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Conditions

Acute hepatic porphyria

Acute hepatic porphyria is a genetic condition with a variety of exacerbating factors, including genomic factors that determine if symptoms will occur. It is a challenging diagnosis to make. Clinicians should be aware how to achieve diagnosis so as to reduce complications.

Overview

Acute hepatic porphyria is an autosomal dominant disorder with low penetrance. It is characterised by acute episodes of neurovisceral symptoms with elevations in urinary porphyrin precursors and porphyrins. These affect women more (1.5–2 fold) than men and are rare before puberty. Attacks develop over hours/days and persist for days/weeks. An exacerbating factor (medications, sex hormones, smoking, alcohol, infection or fasting) is often apparent. A high index of suspicion is required for those in whom no alternative diagnosis is found.

Clinical features

The presentation is highly variable and the symptoms are non-specific. The most common symptoms are gastrointestinal and neurologic. These, with percentage proportions of patients that have that symptom, include:

  • abdominal pain (85%–95%);
  • vomiting (43%–88%);
  • constipation (48%–84%);
  • muscle weakness (42%–60%);
  • psychiatric symptoms (40%–58%);
  • limb, head, neck or chest pain (50%–52%);
  • hypertension (36%–54%);
  • tachycardia (28%–80%);
  • convulsion (10%–20%);
  • sensory loss (9%–38%);
  • fever (9%–37%);
  • respiratory paralysis (9%–14%); and
  • diarrhoea (5%–12%).

Most patients have complete resolution of their symptoms between attacks, which can develop over hours/days and persist for days/weeks.

Some patients develop chronic symptoms. These include:

  • severe chronic pain;
  • depression and anxiety;
  • persistent elevations in serum transaminases;
  • increased risk of liver cancers (hepatocellular carcinoma and cholangiocarcinoma), especially in those over 50 years of age;
  • hypertension; and
  • hypertensive chronic kidney disease.

Genomics

Acute hepatic porphyria results from a partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (HMBS). The estimated prevalence of patients with symptoms is about 1 in 100,000.

Disease severity is affected by various environmental factors that act primarily by increasing expression of delta-aminolaevulinic acid synthase (ALAS1), the initial and rate-controlling enzyme in the heme biosynthetic pathway in the liver.

A pathogenic variant in the HMBS gene can be identified by DNA testing (single gene sequencing). Data from population-level genomic studies show the pathogenic variants for acute porphyria are between 1 in 1,300 and 1 in 1,785.

Diagnosis

Acute hepatic porphyria is a rare and challenging diagnosis to make because there are numerous, more common, causes of non-specific neurovisceral abdominal pain. As such, diagnosis and treatment is often delayed. Therefore, a high index of suspicion for acute porphyria is needed, as the presenting findings are non-specific. Early diagnosis and treatment of symptomatic porphyria can avert future complications.

Diagnosis is based on biochemical findings in patients with symptoms. DNA testing is important for confirming the diagnosis and enables detection of family members with latent porphyria, who are at some risk for developing future symptoms.

Importantly, a negative family history is not helpful in excluding the diagnosis, because symptomatic porphyria may skip generations. Ethnicity is also not helpful, since porphyria occurs in individuals of all races and ethnicities. Imaging is not useful for diagnosing porphyria, but it may be performed to look for alternative aetiology.

Individuals with suspected acute porphyria should be tested to confirm the diagnosis.

  • Increased urinary delta-aminolaevulinic acid (ALA), porphobilinogen (PBG)(at least 5-fold), and porphyrin excretion during acute attacks. These levels may decline between attacks, so testing when symptoms are present is of greatest value.
  • Measurement of urine creatinine is important so PBG and porphyrin results can be expressed per gram or per millimoles of creatinine (PBG to creatinine ratio and porphyrin to creatinine ratio).
  • Substantial elevations in PBG (>10mg/L or >10mg/g creatinine, which is always accompanied by elevation in total porphyrins) is a highly specific finding and establishes the diagnosis.
  • Urine porphyrins should not be used alone as a screening test for acute porphyria.

DNA testing is usually obtained after a biochemical diagnosis is established. This strengthens the diagnosis and allows DNA testing of asymptomatic relatives.

Inheritance and genomic counselling

Acute porphyria is an autosomal dominant condition with low penetrance; because the individual is heterozygous for a pathogenic variant, activity of the affected enzyme is about half the usual level. Therefore, additional genomic, environmental or metabolic factors are necessary for the disease to become manifest. Most heterozygous individuals never develop symptoms. The estimated phenotypic penetrance of symptomatic disease is about 1% of porphyria gene carriers, with a penetrance of >20% in families with symptomatic patients.

Among symptomatic patients with porphyria, more than 90% experience only one to a few acute attacks in their lifetime. An estimated 3%–5% of patients with symptomatic porphyria experience frequent recurrent attacks (defined as four or more attacks per year).

Asymptomatic first-degree relatives are most readily diagnosed by DNA testing. Those found to have the variant should be counselled.

An individual with a pathogenic variant in HMBS but no symptoms is referred to as ‘having latent porphyria’, or, if urinary PBG is elevated, as ‘an asymptomatic high excretor’.

Management

Acute attacks

  • Symptomatic therapy with analgesia, anti-emetics, management of hypertension, electrolyte disturbance and treatment of paralysis, seizures and other potential disease manifestations can be initiated before a diagnosis of porphyria is confirmed.
  • Intravenous hemin infusion is usually given once daily at a dose of 3–4mg/kg (typically for four days). It is best given via a central vein owing to a risk of thrombophlebitis. Hemin rapidly down-regulates ALAS1 protein expression and activity in the liver, thus ameliorating the continued overproduction and accumulation of ALA and PBG. Symptom relief depends on elimination of excess ALA and PBG and typically requires 48–72 hours, although recovery from neurologic symptoms can vary significantly.
  • Patients should be counselled to avoid identifiable triggers that may precipitate an acute attack. Triggers can include alcohol, smoking, fasting or medications that induce cytochrome P450.
  • Patients with confirmed recurrent attacks could be considered for givosiran – a small interfering RNA (siRNA) therapeutic directed against hepatic ALAS1, the gene that is induced in individuals with active acute porphyria and thereby contributes to the accumulation of the heme intermediates ALA and PBG.
    • Givosiran is given at a dose of 2.5mg/kg once monthly by subcutaneous injection. Balwani and others showed, in a double-blind placebo-controlled phase-3 trial, that givosiran reduced acute attacks (by about 75%), pain score, urinary ALA and PBG levels and the use of hemin.

Long-term management

  • Monitoring of blood pressure, renal function, liver fibrosis and screening for liver cancer should be considered. In those over 50 years of age, an ultrasound for surveillance for hepatocellular carcinoma once every six months is advisable.
  • In rare cases, liver transplantation may be considered for patients disabled by recurrent attacks, without advanced motor neuropathy and who are unresponsive to treatment. However, it is difficult to weigh the risks and benefits of transplantation due to unpredictable natural course of the disease, which may progress or improve. These factors also complicate the decision regarding the timing of transplantation.
  • Primary liver cancer is another indication for liver transplantation in porphyria.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 28/02/2025
  • Next review due: 28/02/2027
  • Authors: Dr Robert A D Scott
  • Reviewers: Professor Guruprasad P Aithal