Introduction:
Porphyrias are a group of inherited or acquired metabolic disorders caused by defects in the enzymes involved in heme (porphyrin) biosynthesis. These enzyme deficiencies lead to the accumulation and excessive excretion of porphyrins or their precursors in urine and feces.
Depending on the enzyme affected, porphyrins may accumulate in specific tissues such as the liver or bone marrow. The disease can be inherited (autosomal) or acquired due to exposure to certain drugs or toxins.
Classification of Porphyrias:
Porphyrias are classified into two main categories based on the primary site of enzyme deficiency:
- 1) Erythropoietic Porphyrias – affect the bone marrow and red blood cells.
- 2) Hepatic Porphyrias – affect the liver, where heme is synthesized.
Erythropoietic Porphyrias
- Congenital (or hereditary) erythropoietic porphyria
- Erythropoietic protoporphyria
Hepatic Porphyrias
- Acute intermittent porphyria (AIP)
- Variegate porphyria (VP)
- Hereditary coproporphyria (HCP)
- Porphyria cutanea tarda (PCT)
1) Congenital (or Hereditary) Erythropoietic Porphyria
This type of porphyria results from a deficiency of uroporphyrinogen III cosynthase. The deficiency causes accumulation and excretion of large amounts of uroporphyrinogen I and coproporphyrinogen I in urine.
High levels of uroporphyrin I in red blood cells lead to premature destruction (hemolysis). When the urine is left standing, it turns red due to oxidation of porphyrinogens to porphyrins.
Clinical symptoms include:
- Photosensitivity (skin sensitivity to sunlight)
- Pink-colored bones and teeth
- Hemolytic anemia
- Cutaneous lesions
2) Erythropoietic Protoporphyria
This disorder occurs due to partial deficiency of the enzyme ferrochelatase. As a result, protoporphyrin IX accumulates in red blood cells, plasma, and feces, while urine porphyrins remain normal.
Clinical symptoms:
- Severe photosensitivity (solar urticaria)
- Liver cirrhosis (in later stages)
- Anemia
3) Acute Intermittent Porphyria (AIP)
AIP is caused by a partial deficiency of the enzyme uroporphyrinogen I synthase. This results in the accumulation of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) in the liver and other tissues. These compounds are excreted in large amounts in the urine.
When exposed to air, the urine darkens because PBG and ALA polymerize to form porphobilin.
Clinical features:
- Severe abdominal pain and muscle spasms
- Neuropsychiatric symptoms (anxiety, depression, hallucinations)
- Hypertension and constipation
- No photosensitivity
Symptoms often appear after puberty and may be triggered by barbiturates, steroids, alcohol, or stress. The neurological effects are due to the toxicity of accumulated ALA and PBG on the nervous system.
4) Variegate Porphyria (VP)
This type is due to deficiency of the enzyme protoporphyrinogen oxidase. As a result, ALA synthase activity increases because of reduced heme feedback inhibition. Patients excrete large amounts of PBG, ALA, uroporphyrins, and coproporphyrins in urine and feces.
Clinical features:
- Photosensitivity (common and consistent symptom)
- Dark-colored urine due to porphyrin excretion
- Aggravation by alcohol and certain drugs
5) Hereditary Coproporphyria (HCP)
HCP occurs due to partial deficiency of coproporphyrinogen III oxidase. This defect leads to accumulation and excretion of coproporphyrinogen III in urine and feces. Urine may appear red upon exposure to light.
Symptoms include:
- Photosensitivity
- Abdominal pain and neuropsychiatric problems similar to AIP
6) Porphyria Cutanea Tarda (PCT)
PCT is caused by partial deficiency of uroporphyrinogen decarboxylase. This results in excessive excretion of uroporphyrin I and III in urine, which may appear pinkish or brown. PBG excretion may also increase.
Clinical features:
- Photosensitivity with skin blistering
- Occurs commonly in adults (ages 40–60)
- Liver damage, often associated with alcoholism or hepatitis
PCT is the most common type of porphyria.
Acquired (or Toxic) Porphyrias
Acquired porphyrias occur due to exposure to certain toxins, heavy metals, or drugs that inhibit enzymes of heme biosynthesis. Examples include lead, alcohol, and hexachlorobenzene.
Lead poisoning inhibits ALA dehydratase and heme synthase, leading to marked elevation of ALA in urine. Urinary porphyrin excretion can increase up to 10 mg per day.
Common causes:
- Exposure to lead (e.g., automobile exhaust, contaminated water)
- Drugs such as barbiturates, steroids, oral contraceptives, and pesticides
These toxins interfere with normal heme synthesis, leading to symptoms like abdominal pain, anemia, neurological issues, and dark-colored urine.
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