Knowledge on rare diseases and orphan drugs

In most European countries, the prevalence of acute hepatic porphyria (AHP) is about 1/75,000.

In 80% of cases, patients are women between 20 and 45 years old. In all acute hepatic porphyrias, neurovisceral attacks may occur and manifest by intense abdominal pain (85-95% of cases) lasting one to two weeks, neurological disorders (muscle weakness, sensory disturbance or convulsions), and psychological disturbances (irritability, anxiety, auditory or visual hallucinations, mental confusion). The episodes 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). In the majority of VP patients and in less than 15% of HC patients, skin lesions are present.

Each of the acute hepatic porphyrias is due to a deficiency of one of the enzymes in the heme biosynthesis pathway. These deficiencies lead to an accumulation of porphyrin precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver, and also, in the case of VP and HC, to an accumulation of porphyrins inducing cutaneous symptoms.

Diagnosis is based on the demonstration of significantly elevated ALA levels, and above all, PBG (pathognomonic of acute porphyria attack) and, occasionally, porphyrins in urine, stool and/or plasma. Biochemical and enzymatic assays followed by characterization of mutations in the corresponding gene help defining the type of porphyria.

The differential diagnosis includes Guillain-Barré syndrome and all causes of acute abdominal pain. For VP and HC, the differential diagnosis also includes photodermatoses. For ADP, the differential diagnosis must include type I tyrosinemia and lead poisoning.

Antenatal diagnosis may be proposed in families at risk of homozygous acute hepatic porphyrias.

Acute hepatic porphyrias are monogenic disorders with autosomal dominant pattern of inheritance (except for ADP, which is autosomal recessive). There is a 50% risk of transmitting the pathogenic variant from an affected individual to their offspring. Genetic counseling is recommended to patients and 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 attacks prevention (avoidance of triggers) and skin protection against light in the case of cutaneous symptoms.

In most cases, acute attacks do not recur throughout adult life, and the disease is rarely progressive. However, in some patients, episodes can reoccur necessitating repeated injections of human hemin. A new treatment based on ALAS1 siRNA, which prevents the recurrence of crippling acute episodes, may be proposed, thus removing the need for liver transplantation. AHP 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