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This is the most frequent and severe form of acute hepatic porphyria. Its prevalence in Europe is about 1/75,000. The disease generally manifests after puberty, predominantly affecting women (80% of cases).

Patients suffer intermittent neurovisceral attacks lasting several days and repeat over several weeks. They manifest as severe abdominal pain (>95% of patients), neurological disorders, and/or psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, nausea, vomiting, and severe constipation. Several psychological disturbances can be observed: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during attacks. In the rare case of cardiac arrhythmia or respiratory paralysis, the attacks can be fatal. The attacks are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle).

The disease is caused by a deficiency in porphobilinogen deaminase (PBG-D, the third enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrins and their precursors (aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the HMBS gene (11q23.3; NM_000190.4) coding for PBGD.

Reddish or brown coloration of urine following exposure to warm light is suggestive of the disease. Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria) and ALA in urine, and 50% residual PBGD activity in red blood cells (but not always found during attacks). Identification of a causal mutation of the HMBS gene confirms the diagnosis.

Differential diagnosis includes other acute hepatic porphyrias, and is based on porphyrin analysis in urine, stool, and plasma.

Antenatal diagnosis may be offered in families at risk of homozygous acute intermittent porphyria (AIP).

Transmission is autosomal dominant, with very low penetrance. Genetic counselling is recommended to patients and their families to identify individuals at risk of developing or transmitting the disease.

Acute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of attacks (avoidance of triggers, particularly drugs).

In most cases, acute attacks of AIP do not recur throughout adult life, and the disease is rarely progressive. However, in some patients, attacks can reoccur, necessitating repeated injections of human hemin. A new ALAS1 siRNA-based treatment to prevent the recurrence of crippling acute attacks may be proposed, thereby delaying the need for liver transplantation. AIP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.

Last update: March 2024 - Expert reviewer(s): Dr Neila TALBI | MetabERN*

* European Reference Network