Journal of Hepatology
Volume 45, Issue 4 , Pages 600-606, October 2006

Hepatic histology in obese patients undergoing bariatric surgery

  • Mariana Machado

      Affiliations

    • Departamento de Gastrenterologia, Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal
    • ,
  • Pedro Marques-Vidal

      Affiliations

    • Departamento de Gastrenterologia, Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal
    • ,
  • Helena Cortez-Pinto

      Affiliations

    • Departamento de Gastrenterologia, Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal
    • Unidade de Nutrição e Metabolismo, Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal
    • Corresponding Author InformationCorresponding author. Tel.: +351 21 7985187; fax: +351 21 7985142.

Received 15 May 2006; received in revised form 5 June 2006; accepted 7 June 2006. published online 25 July 2006.

Article Outline

Background/Aims

Obesity is one of the most important clinical associations with non-alcoholic steatohepatitis (NASH). Our aim was to assess the prevalence of non-alcoholic fatty liver disease (NAFLD)/NASH in morbidly obese patients and the risk factors to more aggressive liver disease in this population.

Methods

Review of available studies on prevalence of NAFLD/NASH in severely obese patients submitted to bariatric surgery.

Results

Twelve observational and transversal studies were included, with consecutive recruitment, and prospective evaluation of data, summing 1620 patients with severe obesity. Prevalence of steatosis and NASH was 91% (range: 85–98%) and 37% (24–98%), respectively, with unexpected cirrhosis in 1.7% (1–7%). NASH was not related with age or body mass index, but there was an association between male sex and NASH/hepatic fibrosis. Diabetes mellitus and insulin resistance were the conditions most frequently associated with NASH, and hypertension with advanced hepatic fibrosis.

Conclusions

There is a very high prevalence of NAFLD in asymptomatic morbidly obese patients, more than one-third presenting histological criteria for NASH. This review underscores the large variations in prevalence of NASH between studies, calling for the need for a better agreement in the use of the histological criteria.

Abbreviations: NAFLD, non-alcoholic fatty liver disesase, NASH, non-alcoholic steatohepatitis, IR, insulin resistance, BMI, body mass index, DM, diabetes mellitus, WHR, waist to hip ratio, AST, alanine aminotransferase, ALT, aspartate aminotransferase

Keywords: Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Morbid obesity, Bariatric surgery

 

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1. Introduction 

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease that encompasses steatosis alone to non-alcoholic steatohepatitis (NASH) and can progress to cirrhosis and liver failure. NAFLD is one of the most important forms of liver disease in the developed countries, occurring in 20% to 25% of the general population [1], whereas NASH occurs in about 3% [2], [3].

Obesity and insulin resistance (IR) are believed to exert the main pathophysiological role in the development of NAFLD [4], [5], [6], [7], [8]. The prevalence of obesity has increased tremendously in the last half century [9]. A further increase in the prevalence of NAFLD is expected in the future. However, until recently, few data were available on the prevalence of NAFLD and NASH in severely obese patients, defined as a body mass index (BMI) higher than 35kg/m2. Further, the risk factors for a more aggressive liver disease in this population have yet to be clearly defined.

In the last 5 years, investigators have been trying to identify the real prevalence of NAFLD and NASH in the population of severely obese patients admitted to bariatric surgery, with systematic liver biopsy at the time of surgery. Although most studies had a very similar design, still their results were quite dissimilar. Thus, we conducted an in-depth review of available studies on the prevalence and risk factors for NAFLD in morbidly obese subjects, in order to summarize and evaluate the published data and to discuss discrepant findings.

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2. Materials and methods 

We conducted a literature search using MEDLINE and Current Contents to identify relevant articles published in any language, until December 2005. We also manually searched the references of retrieved articles to identify additional relevant published studies. Search criteria included MEDLINE medical subject heading terms for NAFLD, NASH, morbidly obesity and bariatric surgery. Studies were eligible if they reported prevalence data regarding systematic liver biopsy in morbidly obese patients submitted to bariatric surgery.

Data elements sought from each included study were protocol-specified (including histological criteria of NASH/NAFLD, and maximum alcohol consumption allowed), study location, demographical data, prevalence of steatosis, inflammation, fibrosis, cirrhosis, NAFLD and NASH, as well as, risk factors for steatosis or NASH. For calculations, we computed the actual number of subjects from each study and performed a pooled analysis of the data.

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3. Results 

Seventeen studies were selected [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], of which five [10], [17], [20], [21], [26] were excluded because of their retrospective design or other methodological issues. The remaining twelve publications were transversal, observational studies with a prospective and consecutive recruitment of patients, enrolling a total of 1620 severely obese patients. Their main characteristics are summarized in Table 1.

Table 1. Main characteristics of the studies
StudyYearStudy locationNo. of patientsWomen (%)Age (years)BMI (kg/m2)NASH (%)
Marceau et al. [11]1999USA, Canada5518036±947±9–
Dixon et al. [12]2001Australia1057841±1147±725
Sepulveda-Flores et al. [13]2002Mexico357433±1044±891
Poniachik et al. [14]2002Chile688539±1244±8–
Beymer et al. [15]2003USA486942±1060±1233
Spaulding et al. [16]2003USA4883NR51±2056
Abrams et al. [18]2004USA1958841±948±736
Shalhub et al. [19]2004USA688742±1*51±1*37
Ong et al. [22]2005USA2128042±1048±924
Boza et al. [23]2005Chile1276240±1142±626
Lima et al. [24]2005Brazil1127436±1049±857
Stratopoulos et al. [25]2005Greece5165NR53±1*98
Total––16207739±1048±837

BMI=body mass index, *standard average error instead of standard deviation. NR, not reported.

Inclusion criteria were similar in all studies:

•Indication for bariatric surgery, defined as BMI higher than 40kg/m2, or higher than 35kg/m2 and significant co-morbidity attributable to obesity;

•Age equal or above 18 years.

Exclusion criteria were also similar in all studies:

•Significant alcohol consumption (this criterion was the most variable among all studies, the most frequent cut-off being 30g per week in males and 20g per week in females). Two exceptions were the study of Marceau et al. [11], in which alcohol consumption was not an exclusion criterion, although the majority of patients were abstinent, and the study of Spaulding et al. [16], which did not allow any alcohol consumption;

•Exclusion of other causes of liver disease: hepatitis B and C viruses and metabolic (hemachromatosis, α1-antitrypsin deficiency or Wilson’s disease), autoimmune liver disease or drug-induced liver disease;

•Previous jejunoileal bypass or small bowel resection surgery.

Stratopoulos et al. [25] also excluded patients with known diabetes mellitus (DM).

The definitions of NASH were not uniform in all studies. Marceau et al. used a semi-quantitative grading of steatosis, inflammation and fibrosis [11]; seven studies [13], [16], [18], [19], [23], [24], [25] used the histopathological classification of Brunt et al. [27], although in a modified form in some cases [24] as well as her stratification model (grading necroinflammation and staging fibrosis). In that classification, NASH diagnosis requires the presence of steatosis in at least 5% to 10% of hepatocytes, as well as lobular inflammation and hepatocellular ballooning, typically in zone 3. Two studies [12], [15] used the NASH diagnostic criteria proposed by Lee et al. [28], which require the presence of steatosis and two of the following three: (1) necroinflammatory foci with mononuclear cells and/or neutrophils; (2) ballooning degeneration of hepatocytes with or without Mallory bodies, and (3) pericellular fibrosis. The remaining two studies [14], [22] did not clearly specify their diagnostic criteria defining NASH.

3.1. Steatosis 

The mean prevalence of steatosis was 91%, ranging from 85% to 98% (Table 2), but the criteria for defining steatosis were not uniform among studies, most of them requiring the presence of steatosis in at least 5% to 10% of hepatocytes [13], [14], [15], [16], [18], [25] and others accepting any degree of steatosis [11], [12], [19], [22], [24]. However, there was not a significant difference in the prevalence of steatosis between studies with different criteria, which might be explained by the high prevalence of steatosis in this population.

Table 2. Histological features
StudyNASH (%)Steatosis (%)Inflammation (%)Fibrosis (%)Cirrhosis (%)
Marceau et al. [11]–8624742
Dixon et al. [12]259658261
Sepulveda-Flores et al. [13]91–9797–
Poniachik et al. [14]–9146471
Beymer et al. [15]338550480
Spaulding et al. [16]569075522
Abrams et al. [18]369898672
Shalhub et al. [19]37––137
Ong et al. [22]2493–251
Boza et al. [23]26––242
Lima et al. [24]579960210
Stratopoulos et al. [25]9898–940
Total379150601.7

3.2. NASH 

3.2.1. Prevalence 

As seen in Fig. 1, a striking variability in prevalence of NASH was found, ranging from 24% [22] to 98% [25], with an overall prevalence of 37% (Table 2). This difference could not be explained by geographic (since different groups in the same country showed a remarkable variability), demographic (female/male ratio, age, BMI or co-morbidities) or even by differences in histological definitions of NASH between studies.

In the four studies [13], [19], [23], [25] that stratified patients with NASH in 3 grades (1 to 3) according to Brunt’s classification [27], a diagnosis of NASH was established in 139/281 (48%) patients, of whom 38% were classified as having grade 1 (mild), 34% grade 2 (moderate) and 28% grade 3 (severe) (Table 3). The latter group represents 11% of all patients submitted to bariatric surgery in these four studies.

Table 3. Grading of NASH
StudyPatients with NASH (n)Grade 1 (%)Grade 2 (%)Grade 3 (%)
Sepulveda-Flores et al. [13]312651.522.5
Shalhub et al. [19]25484012
Boza et al. [23]33671518
Stratopoulos et al. [25]50223246
Total139383428
3.2.2. Demographic associations 

In seven studies analyzing a possible association between gender and NASH [12], [15], [16], [18], [22], [23], [24], three did find a higher percentage of males in NASH, [12], [22], [23] whereas no relationship was found in the other studies [15], [16], [18], [24].

Six prospective studies reported data on age and prevalence of NASH [12], [15], [18], [22], [23], [24]. Of those, four [12], [15], [22], [24] found no relationship between age and NASH. The remaining two studies found a statistical, albeit not clinically relevant, difference (42 vs 40 years and 42.3 vs 41.5 years, respectively) [18], [23].

No association between body weight and NASH was found in seven studies assessing it [12], [15], [16], [18], [22], [23], [24]. However, three studies evaluating the relationships between waist to hip ratio (WHR) and NASH [12], [16], [22] found a higher WHR in patients with NASH, although only significant in two studies: 0.97 vs 0.87 (p<0.001) [12] and 0.99 vs 0.95 (p=0.016) [22].

3.2.3. Associated diseases 
3.2.3.1. Diabetes 

A strong association between NASH and diabetes was found in all seven studies evaluating it [12], [15], [16], [18], [22], [23], [24], three of them reporting odds ratio (OR) for NASH in diabetic subjects between 5 and 128 [15], [18], [23]. Hyperglycaemia also had a positive association with NASH in two studies [12], [18], whereas two others [22], [23] failed to demonstrate it. Higher serum insulin levels in NASH were found in three studies [12], [18], [23], although only two [12], [23] with significant differences. Finally, IR, as assessed by the homeostatic model assessment (HOMA), was associated with NASH in two studies [12], [23] (Table 4).

Table 4. Diabetes mellitus/insulin resistance and NASH
StudyDM (%) (NASH vs non-NASH)Glicaemia (mmol/L) (NASH vs non-NASH)Insulin (μU/L) (NASH vs non-NASH)HOMA (IR) (NASH vs non-NASH)
Dixon et al. [12]50 vs 6, p<0.0017.2 vs 5.2, p<0.00125 vs 17.2, p<0.0015.3 vs 4.5, p<0.001
Beymer et al. [15]50 vs 3, p<0.001nanana
Spaulding et al. [16]na, p=0.029nanana
Abrams et al. [18]56.3 vs 15.3, p<0.0016.9 vs 5.5, p=0.00821.7 vs 15.0, nsna
Ong et al. [22]37.2 vs 20.6, p=0.026.4 vs 6.0, nsnana
Boza et al. [23]30 vs 2, p=0.0025.5 vs 5.1, nsna8 vs 4.6, p=0.001
Lima et al. [24]34 vs 19, p=0.018nanana

na=not available; ns=not significant.

3.2.3.2. Hypertension and dyslipidaemia 

In six studies [12], [16], [18], [22], [23], [24] evaluating a possible association between hypertension and NASH, only one study found a significant association (OR of 5.2, 95% CI 2.0–13.5) [12], although there was a trend to a higher prevalence of hypertension in patients with NASH. Three studies found higher triglyceride levels among NASH patients [12], [18], [23], but the other four [15], [16], [22], [25] failed to show any statistical significant difference (Table 5).

Table 5. Hypertension, hypertriglyceridaemia, ALT elevation and NASH
StudynHypertension (%)% Hypertension (NASH vs non-NASH)PTriglycerides (mmol/L) (NASH vs non-NASH)PALT elevation (%) (NASH vs non-NASH)P
Dixon et al. [12]1053865 vs 30<0.0012.3 vs 1.70.04748 vs 200.001
Beymer et al. [15]48–––2.8 vs 1.8ns––
Spaulding et al. [16]4848nansnansna0.09
Abrams et al. [18]1957170.4 vs 66.1ns2.4 vs 0.20.0437.5 vs 23.70.002
Ong et al. [22]2124550 vs 43.1ns2.1 vs 1.8ns44 vs 26<0.0001
Boza et al. [23]1274154 vs 30ns1.6 vs 1.40.038––
Lima et al. [24]1126869 vs 68nsnans38 vs 23<0.001

na=not available; ns=not significant.

3.2.4. Biochemical abnormalities 

Elevated aminotransferases, alanine aminotransferase (AST) and aspartate aminotransferase (ALT) levels were positively and consistently related to NASH in the five studies [12], [16], [18], [22], [24] that assessed this relationship; still, no association was found between the ALT/AST ratio and the presence of NASH in two of them [12], [22].

3.2.5. Histological correlations 

Two studies evaluated if the steatosis score – as found on biopsy – was predictive of NASH, finding opposite results [12], [15]. Also, steatosis score correlated with advanced fibrosis in Marceau et al. [11], (r=0.56, p<0.001), although Ong et al. did not find any correlation [22].

3.3. Fibrosis/cirrhosis 

In ten studies [12], [13], [15], [16], [18], [19], [22], [23], [24], [25], fibrosis was further stratified in four stages according to Brunt’s classification [27]. Globally, at the time of surgery, 40% of the patients had some degree of fibrosis: 30% (range: 8% to 80%) had mild/moderate and 10% (range: 4% to 16%) had advanced fibrosis. Conversely, the prevalence of cirrhosis was very uniform, occurring in 1.4% (range: 1% to 7%) of patients (Table 2).

Isolated portal fibrosis was referred to in only two studies, occurring in 18% [12] and 33% [18] of the patients.

Three studies [12], [15], [22] found an association between hepatic fibrosis and male sex, which was statistically significant in Dixon’s report. There were no associations between fibrosis and either age or BMI [15], [18], [22], except a weak positive correlation index with BMI in two studies [11], [14]. WTH showed a positive correlation with hepatic fibrosis in three studies [11], [12], [22].

A strong association between severe fibrosis and DM was found in four studies, as well as with IR in Dixon’s report. Similarly, hypertension was more prevalent in patients with hepatic fibrosis [12], [22]. There was no association between hypertriglyceridaemia and fibrosis [12], [15], [19].

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4. Discussion 

The present review found an enormous discrepancy in the prevalence of NASH in individuals with severe obesity. This is unexpected, given the fact that study design and patients demographics were quite similar in all studies. The first logical explanation would be a difference in geographic location with associated ethnic or dietary/life style differences. In fact, if we consider studies from the USA alone, there is a more uniform prevalence of NASH, with a relatively lower prevalence. On the other hand, the highest prevalences were found in Mexican and Greek series, with Brazil in an intermediate position. From the studies evaluated, it is difficult to draw conclusions about the association with ethnicity or dietary habits. The second possible explanation would be that different histological criteria for defining NASH were used, but that is not the case, as in fact, the majority of studies used the well-accepted Brunt classification [13], [16], [18], [19], [23], [24], [25], and a minority of studies used the Lee criteria [12], [15] that is not very different from Brunt’s for what concerns the criteria for defining NASH. The issue raises concern on how reproducible the methods of diagnosis and semi-quantification are, as recently reviewed by Brunt [29]. It is however interesting that the prevalence of steatosis and cirrhosis shows a much more uniform pattern among series, suggesting that the main discrepancy relates to the definition of NASH; it is possible that the use of NAS (NAFLD activity score), the recently developed scoring system of the NASH clinical research network [30], will be able to simplify the discrimination between NASH and non-NASH fatty liver disease in this patient population, resulting in a more uniform prevalence of NASH. Another explanation relates to sample error in liver biopsies; in fact, Ratziu et al. [31] have recently shown that sampling error may influence the definition of NASH. However, in surgical liver biopsies there should be less sampling error and it is unlikely that a sampling error could explain such huge differences in the prevalence of NASH among series.

The present summary also revealed a prevalence of steatosis higher than the previously described in an autopsy study reporting it to be present in 29.2% of individuals with grade 2 obesity (40% of ideal body weight or grossly obese), considering steatosis if present in more than 5% of cells [2]. Indeed, defining the minimum level of steatosis to be considered as pathological is critical, and a consensus should be reached. In fact, authoritative textbooks as Sheila Sherlock’s [32] defined steatosis such as more than 5% of liver weight, and Brunt’s classification [27] or the recently updated scoring from the Non-alcoholic Steatohepatitis Clinical Research Network [30] also defined steatosis if present in more than 5% of cells. Furthermore, a recent study using localized proton magnetic resonance spectroscopy to accurately measure hepatic triglyceride content (HTGC) established an “upper limit of normal” for HTGC of 5.56% [33]. These data suggest that a minimum cut-off of 5% should be used to define steatosis in order to avoid the overestimation of its prevalence between studies.

The finding of DM or evidence of IR as the most important risk factor for NASH and advanced hepatic fibrosis supports the role of IR as central in NASH development and progression [4], [5], [6], [7], [8]. Hypertension, although not correlating with NASH in four out of five studies, was the more predictive condition of advanced hepatic fibrosis in two studies. In fact, hypertension may be a marker of activation of the renin–angiotensin system, which might explain its association with fibrosis, as angiotensin II seems to play a major role in liver fibrogenesis [34]. Recently, Yokohama et al. found that the angiotensin II receptor antagonist losartan improves hepatic necroinflammation and inhibits the progression of hepatic fibrosis through the inactivation of hepatic stellate cells, in patients with NASH [35], [36].

Although there was a strong association between AST, ALT and γ-GT elevation and NASH/fibrosis, these parameters were not sensitive enough, with a high proportion of patients with NASH (and even severe NASH and hepatic cirrhosis) presenting with normal serum concentrations of hepatic enzymes, as previously shown by Mofrad et al. [37].

In this group of patients, the presence of risk factors like DM and hypertension should raise a high level of suspicion. However, the best strategy is probably, as suggested by Shalhub et al. [19], perform routine liver biopsy during bariatric surgery rather than selective liver biopsy in patients with a grossly fatty liver appearance, as two studies suggested that the macroscopic appearance of the liver is not predictive of NASH [12], [19].

In conclusion, NAFLD seems to be an obese-related condition with more than one-third of asymptomatic morbidly obese patients having histological NASH. An attempt to evaluate reproducibility of histological findings, in order to avoid such marked discrepancies, is needed, as well as further consensus on histological definitions. The widespread use of the NASH Clinical Research Network score may be of great help in implementing criteria uniformity. This review also emphasized IR and male sex as strongly associated with NASH.

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PII: S0168-8278(06)00384-9

doi:10.1016/j.jhep.2006.06.013

Journal of Hepatology
Volume 45, Issue 4 , Pages 600-606, October 2006

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