Introduction

The porphyrias are metabolic disorders each resulting from mutations that alter the activity of a specific enzyme in the heme biosynthetic pathway (Figure 30.1 and Table 30.1) [1–6]. These enzyme deficiencies are inherited as autosomal dominant, autosomal recessive and X-linked traits, with the exception of porphyria cutanea tarda (PCT), which usually is sporadic. The porphyrias are classified as either hepatic or erythropoietic depending on the primary site of overproduction and accumulation of porphyrin precursors or porphyrins (Table 30.2) although some have overlapping features. The hepatic porphyrias are characterized by overproduction and initial accumulation of porphyrin precursors and/or porphyrins primarily in the liver, whereas in the erythropoietic porphyrias, overproduction and initial accumulation of the pathway intermediates occur primarily in bone marrow erythroid cells.

Figure 30.1 The human heme biosynthetic pathway.

The major manifestations of the acute hepatic porphyrias, which typically present after puberty, are neurologic, including neuropathic abdominal pain, neuropathy, and mental disturbances. The neurologic involvement appears to be the result of hepatic overproduction and accumulation of neurotoxic porphyrin precursors, as liver transplantation has prevented further occurrences of acute attacks in patients with acute intermittent porphyria (AIP) [7–9]. Steroid hormones, drugs, and nutrition influence the hepatic production of porphyrin precursors and porphyrins, thereby precipitating or increasing the severity of some hepatic porphyrias. Rare homozygous variants of the autosomal dominant hepatic porphyrias have been identified and usually manifest clinically before puberty. The symptoms in these patients are usually more severe and occur earlier than those of patients with the respective autosomal dominant porphyria [1].

The erythropoietic porphyrias usually present with cutaneous photosensitivity at birth or in early childhood, or in the case of congenital erythropoietic porphyria (CEP), even in utero as non-immune hydrops fetalis [1, 10, 11]. Cutaneous sensitivity to sunlight results from excitation of excess porphyrins in the skin by long-wave ultraviolet light, leading in CEP to cell damage, scarring, and deformation. Therefore, the porphyrias are metabolic disorders in which environmental, physiologic, and genetic factors interact to cause disease.

Because many symptoms of the porphyrias are nonspecific, diagnosis is often delayed [2]. First-line diagnostic testing involves the determination of the porphyrin precursors and/or porphyrins in urine, feces, plasma, or erythrocytes. A definitive diagnosis is based on demonstration of the specific enzyme deficiency and/or gene mutation(s). The isolation and characterization of the genes encoding the heme biosynthetic enzymes have permitted identification of the pathogenic mutations causing each porphyria. Molecular genetic analyses now make it possible to provide precise heterozygote or homozygote identification and prenatal diagnoses in families with known mutations.

Recent reviews of the porphyrias are available [1–6]. Informative and up-to-date websites are sponsored by the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria Initiative (https://porphyria.eu). An extensive list of unsafe and safe drugs for individuals with porphyria is given at the Drug Database for Acute Porphyrias (www.drugs-porphyria.org).

Heme Biosynthesis

Heme biosynthesis involves eight enzymatic steps in the conversion of glycine and succinyl-coenzyme A (CoA) to heme (Figure 30.1 and Table 30.1) [12]. These eight enzymes are encoded by nine genes, as the first enzyme in the pathway, 5-aminolevulinate synthase (ALA-synthase), has two genes that encode unique housekeeping and erythroid-specific isozymes. The first and the last three enzymes in the pathway are located in the mitochondrion, whereas the other four are in the cytosol. Heme is required for a variety of hemoproteins, such as hemoglobin, myoglobin, respiratory cytochromes, and the cytochrome P450 enzymes (CYPs). Hemoglobin synthesis in erythroid precursor cells accounts for approximately 85% of daily heme synthesis in humans. Hepatocytes account for most of the rest, primarily for synthesis of CYPs, which are particularly abundant in the liver endoplasmic reticulum and turnover more rapidly than many other hemoproteins, such as the mitochondrial respiratory cytochromes. As shown in Figure 30.1, pathway intermediates are the porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), and porphyrins (mostly in their reduced forms, known as porphyrinogens). At least in humans, these intermediates do not accumulate in significant amounts under normal conditions or have important physiologic functions.

The first enzyme, ALA-synthase, catalyzes the condensation of glycine, activated by pyridoxal phosphate and succinyl-CoA, to form ALA. In the liver, this rate-limiting enzyme can be induced by a variety of drugs, steroids, and other chemicals. The distinct non-erythroid (i.e., housekeeping) and erythroid-specific forms of ALA-synthase are encoded by separate genes located on chromosomes 3p21.1 (ALAS1 encoding ALA-synthase 1 (ALAS1)) and Xp11.2 (ALAS2 encoding ALA-synthase 2 (ALAS2)). Loss-of-function mutations in the erythroid gene ALAS2 cause X-linked sideroblastic anemia [1], while gain-of-function mutations in the last exon of ALAS2 cause X-linked protoporphyria (XLP) [13, 14].

The second enzyme, ALA-dehydratase, catalyzes the condensation of two molecules of ALA to form PBG. Four molecules of PBG condense to form the tetrapyrrole uroporphyrinogen (URO) III by a two-step process catalyzed by the third enzyme, hydroxymethylbilane (HMB) synthase (also known as PBG-deaminase), and the fourth enzyme, URO-synthase. The third step, catalyzed by HMB-synthase, is the head-to-tail condensation of four PBG molecules by a series of deaminations to form the linear tetrapyrrole HMB. The fourth enzyme, URO-synthase, catalyzes the rearrangement and rapid cyclization of HMB to form URO III, the asymmetric, physiologic URO isomer required for heme synthesis.

The fifth enzyme in the pathway, URO-decarboxylase, catalyzes the sequential removal of the four carboxyl groups from the acetic acid side-chains of URO III to form coproporphyrinogen (COPRO) III, a tetracarboxyl porphyrinogen. This then enters the mitochondrion, where COPRO-oxidase, the sixth enzyme, catalyzes the decarboxylation of two of the four propionic acid groups to form the two vinyl groups of protoporphyrinogen (PROTO) IX, a dicarboxyl porphyrinogen. Next, PROTO-oxidase, the seventh enzyme, oxidizes PROTO IX to protoporphyrin IX by the removal of six hydrogen atoms. The product of the reaction is a porphyrin (oxidized form), in contrast to the preceding tetrapyrrole intermediates, which are porphyrinogens (reduced forms). Finally, ferrous iron is inserted into protoporphyrin IX to form heme, a reaction catalyzed by the eighth enzyme in the pathway, ferrochelatase (FECH; also known as heme synthetase or protoheme ferrolyase).

Regulation of Heme Biosynthesis

Regulation of heme synthesis differs in the two major heme-forming tissues, the liver and erythron. In the liver, “free” heme regulates the synthesis and mitochondrial translocation of the housekeeping form of ALAS1 [9, 12, 15]. Heme represses the synthesis of the ALAS1 mRNA and interferes with the transport of the enzyme from the cytosol into mitochondria. Hepatic ALAS1 is increased by many of the same chemicals that induce CYPs in the endoplasmic reticulum of the liver. Because most of the heme in the liver is used for the synthesis of CYPs, hepatic ALAS1 and CYPs are regulated in a coordinated fashion, and many drugs that induce hepatic ALAS1 also induce CYPs. The other hepatic heme biosynthetic enzymes are presumably synthesized at constant levels, although their relative activities and kinetic properties differ. For example, normal individuals have much higher activities of ALA-dehydratase than HMB-synthase, the latter being the second rate-limiting step in the pathway [1].

In the erythron, novel regulatory mechanisms allow for the production of the very large amounts of heme needed for hemoglobin synthesis. The response to stimuli for hemoglobin synthesis occurs during cell differentiation, leading to an increase in cell number. The erythroid-specific ALAS2 is expressed at higher levels than the hepatic form, and an erythroid-specific control mechanism regulates iron transport into erythroid cells. During erythroid differentiation, the activities of other heme biosynthetic enzymes may be increased. Separate erythroid-specific and non-erythroid or “housekeeping” transcripts are known for the first four enzymes in the pathway. As noted above, ALAS1 and ALAS2 are encoded by genes on different chromosomes, but for each of the next three genes in the pathway, both erythroid and non-erythroid transcripts are transcribed by alternative promoters from their single respective genes.

Classification of the Porphyrias

The porphyrias can be classified as either hepatic or erythropoietic, depending on whether the heme biosynthetic intermediates that accumulate arise initially from the liver or the developing erythrocytes, or as acute or cutaneous, based on their clinical manifestations. Table 30.2 lists the porphyrias, their principal symptoms, and major biochemical abnormalities. Of the five hepatic porphyrias, AIP, hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA-dehydratase deficient porphyria (ADP), present with acute attacks of neurologic manifestations and elevated levels of one or both of the porphyrin precursors, ALA and PBG; they are, therefore, classified as acute hepatic porphyrias. Symptoms of neuropathic abdominal pain, peripheral neuropathy, and mental disturbances typically develop during adult life [1, 7, 9, 16]. The fifth hepatic porphyria, PCT, usually presents in adults with blistering skin lesions but not acute attacks. Both HCP and VP may cause cutaneous manifestations similar to those of PCT in addition to acute neurologic symptoms.

The erythropoietic porphyrias CEP and erythropoietic protoporphyria (EPP), including the recently described X-linked form, XLP, are characterized by elevations of porphyrins in bone marrow and erythrocytes and usually present in infancy or early childhood with cutaneous photosensitivity [14, 17]. The skin lesions in CEP resemble those of PCT but are usually much more severe, whereas EPP and XLP cause a more immediate, painful, non-blistering type of photosensitivity. Around 20% of patients with EPP (and presumably XLP) develop minor abnormalities of liver function, and up to 5% develop more severe hepatic complications that may be life threatening.

Diagnosis of Porphyrias

A few specific and sensitive first-line laboratory tests should be used whenever symptoms or signs suggest the diagnosis of porphyria [1–4, 17]. If a first-line test is significantly abnormal, more comprehensive testing should follow to establish the type of porphyria. An international consensus article describing the best practice guidelines for the biochemical and genetic diagnosis of the acute hepatic porphyrias has been recently reported [17].

The Acute Hepatic Porphyrias

The major manifestations of the hepatic porphyrias, which typically present after puberty, are neurologic, although some also have cutaneous symptoms. Recommendations for the evaluation and long-term management of these disorders have recently been published [21].

Acute Intermittent Porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant condition resulting from the half-normal level of HMB-synthase activity. The disease is widespread, but may be more common in Scandinavia and Great Britain. In most heterozygous individuals, clinical expression is highly variable. Activation of the disease is often related to environmental or hormonal factors, such as drugs, diet, and steroid hormones. Attacks can often be prevented by avoiding known precipitating factors. Rare homozygous dominant AIP patients have been described.

Clinical Features

Induction of the rate-limiting hepatic enzyme ALAS1 underlies the acute attacks in AIP and the other acute hepatic porphyrias. In the great majority of heterozygous carriers of HMBS mutations, AIP remains latent (or asymptomatic) [26, 27], and this is almost always the case before puberty [1, 2]. In patients with no history of acute symptoms, porphyrin precursor excretion is usually normal, suggesting that half-normal hepatic HMB-synthase activity is sufficient for normal hepatic heme synthesis, and that ALAS1 activity is not increased. When heme synthesis is increased in the liver, half-normal HMB-synthase activity may become limiting and ALA, PBG, and other heme pathway intermediates may accumulate. Common precipitating factors include endogenous and exogenous gonadal steroids, porphyrinogenic drugs, alcohol ingestion, and low-calorie diets, usually instituted for weight loss.

The fact that AIP is almost always latent before puberty suggests that adult levels of steroid hormones are important for clinical expression. Symptoms are more common in women, which suggest a role for female hormones. Premenstrual attacks are probably the result of endogenous progesterone. Acute porphyrias are sometimes exacerbated by exogenous steroids, including oral contraceptive preparations containing progestins. Surprisingly, pregnancy is usually well tolerated, suggesting that beneficial metabolic changes may ameliorate the effects of high levels of progesterone. Table 30.3 is a partial list of the major drugs that are harmful in AIP (and also in HCP, VP, and probably ADP). An extensive list of unsafe and safe drugs for individuals with porphyria is given at the Drug Database for Acute Porphyrias (www.drugs-porphyria.org). Reduced intake of calories and carbohydrates, as may occur with illness or attempts to lose weight, may also increase porphyrin precursor excretion and induce attacks of porphyria. It is not clear that increased carbohydrate intake may prevent or reduce the severity of attacks. Recent findings indicate that hepatic ALAS1 is regulated by the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which may represent an important link between nutritional status and the acute porphyrias [28]. Attacks also may be provoked by infections, surgery, and ethanol. Some patients have repeated attacks without identifiable precipitants.

Table 30.3 Some major drugs considered unsafe and safe in acute porphyrias^a

Unsafe	Safe
Alcohol	Acetaminophen
Barbituratesb	Aspirin
Carbamazepineb	Atropine
Carisoprodolb	Bromides
Clonazepam (high doses)	Cimetidine
Danazolb	Erythropoietinb, c
Diclofenac and possibly other	Gabapentin
Non-steroidal anti-inflammatory	Glucocorticoids
drugsb
Ergots	Insulin
Estrogensc,d	Narcotic analgesics
Ethchlorvynolc	Penicillin and derivatives
Glutethimideb	Phenothiazines
Griseofulvinb	Ranitidineb,c
Mephenytoin	Streptomycin
Meprobamateb (also mebutamate,b tybutamateb)
Methyprylon
Metoclopramideb
Phenytoinb
Primidoneb
Progesterone and synthetic progestinsb
Pyrazinamideb
Pyrazolones (aminopyrine, antipyrine)
Rifampinb
Succinimides (ethosuximide, methsuximide)
Sulfonamide antibioticsb
Valproic acidb

^a A more extensive list of drugs and their status is available in Anderson et al. [1] and at the following websites: www.porphyriafoundation.com, www.porphyria-europe.com and www.drugs-porphyria.com.

^b Porphyria is listed as a contraindication, warning, precaution, or adverse effect in US labeling for these drugs. For drugs listed as unsafe, absence of such cautionary statements in US labeling does not imply lower risk.

^c Although porphyria is listed as a precaution in US labeling, these drugs are regarded as safe by other sources.

^d Estrogens have been regarded as harmful, mostly from experience with estrogen–progestin combinations and because they can exacerbate porphyria cutanea tarda. Although evidence that they exacerbate acute porphyrias is weak, they should be used with caution. Low doses of estrogen (e.g. transdermal) have been used safely to prevent side effects of gonadotropin-releasing hormone analogues in women with cyclic attacks.

Because the neurovisceral symptoms are often nonspecific, the index of suspicion may not be high. The disease is rarely fatal if diagnosed promptly. Severe abdominal pain, the most common symptom, is usually steady and poorly localized but may be cramping. Constipation, abdominal distension, and decreased bowel sounds are common. Increased bowel sounds and diarrhea are less common. Because inflammation is absent, abdominal tenderness, fever, and leukocytosis are usually not prominent. Additional common manifestations include nausea; vomiting; tachycardia; hypertension; mental symptoms; extremity, neck, or chest pain; headache; muscle weakness; sensory loss; tremors; sweating; dysuria; and bladder distension.

The peripheral neuropathy is the result of axonal degeneration (rather than demyelinization) and primarily affects motor neurons. Findings such as tachycardia, hypertension, sweating, and tremors may be the result of sympathetic overactivity. Motor neuropathy affects the proximal muscles initially, more often in the shoulders and arms. Muscle weakness may progress to respiratory and bulbar paralysis and death, particularly when diagnosis and treatment are delayed. Sudden death occurs occasionally, perhaps from sympathetic overactivity or cardiac arrhythmia.

Mental symptoms are often prominent during attacks and may include insomnia, agitation, disorientation, hallucinations, and depression. Seizures may be a neurologic manifestation of the disease or may be the result of hyponatremia. The latter results from inappropriate vasopressin secretion or electrolyte depletion. Abdominal pain may resolve within hours and paresis within days. However, severe motor neuropathy may continue to improve over several years. Long-term risks for hypertension, impaired renal function, and hepatocellular carcinoma are increased.

Recently, it was recognized that a significant percentage of patients with AIP develop renal insufficiency, which can lead to renal failure [29, 30]. Investigation of these patients led to the recognition that a polymorphism in the PEPT2 gene (*1*1 or *1*2) caused the reabsorption of ALA from the urine, resulting in renal cell toxicity and declining renal function. Thus, all acute hepatic porphyria patients should have this PEPT2 polymorphism analyzed, and those at-risk for renal insufficiency and failure should have their renal function evaluated at least annually.

Diagnosis

Both ALA and PBG levels are increased in plasma and urine during acute attacks [1, 2]. Although the diagnosis of an acute attack is based on clinical findings and not the absolute level of these porphyrin precursors, the increase is expected to be substantial. Excretion of PBG is usually 50–200 mg/24 hours (220–880 mmol/24 hours; normal, 0–4 mg/24 hours (0–18 mmol/24 hours)), and urinary ALA excretion is 20–100 mg/24 hours (150–760 mmol/24 hours; normal, 1–7 mg/24 hours (8–53 mmol/24 hours)). Levels of these porphyrin precursors decrease after an attack, but usually remain elevated, except with prolonged remissions. Decreases after hemin infusions are dramatic, but usually transient. A normal urinary or plasma PBG level effectively excludes AIP as a cause for current symptoms. Fecal and plasma porphyrins are normal or minimally increased in AIP, in contrast to HCP and VP.

Most asymptomatic (“latent”) heterozygotes with HMB-synthase deficiency, particularly those who have never had symptoms, have normal urinary excretion of ALA and PBG. The enzyme deficiency is detectable in erythrocytes from most AIP heterozygotes (Table 30.4). However, the activity is higher in young erythrocytes, and a concurrent condition that increases erythropoiesis may increase the enzyme into the normal range in a patient with AIP. Of note, the erythroid and housekeeping forms of HMB-synthase are encoded by a single HMBS gene with two promoters [18, 19]. Some mutations, usually found within exon 1, particularly in the initiation of translation codon, affect only the non-erythroid enzyme, while the erythroid enzyme is transcribed normally. Therefore, patients with the rare “erythroid form” of AIP “or variant AIP” have normal enzyme levels in erythrocytes and deficient activity in non-erythroid tissues [1, 18, 19]. Thus, normal erythrocyte HMB-synthase activity occurs in the “variant form” of AIP, as noted above. Therefore, the detection of AIP family’s HMBS gene mutation is important for diagnostic confirmation of all symptomatic patients and for identification of asymptomatic family members with this enzyme deficiency.

Table 30.4 Homozygous forms of porphyria

Porphyria	Deficient enzyme	Clinical onset	Principal symptoms		Other symptoms
			Neurovisceral	Cutaneous photosensitivity
Hepatic
Homozygous dominant acute intermittent porphyria	HMB synthase	Infancy & childhood	+	–	Absence of acute attacks, development delay
Hepatoerythropoietic porphyria	URO decarboxylase	Childhood	–	+	Rare anemia
Homozygous dominant coproporphyria	COPRO oxidase	Childhood	+	+	Growth retardation
Harderoporphyria	COPRO oxidase	Infancy & childhood	–	+	Neonatal hemolytic jaundice & anemia
Homozygous dominant variegate porphyria	PROTO oxidase	Infancy & childhood	+	+	Absence of acute attacks, mental retardation, hand deformities
Erythropoietic
Homozygous erythropoietic protoporphyria	Ferrochelatase	Childhood	–	+
Congenital erythropoietic porphyria	URO synthase	Infancy, childhood and later onset	–	+	Anemia

COPRO, coproporphyrinogen; HMB, hydroxymethylbilane; PROTO, protoporphyrinogen; URO, uroporphyrinogen.

Source: modified from Elder, 1997 [5].

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