Acute Hepatic Porphyrias – AHP
The acute hepatic porphyrias (AHP) are a group of rare inherited disorders that can be directly life-threatening. Each is caused by a deficiency of one of the enzymes in the liver's heme production pathway, which leads to a buildup and sudden surge of two neurotoxic precursors: delta-aminolevulinic acid (ALA) and porphobilinogen (PBG).
Unlike the purely cutaneous porphyrias, which only damage the skin surface after sun exposure, an acute AHP attack behaves like a "neurovisceral storm." Patients suffer severe, unexplained abdominal pain, autonomic disturbances, progressive muscle paralysis and acute psychiatric complications. Without an accurate differential diagnosis and prompt treatment with modern gene- and enzyme-targeted therapies, an attack can lead to respiratory failure, seizures and death.
At Haute-Derma, alongside treating the skin manifestations seen in some mixed forms of AHP, we run a rapid biochemical screening pathway for photosensitive patients suspected of carrying an AHP gene, and we work closely with emergency and neurology centers to put a comprehensive protection plan in place.
Clinical Types of AHP
There are four main inherited types of AHP, and AIP accounts for most cases presenting with acute attacks:
- Acute intermittent porphyria (AIP):
- Cause: deficiency of the enzyme HMBS (hydroxymethylbilane synthase, also called PBG deaminase).
- Features: responsible for more than 80% of acute AHP attacks. This type causes only neurovisceral symptoms and has NO skin involvement.
- Variegate porphyria (VP):
- Cause: deficiency of the enzyme PPOX (protoporphyrinogen oxidase).
- Features: a mixed form. Patients can have acute neurological attacks and also develop skin lesions (blisters and skin fragility resembling PCT) after sun exposure.
- Hereditary coproporphyria (HCP):
- Cause: deficiency of the enzyme CPOX (coproporphyrinogen oxidase).
- Features: similar to VP, with both acute neurological symptoms and light-induced skin damage.
- ALAD deficiency porphyria (ADP):
- Cause: deficiency of the enzyme ALAD (a very rare recessive condition).
- Features: severe neurological symptoms beginning in early childhood.
Pathophysiology and Neurotoxicity
The Sudden Buildup of ALA and PBG
An acute AHP attack requires two things: an underlying genetic defect and an external trigger.
- Loss of feedback inhibition: normally, the heme produced switches off the first enzyme in the pathway, ALAS1 (ALA synthase 1). When a trigger raises the demand for heme, the shortage of a downstream enzyme (such as HMBS) creates a bottleneck in the pathway.
- Massive ALAS1 induction: liver cells respond by making dozens of times more ALAS1. As a result, the two precursors upstream of the block, ALA and PBG, are overproduced and spill into the circulation.
- Direct neurotoxicity of ALA:
- ALA is chemically very similar to GABA, an inhibitory neurotransmitter. It binds GABA receptors in the brain and spinal cord and disrupts nerve signaling.
- ALA also promotes the formation of reactive oxygen species (ROS), which injure nerve axons (axonal neuropathy) and strip the myelin from motor and autonomic nerves.
Typical Clinical Features of an Acute AHP Attack
Acute attacks most often occur in women of reproductive age (20–40 years), driven by changes in progesterone levels over the menstrual cycle.
The Classic Triad
- Severe abdominal pain: the presenting symptom in more than 90% of patients. The pain is constant, cramping and spread across the whole abdomen, yet on examination the abdomen is soft, with no signs of peritonitis, a striking mismatch between what the patient feels and what the doctor finds.
- Autonomic dysfunction: rapid heart rate (over 100 beats per minute), fluctuating high blood pressure, severe vomiting and marked constipation from bowel paralysis.
- Psychiatric symptoms: acute anxiety, insomnia, hallucinations, depression, paranoia and acute confusion (delirium).
Motor and Life-Threatening Symptoms
- Progressive weakness (peripheral motor neuropathy): weakness starts in the limbs, particularly the upper arms and other proximal muscles, and then spreads. Severe cases progress to quadriplegia.
- Acute respiratory failure: paralysis of the nerves to the diaphragm and intercostal muscles leaves the patient unable to breathe unaided, requiring emergency intubation.
- Seizures and severe hyponatremia: low blood sodium occurs in 30–50% of attacks, caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or by salt loss through the gut. Hyponatremia raises the risk of generalized seizures and brain swelling.
Triggers of Acute Attacks
Acute attacks rarely happen on their own; they usually follow a factor that increases the liver's demand for porphyrins:
- Liver-stressing drugs (P450 inducers): drugs that induce cytochrome P450 enzymes (such as barbiturates, sulfonamides, carbamazepine, valproate, ketoconazole and metoclopramide) deplete heme in the liver and switch on ALAS1.
- Sex hormones: high progesterone levels in the luteal phase of the menstrual cycle, during pregnancy or with progestin-containing contraceptives.
- Infection and surgery: intense inflammation and physiological stress.
- Fasting and strict dieting (caloric restriction): a lack of glucose strongly switches on the co-activator PGC-1α, which directly induces the ALAS1 gene, so ALAS1 is strongly activated.
- Alcohol and other stimulants: an increased metabolic load on the liver.
Rapid Emergency Diagnosis and Treatment at Haute-Derma
Rapid Tests
- Quantitative urinary PBG: the gold-standard test for an acute attack. During an attack, urinary PBG rises from 5 to several dozen times the normal level.
- Urine color change on light exposure: when the patient's urine is left in sunlight for a few hours, PBG polymerizes into porphobilin and porphyrins, turning the urine from a normal color to dark red or wine-colored.
Identifying the Type and Genetic Testing
- Plasma and fecal porphyrins: help distinguish AIP (normal fecal porphyrins) from VP (plasma fluorescence peak at 626 nm) and HCP (markedly raised fecal coproporphyrin III).
- Gene sequencing: identifies mutations in the HMBS, PPOX, CPOX or ALAD genes.
Emergency Treatment
AHP treatment has two phases: emergency management to stop the attack, and long-term prevention.
Acute Attack Management
- Emergency heme infusion (hemin / Panhematin / Normosang):
- Dose: 3–4 mg/kg by intravenous infusion once daily for 4 consecutive days.
- How it works: infused heme immediately restores heme levels in the liver, restoring the feedback signal that shuts down ALAS1 production, so ALA and PBG fall back to normal within 48 hours.
- High-dose carbohydrate loading:
- Used for mild attacks or while waiting for hemin to become available.
- Intravenous 10% glucose (300–400 g of glucose per day). Glucose stimulates insulin and suppresses PGC-1α, which reduces ALAS1 production.
- Stopping all triggering drugs: every drug suspected of stressing the liver is stopped at once. Safe alternatives are checked against the Drug Database for Acute Porphyria.
- Symptom control and supportive care:
- Opioid painkillers (morphine, fentanyl) to control abdominal pain.
- Beta-blockers (propranolol) to control rapid heart rate and high blood pressure.
- Slow, careful correction of hyponatremia to avoid osmotic demyelination syndrome.
A Modern Breakthrough: Givosiran (Givlaari)
- Small interfering RNA (siRNA): givosiran is an interfering RNA linked to N-acetylgalactosamine (GalNAc), which directs it specifically to liver cells.
- Action: givosiran directly degrades the mRNA of the ALAS1 gene, preventing liver cells from making the ALAS1 enzyme.
- Benefit: a monthly subcutaneous injection of 2.5 mg/kg reduces the annual number of attacks by more than 70%, lessens reliance on intravenous hemin and improves overall quality of life for people with chronic AHP.
