acute hepatic porphyria (AHP)

Last edited 11/2021 and last reviewed 12/2021

Acute hepatic porphyria (AHP) is a rare inherited metabolic disorder caused by a deficiency of the enzymes needed to make haem

• characterised by high levels of porphyrin precursors, including delta-aminolevulinic acid and porphobilinogen, in the liver and other tissues
• high levels of these substances damage nerve cells and can provoke acute attacks of physical pain
• acute attacks are very rare before puberty and usually start between 15 and 35 years
• are more common in women, who may be at increased risk of having an acute attack during or after pregnancy.
• acute attacks are often triggered by factors such as drugs, alcohol, hormones, and infection
• AHP is life-threatening because it can lead to seizures and paralysis during acute attacks
• can be debilitating in the long term because of chronic pain, fatigue, nausea and vomiting. AHP is progressive, with attack frequency and severity increasing over time
• condition varies from person to person
• are 4 types of AHP (1,2):
  • acute intermittent porphyria
    • Acute intermittent porphyria is the most common form of AHP in the UK and has the highest symptom burden (3)
  • hereditary coproporphyria,
  • variegate porphyria
  • aminolevulinate dehydratase porphyria - the rarest one, aminolevulinic acid dehydratase porphyria (ADP), of which only six definite cases have been reported (1)

Prevalence of symptomatic AHP

• estimated to be 1 in 100,000 people in Europe, which equates to about 560 people in England
• most people recover after 1 attack or a few attacks, but attacks can be recurrent in about 10% of people
• people with recurrent severe attacks often have chronic symptoms and may not fully recover from an attack
• according to the National Acute Porphyria Service, there are 27 people in the UK having treatment for recurrent severe attacks

Treatment of AHP:

• treatment options for AHP aim to prevent attacks or manage symptoms
  • include pain management, stopping medication that could have triggered symptoms, gonadotrophin releasing hormone (GnRH) analogues for hormone-induced attacks in women, and oral or intravenous glucose for acute attacks
  • haem arginate is indicated for treating acute attacks of AHP
    • also used outside its marketing authorisation to prevent attacks
  • liver transplant may be an option for some people with recurrent severe attacks when other treatment options have not worked
  • givosiran is recommended as an option for treating acute hepatic porphyria (AHP) in adults and young people aged 12 and older, only if:
    • they have clinically confirmed severe recurrent attacks (4 attacks or more within 12 months)
    • is a small-interfering ribonucleic acid that suppresses delta-aminolevulinic acid synthase 1 production by the liver. This reduces the level of toxic precursors of porphyrin

Notes:

• accumulated precursors are excreted in the urine, in the feces, or in both - according to their solubility -and measuring their level is the basis of porphyria biochemical diagnosis and typing
• heme
  • is the final product of the pathway
  • is essential for the synthesis of hematoproteins such as hemoglobin, myoglobin, microsomal cytochromes, catalase and others
    • all of which play an important role in oxygen transport and/or oxidation-reduction reactions
    • most of heme synthesis in human beings (80%) takes place in erythropoietic cells, while about 15% is produced in the liver parenchymal cells
  • the most important site of control is the first step in the synthesis, ALA formation
    • catalyzed by the enzyme ALA synthase (ALAS), which has two subtypes
      • ALAS1, the ubiquitous one, encoded on chromosome 3,
      • ALAS2, erythroid-specific, encoded on chromosome X
      • in the erythropoietic tissue, regulation of heme synthesis is influenced by erythroid differentiation and erythropoietin and iron availability
      • in the liver, ALAS1 is under negative feedback regulation by the intracellular heme pool
    • the levels of delta-aminolevulinate are elevated in all patients with porphyria because of the loss of feedback inhibition of d-ALA synthase by haem
    • haem usually prevents the translation of d-ALA synthase by activating a protein which binds to the 5'-untranslated region of the mRNA
    • in acute porphyrias the activity of porphobilinogen deaminase is either normal or low resulting in the accumulation of porphobilinogen (PBG). The combination of high d-ALA and PBG results in the abdominal pain and neuropsychiatric features
    • in non-acute porphyrias the acitivity of PBG deaminase is elevated and so PBG does no accumulate. There are specific defects in the the subsequent metabolism of proto-porphyrins. Accumulation of protoporphyris causes the photosensitivity

Reference:

• Edel Y, Mamet R. Porphyria: What Is It and Who Should Be Evaluated?. Rambam Maimonides Med J. 2018;9(2):e0013. Published 2018 Apr 19. doi:10.5041/RMMJ.10333
• Karim Z, Lyoumi S, Nicolas G, Deybach JC, Gouya L, Puy H. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39:412-425
• NICE (November 2021). Givosiran for treating acute hepatic porphyria