Acute Intermittent Porphyria (AIP)
AIP is the most common of the acute porphyrias, with a world-wide prevalence of clinically manifest, symptomatic disease of approximately 5-10 per 100,000. AIP results from autosomal dominant inheritance of a mutation in the gene for the enzyme hydroxymethylbilane-synthase (HMBS), which is also known as porphobilinogen deaminase (PBGD) or uroporphyrinogen I synthase. Recent evidence both from Europe and the USA indicates that potential disease-causing mutations in the HMBS gene are far more common than previously believed; in western Europeans and European-Americans, the prevalence of such mutations is about 1/1700 [Nordmann et al, 1997, J Intern Med; Chen et al, 2016, Hum Mutat]. These observations emphasize that the enzyme deficiency alone is not sufficient to produce the symptoms of AIP; other factors, such as gender, menarche/puberty, drugs, hormones, excess alcohol use, smoking, dietary factors, and/or other genetic factors are also important. Sometimes, triggering factors cannot be identified.
Most people who have a potential disease-causing mutation in the HMBS gene never develop symptoms; this is referred to as “latent” AIP. Symptoms rarely develop prior to puberty, and the clinical disease is mainly a disease of women in their child-bearing years [ages ~18-50 years]. Acute attacks almost always start with pain in the abdomen but sometimes in the chest, back, or thighs, and are often accompanied by nausea, vomiting, and constipation. The severity of the pain typically escalates over a few hours; it may become very severe and be described as the worst pain women have ever experienced, more severe than the pain of child birth. During moderate to severe attacks, heart rate and blood pressure are commonly increased. These symptoms and signs are all due to the effects of the disease on the nervous system. Confusion, convulsions, and muscular weakness, due to impairment of the nerves controlling the muscles, may lead to paralysis. An acute attack usually lasts for days or weeks. Recovery from severe paralysis is generally slow and often incomplete, with residual wrist drop or foot drop.
Acute attacks are often provoked by drugs such as barbiturates, sulfonamide antibiotics, anti-seizure drugs [barbiturates, hydantoins, valproate], rifampin, metoclopramide, and excess alcohol. Attacks in women may occur after ovulation and during the second half [luteal phase] of the menstrual cycle when progesterone levels are high. Reduced food intake, often in an effort to lose weight, as well as infections, surgery, and stressful situations may also precipitate attacks. Risks for developing chronic renal disease and liver cancer (hepatocellular carcinoma) are increased in AIP. The skin is not affected, except in some AIP patients who have developed kidney failure, in whom plasma levels of uroporphyrin may increase due to impaired renal clearance.
The finding of a substantial increase of porphobilinogen (PBG) in urine establishes that one of the three most common acute porphyrias (AIP, HCP or VP) is present. Therefore, measuring PBG and creatinine concentrations in a random urine, obtained while the woman is having abdominal pain, is the most important test for diagnosing acute porphyria, especially in an acutely ill patient. Because concentrations of PBG in the urine depend in part upon how dilute the urine is, they are best expressed normalized to urinary creatinine concentrations [mg PBG/ g creat or mmol PBG/mol creatinine]. Deficiency of HMBS activity in red blood cells helps to establish the diagnosis of AIP. However, normal HMBS activity in red blood cells does not exclude AIP because ~10% of patients harbor a mutation that is not expressed in erythrocytic HMBS, but only in hepatic HMBS. A diagnosis of AIP is established in a patient by DNA studies, which demonstrate a disease-associated HMBS gene mutation in almost all cases.
Many different mutations have been identified in the HMBS gene. Almost every family with AIP has a different mutation in this gene. Within one family, however, everyone who inherits a deficiency of HMBS has the same mutation. Knowing the mutation that causes AIP in a particular family member means that others who carry the mutation can be reliably identified and counseled to avoid excess alcohol, drugs, dietary practices, etc. that may trigger symptoms. Measuring red blood cell HMBS activity has been useful in family studies but is less accurate than DNA analysis.
Treatment and Prognosis
The prognosis is usually good if the disease is recognized and if treatment is prompt, before severe nerve dysfunction or death develops. Although acute symptoms usually resolve after an attack, repair of nerve damage and associated muscle weakness may require several months or longer. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.
Hospitalization is often necessary for acute attacks. Medications for pain, nausea, and vomiting and close observation are generally required. Hyponatremia, sometimes severe, with serum Na < 125 mEq/L, and hypomagnesemia are not uncommon during acute attacks. During treatment of an attack, attention should be given to sodium (salt) and water balance and to repletion of magnesium. Harmful drugs should be stopped.
Attacks are treated with glucose loading and hemin. These are specific treatments that lower activity of hepatic ALA synthase-1, the first and normally rate-controlling enzyme of the heme biosynthetic pathway. Marked up-regulation of hepatic ALA synthase-1 is the hallmark of acute porphyric attacks, regardless of which gene farther down the pathway is deficient in activity. Glucose or other metabolizable carbohydrates down-regulate hepatic ALA synthase-1. This has been called the ‘glucose effect’ or ‘carbohydrate repression’ of ALA synthase-1. Dextrose and more complex carbohydrates are given by mouth if possible. However, women with moderate to severe acute attacks usually have nausea, vomiting, and anorexia and are unable to eat sufficient quantities of dextrose or other nutrients. Therefore, these often must be administered by vein. Intravenous glucose is usually given as a 10% solution, at least 3 liters daily. Administration of 300 g of dextrose per day via a pediatric feeding [Dobhoff-type] tube can also be used, if there is adequate gut motility.
However, unless an attack is mild, it is now common practice to begin treatment with hemin, which is more effective than glucose loading. Hemin therapy can be started after a trial of glucose therapy, but the response to hemin therapy is best if started early in an attack. For all patients with acute porphyric attacks who are sick enough to require hospital admission, we recommend institution of IV heme therapy as quickly as possible.
Hemin must be administered intravenously. Panhematin®, from Recordati Rare Chemicals [Milan, IT], is the only hemin preparation available in the United States. Panhematin® is more stable and less likely to produce phlebitis (an inflammation of the vein; a known possible side effect of hemin therapy) if it is reconstituted in human serum albumin before it is given. Because of the high frequency of thrombophlebitis, Panhematin is best given into a large-bore, high-flow central vein, such as a subclavian vein, either by PICC line or by a central port. Normosang, which is heme arginate, is available in most European and some other countries around the world. It, too, is now supplied by Recordati Rare Chemicals, and it, too, seems less prone to cause thrombophleibitis or other adverse effects if it is mixed with human serum albumin and administered into a central vein.
Individuals with AIP who are prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intake of carbohydrate and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician and a dietitian to have them prescribe an individualized diet that is not more than 20% below the normal level of calories for the patient. This should result in a gradual weight loss and usually will not cause an attack of porphyria. Gastric bypass surgery for obesity has occasionally led to first attacks of acute hepatic porphyria.
Pregnancy is usually well tolerated, but the hormonal changes may exacerbate AIP in some women. Proper nutrition and hydration are important during pregnancy and labor, after delivery, and for the duration of breastfeeding. As always, only drugs and anesthetics classified as safe in porphyria should be used. Acute attacks are treated with glucose or hemin; there is no evidence of adverse effects of hemin therapy on the mother or fetus. Patients are prone to more frequent and severe attacks in the post-partum period, as well as during pregnancy. IV heme can be given also to mothers who are breast-feeding, if required, without fear of adverse effects on their infants.
Attacks can be prevented in many cases by avoiding harmful drugs and unwise dietary practices. Wearing a Medic Alert bracelet is advisable for patients who have had attacks, but is probably not warranted in most latent cases. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent, cyclic attacks can be prevented by once weekly infusions of hemin.
An attractive alternative for prevention of frequent, recurrent acute attacks is the subcutaneous administration of givosiran [Givlaari, Alnylam Pharma, Cambridge, MA]. Givosiran is an siRNA specifically directed against hepatic ALA synthase-1, which has proven remarkably effective in decreasing the numbers of recurrent acute attacks [Sardh et al, 2019, NEJM; Balwani et al, , 2020, NEJM]. It is administered once per month, and it has generally been well-tolerated and highly effective. IV heme and high glucose intakes can still be used, as may be required, in persons receiving givosiran. Patients with severe renal disease tolerate hemodialysis or kidney transplantation. Liver transplantation has been very effective for patients with classical AIP who have repeated attacks and who are resistant to other treatments. However, experience with transplantation as a treatment for AIP is still limited, and it seems likely that the availability of givosiran will decrease the numbers of patients with AIP who need liver transplantation.. Unfortunately, the very rare patients, mostly young children, with biallelic and severe deficiencies of HMBS activity, have not been helped by liver transplantation.
Because AIP is an autosomal dominant disorder, a person with a mutation in his or her HMB-synthase gene has a 50% chance with each pregnancy of passing that mutation on to his/her offspring. The outlook for such offspring is generally good, since most individuals who inherit an HMBS gene mutation never become ill or have only a few attacks.