Authors: Mahagna Antonio Abed, Vissio Elena
Porphyrias are a group of rare hereditary disorder in which an important part of hemoglobin, called heme, is not made properly.
Heme is synthesized in every human aerobic cell, but mainly in erythroid cells (85%) and in the liver (15%), and it is used as a prosthetic group of haemoproteins.
Each of seven porphyrias results from a genetically determined partial deficiency of one of the enzymes in the heme biosynthetic pathway.
Within this group, there is a form of porphyria characterized by acute attacks, precisely defined Acute Porphyria.
Acute porphyria includes three similar inherited diseases: acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Acute intermittent porphyria is the most common form. In this type of porphyria you may experience acute attacks, but you never have skin problems. If you are suffering from variegate porphyria or hereditary coproporphyria, your skin may also be affected.
Acute Intermittent Porphyria is an autosomal dominant porphyria that is due to a deficiency of HYDROXYMETHYLBILANE SYNTHASE in the LIVER, the third enzyme in the 8-enzyme biosynthetic pathway of HEME. Clinical features are recurrent and life-threatening neurologic disturbances, ABDOMINAL PAIN, and elevated level of AMINOLEVULINIC ACID and PORPHOBILINOGEN in the urine.
AIP is also known as “The Little Imitator” since it resembles diseases like Korsakoff syndrome, acute appendicitis, bowel obstruction.
AIP occurs with very low prevalence, perhaps 1 in 50,000, probably in all ethnic groups. Higher prevalence of AIP is known in northern Europe, especially in Sweden. It was identified a mutation in the HMBS gene in 15 of 33 AIP families from Lappland, Sweden. Genealogic data showed that 12 of the 15 were related, suggesting a founder effect.
Figures for prevalence based on manifest AIP, i.e., acute attacks, greatly underestimate the number of persons with latent AIP. The penetrance of AIP has varied from 10 to 40 % based on different patient data. Thus, the phenotype must be modified by other often polymorphic genes especially by those in metabolic pathways and survival of the neurons and resistance of vascular structures.
Sex and age
Acute attacks rarely occur before puberty, and they are more common in women, probably due to hormonal influences.
Acute intermittent porphyria manifests with occasional acute attacks due to overproduction of porphyrin precursors (porphobilinogen, PBG and delta-aminolevulinic acid, ALA) in the liver.
An acute attack involves different symptoms, which are all thought to be of neuronal origin (The little imitator--porphyria: a neuropsychiatric disorder, 1997).
Autonomic neuropathy mainly causes abdominal pain or cramping due to splanchnic dysfunction such as intestinal dilatation or spasm. They have also been suggested, as alternative mechanisms, local vasoconstriction and intestinal ischemia. Other symptoms are bladder paresis, hypertension and cardiac problems.
Acute peripheral neuropathy (PNP) is responsible for diffuse muscle weakness, especially in the proximal and distal muscle groups of the upper extremities and in the proximal muscles of the lower extremities. Respiratory failure because of diaphragm paresis is the most severe complication of muscle weakness. PNP can also be characterized by symmetric hyporeflexia and sensory loss.
Acute encephalopathy leads to headache, altered consciousness and behaviour or seizures. Mental symptoms such as anxiey and insomnia may also be present. These clinical symptoms resembles Posterior Reversible Encephalopathy Syndrome (PRES), a syndrome characterized by headache, confusion, seizures and visual loss, mostly caused by immunosuppressive therapy, renal failure, eclampsia, severe high blood pressure, and lupus in which sufferers present edema.
Some patients show hyponatremia, which in absence of diarrhea, vomiting or polyuria, is usually a manifestation of inappropriate secretion of antidiuretic hormone (ADH), due to an inappropriate release rather than inappropriate synthesis.
The pathogenesis of porphyric neuropathy is complex but overproduction of ALA, which acts via direct neurotoxicity, oxidative damage, infact ALA can lead to production of free radicals, and modification of glutamatergic action, may initiate the neuronal damage (Neurological manifestation of acute intermittent porphyria, 2009). Lack of heme in neuronal enzyme may contribute to the pathology too. Furthermore ALA synthase (ALAS1) can be induced directly by many drugs (barbiturates), chemicals and alcohol or indirectly by low glucose concentration and stress. These factors may provoke accumulation of porphyrin precursors. On the other hand, ALAS1 can be inhibited via negative feedback mechanism using haem, the end-product of the biosynthesis. Therefore, both haem preparations and glucose infusions have been used to treat acute attacks.
Vagus nerve demyelination, axonal loss and chromatolysis of sympathetic ganglion cell in autopsies support the direct involvement of autonomic fibers and explain partly dysautonomic features.
Diffuse axonopathy of the motor nerves is the main cause of peripheral neuropathy. In addiction the values of velocities in nerve transmission are significantly decreased suggesting a demyelinating neuropathy.
The similarity with PRES had suggested as a possible reason for encephalopathy the breakage of blood-brain barrier. The hypertension observed is not so elevated to explain the higher permeability of the barrier, so the main cause is most likely to be the endothelial toxicity.
The cause of the symptoms is not yet clarified. Some of the symptoms may be caused by a deficiency of heme-containing enzymes. The cytochrome C is, for example, a component of the electron transport chain. Its reduced activity leads to the reduction of ATP available to the cell and an increase in the AMP. The increase in AMP is a stimulus to the activation of AMPK. AMPK has among its effects to increase the ALAS, thus potentially contributing to the worsening of the symptoms, as the products of ALAS, toxic for several reasons as said in the previous section, accumulate further.
Heme synthesis regulation and risk factors
The onset of symptoms mainly depends on heme synthesis regulation, because ALA accumulates when the activity of ALAS increases.
ALAS is the limiting enzyme of heme synthesis and is regulated by many factors.
Free heme and hematin inhibit both ALAS synthesis and activity, and they are thought to bind an allosteric site because they are not similar to the reagents.
Almost 100 metabolites can stimulate ALAS activity, which can increase by 40 times.
Glucose inhibits heme synthesis through transcription factors. Because of this, a low-calories diet often triggers the disease. Other regulators of heme synthesis are steroids so oral contraceptives can be involved in the onset of an acute attack.
Drugs like barbiturates, phenytoin, and griseofulvin induce acute attack because they stimulate Cytochrome P450 synthesis that consumes heme. As a result free heme is reduced and heme synthesis is no longer inhibited.
For this reason a correct diagnosis is essential: it is possible to mistakenly consider the symptoms as psychosomatic, and treat the patient with psychotropic drugs that induce heme synthesis themselves, worsening the situation.
Currently many patients with acute porphyria are diagnosed with a mutation analysis at their symptom-free stage, and acute attacks can be treated properly already at the early phase preventing progression of an acute attack to more severe polyneuropathy and encephalopathy.
Effective management of Acute Intermittent Porphyria relies on early diagnosis
Recommended tests 1
Initial testing or screening:
• Urine PBG level on a random spot urine sample
Urinary excretion of PBG is normally less than 8.8 µmol/L (2 mg/L). Values above 25 µmol/L (6 mg/L) usually indicates the presence of disease. Urine PBG is usually greater than 100 µmol/L (23 mg/L) during an attack of porphyria. Therefore, screening testing for urine PBG should be done at or near the time of symptoms to determine if PBG level is elevated.
Once Acute Intermittent Porphyria is suspected, it should be confirmed.
Laboratory findings which differentiate AIP from other acute porphyrias may include:
• Erythrocyte PBG deaminase levels decreased by ~ 50%
• Urine porphyrin levels markedly increased, mostly uroporphyrin
• Fecal porphyrin levels normal or slightly increased
• Plasma porphyrin levels normal or slightly increased
Some of the medicines used to treat a sudden (acute) attack of porphyria may include:
• Hematin given through a vein (intravenously)
• Pain medication
• Propranolol to control the heartbeat
• Sedatives to help you feel sleepy and less anxious
Other treatments may include fluids and glucose to boost carbohydrate levels, which helps limit the production of porphyrins.
Depending on the type of porphyria you have, your doctor may tell you to:
• Avoid all alcohol
• Avoid drugs that may trigger an attack
• Avoid injuring the skin
• Eat a high-carbohydrate diet
Do not ever forget that people suffering from acute porphyria are able to lead a normal life. Even the few who do become ill, after proper treatment, they make a complete recovery and have no more than one-two attacks in a lifetime. With age, the risk of an acute attack decreases, usually after age 40, but does not become zero.