Clinical features of hepatocellular carcinoma associated with nonalcoholic fatty liver disease: a review of human studies.
Oda Kohei,Uto Hirofumi,Mawatari Seiichi,Ido Akio
Clinical journal of gastroenterology
Most cases of hepatocellular carcinoma (HCC) in Japan develop in the background of chronic liver disease caused by hepatitis C virus (HCV). Recently, however, HCV-associated HCC has been shown to be decreasing, while non-B and non-C HCC (NBNC-HCC), which is negative for HCV and hepatitis B virus infection, has increased. The main cause of NBNC-HCC is alcoholic liver disease, but the recent increase of NBNC-HCC is thought to be due to an increase in patients with nonalcoholic fatty liver disease (NAFLD). Approximately 10% of NAFLD cases involve nonalcoholic steatohepatitis (NASH), and NASH can progress to liver cirrhosis and its associated complications such as HCC. There are no accurate data on the percentage of NASH-related HCC among all-cause HCC in Japan, because no large-scale investigation has been performed. However, the rate is thought to be about 3% of overall HCC, which is lower than that in the United States. The incidence of HCC in patients with NASH-related cirrhosis is thought to be 2% per year, which is lower than that in HCV-related cirrhosis. Risks for NASH-related HCC include advanced hepatic fibrosis, older age, and being male. NAFLD that includes NASH is associated with metabolic syndrome, which includes obesity and diabetes, and metabolic syndrome is a risk factor for HCC. Genetic factors and dietary patterns may also be related to NASH-related HCC. Thus, regular HCC surveillance, as performed for patients with viral chronic liver disease, is required for patients with NAFLD, and diagnostic markers are required for simple, rapid and specific detection of NASH-related HCC.
Improved survival after treatments of patients with nonalcoholic fatty liver disease associated hepatocellular carcinoma.
Benhammou Jihane N,Aby Elizabeth S,Shirvanian Gayaneh,Manansala Kohlett,Hussain Shehnaz K,Tong Myron J
Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Despite the rise in these disease entities, detailed long-term outcomes of large NAFLD-associated HCC cohorts are lacking. In this report, we compared the overall and recurrence-free survival rates of NAFLD HCC cases to patients with HBV and HCV-associated HCC cases. Distinguishing features of NAFLD-associated HCC patients in the cirrhosis and non-cirrhosis setting were also identified. We conducted a retrospective study of 125 NAFLD, 170 HBV and 159 HCV HCC patients, utilizing clinical, pathological and radiographic data. Multivariate regression models were used to study the overall and recurrence-free survival. The overall survival rates were significantly higher in the NAFLD-HCC cases compared to HBV-HCC (HR = 0.35, 95% CI 0.15-0.80) and HCV-HCC (HR = 0.37, 95% CI 0.17-0.77) cases. The NAFLD-HCC patients had a trend for higher recurrence-free survival rates compared to HBV and HCV-HCC cases. Within the NAFLD group, 18% did not have cirrhosis or advanced fibrosis; Hispanic ethnicity (OR = 12.34, 95% CI 2.59-58.82) and high BMI (OR = 1.19, 95% CI 1.07-1.33) were significantly associated with having cirrhosis. NAFLD-HCC cases were less likely to exhibit elevated serum AFP (p < 0.0001). After treatments, NAFLD-related HCC patients had longer overall but not recurrence-free survival rates compared to patients with viral-associated HCC. Non-Hispanic ethnicity and normal BMI differentiated non-cirrhosis versus cirrhosis NAFLD HCC. Further studies are warranted to identify additional biomarkers to stratify NAFLD patients without cirrhosis who are at risk for HCC.
[Hepatic resection for hepatocellular carcinoma--results and analysis of the current literature].
Neeff H,Makowiec F,Harder J,Gumpp V,Klock A,Thimme R,Drognitz O,Hopt U T
Zentralblatt fur Chirurgie
BACKGROUND:Hepatocellular carcinoma (HCC) is the fifth-leading cause of cancer death world-wide. Although less frequent in Western Europe, its incidence is increasing in this region. Causes involved in the pathogenesis of HCC are, besides viral hepatitis, metabolic and nutritional factors (alcohol, diabetes, obesity). The therapeutic management depends strongly on the initial extent of disease and includes hepatic resection, liver transplantation and local ablation. In this context, we present our results on liver resection for HCC and a discussion of the current literature about (potentially curative) treatment for HCC. PATIENTS:From 1999 until 2008 93 patients [83 % male, median age 64 (range: 39-94) years] underwent hepatic resection for HCC. Postoperative follow-up was available in 85 patients [median follow-up: 1.2 (0.25-8) years]. RESULTS:In contrast to data, especially from Asia, a viral hepatitis as the origin of HCC was found in only 28 % of the patients in our series. Half of the patients had proven liver cirrhosis. The median number of intrahepatic tumours was one (1-11), median size of the largest tumour was 55 mm (5-250 mm). 58 % of the HCC were removed by atypical or segmental resection, 42 % of the patients underwent hemihepatectomy or extended -hemihepatectomy. Tumor-free resection margins were -achieved in 95 %. Total postoperative morbidity was 61 %. A reoperation for complications was -necessary in 10 %. Hospital mortality was 8.6 % in the entire study period but decreased from 14.9 % in 1999-2004 to 2.2 % in 2005 to 2008 (p = 0.03). Actuarial survival was 81 % after 1 year, 58 % after 3 years and 26 % after 5 years. The T-stage could be identified tendentially as a prognostic factor influencing survival. CONCLUSION:With the proper selection of patients, liver resection for HCC may be performed with a curative intention (i. e., free resection margins) in over 90 %. Although it decreased during the study period peri-operative mortality was higher than after resection of other hepatic tumours. Long-term survival in our series was comparable to reports from other European centres.
Diabetes Mellitus and/or Nonalcoholic Steatohepatitis-related Hepatocellular Carcinoma Showed Favorable Surgical Outcomes After Hepatectomy.
Liang Jing,Ariizumi Shun-Ichi,Nakano Masayuki,Yamamoto Masakazu
BACKGROUND/AIM:Diabetes mellitus (DM) is known as an important risk factor for hepatocellular carcinoma (HCC). However, surgical outcomes in patients with DM and HCC have not been evaluated in detail. PATIENTS AND METHODS:We retrospectively studied 177 patients with type 2 DM who underwent curative hepatectomy for HCC. Surgical outcomes after curative hepatectomy and prognostic factors were evaluated among 75 patients with DM and/or nonalcoholic steatohepatitis (NASH)-related HCC and 102 patients with DM and viral or alcoholic hepatitis (VAH)-related HCC. RESULTS:The 5-year survival rate and 5-year recurrence-free survival rate were significantly higher in the DM and/or NASH-related HCC group (87% and 51%) than in the DM and VAH-related HCC group (68%: p=0.0001 and 26%: p=0.0002). Multivariate analysis showed DM and/or NASH-related HCC to be significant independent prognostic factors for overall survival and recurrence-free survival. CONCLUSION:Patients with DM and/or NASH-related HCC showed more favorable surgical outcomes after hepatectomy in patients with DM and HCC.
INFLUENCE OF HEPATOCELLULAR CARCINOMA ETIOLOGY IN THE SURVIVAL AFTER RESECTION.
Lopes Felipe de Lucena Moreira,Coelho Fabricio Ferreira,Kruger Jaime Arthur Pirolla,Fonseca Gilton Marques,Araujo Raphael Leonardo Cunha de,Jeismann Vagner Birk,Herman Paulo
Arquivos brasileiros de cirurgia digestiva : ABCD = Brazilian archives of digestive surgery
BACKGROUND:Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and its incidence is increasing around the world in the last decades, making it the third cause of death by cancer in the world. Hepatic resection is one of the most effective treatments for HCC with five-year survival rates from 50-70%, especially for patients with a single nodule and preserved liver function. Some studies have shown a worse prognosis for HCC patients whose etiology is viral. That brings us to the question about the existence of a difference between the various causes of HCC and its prognosis. AIM:To compare the prognosis (overall and disease-free survival at five years) of patients undergoing hepatectomy for the treatment of HCC with respect to various causes of liver disease. METHOD:Was performed a review of medical records of patients undergoing hepatectomy between 2000 and 2014 for the treatment of HCC. They were divided into groups according to the cause of liver disease, followed by overall and disease-free survival analysis for comparison. RESULTS:There was no statistically significant difference in the outcomes of the groups of patients divided according to the etiology of HCC. Overall and disease-free survival at five years of the patients in this sample were 49.9% and 40.7%, respectively. CONCLUSION:From the data of this sample, was verified that there was no prognostic differences among the groups of HCC patients of the various etiologies.
Association of nonalcoholic fatty liver disease and liver cancer.
Schulz Perla Oliveira,Ferreira Fabio Gonçalves,Nascimento Maria de Fátima Araújo,Vieira Andrea,Ribeiro Mauricio Alves,David André Ibrahim,Szutan Luiz Arnaldo
World journal of gastroenterology
AIM:To investigate the association between nonalcoholic fatty liver disease (NAFLD) and liver cancer, and NAFLD prevalence in different liver tumors. METHODS:This is a retrospective study of the clinical, laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation, with subsequent evaluation of the explant or liver biopsy. The following criteria were used to exclude patients from the study: a history of alcohol abuse, hepatitis B or C infection, no tumor detected in the liver tissue examined by histological analysis, and the presence of chronic autoimmune hepatitis, hemochromatosis, Wilson's disease, or hepatoblastoma. The occurrence of NAFLD and the association with its known risk factors were studied. The risk factors considered were diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, body mass index, dyslipidemia, and arterial hypertension. Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson's trichrome and silver impregnation. Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade. RESULTS:No difference was found in the association of NAFLD with the general population (34.2% and 30.0% respectively, 95%CI: 25.8-43.4). Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma (OR = 3.99, 95%CI: 1.78-8.94, P < 0.001 vs OR = 0.60, 95%CI: 0.18-2.01, P = 0.406 and OR = 0.70, 95%CI: 0.18-2.80, P = 0.613, respectively). There was a higher prevalence of liver fibrosis in patients with hepatocellular carcinoma (OR = 3.50, 95%CI: 1.06-11.57, P = 0.032). Evaluation of the relationship between the presence of NAFLD, nonalcoholic steatohepatitis, and liver fibrosis, and their risk factors, showed no significant statistical association for any of the tumors studied. CONCLUSION:NAFLD is more common in patients with liver metastases caused by colorectal cancer.
Genome sequencing analysis of liver cancer for precision medicine.
Nakagawa Hidewaki,Fujita Masashi,Fujimoto Akihiro
Seminars in cancer biology
Liver cancer is the third leading cause of cancer-related death worldwide. Some thousands of liver cancer genome have been sequenced globally so far and most of driver genes/mutations with high frequency are established in liver cancer, including Wnt/β-catenin pathway, TP53/cell-cycle pathways, telomere maintenance, and chromatin regulators. HBV integration into cancer-related genes is also a driver event in hepatocarcinogenesis. These genes are affected by structural variants, copy-number alterations and virus integrations as well as point mutations. Etiological factors of liver cancer is most understood among common cancers, such as hepatitis, aflatoxin, alcohol, and metabolic diseases, and mutational signatures of liver cancer can provide evidence of the association between specific etiological factors and mutational signatures. Molecular classifications based on somatic mutations profiles, RNA expression profiles, and DNA methylation profiles are related with patient prognosis. For precision medicine, several actionable mutations with solid evidence such as targets of multi-kinase inhibitors is observed in liver cancer, but there is few molecular target therapy so far. It is possible that rare actionable mutations in liver cancer can guide other specific molecular therapy and immune therapy.
Hepatocellular carcinoma and non-alcoholic fatty liver disease.
Golabi Pegah,Rhea Logan,Henry Linda,Younossi Zobair M
Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder worldwide, affecting 25.2% of the general population. In fact, NAFLD is among the most common etiologies for hepatocellular carcinoma (HCC). The burden of NAFLD is primarily driven by the epidemic of obesity and type 2 diabetes which are expected to worsen throughout the world. In this context, the burden of NAFLD and associated HCC and cirrhosis are also expected to increase. Despite its growing disease burden, diagnostic tools and treatment modalities remain very limited. This conundrum of increasing prevalence and limited treatment options will be reflected as increasing number of NAFLD-related cirrhosis and HCC cases. This article reviews the most updated information about NAFLD-related HCC and provides some insight into strategies that must be considered to reduce its potential disease burden.
The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies.
Chen Jin,Bian Dongxue,Zang Shufei,Yang Zongxing,Tian Guoyan,Luo Yan,Yang Jing,Xu Beibei,Shi Junping
Expert review of gastroenterology & hepatology
BACKGROUND & AIM:Lifestyle modification plays a key role in nonalcoholic fatty liver disease (NAFLD) and colorectal adenoma and/or cancer (CRA/CRC) development. However, the association between NAFLD and the risk of CRA/CRC has not been carefully evaluated. METHODS:In this meta-analysis, we assessed 21 eligible studies including 124,206 participants to determine the association between NAFLD and the risk of incident and recurrent CRA/CRC. RESULTS:NAFLD presence was associated with an increased risk of any incident CRA (aOR: 1.30, 95% CI: 1.19-1.43) and advanced incident CRA/CRC (aOR: 1.57, 95% CI: 1.21-2.04). The severity of NAFLD affected this correlation: compared to mild and/or moderate NAFLD, severe NAFLD was associated with an increased risk of incident CRA/CRC (aOR: 2.19, 95% CI: 1.33-3.60). Although pooled cOR revealed that NAFLD was associated with an increased risk of recurrent CRA/CRC (cOR = 1.73; 95% CI: 1.12-2.68), after adjustment for confounding factors, NAFLD had less correlation with the risk of recurrent CRA/CRC (aOR: 1.81, 95% CI: 0.70-4.65). CONCLUSIONS:The presence and severity of NAFLD are associated with an increased risk of incident CRA/CRC. However, there is insufficient evidence to indicate that NAFLD is associated with an increased risk of recurrent CRA/CRC.
Nonalcoholic fatty liver disease-associated hepatocellular carcinoma in a hepatitis B virus-endemic area.
Yoon Chang Hwi,Jin Young-Joo,Lee Jin Woo
European journal of gastroenterology & hepatology
BACKGROUND:This study was carried out to evaluate the association between nonalcoholic fatty liver disease (NAFLD) and the development of hepatocellular carcinoma (HCC) between 2005 and 2015 in a hepatitis B virus (HBV)-endemic area. PATIENTS AND METHODS:The medical records of 1327 patients initially diagnosed with HCC at our institution between January 2005 and December 2015 were analyzed retrospectively. Patients with other malignancies in addition to HCC were excluded. During the study period, changes in the proportion of NAFLD-associated HCC among all HCCs were assessed longitudinally. In addition, the clinical characteristics of NAFLD-associated HCC were evaluated. RESULTS:Among the 1327 patients, HBV was the most common (65.5%) cause of HCC, and the overall rate of NAFLD-associated HCC was 4.7%. Compared with HBV-associated HCC patients, NAFLD-associated HCC patients were older, had a higher median body mass index, and a larger median tumor size (P<0.05 for all). Liver cirrhosis was less frequent in NAFLD-associated than in HBV-associated HCC patients (P<0.05). The annual proportions of NAFLD-associated HCC patients were 3.4% in 2005, 3.6% in 2006, 3.5% in 2007, 3.2% in 2008, 4.2% in 2009, 4.4% in 2010, 5.6% in 2011, 5.2% in 2012, 5.8% in 2013, 7.0% in 2014, and 6.7% in 2015. From 2008 to 2015, these percentages increased steadily. CONCLUSION:The annual proportion of NAFLD-associated HCC patients among all HCC patients ranged from 3.2 to 3.5% before 2008, but thereafter, it increased gradually and had doubled to 7.0% by 2014.
Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation.
Younossi Zobair M,Marchesini Giulio,Pinto-Cortez Helena,Petta Salvatore
Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global adult population with a range of 13.5% in Africa and 31.8% in the Middle East. Nonalcoholic fatty liver disease is closely associated with a constellation of metabolic comorbidities which include: obesity, type 2 diabetes mellitus, hypertension, and hypercholesteremia. In fact, the increasing number of metabolic comorbidities not only increases the prevalence of NAFLD but also places patients at higher risk for progressive liver disease. As such, NAFLD is presently among the top etiologies for hepatocellular carcinoma and an indication for liver transplantation (LT) in the United States. Therefore, the following recommendations are made based on our current knowledge of NAFLD and its consequences: (1) the evaluation of the risk of liver disease progression can be affected by patient's ethnic origin and sex; (2) fibrosis in NAFLD is the most important predictor of mortality; (3) we recommend that individuals who present with features of metabolic syndrome in the presence of elevated liver enzymes should be screened for NAFLD and, more importantly, nonalcoholic steatohepatitis (NASH); (4) we recommend that NAFLD patients, especially those with multiple risk factors, should be screened for cardiovascular diseases and managed accordingly; (5) comorbidities in NAFLD/NASH patients who are considered for LT need to be assessed in the pretransplant and posttransplant settings because these factors can affect waitlist mortality, resource utilization, as well as posttransplant complications, morbidity, and perhaps, mortality; (6) any attempt to decrease the incidence of NAFLD should ideally address the development of obesity in childhood and early adulthood, favoring the adoption of healthy lifestyles through comprehensive health policy programs.
Nonalcoholic fatty liver disease and hepatocellular carcinoma.
Zoller Heinz,Tilg Herbert
Metabolism: clinical and experimental
The fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is at least partly attributable to the rising prevalence of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to malignant transformation into hepatocellular cancer. The estimated annual HCC incidence in the progressive form of NAFLD - non-alcoholic steatohepatitis (NASH) - is about 0.3%. The risk of HCC development is higher in men and increases with age, more advanced fibrosis, progressive obesity, insulin resistance and diabetes mellitus. Studies on the molecular mechanism of HCC development in NAFLD have shown that hepatocarcinogenesis is associated with complex changes at the immunometabolic interface. In line with these clinical risk factors, administration of a choline-deficient high-fat diet to mice over a prolonged period results in spontaneous HCC development in a high percentage of animals. The role of altered insulin signaling in tumorigenesis is further supported by the observation that components of the insulin-signaling cascade are frequently mutated in hepatocellular cancer cells. These changes further enhance insulin-mediated growth and cell division of hepatocytes. Furthermore, studies investigating nuclear factor kappa B (NF-κB) signaling and HCC development allowed dissection of the complex links between inflammation and carcinogenesis. To conclude, NAFLD reflects an important risk factor for HCC, develops also in non-cirrhotic livers and is a prototypic cancer involving inflammatory and metabolic pathways. STRENGTHS/WEAKNESSES AND SUMMARY OF THE TRANSLATIONAL POTENTIAL OF THE MESSAGES IN THE PAPER: The systematic review summarizes findings from unbiased clinical and translational studies on hepatocellular cancer in non-alcoholic fatty liver disease. This provides a concise overview on the epidemiology, risk factors and molecular pathogenesis of the NAFL-NASH-HCC sequence. One limitation in the field is that few HCC studies stratify patients by underlying etiology, although the etiology of the underlying liver disease is an important co-determinant of clinical disease course and molecular pathogenesis. Molecular profiling of NAFL and associated HCC holds great translational potential for individualized surveillance, prevention and therapy.
Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period.
Pais R,Fartoux L,Goumard C,Scatton O,Wendum D,Rosmorduc O,Ratziu V
Alimentary pharmacology & therapeutics
BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) worldwide. NAFLD-HCC often occurs in noncirrhotic liver raising important surveillance issues. AIM:To determine the temporal trends for prevalence, clinical characteristics and outcomes of NAFLD-HCC in patients undergoing liver resection. METHODS:Consecutive patients with histologically confirmed HCC who underwent liver resection over a 20-year period (1995-2014). NAFLD was diagnosed based on past or present exposure to obesity or diabetes without other causes of chronic liver disease. RESULTS:A total of 323 HCC patients were included, 12% with NAFLD. From 1995-1999 to 2010-2014, the prevalence of NAFLD-HCC increased from 2.6% to 19.5%, respectively, P = .003, and followed the temporal trends in the prevalence of metabolic risk factors (28% vs 52%, P = .017), while hepatitis C-HCC decreased (from 43.6% to 19.5%, P = .003). NAFLD-HCC occurred more frequently in the absence of bridging fibrosis/cirrhosis (63% of cases, P < .001 compared to other aetiologies). Within the NAFLD group, tumour characteristics were similar between F0-F2 and F3-F4 patients, except for a higher proportion of single nodules (95% vs 54%, P < .01). A total of 53% patients had tumour recurrence and 40% died. NAFLD-HCC had similar time to recurrence and survival as HCCs of other aetiologies. Satellite nodules, tumour size, microvascular invasion and male sex but not the aetiology were independently associated with recurrence. CONCLUSION:Non-alcoholic fatty liver disease increased substantially over the past 20 years among resectable HCCs. It is now the leading cause of HCC occuring without/or with only minimal fibrosis. NAFLD patients are older, with larger tumours while survival and recurrence rates are as severe as in other aetiologies.
Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma.
Duan Xiao-Yan,Qiao Liang,Fan Jian-Gao
Hepatobiliary & pancreatic diseases international : HBPD INT
BACKGROUND:Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis, is a recognized risk factor for hepatocellular carcinoma (HCC). However, detailed analysis of the clinical features in patients with NAFLD and their association with HCC is lacking. This study aimed to update the clinical features of patients with NAFLD-associated HCC. DATA SOURCES:The clinical data of patients with NAFLD-associated HCC from 25 studies published between 1990 and 2010 in the Pubmed database were comprehensively reviewed. RESULTS:In a total of 169 patients with NAFLD-associated HCC, 72.8% were male. The median age at abnormal liver function tests and diagnosis of NAFLD and HCC was 60, 64 and 67 years, respectively. Most patients were obese (75%) and diabetic (59.8%), 32.3% had dyslipidemia, and 53% had hypertension. Nearly all patients (98.6%, 71/72) were complicated with at least one metabolic disorder. The majority (76%) of the HCC patients had a solitary tumor nodule, with the tumor size ranging from 0.8 to 20 cm in diameter (mean 3.4 cm). Most (61.1%) of the patients had moderately-differentiated HCC. In 40.2% of the patients, HCC occurred in the absence of cirrhosis. Among 130 patients, 57.7% underwent hepatectomy and 14.6% received liver transplantation. The mean follow-up of the treated patients for 25 months showed that 32.4% (24/74) died and 18.8% (9/48) had recurrence. CONCLUSIONS:Patients with NAFLD-associated HCC are usually accompanied with metabolic disorders. Regular surveillance in patients with NAFLD for HCC is necessary, especially for elderly men with metabolic syndrome.
Liver Resection for Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma.
Koh Ye Xin,Tan Hiang Jin,Liew Yi Xin,Syn Nicholas,Teo Jin Yao,Lee Ser Yee,Goh Brian K P,Goh George B B,Chan Chung Yip
Journal of the American College of Surgeons
BACKGROUND:Nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is on the rise worldwide, but data on long-term outcomes after curative operations are limited. The primary aim of this study was to characterize the perioperative and long-term outcomes after liver resection. The secondary aim was to investigate the influence of the histologic severity of nonalcoholic steatohepatitis and its impact on perioperative outcomes and long-term survival. METHODS:A total of 996 patients who underwent liver resection for HCC in our institution were analyzed. Patients were categorized into subgroups of NAFLD vs non-NAFLD HCC based on histologic evidence of hepatic steatosis. Comparisons of patients' demographic, clinical, and surgical characteristics; postoperative complications; and survival outcomes were performed. RESULTS:Eight hundred and forty-four patients had non-NAFLD HCC and 152 patients had NAFLD HCC. Comorbidities were significantly more common in the NAFLD group (p < 0.0001). In the non-NAFLD group, larger median tumor size, higher liver cirrhosis, and lower median neutrophil to lymphocyte ratio were observed (p < 0.0001). The NAFLD group had a greater amount of intraoperative blood loss, more postoperative complications, and longer length of stay. Five-year overall survival was significantly better in the NAFLD group (p = 0.0355). Significant factors that contribute to poorer survival outcomes include age, congestive cardiac failure, Child-Pugh's class B, cirrhosis, tumor size, multinodularity, and R1 resection. For NAFLD group, patients with abnormal parenchyma showed poorer survival and 5-year overall survival rates (64.8% vs 75.6%; p = 0.2291). CONCLUSIONS:Nonalcoholic fatty liver disease-related HCC is associated with greater surgical morbidity and post-hepatectomy liver failure. Despite this, long-term survival outcomes are favorable compared with non-NAFLD etiologies.
Nonalcoholic fatty liver disease: a negative risk factor for colorectal cancer prognosis.
You Jie,Huang Sha,Huang Gui-Qian,Zhu Gui-Qi,Ma Rui-Min,Liu Wen-Yue,Shi Ke-Qing,Guo Gui-Long,Chen Yong-Ping,Braddock Martin,Zheng Ming-Hua
Nonalcoholic fatty liver disease (NAFLD) is known to be associated with an increased risk of colorectal cancer (CRC). However, the relationship between NAFLD and the prognosis of CRC remains unclear. The primary objective of this study was to evaluate the overall survival (OS) and disease-free survival (DFS) rates in patients with CRC and the secondary objective was to compare clinicopathologic variables which were stratified by NAFLD. We performed a large cohort study of 1314 patients who were first diagnosed with CRC between January 2006 and April 2011. Postoperative follow-up data were collected from out-patient medical records, telephone consultations, and social security death indices. The Kaplan-Meier method was used to calculate the cumulative survival rate. Clinicopathologic variables were analyzed by univariate analysis and multivariate analysis through a Cox proportional hazard regression model. The mean follow-up time was 52.7 ± 25.3 months. Upon baseline comparison, the NAFLD group had significantly higher values of body mass index, triglycerides, and uric acid and significantly lower values of high-density lipoprotein, compared with the non-NAFLD group (P < 0.05 for all). There were no significant differences between the 2 groups with regard to tumor location, TNM staging, tumor differentiation, carcinoembryonic antigen, and vascular invasion. The cumulative 1-, 3-, and 5-year OS rates were 96.1%, 85.2%, and 80.6%, respectively, in the NAFLD group, which were statistically significantly higher than the OS rates of 91.6%, 76.2%, and 67.8%, respectively, in the non-NAFLD group (P = 0.075, P = 0.002, P = 0.030, respectively). There was no difference in DFS rates between the CRC patients with and without NAFLD (P = 0.267). Multivariate analysis showed that the presence of NAFLD was an independent negative risk factor for OS after adjusting for clinicopathologic covariates (hazard ratio = 0.593; 95% confidence interval 0.442, 0.921; P = 0.020), but not for DFS (P = 0.270). NAFLD may play a protective role in OS for CRC patients. Further studies are needed to elucidate the molecular mechanisms of putative protective effects in CRC patients with NAFLD.
Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.
Donati Benedetta,Pietrelli Alessandro,Pingitore Piero,Dongiovanni Paola,Caddeo Andrea,Walker Lucy,Baselli Guido,Pelusi Serena,Rosso Chiara,Vanni Ester,Daly Ann,Mancina Rosellina Margherita,Grieco Antonio,Miele Luca,Grimaudo Stefania,Craxi Antonio,Petta Salvatore,De Luca Laura,Maier Silvia,Soardo Giorgio,Bugianesi Elisabetta,Colli Fabio,Romagnoli Renato,Anstee Quentin M,Reeves Helen L,Fracanzani Anna Ludovica,Fargion Silvia,Romeo Stefano,Valenti Luca
In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron-exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P = 0.048) and healthy controls (P = 0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P = 0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency = 0.025 vs. <0.001; P = 0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding domain (P = 0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.
Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009.
Younossi Zobair M,Otgonsuren Munkhzul,Henry Linda,Venkatesan Chapy,Mishra Alita,Erario Madeline,Hunt Sharon
Hepatology (Baltimore, Md.)
UNLABELLED:Hepatocellular carcinoma (HCC) is increasingly reported in patients with nonalcoholic fatty liver disease (NAFLD). Our aim was to assess the prevalence and mortality of patients with NAFLD-HCC. We examined Surveillance, Epidemiology and End Results (SEER) registries (2004-2009) with Medicare-linkage files for HCC, which was identified by the International Classification of Diseases for Oncology, third edition codes using topography and morphology codes 8170-8175. Medicare-linked data was used to identify NAFLD, hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease (ALD), and other liver disease using International Classification of Diseases, Ninth Revision, Clinical Modification codes. NAFLD was also defined by clinical diagnosis (cryptogenic cirrhosis, obese-diabetics with cryptogenic liver disease). A logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HCC. In addition, adjusted hazard ratios for 1-year mortality were estimated by Cox's proportional hazard regression. A total of 4,929 HCC cases and 14,937 controls without HCC were included. Of the HCC cases, 54.9% were related to HCV, 16.4% to ALD, 14.1% to NAFLD, and 9.5% to HBV. Across the 6-year period (2004 to 2009), the number of NAFLD-HCC showed a 9% annual increase. NAFLD-HCC were older, had shorter survival time, more heart disease, and were more likely to die from their primary liver cancer (all P < 0.0001). Of those who received a transplant after HCC (n = 488), only 5% were related to NAFLD-HCC. In multivariate analysis, NAFLD increased the risk of 1-year mortality (OR, 1.21; 95% CI: 1.01-1.45). Additionally, older age, lower income, unstaged HCC increased risk of 1-year mortality while receiving a liver transplant (LT), and having localized tumor stage were protective (all P < 0.05). CONCLUSIONS:NAFLD is becoming a major cause of HCC in the United States. NAFLD HCC is associated with shorter survival time, more advanced tumor stage, and lower possibility of receiving a LT.
MicroRNAs in nonalcoholic fatty liver disease: novel biomarkers and prognostic tools during the transition from steatosis to hepatocarcinoma.
Gori Manuele,Arciello Mario,Balsano Clara
BioMed research international
Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). The influence of NAFLD on HCC development has drawn attention in recent years. HCC is one of the most common malignant tumors and the third highest cause of cancer-related death. HCC is frequently diagnosed late in the disease course, and patient's prognosis is usually poor. Early diagnosis and identification of the correct stage of liver damage during NAFLD progression can contribute to more effective therapeutic interventions, improving patient outcomes. Therefore, scientists are always searching for new sensitive and reliable markers that could be analysed through minimally invasive tests. MicroRNAs are short noncoding RNAs that act as posttranscriptional regulators of gene expression. Several studies identified specific miRNA expression profiles associated to different histological features of NAFLD. Thus, miRNAs are receiving growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets. This review focuses on the current knowledge of the miRNAs involved in NAFLD and related HCC development, highlighting their diagnostic and prognostic value for the screening of NAFLD patients.
Current therapies for nonalcoholic fatty liver disease.
Gossard A A,Lindor K D
Drugs of today (Barcelona, Spain : 1998)
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in adults and children in many regions of the world. Although a relatively benign condition in some, for others the disease will progress to cirrhosis and end-stage liver disease with associated complications including hepatocellular cancer. Pharmaceutical therapies have had mixed results and none are accepted as standard therapy. Depending on the metric used to assess response (biochemical or histological), there are some therapies which may afford benefit. Others, however, have caused less than desirable adverse effects. Unfortunately, no particular treatment has emerged as safe and highly effective. The cornerstones of management of this problematic condition should include exercise and efforts at weight reduction through dietary changes and increased physical activity. Weight reduction does indeed seem to be beneficial in this setting, as evidenced by studies including those evaluating the effect of bariatric surgery. Less is known, however, about the effort of exercise in and of itself as a treatment strategy, even in the absence of a reduction in body weight. In this paper, we review the literature pertaining to the current state of NAFLD management with an emphasis on pharmacotherapy.
Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: A Problem of Growing Magnitude.
Pocha Christine,Kolly Philippe,Dufour Jean-Francois
Seminars in liver disease
Hepatocellular carcinoma (HCC) is a cancer with globally rising incidence. Growing evidence supports associations between metabolic syndrome and diabetes as well as obesity and HCC arising in patients with nonalcoholic fatty liver disease (NAFLD). This constitutes a problem of alarming magnitude given the rising epidemic of these conditions. The role of diabetes seems to be particularly important when associated with obesity or cirrhosis. Excess hepatic iron may be another potential risk factor for the development of NAFLD-associated HCC. In the context of NAFLD, HCC frequently develops in a not-yet cirrhotic liver. As there are no surveillance programs for these patients, diagnosis often occurs at a tumor stage beyond curative options. Clinical, tumor, and patient characteristics in NAFLD-associated HCC differ from other etiologies. Older age and cardiovascular comorbidities may limit treatment options further. The outcome in patients with NAFLD-associated early HCC is excellent and therefore aggressive treatment should be pursued in appropriate patients. Population-based prevention to reduce the culprit-NAFLD-early recognition through targeted surveillance programs in risk-stratified patients and effective treatment of HCC associated with NAFLD are urgently needed. In this review, the authors summarize the epidemiology, risk factors, features, and prevention of NAFLD-associated HCC.
Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.
Inayat Faisal,Ur Rahman Zia,Hurairah Abu
Our objective was to study nonalcoholic fatty liver disease (NAFLD) as a relevant risk factor associated with hepatocellular carcinoma (HCC) in patients with and without cirrhosis. HCC is a common cancer worldwide that predominantly involves patients with hepatic cirrhosis. HCC has recently been linked to NAFLD, the hepatic manifestation of obesity and related metabolic disorders. This association is alarming due to the high prevalence of NAFLD globally, which may contribute to the rising incidence of HCC. A 31-year-old female with a history of dyslipidemia, hypertension, and diabetes mellitus presented with abdominal pain that persisted for six months. The pain was associated with gastrointestinal symptoms and weight loss. She was drug-free and a nonalcoholic and a nonsmoker. The physical examination was unremarkable. The abdominal exam showed a soft and non-tender abdomen, with no organomegaly or ascites. The laboratory evaluation was unremarkable. The imaging studies showed a hypodense lesion in the right hepatic lobe with strong arterial enhancement. Subsequently, the patient underwent a liver biopsy. The histopathology results were consistent with HCC. The patient underwent an uneventful segment VI liver resection and tumor-free margins were achieved. In our patient, NAFLD was designated as an independent etiology for HCC, without cirrhosis. Our patient recovered well and has been disease free for over a year. HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk of HCC. These results provide new targets for surveillance, prevention, early recognition, and effective treatment of HCC associated with NAFLD.
New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance.
Precision clinical medicine
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC initiates as a consequence of chronic liver damage and inflammation caused by hepatitis B and C virus infections, excessive alcohol consumption, or non-alcoholic fatty liver disease (NAFLD). Until recently, no effective treatments for advanced HCC were available and the 5-year survival rate had remained below 8% for many years. New insights into the mechanisms that drive the development of NAFLD-related HCC indicate that loss of T-cell-mediated immunosurveillance plays a cardinal role in tumor growth and malignant progression, in addition to previously identified inflammation-driven compensatory proliferation. Recently completed groundbreaking clinical studies have shown that treatments that restore antitumor immunity represent a highly effective therapeutic option for approximately 20% of advanced HCC patients. Understanding the causes of inflammation-driven immunosuppression and immune system dysfunction in the 80% of patients who fail to reignite antitumor immunity despite treatment with checkpoint inhibitors should lead to further and even more dramatic improvements in HCC immunotherapy.
A global view of hepatocellular carcinoma: trends, risk, prevention and management.
Yang Ju Dong,Hainaut Pierre,Gores Gregory J,Amadou Amina,Plymoth Amelie,Roberts Lewis R
Nature reviews. Gastroenterology & hepatology
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.