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INTRODUCTION

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The porphyrias are a group of inherited disorders of hemoglobin biosynthesis, commonly classified according to the broad definitions of neuropsychiatric, dermatological (cutaneous), or mixed. Other classifications of the porphyrias are based on the deficient enzyme, the location of abnormal porphyrin production, or according to the risk of an acute attack (Table 101-1). There are eight susceptible enzymes in the biosynthetic pathway, each characterized by accumulation of porphyrins in body tissues as a result of overproduction or accumulation of porphyrin precursors (Figure 101-1). Abnormal porphyrin production is seen in either the hepatic or the erythropoietic system.

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TABLE 101-1Classification of Porphyrias
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FIGURE 101-1

The human heme biosynthetic pathway. (Reproduced with permission from Kasper DK, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill Education, Inc.; 2015: Fig. 430-1.)

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PATHOPHYSIOLOGY

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The terms porphyrin and porphyria derive from the Greek word porphyra (porphura), meaning purple. The urine of some patients may appear reddish in color due to the excess porphyrins present and exposure to light. Heme is the most important porphyrin as it relates to human physiology. Heme is then bound to numerous proteins to form hemoproteins, including hemoglobin, myoglobin, nitric oxide synthetase, and all of the cytochromes, among others. The majority of the enzyme deficiencies are inherited as autosomal dominant or recessive traits, porphyria cutanea tarda (PCT) being the exception.

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Aminolevulinic acid (ALA) synthetase appears to be the rate-limiting step in heme biosynthesis and enzymatically forms δ-aminolevulinic acid from succinyl coenzyme A and glycine. The end-product heme then exerts negative-feedback regulation on ALA synthetase, resulting in a very efficient biosynthetic pathway. ALA synthetase is also rapidly inducible as it relates to the drugs causing an increased demand on heme products, namely cytochromes. The manifestations of the disease are thought to be due to an increase in the activity of this enzyme, a decrease in heme production, or an increased porphyrin accumulation in tissues. The increased levels of precursors, as a result of specific enzyme deficiency, are irreversibly oxidized to the porphyrins, which have no other known physiologic function, and lead to tissue accumulation and neuronal damage.

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Though the pathogenesis of the clinical manifestations is poorly understood, multiple mechanisms have been postulated: direct neurotoxicity of ALA on peripheral and autonomic neurons, inhibition of γ-aminobutyric acid release by ALA, heme deficiency in nervous tissue, decreased activity of a heme-dependent hepatic enzyme, leading to elevated brain tryptophan, and increased ...

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