Chapter 30 – Heme Biosynthesis and the Porphyrias in Children




Abstract




The porphyrias are metabolic disorders each resulting from the deficiency 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.





Chapter 30 Heme Biosynthesis and the Porphyrias in Children


Robert J. Desnick , Manisha Balwani , and Karl E. Anderson



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) [16]. 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.




Table 30.1 Human heme biosynthetic enzymes and genes












































































































































































Enzyme Gene symbol Chromosomal location cDNA (bp) Gene Protein (aa) Subcellular location Known mutationsb 3D structurec
Size (kb) Exonsa
5′-Aminolevulinate synthase
Housekeeping ALAS1 3p21.1 2199 17 11 640 M
Erythroid-specific ALAS2 Xp11.2 1937 22 11 587 M 6 (?)
5′-Aminolevulinate dehydratase
Housekeeping ALAD 9q32 1149 15.9 12 (1A + 2–12) 330 C 14 Y
Erythroid-specific ALAD 9q32 1154 15.9 12 (1B + 2–12) 330 C
Hydroxymethylbilane synthase
Housekeeping HMBS 11q23.3 1086 11 15 (1 + 3–15) 376 C 510 E
Erythroid-specific HMBS 11q23.3 1035 11 15 (2–15) 344 C
Uroporphyrinogen III synthase
Housekeeping UROS 10q26.2 1296 34 10 (1 + 2B–10) 265 C > 55 H
Erythroid-specific UROS 10q26.2 1216 34 10 (2A+ 2B–10) 265 C > 5 (?)
Uroporphyrinogen decarboxylase UROD 1p34.1 1104 3 10 367 C > 155 H
Coproporphyrinogen oxidase CPOX 3q12.1 1062 14 7 354 M 92 H
Protoporphyrinogen oxidase PPOX 1q23.3 1431 5.5 13 477 M 205
Ferrochelatase FECH 18q21.31 1269 45 11 423 M > 220 B


3D, three-dimensional; aa, amino acid residues; C, cytoplasm; M, mitochondria.




a Number of exons and those encoding separate housekeeping and erythroid-specific forms indicated in parentheses.



b Number of known mutations from the Human Gene Mutation Database (www.hgmd.org) as of March 2020.



c Crystallized from human (H), murine (M), Escherichia coli (E), Bacillus subtilis (B), or yeast (Y) purified enzyme; references in Protein Data Bank (www.rcsb.org).


Source: from Anderson et al. [1].

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) [79]. 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 [16]. Informative and up-to-date websites are sponsored by the American Porphyria Foundation (www.porphyriafoundation.com) and the European Porphyria Initiative (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.




Table 30.2 Human porphyrias: major clinical and laboratory features


















































































































Porphyria Deficient enzyme Inheritance Principal symptoms Enzyme activity (% normal) Increased porphyrin precursors and/or porphyrinsa
Erythrocytes Urine Stool
Hepatic
5-ALA dehydratase- deficient porphyria ALA dehydratase AR NV ~5 Zn- protoporphyrin ALA, coproporphyrin III
Acute intermittent porphyria HMB synthase AD NV ~50 ALA, PBG, uroporphyrin
Porphyria cutanea tarda URO decarboxylase AD CP ~20 Uroporphyrin, 7- carboxylporphyrin Isocoproporphyrin
Hereditary coproporphyria COPRO oxidase AD NV & CP ~50 ALA, PBG, coproporphyrin III Coproporphyrin III
Variegate porphyria PROTO oxidase AD NV & CP ~50 ALA, PBG, coproporphyrin III Coproporphyrin III, protoporphyrin
Erythropoietic
Congenital erythropoietic porphyria URO synthase AR CP 1–5 Uroporphyrin I, coproporphyrin I Uroporphyrin I, coproporphyrin I Coproporphyrin I
Erythropoietic protoporphyria Ferrochelatase ARb CP ~20–30 Protoporphyrin Protoporphyrin (free)
X-linked protoporphyria ALA synthase 2 XL CP ~100c Protoporphyrin Protoporphyrin (Zn & free)


AD, autosomal dominant; ALA, 50-aminolevulinate; AR, autosomal recessive; COPRO, coproporphyrinogen; CP, cutaneous photosensitivity; HMB, hydroxymethylbilane; NV, neurovisceral; PROTO, protoporphyrinogen; URO, uroporphyrinogen; XL, X-linked.




a Increases that may be important for diagnosis.



b A polymorphism in intron 3 of the wild-type allele affects the level of enzyme activity and clinical expression.



c Increased activity from “gain-of-function” mutations in ALAS2 exon 11.


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 [14, 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].



Acute Hepatic Porphyrias


An acute hepatic porphyria should be suspected in patients with neurovisceral symptoms after puberty, such as abdominal pain, when the initial clinical evaluation does not suggest another cause, and the urinary and/or plasma porphyrin precursors (ALA and PBG) should be measured. Urinary and plasma PBG levels are always increased during acute attacks of AIP, HCP, and VP and are not substantially increased in any other medical condition. Therefore, this measurement is both sensitive and specific. A method for rapid, in-house testing for urinary PBG should be available. Results from spot (single-void) urine specimens are highly informative because very substantial increases in PBG are expected during acute attacks of porphyria. A 24-hour collection may unnecessarily delay diagnosis. The same spot urine specimen should be saved for quantitative determination of ALA and PBG to confirm the qualitative PBG result and also to detect elevations of ALA in rare patients with ADP. Urinary porphyrins may remain increased longer than porphyrin precursors in HCP and VP. Therefore, it is useful to measure total urinary porphyrins in the same sample, keeping in mind that urinary porphyrin increases are often nonspecific. Measurement of urinary porphyrins alone should be avoided for screening because these may be increased in disorders other than porphyrias, such as chronic liver disease, and misdiagnoses of porphyria may result from minimal increases in urinary porphyrins that have no diagnostic significance. Measurement of erythrocyte HMB-synthase is not useful because it does not differentiate latent from active AIP, and there is significant overlap of low normal and high heterozygote values. Also, there is a variant form of AIP in which the HMB-synthase is normal in erythrocytes, but deficient in the liver [18, 19]. Thus, the enzyme activity is not decreased in all patients with AIP and is never deficient in other acute porphyrias. Once a biochemical diagnosis is established, mutation analysis of the appropriate heme biosynthetic gene should be undertaken. Molecular diagnostic studies are also useful to identify at-risk family members who have “latent” or asymptomatic AIP once the specific mutation is known in the index case.



Cutaneous Porphyrias


Blistering skin lesions caused by porphyria are virtually always accompanied by increases in total plasma porphyrins. A fluorometric method is preferred because the porphyrins in plasma in VP are mostly covalently linked to plasma proteins and may be less readily detected by high-performance liquid chromatography. The normal range for plasma porphyrins is somewhat increased in patients with end-stage renal disease. Although a total plasma porphyrin determination will usually detect EPP and XLP, which have symptoms of non-blistering photosensitivity, an erythrocyte protoporphyrin determination is more sensitive. However, because increases in erythrocyte protoporphyrin occur in many other conditions, the diagnosis of EPP must be confirmed by showing a predominant increase in metal-free protoporphyrin rather than zinc protoporphyrin. In XLP, both metal-free and zinc protoporphyrin are markedly increased, the zinc protoporphyrin being 15–50% of the total erythrocyte porphyrins [14, 20].


More extensive testing is justified when an initial test is positive [14]. A substantial increase in PBG may be caused by AIP, HCP, or VP. These acute porphyrias can be distinguished by measuring urinary porphyrins (using the same spot urine sample), fecal porphyrins, and plasma porphyrins. Enzymatic assays for COPRO-oxidase and PROTO-oxidase are not widely available. The various porphyrias that cause blistering skin lesions are differentiated by measuring porphyrins in urine, feces, and plasma. Confirmation at the DNA level by the demonstration of the causative mutation(s) is important after the diagnosis is established by biochemical testing and also permits family studies. Further details are provided in the following sections on each type of porphyria.



Testing for Subclinical Porphyria


It is often difficult to diagnose or “rule out” porphyria in patients who had suggestive symptoms months or years in the past, and in relatives of patients with acute porphyrias, because porphyrin precursors and porphyrins may be normal. More extensive testing and consultation with a specialist laboratory and physician may be needed. Before evaluating relatives, the diagnosis of porphyria should be firmly established in an index case and the laboratory results reviewed to guide the choice of tests for the family members. The index case or another family member with confirmed porphyria should be retested if necessary. Identification of a disease-causing mutation in an index case greatly facilitates detection of additional gene carriers.



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].



5’-Aminolevulinate-Dehydratase Deficient Porphyria


Severe deficiency of ALA-dehydratase activity gives rise to a rare autosomal recessive acute hepatic porphyria [1, 7]. To date, there are only a few documented cases, including five in children or adolescents, in which specific gene mutations have been identified [1, 2224]. These affected homozygotes had less than 10% of normal ALA-dehydratase activity in erythrocytes, but their clinically asymptomatic parents and heterozygous relatives had about half-normal levels of enzyme activity and did not excrete increased levels of ALA. The frequency of ALA-dehydratase deficient porphyria (ADP) is not known, but the frequency of heterozygous individuals with less than 50% normal ALA-dehydratase activity was approximately 2% in a population screening study in Sweden. Because there are multiple causes for deficient ALA-dehydratase activity, it is important to confirm the diagnosis of ADP by mutation analysis.



Clinical Features

The clinical presentation is variable, presumably depending on the amount of residual ALA-dehydratase activity. All patients had significantly elevated levels of plasma and urinary ALA and markedly decreased ALA-dehydratase activity. Four of the reported patients were male adolescents with symptoms resembling those of AIP, including abdominal pain and neuropathy [22]. One patient was an infant with more severe disease, including failure to thrive beginning at birth. Earlier onset and more severe manifestations in this patient reflected a more significant deficiency of ALA-dehydratase activity [22, 24]. Another patient was essentially normal until age 63, when he developed an acute motor polyneuropathy that was associated with a myeloproliferative disorder. This patient was heterozygous for an ALA-dehydratase mutation that presumably was present in erythroblasts that underwent clonal expansion because of the bone marrow malignancy.



Diagnosis

Patients have increased urinary levels of ALA and COPRO III. Urinary PBG is normal or slightly increased. In erythrocytes, ALA-dehydratase activity is less than 10% of normal, and zinc protoporphyrin is markedly elevated. Hereditary tyrosinemia type I (fumarylacetoacetase deficiency) and lead intoxication should be considered in the differential diagnosis because either succinylacetone (which accumulates in hereditary tyrosinemia type I and is structurally similar to ALA) or lead can inhibit ALA-dehydratase, increase urinary excretion of ALA and erythrocyte zinc protoporphyrin, and cause manifestations that resemble those of the acute porphyrias. Heterozygotes are clinically asymptomatic and do not excrete increased levels of ALA but can be detected by demonstration of intermediate levels of erythrocyte ALA-dehydratase activity or a specific mutation in the gene for ALA-dehydratase. To date, molecular studies of patients with ADP have identified nine missense/nonsense and two splice-site mutations, as well as a two-base deletion in the ALAD gene encoding ALA-dehydratase (Human Gene Mutation Database, www.hgmd.org) [23]. The parents in each case were not consanguineous, and the index cases had inherited a different ALAD mutation from each parent. Prenatal diagnosis of this disorder is possible by determination of the ALA-dehydratase activity and/or ALAD gene mutations in cultured chorionic villi or amniocytes. Of note, a common polymorphism (K59 N) has been identified that alters zinc binding, but retains normal activity [25].



Treatment

The treatment of acute attacks in the four males who developed symptoms during adolescence was similar to that of AIP (see below) and included decreased symptoms from intravenous hemin treatment. The severely affected patient who did not survive infancy was supported by hyperalimentation and periodic blood transfusions, but did not respond biochemically or clinically to hemin or liver transplantation.



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 porphyriasa



























































































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

Feb 26, 2021 | Posted by in GASTROENTEROLOGY | Comments Off on Chapter 30 – Heme Biosynthesis and the Porphyrias in Children
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