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Bevilacqua M, De Marco L, Stupia R, Cattazzo F, Zoncapé M, Paon V, Ieluzzi D, Dalbeni A, Sacerdoti D. Hepatofugal portal flow is highly predictive of acute-on-chronic liver failure: A new hemodynamic patho-physiological hypothesis. Dig Liver Dis 2024; 56:1522-1528. [PMID: 38281869 DOI: 10.1016/j.dld.2024.01.190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/22/2023] [Accepted: 01/10/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND AND AIMS Acute-on-chronic liver failure (ACLF) is a severe complication of advanced liver disease. A significant number of ACLF patients have not clear precipitating factors. The aim of the study was to investigate the role of alterations in porto-hepatic hemodynamics, especially non-forward portal flow (NFPF), in ACLF and liver-related mortality. METHODS 233 cirrhotic patients were included in the study with a median follow-up of 24 months. Color-Doppler ultrasound was used to assess portal vein patency, flow direction and significant porto-systemic collaterals (>8 mm). Patients with active cancer, both at baseline and during follow-up and severe non liver-related comorbidities were excluded. ACLF and liver-related mortality were recorded during follow-up. RESULTS Fifty-six patients (24%) developed ACLF; 24 (10,3%) had baseline NFPF. In survival analysis, NFPF, but not portal vein thrombosis, was independently associated with ACLF development (HR 2.85 95% C.I. [1.49-5.42], p = 0.001) and liver-related mortality (HR 2.24 95% C.I. [1.16-4.28], p = 0.015), even after adjustment for liver disease severity scores, age and etiology of liver disease. CONCLUSION NFPF is independently associated with ACLF development and liver-related mortality, regardless of etiology, severity disease scores and portal vein thrombosis. Although there is no specific measure to reverse NFPF, patients with NFPF should receive prompt intensive management and urgent prioritization for liver transplantation. CLINICAL TRIAL NUMBER 2730 CESC.
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Affiliation(s)
- Michele Bevilacqua
- General Medicine C, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Leonardo De Marco
- General Medicine C, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Roberta Stupia
- General Medicine C, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Filippo Cattazzo
- General Medicine C, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Mirko Zoncapé
- General Medicine C, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Veronica Paon
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Donatella Ieluzzi
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Andrea Dalbeni
- General Medicine C, Department of Medicine, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - David Sacerdoti
- Liver Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
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A return to harmful alcohol consumption impacts on portal hemodynamic changes following alcoholic hepatitis. Eur J Gastroenterol Hepatol 2018; 30:967-974. [PMID: 29727387 DOI: 10.1097/meg.0000000000001148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Increased hepatic venous pressure gradient (HVPG) plays a role in the clinical manifestations of alcoholic hepatitis (AH). The evolution of HVPG and the influence of alcohol use in the intermediate term are unclear. AIM The aim of this study was to explore HVPG modifications following AH taking into consideration alcohol use and clinical manifestations. PATIENTS AND METHODS Patients with AH (n=37; age 52 years; model for end-stage liver disease: 18.5; Maddrey score: 43) and chronic excessive drinkers with compensated cirrhosis (n=19; age: 54 years; model for end-stage liver disease: 9.2) underwent HVPG measurement and liver biopsy. Ten long-standing abstinent alcoholic cirrhotics served as controls. After discharge, patients were monitored for alcohol use and clinical complications, with repeated HVPG after a median duration of 100 days. Inflammation was determined using plasma C-reactive protein. RESULTS At baseline, compared with chronic excessive drinkers and alcoholic cirrhotics, patients with AH had increased HVPG (18.1±0.6 vs. 13.8±1.4 vs. 15±1.3 mmHg, P<0.05). During follow-up, patients who became abstinent or reported occasional drinking were more likely to achieve a greater than 20% reduction in HVPG compared with those returning to harmful alcohol (45 vs. 0%, P<0.01), and suffered from fewer complications (25 vs. 68%, P<0.03). High baseline C-reactive protein levels correlated to the Maddrey (r=0.38), but no relationship was observed between changes in inflammation and HVPG. CONCLUSION Elevated HVPG is a feature of AH, with a clinically significant reduction in values in abstinent or occasional drinkers after weeks of follow-up. A return to harmful alcohol has a negative impact on portal hemodynamics and associated clinical complications.
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Thursz M, Gual A, Lackner C, Mathurin P, Moreno C, Spahr L, Sterneck M, Cortez-Pinto H. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol 2018; 69:154-181. [PMID: 29628280 DOI: 10.1016/j.jhep.2018.03.018] [Citation(s) in RCA: 574] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
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Roth NC, Saberi B, Macklin J, Kanel G, French SW, Govindarajan S, Buzzanco AS, Stolz AA, Donovan JA, Kaplowitz N. Prediction of histologic alcoholic hepatitis based on clinical presentation limits the need for liver biopsy. Hepatol Commun 2017; 1:1070-1084. [PMID: 29404443 PMCID: PMC5721404 DOI: 10.1002/hep4.1119] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/01/2017] [Accepted: 10/09/2017] [Indexed: 12/17/2022] Open
Abstract
The clinical presentation of alcoholic hepatitis (AH) can be mimicked by other alcoholic liver diseases. The aim of this study was to identify clinical features that predict AH on liver biopsy. Biopsies from patients hospitalized for presumed severe AH were used to identify a derivation cohort (101 patients) and validation cohort (71 patients). Using histologic scores for hepatocyte ballooning, Mallory-Denk bodies, and lobular inflammation, 95 patient biopsies (55%) were classified as definite AH, 55 (32%) as possible AH, and 22 (13%) as no AH. Survival was similar among the groups, but mortality was significantly increased for patients with fatty change ≤50% on initial liver biopsy. An analysis limited to uninfected patients with definite AH or no AH in the derivation cohort identified a greater leukocyte count at admission and radiographic evidence of liver surface nodularity as independent predictors of definite AH on biopsy (P < 0.05). In the derivation cohort, the leukocyte count thresholds for ensuring 100% specificity for diagnosing definite AH were 10 × 109/L if the liver surface was nodular and 14 × 109/L if the liver surface was smooth, with a sensitivity of 76% and an area under the receiver operator characteristic curve of 0.88. In the validation cohort, these thresholds had a specificity of 86%, a sensitivity of 59%, and an area under the receiver operator characteristic curve of 0.72. Conclusion: The combination of an elevated leukocyte count and a nodular liver surface in the absence of active infection retrospectively identified patients with a high likelihood of histologic AH for whom liver biopsy may not be necessary. For patients with suspected severe AH who do not fulfill these criteria, liver biopsy is important to exclude other variants of alcoholic liver disease. (Hepatology Communications 2017;1:1070-1084).
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Affiliation(s)
- Nitzan C. Roth
- Keck School of MedicineDivision of Gastrointestinal and Liver Diseases, University of Southern CaliforniaLos AngelesCA
| | - Behnam Saberi
- Division of Liver DiseasesIcahn School of Medicine at the Mount Sinai HospitalNew YorkNY
| | - Jared Macklin
- Keck School of MedicineDivision of Gastrointestinal and Liver Diseases, University of Southern CaliforniaLos AngelesCA
| | - Gary Kanel
- Department of PathologyUniversity of Southern CaliforniaLos AngelesCA
| | - Samuel W. French
- Department of Pathology and Laboratory Medicine, Harbor‐University of CaliforniaLos Angeles Medical CenterTorranceCA
| | - Sugantha Govindarajan
- Department of Pathology and Laboratory Medicine, Harbor‐University of CaliforniaLos Angeles Medical CenterTorranceCA
| | - Anthony S. Buzzanco
- Department of Pathology and Laboratory Medicine, Harbor‐University of CaliforniaLos Angeles Medical CenterTorranceCA
| | - Andrew A. Stolz
- Keck School of MedicineDivision of Gastrointestinal and Liver Diseases, University of Southern CaliforniaLos AngelesCA
| | - John A. Donovan
- Keck School of MedicineDivision of Gastrointestinal and Liver Diseases, University of Southern CaliforniaLos AngelesCA
| | - Neil Kaplowitz
- Keck School of MedicineDivision of Gastrointestinal and Liver Diseases, University of Southern CaliforniaLos AngelesCA
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Singal AK, Kodali S, Vucovich LA, Darley-Usmar V, Schiano TD. Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review. Alcohol Clin Exp Res 2016; 40:1390-402. [PMID: 27254289 PMCID: PMC4930399 DOI: 10.1111/acer.13108] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 04/24/2016] [Indexed: 12/16/2022]
Abstract
Alcoholic hepatitis (AH) occurs in about one-third of individuals reporting long-term heavy alcohol use. It is associated with high short-term mortality, economic burden, and hospital resources utilization. We performed this systematic review to (i) describe clinical characteristics and genomics associated with the risk of AH; (ii) discuss role and limitations of liver biopsy and prognostic scoring systems; (iii) summarize evidence regarding the currently available therapies including liver transplantation; and (iv) outline emerging therapies with areas of unmet need. Literature search was performed for studies published in English language (January 1971 through March 2016). The following search engines were used: PubMed, Elsevier Embase, PsycINFO, and Cochrane Library. For the treatment section, only randomized controlled studies were included for this review. A total of 138 studies (59 randomized, 22 systematic reviews or meta-analyses, 7 surveys or guidelines, 7 population-based, and 43 prospective cohorts) were cited. There are over 325,000 annual admissions with AH contributing to about 0.8% of all hospitalizations in the United States. Liver biopsy may be required in about 25 to 30% cases for uncertain clinical diagnosis. Corticosteroids with or without N-acetylcysteine remains the only available therapy for severe episodes. Data are emerging on the role of liver transplantation as salvage therapy for select patients. Abstinence remains the most important factor impacting long-term prognosis. Results from the ongoing clinical trials within the National Institute on Alcohol Abuse and Alcoholism-funded consortia are awaited for more effective and safer therapies. AH is a potentially lethal condition with a significant short-term mortality. A high index of suspicion is required. There remains an unmet need for noninvasive biomarkers for the diagnosis, and predicting prognosis and response to therapy.
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Affiliation(s)
- Ashwani K Singal
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Sudha Kodali
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Lee A Vucovich
- UAB Lister Hill Library of the Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | - Victor Darley-Usmar
- Department of Pathology and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Thomas D Schiano
- Division of Liver Diseases, Mount Sinai School of Medicine, New York City, New York
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Dhanda AD, Collins PL, McCune CA. Is liver biopsy necessary in the management of alcoholic hepatitis? World J Gastroenterol 2013; 19:7825-7829. [PMID: 24307775 PMCID: PMC3848129 DOI: 10.3748/wjg.v19.i44.7825] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/23/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
Acute alcoholic hepatitis (AAH) is characterised by deep jaundice in patients with a history of heavy alcohol use, which can progress to liver failure. A clinical diagnosis of AAH can be challenging to make in patients without a clear alcohol history or in the presence of risk factors for other causes of acute liver failure. Other causes of acute on chronic liver failure such as sepsis or variceal haemorrhage should be considered. Liver biopsy remains the only reliable method to make an accurate diagnosis. However, there is controversy surrounding the use of liver biopsy in patients with AAH because of the risks of performing a percutaneous biopsy and limitations in access to transjugular biopsy. We review the existing literature and find there are few studies directly comparing clinical and histological diagnosis of AAH. In the small number of studies that have been conducted the correlation between a clinical and histological diagnosis of AAH is poor. Due to this lack of agreement together with difficulties in accessing transjugular liver biopsy outside tertiary referral centres and research institutions, we cannot advocate universal biopsy for AAH but there remains a definite role for liver biopsy where there is clinical diagnostic doubt or dual pathology. It also adds value in a clinical trial context to ensure a homogeneous trial population and to further our understanding of the disease pathology. Further prospective studies are required to determine whether non-invasive markers can be used to accurately diagnose AAH.
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Clinical and histological recovery from “life-threatening” severe acute alcoholic hepatic failure with complete hepatofugal portal blood flow. Clin J Gastroenterol 2011; 4:39-42. [DOI: 10.1007/s12328-010-0193-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Accepted: 11/11/2010] [Indexed: 10/18/2022]
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Abstract
Alcoholic liver disease (ALD) is the second commonest indication for liver transplantation after viral hepatitis in the United States and Europe. Controversies surround the indications and allocation of scarce and expensive resource for this so called self inflicted disease. Controversies stem from the apprehension that alcoholic recipients are likely to relapse and cause damage to the graft. There is a need to select those candidates with lower risk for relapse with the available predictive factors and scores. Substance abuse specialist and psychiatrists are mandatory in the pre-transplant evaluation and in the post-transplant follow-up. There is conflicting evidence to support a fixed period of pretransplant abstinence, although most units do follow this. Alcoholic hepatitis (AH) continues to be a contraindication for transplantation, however there is a need for further research in this field as a subset of patients with AH who do not respond to medical treatment, have high early mortality and could benefit from transplantation. One year, 3-year, and 5-year survival post-transplant is similar for both ALD and non-ALD recipients. The incidence of post-transplant rejection and retransplantation is also similar to other recipients. ALD with viral hepatitis especially hepatitis C virus leads to a more aggressive liver disease with early presentation for transplantation. ALD patients are more prone to develop de-novo malignancy; this is attributed to the long term effect of alcohol, tobacco combined with immunosuppression. Post-transplant surveillance is important to detect early relapse to alcoholism, presence of de-novo malignancy and treat the same adequately.
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Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology 2009; 137:541-8. [PMID: 19445945 DOI: 10.1053/j.gastro.2009.04.062] [Citation(s) in RCA: 271] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Revised: 03/16/2009] [Accepted: 04/23/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS In severe (Maddrey score >or=32) alcoholic hepatitis (AH), infection is classically viewed as a contraindication for corticosteroids, although specific data are lacking. This study's aims were (1) to evaluate the incidence of infection in patients with severe AH before and after corticosteroid treatment; (2) to determine whether infection contraindicates corticosteroids; and (3) to focus on predictive factors of development of infection. METHODS At admission, systematic screening of infection consisted of chest x-ray and blood, ascites, and urinary cultures. All patients were treated with prednisolone. Response to steroids was defined using the Lille model. RESULTS Two hundred forty-six patients with severe AH were prospectively included. Infections at admission were as follows: 63 infections (25.6%) were diagnosed: 28 (44.4%) spontaneous bacterial peritonitis or bacteremia, 8 (12.7%) pulmonary infections, 20 (31.7%) urinary tract infections, and 7 (11.2%) other infections. Patients infected before using corticosteroids had 2-month survival similar to that of others: 70.9% +/- 6.1% vs 71.6% +/- 3.4%, respectively, P = .99. Development of infection after steroids: 57 patients (23.7%) developed infection: 16 (28.1%) spontaneous bacterial peritonitis or bacteremia, 23 (40.3%) pulmonary, 10 (17.5%) urinary tract, and 8 (14.1%) other infections. Infection occurred more frequently in nonresponders than in responders: 42.5% vs 11.1%, respectively, P < .000001. In multivariate analysis, only the Lille model (P = .0002) independently predicted infection upon steroids use. The Lille model (P = .000001) and Model for End-Stage Liver Disease score (P = .006) were independently associated with survival, whereas infection was not (P = .52). CONCLUSIONS Severe AH is associated with high risk of infection. Infection screening is warranted but should not contraindicate steroids. In terms of mechanisms, nonresponse to steroids is the key factor in development of infection and prediction of survival.
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Affiliation(s)
- Alexandre Louvet
- Service des Maladies de l'Appareil digestif, Hôpital Huriez, Lille, France.
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Catalano D, Trovato GM, Martines GF, Randazzo M, Tonzuso A. Bright liver, body composition and insulin resistance changes with nutritional intervention: a follow-up study. Liver Int 2008; 28:1280-7. [PMID: 18435716 DOI: 10.1111/j.1478-3231.2008.01742.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) because of its association with obesity, diabetes and insulin resistance (IR), is the hepatic expression of metabolic syndrome. Exercise and nutritional intervention can improve and prevent these inter-related conditions; the relationships between the degree of IR and ultrasound (US) morphological post-interventional changes are not defined. AIMS The aim of our study was to assess the relationship, if any, in NAFLD patients, among IR, BMI and degree of bright liver, before and after 6 months of a moderately hypocaloric/balanced dietary/lifestyle treatment. Fifty outpatients with a clinical and US diagnosis of NAFLD were studied. METHODS Liver echogenicity [Bright Liver Score (BLS)] was scored on a four-graded scale. IR was assessed by homoeostasis model-insulin resistance (HOMA-IR). Body composition was assessed by bioimpedance assessment and skinfold measurements. RESULTS A significant decrease of BLS was observed, with a concurrent decrease of body weight, body mass index (BMI) and HOMA-IR. Bright liver decrease has a trend parallel to IR, much less steep than the trend of bright liver reduction against US liver dimensions, body weight and BMI decrease. HOMA-IR is the only baseline variable that enters significantly in the multiple regression and, alone, explains 21.4% of variance in predicting bright liver degree. After dietary interventions, both HOMA-IR and BMI are significantly involved in the multiple regression and explain, together, 42.3% of variance in predicting bright liver degree; variation in BLS can be predicted by variation of body weight and of US longitudinal measurement of the liver. CONCLUSIONS Liver US BLS appears to be a useful tool, both alone and along with other US measurements and body weight changes, for the assessment of clinical-metabolic amelioration in patients treated with dietetic interventions. The clinical-diagnostic role, if any, of other assessed laboratory analyses, in the subset of NAFLD, does not appear to be definite.
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Affiliation(s)
- Daniela Catalano
- Dipartimento di Medicina Interna, Istituto di Medicina Interna e Terapia Medica, Facoltà di Medicina e Chirurgia, Università di Catania, Catania, Italia.
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Slimani L, Kudomi N, Oikonen V, Jarvisalo M, Kiss J, Naum A, Borra R, Viljanen A, Sipila H, Ferrannini E, Savunen T, Nuutila P, Iozzo P. Quantification of liver perfusion with [(15)O]H(2)O-PET and its relationship with glucose metabolism and substrate levels. J Hepatol 2008; 48:974-82. [PMID: 18384905 DOI: 10.1016/j.jhep.2008.01.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Revised: 12/28/2007] [Accepted: 01/16/2008] [Indexed: 01/21/2023]
Abstract
BACKGROUND/AIMS Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism. METHODS Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods. RESULTS Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009). CONCLUSIONS Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.
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Affiliation(s)
- Lotfi Slimani
- Turku PET Centre, Turku University Hospital, University of Turku, P.O. Box 52, FIN-20521 Turku, Finland.
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Louvet A, Diaz E, Dharancy S, Coevoet H, Texier F, Thévenot T, Deltenre P, Canva V, Plane C, Mathurin P. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J Hepatol 2008; 48:465-70. [PMID: 18164508 DOI: 10.1016/j.jhep.2007.10.010] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2007] [Revised: 10/01/2007] [Accepted: 10/11/2007] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS In severe alcoholic hepatitis (AH), 40% of patients will obtain no benefit from corticosteroids. Improvement in management of non-responders is warranted and only pentoxifylline can be considered an alternative. A two-step strategy was evaluated consisting of early withdrawal of corticosteroids and a switch to pentoxifylline for 28 additional days in non-responders identified using early change in bilirubin level. METHODS One hundred and twenty-one patients with AH were treated prospectively with corticosteroids, and the two-step strategy was proposed to 29 non-responders treated according to a two-step strategy who were compared to 58 matched non-responders treated with corticosteroids only. RESULTS Clinical and biological features of the two groups were similar. There was no survival improvement at 2 months in patients treated with the two-step strategy compared to controls: 35.5+/-6.3% vs 31+/-8.6%. After 21 days, biological evolution was similar for prothrombin time (-0.25s vs +0.2s), bilirubin (0.8 mg/dl vs 2.03 mg/dl) and creatinine (+0.16 mg/dl vs -0.7 mg/dl). In multivariate analysis, only age, evolution of bilirubin during the first week, creatinine and DF were associated with 2-month survival. CONCLUSIONS Non-responders to corticosteroids do not obtain any benefit from an early switch to pentoxifylline. Thus, the issue of management of non-responders remains unresolved.
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Affiliation(s)
- Alexandre Louvet
- Services d'Hépato-Gastroentérologie, Hôpital Huriez, rue Polonovski, Lille, France
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Balci A, Karazincir S, Sumbas H, Oter Y, Egilmez E, Inandi T. Effects of diffuse fatty infiltration of the liver on portal vein flow hemodynamics. JOURNAL OF CLINICAL ULTRASOUND : JCU 2008; 36:134-140. [PMID: 18196595 DOI: 10.1002/jcu.20440] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
PURPOSE To investigate the effects of various degrees of diffuse fatty infiltration of the liver on portal vein blood flow with Doppler sonography. METHODS One hundred forty subjects were examined with color and spectral Doppler sonography. The subjects were divided into 4 groups of 35 subjects each according to the degree (normal, grade 1, grade 2 and grade 3) of hepatic fatty infiltration assessed on gray-scale images. The portal vein pulsatility index (VPI) and time-averaged mean flow velocity (MFV) were calculated for each subject. VPI was calculated as (peak maximum velocity - peak minimum velocity) / peak maximum velocity. RESULTS VPI and MFV values were, respectively, 0.32 +/- 0.06 and 16.8 +/- 2.6 cm/second in the normal group, 0.27 +/- 0.07 and 14.2 +/- 2.2 cm/second in the group with grade 1 fatty infiltration, 0.22 +/- 0.06 and 12.2 +/- 1.8 cm/second in the group with grade 2 fatty infiltration, and 0.18 +/- 0.04 and 10.8 +/- 1.5 cm/second in the group with grade 3 fatty infiltration. There was a negative inverse correlation between the grade of fatty infiltration and both VPI (f = 55.3, p < 0.001) and MFV (f = 43.9, p < 0.001). CONCLUSION The pulsatility index and mean velocity of the portal vein blood flow decrease as the severity of fatty infiltration increases.
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Affiliation(s)
- Ali Balci
- Department of Radiology, Mustafa Kemal University Faculty of Medicine, Bağriyanik Mh. Uğur Mumcu Cad., 31100 Antakya, Hatay, Turkey
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Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 2007; 45:1348-54. [PMID: 17518367 DOI: 10.1002/hep.21607] [Citation(s) in RCA: 511] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Early identification of patients with severe (discriminant function > or = 32) alcoholic hepatitis (AH) not responding to corticosteroids is crucial. We generated a specific prognostic model (Lille model) to identify candidates early on for alternative therapies. Three hundred twenty patients with AH prospectively treated by corticosteroids were included in the development cohort and 118 in its validation. Baseline data and a change in bilirubin at day 7 were tested. The model was generated by logistic regression. The model combining six reproducible variables (age, renal insufficiency, albumin, prothrombin time, bilirubin, and evolution of bilirubin at day 7) was highly predictive of death at 6 months (P < 0.000001). The area under the receiver operating characteristic (AUROC) curve of the Lille model was 0.89 +/- 0.02, higher than the Child-Pugh (0.62 +/- 0.04, P < 0.00001) or Maddrey scores (0.66 +/- 0.04, P < 0.00001). In the validation cohort, its AUROC was 0.85 +/- 0.04, still higher than the other models, including MELD (0.72 +/- 0.05, P = 0.01) and Glasgow scores (0.67 +/- 0.05, P = 0.0008). Patients above the ideal cutoff of 0.45 showed a marked decrease in 6-month survival as compared with others: 25% +/- 3.8% versus 85% +/- 2.5%, P < 0.0001. This cutoff was able to identify approximately 75% of the observed deaths. CONCLUSION In the largest cohort to date of patients with severe AH, we demonstrate that the term "nonresponder" can now be extended to patients with a Lille score above 0.45, which corresponds to 40% of cases. Early identification of subjects with substantial risk of death according to the Lille model will improve management of patients suffering from severe AH and will aid in the design of future studies for alternative therapies.
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Affiliation(s)
- Alexandre Louvet
- Services d'Hépato-Gastroentérologie, Hôpital Claude Huriez, Avenue Michel Polonovski, CHRU Lille, 59037 Lille, France
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15
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Rincon D, Lo Iacono O, Ripoll C, Gomez-Camarero J, Salcedo M, Catalina MV, Hernando A, Clemente G, Matilla A, Nuñez O, Bañares R. Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients with severe acute alcoholic hepatitis. Aliment Pharmacol Ther 2007; 25:841-8. [PMID: 17373923 DOI: 10.1111/j.1365-2036.2007.03258.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic venous pressure gradient (HVPG) has prognostic value in complications and survival of patients with liver cirrhosis. However, the relationship between HVPG and the outcome of acute alcoholic hepatitis (AAH), as well as the specific features of portal hypertension syndrome in this setting, have not been defined. AIMS To evaluate the prognostic value of HVPG and to analyse the degree of portal hypertension and hyperdynamic circulation in patients with severe AAH. METHODS Early measurements of HVPG were performed in 60 patients with severe AAH, and compared with the haemodynamic findings of 37 and 29 liver transplantation candidates with alcoholic or viral end-stage cirrhosis respectively. RESULTS Twenty-three patients (38%) died during hospitalization. Portal hypertension and hyperdynamic circulation were more severe in AAH patients. HVPG was greater in non-survivors [26.9 (7.4) vs. 19.4 (5.2) mmHg, P < 0.001]. Only 4/31 (13%) patients with HVPG <or= 22 mmHg died from the episode of AAH, vs. 19/29 (66%) patients with HVPG > 22 (P < 0.001). Encephalopathy (OR 9.4; CI 1.4-64.8), Model for End-Stage Liver Disease (MELD) score > 25 (OR 7.4; CI 1.4-39.9) and HVPG > 22 mmHg (OR 6.7; CI 1.1-39.9) were independently associated to in-hospital mortality. CONCLUSIONS Early measurement of HVPG provides important prognostic information on the short-term outcome of patients with severe AAH. In addition, MELD score also seems to be a strong prognostic factor in these patients.
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Affiliation(s)
- D Rincon
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Gregorio Marañon, Madrid, Spain
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Elphick DA, Dube AK, McFarlane E, Jones J, Gleeson D. Spectrum of liver histology in presumed decompensated alcoholic liver disease. Am J Gastroenterol 2007; 102:780-8. [PMID: 17222323 DOI: 10.1111/j.1572-0241.2006.01034.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND In presumed decompensated alcoholic liver disease (ALD; liver decompensation, heavy alcohol intake, and negative results of noninvasive screening for other causes), liver biopsy is often performed to assess severity of liver injury and to rule out other liver diseases. AIM The aim of the study is to describe the spectrum of liver histology in such patients. METHODS We reviewed all patients with presumed decompensated ALD seen between 1998 and 2004, in whom liver tissue was available for histology (N = 110). RESULTS A total of 104 of the 110 patients had at least one of the histological features suggestive of ALD: fat, Mallory's hyalin, neutrophilic infiltrate, and hepatocyte ballooning. These features were more prevalent in tissue obtained within a month after presentation with decompensation than in that obtained before decompensation or more than 1 month after. These features were also associated with more severe liver dysfunction. Histology revealed a major additional diagnosis (Budd-Chiari syndrome) in only one case. In 41 patients biopsied within a month of first presentation with decompensation, Child score and Maddrey discriminant function (DF), but none of the histological features, were predictive of survival by Cox multivariate analysis. Of the 26 of these 41 patients with a Maddrey DF >32, 22 (85%) had alcoholic hepatitis. CONCLUSIONS In patients with presumed decompensated ALD, other liver diseases are uncommon. Routine liver biopsy is of limited added value but biopsy should be considered in those in whom the noninvasive workup, or failure to recover despite abstinence, raises the possibility of other liver diseases.
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17
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Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, Sen S, Williams R, Leiper J, Vallance P, Jalan R. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 2007; 45:62-71. [PMID: 17187433 DOI: 10.1002/hep.21491] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. CONCLUSION Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.
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Affiliation(s)
- Rajeshwar P Mookerjee
- Liver Failure Group, The UCL Institute of Hepatology, Division of Medicine, University College London, UK
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Abstract
The treatment of alcoholic hepatitis remains one of the most debated topics in medicine and a field of continued research. In this review, we discuss the evolution of scoring systems, including the recent development of the Glasgow alcoholic hepatitis score, role of liver biopsy and current treatment interventions. Studies of treatment interventions with glucocorticoids, pentoxifylline, infliximab, s-adenosyl-methionine, and colchicine are reviewed with discussion on quality. Glucocorticoids currently remain the mainstay of treatment for severe alcoholic hepatitis.
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Affiliation(s)
- Catherine Rongey
- Robert Wood Johnson Clinical Scholars Program, University of California at Los Angeles, 911 Broxton Avenue, Los Angeles, CA 90024, USA.
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Ceccanti M, Attili A, Balducci G, Attilia F, Giacomelli S, Rotondo C, Sasso GF, Xirouchakis E, Attilia ML. Acute alcoholic hepatitis. J Clin Gastroenterol 2006; 40:833-41. [PMID: 17016141 DOI: 10.1097/01.mcg.0000225570.04773.5d] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Acute alcoholic hepatitis (AAH) is a frequent inflammatory liver disease with high short-term mortality rate. In this review, relationships between alcohol abuse and the epidemiology and the outcomes of AAH are discussed, as well as AAH pathogenesis. The role of endotoxins, tumor necrosis factor alpha, fibroblasts, and immune response to altered hepatocyte proteins is discussed. The need of a careful prognosis, supported by the use of Maddrey score, by the model for end-stage liver disease [Mayo end-stage liver disease (MELD)] score or by the Glasgow alcoholic hepatitis score, is outlined, as the use of the most effective drugs (glucocorticoids and anti-tumor necrosis factor alpha infliximab) is recommended only in severe AAH cases. The problems of liver transplant in severe AAH, and the need of a 6-month alcohol abstinence before transplant, are discussed, as well as the need of a careful psychologic assessment before the transplant.
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Affiliation(s)
- Mauro Ceccanti
- Alcohol Liver Disease Unit, University "La Sapienza", Roma, Italy.
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21
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Abstract
1. In the absence of treatment, 50% of patients with severe alcoholic hepatitis (AH) [Maddrey function (DF) >or= 32] die 2 months later. Among patients with severe AH treated by corticosteroids, 80% had 2-month survival. Pentoxifylline is considered by some investigators to be an alternative option to corticosteroids. 2. Non-responders to corticosteroids (NRCs) have poor survival and require new strategies. Liver transplantation should be considered in order to improve survival of non-responders to therapeutic agents. 3. Prognostic models such as the Model for End-Stage Liver Disease (MELD) and DF are useful tools for predicting short-term mortality of patients with severe AH. Specific models taking into account the particular settings of treated patients are warranted. 4. In an era of organ shortage, use of liver transplants in patients with severe AH may negatively affect the public attitude on transplantation and organ donation, and may cause reluctance on the part of clinicians to modify guidelines for alcoholic patients. 5. Therefore, a reasonable approach would be to carry out only pilot studies on only a small cohort of patients to determine whether transplantation improves survival in patients with severe AH.
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Affiliation(s)
- Philippe Mathurin
- Service d'Hépatogastroentérologie Hôpital Claude Huriez and Equipe mixte INSERM 0114, CHU Lille, France.
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Affiliation(s)
- Philippe Mathurin
- Service d'Hépato-Gastroentérologie Hôpital Claude Huriez 2(ème) étage Est, Avenue Michel Polonovski, CHRU Lille 59037, France.
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Abstract
PURPOSE OF REVIEW To highlight salient recent discoveries and results of clinical trials in alcoholic liver disease (ALD). The burden of care for ALD patients is hefty and the prevalence of alcohol abuse may be increasing in both the developed and the underdeveloped world. RECENT FINDINGS Molecular mechanisms of alcoholism are being identified but not of the predisposition to alcoholic liver injury, except perhaps for polymorphism of a cytotoxic T-cell antigen. The Mayo End-stage Liver Disease (MELD) score performs well in assessing the prognosis of ALD; serological biomarkers for predicting ALD outcome are of uncertain value. Concomitant liver disease (e.g., obesity, hepatitis C, and iron overload) aggravates the severity of ALD; conversely, alcohol abuse may be a cryptic co-factor in some cases of non-alcoholic fatty liver. For alcoholic hepatitis, nutritional support is the mainstay of treatment; steroids are considered by some (but not all) as safe and effective therapy, whereas manipulations of tumor necrosis factor-alpha activity have been disappointing, or of unproven benefit at best. In liver transplantation for ALD, methods are being devised to monitor recidivism and to ameliorate its risk and that of co-morbid psychiatric conditions. SUMMARY Much of the pathogenesis of ALD has been identified and headway has been made in predicting its prognosis. However, much remains to be done to elucidate the molecular genetics of the risk of developing ALD and in formulating safe, effective therapies for alcoholic hepatitis.
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Affiliation(s)
- Ira R Willner
- Liver Transplantation Division of Gastroenterology/Hepatology Medical University of South Carolina, Charleston, 29425, USA.
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