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Chronic skin lesions of EPP

Image: “ Chronic skin lesions of EPP” by M Lecha, H Puy, JC Deybach. License: CC BY-SA 2.0


Definition

Porphyria is a condition characterized by a defective heme synthesis pathway due to some enzyme defects, resulting in a clinical syndrome involving the skin, nervous system, and liver at individual levels or cumulatively. Heme production is considered to be a multi-level process controlled by various enzymes.

The Locations of the Heme Synthesis

The heme is a porphyrin-containing compound that is synthesized in the human body in 8 steps. In 2 organ systems of the human body, the heme synthesis occurs independently from each other, such that 1 speaks of heme pools here:

  • The erythropoietic heme pool is formed in the bone marrow and is used in the series of hemoglobin synthesis for the erythrocytes.
  • The hepatic heme pool is formed in the liver and is used for the synthesis of hepatic enzymes that contain a heme. Here it is mainly about the cytochrome P450 enzymes.

From the localization of the essential expression of the affected enzyme, it results in the classification of porphyria into erythropoietic and hepatic porphyria. Hepatic porphyrias are much more common than erythropoietic.

Image: “Heme synthesis” by Wmheric. License: CC BY-SA 3.0

The Pathogenesis of Porphyria

All porphyrias have a similarity in the pathogenesis, that an enzyme of the biosynthesis of the heme is impaired in its activity by a genetic defect. This results in an accumulation of the substrate of the affected enzyme. These intermediates can cause various kinds of organ damage and symptoms in increased concentrations. In addition, there is an increased excretion through the urine and stool. The allocation of the affected enzyme and type of porphyria following the steps of the heme synthesis is listed here:

Defective enzyme Form of porphyria
δ -aminolevulinic acid synthase 2 X-chromosomal protoporphyria
δ -aminolevulinic acid dehydratase Doss porphyria
Porphobilinogen deaminase Acute intermittent porphyria (AIP)
Uroporphyrinogen 3 synthase M Gunther
Uroporphyrinogen decarboxylase Porphyria cutanea tarda
Coproporphyrinogen oxidase Hereditary coproporphyria
Protoporphyrinogen oxidase Porphyria variegata
Ferrochelatase Erythropoietic protoporphyria

Epidemiology

  • The incidence rate of porphyria is almost the same all over the world; that is 5 cases/100,000 population. The incidence of symptoms of porphyria in Europe is 0.13–0.51 cases per million per year.
  • The estimated risk of porphyria in Europe is 4%.

The Classification of Porphyrias

The clinical classification of porphyrias depends upon the pattern of involvement of the organ.

The various types of porphyria are distinguished as follows. Generally, chronic forms show increased skin manifestations, whereas acute porphyria causes more systemic complaints. The most common forms are the porphyria cutanea tarda (PCT), the acute intermittent porphyria (AIP) and the erythropoietic protoporphyria (EPP). Other forms such as the Doss-porphyria for instance, are extremely seldom.

  1. Erythropoietic porphyria
  • Congenital erythropoietic porphyria (also: M. Gunther, autosomal recessive)
  • Erythropoietic protoporphyria (autosomal dominant)
Photograph showing presence of lesions and scars on both hands of patient with congenital porphyria

Image: “Photograph showing the presence of lesions and scars on both hands of a patient with congenital porphyria” License: CC BY 2.0

  1. Hepatic porphyria
  2. Acute hepatic porphyria
  • Acute intermittent porphyria (autosomal dominant).
  • Hereditary coproporphyria (autosomal dominant).
  • Porphyria variegata (autosomal dominant).
  • Doss porphyria (autosomal recessive).
  1. Chronic hepatic porphyria

Note: The porphyria variegata is an acute, autosomal dominant inherited form of the porphyria and occurs with a significantly higher prevalence in the white population of South Africa. It is therefore also called South African genetic porphyria.

Clinical manifestations vary according to the level of metabolism affected. If enzyme defects are at the initial stage of the metabolism, then the neurological region is mainly affected. If defects occur there at the final stages, then cutaneous involvement is there.

Clinical features

Some common signs and symptoms of porphyria are as follows:

  • Acute colicky abdominal pain in the left lower abdomen which lasts for hours to days. The pain is rarely accompanied by fever, leukocytosis, or peritonitis. There is a considerable discrepancy between a patient’s clinical presentation of pain and objective findings.
  • Nausea and vomiting
  • Muscular weakness
  • Limb pain
  • Quadriplegia
  • Psychiatric symptoms like psychosis
  • Anxiety
  • Skin rash
  • Blisters on sun-exposed areas
  • Red-brown colored urine

 Diagnosis

  • The diagnosis is made on the basis of a typical presentation of signs and symptoms in the absence of other obvious causes and urine examination. On urine examination, it is found that excretion of porphobilinogen (PBG) is increased 5–100 times.

The Porphyria Cutanea Tarda (PCT)

Etiology and pathogenesis of the PCT

The most common porphyria is the porphyria cutanea tarda with an incidence of about 15/100,000, which is based on a decrease in the activity of the uroporphyrinogen decarboxylase (URO-D). In this case, it is about a chronic, hepatic porphyria. This progressive form can occur either as autosomal dominant hereditary or acquired; the peak incidence occurs after the age of 40. The acquired form results from a deficiency of the enzyme from liver damage. The transition of a latent PCT inherited from chromosome 1 in the manifest form, is often triggered by alcohol abuse, estrogens or infection, often with hepatitis C.

Note: With 70% of all cases, alcohol is the most common cause of a manifest porphyria cutanea tarda.

The symptoms of PCT

The most noticeable symptom of porphyria cutanea tarda is certainly the photodermatosis. The skin is extremely light-sensitive and responds to exposure with blistering and delayed healing. Scars on the face and at the back of the hands can often be found. Similarly, patients show increased hair growth (hypertrichosis) and hyperpigmentation. The skin manifestation of the PCT can be presumed without a prophylaxis disfiguring extent.

Erosions, crust, and blisters are evident on the hands of this patient with PCT

Image: ‘Erosions, crust, and blisters are evident on the hands of this patient with PCT’, License: CC BY 2.5

In addition, the porphyrin deposits cause progressive liver damage with pathologically elevated liver function values up to the sonographically detectable nodules. A characteristic symptom is dark-colored urine by porphyrins. This is referred to as porphyrinuria.

Note: The most common localizations of skin damage caused by PCT are on the back of the hand, on the face, and on the neck.

Diagnosis and treatment of the PCT

The diagnosis arises on the basis of anamnesis and symptoms, dark red or brownish discolored urine, a proven porphyrinuria and possibly a liver biopsy can be detected in the metabolites by fluorescence.

There is no causal treatment. The treatment primarily consists of the avoidance of triggering noxae and consistent avoidance of light exposure. Repeated bloodletting can provide recovery through a decreased erythrocyte count.

In addition, medicamentous can be treated with chloroquine, which makes porphyrins complexed and renally excretable. In the case of consistent protection from light exposure with clothing and sunscreen and avoidance of triggering noxae, a good prognosis exists for patients with porphyria cutanea tarda, which is determined by the extent of the liver damage.

The acute intermittent porphyria (AIP)

Etiology and pathogenesis of AIP

The 2nd most common form of porphyria is the acute intermittent porphyria (AIP). It is counted as the acute hepatic porphyria and has its peak incidence in the 3rd decade of life. It has been shown that only about 10% of the autosomal dominant inherited genetic defects turn into a manifest porphyria. On the other hand, about a quarter of unrelated patients show de novo mutations. The affected enzyme is porphobilinogen deaminase with increase in the preceding intermediates: porphobilinogen, δ-aminolevulinic acid, and porphyrins. The genetic defect is located at various points of the gene on chromosome 11.

Apart from stress, infections, and hypoglycemia, a variety of medications in particular and other porphyrinogenic substances, are triggers of an acute manifestation, in this form. These include alcohol, metoclopramide, furosemide, diclofenac, Angiotensin-converting enzyme (ACE) Has inhibitors, statins and many anesthetics such as barbiturates, among others.

The symptoms of the AIP

An acute porphyria syndrome is very diverse from the clinical presentation and often results in misdiagnoses. Leading the way are 3 main symptoms and the frequent association with intake of medication.

Abdominal discomfort with colicky pain and vomiting are key symptoms of the AIP. In the case of acute abdominal pain with fever, the suspicion of appendicitis is obvious. An appendectomy scar is thus often found amongst porphyria patients.

Note: The cases of acute porphyria are often primarily treated surgically; thereby, anesthesia poses a great risk for the patients.

Neurological-psychiatric symptoms of AIP are diverse and can occur in the form of peripheral nerve palsies, neuralgic pains, paresthesias, epilepsies, resentment, and psychoses. The triad of cardiovascular symptoms, especially tachycardia and hypertension is completed. The acute intermittent porphyria is not associated with increased photosensitivity.

Note: In the case of the triad of abdominal pain, neurological-psychiatric symptoms, and tachycardia, one should always think about the differential diagnosis of porphyria!

Diagnosis and treatment of the AIP

Darkend urine after 3 days of light exposure

Image: “Darkend urine after 3 days of light exposure” License: CC BY 3.0

Even in this form, the anamnesis and symptoms are leading the way in the diagnosis, especially in the presence of the typical triad. In an acute episode, metabolites, such as porphobilinogen and δ-aminolevulinic acid, can be detected in the blood and urine. Often, one will also find discolored urine, which gets discolored to dark red between acute attacks in 50% of cases with prolonged standing. Porphobilinogen can also be detected in stool.

Genetic tests are possible to confirm the diagnosis and determine the mutation. The discontinuation of possible causative medication is therapeutically the top priority. Education of the patients about the possible triggers is very important here. In order to treat the symptoms, one resorts to harmless medicines such as beta-blockers and paracetamol. A current list of medications classified as safe can be found on the Internet. Subsequently, the heme synthesis can be curbed with glucose and heme arginate over the δ-aminolevulinic acid dehydratase. The use of heme arginate is also possible for relapse prevention. A measure of the last choice is liver transplantation.

Secondary Porphyria

Secondary, i.e. acquired porphyria can have various causes. Progressive hepatocellular damage can, for example, imitate the image of porphyria cutanea tarda through decreased enzyme activity. Blood diseases, infections, and intoxications continue to be a probable cause. An important differential diagnosis of the AIP is chronic lead poisoning. The lead inhibits the δ-aminolevulinic acid dehydratase and the ferrochelatase of the heme synthesis and, in this way, leads to the accumulation of aminolevulinic acid and porphyrins, which can also be detected in the urine. A test should be done for the diagnosis of lead in the blood.

Iron transport and storage

  • Iron is a limiting micro-nutrient.
  • Needed for heme, enzymes, electron transport, and oxygen transport.
  • Can gain or lose electrons, depending on the oxidative state.
  • Very reactive and toxic to cells.
  • Can create radicals with the review of systems (ROS) in the cell via the Fenton reaction

  • Uptake into body tightly controlled — no regulated means of excretion.
  • Hemochromatosis occurs with an unregulated uptake of iron — genetic cause.
  • Most common among the Irish and Norwegians.
  • Iron storage in cells is very carefully regulated.
Primary — genetic cause (0.6% of the population) Secondary — acquired
Cirrhosis of liver
Diabetes — deposition of iron in pancreas cells
Cardiomyopathy
Arthritis

Complications of porphyria

Long-term complications of porphyria include:

  • Chronic hypertension
  • Chronic kidney dysfunction
  • Chronic pain syndrome
  • Hepatocellular carcinoma

Prognosis of porphyria

  • Repeated attacks of porphyria are associated with paresis.
  • Erythropoietic porphyria is a severely crippling and painful disease impacting the quality of life. It may lead to hepatocellular carcinoma.
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