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Chapter 38 Heme Biosynthesis and Its Disorders 503

Differential Diagnosis of Acute Intermittent Porphyria Management of Acute Porphyria
Attacks of acute porphyria must be distinguished from other causes of Treatment of Acute Attack
acute abdominal pain or peripheral neuropathy sometimes associated A carbohydrate intake of 1500–2000 kcal/24 hours should be
with psychosis. Heavy metal poisoning (i.e., lead or arsenic) and maintained throughout the attack to reduce porphyrin synthesis; give
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Guillain-Barré syndrome must be considered, as well as paroxysmal this orally or, for more severe attacks, through a fine-bore Teflon
nocturnal hemoglobinuria with its characteristic early morning hemo- nasogastric tube. If this cannot be tolerated, intravenous dextrose (e.g.,
globinuria and abdominal pain. 65 20% solution, 2 L/day) should be given. If early in the attack (2–4 days
During an attack, all patients excrete a massive excess of the porphy- from onset), give intravenous hematin as heme arginate (Normosang,
rin precursors, 5-aminolevulinate (ALA) and porphobilinogen (PBG), in Orphan Europe, Normosang, Medunik Canada) at 2–4 mg/kg over 30
their urine. Urine, when first voided, is clear and darkens on exposure minutes once or twice each day to further reduce the overproduction
to light as the hexa-hydroporphyrins, the porphyrinogens, are oxidized of porphyrin and precursors. 81,82 Hematin (Panhematin, Recordati Rare
to porphyrins. Diseases, Lebanon, NJ) in similar doses may also be used, although it
A rapid screening test during an acute attack is to mix equal volumes should be reconstituted in human albumin solution to avoid phlebitis
of urine and Ehrlich aldehyde reagent and observe for the pink color of and mild transient prolongation of coagulation times. No renal compli-
porphobilinogen; alternatively, the urine can be left standing in sunlight cations have occurred with the standard recommended dosages, and
to observe darkening in color. The differential diagnosis of porphyrias even patients with renal insufficiency tolerate hematin well, although
uses qualitative and quantitative measurement of porphyrins and the dosage should be reduced slightly. Severe hepatic toxicity has been
precursors, with subsequent use of enzymatic assay and identification associated with rapid infusion of higher doses of heme arginate. The
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of familial genetic alterations. 66 action of heme therapy may be extended by heme oxygenase blockers
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such as tin protoporphyrin. Liver transplantation may be an effective
treatment for life-threatening acute intermittent porphyria that fails to
respond to medical therapy. 84
Prophylaxis
Many drugs are contraindicated, and the patient must be warned to
avoid precipitating factors. Alcohol should be restricted and smoking
discouraged. Dieting (<800 kcal/day) must be avoided. Pregnancy
should also be avoided if the disease is active. If a patient requires
an anesthetic, nitrous oxide, ether, and cyclopropane are safe, and
suxamethonium appears to be a safe muscle relaxant. The opiates and
belladonna derivatives can be used for premedication and propofol for
maintenance of anesthesia. Infection can precipitate an attack and
should therefore be sought and treated. Blood relatives of patients
should be screened to see if they carry the gene.
Luteinizing hormone-releasing hormone (LH-RH) antagonists that
suppress ovulation are a valuable form of prophylaxis in menstrually
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related attacks. Estrogens and progestogens such as those in the con-
traceptive pill must be avoided in acute porphyria. The same applies to
most steroids and receptor antagonists such as mifepristone. 86

Fig. 38.5 CUTANEOUS LESIONS AND SCARRING IN A PATIENT been described leading to 50% reduction in enzyme activity. The
WITH VARIEGATE PORPHYRIA.
functional consequences of many of these mutations have been pre-
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dicted based on the crystal structure of the enzyme. In a few cases,
the activity of which is decreased, 67,68 leading to overproduction of homozygosity or compound heterozygosity has been described. 49,75
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coproporphyrin. A clinically distinct variant of hereditary copropor-
phyria, harderoporphyria, is associated with severe jaundice and
hemolysis and is caused by specific mutations that lead to accumula- Acute Hepatic Porphyria
tion of harderoporphyrins. 70
The porphyrin precursors ALA and PBG and the more water- In this porphyria (also known as ALA dehydratase deficiency por-
soluble porphyrins (with multiple carboxyl groups) are excreted phyria or plumboporphyria), the ALA dehydratase activity is
mainly in the urine. Other porphyrins are mainly excreted in the feces depressed, such as seen with a low-function variant of the enzyme in
by way of bile. a subject exposed to lead. The clinical picture resembles AIP, but very
few cases have been described, and the disease only manifests in
homozygous cases when there is a precipitating factor. 76,77
Variegate Porphyria

Variegate porphyria is similar to hereditary coproporphyria, except Concurrent Porphyrias
that there are more severe skin lesions, sometimes with scarring (Fig.
38.5). Protoporphyrinogen oxidase is the affected enzyme, and pro- The concurrent porphyrias are a rare group of conditions in which
toporphyrin is the major circulating porphyrin. Conventionally, there is concurrent inheritance of two different defects within the
variegate porphyria is most readily diagnosed by measurement of fecal heme biosynthetic pathway, although this requires confirmation from
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porphyrin concentrations. However, it has been reported that molecular evidence. Previous descriptions 52–54 have shown the pres-
biliary porphyrin levels may provide a better discriminator from ence of concurrent porphyria within a family, and toxicologically
normal patients in the asymptomatic phase. As in erythropoietic there is good evidence that exposure to poisons such as lead can
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protoporphyria, there is a tendency toward cholelithiasis. The mecha- induce multiple changes within the pathway. The first reported
nism by which gallstones form is not certain, but some studies have example of concurrent porphyria in a family combined the clinical
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suggested that porphyrins are cholestatic. In hereditary copropor- features of acute and cutaneous porphyria, and biochemical analysis
phyria and variegate porphyria, the pathway intermediates produced confirmed the segregation of variegate porphyria and PCT as inde-
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in excess, coproporphyrinogen and protoporphyrinogen, respectively, pendent inherited traits. In another patient, dual genetic defects
are inhibitors of the secondary rate-controlling enzyme PBGD. 35,73 involving ALA dehydratase and coproporphyrinogen oxidase have
52
Numerous mutations in the protoporphyrinogen oxidase gene have been described (see box on Management of Acute Porphyria).