Acute porphyrias : Diagnosis, complications and treatment options

Transcription

1 Porphyrins & Porphyrias / Patients Day Lucerne, May 18 th, 2013 Acute porphyrias : Diagnosis, complications and treatment options Pr Jean-Charles Deybach, MD, PhD Centre National Maladies Rares Porphyries INSERM U773 Hôpital Louis Mourier Hôpitaux Universitaires Paris Nord val de Seine Université D. Diderot Paris 7 Hôpital Louis Mourier U773

2 Human Porphyrias Obscure diseases with confusing names considered only when the need for a diagnosis is desperate (Pr Antony McDonagh, 1997) Red Urines Genetic disorders affecting the Heme biosynthetic pathway characterized by overproduction of reddish pigments called porphyrins and/or their precursors ALA & PBG

3 Heme Protoporphyrine IX + Fe 2+ O2 2 transport and storage Hemoglobin / Myoglobin CH 2 CH 3 Cellular respiratory chain Cytochromes H 3 C A N N B CH 2 O 2 Hepatic detoxification Cytochromes P450 H 3 C D N Fe N C CH 3 e- H2O2 2 metabolism Catalase / peroxydase Fe reduction Dcytb (duodenal cytochrome b) HOOC COOH Tryptophan catabolism Tryptophan 2,3 dioxigenase Prostaglandins synthesis Cyclooxigenase

4 Heme Biosynthesis "Precursors" ALA > PBG Porphyrin(ogen)s Uro > Copro > Proto Fe 2+ Heme Raw materials Intermediate products Final product ALA : δ Aminolevulinic acid, PBG : Porphobilinogen

5 Heme Biosynthesis in Human Cell MITOCHONDRIE CYTOSOL Ferrochélatase Protoporphyrine IX PROTOgène 7 oxydase Protoporphyrinogène IX Succinyl CoA 1 ALA-déshydrase + Acide Porphobilinogène glycine -aminolévulinique 2 ALA-synthase HMB-synthase HEME 8 Fe 2+ 6 COPROgène III oxydase Uroporphyrinogène III 5 UROgène III synthase UROgène III décarboxylase Copr oporphyrinogène III 4 3 Hydroxyméthylbilane

6 I Heme Synthesis and Human Porphyrias (Mitochondria) (Cytosol) EPP Ferroche latase Protoporphyrin IX Fe 2+ PROTO gen oxydase VP Protoporphyrinogen IX ADP XLDPP Succinyl CoA ALA-dehydratas e + ALA-synthase 2 Acide Porphobilinogen glycine -aminolevulinique (PBG) ALA-s ynthase 1 PBG-deaminase HAEM COPROgen III oxydase HCP UROgen III synthase Uroporphyrinogen III C oproporphyrinogen III Hydroxymethylbilane CEP UROgen III dé carboxylase PCT AIP Spontane ous cy clisation Uroporphyrinogen I Coprop orph yrinogen I

7 Classification Hepatic porphyrias (adult) (ALAD Deficiency Porphyria, ADP) Acute Intermittent Porphyria, AIP Hereditary Coproporphyria, HC Variegate Porphyria, VP Porphyria cutanea tarda, PCT Erythropoietic porphyrias (child) symptoms Acute attacks Bullous Skin lesions Congenital Erythropoietic Porphyria, CEP Erythropoietic Protoporphyria, EPP X linked Dominant Protoporphyria, XLDPP Acute Photo sensitivity

8 Acute Hepatic Porphyrias AIP acute intermittent porphyria VP variegate porphyria HCP hereditary coproporphyria

9 I Heme Synthesis and Human Porphyrias (Mitochondria) (Cytosol) EPP Ferroche latase Protoporphyrin IX Fe 2+ PROTO gen oxydase VP Protoporphyrinogen IX ADP XLDPP Succinyl CoA ALA-dehydratas e + ALA-synthase 2 Acide Porphobilinogen glycine -aminolevulinique (PBG) ALA-s ynthase 1 PBG-deaminase HAEM COPROgen III oxydase HCP UROgen III synthase Uroporphyrinogen III C oproporphyrinogen III Hydroxymethylbilane CEP UROgen III dé carboxylase PCT AIP Spontane ous cy clisation Uroporphyrinogen I Coprop orph yrinogen I

10 Clinical manifestations Acute neurovisceral symptoms associated with accumulation of precursors (ALA,PBG) and/or cellular heme deficiency Skin lesions sunlight-induced (photosensitivity), due to porphyrin accumulation in the skin

11 Clinical Presentation in Hepatic Porphyrias

12 Skin lesions in Variegate Porphyria similar in PCT bullous photodermatosis

13 Common case report of acute attacks of porphyria (1) Woman, age 30-40, recurrent periods of abdominal pain sufficiently severe for hospitalization associated with back pain, nausea, vomiting, constipation, insomnia, irritability frequently before the menses. Important loss of weight and weakness after weeks, and sometimes dark or red urines

14 Common case report of acute attacks of porphyria (2) At first attack : No diagnosis at Emergency Dept All physical examination normal. Opiates only active on pain But after recurrent venue : Surgeon or psychiatrist or both consulted differential diagnosis of opiates addiction, polyradiculonevritis, appencitis Often severe consequences with increased pain, extensive paralysis, mental disturbances Diagnosis too often made in ICU on red urine and differential diagnosis of polyradiculonevritis

15 Acute Porphyrias Symptoms in Patients Needing Hospitalization Copyright H Bonkovsky 15

16 Acute Porphyrias Signs in Patients Needing Hospitalization Copyright H Bonkovsky 16

17 Porphyric Neuropathy Autonomic Abdominal pain Constipation Vomiting Hypertension Tachycardia Peripheral Motor neuropathy Extremity pain CNS Anxiety Hallucinations Agitation Epilepsy

18 Acute Porphyria s Neuropathy More common in females than males (5:1) Acute attacks are very rare before puberty and less common after menopause. The peak incidence is in the 3 rd & 4 th decade. Symptoms/signs. Severe abdominal pain mimicking acute abdomen without localising features is almost universal. Vomiting, constipation Psychiatric symptoms include anxiety, confusion, hallucinations occur during an attack but this does not result in chronic psychiatric illness Hypertension, tachycardia, due to autonomic dysfunction Convulsions: may be primary or secondary to a rapid onset of profound hyponatraemia Motor neuropathy may progress from a mild initial presentation to progressive, severe with complete paralysis 18

19 Diagnosis First Line- Acute porphyric attack Urine porphobilinogen (random urine) protected from light, preferably first morning sample Second Line -Establish Type of Porphyria Total Urine and faecal porphyrin and individual porphyrins measured by HPLC as well as a plasma porphyrin scan allows an unequivocal biochemical diagnosis in symptomatic patients. AIP Urine Faeces PlasmaFluorescence EmissionPeak(nm) ALA,PBG Uroporphyrin Normal HCP ALA,PBG,Copro(III) CoproIII VP ALA,PBG,Copro(III) Proto>CoproIII

20 Management of acute porphyria attack 1. General Remove/treat precipitating factors such as drugs, infection Symptomatic relief with analgesics (opiates+chlorpromazine) IV fluids (N-saline) plus carbohydrates (dextrose/glucose) Specific : IV human Hemin (Normosang) binds albumin, is taken up by the liver and suppresses the metabolic pathway by down regulating ALA Synthase 2. Prevention Identify relatives at risk through family studies. This requires mutation screening of the proband first and then mutation testing in relatives. Affected relatives are then advised to avoid known precipitants

21 Human haemin in acute attacks Haem arginate NORMOSANG Orphan Europe Composition per ampoule Human haemin : 250 mg Arginine : 267 mg ethanol 96% : 1000 mg propylene glycol : 4000 mg water for injection Haemin PANHEMATIN Lundbeck, USA Per vial : Human haemin : 313 mg Sodium carbonate : 215 mg Sorbitol : 300 mg Both now in Recordati panel

22 Human haemin in acute attacks Early human haemin infusion is highly effective Rapid clinical improvement Decreased urinary ALA/PBG Mean abdominal pain duration 2-3 days 2-3 days Hift & Meissner, 2005 Effect of haem therapy on symptom severity score

23 Human haemin in acute attacks Early human haemin infusion is highly effective Rapid clinical improvement Decreased urinary ALA/PBG Mean abdominal pain duration 2-3 days 2-3 days No further severe neurological complications No major side effects in acute administration Safe use during pregnancy (Badminton & Deybach, 2006; Marsden & Rees, 2010)

24 Management of different clinical presentations in AHP Acute attack >severe enough pain for hospitalization Rational for Human Hemin (Normosang ) use : In unknown patients : if ALA/PBG and clinical signs of severity (neurological symptoms) In all patients with neurological symptoms In recurrent patients, start with one prophylactic dose In sporadic known patients, try first symptomatic treatment : glucose, opiates, chlorpromazine

25 Precipitating or Aggravating Factors in Acute Porphyric Attack Drugs and chemicals Alcohol Estrogens Sulfonamides Hydantoins Barbiturates Progestagens Other inducers of hepatic cytochrome(s) P ALA synthase-1 Luteal phase of menstrual cycle Pregnancy and post-partum period Infection Stress / exhaustion Fasting / starvation Surgery / anesthesia

26 Prevention through Family Screening (Presymptomatic Patients Detection) to minimize risk of acute attack Specific Heme Synthesis Enzyme Defect : porphyria reference lab only (! probabilistic approach) Specificity ~ 90% Sensitivity ~ 80% DNA analysis : Molecular diagnosis identification of specific family mutation identification of presymptomatic carriers in patient family (certitude) Specificity >90% Sensitivity >90%

27 Pathophysiology (1) : Specific Biochemical Condition in Acute Porphyric Attacks Markedly increased activity of ALA synthase In the liver Increased production, accumulation and excretion of ALA and PBG specific porphyrin excretion profile depending on the location of the enzymatic defect

28 Pathophysiology (2) : Evidence for ALA implication 1. Acute attacks of porphyria associated with increased activity of hepatic ALA synthase and increased ALA production and excretion 2. Treatments considered effective for AIP, e.g., heme infusion, high carbohydrate intake, also lower ALA synthase 1 activity and ALA production 3. In ALAD-deficiency porphyria, tyrosinemia type I, and acute lead poisoning, urinary ALA excretion is markedly increased (PBG is not) 4. In these conditions, symptoms resembling those of acute porphyria, such as abdominal pain and peripheral neuropathy, occur 28

29

30 Hepatic heme synthesis FECH ALAD UROIIIS UROD Glyc ALAS PBGD CPO PPOX Fe + Succ _ AIP HC VP HEME ALA, PBG, Porphyrins

31 Genetics and epidemiology of Acute Hepatic Porphyrias Autosomal dominant (mutation in one of the 2 alleles of the gene) Low penetrance (carrier/patients : 1-10%) Prevalence : 1/ ? Mutated gene (AIP) : 1/1600 or less Molecular defect : wide allelic heterogeneity Low rate of de novo mutation (3%) No phenotype genotype relationship? Incidence EU countries : 0.12 new case/10 6 /year (Switzerland and Sweden : 0.52 ; founder effect?)

32 Complications in Acute Hepatic Porphyrias Recurrent Porphyric Attacks (2-8%) Chronic renal failure (35 to 60 %?) Progressive tubulo interstitial nephropathy Hepato-Cellular Carcinoma (1%) Relative risk x 36

33 New patients 40,000 asymptomatic carriers (Nordmann et al, 1997) AIP clinical course in France 581 symptomatic patients (81% female) Acute attack Patients in remission 88%? Intermittent patients 5% >1 attack <4 / year Types of clinical course Recurrent patients >4 attacks 7% / year Classification

34 Recurrent patients in France Cumulative number of recurrent patients 1 st use Marketing authorization Already exist before the introduction of human haemin treatment (1986 in CFP) Haem treatment seems to have : - selected a small number of recurrent patients - shortened the interval between crisis

35 Recurrent patients in France Since 1974 : 43 patients with recurrent acute attacks : AIP only - 35 women (81%) - 8 men (19%) Currently : 32 recurrent patients of whom 18 receive prophylactic human haemin & opiates + 4 in remission since many years + 4 had liver transplantation (one died) + 3 died

36 Liver Transplant as a Therapy for AIP Lancet (2004) 363: Acute porphyric attacks always associated with increased hepatic production of ALA and PBG Liver transplantation corrects hepatic enzyme defects and normalizes excretion of ALA & PBG Limitations : Transplant patients continue to have partial defects in normal heme synthesis in all nonhepatic tissues and organs, including neurons and glia Morbidity and Mortality? Not reversible Which patients? 36

37 Recurrent AIP patients Almost all of the patients have : Poor quality of life Nutritional deficiency (Delaby et al, 2009) Hard smocking addiction (Lip et al, 1991) Opiate addiction

38 Human Hemin Long-term Toxicity Venous network toxicity Indwelling venous access (Portacath ) is mandatory High cumulative dose of haem and iron (22 mg/amp) High ferritin level

39 Iron status in recurrent AIP patients 26 patients : Serum Ferritin levels - Median : 680 µg/l (range : ) - Increased for 84% of these patients - Above 1000 µg/l for 7 patients Liver MRI in 10 patients : - Confirmed iron overload in 9 patients - Iron liver content > 230 µmol/g (N<30) in 5 patients Serial phlebotomies or chelator treatment for 10 patients

40 Recurrent patients in Europe 3 year study in 11 european countries (Elder et al, J Inherit Metab Dis 2012) 67 patients with recurrent acute attacks - 64 AIP: 53 females, 11 males - 3 VP: 2 females, 1 male - 0 HCP In Europe : 3-5% AIP patients with recurrent acute attacks

41 Summary on recurrency Recurrent AIP patients spread all over Europe Recurrency already known before the introduction of human haemin but to a lesser extent Recurrent AIP patients under frequent human haemin infusion : - Increased risk of Iron overload - Moderate signs of inflammation in the liver - Balanced induction between HO1 and ALAS1 in the liver

42 Treatment and Future Options Human haemin Treatment of choice for severe acute attacks However..repeated infusions could lead to severe side effects A two face molecule New treatment strategies for recurrent patients Gene therapy (AIPGENE Project) ongoing sirna targeting ALAS1 (Alnylam) 2014?

43 European Porphyria Network (EPNET) European Network of Center of Expertise for Porphyria : To Improve knowledge for patients and healthcare professionals, therapeutic care of patients and to promote research in the field BOARD Jean-Charles Deybach Mike Badmington Pauline Harper Samantha Parker Sverre Svandberg INSERM U773 Centre Français des Porphyries Jean Charles Deybach Laurent Gouya Hervé Puy Sarah Ducamp Saïd Lyoumi Caroline Schmitt Neila Talbi

44

45

46

47

48