Acute Intermittent Porphyria

AIP is an autosomal dominant disease that, like all forms of porphyria, is due to disruption of the pathway for the synthesis of heme. Specifically, AIP results from defects in the enzyme porphobilinogen deaminase (PBGD; also known as hydroxymethylbilane synthase [HMBS]), which catalyzes the conversion of porphobilinogen to hydroxymethylbilane. Impaired function of PBGD leads to the accumulation of the porphyrin precursors porphobilinogen and amino-levulinic acid (ALA). The predominant clinical problem appears to be neurologic damage that leads to peripheral and autonomic neuropathies and psychiatric manifestations.[3]

Although levels of porphobilinogen and ALA are always elevated during acute attacks, how this leads to the symptomatic disease is still unclear because most patients with the genetic defect have excessive porphyrin secretion but no symptoms.

A case-control study in 50 patients by Storjord et al found evidence that AIP is associated with systemic inflammation. Levels of prealbumin, C-peptide, and insulin, along with measures of kidney function, were all decreased in symptomatic patients, but not in asymptomatic ones. The decrease in C-peptide levels in symptomatic AIP cases indicates that reduced insulin release is associated with enhanced disease activity and reduction in kidney function.[4]

Acute intermittent porphyria (AIP) is due to a combination of a genetic defect—mutations in the HMBS (hydroxymethylbilane synthase) gene that encodes the enzyme porphobilinogen deaminase[5] —and acquired factors. In patients with AIP, the function of porphobilinogen deaminase is only 40-60% of normal. With the advent of molecular technique, it has become clear that carriage of the genetic defect is much more common than symptomatic AIP. On average, out of 100 patients with the genetic defect, perhaps 10-20 secrete excess porphyrin precursors and only 1-2 have symptoms.

The classic inducers of porphyria attacks are chemicals or situations that boost heme synthesis. This includes fasting and many medications. Although very large lists of "safe" and "unsafe" drugs exist, many of these are based on anecdotes or laboratory evidence and do not meet strict criteria. In general, drugs that lead to increased activity of the hepatic P450 system, such as phenobarbital, sulfonamides, estrogens, and alcohol, are associated with porphyria. See the tables below. A large and detailed list is available on the University of Queensland, Department of Medicine Web site. However, many attacks occur without any obvious provocation.

Table 1. Drugs Thought Unsafe in Porphyria^† (Open Table in a new window)

Table 2. Drugs Thought Safe in Porphyria* (Open Table in a new window)

Frequency

Estimates of the prevalence of AIP in the United States vary from 1-5 cases per 100,000 population. European studies indicate that the prevalence of AlP is approximately five per 100,000 population.[7] The prevalence can be as high as 60-100 cases per 100,000 population in northern Sweden.[8] In Japan, the prevalence of acute hepatic porphyria (most of which is AIP) is estimated to be 1.18 cases per 100 000 population.[9]

Sex- and Age-related Demographics

In most series, AIP affects women more than men, with a ratio of 1.5-2:1.

Most patients become symptomatic at age 18-40 years. Attacks occurring before puberty or after age 40 years are unusual unless a major provocation, such as new use of phenobarbital or estrogens, had occurred.

Untreated AIP is associated with significant morbidity and can lead to pareses and death. Long-term complications include chronic hypertension, chronic neuropathy, chronic kidney disease, and hepatocellular carcinoma.[10, 11]  

The onset of attacks in individuals with acute intermittent porphyria (AIP) typically occurs at age 18-40 years. Attacks before puberty or after age 40 years may be triggered by a major provocation, such as new use of phenobarbital or estrogens. Attacks generally last for 3 to 7 days. 

The usual sequence of events in attacks of AIP is as follows:

1. Abdominal pain
2. Psychiatric symptoms
3. Peripheral neuropathies

The abdominal pain often is epigastric and colicky in nature; it is severe and lasts for several days. Constipation or vomiting may also occur. Severe abdominal pain of short (< 1 d) duration or chronic abdominal pain is unusual. Diffuse pain, especially in the upper body, may also be observed.

Patients can have a wide variety of psychiatric symptoms. Depression is very common. Usually, patients have concurrent neurologic or abdominal symptoms. A Swedish study documented a fourfold increased risk of schizophrenia or bipolar disorder in patients with AIP. The risk in relatives of individuals with AIP was increased twofold, suggesting common genetic influences with these diseases.[12]

Peripheral neuropathies tend to be predominantly motor and can mimic Guillain-Barré syndrome. The weakness usually starts in the lower limbs and ascends, but neuropathies can be observed in any nerve distribution. Autonomic neuropathies that produce hypertension and tachycardia may also occur.

Central nervous system signs may include the following:

• Seizures
• Delirium
• Cortical blindness
• Coma

Skin manifestations are not a feature of AIP attacks, as they are of other forms of porphyria (eg, porphyria cutanea tarda). 

Between attacks, patients may be completely free of symptoms. However, emerging evidence points to chronic manifestations as a feature in 20-64% of patients with AIP. In a study of patients with frequent attacks of AIP, 18 of the 19 patients interviewed also described chronic symptoms, which were often disabling. Key chronic symptoms were pain, nausea, fatigue, and features of neuropathy (eg, tingling and numbness).[13]

Vital signs during attacks of acute intermittent porphyria (AIP) include the following:

• From 30-80% of patients have tachycardia
• Fever can be present in some patients
• Hypertension is observed in half of patients and may persist between attacks

Neurological manifestations are as follows:

• Usually, the neuropathy is a motor neuropathy that is more predominant in the lower limbs
• Areflexia often is present on examination
• Any nerve can be involved, and cranial neuropathies also are observed
• Patients also may have cortical blindness

Despite the intense pain, the findings on abdominal examination often are nonspecific. Skin examination is noncontributory; unlike many other porphyrias, AIP is not associated with a skin rash.

The fundamental step in diagnosing acute intermittent porphyria (AIP) is to demonstrate increased urinary porphobilinogen secretion. If a patient has no increased secretion of porphobilinogen, (ie, a level of 0-4 mg/L during acute symptoms), acute porphyria is eliminated as a cause of the neurovisceral symptoms.[15, 16]

A spot urine test for porphobilinogen can rapidly provide the diagnosis; these tests detect porphobilinogen at levels greater than 6 mg/L. A common error is to order a urine porphyrin screen. Porphobilinogen, a porphyrin precursor, usually is not included in a urine porphyrin screen; it must be ordered specially.

AIP patients have elevated porphobilinogen between attacks. However, in some patients with a remote (years ago) history of attacks, porphobilinogen can return to the reference range.

Elevation of urine porphyrins, especially coporphobilinogen, is observed. This is caused by spontaneous polymerization of porphobilinogen in the urine. Nonspecific (1-2 times reference range) elevation of urine porphyrins, especially coproporphyrins, is common and is not specific for porphyria. Stool porphyrins are within the reference range or mildly elevated.

Other nonspecific signs in an attack of AIP include the following:

• Hyponatremia
• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
• Mild leukocytosis

Although a defective enzyme causes AIP, measuring the activity of porphobilinogen deaminase is of little value. Approximately 10% of AIP patients will have normal activity because a different form of the enzyme is expressed in the hematopoietic tissues. The vast majority of patients with the defective enzyme do not have any symptoms of the disease.

Imaging studies are usually not helpful. Abdominal films will sometimes demonstrate an ileus. Findings on cranial computed tomography (CT) scan are normal.

Brain magnetic resonance imaging (MRI) scans occasionally show signs of increased edema in patients having very severe attacks. In patients with seizures, MRI may demonstrate parieto-occipital gyriform lesions on T2-weighted images that are characteristic of posterior reversible encephalopathy syndrome (PRES).[17]

Attacks of AIP are clinically indistinguishable from those of hereditary coproporphyria and variegate porphyria, and there are few evidence-based diagnostic strategies for these conditions. Whatley et al conducted a retrospective analysis of 467 unrelated patients to determine the diagnostic sensitivity of mutation analysis of the HMBS, CPOX, or PPOX gene.[18] Findings included the following[18] :

• In the presence of increased porphobilinogen excretion, plasma fluorescence scanning and the coproporphyrin ratio can identify the type of acute porphyria, with rare exceptions.

• In cases in which the porphobilinogen, 5-aminolevulinate, and porphyrin analyses are within reference intervals and in which there is high suspicion of a previous illness caused by an acute porphyria, mutation analysis of the HMBS gene followed by porphobilinogen deaminase assay is an effective strategy for diagnosis or exclusion of AIP.

The treatment goal for acute attacks of acute intermittent porphyria (AIP) is to decrease heme synthesis and reduce the production of porphyrin precursors. High doses of glucose can inhibit heme synthesis and are useful for treatment of mild attacks. United Kingdom guidelines recommend administering 5% glucose in 0.9% sodium chloride solution, infused intravenously at a rate of 2 L/24 h. Intravenous solutions of glucose in water (eg, dextrose 5% or 10% [D5W, D10W]) should be avoided as they may aggravate hyponatremia.[19]

Patients experiencing severe attacks, especially those with severe neurologic symptoms, should be treated with hematin in a dose of 4 mg/kg/d for 4 days. Once hematin is initiated, glucose therapy no longer has a role.[19]

Pain can be remarkably severe, and pain control is best achieved with narcotics. Laxatives and stool softeners should be administered with the narcotics to avert exacerbating existing constipation.

Symptomatic treatment also includes the use of beta-blockers to control tachycardia and prevent arrhythmia; beta- blockers, clonidine, or other recommended antihypertensives can also be used to treat hypertensive crisis. Nausea and vomiting can be controlled with olanzapine, lorazepam, or prochlorperazine.[20]

Treat seizures with gabapentin. Most classic antiseizure medicines are contraindicated, as they can lead to acute porphyria attacks.

A minority of patients with AIP experience recurrent attacks. In addition to avoidance of precipitating factors, treatment options that may be considered in those cases include gonadotrophin-releasing hormone analogues (for women with attacks related to their menstrual cycles) and prophylactic hematin infusions.[19]

Givosiran (Givlaari) is approved by the US Food and Drug Administration (FDA) for adults with acute hepatic porphyrias, in which attacks are caused by induction of the enzyme 5-aminolevulinic acid synthase 1 (ALAS1). Givosiran is a small-interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) messenger RNA (mRNA) in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. It is given monthly by subcutaneous injection.[21] Reported adverse reactions include injection-site reaction, fatigue, nausea, chronic kidney disease, and increased alanine aminotransferase.[2] In rare instances, drug-induced liver injury may develop, mandating cessation of givosiran.[22]

Rarely, liver transplantation may be indicated for patients with intractable recurrent attacks that are life-threatening or severely affect quality of life. Liver transplantation cures AIP.[19]

A comprehensive rehabilitation program, overseen by a physiatrist, can help patients regain functional independence after attacks of AIP.[23]

Gene therapy for AIP is currently under investigation.  A phase I trial using intravenous delivery of normal PBGD genes to hepatocytes using an adeno-associated virus vector confirmed the safety and tolerability of this approach, but demonstrated the need for higher doses and/or more efficient vectors in order to achieve full clinical benefit.[24]  In an animal model, improved vector efficiency has been accomplished by insertion into the promoter of a short enhancer element that can induce transgene expression during exposure to endogenous and exogenous stimuli that can trigger attacks.[25]

The patient should receive a high-carbohydrate diet during the attack. If the patient is unable to eat, intravenous glucose should be administered. Between attacks, eating a balanced diet is more important than eating one rich in glucose.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Intravenous hematin is the treatment of choice, both for treatment of severe acute attacks and for prevention of recurrent attacks.[14]  Givosiran, which is given monthly by subcutaneous injection, is a newer treatment option.[21]

Givosiran (Givlaari)

Small interfering RNA agents. Via RNA interference, they lead to degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes, which in turn lowers elevated liver ALAS1 mRNA levels. This decreases circulating levels of the neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), both of which are linked to attacks and other manifestations of the acute hepatic porphyrias (AHP).

Hemin (Panhematin)

Provides negative feedback to the heme synthetic pathway and shuts down productions of porphyrins and porphyrin precursors.