Acute porphyria refers to a group of rare disorders characterized by an enzymatic defect in the heme biosynthetic pathway. Patients present with acute debilitating, life-threatening attacks that may be precipitated by medications, hormonal changes, starvation, and other factors. In this review, we cover the clinical presentation, diagnosis, and management of acute porphyria.
Acute porphyrias are inherited conditions however environmental, e.g., drugs and physiological factors are crucial for clinical manifestation.
The autosomal dominant acute porphyrias affect males and females equally. Acute porphyria presents in all ethnic and racial groups worldwide.[ Due to the founder effect, certain populations have an unusually high prevalence of porphyrias. Examples of these are the Afrikaner (original settlers from the Netherlands) population in South Africa which have a high incidence of variegate porphyria (VP) and northern Scandinavian populations with increased numbers of acute intermittent porphyria (AIP). The prevalence of AIP has been estimated to be 5-10 cases per 100,000.
Heme is a 64 kDa tetrameric protein present in hemoglobin, myoglobin, respiratory cytochromes and cytochrome P450 enzymes. The heme biosynthetic pathway involves the conversion of the substrates glycine and succinyl coenzyme A to heme. The pathway consists of 8 enzymatic steps, four enzymes are present in the cytosol, and four enzymes are present in the mitochondria.
The rate-limiting enzyme in the formation of heme is the hepatic ALA synthase1 enzyme, which heme inhibits. The enzyme ALA dehydratase then catalyzes the conversion of ALA to porphobilinogen (PBG). Porphobilinogen deaminase converts PBG to hydroxymethylbilane. Uroporphyrinogen converts this to uroporphyrinogen III which is then acted upon by uroporphyrinogen decarboxylase to form coproporphyrinogen-III; this undergoes oxidation to protoporphyrinogen IX. The last step is the conversion of this to heme in the presence of iron by ferrochelatase.
Porphyrias fall into two classes: either erythropoietic or hepatic forms depending on the site of the major enzyme deficiency. The enzyme deficiencies are inherited as either autosomal dominant (AD), autosomal recessive (AR) or less commonly as X- linked.
The liver is the source of the four acute porphyrias and also to one of the cutaneous porphyrias (PCT). The most common acute porphyria is acute intermittent porphyria (AIP). AIP is an autosomal dominant acute hepatic porphyria. The enzyme affected is porphobilinogen (PBG) deaminase also referred to as Hydroxymethylbilane synthase (HMBS.) Hereditary coproporphyrin (enzyme defect coproporphyrinogen oxidase) and variegate porphyria (enzyme defect protoporphyrinogen oxidase) are also autosomal dominant inherited porphyrias and both present with cutaneous manifestations. AIP, VP, and HCP have a 50% deficiency of the respective enzymes and show low penetrance thus around 90% of heterozygotes are asymptomatic for life. The rarest acute porphyria is caused by a defect in the enzyme ALA dehydratase, is known as delta-aminolevulinic aciduria or ALA dehydratase deficiency (ALAD) and has an autosomal recessive inheritance pattern.]
Pathophysiology of symptoms
The pathogenesis of neurovisceral symptoms in acute porphyria has not been fully elucidated. One hypothesis is that the deficiency of heme affects neuronal function; the other hypothesis is that the precursors aminolevulinic acid (ALA) and porphobilinogen PBG may have direct neurotoxic effects.
Patients present initially in adolescence or young adulthood. Attacks in females often have associations with the onset of menstruation. Acute attacks, typically consist of severe abdominal pain, nausea, constipation, palpitations, sweating, confusion, and other neurological manifestations such as peripheral neuropathy, seizures, and paresis, tachycardia and hypertension.. Psychiatric manifestations, which are present in up to 80% of acute attacks include behavior change, agitation, depression, hallucinations, altered mental status and acute psychosis. The most frequent cause of admission in acute porphyria is acute abdominal pain. The patient may also report darkening of urine (red color) particular on exposure to light.
A detailed drug history is essential to exclude the intake of precipitating agents. A family history of porphyrias, use of hormonal therapy and menstrual history in females are also important to elicit on history taking. Online drug databases that provide information about the safety of different drugs in porphyria are available. It is best to refer to the website: www.porphyria foundation.com/drugs for details. History of recent alcohol intake is also important to note as reports exist of this as a trigger factor for acute attacks.
On examination, the patient may be hypertensive with tachycardia or have evidence of arrhythmias. Motor paresis or poor respiratory effort may be present. Evidence of peripheral neuropathy is common in the acute hepatic porphyrias.
Cutaneous manifestations may be found with certain types of acute porphyrias such as variegate porphyria and HCP. The skin lesions include bullous type lesions and erosions occurring in sun-exposed areas.
Due to the significant degree of overlap with other conditions and varied range of presentation, it is essential to have a high index of suspicion when making the diagnosis. A triad of the following symptoms: visceral abdominal pain, neurological dysfunction, and psychiatric disturbances suggest acute porphyria.
The cornerstone of diagnosis of the acute porphyrias remains biochemical testing. The profile of heme precursors and porphyrins in urine, feces or blood show a distinct pattern for the different porphyrias. Precursor concentrations are raised in acute attacks but may be normal in periods of remission or asymptomatic individuals. The different porphyrins have different solubilities, and thus some may occur predominantly in urine and others in feces.
In acute attacks, routine biochemical investigation analysis may show the presence of hyponatremia. Additionally, urea and creatinine may be elevated either due to dehydration or renal impairment. Mild elevation of transaminases is common. White cell count is generally normal in the absence of concomitant infection.
The acute porphyrias are characterized by an increase in the intermediate precursor porphobilinogen (PBG). Elevated PBG levels may present around tenfold or greater.
Screening: Fresh random urine samples are useful for screening. Use of Ehrlich's reagent in the Watson-Schwartz test provides a bedside qualitative assessment of the presence of PBG. Performance of quantitative analysis of PBG in urine is by spectrophotometric or chromatographic analysis. In AIP PBG is usually ten times the upper limit of normal. Occasionally PBG levels may be elevated in genetic carriers who are asymptomatic. Urine PBG may return to normal a few days to weeks after the initial acute attack, hence is it imperative that samples be collected and sent for analysis as soon as acute porphyria suspected. If suspicious of ALAD, then measurement of ALA is in order, as this condition will show increased ALA as compared with other acute porphyrias, but it is otherwise is unnecessary.
Once the diagnosis of acute porphyria has been made the next step is to determine which type of acute porphyria is present. High-performance liquid chromatography (HPLC) can identify the different urine porphyrins. Additionally, total fecal porphyrin analysis via spectrophotometry a fractionation with HPLC/paper chromatography is used to distinguish AIP from HCP. Fecal porphyrins are generally within normal limits in AIP, In HCP with certain III series Coproporphyrins are increased in both urine and feces, and the magnitude of increase is greater than protoporphyrins in feces. In VP, protoporphyrin and coproporphyrin show increases on fecal analysis with the major increase in protoporphyrins. Plasma fluorescence scanning via a fluorescence spectrophotometer is also used to determine the type of porphyria with VP showing a characteristic emission peak at 624-627 nm. The enzymatic analysis may also be performed to determine the enzyme affected.
All urine, plasma, and fecal samples must be protected from light on collection and transportation before analysis.
Genetic testing for mutational analysis can be used to assist the diagnosis in an individual or to screen family members. However, the failure to find a mutation in an individual with a diagnostic history of active acute porphyria does not exclude the diagnosis. Genetic counseling must accompany any such testing.
Initial management is primarily directed at managing or eliminating factors such as medications, caloric deprivation, and dehydration and Psychiatric manifestations may have precipitated the attack. As such ensuring rehydration using IV normal saline, glucose infusions and cessation of any suspected inducer medications is a vital part of the management of the acute attack. Pain relief also forms part of the initial management and opioids are considered safe. Definitive treatment involves the administration of IV hemin which reverses the increase in ALAS1. Studies are being conducted with small interfering RNA (siRNA) to ALAS1and appear promising.
Ongoing management: some individuals may have recurring attacks. This scenario most often occurs in females and is related to menstruation. These patients should receive a specialist porphyria service referral. Use of gonadotropin-releasing hormone analogs to prevent ovulation in women that present with current premenstrual related acute porphyria. A small number of patients with recurrent attacks have also had liver transplantation.
Lead poisoning may be present with similar symptoms as an acute porphyria attack. There may also be elevated zinc protoporphyrin levels, however, blood lead levels are more specific. Acute abdomen from surgical or gynecological causes as well as acute viral gastroenteritis are other common differentials, but with acute porphyria, there is no rebound tenderness.
Several decades ago the prognosis for acute porphyria with neurological complications was poor, with a reported mortality of 35%. The prognosis remains guarded for those that present with acute porphyria. However, the number of cases progressing to advanced disease has declined.
Reports exist of an association of acute porphyria with hepatocellular carcinoma, particularly AIP. AIP also has associations with an increased risk of hypertension and chronic kidney disease. Chronic pain is also a complication of recurrent attacks.
Porphyrias are largely still under-diagnosed, and the index of suspicion must be high to diagnose. Diagnosis is essential to initiate appropriate treatments as soon as possible.
Because of its diverse presentation, the condition is best diagnosed and managed by a multidisciplinary team. Biochemical diagnosis remains the crux inherited conditions of acute porphyria. Given the urgency to identify an acute attack, it is essential that laboratory services offer screening tests with rapid turnaround time. Patient education regarding trigger factors for acute attacks and avoidance of these trigger factors is important. Education regarding the inheritable nature of the disease is important for the patient and family members.