The group of acute porphyrias includes four types of porphyria: acute intermittent porphyria (AIP), which is the most common one; hereditary coproporphyria (HCP); variegate porphyria (VP); and the rarest one, aminolevulinic acid dehydratase porphyria (ADP), of which only six definite cases have been reported so far and will be discussed later.
Two of these four diseases, HCP and VP, are associated with both acute attacks and skin bullous lesions,8 similar to those of non-acute cutaneous porphyrias, which will be discussed later in this review.
Acute intermittent porphyria (AIP), HCP, and VP are inherited in an autosomal dominant way and result from a deficiency of one of the enzymes, hydroxymethylbilane synthase (HMBS), coproporphyrinogen oxidase (CPOX), and protoporphyrinogen oxidase (PPOX), respectively (Figure 1). Since the deficiency is inherited from one affected parent, in all three porphyrias, the residual enzyme activity is about 50%, which is sufficient for regular heme homeostasis,9 keeping the disease latent. In fact, most patients will remain asymptomatic during their whole life without experiencing any porphyria symptoms.10
An acute attack usually occurs following an exposure to any one of the known precipitating factors. Most known precipitating factors are medications metabolized by the cytochrome P450 system—which are regarded as unsafe for porphyria patients.
Other factors include alcohol use, infections, low caloric intake, and changes in sex hormone balance during the menstrual cycle.11,12
Each of these precipitating factors induces ALAS1, either directly13,14 or indirectly by increasing demand for hepatic heme, mainly through the consumption of CYT P450 enzymes.1
Low carbohydrate intake might induce ALAS1 via peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), a protein which directly induces transcription of ALAS1.15
When ALAS1 is up-regulated, the heme synthesis is accelerated and the deficient enzyme becomes a rate-limiting one. This leads to excess of heme precursors preceding the defective step.
Animal models5,16,17 and clinical evidence4 support the theory that delta aminolevulinic acid is neurotoxic, leading to the central, peripheral, and autonomic nervous system symptoms seen in an acute attack. In addition, some studies support the hypothesis suggesting that some of the symptoms of an acute attack might be mediated by increased serotonergic activity.5 Elevated levels of blood tryptophan and 5-OH tryptamine were reported in AIP patients,18 indicating abnormal tryptophan metabolism.
While, from the clinical point of view, acute porphyria attacks of all three types have similar symptoms and are indistinguishable, since they differ from each other in the defective enzyme, each subtype of porphyria has its own typical pattern of heme precursor excretion, which enables biochemical distinction between the three.7
The majority of acute attacks begin as a combination of abdominal pain, mild mental symptoms, such as severe fatigue and inability to concentrate, with or without autonomic dysfunction.2,19
Although all components of the peripheral, central, and autonomic nervous systems have been reported to be involved in an acute porphyria attack, the most common symptoms are severe abdominal pain, nausea, vomiting, and constipation. Tachycardia, hypertension, and signs of increased sympathetic activity are often associated with abdominal pain.3 Hyponatremia occurs in 40% of patients, probably as a result of inappropriate anti-diuretic hormone secretion syndrome. Additional factors that might contribute to hyponatremia include vomiting and resuscitation with high volumes of dextrose solutions given intravenously.1 Seizures, which are characteristic in severe attacks, may be due to severe hyponatremia, or, less commonly, due to posterior reversible encephalopathy syndrome (PRES).20
Liver enzymes might be mildly elevated during an attack.19 Severe attacks may also present with muscular weakness and or mental disturbance, such as anxiety, disorientation, or hallucinations.1,2 In rare cases of AIP, psychosis may be the only clinical manifestation.21,22
If a patient is not diagnosed early in the course of an attack, these symptoms can become very severe with full paralysis, respiratory failure, seizures, and even death.
Historically, the purple color of porphyrins, causing the dark colored urine in porphyria patients due to oxidation of PBG to uroporphyrin and porphobilin,23 gave the disease its name “porphyria.”
Commonly reported symptoms can be found in more detail in Table 1.
Clinical Manifestations of Acute Attacks, with Symptoms Listed in the Order of Incidence In Each Box Separately.19
Acute Porphyria Attack Diagnosis
The most rapid and accurate way to diagnose an acute porphyria attack is to measure urinary ALA and PBG levels, which are highly elevated during an acute attack. However, it should be pointed out that, in ADP porphyria, only urinary ALA and not PBG values will be increased.
Once diagnosis has been made, then full biochemical evaluation, using stool, urine, and blood samples, is necessary to differentiate the type of acute porphyria affecting the patient (Figure 2).7
Diagnosis Algorithm for Acute Neurovisceral Symptoms Leading to Suspicion of Porphyria
Latent Acute Porphyria Diagnosis
Biochemical studies, performed on urine, feces, and blood, may identify each of the common acute porphyrias—AIP, HCP, and VP—even in silent patients.
Genetic testing is now available for all acute hepatic porphyrias following biochemical diagnosis, allowing family members to be screened for the specific mutation. Once a family member has been diagnosed with porphyria, he is considered a “latent patient” and should be advised to avoid all known manageable environmental factors which may trigger an attack.
At the time of writing, there have been over 400 different mutations identified only in AIP, and yet there is little evidence that a certain genotype could predict the phenotype.
Acute Attack Treatment
As mentioned earlier, acute porphyria attacks may be life-threatening if not treated, due to severe neurological complications such as motor paralysis. Therefore, whenever an acute porphyria attack is diagnosed, the patient should be treated as early as possible.
The initial step of porphyria treatment should be to determine and withdraw any possible trigger.
Specific treatment, aimed at stopping the acceleration in heme synthesis which occurs during an acute attack, is targeted to down-regulate ALAS1 activity. This might be achieved, in very mild cases, by hydration and administration of carbohydrates, or much more effectively, in severe attacks, by blood-derived heme, such as Normosang (Orphan Europe, Puteaux, France) in Europe or Hematin (Xellia Pharmaceuticals, Nourth Carolina, USA) in the US.2
Palliative treatments given during an acute attack for pain, nausea, and other symptom relief should be performed using only “safe” drugs for porphyria patients. Data regarding safe drugs can be found on several web sites (including The Drug Database for Acute Porphyria at: www.drugs-porphyria.org).
Once an attack is over, a patient will usually gradually return to normal with no residual symptoms between attacks, unless exposure to precipitating factors is not withdrawn.
Some 3%–5% of newly diagnosed patients may suffer recurrent acute attacks.10,24 Management of these patients is challenging and, so far, has been based on one of the treatments below:
Heme therapy which could be given as needed, or in severe refractory patients given at regular intervals as prophylactic therapy.25 Complications of long-term heme infusions could include: iron overload, thrombotic superficial veins which could appear after transfusions, and dependence on the exogenic heme in some patients.26
In women suffering from menstrual cycle-related acute attacks, gonadotropin-releasing hormone (GnRH) agonist treatment could be given to avoid the attacks.27 Since these recurrent attacks tend to target young women, this treatment should be given only after considering other choices and discussing the physical and emotional issues carefully.
When no standard treatment is helpful and quality of life is poor, liver transplantation could be an option. Currently over 10 AIP patients have undergone liver transplantation since 2004.10,26 The potential of long- and short-term risks of liver transplantation and the prolonged immunosuppression leave this drastic option as a last resort.10
Lately, a subcutaneous therapy, based on RNAi targeted to silence ALAS1 expression (Givosiran, Alnylam Pharmaceuticals, Cambridge, MA, USA), has been developed and so far has shown preliminary promising results. This drug has recently been granted Food and Drug Administration (FDA) breakthrough therapy status.
Some patients are at risk for late complications. One of these complications includes chronic abdominal pain which is usually a late complication of recurrent acute attacks. It is important to differentiate this pain from an acute attack since it rarely responds to the same treatment.28
As for other possible complications, several studies suggest that patients with AIP are at higher risk for chronic kidney disease,29,30 with evidence showing this to be due to vascular toxicity of porphyrin metabolites to the tubular interstitium.31
There is also evidence showing an association between hepatocellular carcinoma and acute porphyria. This evidence has been mainly shown in northern European patients with AIP, although there are case reports in patients with VP and HCP32 too. Although the data are still lacking, currently, many porphyria services offer screening for porphyria patients over the age of 50.
As mentioned earlier, AIP is the most common acute hepatic porphyria affecting all ethnic and racial groups. In Europe the prevalence of symptomatic diagnosed AIP has been shown to be 5.9 per million.24
The actual prevalence of pathogenic mutations is unknown and thought to be much higher, with a clinical penetrance of only 1%–10%.33–35
Attacks occur more commonly in young females after puberty than in men and are rare after menopause.29 In AIP this female tendency is strongly observed, with up to 80%–90% of patients being female,2 while, in our experience, this is not as obvious in the case of other acute porphyrias.
Variegate porphyria (VP) is the second most common acute hepatic porphyria, and HCP is the third.24
While, as mentioned, all these acute porphyrias are inherited as an autosomal dominant disease, ADP is inherited in an autosomal recessive way, therefore being an extremely rare porphyria with only six certain reported cases confirmed by DNA studies.36 This type of porphyria results from a deficiency of the aminolevulinic acid dehydratase (ALAD) enzyme, resulting in a unique biochemical pattern during an acute attack with elevated urinary ALA level and a normal urinary PBG level (Figure 1).
Homozygous Acute Porphyrias
Reported cases of homozygous AIP,37
are rare. Homozygous AIP is associated with mental retardation, homozygous HCP with photosensitivity and neurological symptoms, and homozygous VP with severe photosensitivity and finger shortening.
An acquired ALAD inhibition, mimicking ADP, occurs in lead poisoning, in which symptoms may mimic those of acute porphyria.40,41
Treatment in this case should first address washing out the poisoning factor.