What are the other Names for this Condition? (Also known as/Synonyms)

• AIP (Acute Intermittent Porphyria)

What is Acute Intermittent Porphyria? (Definition/Background Information)

• Porphyrias are disorders resulting from excess porphyrin buildup in the liver and bone marrow. Manufacturing hemoglobin and related proteins (heme synthesis) involves a class of molecules, called porphyrins. Porphyrias are either inherited or acquired, and are described as acute, chronic, and cutaneous
• Acute Intermittent Porphyria (AIP) is a genetic condition affecting heme metabolism that is seen in children and adults. Among porphyrias, AIP presents with the most severe symptoms during episodes of acute attacks, which are triggered by certain internal or external factors
• Acute Intermittent Porphyria is an acute form of porphyria that is typically inherited in an autosomal dominant manner, due to mutations in the HMBS gene, which causes a defect in heme production in the bone marrow and liver
• During acute attacks (presentation of severe symptoms), the disorder is characterized by severe abdominal pain, constipation or diarrhea, and neurological symptoms that include muscle pain and weakness. This may affect the function of the vascular and respiratory system. Skin associated signs and symptoms are not observed in Acute Intermittent Porphyria
• A healthcare provider typically diagnoses this genetic disorder by testing porphyrin levels in urine and blood samples, along-with symptom assessment. During episodes of acute attacks, it can be noted that the urine of the affected individual turns reddish-brown on exposure to sunlight
• The treatments for Acute Intermittent Porphyria involves removing or treating the triggers causing AIP and symptomatic treatment. It can also involve the administration of glucose and bringing about dietary changes to include more carbohydrates. In many, the symptoms of an acute attack subside on their own
• The prognosis of Acute Intermittent Porphyria is determined by the severity of symptoms and whether complications have developed. In many individuals, the prognosis is good with adequate treatment

Who gets Acute Intermittent Porphyria? (Age and Sex Distribution)

• Acute Intermittent Porphyria is a genetic condition affecting approximately 1 in 185,000 individuals globally
• Since, it is a congenital disorder, the condition is manifested at birth. However, the symptoms may be seen in childhood or adulthood
• AIP affects females slightly more than males, though both genders are affected
• The disorder occurs without any racial or ethnic bias

What are the Risk Factors for Acute Intermittent Porphyria? (Predisposing Factors)

• A family history of Acute Intermittent Porphyria increases the risk of a newborn being diagnosed with the condition, since AIP is an inherited disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Acute Intermittent Porphyria? (Etiology)

Acute Intermittent Porphyria is caused by several mutations in the HMBS gene on chromosome 11, which is involved in the production of “heme”.

• Heme is a critical component of iron-containing proteins called hemoproteins. Hemoglobin is one such protein, which is the oxygen carrier in blood. Blood, bone marrow, and liver have the most heme protein in them
• Mutations in this gene cause a decrease in porphyrin metabolism. A compromised porphyrin metabolism causes a buildup of porphyrins in the body
• This mutation affects the function of the specific enzyme porphobilinogen deaminase (PBG.D), in the red blood cells and liver. Up to 50% of the function of the enzyme is affected, which is important for the multistep-wise process of generating heme
• However, this does not manifest as symptoms, since the body can manage with 50% enzyme function. But, the presence of other internal or external factors may hinder its function further resulting in an acute attack
• This causes an abnormal accumulation of certain compounds (such as PBG and ALA), resulting in the associated symptoms. Aminolevulinic acid (ALA) is believed to accumulate in nerve endings resulting in neurological symptoms
• Mutations in the HMBS gene are inherited in an autosomal dominant manner in about 9 in 10 cases. AIP can also be inherited as an autosomal recessive trait in 10% of the cases

The external factors or triggers may include:

• Environmental stimuli
• Eating an unusual diet, starving
• Illegal drug abuse
• Alcoholism
• Use of certain medications

The internal factors may include:

• Emotional or psychological stress
• Menstruation in women
• Any illness or infection
• Other hormonal factors

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Acute Intermittent Porphyria?

The various signs and symptoms of Acute Intermittent Porphyria stem from porphyrin buildup in the body. These may be mild or severe and vary from one individual to another. The signs and symptoms may include:

• Stomach pain and cramping abdominal pain
• Diarrhea or constipation
• Retention of urine
• Neurological signs and symptoms may include:
  • Peripheral neuropathy
  • Muscular pain and weak muscles
  • If the respiratory muscles are affected, it may cause breathing difficulties
  • Seizures in some cases
• When the nervous system of the internal organs is affected, it gives rise to neurovisceral crises
• Psychiatric signs and symptoms may include:
  • Change in sensation
  • Feeling confused
  • Hallucinating
• Abnormal color of urine (reddish) on exposure to sunlight, which tends to resolve following treatment, or when the symptoms go away

How is Acute Intermittent Porphyria Diagnosed?

The diagnosis of Acute Intermittent Porphyria is made by the following tools:

• A complete physical examination and an assessment of symptoms
• An evaluation of the affected individual’s full medical history
• Measurement of the porphyrin levels in blood, urine, or feces
  • Urine screening test (24 hours): Urine may turn red-brown on exposure to sunlight (due to the presence of complex porphyrin compounds), if urine is taken during the acute attack phase. This property is a key diagnostic find
  • Assessment of blood levels of PBG and ALA
• Measurement of porphobilinogen deaminase enzyme activity
• Molecular genetic testing before or after birth, to confirm HMBS gene mutations

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Acute Intermittent Porphyria?

The potential complications of Acute Intermittent Porphyria may include:

• Severe pain and emotional stress during periods of acute attacks
• Anemia and related conditions, due to low levels of oxygen transport
• Increased heart rate and increased blood pressure may be the outcome of autonomic nervous system being affected
• If the neuroendocrine region of brain is affected, it can lead to hyponatremia and hypomagnesemia (low sodium and magnesium levels in blood respectively), resulting in additional complications

How is Acute Intermittent Porphyria Treated?

The treatment of Acute Intermittent Porphyria symptoms may include:

• When the first signs of disease are recognized, the individual is given oral/intravenous glucose (called glucose loading) and carbohydrate-rich diet
• Medications to control severity of the acute attacks
• Large dose and strong painkillers (narcotic analgesics or opiates) may be given for severe pain
• Antipsychotic medication (chlorpromazine) to treat some of the neurological symptoms, antidepressants for depression
• Beta-blockers, such as propanalol, for cardiovascular conditions (such as hypertension and tachycardia)
• Anti-seizure medications (such as gabapentin) for seizure
• Blood disorder medications (intravenous heme or hematin) may be used to treat accumulation of ALA, which can stop the attacks
• If the symptoms are because of normal menstrual cycles, birth control hormonal pills or synthetic peptide drugs (luteinizing hormone releasing hormone agonist, or LHRH agonist) may be helpful
• Blood transfusions, based on the severity of anemia
• A splenectomy (removal of the spleen) to alleviate bleeding and worsening anemia (due to spleen enlargement)
• Bone marrow transplant for severe cases

In many individuals, the symptoms of an acute attack subside on their own. Sometimes, it may be severe as to requiring treatment in a hospital setting. The treatment also involves removing or treating any internal or external triggers.

How can Acute Intermittent Porphyria be Prevented?

• Currently, there are no specific methods or guidelines to prevent Acute Intermittent Porphyria, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Acute Intermittent Porphyria

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

Once the triggers or precipitating factors for AIP are identified, certain steps may be taken to avoid them to the extent possible, such as:

• Having a healthy lifestyle and a regular diet
• Stress avoidance, when possible
• Avoid the use of illegal drugs; avoiding alcohol
• Discontinuing medicines that trigger AIP, instead using alternatives
• Undertaking prompt treatment for any illness or infection

Individuals with Acute Intermittent Porphyrias are encouraged to wear an emergency (medical) identification tag or suitable bracelet to inform providers/others about their condition, which is particularly helpful in case of an acute attack.

What is the Prognosis of Acute Intermittent Porphyria? (Outcomes/Resolutions)

• The prognosis of Acute Intermittent Porphyria varies with the severity of the condition. But, it is generally good for mild cases and the symptoms go away with adequate treatment
• If neurological symptoms are severe involving the muscle and sensory faculties, then recovery may be prolonged and it may take many months

Additional and Relevant Useful Information for Acute Intermittent Porphyria:

The other acute porphyria forms include hereditary coproporphyria (HCP), amino levulinic acid dehydratase deficiency porphyria (ALAD porphyria), and variegate porphyria (VP).