Acute hepatic porphyrias (e.g., acute intermittent porphyria)

Acute hepatic porphyrias are a group of rare genetic neurometabolic disorders of heme biosynthesis that can cause neuropsychiatric and multisystemic manifestations; acute intermittent porphyria (AIP) is the prototypical and most frequently symptomatic form. The group comprises AIP, hereditary coproporphyria (HCP), variegate porphyria (VP), and the exceptionally rare ALA dehydratase deficiency porphyria (ADP).

They occur as inherited genetic disorders, although the inheritance pattern varies: AIP, HCP, and VP are autosomal dominant, whereas ADP is autosomal recessive. A relevant family history may be absent because many individuals with pathogenic variants remain clinically asymptomatic. They can affect both sexes, but clinically manifest acute attacks are substantially more common in women, particularly after puberty.

They can present with psychiatric features such as anxiety, insomnia, irritability, emotional lability, depression, agitation, behavioural change, confusion, and psychosis. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood and may occur as part of an acute neurovisceral attack, sometimes dominating the initial presentation. Psychotic symptoms have been reported across the four acute hepatic porphyrias.

Other characteristic features include recurrent acute attacks of severe, often diffuse abdominal pain, nausea and vomiting, autonomic dysfunction, peripheral motor neuropathy, muscle weakness, sensory symptoms, seizures, and altered consciousness or acute encephalopathy. Motor neuropathy may progress rapidly and, in severe cases, involve bulbar or respiratory muscles. Attacks may be precipitated by certain medications (including several psychotropics, particularly some anticonvulsant mood stabilizers such as valproate and carbamazepine), hormonal changes, fasting or restrictive dieting, alcohol, and other metabolic or physiologic stressors.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: tachycardia, hypertension, and other manifestations of autonomic dysfunction may occur during acute attacks.

• Respiratory: respiratory muscle weakness or paralysis may occur during severe motor neuropathy and can result in respiratory failure.

• Renal/electrolytes: hyponatremia is common during acute attacks; chronic kidney disease and progressive renal impairment may occur in individuals with recurrent or symptomatic acute porphyria.

• Hepatobiliary: individuals with acute hepatic porphyria have an increased risk of hepatocellular carcinoma.

• Gastrointestinal: severe abdominal pain, nausea, vomiting, constipation, and intestinal dysmotility are characteristic manifestations of acute attacks.

• Dermatologic: photosensitivity with blistering skin lesions may occur in VP and HCP; cutaneous manifestations are not a feature of AIP.

Early diagnosis is important to recognize acute neurovisceral attacks, avoid potentially precipitating medications and other triggers, including several psychotropics, initiate appropriate treatment promptly, prevent severe neuropathy, respiratory failure, seizures, and other potentially life-threatening complications, identify and manage chronic renal and hepatic complications, distinguish porphyria-related psychiatric manifestations from primary psychiatric illness, and enable appropriate genetic counselling and family testing.