Acute Intermittent Porphyria (AIP) is one of a group of disorders known as the Porphyrias. All forms of Porphyria are the result of a genetic defect that impedes the functioning of one of the enzymes that is part of the process of making heme, which is needed for hemoglobin among other things. Which enzyme is affected determines which form of Porphyria a person has. AIP is due to a deficiency of the enzyme porphobilinogen
deaminase (also known as hydroxymethylbilane synthase) that leads to
accumulation of the heme precursors delta-aminolevulinic acid and
porphobilinogen initially in the liver. When any step in the process of heme synthesis is reduced or blocked, the accumulation of the precursors in the cell can lead to oxygen depletion. The precursors (called porphyrins) generally build up in either the liver, the bone marrow, or the skin.
SYMPTOMS
Symptoms vary from one form of the disease to another, between patients with the same form of the disease, and from one attack to another in one patient. Symptoms generally affect the skin or nervous system and include: abdominal pain, constipation, nausea, vomiting, mental agitation and confusion; anxiety, depression, psychosis and even hallucinations; insomnia, muscle weakness (can progress to breathing muscles, and can take months or years to recover from), tremors, and sometimes seizures, dark urine, tachycardia, high blood pressure, sweating, irregular heart rhythm, also pain in arms, legs, back, and neck (for a longer list of symptoms, and their relative frequency, see the NIH page on AIP). One of the characteristic features of AIP is the intensity of the pain. It is described as unbelievably painful, one patient describes it as "not compatible with life". The abdominal pain is described as being a burning pain, as if there is an actual fire inside the abdomen. In AIP symptoms occur as distinct "attacks" that can last hours to days and often require hospitalization due to the severity of the pain.
AIP attacks occur when too many of the heme precursors build up, which can occur when the body encounters something that increases the demand for and production of heme. Some of the known triggers cause the enzyme ALAS1 to be upregulated which increases production of heme precursors (glucose and heme downregulate this enzyme). This includes many drugs, premenstrual hormone
changes in women (elevated progesterone), alcohol, smoking, exposure to organic
solvents, emotional stress, infection, low-calorie/low-carb diet. Any one factor on its own is often not enough to trigger an attack, it may take several factors occurring together. In AIP levels of sodium and chloride can drop suddenly and this is the cause of some of the symptoms. Occasionally AIP attacks also include a severe adrenergic crisis. If the disease has progressed far without diagnosis and treatment nerve damage can result, which can lead to long-term muscle weakness among other things.
DIAGNOSIS
Porphyrias are diagnosed with blood, urine, and stool testing, as well as genetic testing. The Porphyrias Consortium has more information about testing here, and more detailed information specific to AIP here. From the site "The most common tests used for porphyrias are measurements of substances that accumulate in large amounts in the body, especially when someone has active Porphyria. These substances, porphyrin precursors and porphyrins, can be measured in red blood cells (erythrocytes), blood plasma, urine and feces. Measuring enzymes in cells and looking for changes (mutations) in DNA is useful for confirmation and for family studies." In AIP it is the HMBS gene that has the mutation. Some of these tests will only be abnormal during an acute attack, such as the levels of the precursors that can build up.
TREATMENT
Avoidance of potential triggers is the basis for managing Porphyrias. A database called Porphyria Drug Safety provides information about which drugs can trigger an acute attack for people with Porphyria. Once an attack begins, treatment should start as soon as possible to minimize the severity of the attack. This is usually done by giving large amounts of glucose and/or the drug Panhematin (Panhematin is now the preferred treatment, while in the past it was often given only after several days of glucose therapy proved not effective enough). According to the American Porphyria Foundation's site "Three to four mg/kg of Panhematin® given once daily for four days early in an attack produces a highly beneficial effect in most patients. Commonly noted are decreases in pulse rate, blood pressure, abdominal pain, as well as decreased levels of urinary porphobilinogen (PBG). These effects can occur within a day." According to the European Porphyria Network site glucose can be administered as "Two litres of normal saline with 10-20% glucose given in divided doses of 500 ml over 24 hours through a central venous catheter." Pain management during an attack is central to treatment, as the pain can be excruciatingly intense. Carefully monitoring fluid and electrolyte levels is also important. In certain cases additional treatment measures are needed "Recurrent attacks related to the menstrual cycle can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by prophylactic infusions of hemin, which are titrated to patient response. " (from The Porphyria Consortium).
Is there a connection between Porphyria and Mast Cell Disease?
Increased mast cell numbers in the sclerotic skin of porphyria cutanea tarda.
Mast cells and transforming growth factor-beta expression: a possible relationship in the development of porphyria cutanea tarda skin lesions.
Differential Effects of Protoporphyrin and Uroporphyrin on Murine Mast Cells
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