Acute Porphyria Clinical Presentation

Recent provoking factors for acute porphyria include the following:

• Alcohol ingestion

• Infection

• Surgical procedure

• Known provoking drug (see Deterrence/Prevention)

• Low-carbohydrate diet or fasting

• Menstruation

Seizures that are difficult to control or that worsen with standard anticonvulsants drug administration

Pregnancy can precipitate hereditary coproporphyria (HCP) but not acute intermittent porphyria (AIP). ^[8]

Vital signs

See the list below:

• High blood pressure and tachycardia during acute attacks

• Chronic changes (eg, sustained hypertension in 20% of patients)

GI symptoms

See the list below:

• Abdominal pain

• Nausea, vomiting

• Partial ileus with accompanying severe nonfocal abdominal pain

• Absent peritoneal signs

Neurologic symptoms

Autonomic neuropathy symptoms include the following ^[9] :

• Unstable vital signs

• Excessive sweating

• Dysuria and bladder dysfunction

• Fever

• Restlessness

• Tremor

• Catecholamine hypersecretion

Peripheral neuropathy symptoms include the following:

• Guillain-Barré–like syndrome after prolonged and severe episodes

• Focal, asymmetric, or symmetric weakness beginning proximally and spreading distally with foot or wrist drop

• Focal, patchy mild-to-severe paresthesias, numbness, and dysesthesias

• Tetraplegia (reported in cases of hereditary coproporphyria [HCP])

• Respiratory paralysis (rare but can occur)

Cranial nerve symptoms include the following:

• Motor nerve palsies (particularly cranial nerves VII and X)

• Optic nerve involvement (may lead to blindness)

Seizures symptoms include the following:

• Seizures are most common during acute attacks.

• Tonic-clonic (more common) and/or partial (less common) seizures with secondary generalization are most common.

• The lifetime prevalence of seizures is 4%.

• The risk of seizure during an acute episode is 5%.

Cortical symptoms are as follows:

• Encephalopathy

• Aphasia

• Apraxia

• Cortical blindness

Psychiatric symptoms

Acute symptoms include the following:

• Anxiety

• Agitation

• Confusion

• Depression

• Hallucinations

• Insomnia

• Paranoia

• Violent behavior

Chronic symptoms include the following:

• Depression

• Anxiety

A study by Cederlöf et al indicated that the risk of schizophrenia or bipolar disorder is fourfold higher in persons with acute intermittent porphyria and is twofold higher in first-degree relatives of these individuals. The study included 717 individuals with the disease. ^[10]

Other symptoms

See the list below:

• Muscular symptoms (rhabdomyolysis)

• Urine changes (may turn red or dark when exposed to light)

Porphyria is considered a genetic disorder. Phenotypic expression of the genetic defect is highly variable and appears to be more common in familial cases than in others (see Table 1). ^[11]

A 50% deficit in aminolevulinic acid dehydratase (ALAD) activity occurs in as many as 2% of the general population, although ALAD deficiency requires more than 90% inhibition of this enzyme. The low incidence of homozygous patients, given the relatively high prevalence of the heterozygous enzyme deficit, suggests that the homozygous deficit may result in death in utero.

Both the tissue and erythropoietic isoforms of porphobilinogen (PBG) deaminase are produced from the same gene by means of alternative splicing controlled by separate promoters. More than 100 mutations have been identified. Specific mutations are conserved within families, allowing for the screening of family members when a patient's genetic defect is known. Clinical disease is associated with a 50% or greater reduction in enzyme function. PBG deaminase has 3 mutation patterns:

• Type I is a single-base error resulting in an amino acid substitutions or truncated proteins.

• Type II (the Finish mutation) is localized to the tissue isoform of the enzyme.

• Type III is a deletion in 1 of 2 exons that produces a structurally abnormal protein.

Coproporphyrinogen oxidase is located in the intermembrane space of the mitochondria and loosely associated with the outer face of the inner mitochondrial membrane. A single promoter site appears to be differentially regulated to produce the erythroid and nonerythroid isoforms. Significant genetic heterogeneity accounts for the abnormal function of coproporphyrinogen oxidase in HCP, making routine genetic screening impossible. Heterozygous and homozygous individuals have a 50% and 90-98% reduction in enzyme activity, respectively.

Protoporphyrinogen oxidase is located on the outer face of the inner mitochondrial membrane. A 50% reduction in activity consistently occurs across all tissue tested in affected individuals. The R59W defect may account for 95% of affected individuals in South Africa, whereas mutations in others are heterogeneous. Homozygous and doubly heterozygous individuals typically develop severe photomutilation with brachydactyly, nystagmus, seizures, and sensory neuropathy without acute episodes. Mental retardation is common in this neonatal form of variegate porphyria (VP).