Treatment of the Acute Porphyria's

How Is Acute Porphyria Treated?

We are an educational organization. The following is not intended to be, or is it Medical advice. All information has been compiled and is obtained from the following sources: University Cape Town Porphyria, European Porphyria Network, and the research papers "An update to Clinical Management of AIP", and "..Studies of AIP in 196 patients..", or from other appropriate research papers. A patient and their Doctor must decide together how and when to treat the Acute Porphyria.

How to determine is the patient has an Acute Porphyria:

Attacks have a 1-20% mortality rate if untreated/ undiagnosed. Any of the following tests

confirm the patient is a carrier of an acute Porphyria, and at a risk of death from an untreated attack (the testing section has a comprehensive write up.)

In AIP

1. Below normal Porphobilinogen Deaminase result. In AIP 84% of patients have below normal Porphobilinogen Deaminase enzyme (Kaupinnen "..studies of AIP in 196 Patients.. 2002). HCP and VP patients can also have low PBGD in active disease (Anderson, "Efficacy of Panhematin" 2019) any patient that shows you this result must be taken seriously.

2. 85% of AIP patients have high urinary ALA and or PBG outside of attacks ( Kaupinnen 2002 "..studies of AIP in 196 Patients..) and in attacks as well. So using a positive PBG test to verify an attack in AIP is problematic. On the other hand elevated urinary or plasma PBG and ALA may not occur in HCP or VP in an attack so the test is subject to false positives and false negatives (Lovric, 2015 "Porphyria's diagnostic challenge in the ER")

In HCP

In HCP the patient may present an abnormal Coproporphyrin dominant fecal profile test result. A normal fecal profile is never Coproporphyrin dominant (Doss Compound Heterozygous HCP) it is Protoporphyrin dominant, within certain limits, and should only be 25% Coproporphyrin (Australasian Pathology). It also is frequently not elevated in patients with HCP (Fecal Coproporphyrin Isomers in HCP, Blake 1992).

In VP

In VP the patient may show you a positive plasma fluorescence test result from 625-627

seen in about 80% of adult (22 years and up UCT Porphyria) VP patients who have attack with in the last few years had an this result if tested (Weinlich, 2001), and 60% of affected relatives (European Porphyria Network). In attacks AIP and HCP may less commonly have a positive result at 620+. The VP Patient may also have elevated fecal Coproporphyrin's and Protoporphyrin's, but will be Protoporphyrin dominant.

In HCP, and VP they may not have elevated urinary, or plasma, PBG, ALA, or other porphyrins, can be negative in HCP in and out of an attack (Janus, Henry 2018 "Case report of hereditary Coproporphyria..") and negative VP in attacks, who are well documented to not have elevated urinary ALA or PBG, or only have mild elevations ( Hematin treatment of Acute Porphyria, Peterson, 1976, Weinlich, 2001, Lovric, 2015 "Porphyria diagnostic challenge in ER". HCP and VP may not have elevated fecal porphyrins, and Fecal Coproporphyrin in HCP can be low (Blake, Fecal Isomers in HCP), (and Copro and Proto for VP).

The patient may show you a positive DNA result, or a result of “Uncertain significance” in a Porphyria gene HMBS, CPOX, PPOX or ALAD. When the result is uncertain this gets a little murkier, so please refer to the ALAD, HMBS, CPOX, PPOX signs and symptoms and see if the patient has other positive or borderline porphyria tests and given that untreated attacks can be life threatening it's best to use caution. The patient may also have a number of benign variants on a porphyria gene which may have been, or will be reclassified ((Prevalence of Variant reclassification...Merch, JAMA 2018).

If the Patient has no testing but thinks they are in a porphyria attack full testing can be ordered for them (please see the testing section). All results except urine may take time to return as only a few labs in the country do more extensive porphyria testing.

Where it gets a little murkier is if the patient has borderline positive porphyria testing, then it is best to practice defensive medicine ("What is ethics and why it is important"? Medscape) and evaluate the patient for other signs and symptoms consistent with an acute porphyria attack, listed below by percentage, and treat the patient.

How to determine if the Patient is in an attack:

"Attacks are diagnosed clinically" (Anderson, 2019 Efficacy of Panhematin)

The patient may tell you they are in an attack because this is how their last attack felt.
Pain in the abdomen, but can be other places, and about 10% don’t have pain. The #1 sign is pain, but is not present in all attacks. Tachycardia is the #2 sign of all attack.
The Patient tells you they feel really ill, are a carrier of an Acute Porphyria and there doesn’t seem to be another cause for the signs and symptoms.
There are numerous signs to an attack, and each attack presents a little differently, so we will list the top 10-20 here.

From "AIP and important and rare.." Porphyric crisis most frequent presentation" (Rogerio, Acute Intermittent Porphyria.. 2011)

Abdominal Pain 85-95%

Tachycardia 64-85%

Nausea and vomiting 43-88%

Obstipation (severe constipation) 48-84%

Agitation, Hallucinations, and Depression 40-58%

Pain in extremities back chest and head 50-70%

Arterial hypertension 36-55%

Paresis 42-68%

Respiratory Palsy 9-20%

Seizures 10-20%

Often seen abnormal Lab work (an extensive list is elsewhere):

Hyponatremia, Hyomagnesia, Hypokalemia,

Leukocytosis, elevated AST and or ALT, elevated ANA's, and many others the patient may have one or more of these.

If the patient is female (60-80% are female) may be on her menses or has just passed ovulation.

Treating the Attack:

The experts give similar advice listed in detail below:

In general the treatment of the attack is to do routine ER testing, exclude any unsafe medications, look for causative factors (infections, unsafe medications, hormonal fluctuations,) admit the patient, order the Panhematin, balance electrolytes (hyponatremia is fairly common), provide IV glucose, and pain management, with safe medications, treat any seizures or anxiety (with safe medications see cautions below), treat nausea, and offer other psychiatric medications like Thorazine (low dose) if needed, and treat severe adrenergic crises, carefully monitor the patient, as respiratory failure and death has occurred. Tachycardia and labile hypertension are seen but can resolve at the end of the attack (although hypertension and tachycardia can continue after the attack is over).

Most Attacks last 5-7 days, although more severe and prolonged attacks can occur potentially causing paralysis, respiratory failure, and death can occur (Patient Perspective on AIP..Simon 2018).

The following guidance is from "An update to clinical
Management of AIP" Pishik, 2015:

1.Treatment with heme preparations if attack is moderate or severe, 2. symptomatic treatment of autonomic dysfunctions polyneuroapathy and encepholopathy, 3. exclusion of precipitating factors, 4.) adequate nutrition and fluid therapy.

UCT Porphyria Medical Professionals guide to Treating the patient for an Acute Porphyria attack states:

1. 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 (Barbiturates, sulfa drugs, steroids (progesterone), tricyclic antidepressants/some SSRI's, many street drugs, amphetamines, lidocaine (Merck), many seizure medications, are all unsafe). 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. Exclude, by a careful history and examination, any other problem which may require specific attention.

2. Start appropriate supportive treatments using drugs that are safe in acute porphyria. (Recommended drugs and procedures by Porphyria centers and specialists are listed below.) Ideally the patient will be admitted and put in the ICU, (although some do well in Telemetry) due to the risk of respiratory failure.

3. 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, calcium, magnesium, urea, and creatinine.

4. Treatment options for porphyria are Panhematin, Dextrose, and Liver transplant ( rarely done). The Acute Porphyria's are one of the few genetic illnesses with treatment.

Specific Treatment:

Panhematin is made of red blood cells processed from human blood, which is intended to limit the rate of heme synthesis possibly by inhibiting the enzyme aminolevulinic acid synthase 1.

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. Panhematin should not exceed 6 milligrams per kilogram of body weight per 24 hour period.

Recordati has a nice infusion instruction video on their website for the nursing/ infusion staff to view.

Ordering Panhematin must be done quickly, most Hospital pharmacies do not stock Panhematin as it is an orphan drug, and it must be ordered from ASD pharmaceuticals (800) 746-6273 asd.customerservice@asdhealthcare.com in the U.S., as it can take 24-72 hours to be delivered. Another option is to see if a hospital near you has it in stock.

Hematin therapy has been used safely for over forty years in the US ("Hematin treatment of porphyria..." Peterson, 1976). The Acute Porphyria's are one of the few genetic diseases with treatment. The mortality rate has been reduced greatly in attacks since the invention of Panhematin. The risk factors associated with the use of Panhematin are allergic reactions, iron poisoning, and viral infection. Serious allergic reactions are unlikely usually due to the inactive ingredients in Panhematin such as sorbitol or sodium carbonate. Panhematin can cause urinating less than usual or not at all, swelling, weight gain, feeling short of breath, fever, easy bruising or bleeding, or swelling, pain, or irritation around the IV needle. Panhematin has been used safely in pregnancy, but should only be used if clearly needed. Panhematin can be hard on the veins and so a Picc line or Port is usually required. If administered through a vein please switch arms daily and continuously monitor the infusion for extravation which can cause severe tissue injury. The medication must be administered immediately after mixing. (-EP network)

Dextrose is intended to limit the rate of heme synthesis possibly by inhibiting the enzyme aminolevulinic acid synthase 1. Dextrose comes in a variety of options, 5% with saline, 10% with saline, and dextrose 50% with saline. Two litres of normal saline with 10% glucose given in divided doses of 500 ml over 24 hours through a central venous catheter. It is suggested that when patients cannot consume carbohydrates due to nausea or vomiting, glucose should be administered intravenously. Some physicians have prepared a standing order for patients who are prone to attacks to help facilitate intravenous glucose in the emergency room, which can prevent further hospitalization, however it should only be used in mild attacks without seizures, ideally patients in attacks are admitted and monitored in the ICU, attacks are serious and the mortality rate is 5-20% if the attack is undiagnosed and untreated. Side effects may include irritation of the vein in which it is given, high blood sugar, and swelling. Excess use may result in low blood sodium and other electrolyte problems.

Liver transplant is curative. has been used successfully in a limited number of patients. The liver transplant must be done when the patient is strong enough to withstand the surgery and recovery, and must be a liver from a donor who does not have an acute porphyria.

Research has been done into other treatments for Acute Porphyria attacks with limited success and some deadly failures. Carbohydrate loading, Cimitidine, Hyperbaric Oxygen, Oxygen, and hemodialysis. Hemodialysis was documented to be used in conjunction with Panhematin with great results (Attarian, 2017, Prabahar, 2008). Some patients choose to use these in addition to Panhematin.

A new drug called Givlaari has been used in the US. Some patients report great benefit and others stopped it after feeling worse on it. There was a pregnancy miscarriage and documented increases in Liver AST and or ALT in patients on the medication. It is $575,000 a year.

5. Supportive treatment:

(Things that have been documented to occur in Acute Porphyria
Patients in A-Z order and how the experts treat the problem):

Adrenergic Crisis

Very occasionally, the acute attack is accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures and ischemic 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. (UCT Porphyria) *Bad reactions which triggered or worsened an attack to both beta and alpha blockers have been reported.

Anxiety and or Insomnia

most benzodiazeprines (most benzos are well tolerated except Diazapam, the patient may have a reaction to one type, but not another, and the patient may already know which is most beneficial for them.)

Arrhythmia/ Tachycardia

Clinical management recommends:

beta blockers/ telemetry

EP net recommends:

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.

UCT states:

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 ischemic 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.

Carbohydrate loading

The patient can also try to consume a high carbohydrate diet that consists of 300-500 grams of carbohydrates daily, however many patients report the IV Glucose infusion helps them more.

Constipation

Lactulose

Convulsions

These are occasionally due to the porphyria itself, but are often secondary to Hyponatremia. 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 (U.S. often uses Lorazapam) Clonazepam  Magnesium sulphate.

Lamictal has been used safely (most seizure medications are classified as unsafe for use in acute porphyria) in patients with Epilepsy

Encephalopathy

(See hallucinations or psychosis)

Epilepsy

In patients with an acute Porphyria who also have Epilepsy, Lamictal, Gabapentin, or Clonazepam have been used safely (most seizure medications are classified as unsafe for use in acute porphyria.)

Fluid balance

Careful management of fluid balance, avoiding large volumes of hypotonic dextrose, is required to minimize the risk of severe hyponatremia 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.

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 Hyponatremia. They should therefore not receive intravenous dextrose alone. UCT Porphyria recommends: normal saline with five percent dextrose.

Hyponatraemia

There are 2 schools of thought on treating Hyponatraemia 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 porphyria’s present with similar signs in an attack, testing and skin involvement is quite different in AIP, from HCP and VP.

UCT:

Mild degrees of Hyponatremia 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:

Hyponatraemia (SIADH) P-Na >125 mmol/L: water restriction due to syndrome of inappropriate anti-diuretic 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.

Hallucinations

Phenothiazines, Olanziprine

Hypertension

*beta blockers

clonidine

*please try a very low dose initially as some patients have had extremely bad reactions and the elevated blood pressure is often labile and decreases when the attack ends.

Insomnia

Most benzodiazepines are OK, typically Lorazapam is used in the US.

(Most benzo’s are well tolerated except Diazepam which should be avoided, the patient may have a reaction to one type, but not another, and the patient may already know which is most beneficial for them.)

Muscle weakness

(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:

Monitor progress

Early physiotherapy

Menstrual attacks in females (suppression of)

Is currently being done several ways, GnRH analogs, birth control pills which are taken with no breaks for 3 months at time, and many women with Acute Porphyria have underwent hysterectomies. The success rate of these options varies, with a large number having benefit and a smaller number have been linked to increased attacks.

According to the findings in the paper "Influence of age and gender in acute porphyria" attacks did not stop at menopause, 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 suppression are not a "cure-all".

Neuropathy, Autonomic

Clinical management of AIP recommends:

Abdomen and back pain: Opiates in IV/ IM bolus or in severe cases as infusions.

Euro Porphyria Network:

*Morphine (oral, sublingual, intravenous or subcutaneous) *Pethidine (Demerol) *Diamorphine

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.

UCT “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. 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.

Neuropathy, Cranial

Nasogastric tube for the bulbar paresis

Neuropathic pain (Residual)

“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.

Pain

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.

Paralysis (extreme caution)

(University Cape Town Porphyria)

European Porphyria network also recommends:

Monitor progress

Early physiotherapy

Pregnancy

Is 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, in fact it is thought several very famous artists had Porphyria, as well as certain Royalty.

Psychosis

(Courtesy of University Cape Town) such as chlorpromazine are suitable for its control.

Chlorpromazine /Thorazine (50 to 400 mg/day) for agitation or anxiety

https://www.rxlist.com/thorazine-side-effects-drug-center.htm

Acute Renal failure

Fluid therapy, hemodialysis

Rhabdomyolysis

Fluid therapy

Sedation

UCT: decrease Chlorpromazine

Analgesic requirement Promazine

Seizures / Convulsions

UCT: These are occasionally due to the porphyria itself, but are often secondary to hyponatremia. 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; clonazepam 0.5 mg bd will prevent further seizures. Correct any Hyponatraemia.

Intravenous diazepam (U.S. often uses Lorazapam) Clonazepam, Magnesium sulphate,

In Patients who also have Epilepsy

Lamictal, Gabapentin or Clonazepam have been used safely (most seizure medications are classified as unsafe for use in acute porphyria)

Status Epileticus/ Acute Seizure

EP Net: “Seizures may occur (a) as a manifestation of acute porphyria, where they may be secondary to the hyponatremia which develops in up 35% of acute attacks or (b) due to a cause unrelated to porphyria. Treatment firstly involves terminating the seizure and then assessing the likely cause and planning the most appropriate therapy. In the case of hyponatremia this involves slow correction of the electrolyte imbalance by fluid restriction and isotonic or hypertonic saline where necessary.

A major problem in the management of seizures is that many of the commonly used anticonvulsants can precipitate or worsen acute attacks. Therefore where a primary seizure disorder is suspected this should be fully investigated by an epilepsy expert to ensure that treatment is absolutely necessary.”

Termination of an acute convulsion should be with IV benzodiazepine such as Lorazapam, or clonazepam. When Benzo's fail Magnesium Sulphate or Paraldehyde can also be used* Diazepam is a controversial choice. Under no circumstances should Phentoyin or Phenobarbitione be used.

Suicide (risk of)

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.

Tachycardia/Arrhythmia

Clinical management recommends:

Beta blockers/ Telemetry

EP net recommends:

Propranolol 1 Atenolol for both Tachycardia and hypertension

Extreme caution at least one U.S. patient had bad reactions which triggered severe attacks to beta and alpha blockers.

1. Even low doses may provoke severe hypotension and bradycardia.

UCT states:

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.

Urinary retention

Urethral catheter

Vomiting

Prochlorperazine  Promazine (U.S. Ondansetron, Zofran)

Since impaired nutrition may aggravate acute porphyria, it is important to ensure that adequate calories are given. When vomiting prevents enteral administration, carbohydrate may be provided as normal saline with 5% dextrose, two liters of which provide 100 g of glucose per day. Avoid infusing large volumes of hypotonic dextrose as this aggravates Hyponatraemia. It is very important that the infusion be done slowly and that the patient’s electrolytes are monitored, as Hyponatraemia is seen fairly often in attacks, and SIADH is also seen. It is very important to understand that giving the Patient only dextrose and not used in combination with Panhematin is done only in mild attacks.

Porphyria Alliance

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