Porphyria

Everything you need to know ....well almost!

Cerys Lockett

UKPMIS, WMIC, Cardiff

Definition of Porphyria

Porphyrias are a group of inherited metabolic disorders of the haem biosynthesis pathway,

caused by a deficiency of one of the eight enzymes involved, leading to accumulation of

neurotoxic or phototoxic haem precursors. The conditions are characterised by acute

neurovisceral crises, skin lesions or both.

Ref: http://www.stepwards.com/wp-content/uploads/2015/12/porphyria-9-638.jpg

Haem biosynthesis pathway

Types of porphyria

ACUTE PORPHYRIAS

AIP = Acute intermittent porphyria

VP = Variegate porphyria

HCP = Hereditary coproporphyria

ALAD-deficiency porphyria = 5-aminolevulinic acid dehydratase deficiency porphyria

NON-ACUTE PORPHYRIAS

PCT = porphyria cutanea tarda

EPP = erythropoietic protoporphyria

CEP = congenital erythropoietic porphyria

There are many types of porphyria. What type of porphyria does your patient have?

Mechanism of an acute attack

• Acute porphyrias (AIP, VP and HCP) are conditions that can present with acute porphyria attacks.

• Due to the genetic defect there is a deficiency in one of the enzymes so

patients have a rate limiting step in the biosynthetic pathway during periods of increased requirements of hepatic haem biosynthesis.

• Although haem is produced, it is at the expense of excessive production of

neurotoxic precursors, porphyrins, 5-aminolevulinic acid (ALA) and porphobilinogens (PBGs).

• The consequence of which is the range of symptoms • Many things can increase requirements of hepatic haem biosynthesis

including reproductive hormones, fasting, stress, infection or certain porphyrinogenic drugs or alcohol.

Symptoms of acute attacks

• Gastro-intestinal: • Severe abdominal pain incl. nausea, vomiting, constipation

• Cardiovascular: • Hypertension, tachycardia, arrhythmias

• Peripheral motor neuropathy: • muscle weakness, loss of sensation, progressing to flaccid paralysis,

respiratory insufficiency

• Psychiatric: • Agitation, insomnia, confusion, delirium, disorientation, psychosis

• Central nervous system: • Hyponatraemia, convulsions

• Urine that turns orange / red / purple on exposure to visible light.

• Can be fatal

Acute porphyria attacks can be life threatening and severely disabling

• Early symptoms of an acute attack are:

• acute severe abdo pain, • nausea, vomiting, • constipation, • peripheral motor neuropathy, • paraesthesia

Acute Porphyria Attack Management

• Contact National Acute Porphyria Service (NAPS) for clinical support / advice

• Supportive treatments e.g. haem arginate

• BIPNET acute attack management guidelines

• UKPMIS for drug safety advice and guidance

How to assess risk of an attack Precipitating Factors

• Excessive alcohol

• Fasting / starvation

• Stress

• Infection

• Porphyrinogenic drugs – prescribed and illicit

• Hormone fluctuations

Risk Factors

• Women > men

• AIP > VP > HCP

• Susceptible age

• Previously suffered acute attacks (esp drug-induced)

• Recent / current porphyria attack

All factors are cumulative

How do drugs become involved?

• Induction of the haem synthetic pathway • Induce ALA synthase-1

• Induction of cytochrome P450 enzymes

• Female Sex Hormones • Mechanism unclear, but known to be porphyrinogenic

• Adverse drug reactions • e.g. nausea and vomiting ADRs may induce sufficient

physiological disturbance to trigger an acute attack

Precipitating factors are cumulative

Risk of Acute Attack

Stress

Hormonal fluctuations

Excessive alcohol

Porphyrinogenic drugs

Fasting / Starvation

Infection

Susceptible age

Female > Male

Porphyria history

“Is this drug safe to use in my patient who has porphyria?”

• Obtain patient details, porphyria type and history, indication of drug, etc.

• Consider all precipitating factors • UKPMIS safe list • BNF unsafe list • NAPOS / French / American safe lists • If any doubt, conflicting information, or enter the

‘grey area’ contact UKPMIS to discuss

N.B. Porphyrinogenic drugs only affect acute porphyria patients.

YES = AVOID

NO = AVOID YES = Seek specialist

advice from UKPMIS

Obtain patient details:

Porphyria type & status / Indication for the

drug in question

Is medication on the UKPMIS safe list?

N.B. check group names.

NO

On BNF unsafe list?

N.B. Check group names

NO

Safety information available?

e.g. NAPOS, French or American lists Benefit > Risk

YES = OK to USE

YES = OK to USE

Benefit > Risk

Confident that medication is safe

to use?

Acute Porphyria Drug Safety Enquiries Process

YES

NO

NO

UKPMIS Safe List

BNF Unsafe List

Your new BFFs….

UKPMIS safe list BNF unsafe list

UKPMIS

Any questions......?

Cerys.lockett@wales.nhs.uk

UKPMIS, WMIC, Cardiff

02920 742251 / 02920 743877

Useful resources 1 • National Acute Porphyria Service (NAPS) – 029 20747747 and ask for

NAPS. Available 24hr / day, 7 days / week

• UK Porphyria MI Service (UKPMIS) – 029 20742251 or via welshmedicines.information@wales.nhs.uk

• UKPMIS Safe List: http://www.wmic.wales.nhs.uk/pdfs/porphyria/2016PorphyriaSafeList.pdf

• BNF Unsafe List: accessed via BNF and search for ‘unsafe’

• Welsh MI Centre (WMIC): http://www.wmic.wales.nhs.uk/porphyria_info.php

• Multiple UKMi Q+A around the topic of acute and non-acute porphyrias available via https://www.sps.nhs.uk

• Scandinavian drug lists via NAPOS: http://www.drugs-porphyria.org/

• French lists: http://www.porphyrie.net/porphyries-et-medicaments/

• American lists: http://www.porphyriafoundation.com/drug-database

Useful resources 2 • British and Irish Porphyria Network (BIPNET) - Guidelines on managing

an acute porphyria attack: Ann Clin Biochem May 2013; Vol 50; No 3: pp. 217 – 223. Accessed via: http://acb.sagepub.com/content/50/3/217.full.pdf+html

• Lockett C, Badminton M. Safe Prescribing in the autosomal dominant acute porphyrias: a practical approach: Part I. Adverse Drug Reaction Bulletin August 2015; No 293: pp. 1131 – 1134

• Lockett C, Badminton M. Safe Prescribing in the autosomal dominant acute porphyrias: a practical approach: Part II. Adverse Drug Reaction Bulletin October 2015; No 294: pp. 1135 – 1138

• Puy H, Gouya L, Deybach J-C. Porphyrias. The Lancet 2010; Vol 375: pp. 924 – 937

• Harper P, Sardh E. Management of acute intermittent porphyria. Expert Opinion on Orphan Drugs 2014; Vol 2 (4): pp. 349 - 368

• European Porphyria Network (EPNET): http://porphyria.eu/