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Acute hepatic porphyrias

Author: Dr CR Towns, University of Otago, Wellington Hospital, Wellington, New Zealand. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. June 2020.


What is porphyria?

Porphyria is a group of inherited metabolic disorders in which there is a build-up of haem precursors. They are classified into the acute hepatic porphyrias and the chronic cutaneous types of porphyria.

The resultant health problems depend on specific enzyme deficiencies in the haem pathway.

What is an acute hepatic porphyria?

There are 4 acute hepatic porphyrias. They are characterised by recurrent acute attacks of severe ‘neurovisceral’ abdominal pain.

The autosomal dominant acute porphyrias are:

  • Acute intermittent porphyria (AIP)
  • Variegate porphyria (VP)
  • Hereditary coproporphyria (HCP)
  • Delta aminolaevulinic acid dehydratase porphyria.

The presentation, initial diagnosis, and management of acute attacks are identical for AIP, VP, and HCP. Skin lesions can occur in variegate porphyria and hereditary coproporphyria, but do not occur in acute intermittent porphyria [1].

Delta aminolaevulinic acid dehydratase porphyria, a hepatic porphyria resulting from low levels of the enzyme delta-aminolevulinic acid dehydratase, has autosomal recessive inheritance with very few case reports in the literature and is not considered here.

Who gets acute hepatic porphyria?

Acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria occur globally, but some regions have higher prevalence due to founder effects (eg, acute intermittent porphyria in Sweden and variegate porphyria in South Africa). Worldwide, acute intermittent porphyria is the most common and hereditary coproporphyria is the least common. Both men and women are equally affected.

Most patients with acute porphyria will not suffer acute attacks — penetrance is low at 10% or less [1].

What causes acute hepatic porphyria?

The porphyrias are due to inherited mutations in the haem synthesis pathway [2]. The reduced enzymatic function results in a build-up of haem precursors.

The accumulation of aminolaevulinic acid and porphobilinogen is believed to cause the neurovisceral features, but the pathophysiology is poorly understood.

Acute attacks occur when the first enzyme in the pathway, aminolaevulinic acid synthase (ALAS1), is induced. Triggers include:

  • Prescribed or recreational drugs
  • Endogenous female hormones
  • Decreased carbohydrate intake (from fasting, dieting, or intercurrent illness)
  • Alcohol.

What are the clinical features of acute porphyria?

The three autosomal dominant forms of acute porphyria have similar features.

Acute neurovisceral attacks

Porphyria attacks can range from mild to severe. Patients typically describe severe but diffuse abdominal pain during attacks. Similar pain can occur in the proximal limbs and back.

Non-specific symptoms are common, such as subjective sensory changes, fatigue, nausea, vomiting, and constipation. Up to 60% of patients with an acute porphyria will develop chronic pain between attacks [3].

Cutaneous features

Variegate porphyria and hereditary coproporphyria may have coexisting skin lesions in the context of an acute neurovisceral attack or separately. They are similar to those found in porphyria cutanea tarda.

The most common skin symptom is photosensitivity. Blistering, erosions, and milia may also occur.

Variegate porphyria

What are the complications of acute hepatic porphyria?

Complications of porphyria can include [4,5]:

  • Seizures, neuropathies, and rarely, posterior reversible encephalopathy
  • Hyponatraemia due to secretion of inappropriate antidiuretic hormone
  • Tachyarrhythmias
  • A variety of psychiatric features.

Longer-term complications include:

  • Deranged liver enzymes and higher rates of hepatocellular cancer
  • Renal impairment
  • Hypertension
  • Scarring and thickened skin in those with skin lesions.

Given the severity and recurrent nature of the pain, porphyria patients may be at increased risk of opioid misuse and dependence [6,7].

How is an acute porphyria diagnosed?

Porphyria may be suspected clinically, but must be confirmed by laboratory tests [1,2].

The most important immediate test is a measurement of light-protected urinary porphobilinogen.

  • A normal porphobilinogen in an unwell patient excludes acute porphyria.
  • A false positive can occur in dehydrated patients with concentrated urine; a quantitative urinary porphobilinogen corrects for creatinine and can overcome this problem.

Urinary porphyrins may also rise in an acute attack, but are less specific as urinary porphyrins may occur in infections, hepatobiliary disease, haematological disorders, heavy metal exposure, and lead poisoning.

Once an acute attack is confirmed, blood and faecal samples are tested to determine the subtype of porphyria. Samples should be sent to an accredited laboratory or one familiar with porphyria testing (listed on the Australia Porphyria Association website).

A skin biopsy of cutaneous lesions in variegate porphyria and hereditary coproporphyria has similar findings to porphyria cutanea tarda.

What is the treatment of an acute porphyria?

The pain of acute attacks can be severe, requiring hospitalisation for pain management and a lead-up to other possible causes of pain. Severe electrolyte imbalance, respiratory distress, or seizures should prompt admission to intensive care.

Recommended treatments to suppress ALAS1 include [1,2]:

  • Glucose (or dextrose), providing sodium is normal and stable (this approach is considered controversial) [1]
  • Intravenous haematin (haem arginate) given through a central line (a peripherally inserted central catheter (PICC) line or an implanted Portacath®
  • Recent evidence has suggested that haematin may promote inflammation and increase the risk of recurrent attacks so it should only be used in confirmed attacks [8].

Drugs that are potential triggers of acute attacks must be avoided. The drugs below are considered safe at the time of writing (June 2019) [9].

Safe drugs for pain

Pain-management drugs that are safe to use during treatment for acute porphyria include:

Safe drugs for vomiting

Emetics that are safe to use during treatment for acute porphyria include:

  • Metoclopramide
  • Prochlorperazine
  • Ondansetron.

Safe drugs for seizures

Anticonvulsants that are safe to use during treatment for acute porphyria include:

  • Midazolam
  • Lorazepam
  • Levetiracetam.

Sun protection is important for patients with cutaneous porphyria, using covering clothing and an opaque sunscreen that blocks visible light. Topical dihydroxyacetone (tanning cream) may also be useful in blocking some of the visible light. Vitamin D supplements may be required.

All porphyria patients should wear a medical alert bracelet.

Porphyria patients have increased risk for hypertension and renal impairment as well as hepatocellular cancer; some services recommend annual screening with liver ultrasound [1].

Future treatment

Givosiran is a synthetic small interfering ribonucleic acid (siRNA) molecule currently in clinical trials. It has been shown in a Phase 1 study to reduce aminolaevulinic acid and porphobilinogen as well as decrease acute attacks [10].

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References

  1. Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematology 2017; 176: 527–38. DOI: 10.1111/bjh.14459. PubMed
  2. Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. Review Article. N Engl J Med 2017; 377: 862–72. DOI: 10.1056/NEJMra1608634. Journal
  3. Gouya L, Ventura P, Balwani M, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology 2020; 71: 1546–58. DOI: 10.1002/hep.30936. PubMed
  4. Dagens A, Gilhooley MJ. Acute intermittent porphyria leading to posterior reversible encephalopathy syndrome (PRES): a rare cause of abdominal pain, and seizures. BMJ Case Rep 2016; 2016: bcr2016215350. DOI: 10.1136/bcr-2016-215350. PubMed
  5. Lambie D, Florkowski C, Sies C, Raizis A, Siu WK and Towns C. A case of hereditary coproporphyria with posterior reversible encephalopathy and novel coproporphyrinogen oxidase gene mutation c.863T>G (p.Leu288Trp). Ann Clin Biochem 2018; 55: 616–9. DOI: 10.1177/0004563218774597. PubMed
  6. 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; 84: 48–60. DOI: 10.1097/01.md.0000152454.56435.f3. PubMed
  7. Towns C, Mee H, McBride S. Opioid dependence with successful transition to suboxone in a young woman with hereditary coproporphyria. New Zealand Medical Journal 2020. In press. Journal
  8. Schmitt C, Lenglet H, Yu A, et al. Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver. J Intern Med 2018; 284: 78–91. DOI: 10.1111/joim.12750. PubMed
  9. The Drug Database for Acute Porphyria. ‘Safe Drugs List’, 2019. Available from: www.drugs-porphyria.org [cited June 2020].
  10. Sardh E, Harper P, Balwani M, et al. Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med 2019; 380: 549–58. DOI: 10.1056/NEJMoa1807838. Journal

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