Porphyrias, Porphyrins, Porphobilinogen
Sample for Porphyrias
- Collect fresh urine.
- Random urine can be used.
- Protect the sample from light.
- Add 5 g Na2CO3.
- Store the sample at 4 to 8 °C.
Purpose of the test (Indications) for Porphyrias
- This test will quantitate porphyrins and porphobilinogen.
- This can be used to find various forms of porphyria.
Definition of Porphyrias
- Acute porphyrias are inherited disorders of heme synthesis characterized by an acute attack of neurovisceral symptoms.
- It is life-threatening and diagnosed by a raised level of porphobilinogen in the urine.
- A partial deficiency of the heme biosynthesis enzymes will lead to the increased formation and excretion of porphyrins, their precursors, or both.
- Porphyrias are a group of disorders characterized by a deficiency of or defect in the enzymes involved in porphyrin metabolism and heme synthesis.
- Porphyrias are a group of inherited metabolic diseases caused by defects in heme synthesis.
- Porphyrias are diagnosed by the pattern of porphyrins and their metabolites in urine, stool, plasma, and RBCs.
- It is diagnosed by measuring deficient enzymes and genetic analysis.
- >80% of heterozygotes are asymptomatic.
Pathophysiology of Porphyrias
- The term “porphyria” is derived from the Greek word porphyria, meaning “purple pigment.”
- Porphyria is a group of disorders that result in an accumulation of chemicals called porphyrins in the body.
- This is a group of genetic abnormalities with associated enzyme deficiency involved in the porphyrin synthesis or metabolism.’
- The porphyrins are building blocks in the synthesis of heme.
- Porphyrins are a byproduct of heme synthesis.
- There is overproduction of the intermediates of the pathway.
- These intermediates are excreted in the urine, feces, or both.
- The excess of porphyrins precursors is associated with potentially fatal acute neurovisceral attacks like:
- 5-aminolevulinic acid (ALA).
- Porphobilinogen (PBG).
- Initiating the acute attack of porphyrias are the following:
- There is a deficiency of the various enzymes in the synthesis of heme. Some of the examples are:
- 5-Aminolevulinate synthase.
- 5-Aminolevulinic acid dehydratase.
- Hydroxymethylbilane synthase.
- Uroporphyrinogen-III synthase.
- Uroporphyrinogen Decarboxylase.
- Coproporphyrinogen Oxidase.
- Protoporphyrinogen Oxidase.
Mechanism of toxic action of porphyrias:
- Porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, respiratory, and P450 liver cytochromes.
- Accumulation of porphyrins, the heme precursors, is toxic to tissue in high concentrations.
- The primary porphyrins of RBC are :
- The primary porphyrins of RBC are :
- Then heme combines with globin in the RBC, and hemoglobin is formed.
- Porphyrias are classified according to the location of the accumulation of porphyrins and precursors.
- In most porphyrias, there is an increased level of porphyrins and porphobilinogen in the urine.
Classification of porphyrias:
- Symptomatically, acute porphyrias.
- Primarily present with nervous system involvement.
- Often with severe abdominal pain and vomiting.
- Neuropathy and mental disturbances.
- Cutaneous porphyrias present with :
- Skin manifestations often occur after exposure to the sun due to the accumulation of excess porphyrins near the skin’s surface.
The most common classification of porphyria:
- It is based on the accumulation of heme precursors in the liver or bone marrow and red blood cells.
- Hereditary Hepatic porphyria:
- These are subdivided into:
- A. Acute intermittent porphyria (Swedish genetic porphyria).
- B. Variegate porphyria.
- C. Hereditary porphyria.
- It has S/S of :
- All three types are inherited as autosomal dominant.
- All three may be associated with episodes of acute porphyric attacks.
- Acute neurological attacks (seizures, psychosis).
- Extreme back and abdominal pain.
- Acute polyneuropathy.
- These are subdivided into:
- Erythropoietic porphyria:
- It has S/S of :
- These are rare congenital disorders.
- Skin problems, usually a light-sensitive blistering rash and increased hair growth.
- There is no skin vesicle formation.
- There is discoloration of the teeth that fluoresce under ultraviolet light.
- There may, in some cases, mild hemolytic anemia.
- Diagnosis: The best test is RBC porphyrin measurement.
- Porphyria cutanea tarda shows the following signs and symptoms :
- Photosensitivity of eyes and skin.
- Mixed porphyria.
- Acquired toxic porphyria.
Clinical classification of Porphyrias:
- Porphyria that produces skin manifestation without the presence of neurological symptoms are:
- Porphyria cutanea tarda.
- Congenital erythropoietic porphyria.
- Erythropoietic porphyria.
- Porphyria that is manifested by neurological symptoms (cutaneous symptoms are absent) are:
- Acute intermittent porphyria.
- Porphyria that has both cutaneous and neurological manifestations are:
- Hereditary coproporphyria.
- Variegate porphyria.
Another classification of Porphyrias according to symptoms:
- Neurologic only.
- Cutaneous only.
- Both neurologic and cutaneous types.
Excretion of Porphyrins:
- Aminolevulinic acid and porphobilinogens are excreted in the urine.
- Uroporphyrins are also excreted in the urine; a minimal amount is excreted in the feces.
- Most coproporphyrins are eliminated in the feces, and a small amount is in the urine.
- Protoporphyrins are eliminated through bile; the average fecal content is 1 mg/day.
- Coproporphyrins’ urinary excretion increases in obstructive jaundice, liver diseases, lead poisoning, and hemolytic anemias.
|Acute Intermittent Porphyria||Porphobilinogen||Hydroxymethylbilane synthase|
|Porphyria Cutanea Tarda||Uroporphyrinogen III||Uroporphyrinogen decarboxylase|
|Hereditary coproporphyria||Coproporphyrinogen III||Coproporphyrinogen Oxidase|
Signs and Symptoms of Porphyrins:
- The following factors may initiate an acute attack:
- Some of the drugs.
- Smoking may initiate the attack.
- Use of alcohol.
- By some surgical procedures.
- Emotional upset.
- In females by the menstrual cycle.
- In females during pregnancy.
- Sometimes an infection may give rise to an attack.
- The acute attack may start with anxiety, restlessness, and difficulty sleeping.
- The patient may develop a painful abdomen, and this may be very severe.
- There may be nausea and vomiting.
- The patient may develop constipation.
- There may be tachycardia and hypertension.
- Urine is dark or reddish.
- Rarely there may be sudden death, which may be due to cardiac arrhythmias.
- Fresh urine or 24 hours sample = Negative
- Spectrophotometric method (24 hours of urine)
- <2.0 mg/L
- <3.4 mg/day
- ≤2.0 mg/day
- To convert into SI unit x 4.42 = µmol/L
- Urine fresh random = Negative
- Total porphyrin (whole blood) = <60 µg/dL
- 20 to 320 nmol/L (urine)
Uroporphyrin fraction = <33 µg/24 hours urine
= 17 to 52 µg/24 hours urine
Coproporphyrins fraction = <183 µg/24 hours urine
= <294 µg/24 hours urine
= 52 to 163 µg/24 hours urine
Urine 24 hours or fresh:
- Negative or trace.
- Total porphyrin:
- Male = 8 to 149 mcg/24 hours of the urine
- Female = 3 to 78 mcg/24 hours of the urine
- Male = 4 to 46 mcg/24 hours of urine
- Female = 3 to 22 mcg/24 hours of the urine
- Male = <96 mcg/24 hours of the urine
- Female = <60 mcg/24 hours of the urine
- Porphobilinogen = 0 to 2 mg /24 hours of the urine
- another source <1 mg/24 hours of the urine
- δ-Aminolevulinic acid = 1.5 to 7.5 mg/day of the urine
- Random specimen = 0 to 2.0 mg/L
- 24-hour sample = 0 to 1.5 mg/24 hours
- Δ-aminolevulinic acid
- Random specimen = 0. to 4.5 mg/L
- 24-hour specimen = 1.5 to 7.5 mg/24 hours
|Test||µg/24 hours Urine|
|Uroporphyrin||8 to 44||4 to 22|
|Coproporphyrin||10 to 109||3 to 56|
|Heptacarboxyporphyrin||0 to 12||0 to 9|
|Pentacarboxy porphyrin||0 to 4||o to 3|
|Hexacarboxyporphyrin||0 to 5||0 to 5|
Diagnosis of Porphyrins:
- A urine sample is not as accurate as the plasma concentration.
- Urine is suitable as a screening test for porphyria.
Treatment of Porphyrins:
- Treat to relieve the symptoms.
- Drug-like heme arginate is given to stop the process.
Questions and answers:
Question 1: What is the mechanism of toxic injury in porphyrias?
The toxic injury is due to intermediate products of heme synthesis.
Question 2: How you will diagnose porphyrias?
Urine sample is best to diagnose porphyria's.