Acute Hepatic Porphyria: Failure of Heme Formation

Introduction

Acute hepatic porphyria (AHP) is a family of rare inherited metabolic disorders involving a heterocyclic organic compound-porphyrins. Porphyrins are the major precursors of heme which then undertakes an eight-step heme metabolism pathway to form hemoglobin or form significant pieces of myoglobin, catalase, peroxidase, and P450 liver cytochromes. In pathological states, there is a deficiency of enzymes involved in the porphyrin pathways, which causes the abnormal concentration of heme precursors and metabolites in the liver, primarily PBG (porphobilinogen) and ALA (aminolevulinic acid).

What Are the Types of Acute Hepatic Porphyria?

The various subtypes of AHP are:

1. Acute intermittent porphyria.

2. Variegate porphyria.

3. Hereditary coproporphyria.

4. ALAD deficiency porphyria (aminolevulinic acid dehydratase deficiency).

Who Is Susceptible to Acute Hepatic Porphyria?

AHP shows a global prevalence in the range of one in 500 to one in 50,000 individuals, with the US at one in 25,000 individuals. The condition shows no apparent racial or ethnic predisposition. The exact prevalence is difficult to predict as the condition goes mostly undiagnosed as just one in ten cases develop any detectable symptoms. The acute intermittent variant covers more than 80 % of the diagnosed cases (prevalence of 5 to 10 per 100,000 individuals), while the ALAD deficiency variant is the least common subtype. The overall condition shows no gender predilection, but the dominant variant shows a predisposition to females with five times the symptomatic bouts in non-Hispanic females than males.

What Causes Acute Hepatic Porphyria?

Acute hepatic porphyria is an inherited group of disorders showing autosomal dominant or recessive hereditary patterns. The acute intermittent, variegate, and hereditary coproporphyria variants are autosomal dominant, while the ALAD deficiency is autosomal recessive.

• Acute Intermittent Porphyria: This is caused by a mutation in the HMBS gene that causes deficiency in the hydroxymethylbilane synthase enzyme (also known as porphobilinogen deaminase enzyme).

• Variegate Porphyria: This is caused by a mutated PPOX gene causing deficiency in the protoporphyrinogen oxidase enzyme.

• Hereditary Coproporphyria: A mutated CPOX gene, resulting in a deficient coproporphyrinogen oxidase enzyme, is the causative agent of this subtype.

• ALAD-Deficiency Porphyria: Mutations in the ALAD gene make deficient delta-aminolevulinic acid dehydratase enzyme, which is the causality.

What Is the Pathophysiology of Acute Hepatic Porphyria?

AHP is basically caused due to lack of deficiency of certain enzymes required in various stages of the eight-step metabolic pathway of heme synthesis from succinyl CoA and glycine. Acute intermittent is caused by a deficiency in step three, variegate from the deficient enzyme in step seven, hereditary coproporphyria occurs as dysfunction in step six, and ALAD deficiency in step two malfunction. The clinical manifestations of AHP are due to the neurotoxic effect of accumulated porphobilinogen and aminolevulinic acid, along with depleted levels of heme and other heme proteins in various tissues.

The mechanism of AHP manifestations are:

1. ALA affects GABA (neurotransmitter) receptors in the central nervous system and myenteric plexus of the intestine resulting in dysfunctional peristalsis and muscle tone.

2. ALS-induced melatonin release from the pineal gland dysregulates the circadian rhythm.

3. Increased production of ROS (reactive oxygen species) due to compromised mitochondrial membrane causing chronic neurovisceral problems and liver carcinogenesis.

4. ALA and PBG affect the neurotransmitters and amino acid metabolism of the central and peripheral nervous systems.

5. Cerebral and enteral vascular activity due to nitric oxide synthase dysfunction following vasomotor dysfunction.

6. ALA reduces neuronal mitochondrial oxidative phosphorylation and compromises mitochondrial membranes and respiratory chain complexes.

7. ALA damages the mitochondrial membrane, thereby increasing permeability and membrane lipid oxidation.

8. Both ALA and PBG cause axonal membrane dysfunction due to detrimental effects on sodium-potassium-gated ATPase pumps.

9. Pathologic protein oxidation and accumulation.

10. Decreasing pyridoxal-phosphate levels translated to secondary axonal and small-fiber neuropathies.

11. Secondary effects of adrenal hormone imbalance.

What Are the Clinical Manifestations of Acute Hepatic Porphyria?

AHP manifests several gastrointestinal, neurologic, psychiatric, cardiovascular, and cutaneous symptoms, which are trickled-down neurotoxic effects of accumulated ALA and PBG. AHP mostly remains asymptomatic and undiagnosed. It is recognized due to occasional acute attacks, which widely vary in severity, lasting a few days, and getting progressively worse before improving. The intensity requires ER visits in situations like respiratory paralysis.

Gastrointestinal Manifestations

• Abdominal pain.

• Abdominal discomfort.

• Nausea.

• Vomiting.

• Constipation.

• Diarrhea.

• Indigestion.

Central Nervous System Manifestations

• Anxiety.

• Insomnia.

• Depression.

• Delirium.

• Hallucinations.

• Seizure.

Peripheral Nervous System Manifestations

• Muscle weakness.

• Numbness.

• Tingling.

• Fatigue.

• Sensory loss.

• Muscle paralysis

• Respiratory paralysis.

Autonomic Nervous System Manifestations

• Heart palpitations.

• Hypertension.

Urological Manifestations

• Purple-red urine.

Cutaneous Manifestations

• Increased sensitivity.

• Blistering rash.

• Pigmentation.

• Scarring.

How to Diagnose Acute Hepatic Porphyria?

AHP remains largely unrecognized, and an ER visit during acute attacks may bring about an astute diagnosis following several investigational studies.

• Urine analysis is the first-line screening test and is highly sensitive and specific for AHP diagnosis. The urine is purple-red tinged. Urinary PBG is seen to be significantly elevated and may remain normal between attacks. A urine test is also done for ALA levels and total porphyrins.

• Blood analysis shows decreased PBGD (erythrocyte porphobilinogen deaminase) activity even in asymptomatic patients.

• Plasma and stool samples are collected to determine ALA, PBG, and total porphyrin levels.

• A basic metabolic panel shows hyponatremia (low sodium in the body) which may be resultant of the neurotoxic effect of metabolites on the CNS, gastrointestinal, and renal sodium loss.

• The liver panel shows mild elevation of transaminases.

• The genetic study is considered the gold standard for accurately determining the mutated genes, the subtype of AHP, and the severity of enzyme deficiency.

How to Treat Acute Hepatic Porphyria?

In the ER, the focus remains on managing the acute attack, which is done by Hemin injection, which is a blood-derived salt that inhibits porphyrin production, thereby reducing the levels in the body. Further treatment involves pain management, controlling nausea and vomiting, and seizure control. Intravenous fluids and supplements of glucose, sodium, magnesium, and electrolytes are administered to compensate for the loss from gastrointestinal manifestations.

Long-term management focuses on preventing future acute attacks. This is done by weekly low-dose prophylactic Hemin injections to prevent porphyrin buildup in the body. Gene therapy medication, called Givosiran, is a newly approved monthly injection that prevents porphyrin precursor production. If the studies determined that the attacks are triggered by the menstrual cycle, then GnRH (Gonadotropin-releasing hormone) analogs are prescribed to inhibit estrogen and progesterone production. Additionally, hypertension is managed by a separate protocol. People who are suffering from frequent attacks, even with established management protocols, may be eligible for a liver transplant.

What Is the Prognosis of Acute Hepatic Porphyria?

It is not possible to prevent AHP, but the appearance of symptoms can be prevented by isolating and avoiding the triggers. Certain medications, substance abuse, stress, infections, and diets can trigger acute attacks and should be avoided. The disease mostly responds positively to the management protocol, and most people experience just a handful of attacks throughout their lifetime. Only about 5 % of patients have frequent and chronic symptoms, for whom transplant may be the only option.

What Is the Differential Diagnosis of Acute Hepatic Porphyria?

• Fibromyalgia (muscle pain).

• Endometriosis (endometrium or uterine lining found outside the uterus).

• Irritable bowel syndrome (gastrointestinal disorder causing pain and diarrhea or constipation).

• Guillain-Barre syndrome (immune system attacks the nerves).

• Hepatitis (liver inflammation).

• Psychosis (individuals lose touch with reality).

• Seizure disorders (sudden uncontrolled electrical disturbance in the brain).

• Posterior reversible encephalopathy syndrome (PRES- a neural disorder showing a rapid onset of headache, seizures, altered consciousness, and visual disturbances).

What Are the Complications of Acute Hepatic Porphyria?

• Quadriplegia (paralysis from the neck down).

• Coma (state of prolonged unconsciousness).

• Hypertension (high blood pressure).

• Chronic renal failure (kidney failure).

• Iron deficiency anemia. (blood disorder due to low iron in the body)

• Hepatocellular carcinoma (liver cancer).

• Psychosis (individuals lose touch with reality).

Conclusion

AHP is a very rare disorder, and even the ones who carry it may not know its existence throughout their lives. Acute attacks can be scary and require emergency intervention. Since it is an inherited condition, genetic testing and counseling are advised before family planning if someone is diagnosed within the family. Due to its rarity, the condition may be misdiagnosed with one of its differentials, and the patient may struggle with attacks without any true treatment. Hence, awareness and knowledge of the condition are essential to pinpoint the diagnosis and take a step toward establishing the true prevalence. Following this, trials and research may be fast-tracked in search of a better cure.