CLINICAL CASES
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395 nm to 398 nm, while protoporphyrin is detected at 626 nm. The excretion
pathway of the porphyrins is determined by their water solubility. The first
possible porphyrin byproduct of the heme biosynthetic pathway, uroporphyrin
is by far the most water-soluble, while protoporphyrin the least soluble.
Accordingly, uroporphyrin is excreted predominantly in urine, coproporphyrin
in urine and in bile, and protoporphyrin exclusively in bile.
In most cases, these disorders are inherited in an autosomal dominant man-
ner where the individual carries one normal allele and one loss-of-function
allele. Under normal circumstances, the wild type allele allows for expression
of enough functional enzymes to meet the individual’s requirement for heme
(symptom-free carriers). However certain environmental triggers for example,
drugs, alcohol, steroids, fasting, trauma, and/or high stress can increase this
demand beyond a level which can be compensated by the single functional
allele. Upon exposure to the trigger(s), patients with acute hepatic porphyrias
can shift from a compensated phase to a decompensated latent phase
(increased precursor production and excretion without symptoms) or to a clin-
ically manifest stage (marked by abdominal, peripheral neurologic, cardiovas-
cular, and psychiatric symptoms).
Alcohol ingestion induces increased activity of ALAS significantly in the
liver and moderately in peripheral tissues. This effect is mediated by alleviat-
ing the negative regulation of ALAS by free heme. Mitochondrial concentra-
tions of free heme are diminished by increased heme utilization and/or
reduced activity of downstream pathway enzymes. In the liver, the demand for
heme is exacerbated by requirement for heme incorporation into alcohol-
eliminating cytochromes P450. Upon increased activity of ALAS, a genetic
defect in either ALAD or PBGD would cause the rapid accumulation of ALA
or both ALA and PBG, resulting in ALAD deficiency porphyria (very rare)
or acute intermittent porphyria, respectively. During an attack, excess ALA
and PBG produced in the liver are secreted into systemic circulation and are
later excreted in the urine. In circulation, these neurotoxic compounds have the
greatest effect on the autonomic and peripheral nervous systems resulting in
the peripheral neuropathy and neurovisceral symptoms, that is, abdominal
pain, nausea and vomiting, tachycardia, and hypertension.
Alternatively, patients with cutaneous porphyrias, for example, porphyria
cutanea tarda or hereditary coproporphyria, chronic symptoms develop as
a result of sun exposure (400 nm radiation). The excess porphyrins accumu-
lated in the skin can absorb light energy and transfer it to damaging chemical
reactions, such as peroxidation of membrane lipids. This manifests as thick-
ening of the dermal vessel walls leading to damage of the epidermal basement
membrane, excessive fragility, blistering, and scarring. In variegate por-
phyria, patients can present with neurovisceral symptoms (acute symptoms
are identical but often milder than those of AIP) and/or cutaneous symptoms.
Porphyrias are diagnosed after demonstration and biochemical identifica-
tion of the increased porphyrin precursor(s). Acute porphyrias are often mis-
diagnosed, and attacks can be fatal. The intravenous administration of heme or
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