Acute intermittent porphyria (AIP) is a rare metabolic disorder that is characterized by partial deficiency of the enzyme hydroxymethylbilane synthase (also known as porphobilinogen deaminase). This enzyme deficiency can result in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the HMBS gene which is inherited as an autosomal dominant trait (only one HMBS gene copy is affected). However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with an HMBS gene mutation do not develop symptoms of AIP. Additional factors such as hormonal changes associated with puberty, the use of certain prescribed or recreational drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Symptoms include severe abdominal pain, constipation, a rapid heartbeat and increased blood pressure (tachycardia and hypertension), behavioral changes, seizures, and damage of the nerves to muscles (peripheral neuropathy) which can lead to profound muscle weakness (paralysis). Treatment is focused on preventing attacks by educating patients to avoid potential triggers. Acute attacks usually require hospital care and can be effectively treated with intravenous hematin.
AIP belongs to a group of disorders known as the porphyrias. This group of disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors which accumulate due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins found in all cells. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are often referred to as “cutaneous porphyrias.” The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Two porphyrias can have cutaneous and acute symptoms, sometimes together. Most forms of porphyria are genetic inborn errors of metabolism. AIP is an acute, hepatic form of porphyria.
Symptoms
AIP can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks are highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can potentially cause life-threatening complications. It is important to note the highly variable nature of AIP and that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.
The symptoms of AIP usually occur as episodes or “attacks” that develop over several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. The onset of attacks usually occurs in the 20s or 30s, but may rarely occur at or just after puberty. Onset before puberty is extremely rare. Attacks are much more common in women than men, probably because of the menstrual cycle hormones. Approximately 3%-5% of affected individuals, predominately women, experience recurrent attacks, which are defined as more than 4 per year, for many years.
Abdominal pain, which is usually severe, is the most common symptom associated with AIP and often the initial sign of an attack. Abdominal pain is usually severe, steady (unremitting), and widespread (diffuse). Less often, abdominal pain is described as cramping. Pain may also occur in the neck, lower back, buttocks, or arms, and legs.
Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention). A painful blockage or obstruction (ileus) of part of the small intestines may also occur. Difficulty passing urine (urinary retention) can also occur.
Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and burning sensations that usually begin in the feet and sometimes the arms. Affected individuals may develop muscle weakness in the legs that may progress to affect the arms and the trunk of the body, eventually causing partial loss or impairment of motor function (motor paralysis). In rare cases, the muscles used to breathe can become involved and potentially cause life-threatening respiratory failure which requires mechanical ventilation.
During attacks, some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases, coma.
Affected individuals may also experience a faster than normal heart rate (tachycardia), high blood pressure (hypertension), and irregular heartbeats (cardiac arrhythmias). Seizures have also been reported. Abnormally low sodium levels (hyponatremia) may develop rapidly during an attack and contribute to the onset of seizures.
Individuals with chronic AIP may develop complications that occur after many years (long-term complications) such as high blood pressure (hypertension), kidney damage potentially resulting in kidney failure, and liver cancers such as hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC).
Causes
AIP is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for developing symptoms of the disorder. Individuals with AIP have a mutation in the HMBS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
However, the majority of people with a mutation in this gene do not develop symptoms of AIP; additional factors, often called “triggers” are also required to cause symptomatic acute porphyria. These factors are not necessarily the same for each individual, and susceptibility to specific triggers may vary during a patient’s lifetime. Most of these triggers are believed to stimulate increased heme production (synthesis) in the liver and include certain drugs, excessive alcohol consumption, fasting or dieting (e.g. caloric restriction), stress, infections, or certain hormonal (endocrine) factors, often in combination.
The HMBS gene mutation that predisposes individuals to develop AIP is inherited in an autosomal dominant pattern. Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is sufficient for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
The HMBS gene creates (encodes) the enzyme porphobilinogen deaminase (PBG-D), which is also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase. This enzyme is the third enzyme in the process of heme biosynthesis. Mutations in the HMBS gene lead to deficient levels of PBG-D in the body, which in turn can lead to the accumulation and release of porphyrin precursors, 5-aminolevulinic acid (ALA), and porphobilinogen (PBG) from the liver.
Symptomatic AIP is always accompanied by increased production and excretion of porphyrin precursors. However, for unknown reasons, some affected individuals have elevated porphyrin precursors without symptoms of AIP. As discussed above, triggering factors are required for symptom development. The exact, underlying reasons why symptoms develop in some individuals with AIP are not fully understood. There are several theories as to the underlying pathogenesis of AIP. One theory states that a specific porphyrin precursor (most likely ALA) is a neurotoxin that damages nerve tissue. This theory is supported by the information obtained from patients who have had a liver transplant, which corrects both the clinical and biochemical features of the condition. A second theory suggests that heme deficiency in nerve cells (neurons) contributes to the development of symptoms. More research is necessary to determine the exact underlying mechanisms that are involved in the development of symptomatic episodes in individuals with AIP.
Diagnosis
A diagnosis of AIP can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon the identification of characteristic symptoms from detailed patient history, a thorough clinical evaluation, and certain specialized tests. AIP should be suspected in individuals with unexplained abdominal pain, especially repeated episodes, and when occurring along with psychological symptoms, neurological findings with muscle weakness, or unexplained hyponatremia. Dark or reddish urine in such individuals is also suggestive of AIP. However, the absence of this feature does not exclude AIP.
Clinical Testing and Workup
Screening tests to measure the levels of the porphyrin precursor porphobilinogen (PBG) in urine are essential to confirm a diagnosis of acute porphyria. Acute attacks are always accompanied by increased production and excretion of PBG in AIP. If urinary PBG excretion is increased, then further testing (fecal and blood porphyrin measurement) is necessary to distinguish AIP from variegate porphyria or hereditary coproporphyria. This should not delay the treatment of acutely unwell patients. Delta-aminolevulinic acid (ALA) excretion will also be elevated in urine samples from individuals with AIP, but the measurement is less widely available and is not essential. These tests can be performed on a random (spot) urine sample that should be protected from light after collection and during transport to the laboratory. There is now good evidence that once urine PBG excretion is increased in AIP it takes many years to return to normal. Increased urine PBG excretion in a known AIP patient does not, therefore, prove that a patient is having an acute attack.
Family Testing
Molecular genetic testing is not essential to confirm a diagnosis as the porphyrin biochemical findings are characteristic. However molecular genetic testing to detect a mutation in the HMBS gene is usually required so that family members can be offered to test for this mutation. Genetic testing is available mainly from laboratories specializing in porphyria diagnosis.
Patients and family members who have inherited AIP should be advised on how to limit their risk of any future acute attacks. This should include information about AIP and what causes attacks, how to check if a prescribed medication is safe or unsafe, and details of relevant patient support groups.
Associated Laboratory Abnormalities (During An Acute Attack)
- Hyponatremia – most common
- Hypomagnesemia is also common
- Mild aminotransferase elevations
- Mild leucocytosis
Differentiating Between Acute Porphyrias
As mentioned below (vide infra), most acute porphyrias’ symptomatology shows significant overlap. Symptoms of AIP are often clinically indistinguishable from those of hereditary coproporphyria and variegate porphyria. Although the diagnostic approach to distinguish AIP from other acute porphyrias has little evidence backing at present, new evidence-based diagnostic strategies are under development for these conditions.
Plasma Fluorescence Staining
In contrast to AIP, HCP, and other porphyrias in which the sera of subjects with biochemically active disease have emission peaks at approximately 619 nm to 620 nm, the serum from patients with VP have a unique porphyrin-peptide in plasma that has its peak fluorescence at approximately 626 nm, following excitation by light of 410 nm (the Soret band). This reaction forms the basis of the utility of fluorescence of diluted sera at physiologic pH to differentiate VP from other acute as well as cutaneous porphyrias.[rx]
Emerging Role of Genetic Mutation Analysis in Diagnostic Confirmation
The specific type of acute porphyria is now discernable by genetic testing, which is available commercially at several labs. The approach involves sequencing of the four genes that are defective in the acute porphyrias:[rx]
Gene/Type of Acute Porphyria
- ALAD/ALAD-deficient porphyria (Doss porphyria)
- HMBS/AIP
- CPOX/HCP
- PPOX/VP
The evolution of next-generation sequencing (NGS) to porphyria diagnosis is ongoing, with investigators having recently designed a panel containing four genes – ALAS1, HMBS, CPOX, and PPOX for mutational analysis of AIP, HCP, and VP.[rx]
Treatment
The treatment of AIP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment. Genetic counseling may benefit affected individuals and their families.
The treatment objective is to manage symptoms prevent complications, and suppress heme creation (synthesis) in the liver with hematin, which reduces the production of porphyrin precursors. Initial treatment steps also include stopping any medications that can potentially worsen AIP or cause an attack and ensuring proper caloric intake, which can include intravenous infusion of sufficient nutrients (glucose and salt). Carbohydrate loading in conjunction with good pain medication may be sufficient for mild attacks.
An acute neurovisceral attack often necessitates hospitalization and may require treatment with human hemin. In the United States, affected individuals may be treated with Panhematin (hemin for injection), an enzyme inhibitor derived from red blood cells that are potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) approved Panhematin for the treatment of recurrent attacks of AIP related to the menstrual cycle in susceptible women, after a trial of glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. Based on many experiences, it is used for treating and even preventing acute attacks, often without an initial trial of glucose, and is safe during pregnancy.
In 2019, the FDA approved Givlaari (givosiran) for the treatment of adult patients with acute hepatic porphyria, including AIP. Givlaari aims to reduce the number of attacks patients experience.
Formosan (heme arginate) is another heme preparation that can be used to treat individuals with AIP. Formosan is not available in the United States but is used in many other countries where Panhematin is not available.
Treatment for AIP also includes drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. The pain is usually very severe and generally requires opiates (e.g. morphine) for adequate relief. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Although many types of drugs are believed to be safe in individuals with AIP, recommendations about drugs for treating AIP are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database.
Additional treatment for individuals undergoing an attack includes monitoring fluid and electrolyte balances. For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion.
In some patients, an attack is precipitated by a low intake of carbohydrates in an attempt to lose weight. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal balanced diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods. If weight loss is desired, it is advisable to contact a physician and dietician.
Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks and some affected women have been treated with gonadotropin-releasing hormone analogs to suppress ovulation and prevent frequent cyclic attacks. Some individuals who experience recurrent attacks may benefit from regular hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses.
If a proper diagnosis has not been made, AIP can be particularly dangerous, especially if drugs that aggravate the disorder are administered. The prognosis of AIP is usually good if the disorder is recognized before severe nerve damage has occurred and if treatment and preventive measures are begun. Although symptoms usually resolve after an attack, some individuals may develop chronic pain. Nerve damage and associated muscle weakness from a severe attack improve over time, but such improvement may take many months to resolve fully.
Liver transplantation has been used to treat some individuals with AIP, specifical individuals with severe diseases who have failed to respond to other treatment options. A liver transplant in individuals with AIP is an option of last resort. Affected individuals who experience kidney failure may require a kidney transplant. Some individuals have required a combined kidney and liver transplant.
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Initial And Symptom-Oriented Treatment
Owing to the simulation of symptoms of acute intermittent porphyria by several abdominal, metabolic, and neuropsychiatric conditions, establishing a confirmed diagnosis forms the core of the management of AIP.
Avoidance of precipitants, especially drugs, requires extreme emphasis, ingraining it in the patient and relatives’ psyche. (vide infra)
When a patient with confirmed AIP presents with an acute attack, the usual first approach is to load the patient with a high carbohydrate diet or intravenously administered dextrose to inhibit hepatic ALAS1 transcription. Administration of 10% dextrose in 0.45% saline should start immediately. If the patient does not present with weakness, vomiting, or hyponatremia, a trial of a high carbohydrate diet for 48 hours before starting specific treatment is the current recommendation.[rx][rx][rx]
For pain, parenteral opiates are the best option (morphine, diamorphine, and fentanyl). Nausea and vomiting are controllable with prochlorperazine, promazine, and ondansetron. These symptoms usually start abating in 72 to 96 hours.[rx] For tachycardia and hypertension, preferred medications are beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers (diltiazem). If the patient presents with seizures, they are controllable with diazepam, magnesium sulfate, or clonazepam.[rx]
Specific Treatment
Intravenous administration of heme is the specific therapy. It replenishes the hepatocyte heme pool and down-regulates ALAS1, resulting in reduced production of porphyrin precursors and corresponding improvement in symptoms.[rx] Heme not only controls hepatic ALAS1 by down-regulating ALAS1 transcription but also by inducing mRNA destabilization or by blocking the mitochondrial import of the mature enzyme.[rx]
Owing to the delayed effect of heme therapy on reducing plasma ALA and PBG levels, intravenous heme therapy (IHT) should be administered without delay in severe acute attacks and maintained for four days (3 to 4 mg/kg of heme/day). A response usually appears on the third day with a decrease of urine and serum PBG. Panhematin administration should be through a large peripheral vein or central line due to the risk of phlebitis in small veins, a risk also reduced by preparing it with human albumin instead of water. Other complications are an increase in prothrombin time during the first 2 hours and increased iron production in the liver. Patient discharge can take place when parenteral opioids can stop, and they can tolerate oral drugs.[rx]
Excepting occasional complaints of headache or pyrexia, IHT is well tolerated. However, there are inherent risks associated with recurrent treatments with IHT, of which every caregiver should be cognizant.
Risks Associated With Recurrent IHT
The following enumerates the significant issues associated with recurrent IHT – the need to replace the venous access to prevent thromboembolic disease, risk of liver fibrosis, hepatic iron overload, and development of therapeutic ‘tolerance’ to heme infusion. Research has shown that heme infusion can induce the expression of hepatic heme oxygenase 1 (HMOX1, EC 1.14.99.3, HGNC: 5013).[rx][rx][rx] HMOX1 is the crucial enzyme of heme catabolism. Its induction by heme therapy results in the reduction of hepatocyte heme pool and consequently enhanced expression of ALAS1.[rx] This heme-induced auto-catabolic effect generates the tolerance reported in some patients.
Currently, the only established cure for acute intermittent porphyria is orthotopic liver transplantation (OLT) with a reported survival rate of around 80%.[rx] However, a high risk (40%) of hepatic artery thrombosis with OLT prompted the same authors to recommend reserving the procedure for patients with severe recurrent acute attacks and highly impaired quality of life (QoL).
Some studies are looking for other alternatives. These are in different phases of clinical trials, and this CME chapter at present, only seeks to inform the readers of these potential and futuristic therapies:
Potential/Experimental Therapies For AIP
Enzyme Replacement Therapy [ERT] – Based on the experience of administering doses of recombinant human HMBS/PBGD (rhPBGD) protein in a mouse model of AIP that reduced plasma PBG accumulation during an acute attack induced after phenobarbital challenge, in 2002 the European Medicines Agency (EMA) granted recombinant human HMBS/PBGD an orphan designation (EU/3/ 02/103). Researchers conducted clinical trials in healthy subjects, asymptomatic HMBS-deficient subjects with increased porphyrin precursor excretion, and AIP patients with repeated attacks.[rx][rx] Although the enzyme was able to detoxify PBG metabolites, the treatment approach limitations included its short half-life in circulation and the lack of liver targeting.
Liver Gene Therapy – Clinical trials using two strategies, HMBS-gene therapy and interference RNA for ALAS1 gene inhibition, are being conducted in patients with AIP. The two strategies include – the delivery of the HMBS gene to the hepatocytes using a viral vector. The other option is a small interfering RNA (siRNA) directed against aminolevulinic acid synthase, with the objective of reducing delta ALA production. Both of them are still in the trial phase and await approval, pending larger trials that would hopefully provide consistent efficacy and safety.[rx][rx]
References
