Acute Intermittent Porphyria

Biochemical Testing

Urinary PBG. Evidence of an increased concentration of PBG in urine, using a specific quantitative assay, is essential to establish an unequivocal diagnosis of acute porphyria in a symptomatic individual. The concentration of PBG in urine is invariably increased in individuals with symptoms of AIP: during an acute attack, PBG concentration is often more than 10-20 times the upper reference limit [Elder et al 2013].

PBG is best analyzed in a fresh random 10-mL urine sample collected without preservative, and protected from prolonged exposure to bright light [Woolf et al 2017]. Urgent testing in new patients will typically require specific arrangements to be made with the biochemistry laboratory but results should be available within 24 hours of sample receipt.

Note that positive results on qualitative or semi-quantitative urine PBG tests must be confirmed by a specific quantitative measurement to avoid reporting of false positive test results.

Biochemical confirmation that the increased urinary PBG is caused by AIP requires evidence that:

• Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal;
• Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal.

Molecular Genetic Testing

Single-gene testing. Molecular genetic testing is not a first-line test for AIP because the relatively high prevalence of HMBS pathogenic variants in the general population (1:1299) and low penetrance (0.5%-1%) can lead to misdiagnosis and inappropriate treatment of individuals with nonspecific symptoms of abdominal pain [Chen et al 2019].

Following biochemical confirmation of increased urinary PBG, sequence analysis of HMBS is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the method used, exon or whole-gene deletions/duplications may not be detected. If no variant is detected by a sequencing method that is not able to detect exon or whole-gene deletions/duplications, the next step is to perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.

Overt AIP

Symptoms of AIP are more common in women than men and very rare before puberty. Onset typically occurs in the third or fourth decade [Elder et al 2013, Bonkovsky et al 2014].

The visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life threatening. The course of acute attacks is highly variable within and between individuals.

Affected individuals may recover from acute AIP attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified.

Acute attack. Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, abdominal distention, and ileus are also common. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present.

Peripheral neuropathy is predominantly motor and is less common now than in the past. Muscle weakness often begins proximally in the legs but may involve the arms or legs distally and can progress to include respiratory muscles resulting in complete paralysis with respiratory failure. Bilateral axonal motor neuropathy may also involve the distal radial nerves. Motor neuropathy may also affect the cranial nerves or lead to bulbar paralysis.

Patchy sensory neuropathy may also occur

Mental changes are present in up to 30% of symptomatic individuals but are very rarely the dominant feature of AIP [Puy et al 2010]. Changes include insomnia, anxiety, depression, hallucinations, confusion, paranoia, amnesia, and/or altered consciousness ranging from somnolence to coma. These manifestations resolve after the attack, though anxiety may persist.

Seizures may occur in acute attacks, especially in individuals with hyponatremia, which may be worsened by vomiting and/or inappropriate fluid therapy. The cause of hyponatremia is not clear; both SIADH (syndrome of inappropriate antidiuretic hormone release) and renal salt wasting have been proposed as mechanisms.

Seizures may also be a manifestation of central nervous system involvement of the acute attack.

MRI findings. MRI changes were observed in two out of seven individuals with signs of CNS involvement. The main finding is posterior reversible encephalopathy syndrome [Pischik & Kauppinen 2009]. Twenty-two individuals with AIP presenting with posterior reversible encephalopathy syndrome were investigated with MRI imaging [Zheng et al 2018]; 95% of these presented with seizures that may be related to hyponatremia.

Cutaneous manifestations of porphyria do not occur in AIP.

Precipitating factors. Attacks of acute porphyria may be precipitated by endogenous or exogenous factors [Wang et al 2018]. These include:

• Prescribed and illicit drugs that are detoxified in the liver by cytochrome P450 and/or result in induction of 5-aminolevulinic acid (ALA) synthase and heme biosynthesis. Prescription drugs that can precipitate an attack include, for example, barbiturates, sulfa-containing antibiotics, some antiepileptic drugs, progestagens, and synthetic estrogens (see Agents/Circumstances to Avoid).
• Endocrine factors. Reproductive hormones play an important role in the clinical expression of AIP. In women, acute neurovisceral attacks related to the menstrual cycle, usually the luteal phase, are common [Wang et al 2018]. However, the majority of women with AIP fare well during pregnancy, despite substantial increases in the serum concentration of various steroid hormones [Marsden & Rees 2010].
• Fasting. A recognized precipitating factor is inadequate caloric intake [Wang et al 2018] in connection with, for example, dieting or heavy exercise schedules.
• Stress. Psychosocial and other stresses, including intercurrent illnesses, infections, alcoholic excess, and surgery, can precipitate an attack.

Chronic complications

• Hepatocellular carcinoma (HCC). Individuals with AIP, whether clinically manifest or latent, appear to be at increased risk of developing primary HCC [Innala & Andersson 2011], usually after age 54 years. The highest risk has been reported from Sweden; at present, it is unclear why the risk appears to be lower in other populations [Deybach & Puy 2011, Elder et al 2013]. The increased incidence of HCC appears to justify radiologic surveillance in individuals with AIP over age 50 years in order to allow early detection and improve outcomes [Peoc'h et al 2018].
• Renal involvement. Approximately 70% of individuals with recurrent attacks will develop progressive renal dysfunction as shown by declining estimated glomerular filtration rate (eGFR) (<90 mL/min/1.73m²). This may be a result of chronic renal exposure to high concentrations of ALA and porphobilinogen (PBG), influenced by genetic variation in the ALA transporter PEP2 [Tchernitchko et al 2017].
• Recurrent acute attacks. Approximately 3%-8% of individuals with AIP, mainly women, experience repeat attacks (defined as >3/yr in the EXPLORE study) for a prolonged period, often many years [Gouya et al 2019].

Mortality. Mortality directly related to acute attacks is now very rare in most countries as a result of improved treatment (use of human hemin; see Management, Treatment of Manifestations) and identification and counseling of presymptomatic relatives (see Management, Evaluation of Relatives at Risk). Deaths may occur as a complication of HCC or liver transplantation.

Latent AIP

Symptoms are present in only a minority of those heterozygous for an HMBS pathogenic variant that predisposes to AIP, and it may be difficult to be certain whether or not these are porphyria-related. The risk that an individual with latent AIP will later develop symptoms depends on age, sex, exposure to provoking agents, and other factors; however, the majority will remain asymptomatic throughout their lives.

Up to 50% of adults with latent AIP may have increased urinary PBG excretion.

Acute Neurovisceral Attack

Immediate treatment of an acute neurovisceral attack does not require confirmation of the specific type of acute porphyria.

Clinical assessment should include a full neurologic evaluation.

In persons known to have AIP consider other causes of abdominal pain in addition to porphyria.

Investigations should include the following:

• Full blood count
• Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes
• Serum and urine osmolality if hyponatremic
• Urine sodium concentration if hyponatremic
• Other blood tests as indicated by the patient's condition and possible cause of the attack (e.g., CRP, blood cultures, CK, magnesium)

MRI should be considered if CNS symptoms are present.

General measures

• Review all medications and discontinue any that can exacerbate acute porphyria [Stein et al 2017]. See Agents/Circumstances to Avoid.
• Restore energy balance using an enteral route if possible. When required, intravenous fluid should contain a minimum of 5% dextrose; however, hypotonic dextrose-water solutions should be avoided because of the risk of hyponatremia.
• Treat intercurrent infections and other diseases promptly.

Supportive treatment

• Pain relief. Effective analgesia should be provided as soon as possible, usually in the form of parenteral opiates (morphine, diamorphine, and fentanyl are safe). Very large quantities may be required in a severe acute attack. Consider patient-controlled analgesia and support from a pain team.
• Nausea and vomiting. Prochloperazine, promazine, or ondansetron are considered safe.
• Hypertension. Beta blockers are considered safe. Note: End-stage renal disease, which is thought to result from chronic systemic arterial hypertension, may be delayed through effective blood pressure control [Stewart 2012].
• Convulsions can be terminated with intravenous diazepam, clonazepam, or magnesium sulphate.
• Fluid balance and electrolytes. Intravenous fluid replacement may be required to correct dehydration or electrolyte imbalance. Dextrose in water solutions should be avoided because of the risk of hyponatremia. Chronic hyponatremia (developing over >48 hours) should be corrected slowly to minimize the risk of central pontine myelinolysis [Stein et al 2017].

Specific treatment

• For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral and together with other supportive measures (see Acute Neurovisceral Attack), may be used for up to 48 hours. If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended.
• Intravenous human hemin is the most effective treatment for acute neurovisceral attacks. Intravenous administration of hemin preparations may be life saving if employed early, when neuronal damage is still reversible, and may help to avoid paresis or prevent its progression.
  • The recommended dose for hemin is 3-4 mg/kg IV, given once daily for four days. Treatment may be extended, depending on the clinical course. Note: Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin.
  • Panhematin™ (Ovation Pharmaceuticals, Inc) is approved for treatment of acute attacks in the US. This product is supplied as a dried powder, which must be reconstituted with sterile water immediately before intravenous injection and administered over 10-15 minutes. Because the administration of Panhematin™ reconstituted with sterile water is associated with transient, mild coagulopathy, concurrent anticoagulant therapy should be avoided.
  • Heme arginate (Normosang Recordati Rare Diseases, Paris) is an arginine-stabilized form of human hemin available nearly worldwide, including in Europe, Africa, the Middle East, and South America. It is infused over at least 30 minutes. It has the same advantage as hemin in treating an acute neurovisceral attack, but has fewer reported side effects [Puy et al 2010].

Note: (1) Phlebitis after intravenous injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 100 mL is recommended.

Advice on safe treatment of persons with porphyria in some specific clinical situations (e.g., epilepsy, HIV, malaria, tuberculosis, hyperlipidemia, and hypertension) is available on the Porphyria South Africa website.

Recurrent Acute Attacks

Recurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at the European Porphyria Network website.

Medical therapy aims to reduce the frequency and or severity of acute attacks by the following measures:

• Ovulation suppression with gonadorelin analogs for patients with recurrent menstrual cycle-related acute neurovisceral attacks [Schulenburg-Brand et al 2017]. Long-acting analogs can be used to prevent ovulation and should be administered during the first few days of the menstrual cycle to minimize the early stimulation effect on hormone release which can trigger an attack. Side effects can be minimized by administering estrogen, preferably by patch. Gynecologic review and bone density monitoring are recommended.
• Prophylactic hemin infusion. The minimum effective infusion frequency should be employed, usually a weekly dose of hemin infused via an indwelling venous catheter. Problems include those associated with a venous access device (infection, blockage) and iron overload (see Prevention of Primary Manifestations).
• Givosiran (ALN-AS1), an interference RNA that represses ALAS1, has completed Phase I and III clinical trials and was approved by the US Food and Drug Administration (FDA) in November 2019. The trial showed a reduction of ALA and PBG excretion to near normal levels and a reduction in the rate of porphyria attacks when compared to a placebo. Adverse events included elevated liver enzymes and chronic kidney disease [Sardh et al 2019].

Other Treatments

Liver transplantation is curative and reported from several centers [Wahlin et al 2010]. Indications include repeated life-threatening acute attacks, failure of medical therapy, and poor quality of life.

Combined liver and kidney transplantation, which has been successful, can be considered in those with AIP with repeated severe attacks and renal failure [Wahlin et al 2010]. Patients with AIP may require dialysis or renal transplantation [Wang et al 2018].

Individuals with Overt AIP

Annual hepatic imaging for HCC in individuals older than age 50 years has been shown to improve survival [Innala & Andersson 2011]. The incidence of HCC in this group of patients with AIP is 0.6% and it has been recommended in Europe that imaging should probably be biannual to bring it in line with other liver diseases that infer an increased risk for HCC [Peoc'h et al 2018].

Note: (1) Serum α-fetoprotein measurement is not helpful. (2) Protein induced by Vitamin K absence (PIVKA-II) may be useful as a biomarker [Peoc'h et al 2018].