Acute Intermittent Porphyria

Clinical characteristics: An acute porphyria attack is characterized by a urine porphobilinogen (PBG)-to-creatinine ratio ≥10 times the upper limit of normal (ULN) and the presence of ≥2 porphyria manifestations (involving the visceral, peripheral, autonomic, and/or central nervous systems) persisting for >24 hours in the absence of other likely explanations. Onset of acute attacks typically occurs in the second or third decade of life. Acute attacks are more common in women than men. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, often no precipitating factor can be identified. The course of acute porphyria attacks is highly variable in an individual and between individuals. Recovery from acute porphyria attacks may occur within days; however, recovery from severe attacks that are not promptly recognized and treated may take weeks or months.

The five categories of acute intermittent porphyria (AIP), caused by a heterozygous HMBS pathogenic variant, are based on the urine PBG-to-creatinine ratio and occurrence of acute attacks.

Active (symptomatic) AIP: An individual who has experienced at least one acute attack within the last two years.

Symptomatic high excreter: Urine PBG-to-creatinine ratio ≥4 times ULN and no acute attacks in the last two years but chronic long-standing manifestations of acute porphyria.

Asymptomatic high excreter: Urine PBG-to-creatinine ratio ≥4 times ULN and no acute attacks in the last two years and no porphyria-related manifestations.

Asymptomatic AIP: Urine PBG-to-creatinine ratio <4 times ULN and no acute attacks in the last two years but has had ≥1 acute attack in the past.

Latent (inactive) AIP: Urine PBG-to-creatinine ratio <4 times ULN and no acute porphyria-related manifestations to date.

Diagnosis/testing: When the diagnosis of an AIP attack is suspected based on clinical findings, establishing the diagnosis begins with biochemical testing. If the urinary concentration of PBG is increased, molecular genetic testing is performed to confirm the diagnosis and/or to facilitate cascade screening of family members. When a multigene panel or genomic testing has identified an HMBS pathogenic variant, the diagnosis of an AIP attack is confirmed when the urinary concentration of PBG is increased.

Management: Treatment of manifestations: Treat intercurrent infections and other diseases promptly. For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral. When required, intravenous (IV) fluid may be used for up to 48 hours. IV fluid should contain a minimum of 5% dextrose; the recommendation in most countries is 10% glucose with added sodium (40 mmol) and potassium (20 mmol) given at a rate of 1,000 mL over 12 hours. Note that hypotonic dextrose in water solutions should be avoided because of the risk of hyponatremia. Referral to a porphyria specialist for more detailed clinical advice on treatment of AIP.

Targeted therapies: For sporadic acute neurovisceral attacks (i.e., when an individual has experienced one to ≤3 acute porphyria attacks in any 12-month period in the last two years): IV human hemin is the most effective treatment and may be lifesaving if employed early when neuronal damage is reversible. If the criteria for recurrent attacks are met, Givlaari^® (givosiran) should be considered, as long-term complications of hemin such as iron overload, phlebitis, and loss of venous access can be avoided. Liver transplantation, as reported from several centers, is curative. Indications include repeated life-threatening acute porphyria attacks and poor quality of life when givosiran is not available or has shown insufficient medical efficacy. Alternative medical therapies to reduce frequency and/or severity of acute attacks when givosiran is not available include suppression of ovulation and prophylactic hemin infusion.

Supportive care: To reduce the frequency and/or severity of acute attacks, maintain adequate nutrition and seek timely treatment of systemic illness or infection. Supportive treatment involves pain relief, treatment of hypertension, prevention of nausea and vomiting, prompt treatment of seizures, and maintenance of fluid and electrolyte balance. Combined liver and kidney transplantation can be considered in individuals with AIP who have recurrent acute porphyria attacks and end-stage kidney disease.

Surveillance: For all individuals heterozygous for an HMBS pathogenic variant who are older than age 50 years, annual or twice a year hepatic imaging is recommended for early detection of primary liver cancer (PLC), which improves survival.

Agents/circumstances to avoid: Individuals with AIP are advised to avoid excessive alcohol consumption, as alcohol upregulates the enzyme ALAS1, the first enzyme of hepatic heme biosynthesis, and thus could be a trigger for acute attacks. In all the acute porphyrias, information on the safety of many drugs and other over-the-counter preparations is incomplete; however, evidence-based guidelines for assessment of drug porphyrogenicity have been published.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an individual with a known HMBS pathogenic variant (regardless of the presence or absence of acute porphyria-related manifestations and/or a highly elevated urine PBG-to-creatinine ratio in that individual) so that those who are heterozygous for the familial HMBS pathogenic variant (and thus at increased risk of developing AIP attacks and PLC) can be identified early and counseled about preventive measures and surveillance. For the same reasons it is also appropriate to try to clarify the genetic status of apparently asymptomatic family members of an individual with a biochemical diagnosis of AIP and an unknown HMBS pathogenic variant by assessing erythrocyte HMBS activity; however, this method is less sensitive and specific than molecular genetic testing.

Pregnancy management: Preconception counseling is recommended to advise women with AIP about the clinical manifestations of porphyria, self-care, preventative measures to avoid exacerbations (i.e., adequate and regular nutrition, rest, and carbohydrate intake for treating mild-to-moderate manifestations), and agents/circumstances to avoid. Additionally, there is a higher risk for pregnancy-induced hypertensive disorder, gestational diabetes, and fetuses with intrauterine growth restriction. In general, risk ratios are higher among women with AIP who have high lifetime urinary PBG concentrations.

Genetic counseling: AIP is inherited in an autosomal dominant manner. The majority of individuals diagnosed with AIP inherited an HMBS pathogenic variant from one of their parents, who may or may not have experienced manifestations of porphyria. Rarely, individuals diagnosed with AIP have the disorder as the result of a de novo HMBS pathogenic variant. Each child of an individual with an HMBS pathogenic variant has a 50% chance of inheriting the pathogenic variant. Because clinical penetrance is low, it is not possible to predict whether offspring who inherit an HMBS pathogenic variant will be symptomatic or, if they are symptomatic, the age of onset, severity, or type of manifestations. However, all individuals who inherit an HMBS pathogenic variant should be counseled about preventive measures and surveillance. Once the familial HMBS pathogenic variant has been identified, prenatal and preimplantation genetic testing for AIP are possible.