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Herrera I, Almenara S, Bellot P, Miralles C, Rodriguez M, Gómez-González L, Palazón JM, Pascual S, Zapater P. Tobacco is a Leading Risk Factor for Liver and Extrahepatic Cancers in Patients With Liver Cirrhosis: A Prospective Cohort Study. J Clin Exp Hepatol 2024; 14:101472. [PMID: 39100888 PMCID: PMC11292550 DOI: 10.1016/j.jceh.2024.101472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/17/2024] [Indexed: 08/06/2024] Open
Abstract
Background & aims This study aims to assess the incidence and characteristics of all cancers, hepatocellular carcinoma (HCC), and extrahepatic cancers in patients with cirrhosis of various etiologies. Methods Prospective cohort study in patients with cirrhosis but no cancer, followed every 6-9 months through the HCC early detection program. Cancer incidence was compared with Spanish population data to calculate standardized incidence ratios (SIR), and cumulative incidence was calculated separately for cancer and competing events. Longitudinal outcomes were assessed with multivariate Fine-Gray and Cox regression models. Results A total of 215 patients (68.4% male, median age 61 years) were included. Cirrhotic etiology was alcohol (38%), hepatitis B or C virus infection (36%), alcohol plus hepatitis B or C virus infection (9%), and other causes (17%). Sixty percent were current or former smokers. Thirty-nine cancers were observed (56% liver cancer), while 3.3 were expected (SIR 11.7; 95% confidence interval [CI] 8.6-16.1). Ten (4.6%) patients were censored for liver transplantation and 34 (15.8%) for death, constituting relevant competing risks. Smoking was significantly associated with overall cancer incidence (smokers: subdistribution hazard ratio [SHR] 3.14, 95% CI 1.33-7.38; former smokers: SHR 2.54, 95% CI 1.08-5.98). In the multivariable regression analysis, viral etiology, Child-Pugh score (B or C versus A), and smoking were associated with liver cancer, and smoking with extrahepatic cancer. Conclusions Patients with cirrhosis have an 11-fold risk of cancer compared to the general population. Risk is increased in liver and non-liver cancers. Active surveillance of any type of cancer and smoking cessation interventions are needed in these patients.
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Affiliation(s)
- Iván Herrera
- Liver Unit, Dr. Balmis General University Hospital, Alicante, Spain
- Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), University Miguel Hernández de Elche, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Susana Almenara
- Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), University Miguel Hernández de Elche, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Clinical Pharmacology Unit, Dr. Balmis General University Hospital, Alicante, Spain
| | - Pablo Bellot
- Liver Unit, Dr. Balmis General University Hospital, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- CIBERehd, Health Institute Carlos III, Madrid, Spain
| | - Cayetano Miralles
- Liver Unit, Dr. Balmis General University Hospital, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Maria Rodriguez
- Liver Unit, Dr. Balmis General University Hospital, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | | | - José M. Palazón
- Liver Unit, Dr. Balmis General University Hospital, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
| | - Sonia Pascual
- Liver Unit, Dr. Balmis General University Hospital, Alicante, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- CIBERehd, Health Institute Carlos III, Madrid, Spain
| | - Pedro Zapater
- Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), University Miguel Hernández de Elche, Spain
- Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain
- Clinical Pharmacology Unit, Dr. Balmis General University Hospital, Alicante, Spain
- CIBERehd, Health Institute Carlos III, Madrid, Spain
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Schönau J, Wester A, Schattenberg JM, Hagström H. Risk of Cancer and Subsequent Mortality in Primary Biliary Cholangitis: A Population-based Cohort Study of 3052 Patients. GASTRO HEP ADVANCES 2023; 2:879-888. [PMID: 39130771 PMCID: PMC11307889 DOI: 10.1016/j.gastha.2023.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 05/12/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Primary biliary cholangitis (PBC) is a rare cholestatic liver disease. Incident cancer is a concern. Previous studies have described an increase in hepatocellular carcinoma (HCC), but the risk of nonhepatic cancer and cancer risk across subgroups is largely unknown. Methods We used the Swedish National Patient Register to identify all patients diagnosed with PBC between 2002 and 2019. Patients were matched for age, sex, and municipality with up to 10 reference individuals from the general population. Incident cancer was recorded from the National Cancer Register. Cox regression was used to investigate the rates of cancer and postcancer mortality, adjusted for potential confounders. The cumulative incidence of cancer was calculated while accounting for the competing risk of death. Results At 10 years of follow-up, the cumulative incidence of any cancer in patients with PBC (n = 3052) was 14.3% (95% confidence interval (CI) = 12.8-15.9), compared to 11.8% (95% CI 11.3-12.2) in the reference population (n = 26,792) (adjusted hazard ratio aHR = 1.4, 95% CI = 1.2-1.5). The rate of HCC was particularly high (aHR 30.9; 95% CI = 14.8-64.6). The rate of cancer was higher in patients with cirrhosis (aHR 2.1; 95% CI 1.4-3.0), but similar across categories of age and sex. Increased rates of other cancer subtypes, including gastrointestinal (aHR = 1.5, 95% CI = 1.1-1.9), lung (aHR = 1.5, 95% CI = 1.1-2.2), and lymphoma (aHR = 2.9, 95% CI = 1.9-4.6) were seen. Following a diagnosis of cancer, patients with PBC had higher mortality rates compared to reference individuals (aHR = 1.4, 95% CI = 1.2-1.7). This was mainly driven by HCC (non-HCC-related mortality: aHR = 1.1, 95% CI = 0.9-1.5). Conclusion Patients with PBC have a significantly higher risk of HCC compared to matched individuals from the general population, but only a low risk increase of non-HCC cancer.
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Affiliation(s)
- Johanna Schönau
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Axel Wester
- Department of Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Jörn M. Schattenberg
- Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden
- Unit of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
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Braga MH, Cançado GGL, Bittencourt PL, Couto CA, Guedes LV, Lima AMC, Ferraz MLG, Villela-Nogueira CA, Nardelli MJ, Faria LC, Gomes NMDF, Oliveira EMG, Rotman V, Oliveira MB, da Cunha SMCF, Cunha-Silva M, Mendes LSC, Ivantes CAP, Codes L, de Almeida E Borges VF, Pace FHDL, Pessoa MG, Signorelli IV, Coral GP, Filho JG, Chagas AL, Terrabuio DRB, Cançado ELR. Risk factors for cancer in patients with primary biliary cholangitis and autoimmune hepatitis and primary biliary cholangitis overlap syndrome. Ann Hepatol 2023; 28:101105. [PMID: 37088418 DOI: 10.1016/j.aohep.2023.101105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 03/01/2023] [Accepted: 03/16/2023] [Indexed: 04/25/2023]
Abstract
INTRODUCTION AND OBJECTIVES Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC. MATERIALS AND METHODS The Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer. RESULTS Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p=<0.001), smoking (55% vs. 12.3%, p=<0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p= <0.001), AMA positivity (96.6% vs 80.1%, p=<0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk. CONCLUSIONS The prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC.
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Affiliation(s)
- Michelle Harriz Braga
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Guilherme Grossi Lopes Cançado
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.; Hospital da Polícia Militar de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil..
| | - Paulo Lisboa Bittencourt
- Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil;; Hospital Português, Salvador, Bahia, Brazil
| | - Cláudia Alves Couto
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Laura Vilar Guedes
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - André Mourão Costa Lima
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria Lucia Gomes Ferraz
- Disciplina de Gastroenterologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Cristiane Alves Villela-Nogueira
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mateus Jorge Nardelli
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Luciana Costa Faria
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | | | - Vivian Rotman
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Beatriz Oliveira
- Ambulatório Municipal de Hepatites Virais de São José dos Campos, São José dos Campos, São Paulo, Brazil
| | | | - Marlone Cunha-Silva
- Divisão de Gastroenterologia (Gastrocentro), Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil
| | | | | | | | - Valéria Ferreira de Almeida E Borges
- Instituto de Gastroenterologia, Endoscopia e Proctologia, Uberlândia, Minas Gerais, Brazil.; Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Fabio Heleno de Lima Pace
- Serviço de Gastroenterologia e Hepatologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
| | - Mario Guimarães Pessoa
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Izabelle Venturini Signorelli
- Hospital Universitário Cassiano Antônio Moraes, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Gabriela Perdomo Coral
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - João Galizzi Filho
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Aline Lopes Chagas
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | | | - Eduardo Luiz Rachid Cançado
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
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Wang S, Guo XZ, Xu SX, Qi XS. Risk and treatment of non-hepatic cancers in patients with cirrhosis. Shijie Huaren Xiaohua Zazhi 2020; 28:655-659. [DOI: 10.11569/wcjd.v28.i15.655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Patients with cirrhosis are at a high risk for hepatocellular carcinoma. However, it remains controversial about whether or not there is a high risk for non-hepatic cancers in patients with liver cirrhosis. Additionally, the management of non-hepatic cancers in cirrhotic patients is a clinical challenge, because the use of surgery and anticancer drugs is often compromised by the presence of liver dysfunction. This editorial aims to briefly summarize the findings on the risk and management of non-hepatic cancers in patients with cirrhosis.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China,Postgraduate College, China Medical University, Shenyang 110122, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Shi-Xue Xu
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China,Postgraduate College, China Medical University, Shenyang 110122, Liaoning Province, China
| | - Xing-Shun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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Kamaraju S, Depke J, Povletich J, Currey A, Weil E. Cutaneous Metastasis due to Breast Cancer in a Patient with Primary Biliary Cirrhosis: A Case Report. Case Rep Oncol 2016; 9:718-725. [PMID: 27920708 PMCID: PMC5126598 DOI: 10.1159/000452145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 09/29/2016] [Indexed: 12/19/2022] Open
Abstract
Background Breast cancer is the most common solid tumor to cause cutaneous metastases. These are incurable and the treatment goal is geared toward local control with surgical excision, radiation, and chemotherapy. However, treatment can be challenging in subjects with end-stage liver disease and a multidisciplinary approach is warranted. Case Report In this case report, we present a 61-year-old female with primary biliary cirrhosis and human epidermal growth factor-2 (HER-2)-positive breast cancer, who subsequently developed cutaneous metastases. We briefly describe the treatment challenges due to underlying end-stage liver disease, and an exceptional response to trastuzumab and nab-paclitaxel. Conclusion A multidisciplinary approach to local control and attenuated doses of nab-paclitaxel and trastuzumab suggest a durable response to HER-2-positive breast cancer with cutaneous metastasis. Subjects with end-stage liver disease pose unique challenges and toxicities, warranting additional research and drug development for less hepatotoxic antineoplastic agents.
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Affiliation(s)
- Sailaja Kamaraju
- Department of Internal Medicine, Department of Clinical Nursing, Department of Radiation Oncology, and Department of Pharmacy, Froedtert/Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jill Depke
- Department of Internal Medicine, Department of Clinical Nursing, Department of Radiation Oncology, and Department of Pharmacy, Froedtert/Medical College of Wisconsin, Milwaukee, WI, USA
| | - Janice Povletich
- Department of Internal Medicine, Department of Clinical Nursing, Department of Radiation Oncology, and Department of Pharmacy, Froedtert/Medical College of Wisconsin, Milwaukee, WI, USA
| | - Adam Currey
- Department of Internal Medicine, Department of Clinical Nursing, Department of Radiation Oncology, and Department of Pharmacy, Froedtert/Medical College of Wisconsin, Milwaukee, WI, USA
| | - Elizabeth Weil
- Department of Internal Medicine, Department of Clinical Nursing, Department of Radiation Oncology, and Department of Pharmacy, Froedtert/Medical College of Wisconsin, Milwaukee, WI, USA
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Abstract
Male breast cancer is a rare disease, accounting for only 1% of breast cancer diagnoses in the USA. The current literature suggests that genetic factors including BRCA2 mutations, family history, age, androgen/estrogen imbalance, and environmental exposures may predispose to male breast cancer. In this manuscript, we will review known and possible risk factors for male breast cancer, as well as describe the clinical patterns of the disease.
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Affiliation(s)
- Raina M Ferzoco
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
| | - Kathryn J Ruddy
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
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Risk and Surveillance of Cancers in Primary Biliary Tract Disease. Gastroenterol Res Pract 2016; 2016:3432640. [PMID: 27413366 PMCID: PMC4930812 DOI: 10.1155/2016/3432640] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/14/2016] [Accepted: 05/18/2016] [Indexed: 12/20/2022] Open
Abstract
Primary biliary diseases have been associated in several studies with various malignancies. Understanding the risk and optimizing surveillance strategy of these malignancies in this specific subset of patients are an important facet of clinical care. For instance, primary sclerosing cholangitis is associated with an increased risk for cholangiocarcinoma (which is very challenging to diagnose) and when IBD is present for colorectal cancer. On the other hand, primary biliary cirrhosis patients with cirrhosis or not responding to 12 months of ursodeoxycholic acid therapy are at increased risk of hepatocellular carcinoma. In this review we will discuss in detail the risks and optimal surveillance strategies for patients with primary biliary diseases.
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Extrahepatic malignancies in primary biliary cirrhosis: a comparative study at two European centers. Clin Rev Allergy Immunol 2016; 48:254-62. [PMID: 25205363 DOI: 10.1007/s12016-014-8446-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Limited information and divergent results are available on the prevalence/incidence, survival, and risk factors for developing extrahepatic malignancies (EMs) in primary biliary cirrhosis (PBC). The aim of the study was to analyze the epidemiology and survival rates for EM in PBC patients. The study was conducted on two series of patients followed up at two European centers (361 in Padova, Italy, and 397 in Barcelona, Spain) for a mean 7.7 ± 7 and 12.2 ± 7 years, respectively. The cancer incidence was compared with the standardized incidence ratios (SIRs) calculated using the Cancer Registry of the Veneto Region (Italy) and the Cancer Registry of Tarragona (Spain). Seventy-two patients developed EM. The prevalence of cases was similar in Padova (9.7 %) and Barcelona (9.4 %). The overall cancer incidence was similar to the expected incidence for the general population in the same geographical area (SIR = 1.2), and so was the crude EM rate (855.01 vs 652.86 per 100,000 patient-years, respectively, RR = 1.3). Logistic regression analysis showed that advanced histological stage and extrahepatic autoimmune diseases were significantly associated with the onset of EM. Survival was similar for PBC patients with and without EM (p = n.s.), and actual survival was similar to the one predicted by the Mayo model. The incidence of EM in PBC patients was found similar in Italy and Spain and no different from that of the general population. Advanced histological stage and extrahepatic autoimmune disease were risk factors significantly associated with EM developing in PBC. The onset of cancer in PBC patients does not influence the natural history of their liver disease.
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Liang Y, Yang Z, Zhong R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology 2012; 56:1409-17. [PMID: 22504852 DOI: 10.1002/hep.25788] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Accepted: 04/06/2012] [Indexed: 12/13/2022]
Abstract
UNLABELLED Several studies have indicated that primary biliary cirrhosis (PBC) may be associated with increased risk of some cancers, but the results are controversial. We conducted a systematic review of studies to examine the association of PBC with cancer risk by meta-analysis. We searched the PubMed and EMBASE databases for English-language studies published before November 2011. Studies were included if they reported relative risk estimates with 95% confidence intervals (CIs) or related data for the association between PBC and cancer risk. Approximately 16,300 PBC patients from several countries were included in this analysis. Of the 3510 titles identified, 16 publications involving 17 studies meeting the inclusion criteria were included in the meta-analysis. Compared with the general population, PBC patients had a significantly higher risk of overall cancer (pooled rate ratio [RR], 1.55; 95% CI, 1.28-1.83) and hepatocellular carcinoma (HCC) (pooled RR, 18.80; 95% CI, 10.81-26.79). For stomach and pancreas cancers, the results of one study that only examined male patients with PBC indicated that PBC patients had increased risk of stomach cancer and pancreatic cancer, whereas the results of other studies of mixed-sex patients showed no significant association. Therefore, despite inconsistent results, the meta-analysis could not be conducted for assessing the association. PBC was not significantly associated with increased risk of other cancers. CONCLUSION The present systematic review and meta-analysis demonstrate that PBC is closely associated with a greater risk of overall cancer and HCC, but not with other cancers. The data regarding the association between PBC and risks of several cancers need to be further confirmed in future studies.
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Affiliation(s)
- Yan Liang
- Department of Laboratory Diagnostics, Changzheng Hospital, Second Military Medical University, Shanghai, China
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10
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Ngu JH, Gearry RB, Frampton CM, Stedman CAM. Mortality and the risk of malignancy in autoimmune liver diseases: a population-based study in Canterbury, New Zealand. Hepatology 2012; 55:522-9. [PMID: 21994151 DOI: 10.1002/hep.24743] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Population-based quantitative data on the mortality and cancer incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are scarce. Our aim was to systematically investigate the survival and risk of malignancy on population-based cohorts of AIH, PBC, and PSC in Canterbury, New Zealand. Multiple case-finding methods were employed, including searches of all public and private, adult and pediatric outpatient clinics, hospital notes, laboratory, radiology, and pathology reports. Cases that fulfilled standardized diagnostic criteria were included. Kaplan-Meier survival estimates, standardized mortality ratios (SMR), and standard incidence ratios (SIR) for malignancy were calculated. A total of 130 AIH, 70 PBC, and 81 PSC patients were included contributing to 1,156, 625, and 613 person-years at risk, respectively. For AIH, PBC, and PSC cohorts, SMRs for all-cause mortality were 2.1 (95% confidence interval [CI] 1.4-3.1), 2.7 (95% CI 1.7-4.0), and 4.1 (95% CI 2.6-6.3), SMRs for hepatobiliary mortality were 42.3 (95% CI 20.3-77.9), 71.2 (95% CI 30.7-140.3), and 116.9 (95% CI 66.8-189.8), SIRs for all cancers were 3.0 (95% CI 2.0-4.3), 1.6 (95% CI 0.8-2.9), and 5.2 (95% CI 3.3-7.8), and SIRs for extrahepatic malignancy were 2.7 (95% CI 1.8-3.9), 1.6 (95% CI 0.8-2.9), and 3.0 (95% CI 1.6-5.1), respectively. CONCLUSION This is the first population-based study to examine and compare the survival and cancer incidence in AIH, PBC, and PSC in the same population. The mortality for all three cohorts was significantly increased due to liver-related death, demonstrating the inadequacy of current management strategies. The risk of hepatic and extrahepatic malignancy was significantly increased in AIH and PSC patients.
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Affiliation(s)
- Jing Hieng Ngu
- Department of Gastroenterology, Christchurch Hospital, Christchurch, Canterbury, New Zealand
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Abstract
Primary biliary cirrhosis is a chronic autoimmune inflammatory disease of the liver with a striking female preponderance. It has an insidious onset and typically affects middle-aged women. The disease manifests gradually with symptoms of fatigue, pruritis, and increased alkaline phosphatase levels on laboratory evaluation. The hallmark of the disease is the circulating antimitochondrial antibody. Histology is characterized by inflammation of the bile ducts, destruction of cholangiocytes, and subsequent cholestasis, progressing to biliary cirrhosis. The standard treatment for primary biliary cirrhosis is ursodeoxycholic acid, which improves survival, but the disease can still lead to cirrhosis and liver failure over decades.
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Affiliation(s)
- Bhavik M Bhandari
- Division of Gastroenterology & Hepatology, Drexel University College of Medicine, 219 North Broad Street, Fifth Floor, Philadelphia, PA 19107, USA.
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12
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Berman K, Tandra S, Vuppalanchi R, Ghabril M, Sandrasegaran K, Nguyen J, Caffrey H, Liangpunsakul S, Lumeng L, Kwo P, Chalasani N, Chalasani N. Hepatic and extrahepatic cancer in cirrhosis: a longitudinal cohort study. Am J Gastroenterol 2011; 106:899-906. [PMID: 21179013 DOI: 10.1038/ajg.2010.477] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES We conducted a retrospective cohort study in cirrhotic patients to understand (i) the risk of developing hepatocellular carcinoma (HCC) after an initial negative screening computed tomography (CT) scan and its relationship with underlying etiology and (ii) the risk of extrahepatic cancers (EHCs). METHODS Our cohort consisted of 952 cirrhotics who had at least one contrast-enhanced CT scan over a 5-year period from 1997 to 2002. We assessed their risk of HCC and EHC until the study closure (31 December 2007). Using data from the Indiana State Cancer Registry (ISCR), standardized incidence ratios (SIRs) were calculated for HCC and EHC. RESULTS The cohort's follow-up was 4.7±3.0 years. The frequency of HCC at baseline and during follow-up was 6.9 and 7.2%, respectively. The 1-, 3-, and 5-year HCC incidence after an initial negative CT scan was 1.2, 4.4, and 7.8%, respectively. The 1-, 3-, and 5-year EHC incidence was 2.2, 4.5, and 6.8%, respectively. The most common EHCs were breast, lung, and lymphoma. Incidence of both HCC (P=0.016) and EHC (P=0.004) varied significantly by the etiology of underlying cirrhosis. The SIRs for HCC and EHC were 186 (95% confidence interval (CI) 140-238) and 1.83 (95% CI 1.36-2.36), respectively. Compared with adjusted ISCR data, cirrhosis due to alcohol (SIR 2.73, 95% CI 1.14-4.33) but not other etiologies had significantly higher incidence of EHC. CONCLUSIONS This study furthers our understanding of HCC and EHC risk in cirrhosis. If confirmed by other studies, these data will assist in developing optimal strategies for monitoring of cancer in individuals with cirrhosis.
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Affiliation(s)
- Kenneth Berman
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
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Hohenester S, Oude-Elferink RPJ, Beuers U. Primary biliary cirrhosis. Semin Immunopathol 2009; 31:283-307. [PMID: 19603170 PMCID: PMC2758170 DOI: 10.1007/s00281-009-0164-5] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Accepted: 05/22/2009] [Indexed: 12/13/2022]
Abstract
Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.
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Affiliation(s)
- Simon Hohenester
- Department of Gastroenterology & Hepatology/Liver Center, Academic Medical Center, G4-213, University of Amsterdam, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands
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Liver cirrhosis, other liver diseases, pancreatitis and subsequent cancer: record linkage study. Eur J Gastroenterol Hepatol 2008; 20:384-92. [PMID: 18403939 DOI: 10.1097/meg.0b013e3282f4489f] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To determine the risk of cancer in cohorts of patients with alcoholic cirrhosis, other alcoholic liver diseases, other and unspecified cirrhosis, primary biliary cirrhosis, viral hepatitis, acute pancreatitis and chronic pancreatitis compared with the risk in a control cohort. METHODS Analysis of statistical database of linked hospital and mortality data in an area in southern England. RESULTS Compared with the control cohort, rate ratios were elevated for cancer overall and were particularly high for liver cancer in patients with alcoholic cirrhosis (rate ratio for cancer overall 2.4, 95% confidence interval 2.0-3.0 and 27.8, 17.7-41.7 for liver cancer); with other and unspecified cirrhosis (3.1, 2.7-3.6 and 35.1, 25.4-47.6); with other alcoholic liver diseases (2.3, 2.0-2.7 and 17.7, 11.5-26.0); with primary biliary cirrhosis (1.4, 0.9-2.0 and 19.6, 8.4-39.1) and with viral hepatitis (1.5, 1.2-1.9 and 18.6, 9.8-32.2). Pancreatic cancer risk was significantly and substantially elevated in all cohorts except that with primary biliary cirrhosis. Lung cancer risk was significantly high in all cohorts except those with primary biliary cirrhosis and viral hepatitis. Oral cavity cancers were elevated in alcoholic cirrhosis cohort (8.6; 3.1-18.9) and the other alcoholic liver diseases cohort (10.1; 5.9-16.2), as was colon cancer (2.8; 1.4-5.0 and 2.0; 1.2-3.3, respectively). Non-Hodgkin's lymphoma was significantly elevated in the group of 'other and unspecified cirrhosis' (11.4; 7.2-17.3). CONCLUSION All seven conditions carry an increased risk of cancer, but each condition has a somewhat different profile of cancer risk associated with it.
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Abstract
OBJECTIVES In primary biliary cirrhosis (PBC), the development of hepatocellular carcinoma (HCC) was thought to represent a rare complication. In contrast, extrahepatic malignancies have been reported to be significantly associated with PBC. The aim of this study was to determine the incidence of HCC and of extrahepatic malignancies in a large cohort of patients with PBC. METHODS A total of 212 patients with documented PBC (19 men and 193 women) were followed up for a median of 6 (range, 1-23) years. RESULTS In total, 23 (10.8%) cases of malignancy were diagnosed; eight (3.8%) patients with HCC and 15 (7.0%) with extrahepatic malignancies. PBC patients were found to have a 10-year risk of 4% for developing HCC and of 13% for developing extrahepatic malignancies. The risk for HCC was significantly higher in the PBC patients with cirrhosis (15% at 10 years of follow-up). In contrast, the histologic stage of PBC does not influence the risk for extrahepatic malignancy. CONCLUSION Our study confirms that there is a risk of HCC in Greek patients with PBC, particularly in patients with stage IV PBC. The risk of extrahepatic malignancies is higher than that of HCC, but it is not influenced by the histologic stage of the liver disease.
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Abstract
(Table is included in full-text article.)PBC in the advanced stage, corresponding to PBC stage IV, was shown in the past to be associated with an increased incidence of hepatocellular carcinoma (HCC). There is currently a debate, about the increase in incidence of extrahepatic malignancies, as some, but not all studies reported these neoplasms to be more common, especially breast cancer, irrespective of the PBC disease stage. In this issue of the journal a case series is reported on the incidence of various malignancies in a cohort of 212 patients with PBC from Greece. Considering as reference the cancer registries of another Mediterranean Country, like Italy, we could suggest that the incidence of extrahepatic malignancy, breast included, is not increased in PBC patients. Indeed, a more accurate analysis of the literature, shows that higher incidence of breast cancer were reported only for PBC patients evaluated in the 1970s and early 1980s, for whom a contribution of immunosuppressive agents, largely under investigation at that time, could be speculated. PBC patients do not need, therefore, to be submitted to stricter surveillance programs for extrahepatic cancer than the general population. As far as the development of HCC is concerned, instead, PBC patients should undergo the usual surveillance reserved to other categories of cirrhotic patients, according to published guidelines for the management of HCC. Such surveillance should start only when PBC patients have reached disease stage IV (frank cirrhosis).
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Alvaro D, Mancino MG, Glaser S, Gaudio E, Marzioni M, Francis H, Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007; 132:415-31. [PMID: 17241889 DOI: 10.1053/j.gastro.2006.07.023] [Citation(s) in RCA: 220] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Accepted: 07/12/2006] [Indexed: 12/16/2022]
Abstract
In the last 15 years, the intrahepatic biliary tree has become the object of extensive studies, which highlighted the extraordinary biologic properties of cholangiocytes involved in bile formation, proliferation, injury repair, fibrosis, angiogenesis, and regulation of blood flow. Proliferation is a "typical" property of cholangiocytes and is key as a mechanism of repair responsible for maintaining the integrity of the biliary tree. Cholangiocyte proliferation occurs virtually in all pathologic conditions of liver injury where it is associated with inflammation, regeneration, and repair, thus conditioning the evolution of liver damage. Interestingly, proliferating cholangiocytes acquire the phenotype of neuroendocrine cells, and secrete different cytokines, growth factors, neuropeptides, and hormones, which represent potential mechanisms for cross talk with other liver cells. Many studies suggest the generation of a neuroendocrine compartment in the injured liver, mostly constituted by cells with cholangiocyte features, which functionally conditions the progression of liver disease. These insights on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte biology.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, University La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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Alvaro D, Mancino MG, Onori P, Franchitto A, Alpini G, Francis H, Glaser S, Gaudio E. Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol 2006; 12:3537-45. [PMID: 16773710 PMCID: PMC4087569 DOI: 10.3748/wjg.v12.i22.3537] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The scientific framework concerning estrogen effects on different tissues has expanded enormously during the last decades, when estrogen receptor (ER) subtypes were identified. Estrogens are not only essential for the female reproductive system, but they also control fundamental functions in other tissues including the cardiovascular system, bone, brain and liver. Recently, estrogens have been shown to target the biliary tree, where they modulate the proliferative and secretory activities of cholangiocytes, the epithelial cells lining bile ducts. By acting on both estrogen receptors (ER-α) and (ER-β) subtypes, and by activating either genomic or non-genomic pathways, estrogens play a key role in the complex loop of growth factors and cytokines, which modulates the proliferative response of cholangiocytes to damage. Specifically, estrogens activate intracellular signalling cascades [ERK1/2 (extracellular regulated kinases 1/2, PI3- kinase/AKT (phosphatidylinositol-3’ kinase/AKT)] typical of growth factors such as insulin like growth factor (IGF1), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), thus potentiating their action. In addition, estrogens stimulate the secretion of different growth factors in proliferating cholangiocytes. This review specifically deals with the recent advances related to the role and mechanisms by which estrogens modulate cholangiocyte functions in normal and pathological conditions.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, University of Rome, La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, Sferra R, Ginanni-Corradini S, Mancino MG, Maggioni M, Attili AF, Podda M, Gaudio E. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol 2004; 41:905-12. [PMID: 15645536 DOI: 10.1016/j.jhep.2004.08.022] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Estrogen receptors (ER) in cholangiocytes of primary biliary cirrhosis (PBC) patients and their relationship with cell proliferation and death were evaluated. METHODS Liver biopsies from PBC patients with different histological stages were investigated by immunohistochemistry for ER-alpha and -beta, cytokeratin-19, proliferating cellular nuclear antigen (PCNA), Fas and terminal deoxynucleotide transferase end labelling (TUNEL). Normal livers and livers from primary sclerosing cholangitis and alcoholic cirrhosis were investigated as controls. RESULTS ER-alpha and -beta were observed in cholangiocytes of PBC patients but not in normal liver. In PBC, positivity for ER-beta was high (50-65 %) in all histological stages while, positivity for ER-alpha increased from 1% in stage I to 12 % in stage III (positivity correlated and co-localized in the same cell with PCNA). In stage IV of PBC, cholangiocytes were negative for ER-alpha in association with a lower PCNA positivity and with maximal degree of ductopenia. ER-alpha positivity in cholangiocytes of PBC patients was markedly lower than primary sclerosing cholangitis and alcoholic cirrhosis. CONCLUSIONS ER are expressed in PBC and other pathologies associated with cholangiocyte proliferation but not in normal subjects. The low expression of ER-alpha in PBC and their disappearance in the advanced histological stages suggests that an estrogenic deficiency could favour the evolution of this disease toward ductopenia.
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MESH Headings
- Apoptosis
- Bile Ducts, Intrahepatic/metabolism
- Bile Ducts, Intrahepatic/pathology
- Biomarkers/metabolism
- Case-Control Studies
- Cell Division
- Cholangitis, Sclerosing/metabolism
- Cholangitis, Sclerosing/pathology
- Cholangitis, Sclerosing/physiopathology
- Disease Progression
- Estrogen Receptor alpha/metabolism
- Estrogen Receptor beta/metabolism
- Humans
- Immunohistochemistry
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Alcoholic/metabolism
- Liver Cirrhosis, Alcoholic/pathology
- Liver Cirrhosis, Alcoholic/physiopathology
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Biliary/physiopathology
- Proliferating Cell Nuclear Antigen/metabolism
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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Abstract
Primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are chronic liver diseases that likely have an autoimmune basis to their pathogenesis. Although significant strides have been made in the clinical management of these conditions, their pathogenesis remains obscure. Understanding of various epidemiological factors may shed light on predisposing or causative factors for these diseases. Most is known about the epidemiology of PBC, with only minimal information on that of PSC and AIH. In this review, the current data on the epidemiology of PBC, AIH and PSC are summarized and suggestions are made for future work in this important area.
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Affiliation(s)
- J J Feld
- Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
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Abstract
Primary biliary cirrhosis is a chronic cholestatic liver disease of adults. This disorder is characterised histologically by chronic non-suppurative destruction of interlobular bile ducts leading to advanced fibrosis, cirrhosis, and liver failure. The precise aetiopathogenesis of primary biliary cirrhosis remains unknown, although dysregulation of the immune system and genetic susceptibility both seem to be important. Affected patients are typically middle-aged women with abnormal serum concentrations of alkaline phosphatase. Presence of antimitochondrial antibody in serum is almost diagnostic of the disorder. Identification of primary biliary cirrhosis is important, because effective treatment with ursodeoxycholic acid has been shown to halt disease progression and improve survival without need for liver transplantation. However, therapeutic options for disease-related complications-including fatigue and metabolic bone disease-remain unavailable. Mathematical models have been developed that accurately predict the natural history of primary biliary cirrhosis in individuals. Despite advances in understanding of the disease, it remains one of the major indications for liver transplantation worldwide.
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Affiliation(s)
- Jayant A Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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Prince M, Chetwynd A, Newman W, Metcalf JV, James OFW. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002; 123:1044-51. [PMID: 12360466 DOI: 10.1053/gast.2002.36027] [Citation(s) in RCA: 228] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Although several excellent studies have described the natural history of primary biliary cirrhosis, most were reported from tertiary referral centers. We examined the prognosis of primary biliary cirrhosis in a comprehensive geographically defined cohort. METHODS We followed up 770 primary biliary cirrhosis patients prevalent between January 1987 and December 1994 until death, transplantation, or censor on January 1, 2000, by interview and review of case notes and death certificates. Analysis of survival data was performed with Kaplan-Meier methods and Cox regression. RESULTS Median patient survival was 9.3 years from diagnosis. Patient age, alkaline phosphatase, albumin, and bilirubin at diagnosis independently predicted survival in Cox modeling. Prothrombin time and histologic stage did not independently affect survival. Observed survival was predicted well by this model and by the Mayo prognostic score (R2(M) = 0.37 and 0.18, respectively; R2(M) is a likelihood-based measure of the percentage information gain from the model due to covariates). Forty-two percent of deaths were caused by liver disease. Thirty-nine patients had liver transplantations by the censor date. Survival was much poorer than for an age- and sex-matched control population (standardized mortality ratio = 2.87 [1.73 excluding liver deaths]). The most common symptoms at diagnosis were pruritus (18.9%) and fatigue (21.0%). Twenty-six percent of patients developed liver failure by 10 years after diagnosis. CONCLUSIONS Although primary biliary cirrhosis is often now diagnosed at an early stage, the diagnosis still carries important prognostic implications. A significant proportion of patients develop liver failure, require transplantation, or die prematurely after this diagnosis.
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Affiliation(s)
- Martin Prince
- Centre for Liver Research, The Medical School, Framlington Place, Newcastle-Upon-Tyne, United Kingdom
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Alvaro D, Alpini G, Onori P, Franchitto A, Glaser S, Le Sage G, Gigliozzi A, Vetuschi A, Morini S, Attili AF, Gaudio E. Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes. Gastroenterology 2002; 123:336-44. [PMID: 12105861 DOI: 10.1053/gast.2002.34169] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND & AIMS We evaluated the effects of ovariectomy (OVX) and estrogen replacement treatment on cholangiocyte proliferation induced by bile duct ligation (BDL). METHODS BDL (2 weeks) was performed in ovariectomized rats and the proliferative and apoptotic activity compared with normal, with BDL control rats, and with BDL +/- OVX rats treated with 17-beta estradiol. RESULTS OVX induced a significant (P < 0.01) reduction of bile duct mass in BDL rats. The reduction of bile duct mass induced by OVX was associated with a decreased expression of estrogen receptor (ER)-alpha (2.5-fold) and, mainly, ER-beta (35-fold). Proliferating cellular nuclear antigen (PCNA) expression in cholangiocytes was impaired by OVX, indicating depression of proliferation, whereas terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and Fas positivity were markedly enhanced, indicating activation of Fas-mediated apoptosis. Administration of 17-beta estradiol during BDL in OVX rats induced a normalization of bile duct mass, ER expression, cholangiocyte proliferation, and apoptosis (Fas and TUNEL) in comparison with untreated BDL rats. CONCLUSIONS Our findings support the role of endogenous estrogens in sustaining the enhanced proliferative and secretory activities of cholangiocytes in cholestasis. On the basis of these data, the hypothesis of an estrogenic functional deficiency in chronic cholestatic liver diseases should merit careful attention.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, University La Sapienza, Rome, Italy
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Tanaka A, Leung PS, Kenny TP, Au-Young J, Prindiville T, Coppel RL, Ansari AA, Gershwin ME. Genomic analysis of differentially expressed genes in liver and biliary epithelial cells of patients with primary biliary cirrhosis. J Autoimmun 2001; 17:89-98. [PMID: 11488641 DOI: 10.1006/jaut.2001.0522] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The characterization of differentially expressed genes provides a powerful tool for identifying molecules that may be involved in the pathogenesis of disease. We have used two independent techniques to identify overexpressed transcripts in bile duct cells and in liver from patients with primary biliary cirrhosis (PBC). In the first method, we used suppressive subtractive hybridization to compare mRNA from isolated PBC bile duct epithelial cells (BECs) to normal BECs and identified 71 clones as transcribed at higher levels in PBC-BECs. Amongst these clones, 62/71 had matches in a non-redundant nucleotide database and 9/71 had matches in an EST database. Of the 62 clones, 51/62 include a complexity of genes involved in cell proliferation, signal transduction, transcription regulation, RNA processing, carbohydrate metabolism and hypothetical/unknown proteins; 4/62 were identified as interstitial collagenase and collagenase precursors, 4/62 as ribosomal proteins, 3/62 as mitochondrial DNA. The mitochondrial cDNA sequences included cytochrome c oxidase, Wnt-13, and the pHL gene, a c-myc oncogene containing coxIII sequence. In the second method, we constructed cDNA libraries from three different PBC livers and sequenced a total of 12,324 independent clones. These 12,324 clones underwent virtual subtraction with 2,814,148 independent clones from Incyte LifeSeq libraries. Twenty one sequences were identified as unique to PBC liver. Collectively, these approaches identified a number of genes involved in signalling, RNA processing, mitochondrial function, inflammation, and fibrosis. Interestingly, both Wnt-13 and Notch transcripts are overexpressed in PBC liver. Further studies are needed to focus on the significance of these genes during the natural history of disease.
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Affiliation(s)
- A Tanaka
- Division of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, University of California at Davis, CA 95616, USA
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Abstract
The global cancer burden in women appears to have stabilized according to the most recent estimates available although the distribution of cancer types appears to be changing with a sharp contrast between the increase in the absolute numbers of breast cancers and a decline in cervix cancers. Prospects for cancer control in women appear to be good within our current knowledge and deserve close attention. Rates of lung cancer in women are increasing substantially in many countries and seem set to overtake breast cancer as the commonest form of cancer death in women in many parts of the world. These changes are due to the effects of cigarette smoking, a habit which women widely embraced during the second half of the last century. The high levels of smoking currently in young women, which have yet to have their full impact on death rates, constitute an important hazard not only for future cancer risks but for several other important causes of death. There is strong and consistent evidence that increased consumption levels of fruit and vegetables is associated with reduced risks of many common forms of cancer including breast cancer. Although the breast is the commonest form of cancer in women in most western countries, the etiology of this disease remains elusive and preventable causes remain to be identified. Endogenous hormones also appear to have a role in cancer risk in women: oral contraceptives seem to increase slightly the risk of breast cancer in users in the use and in the immediate post-use period, but 10 years after cessation the risk again returns to that of never users. Oral contraceptive usage also appears to be protective against ovarian and endometrial cancer. The use of hormonal replacement therapy (HRT) appears to increase the risk of endometrial cancer and a positive association with breast cancer risk appears to exist. Within our current knowledge of the epidemiology of cancer in women, the most important preventive strategies would appear to be the prevention of cigarette smoking and increased dietary intake of vegetables and fruits. Screening has also shown to be effective in reducing incidence and mortality of cervix cancer and mortality from breast cancer. Although more work is needed, it is becoming clear that there could be an important role of HPV testing to further enhance cervix cancer screening. There are important variations in survival from a variety of cancers which are due to factors unrelated to the tumor behavior and that there are significant variations in survival from cancer. Reduction of these gaps could lead to a reduction in cancer mortality and contribute towards increased prospects for cancer control in women.
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Affiliation(s)
- P Boyle
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
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Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology 2000; 31:1005-13. [PMID: 10733559 DOI: 10.1053/he.2000.5984] [Citation(s) in RCA: 320] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.
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Affiliation(s)
- E J Heathcote
- Division of Gastroenterology, University of Toronto, The Toronto Hospital, Toronto, Ontario, Canada.
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Abstract
Primary biliary cirrhosis (PBC) is a chronic autoimmune disease characterised by cholestatic liver function tests, antimitochondrial antibodies, and abnormal liver histology. Early descriptions of a rare rapidly progressive disease no longer reflect the more indolent progress often seen today. Many patients have significant long term morbidity through symptoms such as fatigue and itch with a minority progressing to liver failure and need for transplantation. The current data on the diagnosis, clinical progression, and treatment of PBC are reviewed.
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Affiliation(s)
- M I Prince
- Centre for Liver Research, University of Newcastle, UK
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28
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Floreani A, Baragiotta A, Martines D, Naccarato R, D'odorico A. Plasma antioxidant levels in chronic cholestatic liver diseases. Aliment Pharmacol Ther 2000; 14:353-8. [PMID: 10735930 DOI: 10.1046/j.1365-2036.2000.00729.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND [corrected] A predictable consequence of cholestasis is malabsorption of fat-soluble factors, (vitamins A, D, E, K) and other free radical scavengers, such as carotenoids. It has been suggested that oxygen-derived free radicals may be involved in the pathogenesis of chronic liver damage. AIMS (i) To evaluate retinol, alpha-tocopherol and carotenoid plasma levels in two groups of patients with chronic cholestatic liver disease (primary biliary cirrhosis and primary sclerosing cholangitis); (ii) to compare the respective plasma levels with those of the general population; (iii) to correlate the plasma levels with disease severity. METHODS A total of 105 patients with chronic cholestasis were included in the study: 86 with primary biliary cirrhosis (81 female, five male, mean age 55.5 +/- 11 years), 19 with primary sclerosing cholangitis (seven female, 12 male, mean age 35 +/- 11 years; six patients had associated inflammatory bowel disease); 105 sex- and age-matched subjects from the general population in the same geographical area (88 female, 17 male, mean age 51.3.5 +/- 10 years) served as controls. Carotenoids (lutein zeaxanthin, lycopene, beta-carotene, alpha-carotene, beta-cryptoxanthin), retinol and alpha-tocopherol were assayed by high-pressure liquid chromatography. A food frequency questionnaire was administered to each subject to evaluate the quality and the quantity of dietary compounds. Data were processed by analysis of variance and linear regression analysis, as appropriate. RESULTS Both primary biliary cirrhosis and primary sclerosing cholangitis patients had significantly lower levels of retinol, alpha-tocopherol, total carotenoids, lutein, zeaxanthin, lycopene, alpha- and beta-carotene than controls (P < 0.0001). Among the cholestatic patients, no significant difference in the concentration of antioxidants was observed between primary biliary cirrhosis and primary sclerosing cholangitis subjects. Anti-oxidant plasma levels were not affected by the severity of the histological stage in primary biliary cirrhosis, but a negative correlation was found between total carotenoids and both alkaline phosphatase (ALP) and gammaglutamyl transpeptidase (GGT) (P < 0.013 and P < 0.018, respectively). Within the primary sclerosing cholangitis group, no correlation was found between total carotenoids and cholestatic enzymes. Nutritional intake in cholestatic patients was comparable to controls, including fruit and vegetable intake. CONCLUSIONS Although no clinical sign of deficiency is evident, plasma levels of antioxidants are low in cholestatic patients even in early stages of the disease. This is probably due to malabsorption of fat-soluble vitamins, as well as other mechanisms of hepatic release, suggesting the need for dietary supplementation.
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Affiliation(s)
- A Floreani
- Department of Surgical and Gastroenterological Sciences, University of Padova, Italy.
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Howel D, Metcalf JV, Gray J, Newman WL, Jones DE, James OF. Cancer risk in primary biliary cirrhosis: a study in northern England. Gut 1999; 45:756-60. [PMID: 10517916 PMCID: PMC1727737 DOI: 10.1136/gut.45.5.756] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Suggestions that breast cancer may be more common in patients with primary biliary cirrhosis (PBC) have been challenged. It has recently been proposed that total cancer rates may be higher in patients with PBC, as well as liver cancers. AIMS To investigate these proposals on a strictly defined case series. SUBJECTS A total of 769 prevalent or incident PBC patients with "definite" or "probable" disease detected in a defined area of the north-east of England during 1987-94. METHODS Cancer events and deaths were identified by obtaining information from one or more of the following sources: Office for National Statistics (ONS) Central Registers, Regional Cancer Registry, and clinical case records. Standardised cancer incidence (SIR) and mortality ratios (SMR) were calculated using the local region as the standard population. RESULTS There were 97 cancer events during 1987-96. SIR from cancer registrations for all cancers was 1.7 (95% confidence interval (CI) 1.3 to 2.2), for liver cancer was 74 (95% CI 32 to 146), and for breast cancer was 1.1 (95% CI 0.4 to 2.4). SMR for all cancers was 1. 8 (95% CI 1.4 to 2.4), for liver cancer was 39 (95% CI 20 to 68), and for breast cancer was 0.4 (95% 0.1 to 1.6). The results were similar after excluding the first year of follow up after PBC diagnosis. CONCLUSIONS There was some evidence of a small increase in overall cancer incidence and mortality in PBC patients. With the exception of liver cancer, it is unlikely that there is a high excess incidence for PBC patients from any cancer at a particular site, and specifically breast cancer.
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Affiliation(s)
- D Howel
- Department of Epidemiology and Public Health, The Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK
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30
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Abstract
Primary biliary cirrhosis and primary sclerosing cholangitis are the most common chronic cholestatic liver diseases in adults that lead to biliary cirrhosis and its inherent complications such as portal hypertension and liver failure. Although important advances in the understanding of the pathogenesis of these conditions have been accomplished in the last two decades, much work is needed to uncover the interaction of genetic and immunologic mechanisms involved in their pathogenesis. Ursodeoxycholic acid at dosage of 13 to 15 mg/kg/d is the only agent that can currently be recommended in the treatment of PBC. No medical therapy aimed at disrupting disease progression is available for patients with primary sclerosing cholangitis, although several agents with different properties are currently under evaluation. Liver transplantation is the treatment of choice for patients with primary biliary cirrhosis and primary sclerosing cholangitis with end-stage liver disease.
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Affiliation(s)
- P Angulo
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, USA
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31
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Nijhawan PK, Therneau TM, Dickson ER, Boynton J, Lindor KD. Incidence of cancer in primary biliary cirrhosis: the Mayo experience. Hepatology 1999; 29:1396-8. [PMID: 10216121 DOI: 10.1002/hep.510290511] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Patients with primary biliary cirrhosis (PBC) may be at increased risk for malignancies. Several studies have addressed the risk of specific malignancies; however, there is little information about overall incidences of malignancies in these patients. We hypothesize that these patients may be at an increased risk for cancer. We performed a retrospective chart review evaluating patients with the diagnosis of PBC and malignancies. We reviewed records of patients with PBC presenting to the Mayo Clinic between 1976 and 1985. The diagnosis of PBC was made using evidence of cholestasis, positive antimitochondrial antibody titers and liver biopsy findings consistent with PBC. The incidence of malignancies were then compared with published data by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute. Of the 1,692 patients with PBC in the Mayo Clinic data base, 114 patients were identified with primary cancer. The number of malignancies was higher than would be anticipated by chance alone; with 93 observed versus 62.4 expected events (P <.001). Hepatobiliary malignancies had a relative risk of 46 (P <.0001) for women and 55 (P <.0001) in men. There was a dramatic increased risk for development of hepatobiliary malignancies. PBC patients might benefit from more aggressive surveillance for hepatobiliary malignancies during their lifetime.
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Affiliation(s)
- P K Nijhawan
- Department of Gastroenterology and Hepatology, The Mayo Clinic, Rochester, MN 55905, USA
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32
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Sorensen HT, Friis S, Olsen JH, Thulstrup AM, Mellemkjaer L, Linet M, Trichopoulos D, Vilstrup H, Olsen J. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 1998; 28:921-5. [PMID: 9755226 DOI: 10.1002/hep.510280404] [Citation(s) in RCA: 217] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cancer risk in patients with cirrhosis could be modified by factors such as changes in hormonal levels, impaired metabolism of carcinogens, or alteration of immunological status. We investigated the risk of liver and various forms of cancer in patients with cirrhosis in a follow-up study. We identified 11,605 1-year survivors of cirrhosis from the files of the Danish National Registry of Patients (NRP) from 1977 to 1989. Occurrence of cancer through 1993 was determined by linkage to the Danish Cancer Registry. For comparison, the expected number of cancer cases was estimated from national age-, sex-, and site-specific incidence rates. Overall, 1,447 cancers were diagnosed among the study subjects, as compared with 708.1 expected, to yield a standardized incidence ratio (SIR) of 2.0 (95% CI: 1.9 to 2.2). In all diagnostic subgroups of cirrhosis, the risk of primary liver cancer, mainly hepatocellular carcinoma, was markedly elevated, with 245 observed cases and an overall 36-fold elevated risk (59.9-fold elevated for hepatocellular carcinoma and 10-fold for cholangiocarcinoma). Substantial and persistent excesses during follow-up were seen for all types of cancer associated with tobacco and alcohol habits (cancer of the lung, larynx, buccal cavity, pharynx, pancreas, urinary bladder, and kidney), while moderate excesses were seen for cancers of the colon and breast. The latter, however, were not complemented by any decrease in the risk of prostate cancer (SIR: 1.0; 95% CI: 0.7 to 1. 3). A slightly increased risk was seen for testis cancer, but disappeared after 10 years. We found evidence of an increased risk for liver and several extrahepatic cancers in patients with cirrhosis. Although part of this increase is likely attributable to alcohol and tobacco consumption, our study opens up the possibility that cirrhosis plays a role in the carcinogenesis of types of cancer other than liver cancer.
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Affiliation(s)
- H T Sorensen
- Department of Medicine V, Aarhus University Hospital, Aarhus, Denmark
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33
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Akisawa N, Maeda T, Tsuda K, Nishimori I, Morita M, Iwasaki S, Tomita A, Saibara T, Onishi S, Kiyoku Y, Enzan H. Primary biliary cirrhosis associated with cholangiocarcinoma. Dig Dis Sci 1998; 43:2138-42. [PMID: 9753283 DOI: 10.1023/a:1018831903371] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- N Akisawa
- First Department of Internal Medicine, Kochi Medical School, Nankoku, Japan
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34
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Tanaka K, Shibuya A, Naitoh M, Komatsu T, Amaki S, Shibata M, Miyakawa H. Hepatocellular carcinoma arising from primary biliary cirrhosis in Japan. Am J Gastroenterol 1998; 93:1190-1. [PMID: 9672372 DOI: 10.1111/j.1572-0241.1998.01190.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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35
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Abstract
Primary biliary cirrhosis (PBC) is a liver disease of unknown etiology characterized by chronic nonsuppurative destructive cholangitis (CNSDC) of intrahepatic septal and interlobular bile ducts. It is generally defined as an autoimmune disease. Characteristically, patients with PBC have a cholestatic serum hepatic profile and circulating antimitochondrial antibodies (AMA). PBC is progressive and ultimately leads to biliary cirrhosis and liver failure. It occurs at least three times more often in women than in men and it is the most common indication for liver transplantation in women around the world. There is no known cure for PBC. Despite the remarkable progress elucidating the genetics of breast cancer, and the effort placed on breast cancer education and screening methods, the mortality of breast cancer remains unacceptably high. In this essay, we describe the similarities between breast cancer and PBC and how their pathogenesis may be related. The hypothesis stated herein has evolved from reports from the early 1980s that linked an increased risk for breast cancer with PBC, and from the author's clinical experience with patients who suffer from both diseases. The association between these two diseases in the USA merits further investigation. If it is confirmed, risk factors involved in their pathogenesis will be identified.
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Affiliation(s)
- N V Bergasa
- Division of Gastroenterology and Liver Disease, Beth Israel Medical Center, New York, NY 10003, USA
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36
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Sørensen HT, Friis S, Olsen JH, Thulstrup AM, Mellemkjaer L, Linet M, Trichopoulos D, Vilstrup H, Olsen J. Risk of breast cancer in men with liver cirrhosis. Am J Gastroenterol 1998; 93:231-3. [PMID: 9468249 DOI: 10.1111/j.1572-0241.1998.00231.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Liver cirrhosis is associated with increased levels of estrogens, which may be causally related to breast cancer. Because background estrogen levels are lower in men than in women, an estrogen-mediated link between liver cirrhosis and breast cancer would be easier to detect in men. METHODS Men hospitalized with liver cirrhosis in Denmark from January 1, 1977, to December 31, 1989, were followed up, through record linkage, until the end of December 1993 for the possible occurrence of breast cancer. RESULTS A total of 11,642 men with liver cirrhosis were identified and were followed for a mean period of 4.3 yr, for a total of 49,687 person-years. Three cases of male breast cancer were observed whereas 0.75 was expected, for a standardized incidence ratio of 4.0 (95% confidence interval, 0.8-11.7). CONCLUSIONS Cirrhosis, possibly via high levels of endogenous estrogens, increases the risk of breast cancer in men.
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Affiliation(s)
- H T Sørensen
- The Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, Aarhus University, Denmark
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37
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Van Dam GM, Gips CH. Primary biliary cirrhosis in The Netherlands. An analysis of associated diseases, cardiovascular risk, and malignancies on the basis of mortality figures. Scand J Gastroenterol 1997; 32:77-83. [PMID: 9018771 DOI: 10.3109/00365529709025067] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/METHODS In 1979 death rate registration for primary biliary cirrhosis (PBC) became available in The Netherlands. In the 14-year period 1979-92, 417 persons died of and 179 with PBC. We investigated secondary causes of death using standardized mortality ratios (SMR) (1.0 as reference, P < 0.001 regarded as significant). RESULTS Median age was 70-74 (35 to > 85) years. Secondary causes of death originated from the circulatory, digestive, and respiratory tracts and malignancies. Younger persons (< 60 years), dying of PBC, more often died with "toxicity related to immunosuppression' than older persons (P < 0.01). Younger persons (< 60) dying with PBC, more often died of hepatocellular carcinoma (HCC) than older ones (P < 0.05). In patients with PBC the frequency of HCC (SMR, 25.5; P < 0.0001) and diseases of the musculoskeletal system/connective tissue (SMR, 5.1; P < 0.0001) was higher than in the general population. Malignancies in general (SMR, 0.7), pancreatic carcinoma (SMR, 2.5), breast cancer (SMR, 0.1) and diseases of the circulatory system (SMR, 0.8) differed but not significantly (P < 0.05 - < 0.01). No difference existed in the localization of malignancies in patients dying of as compared with those dying with PBC. CONCLUSIONS Deaths occurred predominantly in the older age classes, with an age-related difference in some associated disorders. Patients with PBC showed an increased risk of HCC and diseases of the musculoskeletal system. Similar studies from different countries are needed.
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Affiliation(s)
- G M Van Dam
- International School of Hepatology and Tropical Medicine GISH-T, Faculty of Medical Sciences, State University Groningen, The Netherlands
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38
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Hassanein T, Van Thiel DH. Biochemical abnormalities in liver disease. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1995; 9:679-88. [PMID: 8903800 DOI: 10.1016/0950-3528(95)90056-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
A wide array of biochemical findings can be seen in patients with liver disease. Depending upon the setting, these findings can either be used to confirm the presence of a liver disease, document its complications or suggest its presence. Thus, physicians need to be aware of them and recognize and use them as the specific case indicates.
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39
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Lööf L, Adami HO, Sparén P, Danielsson A, Eriksson LS, Hultcrantz R, Lindgren S, Olsson R, Prytz H, Ryden BO, Sandberg-Gertzen H, Wallerstedt S. Cancer risk in primary biliary cirrhosis: a population-based study from Sweden. Hepatology 1994. [PMID: 8020878 DOI: 10.1002/hep.1840200116] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
A cohort of 559 patients in Sweden who satisfied predetermined criteria for the diagnosis of primary biliary cirrhosis was followed with respect to the incidence of cancer during the period of 1958 to 1988. The mean follow-up time from the time of primary biliary cirrhosis diagnosis was 9.0 +/- 5.4 yr. During the follow-up period, 148 patients died and the primary cause of death was liver insufficiency. An overall excess risk for cancer, standardized incidence ratio 1.6; 95% confidence interval, 1.1 to 2.2, was found in the cohort. In contrast to previous reports, we found no excess risk for breast cancer (standardized incidence ratio, 0.9; 95% confidence interval, 0.3 to 2.1). The number of hepatocellular cancers in the primary biliary cirrhosis cohort did not significantly differ from expected (standardized incidence ratio, 2.91; 95% confidence interval, 0.4 to 10.5).
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Affiliation(s)
- L Lööf
- Department of Internal Medicine, University Hospital, Uppsala, Sweden
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40
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Pearce S, Bassendine M, Dowsett M. Sex hormone binding globulin and non-protein-bound oestradiol in postmenopausal patients with primary biliary cirrhosis and normal controls. J Steroid Biochem Mol Biol 1993; 44:273-6. [PMID: 8461259 DOI: 10.1016/0960-0760(93)90087-d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Several studies have suggested that patients with primary biliary cirrhosis (PBC) have an increased risk of a number of medical conditions related to their oestrogen levels. This study has measured sex hormone binding globulin (SHBG) binding capacity, total oestradiol levels and percentage non-protein-bound (NPB) oestradiol and calculated the concentration of NPB oestradiol, in postmenopausal subjects in the following groups; normal controls, early PBC, advanced PBC and advanced PBC who were receiving therapy. Mean SHBG levels were higher in all groups of patients with PBC than in controls. No significant difference was observed in total or biologically active oestradiol between the four groups.
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Affiliation(s)
- S Pearce
- Department of Biochemical Endocrinology, Royal Marsden Hospital, Chelsea, London, England
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41
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Goldin R, Sayer J, Wilkins M, Price P, Thomas H. Primary liver lymphoma associated with primary biliary cirrhosis. Histopathology 1993; 22:184-5. [PMID: 8454265 DOI: 10.1111/j.1365-2559.1993.tb00102.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Affiliation(s)
- R Goldin
- Department of Histopathology, St Mary's Hospital Medical School, London, UK
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42
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Abstract
Improved immunosuppressive regimens, better postoperative intensive care and judicious patient selection have all resulted in increased patient survival following orthotopic liver transplantation (OLT), which has become the preferred option for most patients with end-stage primary biliary cirrhosis (PBC). As with most other clinical series, PBC is now the most common indication for OLT in the King's College hospital and Cambridge programmes. To date (30 July 1990), 129 patients with PBC have been transplanted, with overall actual 1 and 5 year survival rates of 65 and 63% respectively. When patients transplanted since 1985 are considered, both the 1 and 2 year survival rates are 78%. Immediate operative mortality was 4.5%, generally due to uncontrollable bleeding, while further mortality within 30 days of operation--mainly consequent upon infection and multi-organ failure--has fallen from 40% prior to 1985 to 9% since 1988. Thirteen per cent of patients have been retransplanted for vanishing bile duct syndrome, manifest in this series invariably within the first 6 months following OLT. Although rehabilitation in this series was excellent, a significant percentage of cases have continuing problems with metabolic bone disease, hypertension and renal impairment, mainly due to cyclosporin toxicity.
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Affiliation(s)
- R Sallie
- Institute of Liver Studies, King's College Hospital, London, UK
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43
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Farrant JM, Hayllar KM, Wilkinson ML, Karani J, Portmann BC, Westaby D, Williams R. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991; 100:1710-7. [PMID: 1850376 DOI: 10.1016/0016-5085(91)90673-9] [Citation(s) in RCA: 301] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The clinical features at the time of presentation and the outcome in 126 patients with primary sclerosing cholangitis were studied to clarify the natural history and prognosis in symptomatic and asymptomatic individuals. The median age of the patients at the time of presentation was 36 years, 62% were male, and 16% were asymptomatic. The median follow-up from time of presentation was 5.8 years. There were more patients who had liver transplants (21%) than patients who died of liver-related disease (16%); the estimated median survival to these end points was 12 years. Cholangiocarcinoma was found in 8 patients and in 23% of those undergoing liver transplantation. Asymptomatic patients had milder disease than symptomatic patients, but in a univariate analysis the presence of symptoms was not prognostically significant. On multivariate analysis, the following independent prognostic factors were found: hepatomegaly, splenomegaly, serum alkaline phosphatase, histological stage, and age. These features were combined to produce a prognostic model that should be valuable in the stratification of patients in clinical trials and in the timing of liver transplantation, particularly in those patients seen soon after presentation.
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Affiliation(s)
- J M Farrant
- Department of Radiology, King's College Hospital, Denmark Hill, London, England
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44
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Floreani A, Chiaramonte M, Giannini S, Malvasi L, Lodetti MG, Castrignano R, Giacomini A, D'Angelo A, Naccarato R. Longitudinal study on osteodystrophy in primary biliary cirrhosis (PBC) and a pilot study on calcitonin treatment. J Hepatol 1991; 12:217-23. [PMID: 2051000 DOI: 10.1016/0168-8278(91)90941-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The aims of this study were to evaluate bone metabolism in primary biliary cirrhosis (PBC) and the effect of ADFR (activate, depress, free, repeat) therapy with vitamin D, calcium and calcitonin in preventing bone resorption. Sixty-nine female subjects entered the study: 38 PBC (AMA + ve) patients, 11 AMA-negative chronic liver disease patients and 20 age-matched healthy controls. Bone metabolism was evaluated by biochemical parameters and dual-photon absorptiometry of the lumbar spine at time 0, 6 and 18 months. Both PBC and chronic liver disease (CLD) patients showed low levels of serum 25-hydroxyvitamin D, osteocalcin and bone mineral content expressed as AAD (average area density) compared to healthy controls. Serum parathyroid hormone in PBC patients was at the lower limit of the normal range and was significantly lower than patients with chronic liver disease. At a 6-month interval, AAD significantly decreased in PBC patients (p less than 0.005). At the 6-month period PBC patients were allocated into two groups according to a cut-off AAD of 0.800 g/cm2: group A (no treatment, AAD greater than 0.800, n = 11), group B (treatment, AAD less than 0.800, n = 13). The latter group received a 4-week course with oral calcium carbonate (1500 mg daily) + oral 1,25-dihydroxyvitamin D (0.5 micrograms twice a day for 5 days) + carbocalcitonin (40 U MRC) i.m. thrice a week. The treatment was repeated with the same protocol at 2-month intervals for 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- A Floreani
- Department of Gastroenterology, University of Padova, Italy
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45
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Notghi A, Nestle U, Rittner G, Brissot P, Jouanolle H, Manns M, Schleiermacher E, Rittner C. Chromosomal aberrations in patients with primary biliary cirrhosis. Hum Genet 1990; 85:546-50. [PMID: 1699877 DOI: 10.1007/bf00194235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Chromosomal aberrations in untreated lymphocyte cultures, bleomycin (BLM)-induced aberrations and sister chromatid exchanges (SCE) in the peripheral blood lymphocytes of 11 patients suffering from primary biliary cirrhosis (PBC) and 14 matched control individuals were analysed. The lymphocytes of the PBC patients had on average a lower mitotic index (2.3) compared with controls (3.5) in the untreated cultures. The mean baseline rate of aberrations of the cultured lymphocytes of the patients was 5.3 aberrations per 100 metaphases (%); this was significantly different (P = 0.0291) from that of the controls with a mean of 2.3%. In lymphocytes of the patients and controls, most of the aberrations observed took the form of gaps; there was an almost equal breakage rate in both groups (0.5% and 0.4%, respectively). The average number of mitoses with aberrations in the PBC patients studied was double that of the controls (4.9% and 2.3% respectively, P = 0.0323). The mean number of the BLM-induced aberrations was 54.0% and 27.7% for the lymphocytes of the patients and controls, respectively. The mean number of the aberrant mitoses in the BLM cultures was 6 times higher than that of the untreated cultures for both groups, 25.7% and 14.6% respectively (P = 0.018). The chromosomal distribution of baseline and induced aberrations was not random. The PBC patients had a mean number of 8.7 SCE per mitosis, which was significantly higher than the SCEs in the controls (6.3 SCE per mitosis; P = 0.0156). The evidence suggests that the chromosomes of the lymphocytes of PBC patients may be less stable than those of the control individuals in this study.
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Affiliation(s)
- A Notghi
- Institut für Rechtsmedizin der Universität, Mainz, Federal Republic of Germany
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46
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Witt-Sullivan H, Heathcote J, Cauch K, Blendis L, Ghent C, Katz A, Milner R, Pappas SC, Rankin J, Wanless IR. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990; 12:98-105. [PMID: 2197212 DOI: 10.1002/hep.1840120116] [Citation(s) in RCA: 134] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The demographics of primary biliary cirrhosis in Ontario, Canada, are described. Two hundred and twenty-five primary biliary cirrhosis patients were identified by 85 of 502 gastroenterologists (or internists) practicing in Ontario acute care hospitals that have 150 or more beds. Two hundred and six patients were verified as being antimitochondrial antibody-positive, resulting in an incidence of 3.26 per million per year and a prevalence of 22.39 per million. Questionnaire data were obtained on 88.5% of these patients. Twenty-nine percent of the patients were found to be asymptomatic. Geographical clustering and racial predisposition were not seen. No increase in breast cancer prevalence was noted. By the time the diagnosis of primary biliary cirrhosis was established, the patients had consulted a median number of 3.5 physicians. Fatigue was reported as the most disabling symptom. The diagnosis of primary biliary cirrhosis in patients referred from across the province of Ontario was independently confirmed by us, using standard criteria (antimitochondrial antibody testing and liver biopsy), and was found to be reliable.
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Affiliation(s)
- H Witt-Sullivan
- Department of Medicine, University of Toronto, Ontario, Canada
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47
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Burroughs AK, Biagini M, McCormick PA, Rolles K. Liver transplantation and primary biliary cirrhosis. Postgrad Med J 1989; 65:553-8. [PMID: 2690049 PMCID: PMC2429510 DOI: 10.1136/pgmj.65.766.553] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- A K Burroughs
- Hepato-biliary and Liver Transplantation Unit, Royal Free Hospital, London, UK
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48
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Abstract
Primary biliary cirrhosis is a chronic liver disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to an inflammatory destruction of small intrahepatic bile ducts. The clinical course of PBC is variable ranging from a few years in rapidly progressive cases to a normal life-expectancy in a proportion of asymptomatic cases. The typical patient is a middle-aged woman who may present with pruritus, increasing pigmentation of the skin, and eventually jaundice. The level of serum alkaline phosphatase is almost invariably elevated, serum mitochondrial antibodies are present in more than 90 per cent, and an elevated serum IgM is usually present. PBC is associated with many immunologic abnormalities and appears to be a classic autoimmune disease. Some of the immune defects may be epiphenomena; others such as a marked defect in suppressor T cell function seem to be related to the pathogenesis of the disease. All drug therapy that is aimed at slowing the disease process is experimental. A place for immunosuppressive drugs in the management of PBC would be anticipated. However, no drug has to date been definitively shown to have a beneficial effect on the disease. Currently, the main treatments used are aimed at preventing or correcting the complications of intractable cholestasis. Patients with PBC and evidence of hepatic decompensation and/or poor quality of life make good candidates for liver transplantation. The current aim of therapy is to find an effective regime of immunosuppression that will make hepatic transplantation redundant for this disease.
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Affiliation(s)
- R Moreno-Otero
- Liver Diseases Section, National Institute of Diabetes, and Digestive and Kidney Diseases, Bethesda, Maryland
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49
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Abstract
Sexual behavior in women with liver disease was examined in 150 women to determine whether liver disease influenced sexual desire, frequency or performance. The average age of women studied was 53 years (range: 26 to 76 years), and a wide variety of liver diseases were represented. Sexual desire was reduced in 33%. Difficulty in becoming sexually aroused was noted by 18%. Orgasm during intercourse was not experienced by 25%. The frequency of sexual intercourse decreased since onset of disease in 27%. Dyspareunia was a complaint by 21%, most often attributed to decreased vaginal lubrication. Liver disease was considered a significant factor interfering with sexual function in 17%. No statistical difference was found between sexual desire or function in our study and in large studies of sexual behavior in women. Each category was subdivided by presence or absence of cirrhosis, pre- or postmenopausal state, laboratory values and duration of disease. Except for a greater number of postmenopausal women with complaints of painful intercourse, no statistical differences or trends were found. Nonalcoholic liver disease does not affect sexual desire, function or performance. Variables other than liver disease influence sexuality. Women with liver disease can thus be reassured that they can maintain normal sexual relations.
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Affiliation(s)
- N Bach
- Department of Medicine, Mount Sinai School of Medicine, City University of New York, New York 10029
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Affiliation(s)
- F Schaffner
- Mount Sinai School of Medicine, New York, New York 10029
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