Invitae Acute Hepatic Porphyrias Panel

Acute hepatic porphyrias are a group of diverse disorders associated with altered activity of porphyrin enzymes in the heme biosynthetic pathway, which results in accumulation and excess excretion of pathway intermediates and products. Each type of porphyria has characteristic patterns and levels of excess intermediates, which result in different clinical manifestations. For example, the excess porphyrins seen in individuals with hereditary coproporphyria (HCP) and variegate porphyria (VP) have photosensitive effects, causing cutaneous manifestations such as blistering skin lesions, features which are not typically present in individuals with δ-aminolevulinic acid dehydratase deficiency porphyria (ADP) or acute intermittent porphyria (AIP).

Age of onset varies depending on the type of porphyria, inheritance pattern, and certain environmental factors including certain drugs, steroid hormones, and exposure to heavy metals, which may cause previously asymptomatic individuals to display clinical symptoms of porphyria.

Individuals with acute intermittent porphyria (AIP) typically remain clinically asymptomatic throughout life. If clinical symptoms do manifest, onset is typically in adulthood. Individuals present with acute neurovisceral attacks that may last for several days at a time. Symptoms include abdominal pain, cramps, nausea, tachycardia, muscle pain and weakness, tremors, hyponatremia, hypertension, and excess sweating. Peripheral motor neuropathy, characterized by muscle weakness which begins in the proximal upper extremities, may also develop. δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP) is characterized by adolescent-onset attacks of abdominal pain and neuropathy. Exposure to heavy metals such as lead can cause symptoms in heterozygous carriers who would otherwise be asymptomatic. Hereditary coproporphyria (HCP) and variegate porphyria (VP) are characterized by neurovisceral attacks as well as cutaneous manifestations including blistering or non-blistering skin lesions, which are caused by photosensitivity.

First line laboratory testing for individuals displaying acute neurovisceral symptoms includes urinary 5-aminolevulinic acid (5-ALA), porphobilinogen and total porphyrins. All four acute hepatic porphyrias are associated with significant increases in urinary 5-aminolevulinic acid (5-ALA). AIP, HCP, and VP are also associated with increased urinary excretion of porphobilinogen. For individuals with blistering or non-blistering skin lesions, total plasma porphyrins or erythrocyte porphyrins should be tested.

Treatment for the neurological symptoms of acute hepatic porphyrias most commonly consists of intravenous hemin therapy (typically heme arginate) and avoidance of drugs and other environmental factors which are known to be harmful in individuals with acute porphyrias. Cutaneous symptoms are more difficult to treat and center around protection from sunlight exposure. Currently, there is no officially approved treatment available to prevent recurrent attacks.

*Incomplete penetrance has been reported in all of the autosomal dominant acute hepatic porphyrias.

Acute intermittent porphyria (AIP) is the most common acute hepatic porphyria, with an estimated prevalence of 5.9 per 1,000,000 individuals in Europe (PMID: 23114748). Variegate porphyria (VP) has an estimated prevalence of approximately 0.5 per 100,000 individuals in Europe and the United States and 3 per 1,000 individuals in South Africa, where VP is particularly common (PMID: 23409300, 8673113). Hereditary coproporphyria (HCP) and δ-aminolevulinic acid dehydratase deficiency porphyria (ADP) are both rare conditions, and prevalence is unknown.

Clinicians may consider ordering the Invitae Acute Hepatic Porphyria panel for individuals with an indication of:

• Elevated urinary porphobilinogen (PBG) or aminolevulinic acid (ALA) levels
• Recurrent, prolonged (>24 h) episodes of severe abdominal pain
• Neurological symptoms that occurred around the time of severe abdominal pain (i.e. muscle weakness, sensory loss, confusion, hallucinations, seizures)
• Gastrointestinal manifestations that occurred around the time of severe abdominal pain (i.e. nausea/vomiting, diarrhea, constipation)
• Hyponatremia around the time of severe abdominal pain
• Red to brownish urine on exposure to light
• Chronic blistering lesions on sun-exposed areas

For management guidelines, please refer to:
Balwani, M et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017 Oct; 66(4):1314-1322 (PMID: 28605040).
Pischik, E, Kauppinen, R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015; 8:201-14 (PMID: 26366103).