Introduction
The term ‘Porphyria’ originates from the ancient Greek word ‘porphura’, signifying purple, a nod to the characteristic color of porphyrins. These porphyrins are vital precursors in the synthesis of heme, a crucial component of hemoglobin. Hemoglobin, essential for oxygen transport, comprises subunits of globular proteins, each housing a heme group with an iron atom capable of binding oxygen. The creation of heme is a complex, multi-step process, with each step facilitated by a specific enzyme. Consequently, porphyrias are a group of distinct clinical syndromes arising from deficiencies or defects in these enzymes at various stages of the heme synthesis pathway. While traditionally classified based on the primary system affected (cutaneous vs. neurohepatic), in reality, these porphyrias often exhibit overlapping symptoms, presenting as mixed syndromes.
The clinical presentation, severity, and prognosis of each porphyria are determined by the specific enzyme deficiency and the resulting accumulation of heme precursors or porphyrins. Acute intermittent porphyria (AIP) stands out as the most prevalent and severe form among the acute porphyrias. Other acute porphyrias include hereditary coproporphyria (HCP), variegate porphyria (VP), and the very rare 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, also known as Doss porphyria.1
AIP, like most porphyrias, follows an autosomal dominant inheritance pattern. Acute porphyrias, particularly AIP, are marked by acute neurovisceral symptom episodes, which can remain latent for extended periods. AIP typically manifests with episodes of severe abdominal pain, neuropathies, and constipation. Unlike many other porphyrias, AIP does not cause a cutaneous rash. The fundamental enzymatic defect in AIP is a deficiency in porphobilinogen-deaminase, also known as hydroxymethylbilane synthase (HMBS), the third enzyme in the heme synthesis pathway. Acute attacks in AIP are triggered by the uncontrolled upregulation of the ALA synthase enzyme. Aip Disease Diagnosis is often delayed due to the non-specific nature of its symptoms, which can mimic other conditions. Currently, orthotopic liver transplantation is the only definitive cure for AIP.2, 3
Etiology
Acute intermittent porphyria is caused by mutations in the HMBS gene, leading to approximately 50% reduction in HMBS enzyme activity. This gene is located on chromosome 11q24.1-q24.2. To date, 391 mutations in the HMBS gene have been identified.4 This enzymatic deficiency becomes particularly significant during acute attacks, when the liver’s heme reserves are depleted, leading to the induction of delta-aminolevulinic acid synthase 1 (ALAS1). This induction results in the accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), which are precursors immediately proximal to HMBS in the heme synthesis pathway.3
Various factors can induce acute AIP attacks, including alcohol consumption, infections, reduced caloric intake, hormonal fluctuations related to the menstrual cycle, and exposure to certain porphyrogenic drugs. The Norwegian Porphyria Centre (NAPOS), in collaboration with the European Porphyria Network (Epnet), has compiled a list of medications that should be avoided in patients with porphyria. These high-risk drugs include anesthetics like ketamine and thiopental, antibiotics such as chloramphenicol, erythromycin, nitrofurantoin, rifampicin, and trimethoprim/sulfamethoxazole, diuretics like spironolactone, antihypertensives like methyldopa, and anticonvulsants including valproic acid, carbamazepine, phenytoin, phenobarbital, and primidone, as well as the antipsychotic risperidone.5
Epidemiology
The combined prevalence of all acute porphyrias is estimated to be around 5 in 100,000 individuals. Porphyria cutanea tarda (PCT), characterized by prominent cutaneous symptoms, is the most common porphyria overall, with an estimated prevalence of 1 in 10,000. AIP, the most frequent acute porphyria, has a European prevalence of approximately 1 in 20,000, with a higher incidence of 1 in 1,000 in Sweden, attributed to a founder effect. Founder effects, resulting in higher AIP prevalence within specific ethnic groups, have also been reported in Argentina and Spain recently.6, 7
Acute intermittent porphyria is considered a low-penetrance genetic metabolic disorder, with penetrance estimated between 10% and 20%.8 In the general population, excluding specific high-prevalence AIP groups, the penetrance is believed to be less than 1%.9 Manifest AIP (MAIP) is diagnosed when carriers of the genetic mutation develop typical acute neurovisceral attacks accompanied by elevated porphyrin precursors. In the absence of clinical episodes, the condition is termed latent AIP (LAIP). While specific mutations are linked to higher penetrance, the broader genetic factors influencing penetrance remain largely unknown.
AIP affects women more frequently than men, with a female-to-male ratio of approximately 1.5 to 2:1. Attacks are rare before puberty, and the typical age of symptom onset is between 18 and 40 years.
Pathophysiology
Acute attacks of AIP are more common in women, particularly in the post-pubertal age group. These attacks are typically triggered by factors such as certain drugs, infections, fasting, alcohol, and steroid hormones.
In AIP, neurological damage is attributed to the accumulation of porphyrin precursors, specifically porphobilinogen and aminolevulinic acid (ALA). This accumulation leads to peripheral and autonomic neuropathies, as well as psychiatric manifestations.
However, the precise mechanism by which elevated levels of porphobilinogen and ALA cause symptomatic disease remains unclear. Many individuals with the genetic defect do not develop symptoms despite increased porphyrin secretion.
A 2017 case-control study involving 50 patients suggested a link between AIP and systemic inflammation. Storjord et al. observed that symptomatic patients had decreased levels of insulin, C-peptide, prealbumin, and markers of kidney function, while asymptomatic carriers did not. They proposed that reduced insulin release in symptomatic AIP patients might be associated with increased disease activity and impaired kidney function.10
History and Physical Examination
Acute attacks of AIP typically last for up to a week, with symptoms often progressing in a characteristic sequence:6 first abdominal pain, followed by psychiatric symptoms, and finally peripheral neuropathies.
Abdominal pain is usually severe, epigastric, and colicky, often lasting several days. It can be accompanied by constipation and vomiting.11
Patients may exhibit a wide range of psychiatric symptoms, including depression, often concurrent with abdominal and/or neurological symptoms. A Swedish study indicated an increased risk of schizophrenia or bipolar disorder in AIP patients and their relatives.12
Peripheral neuropathies can manifest as weakness, typically starting in the lower extremities and ascending, although any nerve distribution can be affected. This presentation can resemble Guillain-Barré syndrome (GBS). Autonomic neuropathies can lead to hypertension and tachycardia.
Central nervous system involvement may include delirium, weakness progressing to quadriplegia and respiratory failure, cortical blindness, and even coma. Seizures occur in about 5% of cases, with partial seizures being the most common type.13 Red or brown urine, which darkens upon exposure to air, light, and warmth, may be observed. It is important to note that AIP, unlike porphyria cutanea tarda, does not present with cutaneous manifestations.
While traditionally patients were believed to be completely asymptomatic between attacks, recent evidence suggests that 20% to 64% may experience persistent, debilitating chronic symptoms such as pain, nausea, fatigue, and neuropathic symptoms like numbness and tingling.14
Evaluation and Diagnosis of AIP
The cornerstone of AIP disease diagnosis is the detection of elevated porphobilinogen (PBG) in a random urine sample, protected from light. Confirmatory diagnosis should include quantitative measurements of PBG, ALA, and total porphyrins from the same urine sample. Normal urinary PBG levels range from 0 to 4 mg/L, but during an acute AIP attack, levels can reach as high as 50 to 200 mg/L for PBG and 25 to 100 mg/L for ALA.
A urinary PBG level within the normal range (0-4 mg/L) during acute neurovisceral symptoms effectively rules out acute porphyria as the cause.
Ideally, urine collection for PBG and ALA quantification should occur during the peak of an AIP attack. However, due to persistent elevation of urinary ALA and PBG for months or even years post-attack, samples can be collected within a few days to weeks after the acute episode.15 The exception to this is timed urine collection following a 4- to 5-day course of intravenous heme treatment.1
Elevated urine porphyrins, particularly coproporphyrin (resulting from spontaneous polymerization of porphobilinogen in urine), are frequently observed. However, it is important to note that non-specific elevation of urine porphyrins, especially coproporphyrins (1 to 2 times the reference range), is common and not specific to porphyria. Stool porphyrin levels are typically within the normal range or only slightly elevated.
Increased plasma porphyrin, confirmed by a fluorescence emission scan peak at 619 nm, may also be present. Molecular and DNA testing for HMBS deficiency is not essential for AIP disease diagnosis in acute settings but is valuable for family screening and confirming specific mutations.16, 11, 17
Associated Laboratory Abnormalities During an Acute Attack:
- Hyponatremia (most common)
- Hypomagnesemia (common)
- Mild aminotransferase elevations
- Mild leukocytosis
Differentiating Between Acute Porphyrias
As previously mentioned, the symptoms of acute porphyrias often overlap significantly. Clinically, AIP symptoms can be indistinguishable from those of hereditary coproporphyria (HCP) and variegate porphyria (VP). While current diagnostic approaches to differentiate AIP from other acute porphyrias are not strongly evidence-based, new strategies are under development.
Plasma Fluorescence Staining
Unlike AIP, HCP, and other porphyrias where sera from affected individuals show emission peaks around 619 nm to 620 nm, serum from VP patients exhibits a unique porphyrin-peptide with a fluorescence peak at approximately 626 nm when excited by 410 nm light (the Soret band). This difference in fluorescence at physiological pH is used to differentiate VP from other acute and cutaneous porphyrias.18
Emerging Role of Genetic Mutation Analysis in Diagnostic Confirmation
Genetic testing is increasingly used to identify the specific type of acute porphyria. Commercial genetic testing is available, involving sequencing of the four genes associated with acute porphyrias:1
Gene / Type of Acute Porphyria
- ALAD / ALAD-deficient porphyria (Doss porphyria)
- HMBS / AIP
- CPOX / HCP
- PPOX / VP
Next-generation sequencing (NGS) is evolving in porphyria disease diagnosis. Researchers have designed panels containing genes like ALAS1, HMBS, CPOX, and PPOX for mutational analysis of AIP, HCP, and VP.19
Treatment and Management
Initial and Symptom-Oriented Treatment
Given that symptoms of AIP can mimic various abdominal, metabolic, and neuropsychiatric conditions, confirming the diagnosis is crucial for effective management.
Avoiding precipitating factors, particularly drugs, is paramount and requires continuous patient and family education.
In patients with confirmed AIP presenting with an acute attack, the initial approach involves a high-carbohydrate diet or intravenous dextrose to inhibit hepatic ALAS1 transcription. Administration of 10% dextrose in 0.45% saline should be initiated promptly. For patients without weakness, vomiting, or hyponatremia, a 48-hour trial of a high-carbohydrate diet is recommended before starting specific treatments.20, 13, 11
For pain management, parenteral opiates like morphine, diamorphine, and fentanyl are preferred. Nausea and vomiting can be managed with prochlorperazine, promazine, and ondansetron. Symptom relief typically begins within 72 to 96 hours.20 Tachycardia and hypertension are managed with beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers like diltiazem. Seizures can be controlled with diazepam, magnesium sulfate, or clonazepam.11
Specific Treatment
Intravenous heme administration is the specific therapy for acute AIP attacks. Heme replenishes the hepatic heme pool, downregulating ALAS1 and reducing porphyrin precursor production, leading to symptom improvement.21 Heme reduces hepatic ALAS1 not only by suppressing ALAS1 transcription but also by destabilizing mRNA or blocking mitochondrial import of the mature enzyme.3
Due to the delayed effect of heme therapy on plasma ALA and PBG levels, intravenous heme therapy (IHT) should be started immediately in severe acute attacks and continued for four days (3 to 4 mg/kg of heme/day). Improvement, indicated by reduced urine and serum PBG, is usually observed by the third day. Panhematin should be administered through a large peripheral vein or central line to minimize phlebitis risk, which can also be reduced by preparing it with human albumin instead of water. Other potential complications include a transient increase in prothrombin time and increased liver iron deposition. Patients can be discharged once parenteral opioids are no longer needed, and they can tolerate oral medications.20
IHT is generally well-tolerated, with occasional reports of headache or pyrexia. However, recurrent IHT carries inherent risks that caregivers should be aware of.
Risks Associated with Recurrent IHT
Recurrent IHT poses several significant risks: the need for repeated venous access, increasing thromboembolic disease risk, liver fibrosis, hepatic iron overload, and the development of therapeutic ‘tolerance’ to heme infusion. Research has shown that heme infusion can induce hepatic heme oxygenase 1 (HMOX1) expression.22, 23, 24 HMOX1 is a key enzyme in heme catabolism. Its induction by heme therapy can reduce the hepatocyte heme pool, paradoxically enhancing ALAS1 expression.25 This heme-induced auto-catabolic effect contributes to the tolerance observed in some patients.
Currently, orthotopic liver transplantation (OLT) is the only established cure for AIP, with reported survival rates around 80%.26, 27 However, the high risk (40%) of hepatic artery thrombosis associated with OLT has led to recommendations to reserve this procedure for patients with severe, recurrent acute attacks and significantly impaired quality of life (QoL).
Ongoing research explores alternative therapies, currently in various clinical trial phases. These potential future therapies include:
Potential/Experimental Therapies for AIP
Enzyme Replacement Therapy (ERT): Based on studies in AIP mouse models showing reduced plasma PBG accumulation after recombinant human HMBS/PBGD (rhPBGD) administration during induced acute attacks, the European Medicines Agency (EMA) granted rhPBGD orphan designation (EU/3/02/103) in 2002. Clinical trials in healthy subjects, asymptomatic HMBS-deficient individuals with increased porphyrin precursor excretion, and AIP patients with recurrent attacks have been conducted.28, 29 While the enzyme effectively detoxifies PBG metabolites, limitations include its short circulatory half-life and lack of liver targeting.
Liver Gene Therapy: Clinical trials are evaluating two gene therapy strategies for AIP: HMBS-gene therapy and RNA interference for ALAS1 gene inhibition. These strategies involve delivering the HMBS gene to hepatocytes using viral vectors or using small interfering RNA (siRNA) to reduce delta ALA production. Both approaches are still in clinical trials, awaiting larger studies to confirm consistent efficacy and safety before approval.20, 30
Differential Diagnosis
In an observational study of acute porphyrias involving 90 AIP patients, the average diagnostic delay was 15 years.31 Due to abdominal pain being a primary symptom of acute AIP attacks, patients often undergo appendectomies or cholecystectomies before porphyria is suspected or diagnosed.
Given the broad neuro-visceral clinical presentation of AIP, the differential diagnosis list is extensive:
- Other acute porphyrias: Clinically differentiating AIP from other acute porphyrias like HCP, VP, and Doss porphyria can be challenging.
- Causes of acute abdomen: Peritonitis, appendicitis, acute cholecystitis, acute gastritis, acute pancreatitis, intestinal obstruction, strangulated abdominal hernia, acute mesenteric ischemia, ileus, diverticulitis, esophagitis, endometriosis, gastric outlet obstruction, intussusception, pelvic inflammatory disease, ovarian cysts, acute pyelonephritis, aortic dissection.
- Lead poisoning: This is a significant differential diagnosis. Anemia and blood lead levels should be checked to differentiate between the two.11
- Conditions associated with autonomic neuropathy: Hypertensive crisis, tachyarrhythmias, adrenal crisis, familial Mediterranean fever, fibromyalgia.
- Neuropsychiatric mimics: Acute psychotic attack, delirium, panic attack, Guillain-Barré syndrome.
Prognosis
The prognosis for AIP is generally good with early disease diagnosis and prompt treatment during acute attacks. Mortality rates during acute attacks have decreased to 5% to 20% in recent decades, thanks to improved diagnostic methods and treatments. However, in cases resistant to heme therapy or with recurrent attacks, orthotopic liver transplantation remains the only currently approved method to reduce mortality.17, 2, 1
Ongoing clinical trials of ERT and liver gene therapy offer hope for further improving the prognosis of AIP in the near future.
Long-term complications of AIP, including arterial hypertension, chronic kidney disease, neurological deficits, and increased risk of hepatocellular carcinoma, require continuous monitoring and management.32, 33, 34, 35
Complications
- Chronic kidney disease
- Arterial hypertension
- Hepatocellular carcinoma
- Chronic pain
- Peripheral neuropathy
- Recurrent acute attacks
- Liver fibrosis (from recurrent heme therapy)
- Hepatic iron overload (from recurrent heme therapy)
Deterrence and Patient Education
AIP is a rare, autosomal dominant condition characterized by a chronic course with recurrent acute neurovisceral symptom episodes. Ongoing trials offer promise for a definitive cure for this lifelong disease. Once AIP disease diagnosis, or another acute hepatic porphyria diagnosis is confirmed, patients should receive thorough counseling and be provided with a comprehensive list of trigger factors (that can precipitate attacks), particularly safe and unsafe medications. They should understand that current treatments are primarily for acute attacks and that preventing attacks by avoiding triggers is the best strategy for remaining asymptomatic. Patients should be advised to seek immediate medical attention at the emergency department if they experience abdominal pain. Education on prognosis and potential complications is essential, and genetic testing for offspring is strongly recommended.
Enhancing Healthcare Team Outcomes
Clinicians should consider AIP in patients presenting with abdominal pain and neuropsychiatric symptoms or signs. Patients with AIP, often presenting with acute abdomen, may initially be seen by surgeons and undergo unnecessary surgical procedures. Therefore, surgical teams should be aware of non-surgical causes of acute abdomen like AIP and maintain a high index of suspicion in patients with recurrent attacks or those with concurrent neuropsychiatric symptoms.
Interprofessional collaboration among primary care physicians, nurse practitioners, metabolic/genetic disease experts, hematologists, biochemists, pharmacists, nurses, and surgeons is crucial for early AIP disease diagnosis and minimizing long-term complications. Clinical geneticists play a vital role in genetic counseling for AIP patients considering having children, discussing inheritance risks, prenatal testing options, and early identification of carrier status in offspring. Nurses are responsible for administering heme therapy, monitoring treatment progress and adverse reactions, and communicating any concerns to the medical team. Pharmacists should verify medication dosages and conduct medication reviews to identify potential drug interactions and porphyria-precipitating drugs, reporting any concerns to the managing physicians. Open communication and collaboration among all interprofessional team members are essential to reduce the morbidity associated with this disorder. [Level V]
Review Questions
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References
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Disclosure: Luis Gonzalez-Mosquera declares no relevant financial relationships with ineligible companies.
Disclosure: Sidharth Sonthalia declares no relevant financial relationships with ineligible companies.
