Acute intermittent porphyria

AIP is one of the four porphyrias that presents as an acute attack. 90% of affected individuals never experience an acute attack and are asymptomatic, while an estimated 5% of affected individuals experience repeat attacks.[8] Attacks are most common in young adult women and are rare before puberty or after menopause.[9] Severe acute attacks may require hospitalization. Patients usually experience symptoms in attacks that last from several hours to a few days. Between attacks, patients are asymptomatic.

The most frequent presenting symptoms are abdominal pain and tachycardia.[10] The abdominal pain is typically severe, colicky, poorly localized, and often associated with pain in back and legs.[10][11] Patients may also present with vomiting and constipation, but diarrhea is unusual.[11] The onset of back and leg pain is characterized by severe pain and stiffness in back and thighs followed by loss of tendon reflexes and paralysis.[12] Psychiatric symptoms are present, such as paranoid schizophrenia-like features but rarely psychosis and hallucinations.[4] The acute attacks classically present with dark-red photosensitive urine (often called port-wine urine), but this is a nonspecific symptom.[13] Physical examination often shows no abnormalities.[14]

Hyponatremia is the most common electrolyte abnormality during acute attacks, occurring in 40% of patients and presenting as SIADH.[15] Hypomagnesemia is also common. There are no pathognomonic signs or symptoms.

The most common identified triggers for acute attacks are medications, weight loss diets, and surgery.[16] Many medications have been associated with AIP including antibiotics, hormonal contraceptives, seizure medications, anesthetics, and HIV treatment drugs.[17]

AIP has an autosomal dominant pattern of inheritance.[26] The dominance pattern is a result of partial deficiencies from the heme biosynthesis enzymes, hydroxymethylbilane synthase  (HMBS;  EC  2.5.1.61).[27] Due to the rarity of this disease it is difficult to estimate the prevalence of AIP and the inclusion criteria differs widely among studies causing varying statistics. AIP has a low penetrance when considering the general population, but within families the penetrance increases.[28] This is indicative of another interaction affecting the inheritance pattern. It is speculated that this pattern is due to AIP propensity caused by the inheritance of an additional gene mutation, HMBS, in addition to other genetic and environmental influences. There have been 421 HMBS mutations that have been linked to AIP. This suggests that AIP inheritance instead follows an oligogenic or polygenic inheritance pattern. Research shows that HMBS mutations are estimated to occur in approximately 1 in 1700 caucasians (there is not enough data in other populations) while AIP symptoms are shown to be present in approximately 1 in 200,000 caucasians. It can be inferred that the penetrance of AIP is approximately 1% of the HMBS heterozygous community, concluding that there are other factors needed to induce AIP symptoms.

There have been more than 400 mutations in the heme biosynthesis identified to cause AIP. In the erythroid variant, mutations in the exon 1 sequence of the housekeeping gene, splicing of exon 1, and splicing of exon 3 causes an alternative form of AIP wherein there is decreased activity of the liver enzyme but erythroid cells have regular activity. HMBS has two isoforms, housekeeping and erythroid. Additionally, there is also the non-erythroid variant of AIP in which there are mutations in exons 3-15 and there is decreased activity in both isozymes. Most individuals with AIP have mutations in exons 3–15. Loss of function mutations of HMBS cause decreased activity of the enzymes normally present.

With advancement and increased accessibility to genetic testing and follow up counseling, the morbidity of AIP has decreased because of early diagnosis. The combination of targeted mutation analysis and biochemical activity tracking have provided positive results for identifying the risk of AIP development. Mutation analysis has a 95% sensitivity and a 100% specificity for confirmation of pathogenicity of a mutation. Genetic testing can detect AIP in patients with symptoms that would have otherwise gone undiagnosed or misdiagnosed. The biochemical analysis route of detection is slightly less accurate compared to genetic testing, which has 84% sensitivity and 71% specificity, but is still chosen over other alternatives and can provide some of the predictive information that genetic testing does. Patients diagnosed with genetic testing at the asymptomatic stage were less likely to develop symptoms throughout their life. Additionally, individuals who were diagnosed at the symptomatic stage encountered more mild attacks after diagnosis, although they still had symptoms. Genetic testing availability has decreased the rate of patients seeking treatment by medical staff, as patients experiencing less severe symptoms instead opt to self treat at home.