Purpurinuria, porphyrinuria (porphyrins in the urine)

Understanding Porphyrinuria and Porphyrins

Porphyrinuria refers to an increased excretion of porphyrins in the urine. Porphyrins are a group of organic, pigmented compounds that are essential precursors in the biosynthesis of heme. Heme is a crucial component of hemoglobin (the oxygen-carrying protein in red blood cells), myoglobin (oxygen storage in muscles), and various cytochromes (enzymes involved in electron transport and detoxification).

While some level of porphyrin excretion is normal, significantly elevated levels (porphyrinuria) can be a symptom of an underlying metabolic disorder known as **porphyria**, or it can occur secondary to other diseases, intoxications, or physiological states.

 

Definition and Physiology of Porphyrins

Porphyrins are intermediate compounds in the complex biochemical pathway of heme synthesis. This pathway involves a series of enzymatic steps, starting from simpler precursors like the amino acid glycine and succinyl-coenzyme A (a derivative of succinic acid from the Krebs cycle). The primary sites of porphyrin synthesis in the body are:

• Bone Marrow: For the formation of hemoglobin heme required for red blood cell production.
• Liver: For the synthesis of heme for various heme-containing enzymes (e.g., cytochrome P450 enzymes involved in drug metabolism), myoglobin (for muscle tissue), and heme for other tissues like myelin and bone.

Various types of porphyrins and their precursors exist, including uroporphyrins, coproporphyrins, protoporphyrins, porphobilinogen (PBG), and delta-aminolevulinic acid (ALA).

Normal Excretion and Porphyrinuria as a Symptom

Normally, only small amounts of certain porphyrins, primarily uro- and coproporphyrins, are excreted in the urine and feces. Increased excretion of porphyrins in the urine (porphyrinuria) is generally considered abnormal and indicates a disruption in heme metabolism or an increased load on the porphyrin pathway.

Porphyrinuria can occur in several contexts:

• Primary Porphyrinuria (Porphyrias): This is due to inherited or (rarely) acquired defects in the enzymes of the heme biosynthesis pathway. Each type of porphyria is characterized by the accumulation and excretion of specific porphyrins or their precursors.
• Secondary Porphyrinuria (Acquired Porphyrinuria): This is an increased excretion of porphyrins (usually coproporphyrin) that is not due to a primary genetic defect in heme synthesis but is a consequence of another underlying condition or exposure. Examples include:
  • Liver Disease: A healthy liver is able to metabolize and excrete porphyrin products (mainly copro- and protoporphyrins) into the feces via bile. When liver function is impaired (e.g., hepatitis, cirrhosis), this excretory pathway can be compromised. As a result, porphyrin metabolites may return to the bloodstream, be filtered by the kidneys, and excreted in increased quantities in the urine, leading to porphyrinuria.
  • Intoxications: Exposure to certain toxins, particularly heavy metals like lead (lead poisoning classically causes increased ALA and coproporphyrin excretion), arsenic, or organic solvents.
  • Cytostatic Therapy (Chemotherapy): Some cancer drugs can affect heme metabolism.
  • Infections: Certain severe infections.
  • Hematological Conditions:
    • Iron deficiency anemia (can sometimes cause mild coproporphyrinuria).
    • Hemolytic anemias (due to increased heme turnover).
    • Lymphogranulomatosis (Hodgkin's lymphoma).
    • Leukemia.
  • Alcohol Intake: Can induce or exacerbate some porphyrias and cause secondary coproporphyrinuria.
  • X-rays (High-Dose Radiation): Can potentially affect rapidly dividing cells, including those in the bone marrow involved in heme synthesis.
  • Physical Stress: Strenuous exercise.
  • Hemolysis of Erythrocytes or Myoglobinuria: Conditions leading to the release of large amounts of heme or heme precursors can increase porphyrin levels.

Conversely, with significant renal failure, the urinary excretion of porphyrins may decrease, even if their production is high, due to impaired kidney filtration.

Urinary excretion of **porphobilinogen (PBG)**, a porphyrin precursor, is a key diagnostic feature of acute porphyrias, particularly **Acute Intermittent Porphyria (AIP)**. Urine containing PBG (and often uroporphyrin) may appear normal initially but can darken to a reddish, pink, or port-wine color upon standing and exposure to light and air. AIP is an autosomal dominant disorder characterized by acute neurovisceral attacks, which can involve severe abdominal pain, peripheral and central nervous system dysfunction (e.g., neuropathy, weakness, paralysis, seizures, psychiatric symptoms). The heterozygous form of AIP often has a long latent course, with attacks triggered by factors like certain drugs, alcohol, fasting, or hormonal changes. The homozygous form (very rare) typically results in a severe, polysyndromic disease from an early age.

 

Causes of Porphyrinuria (Distinction between Porphyria and Secondary Porphyrinuria)

It's crucial to distinguish between primary porphyrias and secondary porphyrinuria.

 

Porphyrias (Inherited Disorders of Heme Synthesis)

Porphyrias are a group of mostly inherited metabolic disorders caused by specific enzyme deficiencies in the heme biosynthesis pathway. This leads to the accumulation and increased excretion of specific porphyrins or their precursors (ALA and PBG). Porphyrias are broadly classified as:

• Acute Porphyrias: Characterized by acute neurovisceral attacks. These include:
  • Acute Intermittent Porphyria (AIP) - *most common acute porphyria*
  • Variegate Porphyria (VP) - *can also have skin symptoms*
  • Hereditary Coproporphyria (HCP) - *can also have skin symptoms*
  • ALA Dehydratase Deficiency Porphyria (ALADP) - *very rare*
  In acute porphyrias, urinary excretion of ALA and PBG is typically markedly elevated during attacks, and porphyrins (uroporphyrin, coproporphyrin) may also be increased.
• Cutaneous Porphyrias: Characterized by photosensitivity and skin lesions due to porphyrin accumulation in the skin. These include:
  • Porphyria Cutanea Tarda (PCT) - *most common porphyria overall*
  • Erythropoietic Protoporphyria (EPP)
  • Congenital Erythropoietic Porphyria (CEP or Günther disease) - *very rare and severe*
  Urinary porphyrin patterns vary: PCT shows increased uroporphyrin and hepta/hexa/penta-carboxyl porphyrins. EPP primarily involves increased fecal and red blood cell protoporphyrin; urinary porphyrins are usually normal. CEP shows markedly increased urinary uroporphyrin I and coproporphyrin I.

 

Secondary Porphyrinuria (Acquired Causes)

As listed previously, various conditions can cause a non-specific increase in urinary porphyrin excretion (most commonly coproporphyrin III) without a primary defect in heme synthesis enzymes. These include liver disease, alcohol abuse, lead poisoning, iron deficiency, hemolytic anemias, infections, certain medications, and toxic exposures. In these cases, the porphyrinuria is a consequence of the underlying disorder affecting heme metabolism or excretion, or general cellular stress.

 

Clinical Manifestations Associated with Porphyrinuria and Porphyrias

Porphyrinuria itself is a laboratory finding. The clinical symptoms are those of the underlying condition causing it.

• Acute Porphyrias (e.g., AIP):
  • Severe, diffuse abdominal pain (often colicky).
  • Nausea, vomiting, constipation, or diarrhea.
  • Peripheral neuropathy (pain, weakness, paralysis).
  • Autonomic neuropathy (tachycardia, hypertension, sweating).
  • Central nervous system symptoms (anxiety, confusion, seizures, psychosis, coma).
  • Muscle weakness.
  • Dark reddish-brown urine (especially on standing).
• Cutaneous Porphyrias (e.g., PCT, EPP):
  • Photosensitivity: Skin fragility, blistering, erosions, scarring, hyperpigmentation, hypertrichosis in sun-exposed areas (PCT).
  • Acute painful photosensitivity with burning, itching, redness, swelling within minutes of sun exposure, often without visible blisters (EPP).
• Secondary Porphyrinuria: Symptoms are those of the primary disease (e.g., symptoms of liver disease, anemia, lead poisoning like abdominal colic, neuropathy, encephalopathy). The porphyrinuria itself is usually asymptomatic or a minor component.

 

Diagnosis of Porphyrinuria and Porphyrias

Diagnosis involves a stepwise approach:

1. Clinical Suspicion: Based on characteristic symptoms (e.g., acute neurovisceral attacks, photosensitivity, unexplained abdominal pain).
2. Screening Tests for Acute Porphyrias:
   • **Urinary Porphobilinogen (PBG) and Delta-Aminolevulinic Acid (ALA):** Markedly elevated PBG (and often ALA) in a random/spot urine sample is highly suggestive of an acute porphyria attack (AIP, VP, HCP). This is a critical first-line test. A qualitative Watson-Schwartz or Hoesch test for PBG can provide rapid screening, but quantitative measurement is preferred.
3. Quantitative Urinary Porphyrin Fractionation: Measurement of specific porphyrins (uroporphyrin, coproporphyrin, and their isomers; hepta-, hexa-, penta-carboxyl porphyrins) in a 24-hour or spot urine collection. This helps differentiate types of porphyria and detect secondary porphyrinuria.
4. Fecal Porphyrin Analysis: Important for diagnosing VP and HCP (which show elevated fecal protoporphyrin and coproporphyrin, respectively) and EPP (elevated fecal protoporphyrin).
5. Erythrocyte Porphyrin Analysis: Measurement of protoporphyrin in red blood cells is key for diagnosing EPP and CEP.
6. Enzyme Assays: Measurement of specific enzyme activities in red blood cells or fibroblasts can confirm the diagnosis of a particular porphyria by identifying the deficient enzyme.
7. Genetic Testing (DNA Analysis): Identifies specific mutations in the genes encoding the enzymes of the heme pathway. This is definitive for confirming inherited porphyrias and for family screening.
8. Tests for Secondary Causes: If secondary porphyrinuria is suspected, investigations for liver disease (LFTs), lead levels, iron studies, hemolytic screen, etc., are performed.

 

Management and Treatment Principles

Treatment depends on the type of porphyria or the cause of secondary porphyrinuria.

• Acute Porphyria Attacks (e.g., AIP):
  • This is a medical emergency requiring hospitalization.
  • Discontinuation of any precipitating drugs.
  • Intravenous hemin (heme arginate or hematin) administration to downregulate ALA synthase and reduce porphyrin precursor production.
  • High carbohydrate intake (oral or intravenous glucose) to suppress heme synthesis.
  • Pain management (opioids are often required).
  • Management of nausea, vomiting, seizures, hypertension, electrolyte imbalances.
  • Avoidance of known trigger medications in the future.
• Cutaneous Porphyrias:
  • PCT: Phlebotomy (regular blood removal) to reduce iron stores, and/or low-dose hydroxychloroquine or chloroquine. Strict sun avoidance and protective clothing/sunscreens. Avoid alcohol and estrogens.
  • EPP: Sun avoidance, protective clothing, beta-carotene, afamelanotide (synthetic alpha-MSH analogue) to increase melanin and sun tolerance. Liver protection is important.
  • CEP: Sun protection, blood transfusions for severe anemia, bone marrow transplantation in some cases.
• Secondary Porphyrinuria: Treatment is directed at the underlying cause (e.g., chelation therapy for lead poisoning, treatment of liver disease, correction of iron deficiency). The porphyrinuria usually resolves once the primary condition is managed.

 

Differential Diagnosis of Conditions Causing Porphyrinuria or Red/Dark Urine

Dark or reddish urine can have multiple causes, and porphyrinuria is just one possibility:

Condition/Substance	Urine Color	Key Diagnostic Tests for Differentiation
Porphyrias (Acute Attack or some Cutaneous types)	Red, pink, purple, dark brown (often darkens on standing/exposure to light)	Urinary PBG, ALA, porphyrin fractionation; fecal and erythrocyte porphyrins.
Hematuria (Blood in Urine)	Pink, red, brown, "cola-colored"; may have clots	Urinalysis (positive for blood, RBCs on microscopy).
Hemoglobinuria (Free Hemoglobin)	Red, brown, "cola-colored"	Urinalysis (positive for blood, few/no RBCs on microscopy), low serum haptoglobin, high plasma free Hb.
Myoglobinuria (Myoglobin)	Red, brown, "tea-colored"	Urinalysis (positive for blood, few/no RBCs), markedly elevated serum CK, urine myoglobin test. Plasma usually clear.
Bilirubinuria/Urobilinogenuria	Dark yellow, orange, brown, "tea-colored"	Urinalysis (positive for bilirubin, increased urobilinogen), liver function tests.
Medications	Variable (red, orange, brown, black) - e.g., rifampin, phenazopyridine, senna, metronidazole, levodopa	History of medication use. Urine typically negative for blood/porphyrins unless drug causes these.
Foods	Pink, red - e.g., beets, blackberries, rhubarb	Dietary history. Urine negative for blood/porphyrins.
Alkaptonuria (Homogentisic Acid)	Urine darkens to black on standing/alkalinization	Test for homogentisic acid.
Melanuria (Melanin - rare, with metastatic melanoma)	Urine darkens to brown/black on standing	Test for melanin/melanogens.

 

Complications and Prognosis

Complications depend on the type of porphyria or the cause of secondary porphyrinuria:

• Acute Porphyrias: Severe neurological damage (paralysis, respiratory failure), chronic pain, hypertension, chronic kidney disease, hepatocellular carcinoma (increased risk with AIP). Attacks can be life-threatening if not managed promptly.
• Cutaneous Porphyrias: Severe skin damage, scarring, infection, liver disease (especially in EPP and sometimes PCT).
• Secondary Porphyrinuria: Complications are those of the underlying disease.

The prognosis varies widely. With early diagnosis, avoidance of triggers, and appropriate management, many individuals with porphyria can lead relatively normal lives. Secondary porphyrinuria resolves with treatment of the primary cause.

 

When to Seek Medical Attention

Medical evaluation is crucial if porphyria or significant porphyrinuria is suspected. Seek attention if:

• Experiencing acute attacks of severe abdominal pain, neurological symptoms (weakness, confusion, seizures), or psychiatric disturbances, especially if urine is dark.
• Developing skin photosensitivity, blistering, or fragility in sun-exposed areas.
• Urine consistently appears abnormally colored (red, purple, dark brown) without a clear dietary explanation.
• There is a family history of porphyria and symptoms develop.
• Porphyrinuria is incidentally found on urine testing.
• Symptoms suggestive of lead poisoning or severe liver disease are present.

Diagnosis and management of porphyrias often require consultation with specialists such as hematologists, hepatologists, neurologists, dermatologists, and geneticists with expertise in these rare disorders.