Review article: the metabolic syndrome and non-alcoholic fatty liver disease
Dr P. Loria, University of Modena and Reggio Emilia, Modena, Italy.
Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with non-alcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non-alcoholic fatty liver disease affect the same insulin-resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non-alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator-activated receptor agonists, statins, ACE (angiotensin I-converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non-alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non-alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance-related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non-alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non-alcoholic fatty liver disease.
Commonly occurring disease states are expected to concur by chance. This is not the case of the metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) which are closely and not casually related to each other. This has significant physiopathological and clinical implications that are focused in this review addressing definitions of and analogies between MS and NAFLD.
Metabolic syndrome (MS) is a common multiplex cluster of metabolic-haemodynamic phenotypes strongly related to abnormal production of cytokines, chronic subclinical inflammatory state and abnormal coagulation, sharing insulin resistance as a chief pathogenetic feature. Such complex physiopathological changes of MS – whose core includes visceral obesity with hypertension, dyslipidaemia, and type 2 diabetes (T2DM) originally alluded to as the ‘deadly quartet’– are eventually conducive to excess morbidity and mortality from premature cardiovascular disease (CVD), diabetes and some kinds of cancer.1, 2 MS appears to result from a collision between susceptible ‘thrifty genes’ and a society characterized by an increased prevalence of obesity and a sedentary lifestyle.1 It has been recently proposed to differentiate the term ‘insulin resistance syndrome’ [abnormalities and clinical syndromes that are increased in prevalence in insulin-resistant (IR) individuals] from the ‘MS’ (clinical criteria to diagnose the syndrome)3 however, the terms ‘MS’ and ‘IR syndrome’ often are used interchangeably.2 Criteria proposed for the diagnosis of MS,4–6 share the evaluation of anthropometric parameters exploring (central) obesity [body mass index (BMI) or W/H or waist girth], arterial hypertension, atherogenic dyslipidaemia [hyper-TG (triglycerides) or low high-density lipoprotein (HDL)] and glucose tolerance (presence of diabetes, fasting glucose, insulin resistance) with varying cut off values. There are, although, major limitations of such definitions such as: (i) gender-related variability in the MS are only partially taken into account; (ii) ethnic differences are not included; (iii) those classifications based on the use of glucose clamping [World Health Organization (WHO), European Group for the Study of Insulin Resistance (EGIR)] are unlikely to become clinically popular and, conversely (iv) failure to measure IR directly will result in low diagnostic sensitivity; (v) none of the classifications includes important diseases/conditions in which IR is present, such as hyperuricaemia, gallstones, thrombophilia, endothelial dysfunction, increased sympathetic activity, polycystic ovary syndrome (PCOS) and NAFLD. Non-alcoholic fatty liver disease defines a broad spectrum of alcohol-like histological liver damage in patients without significant alcohol intake.7 NAFLD is among the most common aetiologies of altered liver function tests (LFTs) and otherwise unexplained alanine aminotransferase (ALT) elevation has been adopted as a surrogate marker of NAFLD in epidemiological studies. However, NAFLD can be seen in individuals with normal ALT values and liver damage in these individuals is no better than that observed in patients with elevated ALT.8 As the clinician cannot predict the entity of histological liver lesion in a given NAFLD patient, likewise the histologist unaware of clinical data cannot make a correct diagnosis of NAFLD.7 The diagnosis of NAFLD, therefore, rests on clinico-histological criteria, including absent to low alcohol consumption (<20 g/daily) and a compatible liver biopsy showing steatosis, hepatocyte ballooning, apoptosis, Mallory bodies, mixed lobular inflammation associated or not with fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The main limitations of a ‘negative’ (non-alcoholic) definition of disease have recently been reviewed elsewhere by various authors, our group included, who proposes that insulin resistance should be mentioned in NAFLD's name, i.e. metabolic liver disease (MeLD) or steatohepatitis (MeSH).9
Analogies between MS and NAFLD
Similarities between MS and NAFLD include epidemiology, pathogenesis (genetics and metabolism) and clinical features (associated diseases, natural history and treatment).
The prevalence of MS (22%) and of NAFLD (20%) in the general USA population10, 11 are amazingly similar. MS increases from 6.7 (20–29 years age-group) to 43.5% (60–69 years).10 Also the prevalence of ultrasonographic fatty liver increases as a function of age from 12.2 (20–29 years) up to 25.5% (50–59 years). However, at variance with MS, fatty liver declines in those aged >60.12 The reasons for such phenomenon are unknown. It could be that NAFLD is an early manifestation of the MS, progressing in time to those advanced forms of liver disease (e.g. cryptogenic cirrhosis/HCC) in which steatosis disappears. Alternatively, patients with NAFLD who are over 60 years old might be prone to increased mortality.
Genetics. Genetic factors influence the development of the core cluster components of MS. The so-called ‘thrifty genes’ are selectively advantaged in famine but turn into a deleterious trait predisposing to the MS when food supply abounds as in western society. Theoretically, polymorphisms of genes involved in IR, fat metabolism and inflammation might be responsible for insulin resistance and therefore be involved in the pathogenesis of both the MS and NAFLD.13 Intrahepatic gene expression profile of subjects with cirrhotic stage NAFLD provides evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function and diminished insulin sensitivity.14 Such findings further link NAFLD and the MS.
Metabolic aspects. The MS and NAFLD share IR such as reviewed elsewhere in this supplement.15
Inflammatory alterations. Low-grade systemic inflammation occurring in MS links IR, endothelial dysfunction and CVD. Elevated C-reactive protein (CRP) concentrations are related to insulin resistance, to MS, predict coronary heart disease, diabetes and have also been reported in NAFLD.16, 17 A high prevalence of non-organ-specific autoantibodies, has been found in NAFLD associated with insulin resistance18 and in patients with coronary atherosclerosis as well.19 These data indicate that systemic subclinical inflammation typically associated with MS are also found in NAFLD.
High-risk groups MS and NAFLD. Core cluster conditions of the MS correspond to high-risk categories for NAFLD. For instance, the prevalence of NAFLD in patients with obesity;20 T2DM;21 arterial hypertension,22 hypertriglyceridaemia23 and low physical activity24 is more elevated than in the general population. Although the exact prevalence of NAFLD in patients with MS is unknown, a high proportion of subjects with MS have altered LFTs. Conversely, in patients with NAFLD the prevalence of core cluster components of MS is higher than in the general population. In our series of 161 unselected NAFLD patients 74.5% were hyperlipidaemic (hypertriglyceridaemic 45.9%); 57.2% had hypertension; 17.0% T2DM and 35.3% were obese and 19.88% had gallstones.9, 25 As a consequence, the prevalence of MS in NAFLD tends to be higher than in the general population with values ranging from 24 to 63% according to the definition of MS.
Independent predictors of NAFLD and their relationship with MS. In the NHANES study, NAFLD correlated with hyperinsulinaemia independent of BMI and fat distribution11 indicating that other factors beside visceral obesity contribute to the association between NAFLD and IR. Uric acid and not parameters of iron metabolism are associated with NAFLD.26 Serum uric acid levels associated with insulin resistance,27 damage the endothelium strongly predict mortality from CVD in middle-aged men.28
Cardiovascular diseases. The association of MS with cardiovascular risk is well-established. Premature atherosclerosis derives in these subjects from the synergistic interaction of metabolic and haemodynamic changes summing up with inflammation, endothelial dysfunction, altered nitric oxide (NO) synthesis, small dense LDL and oxidized LDL, oxidative stress, increased thrombosis and decreased fibrinolysis.29 Studies indicate that also NAFLD might be a cardiovascular risk factor-like MS. Non-obese patients with NAFLD have a more severe cardiovascular risk profile than obese patients (with or without NAFLD)30 and premature atherosclerosis has recently been observed in humans with NAFLD.31 Subjects with NASH have significantly higher systemic levels of lipid peroxidation products.32 Furthermore, plasma plasminogen activator inhibitor (PAI)-1 levels are more closely related to fat accumulation and PAI-1 expression in the liver than in adipose tissue.33 In our series IR predicts carotid atherosclerosis irrespective of age in patients with NAFLD (unpublished data). In addition, a significant proportion of NAFLD patients develops diabetes, hypertension and dyslipidaemia as soon as 3–4 years after diagnosis.34 Therefore, an early diagnosis of NAFLD helps to identify those subjects who are more prone to develop metabolic disorders and premature atherosclerosis.
Hepatic diseases (cirrhosis/fibrosis). It is not known if patients with MS develop more frequently cirrhosis/fibrosis than the general population. However, diabetic patients have a high-risk mortality for cirrhosis35 and obesity is a risk factor for cirrhosis.36 Furthermore, advanced NAFLD stages associate with components of the MS such as increased uric acid, higher waist and Homeostasis Model Assessment of Insulin Resistance HOMA-IR.9 These data suggest that the MS plays a major role in the development and in the evolution of NAFLD.
Excess mortality (cancer). Obesity contributes to 14 and 20% of cancer deaths in men and in women, with a particular increase in risk of colon and rectal, stomach, pancreas and liver cancers in men and ovary, non-Hodgkin's lymphoma, breast, uterine and liver cancers in women.37 Also NAFLD is associated with cancer and this will be reviewed elsewhere in this issue.38
Excess mortality (all causes). The presence of MS associates with CVD risk and all-causes mortality.39 Interestingly, such risk increases with the growing number of criteria for the MS.40 In NAFLD – but not in pure fatty liver – there is an increased overall all-causes mortality risk.41, 42
Impact of the association of MS and NAFLD on treatment
Treatment of MS should not be directed at single core alterations but aimed at reducing insulin resistance and all associated diseases.43 In this connection, treatment of NAFLD and its inherent hepatic insulin resistance is of strategic importance in treatment of MS and conversely those treatments proven to be most effective in MS also appear effective NAFLD. For instance, those low-saturated fats, high-fibre diets also rich in ω-3 fatty acids that prevent IR and T2DM43 also might cure hepatic steatosis.44 Similarly, a restricted diet and moderate to high degree of physical activity improves IR, MS and liver histology in NAFLD.45 Several drugs, such as metformin, statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or peroxisome proliferator-activated receptor (PPAR) agonists, prevent diabetes, CVD and possibly also cure NAFLD. Several of these drugs improve peripheral and hepatic IR and also have pleiotropic effects on endothelial dysfunction, coagulation and inflammation. Metformin effectively reduces IR but its mechanism of action goes beyond glucose lowering alone.46 Its utility in NAFLD, although, is controversial. ACE inhibitors and angiotensin II receptor antagonists – originally used as antihypertensive agents – also decrease insulin resistance and prevent T2DM.47 Angiotensin II receptor antagonists might activate PPARs-γ activity.48 Considered first choice drugs in hypertensive patients with MS, they also have beneficial effects in fatty liver.49 PPARs, a family of nuclear receptors that control lipid and glucose metabolism are an ideal target class to address the multiple anomalies associated with MS. PPARs-α agonist (fibrates) reduce CVD in patients with atherogenic dyslipidaemia typical of MS. PPARs-γ agonist (glitazones) improve glucose and lipids homeostasis and reduce blood pressure in humans and atherosclerotic lesions in rats29, 50 and hold promise for effective treatment of NAFLD.51 Other candidates for treatment of MS and NAFLD include folate and vitamin B12 that decrease hyper-homocysteinaemia, improve insulin resistance and endothelial dysfunction,52 and aspirin, an antiaggregant and anti-inflammatory agent which in high doses also improves insulin resistance and glucose metabolism in diabetic subjects.53
The MS should be no longer considered as the ‘deadly quartet’ alone. Studies are needed to widen the clinical spectrum and the prognosis of insulin resistance-related diseases. The liver is, along with vessels, a target organ in MS patients. Such target organs alterations and extent of insulin resistance do play a critical role in the natural history of MS.
Future studies should be aimed at evaluating which – among the core cluster – are the most specific clinical predictors of MS and of NAFLD; which is their intraindividual variability over the time; what is the importance of relatively new factors such as CRP or fibrinogen, smoking and albuminuria with particular regard to the development and progression of NAFLD.
This study was funded by grants from MIUR (Ministero Istruzione Universitàe Ricerca) Anno 2002-prot.2002062883_001 and Anno 2004-prot.2004061213_001. We thank Azienda Ospedaleira Policlinico, AUSL of Modena and family doctors for their collaboration.