AGA technical review on nonalcoholic fatty liver disease

doi:10.1053/gast.2002.36572

Gastroenterology

Volume 123, Issue 5, November 2002, Pages 1705-1725

https://doi.org/10.1053/gast.2002.36572 Get rights and content

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of conditions characterized histologically by mainly macrovesicular hepatic steatosis and occurs in those who do not consume alcohol in amounts generally considered to be harmful to the liver. There are 2 histologic patterns of NAFLD: fatty liver alone and steatohepatitis. NAFLD is an increasingly recognized cause of liver-related morbidity and mortality. In this review, the existing literature regarding the nomenclature, clinical and histologic spectrum, natural history, diagnosis, and management of this condition are discussed.

GASTROENTEROLOGY 2002;123:1705-1725

Section snippets

Methods

This report is based on the following: (1) a formal review and analysis of the literature on NAFLD (Index Medicus, 1950–1966; MEDLINE, 1966–2001), (2) several published guidelines and meta-analyses, including the American Gastroenterological Association's policy statement on guidelines, (3) the Manual for Guideline Development (American Gastroenterological Association: Clinical Practice and Practice Economics Committee)¹ as well as the policy statement on the development and use of practice

History of discovery of NAFLD

The association of macrovesicular steatosis of the liver with inflammatory changes and fibrosis in obese subjects has been known for several decades.⁴ However, it was largely ignored as a clinical entity until several reports5, 6, 7 documented the development of liver failure in some patients following surgical jejunoileal bypass for morbid obesity. The hepatic histology in such patients was indistinguishable from that seen in alcoholic hepatitis and included macrovesicular steatosis, Mallory

Nomenclature

A complete diagnosis of fatty liver disease ideally should define the histology, including the stage and grade of the disease as well as its etiology (Table 1).Traditionally, fatty disorders of the liver have been classified as alcoholic or nonalcoholic. NAFLD includes both nonalcoholic fatty liver and NASH. NAFLD is associated with numerous etiologies (Table 2), and the underlying mechanisms as well as the natural history of the disease may vary with the specific etiology.

. Conditions associated

Histologic criteria for the diagnosis of fatty liver and steatohepatitis

The principal histologic feature of NAFLD is the presence of macrovesicular fatty change in hepatocytes with displacement of the nucleus to the edge of the cell.18, 19, 20, 21 The original descriptions of steatohepatitis included the additional presence of Mallory bodies, ballooning degeneration, predominantly lobular neutrophilic inflammation, and Rappaport zone III perisinusoidal fibrosis.9, 13, 15, 18 It is now appreciated that, in a given patient, only some of these features may be present.

Grading and staging of steatohepatitis

An universally accepted histologic grading and staging system for steatohepatitis does not exist. The histologic grade indicates the activity of the steatohepatitic lesion, whereas the stage reflects the degree of fibrosis (Table 1). In a retrospective analysis,²⁶ those with florid steatohepatitis characterized by fat, ballooning degeneration, Mallory bodies, or perisinusoidal fibrosis had a poorer long-term outcome than those with fat and only nonspecific lobular inflammation. Based on these

Clinical spectrum of NAFLD

NAFLD is a heterogeneous disorder. The heterogeneity stems from the variability in the definitions of the term “steatohepatitis” as well as its varied clinical associations. The epidemiology, clinical associations, and clinical features of NAFLD are reviewed below.

How good are the diagnostic criteria?

Powell et al.⁴⁸ originally proposed 3 criteria for the diagnosis of NASH: (1) a histologic picture of steatohepatitis, (2) convincing evidence of minimal or no alcohol consumption (<40 g/wk), and (3) absence of serologic evidence of viral hepatitis. Although these criteria are used widely in clinical practice, each criterion has specific limitations that bear discussion.

The variability in the histologic expression of NASH has been a source of debate and has prevented the development of a

What is the natural history of NAFLD?

Only limited data are available on the natural history of the spectrum of histologic lesions seen in macrovesicular fatty disorders of the liver that are not associated with the use of alcohol. It is generally believed that there are several distinct histologic states in the natural history of these disorders that indicate progression of the lesion (Figure 2).

. Stages in the progression of NAFLD.

These include a fatty liver alone, steatohepatitis, steatohepatitis with fibrosis, and eventually

NAFLD in children

NAFLD has been reported in the pediatric population. In a retrospective review of liver biopsy specimens, Baldridge et al.⁴⁷ found that 82 of 650 cases had hepatic steatosis, of which 14 were considered to have NASH with varying degrees of fibrosis. Similar data have been reported by others.30, 39, 155 Although most reported cases of fatty disorders of the liver in children have been noted around the age of puberty, isolated instances have been reported in those as young as 7–8 years of age.³³

Treatment of NAFLD

The treatment of any condition requires consideration of the natural history of the condition, the relative efficacy and safety of the therapeutic options, and cost. As previously noted, NASH can progress to cirrhosis.22, 75, 199 This is particularly true in the presence of bridging fibrosis.²⁶ Also, those with fat and ballooning degeneration or fat, ballooning degeneration and Mallory bodies or perisinusoidal fibrosis may be at greater risk for progression.²⁶ Older subjects and those with

Summary

NAFLD is a major cause of liver-related morbidity in North America. It is frequently associated with the presence of insulin resistance. There is increasing evidence that NAFLD can progress to cirrhosis and liver failure. Physicians should actively check for the presence of NAFLD in those who are overweight and/or diabetic. There is no established treatment for NAFLD. Treatment usually is directed toward optimizing body weight. The role of pharmacologic agents remains to be established, and

Acknowledgements

The Clinical Practice Committee acknowledges the following individuals whose critiques of this review paper provided valuable guidance to the author: Alfred Baker, M.D., Helen Te, M.D., Karen Eun-Young Kim, M.D., and J. Sumner Bell, M.D. The members of the American Association for the Study of Liver Diseases Practice Guidelines Committee who contributed to the development of these papers include Henry Bodenheimer, M.D., David E. Bernstein, M.D., Gary L. Davis, M.D., James Everhart, M.D., Thomas

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Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide and poses serious harm to human health. There is growing evidence suggesting that the administration of specific supplements or nutrients may slow NAFLD progression. Silymarin is a hepatoprotective extract of milk thistle, but its efficacy in NAFLD remains unclear.
Relevant studies were searched in PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrails.gov, and China National Knowledge Infrastructure and were screened according to the eligibility criteria. Data were analyzed using Revman 5.3. Continuous values and dichotomous values were pooled using the standard mean difference (SMD) and odds ratio (OR). Heterogeneity was evaluated using the Cochran's Q test (I² statistic). A P<0.05 was considered statistically significant.
A total of 26 randomized controlled trials involving 2,375 patients were included in this study. Administration of silymarin significantly reduced the levels of TC (SMD[95%CI]=-0.85[-1.23, -0.47]), TG (SMD[95%CI]=-0.62[-1.14, -0.10]), LDL-C (SMD[95%CI]=-0.81[-1.31, -0.31]), FI (SMD[95%CI]=-0.59[-0.91, -0.28]) and HOMA-IR (SMD[95%CI]=-0.37[-0.77, 0.04]), and increased the level of HDL-C (SMD[95%CI]=0.46[0.03, 0.89]). In addition, silymarin attenuated liver injury as indicated by the decreased levels of ALT (SMD[95%CI]=-12.39[-19.69, -5.08]) and AST (SMD[95% CI]=-10.97[-15.51, -6.43]). The levels of fatty liver index (SMD[95%CI]=-6.64[-10.59, -2.69]) and fatty liver score (SMD[95%CI]=-0.51[-0.69, -0.33]) were also decreased. Liver histology of the intervention group revealed significantly improved hepatic steatosis (OR[95%CI]=3.25[1.80, 5.87]).
Silymarin can regulate energy metabolism, attenuate liver damage, and improve liver histology in NAFLD patients. However, the effects of silymarin will need to be confirmed by further research.
Serum vitamin D is associated with ultrasound-defined hepatic fibrosis
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Evidences from population-based investigations on the exact relationship between vitamin D and the severity of liver fibrosis remain debated and conflicting. Here, we aim to explore the relationship between serum vitamin D and ultrasound-defined advanced hepatic fibrosis in the US participants with nonalcoholic fatty liver disease (NAFLD).
In the retrospective study, individuals with intact information on interesting variables from the 2017–2018 National Health and Nutrition Examination Survey (NHANES) were included. NAFLD was diagnosed on the basis of controlling attenuation parameter (CAP) value≥ 274 dB/m without causes of other chronic hepatic diseases. We identified advanced fibrosis grades (F2) by liver stiffness measurement (LSM) score of ≥ 8.2 kPa in NAFLD patients. The impact of elevated serum vitamin D on the prevalence of hepatic fibrosis was assessed by multivariate logistic regression models on the basis of the NHANES recommended weights.
The study involved 1624 subjects with NAFLD in total, and 305 (18.28 %, weighted%) of whom were diagnosed with advanced hepatic fibrosis according to the definition based on parameters obtained from vibration controlled transient elastography (VCTE). In the multivariate logistic regression analysis, serum vitamin D presented a negative relationship to hepatic fibrosis with lower odds in patients with hepatic steatosis after being adjusted for potential confounding factors (fully adjusted: OR=0.47, 95 % CI: 0.24–0.90, p = 0.034). Our subgroup analysis revealed that the inverse relationship was still existed in males (fully adjusted: OR = 0.34, 95 % CI: 0.17–0.70, p = 0.014), non-obese subjects (fully adjusted: OR = 0.20, 95 % CI: 0.04–0.89, p = 0.042) and participants below 60 years (fully adjusted: OR = 0.43, 95 % CI: 0.21–0.90, p = 0.033), whereas in models adjusted for the potential confounding factors, no statistically significant correlation was noted in females, obese subjects or subjects with age≥ 60 years.
This large population-based investigation indicated that elevated serum vitamin D reduced the onset of advanced fibrosis diagnosed by ultrasound in males, non-obese subjects and younger participants with NAFLD.
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To investigate the association between non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), mental symptoms (mood, anxiety disorders and distress) by sex.
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Among 7241 participants (70.5% men, median age: 45 years), the frequency of steatosis was of 30.7% (25.1% NAFLD), being higher in men than women (70.5% vs. 29.5%, p < 0.0001), regardless of the steatosis subtype. Metabolic risk factors were similar in both subtypes of steatosis, but not mental symptoms. Overall, NAFLD was inversely associated with anxiety (OR = 0.75, 95%CI 0.63–0.90) and positively associated with depression (OR = 1.17, 95%CI 1.00–1.38). On the other hand, ALD was positively associated with anxiety (OR = 1.51; 95%CI 1.15–2.00). In sex-stratified analyses, only men presented an association of anxiety symptoms with NAFLD (OR = 0.73; 95%CI 0.60–0.89) and ALD (OR = 1.60; 95%CI 1.18–2.16).
The complex association between different types of steatosis (NAFLD and ALD), mood and anxiety disorders indicates the need for a deeper understanding of their common causal pathways.
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^*: Address requests for reprints to: Chair, Clinical Practice Committee, AGA National Office, c/o Membership Department, 7910 Woodmont Avenue, 7th Floor, Bethesda, Maryland 20814. Fax: (301) 654-5920.

^**: This literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice Committee and the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines Committee. The paper was approved by the Clinical Practice Committee on March 3, 2002, and by the AGA Governing Board on May 19, 2002. It was approved by the AASLD Governing Board and AASLD Practice Guidelines Committee on May 24, 2002.

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American Gastroenterological AssociationAGA technical review on nonalcoholic fatty liver disease*,**

Abstract

Section snippets

Methods

History of discovery of NAFLD

Nomenclature

Histologic criteria for the diagnosis of fatty liver and steatohepatitis

Grading and staging of steatohepatitis

Clinical spectrum of NAFLD

How good are the diagnostic criteria?

What is the natural history of NAFLD?

NAFLD in children

Treatment of NAFLD

Summary

Acknowledgements

Am J Surg

Gastroenterology

Am J Med

Clin Gastroenterol

Gastroenterology

Hepatology

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

Hepatology

J Nutr

J Nutr

J Pediatr

Gastroenterology

Hum Pathol

Am J Med

Gastroenterology

Am J Med

Metabolism

Gastroenterology

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Gastroenterology

J Hepatol

Am J Gastroenterol

Position and policy statement: policy statement on the use of medical practice guidelines by managed care organizations and insurance carriers

Gastroenterology

Purpose of quality standards for infectious diseases. Infectious Diseases Society of America

Clin Infect Dis

undertaking systematic reviews of research on effectiveness: CRD guidelines for those carrying out or commissioning reviews. CRD report #4

The liver in obesity

Arch Intern Med

Liver dysfunction after intestinal bypass

JAMA

Post-jejuno-ileal bypass hepatic disease. Its similarity to alcoholic liver disease

Am J Clin Pathol

Hepatic morphology in obesity

Dig Dis Sci

Five patients with nonalcoholic diabetic cirrhosis

Acta Hepatogastroenterol Stuttg

Fatty changes in the liver: the relation to age, overweight and diabetes mellitus

Acta Pathol Microbiol Immunol Scand A

Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease

Mayo Clin Proc

Nonalcoholic steatonecrosis: a unique histopathologic lesion of the liver with multiple causes

Surv Dig Dis

Nonalcoholic fatty hepatitis: an important clinical condition

Can J Gastroenterol

The pathology of diabetic hepatitis

J Pathol

Pathological spectrum of alcoholic liver disease

Alcohol Alcohol Suppl

Morphological features in non-cirrhotic livers from patients with chronic alcoholism, diabetes mellitus or adipositas. A comparative study

Acta Pathol Microbiol Scand A

Occurrence and significance of Mallory bodies in morbidly obese patients. An immunohistochemical study

Acta Pathol Microbiol Immunol Scand A

Agreement in pathologic interpretation of liver biopsy specimens in posttransplant hepatitis C infection

Arch Pathol Lab Med

The liver in consecutive patients with morbid obesity: a clinical morphological and biochemical study

Int J Obes

American Gastroenterological Association
AGA technical review on nonalcoholic fatty liver disease*,**