Histopathologische Diagnose der nichtalkoholischen und alkoholischen Fettlebererkrankung

Both alcoholic (AFL) and non-alcoholic fatty liver (NAFL) are characterized by lipid deposition in hepatocytes. The diagnosis of steatosis is made when lipid deposition exceeds 5% of hepatocytes, while involvement of more than 50% is called “fatty liver “. An additional inflammatory reaction leads to alcoholic (ASH) or non-alcoholic steatohepatitis (NASH). Steatohepatitis is present when both inflammatory infiltrates of mixed cells in the small liver lobules as well as liver cell injury in terms of ballooning can be detected. Liver biopsy represents the “gold standard” for confirming diagnosis and determining inflammatory activity and potential fibrosis of fatty liver disease. The differential diagnosis of ASH–NASH cannot be made on the basis of histological criteria alone. Steatosis, inflammatory changes and hepatocytic injury can be semiquantified as a “Brunt Score” or “NAS” (NAFLD activity score), providing the basis on which to decide whether or not steatohepatitis is present. People at increased risk of developing a fatty liver possess an increased risk of developing chemotherapy-associated steatohepatitis (CASH). Histologically, pediatric NASH differs from adult NASH and is often only clinically manifest through a mild if persistent elevation in transaminases.     

Non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD), also referred to as metabolic associated fatty liver disease (MAFLD), is the commonest form of chronic liver disorder arising from metabolic dysregulation. It encompasses a wide spectrum of fatty liver phenotypes including isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is considered more likely to lead to grave clinical consequences such as cirrhosis and hepatocellular carcinoma, compared to simple steatosis. NASH is characterised by steatosis, inflammation, and damage to hepatocytes. Here, we present a case of a middle-aged gentleman with a background of infectious hepatitis who presented with NASH, with emphasis on terminology and histological assessment criteria of NAFLD and NASH. Reflection on and consistent effort to standardise terminology and assessment criteria will aid in addressing the scientific and clinical needs of NAFLD and NASH.     

Histopathological diagnosis of non-alcoholic and alcoholic fatty liver disease

The diagnostic procedures in patients with suspected fatty liver disease-with or without known alcohol consumption-should be standardized and generally accepted. We therefore present a guideline, summarizing the current concepts of etiology, diagnostic as well as differential diagnostic of patients with fatty liver disease. Alcoholic as well as and non-alcoholic fatty liver are characterised by lipid deposition in hepatocytes. The diagnosis of steatosis is made when lipid deposition exceeds 5% of hepatocytes, while involvement of more than 50% is called "fatty liver". An additional inflammatory reaction leads to alcoholic (ASH) or non-alcoholic steatohepatitis (NASH). Steatohepatitis is present when both inflammatory infiltrates of mixed cells in the small liver lobules as well as liver cell injury in terms of ballooning can be detected. Liver biopsy represents the "golden standard" for confirming diagnosis and determining inflammatory activity and potential fibrosis of fatty liver disease. The differential diagnosis of ASH vs. NASH cannot be made on the basis of histological criteria alone. Steatosis, inflammatory changes and hepatocytic injury can be semiquantified as a "Brunt Score" or "NAS" (NAFLD activity score), providing the basis on which to decide whether or not steatohepatitis is present. People at increased risk of developing a fatty liver possess an increased risk of developing chemotherapy-associated steatohepatitis. Histologically, pediatric NASH differs from adult NASH and is often only clinically manifest through a mild if persistent elevation in transaminases.     

Manganese superoxide dismutase is reduced in the liver of male but not female humans and rodents with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases. Oxidative stress is one of the pathogenic mechanisms contributing to the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH). Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidative enzyme and here its expression in rodent and human NAFLD has been analyzed. MnSOD is found reduced in the liver of male mice fed a high fat diet and male ob/ob mice. Female mice fed an atherogenic diet to induce NASH have MnSOD protein levels comparable to controls. In a cohort of 30 controls, 41 patients with fatty liver and 39 NASH patients, MnSOD mRNA is significantly lower in the steatotic and NASH liver. When analyzed in both genders separately reduction of MnSOD expression is only found in males. Here, MnSOD mRNA negatively correlates with steatosis grade but not with extent of fibrosis or inflammation. MnSOD is, however, not reduced in primary human hepatocytes (PHH) treated with palmitate or oleate to increase cellular triglycerides. Lipopolysaccharide, TNF, IL-6, TGFβ and leptin which are all raised in NAFLD do not affect MnSOD in PHH. Adiponectin which attenuates oxidative stress partly by increasing MnSOD in macrophages does not induce MnSOD in PHH. In summary, current data show that hepatic MnSOD is reduced in male but not female humans and rodents with NAFLD.     

Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis

Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.     

Hepatocellular carcinoma in a mouse model fed a choline‐deficient,L‐amino acid‐defined,high‐fat diet

Hepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). However, details of the liver‐specific molecular mechanisms responsible for the NAFLD–NASH–HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis‐associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis.     

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease

Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45+ (P<0.0001) and CD163+ (P<0.0001) cells were markedly increased in children with severe histological activity (NAS≥5) compared to children with lower activity (NAS<5), whereas CD3+ cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45+, CD3+ and CD163+ cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3+ cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores.     

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-fed db/db mice

Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3(-/-) or GP130(-/-) mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD diet-fed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.     

Molecular mechanisms involved in NAFLD progression

Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic-related disorder characterized by fatty infiltration of the liver in the absence of alcohol consumption. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which might progress to end-stage liver disease. This progression is related to the insulin resistance, which is strongly linked to the metabolic syndrome consisting of central obesity, diabetes mellitus, and hypertension. Earlier, the increased concentration of intracellular fatty acids within hepatocytes leads to steatosis. Subsequently, multifactorial complex interactions between nutritional factors, lifestyle, and genetic determinants promote necrosis, inflammation, fibrosis, and hepatocellular damage. Up to now, many studies have revealed the mechanism associated with insulin resistance, whereas the mechanisms related to the molecular components have been incompletely characterized. This review aims to assess the potential molecular mediators initiating and supporting the progression of NASH to establish precocious diagnosis and to plan more specific treatment for this disease.     

Nonalcoholic fatty liver disease and HIV infection

As persons with HIV live longer, chronic liver disease is increasingly important. Nonalcoholic fatty liver disease (NAFLD) is characterized by excess fat in hepatocytes in patients without significant alcohol use. It can progress from steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Visceral obesity and insulin resistance are integral to the pathogenesis of NAFLD. Patients with HIV are at greater risk of NAFLD due to antiretroviral therapy and viral hepatitis coinfection. Antiretroviral therapy can lead to patterns of injury that include steatosis and NASH. Coinfection with hepatitis C virus increases the risk of insulin resistance and hepatic steatosis, and co-existent features of NASH have also been reported. Histological-based, longitudinal studies are needed that address the interactions of NAFLD and HIV infection, the effects of antiretroviral therapy and hepatotropic virus coinfection, and inform better management strategies.     

The Role of Innate Immune Cells in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a very common hepatic pathology featuring steatosis and is linked to obesity and related conditions, such as the metabolic syndrome. When hepatic steatosis is accompanied by inflammation, the disorder is defined as nonalcoholic steatohepatitis (NASH), which in turn can progress toward fibrosis development that can ultimately result in cirrhosis. Cells of innate immunity, such as neutrophils or macrophages, are central regulators of NASH-related inflammation. Recent studies utilizing new experimental technologies, such as single-cell RNA sequencing, have revealed substantial heterogeneity within the macrophage populations of the liver, suggesting distinct functions of liver-resident Kupffer cells and recruited monocyte-derived macrophages with regards to regulation of liver inflammation and progression of NASH pathogenesis. Herein, we discuss recent developments concerning the function of innate immune cell subsets in NAFLD and NASH.     

The role of the circadian clock in the development,progression, and treatment of non-alcoholic fatty liver disease

The circadian clock comprises a cellular endogenous timing system coordinating the alignment of physiological processes with geophysical time. Disruption of circadian rhythms has been associated with several metabolic diseases. In this review, we focus on liver as a major metabolic tissue and one of the most well-studied organs with regard to circadian regulation. We summarize current knowledge about the role of local and systemic clocks and rhythms in regulating biological functions of the liver. We discuss how the disruption of circadian rhythms influences the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We also critically evaluate whether NAFLD/NASH may in turn result in chronodisruption. The last chapter focuses on potential roles of the clock system in prevention and treatment of NAFLD/NASH and the interaction of current NASH drug candidates with liver circadian rhythms and clocks. It becomes increasingly clear that paying attention to circadian timing may open new avenues for the optimization of NAFLD/NASH therapies and provide interesting targets for prevention and treatment of these increasingly prevalent disorders.     

Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV

Abnormal liver enzymes (LE) are common in patients infected with the human immunodeficiency virus (HIV) even in the absence of viral hepatitis or alcohol abuse. With availability of antiretroviral combination therapy, life expectancy has improved dramatically and as a consequence the spectrum of liver disease is changing. Increased reports on the development of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in HIV coinfected patients raise questions around prevalence, clinical manifestations, and clinical outcome of these liver diseases in HIV coinfection. Moreover, the potential impact of combination antiretroviral therapy as well as direct HIV effects on the emergence of non-alcoholic fatty liver disease needs to be explored. This review summarizes the recent literature on NAFLD and NASH in HIV.     

Serum lipocalin-2 is a potential biomarker for the clinical diagnosis of nonalcoholic steatohepatitis

Background/AimsNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. We aimed to investigate the usefulness of a key biomarker, lipocalin-2 (LCN2), for the detection of NASH progression.MethodsA mouse NASH model was established using a high-fat diet and a high-sugar drinking water. Gene expression profile of the NASH model was analyzed using RNA sequencing. Moreover, 360 NAFLD patients (steatosis, 83; NASH, 277), 40 healthy individuals, and 87 patients with alcoholic fatty liver disease were recruited.ResultsInflammatory infiltration, focal necrosis in the leaflets, steatosis, and fibrosis were documented in the mouse liver. In total, 504 genes were differentially expressed in the livers of NASH mice, and showed significant functional enrichment in the inflammation-related category. Upregulated liver LCN2 was found to be significantly interactive with various interleukins and toll-like receptors. Serum LCN2 levels were significantly increased in NAFLD patients. Serum LCN2 levels were correlated with steatosis, intralobular inflammation, semiquantitative fibrosis score, and nonalcoholic fatty liver disease activity score. The area under the curve of serum LCN2 was 0.987 with a specificity of 100% and a sensitivity of 93.5% for NASH diagnosis, and 0.977 with almost the same specificity and sensitivity for steatosis.ConclusionsLCN2 might be involved in the transition from NAFL to NASH by mediating inflammation. Serum LCN2 levels might be a novel biomarker for the diagnosis of NASH.     

Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, nonprogressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest that oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis, and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation; additionally, the potential pathogenetic role of extracellular sources of reactive oxygen species in NAFLD, including increased myeloperoxidase activity and oxidized low density lipoprotein accumulation, will be reviewed. We will discuss how these mechanisms converge to determine the whole pathophysiological spectrum of NAFLD, including hepatocyte triglyceride accumulation, hepatocyte apoptosis, hepatic inflammation, hepatic stellate cell activation, and fibrogenesis. Finally, available animal and human data on treatment opportunities with older and newer antioxidant will be presented.     

MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis

Adiponectin protects from inflammation and fibrosis in metabolic liver disease. In the present study we analyzed whether this adipokine may directly affect the activity of matrix metalloproteinases (MMPs), central regulators of fibrinolysis, in hepatocytes. Global gene expression analysis indicated upregulation of MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in primary human hepatocytes (PHH) in response to stimulation with adiponectin, and these results were confirmed by real-time RT-PCR. Furthermore, gelatin zymography revealed that MMP-9 activity was significantly induced in supernatants of adiponectin stimulated PHHs. In a murine model of hepatic steatosis and in human steatotic liver samples hepatic MMP-9 activity was not significantly altered. However, in two different murine models of non-alcoholic steatohepatitis (NASH) MMP-9 activity was significantly elevated compared to chow fed control mice. Of note, MMP-9 activity did not or even negatively, respectively, correlate with adiponectin serum levels in these models.The current data indicate that in NASH hepatic inflammation and fibrosis but not hepatic steatosis induce liver MMP-9 activity, and this induction seems to be related to the anti-inflammatory activity of adiponectin rather than its effect on hepatocellular MMP-9 expression.     

NLRP3 Deletion Inhibits the Non-alcoholic Steatohepatitis Development and Inflammation in Kupffer Cells Induced by Palmitic Acid

The cleavage and secretion of pro-inflammatory cytokines IL-1β and IL-18 is regulated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome activation. Kupffer cells (KCs) are implicated in the pathogenesis of various liver diseases, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and liver fibrosis. However, the role of NLRP3 played in the non-alcoholic steatohepatitis (NASH) has yet to be evaluated. In the present study, methionine–choline-deficient (MCD) diet was used to establish the mice NASH model. The expression levels of F4/80 and NLRP3 in liver tissues were evaluated, and the IL-1β and IL-18 in serum were also evaluated. KCs were isolated from wild-type (WT) mice and NLRP3 knockout (NLRP3^?/?) mice and then randomly divided into two groups: the control and palmitic acid (PA) groups. The expression levels of NLRP3, ASC, and caspase-1 in KCs were determined by RT-PCR, western blotting, and immunofluorescence. The levels of IL-1β and IL-18 in the supernatant (SN) of KCs were evaluated by enzyme-linked immunosorbent assay (ELISA). We found that KCs and NLRP3 play pro-inflammatory roles in the progression of NASH, probably through secretions of IL-1β and IL-18 by KCs induced by PA. PA could act as a kind of damage-associated molecular patterns to elevate the messenger RNA and protein expression levels of NLRP3, ASC, and caspase-1 in KCs from WT mice. In the contrast, NLRP3 deletion could inhibit the NLRP3 inflammasome upregulation and activation in KCs induced by PA. Furthermore, the levels of pro-inflammatory cytokines IL-1β and IL-18 in the SN of KCs from WT mice were all elevated with the stimulation of PA, and the increase of these cytokines in the SN was blocked by NLRP3 deletion. In conclusion, our novel findings demonstrate that NLRP3 plays a pivotal role in NASH development and pro-inflammatory cytokines IL-1β and IL-18 secretion induced by PA stimulation, and NLRP3 might be an effective potential target for the treatment of liver inflammatory diseases associated with NLRP3 inflammasome activation.     

Elevated systemic monocyte chemoattractrant protein-1 in hepatic steatosis without significant hepatic inflammation

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and the metabolic syndrome. It encompasses a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter develops upon pro-inflammatory cell infiltration and is widely considered as the first relevant pathophysiological step in NAFLD-progression. The chemokine monocyte chemoattractant protein 1 (MCP-1) plays an important role in the progression of hepatic inflammation and fibrosis, and both increased hepatic expression and circulating serum levels have been described in NASH. Here, we aimed to investigate MCP-1 expression in simple hepatic steatosis. Upon feeding a high-fat diet mice developed hepatic steatosis in the absence of significant hepatic inflammation, but elevated hepatic MCP-1 expression compared to control mice fed a standard chow. Interestingly, high-fat diet fed mice had significantly higher MCP-1 serum levels, and MCP-1 mRNA expression was significantly increased in visceral adipose tissue. Furthermore, MCP-1 serum levels were also elevated in patients with ultrasound-diagnosed NAFLD and correlated with the body-mass index and fasting glucose. In conclusion, our data indicate both the liver and adipose tissue as cellular sources of elevated circulating MCP-1 levels already in the early phase of hepatic steatosis. Since MCP-1 derived from visceral adipose tissue reaches the liver via portal circulation at high concentrations it may significantly contribute to the progression of simple steatosis to NASH.     

Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia

Chronic inflammation is a common theme in a variety of disease pathways, including autoimmune diseases. The pathways of chronic inflammation are well illustrated by nonalcoholic steatohepatitis (NASH), which is of a serious concern due to its increasing prevalence in the westernized world and its direct correlation with lifestyle factors, particularly diet. Importantly, NASH may ultimately lead to the development of hepatocellular carcinoma. We previously reported that injection of monosodium glutamate (MSG) in ICR mice leads to the development of significant inflammation, central obesity, and type 2 diabetes. To directly address the long-term consequences of MSG on inflammation, we have performed serial analysis of MSG-injected mice and focused in particular on liver pathology. By 6 and 12 months of age, all MSG-treated mice developed NAFLD and NASH-like histology, respectively. In particular, the murine steatohepatitis at 12 months was virtually undistinguishable from human NASH. Further, dysplastic nodular lesions were detected in some cases within the fibrotic liver parenchyma. We submit that MSG treatment of mice induces obesity and diabetes with steatosis and steatohepatitis resembling human NAFLD and NASH with pre-neoplastic lesions. These results take on considerable significance in light of the widespread usage of dietary MSG and we suggest that MSG should have its safety profile re-examined and be potentially withdrawn from the food chain.