Porphyrias

What sample is used to diagnose Porphyrias?

1. Collect fresh urine.
2. Random urine can be used.
3. Protect the sample from light.
   1. Add 5 g Na₂CO₃.
4. Store the sample at 4 to 8 °C.

What are the Indications for Porphyrias?

1. This test will quantify porphyrins and porphobilinogen.
2. This can be used to find various forms of porphyria.

How will you define Porphyrias?

1. Acute porphyrias are inherited disorders of heme synthesis characterized by an acute attack of neurovisceral symptoms.
   1. It is life-threatening and diagnosed by a raised level of porphobilinogen in the urine.
   2. A partial deficiency of the heme biosynthesis enzymes will increase the formation and excretion of porphyrins, their precursors, or both.
2. Porphyrias are a group of disorders characterized by a deficiency of or defect in the enzymes involved in porphyrin metabolism and heme synthesis.
3. Porphyrias are a group of inherited metabolic diseases caused by defects in heme synthesis.
4. What are the types of porphyrins?
   1. Uroporphyrin.
   2. Coproporphyrin.
   3. Protoporphyrin.
5. Porphyrias are diagnosed by the pattern of porphyrins and their metabolites in urine, stool, plasma, and RBCs by:
   1. Plasma fluorescence screening.
   2. Measuring deficient enzyme.
   3. Genetic testing.
6. >80% of heterozygotes are asymptomatic.

How will you discuss the Pathophysiology of Porphyrias?

1. The term “porphyria” is derived from the Greek word porphyria, meaning “purple pigment.”
2. Porphyria is a group of disorders that result in an accumulation of chemicals called porphyrins in the body.
3. This is a group of genetic abnormalities with associated enzyme deficiency involved in the porphyrin synthesis or metabolism.’
4. The porphyrins are building blocks in the synthesis of heme.
   1. Porphyrins are a byproduct of heme synthesis.
5. There is overproduction of the intermediates of the pathway.
6. These intermediates are excreted in the urine, feces, or both.
7. The excess of porphyrins precursors is associated with potentially fatal acute neurovisceral attacks like:
   1. 5-aminolevulinic acid (ALA).
   2. Porphobilinogen (PBG).
8. Initiating the acute attack of porphyrias are the following:
   1. Drugs.
   2. Alcohol.
   3. Starvation.
   4. Hormones.
   5. Infections.
   6. Stress.

1. There is a deficiency of the various enzymes in the synthesis of heme. Some of the examples are:
   1. 5-Aminolevulinate synthase.
   2. 5-Aminolevulinic acid dehydratase.
   3. Hydroxymethylbilane synthase.
   4. Uroporphyrinogen-III synthase deficiency leads to Erythropoietic porphyria.
   5. Uroporphyrinogen Decarboxylase deficiency leads to Porphyria cutanea tarda.
   6. Coproporphyrinogen Oxidase deficiency leads to Hereditary coproporphyria.
   7. Protoporphyrinogen dehydrogenase deficiency leads to Variegated porphyria.
   8. Ferrochelatase leads to Erythropoietic protoporphyria.

What is the mechanism of the toxic action of porphyrias?

1. Porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, respiratory, and P450 liver cytochromes.
2. Accumulation of porphyrins, the heme precursors, is toxic to tissue in high concentrations.
   1. The primary porphyrins of RBC are :
      1. Protoporphyrin.
      2. Uroporphyrin.
      3. Coproporphyrin.

3. Then, heme combines with globin in the RBC, and hemoglobin is formed.
4. Porphyrias are classified according to the location of the accumulation of porphyrins and precursors.
5. In most porphyrias, there is an increased level of porphyrins and porphobilinogen in the urine.

How will you classify porphyrias?

1. Symptomatically, acute porphyrias.
   1. Primarily present with nervous system involvement.
   2. Often with severe abdominal pain and vomiting.
   3. Neuropathy and mental disturbances.
2. Cutaneous porphyrias present with :
   1. 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:

1. It is based on the accumulation of heme precursors in the liver or bone marrow and red blood cells.
2. Hereditary Hepatic porphyria:
   1. These are subdivided into:
      1. A. Acute intermittent porphyria (Swedish genetic porphyria).
      2. B. Variegate porphyria.
      3. C. Hereditary porphyria.
   2. It has S/S of :
      1. All three types are inherited as autosomal dominant.
      2. All three may be associated with episodes of acute porphyric attacks.
      3. Acute neurological attacks (seizures, psychosis).
      4. Extreme back and abdominal pain.
      5. Acute polyneuropathy.
3. Erythropoietic porphyria:
   1. 1. It has S/S of :
      2. These are rare congenital disorders.
      3. Skin problems, usually a light-sensitive blistering rash and increased hair growth.
      4. There is no skin vesicle formation.
      5. The teeth are discolored, and they fluoresce under ultraviolet light.
      6. There may, in some cases, mild hemolytic anemia.
      7. Diagnosis: The best test is RBC porphyrin measurement.
4. Porphyria cutanea tarda shows the following signs and symptoms :
   1. 1. Photosensitivity of eyes and skin.
5. Mixed porphyria.
6. Acquired toxic porphyria.

How will you clinically classify Porphyrias?

1. Porphyria that produces skin manifestation without the presence of neurological symptoms are:
   1. Porphyria cutanea tarda.
   2. Congenital erythropoietic porphyria.
   3. Erythropoietic porphyria.
2. Porphyria that is manifested by neurological symptoms (cutaneous symptoms are absent) are:
   1. Acute intermittent porphyria.
3. Porphyria that has both cutaneous and neurological manifestations are:
   1. Hereditary coproporphyria.
   2. Variegate porphyria.

How will you classify Porphyrias according to symptoms?

1. Neurologic only.
2. Cutaneous only.
3. Both neurologic and cutaneous types.

How is the excretion of Porphyrins?

1. Aminolevulinic acid and porphobilinogens are excreted in the urine.
2. Uroporphyrins are also excreted in the urine; a minimal amount is in the feces.
3. Most coproporphyrins are eliminated in the feces, and a small amount is in the urine.
4. Protoporphyrins are eliminated through bile; the average fecal content is 1 mg/day.
5. Coproporphyrins’ urinary excretion increases in obstructive jaundice, liver diseases, lead poisoning, and hemolytic anemias.

What are the signs and symptoms of Porphyrins?

1. The following factors may initiate an acute attack:
   1. Some of the drugs.
   2. Smoking may initiate the attack.
   3. Use of alcohol.
   4. By some surgical procedures.
   5. Emotional upset.
   6. In females by the menstrual cycle.
   7. In females during pregnancy.
   8. Sometimes, an infection may give rise to an attack.
   9. The acute attack may start with anxiety, restlessness, and difficulty sleeping.
2. The patient may develop a painful abdomen, and this may be very severe.
3. There may be nausea and vomiting.
4. The patient may develop constipation.
5. There may be tachycardia and hypertension.
6. Urine is dark or reddish.
7. Rarely, there may be sudden death, which may be due to cardiac arrhythmias.

What are the normal values of Porphyria?

Source 1

Porphobilinogen

• 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

Porphyrins 

• Urine fresh random = Negative
• Total porphyrin (whole blood) = <60 µg/dL

Total porphyrins

• 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

Source 2

Urine 24 hours or fresh:

1. Negative or trace.
2. Total porphyrin:
   • Male = 8 to 149 mcg/24 hours of the urine
   • Female = 3 to 78 mcg/24 hours of the urine
3. Uroporphyrin:
   • Male = 4 to 46 mcg/24 hours of urine
   • Female = 3 to 22 mcg/24 hours of the urine
4. Coproporphyrin:
   • Male = <96 mcg/24 hours of the urine
   • Female = <60 mcg/24 hours of the urine
5. Porphobilinogen = 0 to 2 mg /24 hours of the urine
   1. another source <1 mg/24 hours of the urine
6. δ-Aminolevulinic acid = 1.5 to 7.5 mg/day of the urine

Source 4

• Porphobilinogen 
  • 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

Diagnosis of Porphyrins:

1. A urine sample is not as accurate as the plasma concentration.
   1. Urine is suitable as a screening test for porphyria.

Treatment of Porphyrins:

1. Treat to relieve the symptoms.
2. Drug-like heme arginate is given to stop the process.

Questions and answers: