Molecular mechanisms of dominant expression in porphyria

Summary Summary:#Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified.     

Recommendations for the diagnosis and treatment of the acute porphyrias

The acute porphyrias, 4 inherited disorders of heme biosynthesis, cause life-threatening attacks of neurovisceral symptoms that mimic many other acute medical and psychiatric conditions. Lack of clinical recognition often delays effective treatment, and inappropriate diagnostic tests may lead to misdiagnosis and inappropriate treatment. We review the clinical manifestations, pathophysiology, and genetics of the acute porphyrias and provide recommendations for diagnosis and treatment on the basis of reviews of the literature and clinical experience. An acute porphyria should be considered in many patients with unexplained abdominal pain or other characteristic symptoms. The diagnosis can be rapidly confirmed by demonstration of a markedly increased urinary porphobilinogen level by using a single-void urine specimen. This specimen should also be saved for quantitative measurement of porphobilinogen, 5-aminolevulinic acid, and total porphyrin levels. Intravenous hemin therapy, started as soon as possible, is the most effective treatment. Intravenous glucose alone is appropriate only for mild attacks (mild pain, no paresis or hyponatremia) or until hemin is available. Precipitating factors should be eliminated, and appropriate supportive and symptomatic therapy should be initiated. Prompt diagnosis and treatment greatly improve prognosis and may prevent development of severe or chronic neuropathic symptoms. We recommend identification of at-risk relatives through enzymatic or gene studies.     

The acute hepatic porphyrias: current status and future challenges

The porphyrias are predominantly inherited metabolic disorders, which result from a specific deficiency of one of the eight enzymes along the pathway of haem biosynthesis. Historically, they have been classified into hepatic and erythropoietic forms, based on the primary site of expression of the prevailing dysfunctional enzyme. From a clinical point of view, however, it is more convenient to subdivide them into acute and non-acute porphyrias, thereby primarily considering the potential occurrence of life-threatening acute neurovisceral attacks. Unrecognised or untreated, such an acute porphyric attack is associated with a significant mortality of up to 10%. The acute hepatic porphyrias comprise acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and δ-aminolevulinic acid dehydratase deficiency porphyria. Making a precise diagnosis may be difficult because the different types of porphyrias may show overlapping clinical and biochemical characteristics. To date, the therapeutic possibilities are limited and mainly symptomatic. In this overview we report on what is currently known about pathogenesis, clinic, diagnostics, and therapy of the acute hepatic porphyrias. We further point out actual and future challenges in the management of these diseases.     

The porphyrias

The porphyrias are a group of metabolic disorders arising from defects in the haem biosynthetic pathway. Most forms are inherited as Mendelian autosomal dominant characters, but some are recessive and others acquired. There is a linked group of diseases, which are not porphyrias, but have in common alterations of haem biosynthesis. The haem biosynthetic pathway is now well understood and the molecular biology of its function and dysfunction in the porphyrias is currently an area of major investigation. The acute porphyrias are of most importance since attacks of these may be life-threatening. A variety of factors may precipitate these attacks including various drugs, alcohol, strict dieting or fasting and hormonal fluctuations. The non-acute porphyrias are largely dermatological conditions, which present clinically as cutaneous photosensitivity. The dermatological changes are brought about by the photosensitizing properties of circulating porphyrins. On the basis of this photoactivity, porphyrins are now being used, therapeutically, in the treatment of cancer.     

Update review of the acute porphyrias

Acute porphyrias are rare inherited disorders due to deficiencies of haem synthesis enzymes. To date, all UK cases have been one of the three autosomal dominant forms, although penetrance is low and most gene carriers remain asymptomatic. Clinical presentation is typically with acute neurovisceral attacks characterised by severe abdominal pain, vomiting, tachycardia and hypertension. Severe attacks may be complicated by hyponatraemia, peripheral neuropathy sometimes causing paralysis, seizures and psychiatric features. Attacks are triggered by prescribed drugs, alcohol, hormonal changes, fasting or stress. The diagnosis is made by finding increased porphobilinogen excretion in a light‐protected random urine sample. Management includes administration of intravenous human haemin and supportive treatment with non‐porphyrinogenic drugs. A few patients develop recurrent attacks, a chronic illness requiring specialist management. Late complications include chronic pain, hepatocellular carcinoma, chronic renal failure and hypertension. In the UK, the National Acute Porphyria Service provides clinical advice and supplies haemin when indicated.     

RETRACTED ARTICLE: The porphyrias: pathophysiology

Porphyrias are a group of inherited and acquired metabolic disorders due to a defect in haem biosynthesis. An enzymatic defect at different steps of haem synthesis leads to tissue accumulation and excessive excretion of porphyrins and/or their toxic precursors. The specific patterns of accumulation determine the variety of clinical manifestations, ranging from acute neurovisceral attacks to skin lesions and liver disease. Most enzyme defects represent partial deficiencies, while familial cases are linked to autosomal or recessive traits. The incomplete penetrance of the genetic defects often requires the triggering or aggravating effect of host-related or environmental factors. While genetics has a role in confirming clinical suspicion and in family screening, biochemical and clinical studies are still central in the diagnosis.     

Porphyrias

Seven different porphyrias form a group of inherited metabolic disorders, each resulting from a partial deficiency of a specific enzyme in the haem biosynthesis pathway. Clinically, the three most important entities are an acute porphyric attack and acute and chronic skin symptoms. Porphyrias are rare and sometimes misdiagnosed, because various symptoms and signs mimic other diseases. Once porphyria is suspected, biochemical analyses easily detect porphyrins and their precursors from blood, urine, or faeces. Mutation screening can be done at the quiescent phase of the disease. Pathogenetic mechanisms and clinical manifestations differ in individual porphyrias and most of them require a specific treatment. Early diagnosis and information about precipitating factors can diminish mortality and prevent subsequent attacks among patients with acute porphyrias, so mutation screening is recommended for family members.     

Acute intermittent porphyria

Acute intermittent porphyria (AIP) is characterised by neurovisceral crises the most common clinical presentation of which is abdominal pain. It is an autosomal dominant condition with incomplete penetrance and is potentially life-threatening. The key point in management is to suspect and confirm the diagnosis as early as possible in order to treat the attack and to avoid inappropriate treatments which may exacerbate the crisis. In this chapter we briefly outline the haem biosynthetic pathway and how deficiencies in individual enzymes give rise to the different porphyrias. We then describe the clinical features and diagnosis of AIP, followed by a discussion of pathogenesis, highlighting advances in the molecular biology of AIP and introducing the debate as to whether neurovisceral crises might result from porphyrin precursor neurotoxicity or from haem deficiency. Finally we discuss management, including family screening, avoidance of triggering factors, analgesia, maintenance of a high calorie intake, and administration of haem derivatives.     

A challenging diagnosis for potential fatal diseases: Recommendations for diagnosing acute porphyrias

Acute porphyrias are a heterogeneous group of metabolic disorders resulting from a variable catalytic defect of four enzymes out of the eight involved in the haem biosynthesis pathway; they are rare and mostly inherited diseases, but in some circumstances, the metabolic disturbance may be acquired. Many different environmental factors or pathological conditions (such as drugs, calorie restriction, hormones, infections, or alcohol abuse) often play a key role in triggering the clinical exacerbation (acute porphyric attack) of these diseases that may often mimic many other more common acute medical and neuropsychiatric conditions and whose delayed diagnosis and treatment may be fatal. In order to obtain an accurate diagnosis of acute porphyria, the knowledge and the use of appropriate diagnostic tools are mandatory, even in order to provide as soon as possible the more effective treatment and to prevent the use of potentially unsafe drugs, which can severely precipitate these diseases, especially in the presence of life-threatening symptoms.In this paper, we provide some recommendations for the diagnostic steps of acute porphyrias by reviewing literature and referring to clinical experience of the board members of the Gruppo Italiano Porfiria (GrIP).     

Hepatic porphyria: A narrative review

Porphyrias are a group of metabolic disorders, which result from a specific abnormality in one of the eight enzymes of the heme biosynthetic pathway. These have been subdivided based on the predominant site of enzyme defect into hepatic and erythropoietic types and based on clinical presentation into acute neurovisceral and cutaneous blistering porphyrias. This review focuses on hepatic porphyrias, which include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), aminolevulinic acid dehydratase deficiency porphyria (ADP), and porphyria cutanea tarda (PCT). Of these, AIP and ADP are classified as acute porphyria, PCT as cutaneous, while VP and HCP present with both acute and cutaneous clinical manifestations. Porphobilinogen levels in a spot urine sample is the initial screening test for the diagnosis of acute hepatic porphyria, and plasma with spot urine porphyrin levels is the initial screening test to approach patients suspected of cutaneous porphyria. Specific biochemical porphyrin profile for each porphyria helps in determining the specific diagnosis. Pain relief and elimination of triggering agents are the initial steps in managing a patient presenting with an acute attack. Intravenous glucose administration terminates the mild episode of acute porphyria, with intravenous hemin needed for management of moderate to severe episodes. Liver transplantation is curative and may be needed for patients with a life-threatening acute porphyria attack or for patients with recurrent acute attacks refractory to prophylactic treatment. Of the cutaneous porphyrias, PCT is the most common and is frequently associated with a combination of multiple susceptibility factors such as alcohol use, smoking, hepatitis C virus infection, HIV infection, estrogen use, and mutations of the hemochromatosis gene. Regular phlebotomy schedule and low-dose hydroxychloroquine are effective and safe treatment options for management of PCT.     

Hepatic porphyrias: diagnosis and management

Porphyrias are a group of metabolic disorders in which there are defects in the normal pathway for the biosynthesis of heme, the critical prosthetic group for numerous hemoproteins. The clinical manifestations of the porphyrias can be highly varied, and patients may present to general physicians and be referred to a wide variety of subspecialists because of these manifestations. However, two major clinical forms are represented by the so-called "acute" porphyrias, in which patients suffer recurrent bouts of pain, especially pain in the abdomen, and the "cutaneous" porphyrias, in which patients have painful skin lesions. Knowledge of the factors chiefly responsible for regulating the rate of synthesis of heme has helped to explain how drugs and other factors may cause porphyria. Knowledge of the physical and chemical properties of porphyrins also forms an important part of the foundation for understanding the clinical manifestations of these diseases. Thus, the porphyrias can best be understood after reviewing the chemical properties of porphyrins and heme and the control of their biosynthesis.     

Variegate porphyria in a 46‐year‐old patient taking sibutramine for weight loss

The acute hepatic porphyrias can cause life‐threatening attacks of neurovisceral symptoms that mimic other acute medical conditions. Variegate porphyria caused by mutations in the protoporphyrinogen oxidase (PPOX) gene is a latent disorder characterized by exacerbations induced by fasting, alcohol consumption or certain drugs. We describe the case of a 46‐year‐old female patient presenting with a first episode of symptomatic porphyria after 10 d of sibutramine treatment for weight loss. Genetic analysis showed a heterozygous R168H hot spot mutation in the PPOX gene. A putative effect of sibutramine on the hepatic haem biosynthetic pathway and reduced food intake have likely caused this exacerbation of a porphyria attack. Although this may be the first case report of this kind, the risk of acute porphyria should be considered in patients using pharmacotherapy for obesity.     

Hepatic porphyria]

INTRODUCTION: This review is aimed at presenting classification and diagnosis criteria of hepatic porphyrias and at proposing guidelines for diagnosis and management of these diseases. CURRENT KNOWLEDGE AND KEY POINTS: Porphyrias are inherited disorders: each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of heme biosynthesis. Porphyrias are presently classified as erythropoietic or hepatic, depending on the primary organ in which excess production of porphyrins or precursors takes place. From 1970 to 1998, there have been important advances in the understanding of these diseases: specific enzyme deficiencies have been demonstrated, and genes have been isolated and located. These advances have been followed rapidly by identification of mutations. PERSPECTIVES AND PROJECTS: Treatment of acute attacks by hematin completely changed the disease prognosis. Relationships between porphyria cutanea tarda and hepatitis C virus or hemochromatosis have also been clarified. However, several important issues are still not solved: for instance, pathogenesis of neuronal dysfunction that produces the acute attacks is poorly understood. Differences related to susceptibility to develop acute attacks are not known.     

Erythropoietic and hepatic porphyrias

Porphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10% of patients. Acute hepatic porphyrias (-aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological–psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life-threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic -aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic -aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased metabolites upstream of the enzymatic defect are excreted into urine and faeces. The diagnosis is based on their evaluation. Primary enzymatic or molecular analyses are noncontributary and may be misleading. Acute polysymptomatic exacerbations accompany a high excretory constellation of porphyrin precursors -aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.     

Acute Hepatic Porphyria

The porphyrias comprise a set of diseases, each representing an individual defect in one of the eight enzymes mediating the pathway of heme synthesis. The diseases are genetically distinct but have in common the overproduction of heme precursors. In the case of the acute (neurologic) porphyrias, the cause of symptoms appears to be overproduction of a neurotoxic precursor. For the cutaneous porphyrias, it is photosensitizing porphyrins. Some types have both acute and cutaneous manifestations. The clinical presentation of acute porphyria consists of abdominal pain, nausea, and occasionally seizures. Only a small minority of those who carry a mutation for acute porphyria have pain attacks. The triggers for an acute attack encompass certain medications and severely decreased caloric intake. The propensity of females to acute attacks has been linked to internal changes in ovarian physiology. Symptoms are accompanied by large increases in delta-aminolevulinic acid and porphobilinogen in plasma and urine. Treatment of an acute attack centers initially on pain relief and elimination of inducing factors such as medications; glucose is administered to reverse the fasting state. The only specific treatment is administration of intravenous hemin. An important goal of treatment is preventing progression of the symptoms to a neurological crisis. Patients who progress despite hemin administration have undergone liver transplantation with complete resolution of symptoms. A current issue is the unavailability of a rapid test for urine porphobilinogen in the urgent-care setting.     

RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.The acute hepatic porphyrias are caused by the deficient activities of specific enzymes in the heme biosynthetic pathway and include three autosomal dominant diseases—acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP)—and the autosomal recessive 5-aminolevulinic acid dehydratase deficiency porphyria (ADP) (1). These inherited metabolic disorders are characterized by life-threatening acute neurovisceral attacks that include severe abdominal pain, hypertension, tachycardia, constipation, motor weakness, seizures, and paralysis (1). Various factors, including cytochrome P450 (CYP)-inducing drugs, dieting, and hormonal changes precipitate the acute attacks by increasing the expression of hepatic 5-aminolevulinic acid synthase (ALAS1), the first and rate-limiting enzyme of the heme biosynthetic pathway (2–6). When hepatic ALAS1 is induced, the respective enzyme deficiencies create a metabolic bottleneck, thereby decreasing hepatic heme production and depleting the “free” heme pool. This leads to the loss of the negative feedback inhibition of heme on ALAS1 (7–9) and, consequently, further up-regulation of hepatic ALAS1 expression. As hydroxymethylbilane synthase (HMBS)—the third enzyme in the heme biosynthetic pathway—is less abundant in comparison with the other heme biosynthetic enzymes (10), it becomes rate-limiting when ALAS1 is markedly increased. As a result, the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) are overproduced in the liver and are markedly accumulated in the plasma and urine during the acute attacks (only ALA accumulates in ADP).Currently, the standard therapy for the acute neurovisceral attacks is the i.v. administration of hemin, which provides exogenous heme for the negative feedback inhibition of ALAS1, thereby decreasing ALA and PBG production (11–13). Although patients generally respond well, its effect is slow, typically requiring three to four daily infusions to normalize the elevated plasma and urinary ALA and PBG concentrations (14). Patients who experience recurring attacks are treated prophylactically with weekly to monthly hemin infusions, which are associated with side effects such as phlebitis and iron overload (15). Thus, an alternative therapeutic approach for the acute hepatic porphyrias that is more effective, faster-acting, and safer is desirable.Previously, the pathogenic mechanism of the acute neurovisceral attacks was unclear, particularly whether the attacks were due to the neurotoxic effects of the accumulated ALA and/or PBG or to the heme deficiency in neuronal tissues (16). However, nonporphyric liver transplant recipients who received livers from AIP patients (i.e., “domino” liver transplants) developed acute porphyric attacks despite their presumably normal neuronal heme levels, which demonstrated that the primary pathogenic mechanism is not neuronal heme deficiency but rather the effects of the neurotoxic hepatic metabolites ALA and/or PBG (17). Consistent with this finding, orthotopic liver transplantation in AIP patients and a VP patient with recurrent and incapacitating attacks resulted in the rapid normalization of ALA and PBG levels and the abrupt remission of attacks (18–20). Thus, the liver is the primary site of pathology in the acute hepatic porphyrias, and therapies designed to inhibit the induced overexpression of ALAS1 and the resulting elevation of ALA and PBG would prevent or treat the acute attacks in all four acute hepatic porphyrias.Here, we report preclinical studies of a liver-directed RNA interference (RNAi) therapy using an i.v.-administered small interfering RNA (siRNA) specific for the Alas1 mRNA (designated Alas1-siRNA). To identify a potent Alas1-siRNA, a panel of siRNAs targeting Alas1 was initially screened for their ability to inhibit Alas1 mRNA expression in cultured hepatic cells. The most active compounds were formulated into lipid nanoparticles (LNPs) for efficient hepatic delivery (21–23) and evaluated for their ability to down-regulate hepatic Alas1 mRNA expression in wild-type mice. The selected Alas1-siRNA was then evaluated in the mouse model for AIP for its effectiveness to prevent or treat an induced acute attack. These mice have ∼30% of wild-type HMBS activity and slightly elevated baseline plasma and urinary ALA and PBG levels (24). When phenobarbital (PB), a potent inducer of ALAS1 expression, is administered, ALA and PBG are markedly increased (20- to 30-fold and 40- to 90-fold in plasma, respectively), mimicking the biochemical pathology of a human acute attack (1, 24). Prophylactic administration of Alas1-siRNA in the AIP mice completely prevented the PB-induced accumulation of plasma and urinary ALA and PBG, whereas infusion of Alas1-siRNA after induction of an acute attack rapidly and effectively decreased the markedly elevated plasma ALA and PBG.     

Molecular aspects of the inherited porphyrias

The porphyrias are diseases due to marked deficiencies of enzymes of the haem biosynthetic pathway (Fig. 1). Except for the first enzyme of the pathway, delta-aminolevulinate synthase (ALAS), deficiencies in seven other enzymes are associated with the various forms of porphyria (Fig. 2). Porphyrias can be classified as either hepatic or erythroid, depending on the major site of production of porphyrins or their precursors. The pathogenesis of all inherited porphyrias has now been defined at the molecular level, and it is clear that there is a great deal of genetic heterogeneity in each porphyria [1].     

The porphyrias.

The heterogeneous group of diseases called the porphyrias may all be characterised by derangement of specific stages in the haem biosynthetic pathway. In the acute porphyrias; acute intermittent porphyria, urophorphyrinogen 1 synthase, hereditary coproporphyria, coproporphyrinogen oxidase and variegate porphyria, ferrochelatase or protoporphyrinogen oxidase, are the enzymes affected, whilst in the non acute porphyrias, cutaneous hepatic porphyria, uroporphyrinogen decarboxylase, congenital porphyria, uroporphyrinogen cosynthase; and erythropoietic protoporphyria; ferrochelatase are the enzymes affected. In each of the porphyrias, the activity of the initial and rate controlling enzyme of the pathway, delta-aminolaevulinic acid synthase is raised which constitutes the principal control point of the pathway. Secondary control in each of these diseases lies at the leve of uroporphyrinogen 1 synthase. As a consequence of this secondary control, there is excessive excretion of the porphyrin precursors delta-aminolaevulinic acid and porphobilinogen in the acute porphyrias and excessive excretion of porphyrins leading to solar photosensitivity in the non-acute porphyrias and in variegate and hereditary coproporphyria. There are a number of secondary metabolic aspects in the porphyrias, such as the role of steroid metabolism; the influence of drugs in the potentiation of attacks; and the potential for the pathway to branch at stages prior to porphyrin formation which result in the synthesis of various monopyrroles. The therapy of the two groups of porphyrias are quite different. Prophylaxis is important in both types but is particularly important in the avoidance of various drugs in the acute porphyrias. The acute attack may be specifically treated with carbohydrates, beta-blockers and haematin. Cutaneous hepatic porphyria may be treated by venesection, erythropoietic protoporphyria with beta caratene whilst congenital porphyria may be improved by splenectomy and chloroquine therapy.     

Hematologic aspects of the porphyrias

The porphyrias are disorders that can be inherited and acquired, in which the activities of the enzymes of the heme biosynthetic pathway are partially or almost totally deficient. There are 8 enzymes involved in the synthesis of heme, and, with the exception of the first enzyme, an enzymatic defect at every step leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors, such as delta-aminolevulinic acid and porphobilinogen. Whereas heme, the final product of the biosynthetic pathway, is biologically important, porphyrins and their precursors are not only useless but also toxic. Porphyrias can be classified as either photosensitive or neurologic, depending on the type of symptoms, but some porphyrias cause both photosensitive and neurologic symptoms. Alternatively, they can be classified either hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect. The tissue-specific expression of porphyrias is largely due to the tissue-specific control of heme pathway gene expression, particularly at the level of delta-aminolevulinate synthase, the first and the rate-limiting enzyme of heme biosynthesis. In this chapter, hematologic aspects of the erythropoietic porphyrias will be described. The 3 major erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP) and erythropoietic protoporphyria (EPP).