What Is Porphyria?
Porphyria is a rare hereditary condition characterized by the abnormal metabolism of hemoglobin. A buildup of organic substances that cause porphyrin to form in the body causes porphyria. Hemoglobin is necessary to create a bond with porphyrin, bind iron, and transport oxygen to the organs and tissues. Hemoglobin depends on porphyrins to function efficiently. Several issues might arise when porphyrin concentrations are high. Heme, a crucial part of hemoglobin, is formed from porphyrins. Every step of the multi-step heme production route requires a different enzyme. Porphyrias are unique clinical syndromes resulting from a lack of or a flaw in a specific enzyme necessary for a particular step of the heme production pathway. Although these disorders are typically categorized according to the primary system affected, there is a considerable overlap of affected systems. Therefore, many porphyrias present with mixed symptoms.
What Is Acute Intermittent Porphyria?
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Acute intermittent porphyria is an uncommon metabolic disease characterized by partial deficiency of the enzyme hydroxymethylbilane synthase. This enzyme is also known as porphobilinogen deaminase. This deficiency can cause the accumulation of porphyrin precursors (substances that lead to porphyrin production).
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The clinical features, severity, and prognosis of each porphyria depend on the deficit enzyme and the corresponding porphyrin accumulated. Acute intermittent porphyria is the most prevalent and complex form of acute porphyria.
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A mutation in the HMBS (hydroxymethylbilane synthase) gene, which is inherited as an autosomal dominant pattern, is the cause of this enzyme deficiency. HMBS gene is responsible for providing instructions for the production of hydroxymethylbilane synthase. However, a deficit alone is insufficient to cause disease symptoms, and most people with an HMBS gene mutation do not experience the signs and symptoms of acute intermittent porphyria. Additional factors are necessary to cause symptoms, such as hormonal changes, consumption of specific prescription or recreational medicines, severe alcoholism, infections, fasting, etc.
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The heme synthesis pathway involves eight enzymes, and there are at least seven primary types of porphyria. Different types of porphyria have various symptoms. Moreover, patients with one kind of porphyria do not develop any of the other types of porphyria.
What Are the Other Names of Acute Intermittent Porphyria?
Other names of acute intermittent porphyria are:
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Swedish porphyria.
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AIP.
What Causes Acute Intermittent Porphyria?
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Acute intermittent porphyria is a complex condition, which means that several distinct factors, including environmental and genetic factors, must coexist for the onset of symptoms.
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Mutation in the HMBS gene is the primary cause of acute intermittent porphyria, and it can lead to 50 percent of the hydroxymethylbilane synthase enzyme. HMBS gene is responsible for providing instructions for producing hydroxymethylbilane synthase enzymes. About 391 known mutations of the HMBS gene can cause acute intermittent porphyria. In addition, a gene mutation might result in the production of a protein that is defective, ineffective, or absent. This can have an impact on a variety of body organ systems depending on the specific protein's functions.
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The development of symptoms of acute porphyria also requires the presence of additional factors known as triggers. These factors are sometimes different for some people. However, these triggers frequently occur together, including certain drugs, alcohol abuse, fasting, stress, infections, specific hormonal changes, etc. These triggers are thought to stimulate increased heme production in the liver.
Is Acute Intermittent Porphyria an Inherited Condition?
Acute intermittent porphyria is an inherited condition, so the disease is genetically passed from parents to their children. Acute intermittent porphyria is inherited in an autosomal dominant pattern. Dominant genetic disorders require only a single copy of the defective or mutated gene for the appearance of the disease. Either parent can pass on the defective gene to their offspring. There is a 50 percent chance that the defective gene will be passed from an affected parent to their offspring.
Is Acute Intermittent Porphyria a Common Condition?
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There are five incidences of acute porphyrias overall per 10,000 people.
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The frequency of symptomatic acute intermittent porphyria in the general population in Europe is estimated to be 5.9 per million. Except for Sweden, it is more significant due to the founder effect.
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According to recent population-based genetic studies, one in 2000 people acquired an HMBS gene mutation that causes the disease.
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Women are more frequently affected by acute intermittent porphyria as compared to men.
What Are the Symptoms of Acute Intermittent Porphyria?
The symptoms of acute intermittent porphyria typically manifest between the age of 18 and 40. Moreover, the symptoms progress from abdominal to psychiatric and peripheral neuropathies. The symptoms of acute intermittent porphyria typically manifest as 'attacks' or episodes that last for several hours or days.
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The pain in the abdomen is often colicky, intense, and epigastric. It typically lasts several days. Constipation and vomiting may accompany it.
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Patients may exhibit a wide range of psychological symptoms, such as depression and concomitant neurologic and/or gastrointestinal symptoms.
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Although any nerve distribution may be impacted, peripheral neuropathies might present as a weakness that starts in the lower extremities and progresses upward.
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Secondary to autonomic neuropathies, increased blood pressure, and an increased heart rate can also develop.
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Delirium (confusion and reduced awareness), a paralysis that progresses to quadriplegia (paralysis from the neck down) and respiratory failure, cortical blindness (loss of vision without any ophthalmological causes and with normal pupillary light reflexes), and even coma (prolonged unconsciousness) are examples of central nervous system symptoms.
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Some patients may also develop seizures.
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Occasionally, red or brown urine may be seen; this urine darkens when exposed to air, light, and heat.
How Is Acute Intermittent Porphyria Diagnosed?
The diagnosis of acute intermittent porphyria includes:
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Clinical Evaluation and Medical History: Most acute intermittent porphyria symptoms are ambiguous and episodic, making the diagnosis challenging. A diagnosis is typically made based on recognizing distinctive signs from a thorough clinical evaluation, a complete patient history, and a few specialized tests. Acute intermittent porphyria should be suspected in patients who experience unexplained abdominal discomfort, especially if it frequently occurs when psychological problems accompany it.
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Urine Tests: To confirm a diagnosis of acute porphyria, screening tests to determine the amounts of the porphyrin precursor porphobilinogen (PBG) in urine are essential. During acute attacks, PBG synthesis and excretion are consistently elevated in acute intermittent porphyria. Therefore, to differentiate acute intermittent porphyria from other kinds of porphyria, further testing (fecal and blood porphyrin measurement) is required if urine PBG excretion is high.
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Genetic Testing: It is unnecessary to perform molecular genetic testing to confirm a diagnosis because the biochemical findings related to porphyrin are distinctive. However, molecular genetic testing is frequently necessary to identify an HMBS gene mutation to give family members testing for this mutation. Patients and family members of those with acute intermittent porphyria should be advised to lower their risk of developing acute attacks. This should provide specifics regarding acute intermittent porphyria, what triggers attacks, and determining whether a prescription drug is safe or hazardous.
How Is Acute Intermittent Porphyria Treated?
The treatment of acute intermittent porphyria includes:
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The goal of treatment is to alleviate symptoms, minimize complications, and restrict heme synthesis in the liver using hematin, which lowers the generation of precursors to porphyrin.
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Along with eliminating medications that can increase acute intermittent porphyria or trigger an episode, the first steps in treatment also involve maintaining correct caloric intake, which may include intravenous infusion of adequate nutrition. However, for minor attacks, carbohydrate loading, along with effective painkillers, may be sufficient.
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Acute neurovisceral attacks frequently call for hospitalization and may necessitate hemin therapy. Hemin, an enzyme inhibitor generated from red blood cells that effectively suppresses acute porphyria attacks, may be used to treat affected people in the United States. However, porphyrin and porphyrin precursor levels almost invariably revert to normal following the administration of hemin.
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Analgesics, anti-anxiety medicines, anti-hypertensive medications, and medications for nausea and vomiting, tachycardia, or restlessness are some other medicines used to treat acute intermittent porphyria and its symptoms.
What Are the Complications of Acute Intermittent Porphyria?
Some of the complications of untreated acute intermittent porphyria are:
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Chronic renal disease and arterial high blood pressure are complications of acute intermittent porphyria.
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Muscle denervation (signs of muscle weakness and wasting).
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Hepatocellular carcinoma (primary liver cancer).
Conclusion:
Acute intermittent porphyria is a rare genetic disorder characterized by the deficiency of the hydroxymethylbilane synthase enzyme. The symptoms of the disease often manifest in the form of acute attacks or episodes. The prognosis is good if acute intermittent porphyria is diagnosed promptly and treated. Thanks to modern techniques for detection and treatment, mortality has dropped over the previous few decades from 20 to 5 percent. However, a liver transplant is the only method available to lower the mortality in cases when the disease is resistant to heme treatment.
