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Singal AK. Porphyria cutanea tarda: Recent update. Mol Genet Metab 2019; 128:271-281. [PMID: 30683557 DOI: 10.1016/j.ymgme.2019.01.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/05/2019] [Accepted: 01/05/2019] [Indexed: 12/13/2022]
Abstract
Porphyria cutanea tarda (PCT) is the most common human porphyria, due to hepatic deficiency of uroporphyrinogen decarboxylase (UROD), which is acquired in the presence of iron overload and various susceptibility factors, such as alcohol abuse, smoking, hepatitis C virus (HCV) infection, HIV infection, iron overload with HFE gene mutations, use of estrogens, and UROD mutation. Patients with familial or type II PCT due to autosomal dominant UROD mutation also require other susceptibility factors, as the disease phenotype requires hepatic UROD deficiency to below 20% of normal. PCT clinically manifests with increased skin fragility and blistering skin lesions on sun exposed areas. The common age of presentation is 5th to 6th decade and occurs slightly more commonly in males. Although mild liver biochemical profile are common, advanced fibrosis and cirrhosis with hepatocellular carcinoma (HCC) can occasionally develop. Screening for HCC using ultrasound examination is recommended in PCT patients, especially with cirrhosis and advanced fibrosis. PCT is effectively and readily treatable with the use of either repeated phlebotomy or use of 100 mg hydroxychloroquine orally twice a week, and both the treatments are equally effective and safe. With the advent of new or direct antiviral agents for HCV infection, treatment of concomitant HCV has become safer and effective. Data are emerging on the benefit of these drugs as monotherapy for both PCT and HCV. After the achievement of remission of PCT, there remains a potential for relapse, especially when the susceptibility factors are not adequately controlled. Scanty data from retrospective and observational studies shows the relapse rate to be somewhat higher after remission with low-dose hydroxychloroquine as compared to phlebotomy induced remission. Future studies are needed on exploring mechanism of action of 4-aminoquinolines, understanding interaction of HCV and PCT, and relapse of PCT on long-term follow-up.
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Affiliation(s)
- Ashwani K Singal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL, United States.
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Christiansen AL, Bygum A, Hother-Nielsen O, Rasmussen LM. Diagnosing diabetes mellitus in patients with porphyria cutanea tarda. Int J Dermatol 2018. [DOI: 10.1111/ijd.13938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Anne L. Christiansen
- Department of Clinical Biochemistry and Pharmacology; Odense University Hospital; Odense C Denmark
| | - Anette Bygum
- Department of Dermatology and Allergy Centre; Odense University Hospital; Odense C Denmark
| | - Ole Hother-Nielsen
- Department of Endocrinology; Odense University Hospital; Odense C Denmark
| | - Lars M. Rasmussen
- Department of Clinical Biochemistry and Pharmacology; Odense University Hospital; Odense C Denmark
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Farrell CP, Overbey JR, Naik H, Nance D, McLaren GD, McLaren CE, Zhou L, Desnick RJ, Parker CJ, Phillips JD. The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda. PLoS One 2016; 11:e0163322. [PMID: 27661980 PMCID: PMC5035022 DOI: 10.1371/journal.pone.0163322] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 09/07/2016] [Indexed: 01/08/2023] Open
Abstract
Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT.
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Affiliation(s)
- Colin P. Farrell
- Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Jessica R. Overbey
- Population Health Science and Policy, Mt. Sinai School of Medicine, New York City, New York, United States of America
| | - Hetanshi Naik
- Genetics and Genomics Sciences, Mt. Sinai School of Medicine, New York City, New York, United States of America
| | - Danielle Nance
- Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Gordon D. McLaren
- Veterans Affairs, Long Beach Healthcare System, Long Beach, California, United States of America
- Medicine, Division of Hematology/Oncology, University of California Irvine, Irvine, California, United States of America
| | - Christine E. McLaren
- Epidemiology, University of California Irvine, Irvine, California, United States of America
| | - Luming Zhou
- Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Robert J. Desnick
- Genetics and Genomics Sciences, Mt. Sinai School of Medicine, New York City, New York, United States of America
| | - Charles J. Parker
- Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - John D. Phillips
- Department of Medicine, Hematology Division, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
- * E-mail:
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Horner ME, Alikhan A, Tintle S, Tortorelli S, Davis DMR, Hand JL. Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol 2014; 52:1464-80. [PMID: 24261722 DOI: 10.1111/ijd.12305] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The porphyrias are a group of disorders characterized by defects in the heme biosynthesis pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis, and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes, anemia, and liver disease. With advances in DNA analysis, researchers are discovering the underlying genetic causes of the porphyrias, enabling family members to be tested for genetic mutations. Here we present a comprehensive review of porphyria focusing on those with cutaneous manifestations. In Part I, we have included the epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Treatment and management options will be discussed in Part II.
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Affiliation(s)
- Mary E Horner
- Department of Dermatology, Baylor University Medical Center, Dallas, TX, USA
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Vieira FMJ, Nakhle MC, Abrantes-Lemos CP, Cançado ELR, Reis VMSD. Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients. An Bras Dermatol 2014; 88:530-40. [PMID: 24068123 PMCID: PMC3760927 DOI: 10.1590/abd1806-4841.20132048] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Accepted: 09/09/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Porphyria cutanea tarda is the most common form of porphyria, characterized by
the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several
reports associated HFE gene mutations of hereditary hemochromatosis with porphyria
cutanea tarda worldwide, although up to date only one study has been conducted in
Brazil. OBJECTIVES Investigation of porphyria cutanea tarda association with C282Y and H63D
mutations in the HFE gene. Identification of precipitating factors (hepatitis C,
HIV, alcoholism and estrogen) and their link with HFE mutations. METHODS An ambispective study of 60 patients with PCT was conducted during the period
from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and
histories of alcohol abuse and estrogen intake were investigated. HFE mutations
were identified with real-time PCR. RESULTS Porphyria cutanea tarda predominated in males and alcohol abuse was the main
precipitating factor. Estrogen intake was the sole precipitating factor present in
25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive
patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE
mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly
higher in porphyria cutanea tarda patients, compared to control group. HFE
mutations had no association with the other precipitating factors. CONCLUSIONS Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating
factors in our porphyria cutanea tarda population; however, hemochromatosis in
itself can also contribute to the outbreak of porphyria cutanea tarda, which makes
the research for HFE mutations necessary in these patients
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Caballes FR, Sendi H, Bonkovsky HL. Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int 2012; 32:880-93. [PMID: 22510500 PMCID: PMC3418709 DOI: 10.1111/j.1478-3231.2012.02794.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Accepted: 02/28/2012] [Indexed: 12/23/2022]
Abstract
Porphyria cutanea tarda (PCT) is the most common form of porphyria across the world. Unlike other forms of porphyria, which are inborn errors of metabolism, PCT is usually an acquired liver disease caused by exogenous factors, chief among which are excess alcohol intake, iron overload, chronic hepatitis C, oestrogen therapy and cigarette smoking. The pathogenesis of PCT is complex and varied, but hereditary or acquired factors that lead to hepatic iron loading and increased oxidative stress are of central importance. Iron loading is usually only mild or moderate in degree [less than that associated with full-blown haemochromatosis (HFE)] and is usually acquired and/or mutations in HFE. Among acquired factors are excessive alcohol intake and chronic hepatitis C infection, which, like mutations in HFE, decrease hepcidin production by hepatocytes. The decrease in hepcidin leads to increased iron absorption from the gut. In the liver, iron loading and increased oxidative stress leads to the formation of non-porphyrin inhibitor(s) of uroporphyrinogen decarboxylase and to oxidation of porphyrinogens to porphyrins. The treatment of choice of active PCT is iron reduction by phlebotomy and maintenance of a mildly iron-reduced state without anaemia. Low-dose antimalarials (cinchona alkaloids) are also useful as additional therapy or as alternative therapy for active PCT in those without haemochromatosis or chronic hepatitis C. In this review, we provide an update of PCT with special emphasis upon the important role often played by the hepatitis C virus.
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Affiliation(s)
- F Ryan Caballes
- The Liver-Biliary-Pancreatic Center of Carolinas Medical Center, Charlotte, NC,Department of Medicine, CMC
| | - Hossein Sendi
- The Liver-Biliary-Pancreatic Center of Carolinas Medical Center, Charlotte, NC
| | - Herbert L. Bonkovsky
- The Liver-Biliary-Pancreatic Center of Carolinas Medical Center, Charlotte, NC,Department of Medicine, CMC,Department of Medicine, Universities of CT and NC,Address for Correspondence: Suite 201, Cannon Research Center, 1542 Garden Terrace, Charlotte, NC 28203, Phone: 704-355-3959, Fax: 704-355-7648,
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Fateen E, Abd-Elfattah A, Gouda A, Ragab L, Nazim W. Porphyrins profile by high performance liquid chromatography/electrospray ionization tandem mass spectrometry for the diagnosis of porphyria. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2011. [DOI: 10.1016/j.ejmhg.2011.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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Abstract
Iron overload in humans is associated with a variety of genetic and acquired conditions. Of these, HFE hemochromatosis (HFE-HC) is by far the most frequent and most well-defined inherited cause when considering epidemiological aspects and risks for iron-related morbidity and mortality. The majority of patients with HFE-HC are homozygotes for the C282Y polymorphism [1]. Without therapeutic intervention, there is a risk that iron overload will occur, with the potential for tissue damage and disease. While a specific genetic test now allows for the diagnosis of HFE-HC, the uncertainty in defining cases and disease burden, as well as the low phenotypic penetrance of C282Y homozygosity poses a number of clinical problems in the management of patients with HC. This Clinical Practice Guideline will therefore, focus on HFE-HC, while rarer forms of genetic iron overload recently attributed to pathogenic mutations of transferrin receptor 2, (TFR2), hepcidin (HAMP), hemojuvelin (HJV), or to a sub-type of ferroportin (FPN) mutations, on which limited and sparse clinical and epidemiologic data are available, will not be discussed. We have developed recommendations for the screening, diagnosis, and management of HFE-HC.
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Kristiansen MG, Gutteberg TJ, Mortensen L, Berg LK, Goll R, Florholmen J. Clinical outcomes in a prospective study of community-acquired hepatitis C virus infection in Northern Norway. Scand J Gastroenterol 2010; 45:746-51. [PMID: 20205506 DOI: 10.3109/00365521003690699] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Knowledge on the natural course of the morbidity of unselected community-acquired hepatitis C virus (HCV) infection is limited. The aim of our study was to characterize the clinical outcomes of both hepatic and extrahepatic morbidity in patients infected with HCV in a community-based setting in Northern Norway. MATERIAL AND METHODS This prospective cohort study included 1010 HCV-positive patients diagnosed by recombinant immunoblot assay (RIBA), between 1 January 1990 and 1 January 2000. Questionnaires were sent to those physicians in Northern Norway who had requested the RIBA tests during the relevant period. Data were collected from medical records in the period between 1 January 2004 and 30 June 2006. Access to confidential information was obtained from the Norwegian Directorate of Health. RESULTS Median age at follow-up was 39 and 41 years in females and males, respectively. In patients with positive HCV RNA status following results were found: Alanine aminotransferase was elevated in 27.4%, decompensated liver disease in 2.9% and hepatocellular carcinoma in 0.4%. Median observation period from estimated acquisition of the disease to follow-up in these patients was 26 years. Depression was reported in 10.7% of chronic infected subjects. Renal failure caused by membranoproliferative glomerulonephritis occurred in 0.2%. CONCLUSIONS In an unselected HCV-RNA positive population severe liver disease developed in a sub-group of patients. These observations suggest that chronic HCV disease in relatively young subjects may cause a substantial burden on the health system in the future.
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10
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Pereira PDSF, Silva ISDSE, Uehara SNDO, Emori CT, Lanzoni VP, Silva AEB, Ferraz MLG. Chronic hepatitis C: hepatic iron content does not correlate with response to antiviral therapy. Rev Inst Med Trop Sao Paulo 2010; 51:331-6. [PMID: 20209268 DOI: 10.1590/s0036-46652009000600004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Accepted: 10/28/2009] [Indexed: 12/16/2022] Open
Abstract
The complex interaction between hepatitis C virus infection, iron homeostasis and the response to antiviral treatment remains controversial. The aim of this study was to evaluate the influence of hepatic iron concentration (HIC) on the sustained virological response (SVR) to antiviral therapy in patients with chronic hepatitis C. A total of 50 patients who underwent pretreatment liver biopsy with assessment of HIC by graphite furnace atomic absorption spectroscopy and were subsequently submitted to antiviral treatment with interferon/peginterferon and ribavirin were included in the study. Patients with alcoholism, history of multiple blood transfusion, chronic kidney disease, hemolytic anemia and parenteral iron therapy were excluded. The iron related markers and HIC were compared between those who achieved an SVR and non-responders (NR) patients. The mean age was 45.7 years and the proportion of patients' gender was not different between SVR and NR patients. The median serum iron was 138 and 134 microg/dL (p = 0.9), the median serum ferritin was 152.5 and 179.5 ng/mL (p = 0.87) and the median HIC was 9.9 and 8.2 micromol/g dry tissue (p = 0.51), for SVR and NR patients, respectively. Thus, hepatic iron concentration, determined by a reliable quantitative method, was not a negative predictive factor of SVR in patients with chronic hepatitis C presenting mild to moderate hepatic iron accumulation.
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11
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Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol 2010; 8:297-302, 302.e1. [PMID: 19948245 PMCID: PMC2834813 DOI: 10.1016/j.cgh.2009.11.017] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Revised: 10/20/2009] [Accepted: 11/19/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Porphyria cutanea tarda (PCT) is the most common of the human porphyrias and results from an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Some susceptibility factors have been identified; we examined associations among multiple factors in a large cohort of patients. METHODS Multiple known or suspected susceptibility factors and demographic and clinical features of 143 patients (mean age 52 years, 66% male, 88% Caucasian) with documented PCT (mean onset at 41 +/- 8.8 years) were tabulated; associations were examined by contingency tables, classification and regression tree (CART) analysis, and logistic regression. RESULTS The most common susceptibility factors for PCT were ethanol use (87%), smoking (81%), chronic hepatitis C virus (HCV) infection (69%), and HFE mutations (53%; 6% C282Y/C282Y and 8% C282Y/H63D). Of those who underwent hepatic biopsy or ultrasound, 56% had evidence of hepatic steatosis. Of those with PCT, 66% of females took estrogen, 8% were diabetic, 13% had human immunodeficiency virus (HIV) infection, and 17% had inherited uroporphyrinogen decarboxylase (UROD) deficiency (determined by low erythrocyte UROD activity). Three or more susceptibility factors were identified in 70% of patients. HCV infection in patients with PCT was significantly associated with other behavior-related factors such as ethanol use (odds ratio [OR], 6.3) and smoking (OR, 11.9). CONCLUSIONS Susceptibility factors for PCT were similar to previous studies; most patients had 3 or more susceptibility factors. Associations between PCT and HCV, ethanol or smoking could be accounted for by a history of multiple substance abuse; other factors are distributed more randomly among patients.
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Affiliation(s)
- Sajid Jalil
- Correspondence: Karl E. Anderson, M.D., FACP, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1109, , 409-772-4661 Phone, 409-772-6287 FAX
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Porphyria Cutanea Tarda and Hemochromatosis in Spain. ACTAS DERMO-SIFILIOGRAFICAS 2009. [DOI: 10.1016/s1578-2190(09)70073-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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13
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Ramírez-Santos A, González-Vilas D, García-Gavín J, Concheiro J, Sánchez-Aguilar D, Toribio J. Porfiria cutánea tarda y hemocromatosis en España. ACTAS DERMO-SIFILIOGRAFICAS 2009. [DOI: 10.1016/s0001-7310(09)70830-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Wallace DF, Subramaniam VN. Co-factors in liver disease: the role of HFE-related hereditary hemochromatosis and iron. Biochim Biophys Acta Gen Subj 2008; 1790:663-70. [PMID: 18848602 DOI: 10.1016/j.bbagen.2008.09.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 07/25/2008] [Accepted: 09/09/2008] [Indexed: 12/15/2022]
Abstract
The severity of liver disease and its presentation is thought to be influenced by many host factors. Prominent among these factors is the level of iron in the body. The liver plays an important role in coordinating the regulation of iron homeostasis and is involved in regulating the level of iron absorption in the duodenum and iron recycling by the macrophages. Iron homeostasis is disturbed by several metabolic and genetic disorders, including various forms of hereditary hemochromatosis. This review will focus on liver disease and how it is affected by disordered iron homeostasis, as observed in hereditary hemochromatosis and due to HFE mutations. The types of liver disease covered herein are chronic hepatitis C virus (HCV) infection, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), end-stage liver disease, hepatocellular carcinoma (HCC) and porphyria cutanea tarda (PCT).
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Affiliation(s)
- Daniel F Wallace
- Membrane Transport Laboratory, The Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006, Australia
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Sajjad S, Garcia M, Malik A, Van Thiel DH. Hepatic iron quantitation and its relationship with disease measures and histologically assessed iron content. Dig Dis Sci 2008; 53:1390-4. [PMID: 17934811 DOI: 10.1007/s10620-007-9993-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2007] [Accepted: 08/20/2007] [Indexed: 12/09/2022]
Abstract
PURPOSE The study was undertaken to determine the relationships between the histological finding of hepatic injury, necrosis, fibrosis and iron staining with biochemical measures of hepatic injury and hepatic iron content. METHODS One hundred fourteen consecutive subjects undergoing liver biopsy were studied. Data pertaining to biopsy reports, histology activity index, hepatic iron concentration, hepatic iron index, and histological grading of iron were recorded and analyzed using regression analysis. RESULTS Statistical relationships were found between the hepatic iron index, histological grading of iron and hepatic iron concentration, whereas histology activity index was related to hepatic grading of iron, but not to hepatic iron concentration. CONCLUSIONS The pathologist's assessment of the histological grading of iron relates directly to the histology activity index and hepatic iron concentration. Serum measures of iron, total iron-binding capacity and ferritin can be used to monitor hepatic iron content more economically and simply than with hepatic iron concentration measurement on liver biopsy.
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Affiliation(s)
- Shabbar Sajjad
- Aurora St Luke's Medical Center, Milwaukee, WI 53215, USA
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Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol 2007; 13:4673-89. [PMID: 17729389 PMCID: PMC4611189 DOI: 10.3748/wjg.v13.i35.4673] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 05/01/2007] [Accepted: 05/09/2007] [Indexed: 02/06/2023] Open
Abstract
Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis.
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Affiliation(s)
- Giada Sebastiani
- Venetian Institute of Molecular Medicine (VIMM), Padova and Digestive Diseases, Hepatology and Clinical Nutrition Department, Umberto I Hospital, Venice, Italy.
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Toll A, Celis R, Ozalla MD, Bruguera M, Herrero C, Ercilla MG. The prevalence of HFE C282Y gene mutation is increased in Spanish patients with porphyria cutanea tarda without hepatitis C virus infection. J Eur Acad Dermatol Venereol 2007; 20:1201-6. [PMID: 17062032 DOI: 10.1111/j.1468-3083.2006.01746.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES To investigate the role of C282Y and H63D mutations, and hepatitis C virus (HCV) infection in the pathogenesis of porphyria cutanea tarda (PCT). DESIGN Prospective case-control study. SETTING A large clinical and research institute for the study and treatment of cutaneous diseases in Barcelona, Spain. PATIENTS Ninety-nine consecutive patients with PCT and one hundred and twenty-six control patients (76 healthy subjects and 50 patients chronically infected with HCV), were recruited. MAIN OUTCOME MEASURES The frequency of the C282Y and H63D mutations in patients with PCT vs. controls and the relationship of these mutations with HCV infection, and iron status, as judged by serum iron, liver iron and ferritin levels. RESULTS C282Y mutation was significantly increased in PCT patients. This mutation was more frequent among non-HCV-infected patients. Increased ferritin levels and hepatic iron overload were also observed in PCT patients with heterozygous C282Y state. H63D mutation was only significantly increased among PCT patients with chronic hepatitis C infection. No significant iron overload was observed in patients with H63D mutation. CONCLUSIONS This study confirms the high frequency of C282Y mutation in patients with PCT and its relationship with iron overload. The C282Y mutation has a relevant role in Spanish patients with PCT not associated with HCV chronic infection. On the other hand, the prevalence of the H63D mutation seems not to be increased in patients with PCT. The possibility of an association between HCV infection and H63D mutation in inducing PCT can be hypothesized.
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Affiliation(s)
- A Toll
- Department of Dermatology, Hospital Clinic, University of Barcelona, Spain.
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Silva ISS, Perez RM, Oliveira PV, Cantagalo MI, Dantas E, Sisti C, Figueiredo-Mendes C, Lanzoni VP, Silva AEB, Ferraz MLG. Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study. J Gastroenterol Hepatol 2005; 20:243-8. [PMID: 15683427 DOI: 10.1111/j.1440-1746.2004.03549.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Recently it has been found that iron is an important element in the natural history of hepatitis C. Serum markers of iron stores are frequently increased in chronic hepatitis C virus (HCV)-infected carriers but the real impact of the hepatic iron overload is poorly understood. The purpose of the present paper was to determine the prevalence of iron overload and to study the relationship between hepatic iron concentration (HIC) and clinical, biochemical and histological characteristics in chronic HCV-infected carriers. METHODS Patients presenting with anti-HCV and HCV-RNA were included. Hepatic iron concentration was determined in liver tissue by atomic absorption spectrophotometry. The association between HIC and age, gender, risk factor of transmission, duration of infection, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, iron and serum ferritin, transferrin saturation, HCV-RNA level, grading of inflammatory activity, staging of fibrosis, hepatic steatosis, and stainable iron was analyzed. Statistical analysis included the Mann-Whitney test and a multiple linear regression model. RESULTS Ninety-six patients (58% male) with a mean age of 44 +/- 10 years were studied. Serum iron, ferritin and transferrin saturation were elevated in 28%, 27% and 12.5% of patients, respectively. Stainable iron was detected in few patients (15.6%). Higher grades of stainable iron (2 and 3) were observed in only 7%. The HIC (>30 mmol/g dry weight) was elevated in five patients (5%). Neither grading nor staging were related to HIC. Higher HIC were observed in male patients (P < 0.001), in patients with elevated serum ferritin (P = 0.001) and in patients with stainable iron (grades 2 and 3; P = 0.001). Multiple linear regression analysis showed that only stainable iron was independently correlated with HIC (P = 0.003). CONCLUSIONS Iron overload in chronically HCV-infected patients was uncommon and hepatic iron content seemed not to be related to the liver damage process. In the eventuality of iron overload, histochemical liver iron is a useful marker to estimate HIC.
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Affiliation(s)
- Ivonete S S Silva
- Department of Gastroenterology, Federal University of Sao Paulo, Rua Botucatu 740, 2nd floor, CEP 04023-900 São Paulo-SP, Brazil.
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Abstract
In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1(*)0301 and DRB1(*)11 with self-limiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1(*)0301 and DRB1(*)11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1(*)11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1(*)11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.
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Affiliation(s)
- L J Yee
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Martinelli ALC, Filho ABA, Franco RF, Tavella MH, Ramalho LNZ, Zucoloto S, Rodrigues SS, Zago MA. Liver iron deposits in hepatitis B patients: association with severity of liver disease but not with hemochromatosis gene mutations. J Gastroenterol Hepatol 2004; 19:1036-41. [PMID: 15304122 DOI: 10.1111/j.1440-1746.2004.03410.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Iron deposits in the liver and abnormalities in serum iron biochemistry are frequently observed in patients with chronic liver diseases, but data for patients with hepatitis B virus (HBV) infection are scarce. Moreover, the role of HFE mutations in iron deposits in this condition remains unknown. The aim of the present study was to determine the prevalence of serum iron biochemical abnormalities and iron deposits in the liver of chronic HBV patients, and to evaluate the consequences for the activity and severity of liver disease. Additionally, we studied the role of HFE gene mutations in iron deposits. METHODS Eighty-one male non-cirrhotic HBV patients were studied. Serum iron biochemistry, liver enzymes and C282Y/H63D mutations were investigated. Liver biopsies were scored for necroinflammatory activity (histological activity index [HAI]), fibrosis and iron deposits. RESULTS Elevated transferrin saturation (TS) was found in 27.1% of patients and liver iron deposits in 48.7%; these deposits were mild in 68.4% and moderate in 31.6%. Patients with liver iron deposits exhibited significantly higher scores for HAI and fibrosis than those without iron deposits. HFE mutations were identified in 23.4% of patients (14 H63D heterozygotes, four H63D homozygotes, one compound mutation). No difference in the prevalence of C282Y and H63D mutations was observed between HBV patients (1.2% and 23.4%, respectively) and the general population (4.1% and 27.8%, respectively). No association was detected between HFE mutations and elevated TS or liver iron deposits. CONCLUSIONS Elevated TS and liver iron deposits were frequent in non-cirrhotic HBV patients. Iron deposits were mainly mild and associated with higher activity and severity of liver disease, but not with HFE mutations.
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Affiliation(s)
- Ana L C Martinelli
- Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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Mehrany K, Drage LA, Brandhagen DJ, Pittelkow MR. Association of porphyria cutanea tarda with hereditary hemochromatosis. J Am Acad Dermatol 2004; 51:205-11. [PMID: 15280838 DOI: 10.1016/j.jaad.2003.08.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND An increased frequency of hereditary hemochromatosis gene mutations occurs in patients with porphyria cutanea tarda. Polymerase chain reaction analysis of peripheral blood for hemochromatosis gene (HFE) mutations is available for clinical use. Early detection and treatment of hereditary hemochromatosis limit disease progression and improve life expectancy. OBJECTIVE We present 8 patients with porphyria cutanea tarda subsequently found to have hereditary hemochromatosis or mutations in the HFE gene. METHODS Retrospective review of patients in whom both porphyria cutanea tarda and hereditary hemochromatosis or HFE gene mutations were diagnosed between 1976 and 2000. RESULTS Eight patients with porphyria cutanea tarda (6 males, 2 females; age range, 4-60 years; mean age at diagnosis of porphyria cutanea tarda, 42 years) were subsequently found to have hepatic iron overload or HFE gene mutations. Two patients had liver biopsy findings compatible with homozygous hereditary hemochromatosis. In the other 6 patients, HFE gene analysis revealed 3 homozygous C282Y, 1 compound heterozygous C282Y/H63D, and 2 heterozygous C282Y mutations. Seven patients (88%) had no specific signs or symptoms of hereditary hemochromatosis at diagnosis. In 5 patients (63%), the diagnosis of hereditary hemochromatosis or HFE gene mutation was initially suspected by the dermatologist. CONCLUSION Porphyria cutanea tarda can be an important cutaneous marker for patients with mutations of the HFE gene. HFE gene analysis should be done in patients who present with porphyria cutanea tarda. The dermatologist may play a key role in the early diagnosis of subclinical hereditary hemochromatosis in patients who present with porphyria cutanea tarda.
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Affiliation(s)
- Khosrow Mehrany
- Department of Dermatology, Mayo Clinic, Rochester, MN 55905, USA
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Nagy Z, Kószó F, Pár A, Emri G, Horkay I, Horányi M, Karádi O, Rumi G, Morvay M, Varga V, Dobozy A, Mózsik G. Hemochromatosis (HFE) gene mutations and hepatitis C virus infection as risk factors for porphyria cutanea tarda in Hungarian patients. Liver Int 2004; 24:16-20. [PMID: 15101996 DOI: 10.1111/j.1478-3231.2004.00884.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
AIM It is not clear whether the mutations in hemochromatosis (HFE) gene and hepatitis C virus (HCV) infection act independently in the pathogenesis of porphyria cutanea tarda (PCT). The prevalence of both risk factors varies greatly in different parts of the world. PCT patients from Hungary were evaluated to assess both factors. METHODS The prevalence of C282Y and H63D mutations in the HFE gene was determined in 50 PCT patients and compared with the reported control frequencies. Furthermore, the presence of HCV infection was determined and related to the patients' HFE gene status. RESULTS The C282Y mutation was found in 8/50 cases (three homozygotes and five heterozygotes), with an 11% allele frequency (vs. 3.8% control) (P<0.05). Seventeen patients were heterozygous, one was homozygous for the H63D mutation, allele frequency 19%, which did not differ significantly from the reported control prevalence of 12.3%. Twenty-two patients (44%) were HCV-RNA positive; six out of them were heterozygous for H63D mutation, one only for the C282Y mutation and one was compound heterozygous for both mutations. CONCLUSION HCV infection and HFE C282Y mutation may probably be independent predisposing factors for development of PCT in Hungarian patients.
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Affiliation(s)
- Zsuzsanna Nagy
- First Department of Medicine, Medical Faculty, University of Pécs, Pécs, Hungary
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Martinelli ALC, Ramalho LNZ, Zucoloto S. Hepatic stellate cells in hepatitis C patients: relationship with liver iron deposits and severity of liver disease. J Gastroenterol Hepatol 2004; 19:91-8. [PMID: 14675249 DOI: 10.1111/j.1440-1746.2004.03255.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM To determine the relationship between hepatic stellate cell (HSC) populations and severity of liver disease and liver iron deposits in patients with chronic hepatitis C virus (HCV). We also studied the relationship between iron cellular distribution and HSC population and the role of HFE mutations in the determination of iron deposits. METHODS Forty-nine chronic HCV patients with varying degrees of liver damage and liver iron deposits were studied. A liver biopsy was scored for histology activity index (HAI), fibrosis and iron deposits. The number of HSC in the liver was evaluated by an immunohistochemical double-staining method to identify glial fibrillary acid protein (GFAP) and smooth muscle alpha-actin (alpha-SMA). RESULTS The HSC population was significantly higher in HCV patients than in normal controls and was predominant in zones 1 and 3. Liver iron deposits were observed in 49% of patients and were mild/moderate in most cases. We found a significantly higher number of GFAP and alpha-SMA positive cells in patients with liver iron deposits compared with those without iron deposits, and a positive correlation between liver iron scores and number (%) of GFAP and alpha-SMA positive cells. We observed a significantly higher number of GFAP and alpha-SMA positive cells in moderate/severe hepatitis than in minimal/mild hepatitis, and a positive correlation between GFAP and alpha-SMA positive cells and HAI and fibrosis scores. CONCLUSIONS Liver iron deposits in chronic HCV are common and are associated with activation of HSC. Thus, even mild iron deposits might stimulate HSC and contribute to liver damage.
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Affiliation(s)
- Ana L C Martinelli
- Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo-USP, Ribeirão Preto, SP, Brazil.
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Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol 2003; 39:620-7. [PMID: 12971974 DOI: 10.1016/s0168-8278(03)00346-5] [Citation(s) in RCA: 121] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS To conduct a systematic review and meta-analysis on the prevalence of hepatitis C virus (HCV) infection in porphyria cutanea tarda (PCT). METHODS Studies evaluating prevalence of HCV infection in patients with PCT were considered. Bibliographical searches were conducted in several electronic databases. Studies comparing HCV prevalence in PCT (cases) and in a reference group (controls) were included in the meta-analysis, combining the Odds Ratios (OR) of the individual studies. RESULTS Fifty studies including 2,167 patients were identified. Mean HCV prevalence by serology was 47%, and 50% with polymerase chain reaction (PCR). HCV prevalence markedly varied depending on the country and the type of PCT (57% in the sporadic and 26% in the familial form). Eight case-control studies were identified. Seven studies compared HCV prevalence in PCT vs. healthy controls: 40% vs. 0.24%, respectively (OR=275; 95% confidence interval=104-725). Heterogeneity disappeared when only studies evaluating HCV infection by PCR were included. CONCLUSIONS HCV prevalence in patients with PCT is approximately 50%, much higher than that reported in general population, suggesting a possible etiopathogenic role of HCV in PCT. The striking geographical variation in this association suggests that genetic and/or environmental factors may also be involved in the pathogenesis of this disorder.
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Affiliation(s)
- Javier P Gisbert
- Servicio de Gastroenterología y Hepatología, Universidad Autónoma de Madrid, Hospital Universitario de la Princesa, Diego de León, 62. 28006, Madrid, Spain.
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Folmer V, Soares JCM, Gabriel D, Rocha JBT. A high fat diet inhibits delta-aminolevulinate dehydratase and increases lipid peroxidation in mice (Mus musculus). J Nutr 2003; 133:2165-70. [PMID: 12840172 DOI: 10.1093/jn/133.7.2165] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The aim of this study was examine the effects of high starch (HS) vs. high fat (HF) feeding on blood glycated hemoglobin (GHbA(1c)) level, thiobarbituric acid-reactive species (TBA-RS) concentration and delta-aminolevulinate dehydratase (delta-ALA-D) activity in mice. The GHbA(1c) level was significantly higher in mice fed the HF diet compared with those fed the HS diet. Hepatic, renal, and cerebral TBA-RS concentrations in mice fed the HF diet were significantly greater than in mice fed the HS diet. In addition, positive correlations were found between the GHbA(1c) and TBA-RS levels for hepatic (P < 0.05; r = 0.46), renal (P < 0.003; r = 0.65), and cerebral (P < 0.001; r = 0.69) tissues. The delta-ALA-D hepatic, renal and cerebral activities of mice fed the HF diet were significantly lower than those of mice fed the HS diet. Furthermore, a negative correlation was found between the GHbA(1c) level and delta-ALA-D activity in hepatic (P < 0.001; r = -0.77), renal (P < 0.007; r = -0.60), and cerebral (P < 0.007; r = -0.60) tissues. The results of this study indicate that consumption of a high fat diet promotes oxidative stress related to hyperglycemia, which in turn can stimulate glycation of proteins leading to delta-ALA-D inhibition in mice.
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Affiliation(s)
- Vanderlei Folmer
- Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brasil
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Ma Y, Fracanzani AL, Sampietro M, Mattioli M, Cheeseman P, Williams R, Mieli-Vergani G, Vergani D, Fargion S. Autoantibodies to human cytosol: a marker of sporadic porphyria cutanea tarda. Clin Exp Immunol 2001; 126:47-53. [PMID: 11678898 PMCID: PMC1906169 DOI: 10.1046/j.1365-2249.2001.01645.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The enzymes potentially involved in the pathogenesis of sporadic porphyria cutanea tarda (PCT) reside in liver cytosoles and microsomes. PCT is frequently associated with hepatitis C virus (HCV) infection, which is in turn associated with autoimmune manifestations. To investigate whether autoimmune reactions, possibly triggered by HCV, are involved in the pathogenesis of PCT, we measured by immunoblot autoantibodies to human cytosolic and microsomal liver fractions in 82 patients with PCT (77% with HCV infection), 105 with other liver disorders and 40 healthy subjects. Anti-liver cytosolic antibodies were more frequent in PCT patients (38/82, 46%) than in pathological controls (P < 0.05-P < 0.001) or in healthy subjects (3/40, 8%, P < 0.001). Among PCT patients, anticytosolic antibodies were more frequent in HCV positive (36/63, 57%) than in HCV negative (2/19, 11%, P < 0.05) cases. Reactivity to a 40-kDa cytosolic polypeptide was present in 20 PCT patients (19 HCV positive), being more frequent than in all pathological controls (P < 0.01-P < 0.0001). Histological activity index (P = 0.04) and antibodies to HCV (P = 0.027) - but not HCV RNA - were associated independently with anticytosolic antibodies as assessed by multivariate analysis. In contrast, frequency of antiliver microsomal antibodies was similar in PCT patients (24/82, 29%) and pathological controls (8-26%), being higher in the autoimmune hepatitis control group (23/23, 100%, P < 0.0001). In conclusion, anticytosolic antibodies, particularly to a 40-kDa polypeptide, are frequent in PCT and associated with HCV infection and severity of liver damage.
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Affiliation(s)
- Y Ma
- Institute of Hepatology, University College London, London, UK
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Gaa A, Wirth C, Wassmer B, Schaefer HE, Fisch P. Critical Commentary to: Hepatic Failure with Neonatal Tissue Siderosis of Hematochromatotic Type in an Infant Presenting with Meconium Ileus. Pathol Res Pract 2001. [DOI: 10.1078/0344-0338-00149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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