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900 Part VI: The Erythrocyte Chapter 58: The Porphyrias 901

clusters as a result of founder effects occur in some countries. A founder tryptophan in plasma and brain, leading to increased synthesis of the
mutation in northern Sweden is associated with a disease prevalence of neurotransmitter 5-hydroxytryptamine.
1 per 1500 population. The prevalence of low PBG deaminase activity, ALA is increased in a number of disorders with similar neurologic
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which includes latent gene carriers of AIP, is as high as 1 per 500 in the manifestations, including all four of the acute porphyrias, lead poison-
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general population of Finland. Based on DNA studies, the minimal ing, and hereditary tyrosinemia type I, which favors a neuropathic role
prevalence of the AIP-associated genes in France has been calculated to for this porphyrin precursor or perhaps a derivative. ALA can enter cells
be 1 per 1675 population. 187 readily and be converted to porphyrins, which, in turn, may have toxic
potential. ALA is also structurally similar to γ-aminobutyric acid and
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Pathophysiology can interact with γ-aminobutyric acid receptors. 195,196 However, studies
PBG deaminase is also known as HMB synthase, and formerly as uro- of ALA loading have not shown adverse effects.
porphyrinogen I synthase. PBGD mutations have been classified based Impaired motor function with ataxia develops in mice with PBGD
in part on the presence or absence of cross-reactive immunologic deficiency resulting from compound heterozygous or homozygous
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material (CRIM), which indicates the presence of inactive enzyme mutations induced by gene targeting. Induction of hepatic CYPs is
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protein. Type I mutations are CRIM-negative, with reduction of both impaired in these animals and corrected by heme. But motor neur-
enzyme activity and protein to approximately 50 percent of normal in opathy can develop even with normal or only slightly increased ALA
heterozygotes. Type II mutations are associated with reduced PBGD in plasma and urine, suggesting a primary role for heme deficiency in
activity only in nonerythroid tissue. These patients with “variant porphyric neuropathy in this murine model. 199
AIP” comprise less than 5 percent of AIP patients, and have normal Precipitating Factors Acute attacks are precipitated in some hete-
erythrocyte PBGD activity and decreased hepatic activity because, rozygotes by various endogenous or exogenous factors that are additive.
as explained earlier in the section on hydroxymethylbilane synthase, Additional unknown genetic factors are also likely to contribute. Some
transcription of the gene to form the erythroid-specific enzyme individuals remain susceptible to repeated attacks even after avoidance
starts downstream of the site of the mutation. Type III are CRIM- of known precipitants. Many precipitating factors cause induction of
positive mutations that result in decreased activity with structurally hepatic ALAS1, which is closely associated with induction of CYPs and
abnormal enzyme protein. 188 leads to overproduction of ALA and other pathway intermediates.
Drugs and Other Exogenous Chemicals Most drugs that are
Pathogenesis of the Clinical Findings harmful in acute porphyrias are known inducers of hepatic CYPs. These
A partial deficiency of PBGD rarely causes clinical expression of AIP, drugs increase de novo heme synthesis, thereby derepressing hepatic
and most individuals who inherit this enzyme deficiency remain healthy ALAS1, and also directly induce this rate-limiting enzyme. Table 58–4
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with normal porphyrin precursor excretion throughout life. Certain identifies some drugs that are known to be harmful or safe. Information
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drugs and hormones that exacerbate AIP can directly induce ALAS and regarding safety of many drugs in clinical practice is uncertain or lack-
also increase the demand for heme by inducing CYP enzymes, which ing. More extensive drug safety databases are available at the websites
turn over rapidly and use most of the heme synthesized in the liver. 189 of the American Porphyria Foundation (www.porphyriafoundation.
When heme synthesis is stimulated, the partial enzyme deficiency com) and the European Porphyria Initiative (www.porphyria-europe.
in AIP apparently impairs heme synthesis sufficiently to compromise com). These drug classifications are often based on limited evidence
negative feedback by the regulatory heme pool, which controls synthe- and may be controversial. Ethanol and other alcohols are inducers of
sis of the rate-limiting enzyme ALAS1. This leads to marked induction hepatic ALAS1 and some CYPs. Smoking is known to increase CYPs
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of ALAS1 and overproduction of ALA, PBG and porphyrins in the liver. in humans, probably from effects of polycyclic aromatic hydrocar-
It is generally accepted, although not proven, that hepatic PBGD bons, and has been associated with more frequent symptoms of acute
remains constant at approximately 50 percent of normal activity dur- porphyria. 201
ing exacerbations and remissions of AIP, as in erythrocytes. An early Endocrine Factors Rarity of symptoms before puberty and more
report suggested that the enzyme activity is considerably less than half- common clinical expression in women point to hormonal factors as
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normal in liver during an acute attack, but additional data is lacking. important contributors in AIP. Although estrogens are considered
It has been suggested that once the disease becomes activated, excess harmful, it is likely that progesterone is mostly responsible for cyclic
PBG may interfere with assembly of the dipyrromethane cofactor for premenstrual attacks that occur in some women. Progesterone, certain
this enzyme. metabolites of testosterone, and synthetic progestins are potent induc-
Clinical improvement and normalization of porphyrin precursor ers of ALAS1. Thus administration of progestational agents should be
excretion after liver transplantation in patients with severe AIP is a avoided. Diabetes mellitus is not known to precipitate attacks of por-
clear indication that the liver plays an essential role in neuropathic pro- phyria, and has been observed to decrease the frequency of attacks and
cesses in the acute porphyrias. Proposed explanations for neurologic lower porphyrin precursor levels, possibly in relation to high circulating
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dysfunction in the acute porphyrias include the following. (1) Heme glucose levels. 202
pathway intermediates or products derived from them may be neu- Pregnancy Pregnancy is usually well tolerated. Attacks during
203
rotoxic. This hypothesis is most favored, although the evidence is not pregnancy are sometimes a result of harmful drugs or reduced caloric
conclusive. (2) PBG deaminase deficiency in the nervous system tissues intake. Metoclopramide, considered at least by some a contraindicated
may limit heme synthesis and formation of important hemoproteins. drug, is associated with exacerbation of the disease when used to treat
For example, decreased activity of the hemoprotein nitric oxide syn- hyperemesis gravidarum. 204,205 But for reasons that are not clear, some
thase might decrease production of nitric oxide and cause vasospasm, women experience attacks during pregnancy even when harmful fac-
which might account for some cerebral manifestations of AIP, 191,192 and tors are avoided.
possibly compromise intestinal blood flow. However, regulation of Nutrition Reduced intake of calories and carbohydrate can exac-
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heme and hemoprotein synthesis in nervous tissue and blood vessels erbate acute porphyrias. This may occur from efforts to lose weight,
is difficult to study, and convincing evidence is lacking. (3) Impaired bariatric surgery or from metabolic stress from an illness or sur-
hepatic heme synthesis during an attack may lead to decreased activ- gery. Under these conditions, upregulation of PGC-1α can lead to
ity of hepatic tryptophan pyrrolase, which might increase levels of induction of ALAS1, increases in ALA and PBG, and symptoms of

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