The clinical significance of hepatic steatosis remains controversial. Long known to be common,^1,2 fatty liver was once dismissed as an innocuous condition, particularly when discovered incidentally in individuals with normal serum aminotransferases.^3–5 However, as discussed subsequently, emerging evidence challenges this old assumption by demonstrating strong associations between hepatic steatosis and other potentially life threatening diseases.

Reports that some alcohol abusers and non-alcoholic individuals with fatty livers eventually develop cirrhosis and succumb to “typical” complications of advanced liver disease are certainly concerning.^3,4,6–11 Moreover, evidence suggests a detrimental interaction between hepatic steatosis and other types of chronic hepatitis because several studies have identified fatty liver as an independent predictor of progressive liver fibrosis in patients with chronic hepatitis C,^12–14 and at least one study demonstrated that hepatic steatosis conveys an independent risk for hepatocellular carcinoma in this population.¹⁵ Hepatic steatosis is also associated with a poor response to antiviral therapy¹³ although this may be because it is strongly associated with obesity, which independently decreases the efficacy of hepatitis C treatment.¹⁶ In any case, there is no longer any doubt that having a fatty liver increases an individual’s risk for advanced liver disease.

In addition, fatty liver is strongly associated with other disorders that are themselves major causes of morbidity and mortality. As mentioned earlier, fatty liver is often linked with obesity,¹⁷ a condition that significantly increases the risk of dying from any disease.¹⁸ Obesity, particularly visceral adiposity, is also an important component of the insulin resistance metabolic syndrome, a constellation of disorders (for example, dyslipidaemia, type 2 diabetes, and hypertension) that promote cardiovascular disease.¹⁹ The paper by Donati and colleagues²⁰ in this issue of Gut, draws our attention to the relationship between fatty liver and hypertension [see page 1020].

Briefly, the authors of this study used abdominal ultrasonography to detect “bright” (that is, fatty) livers in hypertensive individuals who had normal liver blood tests and no obvious risk factors for hepatic steatosis. The study population was a relatively select subgroup of hypertensive individuals, given that ∼80% of the hypertension clinic population had at least one risk factor for fatty liver or hepatitis that excluded them from enrolment. Surprisingly, despite lacking all of the obvious risk factors for hepatic steatosis, ∼30% of the hypertensive individuals in the present study had fatty livers. These findings demonstrate that the prevalence of hepatic steatosis in non-obese non-diabetic hypertensive adults is at least twice the historical prevalence of fatty liver in the general adult populations¹ and almost three times the prevalence of hepatic steatosis in the age and sex matched group of concurrent controls. Interestingly, although none of the subjects in the present study was obese or overtly diabetic, hypertensive individuals with fatty livers had higher glucose levels, body mass indices, and insulin resistance than hypertensive individuals without fatty livers. Controls with fatty livers also had higher fasting serum levels of insulin and glucose, and greater insulin resistance than controls without fatty livers, although both of the control groups had similar body mass indices.

These results are important because they complement and extend other evidence that correlates hepatic steatosis with insulin resistance.²¹ The strong association between these two conditions has tremendous clinical relevance. On one hand, it suggests that detection of fatty liver identifies an individual who is quite likely to have insulin resistance and hence should be evaluated for other disorders in the insulin resistance syndrome (for example, diabetes, hypertension, dyslipidaemia). On the other hand, it suggests that an individual with features of the metabolic syndrome should be screened for fatty liver disease.

Few would argue against more aggressive screening for diabetes, hypertension, and dyslipidaemia because effective treatment of these disorders is known to reduce subsequent morbidity and cardiovascular mortality.^22–24 However, some may disagree with implementing more widespread screening for hepatic steatosis because there is, as yet, no direct evidence that reducing liver fat is beneficial. To address this concern, it is necessary to understand whether it is the hepatic lipid accumulation per se or the factor(s) that promote(s) hepatic steatosis that is/are to blame for the adverse clinical outcomes that occur in individuals with fatty livers. Studies in experimental animals, as well as in patients, suggest that both are probably involved because hepatic lipid metabolism interfaces with the interactive matrix of metabolic products, hormones, cytokines, and neurotransmitters that coordinates substrate utilisation with the energy requirements for maintaining tissue integrity.^25–27 Fat accumulation within hepatocytes indicates that the master system for regulating energy homeostasis has malfunctioned. However, fatty liver is also more than a mere barometer of metabolic dysfunction because it triggers signals to normalise lipid levels in the liver. The latter may involve altering the activities of the cytokines, hormones, and neurotransmitters that regulate fat turnover in other tissues. As these regulatory factors are quite pleiotropic, collateral neurohumoral and immune dysfunction often ensue. Thus fatty liver is both a consequence of and contributor to the “dys”-metabolic insulin resistance syndrome. As such, it represents a reasonable therapeutic target.

The validity of this concept is supported by emerging evidence that various treatments (for example, lifestyle modifications, certain types of bariatric surgery, thiazolidinediones, metformin) that improve insulin resistance generally also improve hepatic steatosis.²⁸ Thus our therapeutic armoury now includes reasonably effective weapons for these disorders. Questions remain however about when to deploy our “missiles”. All therapeutic interventions incur some cost, and none is 100% effective. For example, no currently available insulin sensitising therapy uniformly prevents (or reverses) features of the metabolic syndrome.^28,29 Furthermore, even when untreated for insulin resistance, most individuals with fatty livers (or with hypertension, dyslipidaemia, or type 2 diabetes) live with these disorders for decades without experiencing significant hepatic or cardiovascular morbidity.^9,30 Because the basis for interindividual differences in clinically significant outcomes of the metabolic syndrome is poorly understood, physicians are uncertain when to “attack” insulin resistance. Therefore, research is needed to characterise factors that modulate the natural histories of hepatic steatosis and other disorders, such as hypertension, that often develop in the context of insulin resistance. This information may help us to understand when treatments to enhance insulin sensitivity are necessary, as well as why these therapies sometimes fail to prevent end organ damage in individuals with the metabolic syndrome. In turn, this knowledge will permit us to select patients who are likely to achieve the greatest benefit from insulin sensitising therapy. If fatty liver is indeed a convenient marker for dangerous insulin resistance, then it will be important to determine if implementing efforts to improve insulin sensitivity when hepatic steatosis is diagnosed prevents dreaded consequences of the metabolic syndrome, such as cardiovascular disease, cirrhosis, and hepatocellular carcinoma.