| Acute intermittent porphyria | |
|---|---|
| Other names | Swedish porphyria, pyrroloporphyria, intermittent acute porphyria |
 | |
| Porphobilinogen | |
| Specialty | Medical genetics |
Acute intermittent porphyria (AIP) is a raremetabolic disorder affecting the production ofheme resulting from a deficiency of the enzymeporphobilinogen deaminase. It is the most common of the acuteporphyrias.[1][2][3]
The clinical presentation of AIP is highly variable and non-specific. The patients are typically asymptomatic, with most gene carriers having no family history because the condition had remained latent for several generations. The syndrome marked by acute attacks affects only 10% of gene carriers.[4] The mean age at diagnosis is 33 years old.[5] Like other porphyrias, AIP is more likely to present in women.[6] A distinguishing feature of AIP that separates it from other porphyrias is the absence ofphotosensitivecutaneous symptoms that occur in addition to acute attacks.[7]
AIP is one of the fourporphyrias that presents as an acute attack. 90% of affected individuals never experience anacute attack and are asymptomatic, while an estimated 5% of affected individuals experience repeat attacks.[5] Attacks are most common in young adult women and are rare before puberty or after menopause.[8] 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.[citation needed]
The most frequent presenting symptoms areabdominal pain andtachycardia.[9] The abdominal pain is typically severe,colicky, poorly localized, and often associated with pain in back and legs.[9][10] Patients may also present with vomiting and constipation, but diarrhea is unusual.[10] The onset of back and leg pain is characterized by severe pain and stiffness in back and thighs followed by loss oftendon reflexes andparalysis.[11] Psychiatric symptoms are present, such as paranoidschizophrenia-like features but rarelypsychosis andhallucinations.[4] The acute attacks classically present with dark-red photosensitive urine (often called port-wine urine), but this is a nonspecific symptom.[12] Physical examination often shows no abnormalities.[13]
Hyponatremia is the most common electrolyte abnormality during acute attacks, occurring in 40% of patients and presenting asSIADH.[13]Hypomagnesemia is also common. There are nopathognomonic signs or symptoms.[citation needed]
The most common identified triggers for acute attacks are medications,weight loss diets, and surgery.[14] Many medications have been associated with AIP includingantibiotics,hormonal contraceptives,seizure medications,anesthetics, andHIV treatment drugs.[15]
Porphyrias are caused bymutations ingenes that encodeenzymes inhemesynthesis. In normalphysiology, heme synthesis begins in themitochondrion, proceeds into thecytoplasm, and finishes back in the mitochondrion. Heme is produced in all cells, but 80% of all heme is produced in erythropoietic cells in bone marrow and 15% in parenchymal cells in the liver, where turnover of hemoproteins is high. In AIP, over 100 mutations have been identified on thelong arm ofchromosome 11 at theHMBS gene, which codes for the cytoplasmic enzyme porphobilinogen deaminase.[16] This deficiency prevents heme synthesis, which can not be completed and the metaboliteporphobilinogen accumulates in the cytoplasm.[17]
AIP is anautosomal dominant porphyria resulting in about 50% normal activity of the affected enzyme.[18] Thepenetrance of AIP is incomplete with only 10% of gene carriers experiencing acute attacks suggesting role for other modifying genes or environment.[19][20][21]
The exact mechanism of acute attacks is not clear. The most favored hypothesis is that porpholobilinogen buildup causes a toxic effects onneurons. Theautonomic andperipheral nervous system are more vulnerable than thecentral nervous system because they are not protected by theblood-brain barrier.[22] This explains findings such as abdominal pain and tachycardia. Some individuals may be more likely to developparesis based on increased susceptibility of neurons to toxins.[23]
AIP has an autosomal dominant pattern ofinheritance.[24] The dominance pattern is a result of partial deficiencies from the heme biosynthesis enzymes,hydroxymethylbilane synthase (HMBS; EC 2.5.1.61).[25] 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.[26] 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 additionalgene 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 anoligogenic orpolygenic 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 HMBSheterozygous community, concluding that there are other factors needed to induce AIP symptoms.[citation needed]
There have been more than 400 mutations in theheme biosynthesis identified to cause AIP. In theerythroid 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 twoisoforms, 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.[citation needed]
The initial diagnosis of acute porphyria is confirmed byurinalysis, including the common method, theWatson-Schwartz test. Elevatedurine porphobilinogen confirms diagnosis of AIP,hereditary coproporphyria (HCP), orvariegate porphyria (VP). A positive test should be indicated with an increase of five times normal, not just a slight increase which can occur withdehydration. To distinguish between AIP from HCP and VP,fecal porphyrin levels are normal in AIP but elevated in HCP and VP.[citation needed]
Rapid, accurate diagnosis is important. Delays in diagnosis may result in permanent neurological damage or death.[citation needed]
With advancement and increased accessibility togenetic testing and follow up counseling, the morbidity of AIP has decreased because of early diagnosis. The combination of targetedmutation 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 theasymptomatic 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.[citation needed]
If drugs have caused the attack, discontinuing the offending substances is essential. A high-carbohydrate (10%glucose) infusion is recommended, which may aid in recovery.[citation needed]
Hematin andheme arginate is the treatment of choice during an acute attack. Heme is not a curative treatment, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare but can be serious.[citation needed]Pain is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible due to its severity.
Nausea can be severe; it may respond tophenothiazine drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls.[27]
Seizures often accompany this disease. Most seizure medications exacerbate this condition due to their induction ofcytochrome P450. Treatment can be problematic:Barbiturates and primidone must be avoided as they commonly precipitate symptoms.[28] Somebenzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such asgabapentin, offer a possible regimen for seizure control.[citation needed]
One of the manyhypothesized diagnoses of the artistVincent van Gogh is that he and his siblings, in particular his brotherTheo, had AIP andsyphilis.[29] Another theorized case was KingGeorge III of the United Kingdom[30] who even had a medallion struck to commemorate his "curing". His descendantPrince William of Gloucester was reliably diagnosed with variegate porphyria in 1968.[31] It is probable that the philosopherJean-Jacques Rousseau had porphyria.[32][33][34][35]