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Metabolic disorders and reticulohistiocytic proliferative disorders
Published in Rashmi Sarkar, Anupam Das, Sumit Sethi, Concise Dermatology, 2021
Porphyria cutanea tarda (PCT) is the most common of all porphyrias and results from the deficiency of uroporphyrinogen decarboxylase (UROD) enzyme, the fifth enzyme in the haem biosynthesis pathway. (A schematic diagram representing haemosynthesis and the enzymes involved is given in Figure 16.1.) This results in the accumulation of haem precursors, called uroporphyrins and coproporphyrins, in the blood, stool, and urine. These substances are responsible for photosensitization. This enzyme defect is acquired/sporadic and is seen only in the hepatocytes in the majority of the cases; however, inherited forms where the enzyme defect is present in all tissues also do occur. A wide variety of factors, especially hepatotoxins, are known to trigger the clinical features of PCT, including alcohol, estrogens, iron, polychlorinated hydrocarbons, and viral infections, like hepatitis C and HIV.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Cutaneous hepatic porphyria is also inherited as an autosomal dominant disease usually beginning in early adulthood and clinical symptoms appear in the 30- to 40-year age group. The photosensitivity observed in the cutaneous form is less severe than in the congenital form and does not lead usually to deformities or scarring. In addition, neurological signs also occur. In this condition hepatic δ-aminolevulinic acid synthetase is enhanced, whereas liver and erythrocyte uroporphyrin synthetase are normal. The defect is mainly hepatic; laboratory findings show increased urinary levels of δ-aminolevulinic acid, porphobilinogen, uro-, and coproporphyrins. In the feces, the excretion of uro- and coproporphyrins and protoporphyrin is also elevated. In remission, urinary porphyrins may be normal, but the fecal excretion remains increased. In addition to the previous defect, there is also an abnormality in the oxidation-reduction system in the liver and other functions.430 Uroporphyrinogens may be oxidized in this condition to the corresponding porphyrins which cannot reversibly return to the biosynthetic pathway and accumulate in the tissue or the excess is excreted.
Drug-Induced Abnormalities of Liver Heme Biosynthesis
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
In hepatic uroporphyria a block in heme metabolism also exists but at a different stage in the biosynthetic sequence, the stage of decarboxylation of uroporphyrinogen (uro’gen) III. In most cases a defect of the relevant enzyme, uro’gen decarboxylase, can be detected, thus accounting for the block in heme biosynthesis and characteristic accumulation of uroporphyrin. However, since the uro’gen intermediate has to be kept in the reduced state (i.e., as a hexahydroporphyrin) in order to be decarboxylated, a block in its metabolism can also be achieved by its oxidation to the corresponding porphyrin which cannot be further metabolized. Such a concept of an oxidative escape of the intermediate from the pathway of heme biosynthesis was first postulated by Heikel et al. (1958), but evidence in its favor has only been obtained more recently. Whether due to inhibition of the decarboxylase or to oxidative escape of the uro’gen intermediate, the block in heme biosynthesis is accompanied by a stimulation of ALA-S, a compensatory response analogous to that encountered in protoporphyria, again resulting from reduction of the heme feedback mechanism and here too contributing to a more severe porphyria.
Porphyria: awareness is the key to diagnosis!
Published in Acta Clinica Belgica, 2022
Benjamin Heymans, Wouter Meersseman
Porphyria Cutanea Tarda (PCT) is the most frequent form of porphyria. It is caused by a reduction in the activity of the enzyme uroporphyrinogen decarboxylase (UROD) to less than 20%. In the majority of cases, there is no genetic defect present; only around 20% of patients have a mutation in one of the alleles of the UROD-gene. The latter is however not enough to cause PCT by itself because the UROD-activity is only decreased by 50%. Hence, additional susceptibility factors are required before PCT develops. In the first place, more than half of the patients with PCT are carrier of a mutation in the hemochromatosis gene HFE, whether or not together with the presence of the disease itself [8]: iron, after all, facilitates the conversion of uroporphyrinogen to uroporphomethene, an inhibitor of UROD activity. Other factors associated with PCT are infection with hepatitis C or HIV1, alcohol, tobacco and estrogen. The PCT susceptibility factors cause iron accumulation or they increase the oxidative stress in the hepatocytes. It is important to note that none of these factors alone is sufficient to explain the development of PCT. In general, at least two of them should be present before symptoms of this disease will arise.
Givosiran, a novel treatment for acute hepatic porphyrias
Published in Expert Review of Precision Medicine and Drug Development, 2021
Manish Thapar, Sean Rudnick, Herbert L. Bonkovsky
The human porphyrias generally are classified according to the principal sites of overproduction of porphyrins or porphyrin precursors as being either hepatic or erythropoietic. The hepatic porphyrias are further classified as being ‘acute’ or ‘inducible’ (due to up-regulation of ALA synthase-1) or as being ‘chronic.’ The acute designation is used for four relatively rare disorders, all due to inherited defects in normal heme synthesis [ALA dehydratase deficient porphyria (ADP); acute intermittent porphyria (AIP), due to partial deficiency of HMBS; hereditary coproporphyria (HCP), due to partial deficiency of CPOX; and variegate porphyria (VP), due to partial deficiency of PPOX]. When these are biochemically active (elevated ALA and PBG), there is induction of ALA synthase-1 in the liver, as already described, leading to marked overproduction of ALA, and usually also of porphobilinogen (PBG). The chronic hepatic porphyrias comprise two disorders, porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP), which, respectively, are due to partial (∼50%) or nearly total (>90%) deficiency of uroporphyrinogen decarboxylase (UROD), the fifth enzyme of the heme synthetic pathway. PCT, the disorder with milder UROD deficiency, occurs mainly in adult men with underlying liver disease, whereas the disorder with severe UROD deficiency is HEP. It is usually manifest in childhood or infancy and continues life-long.
Neurological and neuropsychiatric manifestations of porphyria
Published in International Journal of Neuroscience, 2019
Yiji Suh, Jason Gandhi, Omar Seyam, Wendy Jiang, Gunjan Joshi, Noel L. Smith, Sardar Ali Khan
8 Glycine and 8 succinyl-Coa is used by δ-aminolevulinic acid synthase (ALAS) to make ALA within the mitochondria. ALAS-1 expression is activated by PGC-1α within hepatocytes. PGC-1α normally plays a role in liver energy homeostasis. However, PGC-1α is also an important factor that controls that expression of ALAS-1 [8]. PGC-1α may also be activated by the liver in vivo. ALAS enzymatic action is limiting step in heme production due to its feedback inhibition [1]. The ALA is shuttled into the cytoplasm, and becomes porphobilinogen (PBG) with the use of δ- aminolevulinate dehydratase (ALAD). PBG becomes hydroxymethylbilane (HMB) catalyzed by porphobilinogen deaminase (PBG-D). Then, HMB becomes (uroporphyrinogen III) Uro-P with Uroporphrinogen III cosynthase, and coproporphyrinogen (Copro-P) is made with Uroporphyrinogen decarboxylase. Copro-P is then shuttled into the mitcohondria to become proptoporphyrinogen IX by combining with coproporphyrinogen oxidase (CPO). Proto-P is oxidized by protoporphyrinogen oxidase to become protoporphyrin. Protoporphyrin becomes heme by addition of Fe2+ and ferrochelatase [1, 8]. Heme may be produced within the liver or bone marrow. The difference lies in the regulation, as heme regulates the production of heme by inhibiting ALAS which causes the synthesis of heme to slow. The bone marrow, however, contains erythropoietin which controls the formation of heme. Any disorder within these steps except for ALA synthase can cause toxic precursors to accumulate within the body (Figure 1).