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The Metabolic Syndrome as a Predictor of Nonalcoholic Fatty Liver Disease

Masahide Hamaguchi, MD; Takao Kojima, MD; Noriyuki Takeda, MD; Takayuki Nakagawa, MD; Hiroya Taniguchi, MD; Kota Fujii, MD; Tatsushi Omatsu, MD; Tomoaki Nakajima, MD; Hiroshi Sarui, MD; Makoto Shimazaki, MD; Takahiro Kato, MD; Junichi Okuda, MD; and Kazunori Ida, MD
[+] Article and Author Information

From Asahi University Murakami Memorial Hospital, Gifu, Japan.


Acknowledgments: The authors thank Chisato Nagata, MD, PhD (Department of Public Health, Gifu University, Gifu, Japan), for reviewing the manuscript and for assistance with the statistical analyses.

Grant Support: None.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Masahide Hamaguchi, MD, Department of Gastroenterology, Murakami Memorial Hospital, Asahi University, 3-23 Hashimoto-cho, Gifu 500-8523, Japan; e-mail, seele@mbox.kyoto-inet.or.jp.

Current Author Addresses: Drs. Hamaguchi, Kojima, Nakagawa, Taniguchi, Omatsu, Shimazaki, Kato, Okuda, and Ida: Department of Gastroenterology, Murakami Memorial Hospital, Asahi University, 3-23 Hashimoto-cho, Gifu 500-8523, Japan.

Drs. Takeda and Sarui: Department of Endocrinology and Metabolism, Murakami Memorial Hospital, Asahi University, 3-23 Hashimoto-cho, Gifu 500-8523, Japan.

Drs. Fujii and Nakajima: Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Hirokoji, Kawaramachi, Kamigyo-ku, Kyoto 602-8566, Japan.

Author Contributions: Conception and design: M. Hamaguchi, T. Kojima, N. Takeda.

Analysis and interpretation of the data: M. Hamaguchi, N. Takeda.

Drafting of the article: M. Hamaguchi, N. Takeda.

Critical revision of the article for important intellectual content: M. Hamaguchi, N. Takeda.

Final approval of the article: M. Hamaguchi, T. Kojima, N. Takeda, T. Nakagawa, H. Taniguchi, K. Fujii, T. Omatsu, T. Nakajima, H. Sarui, M. Shimazaki, T. Kato, J. Okuda, K. Ida.

Provision of study materials or patients: T. Kojima, J. Okuda, K. Ida.

Statistical expertise: M. Hamaguchi.

Administrative, technical, or logistic support: T. Kojima, N. Takeda, J. Okuda, K. Ida.

Collection and assembly of data: M. Hamaguchi, T. Kojima, N. Takeda, T. Nakagawa, H. Taniguchi, K. Fujii, T. Omatsu, T. Nakajima, H. Sarui, M. Shimazaki, T. Kato.


Ann Intern Med. 2005;143(10):722-728. doi:10.7326/0003-4819-143-10-200511150-00009
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Between January and December 2001, we invited 8056 participants in the health checkup program to enroll in the study. A total of 6654 Japanese participants (4601 men and 2053 women) gave informed consent to be included in the study. We excluded 290 participants (216 men and 74 women) who had known liver disease. In addition, 1657 participants (1577 men and 80 women) who consumed more than 20 g of ethanol per day and 306 participants (236 men and 70 women) who were currently receiving medication were excluded. As a result, there were 4401 participants (2572 men and 1829 women). Mean age and BMI were 47.6 years (SD, 8.8) (range, 21 to 80 years) and 22.6 kg/m2(SD, 3.0) (range, 14.2 to 38.1 kg/m2), respectively.

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High iron stores in patients with metabolic syndrome and the development of NAFLD
Posted on November 17, 2005
Luca Mascitelli
Comando Brigata alpina Julia, Udine Italy
Conflict of Interest: None Declared

TO THE EDITOR: Hamaguchi and colleagues (1) in their longitudinal study examined healthy Japanese men and women and found that the metabolic syndrome was a strong risk factor for nonalcoholic fatty liver disease (NAFLD). However, among the underlying mechanisms involved in this association, they did not consider the role of elevated body iron stores. Increasing evidence suggests that serum ferritin, a good indicator of body iron stores, is positively associated with both metabolic syndrome (2,3) and NAFLD (4). Furthermore, it has been recently documented in a Japanese population that serum ferritin is associated with visceral fat area and subcutaneous fat area (5). Therefore, high iron stores could be considered as an adjunctive risk factor for the development of NAFLD in persons with metabolic syndrome. Consequently, diet modification aimed at lowering iron intake and adsorption might be useful in this setting (6).

Luca Mascitelli, MD Sanitary Service, Comando Brigata alpina "Julia", Udine, Italy 33100

Francesca Pezzetta, MD Cardiology Service, Ospedale di San Vito al Tagliamento, San Vito al Tagliamento, Italy 33078

REFERENCES

1. Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:722-8.

2. Jehn M, Clark JM, Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults. Diabetes Care. 2004;27: 2422-8.

3. Choi KM, Lee KW, Kim HY, et al. Association among serum ferritin, alanine aminotransferase levels, and metabolic syndrome in Korean postmenopausal women. Metabolism. 2005;54:1510-4.

4. Hsiao TJ, Chen JC, Wang JD. Insulin resistance and ferritin as major determinants of nonalcoholic fatty liver disease in apparently healthy obese patients. Int J Obes Relat Metab Disord. 2004;28:167-72.

5. Iwasaki T, Nakajima A, Yoneda M, et al. Serum ferritin is associated with visceral fat area and subcutaneous fat area. Diabetes Care. 2005;28:2486-91.

6. Mascitelli L, Pezzetta F. Serum ferritin levels in patients with nonalcoholic fatty liver disease. [Letter]. Arch Intern Med. 2005; 165:1070.

Conflict of Interest:

None declared

Importance of substitutes in Nonalcoholic fatty liver disease
Posted on November 29, 2005
Norberto C. Chavez-Tapia
Medica Sur Clinic & Foundation
Conflict of Interest: None Declared

TO THE EDITOR:

We had read the article by Hamaguchi, et al. finding it valuable and insightful. The new evidence provided by the authors on the natural history of Nonalcoholic Fatty Liver Disease (NAFLD), the distribution of risk factors in other populations, and the confirmation that both Metabolic Syndrome (MS) and NAFLD are highly associated, represents an important contribution to the field.

We would like to present some comments. Authors used ultrasonographic images interpreted by a single gastroenterologist to make the diagnoses. However, the lack of a second evaluation conducted by a different reviewer with an inter-reliability analysis restricts the claims that can be done over the accuracy of this specific diagnostic method (1). Secondly, they substituted waist circumference by body mass index (BMI) in all subjects. As Feskens et al. (2) had showed, this strategy alters the diagnosis of obesity because it is not a useful marker of adiposity in older people and because the ethnicity could modify the metabolic profiles associated to a categorical value. The value of 25 kg/m2 used as index of obesity used in this article may not be adequate for the Japanese population. Also, differences between genders should be considered (3), because prevalence of MS could differ over a gender basis (4). Third, the most effective strategy to treat both MS and NAFLD is weight reduction (5), in this paper we observed that subjects with normal follow-up ultrasounds (with baseline diagnosis of NAFLD) had weight reduction, but no information about physical activity or other pharmacologic and non-pharmacologic treatments, such as traditional medicine, were provided.

Finally, although adjusted odds ratios indicate an increased risk of NAFLD among subjects with MS, the dose-dependent effect analysis (ie., increased risk of NAFLD according with increased number of criteria of MS) indicates a stronger association between both factors.

References

1. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745-50. [PMID: 12198701]

2. Feskens EJ, Bowles CH, Kromhout D. Carbohydrate intake and body mass index in relation to the risk of glucose intolerance in an elderly population. Am J Clin Nutr. 1991;54:136-40. [PMID: 2058574]

3. Shiwaku K, Anuurad E, Enkhmaa B, Nogi A, Kitajima K, Yamasaki M, et al. Predictive values of anthropometric measurements for multiple metabolic disorders in Asian populations. Diabetes Res Clin Pract. 2005;69:52-62. [PMID: 15955387]

4. Shiwaku K, Nogi A, Kitajima K, Anuurad E, Enkhmaa B, Yamasaki M, et al. Prevalence of the metabolic syndrome using the modified ATP III definitions for workers in Japan, Korea and Mongolia. J Occup Health. 2005;47:126-35. [PMID: 15824477]

5. Angulo P. Treatment of nonalcoholic fatty liver disease. Ann Hepatol. 2002;1:12-9. [PMID: 15114291]

Conflict of Interest:

None declared

Adiponectin and NASH
Posted on December 7, 2005
Yujiro Kida
Tsurumi University, School of Dental Medicine
Conflict of Interest: None Declared

Hamaguchi and coworkers reported that the metabolic syndrome is a strong predictor of nonalcoholic fatty liver disease (NAFLD) (1). But, only a small portion of NAFLD have features of NASH.

In the discussion section, the authors referrd to the roles of adipocytokines, such as leptin and adiponectin. However, serum leptin was not statistically different between patients with nonalcoholic steatohepatitis (NASH) and their matched control (2). In addition, there was no correlation between serum leptin and hepatic histology (2). In contrast, by multivariate analysis, patients with NASH had reduced serum adiponectin level compared with control (3). Moreover, when compared with simple steatosis, NASH was associated with lower adiponectin levels and higher insulin resistance (3). The majority of patients with NASH (77%) had serum adiponectin levels less than 10 microg/ml, but only 33% of those with pure steatosis had these findings (3).

In treatment of patients with metabolic syndrome, serum adiponectin level could be one of the key factors distinguish the patients developing NASH in the future from those with fatty liver alone.

References: (1) Hamaguchi M, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143: 722-8 (2) Chalasanni N, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol 2003; 98: 2771-6 (3) Hui J, et al. Beyond insulin resistance in NASH: TNF- alpha or adiponectin? Hepatology 2004; 40: 46-54

Conflict of Interest:

None declared

Nonalcoholic fatty liver disease and the metabolic syndrome: the plot thickens.
Posted on January 12, 2006
Giovanni Targher
Department of Internal Medicine, Sacro Cuore Hospital of Negrar (VR), Italy
Conflict of Interest: None Declared

Dear Editor,

I read with interest the article by Hamaguchi et al. (1) regarding the pivotal role of the metabolic syndrome (MetS) in the development of nonalcoholic fatty liver disease (NAFLD); they reported that individuals with the MetS had a markedly higher risk of incident NAFLD, as diagnosed by ultrasonography, than those without the syndrome.

At first glance, these findings extend previous cross-sectional observations supporting the classic notion that NAFLD is a feature of the MetS (2). However, two recent prospective studies (3, 4) found that mild elevations of liver enzymes, as surrogate markers of NAFLD, are strong predictors of MetS; in one of these (3), it has been demonstrated that elevated liver aminotransferases significantly predicted incident MetS in a well-characterized multiethnic cohort, independent of a broad spectrum of risk factors for MetS, including direct measures of insulin sensitivity and insulin secretion.

In my opinion, this novel finding suggests a more complex picture and raises the possibility that NAFLD may play an early role in the development of the MetS. There are a number of possible mechanisms by which NAFLD could contribute to development of the MetS phenotype. First, NAFLD in its more advanced forms might act as a stimulus for increased whole-body insulin resistance and dyslipidaemia. Another possible mechanism could be represented by increased oxidative stress and subclinical inflammation, which are thought to be causal factors in the progression from simple steatosis to more advanced forms of NAFLD. Finally, an inverse, strong, association between NAFLD and adiponectin concentrations has also been demonstrated; this observation is relevant since low adiponectin predicts incident MetS components in prospective studies and may do so in part by enhancing hepatic fatty acid oxidation and thereby lessening liver fat accumulation and liver function tests.

In line with the hypothesis that NAFLD may be relevant for the development for MetS and its sequelae, we have recently shown that NAFLD, as assessed by ultrasonography, is associated with a moderately increased risk for future cardiovascular events among type 2 diabetic individuals, independent of classical risk factors, liver enzymes, and the presence of MetS (5).

Overall, therefore, there is now a growing body of evidence supporting the possibility that NAFLD may play an early role in the development of MetS and may be atherogenic beyond its close relationship to the MetS phenotype, possibly through increased oxidative stress, subclinical inflammation, post-prandial lipemia and decreased adiponectin concentrations.

REFERENCES

1. Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, Omatsu T, Nakajima T, Sarui H, Shimazaki M, Kato T, Okuda J, Ida K. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005; 143: 722-728.

2. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004; 8: 521-533.

3. Hanley AJ, Williams K, Festa A, Wagenknecht LE, D'Agostino RB, Haffner SM. Liver markers and development of the metabolic syndrome. The insulin resistance atherosclerosis study. Diabetes. 2005; 54: 3140-3147.

4. Nannipieri M, Gonzales C, Baldi S, Posadas R, Williams K, Haffner SM, Stern MP, Ferrannini E. Liver enzymes, the metabolic syndrome, and incident diabetes. The Mexico City Diabetes Study. Diabetes Care. 2005; 28: 1757-1762.

5. Targher G, Bertolini L, Poli F, Rodella S, Scala L, Tessari R, Zenari L, Falezza G. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005; 54: 3541-3546.

Conflict of Interest:

None declared

In response
Posted on January 16, 2006
Masahide Hamaguchi
Department of Gastroenterology, Murakami Memorial Hospital, Asahi University
Conflict of Interest: None Declared

Dr. Chavez-Tapia argues that the lack of a second evaluation of ultrasonography conducted by a different reviewer restricts the accuracy of the diagnosis of nonalcoholic fatty liver disease (NAFLD) in our study. We understand that ultrasonography is not a perfect test and may lead to an incorrect diagnosis of NAFLD in a substantial proportion of subjects. However, as reported in the reference he quoted (1), interobserver variability is much larger than intraobserver variability for evaluation of the pattern and severity of NAFLD, and inclusion of a second reviewer would have decreased the power to detect longitudinal changes of ultrasonographic images. We believe that ultrasonographic interpretation by a single experienced gastroenterologist was a better approach for our longitudinal study. Dr. Chapez-Tapia raised a concern regarding substitution of waist circumference by body mass index for the diagnosis of the metabolic syndrome. We used body mass index (BMI), because waist circumference was not available for the entire study population. Cut off value of 25 was adopted because it is used as a criterion of obesity for people in East Asia. The finding of a close correlation between BMI and waist circumference in a recent study with a large number of subjects (2) and similar correlations of BMI and waist circumference with metabolic abnormalities in Japanese people (3) support the substitution of waist circumference by BMI. As stated by Dr. Chapez-Tapia, the cut-off value of BMI 25 may not be optimal for the diagnosis of the metabolic syndrome in the Japanese population. Although not reported, we found that increased numbers of MS criteria were associated positively with the development and negatively with regression of NAFLD. We had no data regarding nonalcoholic steatohepatitis. Nonetheless, we appreciated Dr. Kida's extension of our discussion on the role of adipocytokines in the pathophysiology of NAFLD.

References 1. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology. 2002;123:745-50. [PMID: 12198701] 2. Ford ES, Mokdad AH, Giles WH. Trends in waist circumference among US adults. Obesity Res 2003;11:1223-31. 3. Shiwaku K, Anuurad E, Enkhmaa B, Nogi A, Kitajima K, Yamasaki M, et al. Predictive values of anthropometric measurements for multiple metabolic disorders in Asian populations. Diabetes Res Clin Pract. 2005;69:52-62. [PMID: 15955387]

Conflict of Interest:

None declared

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Summary for Patients

The Metabolic Syndrome and Fatty Liver Disease

The summary below is from the full report titled “The Metabolic Syndrome as a Predictor of Nonalcoholic Fatty Liver Disease.” It is in the 15 November 2005 issue of Annals of Internal Medicine (volume 143, pages 722-728). The authors are M. Hamaguchi, T. Kojima, N. Takeda, T. Nakagawa, H. Taniguchi, K. Fujii, T. Omatsu, T. Nakajima, H. Sarui, M. Shimazaki, T. Kato, J. Okuda, and K. Ida.

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