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it has been proved that it is feasible to replace asbestos with other fibres in manufacturing fibro-cement materials and still obtain products of similar quality.
وقد ثبت أن من المجدي استبدال الأسبست بألياف أخرى لتصنيع مواد الأسمنت الليفي، ولا تزال تحصل على مواد ذات نوعية مماثلة.
abstract non-alcoholic fatty liver disease (nafld) is a clinicopathologic entity increasingly recognized as a major health burden in developed countries. it includes a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (nash), advanced fibrosis, and rarely, progression to cirrhosis. recent studies emphasize the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction in the development and progression of nafld. furthermore, accumulating evidence supports an association between nafld and metabolic syndrome. although the data are mainly epidemiological, the pathogenesis of nafld and metabolic syndrome seems to have common pathophysiological mechanisms, with focus on insulin resistance as a key factor. this review summarizes the current knowledge on the epidemiology, pathophysiology and diagnosis of both nafld and metabolic syndrome and the findings that strongly support the association of nonalcoholic fatty liver disease as a possible component in the cluster of metabolic syndrome. keywords: non alcoholic fatty liver disease, non alcoholic steatohepatitis, metabolic syndrome non alcoholic fatty liver disease (nafld) is the most common liver disease since its prevalence is estimated to be 20-30% in general population of western countries1. nafld occurs as a histological spectrum of disease and includes the subtypes of simple steatosis and nonalcoholic steatohepatitis (nash). it was thought to be a benign condition but is now increasingly recognized as a major cause of liver-related morbidity and mortality. studies introduced that nafld may progress to cirrhosis, liver failure, and hepatocellular carcinoma2. it has been shown that nafld is strongly associated to the features of metabolic syndrome. insulin resistance is a key pathogenic factor in both nafld and metabolic syndrome. available data from clinical, experimental and epidemiological studies indicate that nafld may be the hepatic manifestation of metabolic syndrome3. metabolic syndrome definition – diagnosis the metabolic syndrome is a clustering of risk factors that greatly increases an individual's probability for developing atherosclerotic cardiovascular disease (ascvd), type 2 diabetes mellitus and chronic kidney disease. the predominant underlying risk factors appear to be abdominal obesity, atherogenic dyslipidaemia, hypertension, elevated plasma glucose, a prothrombotic state, and a proinflammatory state4–7. several organizations have attempted to formulate the definition of metabolic syndrome and used simple criteria for its diagnosis, but it is beyond the scope of the present review to delineate the published definitions8–12. in 2001 the national cholesterol education program (ncep) adult treatment panel iii (atp iii) introduced simple clinical criteria which are widely adopted since they are simple to use in clinical practice and since a large number of studies evaluated their reliability13. in 2005 the american heart association (aha) and the national heart lung and blood institute (nhlbi) updated the atp iii criteria with minor modifications5. thus, the metabolic syndrome is identified by the presence of three or more of the following components: abdominal obesity (waist circumference >102 cm in men, >88 cm in women), elevated triglycerides (>150 mg/dl or on drug treatment for elevated triglycerides), reduced hdl-c level (130 mmhg or diastolic blood pressure >85 mm hg or on antihypertensive drug treatment) and impaired fasting glucose (100 - 125 mg/dl or on antidiabetic drug treatment)5. the lack of a standard definition makes comparisons between studies difficult. depending on the definition used, estimates of the prevalence of the metabolic syndrome will differ. however, studies comparing the definitions reported that all definitions will identify persons at increased risk for diabetes, cardiovascular disease, and all-cause mortality7,10. data indicate that the metabolic syndrome prevalence varies widely across populations. according to the national health and examination survey (nhanes) iii (1988-1994) and the nhanes 1999-2000, the age-adjusted prevalence of the ms was 24.1% and 27% respectively14. in greece during 2003 the mets-greece study was carried out and the age- adjusted prevalence of the metabolic syndrome in the general population was 23.6%. this was similar in men (24.2%) and women (22.8%), but the prevalence increased with age in both sexes. this can be attributed to a similar age-related trend in each of the components of the metabolic syndrome. most individuals with ms had three components of the syndrome (61%), 29% had four and 10% had all five components. the most common abnormalities were abdominal obesity (72%) and arterial hypertension (66%). the prevalence of elevated glucose (including patients with diabetes mellitus) was unexpectedly high (53%). the prevalence of elevated triglyceride levels among subjects with ms was 62% and that of low hdl-c levels was 54%15. pathophysiology insulin resistance and compensatory hyperinsulinaemia have central etiologic roles in the development of ms16. evidence from animal models as well as human studies have identified hepatic very low density lipoprotein (vldl) overproduction as a critical underlying factor in the development of hypertriglyceridaemia, one of the main features of ms. the reduction of hdl-cholesterol is a consequence of changes in hdl composition and metabolism17. obesity has been also described as the central causative component in the development of the ms. in both muscle cells and adipocytes of obese individuals, insulin binding to its receptor, receptor phosphorylation, tyrosine kinase activity, and phosphorylation of irss are reduced. increased adipose energy storage in obesity results in increased ffa flux to other tissues and increased triglyceride storage in these tissues, which promote insulin resistance and other adverse effects18. accumulated visceral adipose tissue produces and secretes a number of adipocytokines, such as tnf-α and il-6, which induce development of hypertension19. individuals with ms have significantly higher rate of sodium and water reabsorption at the proximal tubular level20. insulin promotes endothelin-1 (et-1) production from endothelial cells as well as et-1 action in vascular smooth muscle cells, causing vasoconstriction and increased smooth muscle cells proliferation21,22. insulin also increases the activity of the sympathetic nervous system23. chronic inflammation is frequently associated with the ms and the main inflammatory mediators are adipocytokines and ffas. proinflammatory cytokines that have been associated with ms include crp, tnf-α, il-6 and others and they result in more insulin resistance and lipolysis of adipose tissue triglyceride stores, in enhanced hepatic glucose and vldl production. cytokines and ffa also increase the production of fibrinogen and plasminogen activator inhibitor-1 (pai-1) by the liver that complements the overproduction of pai-1 by adipose tissue, so inducing pro-thrombotic state24. non alcoholic fatty liver disease definition nafld is a clinicopathologic entity with wide histological spectrum which includes simple steatosis and steatohepatitis (nash). steatosis is determined by estimating the proportion of hepatocytes containing fat droplets. the suggested lower threshold is 5% of hepatocytes. features of steatohepatitis include hepatocellular injury (ballooning, apoptosis/necrosis, mallory's hyaline, giant mitochondria), inflammation and fibrosis (perisinusoidal, pericellular)25,26. there are different suggestions on the level of alcohol consumption that can reliably distinguish between alcoholic fatty liver and nafld. many centres accept that the maximum allowable level of alcohol intake for definition of nafld is 2 standard drinks a day (140 g ethanol/week) for men, and one standard drink a day (70 g ethanol/week) for women27. nafld may be categorized as primary or secondary depending on the underlying pathogenesis. primary nafld is associated with insulin resistance and metabolic syndrome. other conditions associated with nafld are total parenteral nutrition, acute starvation, abdominal surgery (e.g. extensive small bowel resection, biliopancreatic diversion, and jejunal bypass), use of several drugs (e.g. amiodarone, tamoxifen, glucocorticoids, synthetic estrogens, diltiazem, aspirin, methotrexate, highly active antiretroviral therapy). it is also associated with hepatitis c, hiv and metabolic disorders i.e. hypobetalipoproteinemia, lipodystrophy, hypopituitarism, hypothalamic obesity, weber-christian syndrome, acute fatty liver of pregnancy, reyes syndrome and mauriac syndrome28,29. studies indicate that occupational exposure to organic solvents may play a role in the development of nafld30 and that women with polycystic ovary syndrome may have an increased prevalence of non alcoholic fatty liver disease31. epidemiology – natural history attempts to screen for nafld in the general population have been limited by the low accuracy of non-invasive tools and self-reported ethanol ingestion histories32. despite the limitations studies suggest that 20-30% of individuals in western countries have nafld1. nafld may represent the majority of unexplained cases of aminotrasferase elevation33. the prevalence increases from 16.5% in lean persons to 75% in obese persons34. the disease is reported in all age groups, even in paediatric patients in which is strongly associated with obesity35. the prevalence of nafld also increases with age and the highest prevalence is in those between 40 and 49 years old. whereas in older studies nafld was more frequent in women, the opposite was found in recent series. however, these studies are biased by their selection criteria and especially by the use of an elevated alt as an entry criterion. the dionysos study support that gender is not a risk factor for nafld in general population1,36. studies in usa report that the frequency of nafld varies significantly with ethnicity (45% in hispanics, 33% in whites, 24% in blacks)37. obesity is present in the majority of individuals with nafld2. it is an independent risk factor and it is strongly associated with the progression of the disease1,38. the role of central adiposity seems crucial. visceral fat is an important source of triglycerides leading to steatosis. this probably explains the presence of generally lean, centrally obese individuals with nafld 3,39. the prevalence increases in subjects with impaired glucose tolerance (43%) and in subjects with newly diagnosed diabetes mellitus (62%)40. in a prospective study of 100 patients with type 2 diabetes mellitus the incidence of nafld was 49%, confirming that diabetes mellitus is a strong independent risk factor of nafld41. insulin resistance and hyperinsulinemia are the laboratory findings most closely associated with the presence of nafld in a large series of patients, even in lean subjects with normal glucose tolerance1,3,42. hypertension and especially systolic hypertension is also an independent predictor of nafld43. despite being common and potentially serious, the natural history of nafld remains poorly clarified. mortality is significantly increased among patients with nafld compared with the expected mortality of the general population of same age and sex. liver-related death is a leading cause of mortality, although the absolute risk is low2. patients with simple steatosis have a relatively benign liver-related prognosis with 1.5% developing cirrhosis and 1% dying from liver-related causes over one to two decades44. in contrast, 30-50% of individuals with steatohepatitis will develop fibrosis, 15% will develop cirrhosis and 3% will progress to terminal liver failure3,38. studies report that older age, obesity, and presence of diabetes mellitus are independent predictors of severe hepatic fibrosis in patients with nonalcoholic steatohepatitis (nash)45,46. an important observation is that many patients with cryptogenic cirrhosis have had misdiagnosed nafld. this is due to the decrease of histological evidence of hepatic steatosis as the disease progresses to cirrhosis2. finally nafld may account for a substantial proportion of cases of hepatocellular carcinoma (hcc). a study reports that nafld accounts for at least 13% of the cases of hcc47. pathophysiology (figure 1) figure 1: figure 1: development of nonalcoholic hepatic steatosis. in adipose tissue, insulin resistance decreases the inhibitory action of insulin on hormone sensitive lipase (hsl), thus enhancing triglyceride (tg) lipolysis and free fatty acid (ffa) release. the results ... pathophysiology of nafld still has not been completely clarified. nevertheless, insulin resistance plays a fundamental role in the pathogenesis of fatty liver. insulin resistance may be defined as a condition in which a) higher than normal insulin concentrations are needed to achieve normal metabolic responses or b) normal insulin concentrations fail to achieve a normal metabolic response48. insulin is a pleiotropic hormone which has diverse functions including stimulation of nutrient transport into cells, regulation of gene expression, modification of enzymatic activity and regulation of energy homeostasis49. insulin binds to its receptor in the plasma insulin-dependent cell membrane, resulting in phosphorylation of the receptor and activation by phosphorylation in tyrosine of insulin receptor substrate proteins (irs proteins). irs proteins are linked to the activation of two main signaling pathways: the phosphatidylinositol 3-kinase (pi3k)–akt/protein kinase b (pkb) pathway, which is responsible for most of the metabolic actions of insulin, and the ras–mitogen-activated protein kinase (mapk) pathway, which regulates expression of some genes and cooperates with the pi3k pathway to control cell growth and differentiation. akt/pkb is a serine/ threonine kinase that activates the translocation of the glucose transporter (glut4) to the plasma membrane, thus facilitating cell glucose uptake. another target of akt/pkb is glycogen synthase kinase-3 (gsk3). phosphorylation of gsk3 decreases its activity towards glycogen synthase, which leads to increased glycogen synthesis. akt/pkb also regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (fox) class of transcription factors. akt/pkb effectively activates the mtor pathway which regulates protein synthesis. a number of acquired factors including oxidative stress, ffas, tnfα, and -as intracellular mediators- ceramide, ikkβ (inhibitor of κβ kinase) nfkb (nuclear factor kappa b), pkc-θ (protein kinase c-θ), jnk1 (jun n-terminal kinase-1) cytochrome cyp2e1 and socs (suppressors of cytokine signaling ) have been implicated in altering the above described insulin signaling pathways, resulting in insulin resistance50,51. the most widely accepted model to explain the development of nafld and the progression from simple steatosis to nash is the "two-hit hypothesis". the "first hit" is the accumulation of lipids in the hepatocytes and insulin resistance is the key pathogenic factor for the development of hepatic steatosis .the "second hit" leads to hepatocyte injury, inflammation and fibrosis. factors initiating the second hit are oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction52. liver fat accumulation results from a disturbance in the balance between supply, formation, consumption and hepatic oxidation or disposal of triglycerides. the potential sources of lipids contributing to fatty liver include plasma nonesterified fatty acid (nefa) pool from adipose tissue, newly made fatty acids within the liver through de novo lipogenesis (dnl) and dietary fatty acids, which can enter the liver by two means: through spillover into the plasma nefa pool and through the uptake of intestinally derived chylomicron remnants. nearly 60-80% of liver triacylglycerol is derived from circulating free fatty acids (ffa). insulin resistance decreases the inhibitory effects of insulin on peripheral lipolysis, increasing the availability of free fatty acids (ffas). twenty five percent of liver triacylglycerol is derived from increased de novo lipogenesis (dnl)53. dnl is mediated by enzymes under the transcriptional regulation of sterol regulatory element binding protein-1c (srebp-1c), which is upregulated by insulin and is likely to be activated by hyperinsulinaemia. dnl is also increased by activation of the cannabinoid receptors on hepatocytes. activation of these pathways has been implicated in the pathogenesis of hepatic steatosis54. dietary fat intake is responsible for 15% of ffa supply to the liver. ffa and monoglycerides in intestine are absorbed and packaged into triglycerides in intestinal epithelial cells. then they are secreted in chylomicrons, which release ffa to adipose. lipids are normally exported from the liver in very-low density lipoproteins (vldl), which are formed by microsomal triglyceride transfer protein (mtp) incorporating triglyceride into apolipoprotein b (apo b). a reduction in mtp activity and apo b synthesis and secretion may impair hepatic lipid export and favour hepatic triglyceride accumulation55. recent findings in animal models suggest that triglyceride accumulation in liver may be hepato-protective rather than being hepatotoxic since it decreases the free fatty acids accumulation in hepatocytes, their peroxidation and oxidative stress56. however, according to the "two-hit hypothesis" steatosis increases the vulnerability of the liver to "second hit", oxidative stress. disturbance in the prooxidant/antioxidant balance constitutes oxidative stress. the consequences of oxidative stress are lipid peroxidation, cell degeneration and necrosis, apoptosis, proinflammatory cytokine expression, liver stellate cell activation and fibrogenesis. multiple possible sources of oxidative stress have been identified and include mitochondrial dysfunction, hepatic cytochrome cyp2e1, β-oxidation by peroxisomes in mitochondria and recruited inflammatory cells57–59. the mechanisms responsible for increased mitochondrial β-oxidation in nash are poorly understood. the first mechanism is the increased hepatic uptake and synthesis of free fatty acids in liver60. the large pool of ffas, especially from de novo lipogenesis, activates hepatic ppar-a (peroxisome proliferator activated receptor) which in turn activates the expression of genes involved in fatty acid β-oxidation61. another mechanism is the enhanced cpt-i (carnitine palmitoyltranferase) which increases the entry of long-chain fatty acids into mitochondria62. it is still unclear whether leptin activates fatty acid oxidation through ampk and ppar-a activation63. the mitochondrial abnormalities associated with nafld include ultrastructural lesions, depletion of mitochondrial dna (mtdna), impaired activity of respiratory chain complexes, and impaired mitochondrial β-oxidation. mitochondria are big and swelled, scarce in number, and the mitochondrial matrix has paracrystalline inclusions. mechanisms which explain this dysfunction found in nafld include excessive reactive oxygen species (ros) production, increased tnf-α expression, and altered pgc-1 (peroxisome proliferator-activated receptor-γ coactivator) expression64. recent animal experiments and preliminary human studies support that increased expression and activity of cytochrome p450 2e1 (cyp2e1), a microsomal fatty acid oxidase that generates reactive oxygen species, may play a role in pathogenesis of nash65,66. ros trigger lipid peroxidation which in turn initiates release of ma