Porphyrias

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 “Metal toxicity”). 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.

Description

• 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.

Pathophysiology

• Trigger → ↓ enzyme activity in heme biosynthesis → intermediates of heme production accumulate
  • → Deposited into different tissue, such as the skin and/or liver → symptoms
  • → Increased urinary and fecal elimination → metabolite detection
• The specific intermediates that accumulate depends on which enzymes are affected in the heme biosynthesis pathway.

Classification

Porphyrias can be classified based on inheritance or organ of accumulation.

• Inheritance: primary (inherited) or secondary (acquired)
• Organ of accumulation:
  • Hepatic (more common)
    • Acute (often systemic): Acute intermittent porphyria is most common.
    • Chronic (often cutaneous): Porphyria cutanea tarda is most common.
  • Erythropoietic variants (rare)

Primary porphyrias (hereditary enzyme defect)

• Hepatic porphyrias
  • Acute hepatic porphyrias
    • Acute intermittent porphyria (autosomal dominant)
    • Porphyria variegata (autosomal dominant)
    • Hereditary coproporphyria (autosomal dominant)
    • Doss porphyria (autosomal recessive)
  • Chronic hepatic porphyrias
    • Porphyria cutanea tarda (autosomal dominant or acquired)
    • Hepatoerythropoietic porphyria (autosomal recessive)
  • Erythropoietic porphyrias
    • Congenital erythropoietic porphyria (Gunther disease, autosomal recessive)
    • Erythropoietic protoporphyria (autosomal dominant)

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 metal toxicity)

Epidemiology

• Most common porphyria ^[1]
• Peak incidence: 30–50 years of age ^[2]

Etiology and pathophysiology ^[2][3]

• Reduced activity of heme biosynthesis enzyme uroporphyrinogen III decarboxylase (UROD) → uroporphyrin accumulates in the skin → sunlight-dependent skin damage (chronic photosensitivity)
  • Type I: acquired (sporadic) deficiency of UROD
  • Type II: inherited/familial (autosomal dominant) UROD mutation
• Susceptibility factors
  • Iron overload leading to increased hepatic iron stores (PCT is an iron-related disease)
    • Primary (genetic): hemochromatosis
    • Secondary (acquired): excessive iron supplementation, blood transfusions in chronic kidney or liver disease ^[4][5]
  • Alcohol, smoking
  • Hepatitis C
  • HIV
  • Hepatic steatosis
  • Estrogen therapy
  • Sunlight exposure

Clinical findings ^[2][3]

PCT manifests clinically as a dermatological disease.

• Characteristic cutaneous findings
  • Blistering skin lesions (vesicles, bullae) secondary to the increased fragility of sun-exposed skin (blistering photosensitivity)
  • Scarring and milia secondary to an impaired healing process
  • Hypertrichosis
  • Hyperpigmentation
  • Scleroderma-like changes
• Common locations
  • Dorsum of the hand
  • Face and neck
  • Extensor surface of the forearm
• Red-brown (tea-colored) urine

Consider PCT in a patient presenting with a blistering rash on sun-exposed skin.

Diagnosis ^[2][3]

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

• CBC: typically normal
• Liver chemistries: ↑ AST, ALT, and GGT
• Renal function: may be abnormal
• Iron studies: ↑ serum ferritin
• Hepatitis B screening, hepatitis C screening, and HIV testing (if the patient has susceptibility factors)

Confirmatory diagnostic studies

• First-line testing
  • Spot urine sample test: ↑↑ uroporphyrins
  • Blood test: ↑ serum porphyrins
• Second-line testing: UROD activity analysis and gene mutation detection

Management ^[2][3]

The goal of therapy is to resolve the patient's symptoms by reducing porphyrin levels.

General measures

• 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). ^[6]

Treatment

• Phlebotomy: indicated in all patients with symptomatic PCT
  • Procedure: ∼ 450 mL of blood is removed every 2 weeks
  • Therapeutic targets
    • Serum ferritin level ∼ 15 ng/mL (near the lower limit of normal)
    • Plasma porphyrin level ∼ 1 mcg/dL
• Low-dose hydroxychloroquine or chloroquine
  • Indications include:
    • Patients unable to tolerate phlebotomy (e.g., concurrent anemia)
    • Presence of HFE gene mutation
    • No severe iron overload
  • Duration: until plasma or urine porphyrins have normalized

Ongoing management

• Treatment of hepatitis C (after initiation of treatment for PCT) ^[2]
• Hepatocellular carcinoma screening: α-fetoprotein and liver imaging ^[7]

Epidemiology

• Second most common porphyria ^[1]
• Peak incidence: 20–30 years of age ^[2]
• Sex: ♀ > ♂

Etiology and pathophysiology ^[2]

• 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 ^[2][3]

Most triggers increase the demand for hepatic heme, thereby stimulating heme biosynthesis, which, in the setting of an AIP enzyme mutation, results in the accumulation of heme intermediates.

• Medications (especially inducers of hepatic cytochrome P450 enzymes, which are used in the biosynthesis of heme), including:
  • Anticonvulsants (e.g., barbiturates, phenytoin)
  • Sulfonamides
  • Anesthetics
  • Hormone therapy
  • See “Tips & Links” for the drug safety database of the American Porphyria Foundation.
• Alcohol
• Smoking
• Endogenous sex hormones
• Fasting/crash dieting
• Metabolic stress (e.g., surgery, infection)

Clinical features ^[8]

The clinical presentation of AIP is variable and symptoms are often nonspecific. In contrast to some porphyrias, there are no dermatological findings.

• Acute attacks
  • 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
  • Most patients remain asymptomatic between attacks.
  • Chronic neuropathic pain
  • Depression (increased risk of suicide)

The 5 P's of acute intermittent porphyria: Painful abdomen, Polyneuropathy, Psychologic disturbances, Port wine-colored pee, Precipitated by triggers like drugs

The skin is not involved in acute intermittent porphyria.

Diagnosis ^[2][8]

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 studies

Routine laboratory studies and imaging are often normal, and the diagnosis is confirmed with specialized tests.

• Laboratory studies
  • CBC: normal or nonspecific findings
  • BMP: possible ↓ Na⁺, ↑ Cr
  • Liver chemistries: ↑ AST and ALT
• Imaging: frequently performed in acute attacks to rule out differential diagnoses
  • Abdominal imaging (x-ray or CT):
    • Typically normal
    • May show dilated bowel loops with air-fluid levels representing an ileus
  • MRI or CT brain
    • Typically normal
    • May show white matter vasogenic edema affecting the posterior brain, consistent with posterior reversible encephalopathy syndrome (PRES) ^[9]

Confirmatory studies

• First-line testing: spot urine sample for heme precursor levels
  • Porphobilinogen (PBG): ↑ (∼ 20–200 mg/L)
  • δ-aminolevulinic acid (ALA): ↑ (∼ 10–100 mg/L)
• Second-line testing
  • Porphyrin levels: greatly increased in urine, normal to slightly increased in feces and plasma
  • Erythrocyte porphobilinogen: decreased
• 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.

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.

Approach ^[2][3][8]

• 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:
  • Electrolyte derangements (including magnesium)
  • Evidence of urinary retention, muscle weakness, ileus, or psychiatric changes
  • Respiratory impairment via bedside spirometry

Treatment

• Hemin therapy ^[8]
  • Start as soon as possible and continue for 4 days.
  • Mechanism: Hemin is an iron-containing porphyrin that decreases the activity of δ-aminolevulinate synthase, thereby decreasing heme biosynthesis and the accumulation of intermediates.
• Glucose loading: : consider only for mild attacks or as temporizing measure ^[10][11]
  • Monitor for hyperglycemia and hyponatremia with serial BMPs every 4 hours.
  • Transition to oral intake as early as possible.

Supportive care ^[3]

The choice of medications in porphyria patients is complicated and should ideally be agreed upon with a porphyria specialist.

• General measures
  • IV fluid therapy
  • Electrolyte repletion
  • Nutritional support ^[11]
• Options for symptomatic treatment include: ^[3]
  • Pain management, e.g., acetaminophen , morphine
  • Antiemetics, e.g., ondansetron
  • Anxiolytics, e.g., lorazepam
  • Beta blockers for hypertension and symptomatic tachycardia, e.g., propranolol )
• Seizure management
  • Ensure seizure precautions (especially if the patient has hyponatremia).
  • Treat hyponatremia and hypomagnesemia.
  • Termination of acute seizures: Consider lorazepam.
  • Prevention of further seizures: Consult with a neurologist and porphyria specialist.

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 ^[8]

• 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:
  • Chronic neuropathic pain management
  • Major depressive disorder management (with suicide prevention)

Severe disease with recurring attacks

• Prophylactic hemin infusions ^[8][12]
• Givosiran therapy (specialist management needed) ^[13]
• Consider gonadotropin-releasing hormone agonist therapy in women with frequent cyclical attacks.
• Liver transplant (refractory disease) ^[2]

Congenital erythropoietic porphyria (Gunther disease)

• Epidemiology
  • Very rare
  • Severe
• Etiology
  • Autosomal recessive
  • Defective uroporphyrinogen-III synthase
• Pathophysiology
  • Begins in childhood
  • Bone marrow heme biosynthesis impairment
• Clinical features
  • Severe photosensitivity leads to light-induced damage → burning sensation and redness of the skin with blisters that can develop into ulcers → scarring, sometimes severe:
    • Scarring of the cornea (blindness)
    • Loss of fingers
    • Loss of facial features
  • Hemolytic anemia: enzyme dysfunction reduces heme levels and accumulated intermediates disrupt the membrane of erythrocytes and their precursors → hypersplenism
  • Bone changes
    • Bone marrow hypertrophy → pathologic fractures
    • Acral osteolysis
    • Red stained bones
  • Port-wine colored urine
• Management
  • No causal therapy
  • Avoid exposure to sunlight

Erythropoietic protoporphyria

• Epidemiology: third most common porphyria
• Genetics: autosomal dominant (defective ferrochelatase)
• Clinical features
  • After exposure to sunlight: transient cutaneous findings
  • Protoporphyrin gallstones
  • Rare: chronic hepatic involvement
• Diagnostics: ↑ protoporphyrin in feces and blood
• Management
  • Protection from sunlight, alpha-MSH
  • Ursodeoxycholic acid, cholestyramine
  • Liver/bone marrow transplantation