Author, year [ref.]
Country/setting/period
Study design/cohort definition/control group
Number of patients/follow-up
HCC incidence in cohort vs. control group
HCC mortality in cohort vs. control group
Sorensen et al., 1998 [57]
Denmark/national hospitalizations registry/1977–1989
Population-based, retrospective/ICD nonspecified cirrhosis (ns-C)/ICD alcoholic cirrhosis (AL-C), primary biliary cirrhosis (PBC), chronic hepatitis (CH)
11,605 (2430 ns-C)/5.5 years for men and 5.9 years for women in ns-C
Cumulative incidence: 1.4 % ns-C, 2.0 % AL-C, 1.3 % PBC, 1.1 % CH; standardized incidence ratio Danish population: 43 ns-C, 71 AL-C, 47 PBC, 43 CH
NR
Ratziu et al., 2002 [58]
France/single institution/1988–2000
Clinic-based, retrospective/overweight (O-CC) and lean cryptogenic cirrhosis (L-CC)/HCV-cirrhosis (HCV-C)
27 O-CC, 10 L-CC, 391 HCV-C (85 HCV-C matched with O-CC)/1.8 years in O-CC, 3.6 years in L-CC, 3.4 years in HCV-C (2 years in HCV-C matched with O-CC)
Cumulative incidence: 29.6 % O-CC, 0 % L-CC, 15.6 % HCV-C (21.2 % HCV-C matched with O-CC)
NR
Hui et al., 2003 [24]
Australia/single institution/1985–2002
Clinic-based, prospective/NASH-cirrhosis (biopsy)/untreated and nonresponder HCV-cirrhosis
23 NASH-cirrhosis, 46 age- and sex-matched (23 + 23) HCV-cirrhosis/7 years in NASH-cirrhosis, 6.7 years in untreated HCV, 6.9 in nonresponder HCV
Cumulative incidence: 0 % NASH-cirrhosis, 21.7 % untreated HCV-cirrhosis, 13.0 % nonresponder HCV-cirrhosis
HCC deaths/all cause deaths: 0/6 in NASH-cirrhosis, 3/10 in untreated HCV, 2/8 in nonresponder HCV
Sanyal et al., 2006 [25]
USA/single institution/1992–2004
Clinic-based, Prospective/NASH-cirrhosis (biopsy)/untreated or nonresponder HCV-cirrhosis
152 NASH-cirrhosis, 150 HCV-cirrhosis matched for age, sex, child class, and year of enrollment/10 years
Cumulative incidence: 6.7 % NASH-cirrhosis, 17.0 % HCV-cirrhosis
HCC deaths/all cause deaths: 2/29 in NASH-cirrhosis, 8/44 in HCV-cirrhosis
Kojima et al., 2006 [26]
Japan/single institution/1990–2004
Clinic-based, retrospective/cryptogenic cirrhosis (CC)/HCV-cirrhosis, HBV-cirrhosis
24 CC, 48 HCV-cirrhosis, 24 HBV-cirrhosis matched for age, sex, and child class/5.7 years CC, 5.9 years viral (HCV+HBV) cirrhosis
Cumulative incidence: 37.5 % in CC, 73.6 % in viral cirrhosis
HCC deaths/liver-related deaths: 2/5 in CC, 29/39 in viral cirrhosis
Yatsuji et al., 2009 [29]
Japan/single institution/1990–2006
Clinic-based, prospective/NASH-cirrhosis (biopsy)/HCV-cirrhosis
68 NASH-cirrhosis, 69 sex- and age-matched HCV-cirrhosis/3.4 years in NASH-cirrhosis, 6.2 years in HCV-cirrhosis
5-year incidence rate: 11.3 % in NASH-cirrhosis, 30.5 % in HCV-cirrhosis
HCC deaths/all cause deaths: 9/19 in NASH-cirrhosis, 19/28 in HCV-cirrhosis
Hashimoto et al., 2009 [59]
Japan/single institution/1990–2007
Clinic-based, prospective/NASH with advanced fibrosis (biopsy)/no control group
137/3.4 years
5-year cumulative incidence: 7.6 %
HCC deaths/all cause deaths: 12/26
Ascha et al., 2010 [30]
USA/single institution/2003–2007
Clinic-based, prospective/NASH-cirrhosis/HCV-cirrhosis
195 NASH-cirrhosis, 315 HCV-cirrhosis/2.7 years in NASH-cirrhosis, 3.4 years in HCV-cirrhosis
Yearly cumulative incidence: 2.6 % NASH-cirrhosis, 4.0 % HCV-cirrhosis
NR
Bhala et al., 2011 [27]
International/4 institutions (USA, UK, Australia, Italy)/1984–2006
Clinic-based, prospective/NAFLD with advanced fibrosis or child A cirrhosis/HCV with advanced fibrosis or child A cirrhosis
247 NAFLD, 264 HCV/7.1 years in NAFLD, 6.2 years in HCV
Cumulative incidence: 2.4 % NAFLD, 6.8 % HCV
HCC deaths/all cause deaths: 3/33 in NAFLD, 12/25 in HCV
O’Leary et al., 2011 [28]
USA/single institution/2002–2008
Clinic-based, retrospective/NASH-cirrhosis or cryptogenic cirrhosis (NASH-CC) listed for OLT/HCV-cirrhosis listed for OLT
217 NASH-CC, 645 HCV-cirrhosis/1.0 year in NASH-CC, 1.0 year in HCV-cirrhosis
Yearly cumulative incidence: 2.7 % NASH-CC, 4.7 % HCV-cirrhosis
NR
Amarapurkar et al., 2013 [31]
India/single institution/2010–2011
Clinic-based, prospective/NASH-cirrhosis and cryptogenic cirrhosis (CC)/HBV-cirrhosis and HCV-cirrhosis
41 NASH-cirrhosis, 104 CC, 111 HBV-cirrhosis, 83 HCV-cirrhosis/6.8 years in NASH-cirrhosis, 5.7 years in CC, 5.9 years in HBV-cirrhosis, 6.1 years in HCV-cirrhosis
Yearly cumulative incidence: 0.46 % NASH-cirrhosis, 0.6 % CC, 1.5 % HBV-cirrhosis, 3.6 % HCV-cirrhosis
NR
Hashizume et al., 2013 [60]
Japan/single institution/2003–2011
Clinic-based, prospective/NASH with advanced fibrosis (biopsy)/HCV with advanced fibrosis
Only female patients: 20 NASH, 20 HCV matched for age and BMI/7.1 years in NASH, 6.8 years in HCV
Cumulative incidence: 40 % NASH, 40 % HCV
HCC deaths/all cause deaths: 2/5 in NASH, 7/10 in HCV
Kodama et al., 2013 [61]
Japan/single institution/1990–2010
Clinic-based, retrospective/NASH-cirrhosis (biopsy)/alcoholic cirrhosis
72 NASH-cirrhosis, 85 alcoholic cirrhosis/4.2 years in NASH-cirrhosis, 3.0 years in alcoholic cirrhosis
5-year incidence rate: 10.5 % NASH-cirrhosis, 12.3 % alcoholic cirrhosis
NR
In summary, there is strong evidence to support the risk of HCC in patients with NASH and advanced fibrosis or cirrhosis. However, given the generally small sample size, the modest follow-up period, and the heterogeneity in study design, in cohort definition and severity, and in primary data sources, it is not possible to clearly define the actual size of this risk.
Transversal (case-control and cross-sectional) studies
There are numerous transversal studies from different countries and ethnicities comparing cases with NASH-cirrhosis or cryptogenic cirrhosis-related HCC with at least one HCC control group. A milestone case-control Italian study, dating back to 2002, demonstrated that features suggestive of the MS, including obesity, type 2 diabetes, insulin resistance, and dyslipidemia, are observed more frequently in patients with HCC complicating cirrhosis of unknown etiology than in age- and sex-matched patients with HCC due to alcoholic or viral cirrhosis [62]. In line with those findings, another study from the USA confirmed that a large majority of patients with HCC and cryptogenic cirrhosis had a prior histological diagnosis of NASH or clinical features associated with NAFLD [63]. These seminal studies suggested that the presence of metabolic disorders may first lead to fatty liver and ultimately to HCC through NASH, fibrosis, and cirrhosis. Subsequent case-control and cross-sectional studies found that HCC attributed to NASH-cirrhosis or cryptogenic cirrhosis occurred at an older age and was more often associated with features of the MS, especially diabetes and overweight/obesity, than control groups with HCC complicating other chronic liver diseases (reviewed in [11]). These findings strongly suggest that HCC is a late complication of NAS H.
Case reports and case series
Only two cases of HCC in patients with NASH-cirrhosis had been reported in longitudinal studies until 1999 [6, 56]. Thereafter, several observations of HCC in NASH-cirrhosis have been published, mostly from Japan (reviewed in [10, 11]). The first two case reports, one from Brazil and one from Japan, described a male and a female patient aged 62 and 72 years, both with type 2 diabetes and known, histologically confirmed NASH, who developed HCC on a cirrhotic liver, 4 and 10 years, respectively, after the diagnosis of NASH [64, 65]. In a single-center case series of 82 Japanese patients with NASH, 6 patients presented with or developed HCC, all of them with NASH-cirrhosis [66]. These and subsequent case reports/case series confirmed that HCC is not an unusual event in NASH patients, especially those reaching the cirrhotic stage.
HCC in Non-cirrhotic NASH (Simple Steatosis and Steatohepatitis Without Advanced Fibrosis)
Many reports now suggest that NAFLD-related HCC may also occur in patients with NASH but without advanced fibrosis and even in simple steatosis.
Longitudinal studies
Clinic-based, longitudinal studies assessing the natural history of NAFLD patients, not restricted to those with cirrhosis or advanced fibrosis, showed HCC incidence and mortality rates ranging from 0 to 6 % during follow-up periods of 1–2 decades [6–8, 14–16, 60, 67–73] (Table 14.2). In a prospective US population-based study analyzing the NHANES cohort, none of 817 NAFLD patients, identified on the basis of elevated liver enzymes without other causes of liver disease, developed HCC during a median follow-up of 8.7 years [8]. Similarly, a Danish cohort study with a follow-up longer than 20 years found no HCC in any of the 170 subjects with biopsy-proven NAFLD and no significant fibrosis at baseline [68]. Conversely, a retrospective Japanese study reported a cumulative HCC incidence of 5.3 % at 10 years in biopsy-proven NAFLD patients; interestingly, all six patients who developed HCC had NASH, and two of them had fibrosis stages 1 and 2 at baseline [15]. Also a Swedish cohort study reported cumulative HCC mortality rates of 3 % in biopsy-proven NAFLD and 6 % in NASH patients during a 21-year follow-up; notably, one out of five HCC deaths occurred in a patient with baseline stage 1 fibrosis [71]. Recently Ekstedt et al. confirmed HCC as a cause of death in NAFLD patients. Indeed, they registered 5 HCC-related deaths among 229 biopsy-proven NAFLD patients followed up for 33 years; 3 HCC cases were observed in patients with NASH without advanced fibrosis at baseline; however, all of them had developed cirrhosis during follow-up [16]. A large retrospective study enrolling more than 6000 Japanese patients with ultrasound-diagnosed NAFLD reported 16 (0.25 %) new HCC cases during a 5.6-year follow-up period; patients older than 60 years, with diabetes, increased AST levels, and thrombocytopenia, were at increased risk of HCC [72]. Interestingly, a recent retrospective US population-based study analyzing a national health insurance database covering 18 million lives yearly from 2002 to 2008 found that NAFLD without other chronic liver diseases was the leading cause of HCC, accounting for 38.2 % of HCC cases, while cirrhosis was reported in only 46 % of these patients (by ICD diagnoses) [70]. These findings may suggest that at least in a subset of NAFLD patients, HCC may occur in the absence of advanced fibrosi s.
Table 14.2
Characteristics and outcomes of longitudinal studies assessing HCC risk among NAFLD patients, not restricted to those with cirrhosis or advanced fibrosis
Author, year [ref.] | Country/setting/period | Study design/cohort definition | Number of patients/cirrhosis prevalence/follow-up | HCC cases in the whole cohort/HCC cases in pts without advanced fibrosis-cirrhosis | HCC mortality in the whole cohort/HCC mortality in pts without advanced fibrosis-cirrhosis |
|---|---|---|---|---|---|
Matteoni et al., 1999 [6] | USA/single institution/1979–1987 | Clinic-based, retrospective/NAFLD (liver biopsy) | 132 patients/15 % with cirrhosis/8 years | NR | HCC deaths/all cause deaths: 1/48 |
Adams et al., 2005 [7] | USA/resources of Rochester Epidemiology Project/1980–2003 | Population-based, prospective/NAFLD (imaging or liver biopsy) and cryptogenic cirrhosis with prior metabolic syndrome | 435 patients/5 % with cirrhosis (2 % at diagnosis and 3 % during follow-up)/7.6 years | 2 cases of HCC, all in patients with cirrhosis | HCC deaths/all cause deaths: 1/53 |
Ekstedt et al., 2006 [67] | Sweden/single institution/1988–1993 | Clinic-based, retrospective/NAFLD (liver biopsy for persistently elevated liver enzymes) | 129 patients/3.1 % with cirrhosis at baseline/13.7 years | 3 cases of HCC, all in patients with cirrhosis (1 cirrhosis at baseline and 2 cirrhosis developed during follow-up) | HCC deaths/all cause deaths: 1/25 |
Ong et al., 2008 [8] | USA/NHANES III/1988–2000 | Population-based, prospective/NAFLD (elevated aminotransferases in the absence of other chronic liver diseases) | 817 patients/cirrhosis NR/8.7 years | NR | HCC deaths/all cause deaths: 0/80 |
Dam-Larsen et al., 2009 [68] | Denmark/single institution/1976–2004 | Clinic-based, retrospective/NAFLD without inflammation or significant fibrosis (liver biopsy) | 170 patients/0 % with cirrhosis/20.4 years | NR | HCC deaths: 0 |
Rafiq et al., 2009 [69] | USA/two institutions/NR | Clinic-based, retrospective/NAFLD (liver biopsy) | 173 patients (72 NASH, 101 non-NASH)/NR/10.5 years in NASH, 13.0 years in non-NASH | NR | HCC deaths/all cause deaths: 1/78 |
Sanyal et al., 2010 [70] | USA/National Insurance database/2002–2008 | Population-based, retrospective/NAFLD (ICD codes) | 18 million persons, 4 % with ICD codes for NAFLD/NR | Cumulative incidence: 0.3 % HCC with NAFLD (only 46 % of HCC-NAFLD cases had ICD codes for cirrhosis) | NR |
Soderberg et al., 2010 [71] | Sweden/single institution/1980–2008 | Clinic-based, retrospective/NAFLD (liver biopsy for persistently elevated liver enzymes) | 118 patients/7.6 % with cirrhosis at baseline/21 years | NR | HCC deaths/all cause deaths: 5/47 (3 patients had cirrhosis at baseline, 1 had stage 3 fibrosis and 1 stage 1 fibrosis at baseline) |
Arase et al., 2012 [14] | Japan/single institution/1994–2007 | Clinic-based, retrospective/NAFLD (ultrasonography) | 1600 patients/NR/8.2 years | 10 HCC cases, corresponding to development rate of 0.78/1000 person-years (0.83/1000 person-years in male, 0.63/1000 person-years in female) | NR |
Kawamura et al., 2012 [72] | Japan/single institution/1997–2010 | Clinic-based, retrospective/NAFLD (ultrasonography) | 6508 patients/NR/5.6 years | 16 HCC cases, corresponding to annual rate of 0.043 % | NR |
Hashizume et al., 2013 [60] | Japan/single institution/2003–2011 | Clinic-based, prospective/NASH with mild fibrosis (liver biopsy) | 19 female patients/0 % with cirrhosis/7.6 years | Cumulative incidence: 0 % | HCC deaths/all cause deaths: 0/1 |
Ekstedt et al., 2014 [16] | Sweden/two institutions/1980–1993 | Clinic-based, retrospective/NAFLD (liver biopsy for persistently elevated liver enzymes) | 229 patients/11.8 % advanced fibrosis or cirrhosis at baseline/26.4 years | NR | HCC deaths/all cause deaths: 5/96 (1 patient had fibrosis stage F0 and 2 patients had fibrosis stage F2 at baseline; however all developed cirrhosis during follow-up) |
Onnerhag et al., 2014 [73] | Sweden/Malmo Preventive Project/1974–1992 | Population-based, prospective/NAFLD (liver biopsy) | 36 patients/25 % with cirrhosis/27.0 years | 5 HCC cases, corresponding to cumulative incidence of 13.9 %; all cases occurred in patients with cirrhosis | HCC deaths/all cause deaths: 5/21 |
Seko et al., 2014 [15] | Japan/single institution/1999–2013 | Clinic-based, retrospective/NAFLD (liver biopsy) | 312 patients (176 NASH, 136 non-NASH)/8.5 % with cirrhosis among NASH/4.8 years | 6 HCC cases, corresponding to annual incidence of 0.4 %. All cases occurred in NASH patients. 1 patient had fibrosis stage 1 and 1 fibrosis stage 2 at baseline | HCC deaths/all cause deaths: 1/8 |
Transversal (case-control and cross-sectional) studies
In case-control and cross-sectional studies not restricted to NASH-cirrhosis-related HCC, cirrhosis accounts for the majority albeit not all HCC cases associated with NAFLD. In a Japanese cohort of 34 NASH patients with HCC, Hashimoto et al. found that 12 % of patients presented F1-2 stages of fibrosis [59]. In another Japanese study, Abe et al. described that one out of ten NAFLD-related HCC and four out of seven cryptogenic HCC did not have cirrhosis; moreover, patients with nonviral HCC had a higher rate of early-stage cirrhosis than those with viral HCC [74]. Recently, in a European and US population, 47 % of patients with NAFLD-HCC and 61 % of patients with cryptogenic HCC had no evidence of cirrhosis; this was in striking contrast with the 93–95 % prevalence of cirrhosis in patients with viral or alcohol-related HCC [75]. In a UK population, 23 % of NAFLD-HCC patients had no clinical, radiological, or histological evidence of cirrhosis vs. 0 % and 3.1 % of HCC cases due to alcohol or HCV, respectively [34]. This was confirmed in an American series where only 73 % of NASH HCC had bridging fibrosis or cirrhosis vs. 94 % for HCV- and/or alcohol-related HCC [76]. Finally, Paradis et al. studied 31 patients with HCC and features of the MS as the only risk factor for liver disease. Early fibrosis (F0–F2) was more common than in HCC patients with overt causes of chronic liver disease (65 % vs.26 %). Intriguingly, HCCs that developed in non-fibrotic livers were more often well differentiated despite their larger size and derived from the malignant transformation of a preexisting hepatocellular adenoma in a substantial proportion of cases (5/20) [39].
In summary, NAFLD-related HCC may arise in the absence of significant liver fibrosis, suggesting that liver carcinogenesis related to NAFLD may be more complex than the usual multistep process fibrosis-cirrhosis-HCC.
Case reports and case series
A recent review reported that, between 2004 and 2011, at least 116 cases of HCC have been described in histologically confirmed NAFLD without cirrhosis [10]. Arguably some of these might have been labeled F3 because of sampling error or incomplete cirrhosis. But many reports of HCC in NAFLD without significant fibrosis have since been published, suggesting that non-cirrhotic HCC may be more common in NAFLD than in other chronic liver diseases [34, 76–84]. For instance, in a French surgical series of HCC, 24 % had no or minimal fibrosis in the non-tumoral liver and more than half of these had changes consistent with NAFLD/NASH (hepatocyte steatosis, hepatocyte necrosis, and inflammation) [85]. The largest series of non-cirrhotic NAFLD-related HCC was recently described by Yasui et al. in 87 Japanese patients with NASH and HCC; a significant proportion were stage 1 [10 (11 %)] or 2 [15 (17 %)]. Male gender, obesity, diabetes, and features of the MS predominated in this series. Of note, men developed HCC at a less advanced stage of fibrosis than women, and the prevalence of cirrhosis was significantly lower among males compared to females (39 % vs. 70 %) [40]. NAFLD-related HCC not only has been reported in patients with steatohepatitis and different stages of fibrosis but also in patients with stigmata of MS and histological evidence of NASH without fibrosis and even in patients with steatosis without fibrosis or necroinflammation. Bullock et al. described two male patients aged 74 and 64 years, both with full-blown MS who presented with HCC and histological evidence of moderate macro- and microvesicular steatosis with mild lobular inflammation and absence of fibrosis in the non-tumoral liver parenchyma [86]. Guzman et al. described three cases of HCC, two females and one male, aged from 45 to 70 years, with features of MS and histopathologic evidence of bland steatosis, without hepatocellular ballooning, lobular inflammation, and fibrosis [87]. Recently, another case of HCC on simple steatosis without inflammation and fibrosis has been described in a 72-year-old obese Japanese man [88]. Surprisingly and somehow alarmingly, these findings have been also confirmed in children [81].
In summary, the whole histological spectrum of NAFLD can lead to HCC. This mandates the identification of risk factors of HCC development in NAFLD: apart from advanced fibrosis and cirrhosis, current data only point to male gender, age, and features of MS. Equally critical is to understand the underlying mechanisms of hepatocarcinogenesis in insulin resistance. Hopefully this will lead to monitoring strategies in at-risk patients but current evidence-based data are lacking except for patients with NASH-cirrhosis.
Hepatocellular Adenoma
Over the last decade, the pathogenic paradigm of hepatocellular adenomas (HCAs) , benign tumors occurring predominantly in young women, has evolved from a relatively rare disease, typically associated with long-term first-generation oral contraceptives use [89, 90], to a more common condition occurring in patients with overweight/obesity and related dysmetabolic comorbidities, as a result of ongoing hyperinsulinism, proinflammatory state, and sex hormone unbalance (Table 14.3) [91–98]. Of particular concern, obesity and MS have been linked with tumor growth and malignant transformation of HCAs [91–93]. The first description of an association between HCAs and MS-related fatty liver dates back to 2005 when Brunt and colleagues documented a case of hepatic adenomatosis arising in a non-cirrhotic liver with NASH [99]. Since then, several case series have been published assuming a relationship between metabolic steatopathy and HCAs, particularly inflammatory HCAs, and arguing that these liver tumors should be added to the list of neoplasms associated with overweight/obesity and features of MS. Paradis et al. in their surgical series of 32 telangiectatic/inflammatory HCAs from 27 patients reported for the first time an association with overweight/obesity. Moreover, significant steatosis outside tumors was observed in 69 % of patients and moderate/severe steatosis in more than 30 % [100]. Accordingly, a recent histomorphological investigation of the non-tumorous liver of 32 resected inflammatory HCAs confirmed that steatosis was very common; it was present in adjacent, non-tumoral liver in 59–70 % of cases. Steatohepatitis was only present in 2/32 patients [101]. Recent case reports described patients with inflammatory adenomas within the entire histological spectrum of NAFLD [102–104]. Comparing 24 patients with radiologically and pathologically proven HCAs with age- and sex-matched controls with other benign liver lesions (hemangiomas), Furlan et al. showed that HCAs occurred more frequently and more often were multiple in patients with hepatic steatosis [105]. Interestingly, an American series of 60 patients with HCAs not only confirmed a high prevalence of overweight/obesity (18/55 %) but also demonstrated that tumor progression was more frequent in obese patients [91]. In addition to being involved in size progression of HCAs, obesity and the MS may also favor malignant transformation of HCAs. In their large series of HCAs with malignant changes, Farges et al. noticed an association between the MS and increasing numbers of HCCs developed with the MS [92]. In support of the hypothesis that HCAs are the likely predisposing condition for MS-associated HCC, a seminal French study demonstrated that HCC in patients with features of MS could be considered a distinct biological entity in terms of both pathogenesis and evolution. As opposed to cirrhosis-related HCC, MS-associated HCCs mainly occurred in the absence of significant fibrosis in the background liver, were more often well differentiated despite their larger size, and at least some of them arose through malignant transformation of a preexisting liver cell adenoma, particularly the inflammatory variant [39]. A recent independent study confirmed that a substantial fraction (nearly a third) of non-cirrhotic HCC have some clinical, morphological, or immunophenotypical features currently described in HCAs [106].
Table 14.3
Review of the literature regarding the association between metabolic syndrome, NAFLD and HCAs
Author, year [ref.] | Methods | Main findings |
|---|---|---|
Brunt et al., 2005 [99] | Case report | Hepatic adenomatosis arising in a non-cirrhotic liver with NASH |
Wan der Windt et al., 2006 [96] | Case series of 48 patients with HCAs | 22 patients (46 %) had liver steatosis. Liver steatosis was significantly more common in patients with multiple HCAs (59 % vs. 19 %, p = 0.008) |
Bioulac-Sage et al., 2007 [94] | Genotype–phenotype correlation in a series of 93 HCAs | High BMI, alcohol intake, and elevated GGT were significantly associated with inflammatory HCA |
Paradis et al., 2007 [100] | Review of a surgical series of 32 inflammatory HCAs from 27 patients | Association of telangiectatic/inflammatory HCAs with overweight/obesity: 17 patients (63 %) had a BMI ≥ 25 kg/m2, of whom 9 were obese. Significant steatosis outside tumors was observed in 69 % of patients and moderate and severe steatosis in more than 30 %. 9 patients had at least 1 other inflammatory HCA. Foci of well-differentiated HCC in 1 case |
Furlan et al., 2008 [105] | Case-control study of 24 patients with radiologically and pathologically proven HCAs compared with age- and sex-matched controls with other benign liver lesions (hemangiomas) | Hepatic steatosis was present in 14/24 cases (58 %) vs. 7/24 controls (29 %) (p = 0.042). Steatosis was more common in patients with multiple HCAs (9/11, 82 %) than in those with a single HCA (5/13, 38 %) (p = 0.047). BMI (mean ± SD): 30.1 ± 7.24 kg/m2 vs. 28.1 ± 5.28 kg/m2 in cases and controls, respectively (p = 0.456). 8 cases (33 %) and 2 controls (8 %) had diabetes (p = 0.033) |
Lim et al., 2008 [102] | Case report | Multiple inflammatory HCAs in a background of NASH |
Bioulac-Sage et al., 2009 [95] | Genotype–phenotype correlation in a surgical series of 128 HCAs | Inflammatory HCAs were characterized by a BMI > 25 kg/m2 in 43 % and by steatosis in the non-tumoral liver in 38 % of the cases. Patients with inflammatory HCAs were more frequently exposed to alcohol (22 %) |
Paradis et al., 2009 [39] | Analysis of the pathological characteristics of HCC and non-tumoral liver in 31 patients with MS as the only predisposing condition for liver disease | MS-associated HCCs mainly occurred in the absence of significant fibrosis in the background liver (64.5 % fibrosis F0–F2), were more often well differentiated (64.5 %) despite their larger size (8.8 ± 6 cm), and, at least some of them, arose through malignant transformation of a preexisting HCA (5 cases, 16 %), particularly the inflammatory variant (3/5, 60 %). All HCC that developed from a preexisting HCA were observed in the group of patients without significant fibrosis |
Watkins et al., 2009 [103] | Case report | Inflammatory HCA associated with hepatic adenomatosis arising within advanced-stage NAFLD (pre-cirrhotic) |
Bunchorntavakul et al., 2011 [91] | Survey of 60 patients with HCAs | Overweight and obesity were present in 18 and 55 % of patients. Fatty liver, hypertension, diabetes, and dyslipidemia were reported in 57 %, 42 %, 30 %, and 23 % of patients, respectively. 2 patients had PCOS. 72 % of patients had multiple adenomas. Obesity was more often associated with fatty liver (p = 0.006), diabetes (p = 0.003), hypertension (p = 0.006), dyslipidemia (p = 0.03), and multiple (85 % vs. 48 %, p = 0.005) and bilobar (67 % vs. 33 %, p = 0.01) HCAs. The rate of complete resection of HCAs was significantly lower in obese patients (8 % vs. 69 %, p = 0.004). In the 26 patients without intervention, tumor size progression was more frequently observed in obese patients (33 % vs. 0 %, p = 0.05). 3/15 obese patients (20 %) lost ≥5 % body weight and there was no progression in the liver lesions
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