Think Beyond the Obvious - Think Porphyria

For Patients

What is porphyria?

Haemoglobin is the substance that colours blood red and carries oxygen to all major organs. To produce haemoglobin, in combination with iron that we consume through our diets, our bodies make proteins called porphyrins.

In people with porphyria, there is a deficiency of an enzyme along the haem biosynthesis pathway, which results in an over-production of porphyrins.

There are two types of porphyrias: the first type is the acute porphyrias and are characterised by acute attacks. Some of them include cutaneous manifestations. The other types are the cutaneous porphyrias. These involve a build-up of porphyrins in the skin. They are sensitive to sunlight and result in painful sores and blisters.

Acute porphyrias always present in the form of “acute attacks”. During an acute attack, excess porphyrins build up inside the body and give rise to unpleasant symptoms. The onset of the attack is rapid (over a few hours) and it lasts for a relatively short period of time (a few days or more). The excess porphyrins and porphyrin precursors are tested during an attack, to diagnose the condition.

Misdiagnosis is common, as symptoms of an attack are not unique to the condition. Also, without proper intervention, these severe attacks can be very dangerous and even fatal.

“As a teenager, I began to have extremely severe abdominal pain and rapid pulse and I even had a little bit of confusion, but this pain was so severe that I’d never felt anything like it. I was doubled over in pain.”

Desiree, Acute Intermittent Porphyria Patient ⊕

"Pain in my stomach, pain around my back, pain in my legs."

Liz, Acute Intermittent Porphyria Patient ⊕

What are the symptoms of an acute attack?

Acute attacks usually start with severe, unexplained pain, usually in the abdomen but sometimes in the back or thighs. Severe and unexplained abdominal pain is the most common symptom.

These symptoms may be accompanied by:

These symptoms can become very severe and even life-threatening if not managed early, so it’s vital that a doctor is seen as soon as an attack begins.

For more information on the clinical manifestations of acute porphyria CLICK HERE

“I had horrible abdominal pain.”

Desiree, Acute Intermittent Porphyria Patient ⊕

“I suffered from quite severe paralysis, which tended to start around my hands and fingers, toes and feet and working its way up my legs and arms until eventually I had complete paralysis.”

Liz, Acute Intermittent Porphyria Patient ⊕

How is acute porphyria diagnosed?

Acute porphyria is a rare condition and it is usually diagnosed during an acute attack.

These tests must be carried out as soon as possible after the onset of an acute porphyria attack, as the concentrations of porphyrins and porphyrin precursors may reduce quickly after an attack. Therefore, if samples are not taken at the correct time, acute porphyria may be missed.

There is one simple diagnostic ‘test’ that can aid diagnosis – the colour of the patient’s urine sample on exposure to light. If the urine turns dark on exposure to sunlight (after approx. 30 minutes), this may indicate that the patient is experiencing the onset of an acute attack. It must be noted that this test may not work 100% of the time. Further tests should be carried out on urine, blood and stool samples to confirm the diagnosis and to identify which type of acute porphyria is present.

For more information on the diagnosis of acute porphyrias CLICK HERE

“There was one particular doctor who came out to see me and saw the dark urine and said: “I think I’d like to investigate two things”, one of them was porphyria.”

Liz, Acute Intermittent Porphyria Patient ⊕

Who does acute porphyria affect?

It is a rare condition, with about 1 in 75,000 people in European countries affected by the most common type of porphyria.¹ Most people with acute porphyria never experience any health problems, but less than 1 in 5 will experience an acute attack.² Females are more likely to suffer than males and the most common age for an attack to occur is between late teens and early 40s.

“Porphyria, it may be rare but someone has it and that someone might be you.”

Desiree, Acute Intermittent Porphyria Patient ⊕

Are there different types of acute porphyria?

Three main types of acute porphyria and one extremely rare type have been identified.

They differ in the genes that are faulty, which help to produce different enzymes in the same pathway (haem biosynthetic pathway); however, they all lead to a rapid build-up of porphyrins.

For more information on the types of porphyrias CLICK HERE

How do genes cause acute porphyria?

Sometimes, genes can change (mutate) and become faulty, so that the enzymes they help to create can’t perform the tasks that they are supposed to.

This is what happens in acute porphyria: the gene that usually helps to create an enzyme involved in haemoglobin production has become faulty, leading to a build-up of porphyrins.

For more information on the pathophysiology of acute porphyria CLICK HERE

Can anyone get acute porphyria?

Acute porphyria is inherited (passed down through genes), usually from one parent and rarely from both patents. Most people who inherit a faulty gene won’t suffer an acute attack, as the condition is often latent. The gene can be passed through the generations without an individual realising that it is present in the family, until someone has an acute attack.

There is currently no way of predicting who will suffer from an acute attack, however, it is recommended that family members of sufferers are screened for the gene through molecular testing. This means that all those at risk of an acute attack can be identified.

For more information regarding the diagnosis of acute porphyria CLICK HERE

“Because my sister had the condition and because we had family awareness, I had genetic testing at the age of 16, so I knew I had the gene. The fact that I knew I had the gene meant that I knew what kind of treatment I needed.”

Sue B, Acute Intermittent Porphyria Patient ⊕

How can acute porphyria be treated?

There are now treatments available that can help to lessen the severity of attacks and possibly prevent future attacks.

If you are an acute porphyria patient, or suspect that you may have the condition, please contact your doctor for further information on the types of tests and treatments available.

For more information on medical management of an acute attack CLICK HERE

“For porphyria patients, those who know the most, do the best. ”

Desiree, Acute Intermittent Porphyria Patient ⊕

Can an acute attack be prevented or avoided?

Acute attacks can be triggered by alcohol, medications and very low calorie diets. Variations in hormone levels are also a common factor, which is why females tend to experience more attacks than males.

Acute attack trigger:

Recommendations:

For people who carry an acute porphyria gene, an absolute avoidance of alcohol is recommended

Recommendations:

Many medications contain ingredients that are capable of initiating an acute attack
The safety of any medicine must always be checked before it is taken
Basic lists of the safety of drugs can be found online (i.e. http://www.drugs-porphyria.org/)
A doctor should be the first source of information for which medicines are safe for use (as lists are subject to change)
Dentists and anaesthetists should be informed of your condition
All vaccines are safe for use in acute porphyria patients

Recommendations:

For people with an acute porphyria gene, low calorie diets may provoke an acute attack
It is important to maintain a healthy body weight, have a normal or high carbohydrate diet with at least three regular meals per day.

Recommendations:

There is an increased risk of acute attack in pregnant females if porphyria has not been diagnosed⁴

Recommendations:

Women are more prone to acute attacks than men due mostly to female hormones, particularly progesterone
This is found in the combined oral contraceptive pill, as well as in HRT
Women with acute porphyria should avoid contraceptives and HRT containing progesterone³

For more information on medical management an acute attack CLICK HERE

“I follow very closely the safe and unsafe drug list.”

Desiree, Acute Intermittent Porphyria Patient ⊕

“No hormones, no hunger.”

Karina, Acute Intermittent Porphyria Patient ⊕

For HCPs

Clinical definitions of the porphyrias

Porphyrias are a group of metabolic disorders that result from a specific deficiency of one of the eight enzymes along the haem biosynthesis pathway. This deficiency results in an accumulation of haem porphyrins, which may lead to clinical manifestations.⁵Porphyrias are also classified as hepatic or erythropoietic, based on the organ system in which haem precursors are overproduced.⁶Porphyrias are generally either autosomal dominant (AD) or autosomal recessive (AR).

One of the eight main forms of porphyria will occur, depending on which of the enzymes is defective. They are classified according to the type of illness they cause.⁵ Acute disease is characterised by episodic acute neurovisceral attacks and non-acute disease is characterised by light-sensitive lesions but without acute attacks.

Table 1: Classification of the types or porphyrias ^6-9

Acute
Non-acute

A comparison of the clinical features of each porphyria is described in Figure 1.

Figure 1. Clinical features of the porphyrias. Adapted from Karim et al. 2015

Pathophysiology of acute porphyria

The acute porphyrias are inherited metabolic disorders of haem biosynthesis in which specific patterns of accumulation of haem precursors are associated with specific clinical manifestations.⁶

Haem is required for the synthesis of haemoproteins like haemoglobin and myoglobin, which play important roles in oxidation-reduction reactions and oxygen transport.⁵

In acute porphyria, specific enzymes within the haem biosynthesis pathway are defective.

An acute porphyria attack occurs when the requirement for haem is increased to the point where the defective enzyme becomes rate-limiting. This leads to an accumulation of porphyrins and porphyrin precursors (such as ALA and PBG) on the haem biosynthetic pathway (Figure 2).

The exact mechanisms underlying acute attacks are not yet well understood, however, the leading hypothesis is that during an attack, ALA and/or PBG overproduced by the liver are neurotoxic.⁶

Figure 2. The haem biosynthetic pathway, indicating the enzymes and intermediates responsible for haem synthesis and the form of porphyria, which results from deficiency of that particular enzyme. Human hepatic porphyrias are in the green boxes. Adapted from Karim et al. 2015.

Types of acute porphyria

This is the most common type of porphyria. In Europe, the incidence has been estimated as 1 in 75,000.¹

Symptoms of an AIP attack and their severity vary greatly, but the skin is never affected. The majority of people make a full recovery from an attack, although about 1 in 10 people will suffer a repeat attack.⁵

People with VP are at risk of both acute attacks and experiencing skin problems, though not necessarily at the same time. The prevalence of VP depends on location. In Europe, it is half as prevalent as AIP.

Skin disease is present in approx. 40% of patients with VP, whereas acute attacks are present in approx. 10%. VP is an autosomal dominant disorder which presents in both males and females and usually only becomes expressed after puberty.¹⁰

HCP is about seven times less common then AIP¹ and the major difference is that people with HCP can have acute attacks at the same time as skin problems.

This type is sometimes called plumboporphyria and is extremely rare, but is similar in outlook to AIP. The severity of the condition as a whole may vary.¹⁰

Clinical manifestations of acute porphyria

Acute porphyrias are characterised by episodic acute neurovisceral attacks.^{5 , 11, 12}Attacks can become very severe and/or life-threatening, if not managed early.

Without appropriate treatment, acute attacks may evolve into acute motor neuropathy which progresses quickly to severe quadriparesis with possible respiratory failure. Other possible complications include severe hyponatraemia, seizures, coma and the posterior reversible encephalopathy syndrome.¹⁰

The cause of neurological dysfunction in acute porphyrias has not been determined, however, there is evidence for a direct toxic effect of 5-aminolevulinic acid (ALA) on the neuron and a possible indirect effect of haem deficiency within the neuron.¹⁰ Research has also shown that both symptomatic and latent patients are more likely to suffer from chronic renal failure with progressive tubulointerstitial nephropathy and hepatocellular carcinoma (HCC).⁶

“Doctors should really pay attention to someone with abdominal pain.”

Karina Lammertz, Acute Intermittent Porphyria Patient ⊕

Diagnosis and misdiagnosis of acute porphyrias

Acute porphyrias are very rare conditions and as the symptoms are non-specific, they are often misdiagnosed.^7, 13

Incorrect diagnosis may lead to inappropriate treatments and the use of unsafe medication, and possible inappropriate interventions (e.g. exploratory abdominal surgery). These actions may aggravate the attack and lead to serious neurological complications.

An acute attack of porphyria should be suspected in any patient with moderate to severe pain and a soft abdomen, especially when accompanied by an increased pulse rate and high blood pressure.¹⁰

Acute attacks of porphyria always result in an increased urinary excretion of the porphyrin precursors porphobilinogen (PBG) and ALA, but ALA is generally not measured in most laboratories and requires specialist interpretation. The first line diagnostic step is a PBG test on a urine sample. It is important that the urine sample is taken during an acute attack so that the diagnosis is not missed.^14, 15

The next step is the identification of the specific porphyria. When analysing porphyrin type, no single test is uniformly applicable. As each porphyrin varies in its water solubility, some accumulate in the urine, whereas others will appear in the stool. Porphyrins may also accumulate in certain patterns in plasma. Therefore, patients are required to submit blood, urine and stool samples for testing.¹⁰

In an emergency setting, the patient should be stabilised before this occurs. The test requires a sample of EDTA preserved blood and a small faeces sample. These samples are generally sent to a specialist, accredited porphyrin laboratory. These laboratories have the facilities to perform both plasma porphyrin fluorescence emission scanning and to determine the faecal coproporphyrin isomer ratio (FCR). The plasma scan is used to distinguish VP from AIP. Once VP is excluded, the FCR can distinguish AIP from HCP.

Retrospective diagnoses are more complicated due to possible PBG concentration depletion.^14, 15

Molecular testing is also extremely important in porphyria diagnosis, but is rarely appropriate in the initial diagnosis stage. It allows a patient to be assigned with a particular genetic mutation. This information can then be used to screen family members and detect carriers. Although many carriers may never present symptoms clinically, it is still important to identify possible carriers.¹⁰

“The first hypothesis was shingles and my symptoms were treated accordingly, but with time the pain worsened and passed through my chest. ”

Karina, Acute Intermittent Porphyria Patient ⊕

“I really stopped even going to doctors because it made me feel ashamed that they thought I was a hypochondriac.”

Desiree, Acute Intermittent Porphyria Patient ⊕

Medical management of an acute attack

The treatment of acute porphyria should be initiated as soon as possible to prevent progression, to encourage rapid remission and to shorten patient time in hospital.^{5 , 16, 17}

Medical management of acute porphyria include:

Confirmation of attack prior to treatment by measurement of urine PBG for all newly presenting patients¹⁸
Check medication for safety in acute porphyria, stop unsafe drugs (porphyrogenic drugs)^18, 19
Withdrawal of all common precipitants and assure sufficient carbohydrate level in the diet⁶
Treat intercurrent infection or other illnesses with safe drugs¹⁹
Treat the symptoms with safe drugs and good pain management¹⁹
Monitor fluid balance, correct hyponatraemia with saline infusions not fluid restrictions, avoid hypotonic dextrose in water infusions¹⁹
Monitor neurological status^18, 19

The fatality rate of acute porphyrias has been dramatically reduced due to early and accurate diagnosis and efficient treatment.⁶

“I think it’s important particularly that the doctors know more about it and are aware of it. Testing for porphyria is very important.”

John, Variegate Porphyria Patient ⊕

Videos

References

1. Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis 2013;36:849-57.

2. Ventura P, Cappellini MD, Biolcati G, Guida CC, Rocchi E, Grupo Italiano Porfiria. A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias. Eur J Intern Med 2014;25:497-505.

3. Calvo de Mora Almazan M, Acuna M, Garrido-Astray C, Arcos Pulido B, Gomez-Abecia S, Chicot Llano M, Gonzalez Parra E, Gracia Iguacel C, Alonso Alonso PP, Egido J Enriquez de Salamanca R. Acute porphyria in an intensive care unit. Emergencias 2012;24:454-458.

4. Marsden JT, Rees DC. A retrospective analysis of outcome of pregnancy in patients with acute porphyria. J Inherit Metab Dis 2010;33:591-596.

5. Puy H, Gouya L, Deybach JC. Porphyrias.
Lancet 2010;375:924-37.

6. Karim Z, Lyoumi S, Nicholas G, Deybach JC, Gouya L, Puy H. Porphyrias: A 2015 update. Clin Res Hepatol Gastroenterol 2015;39:412-425.

7. Siegesmund M, van Tuyll van Serooskerken AM, Poblete-Gutierrez P, Frank J. The acute hepatic porphyrias: Current status and future challenges. Best Pract Res Clin Gastroenterol 2010;24:593-605.

8. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematology Am Soc Hematol Educ Program 2012;2012:19-27.

9. The American Porphyria Foundation.
http://www.porphyriafoundation.com/about-porphyria/types-of-porphyria/HEP

10. Hift RJ. The acute porphyrias. Eur Gastroenterol Hepatol Rev. 2012;8:17-21.

11. Cappellini MD, Brancaleoni V, Graziadei G, Tavazzi D, Di Pierro E. Porphyrias at a glance: Diagnosis and treatment. Intern Emerg Med 2010;5 Suppl 1:S73-80.

12. Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, et al. C-terminal deletions in the alas2 gene lead to gain of function and cause x-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 2008;83:408-14.

13. Farfaras A, Zagouri F, Zografos G, Kostopoulou A, Sergentanis TN, Antoniou S. Acute intermittent porphyria in pregnancy: A common misdiagnosis. Clin Exp Obstet Gynecol 2010;37:256-60.

14. Whatley SD, Mason NG, Woolf JR, Newcombe RG, Elder GH, Badminton MN. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem 2009;55:1406-14.

15. Marsden JT, Rees DC. Urinary excretion of porphyrins, porphobilinogen and δ-aminolaevulinic acid following an attack of acute intermittent porphyria. J Clin Pathol 2014;67:60-5.

16. Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: A diagnostic and therapeutic challenge in internal and emergency medicine. Intern Emerg Med 2009;4:297-308.

17. Fuchs T, Ippen H. Treatment of acute intermittent porphyria with a new protein-bound lyophilized hematin. Dtsch Med Wochenschr 1987;112:1302-5.

18. The European Porphyria Initiative.
http://www.porphyria.eu.

19. Mehta M, Rath GP, Padhy, UP, Marda M, Mahajan C, Dash HH. Intensive care management of patients with acute intermittent porphyria: Clinical report of four cases and review of literature. Indian J Crit Care Med 2010;14:88-91.

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