Non-cirrhotic Non-alcoholic Steatohepatitis Research Articles

Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management.

With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

Hepatocellular Carcinoma Developed From Non-Cirrhotic Liver: A Case Report

Non-alcoholic steatohepatitis (NASH) is recognized as a crucial factor in the development of hepatocellular carcinoma (HCC) from non-viral cirrhosis. It is generally known that cirrhosis, fibrosis of the liver, works as a carcinogenic promoter, and it is uncommon for non-cirrhotic liver to develop into HCC. Here we report a case of HCC that developed from non-cirrhotic NASH. A 76-year-old male presented to our hospital with abdominal distention. His medical history included impaired glucose tolerance and hypertension. He denied any use of alcohol. Ultrasonography revealed a lobular mass in S5 of the liver with a marginal low echo that measured 50 × 40 mm. Contrast-enhanced computed tomography confirmed HCC. Laboratory analysis revealed normal hepatic and biliary enzymes, as well as normal levels of tumor markers, including alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II. Virus markers were negative for HBs-Ag, HBV-DNA, HCV-Ab, and HCV-RNA. As a result, he was chosen as a candidate for surgical resection; subsegmental resection of S5 and S6 was performed. The resected specimens of the tumor revealed moderately differentiated HCC; rich macrovesicular lipid depositions were observed over the background liver, which was compatible with A2F1. Based on the histological findings, he was diagnosed with HCC developed from non-cirrhotic NASH. This case report is informative for clinicians by raising awareness of the potential risk of HCC in non-cirrhotic NASH. J Med Cases. 2016;7(11):508-511 doi: https://doi.org/10.14740/jmc2681w

PWE-136 The non-invasive detection of non-alcoholic fatty liver disease using urinary volatile organic compound analysis: a pilot study

Introduction Non Alcoholic Fatty Liver Disease (NAFLD) is the commonest cause of chronic liver disease in the western world. Current diagnostic methods, including that of the Fibroscan, have limitations, thus there is a clinical need for more robust, non-invasive screening tools. The gut microbiome is altered in several gastrointestinal and hepatic disorders resulting in altered, unique gut fermentation patterns. These patterns are detectable by analysis of volatile organic compounds (VOCs) in urine, breath and faeces. We aimed to determine if progressive fatty liver disease produced an altered VOC pattern in urine; specifically NAFLD and Non-Alcoholic Steatohepatitis (NASH). Method 34 patients were recruited; 8 NASH cirrhotics (NASH-C); 7 non-cirrhotic NASH; 4 NAFLD and 15 controls. Urine was collected and stored frozen. For assay, the samples were defrosted and aliquoted into vials, which were heated to 40 ± 0.1°C and the headspace analysed by FAIMS (Field Asymmetric Ion Mobility Spectroscopy). A previously used data processing pipeline employing a ‘Random Forrest’ classification algorithm and a 10 fold cross validation method was applied. Results Urinary VOCs could distinguish liver disease patients from controls with a sensitivity of 0.58 (0.33–0.88) but specificity of 0.93 (0.68 – 1.00); Area Under Curve (AUC) 0.73 (0.55 – 0.90). NASH/NASH-C was similarly separated from the NAFLD/control patients with a sensitivity of 0.73 (0.45–0.92), a specificity of 0.79 (0.54–0.94) and AUC of 0.79 (0.64–0.95), respectively. Conclusion This pilot study offers the potential for early non-invasive tracking of liver disease using urinary VOC bio-odorant fingerprints to distinguish patients with a disease within the spectrum of fatty liver disease from healthy controls, but also to distinguish subsets of the spectrum from each other, such as NASH from NAFLD. This may develop into a viable alternative surveillance or diagnostic tool in patients unable or unwilling to undergo liver biopsy. Disclosure of interest None Declared.

Non-invasive distinction of non-alcoholic fatty liver disease using urinary volatile organic compound analysis: early results.

Non-Alcoholic Fatty Liver Disease (NAFLD) is the commonest cause of chronic liver disease in the western world. Current diagnostic methods including Fibroscan have limitations, thus there is a need for more robust non-invasive screening methods. The gut microbiome is altered in several gastrointestinal and hepatic disorders resulting in altered, unique gut fermentation patterns, detectable by analysis of volatile organic compounds (VOCs) in urine, breath and faeces. We performed a proof of principle pilot study to determine if progressive fatty liver disease produced an altered urinary VOC pattern; specifically NAFLD and Non-Alcoholic Steatohepatitis (NASH). 34 patients were recruited: 8 NASH cirrhotics (NASH-C); 7 non-cirrhotic NASH; 4 NAFLD and 15 controls. Urine was collected and stored frozen. For assay, the samples were defrosted and aliquoted into vials, which were heated to 40±0.1°C and the headspace analyzed by FAIMS (Field Asymmetric Ion Mobility Spectroscopy). A previously used data processing pipeline employing a Random Forrest classification algorithm and using a 10 fold cross validation method was applied. Urinary VOC results demonstrated sensitivity of 0.58 (0.33 - 0.88), but specificity of 0.93 (0.68 - 1.00) and an Area Under Curve (AUC) 0.73 (0.55 - 0.90) to distinguish between liver disease and controls. However, NASH/NASH-C was separated from the NAFLD/controls with a sensitivity of 0.73 (0.45 - 0.92), specificity of 0.79 (0.54 - 0.94) and AUC of 0.79 (0.64 - 0.95), respectively. This pilot study suggests that urinary VOCs detection may offer the potential for early non-invasive characterisation of liver disease using 'smell prints' to distinguish between NASH and NAFLD.

Hepatocellular Carcinoma Arising from Non-Cirrhotic Non-Alcoholic Steatohepatitis

The major risk factors of hepatocellular carcinoma (HCC) include hepatitis B virus (HBV), hepatitis C virus (HCV) infec-tion and alcohol in Korea, but the prevalence of non-alcoholic fatty liver disease (NAFLD)-related HCC is rising worldwide, as 4~22% of HCC cases in Western countries are now attributed to NAFLD [1,2]. Most cases of non-alcoholic steatohepatitis (NASH), an ad-vanced form of NAFLD, do not have poor outcomes, but ad-vancement to liver fibrosis is noted in around 30% of patients and liver cirrhosis develops within 5.6 years in approximately 9% of patients. Among these patients with liver cirrhosis, 4% to 27% eventually develop HCC [3]. Recently, cases of HCC in patients with non-cirrhotic NASH have been reported [4,5]. However, HCC development in patients with NASH who do not first develop liver cirrhosis is rare and has not been previously reported in Korea. Here, we report the first known case of HCC development in a Korean patient with non-cirrhotic NASH.

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S03 * ALCOHOL, CANCER, HEPATITIS AND FATTY LIVER: INTERACTIONS AND CO-MORBIDITIES

S03 * ALCOHOL, CANCER, HEPATITIS AND FATTY LIVER: INTERACTIONS AND CO-MORBIDITIES

Propranolol, a β-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis

Prazosin an α1-adrenoceptor (AR) antagonist has been shown to reduce liver injury in a mouse model of non-alcoholic steatohepatitis (NASH) and is suggested as a potential treatment of NASH especially given its concomitant anti-fibrotic properties. The effect however, of β-AR blockade in non-cirrhotic NASH is unknown and is as such investigated here. In the presence of the β-blocker propranolol (PRL), mice fed normal chow or a half methionine and choline deficient diet, supplemented with ethionine (HMCDE), to induce NASH, showed significantly enhanced liver injury, as evidenced by higher hepatic necrosis scores and elevated serum aminotransferases (ALT). Mechanistically, we showed that murine hepatocytes express α and β adrenoceptors; that PRL directly induces hepatocyte injury and death as evidenced by increased release of lactate dehydrogenase, FASL and TNF-α from hepatocytes in the presence of PRL; and that PRL activated the apoptotic pathway in primary hepatocyte cultures, as indicated by upregulation of Fas receptor and caspase-8 proteins. The β-AR antagonist PRL therefore appears to enhance liver injury through induction of hepatocyte death via the death pathway. Further studies are now required to extrapolate these findings to humans but meanwhile, β-AR antagonists should be avoided or used with caution in patients with non-cirrhotic NASH as they may worsen liver injury.

Epidemiology and Natural History of Patients with NAFLD

Non-alcoholic fatty liver disease (NAFLD) currently represents the most common liver disease in Western countries, being found in 25-30% of the general population. NAFLD embraces a wide range of metabolic hepatic damage characterised by steatosis and, in some cases, associated non-alcoholic steatohepatitis (NASH). The long-term hepatic prognosis of NAFLD patients depends on the histological stage at diagnosis: simple steatosis has a favourable outcome, whereas patients with NASH can develop cirrhosis and other liver-related complications, including hepatocellular carcinoma. Progression of fibrosis is thought to develop in up to one third of NASH patients, including the development of cirrhosis, but regression is also possible in pre-cirrhotic stages. Independent predictors of fibrosis are older age, diabetes, obesity, hypertension, and the degree of insulin resistance. Patients with NAFLD, particularly those with NASH, have a higher prevalence and incidence of clinically manifested cardiovascular disease, independently of classical cardiometabolic risk factors. Hepatocellular carcinoma (HCC) is usually diagnosed at a late stage, but it may also occur in non-cirrhotic NASH, as obesity and diabetes both independently increases the risk of developing HCC. Liver-related mortality is increased up to ten-fold in patients with NASH.

Nonalcoholic Steatohepatitis and Noncirrhotic Hepatocellular Carcinoma: Fertile Soil

Nonalcoholic fatty liver disease (NAFLD) is easily the most common cause of chronic liver disease in the United States (U.S.) as the hepatic manifestation of the metabolic syndrome. Although only 5 to 20% of patients with NAFLD are generally considered to meet criteria for nonalcoholic steatohepatitis (NASH), with its inherent risk for progression to cirrhosis, this still represents an alarmingly large number of individuals. The exponentially growing rates of hepatocellular carcinoma (HCC) in the U.S. may be partially attributable to increased numbers of NASH cirrhotics, although recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis. This review focuses on HCC in noncirrhotic NASH with an emphasis on clinical presentation, pathogenesis, and implications for screening.

Is nonalcoholic steatohepatitis associated with a high-though-normal thyroid stimulating hormone level and lower cholesterol levels?

Hypothyroidism is associated with the risk of development of the metabolic syndrome (MS) and hypercholesterolemia. Direct evidence that hypothyroidism might be associated with advanced chronic liver disease via nonalcoholic steatohepatitis (NASH) is limited. We studied the relationship between thyroid hormones, thyroid stimulating hormone (TSH), cholesterol, and NASH. In consecutive euthyroid patients with biopsy-proven nonalcoholic fatty liver disease, TSH and thyroid hormone (FT3 and FT4) concentrations were compared in 25 patients with steatosis and 44 non-cirrhotic NASH patients featuring concurrent ballooning, lobular inflammation and steatosis. The MS was diagnosed according to ATP III criteria. A meta-analysis of previously published studies was performed to evaluate whether NASH, compared to simple steatosis, is associated with lower cholesterol levels. At univariate analysis, compared to those with steatosis, patients with NASH have a wider waist, elevated levels of BMI, ALT, AST, fasting insulin, HOMA-IR, ferritin, TSH and a lower serum cholesterol. At stepwise multivariable logistic regression analysis, the independent predictors of NASH are high HOMA and TSH and lower total cholesterol (Model 1); MS and high TSH (Model 2). At meta-analysis, serum total cholesterol levels are significantly lower in predominantly non-cirrhotic NASH than in simple steatosis. This study provides cross-sectional and meta-analytic evidence that, in euthyroid patients, high-though-normal TSH values are independently associated with NASH. Further work is needed to ascertain the role, if any, of lower cholesterol serum levels in assisting in the diagnosis of NASH.

Decreased immunoexpression of survivin could be a potential marker in human non-alcoholic fatty liver disease progression?

Regulation of apoptosis in non-alcoholic fatty liver disease (NAFLD) has been a theme of growing debate. Although no other study assessed the role of survivin in NAFLD, its expression has been reported in hepatic carcinogenesis because of other aetiological factors with relevant discrepancies. The aim of this study was to assess the pattern of survivin immunoexpression by tissue microarray along the whole spectrum of NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Liver biopsies from 56 patients with NAFLD were evaluated: 18 with steatosis, 21 non-cirrhotic NASH, 10 NASH-related cirrhosis, seven NASH-related HCC, as compared with 71 HCC related to other causes and with 12 normal livers. Survivin immunoexpression in NAFLD was restricted to cytoplasm and was found to be progressively lower in advanced stages, including cirrhosis and HCC: steatosis vs NASH-related cirrhosis (P=0.0243); steatosis vs NASH-related HCC (P=0.0010); NASH vs NASH-related cirrhosis (P=0.0318); and NASH vs NASH-related HCC (P=0.0007), thus suggesting a deregulation of apoptosis from NAFLD towards HCC. Interestingly, survivin immunoreactivity in NASH-related HCC was also found to be significantly lower than in HCC related to other causes (P<0.05). Remarkably, nuclear staining for survivin was not detected in any case of NAFLD, contrasting to its presence in all other cases of HCC. Survivin immunoexpression in NASH-related HCC is herein originally found substantially different than in HCC related to other causes, thus requiring further studies to elucidate the role of survivin in human NAFLD progression.

Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: Our case series and literature review

Recently, nonalcoholic steatohepatitis (NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma (HCC). The natural history and prognosis of NASH are controversial. Accordingly, we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC. We experienced 11 patients with NASH-associated HCC (6 male, 5 female; mean age 73.8 +/- 4.9 years) who received curative treatments. Most (91%) patients had been diagnosed with obesity, diabetes, hypertension, or dyslipidemia. Seven patients (64%) also had a non-cirrhotic liver. The recurrence-free survival rates at 1, 3 and 5 years were 72%, 60%, and 60%. We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature (64 male; mean age 66 years). The majority of patients (68%) were obese, 66% of patients had diabetes, and 24% had dyslipidemia. Furthermore, 26% of the HCCs arose from the non-cirrhotic liver. In conclusion, patients with non-cirrhotic NASH may be a high-risk group for HCC, and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.

NASH and cryptogenic cirrhosis: A histological analysis

Introduction. Epidemiological studies indicate that nonalcoholic steatohepatitis (NASH) is a common cause of cirrhosis described as ‘cryptogenic’. To address this from a histological perspective and to examine the significance of residual histological findings as an indication of prior NASH, we looked back at biopsies in patients who presented with cirrhosis without sufficient histological features to diagnose NASH but who had prior histologically confirmed non-cirrhotic NASH.Methods. Seven patients were identified with biopsy pairs showing non-specific (cryptogenic) cirrhosis in the latest specimen and a prior biopsy showing non-cirrhotic NASH. Using an expanded NASH-CRN system scored blindly by light microscopy, we compared the early and late biopsies to each other and to a cohort of 13 patients with cirrhosis due to hepatitis C without co-existing metabolic syndrome.Results. Macrosteatosis, although uniformly present in the non-cirrhotic NASH specimens, declined in the late stage cirrhotic NASH specimens and was not useful in the distinction of late cirrhotic NASH from cirrhotic viral hepatitis. However, the presence of ballooned cells, Mallory-Denk bodies, and megamitochondria and the absence of apoptotic bodies were significantly different in late stage cirrhotic NASH compared to cirrhosis due to hepatitis C.Conclusions. Histologically advanced NASH presenting as non-specific or cryptogenic cirrhosis has residual changes which are consistent with prior steatohepatitis but which differ from cirrhosis due to hepatitis C. These results provide histological support for the more established epidemiological associations of NASH with cryptogenic cirrhosis and for criteria used in several proposed classifications of cryptogenic cirrhosis.

Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis

Characteristics of hepatocellular carcinoma (HCC) complicating nonalcoholic steatohepatitis (NASH) are still controversial. Most NASH related HCCs are believed to develop from cirrhotic liver, but case reports about HCC arising from non-cirrhotic NASH have been accumulating recently. This study is designed to elucidate characteristics of NASH related HCC diagnosed with high accuracy by using surgically resected specimens that contain larger areas to validate than biopsy specimens. For this study, 1168 patients who underwent hepatic resection at Osaka Medical Center for Cancer and Cardiovascular Diseases were enrolled. Patients who had clinically obvious causes of chronic liver dysfunction, such as viral and alcoholic hepatitis, were excluded. Histological diagnosis of NASH was confirmed according to Brunt's criterion. Eight (1%) patients were diagnosed with NASH. Six (75%) of them showed non-cirrhosis in non-cancerous areas. Stages of fibrosis in the non-cirrhotic patients were mild fibrosis (F2) in five and moderate fibrosis (F3) in one. All patients complicated with metabolic diseases. Although all these patients without cirrhosis were evaluated pathologically at tumor-node-metastasis stages I or II, three (50%) had multiple recurrences of tumor within a short time after surgery. This study indicates HCC might arise frequently from non-cirrhotic NASH. While further studies are needed to confirm this observation, both cirrhotic and non-cirrhotic NASH warrant regular screening for HCC.

Noninvasive laboratory tests proposed for predicting cirrhosis in patients with chronic hepatitis C are also useful in patients with non-alcoholic steatohepatitis

Several noninvasive tests have been proposed to predict cirrhosis in patients with chronic hepatitis C, but not in patients with non-alcoholic steatohepatitis (NASH). We assessed whether noninvasive laboratory tests designed to predict the risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection could be used in patients with NASH. The subjects were 50 patients with biopsy-proved NASH and 100 age- and sex-matched patients with HCV. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet (AP) index, AST-to-platelet ratio index (APRI), cirrhosis discriminant score (CDS), and the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) model were calculated. The areas under the receiver-operating characteristic curves of the AAR, AP index, APRI, CDS, and HALT-C model for predicting cirrhosis were respectively 0.813, 0.877, 0.786, 0.949, and 0.908 in patients with NASH and 0.555, 0.652, 0.761, 0.782, and 0.782 in patients with HCV. A CDS cutoff value of less than 5 misclassified none of the 9 patients with NASH who had cirrhosis, while a value of more than 8 misclassified none of the 41 patients with NASH without cirrhosis. With the HALT-C model, a cutoff value of less than 0.6 classified non-cirrhotic NASH, while a cutoff value of 0.97 or higher classified cirrhotic NASH. The use of CDS and HALT-C model could avoid liver biopsy for predicting cirrhosis in 60 and 48% of the patients with NASH, respectively. Noninvasive laboratory tests designed to predict cirrhosis in patients with HCV are also useful in patients with NASH.

Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious

Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious

Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid

We report a case of hepatocellular carcinoma (HCC) arising in nonalcoholic steatohepatitis (NASH). The patient, a 64-year-old man, was incidentally found to have multiple tumors in the liver when admitted for pneumonia. He had been obese, had been receiving a standard dose of valproic acid since clipping surgery for subarachnoid hemorrhage 17 years previously, and had not consumed any alcohol since the surgery. Laboratory data revealed moderate hyperlipidemia and no evidence of diabetes mellitus, hepatitis B or C infection. The patient died of hepatic insufficiency, and an autopsy was performed. A tumor, a maximum of 13 cm in diameter, grossly occupied the entire left lobe and one third of the right lobe of the liver. Histologically, moderately differentiated HCC was found with foci of poorly differentiated HCC. The non-tumorous area showed NASH with moderate bridging fibrosis, without interface hepatitis, hemochromatosis, or copper accumulation. In this patient, obesity, hyperlipidemia, and long-term treatment with valproic acid could have all been associated with induction of NASH. The present case suggests that HCC could develop in non-cirrhotic NASH liver, and that chronic inflammation in itself could be an important risk factor in the development of HCC.