Nonalcoholic fatty liver disease in individuals with severe obesity

Clin Liver Dis 8 (2004) 535–547

Nonalcoholic fatty liver disease in individuals

with severe obesity

Paul Haynes, MD, Suthat Liangpunsakul, MD,Naga Chalasani, MD*

Division of Gastroenterology & Hepatology, Indiana University School of Medicine, Indianapolis,

IN 46202, USA

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disorder

occurring in individuals without significant alcohol consumption [1]. It consists

of a spectrum of liver disease, ranging from simple steatosis to steatohepatitis,

cirrhosis, liver failure, and hepatocellular carcinoma [1]. Although a number of

conditions have been identified as risk factors, obesity is by far the most

dominant risk factor for developing NAFLD [1,2]. Over the past decade, it

became apparent that NAFLD in some patients is a progressive disorder, leading

to cirrhosis and liver failure [3]. Despite lack of direct evidence, due to the

ongoing epidemic of obesity in western countries, it is believed that the incidence

of NAFLD is increasing, and patients with complicated and uncomplicated

NAFLD will present in increasing numbers to primary care physicians as well

as specialists.

This article discusses the prevalence, histologic spectrum, and natural history

of NAFLD in subjects with severe obesity as well as the hepatic effects of drastic

weight loss induced by bariatric surgery or severe calorie restriction. The

National Heart, Lung, and Blood Institute categorizes obesity into underweight

(BMI < 18.5 kg/m2), normal weight (BMI 18.5 to 24.9 kg/m2), overweight (BMI

25 to 29.9 kg/m2), obesity class 1 (BMI 30 to 34.9 kg/m2), obesity class 2 (BMI

35 to 39.9 kg/m2), and extreme obesity class 3 (BMI � 40 kg/m2) [4]. The

National Heart, Lung, and Blood Institute states that ‘‘clinical severe obesity’’ is a

preferred term instead of once commonly used term ‘‘morbid obesity,’’ and it is

defined as BMI � 40 or a BMI � 35 kg/m2 in conjunction with obesity induced

co-morbid conditions [4].

1089-3261/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.cld.2004.04.007

* Corresponding author. Indiana University School of Medicine, WD OPW 2005, 1001 West

10th Street, Indianapolis, IN 46202.

E-mail address: [email protected] (N. Chalasani).

P. Haynes et al / Clin Liver Dis 8 (2004) 535–547536

Prevalence of nonalcoholic fatty liver disease in subjects with severe obesity

NAFLD is thought to be frequent in subjects with severe obesity. However,

population-based studies that established the true prevalence of NAFLD in

subjects with severe obesity are rare. The reported prevalence of NAFLD in

individuals with severe obesity varied depending on whether ultrasound or blood

tests were used to define NAFLD. When ultrasonography was used, the reported

prevalence of NAFLD in North Italian subjects with obesity was 76% (Dionysos

study) [5]. In our exploration of the National Health and Nutrition Examination

Survey (NHANES) III database, prevalence of NAFLD in the United States adult

population with severe obesity ranged between 6.8% and 24% depending on the

biochemical criteria used to define NAFLD (Table 1). As 7.6% of the adult

population in the United States has severe obesity, it can be estimated that a

minimal 0.86 million to 3.05 million severely obese adults have NAFLD.

Although severely obese represent only 7.6% of the adult population in the

United States, they are estimated to account for nearly a third of all adult NAFLD

cases (Fig. 1). However, as alanine aminotransferase (ALT) is not a good marker

for underlying liver disease in individuals with severe obesity (see later

discussion), ALT-based definitions are very likely to underestimate the preva-

lence of NAFLD in severe obese NHANES III participants.

Spectrum of nonalcoholic fatty liver disease in patients with severe obesity

Our knowledge about the spectrum of NAFLD in patients with severe obesity

is derived from autopsy and bariatric surgery studies. In an autopsy study,

Wanless and Lentz [6] reported liver histology in 351 nonalcoholic individuals at

autopsy. In this study, prevalence of steatosis and steatohepatitis correlated

Table 1

Prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States adult population (Na-

tional Health and Nutrition Examination Survey III) according to body mass index and different criteria

Body mass index (kg/m2)

< 18.5 18.5–24.9 25–29.9 30–34.9 � 35

US population at risk (%) 2.5 43.5 32.2 14.2 7.6

Prevalence of NAFLD (%)

- Modified Ruhl criteriaa 0.9 1.8 4.0 6.6 6.8

- Clark criteriab 4.8 4.2 6.3 9.3 11.6

- Italian Criteriac 3.9 6.7 12.5 18.1 24

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.a ALT > 40 U/L in the absence of hepatitis C or B or significant alcohol consumption or

transferrin saturation > 50%.b AST > 37 U/L or ALT > 40 U/L in men and AST or ALT > 31 U/L in women in the absence

of hepatitis C or B or significant alcohol consumption or transferrin saturation > 50%.c ALT > 30 U/L in men and > 19 U/L in women in the absence of hepatitis C or B or significant

alcohol consumption or transferrin saturation > 50%.

35%

28%

19%

10%

6%

BMI = 35

BMI 30-34.9

BMI 25-29.9

BMI 18.5-24.9

BMI = 18.5

Fig. 1. Proportion of nonalcoholic fatty liver disease cases in the adult United States population

stratified according to their body mass index (BMI). (Estimated from NHANES III.)

P. Haynes et al / Clin Liver Dis 8 (2004) 535–547 537

significantly with the degree of obesity [6]. Nonalcoholic steatohepatitis (NASH)

was found in 18.5% of markedly obese patients as opposed to 2.7% in lean

individuals. Type II diabetes, weight loss during the pre-terminal period, and

intravenous glucose therapy during the last weeks of life were additional risk

factors for steatohepatitis. A number of studies in the literature have described the

spectrum of liver histology in selected patients undergoing bariatric surgery

[7–15] (Table 2). Most patients undergoing bariatric surgery had varying degrees

of steatosis, as many as 36% had NASH, and up to 4% had unsuspected cir-

rhosis.Only a small percentage of patients undergoing bariatric surgery had

normal hepatic histology. Although corresponding histologic figures for patients

with less severe degrees of obesity are not systematically evaluated, it is generally

Table 2

Histologic spectrum of nonalcoholic fatty liver disease in patients undergoing bariatric surgery: se-

lected series from 1981–2003

n Age (yrs)

Body mass

index (kg/m2)

Steatosis

(%)

Nonalcoholic

steatohepatitis (%)

Cirrhosis

(%)

Narsallah et al [7] 242 - 45 60a 9 2.7

Anderson [8] 1429 - - 80 29 3

Silverman et al [9] 100 36 ± 9 49 ± 9 94 36 4

Lucykx et al [10] 528 36 ± 11 43 ± 7 74 12 0.5

Marceau et al [11] 551 36 ± 9 47 ± 9 86 24 2

Crespo et al [12] 181 - 47 72 23 0

Dixon et al [13] 105 41 ± 11 48 73 25 1

Del Gaudio et al [14] 216 38.5 > 35 (35–66) 78 21 2.3

Harnois et al [15] 96 38 ± 11 46 ± 5 98 10 0

a This report defined steatosis as > 33% of hepatocytes with fatty deposition.


believed that subjects with severe obesity have advanced histology (ie, NASH

and cirrhosis) more frequently than those with less severe forms of obesity.

Discordance between hepatic histology and transaminases in nonalcoholic

fatty liver disease

As it is the case with some other chronic forms of liver disease (eg, hepati-

tis C), levels of transaminases do not seem to correlate with hepatic histology in

patients with NAFLD. In a series of 242 patients undergoing liver biopsy before

jejuno-ileal bypass, Galambos and Wills [16] reported the relationship between

liver biochemistries and hepatic histology (Table 3). This series, which was

published before it was possible to exclude hepatitis C infection, showed that in

the severely obese undergoing jejuno-ileal bypass: (1) liver test abnormalities are

usually mild, regardless of degree of liver injury, (2) up to 15% of patients with

abnormal histology will have normal tests, and (3) liver biochemistries do not

predict the hepatic histology. Although hepatitis C might have contributed to

some of the patients with portal inflammation, it is unlikely that 22% of the

severely obese would have been infected with HCV (a rate �20 to 40 times

higher than the expected infection rate in the United States population). Mofrad

et al [17] recently showed a similar discordance between hepatic histology and

ALT even in less severely obese with NAFLD. In this study, the hepatic his-

tology of 51 NAFLD patients with normal ALT (defined as � 52 U/L for women

and � 75 for men) was compared with the liver histology of 50 NAFLD patients

with elevated ALT. This study showed that the entire spectrum of NAFLD can be

seen in individuals with normal ALT and their histologic spectrum is not

significantly different from those with elevated ALT levels. When the relation-

ship between ALT and BMI of NHANES III participants was examined, ALT

values progressively decreased after BMI > 30 kg/m2 (Fig. 2). It is not clear

Table 3

Relationship between hepatic histology and liver biochemistries in patients undergoing jejuno-ileal

bypass (n = 242)

Percent of patients with test abnormalities

Histologic finding Overall prevalence Mild Moderate

Lobular hepatitis 9% 66% 14%

Steatosis 28% 72% 12%

Fibrosis 31% 60% 12%

Portal hepatitis 22% 60% 12%

Mild test abnormalities were defined as any abnormality of glutamate-oxaloacetate transaminase

(SGOT or AST), alkaline phosphatase, or bilirubin.

Moderate test abnormalities were AST or alkaline phosphatase over twice normal, bilirubin over 1.5,

or albumin less than 3.

Steatosis was defined as more 33% of hepatocytes containing a fat droplet.

Lobular hepatitis was defined as inflammation in the lobule with necrosis of hepatocytes.

Adapted from Galambos JT, Wills CE. Relationship between 505 paired liver tests and biopsies in

242 obese patients. Gastroenterology 1978;74:1191–5; with permission.

BMI

908070605040302010

ALT

(IU

/L)

500

400

300

200

100

0

Fig. 2. Relationship between ALTadn body mass index (BMI) in the adult participants of National

Health and Nutrition Examination Survey.


why ALT activity decreases after a threshold BMI (�30 kg/m2) but it in part

could be related to increasing prevalence of cirrhosis (burn-out) in individuals

with severe obesity.

Pathogenesis of nonalcoholic fatty liver disease and nonalcoholic

steatohepatitis in severe obesity

In the current issue, specific aspects of pathogenesis of NAFLD and NASH

are reviewed in other chapters of this issue and therefore will not reviewed again

in this article. However, it is important to discuss why NAFLD is so frequent in

individuals with severe obesity and furthermore why its histology is significantly

more advanced. Insulin resistance, oxidative stress, and cytokine toxicity are the

common mechanisms thought to play a role in the pathogenesis of NAFLD and

NASH in average-risk individuals. It is reasonable to assume that these factors

are likely operative in those with severe obesity and NAFLD but at a significantly

greater intensity. It is documented in the literature that severely obese people have

higher degrees of insulin resistance and diabetes, higher levels of oxidative stress,

and circulating cytokines [18–22]. In addition, several unique mechanisms may

also play a role in the pathogenesis of NAFLD of severe obesity. These may


include microsomal oxidative stress (CYP 2E1 and CYP 4A11), hepatic effects of

systemic hypoxemia, and nutritional toxicities. CYP 2E1 is thought to play a role

in the pathogenesis of NAFLD and NASH [23,24], and it is now known that

subjects with severe obesity have a significantly increased hepatic CYP 2E1

activity compared with less severely obese and lean controls [24,25]. Further-

more, preliminary data suggest that hepatic CYP4A11 is significantly induced in

individuals with severe obesity likely due to higher levels of very long chain fatty

acids in the liver (unpublished observations). As severely obese people have a

significant higher prevalence of obstructive sleep apnea, intermittent chronic

hypoxemia may play a role in the pathogenesis of NAFLD in this group due to its

effects on hepatic CYPs [24] or insulin resistance [26,27]. Severely obese people

consume greater amounts of dietary fat, which can lead to higher levels of

oxidative stress and lipid peroxidation and higher levels of carbohydrates, which

can exacerbate the degree of insulin resistance.

Predictors of advanced histology in severely obese people with nonalcoholic

fatty liver disease

A number of studies have found that certain clinical characteristics can predict

advanced histology in the severely obese with NAFLD (Table 4) [9,12,13,15,28].

In an autopsy study, Wanless and Lentz [6] found that obese individuals with

diabetes or a history of terminal weight loss were at significantly higher risk

to have steatohepatitis. The most detailed study in this context was published by

Dixon and colleagues [13] who reported the predictors of NASH in 105 con-

secutive severely obese patients undergoing laparoscopic bariatric surgery. In

this study, the prevalence of NASH was 25% and insulin resistance index > 5.0

(OR 9.3, 95% CI 3.4 to 26, P < 0.001), ALT > 40 U/L (OR 8.6, 95% CI 3.1 to

23.5, P < 0.001), and hypertension (OR 5.2, 95% CI 2.0 to 3.5, P = 0.001)

independently predicted its presence in this cohort. Based on these data, the

Table 4

Predictors of nonalcoholic steatohepatitis (NASH) in severely obese individuals undergoing bar-

iatric surgery

n Age (years)

Body

mass index NASH (%) Predictors of NASH

Klain et al [28]a 100 37.5 ± 9.9 N/A ? Age, body weight, cholesterol

and TG

Silverman et al [9] 100 35.7 ± 9.1 49 ± 9 36 Diabetes

Dixon et al [13] 105 41 ± 11 47 ± 7 25 HTN, insulin resistance,

and ALT

Crespo et al [12] 181 - 47 ± 6 23 Age

Harnois et al [15] 92 38 ± 11 46 ± 5 10 Body mass index

Abbreviations: TG, triglycerides; HTN, hypertension; ALT, alanine aminotransferase.a This study from 1989 did not report BMI, and the precise proportion of patients with NASH

is unclear.

0

10

20

30

40

50

60

70

80

No DM orHTN

HTNalone

DM alone Both HTNand DM

Pro

po

rtio

n w

ith

NA

SH

(%

)

Fig. 3. Association between nonalcoholic steatohepatitis (HTN) and type 2 diabetes (DM) in the

severly obese undergoing bariatric surgery. (Adapted from Dixon JB, Bhathal PS, O’Brien PE.

Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the

severly obese. Gastroenterology 2001;121:91–100; with permission from the American Gastroenter-

ological Association.)


investigators were able to construct user-friendly ROC curves that predicted

NASH with good sensitivity and specificity. For example, the presence of at least

two of the three variables predicted the presence of NASH with sensitivity of

0.8 and specificity of 0.9. Furthermore, this study showed a strong association

between type 2 diabetes and hypertension with NASH (and therefore metabolic

syndrome). If a patient had neither diabetes nor hypertension, the prevalence of

NASH was 7%, whereas its prevalence was 75% if both of these conditions were

present (Fig. 3).

Natural history of nonalcoholic fatty liver disease in the severely obese

As the natural history of NAFLD has been discussed by McCullough and

colleagues elsewhere in this issue, it will not reviewed entirely in this article.

Although the natural history of NAFLD in untreated patients with severe obesity

has not been specifically studied, due to the greater proportion of patients with

advanced histology, it is likely that these individuals have worse outcomes than

those with less severe forms of obesity and NAFLD. Hui and colleagues [29]

recently described the natural history of 23 patients with well-documented NASH

cirrhosis in a predominantly obese cohort (proportion with severe obesity not

reported). During a median follow-up of 60 months, the complication-free sur-

vival was 83%, 77%, and 48%, respectively, and the cumulative overall survival

was 95%, 90%, and 84% at 1, 3, and 10 years, respectively. Another recent report

by Ioannou and colleagues [30] showed that NHANES I participants with obesity

(but no alcohol consumption) are at significantly higher risk to have cirrhosis-


related death or hospitalizations during a mean follow-up of 12.9 years . These

two studies provide indirect evidence that cirrhosis-related complications and

mortality are common in severely obese patients with NAFLD.

Jejuno-ileal bypass surgery and liver disease

Jejuno-ileal bypass surgery was widely popular from the mid-1950s to the

mid-1970s as the surgical treatment of choice for severe obesity [31]. This

procedure is now abandoned due to a number of predictable complications

including electrolyte abnormalities, kidney problems, gallstones, severe mal-

nutrition, and significant liver disease [32–35]. The hepatic effects of jejuno-ileal

bypass include fatty infiltration, cirrhosis, and progressive liver failure. Although

jejuno-ileal bypass is no longer performed, patients who had this procedure

decades ago may present with end-stage liver disease and are occasionally

referred for consideration of liver transplantation. Although uncommon, non-

alcoholic steatohepatitis has been reported after gastric partitioning surgery as well

[36]. Numerous mechanisms such as malabsorption of essential micronutrients,

bacterial overgrowth, and rapid weight loss with resulting massive influx of free

fatty acids have been implicated in the pathogenesis of NAFLD associated with

jejuno-ileal bypass. The most common histologic findings include macrovesicu-

lar steatosis, Mallory’s hyaline, zone III fibrosis, and infiltration of neutrophils

[37,38]. The hepatic histology is often at its worst in the first year after surgery

and may show continued progression to cirrhosis and liver failure in several

patients. Vyberg and coworkers [39] evaluated the serial hepatic histology in

34 morbidly obese patients undergoing jejuno-ileal bypass. At baseline, 44% of

patients had no or minimal histologic abnormalities while the remainder had

varying degrees of steatosis, steatohepatitis, and zone III fibrosis. Within 5 to

9 months after surgery, liver biopsies revealed progression of liver injury in almost

all patients. In the group of patients with minimal baseline liver injury, 85% had

developed moderate to marked steatosis. Those patients with more severe

baseline changes showed worsening steatohepatitis and fibrosis; 18% developed

bridging fibrosis and 9% had histologic evidence of cirrhosis. Requarth and co-

workers [40] reported the long-term morbidity after jejuno-ileal bypass in 453 pa-

tients. During the follow-up, 24 patients developed acute liver failure (7%) and

the 15-year probability of established cirrhosis was 8.1%.

Patients who develop progressive liver injury may benefit from reversal of

jejuno-ileal bypass [35,41]. However, it should be avoided in patients with

decompensated liver disease unless it is done concomitantly with liver transplan-

tation. For those who developed liver failure, liver transplantation is a possible

therapeutic option available to prolong survival [42–45]. In general, it is

recommended that jejuno-ileal bypass should be reversed either during or

immediately after transplantation [43,44]. If the jejuno-ileal bypass is not reversed,

there is a substantial risk of recurrent steatosis and progressive liver damage in the

allografts [45]. In patients who had their jejuno-ileal bypass reversed, substantial


weight gain is common in the post-transplant period, but allograft failure resulting

from such a weight gain is uncommon [43–45].

Effect of gastric weight loss surgery on nonalcoholic fatty liver disease

The National Heart, Lung, and Blood Institute recommends that surgical

therapy is an option for well-informed and motivated patients who have clinically

severe obesity (BMI � 40 kg/m2) or a BMI � 35 with serious co-morbid

conditions [4]. A variety of gastric weight loss procedures are performed in the

United States and worldwide to achieve a sustained weight loss, but a detailed

review of their technical aspects is beyond the scope of this article. Several

studies have reported the hepatic effects of gastric weight loss surgery in patients

with severe obesity. Busetto et al [46] reported a significant decrease in liver

volume after gastric banding in women with steatosis, and it correlated with a

reduction in visceral fat mass. In a study of 15 consecutive individuals

undergoing gastroplasty or gastric bypass, it was reported that hepatic steatosis

and inflammation improved significantly when re-biopsied at 12 months after

weight-loss surgery [47]. In the most detailed study to date, Luyckx et al [10]

reported the hepatic histology in 69 patients with severe obesity before and 27 ±

15 months after gastroplasty (Table 5). After a mean follow-up of 27 months and

a mean weight loss of 32 kg, 45% of the biopsies were considered normal

compared with 13% at baseline. Steatosis was observed in only 38% of biopsies

compared with 83% preoperatively. In addition, the severity of the steatosis was

reduced: mild 62% versus 21%, moderate 23% versus 37%, and severe 15%

versus 42%. The reduction in prevalence and severity of steatosis correlated with

significant reduction of ALT levels by 14%. The regression of liver steatosis

occurred even in the absence of normalization of weight. It appears that weight

loss resulted in a significant improvement of insulin sensitivity and the severity of

liver steatosis; however, in some cases, at the expense of progression of the

underlying steatohepatitis. More recently, Solga and colleagues [48] reported the

effect of gastric bypass surgery on liver histology in 10 severely obese with

NASH. After a mean follow-up of 280 days, 100% of patients had improved

Table 5

Effect of gastroplasty on hepatic histology in 69 individuals with severe obesitya

NormalSteatosis (%)

Nonalcoholic Fibrosis Cirrhosis

(%) Mild Moderate Severe steatohepatitis (%) (%) (%)

Before surgery 13 21 37 42 14 1.5 0

After surgery

(27 ± 15 mo)

45** 62** 23** 15** 26* 1.5 0

a Mean weight loss achieved by this cohort during the follow-up period was 32 ± 19 kg.

* P < 0.05; ** P < 0.001.

Data from Luyckx, Desaive C, Thiry A, Dewe W, Scheen AJ, Gielen JE, et al. Liver abnormalities in

severely obese subjects: effect of drastic weight loss after gastroplasty. Int J Obes Relat Metab Disord

1998;(22):222–6.

Table 6

Effect of very low calorie diet (900 kcal/d) on hepatic histology in 41 individuals with severe obesity

Steatosis (%)Portal Portal Lobular

Normal None Mild Moderate inflammation (%) fibrosis (%) inflammation (%)

Baseline 10 10 41 46 15 0 36

After 34 kg

weight loss

46* 71* 29* 0* 34* 12** 20

* P < 0.05; ** P = 0.063.

Modified from Andersen T, Gluud C, Franzmann M, Christoffersen P. Hepatic effects of dietary weight

loss in morbidly obese subjects. J Hepatol 1991;12:224–9; with permission from EASL.


NASH grade, 44% had improved NASH stage, 66% had improved inflammation,

and 33% had improved fibrosis. In this report, no one exhibited worsening

hepatic histology.

Effect of dietary weight loss on nonalcoholic fatty liver disease in the severely

obese

While the hepatic effects of drastic weight loss induced by surgery have been

studied extensively, few studies documented the hepatic effects of weight-loss

induced by dietary modification in individuals with severe obesity. Scattered

reports suggested that weight loss induced by dieting or starvation without sur-

gical intervention can either lead to improvement or worsening of liver histology

[49–51]. In a seminal study, Andersen et al [52] prospectively evaluated the

hepatic effects of very low calorie formula diet in 41 individuals with severe

obesity (median age 34 years [range, 20–53], BMI 43.3 [range, 37–74]).

Subjects achieved a median weight loss of 34 kg on a very low calorie diet

(900 kcal) diet over a median duration of 261 days [52]. After the weight loss,

liver histology normalized in a significant number of individuals, and a marked

improvement occurred in the degree of steatosis (Table 6). However, mild de-

grees of portal inflammation and mild portal fibrosis developed in 25% and 12%

of individuals after weight loss, respectively. Five patients who developed portal

fibrosis had twice as rapid weight loss as compared with those who did not

develop portal fibrosis; none of the patients who lost less than 1.6 kg/week

developed fibrosis, whereas 28% of the patients who lost more than 1.6 kg/week

developed portal fibrosis. Based on these data, to prevent worsening hepatic

histology with very low calorie diets, the investigators recommended a target

weight loss less than 1.6 kg per week.

Summary

Obesity is a dominant risk factor for developing NAFLD and subjects with

severe obesity have a very high prevalence of NAFLD. Severely obese people

with NAFLD are more likely to have advanced histologic forms of NAFLD than


those with less severe forms of obesity. In general, serum ALT levels do not

correlate with hepatic histology in the severely obese with NAFLD. Older age,

higher BMI, and the presence of diabetes mellitus predict advanced hepatic

histology in severely obese patients with NAFLD. Weight loss induced by gastric

weight loss surgery or very low calorie diets leads to significant improvement in

hepatic steatosis but in some patients it may lead to worsening hepatic in-

flammation or fibrosis. In the severely obese who are subjected to a very low

calorie diet, the target weight loss should be less than 1.6 kg/week.

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Nonalcoholic fatty liver disease in individuals with severe obesity