All illicit drugs of abuse and addiction (e.g., marijuana, lysergic acid diethylamide, heroin, amphetamines, ecstasy, crack cocaine, hashish, phencyclidine) and nicotine are considered unsafe and at high risk for acute decompensation in patients with acute hepatic porphyria. .
Gastrointestinal drugs	H2 Antagonists (Cimetidine, Ranitidine), Antiemetics (Meclizine, Ondansetron), Bisacodyl, Esomeprazole, Omeprazole, Pantoprazole, Hyoscyamine, Scopolamine, Atropine, Loperamide, Senna.
Neuropsychiatric drugs	Antidepressants (Amitriptyline, Citalopram, Fluoxetine, Mirtazapine), Antiepileptic drugs (Gabapentin, Levetiracetam, Pregabalin, Vigabatrin, Zonisamide), Antimyasthenic agents (Ambenonium, Edrophonium, Neostigmine, Pyridostigmine), Antiparkinsonian drugs (Amantadine, Entacapone, Levodopa, Levodopa/carbidopa, Pramipexole), Benzodiazepines (Clobazam, Lorazepam, Oxazepam, Temazepam, Triazolam), Hypnotics (Chloral hydrate, Zolpidem), Neuroleptics and others (Chlorpromazine, Clozapine, Fluphenazine, Haloperidol, Lithium, Perphenazine, Prochlorperazine, Thioridazine), Trospium, Baclofen.
Pain therapy	Nonsteroidal anti-inflammatory drugs (Acetaminophen, Aspirin, Ibuprofen, Indomethacin, Ketoprofen, Naproxen, Sulindac), Narcotics (Alfentanil, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone); Antiepileptic drugs.
Respiratory agents	Acetylcysteine, Albuterol, Beclomethasone, Budesonide, Cetirizine, Chlorpheniramine, Cyproheptadine, Dextromethorphan, Diphenhydramine, Fexofenadine, Fluticasone, Guaifenesin, Hydrocodone, Ipratropium, Levocetirizine, Loratadine, Promethazine, Montelukast, Phenylephrine, Pseudoephedrine, Terbutaline.
Miscellaneous	Antidiabetic drugs (Metformin, Insulin), Antidotes (Deferoxamine, Dimercaprol, Edetate); Allopurinol, Aurothioglucose, Colchicine, Penicillamine, Pegloticase; Alendronate, Zoledronic acid; Contrast agents (Diatrizoate, Ethiodized, Ferumoxides, Gadopentetate, Iodipamide, Iodixanol, Iohexol, Iopanoic acid, Iopromide), Gadobutrol, Methacholine; Doxazosin, Prazosin, Finasteride; Naloxone.

[1] Correspondence: Wladimir Bocca Vieira de Rezende Pinto; E-mail: wladimirbvrpinto@gmail.com

Brasil

Brasil

Porfirias hepáticas agudas para o neurologista: conceitos atuais e perspectivas

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