porphyria



OVERVIEW

What are porphyrias?

Definition of porphyria

Porphyrias are a group of metabolic disorders caused by a deficiency in the activity of enzymes involved in the heme biosynthesis pathway, resulting in an abnormally high concentration of porphyrins or their precursors, which accumulate in the tissues and cause cellular damage.

Porphyrias are also known as “vampirism” because of the anemia, skin ulceration, and photophobia that resemble those of vampires in mythological stories.

Classification

Classification by enzyme defects

They can be classified as X-linked protoporphyria (XLPP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), delayed cutaneous porphyria (PCT), ALA dehydrogenase porphyria (ADP), acute intermittent porphyria (AIP), hereditary fecal porphyria (HCP), and variegated porphyrias (VP).

Hepatic erythropoietic protoporphyria (HEP) is a type of delayed cutaneous porphyria (PCT).

Classification by site of porphyrin production

Erythropoietic porphyrias, hepatic porphyrias.

Erythropoietic porphyrias: These include X-linked protoporphyria (XLPP), congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP).

Hepatic porphyrias: These include acute hepatic porphyrias and chronic hepatic porphyrias.

Acute porphyrias can cause neurologic symptoms, usually acute attacks, and can be subdivided into ALA dehydratase porphyria (ADP), acute intermittent porphyria (AIP), hereditary fecal porphyria (HCP), and variegated porphyria (VP).

Delayed cutaneous porphyria is the most common type of chronic hepatic porphyria abroad, presenting as chronic blister-like lesions on sun-exposed areas.

Classification by pathogenesis

It can be categorized into hereditary and acquired porphyrias.

Classification according to clinical manifestations

Porphyrias can be classified as cutaneous photosensitive, neurologic and mixed porphyrias.

Cutaneous photosensitive porphyrias: also known as chronic cutaneous porphyrias. These include X-linked protoporphyria (XLPP), congenital erythropoietic porphyria (CEP) and erythropoietic protoporphyria (EPP), hepatic erythropoietic protoporphyria (HEP), and porphyria cutanea tarda (PCT).

Neurologic symptomatic porphyrias: including acute intermittent porphyria (AIP), ALA dehydratase porphyria (ADP).

Mixed porphyrias: including variegated porphyria (VP), hereditary fecal porphyria (HCP).

Morbidity

Different types of porphyrias have different peak ages of onset.

The most common form of delayed cutaneous porphyria abroad has its onset in the 40s and 60s and is more common in men.

Acute intermittent porphyrias mostly develop symptoms in the 20 to 40 years of age and are more common in women than in men.

In China, protoporphyria is more common and develops in children and adolescents.

The most common porphyrias are delayed cutaneous porphyrias and acute intermittent porphyrias, with an incidence of (1-10)/10,000 person-years.

Questions you may have

How long can I live with a porphyria?

The length of time that a person with a porphyria can survive is largely related to the type of disease and the timeliness of treatment.

Life expectancy in patients with cutaneous porphyrias is generally not affected by improved lifestyle and regular treatment, unless hepatic porphyrias develop.

Most patients with acute porphyrias have a good prognosis, and acute attacks usually recover without affecting life expectancy. However, certain patients may have recurrent attacks, and severe acute porphyria attacks may be life-threatening.

Prompt diagnosis and rapid control of acute attacks can improve the prognosis and reduce the rate of death in severe acute hepatic porphyrias.

What are acute intermittent porphyrias?

Acute intermittent porphyria is an autosomal dominant disorder caused by a partial deficiency of porphobilinogen deaminase.

The liver in acute intermittent porphyria overproduces one or more intermediates of the heme pathway or its derivatives, which are known to promote oxygen radical production and neurotoxic effects.

The main manifestations are gastrointestinal and neurologic symptoms such as abdominal colic, peripheral neuropathy, muscle weakness, and urinary retention. There are usually no cutaneous manifestations. The onset and severity of symptoms are influenced by a variety of environmental and other factors.

What medications are contraindicated in porphyria?

Porphyrias require avoidance of medications that may trigger or aggravate the condition in daily life, such as iron, barbiturates, sulfonamides, estrogen, and birth control pills.

It is now believed that medications may be triggers and pathogenic factors in some porphyrias. For example, barbiturates, sulfonamides, estrogens, birth control pills, chloroquine, chloramphenicol, gray flavomycin, etc. may induce acute symptoms of hepatic porphyria; barbiturates and sulfonamides can induce the onset of acute intermittent porphyria; barbiturates, chloroquine, ethanol, and anesthetics can induce acute attacks of variegated porphyria.

Therefore, patients with porphyria should avoid the use of these medications in their daily lives and during medical treatment.

Causes

Causes

Genetic factors

The vast majority of porphyrias are hereditary, and are usually inherited in an autosomal dominant manner.

Acquired Factors

Mild to moderate porphyria can occur secondary to alcohol abuse, estrogens, pesticides, dialysis, or fatty liver disease.

Some drugs, especially those that induce increased activity of hepatic cytochrome enzyme P450, such as carbamazepine, rifampicin, and barbiturates.

Myeloproliferative disorders or myelodysplastic syndromes can also cause acquired adult-onset EPP.

Predisposing factors

Pharmacologic factors

e.g., lead, ashwagandha, phenytoin sodium, p-aminobenzenesulfonamide, sulfadimethylisoxazole, progesterone, etc.

Chemical toxins

Such as hexachlorocyclohexane (HCH), chemical poisons may be a causative factor in some patients.

Viral infections

The incidence of hepatitis C is higher in patients with delayed cutaneous hematoporphyria than in the healthy population. Some porphyrias are associated with viral infections.

Other Factors

Alcohol consumption, starvation, severe infections, trauma, overexertion, mental stimulation, use of iron, progesterone, stress, and fluctuating hormone levels (e.g., menstruation, pregnancy) can also trigger an attack or make symptoms significantly worse during an attack.

Symptoms

Main Symptoms

Skin photosensitivity

The main manifestations are delayed-onset photosensitized dermatitis in light-exposed areas, such as erythema, blisters, vesicles, scarring, and hyperpigmentation or hypopigmentation.

Porphyria herpetiformis

Most commonly seen in congenital erythropoietic porphyria (CEP), hepatic erythropoietic protoporphyria (HEP), delayed cutaneous porphyria (PCT), mixed porphyria (VP), and hereditary fecal porphyria (HCP).

Blisters form on the epidermis in sun-exposed areas, which contain plasma or hemorrhage and may rupture, and after rupture, crusting progresses to scarring and deformity.

Severe skin lesions and deformities may be associated with loss of fingers, eyelids, nose, and ears.

Acute non-herpetic cutaneous porphyrias.

Most commonly seen in X-linked protoporphyria (XLPP), erythropoietic protoporphyria (EPP).

Pins and needles, burning sensation, and significant pain in the skin occur within minutes of sun exposure, and symptoms may last for hours or days.

Blistering, scarring, or deformities rarely occur.

Other manifestations

Patients with porphyria may develop eye damage such as conjunctivitis, keratitis, and iritis.

This manifests as ocular discomfort, photophobia, and pain.

Neurovisceral symptoms

Acute abdominal pain

The most common neurovisceral symptom of porphyria.

Abdominal pain is severe, persistent, vaguely localized, and sometimes accompanied by painful cramps.

It may be accompanied by constipation, abdominal distension, nausea, vomiting manifestations, and sometimes diarrhea.

Sensory and motor neuropathy

Limb pain, numbness, sensory abnormalities and sensory inversions are present.

Motor weakness tends to start in the upper extremities near the heart and progresses toward the lower extremities and away from the heart.

Severe motor neuropathy can lead to quadriplegia, weakness of the respiratory muscles and even respiratory failure.

Autonomic nervous system involvement

Tachycardia, hypertension, agitation, and tremor may be present.

Neurogenic bladder dysfunction may cause painful urination, dysuria, urinary retention and incontinence.

Acute neuropsychiatric manifestations

Insomnia, anxiety, agitation, agitation, hallucinations, hysteria, disorientation, delirium, emotional apathy, depression, phobias, and altered consciousness.

Severe patients may show drowsiness or even coma.

Central Nerve Involvement

May cause epileptic seizures in which the patient experiences involuntary conscious twitching.

Other symptoms

Brownish-red urine: During an acute seizure, the urine may be brownish-red or black.

Hemolysis: Erythropoietic protoporphyria may present with ineffective hematopoiesis of bone marrow erythrocytes, leading to hemolysis. Severe hemolysis may lead to anemia, and the patient may present with pallor, dizziness, and fatigue.

Complications

Chronic renal insufficiency: edema, elevated blood pressure, anemia and other symptoms.

Hepatobiliary system: there can be liver damage and cirrhosis, manifested by fatigue, nausea, vomiting, abdominal distension; gallstones are manifested by the appearance of pain and discomfort in the right upper abdomen. Patients with hepatocellular porphyria have a significantly increased risk of liver cancer.

Electrolyte disorders: Hyponatremia can present with weakness, nausea, and vomiting. Hypomagnesemia is characterized by increased muscle excitability, muscle tremors, twitching and tonicity of the hands and feet, anorexia, nausea, and vomiting. Hypercalcemia hypercalcemia can present with symptoms such as fatigue, difficulty in concentration, insomnia, and so on.

Hypertension: Patients may present with elevated blood pressure, which may be manifested by headache and dizziness.

Consultation

Department of Medicine

Hematology

Erythema, herpes, scabs, vesicles or scarring, hyperpigmentation or hypopigmentation on exposed parts of the body, pallor, dizziness, fatigue, etc. Prompt medical consultation is recommended.

Dermatology

Erythema, herpes, vesicles, hyperpigmentation or hypopigmentation of the skin, etc. Prompt medical consultation is recommended.

Emergency Medicine

If acute abdominal pain, consciousness disorder, epilepsy, mania, respiratory failure, it is recommended to consult the Emergency Department, and continue treatment in the hematology department after the condition is stabilized.

Preparation for medical treatment

Preparation for medical consultation: registration, preparation of information, common problems

Tips for Consultation

If there is any itching or pain before consultation, use cold compress to relieve it and avoid scratching to avoid secondary infection.

Preparation List

Symptom list

Pay particular attention to the time of onset of symptoms, special manifestations, etc.

How long has erythema, herpes, and hyperpigmentation been found, and in what areas?

Is there a relationship between the appearance of symptoms and sun exposure? Is there a burning sensation on sun-exposed skin?

Is there any eye discomfort, such as photophobia or pain?

Is there any numbness of the limbs, drowsiness, etc.?

Are there any signs of insomnia, anxiety, hallucinations, etc.?

Medical History Checklist

Are there any blood disorders in the immediate family?

Any exposure to chemicals, such as hexachlorocyclohexane (HCH)?

Any recent viral infections, such as having hepatitis C?

Checklist

Test results for the last six months, which can be brought to the doctor’s office

Routine blood tests

List of medications

Medication in the last 3 months, if available, bring along the box or package for medical consultation

Melanocyte stimulating hormone: Afanatide

Painkillers: acetaminophen, morphine, etc.

Antiemetics: chlorpromazine, ondansetron, etc.

Other drugs: carbamazepine, rifampicin, barbiturates, paxil, phenytoin sodium, p-aminobenzenesulfonamide, progesterone, etc.

Diagnosis

Diagnosis

Diagnosis is based on clinical manifestations and signs, combined with laboratory tests and genetic testing, and family genetic history.

Medical history

Family history of porphyria, previous episodes of abdominal pain, more severe redness and pain in the skin after sun exposure.

Clinical manifestations

There may be herpes, vesicles, and crusting of the skin.

There may be pain, numbness, and muscle weakness in the extremities.

There may be abdominal pain.

Laboratory Tests

Blood counts

Leukocytes may be elevated in acute abdominal pain, and some may show hemolytic anemia changes.

Porphyrins and their precursors

Uroporphyrinogen sunlight test: Fresh urine from patients exposed to sunlight or acidified and boiled for half an hour turns red.

Uroporphyrinogen assay: A rapid qualitative test of uroporphyrinogen in patients with acute exacerbations, a rapid screening method for porphyrias.

Erythrocyte protoporphyrin assay: In patients with erythrocyte synthetic porphyria, there is a significant increase in free protoporphyrin in erythrocytes, and erythrocytes show red fluorescence by fluorescence microscopy.

Porphobilinogen assay: The dimethylaminobenzaldehyde test (Watson-Schwartz test) is a simple and reliable method of examining porphobilinogen. In acute attacks of the disease, urine is often strongly positive; in remission it is usually positive as well, but can sometimes be negative; in occult cases this test is weakly positive or negative.

α-amino-gamma-ketoglutarate (ALA) test: ALA is elevated in the acute onset of acute intermittent porphyria; ALA is normal in congenital erythropoietic porphyria; ALA is mildly elevated in delayed cutaneous porphyria and normal in porphobilinogen.

Porphyrin assays: These include urine, feces, and plasma porphyrin assays.

Serum hydroxymethylbile synthase (HMBS) assay

HMBS activity decreases during acute attacks, allowing determination of the stage of the porphyria attack.

Plasma Fluorescence Emission Peak Detection

Porphyrins and their derivatives absorb light and are activated to emit red fluorescence. The difference in fluorescence wavelengths can help determine the type of porphyrin derivative.

Liver and Kidney Function and Electrolyte Testing

To determine whether there is liver or kidney function damage. Electrolyte disorders, especially hyponatremia, may be present during acute attacks.

Genetic Testing

Used to screen family members of patients with hematoporphyrinopathies for early detection of those with genetic mutations.

Tissue biopsy

Skin biopsy: A portion of tissue is removed from the lesion for pathologic examination. It cannot be used to confirm porphyria, but is useful in making a differential diagnosis from other photosensitive skin diseases.

Liver biopsy: Pathologic examination of a portion of liver tissue, usually guided by ultrasound and performed with a puncture needle, can confirm the diagnosis of protoporphyria and rule out other liver diseases.

Differential Diagnosis

Differential Diagnosis of Cutaneous Photosensitive Porphyria

Cutaneous porphyrias require differential diagnosis from other photosensitizing skin disorders, such as solar dermatitis, juvenile spring rash, summer dermatitis, botanical or pharmacologic solar dermatitis, polymorphic sun rash, and reticulocytosis-like hyperplasia.

Similarities: all have manifestations of skin lesions such as blisters after exposure to light.

Differences: porphyrias can be red urine, hematoporphyrin and hematoporphyrinogen content increased, lesions of the skin for pathological examination can further clarify the diagnosis.

Differential diagnosis of acute hepatic porphyrias

Acute hepatic porphyria needs to be differentiated from other inflammatory diseases of the abdominal cavity, infections, ischemia, obstruction and other acute abdominal conditions.

Similarities: both present with acute abdominal pain.

Differences: other acute abdominal conditions do not result in elevated uroporphyrinogen, which can be used in the differential diagnosis.

Differential Diagnosis of Neurologic Porphyria

Encephalitis, poliomyelitis, and Guillain-Barre syndrome can have similar neuropsychiatric symptoms without abnormalities in porphyrins and their metabolites.

Treatment

Treatment: Symptomatic treatment is based on the clinical manifestations of the porphyria and the avoidance of disease triggers.

Cutaneous photosensitive porphyrias

General Treatment

Avoid light: Apply physical sunscreen, wear skin protective clothing, protective sunglasses, windows of houses and cars should be equipped with protective tinted glass, and avoid light exposure as much as possible.

Vitamin D supplementation: Due to prolonged light avoidance, patients should routinely take vitamin D supplements.

Bloodletting therapy: Delayed-onset cutaneous porphyrias require periodic bloodletting through incised veins to relieve clinical symptoms.

Avoidance of factors that may predispose to or aggravate the disease: abstaining from smoking and alcohol, not consuming iron, and discontinuing estrogenic drugs.

Analgesia: Analgesics, including acetaminophen, aspirin, or opioid analgesics, may be used for pain.

Medication

Beta-carotene

By inhibiting oxygen free radicals, it can attenuate acute photosensitization in patients with erythropoietic protoporphyria and X-linked protoporphyria, but is not effective in variegated porphyrias.

Alfanatide

Increases skin pigmentation and increases sunlight tolerance in patients with erythropoietic protoporphyria and X-linked protoporphyria by increasing melanogenesis and decreasing free radical formation and cytokine production, but does not affect porphyrin production. Usually applied during the summer months.

Hydroxychloroquine

Low-dose hydroxychloroquine may be used as an alternative treatment when intravenous bloodletting is difficult to perform or tolerate in patients with delayed-onset cutaneous porphyrias.

Other Treatments

Severe liver injury may be treated with artificial liver or liver transplantation.

Allogeneic hematopoietic stem cell transplantation is an option for children with severe erythropoietic protoporphyria.

Neurologic Symptomatic Porphyria

General Treatment

Maintain fluid balance and correct electrolyte disturbances.

Treatment with intravenous infusion of chloroferritin

Treatment of choice for acute porphyria attacks, safe to use in pregnancy.

Iron overload, i.e., too much total body iron deposited in vital organs and tissues leading to organ and tissue damage, may occur after multiple treatments and may be treated with iron chelators and intravenous bloodletting.

Carbohydrate loading therapy

Glucose given orally or intravenously can be effective in relieving symptoms, with sodium supplementation as part of the treatment.

Analgesic treatment

Acetaminophen may be used to treat mild pain, while opioid analgesics such as morphine, hydromorphone, or fentanyl are needed for severe pain.

Pethidine has a risk of causing seizures and is not usually used.

Other treatments

Antiemetics (e.g., chlorpromazine, ondansetron, but metoclopramide is contraindicated) may be used in patients with nausea and vomiting, along with intravenous fluid and carbohydrate replacement.

Patients with anxiety and insomnia may be treated with low doses of short-acting benzodiazepines (e.g., alprazolam) for anxiety and insomnia.

Acute seizures lasting more than 2 minutes may be treated with benzodiazepines (e.g., midazolam or diazepam) or levetiracetam.

Tachycardia and hypertension caused by damage to the autonomic nervous system can be controlled with beta-adrenergic blockers (e.g., metoprolol tartrate, propranolol hydrochloride).

Avoidance of attack triggers and exacerbating factors: Some patients with acute intermittent porphyria have predictable attack triggers, which should be avoided or minimized, such as smoking, alcohol consumption, starvation, fasting, and acute infections. In patients with menstrual cycles, inhibition of ovulation by gonadotropin-releasing hormone (GnRH)-analogues can prevent frequent recurrent attacks of porphyria in the luteal phase.

Liver transplantation: Liver transplantation may be used in patients with acute hepatic porphyria that remains difficult to control with chloroferritin therapy.

Prognosis

Cure

Because the disease is often caused by genetic factors, a complete cure is difficult, but relapses can be prevented with treatment and lifestyle changes.

Patients with acute intermittent porphyrias have a good prognosis if the triggers are removed in time during an acute attack and they receive regular treatment.

Late-onset cutaneous porphyrias are often triggered by external causes, and most patients have a better prognosis if they are treated early, but patients with long-term recurrent attacks have a poor prognosis.

Most patients with erythropoietic protoporphyria have a good prognosis, with more cholelithiasis and chronic intrahepatic cholestasis occurring in some cases.

Allogeneic hematopoietic stem cell transplantation has the potential to cure erythropoietic protoporphyria.

Hazards

Patients with cutaneous photosensitive porphyrias need to avoid light for long periods of time, which can have a serious impact on their lives, work, and psychology.

Patients with cutaneous photosensitive porphyrias may develop extensive blisters and other lesions, and in severe cases, even deformities, which can have a serious impact on the patient’s life, work, and psychology.

Patients with porphyrias may experience severe neuropsychiatric symptoms and liver damage, which may lead to death.

Daily Management

Daily Management

Dietary management

Avoid spicy foods such as onions, ginger, garlic, and chili peppers.

Increase the proportion of carbohydrates in the diet (60% to 70% of total calories ), such as bread, pasta and porridge. Increase the intake of vegetables with high starch content such as potatoes, yams and taro as well as fruits.

Foods such as milk, eggs and beans should also be consumed in moderation.

Life management

Avoiding sunlight is important. Go out and take good shading measures, such as playing a shading umbrella and applying sunscreen.

Maintain skin hygiene, prohibit scratching to prevent damage to the skin infection.

Quit smoking and drinking.

Take rest, avoid exertion and get enough sleep.

Follow-up and review

This disease has a long course and should be followed up regularly according to the doctor’s instructions to monitor the concentration of porphyrins in the urine, the iron load, and liver and kidney function.

If symptoms do not decrease or even worsen, it is necessary to consult a doctor and inform him/her of your medical history before taking any medication.

Urine tests, blood tests, and histopathologic examinations may be performed at follow-up appointments, so please be prepared.

Prevention

Acquired porphyria is a genetically inherited disease and there is no effective method of prevention. A good lifestyle can help prevent acquired porphyrias.

Take rest and avoid exertion.

Avoid prolonged exposure to sunlight.

Treat the primary disease (mainly liver disease).

Stay away from chemical toxins.

Stop smoking and drinking.