How Is Acute Porphyria Treated?
Patients with Acute Porphyria may experience acute attacks which are life endangering if untreated, in addition a recent study found 30% of patients are chronically ill, and about the same number were too sick to work. Certain signs and symptoms may occur outside of an attack, and or in an attack. In addition to the attacks being life threatening it is also very important for both patient and Doctor to understand that Acute Porphyria can be very devastating, and painful, and has a risk of suicide if the patient is left untreated and without help, but it is one of the few genetic illnesses with treatment, so it is imperative to get the patient treatment.
Specific therapy for Acute Hepatic Porphyria attacks is treatment with Panhematin and glucose, symptomatic therapy with a complete guide to treatment is listed below. If the patients attacks are frequent, and Panhematin is ineffective for a patient, a liver transplant could be done.
In the U.S. a Doctor and their patient must decide together, how and when to treat porphyria. We encourage both Doctors and patients, to err on the side of caution, and treat, rather than not treat, especially in patients who have borderline, or abnormal porphyria lab tests, or Variants of unknown significance with the below signs and symptoms. A patient in the US has a "right to try" in a terminal illnesses, and even though Acute Porphyria is highly treatable, given how high an untreated acute Porphyria attacks mortality rate can be (1-20%), it is prudent to see if treatment helps, even in cases where the diagnosis is borderline.
This treating information is from the European Porphyria Network, University Cape Town Porphyria, and from the papers "an Update of Clinical management of Acute Intermittent Porphyria" and "Best practice guidelines on clinical management of acute attacks of porphyria and their complications". Italicized portions were obtained from other porphyria research papers.
Initial Investigations (UCTSA and European Porphyria Network)
Take a careful drug history. Administration of any drug not known to be absolutely safe in porphyria (*a list is available at NAPOS), must immediately be stopped (Barbituates, sulfa drugs, steroids, tricyclic antidepressants/SSRRI's, progesterone, many street drugs, amphetamines, lidocaine, most seizure medications, and many others, are all unsafe). Exclude, by a careful history and examination, any other problem which may require specific attention. Other potentially complicating factors, such as infection, must be treated (please see University Cape Towns write up on safe medications for treating infections). Check sodium, potassium, urea, and creatinine...check calcium, and magnesium as well.
*safe medications may also cause adverse reactions. If a medication is documented as unsafe, or suspected to be unsafe for this patient, please immediately stop, or taper the patient off as quickly and as safely possible.
Clinical manifestations and treatment of an acute attack
Due to the risk of respiratory failure which may occur rapidly ideally acute porphyria patients in an attack will be admitted to hospital and cared for in the I.C.U.
Therapy for Specific Complications of the Acute Attack
"An update to clinical management of patients with AIP" reccomends Heam arginate (US Panhematin) and infusions i.v. Glucose with normal saline ,The EPN discusses infusing Haem arginate (Panhematin) and using 10-20% glucose with normal saline for carbohydrate loading. The University of Cape Town Porpyhria lists heaem arginate and discusses 5% glucose with saline, we will present all perspectives, we have found patients have benefited from all versions of treatment, just Panhematin, both i.v. glucose and Panhematin, and just i.v. glucose.
The only uniformly effective therapy is haem arginate (Panhematin). This is highly effective in aborting the acute attack. Older texts recommend large amounts of carbohydrate as a suppressive therapy for porphyria. This is only ..for...the mildest attack (mild attacks do not have vomiting, seizures, weakness, neuropathy, or paresis), otherwise haem arginate should be given. Most clinicians give both IV dextrose with normal saline (300-500 g daily), and Panhematin during an attack.
Ordering Panhematin must be done quickly, most Hospital pharmacies do not stock Panhematin, it is an Orphan drug, and it must be ordered from ASD pharmaceuticals 1(800) 746-6273 in the U.S., as it takes sometimes 24-72 hours to be delivered. Another option is to see if a hospital near you has it in stock.
Panhematin® (hemin for injection)
Active Ingredient: Hemin 313 mg
Inactive Ingredients: Sodium Carbonate 215 mg, Sorbitol 300 mg
Dosage and Administration
Panhematin® is given at a dose of 1-4 milligrams per kilogram of body weight once daily for 3 to 14 days, based on clinical signs. In more severe cases, Panhematin® is given at the previous dose twice daily. Panhematin® should not exceed 6 milligrams per kilogram of body weight per 24-hour period. Panhematin® is administered intravenously into a large peripheral vein, a central venous catheter, also known as a central line, a central venous line, or a central venous access catheter, or a port. Panhmeatin has no preservative and must be mixed with either sterile water or human albumin and infused immediately after mixing, the glass bottle must be light protected (wrap in foil if a amber bag is not available), some infusion centers also wrap the i.v. tubing to protect from light. If using an arm vein IV please switch arms daily to allow the vein to recover. Warming the arms with blankets or a heating pad before is also a good way to help the IV administration.
Panhematin® is a biologic that is made of red blood cells processed from human blood. Panhematin® is intended to limit the rate of heme biosynthesis by inhibiting the enzyme aminolevulinic acid synthase. Panhematin® prevents porphyria symptoms from progressing, it does not repair damage and is not curative, after discontinuation of Panhematin® symptoms return if the patient is in a porphyria attack. Clinical benefit from Panhematin depends on prompt administration. Attacks of porphyria may progress to a point where irreversible neuronal damage has occurred. Panhematin therapy is intended to prevent an attack from reaching the critical stage of neuronal degeneration. Panhematin is not effective in repairing neuronal damage.
while waiting for the Panhematin it is best to immediately start with infusion of glucose
Carbohydrate loading: Two litres of normal saline with 10-20% glucose given in divided doses of 500 ml over 24 hours through a central venous catheter. Carbohydrate loading has now been replaced by heme preparations as the treatment of choice for an acute attack of porphyria.
Since impaired nutrition may aggravate acute porphyria, it is important to ensure that adequate calories are given. They are preferably given as carbohydrate-rich food supplements orally or, if necessary, via a nasogastric tube. When vomiting prevents enteral administration, carbohydrate may be provided as normal saline with 5% dextrose, two litres of which provide 100 g of glucose per day. Avoid infusing large volumes of hypotonic dextrose as this aggravates hyponatraemia. As soon as patients are able to take food orally, they should be transferred to a diet in which carbohydrate provides 55-60% of the energy needed to maintain their normal weight.
Careful management of fluid balance, avoiding large volumes of hypotonic dextrose, is required to minimise the risk of severe hyponatraemia which may provoke convulsions. Hyponatraemia should be corrected slowly; patients with acute attacks seem particularly prone to cerebral edema and osmotic demyelination. Restriction of water intake to around 500 mL per day may be sufficient alone but, if symptoms necessitate saline infusion, the rate of correction should not exceed 8 mmol/L in any 24 hour period.
Start appropriate supportive treatments using drugs that are safe in acute porphyria. Recommended drugs and procedures are listed below.
Pain is treated with opiates, and IV glucose, and Chlorpromazine or promazine. The pain is extremely severe in 93% of attacks and classified as worse than a broken bone, or child birth.
Clinical management of AIP recommends:
Abdomen and back pain: Opiates in IV/ IM bolus or in severe cases as infusions
Euro Porphyria Network:
(oral, sublingual, intravenous or subcutaneous)
UCT SA adds:
Opiates are the most effective analgesics for use in an acute attack.
*Chlorpromazine or promazine may help to decrease the requirement for analgesics.
The pain of the acute attack is very severe. Frequent, high doses of opiate analgesics are usually necessary. We recommend pethidine in doses of 50, 75 or 100 mg given hourly, 2-hourly or 4-hourly. Though some patients may settle with intramuscular doses given four hourly; others may require pethidine intravenously two hourly or hourly. Typically the pain recurs after several hours, leading to appeals for more pethidine. There is no risk of addiction since the acute attack of porphyria is short-lived. A common error is to give too little pethidine, or to label patients too easily as histrionic or addicted.
*Anecdotally many patients report infusions of IV glucose, also helps to reduce the pain of an attack.
Clinical management recommends:
beta blockers/ telemetry
EP net reccomends
Propranolol 1 Atenolol for both Tachycardia and hypertension
Extreme caution at least one U.S. patient had bad reactions to beta and alpha blockers.
1. Even low doses may provoke severe hypotension and bradycardia.
Cardiovascular complications such as hypertension and tachycardia are rarely sufficiently severe to require therapy in their own right*. Very occasionally, the acute attack is accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures and ischaemic changes on CT brain scanning. Intravenous infusion of magnesium sulphate may be effective in controlling the adrenergic symptoms; human hemin must be administered to abort the attack.
In the rare patient with a severe adrenergic crisis, treatment with intravenous magnesium sulphate and combined alpha- and beta-adrenergic blockade may be helpful.
*The paper 196 patients with AIP found chronic hypertension exists in a number of porphyria patients.
*please try a very low dose initially as some patients have had extremely bad reactions.
Muscle weakness/Paralysis (extreme caution)
(University Cape Town Porphyria)
If haem arginate (Panhematin, U.S.) has not already been commenced, it must be administered as an absolute emergency. The patient should be carefully monitored for the onset of respiratory weakness, preferably in an intensive care unit. Any suggestion of respiratory insufficiency requires immediate intubation and positive pressure ventilation. The motor neuropathy of porphyria is fully reversible. However, as with any other axonal neuropathy, recovery is slow. Ventilation may have to be continued for up to 16 weeks and full recovery may require many months. It is always worthwhile to continue with ventilation, as eventual recovery can be expected.
European Porphyria network also recommends:
Nasogastric tube for the bulbar paresis
Insomnia and or anxiety
(most benzos are well tolerated, the patient may have a reaction to one type, but not another, and the patient may already know which is most beneficial for them.)
Seizures / Convulsions
These are occasionally due to the porphyria itself, but are often secondary to hyponatraemia. Seizures may also arise in response to large doses of intravenous pethidine, and are often preceded by myoclonic jerks. Seizures should be terminated with intravenous clonazepam 1 mg or diazepam 5-10 mg; clonazepam 0.5 mg bd will prevent further seizures.
Correct any hyponatraemia
Intravenous diazepam (U.S. often uses Lorazapam)
Lamictal has been used safely (most seizure medications are classified as unsafe for use in acute porphyria)
(Courtesy of University Cape Town) such as chlorpromazine are suitable for its control.
Chlorpromazine /Thorazine (50 to 400 mg/day) for agitation or anxiety
There are 2 schools of thought on treating hyponatreamia in acute porphyria, and we wanted to include them both, so both the Doctor and the patient, maybe able to make the best decision. We would like to point out UCT primarily has Variegate Porphyria patients, and the Doctors who wrote Update to Clinical management of AIP, deals with AIP patients foremost. While all acute porphria's present with similar signs in an attack, testing and skin involvement is quite different in AIP, from HCP and VP
Mild degrees of hyponatraemia are treated with intravenous infusions of normal saline. Severe hyponatraemia, particularly if accompanied by confusion or seizures, should be partially corrected with hypertonic saline, taking the usual precautions to prevent over-correction and too-rapid correction. Severe hyponatraemia appears to result from excessive renal sodium losses rather from inappropriate ADH secretion (SIADH), and fluid restriction is therefore inappropriate.
An update to Clinical management:
Hyponatremia (SIADH) P-Na >125 mmol/L: water restriction due to syndrome of inappropriate antidiuretic
hormone secretion (SIADH)
P-Na ≤125 mmol/L or patients with seizures or unconscious: infusion of saline.
Correction ≤12 mmol/L/day. Be aware of pontine myelinolysis
Acute renal failure: Fluid therapy, hemodialysis
Rhabdomyolysis: Fluid therapy
Most patients are dehydrated as a result of nausea, vomiting, poor fluid intake and renal dysfunction. They are also at risk of severe hyponatraemia. They should therefore not receive intravenous dextrose alone. UCT Porphyria recommends: normal saline with five percent dextrose.
In some patients, residual neuropathic pain continues once the acute attack has settled. It is important to recognise that this pain differs from that of the acute attack itself and, wherever possible, to avoid using addictive analgesics for its management. In the US gabepentin is often used to treat neuropathy, however, about 50% of porphyria patients reported such extremely bad reactions they discontinued taking it.
Analgesic requirement Promazine
Suppressing menstrual attacks in females
Is currently being done several ways, Lupron, birth control pills which are taken with no breaks for 3 months at time, and many with Acute Porphyria have underwent hysterectomies. The success rate of these options varies, and all have been linked to increased attacks. Several post menopausal women expressed shock that experts have told them their attacks should have ceased, this is defied by the paper "Influence of age and gender in acute porphyria". The truth is hormonal fluctuations are one common cause of attacks in women but since men suffer with porphyria attacks too it is important to note menopause, hysterectomies, or hormonal suppession are not cure alls.
Lupron Depot® (leuprolide acetate for depot suspension)
Active Ingredient: Leuprolide acetate 3.75 mg
Inactive Ingredients: D-mannitol 56.6 mg, DL-lactic and glycolic acids copolymer 33.1 mg, Carboxymethylcellulose Sodium 5 mg,
Polysorbate 80 1 mg, Purified gelatin 0.65 mg
About Lupron Depot®
Lupron Depot® is a gonadotropin-releasing hormone agonist, also known as GnRH agonist or GnRH-A. The body normally makes GnRH in the pituitary gland located in the brain and it is this hormone that stimulates the ovary to develop eggs and produce estrogen, leading to the normal menstrual cycle. If you give GnRH agonists, this floods the system and confuses the delicately controlled balance, leading to a complete block of egg development, estrogen production and menstrual cycle. It effectively makes you 'menopausal' for the time that you use the treatment. The success rate varied from 60-80%.
Lupron Depot® can cause menopausal symptoms such as hot flashes also known as flushing, increased sweating, night sweats, tiredness, headache, upset stomach, breast changes, acne, joint and muscle aches, thinning of the bones, trouble sleeping, reduced sexual interest, vaginal discomfort and dryness, swelling of the ankles and feet, dizziness. Burning, pain, and bruising at the injection site may occur.
Has been used successfully in a limited number of patients. The liver transplant must be done when the patient is strong enough to with stand the surgery and recovery, and must be a liver from a donor who does not have an acute porphyria.
It usually well tolerated after the first trimester, and has been documented to put some patients in remission after child birth. Please be very cautious though as labor and delivery can very hard on the mother. Our organization is in agreement with the South African porphyria experts that an unborn child with an Acute Hepatic Porphyria is not cause to terminate the pregnancy. The disease is treatable and patients have been documented to live long and productive lives.