Porphyria is not a single disease, but a group of at least eight distinct metabolic disorders. Each type is caused by a problem in the complex chemical pathway the body uses to produce heme. Heme is a vital, iron-containing molecule that is essential for life. Its most well-known job is as a key component of hemoglobin, the protein in our red blood cells that is responsible for carrying oxygen throughout the body.

The production of heme is a multi-step process that takes place in a factory-like assembly line within our cells.

• A helpful analogy is to think of this as an eight-step factory assembly line.
• Each step is controlled by a specific, essential “worker,” which is an enzyme.
• In a person with a porphyria, there is a genetic defect that causes one of these eight enzymes to be deficient or faulty.
• This creates a major bottleneck on the assembly line. The work stops at that step, leading to two main problems:
  • Not enough of the final product, heme, may be produced.
  • The raw materials that were supposed to be processed at that step, called porphyrin precursors (like ALA and PBG) or porphyrins, pile up to toxic levels.

These backed-up raw materials are what cause the toxic effects and the symptoms of the disease.

The porphyrias are broadly classified into two main categories, based on where the primary symptoms manifest, which depends on which precursor is building up:

• Acute Porphyrias: These types cause rapid, severe attacks of neurological symptoms. In these forms, the bottleneck occurs early in the heme production pathway, leading to a buildup of the nerve-toxic precursors aminolevulinic acid (ALA) and porphobilinogen (PBG).
• Cutaneous Porphyrias: These types primarily affect the skin. In these forms, the bottleneck is later in the pathway, causing a buildup of different substances called porphyrins. These porphyrins travel to the skin, where they become activated by sunlight, causing severe photosensitivity and skin damage.

In my experience, porphyria is often a diagnostic challenge. Patients go through multiple specialists before the connection between vague symptoms and a rare metabolic disorder is made.

The underlying cause of every type of inherited porphyria is a genetic mutation that leads to a deficiency in one of the eight enzymes involved in the heme synthesis pathway. Each of the eight steps in the pathway has a corresponding enzyme, and each enzyme is built from instructions contained in a specific gene. A “spelling error” or mutation in one of these genes results in a faulty enzyme that cannot do its job properly.

For example:

• The most common acute porphyria, Acute Intermittent Porphyria (AIP), is caused by a deficiency of the third enzyme in the pathway, called hydroxymethylbilane synthase (HMBS).
• The most common porphyria overall, Porphyria Cutanea Tarda (PCT), is caused by a deficiency of the fifth enzyme, uroporphyrinogen decarboxylase (UROD).

Clinically, most types are inherited due to genetic mutations in enzymes involved in the heme pathway, some forms like porphyria cutanea tarda can also be acquired..

The porphyrias are almost always inherited genetic disorders. They are not contagious. How they are passed depends on the specific type.

• Autosomal Dominant Inheritance: Most of the acute porphyrias, including AIP, are inherited in this pattern. This means an individual only needs to inherit one copy of the mutated gene from one parent to have the condition. An affected parent has a 50% chance of passing the gene on to each of their children.
  • Incomplete Penetrance: A crucial concept in the acute porphyrias is incomplete penetrance. This means that many people who inherit the faulty gene will never develop any symptoms in their entire life. They remain “latent” carriers. An acute attack is only “switched on” when a person with the genetic predisposition is exposed to a specific trigger.
• Autosomal Recessive Inheritance: Some very rare forms of porphyria are inherited in this pattern. A child must inherit a mutated gene from both parents to be affected.

In my experience, individuals are typically born with the enzyme deficiency but may remain asymptomatic until triggered by factors like certain medications, alcohol, stress, or fasting.

The signs and symptoms of porphyria are dramatically different depending on whether it is an acute or a cutaneous type.

Signs and Symptoms of Acute Porphyria

The acute porphyrias are characterized by sudden, severe, and often life-threatening attacks of neurological symptoms that can last for days to weeks.

The most common symptoms of an acute porphyria attack include:

• Severe, Diffuse Abdominal Pain: This is often the first and most prominent symptom. The pain can be excruciating but is often accompanied by a surprisingly normal physical exam, which can be very confusing for doctors.
• Neurological Symptoms:
  • Peripheral Neuropathy: Pain, tingling, numbness, or weakness in the limbs, which can progress to paralysis.
  • Autonomic Neuropathy: A rapid heart rate (tachycardia), high blood pressure, and constipation.
• Neuropsychiatric Symptoms: These are very common and can lead to misdiagnosis. They include anxiety, paranoia, hallucinations, disorientation, and confusion.
• Dark, Reddish-Brown Urine: During an attack, the urine may turn a dark, port wine-like color.

An acute porphyria attack is a medical emergency that requires hospitalization. The most dangerous risk is the development of a rapid paralysis that can affect the breathing muscles, leading to respiratory failure.

Signs and Symptoms of Cutaneous Porphyria

These types are characterized by extreme skin sensitivity to sunlight (photosensitivity).

• Painful Blisters and Sores: Upon exposure to the sun, the skin (especially on the hands, arms, and face) becomes very fragile and can develop painful blisters (bullae) and sores.
• Poor Healing and Scarring: The lesions heal slowly and often leave behind areas of scarring and changes in skin pigment.
• Hyperpigmentation: A darkening of the sun-exposed skin.
• Hypertrichosis: An increase in fine hair growth, particularly on the face.

I’ve seen patients present with a range of symptoms: acute attacks include severe abdominal pain, nausea, and confusion, while cutaneous forms cause blistering and photosensitivity.

Because the symptoms are so varied and can mimic so many other conditions, porphyria is notoriously difficult to diagnose. It often requires a high index of suspicion from a doctor. The key is to perform the correct tests during or immediately after an acute attack.

• Diagnosing an Acute Porphyria:
  • Urine Tests: This is the critical first step. A simple spot urine test is performed to measure the levels of the porphyrin precursors, porphobilinogen (PBG) and aminolevulinic acid (ALA). A significantly elevated level of PBG in the urine during a symptomatic attack is the hallmark finding that confirms a diagnosis of an acute porphyria like AIP. Testing between attacks may yield normal results.
• Diagnosing a Cutaneous Porphyria:
  • Urine, Stool, and Blood Plasma Tests: Diagnosis is made by measuring the levels of different types of porphyrins in these samples. The specific pattern of elevated porphyrins points to the specific type of cutaneous porphyria.
• Genetic Testing: Once a biochemical diagnosis is made, a molecular genetic test can be performed on a blood sample to identify the specific mutation in the responsible gene. This definitively confirms the diagnosis and type and is essential for screening family members.

Clinically, I use urine, stool, and blood tests to detect elevated porphyrins or precursors, timing of the sample during an attack greatly increases diagnostic yield.

There is no cure for porphyria’s underlying genetic defect. Treatment is focused on managing and treating acute attacks, preventing future attacks, and managing the symptoms of the cutaneous forms.

Treatment of an Acute Porphyria Attack

An acute attack is a medical emergency requiring hospitalization and urgent treatment.

• Hemin for Injection: This is the specific antidote and primary treatment for a severe attack. Hemin (Panhematin®) is a form of heme that is given intravenously. It acts as a “feedback signal” to the liver, shutting down the body’s own heme production pathway. This stops the production and accumulation of the toxic precursors ALA and PBG.
• Intravenous Glucose: High doses of glucose (dextrose) also help to suppress the heme synthesis pathway and are often given while waiting for hemin to be prepared.
• Supportive Care: This includes strong medications for pain, nausea, and seizures, and careful monitoring for paralysis and respiratory problems.
• Newer Therapies: A newer medication called givosiran (Givlaari®), which works by silencing one of the genes early in the pathway, has been approved to reduce the frequency of attacks in patients with AIP.

Prevention of Acute Attacks

For individuals with a diagnosed acute porphyria, trigger avoidance is the cornerstone of lifelong management. This includes:

• Medication Safety: This is paramount. Patients must avoid a long list of drugs that are known to trigger attacks, including barbiturates, sulfa antibiotics, and many anti-seizure medications. They should carry a list of unsafe drugs at all times.
• Diet and Lifestyle: Avoiding fasting, crash dieting, excessive alcohol consumption, and smoking is crucial.
• Hormonal Management: Some women who have attacks related to their menstrual cycle may be treated with hormones to suppress ovulation.

Treatment of Porphyria Cutanea Tarda (PCT)

• Sun Protection: This is the most critical component. It involves the rigorous use of broad-spectrum sunscreens (especially those containing zinc oxide or titanium dioxide), wearing sun-protective clothing, and avoiding peak sun exposure.
• Phlebotomy: For PCT, which is associated with iron overload, the treatment is regular therapeutic phlebotomy (removal of blood) to reduce the body’s iron stores.
• Antimalarials: Low doses of hydroxychloroquine can help clear porphyrins from the liver.

Clinically, I manage cutaneous forms with sun protection, low-dose antimalarials (like hydroxychloroquine), and phlebotomy in cases of iron overload especially in porphyria cutanea tarda.

The porphyrias are a group of rare and complex genetic disorders that can present a profound diagnostic challenge. They are “great imitators,” with the acute forms causing life-threatening neurological attacks that can be mistaken for abdominal emergencies or psychiatric crises, and the cutaneous forms causing severe sun-induced skin damage. A correct diagnosis, based on measuring the specific porphyrin precursors in the urine during an attack, is the key to proper management. For those with cutaneous porphyria, diligent sun protection can help manage their symptoms. For those with acute porphyria, the power lies in prevention. By understanding and meticulously avoiding the specific triggers, particularly certain medications, individuals can prevent life-threatening attacks. Clinically, I’ve found that a multidisciplinary approach involving hematology, dermatology, and genetics provides the most effective long-term management for porphyria.

The American Porphyria Foundation. (n.d.). About Porphyria. Retrieved from https://porphyriafoundation.org/about-porphyria/

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2020). Porphyria. Retrieved from https://www.niddk.nih.gov/health-information/liver-disease/porphyria

National Organization for Rare Disorders (NORD). (2023). Porphyria. Retrieved from https://rarediseases.org/rare-diseases/porphyria/