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Pyo JH, Cho SJ, Choi SC, Jee JH, Yun J, Hwang JA, Park G, Kim K, Kang W, Kang M, Byun YH. Diagnostic performance of quantitative ultrasonography for hepatic steatosis in a health screening program: a prospective single-center study. Ultrasonography 2024; 43:250-262. [PMID: 38898634 PMCID: PMC11222130 DOI: 10.14366/usg.24040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
PURPOSE This study compared the diagnostic performance of quantitative ultrasonography (QUS) with that of conventional ultrasonography (US) in assessing hepatic steatosis among individuals undergoing health screening using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) as the reference standard. METHODS This single-center prospective study enrolled 427 participants who underwent abdominal MRI and US. Measurements included the attenuation coefficient in tissue attenuation imaging (TAI) and the scatter-distribution coefficient in tissue scatter-distribution imaging (TSI). The correlation between QUS and MRI-PDFF was evaluated. The diagnostic capabilities of QUS, conventional B-mode US, and their combined models for detecting hepatic fat content of ≥5% (MRI-PDFF ≥5%) and ≥10% (MRI-PDFF ≥10%) were compared by analyzing the areas under the receiver operating characteristic curves. Additionally, clinical risk factors influencing the diagnostic performance of QUS were identified using multivariate linear regression analyses. RESULTS TAI and TSI were strongly correlated with MRI-PDFF (r=0.759 and r=0.802, respectively; both P<0.001) and demonstrated good diagnostic performance in detecting and grading hepatic steatosis. The combination of QUS and B-mode US resulted in the highest areas under the ROC curve (AUCs) (0.947 and 0.975 for detecting hepatic fat content of ≥5% and ≥10%, respectively; both P<0.05), compared to TAI, TSI, or B-mode US alone (AUCs: 0.887, 0.910, 0.878 for ≥5% and 0.951, 0.922, 0.875 for ≥10%, respectively). The independent determinants of QUS included skinliver capsule distance (β=7.134), hepatic fibrosis (β=4.808), alanine aminotransferase (β=0.202), triglyceride levels (β=0.027), and diabetes mellitus (β=3.710). CONCLUSION QUS is a useful and effective screening tool for detecting and grading hepatic steatosis during health checkups.
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Affiliation(s)
- Jeung Hui Pyo
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Jin Cho
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Chul Choi
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Hwan Jee
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyeong Yun
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeong Ah Hwang
- Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Goeun Park
- Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Kyunga Kim
- Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
- Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
| | - Wonseok Kang
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mira Kang
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Korea
- Digital Transformation Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young hye Byun
- Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Iwaki M, Fujii H, Hayashi H, Toyoda H, Oeda S, Hyogo H, Kawanaka M, Morishita A, Munekage K, Kawata K, Tsutsumi T, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Kamada Y, Takahashi H, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Prognosis of biopsy-confirmed metabolic dysfunction- associated steatotic liver disease: A sub-analysis of the CLIONE study. Clin Mol Hepatol 2024; 30:225-234. [PMID: 38263684 PMCID: PMC11016478 DOI: 10.3350/cmh.2023.0515] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/21/2024] [Accepted: 01/22/2024] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND/AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. METHODS This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. RESULTS Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4). CONCLUSION Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.
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Affiliation(s)
- Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hideki Hayashi
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Oeda
- Liver Center and Department of Laboratory Medicine, Saga University Hospital, Saga, Japan
| | | | - Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Kensuke Munekage
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Gastroenterology, Kochi Prefectural Hata Kenmin Hospital, Kochi, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tsubasa Tsutsumi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Koji Sawada
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Tatsuji Maeshiro
- Department of Gastroenterology, Urasoe General Hospital, Okinawa, Japan
| | - Hiroshi Tobita
- Department of Hepatology, Shimane University Hospital, Shimane, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka, Japan
| | - Masafumi Naito
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka, Japan
| | - Asuka Araki
- Division of Pathology, Shimane University Hospital, Shimane, Japan
| | - Shingo Arakaki
- Department of Gastroenterology, Urasoe General Hospital, Okinawa, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hidenao Noritake
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Masafumi Ono
- Division of Innovative Medicine for Hepatobiliary & Pancreatology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Eiichi Tomita
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Akihiro Tokushige
- Department of Clinical Pharmacology and Therapeutics School of Medicine University of the Ryukyus, Okinawa, Japan
| | - Yoshihiro Kamada
- Department of Advanced Metabolic Hepatology, Osaka University, Graduate School of Medicine, Osaka, Japan
| | | | - Shinichiro Ueda
- Department of Clinical Pharmacology and Therapeutics School of Medicine University of the Ryukyus, Okinawa, Japan
| | - Shinichi Aishima
- Department of Scientific Pathology Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshio Sumida
- Graduate School of Healthcare Management, International University of Healthcare and Welfare, Tokyo, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
| | - Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
- Liver Center and Department of Laboratory Medicine, Saga University Hospital, Saga, Japan
- Hyogo Life Care Clinic Hiroshima, Hiroshima, Japan
- Department of General Internal Medicine2, Kawasaki Medical Center, Kawasaki Medical School, Okayama, Japan
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Gastroenterology, Kochi Prefectural Hata Kenmin Hospital, Kochi, Japan
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
- Department of Gastroenterology, Urasoe General Hospital, Okinawa, Japan
- Department of Hepatology, Shimane University Hospital, Shimane, Japan
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka, Japan
- Division of Pathology, Shimane University Hospital, Shimane, Japan
- Division of Innovative Medicine for Hepatobiliary & Pancreatology, Faculty of Medicine, Kagawa University, Kagawa, Japan
- Department of Clinical Pharmacology and Therapeutics School of Medicine University of the Ryukyus, Okinawa, Japan
- Department of Advanced Metabolic Hepatology, Osaka University, Graduate School of Medicine, Osaka, Japan
- Liver Center, Saga University Hospital, Saga, Japan
- Department of Scientific Pathology Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Graduate School of Healthcare Management, International University of Healthcare and Welfare, Tokyo, Japan
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan
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Vinokur V, Berenshtein E, Chevion M, Chevion D. A New Concept in Antidiabetic Therapeutics: A Concerted Removal of Labile Iron and Intracellular Deposition of Zinc. Diabetes Metab J 2024; 48:59-71. [PMID: 38173374 PMCID: PMC10850271 DOI: 10.4093/dmj.2022.0292] [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: 08/16/2022] [Accepted: 04/10/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGRUOUND The inflammatory process is known to be an integral part of the pathophysiology of type 2 diabetes mellitus (T2DM). The "labile," redox-active iron, serving as a catalyst in Fenton reaction, producing the deleterious reactive oxygen species, triggering and maintaining inflammation, is hypothesized to play a causative role in this process. Concenter Biopharma continued the development of a new platform of iron chelators (Zygosids), first initiated at the Hebrew University of Jerusalem, Israel (HUJI), acting via the novel mechanism, based on a sequestration of the labile redox-active iron and its substitution by zinc or gallium. The mode of action of Zygosids is based on the higher affinity of the metal-binding moiety of the complex to Fe3+ in comparison to already bound ion, leading to rapid release of the ion of another metal and chelation of Fe3+. Concomitantly, zinc ion, released by the complex, is known for its antidiabetic and anti-inflammatory role. METHODS The therapeutic effect of zinc-desferrioxamine (Zygosid-50) and gallium-desferrioxamine, was tested on fat sand rat (Psammomys obesus) model of diet-induced T2DM and on Leprdb transgenic diabetic mice. RESULTS Zygosids demonstrated an ability to noticeably reduce blood glucose and insulin levels and improve the lipid profile. Moreover, an ability to mitigate insulin resistance by >90% was shown on the sand rat model. In addition, a potent anti-inflammatory effect, expressed as a diminishment of the proinflammatory cytokines in tissue levels, was demonstrated. CONCLUSION Zygosids demonstrated robust therapeutic efficacy in treatment of T2DM. Importantly, no adverse effects were detected, in all the experiments, indicating high safety profile.
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Affiliation(s)
- Vladimir Vinokur
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem (HUJI), Jerusalem, Israel
- Concenter Biopharma, Jerusalem, Israel
| | - Eduard Berenshtein
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem (HUJI), Jerusalem, Israel
| | - Mordechai Chevion
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem (HUJI), Jerusalem, Israel
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Abdulkareem ZA, Mohammed NI, Abdollahi A, Ahmed OR, Ghaffar OR, Khdir HA, Salam DA, Aziz SA, Mustafa MM, Mustafa WM, Abas ZA, Abid OI. Effects of garlic, onion, and apple cider vinegar as a herbal mixture on performance and blood traits of broilers inoculated with chicken infectious anemia virus. Heliyon 2023; 9:e17768. [PMID: 37449102 PMCID: PMC10336684 DOI: 10.1016/j.heliyon.2023.e17768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/24/2023] [Accepted: 06/27/2023] [Indexed: 07/18/2023] Open
Abstract
This study assessed the effects of a herbal mixture (HM) to protect poultry against chicken infectious anemia (CIA) and to modulate the adverse effects of this virus on performance, mortality, blood profile, white blood cells (WBCs) count, liver enzymes, liver histopathology, and intestinal morphology. Therefore, 240 one-day-old male broiler chicks (Ross 308) were divided into four experimental groups, with six replicates and ten chicks per group. The experimental groups consisted of a control group and groups with 2.5%, 5%, and 7.5% HM, all based on corn-soybean meal. All chicks were inoculated with the CIA virus (CIAV) on day 7. The results showed that supplementation of 2.5% of HM to broiler diet increased feed intake (FI) (P < 0.05) and also increased body weight (BW) and weight gain (WG) slightly (P > 0.05). Adding 7.5% HM caused a reversible decrease in FI, BW, and WG and increased FCR. Compared with the control group, mortality rates declined with an additional dose of HM in CIAV-infected chickens. HM supplementation in the diet of CIAV-infected chickens increased hematocrit (HCT), hemoglobin (Hb), and mean corpuscular volume (MCV) and decreased mean corpuscular hemoglobin concentration (MCHC) compared to the control (P < 0.05). Lymphocyte percentage and lymphocyte/heterophile ratio increased in HM-supplemented groups, especially at 2.5% (P < 0.05), and heterophile and granulocyte percentages were reduced (P < 0.05). Liver enzyme alkaline phosphatase (ALP) and liver steatosis declined in the 2.5% HM-treated group compared to the control (P < 0.05). It was concluded that adding 2.5% of the HM to the CIAV-infected broiler's diet did not negatively affect chicken performance. In addition to its hypolipidemic effects, it could prevent HCT and Hb from decreasing in chicks infected with CIAV and positively affect leukocyte types and liver enzymes. Interestingly, an additional dose of HM in the diet of the CIAV-infected broilers reduced mortality. Therefore, adding 2.5% of HM could prevent the adverse effects of CIA on hematological traits in broiler chicken flocks without adverse effects on performance.
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Affiliation(s)
- Zana Azeez Abdulkareem
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Nihayat Ibrahim Mohammed
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Asrin Abdollahi
- Department of Animal Science, University of Kurdistan, Sanandaj, 66177-15175, Iran
| | - Omer Rasool Ahmed
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Osama Rahman Ghaffar
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Hawkar Azad Khdir
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Dashty Akram Salam
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Sarhang Ahmad Aziz
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Mustafa Mama Mustafa
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
| | - Warzer Mohammed Mustafa
- Department of Animal Resources, Collage of Agricultural Engineering Sciences, University of Raparin, Ranya, Sulaymaniyah, 46012, Iraq
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Akbari R, Yaghooti H, Jalali MT, Khorsandi LS, Mohammadtaghvaei N. Capparis spinosa improves the high fat diet-induced non-alcoholic steatohepatitis in rats: the possible role of FGF21. BMC Res Notes 2020; 13:356. [PMID: 32723353 PMCID: PMC7388468 DOI: 10.1186/s13104-020-05200-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/21/2020] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES This study focused on the beneficial effects of Capparis spinosa (CS) treatment on the steatohepatitis induced by the administration of a high-fat emulsion in rats. Changes of hepatic expression and secretion of fibroblast growth factor 21 (FGF21) were also evaluated as a probable mechanism of the CS effects on fatty liver. Male Wistar rats were allocated in different groups to receive a normal diet (NC group), a high-fat diet (HF group), or the high-fat emulsion plus CS extract at a dose of 20 mg/kg (HF+CS group). Body and liver weight, liver index, serum biochemical factors, histopathological examination, and serum level and hepatic gene expression of FGF21 were determined. RESULTS CS administration markedly reduced liver weight and index, serum levels of glucose, lipids, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and improved histological features of nonalcoholic steatohepatitis (NASH) which were induced by HF feeding in this model. CS supplementation also restored the decreased hepatic and serum FGF21 levels in the fatty liver rats. We propose that the FGF21 up-regulation may partly account for the favorable effects of CS in this steatohepatitis model.
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Affiliation(s)
- Rasoul Akbari
- Hyperlipidemia Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Laboratory Sciences, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hamid Yaghooti
- Hyperlipidemia Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Taha Jalali
- Hyperlipidemia Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Department of Laboratory Sciences, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Laya Sadat Khorsandi
- Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Narges Mohammadtaghvaei
- Hyperlipidemia Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. .,Department of Laboratory Sciences, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Kurbatova IV, Dudanova OP. [Features of a necrotic and inflammatory process in different forms of nonalcoholic fatty liver disease]. TERAPEVT ARKH 2017; 89:52-58. [PMID: 28281516 DOI: 10.17116/terarkh201789252-58] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
AIM To identify the features of development of a necrotic and inflammatory process in different forms of nonalcoholic fatty liver disease (NAFLD), by comparatively analyzing a full set of clinical and laboratory parameters, including the cytokine status and the expression level of enzyme genes controlling the apoptosis of peripheral leukocytes. SUBJECTS AND METHODS 86 patients with NAFLD, including 8 (9.3%) with hepatic steatosis (HS), 70 (81.4%) with nonalcoholic steatohepatitis (NASH), 40, 19, and 11 with mild, moderate, and high disease activity, respectively, and 8 (9.3%) with liver cirrhosis (LC), were examined. A control group consisted of 34 healthy donors. Clinical and biochemical blood indices, cytokine profile, and the level of caspase gene transcripts in the peripheral blood leukocytes (PBL) were estimated. RESULTS As compared to the controls, the patients with HS had higher tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels and lower caspase 3, 6, and 8 mRNA in PBL. The concentration of IL-10 in NASH was higher than that in steatosis and positively correlated with the level of proinflammatory cytokines. The levels of TNF-α and IL6 were higher in the patients with NASH than in the controls. Those of C-reactive protein, γ-globulin, IL-6, and cytokeratin-18 fragment increased with the progression of NASH. In the latter, the transcriptional activity of caspase-3 gene decreased relative to the reference value and negatively correlated with the level of proinflammatory cytokines. In the patients with LC, the gene expression profile of caspases in PBL was similar to that in the control group; the level of IL-6 was higher than that in steatosis and NASH, that of IL-1β was higher than in HS and positively correlated the concentration of IL-6 and the activity of alanine aminotransferase and aspartate aminotransferase. CONCLUSION The features of a necrotic and inflammatory process were identified in different forms of NAFLD. When the latter progressed, the cytokine profile and gene expression levels of caspases in PBL altered along with a change in the general clinical picture.
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Affiliation(s)
- I V Kurbatova
- Institute of Biology, Karelian Research Centre, Russian Academy of Sciences, Petrozavodsk, Russia
| | - O P Dudanova
- Petrozavodsk State University, Petrozavodsk, Russia
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Takamura T. [Diabetes mellitus related common medical disorders: recent progress in diagnosis and treatment. Topics: I. Pathophysiology, diagnosis and treatment; 1. Nonalcoholic fatty liver disease]. NIHON NAIKA GAKKAI ZASSHI. THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE 2013; 102:836-844. [PMID: 23772495 DOI: 10.2169/naika.102.836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Affiliation(s)
- Toshinari Takamura
- Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Japan
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Arendt BM, Ma DWL, Simons B, Noureldin SA, Therapondos G, Guindi M, Sherman M, Allard JP. Nonalcoholic fatty liver disease is associated with lower hepatic and erythrocyte ratios of phosphatidylcholine to phosphatidylethanolamine. Appl Physiol Nutr Metab 2012; 38:334-40. [PMID: 23537027 DOI: 10.1139/apnm-2012-0261] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with altered hepatic lipid composition. Animal studies suggest that the hepatic ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) contributes to steatogenesis and inflammation. This ratio may be influenced by dysregulation of the PE N-methyltransferase (PEMT) pathway or by a low-choline diet. Alterations in the liver may also influence lipid composition in circulation such as in erythrocytes, which therefore may have utility as a biomarker of hepatic disease. Currently, no study has assessed both liver and erythrocyte PC/PE ratios in NAFLD. The aim of this study was to compare the PC/PE ratio in the liver and erythrocytes of patients with simple steatosis (SS) or nonalcoholic steatohepatitis (NASH) with that of healthy controls. PC and PE were measured by mass spectrometry in 28 patients with biopsy-proven NAFLD (14 SS, 14 NASH) and 9 healthy living liver donors as controls. The hepatic PC/PE ratio was lower in SS patients (median [range]) (1.23 [0.27-3.40]) and NASH patients (1.29 [0.77-3.22]) compared with controls (3.14 [2.20-3.73]); both p < 0.001) but it was not different between SS and NASH. PC was lower and PE higher in the liver of SS patients compared with controls, whereas in NASH patients only PE was higher. The PC/PE ratio in erythrocytes was also lower in SS and NASH patients compared with controls because of lower PC in both patient groups. PE in erythrocytes was not different among the groups. In conclusion, NAFLD patients have a lower PC/PE ratio in the liver and erythrocytes than do healthy controls, which may play a role in the pathogenesis. The underlying mechanisms require further investigation.
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Affiliation(s)
- Bianca M Arendt
- a Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
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Hamaguchi M, Kojima T, Ohbora A, Takeda N, Fukui M, Kato T. Aging is a risk factor of nonalcoholic fatty liver disease in premenopausal women. World J Gastroenterol 2012; 18:237-43. [PMID: 22294826 PMCID: PMC3261540 DOI: 10.3748/wjg.v18.i3.237] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 09/08/2011] [Accepted: 10/28/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the relationship between age, menopause, and nonalcoholic fatty liver disease (NAFLD) in women.
METHODS: We conducted a follow-up study on nonalcoholic fatty liver disease by using abdominal ultrasonography, and investigated the relationship of age and menopause with the development of NAFLD in women. We followed 1829 women and 2572 men (response rate, 86%) selected in 2001 to represent the non-institutionalized adult population of Gifu, Japan. Data collected included self-reported medical history, lifestyle factors, and menopausal status. The postmenopausal state was defined as beginning 1 year after the cessation of menses. We diagnosed NAFLD with the aid of abdominal ultrasonography by using diagnostic criteria described previously.
RESULTS: The prevalence of NAFLD in women increases with age, but does not alter with age in men. Furthermore, the prevalence of NAFLD in premenopausal women (6%) was lower than that in men (24%) and in postmenopausal women (15%). The associations of the postmenopausal state and hormone replacement therapy with NAFLD were statistically significant in a univariate logistic regression model. At the follow-up examination, 67 women (5%) were newly diagnosed with NAFLD. The incidence of NAFLD was 3.5% (28/802) in premenopausal women, 7.5% (4/53) in menopausal women, 6.1% (24/392) in postmenopausal women, and 5.3% (11/206) in women receiving hormone replacement therapy. The weight gain in premenopausal women was equal to that in postmenopausal women. Metabolic syndrome and weight gain were independent risk factors for NAFLD in pre- and postmenopausal women, but age was an independent risk factor in premenopausal women only.
CONCLUSION: Aging is a risk factor for NAFLD in premenopausal women, independent of weight gain or influence of metabolic syndrome.
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Park SH, Kim DJ, Lee HY. Insulin resistance is not associated with histologic severity in nondiabetic, noncirrhotic patients with chronic hepatitis B virus infection. Am J Gastroenterol 2009; 104:1135-1139. [PMID: 19319126 DOI: 10.1038/ajg.2009.6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES It is still debated whether hepatitis B virus (HBV) infection is associated with the development of diabetes. Our primary objective was to determine whether insulin resistance is associated with HBV-induced histologic severity. METHODS This study included consecutive 80 nondiabetic, noncirrhotic patients with HBV infection who underwent liver biopsy. We evaluated the relationship between histologic findings and clinical parameters and insulin resistance determined by the homeostasis model assessment (HOMA-IR). RESULTS Patients with minimal fibrosis (stage 0 or 1) had significantly higher levels of insulin and HOMA-IR (P = 0.004, P = 0.028, respectively) compared with matched healthy controls. HOMA-IR is independently associated with body mass index (coefficient, 0.16; 95% confidence interval, CI, 0.03-0.28) but not with HBV-induced histologic activity or fibrosis. Insulin resistance was not significantly different among patients with or without significant fibrosis (stage 2 or 3). In multivariate analysis, Hepatitis B e antigen (HBeAg) positivity (odds ratio, OR, 0.04; 95% CI, 0.01-0.31) and portal/periportal inflammation (OR, 18.6; 95% CI, 3.9-88.2) were independent predictors of significant fibrosis. CONCLUSIONS The observed hyperinsulinemia in HBV-infected patients seems to be from altered insulin metabolism rather than HBV-specific effects. Insulin resistance is not associated with significant fibrosis. The data suggest that hepatic fibrosis in HBV-infected patients is attributable to the virus-induced liver injury, but not to insulin resistance.
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Affiliation(s)
- Seung Ha Park
- Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea
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Yalniz M, Bahcecioglu IH, Ataseven H, Ustundag B, Ilhan F, Poyrazoglu OK, Erensoy A. Serum adipokine and ghrelin levels in nonalcoholic steatohepatitis. Mediators Inflamm 2007; 2006:34295. [PMID: 17392582 PMCID: PMC1775029 DOI: 10.1155/mi/2006/34295] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH) and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27%) had diabetes mellitus (n = 5) or impaired glucose tolerance (n = 5). Body mass index (BMI) was less than 30 kg/m2 in 67.6% of patients, while in the remaining 32.4% it was more than 30 kg/m2. Serum adiponectin, leptin,
TNF-α, and ghrelin were determined. Serum leptin (15.49 ± 4.84 vs 10.31 ± 2.53) and TNF-α (12.1 ± 2.7 vs 10.31 ± 2.56) levels were significantly higher in the NASH group compared to in the control group (P < .001 for each). Nevertheless, adiponectin (11.1±2.1 vs 17.3±2.8) and ghrelin (6.46±1.1 vs 7.8±1.1) levels were lower in the NASH group than in the control group (P < .001 for each). Serum levels of the adipokines and ghrelin, however, were comparable in the subgroups of patients regardless of whether BMI was < 30 or > 30 or glucose tolerance was impaired or not (P > .05). Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P > .05). In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.
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Affiliation(s)
- Mehmet Yalniz
- Department of Gastroenterology, School of Medicine, Firat University, 23200 Elazig, Turkey
| | | | - Huseyin Ataseven
- Department of Gastroenterology, School of Medicine, Firat University, 23200 Elazig, Turkey
- *Huseyin Ataseven:
| | - Bilal Ustundag
- Department of Biochemistry, School of Medicine, Firat University, 23200 Elazig, Turkey
| | - Fulya Ilhan
- Department of Immunology, School of Medicine, Firat University, 23200 Elazig, Turkey
| | - Orhan K. Poyrazoglu
- Department of Gastroenterology, School of Medicine, Firat University, 23200 Elazig, Turkey
| | - Ahmet Erensoy
- Department of Microbiology, School of Medicine, Firat University, 23200 Elazig, Turkey
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12
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Sanyal AJ. Review article: non-alcoholic fatty liver disease and hepatitis C--risk factors and clinical implications. Aliment Pharmacol Ther 2005; 22 Suppl 2:48-51. [PMID: 16225473 DOI: 10.1111/j.1365-2036.2005.02596.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis C and non-alcoholic fatty liver disease (NAFLD) are the two most common liver diseases in the Western hemisphere. It is therefore natural that these conditions often co-exist in the same individual. Hepatitis C, especially genotype 3, is often associated with hepatic steatosis. In subjects with genotype 3 infection, a sustained virologic response to treatment is associated with improvement in hepatic steatosis. The diagnosis of NAFLD in a subject with hepatitis C infection is based on the presence of hepatic steatosis. Most investigators require the presence of at least grade II steatosis to warrant a diagnosis of concomitant NAFLD because the significance of minimal steatosis is uncertain. The presence of steatohepatitis is surmised by the additional presence of Mallory bodies, cytologic ballooning and pericellular fibrosis. It is of paramount importance to exclude alcohol as a cause of these histologic findings in this population before a diagnosis of NAFLD is made. The presence of NAFLD in subjects with hepatitis C genotype 1 infection is most strongly associated with the presence of the metabolic syndrome and insulin resistance. The degree of hepatic steatosis correlates with the degree of hepatic fibrosis and the presence of concomitant steatosis is associated with more advanced fibrosis. The presence of cytologic ballooning confers an additional risk for increased fibrosis. Insulin resistance and hyperinsulinemia have been associated with increased collagen production by hepatic stellate cells. Subjects with hepatitis C and NAFLD are more likely to be virologic nonresponders following anti-HCV therapy. The value of treating insulin resistance and NAFLD prior to antiviral therapy remains to be experimentally verified.
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Affiliation(s)
- A J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Health System, Richmond, VA 23298-0711, USA.
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13
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Hui AY, Wong VWS, Chan HLY, Liew CT, Chan JLY, Chan FKL, Sung JJY. Histological progression of non-alcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther 2005; 21:407-13. [PMID: 15709991 DOI: 10.1111/j.1365-2036.2005.02334.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease is an important cause of chronic hepatitis and cryptogenic cirrhosis. The natural history of non-alcoholic fatty liver disease is not well understood especially in Asian populations. AIM To investigate the histological progression in Chinese patients with biopsy-proven non-alcoholic fatty liver disease. METHODS Chinese patients who had liver biopsy at least 3 years ago and confirmed to have non-alcoholic fatty liver disease were invited for a second liver biopsy. Clinical and laboratory parameters related to their liver function and metabolic syndrome were recorded and analysed. Liver biopsies were scored for the degree of steatosis, necroinflammation and fibrosis. Correlation coefficients were calculated to assess the association between changes in histological scores and metabolic parameters. RESULTS Seventeen patients who had been followed up for a median period of 6.1 (range: 3.8-8.0) years underwent a second liver biopsy. Nine (53%) patients had progressive disease with worsening of fibrosis score. No statistically significant correlation was found between the changes in histological scores and metabolic parameters. Seven patients developed hypertension or diabetes mellitus during the period of follow-up. CONCLUSIONS Non-alcoholic fatty liver disease is a progressive disease in Chinese patients as in their Caucasian counterparts. Diagnosis of non-alcoholic fatty liver disease may predate development of new components of metabolic syndrome.
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Affiliation(s)
- A Y Hui
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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YOUNOSSI ZOBAIRM. Interactions between non-alcoholic fatty liver disease and hepatitis C viral infection. J Gastroenterol Hepatol 2004. [DOI: 10.1111/j.1440-1746.2004.03682.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/30/2023]
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Abstract
OBJECTIVES Tumor necrosis factor alpha (TNF alpha) contributes to liver damage and insulin resistance among patients with nonalcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF alpha production. We therefore conducted a 12-month pilot trial to assess the efficacy and safety of pentoxifylline (1,600 mg/day) among 20 patients with NASH. METHODS Patients had biopsy-confirmed NASH with other causes of liver disease and secondary causes of NASH excluded. Patients who drank more than 40 gm of ethanol weekly were also excluded. Pentoxifylline (400 mg q.i.d.) was given for 12 months. Liver enzymes and adverse events were monitored every 3 months until completion. RESULTS The 20 patients had a mean age of 50 +/- 11 yr. Eleven (55%) were female, 14 were obese (body mass index > or =30 kg/m(2)), and 7 (35%) were diabetic. At baseline, median steatosis grade was 2 (range 1-3), median necroinflammatory grade was 1 (1-2), and median fibrosis stage was 2 (0-4). Nine patients withdrew from the study, primarily because of nausea. No serious adverse events occurred. Alanine and aspartate aminotransferase levels were significantly lower at 12 months compared to baseline (84 +/- 64 vs 138 +/- 76, p= 0.002 and 58 +/- 37 vs 102 +/- 62, p= 0.003, respectively). Bilirubin did not change significantly from baseline (0.8 +/- 0.4 vs 0.8 +/- 0.3, p= 0.95), nor did alkaline phosphatase (193 +/- 68 vs 180 +/- 53, p= 0.62) or albumin (4.0 +/- 0.2 vs 4.2 +/- 0.3, p= 0.41). CONCLUSIONS Aminotransferase levels among patients with NASH improve with administration of pentoxifylline. Strategies to overcome side effects will be needed for future trials.
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Affiliation(s)
- Leon A Adams
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
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Madan K, Batra Y, Panda SK, Dattagupta S, Hazari S, Jha JK, Acharya SK. Role of polymerase chain reaction and liver biopsy in the evaluation of patients with asymptomatic transaminitis: implications in diagnostic approach. J Gastroenterol Hepatol 2004; 19:1291-9. [PMID: 15482537 DOI: 10.1111/j.1440-1746.2004.03446.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIM Detection of an asymptomatic rise in the hepatic aminotransferase (ARHA) value has become a distinct and frequent clinical problem. We evaluated a three-step diagnostic algorithm in such patients for maximum yield. METHODS Consecutive patients with an ARHA value 1.5-fold the upper limit of normal for at least 4 weeks and who were apparently healthy were included in the study. Each patient underwent standard biochemical investigations and a stepwise investigative protocol. In the first step, serological markers for hepatitis viruses, serum ferritin, 24-h urinary copper, alpha-1-antitrypsin phenotyping, and autoimmune markers were carried out. In step two, patients who tested negative for all the above markers had polymerase chain reaction (PCR) analysis for hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA. Patients without a diagnosis despite the above investigations underwent a liver biopsy as part of step three. RESULTS Of 105 patients with ARHA, 38 were excluded for various reasons and 67 were included for the final analysis. The mean age was 35.11 +/- 11.96 years and 56 patients were men. The mean body mass index was 24.17 +/- 3.2 kg/m(2). The stepwise diagnostic algorithm achieved a diagnosis in 65/67 (97%) patients. Non-alcoholic steatohepatitis (NASH) and chronic viral hepatitis were the most common diagnoses, in 24 (36%) patients each. Using the diagnostic algorithm a diagnosis was reached in 34% of patients with only serological and biochemical investigations, whereas PCR for HBV and HCV could further detect the presence of active HBV or HCV viremia in 21% (14/97) and a liver biopsy was necessary to establish the diagnosis in 28/67 (42%) patients. CONCLUSIONS A stepwise diagnostic algorithm in patients with ARHA resulted in an optimal use of PCR and invasive tests such as liver biopsy. Cryptic HBV and HCV infection was frequent among these patients and PCR was necessary in such cases. NASH and chronic viral hepatitis were the most frequent causes of ARHA.
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Affiliation(s)
- Kaushal Madan
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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17
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Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99:1946-1952. [PMID: 15447754 DOI: 10.1111/j.1572-0241.2004.40220.x] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) has been incriminated to play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Pentoxifylline, a TNF-alpha inhibitor could prove useful in treating patients with NASH. METHODS Eighteen patients (mean age, 34 +/- 7.8 yr) with histologically proven NASH and with persistently elevated ALT (>1.5 times) were given pentoxifylline at a dosage of 400 mg t.i.d. for 6 months. No lipid-lowering agent or antioxidants were concurrently advised. RESULTS Impaired fasting glycemia, impaired glucose tolerance, diabetes mellitus, and hypertriglyceridemia were noted in 6, 35, 17, and 53% of the patients, respectively. After 6 months of therapy, fatigue improved (55.6 vs 20%, p= 0.016), but serum triglyceride (182 +/- 66 vs 160 +/- 55 mg/dl, p= 0.397), cholesterol (173 +/- 46 vs 162 +/- 40 mg/dl, p= 0.440), and body mass index (BMI) (27.3 +/- 3.1 vs 26 +/- 3.1 kg/m(2), p= 0.087) remained unchanged. Mean AST (66 +/- 29 vs 33 +/- 11 IU/l, p < 0.0001) and ALT (109 +/- 44 vs 47 +/- 20 IU/l, p < 0.0001) reduced significantly. ALT normalized in 23% at month 1 (p= 0.125), 35% at month 2 (p= 0.125), and 60% at month 6 (p= 0.008) of treatment. The insulin resistance index assessed by homeostatic metabolic assessment (HOMA(IR)) improved (5.1 +/- 3.4 vs 2.6 +/- 2, p = 0.046) and the serum TNF-alpha reduced significantly after therapy (22.15 +/- 2.49 vs 17 +/- 2.58 pg/ml, p = 0.011). The drug was well tolerated. CONCLUSIONS In patients with NASH, pentoxifylline therapy effectively achieved significant clinical and biochemical improvement with reduction in HOMA(IR). These benefits are possibly mediated through suppression of TNF-alpha.
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Affiliation(s)
- Sanjay K Satapathy
- Departments of Gastroenterology and Pathology, GB Pant Hospital, New Delhi 110-002, India
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Gupte P, Amarapurkar D, Agal S, Baijal R, Kulshrestha P, Pramanik S, Patel N, Madan A, Amarapurkar A. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol 2004; 19:854-8. [PMID: 15242486 DOI: 10.1111/j.1440-1746.2004.03312.x] [Citation(s) in RCA: 192] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Non-alcoholic steatohepatitis (NASH) is commonly associated with type 2 diabetes mellitus (DM). Prevalence of NASH in type 2 DM has not been well studied and there is an epidemic rise in type 2 DM in Asian and Western populations. Its association with chronic liver disease in the form of NASH makes it an important health problem. Hence we have studied its prevalence and correlation of biochemical parameters with histological grades of non-alcoholic fatty liver disease (NAFLD) in otherwise asymptomatic type 2 DM patients. METHODS One hundred and forty-eight individuals were screened. Forty-eight individuals were excluded due to history of alcohol intake or liver disease as a result of other causes. One hundred non-alcoholic individuals with type 2 DM underwent abdominal ultrasonography (US abdomen). Forty-nine patients had evidence of fatty liver on US abdomen, and 32 of these 49 patients underwent liver biopsy. RESULTS Four of 32 (12.5%) individuals had steatosis alone. Mild, moderate and severe NASH was present in 21/32 (65.5%), 4/32 (12.5%) and 3/32 (9.35%), respectively. Fibrosis was present in 7/32 (21.8%) patients (four grade 1 and three grade 3). There was no significant difference in body mass index (BMI), transaminase levels, serum cholesterol and triglyceride levels among patients with non-alcoholic fatty liver disease. CONCLUSION We conclude that the prevalence of NASH is high in type 2 DM patients and liver biopsy is the only investigation to differentiate between non-alcoholic fatty liver and steatohepatitis.
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Affiliation(s)
- Parijat Gupte
- Gastroenterology Center, Jagjivanram Hospital, Mumbai Central, Mumbai, Maharashtra, India
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Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99:1497-502. [PMID: 15307867 DOI: 10.1111/j.1572-0241.2004.30159.x] [Citation(s) in RCA: 253] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Products of systemic lipid peroxidation are important in the pathogenesis of cardiovascular disease. Subjects with NASH have increased hepatic lipid peroxidation, but it is unknown if they have increased oxidative stress and lipid peroxidation systemically. Therefore, we conducted a study to measure the circulating levels of lipid peroxidation products and their metabolic and nutritional correlates in patients with NASH and controls. METHODS Systemic lipid peroxidation was assessed by measuring the levels of oxidized LDL (ox-LDL) and thiobarbituric acid-reacting substances (TBARS) in 21 subjects with NASH and 19 controls. Correlations were made between serum lipid peroxidation and nutritional determinants of oxidative stress and defense, serum lipids, insulin resistance, transaminases, and liver histology. The short-term nutrient intake was analyzed by maintaining a 3-wk dietary diary. RESULTS The serum levels of ox-LDL were significantly higher in NASH patients compared to controls (56 +/- 16 U/L vs 40 +/- 12 U/L, respectively, p < 0.001). Similarly, serum TBARS were significantly higher in NASH patients compared to controls (3.4 +/- 1.3 vs 1.8 +/- 0.9 nmols/ml, respectively, p= 0.0001). Insulin resistance was independently associated with ox-LDL (p= 0.01) and TBARS levels (p= 0.01). We found no differences in the intake of various macro- and micronutrients between the two groups and there was no association between nutrient intake and ox-LDL or TBARS. CONCLUSION Subjects with NASH have significantly higher systemic levels of lipid peroxidation products and this could indicate an increased risk of cardiovascular disease. More studies are needed to evaluate this possibility.
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Affiliation(s)
- Naga Chalasani
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
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Adams LA, Lindor KD, Angulo P. The prevalence of autoantibodies and autoimmune hepatitis in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol 2004; 99:1316-20. [PMID: 15233671 DOI: 10.1111/j.1572-0241.2004.30444.x] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Autoantibodies may exist in serum of patients with nonalcoholic fatty liver disease (NAFLD) although their prevalence and clinical significance is uncertain. We aimed at examining the prevalence of autoantibodies and autoimmune hepatitis among patients with NAFLD. METHODS Prevalence of antinuclear antibodies (ANA), anti-smooth muscle antibodies (anti-SMA), and autoimmune hepatitis (AIH) based on the International AIH Group were determined in 225 patients with liver biopsy-proven NAFLD. RESULTS Fifty-one patients [23% (95% CI 17.3-28.2%)] had autoantibodies in serum which is significantly higher than the prevalence in the general population. ANA were present in 46 patients (20%), SMA in 6 (3%), and both antibodies in one patient. Positive autoantibodies were associated with higher fibrosis stage (p= 0.03), higher inflammatory grade (p= 0.02), and higher levels of gammaglobulin (p= 0.01). Prior to liver biopsy, 45 of the 51 (88%) patients with positive autoantibodies fulfilled diagnostic criteria for 'probable' or 'definite' AIH. After liver biopsy, however, only four patients fulfilled diagnostic criteria. CONCLUSIONS Routinely measured autoantibodies are present in one quarter of patients with NAFLD and are associated with more severe histological damage. Liver biopsy is required to rule out AIH in most NAFLD patients with positive autoantibodies.
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Affiliation(s)
- Leon A Adams
- Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, Minnesota 55905, USA
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Iftikhar R, Kladney RD, Havlioglu N, Schmitt-Gräff A, Gusmirovic I, Solomon H, Luxon BA, Bacon BR, Fimmel CJ. Disease- and cell-specific expression of GP73 in human liver disease. Am J Gastroenterol 2004; 99:1087-95. [PMID: 15180730 DOI: 10.1111/j.1572-0241.2004.30572.x] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES GP73, a Golgi membrane protein, is expressed at high levels in hepatocytes of patients with decompensated cirrhosis. Its expression in other forms of liver disease has not been investigated. Therefore, we studied GP73 expression in patients with noncirrhotic liver disease. METHODS GP73 expression was detected immunohistochemically and by immunofluorescence microscopy in patients with acute hepatitis of various etiologies, autoimmune hepatitis, chronic HCV infection, and alcoholic liver disease. In order to quantitate hepatocyte GP73 expression, an immunohistochemical scoring system was developed, and validated by a direct comparison with GP73 protein levels as determined by Western blotting. RESULTS GP73 immunostaining and Western blotting data were highly correlated, demonstrating the suitability of the immunohistochemical scoring system to quantitate hepatocyte GP73 expression. Hepatocyte GP73 expression was increased in patients with acute and autoimmune hepatitis. Treatment of autoimmune hepatitis was associated with a normalization of GP73 expression, indicating that the initial upregulation was reversible. Increased levels of GP73 expression were also noted in chronic HCV infection and alcoholic liver disease. Under these conditions, GP73 levels were correlated with disease stage but not grade. GP73 immunoreactivity was occasionally detected in alpha-SMA-positive, sinusoidal lining cells, suggesting activated stellate cells as a potential source of GP73. CONCLUSIONS Hepatocyte GP73 levels are upregulated in acute hepatitis and during the progression of liver disease to cirrhosis. This expression pattern suggests the presence of two regulatory mechanisms, the first triggered during acute hepatocellular injury, the second during the progression of chronic liver disease.
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Affiliation(s)
- Rehan Iftikhar
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
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Festi D, Colecchia A, Sacco T, Bondi M, Roda E, Marchesini G. Hepatic steatosis in obese patients: clinical aspects and prognostic significance. Obes Rev 2004; 5:27-42. [PMID: 14969505 DOI: 10.1111/j.1467-789x.2004.00126.x] [Citation(s) in RCA: 197] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease is a new clinicopathological condition of emerging importance, now recognized as the most common cause of abnormal liver tests. It is characterized by a wide spectrum of liver damage: simple steatosis may progress to advanced fibrosis and to cryptogenic cirrhosis through steatohepatitis, and ultimately to hepatocellular carcinoma. Obesity is the most significant single risk factor for the development of fatty liver, both in children and in adults; obesity is also predictive of the presence of fibrosis, potentially progressing to advanced liver disease. From a pathogenic point of view, insulin resistance plays a central role in the accumulation of triglycerides within the hepatocytes and in the initiation of the inflammatory cascade. Chronic hepatocellular injury, necroinflammation, stellate cell activation, progressive fibrosis and ultimately, cirrhosis may be initiated by peroxidation of hepatic lipids and injury-related cytokine release. In the last few years, several pilot studies have shown that treatment with insulin-sensitizing agents, anti-oxidants or cytoprotective drugs may be useful, but there is no evidence-based support from randomized clinical trials. Modifications in lifestyle (e.g. diet and exercise) to reduce obesity remain the mainstay of prevention and treatment of a disease, which puts a large number of individuals at risk of advanced liver disease in the near future.
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Affiliation(s)
- D Festi
- Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy.
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Chalasani N, Crabb DW, Cummings OW, Kwo PY, Asghar A, Pandya PK, Considine RV. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol 2003; 98:2771-6. [PMID: 14687831 DOI: 10.1111/j.1572-0241.2003.08767.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Obesity is a risk factor for nonalcoholic steatohepatitis (NASH). Leptin plays an important role in the regulation of food intake, body composition, energy expenditure, and body weight. It has been suggested that leptin plays a role in the pathogenesis of NASH; however, adequate studies are lacking. We therefore conducted a study to explore the role of serum leptin in the pathogenesis of human NASH. METHODS We measured the levels of serum leptin and its anthropometric, biochemical, metabolic, and histological correlates in a cohort of patients with NASH (n = 26) and well-matched controls (n = 20). Furthermore, we measured the levels of leptin in the serum and hepatic leptin and leptin receptor messenger RNA (mRNA) expression in liver biopsy specimens of patients with NASH (n = 5) and simple steatosis (n = 5). RESULTS Serum leptin was not statistically different between patients with NASH and their controls (21 +/- 13 vs 18 +/- 11 ng/ml, respectively, p = 0.5). There was no correlation between serum leptin and hepatic histology, serum transaminases, fasting insulin levels, or a measure of insulin resistance. After adjusting for covariates in a multiple regression analysis, only percent body fat (p = 0.04) and subcutaneous abdominal fat area (p = 0.04) had significant correlation with serum leptin. There was no expression of leptin mRNA in the cell lysate of liver biopsy specimens of subjects with NASH or steatosis. Additionally, the serum leptin levels and the hepatic leptin receptor mRNA expression were not statistically different between patients with NASH and those with simple steatosis. CONCLUSION These data do not support a direct role for leptin in the pathogenesis of human NASH.
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Affiliation(s)
- Naga Chalasani
- Department of Medicine, Indiana University School of Medicine, WD OPW 2005, 1001 West 10th Street, Indianapolis, IN 46202, USA
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Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98:2485-90. [PMID: 14638353 DOI: 10.1111/j.1572-0241.2003.08699.x] [Citation(s) in RCA: 483] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease. Although usually indolent, this disease can progress to cirrhosis in some patients. There is currently no proven medical therapy for the treatment of NASH. The aim of our study was to evaluate the efficacy of combination alpha-tocopherol (vitamin E) and vitamin C in reducing histologic inflammation and fibrosis. METHODS This was a prospective, double-blind, randomized, placebo-controlled trial with a total enrollment of 49 patients; 45 patients completed the study. All patients were randomized to receive either vitamins E and C (1000 IU and 1000 mg, respectively) or placebo daily for 6 months, based on their initial histologic diagnosis of NASH. Additionally, all patients were given standard weight-loss counseling and encouraged to follow a low fat diet (<30 fat g/day). The pre- and posttreatment liver biopsies were reviewed by a single pathologist, who was blinded to the patient's medication. Biopsies were scored based on a modification of the scoring system published by Brunt et al. (Am J Gastroenterol 1999;94:2467-74). A score of 0-4 was possible for fibrosis, and a score of 0-6 was possible for inflammation and hepatocyte degeneration and necrosis. In addition, body mass index, glycohemoglobin, lipids, and liver enzymes were followed throughout the study. RESULTS Forty-five patients completed 6 months of therapy without significant side effects. Vitamin treatment resulted in a statistically significant improvement in fibrosis score (p=0.002). No changes were noted in inflammation with treatment. Vitamin E and vitamin C, in the doses used in this study, were well tolerated and were effective in improving fibrosis scores in NASH patients. No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy. A larger, multicenter, longer-term trial with vitamin E and vitamin C seems to be warranted.
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Affiliation(s)
- Stephen A Harrison
- Brooke Army Medical Center, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
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Adams LA, Angulo P. Vitamins E and C for the treatment of NASH: duplication of results but lack of demonstration of efficacy. Am J Gastroenterol 2003; 98:2348-50. [PMID: 14638333 DOI: 10.1111/j.1572-0241.2003.08695.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Miyake T, Michitaka K, Abe M, Konishi I, Tokumoto Y, Kumagi T, Nakanishi S, Minami H, Matsui H, Matsuura B, Horiike N, Onji M. Laparoscopic findings of liver cirrhosis due to non-alcoholic steatohepatitis. Dig Endosc 2003. [DOI: 10.1046/j.1443-1661.2003.00292.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
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Seki S, Sakaguchi H, Kitada T, Iwai S, Fujii H, Enomoto M, Habu D, Tamori A. Laparoscopic findings in non‐alcoholic steatohepatitis. Dig Endosc 2003; 15:306-310. [DOI: 10.1046/j.1443-1661.2003.t01-1-00263.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/08/2023]
Abstract
Background: Non‐alcoholic steatohepatitis (NASH) is prevalent worldwide, but little attention has been paid to the gross visual appearance of NASH. The present study was performed to address the laparoscopic features of NASH and the relationship between laparoscopic and histologicalal findings.Methods: Eleven patients were examined by laparoscopy with liver biopsy. Histological findings were examined according to the criteria of Brunt et al. with minor modification. Mallory bodies were immunohistochemically detected by an antibody to ubiquitin in addition to hematoxylin eosin staining.Results: Laparoscopic features of NASH were swelling of the liver, formation of many depressions, and dull edges of the liver. When steatosis was present in more than one‐third of lobules, yellowish markings appeared on the liver surface. NASH progressed from a smooth liver surface with or without yellowish markings, to formation of depressions on the liver surface, to cirrhosis with or without hepatocellular carcinoma (HCC).Conclusion: Laparoscopy may provide useful information in the diagnosis and progression of NASH.
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Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Stravitz RT, Mills AS. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol 2003; 98:2064-71. [PMID: 14499789 DOI: 10.1111/j.1572-0241.2003.07640.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The objectives of this study were to determine the following: 1) whether chronic hepatitis C virus (HCV) infection was specifically associated with nonalcoholic fatty liver disease (NAFLD); 2) the factors associated with NAFLD in patients with HCV; and 3) the clinical and histological spectrum of NAFLD occurring together with HCV. METHODS A retrospective analysis of 3826 biopsies was performed to compare the prevalence of NAFLD in those with HCV versus that in other liver diseases, e.g., hepatitis B, primary biliary cirrhosis, and alpha(1)-antitrypsin deficiency. Patients with HCV and NAFLD were also compared with an age- and gender-matched control group with HCV and <5% hepatic steatosis. RESULTS The prevalence of NAFLD in patients with HCV was similar to that in hepatitis B, primary biliary cirrhosis, or alpha(1)-antitrypsin deficiency. The risk of having NAFLD in patients with HCV correlated with body weight (r = 0.7, p < 0.02). Compared with a control group with HCV alone (n = 75), patients with HCV and NAFLD (n = 69) were likely to be heavier (mean BMI 27 vs 30, p < 0.003), diabetic (eight vs 21, p < 0.005), hypertensive (14 vs 25, p < 0.05), and hypertriglyceridemic (15 vs 33, p < 0.05). The HCV viral load, genotype distribution, liver enzymes, liver functions, and ferritin levels were comparable across the study groups. Those with HCV and NAFLD were more likely to have advanced fibrosis (bridging fibrosis or cirrhosis) (26% vs 53%, p < 0.03). Weight, diabetes, and cytological ballooning were independent predictors of advanced fibrosis in those with HCV and NAFLD. CONCLUSIONS The presence of NAFLD in patients with HCV is strongly associated with features of the metabolic syndrome and is a risk factor for advanced fibrosis. Advanced fibrosis in such patients is related to weight, presence of diabetes, and presence and degree of cytological ballooning.
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Affiliation(s)
- Arun J Sanyal
- Department of Pathology, Virginia Commonwealth University Health System, Richmond, Virginia, USA
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Harrison SA, Ramrakhiani S, Brunt EM, Anbari MA, Cortese C, Bacon BR. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol 2003; 98:926-30. [PMID: 12738478 DOI: 10.1111/j.1572-0241.2003.07375.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic steatohepatitis is now recognized as a common chronic liver disorder. Up to 16% of affected patients may progress to cirrhosis. The incidence and prevalence of this disease are noted to be increasing, in parallel with the nationwide increase in obesity and diabetes. Treatment options for these patients remain quite limited, however. Weight reduction has been advocated, but there are little data to support this practice, as most patients are unable to comply with the proper dietary modifications. We report three obese patients with biopsy-proven nonalcoholic steatohepatitis treated for 6-12 months with a weight reduction medication, orlistat, who lost between 22-42 lb, and had significant clinical and histopathological improvement on follow-up.
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Affiliation(s)
- Stephen A Harrison
- Saint Louis University Liver Center, Division of Gastroenterology and Hepatology, St. Louis, Missouri 63110, USA
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Abstract
OBJECTIVES Steatosis or steatohepatitis, common conditions associated with obesity, are usually considered to be stable or only slowly progressive. We have encountered a small number of patients with a history of obesity and a subacute course of liver failure over a period of 4-16 wk from the onset of symptoms. The patients had findings suggestive of an acute exacerbation of previously unrecognized nonalcoholic steatohepatitis (NASH). METHODS The patients were ascertained from our liver disease registry, which, at the time of the study, contained 2380 patients: 167 had NASH and 215 had cryptogenic cirrhosis. Five of these patients were identified with a subacute course of their illness. RESULTS The patients were female, aged 41-65 yr, and obese (BMI >30, mean 41 +/- 9, range 32-52). One patient had type 2 diabetes treated by diet alone and one had a history of glucose intolerance. None had known prior liver disease and two had no prior medical problems. All five presented with fatigue and lethargy. Over 4-16 wk, the patients developed frank encephalopathy, ascites, jaundice, and multiorgan failure. An extensive evaluation revealed no clear etiology of their disease, although initial imaging studies consistently showed evidence of previously unrecognized cirrhosis. Four patients died from complications of liver failure and the fifth patient underwent OLT. Histology revealed cirrhosis with variable numbers of balloon cells in all five patients, frank steatohepatitis in three, necrosis in two, and microvesicular (with macrovesicular) steatosis in one. CONCLUSIONS These patients, all obese and middle-aged women with no history of liver disease, had previously unrecognized cirrhosis and sudden deterioration of uncertain cause. We speculate, based on the clinical and histological findings, that these patients had undiagnosed NASH with silent progression to cirrhosis followed by subacute liver failure. We propose that obesity-related liver disease may infrequently present as severe, subacute illness.
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Affiliation(s)
- Stephen H Caldwell
- Department of Internal Medicine, University of Virginia, Charlottesville 22908-0708, USA
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Abstract
BACKGROUND AND AIMS Hepatotoxicity, especially liver fibrosis, is the major concern with long-term, 'low-dose' oral methotrexate (MTX) therapy for psoriasis. The histological features are non-specific and resemble those of non-alcoholic steatohepatitis (NASH). Moreover, most of the risk factors of MTX-induced liver injury are also associated with NASH. In this study, we investigate whether NASH contributes to the prevalence and progression of MTX-induced liver injury in patients receiving MTX for psoriasis. METHODS Clinical details, including MTX dosage schedules and risk factors for liver injury, was documented for 24 patients on long-term MTX therapy for psoriasis. Serial liver biopsies were graded according to the Roenigk classification scale and a recently proposed grading and staging system for NASH. RESULTS Thirteen of the 17 patients who had a NASH-like pattern of liver injury also had the risk factors for NASH obesity and/or diabetes, and all had progressive liver injury. The other four patients had no risk factors, but a mean cumulative dose of 6.5 g. Seven patients, who did not have a NASH-like pattern of injury, had a mean cumulative dose of 3.8 g. There was a positive correlation between the cumulative dose, risk factors and progression when the biopsies were scored by the modified grading and staging classification for NASH, but not with the Roenigk system. CONCLUSIONS Non-steatohepatitis, probably aggravated by MTX, is an important cause of liver injury in patients on long-term, 'low-dose' MTX treatment for psoriasis. In addition, MTX alone can cause a NASH-like pattern of injury that is at least, in part, caused by a higher cumulative dose.
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Affiliation(s)
- G Langman
- Department of Anatomical Pathology, Groote Schuur Hospital and the University of Cape Town, South Africa
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Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001; 96:2711-7. [PMID: 11569700 DOI: 10.1111/j.1572-0241.2001.04129.x] [Citation(s) in RCA: 283] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH. METHODS Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine. RESULTS A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients. CONCLUSIONS Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial.
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Affiliation(s)
- M F Abdelmalek
- Divisions of Gastroenterology and Hepatology and Surgical Pathology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
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Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96:519-25. [PMID: 11232700 DOI: 10.1111/j.1572-0241.2001.03553.x] [Citation(s) in RCA: 273] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Troglitazone is a thiazolidinedione and peroxisome proliferator-activated receptor gamma (PPARgamma) ligand used to treat diabetes mellitus type II. Because hyperinsulinemia may be a factor in nonalcoholic steatohepatitis (NASH), we postulated that troglitazone could have beneficial effects in this disorder. Our study was initiated before reports of idiosyncratic hepatitis induced by this agent and was completed before its recent withdrawal from the market. METHODS We studied 10 female patients (age 44 +/- 16) with histological NASH. All but two were obese (mean body mass index, BMI = 38 +/- 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Troglitazone was given at a dose of 400 mg/day for < or = 6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied. Paired specimens were compared in blinded fashion. Mitochondria were quantitated using ultrathin electron microscopy. RESULTS Seven of ten patients responded with normal ALT at the end of treatment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and the ALT has remained at the baseline level with no other clinical or laboratory findings. In the responders, ALT fell from 87 +/- 38 before to 39 +/- 9 at the end of treatment (p = 0.01), and AST decreased from 77 +/- 23 to 30 +/- 8 (p = 0.002). Biopsy comparisons before and after therapy showed persistent steatohepatitis in all cases, although four of seven showed a one-point improvement in the necroinflammatory grade. Electron microscopy revealed elongation of the mitochondria after therapy. CONCLUSIONS Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.
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Affiliation(s)
- S H Caldwell
- Department of Internal Medicine, University of Virginia, Charlottesville 22906-0013, USA
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Uygun A, Kadayifci A, Yesilova Z, Erdil A, Yaman H, Saka M, Deveci MS, Bagci S, Gulsen M, Karaeren N, Dagalp K. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2000; 95:3584-9. [PMID: 11151896 DOI: 10.1111/j.1572-0241.2000.03297.x] [Citation(s) in RCA: 182] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Leptin is a peptide hormone that mainly regulates food intake and energy expenditure of human body. A close correlation between serum leptin levels and the percentage of body fat stores is well known. Nonalcoholic steatohepatitis (NASH) is a common disorder which causes serum liver enzyme elevation. In this study, the serum leptin levels were investigated in patients with NASH to determine a possible role in the pathogenesis and in patients with chronic viral hepatitis to ascertain the effect of hepatic inflammation on serum leptin level. METHODS Forty-nine patients (38 men, 11 women) with NASH diagnosed by biopsy, 32 patients with biopsy-proven chronic viral hepatitis (21 men and 11 women), and 30 healthy adults (17 men, 13 women) enrolled in the study. Fasting blood samples were obtained, and serum leptin levels were measured by ELISA. Body mass index (BMI) was calculated for all subjects, and serum insulin, C-peptide, and lipoprotein levels were also detected. RESULTS The mean serum leptin levels (+/-SEM) were 6.62 +/- 0.71, 4.24 +/- 1.0, and 4.02 +/- 0.46 ng/ml in NASH, chronic hepatitis, and the control group, respectively. Mean serum leptin level in the NASH group was significantly higher than those in the other groups tested. BMI was also slightly higher in the NASH group when compared to the other groups (26.7 +/- 0.3, 23.7 +/- 0.6, and 24.6 +/- 0.3, respectively). There was a significant correlation between BMI and serum leptin levels when all the subjects were evaluated together (NASH, hepatitis, and control groups, r = 0.337, p = 0.012) but not in the NASH group when evaluated alone (r = 0.238, p = 0.1). Of the predisposing factors for NASH, obesity was observed in 24% of patients and hyperlipidemia in 67%. Serum cholesterol and triglyceride levels were significantly higher in the NASH group than those in controls (p < 0.05). It has been detected that most of these patients consumed high amounts of fat in their dietary habits. CONCLUSIONS The serum leptin levels were significantly higher in patients with NASH, while they were not affected by chronic hepatitis. This elevation is out of proportion to BMI of these patients and may be related to hyperlipidemia in most. Elevated serum leptin levels, therefore, may promote hepatic steatosis and steatohepatitis.
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Affiliation(s)
- A Uygun
- Department of Gastroenterology, Gulhane Military Medical Academy, Ankara, Turkey
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Sonsuz A, Basaranoglu M, Ozbay G. Relationship between aminotransferase levels and histopathological findings in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2000; 95:1370-1. [PMID: 10811364 DOI: 10.1111/j.1572-0241.2000.02046.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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