Acute Porphyria. Penelope Stein Haematological Medicine, King s College Hospital, London

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1 Acute Porphyria Penelope Stein Haematological Medicine, King s College Hospital, London

2 Why is acute porphyria important? Easy to miss - rare, non-specific presentation Severe attacks may be life-threatening

3 Case 1 Female aged 17 Abdominal pain, aching legs, vomiting, constipation for 4 days Symptoms started day after a party Last menstruation 3 weeks earlier Examination - pulse 96, BP 130/85, abdominal tenderness, no guarding/rebound Investigations - Na 133 (fbc, LFTs normal) Admitted to hospital for observation

4 Case 1 - Next few days Weakness, confusion, tachycardia, hypertension Worsening hyponatraemia (Na 110) Red urine noted on day 7 Acute attack of porphyria confirmed by finding increased urine porphobilinogen (PBG) Started intravenous glucose 5% Deteriorated with seizures, hallucinations, Day 10 - Respiratory arrest, died

5 Light-exposed urine in acute attack

6 Case 1 - after death Post mortem - cerebral oedema and herniation of cerebellar tonsils Later biochemical analysis confirmed acute intermittent porphyria Genetic screening of family showed sequence variant in hydroxymethyl bilane synthase (HMBS) gene in mother, brother, maternal grandmother - all asymptomatic

7 Case 1 - what went wrong? Porphyria attack triggered by alcohol, hormonal factors Delayed diagnosis Inappropriate management intravenous glucose potentiated hyponatraemia No haem arginate

8 Porphyrias Partial deficiencies of enzymes in haem synthesis pathway Almost all inherited Haem precursors accumulate in blood and tissues, excreted in urine and faeces

9 Haem synthesis HAEM Bone marrow 85% Liver 14% Other tissues 1%

10 Liver haem synthesis James, M. F. M. et al. Br. J. Anaesth : ; doi: /bja/

11 Acute porphyrias Acute intermittent porphyria, AIP Variegate porphyria, VP Hereditary coproporphyria, HCP (Aminolevulinic acid dehydratase deficiency porphyria, ADP - extremely rare) All characterised by acute attacks -?toxic effects of ALA on central, peripheral and autonomic nervous systems

12 Acute porphyrias - inheritance Inheritance of AIP, VP and HCP is autosomal dominant with low penetrance Less than 5% gene carriers have symptoms (overt), most stay well (latent) Penetrance determined by environmental and genetic factors

13 Acute porphyrias - prevalence Overall prevalence of overt acute porphyria in Europe is 10 per million AIP > VP > HCP Most attacks in females aged 18-45, rare before puberty or after menopause

14 Acute porphyrias - presentation Acute attacks - most common presentation is with 1 or 2 sporadic attacks in lifetime, rarely recurrent attacks Light sensitive skin problems only seen in VP and HCP

15 Light-sensitive skin problems in VP

16 Acute attacks - triggers Hormonal factors - luteal phase of menstrual cycle (high progesterone) Drugs eg hormonal contraception, some antibiotics, anticonvulsants, antiretrovirals Alcohol - especially binge drinking Starvation/dieting Stress, intercurrent illness All induce haem synthesis through direct effect on ALAS1 or depletion of haem

17 Acute attacks - clinical features Severe poorly-localised abdominal pain, pain in back and thighs, nausea, vomiting, constipation Hypertension and tachycardia Hyponatraemia Weakness, paralysis, seizures (axonal neuropathy, posterior reversible encephalopathy syndrome) Agitation, insomnia, confusion, psychosis

18 Mental health problems and porphyria Acute psychiatric features may occur during attacks No excess risk of long term psychiatric disorders (with possible exception of anxiety and depression) No evidence that George III had any form of porphyria

19 Diagnosis of acute attack: urine porphobilinogen (PBG) concentration Random 10ml urine sample Plain bottle with no preservative Protect from light Collect when symptoms present Urine PBG always raised in an acute attack May need to send to specialist centre for testing

20 Identifying type of acute porphyria Need samples of urine, EDTA blood, stool (all protected from light); send to specialist laboratory DNA analysis of relevant gene Not urgent, doesn t affect immediate management

21 Clinical assessment in acute attack Overall condition, hydration, pain score Pulse and blood pressure Check for neuropathy - motor power etc Identify and remove triggers - drugs, infection Exclude other causes of abdominal pain Think about vascular access (for haem arginate) Investigations should include full blood count, serum sodium, light protected urine sample for PBG

22 Check safety of all medication Including prescribed and over-the-counter drugs UK safe drug list updated annually European drug database - interactive

23 Treatment of acute attack Analgesia - opiates, involve pain team Supportive treatment with safe drugs Oral carbohydrate if tolerated Intravenous saline if vomiting or hyponatraemic Haem arginate indicated for all severe attacks Severe pain/vomiting, neuropathy, seizures, hyponatraemia Intravenous carbohydrate loading obsolete in UK (risk of hyponatraemia)

24 Haem arginate (Normosang ) Orphan drug, expensive Suppresses liver haem synthesis Dose: 3 mg/kg daily on 4 consecutive days Dilute in 100 ml saline (or albumin) Infuse over mins, preferably via central line with 15-20m filter, protect from light Flush line immediately with lots of saline Shortens attack, prevents/halts neuropathy

25 Follow up after acute attack Patient information - British Porphyria Association has useful website with leaflets Review medication, up-to-date safe drug list Discuss contraception in females Consider MedicAlert jewellery Genetics and family screening Long term monitoring - increased risk of chronic kidney disease, hypertension, hepatocellular carcinoma

26 Recurrent attacks (> 4 per year) Very rare, patients in UK, most AIP Complex problems - chronic pain, neuropathy, depression, disability, frequent admissions Refer to porphyria specialist Management strategies Ovulation suppression in females Prophylactic haem arginate Liver transplantation (last resort)

27 National Acute Porphyria Service (NAPS) Highly specialised service commissioned in 2012 National centres at King s College Hospital, London and University Hospital of Wales, Cardiff Regional centres at Leeds and Salford Specialist support for patients in mainland Britain with one-off or recurrent attacks Clinics, outreach, phone advice, provide haem 24/7 emergency number (details in BNF under haem arginate)

28 Case 2 Female aged 22, first pregnancy Repeated hospital admissions with abdominal pain and vomiting Confirmed urinary tract infections and bilateral hydronephrosis Ureteric stents inserted at 31/40

29 Case 2 - next 7 days Seizures, abdominal and back pain, vomiting Persistent tachycardia and hypertension Examination and investigations otherwise unremarkable Diagnosis of possible eclampsia Emergency Caesarean section - healthy baby girl

30 Case 2 - after delivery More seizures, agitated, strange behaviour, stayed in bed, stopped eating, incontinent Pulse 120, BP 155/100 Examination showed symmetrical motor weakness of upper and lower limbs Na 125 Brain MRI - consistent with PRES Transferred to teaching hospital. Paramedic elicited family history of porphyria

31 Case 2 - what should you do? Contact National Acute Porphyria Service Urgent urine PBG Symptomatic/supportive management - correct hyponatraemia, respiratory support Check all medication for safety in acute porphyria Start haem arginate when attack confirmed by high urine PBG

32 Case 2 - what happened? Urine PBG 177 mmol/mmol creatinine (N <1.5) and subsequent tests confirmed AIP Treated with haem arginate - several courses Ventilated on intensive care unit for 4 months, further 3 months rehabilitation 1 year later - able to walk Developed recurrent attacks, managed with prophylactic haem arginate 10 years later - weaning from haem, residual neuropathy in hands and feet

33 Summary Suspect acute porphyria in young women with recurrent abdominal pain hyponatraemia Neurological/psychiatric features Confirm diagnosis with urine PBG Haem arginate is specific treatment, avoid iv glucose. Advice available 24/7 from National Acute Porphyria Service

34 ANY QUESTIONS?