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War Day The Infected Book 9. Proxy The Infected Book 1 by P. Power February 7, Book 1 of 9. Add to Wish List. Power April 3, Book 2 of 9. Power June 13, Book 3 of 9. Reunions The Infected Book 4 by P. Power September 30, Book 4 of 9. Cellophane The Infected Book 5 by P. Power February 13, Book 5 of 9. Goblin The Infected Book 6 by P.
Power July 29, Book 6 of 9. Book 7 of 9. Power July 6, Book 8 of 9. Power December 14, Book 9 of 9. More About the Authors. Some people have suggested that the author is not a human being. Perhaps a robot, super computer or a team of industrious souls, bent on writing all the books. Within cells, different water solubilities influence where various porphyrins accumulate.
Due to their hydrophilic nature, uro —and heptacarboxyl- porphyrins accumulate in the cytosol and lysosomes and are not associated with or dissolved in membranes to any appreciable extent. The ability of porphyrins to absorb light of nm the Soret band 1 , 15 - 17 is the key factor in producing the photocutaneous lesions observed on sun-exposed areas in affected individuals.
The delocalized Pi-electrons of aromatic porphyrins readily absorb energy of violet light and enter a higher energy state. The reactive oxygen species give rise to the phototoxic damage characteristic of PCT 18 , as well as further catalyzing the oxidation of porphyrinogens to porphyrins 8 [ Fig 1 ]. These lesions typically first arise and are worse in the summer and often take weeks or months to resolve. Chronic skin damage may result in scarring, changes in cutaneous pigmentation at the sites of blisters and milia [ Fig 2 ].
Other skin manifestations may include a purplish heliotrope suffusion of periorbital areas 2 , hypertrichosis, usually involving the lateral aspects of the face, chloracne, sclerodermatous changes, dystrophic calcification with ulceration, alopecia, and onycholysis 8.
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Due to marked excretions of porphyrins in the urine, patients with PCT may have urine that appears pink, red, or brown, especially after exposure of the urine to air and light 2 , 8. Because the free porphyrins do not contain iron, urine tests for heme, hemoglobin, or myoglobin are all negative.
Thus, despite the pink-red color of urine, routine urinalysis and blood counts are normal in most patients. Persons with active PCT are usually found to have mildly elevated serum aminotransferases and gamma-glutamyl transpeptidase 5. The nonspecific findings of routine laboratory tests make it clear that special studies are needed to diagnose PCT. A useful initial test is direct fluorometric assay of plasma. When this fluorometric pattern is observed, tests for levels of porphyrins and porphyrin precursors in urine, and porphyrins in feces are used to confirm the diagnosis.
If PCT is present, elevated levels of uro- and heptacarboxyl-porphyrins are found in the urine along with elevated fecal isocoproporphyrin, and plasma 8- and 7- carboxylporphyrins, with little or no elevation of erythrocyte porphyrin levels 9. Urinary levels of delta-aminolevulinic acid ALA are normal or slightly increased [less than 2 times the upper limit of normal], and levels of urinary porphobilinogen PBG are normal.
The latter help to distinguish PCT from the acute or inducible hepatic porphyrias [hereditary coproporphyria, variegate porphyria], which may be present with cutaneous features indistinguishable from those of PCT. In addition, in variegate porphyria, the peak emission wavelength of plasma fluorescence is nm, finding of considerable diagnostic value. There is also deposition of periodic acid-Schiff positive, diastase-resistant glycoproteins, various immunoglobulins and complement around both the dermo-epithelial junction and blood vessels.
These lesions are not unique to PCT and are found in other porphyrias of the bullous type. Similarly, liver histopathology is mostly non-specific and includes red fluorescence of unfixed hepatic tissue which is seen in various types of porphyria , necrosis, inflammation, varying siderosis and steatosis 8 , 20 , 21 [ Fig 3 ]. Hemosiderosis is usually mild to moderate but may be severe when accompanied by mutations that underlie hemochromatosis.
In a meta-analysis done by Ellervik and colleagues, CY homozygotes were demonstrated to have the highest risk for PCT while H63D heterozygozity with wild type conferred the lowest risk These crystals have been localized to the areas of cytoplasm that contain ferritin granules further suggesting the role of iron in oxidation of porphyrinogens and subsequent crystallization of porphyrins 8. Fresh unfixed liver fluoresces a bright pin [upper left, unstained, 1X] due to excess porphyrins.
Photomicrographs kindly provided by JR Bloomer. Iron enhances uroporphyrin overproduction in several ways [ Fig 1 ]. First, iron increases reactive oxygen species ROS , which increase the rate at which uroporphyrinogen and heptacarboxylporphyrinogen are oxidized into their respective porphyrins 8.
Third, iron increases intracellular ALA levels providing more substrate for uroporphyrinogen and subsequent uroporphyrin synthesis.
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Despite the importance of hepatic siderosis in PCT, iron by itself is insufficient to cause uroporphyrin overproduction in the absence of other predisposing factors 8 , 15 , 23 - HCV is a hepatotropic member of the flaviviridae family and is known to infect an estimated million people worldwide 8 , 28 , HCV has six known major genotypes 1 - 6 which may be further divided into 50 subtypes 1a, 1b, etc.
Certain genotypes are more prevalent at different parts of the globe. The virus is transmitted mainly by the parenteral route and to a lesser extent by vertical and sexual transmission. Acute HCV infection may begin insidiously or present abruptly.
It has a limited course that usually lasts one or two months. Acute infection is rarely detected because the majority of patients are asymptomatic. Indeed, CHC has become the single most common indication for orthotopic liver transplantation in the western world. While the majority of patients with CHC have elevated serum aminotransferases, about a third of those infected have persistently normal levels despite a high viral load and continued hepatic injury. Patients with chronic infection frequently complain of fatigue.
Other non-specific symptoms such as myalgias, arthralgias, paresthesias, pruritus, and sicca syndrome are also frequent complaints. Although the presence of any single risk factor is likely not sufficient to cause PCT, HCV is thought to be a strong trigger for the development of deranged porphyrin metabolism in those with other known predisposition 1 , 3 , 16 , 20 , 35 , Subjects found to have mildly elevated porphyrins were on a variety of medications that may have influenced porphyrin metabolism, and none had overt PCT In addition, Jalil et al.
They found that most subjects with clinically manifest PCT had three or more known susceptibility factors 17 [ Table 2 ]. Prevalence of susceptibility factors in published series of patients with PCT from different geographic areas. Adapted from Ref Used with permission of the authors and publisher.
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It has been known for many years that 1 most patients with PCT have some degree of iron overload; 2 iron removal ameliorates porphyrin overproduction and clinical features; and 3 administration of iron produces relapse of PCT Serum iron indices and iron content of the liver are often elevated in patients with CHC 20 , The precise molecular mechanisms by which iron may influence HCV-induced liver disease are not fully understood. Among several proposed mechanisms are iron-induced immunologic modifications and iron effects on signal transduction and HCV proliferation Elevated hepatic iron and increased serum iron indices also have been associated with PCT [ Table 2 ] 39 , and iron is known to exert several actions that increase oxidation of porphyrinogens and lead to inhibition of UROD [ Fig 1 ].
Therefore, iron can be considered as a common factor for the development and progression of both CHC- and PCT- induced liver diseases. Based on these facts, it can be anticipated that patients with iron overload like those with hereditary hemochromatosis HH have a higher risk for the development and progression of both CHC- and PCT- induced liver diseases. The preponderance of the evidence suggests that patients with CHC who are heterozygous for H63D or CY mutations are at a higher risk of severe hepatocellular injury and fibrosis Therefore, even in patients harboring HFE mutations that cause milder defects in iron homeostasis, it is possible that the presence of HFE mutations leads to the inactivation of UROD through interaction with other factors like HCV infection, which change iron homeostasis in the liver.
Transgenic mice expressing an HCV polyprotein and fed a high-iron diet were found to have not only higher degrees of hepatic steatosis, lipid peroxidation, and mitochondrial injury, but also a higher risk of development of hepatocellular carcinoma HCC , compared to mice fed a normal diet Using human hepatoma cells, expressing an HCV subgenomic replicon, Fillebeen et al. Recently, Nishina et al. Hepcidin, a amino acid cysteine-rich peptide, is the key regulator of iron absorption and metabolism in humans, which induces internalization and degradation of ferroportin, and this in turn leads to the reduction of iron exported from cells.
Therefore, over-expression of hepcidin in mice and humans leads to iron deficiency, whereas its deficiency leads to iron overload. Interestingly, in a recent study, Ajioka et al. Therefore, they suggested that the hepatic siderosis associated with PCT likely results from dysregulated hepcidin. These associations suggest that viral infection, per se , may play a role in reducing the activity of UROD. Additional studies investigating alteration of UROD activity in HCV infected cell lines may help to unravel the mechanism of this association.
As mentioned above, besides HCV infection and HFE mutations, several environmental factors have been shown to precipitate overt clinical PCT, including alcohol abuse, tobacco use, and use of oral estrogens [ Table 2 ] Alcohol may cause liver damage, ranging from reversible steatosis to alcoholic cirrhosis. Alcohol also exacerbates the hepatopathy of CHC.
Alcohol, estrogens, iron, and CHC all produce increased oxidative stress in liver cells. Besides, it is also anticipated that there might be common molecular pathways for triggering both PCT, and its predisposing factors. In mice, cytochrome PA2 Cyp1A2 plays a major role in the development of uroporphyria. Unlike mice with normal Cyp1A2, knockout mice deficient in Cyp1A2 do not develop uroporphyria following exposure to halogenated polyaromatic hydrocarbons GSTM1 is particularly important in the deactivation of reactive intermediates of polycyclic aromatic hydrocarbons.
In addition, preventing or controlling various predisposing factors [ Table 2 ] should be a routine part of management. Definitive therapy aimed at the pathogenic mechanism of PCT includes iron reduction, and anti-malarials that remove porphyrins from the liver and other tissues. Among these, phlebotomy is the treatment of choice and has generally been shown to be cheap, safe, and effective. Although moderate hepatic iron overload is common in PCT, presence of hepatic siderosis in PCT is not a prerequisite for successful treatment with venesection 52 , Clinical remission is usually evident after removal of L of blood Indeed, with the regimen recommended dose, cutaneous manifestations gradually improve with resolution of bullae in months, improvement of cutaneous fragility in months, and complete biochemical remission in 13 months 59 , Pre-existent anemia, severe serum protein deficiency, e.
Diets somewhat restricted in iron, liver, and red meats the latter are rich in heme are also recommended because with iron reduction there is a compensatory increase of iron absorption from the GI tract. This compensatory mechanism is attributed to the reduction of serum hepcidin post-iron reduction. Reduced hepcidin in turn, increases ferroportin expression and function, which ultimately results in enhanced intestinal iron absorption 61 , Heme iron is particularly well absorbed, so that a modest restriction of heme intake is good general dietary advice, except for those with iron deficiency.
If phlebotomy is contraindicated, low-dose chloroquine mg every other day is usually the next best choice. Indeed, although relapse of PCT following chloroquine treatment occurs earlier than after iron reduction, it has been found to be cheap and effective, and to achieve remission at a similar rate as venesection Chloroquine binds 8 and 7—carboxylate porphyrins, which accumulate in lysosomes, and forms water-soluble complexes with them that lead to tissue mobilization and increased urinary excretion 25 , After initiation of chloroquine treatment, initial elevations of serum aminotransferases and porphyrins sometimes occur.
These elevations are generally mild and usually normalize within two months 59 , At least 3 months of treatment, however, are needed before clinical remission is seen.
Hepatitis C, Porphyria Cutanea Tarda, and Liver Iron: An Update
Similar to phlebotomy-monotherapy, complete biochemical remission usually is not achieved until at least 1 year of chloroquine treatment Another anti-malarial agent, hydroxychloroquine mg twice weekly , has also been shown to be an effective treatment for PCT; however, it is less preferred because remission is shorter than with chloroquine In severe cases, or when the most rapid therapeutic response is sought, phlebotomy and anti-malarials may be used together and may result in faster remission than does either treatment alone although this has not been shown in prospective randomized trials.
The reason for recommending low-dose chloroquine or hydroxychloroquine therapy in PCT is that, if full usual doses are used for initial therapy, a symptomatic acute hepatitis, with fever, right upper quadrant abdominal pain, and marked increases in serum aminotransferase levels often ensue, due to a too rapid removal of accumulated porphyrins from hepatic stores with hepatocyte necrosis.
Iron chelation with deferoxamine has also been described as an alternative treatment for PCT in those who are intolerant of therapeutic phlebotomy 25 , Once normalized, infusions were reduced to days per month or every other month Although not as convenient or cheap as therapeutic phlebotomy, deferoxamine is able to remove the toxic highly reactive, loosely-bound iron implicated in the pathogenesis of PCT.
Furthermore, it may reduce the compensatory increase of intestinal iron absorption often seen in remission induced by the greater degree of iron reduction achieved by phlebotomies. Oral iron chelators [deferasirox, deferiprone] are also available in some countries. They, too, may be effective and relatively safe for therapy of PCT, especially in those with elevated serum ferritins and increased total body iron stores.
However, to the best of our knowledge, prospective randomized controlled trials of their use in PCT have not been performed. Patients with end-stage renal disease undergoing dialysis, who typically are anemic at baseline, may benefit from iron mobilization via a combination of erythropoietin and smaller volume phlebotomies.
Dialyzers with ultra-permeable membranes and plasmapheresis may also be employed. Renal transplantation has been curative in refractory cases of PCT associated with chronic renal failure Although chloroquine effectively reduces uroporphyrin levels, it does not address the loosely-bound hepatic iron thought to be of importance in PCT pathogenesis. While treatment of PCT alone with iron chelators is possible, such therapy is far more expensive and involved and phlebotomy is preferred.
Group 1 received phlebotomy prior to dual therapy with pegylated interferon and ribavirin while group 2 received dual therapy without pretreatment venesection. The investigators measured levels of HCV RNA in serum before and after iron depletion in group 1 and found no significant difference, in keeping with earlier results of others 67 , No comparisons between the viral levels of the two groups were reported in the abstract. Mainly based on the results in their group 1, the investigators concluded that iron depletion did not seem to improve the rate of response to anti-HCV treatment in these patients.
In addition to providing little data on group 2 especially in comparison to group 1 , the study was small in size and thus, lacks statistical power. Furthermore, while group 1 subjects were all infected with HCV of genotype 1b, there were two patients with genotype 2a in group 2. It is well-known that genotype 2 HCV is more responsive to interferon-based therapy.
Thus the two rather small groups were not comparable, rendering interpretation of results problematical. Because iron overload is found in most cases of PCT 8 , 13 , 21 , and iron is a recognized factor that influence severity and course of chronic viral hepatitis 6 , 61 , reduction of iron stores by venesection can lead to improvement of both conditions. Furthermore, the fact that patients with CHC and PCT respond poorly to interferon IFN 69 and that phlebotomy enhances sustained virological response SVR of patients who received IFN monotherapy 70 , suggest that venesection preceding combination anti-viral therapy may be ideal.
Iron reduction prior to combination anti-viral therapy not only helps to reduce possible deleterious effects of iron on UROD, and hence improves symptoms of PCT, but also facilitates decreasing of HCV RNA levels, and impedes the synergistic effect of iron and HCV in the progression of liver disease. These issues will require future study. Venesection prior to ribavirin RBV -based therapy may prove challenging because of the frequent development of hemolytic anemia associated with RBV therapy.
Thus optimal timing of when to stop phlebotomy prior to initiating RBV-based regimen is unknown Prior to the advent of combination therapy with pegylated IFN and ribavirin, multiple clinical trials demonstrated improved clinical response in CHC patients treated with phlebotomy and IFN monotherapy compared to IFN monotherapy alone Some investigators have reported that phlebotomy with dual therapy ribavirin and interferon does not improve viral response 66 , 72 , In this study, sustained responders were defined as having negative HCV RNA at six months after the end of 26 weeks of dual therapy.
The study showed the following results: Although SF was not found to be a reliable predictor of hepatic siderosis by some investigators 12 , raised SF clearly is a predictor of non-response in patients with CHC In an attempt to clarify the effects of dual therapy on iron status, Ferrara et al conducted a prospective observational study in previously untreated subjects with CHC Furthermore, they found that SVR is more likely to occur in subjects with lower baseline SF, who experienced a greater rise in SF levels during treatment than did those who did not achieve SVR.
More specifically, they found an inverse correlation between serum iron, transferrin saturation, and SF with the degree of hemolysis up until week 4 of treatment. Indeed, they noted that a 2. Their results suggest that SF levels after 4 weeks of dual therapy are more reflective of other phenomena than siderosis due to ribavirin-induced hemolysis alone. Perhaps, a greater rise in SF during antiviral therapy is a marker of greater biological responsiveness to therapy, similar to other changes in laboratory variables, previously shown to be associated with responsiveness to therapy Thus, although limited in sensitivity, SF at baseline provides a cheap and effective method to estimate siderosis if phlebotomy is planned prior to treatment, as well as prediction of likelihood of response to therapy.
Similarly, although Pianko et al. In the previously discussed study by Ferrara and colleagues, the presence of iron in the mesenchymal cells Kupffer cells and endothelial cells of the portal tract and not the total iron score TIS correlated with SVR. This finding agrees well with the analysis done by Bonkovsky et al. The distribution of iron among cell types in the liver is thus likely to be more important than HIC. However, in absence of selective iron-removal techniques, pre-treatment phlebotomy is the least expensive and most effective method to decrease HIC and iron in mesenchymal cells.
In subjects with chronic hepatitis C and PCT [and most other conditions associated with iron loading] therapeutic phlebotomies will mobilize iron from storage sites throughout the body. Furthermore, when combined with an iron deficient diet, the concern posed by Ferrara and colleagues in regards to how the down-regulation of hepcidin may affect the targeted iron pool can be reasonably addressed. Of course, larger, adequately-powered prospective studies are needed to confirm these tentative conclusions. Iron reduction by therapeutic phlebotomy did not lead to any significant change in HCV RNA levels in sera, but it did lead to improvements in serum ALT levels 79 , to improvements in hepatic histopathology 68 and to decreases in histological progression and risk of development of HCC Indeed, iron reduction and low iron diets continue to be used, especially in Japan and China, as safe and inexpensive therapy for CHC among those who have not responded to, or have not tolerated, IFN-based anti-viral therapy 81 [H Hayashi, L-Y Zheng, personal communication].
Iron reduction is also used by some clinicians in the USA and Europe, 82 for similar indications [H Bonkovsky, unpublished; T Desai, S Shedlofsky, personal communication] although we acknowledge that this approach is not used in most centers. Recently, investigators from Japan and Italy concluded that patients with CHC are more sensitive to iron hepatotoxicity than patients with HH and recommended venesection to reduce activity of liver disease in both conditions Others in Japan concluded that iron reduction by venesection was superior to dietary iron redirection in CHC Furthermore, other benefits of phlebotomy in CHC patients without PCT include known improvement of serum aminotransferase levels 8 , 37 , 70 , 84 , improvement of fibrosis 70 , and decreased risk of hepatocellular carcinoma 25 , However, additional larger prospective clinical trials are needed in order to better assess whether there is a role for iron reduction in management of some patients with chronic hepatitis C.
Furthermore, with the several new stat-C small molecule drugs with potent activity against the HCV virus now under development, perhaps, in the not-too-distant future, rates of cure and tolerability of therapy will both improve further, and the numbers of subjects for whom iron reduction may be considered will decrease. Nevertheless, especially in less developed countries or in those without the means to afford expensive new multiple drug regimens, the inexpensive and safe measures of iron reduction and low iron diets may retain a useful place in the therapeutic armamentarium.
Other factors associated with PCT, such as excess alcohol and estrogen therapy, also increase oxidative stress in hepatocytes [ Fig 1 ]. The importance of iron is further emphasized by the fact that iron reduction regularly and reliably leads to amelioration of PCT, whether associated with CHC or not.
In addition, studies, especially from the Far East, indicate that iron reduction that is sustained for several years leads to improvement of the histopathological severity of CHC, to reduced risk of histopathological progression, and to reduced risk of development of hepatocellular carcinoma. In addition, iron reduction and maintenance of an iron-reduced state are reasonable therapeutic alternatives for those who do not respond to, who do not tolerate, or cannot afford, dual or triple anti-viral therapy of CHC. Adapted from Ref 99 Used by permission of the authors and publisher.
We thank Melanie McDermid and Kay Snider for assistance with typing and preparation of the manuscript. Statement of Conflicts of Interest: During the past three years, Dr. Bonkovsky has served as an advisor to and has received research support from Clinuvel, Inc and Novartis, Inc.
He has received research support from Vertex, Inc. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jul 1. Bonkovsky 1, 2, 3, 4. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Liver Int. See other articles in PMC that cite the published article. Abstract Porphyria cutanea tarda PCT is the most common form of porphyria across the world. Table 1 Classification of Porphyria Cutanea Tarda. Apparently inherited defect in an as yet unknown gene that leads to a secondary critical decrease in hepatic UROD activity.
Open in a separate window. UROD is uroporphyrinogen decarboxylase. Pathogenesis of Porphyria Cutanea Tarda The figure shows a summary of the normal pathway of heme biosynthesis, with emphasis on uroporphyrinogen decarboxylase [UROD] and its inhibition by an oxidation product thought to be derived from uroporphyrinogen. Typical Cutaneous Manifestations of PCT Cutaneous lesions with bullae, vesicles, and erosions on the dorsum of the hand.
Hepatic Histopathology in PCT Fresh unfixed liver fluoresces a bright pin [upper left, unstained, 1X] due to excess porphyrins. Table 2 Prevalence of susceptibility factors in published series of patients with PCT from different geographic areas. Phlebotomy is the preferred treatment in patients with iron overload or hemochromatosis gene mutations. Rule of thumb for number of unit that will need to be removed: If there are no chronic viral infections e. The goal of therapy is NOT to produce anemia nor to decrease serum transferrin saturation into a sub-normal range, but to deplete total body iron stores gradually, as reflected by SF.