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Premkumar M, Anand AC. Porto-sinusoidal Vascular Disease: Classification and Clinical Relevance. J Clin Exp Hepatol 2024; 14:101396. [PMID: 38601747 PMCID: PMC11001647 DOI: 10.1016/j.jceh.2024.101396] [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: 12/10/2023] [Accepted: 03/05/2024] [Indexed: 04/12/2024] Open
Abstract
Non-cirrhotic portal hypertension (NCPH) is a well-recognized clinico-pathological entity, which is associated with clinical signs and symptoms, imaging, and endoscopic features of portal hypertension (PHT), in absence of cirrhosis. In patients with NCPH without known risk factors of PHT or extrahepatic portal vein thrombosis, the condition is called idiopathic non-cirrhotic portal hypertension (INCPH). There are multiple infectious, immune related causes, systemic diseases, drug and toxin exposures, haematological disorders, and metabolic risk factors that have been associated with this INCPH. However, the causal pathogenesis is still unclear. The Vascular liver disorders interest group group recently proposed porto-sinusoidal vascular disease (PSVD) as a syndromic entity, which provides definite histopathological criteria for diagnosis of NCPH (table 1). The three classical histo-morphological lesions specific for PSVD include obliterative portal venopathy, nodular regenerative hyperplasia, and incomplete septal fibrosis. The PSVD definition includes patients with portal vein thrombosis, PVT, and even those without PHT, thus broadening the scope of diagnosis to include patients who may have presented early, prior to haemodynamic changes consistent with PHT. However, this new diagnosis has pros and cons. The cons include mandating invasive liver biopsy to assess the PSVD histological triad in all patients with NCPH, an erstwhile clinical diagnosis in Asian patients. In addition, the natural history of the subclinical forms of PSVD without PHT and linear progression to develop PHT is unknown yet. In this review, we discuss the diagnosis and treatment of INCPH/PSVD, fallacies and strengths of the old and new schema, pathobiology of this disease, and clinical correlates in an Asian context. Although formulation of standardised diagnostic criteria is useful for comparison of clinical cohorts with INCPH/PSVD, prospective clinical validation in global cohorts is necessary to avoid misclassification of vascular disorders of the liver.
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Affiliation(s)
- Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Anil C. Anand
- Department of Hepatology, Kalinga Institute of Medical Sciences, Bhubaneshwar, Odisha, India
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Malik A, Malik S, Farooq A, Malik MI, Javaid S. Histopathological features of idiopathic portal hypertension: A systematic review and meta-analysis. Sci Prog 2024; 107:368504241264996. [PMID: 39053026 PMCID: PMC11282518 DOI: 10.1177/00368504241264996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
BACKGROUND Portal hypertension (PH) is a clinically significant entity that could present with life-threatening gastrointestinal bleeding. Cirrhosis is the most common cause of PH, with well-documented histopathology and etiology. However, in idiopathic portal hypertension (IPH), no single histopathologic finding is associated with PH. Our systematic review aims to identify and summarize the prevalence of the common histological findings of IPH. METHODS We systematically searched PubMed, Cochrane CENTRAL, Web of Science, and Scopus till 1ST March 2022 for studies describing the histopathological features of IPH. Data were extracted from eligible studies and pooled as events rate and 95% confidence interval (CI) using binary random-effects model by open meta-analyst software. RESULTS We included 23 retrospective studies with a total sample size of 813 patients. The overall incidence of nodular regenerative hyperplasia was 38.6%, 59.8% for portal fibrosis, 51.3% for periportal fibrosis, 39.3% for perisinusoidal fibrosis, 89.8% for portal vein sclerosis, 42.2% for portal inflammation, 53.3% for mega-sinusoids, 39.5% for thickening of portal vein branches, 93.8% for narrowing of portal veins, 53.3% for hepatic veins/venous outflow obstruction, 51.4% for aberrant portal/periportal vessels, 42.4% for shunt vessel, 50.9% for ductular proliferation, and 16.3% for steatosis. CONCLUSION Due to the relatively non-pathognomonic and non-specific nature of IPH, a combination of different histological features such as the portal and periportal fibrosis, portal vein sclerosis, mega-sinusoids, narrowing of portal veins, hepatic venous outflow obstruction, aberrant portal or periportal vessels, and ductular proliferation may be of value in diagnosing IPH as the incidence rate of these features was at approximately 50%.
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Affiliation(s)
- Adnan Malik
- Mountain Vista Medical Center, Midwestern University Program, Mesa AZ, USA
| | - Sohira Malik
- Penn State College of Medicine, Hershey, PA, USA
| | - Ahsan Farooq
- Penn State College of Medicine, Hershey, PA, USA
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Biesterveld BE, Schroder PM, Hitchcock ME, Bolognese A, Kim SC, Al-Adra DP. Nodular regenerative hyperplasia and liver transplantation: a systematic review. FRONTIERS IN TRANSPLANTATION 2023; 2:1221765. [PMID: 38993905 PMCID: PMC11235372 DOI: 10.3389/frtra.2023.1221765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 08/17/2023] [Indexed: 07/13/2024]
Abstract
Nodular regenerative hyperplasia (NRH) is a primary disease of the liver that may cause noncirrhotic portal hypertension. Common causes include autoimmune, hematologic, immune deficiency, and myeloproliferative disorders. Given the limited data regarding the development of NRH in contemporary immunosuppressive protocols and the occurrence of NRH post-liver transplantation, we systematically reviewed NRH as it pertains to liver transplantation. We performed a comprehensive search for NRH and transplantation. Nineteen studies were identified with relevant data for NRH as an indication for a liver transplant. Thirteen studies were identified with relevant data pertaining to NRH development after liver transplant. Pooled analysis revealed 0.9% of liver transplant recipients had NRH. A total of 113 patients identified with NRH underwent liver transplantation. Most series report transplants done after the failure of endoscopic banding and TIPS management of portal hypertension. Reported 5-year graft and patient survival ranged from 73%-78% and 73%-90%. The pooled incidence of NRH after liver transplant for all indications was 2.9% and caused complications of portal hypertension. Complications related to portal hypertension secondary to NRH are a rare indication for a liver transplant. NRH can develop at any time after liver transplantation often without an identifiable cause, which may lead to portal hypertension requiring treatment or even re-transplantation.
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Affiliation(s)
- Ben E. Biesterveld
- Department of Transplant Surgery, University of Wisconsin, Madison, WI, United States
| | - Paul M. Schroder
- Department of Transplant Surgery, University of Wisconsin, Madison, WI, United States
| | | | - Alexandra Bolognese
- Division of Abdominal Organ Transplantation, Oregon Health & Science University School of Medicine, Portland, OR, United States
| | - Steven C. Kim
- Department of Surgery, Division of Transplantation, Emory University, Atlanta, GA, United States
| | - David P. Al-Adra
- Department of Transplant Surgery, University of Wisconsin, Madison, WI, United States
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Larrey D, Meunier L, Valla D, Hillaire S, Hernandez-Gea V, Dutheil D, Plessier A, Bureau C. Drug induced liver injury and vascular liver disease. Clin Res Hepatol Gastroenterol 2020; 44:471-479. [PMID: 32371005 DOI: 10.1016/j.clinre.2020.03.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/03/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Dominique Larrey
- Department of Gastroenterology and Hepatology, Saint-Éloi Hospital, University Hospital of Montpellier, 80, avenue Augustin-Fliche, 34090 Montpellier, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France.
| | - Lucy Meunier
- Department of Gastroenterology and Hepatology, Saint-Éloi Hospital, University Hospital of Montpellier, 80, avenue Augustin-Fliche, 34090 Montpellier, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Dominique Valla
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Hepatology, Beaujon Hospital, AP-HP, 100, boulevard du Général Leclerc, 92118 Clichy, France; Reference center of vascular liver diseases, European Reference Network (ERN) Rare-Liver, Clichy, France
| | - Sophie Hillaire
- Department of Internal Medicine, Foch Hospital, 40, rue Worth, 92150 Suresnes, France
| | - Virginia Hernandez-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd). Health Care Provider of the European Reference Network onRare Liver Disorders (ERN-Liver), Spain
| | - Danielle Dutheil
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Association of patients with vascular liver diseases (AMVF), Department of Hepatology, Beaujon Hospital, 100, boulevard du Général Leclerc, 92118 Clichy, France
| | - Aurélie Plessier
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Hepatology, Beaujon Hospital, AP-HP, 100, boulevard du Général Leclerc, 92118 Clichy, France; Reference center of vascular liver diseases, European Reference Network (ERN) Rare-Liver, Clichy, France
| | - Christophe Bureau
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Gastroenterology and Hepatology, Rangueil Hospital, University Hospital of Toulouse, 1, avenue du Professeur Jean-Poulhès, 31400 Toulouse, France
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Andrade RJ, Robles-Díaz M. Diagnostic and prognostic assessment of suspected drug-induced liver injury in clinical practice. Liver Int 2020; 40:6-17. [PMID: 31578817 DOI: 10.1111/liv.14271] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 09/17/2019] [Accepted: 09/19/2019] [Indexed: 02/13/2023]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a challenging liver disorder because it can present with a range of phenotypes, mimicking almost every other hepatic disease, and lacks specific biomarkers for its diagnosis. Hence, a confident DILI diagnosis is seldom possible as it relies on the precise establishment of a temporal sequence between the exposure to a given prescription drug or sometimes hidden herbal product/over the counter medication as well as the exclusion of other aetiologies of liver disease. However, an accurate diagnosis is of most importance, as prompt withdrawal of the causative agent is essential in DILI management. Indeed, DILI can be severe and even fatal or in a fraction of cases evolve to chronic damage, but specific biomarkers for predicting mortality/liver transplantation or a chronic outcome in the very early phases of DILI are not yet available. In this article, we discuss the best diagnostic and prognostic approach of a DILI suspicion by judiciously choosing and interpreting the standard tests currently used in clinical practice.
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Affiliation(s)
- Raúl J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Malaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Mercedes Robles-Díaz
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Malaga, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Ahmad AK, Atzori S, Taylor-Robinson SD, Maurice JB, Cooke GS, Garvey L. Spleen stiffness measurements using point shear wave elastography detects noncirrhotic portal hypertension in human immunodeficiency virus. Medicine (Baltimore) 2019; 98:e17961. [PMID: 31764798 PMCID: PMC6882591 DOI: 10.1097/md.0000000000017961] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
To assess the utility of spleen stiffness as a diagnostic tool in individuals with human immunodeficiency virus (HIV) and non-cirrhotic portal hypertension (NCPH).The Philips EPIQ7, a new point shearwave elastography (pSWE) technique, was used to assess liver and spleen stiffness in 3 patient groups. Group 1: HIV and NCPH (n = 11); Group 2: HIV with past didanosine (ddI) exposure without known liver disease or NCPH (n = 5); Group 3: HIV without known liver disease or ddI exposure (n = 9).Groups were matched for age, HIV chronicity, and antiretroviral treatment (including cumulative ddI exposure in Groups 1 and 2). Differences in liver and spleen stiffness (in kPa) between groups were analyzed using the Mann-Whiney U test.Liver and spleen stiffness were both significantly higher in NCPH versus ddI-exposed (P = .019 and P = .006) and ddI-unexposed controls (P = .038 and P < .001). Spleen stiffness was more effective than liver stiffness at predicting NCPH, area under receiver operating characteristic (AUROC) 0.812 versus 0.948. Combining the 2 variables improved the diagnostic performance, AUROC 0.961. The optimal cut-off for predicting NCPH using splenic stiffness was 25.4 kPa, with sensitivity 91%, specificity 93%, positive predictive value (PPV) 91%, negative predictive value (NPV) 93%, positive likelihood ratio 12.73, negative likelihood ratio 0.10. Spleen and liver stiffness scores were strongly correlated (P = .0004, 95% confidence interval [CI] 18, 59).Elevated spleen stiffness is observed in HIV with NCPH and can be quantified easily using pSWE with high diagnostic accuracy. Novel strategies such as pSWE for longitudinal monitoring of patients with HIV and NCPH should be considered.
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Affiliation(s)
| | | | | | | | - Graham S. Cooke
- Department of Infectious Diseases, Imperial College, St Mary's Hospital Campus, London W2 1PG
| | - Lucy Garvey
- Jefferiss Wing, Department of HIV Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London W2 1NY
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Can we differentiate HIV-associated obliterative portopathy from liver cirrhosis using MRI? Eur Radiol 2019; 30:213-223. [PMID: 31410601 DOI: 10.1007/s00330-019-06391-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/18/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
AIM To describe the magnetic resonance imaging (MRI) features of HIV-associated obliterative portopathy (HIV-OP) and determine the most indicative appearance of this condition on MRI by using a retrospective case-control study. METHODS MRI examinations of 24 patients with HIV-OP (16 men, 8 women; mean age = 48 ± 6.6 [SD] years; age range, 35-71 years) were analyzed by two blinded observers and compared with those obtained in 18 HIV-infected patients with hepatic cirrhosis (14 men, 4 women; mean age = 51 ± 3.4 [SD] years; age range, 35-60 years). Images were qualitatively and quantitatively analyzed with respect to imaging presentation. Comparisons were performed using uni- and multivariate analyses. RESULTS Regular liver contours had the highest accuracy for the diagnosis of HIV-OP (83%, 35 of 42; 95% confidence interval [CI], 69-93%) and was the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio, 51; 95%CI, 4.96-1272%) (p < 0.0001). At multivariate analysis, the width of segment 4 in millimeters (OR = 1.23 [95%CI, 1.05-1.44%]; p = 0.011) and the presence of regular liver contours (OR = 7.69 [95%CI, 1.48-39.92%]; p = 0.015) were the variables independently associated with the diagnosis of HIV-OP. CONCLUSIONS Regular liver contours are the most discriminating independent variable for the diagnosis of HIV-OP but have limited accuracy. Familiarity with this finding may help differentiate HIV-OP from cirrhosis in HIV-infected patients. KEY POINTS • Regular liver contour is the most discriminating independent variable for the diagnosis of HIV-OP (odds ratio = 51) with 83% accuracy. • At multivariate analysis, the width of segment 4 in millimeters and the presence of regular liver contours are the variables independently associated with the diagnosis of HIV-OP. • MRI helps diagnose HIV-OP in the presence of several categorical findings, which are more frequently observed in HIV-OP patients than in HIV patients with cirrhosis.
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Andrade RJ, Aithal GP, Björnsson ES, Kaplowitz N, Kullak-Ublick GA, Larrey D, Karlsen TH. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 2019; 70:1222-1261. [PMID: 30926241 DOI: 10.1016/j.jhep.2019.02.014] [Citation(s) in RCA: 641] [Impact Index Per Article: 106.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
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Vatsalya V, Cave MC, Kumar R, Srivastava S, Khanal S, Jenson AB, Schwandt ML, Barve SS, Ramchandani VA, McClain CJ. Alterations in Serum Zinc and Polyunsaturated Fatty Acid Concentrations in Treatment-Naive HIV-Diagnosed Alcohol-Dependent Subjects with Liver Injury. AIDS Res Hum Retroviruses 2019; 35:92-99. [PMID: 30280905 DOI: 10.1089/aid.2018.0124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Heavy alcohol drinking causes alterations in the metabolism of fatty acids and zinc that participate in inflammation and liver injury. HIV infection has been reported to cause dysregulated polyunsaturated fatty acid (PUFA) and zinc metabolism. In this pilot study, we examined the role of dysregulated PUFA metabolism and zinc deficiency in the liver injury occurring in heavy drinkers with early-stage HIV diagnosis. Fourteen heavy drinking alcohol-dependent (AD) patients [seven with treatment-naive HIV diagnosis (AD+HIV) and seven without HIV infection (AD)] participated in this study. Liver injury, serum zinc, PUFAs, viral load, CD4+ count, and drinking measures using lifetime drinking history (LTDH), and timeline follow-back past 90 days (TLFB90) were evaluated. Liver injury was also assessed in seven age- and gender-matched socially drinking HIV treatment-naive patients who served as disease controls. HIV viral load by itself did not show any correlation with liver injury. Liver enzymes were significantly elevated in both AD+HIV and AD patients, and AD+HIV patients had significantly higher alanine aminotransferase (ALT) levels than did AD patients, even with lower drinking. Serum zinc was significantly lower in AD+HIV patients. Only AD+HIV patients showed a significant elevation in linoleic acid (LA) and alpha-linoleic acid (ALA) levels. Serum zinc and ALT, LA and ALT, and ALA and ALT were significantly associated only in AD+HIV patients. The association between LA and ALT showed a higher effect than did the ALA and ALT association in the AD+HIV patients. Interestingly, AD+HIV subjects (who drank less), nevertheless, showed more liver injury compared with AD patients, who reported heavier drinking. We speculate that the underlying proinflammatory response resulting from zinc deficiency and an elevation in serum LA likely contributed to liver injury in AD+HIV patients, even with a comparatively lower degree of heavy drinking.
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Affiliation(s)
- Vatsalya Vatsalya
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Section on Human Psychopharmacology, DICBR/NIAAA, National Institutes of Health, Bethesda, Maryland
- Robley Rex VA Medical Center, Louisville, Kentucky
- University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky
| | - Matthew C. Cave
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Robley Rex VA Medical Center, Louisville, Kentucky
- University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, Kentucky
| | - Rajarshi Kumar
- Calcutta National Medical College and Hospital, West Bengal University of Health Sciences, Calcutta, India
| | - Shweta Srivastava
- Division of Cardiology, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Sujita Khanal
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky
| | - Alfred B. Jenson
- Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky
| | - Melanie L. Schwandt
- Office of Clinical Director, NIAAA, National Institutes of Health, Bethesda, Maryland
| | - Shirish S. Barve
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, Kentucky
| | - Vijay A. Ramchandani
- Section on Human Psychopharmacology, DICBR/NIAAA, National Institutes of Health, Bethesda, Maryland
| | - Craig J. McClain
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Robley Rex VA Medical Center, Louisville, Kentucky
- University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky
- Hepatobiology & Toxicology Center, University of Louisville, Louisville, Kentucky
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Abstract
Drug-induced liver injury (DILI) occurs in a small fraction of individuals exposed to drugs, herbs or dietary supplements and is a relatively rare diagnosis compared with other liver disorders. DILI can be serious, resulting in hospitalization and even life-threatening liver failure, death or need for liver transplantation. Toxic liver damage usually presents as an acute hepatitis viral-like syndrome or as an acute cholestasis that resolves upon drug discontinuation. However, un-resolving chronic outcome after acute DILI can ensue in some subjects, the mechanisms and risk factors for this particular evolution being yet scarcely known. Furthermore, the definition of chronicity after acute DILI is controversial, regarding both the time frame of liver injury persistence and the magnitude of the abnormalities required. Besides this, in some instances the phenotypes and pathological manifestations are those of chronic liver disease at the time of DILI diagnosis. These include non-alcoholic fatty liver disease, vascular lesions, drug-induced autoimmune hepatitis, chronic cholestasis leading to vanishing bile duct syndrome and even cirrhosis, and some drugs such as amiodarone or methotrexate have been frequently implicated in some of these forms of chronic DILI. In addition, all of these DILI phenotypes can be indistinguishable from those related to other etiologies, making the diagnosis particularly challenging. In this manuscript we have critically reviewed the more recent data on chronicity in DILI with a particular focus on the epidemiology, mechanisms and risk factors of atypical chronic DILI phenotypes.
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Affiliation(s)
- Aida Ortega-Alonso
- Digestive Diseases Unit, Institute of Biomedical Research of Malaga (IBIMA), Virgen de la Victoria University Hospital, University of Malaga, Malaga, Center of Biomedical Research Network of Liver and Digestive Diseases (CIBERehd), Madrid, Spain
| | - Raúl J Andrade
- Digestive Diseases Unit, Institute of Biomedical Research of Malaga (IBIMA), Virgen de la Victoria University Hospital, University of Malaga, Malaga, Center of Biomedical Research Network of Liver and Digestive Diseases (CIBERehd), Madrid, Spain
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Logan S, Rodger A, Maynard-Smith L, O’Beirne J, Fernandez T, Ferro F, Smith C, Bhagani S. Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to Didanosine: A cross sectional study. World J Hepatol 2016; 8:1623-1628. [PMID: 28083085 PMCID: PMC5192554 DOI: 10.4254/wjh.v8.i36.1623] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/16/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV) positive patients.
METHODS Patients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography (TE). Those with alanine transaminase (ALT) above upper limit normal and/or TE > 7.65 kPa underwent ultrasound scan (U/S). Patients with: (1) abnormal U/S; or (2) elevated ALT plus TE > 7.65 kPa; or (3) TE > 9.4 kPa were offered trans-jugular liver biopsy (TJLB) with hepatic venous pressure gradient (HVPG) assessment.
RESULTS Ninety-nine patients were recruited, median age 50 years (range 31-70), 81% male and 70% men who have sex with men. Ninety-five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years (range 0.5-14.6). Eighty-one had a valid TE readings (interquartile range/score ratio < 0.3): 71 (88%) < 7.65 kPa, 6 (7%) 7.65-9.4 kPa and 4 (6%) > 9.4 kPa. Seventeen (17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mmHg. Commonest histological findings were steatosis (n = 6), normal architecture (n = 4) and NRH (n = 2), giving a prevalence of previously undiagnosed NRH of 2% (95%CI: 0.55%, 7.0%).
CONCLUSION A screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population.
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Natural history of liver disease and effect of hepatitis C virus on HIV disease progression. Curr Opin HIV AIDS 2016; 10:303-8. [PMID: 26248118 DOI: 10.1097/coh.0000000000000187] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Due to high prevalence rates, the hepatitis C virus (HCV) and the HIV cause two viral infections of global importance. Shared routes of transmission lead to a high number of dually infected individuals especially in specific populations such as intravenous drug users or people from highly endemic regions for both viruses. Treatment progress made in the field of HIV in the past three decades diminished the number of HIV patients who die from opportunistic infections and enabled a rise of HCV-associated liver disease in the HIV-HCV-coinfected population. RECENT FINDINGS An HIV-HCV coinfection is mainly characterized by a faster progression to liver cirrhosis that may lead to hepatic decompensation or the development of hepatocellular carcinoma (HCC). The treatment of HIV with highly active antiretroviral therapy (HAART) may only partly reverse this effect by the restoration of the immune system. Although no clear deleterious effect of HCV on the course of HIV infection is described, an increased HIV-associated and non-HIV-associated mortality has been described in patients not cured from their HCV infection. SUMMARY In this article, we review the latest knowledge on the natural course of HCV in the HIV-infected population, the role of HIV treatment, and the possible effects of HCV on HIV disease progression.
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Hollande C, Mallet V, Darbeda S, Vallet-Pichard A, Fontaine H, Verkarre V, Sogni P, Terris B, Gouya H, Pol S. Impact of Obliterative Portal Venopathy Associated With Human Immunodeficiency Virus. Medicine (Baltimore) 2016; 95:e3081. [PMID: 26986141 PMCID: PMC4839922 DOI: 10.1097/md.0000000000003081] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
HIV-associated obstructive portopathy (HIVOP) is an obstruction of the hepatic microvasculature of unknown origin. The purpose of this study was to describe the clinical and paraclinical presentation of the disease and its impact in terms of morbidity. Twenty-nine HIV1-infected patients (average 12 years of infection, nadir of CD4 210/mm, including 7 patients with a history of opportunistic infection) with a biopsy-proven or likely HIVOP have been followed up for an average of 6.1 years. Modes of revelation of the HIVOP were: cytolysis and/or cholestasis (60%), occult (14%) or symptomatic (37%) portal hypertension (esophageal varices 17%, ascites 10%, cytopenia 10%), or fortuitous (8%). Hypoalbuminemia (≤35 g/L) was present in (31%), thrombocytopenia (<150,000 platelets) in 52% and prothrombin rate <70% in 10%. Esophageal varices were detected in 71%. Thrombophilia was present in 23 patients (80%): in head, protein S deficiency (87%). MRI showed in 82% at least 1 morphological abnormality. The average value of the liver stiffness by Fibroscan was 8.3 kPa. During follow-up, there was no radiological improvement, 15 (52%) patients presented with variceal hemorrhage, 10 patients (34%) ascites, 10 (34%) portal vein thrombosis, 7 (24%) an iron deficiency, and 2 (7%) with a protein-losing enteropathy, including 14 patients (48%) with several events. Four patients (14%) were transplanted, 1 (25%) recurred the HIVOP on the graft, and 1 patient is waiting for a transplant. HIVOP is a severe disease associated with high morbidity related to symptomatic portal hypertension, which occurred in 50% and required liver transplantation in 14%.
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Affiliation(s)
- Clémence Hollande
- From the Institut Pasteur, Inserm unit U818, Paris, France; Paris Descartes University, Paris, France (CH), AP-HP, Cochin Port-Royal hospital, Liver unit, Paris, France; Cochin Institute, Paris Descartes University, Sorbonne Paris Cité, Paris, France (VM), Paris-Saclay University, Paris Sud University, CESP, Inserm URM 1178, Villejuif, France; University Pierre et Marie Curie, Paris, France; AP-HP, Beaujon Hospital, Department of Psychiatry and Addictive Medicine, Clichy, France (SD); AP-HP, Cochin Port-Royal hospital, Liver unit, Paris, France (AVP, HF, PS); AP-HP, Necker Enfants Malades hospital, Pathology unit, Paris, France (VV); AP-HP, Cochin Port-Royal hospital, Pathology Unit, Paris, France (BT); AP-HP, Cochin Port-Royal hospital, Radiology Unit, Paris, France (HG); and AP-HP, Cochin Port-Royal hospital, Liver Unit, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Paris, France; Institut Pasteur, Inserm unit UMS 20 and U818, Paris, France (SP)
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Joshi D, Agarwal K. Role of liver transplantation in human immunodeficiency virus positive patients. World J Gastroenterol 2015; 21:12311-12321. [PMID: 26604639 PMCID: PMC4649115 DOI: 10.3748/wjg.v21.i43.12311] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 08/04/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
End-stage liver disease (ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus (HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus (HCV) infection, drug-induced hepatotoxicity related to combined anti-retro-viral therapy, alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore, anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However, HIV-HCV co-infection transplant outcomes remain suboptimal due to recurrence. In this article, we review the key challenges faced by this patient cohort in the pre- and post-transplant period.
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Stine JG, Chalasani N. Chronic liver injury induced by drugs: a systematic review. Liver Int 2015; 35:2343-53. [PMID: 26346512 DOI: 10.1111/liv.12958] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/11/2015] [Indexed: 12/12/2022]
Abstract
To examine the available literature and summarize what is known about chronic drug-induced liver injury. We reviewed PubMed/MEDLINE through March 2015. We developed a MEDLINE search strategy using PubMed medical subject heading terms chronic liver injury, hepatotoxicity, drug-induced liver injury, cirrhosis and chronic liver disease. We reviewed the reference list of included articles to identify articles missed in the database search. Chronic liver injury from drugs is more common than once thought with prevalence as high as 18% based on large national registries. Patients with cholestatic injury, age ≤65 years, and a long latency period (>365 days) are at increased risk. Of the most common drugs associated with drug-induced liver injury, antibiotics (amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin) are most likely to cause chronic injury. The presence of autoantibodies is common with chronic DILI, however, it is not diagnostic nor is it specific to autoimmune-like drug-induced liver injury. Immunosuppressive therapy may be necessary for individual cases of autoimmune-like drug-induced liver injury where cessation of the drug alone does not result in resolution of injury, however, the lowest dose should be used for the shortest duration with careful attention to the development of side effects. The effectiveness of treament of cholestatic liver injury with corticosteroids or ursodiol remains unclear. Cases of drug-induced fatty liver, nodular regenerative hyperplasia and peliosis hepatitis are less common subtypes of chronic drug-induced liver injury that deserve special consideration. A high degree of clinical suspicion is required for the diagnosis of chronic drug-induced liver injury and should be suspected in any patient with liver associated enzyme abnormalities that persist out past 6 months of initial presentation. Treatment with drug removal and/or immunosuppressive therapy appears to be effective for the majority of cases. More study into pharmacogenomics and personalized medicine may aid in predicting which patients will go on to develop chronic drug-induced liver injury.
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Affiliation(s)
- Jonathan G Stine
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Naga Chalasani
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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Schouten JNL, Verheij J, Seijo S. Idiopathic non-cirrhotic portal hypertension: a review. Orphanet J Rare Dis 2015; 10:67. [PMID: 26025214 PMCID: PMC4457997 DOI: 10.1186/s13023-015-0288-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 05/20/2015] [Indexed: 02/07/2023] Open
Abstract
Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease characterized of intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis. The etiology of INCPH can be classified in five categories: 1) immunological disorders (i.e. association with common variable immunodeficiency syndrome, connective tissue diseases, Crohn’s disease, etc.), 2) chronic infections, 3) exposure to medications or toxins (e.g. azathioprine, 6- thioguanine, arsenic), 4) genetic predisposition (i.e. familial aggregation and association with Adams-Oliver syndrome and Turner disease) and 5) prothrombotic conditions (e.g. inherited thrombophilias myeloproliferative neoplasm antiphospholipid syndrome). Roughly, INCPH diagnosis is based on clinical criteria and the formal exclusion of any other causes of portal hypertension. A formal diagnosis is based on the following criteria: 1) presence of unequivocal signs of portal hypertension, 2) absence of cirrhosis, advanced fibrosis or other causes of chronic liver diseases, and 3) absence of thrombosis of the hepatic veins or of the portal vein at imaging. Patients with INCPH usually present with signs or symptoms of portal hypertension such as gastro-esophageal varices, variceal bleeding or splenomegaly. Ascites and/or liver failure can occur in the context of precipitating factors. The development of portal vein thrombosis is common. Survival is manly limited by concomitant disorders. Currently, treatment of INCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied aimed to modify the natural history of the disease. Anticoagulation therapy can be considered in patients who develop portal vein thrombosis.
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Affiliation(s)
- Jeoffrey N L Schouten
- Department of Gastroenterology, University Hospital Ghent, De Pintelaan 185, Ghent, Belgium.
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
| | - Susana Seijo
- Department of Medicine, CTO, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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[Noncirrhotic portal hypertension in a human immunodeficiency virus (HIV) infected adolescent]. REVISTA PAULISTA DE PEDIATRIA 2015; 33:246-50. [PMID: 25913495 PMCID: PMC4516380 DOI: 10.1016/j.rpped.2014.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 09/16/2014] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To alert the pediatrician who is following up HIV-infected patients about the possibility of non-cirrhotic portal hypertension (NCPH) in this period of life, in order to avoid the catastrophic consequences of this disease as bleeding esophageal varices. CASE DESCRIPTION A 13 years old HIV-infected patient by vertical route was receiving didanosine (ddI) for 12 years. Although the HIV viral load had been undetectable for 12 years, this patient showed gradual decrease of CD4+ T cells, prolonged thrombocytopenia and high alkaline phosphatase. Physical examination detected splenomegaly, which triggered the investigation that led to the diagnosis of severe liver fibrosis by transient elastography, probably due to hepatic toxicity by prolonged use of ddI. COMMENTS This is the first case of NCPH in HIV-infected adolescent described in Brazil. Although, the NCPH is a rare disease entity in seropositive patients in the pediatric age group, it should be investigated in patients on long-term ddI or presenting clinical and laboratories indicators of portal hypertension, as splenomegaly, thrombocytopenia and increased alkaline phosphatase.
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Abstract
There are an estimated 40 million HIV infected individuals worldwide, with chronic liver disease being the 2nd leading cause of mortality in this population. Elevated liver functions are commonly noted in HIV patients and the etiologies are varied. Viral hepatitis B and C, fatty liver and drug induced liver injury are more common. Treatment options for viral hepatitis C are rapidly evolving and are promising, but treatments are limited for the other conditions and is primarily supportive. Opportunistic infections of the liver are now uncommon. Irrespective of etiology, management requires referral to specialized centers and with due diligence mortality can be reduced.
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Haubrich R, Soriano V, Lafeuillade A. Statements from the 15th International Symposium on HIV and Emerging Infectious Diseases (ISHEID), Toulon, France, May 28–30, 2008. HIV CLINICAL TRIALS 2015; 9:348-65. [DOI: 10.1310/hct0905-348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Soriano V, Peters M, Rockstroh J. Fourth HIV & Hepatitis Coinfection Workshop; June 19–21, 2008; Madrid, Spain. HIV CLINICAL TRIALS 2015. [DOI: 10.1310/hct1001-52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Barreiro P, Fernández-Montero JV, de Mendoza C, Labarga P, Soriano V. Pharmacogenetics of antiretroviral therapy. Expert Opin Drug Metab Toxicol 2014; 10:1119-30. [DOI: 10.1517/17425255.2014.930128] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Abstract
Liver disease is currently one of the leading causes of hospitalization and death in HIV-positive individuals. Coinfection with the hepatitis C virus (HCV) is a major contributor to this trend. Besides hepatic damage, which is enhanced in the presence of HIV-associated immunosuppression, HCV may contribute to disease in coinfected individuals by potentiating immune activation and chronic inflammation, which ultimately account for an increased risk of cardiovascular events, kidney disease, and cancers in this population. Fortunately, hepatitis C therapeutics has entered a revolutionary era in which we hope that most patients treated with the new oral direct-acting antivirals (DAA) will be cured. However, many challenges preclude envisioning a prompt elimination of HCV from the coinfected population. Issues that should be addressed include the following: (1) rising incidence of acute hepatitis C in men who have sex with men, and expansion/recrudescence of injection drug use in some settings/regions; (2) adverse drug interactions between antiretrovirals and DAA; and (3) high cost of DAA, which may lead many to defer or fail to access appropriate therapy.
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Agrawal M, Rahmani R, Nakkala K, Fiel MI, Schiano T. Hepatoportal sclerosis (obliterative portal venopathy) and nodular regenerative hyperplasia in a patient with myasthenia gravis: A case report and review of the published work. Hepatol Res 2013; 43:999-1003. [PMID: 23675894 DOI: 10.1111/hepr.12045] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Revised: 11/29/2012] [Accepted: 12/13/2012] [Indexed: 12/14/2022]
Abstract
Nodular regenerative hyperplasia (NRH) and hepatoportal sclerosis, also known as obliterative portal venopathy (OPV), are two causes of non-cirrhotic portal hypertension (NCPH). NCPH is an increasingly recognized entity that can be seen in association with collagen vascular diseases and with the use of medications such as azathioprine and didanosine, but oftentimes the etiology remains unidentified. We herein report a case of NCPH occurring due to OPV and NRH in a 64-year-old woman with myasthenia gravis (MG), status post-thymectomy. Portal hypertension was diagnosed incidentally on computed tomography in the absence of predisposing factors. Extensive work-up to determine the etiology of any underlying liver disease was unrevealing. NRH and OPV were identified on liver biopsy. Subsequently, the patient had variceal bleeding that necessitated transjugular intrahepatic portosystemic shunt placement. A few similar cases of NCPH occurring in the setting of MG have been previously reported, suggesting that the immunological mechanisms involved in the pathogenesis of myasthenia may also have contributed to the development of NCPH.
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Affiliation(s)
- Manasi Agrawal
- Department of Internal Medicine, Division of Gastroenterology, Maimonides Medical Center, Brooklyn
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Parikh ND, Martel-Laferriere V, Kushner T, Childs K, Vachon ML, Dronamraju D, Taylor C, Fiel MI, Schiano T, Nelson M, Agarwal K, Dieterich DT. Clinical factors that predict noncirrhotic portal hypertension in HIV-infected patients: a proposed diagnostic algorithm. J Infect Dis 2013; 209:734-8. [PMID: 23911709 DOI: 10.1093/infdis/jit412] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Noncirrhotic portal hypertension (NCPH) is a rare but important clinical entity in human immunodeficiency virus (HIV) populations. The purpose of this study was to describe the clinical factors associated with the condition in an effort to formulate a diagnostic algorithm for easy and early diagnosis. We performed a multicenter, retrospective case-control study of 34 patients with NCPH and 68 control HIV patients. The study found that thrombocytopenia, splenomegaly, didanosine use, elevated aminotransferases, and an elevated alkaline phosphatase level were all significantly more prevalent in the NCPH cohort. Using these easily available clinical parameters, we developed an algorithm for early diagnosis of NCPH in HIV.
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Affiliation(s)
- Neil D Parikh
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Incidence of liver damage of uncertain origin in HIV patients not co-infected with HCV/HBV. PLoS One 2013; 8:e68953. [PMID: 23874824 PMCID: PMC3715524 DOI: 10.1371/journal.pone.0068953] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 06/07/2013] [Indexed: 01/04/2023] Open
Abstract
Background and Aims Several studies have reported that a significant number of HIV patients not co-infected with HCV/HBV develop liver damage of uncertain origin (LDUO). The objective of our study was to evaluate the incidence of and risk factors for the development of LDUO in HIV infected patients not co-infected with HCV/HBV. Methods Prospective longitudinal study that included HIV-infected patients free of previous liver damage and viral hepatitis B or C co-infections. Patients were followed up at 6-monthly intervals. Liver stiffness was measured at each visit. Abnormal liver stiffness (ALS) was defined as a liver stiffness value greater than 7.2 kPa at two consecutive measurements. For patients who developed ALS, a protocol was followed to diagnose the cause of liver damage. Those patients who could not be diagnosed with any specific cause of liver disease were diagnosed as LDUO and liver biopsy was proposed. Results 210 patients matched the inclusion criteria and were included. 198 patients completed the study. After a median (Q1–Q3) follow-up of 18 (IQR 12–26) months, 21 patients (10.6%) developed ALS. Of these, fifteen patients were diagnosed as LDUO. The incidence of LDUO was 7.64 cases/100 patient-years. Histological studies were performed on ten (66.6%) patients and all showed liver steatosis. A higher HOMA-IR value and body mass index were independently associated with the development of LDUO. Conclusion We found a high incidence of LDUO in HIV-infected patients associated with metabolic risk factors. The leading cause of LDUO in our study was non-alcoholic fatty liver disease.
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Verheij J, Schouten JNL, Komuta M, Nevens F, Hansen BE, Janssen HLA, Roskams T. Histological features in western patients with idiopathic non-cirrhotic portal hypertension. Histopathology 2013; 62:1083-91. [PMID: 23600724 DOI: 10.1111/his.12114] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 02/17/2013] [Indexed: 12/13/2022]
Abstract
AIMS In the western world, idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease. This study aimed to investigate the histopathological features in western INCPH patients and to assess pathological differences between liver specimens of INCPH with and without HIV. METHODS AND RESULTS Biopsies of 70 INCPH patients (of which 15 were HIV-infected) were compared to 23 patients with non-cirrhotic portal vein thrombosis (PVT), which served as a control group for non-cirrhotic portal hypertension. Phlebosclerosis, nodular regeneration (NR), sinusoidal dilatation, paraportal shunting vessels, perisinusoidal fibrosis and portal tract remnants were the most prevalent morphological features of INCPH. There were significant (P < 0.01) morphological differences between INCPH and PVT liver specimens with regard to portal tract remnants (46% versus 0%), phlebosclerosis (95% versus 65%), portal vein dilatation (34% versus 78%) and NR (56% versus 22%). The degree of NR correlated with the severity of phlebosclerosis (P < 0.01). NR was seen more frequently in the HIV-INCPH group, compared to the non-HIV-infected patients (P < 0.001). CONCLUSION Portal tract remnants, phlebosclerosis and nodular regeneration are typical features of INCPH. Sinusoidal dilatation, paraportal shunting vessels and increased portal and parenchymal vessels might represent pressure-related morphological signs of portal hypertension. Finally, more nodular regeneration was observed in HIV-associated INCPH.
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Affiliation(s)
- Joanne Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
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Vispo E, Cevik M, Rockstroh JK, Barreiro P, Nelson M, Scourfield A, Boesecke C, Wasmuth JC, Soriano V. Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients. Clin Infect Dis 2013; 56:1117-22. [PMID: 23315321 DOI: 10.1093/cid/cit001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Noncirrhotic portal hypertension (NCPH) is a rare but potentially life-threatening complication in patients with human immunodeficiency virus (HIV). Cases of NCPH have been reported in HIV-negative individuals as result of treatment with thiopurines for leukemia or inflammatory bowel disease. Exposure to didanosine, which is also a purine analogue, predisposes to NCPH in the HIV setting. However, it is unclear why NCPH only develops in a small subset of didanosine-treated patients. METHODS A multicenter, case-control study was conducted to investigate the role of pharmacogenomics in NCPH in HIV patients with prior didanosine exposure. Three controls were chosen for each case, adjusted for sex, age, CD4 counts, plasma HIV-RNA, and site. Tagging 36 single-nucleotide polymorphisms (SNPs) at enzymes involved in the purine metabolism (inosine triphosphatase, 5'-nucleotidase cytosolic-II, purine nucleoside phosphorylase and xanthine oxidase) was performed using SNPlex microarray technology. RESULTS Eighty individuals were examined; 22 with NCPH and 58 matched controls. Two SNPs at the 5'-nucleotidase gene were associated with NCPH: rs11191561 (48% CG/GG vs 17% CC; P=.003) and rs11598702 (40% CC/CT vs 9% TT; P=.003). SNPs at another 2 loci at the xanthine oxidase gene were also associated with NCPH: rs1429376 (71% AA vs 23% CC/AC; P=.015) and rs1594160 (71% AA vs 23% CC/AC; P=.015). There was a cumulative risk of NCPH for these 4 SNPs: 7%, 26%, 42%, 50%, and 100%, respectively, for 0, 1, 2, 3, or all SNPs (P=.001). CONCLUSIONS SNPs at the 5'-nucleotidase and xanthine oxidase genes influence the risk of NCPH in HIV patients treated with didanosine.
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Affiliation(s)
- Eugenia Vispo
- Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain
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Schouten JNL, Van der Ende ME, Koëter T, Rossing HHM, Komuta M, Verheij J, van der Valk M, Hansen BE, Janssen HLA. Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension. Aliment Pharmacol Ther 2012; 36:875-85. [PMID: 22971050 DOI: 10.1111/apt.12049] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 08/15/2012] [Accepted: 08/27/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection. AIM To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome. METHODS All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case–control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed. RESULTS On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3–2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1–19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2–22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003). CONCLUSIONS HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation
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Affiliation(s)
- J N L Schouten
- Department of Gastroenterology Hepatology, University Hospital Rotterdam, Rotterdam, the Netherlands
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Kovari H, Sabin CA, Ledergerber B, Ryom L, Worm SW, Smith C, Phillips A, Reiss P, Fontas E, Petoumenos K, De Wit S, Morlat P, Lundgren JD, Weber R. Antiretroviral drug-related liver mortality among HIV-positive persons in the absence of hepatitis B or C virus coinfection: the data collection on adverse events of anti-HIV drugs study. Clin Infect Dis 2012; 56:870-9. [PMID: 23090925 DOI: 10.1093/cid/cis919] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Liver diseases are the leading causes of death in human immunodeficiency virus (HIV)-positive persons since the widespread use of combination antiretroviral treatment (cART). Most of these deaths are due to hepatitis C (HCV) or B (HBV) virus coinfections. Little is known about other causes. Prolonged exposure to some antiretroviral drugs might increase hepatic mortality. METHODS All patients in the Data Collection on Adverse Events of Anti-HIV Drugs study without HCV or HBV coinfection were prospectively followed from date of entry until death or last follow-up. In patients with liver-related death, clinical charts were reviewed using a structured questionnaire. RESULTS We followed 22 910 participants without hepatitis virus coinfection for 114 478 person-years. There were 12 liver-related deaths (incidence, 0.10/1000 person-years); 7 due to severe alcohol use and 5 due to established ART-related toxicity. The rate of ART-related deaths in treatment-experienced persons was 0.04/1000 person-years (95% confidence interval, .01, .10). CONCLUSIONS We found a low incidence of liver-related deaths in HIV-infected persons without HCV or HBV coinfection. Liver-related mortality because of ART-related toxicity was rare.
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Affiliation(s)
- Helen Kovari
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland.
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Suárez-Zarracina T, Valle-Garay E, Collazos J, Montes AH, Cárcaba V, Carton JA, Asensi V. Didanosine (ddI) associates with increased liver fibrosis in adult HIV-HCV coinfected patients. J Viral Hepat 2012; 19:685-93. [PMID: 22967099 DOI: 10.1111/j.1365-2893.2012.01596.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The role of exposure to antiretrovirals (ARV) and serum matrix metalloproteases (MMPs) on liver fibrosis (LF) progression in human immunodeficiency virus (HIV) mono or HIV- hepatitis C virus (HCV) coinfection is unclear. Thus, 213 Caucasian adult HIV-infected patients were studied, 111 of whom had HCV-coinfection and 68 were HCV-monoinfected. Patients with ethanol consumption >50 g/day, hepatitis B coinfection, non-infective liver diseases or HAART adherence <75% were excluded. LF was assessed by transient elastometry (TE, Fibroscan). Serum levels of MMPs (MMP -1,-2,-3,-8,-9,-10 and -13) and their tissue inhibitors (TIMP-1,-2 and -4) were measured by ELISA microarrays. Associations with LF were statistically analysed. Protease inhibitors, usually administered to patients with advanced LF were excluded from the analysis. Increased LF was significantly associated with d4T (P = 0.006) and didanosine (ddI) use (P = 0.007), months on d4T (P = 0.001) and on ARV (P = 0.025), duration of HIV (P < 0.0001) and HCV infections (P < 0.0001), higher HIV (P = 0.03) and HCV loads (P < 0.0001), presence of lipodystrophy (P = 0.02), male gender (P = 0.02), older age (P = 0.04), low nadir (P = 0.02) and current CD4(+) T-cells (P < 0.0001), low gain of CD4(+) T-cells after HAART (P = 0.01) and higher MMP-2 (P = 0.02) and TIMP-2 serum levels (P = 0.02). By logistic regression the only variables significantly associated with increased LF were: use of ddI (OR 8.77, 95% CI: 2.36-32.26; P = 0.005), male gender (OR 7.75, 95% CI: 2.33-25.64, P = 0.0008), HCV viral load (in log) (OR 3.53, 95% CI: 2.16-5.77; P < 0.0001) and age (in years) (OR 1.21, 95% CI: 1.09-1.34, P = 0.0003). We conclude that only higher HCV viral load, older age, male gender, and use of ddI associated independently with increased LF in our study.
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Affiliation(s)
- T Suárez-Zarracina
- Infectious Diseases-HIV Unit, Hospital Universitario Central de Asturias, Oviedo University School of Medicine, Oviedo, Spain
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Liver injury in HIV monoinfected patients: should we turn a blind eye to it? Clin Res Hepatol Gastroenterol 2012; 36:441-7. [PMID: 23079114 DOI: 10.1016/j.clinre.2012.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 06/03/2012] [Accepted: 06/06/2012] [Indexed: 02/04/2023]
Abstract
With the advent of combined antiretroviral therapies, liver diseases have emerged as a key issue in the management of HIV infection. In addition to hepatitis co-infection, a large spectrum of liver diseases can affect the prognosis of HIV infection. Acute or progressive hepatic injuries require an accurate diagnosis for a better clinical management. Here, we provide an overview of the main liver diseases associated with HIV infection, which are not covered by the widely documented field of viral hepatitis co-infection.
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32
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Splenomegaly and variceal bleeding in a ten-year-old HIV-infected girl with noncirrhotic portal hypertension. Pediatr Infect Dis J 2012; 31:1059-60. [PMID: 22828640 DOI: 10.1097/inf.0b013e3182694126] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Noncirrhotic portal hypertension is an uncommon liver disease of unknown origin, increasingly described in HIV-infected adults. Prolonged antiretroviral exposure, in particular to didanosine, and thrombophilic predisposition have been suggested as potential pathogenic factors. Data are limited in children. We describe a 10-year-old HIV-infected girl with noncirrhotic portal hypertension who presented with progressive spleen enlargement and variceal bleeding.
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33
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Santiago I, Vilgrain V, Cipriano MA, Oliveira C, Ferreira M, Reis D. Case 183: Obliterative portal venopathy. Radiology 2012; 264:297-302. [PMID: 22723566 DOI: 10.1148/radiol.12110585] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Inês Santiago
- Department of Radiology, Hospital Infante D. Pedro E.P.E., Aveiro, Portugal.
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34
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Jackson BD, Doyle JS, Hoy JF, Roberts SK, Colman J, Hellard ME, Sasadeusz JJ, Iser DM. Non-cirrhotic portal hypertension in HIV mono-infected patients. J Gastroenterol Hepatol 2012; 27:1512-9. [PMID: 22497527 DOI: 10.1111/j.1440-1746.2012.07148.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Unexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co-infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono-infected patients with evidence of non-cirrhotic portal hypertension. METHODS HIV-infected patients with evidence of portal hypertension who were anti-HBV and anti-HCV negative and HBV and HCV RNA polymerase chain reaction (PCR) negative were identified from patients managed by the Victorian statewide HIV referral service located at The Alfred Hospital, Melbourne. Portal hypertension was defined as either radiological or endoscopic evidence of varices, portal vein flow obstruction, or elevated hepatic venous pressure gradient (HPVG). RESULTS Five patients were found to have portal hypertension. These patients were male, aged 41 to 65 years, with known duration of HIV infection between 11 to 25 years. All had been treated with antiretroviral therapy, including didanosine. Tests for metabolic, autoimmune, and hereditary causes of liver disease failed to establish an etiology for the liver injury. All had radiological or endoscopic findings of varices, and four patients had radiological features of portal vein obstruction or flow reversal. Only one patient underwent HPVG measurement, which was elevated. Non-invasive fibrosis assessment revealed increased liver stiffness in three (out of four) patients, and no cirrhotic features were found on those who underwent liver biopsy. CONCLUSIONS To our knowledge, this is the largest published series of non-cirrhotic portal hypertension in HIV mono-infected patients in Australia. Further research is needed to understand what relationship, if any, HIV or its treatments might have on liver injury over time.
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Affiliation(s)
- Belinda D Jackson
- Department of Gastroenterology, The Alfred Hospital Infectious Diseases Unit, The Alfred Hospital, Australia
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35
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Glatard AS, Hillaire S, d'Assignies G, Cazals-Hatem D, Plessier A, Valla DC, Vilgrain V. Obliterative portal venopathy: findings at CT imaging. Radiology 2012; 263:741-50. [PMID: 22474672 DOI: 10.1148/radiol.12111785] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE To retrospectively analyze the computed tomographic (CT) findings in a single-center series of adult patients with biopsy-proved obliterative portal venopathy (OPV) and to compare them with those observed in patients with cirrhosis. MATERIALS AND METHODS The requirement for informed consent was waived. This institutional review board-approved study included 42 consecutive patients with a histologically proved diagnosis of OPV who underwent CT at diagnosis. The clinical characteristics at diagnosis were recorded, and CT examination results were reviewed. Two radiologists evaluated portal vein patency and intrahepatic portal branches, the morphologic changes in the liver, the presence of hepatic nodules, and signs of portal hypertension in consensus. The control group consisted of 42 patients who had histologically proved cirrhosis. CT findings were compared between the OPV patient group and the cirrhotic group and also among the conditions associated with patients with OPV. The Fisher exact test was used. P values of .05 or less were considered to indicate significant differences. RESULTS The following CT findings were observed significantly more frequently in OPV than in cirrhosis: extrahepatic portal vein thrombosis (18 [43%] of 42 vs five [12%] of 42); intrahepatic portal abnormalities (18 [58%] of 31 vs one [2%] of 42) such as reduced caliber, occlusive thrombosis, and lack of visibility; focal nodular hyperplasia-like nodules (six [14%] of 42 vs 0 [0%] of 42); and perfusion disorders (15 [36%] of 42 vs six [14%] of 42). Conversely, the combination of hypertrophy of the caudate lobe and atrophy of segment IV (27 [64%] of 42 vs 10 [24%] of 42) and nodular surface (37 [88%] of 42 vs seven [17%] of 42) were seen significantly more often in cirrhosis. CONCLUSION Characteristic CT findings in patients with OPV that differ from those in patients with cirrhosis were shown, the most common being the presence of intra- or extrahepatic portal abnormalities.
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Affiliation(s)
- Anne-Sophie Glatard
- Department of Radiology, Assistance-Publique Hôpitaux de Paris, APHP, Hôpital Beaujon, 100 bd du Général Leclerc, 92110 Clichy, France
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36
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Crane M, Iser D, Lewin SR. Human immunodeficiency virus infection and the liver. World J Hepatol 2012; 4:91-8. [PMID: 22489261 PMCID: PMC3321495 DOI: 10.4254/wjh.v4.i3.91] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 11/04/2011] [Accepted: 03/17/2012] [Indexed: 02/06/2023] Open
Abstract
Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non-alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries.
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Affiliation(s)
- Megan Crane
- Megan Crane, Sharon R Lewin, Department of Medicine, Monash University, Melbourne 3004, Australia
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37
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Manzia TM, Gravante G, Di Paolo D, Orlando G, Toti L, Bellini MI, Ciano P, Angelico M, Tisone G. Liver transplantation for the treatment of nodular regenerative hyperplasia. Dig Liver Dis 2011; 43:929-934. [PMID: 21601542 DOI: 10.1016/j.dld.2011.04.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 03/28/2011] [Accepted: 04/04/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND Nodular regenerative hyperplasia (NRH) is the leading cause of non-cirrhotic portal hypertension in Western countries. Although some patients are successfully managed medically or with shunting procedures, others require liver transplantation. The aim of this review was to assess the overall results obtained with liver transplantation and to better define its role in this setting. METHODS Systematic review of all published studies on liver transplantation for NRH without language restrictions, in Medline, Embase and Cochrane Library databases through March 2010. RESULTS 17 studies including a total of 73 patients were identified; 47 (64.3%) were excluded due to lacking inclusion criteria or clinical data and 26 (35.7%) were analysed. Before liver transplantation, the most frequent clinical presentation was gastroesophageal bleeding (65.3%) followed by ascites (61.5%), hepatic encephalopathy (30.7%) and liver failure (11.5%). The mean follow-up reported after liver transplantation was 30.6±27.6 months and patient and graft survival rate was 78.3%. Only one case reported a NRH recurrence 7 years after liver transplantation (LT). CONCLUSIONS Although there are no hard data supporting the role of liver transplantation in symptomatic NRH, onset of severe portal hypertension in this setting may represent a valid indication.
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38
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Scourfield A, Waters L, Holmes P, Panos G, Randell P, Jackson A, Mandalia S, Gazzard B, Nelson M. Non-cirrhotic portal hypertension in HIV-infected individuals. Int J STD AIDS 2011; 22:324-8. [PMID: 21680667 DOI: 10.1258/ijsa.2010.010396] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Non-cirrhotic portal hypertension (NCPH) has been associated with didanosine (ddI) exposure. We aimed to determine the number of individuals with NCPH within our cohort and define their characteristics. We identified individuals within our cohort with NCPH and performed a retrospective case note review. Cumulative antiretroviral therapy (ART) use was calculated and a statistical analysis performed to compare exposure to the rest of the clinic cohort for the same time period. Where available, data was collated on FibroScan®, echocardiography and coagulation profile. Seventeen patients were identified. Upper gastrointestinal bleeding was the most common presenting feature. Liver biopsy showed mild portal or periportal fibrosis in 13 (81%) and four with features of nodular regenerative hyperplasia. There was significantly greater exposure to ddl in this group (59.5 months) compared to the rest of the HIV cohort (21.1 months) P = <0.001. Eleven subjects has a liver elastography performed, six (55%) had a result greater than 9.6 kPa (consistent with greater than F2 disease by Metavir scoring). Echocardiography was performed in seven patients: four met criteria for pulmonary hypertension. This is consistent with other cohorts demonstrating an association between the didanosine exposure and NCPH. Our data also suggest an increased risk of pulmonary hypertension.
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Affiliation(s)
- A Scourfield
- Department of HIV Medicine, Chelsea and Westminster Hospital, London, UK.
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39
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Francoz C, Belghiti J, Castaing D, Chazouillères O, Duclos-Vallée JC, Duvoux C, Lerut J, Le Treut YP, Moreau R, Mandot A, Pageaux G, Samuel D, Thabut D, Valla D, Durand F. Model for end-stage liver disease exceptions in the context of the French model for end-stage liver disease score-based liver allocation system. Liver Transpl 2011; 17:1137-51. [PMID: 21695771 DOI: 10.1002/lt.22363] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Model for End-Stage Liver Disease (MELD) score-based allocation systems have been adopted by most countries in Europe and North America. Indeed, the MELD score is a robust marker of early mortality for patients with cirrhosis. Except for extreme values, high pretransplant MELD scores do not significantly affect posttransplant survival. The MELD score can be used to optimize the allocation of allografts according to a sickest first policy. Most often, patients with small hepatocellular carcinomas (HCCs) and low MELD scores receive extra points, which allow them appropriate access to transplantation comparable to the access of patients with advanced cirrhosis and high MELD scores. In addition to patients with advanced cirrhosis and HCC, patients with a number of relatively uncommon conditions have low MELD scores and a poor prognosis in the short term without transplantation but derive excellent benefits from transplantation. These conditions, which correspond to the so-called MELD score exceptions, justify the allocation of a specific score for appropriate access to transplantation. Here we report the conclusions of the French consensus meeting. The goals of this meeting were (1) to identify which conditions merit MELD score exceptions, (2) to list the criteria needed for defining each of these conditions, and (3) to define a reasonable time interval for organ allocation for each MELD exception in the general context of organ shortages. MELD exceptions were discussed in an attempt to reconcile the concepts of transparency, equity, justice, and utility.
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Affiliation(s)
- Claire Francoz
- Departments of Hepatology, Beaujon Hospital, Clichy, France.
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40
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Abstract
PURPOSE OF REVIEW Liver disease is a major cause of morbidity and mortality in HIV-infected persons. The long-term beneficial versus potentially harmful influence of antiretroviral therapy (ART) on the liver is debated. We review current data on factors contributing to liver disease in HIV-monoinfected as well as in HIV/viral hepatitis-coinfected patients, highlighting the role of ART, HIV itself, immunodeficiency, patient characteristics, and lifestyle risk factors. RECENT FINDINGS New ART-related clinical syndromes, including noncirrhotic portal hypertension and nonalcoholic fatty liver disease, have emerged, and observational data suggest long-term ART-associated liver injury. Recently, there is increasing evidence that HIV itself and immunosuppression are contributing to liver injury in both HIV-coinfected and HIV-monoinfected patients. In HIV-positive persons, ART attenuates progression of chronic viral hepatitis. SUMMARY Current expert guidelines recommend earlier treatment of HIV infection in persons coinfected with hepatitis B virus and possibly hepatitis C virus. It is unknown whether an earlier start of ART is beneficial for the liver in HIV-monoinfected patients. Future research should focus on long-term ART-related hepatotoxicity.
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Schouten JNL, Garcia-Pagan JC, Valla DC, Janssen HLA. Idiopathic noncirrhotic portal hypertension. Hepatology 2011; 54:1071-81. [PMID: 21574171 DOI: 10.1002/hep.24422] [Citation(s) in RCA: 218] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 04/28/2011] [Indexed: 02/06/2023]
Abstract
Idiopathic noncirrhotic portal hypertension (INCPH) is characterized by an increased portal venous pressure gradient in the absence of a known cause of liver disease and portal vein thrombosis. In contrast to the high prevalence of this disorder in India, INCPH is a rare disease in the Western world. The etiology of INCPH can be divided in five categories: chronic infections, exposure to medication or toxins, thrombophilia, immunological disorders, and genetic disorders. Multifactorial etiology can also be encountered. Chronic abdominal infection is incriminated as the most important etiological factor in Eastern patients and thrombophilia in Western patients. The majority of patients with INCPH initially present with signs or complications of portal hypertension (mainly variceal bleeding and splenomegaly). These patients usually have preserved liver function. Liver function impairment occurs mainly in the context of intercurrent conditions. Patients with INCPH are often clinically and radiologically misdiagnosed as liver cirrhosis, so that a liver biopsy is indispensable to discriminate cirrhosis from INCPH. Histopathological characteristics of INCPH are heterogeneous, demonstrating overlap between several pathological entities (e.g., hepatoportal sclerosis, nodular regenerative hyperplasia, and incomplete septal cirrhosis). Even though hemodynamical changes in INCPH patients are not comparable to those in cirrhotics, prophylaxis and treatment of variceal bleeding are recommended to be similar. Anticoagulation therapy must be considered only in patients who develop portal vein thrombosis. INCPH has been considered a disorder with a relatively benign disease course. However, liver failure, hepatic encephalopathy, and hepatopulmonary syndrome can occur and are considered indications for liver transplantation.
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Affiliation(s)
- Jeoffrey N L Schouten
- Department of Gastroenterology Hepatology, University Hospital Rotterdam, Rotterdam, The Netherlands
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Joshi D, O'Grady J, Taylor C, Heaton N, Agarwal K. Liver transplantation in human immunodeficiency virus-positive patients. Liver Transpl 2011; 17:881-90. [PMID: 21563295 DOI: 10.1002/lt.22329] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
With the successful introduction of combined antiretroviral therapy (cART), human immunodeficiency virus (HIV) is now regarded as a chronic illness with excellent long-term outcomes. However, chronic exposure to viral etiologies (ie, chronic hepatitis B and hepatitis C) and drug-induced toxicity secondary to cART have resulted in increasing rates of mortality and morbidity due to end-stage liver disease. HIV disease is no longer considered an absolute contraindication to liver transplantation (LT) by most transplant centers worldwide. Because the burden of liver disease in this cohort is likely to increase, this review addresses the key etiologies and the management strategies available for HIV-positive patients undergoing LT.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
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Hofmaenner D, Kovari H, Weber A, Weishaupt D, Speck RF. Nodular regenerative hyperplasia of the liver associated with didanosine persists for years even after its interruption. BMJ Case Rep 2011; 2011:bcr.03.2011.3928. [PMID: 22696691 DOI: 10.1136/bcr.03.2011.3928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The authors describe an HIV-positive patient with nodular regenerative hyperplasia of the liver with non-cirrhotic portal hypertension. Despite stopping the culprit drug, didanosine, the radiologic changes persisted for years. When evaluating liver pathologies, antiretroviral drugs must be included in the differential diagnosis, even when they have been stopped years ago.
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Abstract
PURPOSE OF REVIEW Liver disease in the HAART era is one of the leading causes of morbidity and mortality in HIV-infected individuals in Western countries. Even if the majority of cases rely on identifiable causes (viral hepatitis, steatohepatitis, alcohol abuse, drug toxicity, etc.), the cause of liver abnormalities remains unknown for a subset of patients, some of whom present with noncirrhotic portal hypertension (NCPH). RECENT FINDINGS In 2006, the first reports of NCPH in HIV-infected patients attracted special attention. Typically, individuals unaware of any underlying liver illness presented with variceal bleeding, occasionally fatal. Interestingly, severe portal hypertension occurred in the absence of liver function impairment in most cases. Liver biopsy revealed a distinctive histological feature characterized by massive absence of portal veins along with focal obliteration of small portal veins. After extensive ruling out of other causes, the role of antiretroviral toxicity (particularly didanosine exposure) emerged as the major contributor to this condition. Other potential factors could be an enhanced microbial translocation from the gut and prothrombotic conditions. SUMMARY NCPH is an uncommon condition, although increasingly being reported in HIV-infected individuals. It generally presents as a clinical episode of decompensated portal hypertension, generally with gastrointestinal bleeding. Long-lasting HIV infection and prolonged antiretroviral exposure are universally recognized in these patients. The involvement of didanosine has been highlighted in most series. Removal of this drug and prevention of variceal bleeding episodes are currently the most effective prophylactic and therapeutic interventions.
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Abstract
Introduction of effective combined antiretroviral therapy has made HIV infection a chronic illness. Substantial reductions in the number of AIDS-related deaths have been accompanied by an increase in liver-related morbidity and mortality due to co-infection with chronic hepatitis B and C viruses. Increases in non-alcoholic fatty liver disease and drug-induced hepatotoxicity, together with development of hepatocellular carcinoma, also potentiate the burden of liver disease in individuals with HIV infection. We provide an overview of the key causes, disease mechanisms of pathogenesis, and recommendations for treatment options including the evolving role of liver transplantation.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
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46
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Hartleb M, Gutkowski K, Milkiewicz P. Nodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol 2011; 17:1400-9. [PMID: 21472097 PMCID: PMC3070012 DOI: 10.3748/wjg.v17.i11.1400] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 12/22/2010] [Accepted: 12/29/2010] [Indexed: 02/06/2023] Open
Abstract
Nodular regenerative hyperplasia (NRH) is a rare liver condition characterized by a widespread benign transformation of the hepatic parenchyma into small regenerative nodules. NRH may lead to the development of non-cirrhotic portal hypertension. There are no published systematic population studies on NRH and our current knowledge is limited to case reports and case series. NRH may develop via autoimmune, hematological, infectious, neoplastic, or drug-related causes. The disease is usually asymptomatic, slowly or non-progressive unless complications of portal hypertension develop. Accurate diagnosis is made by histopathology, which demonstrates diffuse micronodular transformation without fibrous septa. Lack of perinuclear collagen tissue distinguishes NRH from typical regenerative nodules in the cirrhotic liver. While the initial treatment is to address the underlying disease, ultimately the therapy is directed to the management of portal hypertension. The prognosis of NRH depends on both the severity of the underlying illness and the prevention of secondary complications of portal hypertension. In this review we detail the epidemiology, pathogenesis, diagnosis, management, and prognosis of NRH.
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Cotte L, Bénet T, Billioud C, Miailhes P, Scoazec JY, Ferry T, Brochier C, Boibieux A, Vanhems P, Chevallier M, Zoulim F. The role of nucleoside and nucleotide analogues in nodular regenerative hyperplasia in HIV-infected patients: a case control study. J Hepatol 2011; 54:489-96. [PMID: 21056493 DOI: 10.1016/j.jhep.2010.07.030] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2010] [Revised: 05/29/2010] [Accepted: 07/09/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Nodular regenerative hyperplasia (NRH) leading to non-cirrhotic portal hypertension has been described in HIV-infected patients and has been linked to didanosine. The relation between NRH and other antiretrovirals remains unclear. METHODS A case-control study was performed in 13 patients with NRH and 78 controls matched for time of inclusion, baseline CD4, and duration of follow-up. Univariate and multivariate conditional logistic regression analyses were performed. RESULTS Control patients and patients with NRH were similar at baseline regarding demographics and biological data with the exception of older age for patients with NRH (43.9 vs. 33.5 years, p=0.044). At the time of NRH diagnosis, cases had a lower CD4 count (327 vs. 468/mm(3), p=0.013), a similar CD4 percentage (24 vs. 26.2%, p=0.7), a lower platelet count (169 vs. 228 giga/L, p=0.003) and a higher AST level (33 vs. 26 IU/L, p=0.001) than controls. Univariate analysis demonstrated that patients with NRH had been exposed longer than controls to didanosine, stavudine, tenofovir, didanosine+stavudine, and didanosine+tenofovir. The age at baseline [OR 2.2 (1.0-5.0) per 10 years, p=0.053] and didanosine+stavudine cumulative exposure [OR 3.7 (1.4-10.2) per year, p=0.011] were independently associated with NRH. The age at baseline [OR 2.3 (1.0-5.3) per 10 years, p=0.045], cumulative exposure to didanosine [OR 1.4 (1.1-1.9) per year, p=0.023] and to tenofovir [OR 1.7 (1.0-2.8) per year, p=0.04] were independently associated with NRH when didanosine+stavudine exposure was excluded from the model. CONCLUSIONS NRH in HIV-infected patients seems strongly related to age and the cumulative exposure to didanosine+stavudine, didanosine, and stavudine.
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Scourfield A, Jackson A, Waters L, Gazzard B, Nelson M. The value of screening HIV-infected individuals for didanosine-related liver disease? Antivir Ther 2011; 16:941-2. [DOI: 10.3851/imp1875] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Merchante N, Pérez-Camacho I, Mira JA, Rivero A, Macías J, Camacho A, Gómez-Mateos J, García-Lázaro M, Torre-Cisneros J, Pineda JA. Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: role of didanosine. Antivir Ther 2010; 15:753-63. [PMID: 20710057 DOI: 10.3851/imp1612] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Unexpected cases of severe liver disease in HIV-infected patients have been reported and an association with didanosine (ddI) has been suggested. Transient elastography (TE) might detect patients harbouring such a condition. Our objective was to search for the presence of abnormal liver stiffness (LS) in a cohort of HIV-infected patients without HBV or HCV coinfection and to assess the related factors. METHODS A cross-sectional prospective study was conducted. LS was assessed by TE in 258 HIV-infected patients without HBV or HCV coinfection and with no evidence of acute hepatotoxicity or other origins of liver disease. LS values > or =7.2 kPa were considered abnormal. Multivariate analyses were performed to identify factors associated with abnormal LS. RESULTS Abnormal LS was observed in 29 (11.2%) patients. A total of 18 (16.4%) patients previously treated with ddI and 11 (7.4%) of those who never received ddI had LS values > or =7.2 kPa (P=0.02). The prevalence of abnormal LS was higher in patients previously treated with abacavir than in those who had never received abacavir (15 [21.7%] versus 14 [7.4%]; P=0.001). After multivariate analyses, age (adjusted odds ratio [AOR] 1.05, 95% confidence interval [CI] 1.002-1.1; P=0.004) alcohol intake >50 g/day (AOR 7.2, 95% CI 2.6-19.7; P<0.0001), CD4(+) T-cell count <200 cells/ml (AOR 3.4, 95% CI 1.06-11.007; P=0.03), time on ddI treatment (AOR 1.31, 95% CI 1.12-1.52; P=0.001) and previous abacavir exposure (AOR 3.01, 95% CI 1.18-7.67; P=0.02) were independently associated with abnormal LS. CONCLUSIONS The prevalence of abnormal LS in HIV-infected patients without HBV or HCV coinfection is substantial. Long-term exposure to ddI is a major cause of liver damage in these patients.
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Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol Hepatol 2010; 8:1002-12. [PMID: 20851211 PMCID: PMC2997131 DOI: 10.1016/j.cgh.2010.08.024] [Citation(s) in RCA: 144] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2010] [Revised: 08/25/2010] [Accepted: 08/28/2010] [Indexed: 02/07/2023]
Abstract
Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART era, liver disease is now the most common non-AIDS-related cause of death among HIV-infected patients, accounting for 14%-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV-infected population in the ART era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases.
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Affiliation(s)
- Jennifer C Price
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
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