Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) belongs to a group of hereditary diseases known as porphyrias which are characterized by defective heme metabolism, leading to excessive cellular secretion of porphyrins and their precursors. Patients with AIP will experience abdominal pain, neuropathies and constipation without the characteristic rash observed in other types of porphyria. Neuro-visceral attacks without cutaneous manifestations are characteristic of AIP. Of the acute hepatic porphyrias, AIP is the most common and most severe.

The disease is related to the following processes:  metabolic and has an incidence of about  1 / 100.000.

Overview

Acute intermittent porphyria (AIP) is an autosomal dominant condition with low penetrance that causes defects in the heme biosynthetic pathway [1]. Affected individuals have genetic mutations leading to a deficiency in porphobilinogen deaminase (PBGD, previously called uroporphobilinogen I synthetase) synthesis or activity which causes the excessive production of porphyrin and its precursors [1]. The clinical features of AIP, which are due to effects on the central, peripheral and visceral nervous system, may develop from puberty onward but most often arise from age 20 to age 30. Patients with AIP display a spectrum of signs and symptoms that may include abdominal pain, neuropathies, constipation and mental disturbances that are often amplified by other factors, such as drugs [2]. Symptoms usually occur intermittently and can be life threatening due to neurologic complications, such as seizures and paralysis.

Management of AIP is often challenging due to the diverse manifestations of this disease and potentially fatal attacks. It is important to provide timely intervention in an attempt to resolve and prevent attacks and vigilant long-term monitoring for complications in essential. Along with treating AIP directly, addressing other conditions that may have triggered attacks, such as infection or drug use, is important.

Etiology

AIP may be caused by a combination of a genetic defects coding for the PBGD enzyme and acquired causes that produce symptoms in some patients. The genetic cause of PBGD enzyme deficiency is an autosomal dominant mutation in the hydroxymethylbilane synthase (HMBS) gene (11q23.3) which codes for PBGD [1]. Penetrance of this mutation is very weak. Genetic causes of AIP are more common and patients with an enzyme mutation experience significantly diminished activity of PBGD by 40-60% of normal, leading to excessive porphyrins production. Chemicals that boost heme synthesis along with fasting, stress, infections or surgery are inducers of porphyria. Additionally, drugs such as phenobarbital, sulfonamides, estrogens, anti-seizure drugs, rifampin, metoclopramide and alcohol, which may increase the hepatic P450 system, are associated with porphyria. High levels of progesterone, observed in women after ovulation or during the end of the menstrual cycle, may lead to an acute attack. In some cases, no activating factors are identified. Patients with AIP have an increased risk for developing renal disease and hepatocellular carcinoma.

Epidemiology

Most studies indicate a higher prevalence of AIP in women compared to men (ratio of 1.5-2:1 or about 80% of cases are in females). Symptoms appear in most patients after puberty and between the ages of 18 and 40 years of age. Attacks occurring outside of this timeframe are usually caused by a major provocation, such as use of phenobarbital or estrogens. In the general adult population prevalence of AIP is fairly low, ranging between 1 and 8 per 100,000 (1 per 75,000 in Europe) [1] [3], however, incidences have been reported to be much higher in psychiatric populations (210 per 100,000) [4].

Sex distribution
Age distribution

Pathophysiology

AIP is caused by an autosomal dominant mutation in the HMBS gene which results in a defective PBGD enzyme [1]. PBGD in a vital enzyme in the heme biosynthetic pathway in the liver that catalyzes the conversion of porphobilinogen to hydroxymethylbilane [6]. The dysfunctional PBGD enzyme observed in AIP, leads to accumulation of porphobilinogen and amino-levulinic acid (ALA, porphyrin precursors). Neurologic damage appears to be the predominant problem with AIP which leads to central and peripheral neuropathies and psychiatric manifestations [5]. The connection between elevated porphobilinogen and ALA and acute attacks is unclear, due to the fact that most patients with the HMBS gene mutation have elevated porphyrin but are asymptomatic.

The genetic mutations observed in AIP result in marked deficiencies in the biosynthesis of the metalloporphyrin heme in the liver [6]. Free heme, detected at intracellular and extracellular levels, is degraded by heme oxygenase (HO) into carbon monoxide (CO) and bilirubin. The reasons for neurological involvement in AIP are not well understood, however, an interaction between CO and nitric oxide (NO) in enteric neurons of the internal anal sphincter may explain gastrointestinal dysfunction in some patients [7]. Other hypotheses include the direct neurotoxicity of ALA by interactions with the Gamma-Aminobutyric acid (GABA) receptor, altered tryptophan metabolism, or heme-dependent neural respiratory enzymatic deficiency in nerve cells [8]. Evidence suggests that axonal degeneration rather than demyelination of peripheral and autonomic nerve fibers is responsible. Usually the neurological effects of AIP are reversible although incomplete recovery has been reported in some cases.

Prognosis

Approximately 60-80% of patients that have an AIP attack, do not experience subsequent attacks. However, improperly diagnosing AIP may be dangerous, particularly when treatment involves precipitating factors, such as certain medications. Patients treated for AIP, before severe nerve damage occurs, have a good prognosis and most symptoms resolve after an attack. Some patients develop chronic pain and although nerve damage and muscle weakness from attacks improve over time, this may take several months or longer to fully resolve. Avoiding precipitating factors is the best way to prevent future attacks from occurring.

Presentation

Due to hormonal factors, AIP almost always manifests after puberty, especially in women. AIP attacks typically follow a distinct order of events starting with abdominal pain (>95% of attacks), then psychiatric symptoms (eg. hysteria) and finally peripheral and motor neuropathies. Between attacks patients are symptom free. No skin manifestations are observed in patients with AIP during attacks, but neurovisceral signs and symptoms, including abdominal pain associated with lumbago radiating to the thighs, autonomic neuropathies (causing constipation), vomiting, hypertension and tachycardia, may occur. Epigastric and colicky abdominal pain is severe and often lasts for several days but chronic abdominal pain is unusual. Scattered upper body pain may also occur (back, arm and leg pain). Symptoms may also include urinary retention, palpitations and decreased levels of sodium and chloride in the blood. The central nervous system sings of AIP may include seizures, delirium, cortical blindness, irritability, emotionality, anxiety and coma. Peripheral neuropathies may mimic Guillain-Barré syndrome and include weakness that starts in the lower limbs and rises, although any nerve distribution may be observed. A variety of psychiatric symptoms are observed, including depression in most cases, mental changes (confusion and hallucinations) and seizures. Concurrent neurological or abdominal symptoms can be life-threatening and may progress to paralysis and hyponatremia.

The majority of individuals who inherit the HMBS gene mutation never develop symptoms, however, experts recommend that relatives of AIP patients obtain testing. Individuals who have the trait should be educated on how to avoid attacks. Optimal management should include prevention. AIP attacks are most often triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, fasting and stress), and/or endogenous factors (hormonal).

Workup

To diagnose AIP it is essential to identify increased porphobilinogen and ALA (sometimes erythrocyte hydroxymethylbilane synthase enzyme) in patients’ freshly voided urine. If levels of porphobilinogen are within the normal levels (0-4 mg/L) during acute neurovisceral symptoms, porphyria can be eliminated as the cause [9] [10]. Spot urine tests are commonly used and can rapidly detect levels of porphobilinogen greater than 6 mg/L. Porphobilinogen levels in AIP patients remain elevated between attacks, however, the levels of porphobilinogen in some patients that have been symptom free for years may return to normal.

Coporphobilinogen, which arises from spontaneous polymerization of porphobilinogen, is the primary porphyrin detected in urine. Nonspecific elevation of porphyrins in urine is common and does not indicate AIP. Levels of porphyrins in stool are typically within the reference range or mildly elevated in AIP. Helpful screening tools include the Watson-Schwartz test (with Ehrlich’s aldehyde reagent), observing burgundy red discoloration in long stored urine and observation of pink colored urine after exposure to light, however, quantitative tests of porphobilinogen and ALA must be performed to verify AIP. Identification of the underlying mutation of the HMBS gene may be performed.

Treatment

The goal for treatment of AIP attacks is to decrease heme synthesis and reduce levels of porphyrin precursors. Patients should stop taking any medications or drugs that may worsen their attack. Heme synthesis is inhibited by high doses of glucose, therefore, 400 grams of glucose per day may be administered for one to two days to treat mild attacks. For severe attacks that include neurologic dysfunction or attacks that don’t resolve within 36 hours, 4 mg/kg/day of hematin should be administered for 4 days. Severe pain may be treated with narcotics along with laxatives and stool softeners to prevent further constipation. Patients experiencing seizures should be given gabapentin (Neurontin) and classic antiseizure medication should be avoided because they have been shown to cause acute porphyria attacks. During attacks, patients should be placed on a carbohydrate rich diet and IV glucose should be administered to patients who cannot eat. Other medications to treat anxiety, hypertension, nausea, vomiting, tachycardia or restlessness may also be used as needed. Fluid and electrolyte levels should be monitored and balanced during attacks. Between attacks a balanced diet, rather than a carbohydrate rich diet, is recommended.

In summary, when an AIP attack is confirmed, treatment with an injection of glucose in mild cases or hematin in severe cases along with administration of carbohydrates is recommended. Triggering factors should be suppressed and symptom management, including pain, vomiting and neurological disorders should be addressed. In patients with recurrent attacks, hematin administration may be repeated. In severe cases hepatic transplant may be required although this is rare.

Prevention

Patients should avoid medications that incite porphyria (lists are available) including barbiturates, some antiepileptics, erythromycin and chloramphenicol. Alcohol consumption should be limited and low-caloric diets and fasting should be avoided. Other precipitating factors, including illicit drug use, smoking, stress, hypothermia, infection, fever and dehydration, should also be avoided. Adopting a healthy lifestyle that includes a balanced diet, prompt medical treatment and stress reduction is recommended. Iron status should be monitored in patients receiving regular heme arginate to detect iron overload. Genetic counseling may be beneficial to patients and their families to help identify susceptible individuals and their risk of developing or transmitting the disease.

Patient Information

Acute intermittent porphyria (AIP) is a dominant inherited disorder (only need diseased gene from one parent) that is the most common acute porphyria (disease associated with porphyrin build up). AIP occurs in people from every ethnic group and is more common in women than men. AIP attacks typically occur after puberty and cause a sudden onset of neurologic symptoms along with abdominal pain. Patients with AIP have a deficiency in the enzyme porphobilinogen deaminase, due to a genetic mutation, that leads to the accumulation of heme precursors (porphobilinogen and amino-levulinic acid) in the liver. Symptoms, including developmental abnormalities, may appear in childhood.

The most common symptom is abdominal pain. Gastrointestinal symptoms may also arise including nausea, vomiting, constipation and diarrhea. Some patients may experience difficulty urinating, which may result in an excessively full bladder. Neural dysfunction may lead to muscle weakness that usually starts in the shoulders and arms.

Diagnosis is achieved through testing patients urine during an attack, which will have elevated levels of porphobilinogen and amino-levulinic acid in AIP. Rapid treatment usually results in a full recovery, however, if treatment is delayed recovery may take longer and permanent nerve damage may occur. Primary therapies will aim at decreasing porphyrin levels, but physicians may also administer medications to address other symptoms, such as opioids for pain.

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References

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