Porphyria, Acute Intermittent

Definition, Etiology, PathogenesisTop

Acute intermittent porphyria (AIP) is a hereditary autosomal dominant disorder of heme synthesis. Potential disease-causing mutations occur in ~1 in 1700 Europeans. It is a result of deficiency of hepatic porphobilinogen (PBG) deaminase, which leads to the accumulation of porphyrin precursors PBG and delta-aminolevulinic acid (ALA) in situations associated with increased heme synthesis. This is a probable cause of intermittent peripheral neuropathy and sympathetic overactivity. An acute attack of porphyria is often triggered by factors that increase the synthesis of porphyrins, such as hepatocyte cytochrome P450 inducers (most commonly alcohol, steroid sex hormones [eg, progesterone], barbiturates, sulfonamides, carbamazepine, valproic acid, griseofulvin, and ergot derivatives), fasting (including weight-loss diets with a significantly reduced calorie and carbohydrate intake), tobacco and marijuana smoking, infection, stress, and surgery.

Clinical FeaturesTop

Over 90% of people with PBG deaminase deficiency never develop any features of the disease. The onset of symptoms is usually between the ages of 20 and 40 years. The disease manifests as attacks, ranging from one in a lifetime to several per year, which are most common in young women. The most frequent symptom is paroxysmal severe abdominal pain with concomitant nausea, vomiting, and constipation (or less commonly diarrhea). The syndrome often resembles the “acute abdomen,” but on physical examination the abdomen is soft and signs of peritonitis are absent. Pain can also occur in the back or chest. Patients are often tachycardic and hypertensive and may be febrile. During the attack various neurologic abnormalities develop. These may include paresis or paralysis (usually proximal and symmetric), hyperesthesia, paresthesia, neuropathic pain, and psychiatric symptoms (altered affect, insomnia, confusion, anxiety, hallucinations, paranoia), which either precede or occur simultaneously with the attack. Paresis of respiratory muscles can occur and is life-threatening. During an attack, dark urine or darkening of urine when exposed to light may be observed.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests:

1) Blood tests: Hyponatremia, hypomagnesemia, nonspecific and mild white blood cell (WBC) count elevation.

2) Urine tests: Increased urinary PBG and ALA excretion is always seen during an attack. Levels may be measured in a random urine sample; 24-hour collection is not necessary. Levels remain high for months to years after an attack.

2. Plain abdominal radiographs may reveal features of adynamic ileus during an attack.

Diagnostic Criteria

1. During an attack: Increased urinary excretion of ALA and PBG, adjusted to urine creatinine (a normal result excludes porphyria as the cause of symptoms). Preserve a urine sample and send plasma and stool samples for quantitative determination of PBG, ALA, and porphyrins (to help differentiate the various types of porphyrias).

2. Confirmatory tests that may also be used for screening:

1) Enzyme tests: Decreased activity (~50%) of PBG deaminase in red blood cells (RBCs) or lymphocytes (sometimes also measured in dermal fibroblasts).

2) Genetic testing: The specific type of acute porphyria can be established through sequencing of 4 target genes (ie, ALAD, HMBS, CPOX, and PPOX).

TreatmentTop

General Measures

1. Recommend avoidance of known factors causing porphyria attacks, including drugs. Detailed lists of safe and unsafe drugs can be found on European websites (porphyria.eu, www.drugs-porphyria.org) and North American websites (drug database at porphyriafoundation.com, porphyriadrugs.com) discussing porphyria. Patients should avoid tobacco smoking, marijuana smoking, and heavy alcohol intake.

2. Provide dietary counseling to ensure a well-balanced diet with appropriate carbohydrate intake (~60%-70% of total caloric intake).

3. Encourage the patient to always carry information about their diagnosis (eg, on a wrist bracelet).

Management of Porphyria Attacks

1. Admit the patient to the hospital and closely monitor their heart rate, blood pressure, neurologic status, fluid balance, and serum electrolyte and creatinine levels (at least daily).

2. Discontinue all drugs and eliminate all other factors that may potentiate porphyria attacks (see Definition, Etiology, Pathogenesis, above).

3. If diagnosis is uncertain or IV hemin (see below) is not available, start IV infusion of 10% glucose (dextrose) at a rate of up to 15 g/h (usually 100-125 mL/h and usually <300 g of glucose per day); this may be sufficient to control only a mild porphyria attack (mild pain, no paresis or hyponatremia). Be aware that hypotonic fluids can potentiate dangerous hyponatremia.

4. If available and feasible, as soon as possible start IV hemin at a dose of 3 to 4 mg/kg daily (maximum, 250 mg/d) for 3 to 6 days. Clinical improvement is usually seen after 2 to 4 doses. Of note, the evidence supporting the use of this drug comes from a small case series.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Hafizi D, Argáez C. Injectable hemin for patients with acute porphyria: clinical effectiveness, cost-effectiveness, and guidelines. Ottawa: CADTH; January 22, 2019. https://cadth.ca/injectable-hemin-patients-acute-porphyria-clinical-effectiveness-cost-effectiveness-and-guidelines-0. Accessed June 25, 2019.

5. Start symptomatic treatment using drugs that can be safely administered in porphyria:

1) Treat dehydration and electrolyte disturbances (see Electrolyte, Fluid, and Acid-Base Balance Disorders).

2) Manage pain using acetaminophen (INN paracetamol) and opioid analgesics.

3) Manage nausea or vomiting using ondansetron and phenothiazines (eg, chlorpromazine).

4) Manage symptomatic tachycardia and hypertension using beta-blockers.

5) Treat infection using penicillins, cephalosporins, and aminoglycosides.

6) Other safe drugs include atropine, gabapentin, glucocorticoids, insulin, and acetylsalicylic acid. Some low-dose short-acting benzodiazepines (eg, low-dose lorazepam) are probably safe, yet it is likely safer to avoid the use of this class of drugs altogether. Clinicians are encouraged to check all medications against published lists of safe and unsafe drugs.

7) For patients who have multiple attacks per year despite avoiding triggers, prophylactic hemin, gonadotropin-releasing hormone analogues (for women with recurrent luteal phase attacks), or givosiran (a small interfering RNA therapeutic directed against the gene that is induced in AIP, given as a once-monthly subcutaneous injection) may be indicated. Evidence supporting the use of givosiran in AIP comes from a small randomized controlled trial.Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Balwani M, Sardh E, Ventura P, t al; ENVISION Investigators. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147. PMID: 32521132. Givosiran is currently not approved in many jurisdictions and formal cost-benefit analyses specific to different health-care funding models have not been done.

PrognosisTop

The rate of attack resolution depends on the severity of nerve injury. If treatment is started promptly, the symptoms usually improve within several days. Features of severe motor neuropathy persist for months or even years. Susceptibility to triggering factors and the frequency of attacks decrease with age. Individuals with AIP are more likely to develop cirrhosis, hepatocellular carcinoma, and chronic renal insufficiency. Monitoring of liver enzymes and renal function, abdominal ultrasonography, and blood pressure measurement should be done regularly (eg, annually).