Acute Porphyria Treatment & Management

Consider an appropriate period of first-line conservative therapy in patients with acute porphyria before administering heme for injection. The duration of conservative treatment depends on the patient's presenting condition and clinical course. Start a hematin infusion immediately if clinical deterioration is evident to prevent neuronal damage.

Conservative first-line therapy includes the following:

• Remove potentially offending medications.

• Administer intravenous (IV) fluid with a substantial carbohydrate supply (eg, dextrose 500 g/d).

• Control pain with opiates.

• Relieve nausea and vomiting with phenothiazines.

If conservative treatment proves unsatisfactory, administer an IV heme infusion for 3-14 days.

Hematin is the only heme compound currently approved for use in the United States. Heme arginate (Normosang) is a more stable heme compound and has a lower frequency of adverse effects. Although this compound has been used with success in Europe and South Africa, it has not been approved for use in the United States. ^[12]

Heme requires prompt administration for clinical benefit. Episodes of porphyria can cause irreversible neuronal damage. Heme therapy is intended to prevent an episode from reaching the critical stage of neuronal degeneration.

Fecal urobilinogen increases in proportion to the amount of hematin administered; this observation suggests an enterohepatic pathway as a route of elimination. Bilirubin metabolites are also excreted in the urine after hematin administration.

Urinary concentrations of porphyrins can be followed to monitor treatment efficacy. A decrease in aminolevulinic acid (ALA), uroporphyrinogen, porphobilinogen (PBG), and/or coproporphyrin values indicates successful treatment.

Strictly follow recommended dosing guidelines because asymptomatic reversible renal shutdown can occur when a greatly excessive dose of hematin is administered in a single infusion. However, recommended doses of hematin do not impair renal function.

Studies of gene therapy in animal models to restore PBG activity are ongoing.

Several factors complicate the treatment of seizures in porphyria. The liver metabolizes most anticonvulsants are metabolized, at least to some extent, and most anticonvulsants induce the cytochrome P-450 enzyme system.

Acute seizure control includes the following:

• Magnesium sulfate and diazepam are first-line drugs for acute seizure control.

• Lorazepam is generally the first-line drug for status epilepticus and is safe to use in patients with porphyria.

• Correct acute electrolyte abnormalities because seizures are commonly associated with such abnormalities.

Epilepsy control includes the following:

• Gabapentin is not metabolized by the liver and is reportedly successful for long-term seizure control.

• Diazepam per rectal is useful for outpatient control of prolonged seizures.

Correct electrolyte abnormalities. Hyponatremia can be corrected with an infusion of normal saline or half-normal saline, depending on the level of volume depletion and hyponatremia. However, fluid restriction and diuretics may be needed if the patient exhibits signs of syndrome of inappropriate antidiuretic hormone secretion.

Autonomic outflow is managed by the administration of beta blockers. Acute hypertension must be managed with appropriate emergency agents.

Psychiatric symptoms are typically controlled by administering phenothiazines (eg, chlorpromazine). These medications can also help to relieve nausea.

Givosiran (Givlaari) was approved by the US Food and Drug Administration (FDA) for adults with acute hepatic porphyrias (AHP), in which attacks are caused by induction of the enzyme 5-aminolevulinic acid synthase 1 (ALAS1). Givosiran is a small interfering RNA agent. Via RNA interference, it leads to degradation of ALAS1 mRNA in hepatocytes, which in turn lowers elevated liver ALAS1 mRNA levels.

Approval of givosiran was based on the ENVISION phase 3 trial (n=94). In patients with acute intermittent porphyria, givorsan was associated, relative to placebo, with a 74% mean reduction in the annualized composite rate of porphyria attacks. ^[13]

An expert in porphyria should assist in the diagnosis and treatment of patients with acute and chronic cases, as the management of porphyria involves many disciplines. Such experts may be certified in metabolic diseases, gastroenterology, or hematology.

Consultation with a neurologist may be needed if seizures or neuropathy develop.

Consultation with a physical therapist may be needed if muscle weakness develops.

Consultation with a psychiatrist may be necessary for the management of short-term and/or long-term psychiatric issues.

Consultation with a specialist in reproductive medicine may be necessary for menses and birth control.

Consultation with a cardiologist may be needed if hypertension develops.

Consultation with an anesthesiologist is necessary before a patient is sedated for a minor procedure or surgery. ^[14]

Seek a consultation with an ophthalmologist if ocular manifestations arise.

A high-carbohydrate diet can mitigate the disease. A low-carbohydrate diet is strictly forbidden.

The patient should maintain adequate fluid intake to ensure good clearance of porphyrins.

A low-salt, low-fat, and low-cholesterol diet may be prudent if hypertension develops.

Instruct patients to avoid activities that put them at risk for dehydration, exhaustion, or carbohydrate depletion.

Liver transplantation has been employed as a cure for recurrent episodes of acute intermittent porphyria (AIP), and in a study of outcomes, Lissing et al indicated that the procedure can stop such attacks. Nonetheless, the report also found that the risk for poor outcomes in transplantation therapy is greater in patients with severe neuropathy or impaired renal function. The overall 1- and 5-year survival rates in the study were 92% and 82%, respectively. However, while 19 patients in whom neuropathy was moderate or absent at the time of transplantation had a 5-year survival rate of 94%, 10 individuals who had motor paresis, were wheelchair dependent, were bedridden, or had severe neuropathic pain had a 5-year survival rate of 83%. Moreover, 14 patients with a glomerular filtration rate (GFR) of less than 60 mL/minute prior to transplantation and in whom a liver transplant alone, rather than a combined liver-kidney transplant, was performed had a 71% 5-year survival rate, while 18 patients with a GFR above 60 mL/minute had an 81% 5-year survival rate. ^[15]