• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of gutGutVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Gut. Jul 2004; 53(7): 923–924.
PMCID: PMC1774127

Fatty liver, hypertension, and the metabolic syndrome

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.

Acknowledgments

This work was supported by 2R01 DK53792.

REFERENCES

1. Bellentani S , Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000;132:112–17. [PubMed]
2. Younossi Z , Diehl AM, Ong J. Nonalcoholic fatty lier disease: an agenda for clinical research. Hepatology 2002;35:746–52. [PubMed]
3. Powell EE, Cooksley GE, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: A follow-up study of 42 patients follow for up to 21 years. Hepatology 1990;11:74–80. [PubMed]
4. Teli M , James OF, Burt AD, et al. A natural history of nonalcoholic fatty liver: A follow-up study. Hepatology 1995;22:1714–19. [PubMed]
5. Falck-Ytter Y , Younassi ZM, Marchesini G, et al. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001;21:71–6. [PubMed]
6. Van Waes L , Lieber CS. Early perivenular sclerosis in alcoholic fatty liver: an index of progressive liver injury. Gastroenterology 1977;73:646–50. [PubMed]
7. Worner TM, Lieber CS. Perivenular fibrosis as precursor lesion of cirrhosis. JAMA 1985;254:627–30. [PubMed]
8. Nonomura A , Mizukami Y, Unoura M, et al. Clinicopathologic study of alcohol-like liver disease in non-alcoholics; non-alcoholic steatohepatitis and fibrosis. Gastroenterol Jpn 1992;27:521–8. [PubMed]
9. Matteoni C , Younossi ZM, McCullough A. Nonalcoholic fatty liver disease: A spectrum of clinical pathological severity. Gastroenterology 1999;116:1413–19. [PubMed]
10. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol 2003;98:2042–7. [PubMed]
11. Jepsen P , Vilstrup H, Mellemkjaer L, et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepatogastroenterology 2003;50:2101–4. [PubMed]
12. Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001;33:1358–64. [PubMed]
13. Monto A . Hepatitis C and steatosis. Semin Gastrointest Dis 2002;13:40–6. [PubMed]
14. Hezode C , Lonjon I, Roudot-Thoraval F, et al. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study. Aliment Pharmacol Ther 2003;17:1031–7. [PubMed]
15. Ohata K , Hamasaki K, Toriyama K, et al. Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 2003;97:3036–43. [PubMed]
16. Bressler BL, Guindi M, Tomlinson G, et al. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 2003;38:639–44. [PubMed]
17. Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649–57. [PubMed]
18. Pi-Sunyer FX. The obesity epidemic: pathophysiology and consequences of obesity. Obes Res 2002;10 (suppl 2) :97–104S. [PubMed]
19. Lebovitz HE. The relationship of obesity to the metabolic syndrome. Int J Clin Pract Suppl 2003;134:18–27. [PubMed]
20. Donati G , Stagni B, Piscaglia F, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut 2004;53:1020–23. [PMC free article] [PubMed]
21. Marchesini G , Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–23. [PubMed]
22. Szapary PO, Rader DJ. Pharmacological management of high triglycerides and low high-density lipoprotein cholesterol. Curr Opin Pharmacol 2001;1:113–20. [PubMed]
23. Elliott WJ. Is fixed combination therapy appropriate for initial hypertension treatment? Curr Hypertens Rep 2002;4:278–85. [PubMed]
24. Ali Raza J , Movahed A. Current concepts of cardiovascular diseases in diabetes mellitus. Int J Cardiol 2003;89:123–34. [PubMed]
25. Large V , Arner P. Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemia. Diabetes Metab 1998;24:409–18. [PubMed]
26. Philipson LH. Beta-agonists and metabolism. J Allergy Clin Immunol 2002;110:S313–17. [PubMed]
27. Garg R , Tripathy D, Dandona P. Insulin resistance as a proinflammatory state: mechanisms, mediators, and therapeutic interventions. Curr Drug Targets 2003;4:487–92. [PubMed]
28. Angulo P . Current best treatment for non-alcoholic fatty liver disease. Expert Opin Pharmacother 2003;4:611–23. [PubMed]
29. Tadayyon M , Smith SA. Insulin sensitisation in the treatment of type 2 diabetes. Expert Opin Invest Drugs 2003;12:307–24. [PubMed]
30. Hoffmann IS, Cubeddu LX. Clustering of silent cardiovascular risk factors in apparently healthy Hispanics. J Hum Hypertens 2002;16 (suppl 1) :S137–41. [PubMed]

Articles from Gut are provided here courtesy of BMJ Group
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...