Porphyrias are a group of rare, inherited or (less commonly) acquired metabolic disorders in which defective enzymes impair the biosynthesis of heme in the liver and/or bone marrow. All porphyrias are characterized by the accumulation of porphyrin, or intermediates of its biosynthesis, which can cause a variety of symptoms depending on the organs involved (e.g., skin, liver, CNS). Porphyria cutanea tarda (PCT) is the most common form and manifests with chronic, blistering cutaneous photosensitivity and tea-colored urine. The diagnosis of PCT is confirmed by detecting porphyrins in urine or serum. Management consists of rigorous photoprotective measures, regular phlebotomy or low-dose hydroxychloroquine, and avoiding risk factors. The second most common form, acute intermittent porphyria (AIP), is characterized by life-threatening attacks of severe abdominal pain, nausea and vomiting, tachycardia, and neuropsychiatric abnormalities. Attacks are generally triggered by certain medications, alcohol, infections, or fasting. The diagnosis of AIP is confirmed by detecting metabolic heme precursors in urine, which often appears reddish. An important acquired form of porphyria is lead poisoning, which is discussed in another article (see “ ”). Patients with a known porphyria should avoid potential triggers. Management of AIP consists of supportive care; acute attacks should be treated with hemin to reduce heme production.
- Porphyrias are a rare group of inherited or (less commonly) acquired metabolic disorders in which defective enzymes impair the biosynthesis of heme in the liver and/or bone marrow.
- Trigger → ↓ enzyme activity in heme biosynthesis → intermediates of heme production accumulate
- The specific intermediates that accumulate depends on which enzymes are affected in the heme biosynthesis pathway.
Porphyrias can be classified based on inheritance or organ of accumulation.
- Inheritance: primary (inherited) or secondary (acquired)
- Organ of accumulation:
Primary porphyrias (hereditary enzyme defect)
- Hepatic porphyrias
- Acute hepatic porphyrias
- Chronic hepatic porphyrias
- Erythropoietic porphyrias
Secondary porphyria (acquired)
- Secondary coproporphyria (caused by e.g., intoxication, hepatic diseases, blood disorders, infections, starvation)
- Secondary protoporphyrinemia (caused by e.g., anemia, alcohol, or chronic heavy metal poisoning; see )
- Most common porphyria 
- Peak incidence: 30–50 years of age 
Etiology and pathophysiology 
- Reduced activity of heme biosynthesis enzyme uroporphyrinogen III decarboxylase (UROD) → uroporphyrin accumulates in the skin → sunlight-dependent skin damage (chronic photosensitivity)
- Iron overload leading to increased hepatic iron stores (PCT is an iron-related disease)
- Alcohol, smoking
- Hepatitis C
- Hepatic steatosis
- Estrogen therapy
- Sunlight exposure
Clinical findings 
PCT manifests clinically as a dermatological disease.
- Characteristic cutaneous findings
- Dorsum of the hand
- Face and neck
- Extensor surface of the forearm
- Red-brown (tea-colored) urine
A high index of suspicion is necessary as the symptoms overlap with several other conditions. Consider PCT in adult patients with a blistering rash on sun-exposed areas (especially the back of the hands) and a known susceptibility factor.
Routine blood studies
Confirmatory diagnostic studies
- First-line testing
- Second-line testing: UROD activity analysis and gene mutation detection
The goal of therapy is to resolve the patient's symptoms by reducing porphyrin levels.
- Avoid susceptibility factors; , e.g., smoking, alcohol, and exogenous estrogen.
- Advise patients on photoprotective measures, including reducing exposure to visible light (e.g., using large particle sunscreens). 
- Phlebotomy: indicated in all patients with symptomatic PCT
- Low-dose hydroxychloroquine or chloroquine
Etiology and pathophysiology 
- Autosomal dominant gene mutation, with variable penetrance
- Approx. 80–90% of carriers of the AIP gene mutation are asymptomatic.
- Trigger → ↑ heme demand and biosynthesis → impaired enzyme activity due to a mutation of porphobilinogen deaminase (PBG-D) (previously known as uroporphyrinogen I synthase) → accumulation of heme intermediates porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) → symptoms
Triggers of acute porphyric attacks 
- Medications (especially inducers of hepatic cytochrome P450 enzymes, which are used in the biosynthesis of heme), including:
- Endogenous sex hormones
- Fasting/crash dieting
- Metabolic stress (e.g., surgery, infection)
Clinical features 
The clinical presentation of AIP is variable and symptoms are often nonspecific. In contrast to some porphyrias, there are no dermatological findings.
- GI symptoms: severe abdominal pain, nausea, vomiting, constipation
- Neurological abnormalities: polyneuropathies (nonspecific pain, weakness/fatigue, paresthesia, paresis), seizures, respiratory paralysis
- Autonomic dysfunction: tachycardia, hypertension
- Psychiatric abnormalities: hallucinations, disorientation, anxiety, insomnia
- Red-purple urine
- Chronic symptoms
The 5 P's of acute intermittent porphyria: Painful abdomen, Polyneuropathy, Psychologic disturbances, Port wine-colored pee, Precipitated by triggers like drugs
Diagnosis of AIP is challenging and a high index of suspicion must be maintained. Consider AIP if typical clinical features are seen in the absence of other causes (e.g., unexplained severe abdominal pain accompanied by muscle weakness and dark urine).
Routine laboratory studies and imaging are often normal, and the diagnosis is confirmed with specialized tests.
- Laboratory studies
- Imaging: frequently performed in acute attacks to rule out differential diagnoses
- First-line testing: spot urine sample for heme precursor levels
- Second-line testing
- Enzyme activity measurement and DNA testing
A 24-hour urine collection is not necessary for the diagnosis of an acute AIP attack and delays diagnosis.
Management of acute attacks
The goal of therapy is to stop the acute attack as quickly as possible while providing supportive and symptomatic care. Hospitalization may be required and specialists (i.e., hematology or hepatology) should be consulted.
- Admit all patients with severe pain, an inability to tolerate oral intake, or a new diagnosis.
- Identify potential triggers and withdraw unsafe medications if possible (see “Tips & Links” for the drug safety database of the American Porphyria Foundation).
- Ensure close monitoring (consider ICU admission pending neurological and respiratory status).
- Monitor daily for:
- Hemin therapy 
- Glucose loading: consider only for mild attacks or as temporizing measure 
Supportive care 
The choice of medications in porphyria patients is complicated and should ideally be agreed upon with a porphyria specialist.
- General measures
- Options for symptomatic treatment include: 
- Seizure management
Management of acute attacks of AIP can be challenging; obtain specialist consults early.
Due to the complexity of this rare disease, patients with AIP should receive an evaluation by specialists at a designated porphyria center.
All patients 
- Counsel patients on avoiding triggers and maintaining adequate nutrition.
- Screen for long-term complications: chronic kidney disease, hypertension, and hepatocellular carcinoma.
- Provide medical alert bracelets and wallet cards.
- Organize genetic counseling (for both the patient and relatives).
- Consider the need for: