Seminar
Porphyrias: A 2015 update

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Summary

The hereditary porphyrias comprise a group of eight metabolic disorders of the heme biosynthesis pathway. Each porphyria is caused by abnormal function at a separate enzymatic step resulting in a specific accumulation of heme precursors. Porphyrias are classified as hepatic or erythropoietic, based on the organ system in which heme precursors (δ-aminolevulinic acid [ALA], porphobilinogen and porphyrins) are overproduced. Clinically, porphyrias are characterized by acute neurovisceral symptoms, skin lesions or both. However, most if not all the porphyrias impair hepatic or gastrointestinal function. Acute hepatic porphyrias present with severe abdominal pain, nausea, constipation, confusion and seizure, which may be life threatening, and patients are at risk of hepatocellular carcinoma without cirrhosis. Porphyria Cutanea presents with skin fragility and blisters, and patients are at risk of hepatocellular carcinoma with liver iron overload. Erythropoietic protoporphyria and X-linked protoporphyria present with acute painful photosensitivity, and patients are at risk of acute liver failure. Altogether, porphyrias are still underdiagnosed, but once they are suspected, early diagnosis based on measurement of biochemical metabolites that accumulate in the blood, urine, or feces is essential so specific treatment can be started as soon as possible and long-term liver complications are prevented. Screening families to identify presymptomatic carriers is also crucial to prevent overt disease and chronic hepatic complications.

Introduction

The porphyrias are a group of eight inherited metabolic disorders of heme biosynthesis in which specific patterns of accumulation of heme precursors are associated with characteristic clinical features: acute neurovisceral attacks, skin lesions or both [1]. Each type of porphyria is the result of a specific enzymatic abnormality in the heme biosynthetic pathway (Fig. 1). Delta-aminolevulinic acid (ALA) and/or porphobilinogen (PBG), the initial heme lineage precursors, are overproduced in the porphyrias that cause chronic neuropathy and acute neurovisceral attacks, and porphyrinogens are overproduced in the cutaneous porphyrias [2]. Heme is required for the synthesis of hemoproteins such as hemoglobin, myoglobin, the mitochondrial or microsomal cytochromes, catalase, peroxidase, nitric oxide synthase, prostaglandin endoperoxide synthase, guanylate cyclase and tryptophan dioxygenase, all of which play important roles in oxidation-reduction reactions and oxygen transport [1]. The three terminal enzymes (coproporphyrinogen oxidase [CPO], protoporphyrinogen oxidase [PPOX] and ferrochelatase [FECH]) are associated with the inner mitochondrial membrane in a multienzymatic terminal complex related to the import of iron into mitochondria (Fig. 2) [3]. Zn2+ is also a substrate for the enzyme, and iron deficiency leads to Zinc-Protoporphyrin (PPIX) accumulation, whereas ferrochelatase deficiency leads to free-PPIX accumulation [4], [5]. Although heme is synthesized in every human cell, 80% is produced in erythropoietic cells and 15% in liver parenchymal cells. Heme biosynthesis is differently controlled in these two tissues [6]. ALA synthesis is the most important controlling step for heme formation [4], [6]. The first enzyme, δ-aminolevulinic acid synthase (ALAS; EC 2.3.1.37), is encoded by two genes, one erythroid specific (ALAS2 on the X chromosome) and one ubiquitous (ALAS1 on chromosome 3) [6]. In the liver, newly formed hemoproteins are rapidly turned over in response to current metabolic needs, and the liver ALAS1 is under a negative feedback regulation by the intracellular “uncommitted” heme pool (Fig. 3). Increased hepatic ALAS activity is a secondary phenomenon that results from exposure to several influences (such as drugs, fasting and hormones). This accounts for the especially marked increase in ALA and PBG production and excretion in acute hepatic porphyrias [2].

In erythroid cells, synthesis of the enzymes participating in the formation of heme is regulated during erythroid differentiation by erythropoietin and is finely tuned by iron availability. In these cells, the rate of ALAS2 synthesis is increased only during the period of active heme synthesis and is regulated by iron availability. Ferrochelatase, the final enzyme of heme biosynthesis, and iron, its substrate, also play a significant role in controlling the rate of heme formation in erythroid cells [7].

Spleen and liver macrophages have a special role in degrading heme and recycling iron following phagocytosis of senescent erythrocytes. Heme oxygenase 1 (HO-1, EC 1.14.99.3) is present in especially large amounts in liver and spleen and generates carbon monoxide, biliverdin and iron (Fig. 3). Biliverdin is oxidized to bilirubin and excreted in bile, while the liberated iron is stored as ferritin or is recycled back to the plasma [8].

The porphyrias are generally broadly classified as acute porphyrias and cutaneous porphyrias, based on their clinical presentation (Fig. 4) [9]. Acute intermittent porphyria (AIP) and the rare ALA dehydratase porphyria (ADP) are associated with neuropathy and acute attacks only. Variegate porphyria (VP) and hereditary coproporphyria (HC) are associated with both acute attacks and/or skin lesions. Congenital erythropoietic porphyria (CEP), sporadic and familial porphyria cutanea (PC), erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLPP) present with dermatological symptoms only. Most porphyrias, apart from the sporadic form of porphyria cutanea, are monogenic disorders with an autosomal dominant inheritance and low clinical penetrance. The majority of the individuals who inherit an autosomal dominant porphyria remain asymptomatic throughout life (latent or presymptomatic) but are at risk of chronic liver complications [10]. Accurate diagnosis of clinically overt porphyria requires identification of the unique pattern of overproduction of porphyrin precursors (ALA, PBG) and porphyrins (Uro, Copro, Protoporphyrins) that results from each enzyme deficiency (Table 1). ALA and PBG are excreted only in the urine. Coproporphyrin and uroporphyrin are the predominant porphyrins in normal human urine. Protoporphyrin, a very poorly water-soluble compound, and 70% of coproporphyrin are excreted in feces through the liver, where they may induce cholestasis [11].

Section snippets

Acute porphyrias: AIP, VP, HC, ADP

The autosomal dominant acute porphyrias may present with a sudden life-threatening crisis characterized by severe abdominal pain, neuropsychiatric symptoms, autonomic neuropathy and electrolyte disturbances. These attacks are uncommon and are often difficult to diagnose, mainly because the penetrance is low and approximately 90% of affected individuals never experience an acute attack. In AIP, only acute attacks occur and the skin is never affected. VP and HC can also be associated with skin

Clinical symptoms

Variegata porphyria, hereditary coproporphyria and porphyria cutanea all display the same chronic cutaneous photosensitivity. Worldwide, PC is the most common porphyria and is solely associated with skin symptoms, while VP and HC can also cause abdominal pain and other neurological symptoms (Fig. 4) [32]. Biological diagnosis is essential to avoid misclassification and to avoid an unexpected acute attack. Clinically, bullae, blisters or vesicular lesions are restricted to sun-exposed skin such

Clinical features and diagnosis

Erythropoietic Protoporphyria (EPP, MIM 177000) is the most common form of painful photosensitive porphyria [44]. It is an inherited disorder caused by partial deficiency in mitochondrial ferrochelatase (FECH. EC 4.99.1.1.), the terminal enzyme of heme biosynthesis (Fig. 6 and Table 1). Accumulation of free-PPIX in erythrocytes, and secondarily in other tissues or biological fluids (skin, liver, bile, stools), leads to painful photosensitivity and, in few patients, severe liver disease [44].

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Key points: Liver and porphyria

Acute hepatic porphyrias

Clinical symptoms of acute attacks

  • Severe abdominal pain/back and thigh pain

  • Vomiting, constipation, other signs of automic neuropathy (muscle weakness, hypertension, tachycardia…)

  • Mental symptoms

Associate chronic disease: HCC without cirrhosis

Biology

  • Increased ALA and PBG in the urine

  • ± Hyponatremia

Management

  • Admission to hospital: withdrawal of all common

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