Acute Intermittent Porphyria Guidelines

Gastroenterology 2019;-:1–17
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PERSPECTIVES
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REVIEWS AND
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Q1 Clinical Guide and Update on Porphyrias 64
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6 Q17 Ulrich Stölzel,1 Manfred O. Doss,2,3 and Detlef Schuppan3,4 66
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8 1 68
Saxony Porphyria Center, Department of Internal Medicine II, Klinikum Chemnitz, Chemnitz, Germany; 2German Competence
9 Center for Porphyria Diagnosis and Consultation, Marburg, Germany; 3Institute of Translational Immunology and Research 69
10 Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany; and 4Division of 70
11 Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 71
12 72
13 Physicians should be aware of porphyrias, which could be ubiquitous precursors of heme, which contains a central iron 73
14 responsible for unexplained gastrointestinal, neurologic, atom. The heme-bound iron of hemoglobin or myoglobin in 74
15 or skin disorders. Despite their relative rarity and blood and tissues reversibly binds and transports oxygen; 75
16 complexity, most porphyrias can be easily defined and heme enzymes such as cytochromes, nitric oxide synthases, 76
17 diagnosed. They are caused by well-characterized enzyme cyclooxygenases, peroxidases, catalases, and tryptophan 77
18 defects in the complex heme biosynthetic pathway and are pyrrolase catalyze important biochemical reactions in cells. 78
19 divided into categories of acute vs non-acute or hepatic vs Most of the porphyrins emit red fluorescence when exposed 79
20 erythropoietic porphyrias. Acute hepatic porphyrias (acute to long-wave (366 nm) ultraviolet light, as exemplified by 80
21 intermittent porphyria, variegate porphyria, hereditary brown, high protoporphyrin-containing chicken eggshells 81
22 coproporphyria, and aminolevulinic acid dehydratase (Supplementary Figure 1).1 82
23 deficient porphyria) manifest in attacks and are charac- The liver synthesizes 20% of heme, which regulates its 83
24 terized by overproduction of porphyrin precursors, pro- 84
own production via interaction with 5-aminolevulinate syn-
ducing often serious abdominal, psychiatric, neurologic, or
25 thase 1 (ALAS1).2 Most of the remaining 80% of heme is 85
cardiovascular symptoms. Patients with variegate
26 produced in the bone marrow. In contrast to the liver, iron 86
porphyria and hereditary coproporphyria can present with
27 and erythropoietin, instead of heme, regulate the rate- 87
skin photosensitivity. Diagnosis relies on measurement of
28 controlling bone marrow enzyme ALAS2.3 The known por- 88
increased urinary 5-aminolevulinic acid (in patients with
29 aminolevulinic acid dehydratase deficient porphyria) or phyrias, rare disorders of heme biosynthesis, produce many 89
30 increased 5-aminolevulinic acid and porphobilinogen (in symptoms. The acute hepatic porphyrias (AHPs) (acute 90
31 patients with other acute porphyrias). Management of intermittent porphyria [AIP], variegate porphyria [VP], he- 91
32 attacks requires intensive care, strict avoidance of por- reditary coproporphyria [HCP], and aminolevulinic acid 92
33 phyrinogenic drugs and other precipitating factors, caloric dehydratase deficient porphyria [ALADP]) produce mostly 93
34 support, and often heme therapy. The non-acute por- abdominal, neurologic, psychiatric, and cardiovascular 94
35 phyrias are porphyria cutanea tarda, erythropoietic pro- symptoms. In patients with non-acute porphyrias (porphyria 95
36 toporphyria, X-linked protoporphyria, and the rare cutanea tarda [PCT], hepatoerythropoietic porphyria [HEP], 96
37 congenital erythropoietic porphyria. They lead to the erythropoietic protoporphyria [EPP], X-linked proto- 97
38 accumulation of porphyrins that cause skin photosensi- porphyria [XLP], and congenital erythropoietic porphyria 98
39 tivity and occasionally severe liver damage. Secondary [CEP]), porphyrins that were generated by spontaneous 99
40 elevated urinary or blood porphyrins can occur in patients oxidation from porphyrinogens accumulate upstream of the 100
41 without porphyria, for example, in liver diseases, or iron affected enzyme to cause skin photosensitivity (photo- 101
42 deficiency. Increases in porphyrin precursors and por- dermatosis) and sometimes severe liver damage. 102
43 phyrins are also found in patients with lead intoxication. Porphyrias are diagnosed and differentiated by specific 103
44 Patients with porphyria cutanea tarda benefit from iron biochemical patterns of elevated porphyrins and 104
45 depletion, hydroxychloroquine therapy, and, if applicable, 105
porphyrin precursors in urine, feces, and blood (Table 1,
46 elimination of the hepatitis C virus. An a-melanocyte– 106
stimulating hormone analogue can reduce sunlight sensi-
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tivity in patients with erythropoietic protoporphyria or X-
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linked protoporphyria. Strategies to address dysregulated Abbreviations used in this paper: AHP, acute hepatic porphyria; AIP,
49 acute intermittent porphyria; ALA, 5-aminolevulinic acid; ALAD, 5-
109
or dysfunctional steps within the heme biosynthetic
50 aminolevulinic acid dehydratase; ALADP, 5-aminolevulinic acid 110
pathway are in development.
51 dehydratase–deficient porphyria (Doss porphyria); ALAS, 5-
aminolevulinic acid synthase; CEP, congenital erythropoietic porphyria;
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52 CPOX, coproporphyrinogen oxidase; CQ, chloroquine; CyP450, cyto- 112
53 Keywords: Therapy; Neurologic; Dermatologic; Clinical.
chrome P450; EPP, erythropoietic protoporphyria; FECH, ferrochelatase; 113
HCP, hereditary coproporphyria; HCQ, hydroxychloroquine; HCV, hepa-
54 titis C virus; HEP, hepatoerythropoietic porphyria; mRNA, messenger 114
55 RNA; PBG, porphobilinogen; PBGD, porphobilinogen deaminase; PCT, 115
porphyria cutanea tarda; PPIX, protoporphyrin IX; UROD, uroporphyri-
56 116
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P orphyrins are essential building blocks in the micro-
cosm of organic life. Because of their ability to absorb
electromagnetic radiation from sunlight and their similarity
nogen decarboxylase; UROS, uroporphyrinogen-III-synthase; VP, varie-
gate porphyria; XLP, X-chromosomal erythropoietic protoporphyria. 117
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59 to chlorophyll, which captures energy for photosynthesis, © 2019 by the AGA Institute
0016-5085/$36.00
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60 porphyrins are important pigments of life. Porphyrins are https://doi.org/10.1053/j.gastro.2019.04.050 120
REV 5.6.0 DTD YGAST62648_proof 27 June 2019 6:49 pm ce

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Table 1.Biochemical, Diagnostic, and Clinical Characteristics of Porphyrias and Lead Poisoning, Ordered by Category and Prevalence
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Plasma
Stölzel et al
Porphyria and Enzyme Second-line Screen, Neurovisceral Cutaneous Liver Q10
lead poisoning activities Biochemical testing diagnostics nma symptoms symptoms Anemia damage
AHPs
AIP PBGD Y Urinary ALA [[, PBG [[, and PBGD activityb 615–620 þþ /þ
porphyrins [[ Mutation analysis
VP PPOX Y Urinary ALA [[, PBG [[, and Mutation analysis 625–627 þþ /þ /þ
porphyrins [[
Fecal PPIX [[ and coproporphyrin III [
HCPc CPOX Y Urinary ALA [[, PBG [[, and Mutation analysis 615–620 þþ /þ /þ
porphyrins [[
Fecal coproporphyrin III [
ALADP ALAD Y Urinary ALA [[ and PBG normal or [ ALAD activity 615–619 þþ /þ
and coproporphyrin isomer III [[ Mutation analysis
Other hepatic
porphyrias
PCT and HEP UROD Y Urinary porphyrins [[ UROD activitye 615–620 þ þ
Uro- >> coproporphyrind Mutation analysis þþ /þ þ
Erythropoietic
porphyrias
EPP FECH Y Erythrocyte metal-free PPIX [[ and Mutation analysis 624–635 þþ /þ /þ
Zn-bound PPIXf [
XLP ALAS2 [ Erythrocyte metal-free PPIX [[ and Mutation analysis 624–635 þþ /þ /þ
Zn-bound PPIXg [[
CEP UROS Y Urinary and fecal Mutation analysis 615–620 þþ þ
Uro- and coproporphyrin
Isomer I [[
Other
Lead poisoning ALAD Y Urinary ALA [[ and PBG normal or [ and ALAD activity 615–620 þþ þ þ
coproporphyrin isomer III [[h Lead concentration
Erythrocyte metal-free PPIX [ and [[ (blood, urine)
Zn-bound PPIX [[
[, increased; Y, decreased; , clinical feature not present at time of manifestation; /þ, clinical feature variable at time of manifestation; þ, clinical feature typically present
at time of manifestation.
Gastroenterology Vol.
PPOX, protoporphyrinogen oxidase.
a
Fluorescence emission maximum (nm) of plasma porphyrins on excitation at 405 nm.
b
Decreased enzyme activity in blood, normal only in the non-erythroid splice site mutation variant.
c
A specific homozygous mutation or null allele of the CPOX gene leads to the phenotypically different rare harderoporphyria that lacks abdominal and neurologic
symptoms.
d
Increased fecal isocoproporphyrin is a sufficient but not necessary indicator of PCT/HEP, increased metal-free and zinc-bound protoporphyrin in erythrocytes is only
found in HEP.
e
Decreased enzyme activity in blood, normal activity in blood only in acquired (type 1) PCT.
-,
f
In EPP, the ratio of zinc-bound protoporphyrin to metal-free protoporphyrin is significantly lower (<15%) than in XLP.
No.
g
In XLP, the ratio of zinc-bound protoporphyrin to metal-free protoporphyrin is >25%.
h
Lead poisoning affects 3 enzymes involved in heme biosynthesis (ALAD, CPOX, and FECH).
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- 2019 Clinical Guide and Update on Porphyrias 3
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PERSPECTIVES
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REVIEWS AND
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266 Figure 1. Heme biosynthesis and localization of characteristic enzyme defects in patients with porphyrias or lead poisoning.b 326
a
Porphyrinogens shown are excreted after oxidation to form porphyrins. bIn the liver, heme regulates the first enzyme ALAS1
267 via a negative feedback loop. In contrast to the liver enzyme ALAS1, the rate-limiting bone marrow enzyme ALAS2 is regulated 327
268 by iron and erythropoietin instead of heme. cLead poisoning affects 3 enzymes involved in heme biosynthesis (modified from 328
269 Blau et al144). dTwo isomers of uroporphyrinogen (I and III) derive from hydroxymethylbilane are converted to cop- 329
270 roporphyrinogen I and III. Importantly, only the isomer III is used for heme synthesis, whereas the non-functional isomer I is 330
271 excreted in feces via the hepatobiliary pathway or in urine via the kidneys. 331
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274 Figure 1).4–6 Furthermore, a plasma fluorescence scan can be caused by combinations of genetic alterations. ALADP 334
275 discriminate the characteristic emission maxima of the and CEP are autosomal recessive diseases.2 XLP is caused by 335
276 metabolites and support the biochemical diagnosis mutations on the X-chromosome.15 More than 95% of pa- 336
277 (Table 1).6 Beside the hepatic and erythropoietic por- tients with EPP have a loss of function mutation in 1 allele of 337
278 phyrias, secondary elevation in porphyrins have been the ferrochelatase (FECH) gene and a single-nucleotide 338
279 found in patients with other diseases—especially in pa- polymorphism in the other allele. This reduces FECH ac- 339
280 tients with chronic liver diseases (Supplementary tivity to <35% and leads to overt disease.6,16 Few other 340
281 Table 1).7–13 We review the pathogenesis, symptoms, homozygous or compound heterozygous functional muta- 341
282 and treatment of the most frequent porphyrias (PCT, AIP, tions in the FECH gene have been found. 342
283 and EPP) (Table 2).5,6,14 We present typical cases, di- Compound heterozygous mutations (different mutations 343
284 agnoses, and treatments and discuss therapeutic strategies in each allele of a gene) have been associated with ALADP, 344
285 in development. We also review symptoms and pathol- CEP, and HEP, as well as in rare cases of severe AHP.17–19 345
286 ogies of lead intoxication that affect enzymes that mediate The genetic factors associated with AIP were investigated 346
287 heme synthesis and share features with porphyrias. in a recent study from France.20 Exome sequencing was 347
288 performed in 602 patients with overt AIP, 1968 of their 348
289 relatives, and in population controls, to reveal 42 genetic 349
290
Genetics variants of the hydroxymethylbilane synthase gene (HMBS 350
291 Porphyrias are caused by a range of mutations in many or porphobilinogen deaminase [PBGD]). These were 351
292 genes (Table 2). Most patients are heterozygous for these expressed in Escherichia coli and their enzyme activity 352
293 mutations because homozygous disruption of some of these determined. In this study, the minimal prevalence of AIP in 353
294 genes can be lethal. However, some patients have homozy- France was estimated at 1 of 1299. Notably, 22.9% pene- 354
295 gous mutations that result in a reduced but residual enzyme trance was found in families with AIP, but only 0.5%–1.0% 355
296 activity. Porphyria-associated mutations are listed in the penetrance in the general population. This indicates that 356
297 Human Gene Mutation Database (www.hgmd.cf.ac.uk). disease susceptibility is affected not only by inheritance of 357
298 Porphyrias are often autosomal dominant disorders, an autosomal dominant variant of PBGD, but other genetic 358
299 with variations in penetrance and phenotype; they can also or environmental factors. 359
300 360

4 Stölzel et al Gastroenterology Vol. -, No. -
361 Table 2. Protein and Genetic Features and Prevalence of Porphyrias Q11
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PERSPECTIVES
362 422
REVIEWS AND
No. of
363 mutations No. Prevalencec OMIM 423
364 Porphyria Deficient enzyme Gene locus reported diagnosed a,b
reported no. 424
365 425
366 ALADP ALA-dehydratase 9q33.1 12 3 Rared,e 612740 426
367 AIP PBG deaminase 11q23.3 390 878 5.9f 176000 427
CEP Uroporphyrinogen 10q25.2-10q26.3 48 35 Raree,g 263700
368 428
III synthase
369 PCT, HEPh Uroporphyrinogen 1p34 121 3131 21i 176100
429
370 decarboxylase 430
371 HCP Coproporphyrinogen 3q12 50j 78 0.9i 121300 431
372 oxidase 432
373 VPk Protoporphyrinogen 1q22 174 133 3.2 176200 433
374 oxidase 434
EPP Ferrochelatase 18q21.3 189 289 9.2l 177000
375 435
XLP ALA synthase 2 Xp11.21 4 3 Raree 300752
376 436
377 437
378 OMIM, Online Mendelian Inheritance in Man. 438
a
379 Data from the German Competence Center for Porphyria Diagnostics and Consultation; cases diagnosed between 1965 439
380 and 2017. 440
b
The proportion among 4550 porphyrias was PCT:AIP:EPP:VP:HCP:CEP ¼ 89:25:8:4:2:1.
381 c 441
Prevalence is cases per 1 million inhabitants.14
382 d
Six cases have been described.35,140,145 442
383 e
Rare means that prevalence values are below the lowest estimated prevalence of 0.9 per 1 million for HCP. 443
384 f
High prevalence in Sweden.14,146 444
g
385 Two hundred cases with CEP have been described.135 445
h
386 Forty cases with HEP have been described.147 446
i
387 Because, in general, prospectively analyzed data are lacking, prevalence values were approximated according to the relative 447
prevalence of the large German cohort of 4550 porphyrias in footnote a and the only (European) prospective study that found
388 448
5.9 cases of AIP per 1 million.14 Thus, we estimated a prevalence of PCT that is 3.56-fold higher than for AIP, that is, 21 cases
389 per 1 million, and lower prevalence for the other porphyrias. These numbers may, however, differ in other countries or regions 449
390 of the world, depending on variant genetic and environmental factors. 450
391 j
A variant of HCP is harderoporphyria, with 13 known mutations.40 451
k
392 High prevalence in South Africa (founder effect).148 452
l
393 After the discovery of XLP in 2008, up to 10% of EPP cases were reallocated to XLP.15,111 453
394 454
395 455
396 Rare cases of dual porphyrias (biochemical findings of 2 downstream of the enzyme defect that is apparently medi- 456
397 porphyrias) have been identified and confirmed by mutation ated by the induced synthesis of ALA and an excessive 457
398 analyses. Patients were identified that showed deficiencies accumulation of PBG, corresponds clinically to red-colored 458
399 in coproporphyrinogen oxidase (CPOX) combined with 1 or darkening urine in severe cases. The mechanism of this 459
400 ALAD mutation or with acquired PCT.21,22 phenomenon is ill-defined.23,25 Moreover, a drug-responsive 460
401 sequence in the ALAS1 gene mediates a direct transcrip- 461
402 tional activation via drugs such as barbiturates, hydantoins, 462
Acute Hepatic Porphyrias and metyrapone.26–29
403 463
404
Pathophysiology Glucose activation of peroxisome proliferator-activated 464
405 AIP, HCP, and VP are caused by defects in enzyme receptor g–coactivator 1a prevents transcription of ALAS1. 465
406 (PBGD, CPOX, and protoporphyrinogen oxidase, respec- This might account for the ability of intravenous glucose and 466
407 tively) and are promoted by excess activity of the first other nutritional carbohydrates or gluconeogenic amino 467
408 enzyme in hepatic heme synthesis, ALAS1 (Figure 1). ALAS1 acids to attenuate signals of a fasting state, resulting in 468
409
Q4 is induced via induction of cytochrome P450 (CyP450), such increased expression of ALAS1.30 This is the reason that 469
410 as by xenobiotics, smoking, excess alcohol consumption, patients should avoid glucose-lowering drugs and condi- 470
411 fasting, and female sex hormones.2 Xenobiotics also directly tions. Interestingly, the synthesis of fibroblast growth factor 471
412 induce ALAS1. Induction of ALAS1 in AHPs leads to an 21, a glucose-lowering hormone that is largely produced in 472
413 exaggerated accumulation of the neuropharmacologic active the liver and induces a fasting state, is blocked by heme that 473
414 porphyrin precursors.23 However, it is unclear whether ALA is used in the treatment of acute attacks.31 Heme is not a 474
415 and PBG are the relevant neurotoxins. Their accumulation in direct inhibitor of ALAS1 at physiologically achievable con- 475
416 HCP and VP results from allosteric inhibition of PBGD by centrations, but rather decreases stability of ALAS1 476
417 metabolites, especially coproporphyrinogen and proto- messenger RNA (mRNA) and therefore its protein expres- 477
418 porphyrinogen, which accumulate downstream of the sion. Moreover, heme inhibits mitochondrial uptake of pre- 478
419 affected enzyme.24 A paradoxical increase of porphyrins ALAS1 and promotes the cytosolic breakdown of the mature 479
420 480

481 enzyme.32 The overexpression of heme oxygenase-1 under abnormalities (VP). Harderoporphyria, a variant form of 541
conditions of inflammation, fasting, or physical or oxidative homozygous HCP, presents predominantly in early child-
PERSPECTIVES
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REVIEWS AND
483 stress increases heme degradation and thereby removes hood, mostly with hematologic abnormalities. The cause is a 543
484 feedback inhibition of ALAS1, promoting disease.23,33 dysfunctional homozygous mutation or a null allele in exon 544
485 ALADP is a rare autosomal recessive disease.34,35 ALAD 6 of the CPOX gene.40 Although in HCP, mutations occur in 545
486 is a lead-sensitive enzyme. Patients who are heterozygous the same gene, the CPOX mutation that causes harder- 546
487 for a mutation that reduces ALAD activity by 50% develop oporphyria does not produce abdominal or neurologic 547
488 acute porphyria symptoms once they have an even slight symptoms as in HCP.41,42 548
489 increase in lead exposure.36 Interestingly, all mutations in A subgroup of patients without clinical symptoms but 549
490 ALAD associated with disease cause formation of function- high urinary ALA, PBG, and porphyrin levels have been 550
491 ally compromised enzyme hexamers that are dominant to classified as asymptomatic high excreters. On the other 551
492 normal, high-activity octamers.37 hand, attacks recur in as many as 5% of patients with 552
493 clinically manifest AIP, causing high medical costs, absence 553
494 from work, and often unemployment.14,43,44 554
Clinical Presentation
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AHPs usually do not manifest before puberty. Women
496 Diagnosis 556
more frequently develop symptoms than men, and some
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unfortunate women suffer from monthly attacks with onset Laboratory analysis of the precursors and porphyrins in
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during the luteal phase of their menstrual cycle. Typically, a sample of spot urine, transported in a dark vessel is
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patients have abdominal pain, which is intermittent and mandatory and suffices in most cases (Table 1). A more than
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colicky and can extend to the back and extremities. This is 4-fold increase in ALA and PBG (normal level <6.3 mmol/
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often accompanied by constipation, nausea, vomiting, and mol and <1.4 mmol/mol creatinine, respectively) in urine is
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symptoms of ileus and paresthesia. Tachycardia coupled used to identify patients with AIP, VP, or HCP.45 However,
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with hypertension and a reddish dark urine are further this is not the case for the rare ALADP or lead poisoning
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diagnostic signs (Figure 2A). The pain of acute attacks of (Figure 1, Table 1).34 Patients with rare ALADP or lead
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porphyria typically arises gradually, often with a stereotypic poisoning have a more than 10-fold increase in urine level of
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prodrome, gradually building over hours and lasting for ALA, in the absence of a significant increased PBG (Table 1).
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days. Some patients have pain chiefly in the chest, back, or Type 1 tyrosinemia is not a primary disorder of porphyrin
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extremities, although the more usual presentation is that of metabolism but indirectly leads to similar biochemical
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severe abdominal pain. changes and porphyria-like symptoms as in ALADP, caused
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When these symptoms are misdiagnosed and patho- by the accumulation of succinyl acetone, a potent inhibitor
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genesis is promoted by inadequate treatment (especially of ALAD.46 No enzymatic test is readily available to confirm
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porphyrinogenic medications, hypocaloric feeding, and HCP and VP. However, fecal porphyrins, which are increased
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inadequate pain treatment leading to increased stress), pain patients with HCP (coproporphyrin III) or VP (cop-
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tients may gradually develop peripheral motor neuropathy roporphyrin III and protoporphyrin IX [PPIX]), can
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that first affects the upper proximal extremities and may discriminate among acute porphyrias (Table 1). Mutational
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progress to paralysis of extensor muscles of the hands and analysis can further secure the diagnosis. In patients with
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arms (Figure 2B), tetraparesis, and respiratory arrest. Some AIP, urinary excretion of the porphyrin precursors ALA and
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patients present with anxiety, confusion, and overexcite- PBG and of porphyrins decreases quickly (within 3–6 days)
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ment, including hallucinations, psychosis, or seizures. An during remission, but can remain significantly increased
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inappropriately high secretion of antidiuretic hormone over years.2,45,47 A single analysis of urine level of PBG
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(Schwartz–Bartter syndrome) leads to a potentially life- identified most patients (90%) with AIP in remission.48
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threatening severe hyponatremia, another diagnostic However, only repeated analysis for urine level of ALA
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feature of acute porphyrias. With frequent attacks, the risk and PBG during symptomatic periods can identify all pa-
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of hypertensive renal damage and of hepatocellular carci- tients with AHP. Urinary ALA and PBG are also increased in
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noma is increased. A variant of kidney peptide transporter 2 acute HCP and VP, but fall more rapidly upon remission,
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(PEPT2*1*) has high affinity for ALA and promotes its while elevated porphyrins may persist.
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reabsorption, likely contributing to renal damage.38 Because individual cases and disease phases can have
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PEPT2*1 is also found in the choroid plexus and may be different patterns and because of the relative rarity and
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important in pumping variable amounts of toxic ALA into complexity of the porphyrias, a final evaluation should al-
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the brain, which could explain the variable susceptibility to ways be performed by specialists at porphyria centers
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neuropsychiatric symptoms in patients.39 HCP and VP can (www.porphyriafoundation.com, www.porphyria.uct.ac.za,
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also cause skin photosensitivity that in AIP only occurs www.porphyria.eu). The metabolic (and clinical) activity of
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when severe renal disease leads to further accumulation of the acute porphyrias and the efficacy of therapy can be
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plasma porphyrins. Overall, there is significant variation monitored by assessing metabolite excretion. An annual
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among individuals in clinical manifestations of all hepatic examination is also recommended for asymptomatic pa-
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porphyrias. Rare patients with homozygous acute por- tients. If urine analysis identifies an acute (hepatic)
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phyrias present in childhood with abdominal attacks (AIP, porphyria, it is necessary to measure the activity of PBGD in
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HCP), cutaneous symptoms (HCP, VP), or skeletal erythrocytes and perform genetic analyses, to confirm a
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540 600

601 diagnosis of AIP (Table 1). Both analyses are necessary 661
because in a subvariant of AIP, which occurs in about 5% of
PERSPECTIVES
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REVIEWS AND
603 cases, the activity of PBGD in erythrocytes is normal.49 With 663

604 knowledge of the mutation of the index patient, a targeted 664
605 genetic analysis can be offered to all first-degree relatives to 665
606 identify asymptomatic carriers and to inform them about 666
607 porphyria triggers. Notably, >95% of gene carriers remain 667
608 asymptomatic throughout life.20,50 668
609 669
610 Therapy 670
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There are specific therapies for AHPs (see Table 3). Once
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neurologic symptoms occur, heme therapy is indicated. With
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early intravenous administration of heme, patients begin to
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improve within 48 hours. Intravenous heme (Normosang;
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Orphan Europe, Puteaux, France, in Europe and some other
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regions, and Panhematin; Recordati Rare Diseases, Lebanon,
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NJ, in the United States, Mexico, and elsewhere) acts as a
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transcription factor that reduces expression of the rate-
619 679
limiting hepatic enzyme ALAS1. Studies with heme ther-
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apy date back to 1971.51 Data from 15 uncontrolled studies
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on 420 patients with AHP have been published.52–58 Taken
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together, biochemical remission with a significant drop in
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urinary excretion of ALA and PBG was usually achieved
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after 3–6 days, but not all of the treated patients were
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judged to be responders to heme therapy. In 1 report, only
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half of patients benefited from heme infusions.55 Inadequate
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responses to heme have been attributed to an insufficient
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Figure 2. Clinical signs of different porphyrias. (A, B) AHP. (A) dosage (<3 mg/kg/d), probably non-porphyria–related
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A dark-red urine that further darkens under air/oxygen; (B) symptoms, delayed onset of therapy, and chronic porphyria-
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motor neuropathy of the hand extensors 6 months after the related pathology, such as irreversible neurologic
631 first manifestation. (C–E) PCT. (C) Hypertrichosis on cheeks; 691
damage.52,59 In the only prospective randomized placebo-
632 (D) vulnerability, blisters, and scars on sunlight-exposed skin; 692
controlled trial of heme, comprising 12 patients, there was
633 (E) liver biopsy showing an intense red fluorescence under 693
a significantly more rapid decrease in urine levels of ALA
634 long-wave ultraviolet light (366 nm, Wood’s lamp). (F) EPP. 694
and PBG in patients given heme compared to placebo.
635 Liver biopsy with spherical structures displaying red birefrin- 695
gence under polarized light and with a dark Maltese cross in However, there was only a trend for clinical improvement in
636 696
the center (original magnification 400). this underpowered study.60 Notably, as many as one-third
637 697
638 698
639 699
640 Table 3.Therapy for Acute Porphyrias 700
641 Therapy Description 701
642 702
643 Discontinuation of porphyrinogenic drugs www.drugs-porphyria.org 703
644 and intensive medical monitoring 704
645 Sufficient caloric support Intravenous and/or oral carbohydrates as preferred source of energy; 705
(carbohydrates, protein) beware of dilutional hyponatremia; serum sodium, magnesium,
646 706
and phosphate must be monitored daily
647 Heme treatment For severe cases, neurologic manifestations and associated hyponatremia:
707
648 heme arginate (eg, Normosang), 3 mg/kg body weight/d in 100 mL human 708
649 Albumin (5%–20%), infused in 15 min, for up to 4 consecutive days 709
650 Symptom measures 710
651 For pain Acetylsalicylic acid, morphine derivatives, gabapentin 711
652 For tachycardia and hypertension Propranolol, metoprolol, valsartan 712
For restlessness or vomiting Chlorpromazine, lorazepam, ondansetron
653 713
For symptoms of ileus Neostigmine
654 For respiratory relief Assisted or controlled ventilation (possibly tracheotomy) 714
655 For infections Penicillin, cephalosporins, imipenem, gentamicin, amikacin, vancomycin 715
656 Physiotherapeutic measures 716
657 from the very beginning 717
658 718
659 719
660 720

721 of attacks resolved with supportive care, whereas the other N-acetyl-galactosamine. After subcutaneous injection, Givo- 781
two-thirds required heme therapy.57 siran is directed to and endocytosed by hepatocytes that
PERSPECTIVES
722 782
REVIEWS AND
723 Sufficient caloric support (carbohydrates, protein) is carry the N-acetyl-galactosamine binding asialoglycoprotein 783
724 essential for treatment of AHP—especially when attacks are receptor. Once endocytosed, the small interfering RNA is 784
725 induced or amplified by low caloric intake, nausea, and cleaved from the conjugate to potently reduce levels of 785
726 vomiting, which are usually present in these patients.5,61–63 ALAS1 mRNA and protein.68 The phase 1 trial with once 786
727 After emergency intravenous glucose, oral nutrition with monthly Givosiran demonstrated high efficacy in reducing 787
728 carbohydrates should be initiated as soon as possible. Pa- acute attacks in 6 patients with AIP.69 An interim analysis 788
729 tients presenting with hyponatremia should receive heme from a phase 3 trial (Envision) in 94 randomized patients 789
730 therapy because hyponatremia can worsen with glucose with AHP and at least 2 attacks within 6 months before 790
731 infusions. enrollment has been made public in April 2019, showing a 791
732 Pain should be addressed immediately and strictly pre- significant reduction in the annualized rate of porphyria 792
733 vented. Pain stress contributes to neuroendocrine reactions attacks, days of administered heme, and urinary ALA levels 793
734 that activate ALAS1 and exacerbate symptoms. Well- with Givosiran. Only 1 patient had to be discontinued due an 794
735 tolerated drugs such as opiates and gabapentin, which do 8-fold elevation of alanine aminotransferase, while mild– Q5 795
736 not induce ALAS1 in the liver and are excreted via the moderate alanine aminotransferase elevations subsided Q6 796
737 kidneys, are often insufficiently dosed.64 Pain therapists are with ongoing therapy. Ninety-three of 94 patients elected to 797
738 frequently not trained in management of patients with AHP. continue the treatment beyond the 6 months of the study.70 798
739 Moreover, the usually long period of misdiagnosis coupled A final option is liver transplantation.71,72 Ten patients 799
740 with a traumatic path of suffering and frustration with from the United Kingdom who underwent successful liver 800
741 physicians who are not familiar with the disease can lead to transplantation developed biochemical and symptomatic 801
742 anxiety, depression, and the need for expert psychotherapy, remission. However, 4 developed hepatic artery thrombosis. 802
743 supported with antidepressive or anxiolytic medication. Therefore, post-transplantation anticoagulation is recom- 803
744 Patients with recurrent attacks (more than 3 per year) mended.73 Notably, 3 patients with end-stage non-porphyria 804
745 often receive prophylactic administration (interval therapy) liver disease who were not eligible for standard trans- 805
746 of heme. However, frequent heme infusions often lead to plantation received livers from patients with AIP. Two 806
747 venous obliteration due to heme degradation products that survived and 1 developed symptoms of AIP (abdominal pain 807
748 bind to endothelial cells, platelets, and clotting factors.63,65 and neuropathy) within 3 weeks. This was accompanied by 808
749 Therefore, patients with recurrent attacks often receive increased urinary levels of ALA, which confirmed liver as 809
750 intravenous ports and sometimes arteriovenous shunts for the primary source of increased porphyrin precursors.74 810
751 blood sampling and intravenous therapy. Side effects can be New and alternative therapies are summarized in 811
752 mitigated by administration of heme bound to albumin Supplementary Table 2. International porphyria emergency 812
753 (Table 3). The frequency of clinical manifestations requiring identification cards are provided free of charge by Orphan 813
754 intravenous heme may require up to once weekly dosing in Europe (www.orphan-europe.com). Furthermore, MedicAl- 814
755 some cases.2 High dosages of intravenous heme (250 mg/d) ert (www.medicalert.org) provides bracelets and wallet 815
756 can lead to overexpression of heme oxygenase 1, resulting in cards that contain information on acute porphyrias. 816
757 heme degradation and loss of feedback inhibition of ALAS1. 817
758 This was demonstrated in PBGD-deficient mice.66 A 4.4-fold 818
759 increase of reported AIP patients with recurrent attacks Case Report 819
760 since the introduction of heme therapy (from 4 of 230 in A 24-year-old woman was admitted with generalized 820
761 1985 to 40 of 536 in 2008) may be due to several reasons, abdominal pain, constipation, and recurrent vomiting for 6 821
762 including induction of heme oxygenase 1, but also improved days. She had no history of alcohol, nicotine, or drug abuse. 822
763 survival by heme therapy.66 Therefore, high-frequency She had normal weight (body mass index 19 kg/m2) and 823
764 heme infusions should be avoided. Overall, the rigorous appearance. Physical examination revealed abdominal 824
765 elimination of precipitating factors in daily life remains the tenderness, reduced bowel sounds, and pain on palpation of 825
766 mainstay of prevention and therapy. the upper abdomen. Pregnancy was excluded and abdom- 826
767 Patients with chronic complications, such as loss of inal ultrasound showed normal findings. Laboratory anal- 827
768 venous access, or progressive neurologic symptoms despite ysis revealed a striking hyponatremia (117 mEq/L; normal 828
769 adequate therapy, should be transferred to a porphyria >133 mEq/L) with increased urine level of sodium (154 829
770 center for therapy optimization. There, they might be able to mEq/L). Because the patient vomited, intravenous infusion 830
771 participate in clinical trials of therapeutic agents in devel- of 10% glucose and saline was started. After 4 hours, the 831
772 opment. Nanoparticular PBGD RNA was recently shown to hyponatremia worsened (110 mEq/L) and generalized 832
773 target hepatocytes, restore deficient enzyme activity, and convulsions necessitated the administration of levetir- 833
774 protect from induced porphyria attacks in mice.67 acetam, intubation, stepwise careful compensation of 834
775 Notably, a novel agent (Givosiran) that addresses the hyponatremia with intravenous sodium chloride (3%), and 835
776 underlying pathology of AIP promises high efficacy with a mechanical ventilation for 2 days. Brain magnetic resonance 836
777 tolerable side effect profile. Givosiran is a small interfering imaging, electroencephalograms, cerebrospinal fluid anal- 837
778 RNA that neutralizes excess ALAS1 mRNA in hepatocytes. ysis, drug screening, and extensive laboratory tests did not 838
779 The small interfering RNA is conjugated to trimeric reveal any pathologic features. After extubation, she was 839
780 840

841 transferred to standard care with the diagnosis of syndrome agriculture until 1984, inhibits UROD and causes PCT in 901
of inadequate antidiuretic hormone secretion of unknown humans and animals.81,82 Other factors that can cause this
PERSPECTIVES
842 902
REVIEWS AND
843 etiology. Subsequent interviews raised the suspicion of a disease are infection with hepatitis C virus (HCV) and hu- 903
844 pre-existing eating disorder and she was referred to a man immunodeficiency virus.83–87 HEP is a rare severe form 904
845 psychiatric clinic for 4 weeks. of type 2 PCT that arises in patients with homozygous or 905
846 One month after her dismissal from psychiatry she was compound heterozygous mutations in UROD. 906
847 readmitted due to epigastric colicky cramps for 4 days. 907
848 Laboratory analysis again showed severe hyponatremia Clinical Presentation 908
849 (112 mEq/L) with a urine sodium level of 114 mEq/L. The most striking signs and symptoms of PCT are 909
850 Careful substitution with 3% sodium chloride was started, chronic photo-cutaneous damage, often with blisters, bullae, 910
851 with intensive monitoring and hourly controls of serum milia, hyper- or hypo-pigmentation, and hypertrichosis on 911
852 sodium to prevent pontine myelinolysis. However, her sys- cheeks, temples, and eyebrows (Figure 2C and D). In pa- 912
853 tolic blood pressure increased to 190 mmHg. A dark-reddish tients with PCT, urinary porphyrin excretion >3390 nmol/ 913
854 urine elicited the suspicion of AHP, and a more than 10-fold d (3.4 mmol/d) indicates severe hepatic porphyrin overload. 914
855 increase in concentration of urine ALA and PBG led to the Liver biopsies, which are frequently collected to assess 915
856 diagnosis of AIP (Supplementary Table 3). fibrosis in these patients, have intensive red fluorescence 916
857 She was treated with heme arginate 3 mg/kg body when exposed to long-wave ultraviolet light (366 nm, 917
858 weight/d for 4 days. Porphyrinogenic medications were Wood’s lamp) (Figure 2E). 918
859 strictly avoided, and with oral and intravenous carbohy- Latent or subclinical PCT can occasionally be found in 919
860 drates and other nutrients, she recovered quickly. In patients with otherwise unexplained elevations of liver en- 920
861 retrospect, it was apparent that a vicious cycle of fasting, zymes, and confirmed by elevated plasma or urine levels of 921
862 worsening vomiting, and abdominal pain, likely induced by porphyrins (Table 1). Latent PCT does not cause skin 922
863 a mild eating disorder, caused excessive induction of hepatic symptoms. If liver biopsies are exposed to long-wave ul- 923
864 ALAS1. With adherence to expert advice to avoid trigger traviolet light, those from PCT produce red fluorescence. 924
865 factors for AIP, especially fasting, she remained stable and Abdominal ultrasound may reveal hyperechogenic focal 925
866 free of further acute attacks during a 3-year follow-up liver lesions, possibly regions of steatosis, that have iso- 926
867 period. enhancement in contrast imaging and disappear after 927
868 treatment. 928
869 929
870 Porphyria Cutanea Tarda Diagnosis 930
871 In patients with PCT, but also in patients with HEP, 931
872
Pathophysiology 932
Low activity (<20%) of hepatic uroporphyrinogen levels of porphyrins are greatly increased in urine and
873 plasma, with uro- and heptacarboxy-porphyrins predom- 933
874 decarboxylase (UROD) underlies all cases of PCT (acquired 934
type 1 or familial type 2).75 Patients heterozygous for mu- inating (Table 1, Supplementary Figure 3). Renal failure
875 with loss of urinary excretion requires porphyrin analysis in 935
876 tations in UROD (type 2 PCT) have a 50% reduction in 936
enzyme activity in all tissues, which is necessary but not serum or plasma. Another characteristic finding is the fecal
877 excretion of isocoproporphyrin, which is a sufficient but not 937
878 sufficient to cause overt disease.76 A further decrease of 938
hepatic UROD activity that finally triggers overt clinical necessary indicator of PCT.
879 939
880 disease is usually due to several cofactors (Supplementary 940
881 Figure 2). Iron is the most important cofactor and hemo- Therapy 941
882 chromatosis gene mutations (HFE) (mostly heterozygous) Patients are advised to avoid known precipitating fac- 942
883 are found in up to two-thirds of the patients.77 Iron does not tors, especially alcohol and smoking, that up-regulate 943
884 directly inhibit UROD. In the presence of iron, CyP450 en- CyP450 enzymes and thus the heme synthetic machinery. 944
885 zymes catalyze the conversion of uroporphyrinogen into Alcohol further contributes by down-regulating hepcidin 945
886 uroporphomethene, an inhibitor of UROD, as shown in mice. and enhancing oxidative stress. Women must discontinue 946
887 Moreover, ferrous iron was found to generate uroporpho- hormonal contraception or replacement therapy. Photo- 947
888 methene independently of CyP450-enzymes.75,78 This protection, phlebotomy, and treatment with low-dose 4- 948
889 mechanism has only been confirmed in homogenates of aminoquinolines, chloroquine (CQ) or hydroxychloroquine 949
890 human liver biopsies, where an inhibitor of UROD has been (HCQ) (125 mg or 100 mg twice per week, respectively), are 950
891 identified in patients with PCT. Patients with PCT usually effective first-line therapies.88–90 The aim of phlebotomy, 951
892 carry polymorphic variants of CyP450 genes, leading to introduced in 1977, is the removal of excess iron.91 Usually, 952
893 higher enzyme activities, whereas patients with familial PCT phlebotomy up to 500 mL biweekly is recommended, and 953
894 express a polymorphic variant of glycerol phosphate O- monitoring of serum ferritin concentrations helps guide 954
895 acyltransferase that is associated with iron accumulation in individually adapted iron depletion and avoid iron defi- 955
896 HFE-associated hemochromatosis. The resultant even ciency. A target ferritin near the lower limit of normal is 956
897 modest increase in hepatic iron in the setting of low UROD recommended. Both oral iron chelators or low-dose 957
898 activity in familial PCT then appears to promote clinical 4-aminoquinolines are alternatives when phlebotomy is 958
899 PCT.79,80 Hexachlorobenzene, a fungicide that was used in not possible, as in severe anemia.92 Phlebotomy or low dose 959
900 960

961 4-aminoquinolines are likewise effective treatments in the sometimes turned “dark reddish brown.” His body mass 1021
majority of patients with PCT. index was 29.9 kg/m2 and he received a diagnosis of type 2
PERSPECTIVES
962 1022
REVIEWS AND
963 Low-dose CQ or HCQ are more convenient than phle- diabetes 10 years earlier. He smoked as many as 20 ciga- 1023
964 botomy.93,94 They mobilize intracellular porphyrin depots rettes per day for 15 years and his alcohol consumption was 1024
965 that are mainly eliminated via the urine.6,95,96 During 4 drinks per week. An abdominal ultrasound demonstrated 1025
966 the first 3 months after patients begin receiving a hyperechoic liver suggesting steatosis. His level of alanine 1026
967 4-aminoquinolines, urinary porphyrin excretion usually aminotransferase was 1.0 mmol/L/s (normal <0.85 mmol/ 1027
968 increases more than 2-fold and skin photosensitivity can L/s) and his level of ferritin was 1434.8 pmol/L (normal 1028
969 worsen, but thereafter decreases, resulting in clinical <844 pmol/L). Results from serologic tests for hepatitis B 1029
970 remission and improved liver enzyme activities in 95% of virus, HCV, or human immunodeficiency virus infection 1030
971 patients.77,90,97 In 207 patients with PCT treated exclusively were negative. Genetic analysis revealed that he was ho- 1031
972 with low-dose CQ, 5% of patients with HFE who were homozygous for the H63D mutation and negative for the 1032
973 mozygous for C282Y (3 of a subgroup of 62 patients that C282Y mutation in HFE. Urinary excretion of cop- 1033
974 were genotyped) did not benefit, whereas all patients het- roporphyrin, ALA, and PBG was within the normal range, 1034
975 erozygous for C282Y or H63D and those without disease- but total porphyrins, uroporphyrin, and heptacarboxy- 1035
976 associated variants in HFE responded to CQ therapy.77 porphyrin were increased 22-fold, 66-fold, and 100-fold, 1036
977 Another study reported more non-responders among pa- respectively. All laboratory parameters are shown in 1037
978 tients with PCT who were heterozygous for the C282Y Supplementary Table 4. Based on the characteristic pattern 1038
979 mutation.98 Patients with PCT and iron overload/HFE mu- of urinary porphyrins and normal level of porphyrin pre- 1039
980 tations should be preferentially treated with phlebotomy. cursor, the patient received a diagnosis of PCT. 1040
981 HCQ and CQ are effective and safe therapies. However, On excitation at 405 nm, his plasma emitted a peak 1041
982 HCQ is less toxic and should be the first option.99 Because fluorescence at 619 nm and UROD activity in erythrocytes 1042
983 retinopathy is a side effect of 4-aminoquinolines, baseline was 85% (normal >80%), confirming the diagnosis of PCT 1043
984 and later annual ophthalmologic screening is recom- type 1. The patient was advised to avoid precipitating fac- 1044
985 mended.100 Phlebotomy (in case of increased serum con- tors, especially alcohol and smoking. Treatment was started 1045
986 centrations of ferritin) combined with simultaneous or with biweekly phlebotomy of 500 mL for the first 5 months 1046
987 subsequent low-dose 4-aminoquinolines appears to shorten and low-dose HCQ 100 mg twice a week was given for 9 1047
988 the time to remission. This is supported by 1 study months. 1048
989 comparing phlebotomy or CQ alone with the combined After 9 months, the skin lesions had regressed and uri- 1049
990 regimen in 15, 24, and 20 patients who underwent remis- nary porphyrin excretion normalized (Supplementary 1050
991 sion within 12.5, 10.2 and 3.5 months, respectively.101 More Table 4). We terminated iron depletion when clinical 1051
992 evidence is needed to favor a combined regimen as first-line remission was achieved because the patient refused another 1052
993 option. Liver damage and siderosis—especially in patients phlebotomy. The patient had given up smoking and reduced 1053
994 homozygous for the HFE C282Y mutation—can regress after alcohol consumption to 1 drink per week. Follow-up with 1054
995 phlebotomy and CQ therapy.59,97,102 urinary porphyrin determinations every 6 months 1055
996 In patients with chronic HCV infection, highly effective confirmed stable remission. 1056
997 antiviral therapy coupled with iron depletion induces rapid 1057
998 clinical and biochemical remission.103 All 16 patients with 1058
999 PCT and HCV infection (12 co-infected with human immu- Protoporphyrias 1059
1000 nodeficiency virus) who did not respond to phlebotomy or 1060
4-aminoquinolines achieved clinical and biochemical Pathophysiology
1001 1061
remission after HCV eradication with direct-acting antivi- EPP is caused by a partial deficiency of FECH, which
1002 1062
rals, qualifying this approach as first-line therapy in PCT catalyzes the final step in heme synthesis (Figure 1). There
1003 1063
patients with HCV infection.103 Treatment can be dis- are at least 189 known (pathogenic) mutations in FECH
1004 1064
continued when urinary porphyrin excretion stabilizes (Table 2).105,106 FECH deficiency increases levels of metal-
1005 1065
(approximately 407 nmol/d or 0.4 mmol/d). Mild porphyr- free erythrocyte PPIX, in contrast to secondary elevations
1006 1066
inuria can persist during clinical remission, especially in of zinc-bound erythrocyte protoporphyrin that are caused
1007 1067
patients with PCT type 2 (Supplementary Figure 3). How- by iron deficiency, lead intoxication, or hemolytic anemia.12
1008 1068
ever, clinical and biochemical relapse can occur in 36% and The lipophilic PPIX, which is eliminated via bile, is hepato-
1009 1069
20% of patients within 1 year after pharmacologic treat- toxic at high concentrations, causing varying degrees of liver
1010 1070
ment or phlebotomy, repectively.104 damage.107–109 Protoporphyrin-containing crystals can be
1011 1071
detected as pathognomonic Maltese crosses upon histologic
1012 1072
examination of liver sections under polarized light
1013 1073
Case Report (Figure 2F).110 As many as 23% of patients with EPP
1014 1074
A 50-year-old man was referred from a dermatologist, develop protoporphyrin-containing gallstones that emit red
1015 1075
presenting with increased skin vulnerability, fluid-filled fluorescence under long-wave ultraviolet light.111
1016 1076
blisters, and “badly healing wounds.” The lesions occurred C-terminal deletions in the ALAS2 gene, which is
1017 1077
on sunlight-exposed skin areas, prominently on the dorsal expressed in the bone marrow, in a small percentage of
1018 1078
hands and forearms (Figure 2E). He reported that his urine patients with suspected EPP led to their reclassification as
1019 1079
1020 1080

1081 patients with XLP. XLP is characterized by hypermorphic found no benefit on light-dependent symptoms in 9 of 11 1141
gain-of-function mutations in ALAS2. These mutations in- patients.115
PERSPECTIVES
1082 1142
REVIEWS AND
1083 crease the enzymatic activity of ALAS2 and cause accumu- Patients learn to prevent pain by avoiding sunlight, and 1143
1084 lation of metal-free and zinc-bound PPIX.15 EPP and XLP this impairs quality of life. Light avoidance necessitates 1144
1085 share clinical and biochemical features, such as usually se- vitamin D substitution. The a-melanocyte–stimulating hor- 1145
1086 vere acute photosensitivity, liver damage, and increased mone analogue afamelanotide (Scenesse, Clinuvel Pharma- 1146
1087 levels of (metal-free) PPIX in erythrocytes. A mutation in the ceuticals, Melbourne, VIC, Australia) increases skin 1147
1088 caseinolytic mitochondrial matrix peptidase chaperone pigmentation independent of sunlight via the activation of 1148
1089 subunit gene (CLPX) was associated with a disease that the melanocortin-1 receptor on melanocytes, improving 1149
1090 resembles XLP. This mutation promotes ALAS protein sta- sunlight protection significantly.116–119 In a pilot study, 5 1150
1091 bility and increases ALA, leading to accumulation of PPIX.112 patients with EPP were treated with 2 subcutaneous im- 1151
1092 plants of afamelanotide over 120 days, which increased 1152
1093 tolerance to artificial light from a mean of 2.2 minutes to 1153
Clinical Presentation 13.3 minutes. Furthermore, 168 patients with EPP from
1094 In patients with EPP or XLP, photosensitivity usually 1154
1095 Europe or the United States who were included in 2 phase 3, 1155
develops during early childhood. Patients have symptoms of multicenter, randomized, double-blind, placebo-controlled
1096 burning, itching, pain, erythema, and edema on sun-exposed 1156
1097 trials, received 16 mg of afamelanotide, implanted at in- 1157
skin areas, sometimes but not always resembling sunburn. tervals of 60 days (for as long as 120 days in the United
1098 Patients’ pain and cutaneous symptoms with exposure to 1158
1099 States and as long as 240 days in Europe). Duration of pain- 1159
light are severe, forcing them to strictly avoid light, which free exposure to sunlight in both studies was significantly
1100 substantially decreases their quality of life. In a small pro- 1160
1101 longer in the afamelanotide group, coupled with an 1161
portion of patients, the cutaneous symptoms are associated improved quality of life and a lack of serious adverse events.
1102 with abdominal pain, about one-quarter display abnormal 1162
1103 Afamelanotide has been approved by the European Medi- 1163
liver enzyme activities and rarely develop severe hep- cines Agency in 2014 for patients with EPP or XLP, whereas
1104 atobiliary injury, including jaundice and liver cirrhosis, can 1164
1105 approval by the Food and Drug Administration is pending. 1165
occur.108,111 Therefore, EPP or XLP should be considered for Uncontrolled observations suggest successful treatment
1106 cases of unexplained cholestasis, and physicians should ask 1166
1107 with ursodeoxycholic acid that may increase hepatic clear- 1167
patients if they are photosensitive because patients often do ance, and with cholestyramine that may bind protopor-
1108 not report this spontaneously. Finally, patients often present 1168
1109 phyrin and interrupt its enterohepatic circulation.120,121 1169
with iron deficiency and corresponding microcytic anemia. Erythrocyte concentrates that suppress erythropoiesis and
1110 1170
1111 plasma exchange that removes excess metal-free protopor- 1171
1112 Diagnosis phyrin have been used to treat liver failure or prevent 1172
1113 Diagnoses of EPP or XLP are made based on increased further decompensation.122,123 Patients with advanced 1173
1114 levels of metal-free protoporphyrin (>4.5 mmol/L, normal cholestasis or cirrhosis should receive liver transplants. 1174
1115 <0.09 mmol/L) in hemolyzed anticoagulated whole blood. Before transplantation, excess PPIX in circulating blood 1175
1116 Specialized porphyria laboratories report levels of total must be removed by plasmapheresis. During the procedure 1176
1117 erythrocyte, metal-free, and zinc-protoporphyrin.113 The or other major abdominal procedures, special yellow filters 1177
1118 proportion of zinc-protoporphyrin to metal-free protopor- are used to prevent light-induced damage of visceral or- 1178
1119 phyrin is significantly higher in patients with XLP (>25%) gans.72,124 Sixty-two liver transplants in erythropoietic 1179
1120 than in those with EPP (up to 15%). Notably, urinary por- porphyrias have been reported worldwide.72 In contrast to 1180
1121 phyrins are normal in protoporphyrias. However, with patients with AHP, liver transplantation does not cure pa- 1181
1122 deterioration of liver function, urinary coproporphyrin tients with EPP or XLP because the bone marrow is the 1182
1123 excretion (especially isomer I) increases.109 Noninvasive source of the excessively elevated PPIX. However, a PPIX 1183
1124 measurement of liver stiffness (with ultrasound or magnetic reduction of up to 85% and a resolution of inflammatory 1184
1125 resonance elastography) should be useful for early diagnosis liver damage have been reported after allogeneic hemato- 1185
1126 but has not been validated in patients with XLP or EPP.114 poietic stem cell transplantation, even when performed 1186
1127 before or after liver transplantation.125,126 1187
1128 Drug restriction, as required for AHP, is not required for 1188
1129 Therapy patients with EPP or XLP. Interestingly, iron substitution can 1189
1130 Adequate sun protection is indispensable, and skin decrease protoporphyrin concentrations and improve 1190
1131 should not be exposed to intensive artificial light sources. symptoms in patients with XLP—sufficient iron as second 1191
1132 Importantly, because photosensitivity is due mainly to substrate promotes conversion of toxic PPIX to heme by 1192
1133 visible blue light (Soret band: near 400 nm), conventional FECH.127,128 In contrast, iron substitution can worsen EPP by 1193
1134 sunscreens are less effective. Skin should be protected from stimulating the bone marrow enzyme ALAS2.129 Moreover, 1194
1135 sunlight with zinc oxide or titanium oxide paste. Uncon- mild iron deficiency might protect patients with EPP. Iron 1195
1136 trolled trials and retrospective case series (including a study substitution in patients with EPP, if necessary, such as in 1196
1137 of 337 patients) reported the efficacy of oral b-carotene patients with significant anemia, may be considered during 1197
1138 (moderate or strong effects in 28% and 54% of patients, the darker seasons when the intensity of sunlight is low. Gene 1198
1139 respectively). However, a small controlled cross-over study therapies are also being explored. Administration of an 1199
1140 1200

1201 antisense oligonucleotide that prevents the abnormal splicing splenomegaly may develop later. A prominent clinical 1261
of the nascent mutant FECH mRNA in developing human manifestation is erythrodontia (reddish-brown discolor-
PERSPECTIVES
1202 1262
REVIEWS AND
1203 erythroblasts of a patient with EPP increased the production ation of the teeth). Patients have increased plasma, urine, 1263
1204 of functional FECH and reduced the accumulation of PPIX.130 and fecal levels type I isomer uro- and coproporphyrinogens 1264
1205 (Table 1). Analysis of mutations in UROS and studies of its 1265
1206 Case Report enzymatic activity confirm diagnosis. 1266
1207 A 67-year-old female patient presented with pronounced Light protection and vitamin D supplementation are the 1267
1208 photosensitivity (burning, stinging pain, swelling, and itch- basis of treatment. Some patients with anemia benefit from 1268
1209 ing) on light-exposed skin areas (prominent in the face and splenectomy. Because clinical presentations vary, including 1269
1210 on the back of the hands) since early childhood. Exposure to the need for transfusion and consequences of an enlarged 1270
1211 light caused her levels of 8 on the pain scale (which ranges spleen (eg, thrombocytopenia), the indication for splenec- 1271
1212 from 1 to 10). As long as she could recall, she could hardly tomy should be personalized. Allogeneic hematopoietic stem 1272
1213 be outdoors, had only few friends, and was teased at school. cell transplantation is curative. It is recommended at a 1273
1214 She chose a job with an indoor activity. After many mis- young age.135,136 In 1 case, iron depletion with deferasirox, 1274
1215 diagnoses, dermatology at a tertiary care center made a which reduces the activity of ALAS2, was reported to 1275
1216 diagnosis of EPP 35 years ago, and she was informed that improve photosensitivity.137 In support of this mechanism, 1276
1217 the disease was incurable. Sunscreen (UVA and UVB pro- an ALAS2 gain-of-function mutation was reported to in- 1277
1218 tection) and b-carotene for a few years were without crease the severity of CEP.138 Proteasome inhibitors or 1278
1219 noticeable effect. She continued to wear light-protective chemical chaperones might stabilize abnormal UROS vari- 1279
1220 clothing (long-sleeved tops, gloves, long trousers, closed ants to increase its activity and reduce porphyrin accumu- 1280
1221 shoes, and socks) and used windows with blinds at home. lation and skin photosensitivity in patients with CEP.139 1281
1222 Before seeing us in March 2017, she experienced at least 1282
1223 monthly episodes of painful skin reactions after even short Lead Poisoning 1283
1224 sunlight exposure and lasting up to 2 days. Cold water and Lead affects 3 enzymes involved in heme biosynthesis: 1284
1225 ice packs did not help. Avoiding pressure and heat, and ALAD, CPOX, and FECH (Figure 1). Primarily due to inhibi- 1285
1226 especially showering with lukewarm water, relieved the tion of ALAD, its clinical and biochemical features resemble 1286
1227 symptoms to some degree. Laboratory tests confirmed the those of ALADP. Lead poisoning is likely in patients with 1287
1228 diagnosis of EPP and severe vitamin D deficiency microcytic anemia (which is untypical for ALADP), abdom- 1288
1229 (Supplementary Table 5). Physical examination, ultrasound, inal symptoms, and in some cases neuropsychiatric 1289
1230 and laboratory values did not reveal signs of hepatobiliary symptoms. 1290
1231 involvement. Vitamin D was substituted orally with 20,000 In contrast to ALADP, in lead poisoning, the enzyme 1291
1232 IU of cholecalciferol per week. In late March, June, and activity of ALAD in patients’ lysed erythrocytes can be 1292
1233 August, we implanted a small depot stick of scenesse (16 mg restored completely by adding ionic zinc.140 Patients with 1293
1234 afamelanotide) into the subcutaneous fat above the iliac lead poisoning also have basophilic stippling of erythrocytes 1294
1235 crest via a 14-gauge needle. Photosensitivity decreased in blood smears and a lead line (bluish pigmentation on the 1295
1236 dramatically, while her protoporphyrin level remained un- gum–tooth line). Increased blood and urine levels of lead 1296
1237 changed. The patient could now spend as many as 6 hours confirm the diagnosis. Lead intoxication causes a 10-fold 1297
1238 in normal daylight. In autumn and winter, therapy with increase in urine levels of ALA and normal or only slight 1298
1239 afamelanotide was not required. increases in urine levels of PBG, as in ALADP porphyria. 1299
1240 Erythrocyte zinc-protoporphyrin and urinary cop- 1300
1241 roporphyrin isomer III are increased (Table 1). Heme 1301
1242 Congenital Erythropoietic Porphyria therapy can relieve symptoms of lead intoxication and 1302
1243 Pathophysiology ALADP.46 The primary measure is removal from lead 1303
1244 In CEP, another rare porphyria, the activity of exposure and the use of chelating agents such as 2,3- 1304
1245 uroporphyrinogen-III-synthase (UROS) is low, due to mu- dimercaptosuccinic acid (succimer) or calcium disodium 1305
1246 tations in UROS or GATA1.131,132 GATA1, encoded by a gene ethylenediamine-tetraacetate. 1306
1247 on the X chromosome, is a transcription factor that regulates 1307
1248 heme biosynthesis.133,134 This leads to accumulation of 1308
1249 Secondary Elevation in Porphyrins 1309
hydroxymethylbilane, spontaneously (non-enzymatically) Apart from the genetically determined erythropoietic
1250 forming uroporphyrinogen I, that is further metabolized to 1310
1251 and hepatic porphyrias, clinically asymptomatic secondary 1311
the non-functional end product coproporphyrinogen I. elevation in porphyrins (urine, plasma, erythrocytes, and
1252 Spontaneous oxidation of the porphyrinogens generates 1312
1253 stool) can be detected in several disorders or under certain 1313
porphyrins that accumulate in tissues. medications. These are clinically asymptomatic and usually
1254 1314
1255 consist of coproporphyrin (plasma, urine) or protoporphy- 1315
1256
Clinical Presentation, Diagnosis, and Therapy rin (blood) (mostly zinc bounded protoporphyrin) 1316
1257 Photodermatosis is severe, with mutilations already (Supplementary Table 1). Increased plasma levels of por- 1317
1258 occurring in infancy and early childhood. Most of the pa- phyrins, especially zinc protoporphyrin and cop- 1318
1259 tients display red-colored urine.135 Anemia and roporphyrin, are found in patients with diseases other than 1319
1260 1320

1321 Table 4.Clinical and Biochemical Features of Porphyrias 1381

PERSPECTIVES
1322 1382
REVIEWS AND
AHP PCT Protoporphyrias

1323 1383
1324 Patients after puberty Adult patients Children or 1384
1325 Aged <40 y Aged >18 y adolescents 1385
1326 Unexplained gastrointestinal Blister-forming dermatosis Burning pain 1386
complaints (colic, vomiting, subileus) on light-exposed skin areas Erythema/redness
1327 1387
Neurologic symptoms (paresthesia, Increased skin vulnerability on light-exposed
1328 seizures, paresis) Hyper- and hypopigmentation skin areas 1388
1329 Mental abnormalities (depression, on light-exposed skin Angioedema-like swelling 1389
1330 anxiety, hallucination) Hypertrichosis of cheeks, temples, and the eyebrows, on the face, on the back 1390
1331 Tachycardia, hypertension often associated with: of the hands and on 1391
1332 Red-colored urine without erythr Iron overload the forearms 1392
1333 ocytes or hemoglobin HCV infection Often microcytic anemia 1393
Serum hyponatremia HIV infection Possible family history
1334 Alcohol consumption
1394
1335 Hormone (replacement) therapy 1395
1336 Toxic agents (eg, hexachlorobenzene) 1396
1337 1397
1338 1398
1339 HIV, human immunodeficiency virus. 1399
1340 1400
1341 porphyrias, such as in colorectal adenocarcinoma.141 Sec- References Q7 1401
1342 ondary elevations of porphyrins are often misinterpreted, 1402
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1715 90. Kordac V, Semrádová M. Treatment of porphyria cuta- fibroblasts. J Clin Invest 1975;56:1139–1148. 1775
1716 nea tarda with chloroquine. Br J Dermatol 1974;90:95– 107. Casanova-González MJ, Trapero-Marugán M, Jones EA, 1776
1717 100. et al. Liver disease and erythropoietic protoporphyria: a 1777
1718 91. Ippen H. Treatment of porphyria cutanea tarda by phle- concise review. World J Gastroenterol 2010;16:4526– 1778
1719 botomy. Semin Hematol 1977;14:253–259. 4531. 1779
1720 92. Pandya AG, Nezafati KA, Ashe-Randolph M, et al. 108. Gross U, Frank M, Doss MO. Hepatic complications of 1780
1721 Deferasirox for porphyria cutanea tarda: a pilot study. erythropoietic protoporphyria. Photodermatol Photo- 1781
1722 Arch Dermatol 2012;148:898–901. immunol Photomed 1998;14:52–57. Q15
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1723 93. Malina L, Chlumský J. A comparative study of the results 109. Doss MO, Frank M. Hepatobiliary implications and 1783
1724 of phlebotomy therapy and low-dose chloroquine treat- complications in protoporphyria, a 20-year study. Clin 1784
Biochem 1989;22:223–229.
1725 ment in porphyria cutanea tarda. Acta Derm Venereol 1785
1726 1981;61:346–350. 110. Matilla A, Molland EA. A light and electron microscopic 1786
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1727 94. Singal AK, Kormos-Hallberg C, Lee C, et al. Low-dose 1787
porphyria and in griseofulvin-induced porphyria in mice.
1728 hydroxychloroquine is as effective as phlebotomy in 1788
treatment of patients with porphyria cutanea tarda. Clin J Clin Pathol 1974;27:698–709.
1729 1789
Gastroenterol Hepatol 2012;10:1402–1409. 111. Balwani M, Naik H, Anderson KE, et al. Clinical,
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quine in hematoporphyrin-treated animals. Chem Biol American patients with erythropoietic protoporphyria
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Interact 1996;102:69–78. and X-linked protoporphyria. JAMA Dermatol 2017;
1733 153:789–796. 1793
1734 96. Combrinck JM, Mabotha TE, Ncokazi KK, et al. Insights 1794
into the role of heme in the mechanism of action of an- 112. Yien YY, Ducamp S, Vorm LN van der, et al. Mutation
1735 in human CLPX elevates levels of d-aminolevulinate 1795
1736 timalarials. ACS Chem Biol 2013;8:133–137. 1796
97. Freesemann A, Frank M, Sieg I, et al. Treatment of synthase and protoporphyrin IX to promote erythropoi-
1737 etic protoporphyria. Proc Natl Acad Sci USA 2017; 1797
1738 porphyria cutanea tarda by the effect of chloroquine on 1798
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113. Gou EW, Balwani M, Bissell DM, et al. Pitfalls in eryth- 129. Barman-Aksoezen J, Schneider-Yin X, Minder EI. Iron in
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rocyte protoporphyrin measurement for diagnosis and erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde?
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monitoring of protoporphyrias. Clin Chem 2015; J Rare Dis Res Treat 2017;2:1–5.
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61:1453–1456. 130. Oustric V, Manceau H, Ducamp S, et al. Antisense
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114. Malik R, Lai M, Sadiq A, et al. Comparison of transient oligonucleotide-based therapy in human erythropoi-
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elastography, serum markers and clinical signs for the etic protoporphyria. Am J Hum Genet 2014;94:
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diagnosis of compensated cirrhosis. J Gastroenterol 611–617.
1807 Hepatol 2010;25:1562–1568. 1867
131. Günther H. Die Hämatoporphyrie. Dtsch Arch Klin Med
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115. Minder EI, Schneider-Yin X, Steurer J, et al. A systematic 1911;105:89–146.
1809 review of treatment options for dermal photosensitivity in 1869
132. Freesemann AG, Gross U, Bensidhoum M, et al. Immu-
1810 erythropoietic protoporphyria. Cell Mol Biol (Noisy-le- 1870
nological, enzymatic and biochemical studies of uro-
1811 grand) 2009;55:84–97. porphyrinogen III-synthase deficiency in 20 patients with 1871
1812 116. Fabrikant J, Touloei K, Brown SM. A review and update congenital erythropoietic porphyria. Eur J Biochem 1872
1813 on melanocyte stimulating hormone therapy: afamela- 1998;257:149–153. 1873
1814 notide. J Drugs Dermatol 2013;12:775–779. 133. Phillips JD, Steensma DP, Pulsipher MA, et al. 1874
1815 117. Minder EI, Barman-Aksoezen J, Schneider-Yin X. Phar- Congenital erythropoietic porphyria due to a mutation in 1875
1816 macokinetics and pharmacodynamics of afamelanotide GATA1: the first trans-acting mutation causative for a 1876
1817 and its clinical use in treating dermatologic disorders. human porphyria. Blood 2007;109:2618–2621. 1877
1818 Clin Pharmacokinet 2017;56:815–823. 134. Di Pierro E, Russo R, Karakas Z, et al. Congenital 1878
1819 118. Langendonk JG, Balwani M, Anderson KE, et al. Afa- erythropoietic porphyria linked to GATA1-R216W muta- 1879
1820 melanotide for erythropoietic protoporphyria. N Engl J tion: challenges for diagnosis. Eur J Haematol 2015; 1880
1821 Med 2015;373:48–59. 94:491–497. 1881
1822 119. Harms J, Lautenschlager S, Minder CE, et al. An alpha- 135. Katugampola RP, Badminton MN, Finlay AY, et al. 1882
1823 melanocyte-stimulating hormone analogue in erythro- Congenital erythropoietic porphyria: a single-observer 1883
1824 poietic protoporphyria. N Engl J Med 2009;360:306–307. clinical study of 29 cases. Br J Dermatol 2012; 1884
1825 120. Gross U, Frank M, Doss MO. Hepatic complications of 167:901–913. 1885
1826 erythropoietic protoporphyria. Photodermatol Photo- 136. Karakurt N, Tavil B, Azik F, et al. Successful hemato- 1886
1827 immunol Photomed 1998;14:52–57. poietic stem cell transplantation in a child with congen- 1887
1828 121. Bloomer JR. Pathogenesis and therapy of liver disease in ital erythropoietic porphyria due to a mutation in 1888
1829 protoporphyria. Yale J Biol Med 1979;52:39–48. GATA-1. Pediatr Transplant 2015;19:803–805. 1889
1830 122. Honda Y, Kawakami Y, Kan H, et al. A second attack of 137. Egan DN, Yang Z, Phillips J, et al. Inducing iron defi- 1890
1831 cholestasis associated with erythropoietic protoporphyria ciency improves erythropoiesis and photosensitivity in 1891
1832 was successfully treated by plasma exchange and blood congenital erythropoietic porphyria. Blood 2015; 1892
1833 transfusion. Clin J Gastroenterol 2014;7:333–337. 126:257–261. 1893
1834 123. Balwani M, Bloomer J, Desnick R, et al. Erythropoietic 138. To-Figueras J, Ducamp S, Clayton J, et al. ALAS2 acts 1894
1835 protoporphyria, autosomal recessive. In: Adam MP, as a modifier gene in patients with congenital erythro- 1895
1836 Ardinger HH, Pagon RA, et al, eds. GeneReviews®. poietic porphyria. Blood 2011;118:1443–1451. 1896
1837 Seattle, WA: University of Washington, 1993. Available 139. Blouin J-M, Bernardo-Seisdedos G, Emma Sasso, 1897
1838 at: http://www.ncbi.nlm.nih.gov/books/NBK100826/. et al. Missense UROS mutations causing congenital 1898
1839 Accessed October 8, 2017. erythropoietic porphyria reduce UROS homeostasis that 1899
1840 124. Wahlin S, Srikanthan N, Hamre B, et al. Protection from can be rescued by proteasome inhibition. Hum Mol 1900
1841 phototoxic injury during surgery and endoscopy in Genet 2017;26:1565–1576. 1901
1842 erythropoietic protoporphyria. Liver Transpl 2008; 140. Akagi R, Kato N, Inoue R, et al. delta-Aminolevulinate 1902
1843 14:1340–1346. dehydratase (ALAD) porphyria: the first case in North 1903
1844 125. Wahlin S, Aschan J, Björnstedt M, et al. Curative bone America with two novel ALAD mutations. Mol Genet 1904
marrow transplantation in erythropoietic protoporphyria Metab 2006;87:329–336.
1845 1905
1846 after reversal of severe cholestasis. J Hepatol 2007; 141. Lualdi M, Cavalleri A, Battaglia L, et al. Early detection of 1906
46:174–179. colorectal adenocarcinoma: a clinical decision support
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126. Windon AL, Tondon R, Singh N, et al. Erythropoietic tool based on plasma porphyrin accumulation and risk
1848 1908
protoporphyria in an adult with sequential liver and he- factors. BMC Cancer 2018;18:841.
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matopoietic stem cell transplantation: a case report. Am 142. Tollånes MC, Aarsand AK, Villanger JH, et al. Estab-
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J Transplant 2018;18:745–749. lishing a network of specialist porphyria centres—effects
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127. Landefeld C, Kentouche K, Gruhn B, et al. X-linked on diagnostic activities and services. Orphanet J Rare
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protoporphyria: Iron supplementation improves proto- Dis 2012;7:93.
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porphyrin overload, liver damage and anaemia. Br J 143. Woolf J, Marsden JT, Degg T, et al. Best practice
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Haematol 2016;173:482–484. guidelines on first-line laboratory testing for porphyria.
1855 Ann Clin Biochem 2017;54:188–198. 1915
128. Barman-Aksoezen J, Girelli D, Aurizi C, et al. Disturbed
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1857 association of GDF15 and gender with disease severity. the Diagnosis, Treatment, and Follow-Up of Inherited 1917
1858 J Inherit Metab Dis 2017;40:433–441. Metabolic Diseases. Berlin Heidelberg: Springer, 2014. 1918
1859 1919
1860 1920

Available at: http://www.springer.com/de/book/

1921Q9 Author names in bold designate shared co-first authorship. 1981
9783642403361. Accessed.
PERSPECTIVES
1922 1982
REVIEWS AND
145. Thunell S, Holmberg L, Lundgren J. Aminolaevulinate Received June 27, 2018. Accepted April 10, 2019.
1923 1983
dehydratase porphyria in infancy. A clinical and
1924 biochemical study. J Clin Chem Clin Biochem 1987; Reprint requests 1984
1925 25:5–14.
Address requests for reprints to: Detlef Schuppan, MD, Institute of
Translational Immunology and Research Center for Immune Therapy,
1985
1926 146. Floderus Y, Shoolingin-Jordan PM, Harper P. Acute University Medical Center, Johannes Gutenberg University, 1986
1927 intermittent porphyria in Sweden. Molecular, functional
Langenbeckstrasse 1, 55131 Mainz, Germany. e-mail:Q2 1987
detlef.schuppan@unimedizin-mainz.de.
1928 and clinical consequences of some new mutations found 1988
1929 in the porphobilinogen deaminase gene. Clin Genet Acknowledgments 1989
The authors thank Herbert L. Bonkovsky for valuable comments, Thomas Q16
1930 2002;62:288–297. Stauch for fruitful discussions and expert laboratory porphyria analyses, and 1990
1931 147. Liu LU, Phillips J, Bonkovsky H, et al. Hepatoery- Ilja Kubisch for help preparing tables, figures, and references. The histologic 1991
pictures were kindly provided by J.O. Habeck.
1932 thropoietic porphyria. In: Adam MP, Ardinger HH, Author contributions: Ulrich Stölzel: Idea, composition, literature research,
1992
1933 Pagon RA, et al, eds. GeneReviews®. Seattle, WA: writing, and editing all aspects of the manuscript, creating figures, and tables. 1993
1934 University of Washington, 1993. Available at: http:// Manfred Otto Doss: Providing historical and mechanistic information, especially 1994
as regards mechanisms and laboratory diagnosis, editing the manuscript. Detlef
1935 www.ncbi.nlm.nih.gov/books/NBK169003/. Accessed Schuppan: Idea, composition, literature research, writing, and editing all aspects 1995
1936 November 4, 2017. of the manuscript, creating figures, editing tables, and proofreading. 1996
1937 148. Kirsch RE, Meissner PN, Hift RJ. Variegate porphyria. Conflicts of interest 1997
1938 Semin Liver Dis 1998;18:33–41. The authors disclose no conflicts. 1998
1939 1999
1940 2000
1941 2001
1942 2002
1943 2003
1944 2004
1945 2005
1946 2006
1947 2007
1948 2008
1949 2009
1950 2010
1951 2011
1952 2012
1953 2013
1954 2014
1955 2015
1956 2016
1957 2017
1958 2018
1959 2019
1960 2020
1961 2021
1962 2022
1963 2023
1964 2024
1965 2025
1966 2026
1967 2027
1968 2028
1969 2029
1970 2030
1971 2031
1972 2032
1973 2033
1974 2034
1975 2035
1976 2036
1977 2037
1978 2038
1979 2039
1980 2040

17.e1 Stölzel et al Gastroenterology Vol. -, No. -
2041 2101
2042 2102
2043 2103
2044 2104
2045 2105
2046 2106
2047 2107
2048 2108
web 4C=FPO
2049 2109
2050 2110
web 4C=FPO
2051 2111
2052 2112
2053 2113
Supplementary Figure 1. Porphyrins that are concentrated
2054 2114
in brown vs white eggshells emit a strong red fluorescence
2055 when exposed to long-wave (366 nm) ultraviolet light. 2115
2056 Supplementary Figure 3. Biochemical characteristics of 111 2116
2057 patients with PCT. Characteristic dominance of urinary uro-
2117
and heptacarboxyporphyrin over coproporphyrin in overt
2058 disease and relapse, whereas in remission, this ratio is 2118
2059 inverted. Total urinary porphyrin concentrations are 5- to 10- 2119
2060 fold higher in overt disease or relapse compared to remission 2120
2061 (P < .001) (not shown).11 2121
2062 2122
2063 2123
2064 Supplementary Table 1.Clinical Scenarios That Can Lead to 2124
2065 a Secondary Elevation in Porphyrins 2125
2066 2126
2067 Variable Clinical scenario 2127
2068 2128
Secondary Toxic liver damage, lead intoxication
2069 porphyrinuriasa Alcohol consumption
2129
2070 Fatty liver disease 2130
2071 Hemochromatosis 2131
2072 Hepatitis 2132
2073 Intra- and extrahepatic cholestasis 2133
2074 Dubin–Johnson syndrome, 2134
Rotor syndrome
2075 2135
Various anemias
2076 Diabetes mellitus 2136
2077 Many drugs, especially 2137
2078 inducers of CYPs 2138
2079 Secondary blood Iron deficiency 2139
2080 protoporphyrin Lead intoxication 2140
elevationsb
2081 2141
2082 Supplementary Figure 2. Pathophysiologic components of 2142
2083 PCT. aHFE gene mutations are found in about two-thirds of a
Several hepatobiliary diseases can lead to impaired secre- 2143
2084 the patients.3 bPatients with acquired PCT usually harbor tion of porphyrins (especially of coproporphyrin) in bile and 2144
polymorphic variants of CyP450 genes, leading to higher
2085 enzyme activity, while patients with familial PCT express a
feces, with secondary increases in urine, comparable to the 2145
2086 polymorphic variant of glycerol phosphate O-acyltransferase
signs of enhanced bilirubin turnover.
b
2146
2087 Iron deficiency causes substrate depletion for ferrochela- 2147
(GNPAT) that down-regulates hepcidin and is associated with tase, and lead poisoning inhibits ferrochelatase activity,
2088 iron accumulation in HFE-associated hemochromatosis.4–6 resulting in elevated concentrations of PPIX, mainly zinc-
2148
c
2089 Hexachlorobenzene inhibits UROD and causes PCT in bound PPIX, in blood. 2149
2090 humans and animals.7,8 dFurther trigger factors are hepatitis 2150
2091 C and HIV infection.9,10 eUROD, uroporphyrinogen 2151
decarboxylase.
2092 2152
2093 2153
2094 2154
2095 2155
2096 2156
2097 2157
2098 2158
2099 2159
2100 2160

- 2019 Clinical Guide and Update on Porphyrias 17.e2
2161 Supplementary Table 2.Novel and Alternative Therapies for Acute Hepatic Porphyria 2221
2162 First author, year, or 2222
2163 Drug or measure Mechanism Effectiveness NCT clinical trial no. 2223
2164 2224
2165 Magnesium intravenously Inhibition of neuromuscular Case reports Sadeh, 199112 2225
2166 excitation, treatment of Not consistent Zeiler, 201513 2226
2167 seizures 2227
a 14
LH-RH agonists Inhibition of gonadotropin Case reports Anderson, 1984
2168 secretion, prevention of Not consistent Gross, 1995 1 2228
2169 ovulo-cyclic manifestations De Block, 199915 2229
2170 Marsden, 2015 16 2230
2171 Enzyme replacement therapy Decreasing PBG and 5-ALA Transient decrease of plasma Johansson, 200317 2231
2172 (recombinant human PBG but not 5-ALA Sardh, 200718 2232
2173 PBGD) No clinical benefit 2233
Transfer of PBGD gene in liver Restoring PBGD function in Phase 1, urinary ALA and PBG NCT02076763
2174 2234
cells by viral vectors liver not decreased
2175 Intravenous administration of Inducing PBGD protein Tested successfully in a Jiang, 2018 19 2235
2176 human PBGD mRNA expression in liver mouse model of AIP and 2236
2177 nonhuman primates 2237
2178 Hemodialysis Removing circulating 5-ALA Successfully case reports; Attarian, 201720 2238
2179 and PBG in plasma controlled studies are Q12 2239
2180 lacking; hepatic synthesis 2240
of 5-ALA not inhibited
2181 2241
Pharmacologic chaperone Enhancing PBGD activity and/ Only tested successfully in Bustad HL, Bordeaux, France,
2182 treatment or protection against PBGD-deficient mouse personal communication 2242
2183 proteolysis model 2243
2184 RNAi-mediated silencing Inhibition of the hepatic Successfully tested in ALAS1- Givosiran Phase 1 trial, 2244
2185 (Givosiran) synthesis of 5-ALA overexpressing mouse NCT02452372 2245
2186 model. Phase 3 trial (Envision) 2246
2187 Phase 1a–b clinical study NCT03338816 2247
shows highly efficient
2188 ALAS1 suppression in
2248
2189 patients with AIP 2249
2190 (suppression of ALA and 2250
2191 PBG production, reduction 2251
2192 of clinical activity) 2252
2193 2253
2194 LH-RH, luteinizing hormone-releasing hormone; NCT, National Clinical Trial; RNAi, RNA interference. Q13
2254
2195 a
Initial treatment with a gonadotropin-releasing hormone agonist, if clinically effective, is preferred. This may later be replaced 2255
2196 by oral contraceptives accompanied by regular measurement of urinary porphyrins and porphyrin precursors because this 2256
2197 treatment may also induce ALAS1.1,2 2257
2198 2258
2199 2259
2200 2260
2201 2261
2202 2262
2203 2263
2204 2264
2205 2265
2206 2266
2207 2267
2208 2268
2209 2269
2210 2270
2211 2271
2212 2272
2213 2273
2214 2274
2215 2275
2216 2276
2217 2277
2218 2278
2219 2279
2220 2280

17.e3 Stölzel et al Gastroenterology Vol. -, No. -
2281 Supplementary Table 3.Urinary Excretion of Porphyrin Supplementary Table 5.Laboratory Parameters of a Female 2341
Precursors and Porphyrins, and Patient With Erythropoietic
2282 Plasma Porphyrin Scan in a Female Protoporphyria 2342
2283 Patient With Acute Intermittent 2343
2284 Porphyria Analyte Value Normal value 2344
2285 2345
2286 Normal Hemoglobin, mmol/L 8.09 >7.45 2346
level corrected MCV, fl Normal >80
2287 2347
Analyte Level for creatinine Serum ferritin, pmol/L 32.9 27.4–316.5
2288 Serum transferrin saturation, % 14.1 16–45 2348
2289 5-ALA,a mmol/mol 45.9 <6.3 ALT, mmol/L/s Normal <0.73 2349
2290 PBG,a mmol/mol 74.1 <1.4 AST, mmol/L/s Normal <0.83 2350
2291 Uroporphyrin,a mmol/mol 213.8 <4.5 GGT, mmol/L/s Normal <0.52 2351
2292 Coproporphyrin,a mmol/mol 39.1 <20.7 25-hydroxy-vitamin D, nmol/L 23.9 78–260 2352
2293 Total porphyrins,a mmol/mol 306.0 <28.4 Metal-free erythrocyte PPIX, 36149 <89 2353
Plasma porphyrin scan,b nm 618 Negative nmol/L
2294 Erythrocyte zinc-bound PPIX, 150 <40
2354
2295 mmol/mol heme 2355
2296 NOTE. Emission maximum of the plasma fluorescence Plasma porphyrin scan, nma 634 Negative 2356
2297 spectrum on excitation at 405 nm. 2357
2298 a
XXXX. 2358
2299Q14
b
XXXX. ALT, serum alanine aminotransferase; AST, serum aspartate 2359
aminotransferase; GGT, serum g-glutamyltransferase; MCV,
2300 mean corpuscular erythrocyte volume.
2360
2301 Supplementary Table 4.Laboratory Parameters of a Female
a
Emission maximum of the plasma fluorescence spectrum on 2361
2302 Patient With Porphyria Cutanea excitation at 405 nm. 2362
2303 Tarda 2363
2304 2364
2305 Analyte Level Normal 2365
2306 2366
ALT, mmol/L/s 1.00 <0.85
2307 AST, mmol/L/s 0.81 <0.62 2367
2308 GGT, mmol/L/s 1.95 <1.02 2368
2309 Serum ferritin, pmol/L 1434.8 <844 2369
2310 Serum transferrin saturation, % 71 16–4 2370
2311 Serum antibodies to hepatitis B Negative Negative 2371
2312 (HBs, HBc) and C and HIV 2372
HFE mutations H63D þ/þ, C282Y –/– Negative
2313 2373
5-ALA,a mmol/molb Normal <6.3
2314 PBG,a mmol/molb Normal <1.4 2374
2315 Uroporphyrin,a mmol/molb 296.0 <4.5 2375
2316 Heptacarboxyporphyrin,a 158.0 <1.4 2376
2317 mmol/molb 2377
2318 Coproporphyrin,a 12.4 <20.7 2378
mmol/molb
2319 2379
Total porphyrins,a 615.2 <28.4
2320 mmol/molb
2380
2321 Plasma porphyrin scan,c nm 619 Negative 2381
2322 2382
2323 2383
2324 ALT, serum alanine aminotransferase; AST, serum aspartate 2384
2325 aminotransferase; GGT, serum g-glutamyltransferase. 2385
a
Urinary porphyrin precursors and porphyrins.
2326 b
Corrected for creatinine. 2386
2327 c
Emission maximum of the plasma fluorescence spectrum on 2387
2328 excitation at 405 nm. 2388
2329 2389
2330 2390
2331 2391
2332 2392
2333 2393
2334 2394
2335 2395
2336 2396
2337 2397
2338 2398
2339 2399
2340 2400

- 2019 Clinical Guide and Update on Porphyrias 17.e4
11. Stölzel U, Köstler E, Koszka C, et al. Low prevalence of

2401 Supplementary References 2461
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2402 2462
1. Gross U, Honcamp M, Daume E, et al. Hormonal oral Germany. Hepatology 1995;21:1500–1503.
2403 2463
contraceptives, urinary porphyrin excretion and por- 12. Sadeh M, Blatt I, Martonovits G, et al. Treatment of
2404 2464
phyrias. Horm Metab Res 1995;27:379–383. porphyric convulsions with magnesium sulfate. Epilepsia
2405 2465
2. Anderson KE, Spitz IM, Bardin CW, et al. A gonadotropin 1991;32:712–715.
2406 2466
releasing hormone analogue prevents cyclical attacks of 13. Zeiler FA, Matuszczak M, Teitelbaum J, et al. Magnesium
2407 porphyria. Arch Intern Med 1990;150:1469–1474. 2467
sulfate for non-eclamptic status epilepticus. Seizure 2015;
2408 3. Stölzel U, Köstler E, Schuppan D, et al. Hemochroma-
2468
32:100–108.
2409 tosis (HFE) gene mutations and response to chloroquine 2469
14. Anderson KE, Spitz IM, Sassa S, et al. Prevention of
2410 in porphyria cutanea tarda. Arch Dermatol 2003; 2470
cyclical attacks of acute intermittent porphyria with a
2411 139:309–313. long-acting agonist of luteinizing hormone-releasing 2471
2412 4. Wickliffe JK, Abdel-Rahman SZ, Lee C, et al. CYP1A2*1F hormone. N Engl J Med 1984;311:643–645. 2472
2413 and GSTM1 alleles are associated with susceptibility to 15. De Block CE, Leeuw IH, Gaal LF. Premenstrual attacks of 2473
2414 porphyria cutanea tarda. Mol Med 2011;17:241–247. acute intermittent porphyria: hormonal and metabolic 2474
2415 5. Farrell CP, Overbey JR, Naik H, et al. The D519G poly- aspects—a case report. Eur J Endocrinol 1999;141:50–54. 2475
2416 morphism of glyceronephosphate O-acyltransferase is a 16. Marsden JT, Guppy S, Stein P, et al. Audit of the use of 2476
2417 risk factor for familial porphyria cutanea tarda. PLoS One regular haem arginate infusions in patients with acute 2477
2418 2016;11:e0163322. porphyria to prevent recurrent symptoms. JIMD Rep 2015; 2478
2419 6. Barton JC, Chen W-P, Emond MJ, et al. GNPAT p. 22:57–65. 2479
2420 D519G is independently associated with markedly 17. Johansson A, Möller C, Fogh J, et al. Biochemical charac- 2480
2421 increased iron stores in HFE p.C282Y homozygotes. terization of porphobilinogen deaminase-deficient mice 2481
2422 Blood Cells Mol Dis 2017;63:15–20. during phenobarbital induction of heme synthesis and the 2482
2423 7. Gorman N, Trask HS, Robinson SW, et al. Hexa- effect of enzyme replacement. Mol Med 2003;9:193–199. 2483
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2425 AHR mice without increasing CYP1A2. Toxicol Appl macokinetics and pharmocodynamics of recombinant hu- 2485
2426 Pharmacol 2007;221:235–242. man porphobilinogen deaminase in healthy subjects and 2486
2427 8. Doss MO. Porphyrinurias and occupational disease. Ann asymptomatic carriers of the acute intermittent porphyria 2487
2428 N Y Acad Sci 1987;514:204–218. gene who have increased porphyrin precursor excretion. 2488
2429 9. Fargion S, Piperno A, Cappellini MD, et al. Hepatitis C Clin Pharmacokinet 2007;46:335–349. 2489
2430 virus and porphyria cutanea tarda: evidence of a strong 19. Jiang L, Berraondo P, Jericó D, et al. Systemic 2490
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Acute Intermittent Porphyria Guidelines

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Gastroenterology 2019;-:1–17

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603 cases, the activity of PBGD in erythrocytes is normal.49 With 663

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1321 Table 4.Clinical and Biochemical Features of Porphyrias 1381

AHP PCT Protoporphyrias

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Available at: http://www.springer.com/de/book/

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11. Stölzel U, Köstler E, Koszka C, et al. Low prevalence of

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