Background

Acute Intermittent Porphyria is an uncommon genetic metabolic condition characterized by a deficiency in one of the enzymes involved in heme production, called porphobilinogen deaminase or hydroxymethylbilane synthase. This condition is part of a group of disorders known as porphyrias, which result from the abnormal accumulation of porphyrins or their precursors in the body. 

AIP manifests with intermittent and acute attacks that can involve severe abdominal pain, neurological symptoms, psychiatric disturbances, and potentially life-threatening complications. The disease typically presents during adulthood, often in the second or third decade of life, and both genders can be affected, although it is more common in females. 

Epidemiology

Prevalence: Five incidences of acute porphyrias are thought to occur for every 10,000 people. The most prevalent acute porphyria, AIP, has a prevalence of about 1 in 2000 throughout Europe, however because of the founder effect, Sweden has a higher frequency of 1 in 1000.  

Geographic Distribution: AIP occurs worldwide but may vary in prevalence among different regions and ethnic groups. Some areas show higher incidences due to specific genetic variations.  

Age of Onset: Symptoms of AIP usually manifest during adolescence or early adulthood. However, the penetrance of the disease is highly variable, and some individuals with the genetic mutation may never experience symptoms.  

Gender Predilection: AIP appears to affect women more often than men, possibly due to hormonal influences. Symptoms in women may be linked to hormonal changes during menstruation, pregnancy, or the use of oral contraceptives. 

Anatomy

Pathophysiology

Enzyme Deficiency: AIP is an autosomal dominant disorder resulting from a mutation in the HMBS gene, which encodes the PBGD enzyme. The deficiency of PBGD results in impaired conversion of PBG to hydroxymethylbilane, leading to the accumulation of PBG and ALA.  

Neurotoxic Effects: The accumulated ALA and PBG are neurotoxic and believed to disrupt the normal function of the nervous system, particularly by affecting gamma-aminobutyric acid receptors and ion channels. These neurotoxic effects can result in the characteristic neurological symptoms seen in AIP, such as abdominal pain, seizures, neuropathy, and psychiatric manifestations.  

Heme Feedback Regulation: Heme, a crucial component in hemoglobin and various enzymes, plays a regulatory role in the heme biosynthesis pathway. In AIP, the deficiency of PBGD leads to a decreased feedback inhibition of the pathway, resulting in increased synthesis and accumulation of ALA and PBG. 

Trigger Factors: While the enzyme deficiency exists from birth, symptoms of AIP are typically triggered by various factors such as certain medications (e.g., barbiturates, steroids, some antibiotics), hormonal changes, fasting, alcohol consumption, and other stressors. These triggers induce the hepatic synthesis of heme and subsequently exacerbate the accumulation of porphyrin precursors, precipitating acute attacks. 

Etiology

Hormonal changes: Fluctuations in hormonal levels, particularly during puberty, menstrual cycles, or pregnancy, can trigger symptoms.  

Environmental factors: Certain drugs or chemicals, such as barbiturates, steroids, some antibiotics, alcohol, and certain hormonal medications, can induce an acute attack in susceptible individuals. 

Fasting or dieting: Extreme changes in diet or prolonged fasting can trigger an attack by affecting the availability of necessary nutrients and energy substrates in the body.  

Stress: Physical or emotional stress can also precipitate an acute episode in some individuals. 

Genetics

Prognostic Factors

Unmanaged Acute Intermittent Porphyria is connected to considerable health risks and may result in paralysis and fatality. Over time, it can lead to enduring health issues such as persistent high blood pressure, long-standing nerve damage, chronic kidney problems, and liver cancer. 

Clinical History

• Age group 

Acute Intermittent Porphyria (AIP) typically manifests its symptoms in late adolescence or early adulthood. The age at which symptoms appear can differ greatly, but it often occurs between the ages of 15 and 40. However, it’s important to note that this condition can affect individuals of any age.  

Physical Examination

Laboratory Tests: Urine and blood tests to detect porphyrin precursors and byproducts such as delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). Elevated levels of these substances during acute attacks are suggestive of AIP. 

Genetic Testing: Molecular genetic testing can confirm the presence of specific mutations associated with AIP. 

Imaging Studies: Sometimes, imaging studies like abdominal CT scans or MRI scans might be performed to rule out other causes of abdominal pain or identify complications during acute attacks. 

Age group

Associated comorbidity

Abdominal pain: Severe, diffuse abdominal pain is one of the hallmark symptoms of AIP during an acute attack. This pain can be intense and may last for days. 

Neurological symptoms: Attacks by AIP frequently impact the nervous system, resulting in manifestations like muscular debility, tingling or numbness, seizures, confusion, and psychiatric disturbances like anxiety or hallucinations. 

Autonomic dysfunction: Some individuals may experience symptoms related to autonomic nervous system dysfunction, such as rapid heartbeat (tachycardia), high blood pressure, and gastrointestinal issues like vomiting or constipation.  

Medications: Certain medications are known to trigger AIP attacks by inducing the production of enzymes that exacerbate the accumulation of porphyrins. Examples include certain antibiotics, antiepileptic drugs, hormonal medications, and some psychiatric medications.  

Hormonal Changes: Fluctuations in hormonal levels, particularly during menstruation or pregnancy, can trigger AIP attacks in some individuals.  

Alcohol: Alcohol consumption is a known trigger for acute attacks in individuals with AIP. It’s advised for individuals with AIP to avoid or limit alcohol intake to minimize the risk of triggering an attack.  

Stress and Diet: Emotional stress and certain dietary factors, such as fasting or extreme dieting, can trigger acute attacks in susceptible individuals. 

Infections and Illness: Infections and certain illnesses can also trigger AIP attacks in some cases. 

Associated activity

Acuity of presentation

Abdominal Pain: Severe abdominal pain is one of the characteristics symptoms of AIP. It is often described as colicky and can be localized or diffuse. It might be accompanied by nausea, vomiting, constipation, or diarrhea. 

Neurological Symptoms: AIP can also present with various neurological manifestations, such as: 

Peripheral neuropathy: Numbness, tingling, weakness in limbs. 

Muscle weakness: Often ascending paralysis, affecting arms and legs. 

Seizures: Rare but possible during acute attacks. 

Autonomic Dysfunction: Symptoms like high blood pressure, rapid heartbeat (tachycardia), and urinary retention might also occur.  

Triggers: Attacks can be triggered by various factors such as certain medications (barbiturates, sulfonamides, etc.), hormonal changes (e.g., menstruation), fasting, alcohol consumption, and stress.  

Rapid Onset: The onset of symptoms can be rapid and severe, often leading to hospitalization. 

Differential Diagnoses

Other types of Porphyria: There are several types of porphyria, each caused by a deficiency in a different enzyme involved in heme production. Differential diagnoses may include other types like Variegate Porphyria, Hereditary Coproporphyria, and Porphyria Cutanea Tarda. 

Acute Abdominal Conditions: The symptoms of AIP, especially abdominal pain, can mimic other acute conditions such as appendicitis, pancreatitis, cholecystitis, or other gastrointestinal disorders. Differential diagnosis aims to rule out these conditions based on clinical history, physical examination, and specific tests. 

Neurological Disorders: AIP can manifest with neurological symptoms, including seizures, confusion, and peripheral neuropathy. Differential diagnoses may include epilepsy, other metabolic disorders affecting the nervous system, or psychiatric conditions. 

Other Metabolic Disorders: Some metabolic disorders may present with similar symptoms to AIP. These could include acute hepatic porphyria, metabolic myopathies, or other conditions affecting the nervous system. 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Symptomatic Management during Acute Attacks: 

Pain Management: Severe abdominal pain is a characteristic of acute attacks. Intravenous administration of medications like opioids, anti-nausea drugs, and sometimes low-dose benzodiazepines can help manage pain and associated symptoms.  

Hydration: Intravenous fluids are crucial to prevent dehydration, as dehydration can trigger or exacerbate an attack.  

Carbohydrate Loading: High-carbohydrate meals or glucose infusions can help limit the production of porphyrins, potentially alleviating symptoms. 

Heme Administration: 

Hemin Therapy: Intravenous administration of hemin, a form of heme, can decrease the production of heme precursors and help to shorten the duration of an acute attack. Hemin infusions are often used within the first few days of an attack. 

Identification and Avoidance of Trigger Factors: 

Certain factors such as certain medications, fasting, hormonal changes, alcohol, and stress can trigger acute porphyria attacks. Identifying and avoiding these triggers is crucial in preventing future attacks. 

Long-Term Management: 

Regular Monitoring: Patients may need regular check-ups and monitoring of their porphyrin levels to prevent or detect impending attacks. 

Pain Management Strategies: Chronic pain management strategies may be required for patients experiencing recurrent or chronic pain.  

Genetic Counseling: Since AIP is an inherited disorder, it is advised that patients and their families receive genetic counselling to learn about the inheritance pattern and associated risks. 

Medication Management: 

Avoid Triggering Medications: Certain medications, such as some antibiotics, contraceptives, and others that can induce cytochrome P450 enzymes, should be avoided or used cautiously.  

Symptom Management: Depending on the specific symptoms, medications like anti-nausea drugs, anticonvulsants for neuropathic pain, and others may be prescribed to manage symptoms as needed. 

Lifestyle Modifications: 

Dietary Changes: Maintaining a balanced diet with regular carbohydrate intake can help prevent attacks. Avoiding fasting or extreme diets is essential.  

Avoidance of Alcohol and Smoking: Alcohol consumption can trigger attacks and should be avoided. Smoking can also exacerbate symptoms and should be avoided.  

Consultation with Specialists: 

Consulting Specialists: Collaborating with healthcare professionals like porphyria specialists, gastroenterologists, and geneticists can provide comprehensive care for AIP patients. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

lifestyle-modifications-in-treating-aip

Stay Hydrated: Maintaining good hydration levels is important to prevent attacks.  

Manage Stress: Stress can trigger AIP attacks. Employ stress management techniques such as yoga, meditation, deep breathing exercises, or seeking professional counseling if necessary. 

Protect from Sun Exposure: Some individuals with AIP might be sensitive to sunlight (photosensitivity). Use protective clothing, hats, and sunscreen with a high SPF to avoid triggering skin symptoms. 

Genetic Counseling: Consider genetic counseling for family members to understand the risk of inheriting AIP and appropriate preventive measures. 

Regular Medical Check-ups: Regular visits to healthcare providers specialized in porphyria management can help in monitoring symptoms, managing medications, and adjusting treatment plans as needed. 

Emergency Plan: Develop an emergency plan with your healthcare provider to manage acute attacks promptly, including access to necessary medications and medical care. 

Education and Support: Educate yourself and your close contacts about AIP to understand the condition better. Joining support groups or seeking counseling can also be beneficial. 

Effectiveness of RNAi Agents in treating AIP

givosiran (Givlaari) 

Givosiran is a small interfering RNA (siRNA) medication that works by reducing the production of a specific enzyme involved in the heme biosynthesis pathway.

By decreasing the production of this enzyme, givosiran helps reduce the accumulation of toxic substances responsible for causing symptoms in individuals with acute hepatic porphyria. 

Givosiran was given to individuals with acute intermittent porphyria, and those who got it showed improved outcomes for several different illness symptoms and a much-reduced rate of porphyria attacks than those who received a placebo. 

Role of Blood components in treating AIP

Hemin (Panhematin) 

Restricts the pace of heme production or liver & or marrow porphyria, potentially through the suppression of aminolevulinic acid synthetase enzyme. 

Additionally demonstrated temporary, minor anticoagulant properties during clinical trials. 

role-of-management-in-treating-aip

Diagnosis and Education: 

Identification of symptoms and diagnosis by a healthcare professional is the first crucial step. Educating the patient about the condition, triggers, and symptom management is essential. 

Acute Attack Management: 

Hospitalization: Hospitalisation may be required during an acute attack to manage symptoms and offer supportive treatment. 

Pain Management: Pain is a significant symptom during an acute attack. Medications like opioids and other pain relievers may be used cautiously under medical supervision. 

Symptom Control: Controlling nausea, vomiting, and other associated symptoms is important. 

Intravenous Glucose: Administering intravenous glucose can help suppress porphyrin production and alleviate symptoms. 

Identifying Triggers and Lifestyle Modifications: 

Understanding triggers (such as certain medications, fasting, hormonal changes, etc.) and making necessary lifestyle modifications to avoid these triggers can help prevent future attacks. 

Medication and Preventive Measures: 

Heme Therapy: Heme preparations (hemin) may be used to prevent attacks by suppressing the production of porphyrins. 

Avoidance of Triggering Factors: Patients are advised to avoid known triggers such as certain medications, alcohol, fasting, and stress. 

Monitoring and Follow-Up: 

Regular monitoring by healthcare providers to assess symptoms, manage medication, and ensure the patient’s overall well-being is important. 

Genetic counseling may be recommended for family members, as AIP is an inherited condition. 

Supportive Care and Lifestyle Management: 

Nutrition: A balanced diet and regular eating habits can help prevent attacks triggered by fasting. 

Pain Management: Addressing chronic pain and finding suitable pain management strategies for long-term care. 

Psychological Support: Coping with a chronic condition like AIP might necessitate psychological support to manage stress and anxiety. 

Emergency Preparedness: 

Patients should have an emergency plan in place with clear instructions for healthcare providers in case of an acute attack. 

Genetic Counseling: 

For those with a family history of AIP, genetic counseling can help in understanding the inheritance pattern and making informed decisions. 

Research and New Treatments: 

Ongoing research for new treatments and therapies might provide additional options for managing AIP more effectively in the future. 

Medication

Future Trends

Media Gallary

References

Acute Intermittent Porphyria – StatPearls – NCBI Bookshelf (nih.gov)