Hepatic porphyrias

The porphyrias are metabolic disorders characterized by abnormal heme biosynthesis with excessive accumulation and excretion of porphyrias or porphyrin precursors. Defects in the enzymes of the heme biosynthetic pathway result in porphyria. Several of the disorders have been classified as hepatic because the major site of the biochemical defect has been localized to the liver. This article describes the enzymes of the heme biosynthetic pathway, the clinical features of the hepatic porphyrias and management of the disorders.     

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.     

Hepatic tumors in children

Although they account for only 1% to 4% of solid tumors in children, hepatic tumors and pseudotumors offer a diagnostic challenge to the clinician seeing only an occasional case. Metastatic lesions such as neuroblastoma, Wilms' tumor, and lymphoma are the most common neoplasm seen in the liver, but 10 distinct primary tumors and pseudotumors of the liver occur with some regularity, and a few others may be seen rarely, including leiomyosarcoma, rhabdoid tumor, and endodermal sinus tumor. Five of these neoplasms--hepatoblastoma, infantile hemangio-endothelioma, mesenchymal hamartoma, undifferentiated embryonal sarcoma, and embryonal rhabdomyosarcoma of the biliary tree--occur only in children and are the major focus of the article.     

The porphyrias

Opinion statement  

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.     

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.     

Solar urticaria and porphyrias

The importance of disturbances of porphyrin metabolism in solar urticaria is discussed. 15 cases of porphyrias with sun sensitivity are presented comprising 5 cases of erythropoietic protoporhyria, 8 cases of coproporphyria hereditaria and 2 cases of porphyria variegata, 9 out of these 10 patients presented neuroabdominal symptoms and in 4 cases contraceptive pills have triggered the disease. Due to the risk of severe forms of disease sometimes drugs induced porphyrias must be considered in all cases of solar urticaria and a correct laboratory study done in the suspected cases.     

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.     

Hepatic neoplasia and metabolic diseases in children

Hepatic neoplasia is a rare but serious complication of metabolic diseases in children. The risk of developing neoplasia, the age at onset, and the measures to prevent it differ in various diseases. This article reviews the most common metabolic disorders in humans that are associated with neoplasms, with a special emphasis on the molecular etiopathogenesis of this process. The cellular pathways driving carcinogenesis are poorly understood, but best known in tyrosinemia.     

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).     

Definition and classification of porphyrias

According to the newest recognitions a disease entity is to be ascribed to every deficient enzyme of the chain of haemobiosynthesis, so that the subdivisions of the porphyrin diseases, having often changed since several decades, may be substituted by classifications on ascertained enzymatic basis. An establishment of the well-known porphyrias is given, taking into consideration the first describers, the hereditary factors and first individual of homozygous diseases.     

The incidence of inherited porphyrias in Europe

Retrospective estimates of the prevalence of porphyrias have been reported but there has been no large scale prospective study of their incidence. The European Porphyria Network collected information prospectively over a 3 year period about the number of newly diagnosed symptomatic patients with an inherited porphyria (335 patients from 11 countries). Prevalence was calculated from the incidence and mean disease duration. The incidence of hepato-cellular carcinoma (HCC) in acute hepatic porphyria and the prevalence of patients with recurrent acute attacks of porphyria were also investigated. The incidence of symptomatic acute intermittent porphyria (AIP) was similar in all countries (0.13 per million per year; 95 % CI: 0.10 – 0.14) except Sweden (0.51; 95 % CI: 0.28–0.86). The incidence ratio for symptomatic AIP: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of AIP (5.4 per million; 95 % CI: 4.5–6.3) was about half that previously reported. The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates. Fourteen new cases of HCC (11 from Sweden) were reported in patients with acute porphyria. Sixty seven patients (3 VP; 64 AIP: 53 females, 11 males) with recurrent attacks of acute porphyria were identified. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3–5 %. In conclusion, the prevalence of symptomatic acute porphyria may be decreasing, possibly due to improved management, whereas the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity.     

Anxiety and depression in the acute porphyrias

Summary A previous study of self-rated psychosocial aspects in patients with acute porphyria found that depression, and particularly anxiety, is more common in porphyria patients than in the general population or general medical outpatient attenders. Nearly half of the sample (46%) reported at least some problem with anxiety and/or depression: anxiety caseness was 26% and depression caseness was 13%. This paper extends our previous observations and investigates further the associations between porphyria and anxiety, depression and general mental health in 90 patients (58 acute intermittent porphyria, 32 variegate porphyria). The findings of this study confirm that anxiety is raised in patients with acute intermittent porphyria and with variegate porphyria, in both males and females, compared to the normative population and, using a series of questionnaires exploring the physical and psychosocial features of anxiety, that this anxiety is experienced as a ‘relatively stable personality trait’, rather than a ‘transitory emotional state’ (i.e. intrinsic rather than secondary to the porphyria).