Tuesday, 2 July 2013

Porphyria: A Guide for the Laymen

Note: Some terms are not explained within the main text and are, instead, explained in the glossary which is immediately before the reference list, near the back of the post.


The porphyrias are a collection of rare, often inherited, hematologic (blood) diseases that are often tricky for doctors to diagnose. They all stem from the body having a compromised ability to synthesise the biologically-significant compound, haem, from its chemical precursors, the porphyrins.1

Haem is so significant and important in the human body because it is used to create a class of proteins known as the haemoproteins which, in turn, play pivotal roles in the body – from carrying the oxygen stored within the red blood cells of the blood (this particular type of haemoproteins is known as haemoglobin), to the metabolism of vital bodily hormones and drugs (these haemoproteins are known as cytochromes). Haem is mostly synthesised in the bone marrow (85% of it is), probably due to its crucial role in the formation of haemoglobin, while the remaining 15% is mostly synthesised in the liver. It is synthesised via a very long process involving multiple enzymes (to those of you that do not understand much chemistry, enzymes are basically the helpers or accelerators of chemical reactions). For the details of this process see figure 1. In porphyria one of these enzymes is either faulty or found in substandard quantities usually due to mutations in the gene that regulates their formation.2

Figure 1: Haem Synthesis2
Enzymes are given in boxes, porphyrins are given outside of them (except glycine and succinyl-CoA are not porphyrins). Cytosol and mitochondrion are where, in cells, these reactions occur. This diagram may be helpful later when I go into detail about the different types of porphyria and the specific enzymes implicated in each type. You need not know anything about these porphyrins or the enzymes that catalyse their formation – just pay attention to their names because latter I will tie deficiencies of the specific enzymes involved in haem synthesis with the different types, or varieties, of porphyria.

Haem deficiency is not the only problem that leads to the symptoms and complications of porphyria, a major contributor to the manifestations of the disease are the porphyrins themselves. In unaffected individuals the amount of the different porphyrins in the body are regulated and limited by the enzymes involved in their transformation into haem. This is because the higher the concentrations of these porphyrins the more reactions will be underway transforming them into the next porphyrin in the production line (that is displayed in figure 1). In porphyric individuals, since they are deficient in one of the enzymes involved in haem synthesis, the porphyrin normally transformed by the deficient enzyme (into the next porphyrin, that is) accumulates, and since porphyrins can be toxic in high quantities this can lead to a number of problems, often neurologic (pertaining to nerves, the brain and/or the spinal cord) or cutaneous (pertaining to the skin) in nature.2

The Types of Porphyria and their Usual Manifestations

The porphyrias are commonly divided into two different groups based on their symptoms and pathophysiology (literally means the mechanism(s) of the disease), the acute porphyrias and the cutaneous porphyrias. All of which can potentially cause a, often very dark, red discoloration of the urine and there is some overlap between the two categories: some acute porphyrias can present with cutaneous symptoms (e.g. HCP, VP, ALAD deficiency porphyria, EHP).

Cutaneous Porphyrias

The cutaneous porphyrias present, usually, with almost solely cutaneous (skin) symptoms that occur upon sun exposure they include:3
  • Fragility of the skin
  • Skin blistering
  • Scaring
  • Opportunistic skin infections (i.e. infections that affect the skin when it is already compromised in its health) 
  • Changes in skin coloration
these symptoms persist throughout life in cases of genetic cutaneous porphyrias whenever patients are exposed to sunlight. Although the cutaneous porphyrias are usually limited, almost entirely, to the skin they can, on rare occasions cause significant liver damage and sometimes even liver failure severe enough to warrant a transplant. The cutaneous porphyrias are usually, at least in part, erythropoietic in nature. That is, they arise due to enzyme deficiencies in the bone marrow not the liver. One type is hepatoerythropoietic in nature, namely, hepatoerythropoietic porphyria, this means that it is due to enzyme deficiencies in both the bone marrow and the liver (hence the hepato prefix).

Table 1: Types of Cutaneous Porphyrias2-4

Porphyria Type
Relevant Enzyme
Porphyria cutanea tarda (PCT)
Uroporphyrinogen decarboxylase (UDOC)
PCT is usually (80-90% of cases are) sporadic (i.e. cases in which no mutation in the UDOC gene can be identified). Sporadic cases can be caused by a number of other conditions or even occur without a known cause. Known causes include hepatitis C and other viral infections including HIV, alcoholism, renal (kidney) dialysis, oestrogen supplements, excessive iron supplementation and hemochromatosis (a genetic condition that leads to the accumulation of iron in the body).2,5

10-20% of cases are due to a mutation in the UDOC gene that leads to insufficient quantities or qualities of the UDOC enzyme being present in the liver and bone marrow. These cases are often referred to as familial porphyria cutanea tarda. The UDOC gene is autosomal dominant in inheritance. That is the offspring of an affected individual will have a 50/50 chance of being susceptible to the condition.

PCT is the most common form of cutaneous porphyria and the most common form of porphyria overall, despite this it is still relatively rare and affects around 1/1000 people worldwide.
Hepatoerythropoietic porphyria (HEP)
Uroporphyrinogen decarboxylase (UDOC)
HEP is due to a mutation in the UDOC gene and is similar to cases of familiar porphyria cutanea tarda but more severe and it usually presents (i.e. displays symptoms) earlier on in life. HEP occurs in patients homozygous for subfunctional UDOC genes.4
Erythropoietic protoporphyria (EPP)
Ferrochelatase (FECH)
Usually presents in infancy to early childhood and it can follow both autosomal dominant and autosomal recessive modes of inheritance, although autosomal recessive inheritance is certainly its predominant mode of inheritance.6
Congenital erythropoietic porphyria (CEP)
Uroporphyrinogen III synthase (UROS)
It is incredibly rare (1/1,000,000 people have it) and often presents with other symptoms too like hair loss or excessive hair growth, vision loss, anaemia (low blood count), shortness of stature, abdominal pain, pink- or dark-stained urine, an enlarged spleen, inflammation of the outer layers of the eyes, fractures, abnormally-formed bones, gallstones, etc.3,5 The cutaneous manifestations of this type of porphyria is often more severe than in the other varieties of cutaneous porphyria and can even be triggered by surgical lights, not necessarily sunlight.4

Acute Porphyrias

Acute porphyrias, however, usually present with acute (short-term) bouts (or attacks) of gastrointestinal (digestive), neurologic, psychiatric, hepatic (liver), renal (kidney), cardiovascular (heart and blood vessel) and, depending on the deficient enzyme (and hence the type of acute porphyria since they are all categorised according to the deficient enzyme that causes them), cutaneous (which are not limited to occurring during attacks; they can occur whenever an affected person is exposed to sunlight) symptoms. The symptoms of an acute attack include:2-4,9
  • Severe abdominal pain (which is the single most common symptom of the condition, over 80% of individuals will suffer abdominal pain during attacks)
  • Autonomic dysregulation (Symptoms of autonomic dysregulation that are often seen in the acute porphyrias include: nausea, vomiting, constipation, ileus (paralysis of the bowels), tachycardia (high heart rate), hypertension (high blood pressure), sweating, urinary retention, urinary incontinence)
  • Seizures
  • Paralysis
  • Tremor
  • Restlessness
  • Fever
  • Elevated blood catecholamines (the catecholamines include the fight and flight hormones adrenaline and noradrenaline, hence when people have elevated blood catecholamines they get two previous mentioned symptoms– hypertension and tachycardia. These symptoms can also be due to the damage the porphyrias can do to nerves)
  • Mental changes (these occur in around 30% of cases and include anxiety, depression, hallucinations, delusions, insomnia, excessive drowsiness, irritability, problems with memory, learning, concentration, problem solving, etc. Rarely these might be the most prominent symptoms of an attack)
  • Hyponatraemia (low blood sodium, this often causes the seizures associated with the condition, it can also cause muscle cramping, spasms, loss of appetite, headache, etc.)
  • Opportunistic infections (infections that have just taken the opportunity of your ill-health to kick you while you are down)

due to the potential for acute attacks to cause comas, paralysis of the muscles involved in breathing, tachycardia, hypertension, depression and other potentially deadly complications acute attacks can be fatal. Rare complications that can also eventuate include chronic renal (kidney) failure, often due to the nephrotoxic (toxic to the kidneys) porphyrin metabolites and/or sustained hypertension and it has also been found that those with acute porphyrias are at a heightened risk of developing the, often fatal, liver cancer, hepatocellular carcinoma (HCC).2,

These acute attacks are typically triggered in genetically susceptible individuals by at least one of the following:2-4
  • Stress
  • Drugs (especially sulfa-containing antibiotics, barbiturates, synthetic oestrogens, certain antiepileptic drugs, alcohol and a few others. See http://www.drugs-porphyria.org/ for details regarding safe and unsafe drugs in acute porphyrias)
  • Dietary changes (high protein diets, low-carbohydrate diets and fasts are especially notable for causing acute attacks)
  • Endocrine factors (fluctuations in the levels of the different hormones present in the body; usually the sex hormones such as oestrogens and androgens [e.g. testosterone, dihydrotestosterone]. Acute attacks are often triggered by the hormonal changes that occur in the different stages of development, e.g. puberty, menopause, etc.)

Table 2: Types of Acute Porphyrias

Porphyria Type
Relevant Enzyme
Acute intermittent porphyria (AIP)
Porphobilinogen deaminase (PBG-D) also known as hydroxymethylbilane synthase (HMBS)
It is the second most common type of porphyria and hence the most common type of acute porphyria. Its incidence is estimated to be 5-10/100,000. It is inherited in an autosomal dominant fashion, yet 90% of patients do not display any symptoms despite being heterozygous for the mutated gene.6 It usually presents initially in the 30s and very rarely presents prior to puberty. It more frequently causes symptoms in women than in men, likely due to the fact that oestrogens are well-known triggers for acute attacks. Five cases of homozygous AIP have been described too, and they are usually very severe. It is a hepatic porphyria. Cutaneous symptoms are absent in this subtype of porphyria.2-4;8-9
Aminolevulinic acid dehydratase (ALAD) deficiency porphyria

Aminolevulinic acid dehydratase (ALAD)
This is the rarest form of porphyria with only six cases reported worldwide.2 Symptoms usually first appeared during adolescence in the six cases reported thus far.2 It follows the autosomal recessive inheritance pattern.10 It can cause cutaneous symptoms.4
Chester Porphyria
Porphobilinogen deaminase (PBG-D)
A very rare subtype of AIP. It shows characteristics of variegate and acute intermittent porphyrias yet recently it was demonstrated that it is, in fact, a rare subtype or variant of AIP.11
Erythropoietic harderoporphyria (EHP)
Coproporphyrinogen oxidase (CPOX)
Similar to HCP but more severe and due to more specific mutations in the CPOX gene. It normally occurs due to the affected being homozygous for a specific allele of the CPOX gene known as the K404E allele. Alternatively it can be due to null CPOX allele – that is, an allele that causes absolutely no CPOX to be formed in the body. This type of porphyria can also cause hematologic (blood-related) symptoms such as dyserythropoiesis (the abnormal formation of red blood cells) and iron overload. It can present with cutaneous symptoms.12
Hereditary Coproporphyria (HCP)
Coproporphyrinogen oxidase (CPOX)
Presents with acute attacks and cutaneous symptoms. It is autosomal dominant in inheritence.2
Variegate Porphyria (VP)
Protoporphyrinogen oxidase (PPOX)
Relatively common in the South African (1/300 people have it approximately) and Chilean populations.3,13 It presents with both acute and cutaneous signs.2


The diagnosis of porphyrias is tricky: part of it is ruling out other conditions that could cause the currently manifest symptoms, part of it involves running tests that can confirm porphyria if it is currently active but cannot discount the possibility of the patient having a latent (i.e. one that is not currently causing symptoms) case of porphyria and part of it is genetic testing which requires several months of waiting for the patient to receive the results. Another aspect of AIP and VP, in particular, which makes them such a difficult diagnosis to make without genetic testing is that they been found to be associated chronic anxiety, even in patients that are asymptomatic (i.e. those that are currently not having an attack). In fact it seems like some cases of generalised anxiety disorder (GAD) are in fact due to asymptomatic cases of AIP.14,15

The usual tests that can be performed on symptomatic individuals during an attack to confirm the diagnosis (although they cannot rule it out as the cause of a patient’s symptoms altogether) include urine, faecal and blood tests that look for elevated levels of porphyrins in the aforementioned samples.2,5 These test usually take only a couple of hours but in Australia, of course, with our health care system these tests are likely to take far longer unless your current attack is severe enough to make you a high priority.
Conditions that can mimic the porphyrias vary according to the porphyria in question but the following is a small list of a few that can:2,5
  • Acute leukaemias (in the case of acute porphyrias)
  • Anaemia (acute porphyrias)
  • Bone marrow transplantation complications
  • Hepatic (liver) failure
  • Hepatocellular carcinoma
  • Hepatitis B
  • Hepatitis C
  • HIV infection
  • Lymphoma
  • Diabetes (particularly acute porphyrias)
  • Guillain-Barré syndrome (an autoimmune (the immune system attacks the body in these conditions) condition that causes the destruction of the nerves of the body, it presents with ascending (going upwards in the body, starts at the feet and works its way up) paralysis, peripheral neuropathy (e.g. tingling, numbness, pain, etc. in the parts of the body who’s nerves are affected), etc.)
  • Systemic lupus erythematosus (SLE), a systemic autoimmune condition16


The management of porphyrias varies greatly between the two divisions and hence they shall be mentioned in this document separately.

Acute Porphyrias

Acute Attacks

During acute attacks the acute porphyrias are treated via a number of different ways, often in combination, that depend ultimately on the severity and symptoms of the attack. They are universally treated by identification and removal of the offending agent (i.e. the thing that triggered the attack), and, often, also with a glucose (sugar water) intravenous (into the vein via a needle) infusion. This is because porphyrin synthesis is inhibited by carbohydrates. If the attack is severe and life-threatening enough and it is worth the risk of adverse effects, sometimes patients are given intravenous haemin, which is basically a form of haem. Its purpose in the treatment of acute attacks is that it, among other things conducive to the treatment of acute attacks inhibits the enzyme ALA synthase hence preventing the formation of porphyrins right at their source.2

Symptomatic relief (i.e. treatment of the symptoms) is usually attempted with nausea being treated with the antiemetic drug ondansetron (ZOFRAN), metoclopramide (MAXOLON) and other “safe” antiemetics, pain is usually managed with opioids like morphine or pethidine, seizures are often managed with anticonvulsant drugs that are safe in acute porphyrias (e.g. lorazepam, diazepam [VALIUM] and gabapentin), hypertension and tachycardia being treated with beta blockers (drugs that interfere with noradrenaline binding to its receptors) such as propranolol and pindolol, constipation can be treated with laxatives, or, in laxative-resistant cases of suspected paralytic ileus with acetylcholinesterase inhibitors like neostigmine, pyridostigmine or donepezil due to their excitatory effects on the parasympathetic division of the autonomous nervous system. These medications may also help with the confusion that sometimes accompanies attacks.2

Chronic Management

To prevent future attacks most patients are advised to avoid known triggers, even triggers that have not triggered an attack for them yet. A high carbohydrate diet is often useful in the management of the porphyrias, and if weight loss is desired usually it is done under the supervision of a dietician in order to prevent the new diet from triggering acute attacks. Female patients with acute porphyrias sometimes develop attacks premenstrually and hence drugs that inhibit the menstrual cycle such as oral contraceptives may be helpful in these patients. Abstaining from alcohol is often recommended to prevent future attacks. The drug cimetidine, which is usually used in the management of stomach ulcer disease has been investigated as a potential preventative medication. Patients with acute porphyrias that are known to cause cutaneous manifestations are also advised to avoid sun exposure.2

It is also known that hepatic porphyrias can be cured with a liver transplant and since hepatocellular carcinoma is more common in acute porphyria patients this curative measure has been attempted in some instances. Doctors are unlikely to perform a transplant, however, unless it is the only viable option since liver transplantation in itself is life-threatening.2

Cutaneous Porphyrias

The treatment of cutaneous porphyria is mostly symptomatic and preventative. That is patients are recommended to avoid their trigger, that is, sunlight. Cutaneous porphyrias are often additionally treated with β-carotene, which is found in carrots its purpose is to absorb the free radicals generated when the porphyrins near their skin are exposed to light. Two drugs used in the treatment of malaria, chloroquine and hydroxychloroquine, can also be used to treat cutaneous porphyrias due to their ability to bind to hepatic porphyrins so that the body can excrete them in urine.5


Acetylcholinesterase inhibitor – drugs that inhibit the enzyme acetylcholinesterase (AChE). AChE degrades (converts to biologically less active compounds) the neurotransmitter, acetylcholine, and hence AChE inhibitors elevate the concentrations of acetylcholine in the body, leading to heightened activity of the parasympathetic branch of the autonomic nervous system.
Allele – an alternate form of the same gene.

Autonomous nervous system –The autonomous nervous system controls the body’s involuntary movements like heart rate, the movement of food through the gastrointestinal (digestive) tract, the expulsion of sweat onto the surface of the skin, salivation, the contraction and dilation of the bronchial passages of the lungs, etc. It is further divided into the sympathetic (fight or flight) and parasympathetic divisions (or the rest and digest division).
The sympathetic nervous system involves things that occur pretty much instantly, like changes in heart rate, changes in blood pressure, and even the formation of goose bumps. The neurotransmitters (chemical messengers) of the sympathetic nervous system include adrenaline and noradrenaline. The parasympathetic branch, however, controls the more gradual involuntary movements like that of the gastrointestinal tract, urination, tears secretion, saliva secretion, defecation, etc. (I know that there can be confusion here seeing how urination and defecation is a voluntary action but there are also many involuntary components to it if you go into it). The neurotransmitter of the parasympathetic nervous system is acetylcholine.
The two branches of the autonomous nervous system are actually, usually, in opposition to each other. An increase in the activity of the parasympathetic nervous system leads to a decrease in the activity of the sympathetic nervous system.

Chromosome -- every animal has two copies of each chromosome (on which are contained each individual gene which regulates the formation of proteins like those that lead to the formation of skin), aside from the sex chromosomes (the X and Y chromosomes) of which females get two X’s and males get one X and one Y. These non-sex chromosomes are called autosomes. Sex chromosomes are also called allosomes. You get half your autosomes from your mum, half from your dad. You also get one X chromosome from your mum and if you are a female you also get one X chromosome from your dad and if you are male you get a Y chromosome from your dad.

Dominance – genes are either recessive or dominant. If an organism has even one copy of a particular dominant gene they will exhibit the characteristics that dominant gene confers. An example is black and blonde hair. The gene that encodes black hair is dominant over the gene that encodes blonde hair and hence if a blonde guy and a black haired-woman has a child the child will be black haired, assuming the woman is homozygous (i.e. has two copies of the gene) for the black hair gene. Someone with a copy of a recessive gene on the other hand will only exhibit the characteristics of the gene if they are homozygous for the aforementioned gene.

Emesis – nausea and vomiting. Hence antiemetics are nausea- and vomiting-treating agents
Generalised Anxiety Disorder (GAD) – an anxiety disorder characterised by excessive, disproportionate and irrational worry over everyday things.

Heterozygous – every animal has two copies of each autosome. If a creature is heterozygous for a particular gene that lies on one of these autosomes this means that only one of these two identical chromosomes has the aforementioned gene. Additionally, females can be heterozygous for a particular gene found on the X chromosome since they have two copies of the X chromosome.

Homozygous – this is when, instead of having one copy of a gene found on a particular chromosome one has two copies of the same gene from identical locations on the same chromosome.

Reference List

  1. Billoo AG, Lone SW. A family with acute intermittent porphyria. J Coll Physicians Surg Pak. 2008 May;18(5):316–8. Available from: http://ecommons.aku.edu/cgi/viewcontent.cgi?article=1011&context=pakistan_fhs_mc_women_childhealth_paediatr
  2. Frye RE, Coppes MJ, DeLoughery TG, et al. Acute Porphyria [Internet]. 2012 [cited 2013 Jul 1]. Available from: http://emedicine.medscape.com/article/957604
  3. Porphyria [Internet]. 2013 [cited 2013 Jul 1]. Available from: http://ghr.nlm.nih.gov/condition/porphyria
  4. Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ [Internet]. 2000 Jun 17 [cited 2013 Jul 1];320(7250):1647–51. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1127427/
  5. Kanwar VS, Arceci RJ, DeLoughery TG, Frye RE, Adams DJ, Sarnaik SA, et al. Cutaneous Porphyria. 2012 Sep 28 [cited 2013 Jul 2]; Available from: http://emedicine.medscape.com/article/957765
  6. Rufenacht UB, Gouya L, Schneider-Yin X, Puy H, Schafer BW, Aquaron R, et al. Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria. Am J Hum Genet [Internet]. 1998 Jun [cited 2013 Jul 1];62(6):1341–52. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1377149/
  7. Reynolds NC, Berman SA, Neumeyer AM, et al. Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias. 2012 Jun 17 [cited 2013 Jul 1]; Available from: http://emedicine.medscape.com/article/1148341-overview#a0199
  8. Solis C, Martinez-Bermejo A, Naidich TP, Kaufmann WE, Astrin KH, Bishop DF, et al. Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch. Neurol. [Internet]. 2004 Nov;61(11):1764–70. Available from: http://dx.doi.org/10.1001/archneur.61.11.1764
  9. Whatley SD, Badminton MN. Acute Intermittent Porphyria. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013 [cited 2013 Jul 1]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1193/
  10. Aminolevulinic Acid Dehydratase Porphyria (ADP) [Internet]. Rare Diseases Clinical Research Network. [cited 2013 Jul 1]. Available from: http://rarediseasesnetwork.epi.usf.edu/porphyrias/patients/ADP/
  11. Poblete-Gutiérrez P, Wiederholt T, Martinez-Mir A, Merk HF, Connor JM, Christiano AM, et al. Demystification of Chester porphyria: a nonsense mutation in the Porphobilinogen Deaminase gene. Physiol Res. 2006;55 Suppl 2:S137–144. Available from: http://www.biomed.cas.cz/physiolres/pdf/55%20Suppl%202/55_S137.pdf
  12. Schmitt C, Gouya L, Malonova E, Lamoril J, Camadro J-M, Flamme M, et al. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum. Mol. Genet. [Internet]. 2005 Oct 15 [cited 2013 Jul 1];14(20):3089–98. Available from: http://hmg.oxfordjournals.org/content/14/20/3089
  13. Poh-Fitzpatrick MB, Elston DM, Vinson RP, et al. Variegate Porphyria. 2013 Feb 13 [cited 2013 Jul 1]; Available from: http://emedicine.medscape.com/article/1103846-overview#showall
  14. Patience DA, Blackwood DHR, McColl KEL, Moore MR. Acute intermittent porphyria and mental illness – a family study. Acta Psychiatrica Scandinavica [Internet]. 1994 [cited 2013 Jul 1];89(4):262–7. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0447.1994.tb01511.x/abstract
  15. Millward LM, Kelly P, King A, Peters TJ. Anxiety and depression in the acute porphyrias. Journal of Inherited Metabolic Disease [Internet]. 2005 [cited 2013 Jul 2];28(6):1099–107. Available from: http://dx.doi.org/10.1007/s10545-005-4561-1
  16. Filiotou A, Vaiopoulos G, Capsimali V, Stavrianeas N, Kaloterakis A. Acute intermittent porphyria and systemic lupus erythematosus: report of a case and review of the literature. Lupus [Internet]. 2002 Mar 1 [cited 2013 Jul 2];11(3):190–2. Available from: http://lup.sagepub.com/content/11/3/190

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