Eating Disorders
Which of the following
surgical weight loss
procedures does not alter
stomach hormone levels?
(A) Gastric bypass (B)
Gastric banding (C)
Gastric pouch
Answer
• (B) Gastric banding
A patient presents 2 mo after
gastric bypass surgery with
vomiting, vision problems, and
symptoms of ataxia.
Which of the following nutrient
deficiencies is most likely?
(A) Thiamine (B) Zinc (C)
Copper (D) Potassium
Answer
• (A) Thiamine
Patients with osteoporosis
after gastric bypass surgery
should be supplemented
with calcium:
(A) Bicarbonate (B) Citrate
(C) Lactate (D) Gluconate
Answer
• (B) Citrate
Which of the following cannot be
used to treat iron deficiency in
patients who have had gastric
bypass
surgery?
(A) Iron sucrose (B) Iron
dextrose (C) Iron gluconate (D)
Interferon
Answer
• (D) Interferon
What is the main cause of regain
of weight after gastric bypass
surgery?
(A) Pouch enlargement (C)
Development of binge eating
disorder
(B) Metabolic slowdown (D)
Lack of physical activity
Answer
• (B) Metabolic slowdown
Choose the correct statement about the
difference between constitutional thinness and
anorexia.
(A) Body mass index (BMI) is significantly
higher in constitutional thinness
(B) Body fat percentage is higher in anorexia
(C) Leptin responds more acutely in
constitutional thinness
(D) Anorexic women are amenorrheic, while
constitutionally thin women menstruate
Answer
• (D) Anorexic women are amenorrheic,
while constitutionally thin women
menstruate
Which of the following
drugs is approved for use
in bulimia?
(A) Paroxetine (B)
Sertraline (C) Fluoxetine
(D) Naltrexone
Answer
• (C) Fluoxetine
To prevent refeeding syndrome,
_______ levels should be
checked during the treatment of
patients with
anorexia.
(A) Phosphorus (B) Potassium
(C) Magnesium (D) Albumin
Answer
• (A) Phosphorus
Which of the following
occurs in patients with
bulimia?
(A) Amylase decreases (C)
Bicarbonate decreases
(B) Potassium decreases
(D) Chloride increases
Answer
• (B) Potassium decreases
Choose the correct statement(s) about
psychiatric therapy for bulimia and
anorexia.
(A) Cognitive behavioral therapy useful
for bulimia
(B) Behavior modification allows
patients to focus on normalizing hunger
and satiety
(C) Body image dysfunction usually last
to resolve
(D) All the above
Answer
• (D) All the above
Among the following
eating disorders,
________ is the most
common.
A) Anorexia nervosa
B) Binge eating disorder
C) Bulimia nervosa
Answer
• B) Binge eating disorder
Patients are most
likely to seek
treatment for:
A) Anorexia nervosa
B) Bulimia nervosa
C) Binge eating
disorder
Answer
• C) Binge eating disorder
Older patients with eating
disorders most likely
suffer from:
A) Depression
B) Anxiety
C) Compromised selfworth
D) All the above
Answer
• D) All the above
Most older patients
with an eating
disorder have
_______ illness.
A) De novo
B) Recurring
Answer
• B) Recurring
Which of the following
patients meet(s) the
qualifications for bariatric
surgery?
A) A woman 35 yr of age
with a body mass index
(BMI) of 40
B) A woman 35 yr of age
with a BMI of 35, with
diabetes and hypertension
C) A and B
Answer
• C) A and B
Greater weight loss and
better resolution of
diabetes is achieved with
which bariatric surgical
procedure?
A) Gastric bypass
B) Lap band
Answer
• A) Gastric bypass
Nutritional deficiencies most often
seen in patients who have
undergone gastric bypass surgery
include:
Vitamin B12
Calcium
Iron
Folate
A) 1,2
B) 2,3,4
C) 1,2,3
D) 1,2,3,4
Answer
1. Vitamin B12
2. Calcium
3. Iron
C) 1,2,3
It is recommended that
pregnancy be delayed
_______ mo after
bariatric surgery.
A) 6 to 8
B) 10 to 12
C) 12 to 18
D) 24
Answer
• C) 12 to 18
All the following statements about
bariatric surgery are correct, except:
A) Gastric bypass is a restrictive
procedure, while the lap band is a
restrictive and malabsorptive procedure
B) Eighty percent of patients who
undergo bariatric surgery are women
C) The mortality rate associated with
gastric bypass is related to sex, age, and
BMI
D) The oral glucose challenge test should
not be performed in pregnant patients
who have undergone gastric bypass
surgery
Answer
• A) Gastric bypass is a restrictive
procedure, while the lap band is a
restrictive and malabsorptive
procedure
What is the name of the
hormone that is produced in
the stomach and creates a
sense of hunger that is reduced
after gastric bypass surgery
and results in a reduced
appetite and thus helps to
produce weigh loss in the
patients?
Answer
• Ghrelin
Bariatric surgery in children
and adolescents
• procedures on the rise as obesity rates in
children and adolescents continue to climb, so do
the number of bariatric surgeries performed.
Studies have shown that more than half of
pediatric patients who are obese carry their obesity
into adulthood.
• With that in mind, it is not surprising that bariatric
surgery among teens has quadrupled in recent
years, increasing from an estimate of 200
procedures in the United States in 2000, to almost
800 procedures in 2003, according to data
published in the Archives of Pediatric and
Adolescent Medicine.
Bariatric surgery in children
and adolescents
•
Despite the increase, the results of a 2007 study suggested that the risks for adolescents undergoing
weight loss surgery are relatively low, and perhaps even lower than in adults, according to one of the
researchers, Thomas H. Inge, MD, PhD, surgical director of the Comprehensive Weight
Management Center at Cincinnati Children’s Hospital Medical Center.
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Thomas H. Inge, MD, PhD, has participated in several large-scale studies of the effects of
bariatric surgery in obese adolescents.
Although these results were promising, without long-term data regarding the effects of surgery on
children and adolescents, many in the field have said the lasting consequences are unable to be fully
understood.
Perhaps the solution is the emergence of studies such as Teen-Longitudinal Assessment of Bariatric
Surgery (Teen-LABS), of which Inge is also the principal investigator. Teen-LABS is a large
consortium made up of five clinical centers designed to determine the risks and benefits of gastric
bypass bariatric surgery and compare them with adults.
Endocrine Today interviewed leading researchers in the field to get their perspective on bariatric
surgery in children and adolescents, such as preferred methods, psychological and legal issues, and
other ongoing studies. All said they are aware of the Teen-LABS study. Inge said the results of the
ongoing study will become available over the next few years, but important information, such as the
documentation of severity of cardiovascular, endocrine, renal and psychosocial comorbidities in
morbidly obese teens, were released at Obesity 2009, the Obesity Society’s annual meeting, in
October.
“What I hope we will see is that it makes a lot of sense to perform the surgery before comorbidities
become irreversible,” Inge said.
Teen-LABS study
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Inge said the lack of information on bariatric research may be because there has not been a great deal of funding.
However, the Teen-LABS study has garnered interest from the National Institutes of Health and is funded by the
National Institute of Diabetes and Digestive and Kidney Diseases.
“The adult surgery is good for improving comorbidities of obesity, but there is good reason to believe that reversing
morbid obesity early in life could more effectively reverse complications of obesity,” Inge said.
In adults, bariatric surgery has shown prolonged weight control and improvement in serious obesity comorbidities.
The two most commonly performed bariatric procedures in the United States are laparoscopic adjustable gastric
banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB). The surgery may not be as effective if it is
performed late in the course of comorbid conditions, which is why many have said it is a highly beneficial option for
select teens.
The Teen-LABS consortium began in June 2006, and in addition to Cincinnati’s Children’s Hospital Medical Center,
it includes Texas Children’s Hospital in Houston, Children’s Hospital of Alabama in Birmingham, University of
Pittsburgh Medical Center and Nationwide Children’s Hospital in Columbus, Ohio. Teen-LABS is structured similar
to the Longitudinal Assessment of Bariatric Surgery, established previously by the NIDDK.
The Teen-LABS study is examining standard clinical care of 200 adolescents aged 19 years and younger undergoing
bariatric surgery.
In addition to the risks of bariatric surgery for adolescents, Teen-LABS will examine CV risk factors, fitness,
endocrine changes, sleep disorders, weight loss and body composition, renal disease, liver function and size, nutrition
deficiencies, adherence to nutritional supplements and psychosocial factors.
Inge said one of the interesting results to come from the study is learning what comorbidities bariatric teens have,
some of which have not been described before.
“For instance, we’re looking at the kidneys; not a lot is known about the effect of extreme adolescent obesity on renal
function. And what we are finding in our early results is that there are very real and present signs of kidney
dysfunction in teens with morbid obesity,” he said.
Inge said that he and his co-investigators are committed to following the Teen-LABS cohort for a decade, and
objectively documenting outcomes; this would require extended funding past the 2006 to 2012 initial funding period
— giving an even longer term look after the surgery.
“It’s great to see this type of support for this research,” Inge said.
Support for bariatric surgery
•
Fernando B. Bonanni Jr., MD, director of the Institute for Metabolic and Bariatric Surgery at
Abington Memorial Hospital, Pennsylvania, said bariatric surgery in adolescents was once a hot topic
in the field, but it is beginning to simmer down.
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Fernando B. Bonanni Jr.
“There is no question that adolescents enjoy all the benefits of bariatric surgery,” Bonanni said,
adding that the reduction of comorbidities is the greatest selling point. “Moreover, for adolescents,
the psychosocial benefits are life changing. Like any other surgery, an adolescent will fare better with
regard to handling the surgery.”
The benefit of youth is that patients will have fewer comorbid problems going into the surgery. If
they have comorbid diseases, they have had them for less time.
“Chronic diseases, like diabetes, take its toll on a person, especially an obese patient. We must
remember that the real problem with obesity is that our body systems are equipped with reserves to
handle disease and injury. If you are 100 lb or more overweight, your system is working for two
people or more,” Bonanni said.
It is for this reason that adult obese patients are more likely to develop diseases and conditions at a
higher incidence, such as type 2 diabetes, he said.
Inge was an investigator of a 2009 multicenter study that found teens who underwent gastric bypass
surgery showed “dramatic, often immediate” remission of type 2 diabetes.
Teens who underwent LRYGB lost, on average, one-third of their body weight, and remission of
diabetes was induced in all but one teen. In most cases, patients stopped taking their diabetes
medications by the time they left the hospital.
“The results have been quite dramatic, and, to our knowledge, there are no other antidiabetic
therapies that result in more effective and long-term control than that seen with bariatric surgery,”
Inge said. He noted that the patients also showed significant improvement in blood pressure, insulin,
glucose, cholesterol and triglyceride levels.
Impact of surgery
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Nicole M. Chandler, MD, a pediatric surgeon at All Children’s Hospital, St. Petersburg, Fla., said
although the technique of bariatric surgery and its immediate postoperative care is identical in the
pediatric and adult populations, the adolescent population has unique metabolic and psychological
demands.
“It is important that ongoing nutritional and psychological support is provided to this younger age
group and long-term follow-up is provided far into adulthood,” Chandler said.
It is difficult to assess the effect that bariatric surgery may have on the lives of adolescents and their
family.
“While surgical options may provide sustained weight loss and resolution of comorbid diseases, they
also carry potentially life-threatening complications, the need for continued life-long compliance
with eating and behavioral modifications, and uncertain long-term problems decades after the
operation,” Chandler said.
Bonanni said herein lies the controversy with bariatric surgery in adolescents.
“The question is not: Will they do well with surgery,” he said. “There is no question they do better
than adults; however, the problem lies in the fact that adolescents have not suffered from comorbid
problems for a prolonged period. Therefore, they sometimes do not realize and appreciate the benefit
of the weight loss. This sometimes leads to complacency when it comes to the life changes that are
required to succeed long term. This includes exercise, supplemental vitamins, portion control and
good eating habits.”
It is important that adolescents participate in a rigorous preoperative screening that includes
educational information and how to manage expectations. The program they enter should require
adolescents to attend support group sessions.
“Most importantly, the patient’s family must be actively engaged in the entire process. In
adolescents, the support system they rely on is paramount to their success. This is a support system
that unfortunately in many cases is already broken and needs repair. A good program for surgical
weight loss will take all of this into consideration,” Bonanni said.
Legal and ethical dilemmas
Although there are benefits to bariatric surgery, the procedure is still a major surgery that
has long-reaching consequences, said Brian M. Fidlin, PsyD, program director of the
NEW (Nutrition, Exercise and Weight Management) Kids Program at Children’s
Hospital of Wisconsin. “There are questions that remain about whether a younger
individual possesses the maturity to make such a decision,” Fidlin said.
• He said not all insurance plans consider bariatric surgery a viable option for adolescents;
in addition, many of these younger individuals may be dropped from their parents’
insurance plans at some point.
• “One of the major risks is determining if this adolescent and his or her support system
will be capable of making and maintaining the necessary changes to promote a weight
loss. It is essential that an individual understand the procedure, risks and benefits, as
well as postsurgical requirements,” Fidlin said.
• Evan P. Nadler, MD, co-director of the Obesity Institute at Children’s National
Medical Center in Washington, D.C., said there are many legal and ethical issues with
adolescents and bariatric surgery.
• “Firstly, [LAGB] is not yet FDA-approved for children younger than 18 years of age —
so the safest option isn’t even approved for children/adolescents,” said Nadler, a leading
researcher of bariatric surgery in adolescents. “So it’s an ethical question: Do you
perform a safe procedure or make a 300-lb 15-year-old with diabetes wait another year
or two until the band gets approved?”
• He said it is not a question that is easily answered.
• “My personal feeling is that it’s less ethical to withhold a procedure that you know can
help, than it is to perform a procedure that doesn’t necessarily have long-term studies to
prove its durability,” Nadler said.
Effectiveness of LAGB
•
Nadler was an investigator of a 2007 NYU Medical Center study that showed
LAGB to be an effective procedure to combat obesity in adolescents.
• The study was the first to evaluate LAGB in patients younger than 17 and
revealed that patients on average lost about 50% of their excess weight by one
year after surgery. The surgery was performed on 53 morbidly obese
adolescents aged between 13 and 17, and, in addition to the weight loss, none
of the patients regained any of the weight. Complications were found to be
significantly less severe with LAGB, as well.
• Nadler said the results of the study suggest that LAGB provides a safer and
equally effective weight loss compared with LRYGB.
George Woodman, MD, medical director of the Baptist Weight Loss Center in
Memphis, Tenn., agrees.
• “In general, I would not consider a gastric bypass on an adolescent. This is an
excellent procedure, but one that is not reversible. The lap band and gastric
sleeve procedures, I believe, are a much better option,” Woodman said, citing
that LAGB is reversible and has been documented to be safe in many studies.
• “The sleeve procedure, although not reversible, is safer than a bypass and does
not have the same complication possibilities. The stomach is made smaller, but
the intestines are not ‘rearranged.’ Therefore, absorption is normal, and the
procedure is less morbid,” he said.
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Paucity of data
Saurabh Khandelwal, MD, an acting assistant professor at the Center for
Videoendoscopic Surgery in the department of surgery at the University of Washington,
Seattle, said bariatric surgery in the adolescent population is still a controversial topic
because of the lack of data.
For example, Khandelwal said performing LRYGB in children and adolescents may
cause potentially harmful effects on development and growth and affect physical
maturation.
Saurabh Khandelwal “Long-term data, at this time, do not exist that can give insight
into outcomes from procedures such as the gastric band or sleeve gastrectomy. We don’t
know the long-term consequences of placing a band in an adolescent, in which case he
or she may have it for 60 years or longer,” Khandelwal said. “Young patients
undergoing such procedures should be carefully followed and assessed, preferably
through participation in studies.”
However, despite the lack of data, Nadler said studies such as the Teen-LABS gastric
bypass study and the NYU gastric banding study show that weight loss is as good if not
better than the similar procedures in adults.
“And the procedures are as safe — if not safer — in adolescents,” Nadler added.
“I personally believe that 10 to 20 years from now, there will be as many teenagers
getting bariatric surgery as adults, especially since they do likely have better outcomes,”
he said. More studies are needed on the topic, and Nadler plans to investigate the topic
further in his program at Children’s National Medical Center.
Almost all of the researchers Endocrine Today spoke with viewed bariatric surgery as a
means for helping obese adolescents.
“Bariatric surgery is not a magic bullet,” Bonanni said. “It is a tool. If you do not take
The Fatty Liver Index: a simple and
accurate predictor of hepatic
steatosis in the general population
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Abstract
Background
Fatty liver (FL) is the most frequent liver disease in Western countries. We used data from the
Dionysos Nutrition & Liver Study to develop a simple algorithm for the prediction of FL in the
general population.
Methods
216 subjects with and 280 without suspected liver disease were studied. FL was diagnosed by
ultrasonography and alcohol intake was assessed using a 7-day diary. Bootstrapped stepwise logistic
regression was used to identify potential predictors of FL among 13 variables of interest [gender, age,
ethanol intake, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase (GGT),
body mass index (BMI), waist circumference, sum of 4 skinfolds, glucose, insulin, triglycerides, and
cholesterol]. Potential predictors were entered into stepwise logistic regression models with the aim
of obtaining the most simple and accurate algorithm for the prediction of FL.
Results
An algorithm based on BMI, waist circumference, triglycerides and GGT had an accuracy of 0.84
(95%CI 0.81–0.87) in detecting FL. We used this algorithm to develop the "fatty liver index" (FLI),
which varies between 0 and 100. A FLI < 30 (negative likelihood ratio = 0.2) rules out and a FLI ≥
60 (positive likelihood ratio = 4.3) rules in fatty liver.
Conclusion
FLI is simple to obtain and may help physicians select subjects for liver ultrasonography and
intensified lifestyle counseling, and researchers to select patients for epidemiologic studies.
Validation of FLI in external populations is needed before it can be employed for these purposes.
The Fatty Liver Index: a simple and
accurate predictor of hepatic steatosis in
the general population
• BMC Gastroenterology 2006, 6:33doi:10.1186/1471230X-6-33
• Teh electronic version of this article is the complete one
and can be found online
at: http://www.biomedcentral.com/1471-230X/6/33
• Received:16 August 2006Accepted:2 November 2006Publi
shed:2 November 2006© 2006 Bedogni et al; licensee
BioMed Central Ltd.
This is an Open Access article distributed under the terms
of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
•
Background
Fatty liver (FL) is the most frequent liver disease in Western countries [1-4].
Obesity and its complications, especially type 2 diabetes and
hypertriglyceridemia, are likely to be the main responsible of the current
epidemic of FL, while ethanol intake may play a minor role [5-7]. In a nested
case-control study of the Dionysos Project, we found that body mass index
(BMI) was a stronger risk factor for FL than ethanol intake in the general
population of Northern Italy [6]. Interestingly, this finding was confirmed by a
recent study performed in China [8]. Waist circumference has long been
hypothesized to be a predictor of FL independently from BMI, but data for the
general population were not available until very recently [1,8]. Because BMI is
a surrogate index of body adiposity [9], direct indexes of adiposity such as
skinfolds can be of value when studying the relationship between body
fatness per se and disease [10,11]. Hyperinsulinemia and insulin resistance are
common in subjects with FL independently from BMI and thus are expected to
be markers of FL in the general population [12]. Despite the operational
separation of FL into alcoholic and non-alcoholic fatty liver disease
(NAFLD) [4], the relative contribution of ethanol intake and other factors in
the pathogenesis of FL is still uncertain [3]. Using data collected during the
Dionysos Nutrition & Liver Study [1], we evaluated the contribution of
ethanol intake, anthropometry, liver enzymes and metabolic parameters to the
risk of FL and developed an algorithm for the prediction of FL in the general
population.
Study design
• The protocol of the Dionysos Nutrition & Liver Study was described
in detail elsewhere [1]. Briefly, of 5780 residents of Campogalliano
(Modena, Italy) aged 18 to 75 years, 3345 (58%) agreed to participate
to the study; 3329 (99%) of them had all the data required by the
Dionysos Project[7,13] and were considered for further analysis. 497
(15%) of them had suspected liver disease (SLD) according to at least
one of the following criteria: 1) alanine transaminase (ALT) > 30 U*L1; 2) gamma-glutamyl-transferase (GGT) > 35 U*L-1; 3) presence of
hepatitis B surface antigen (HBsAg); 4) presence of Hepatitis C (HCV)
virus ribonucleic acid (RNA) after detection of anti-HCV antibodies.
The 497 subjects with SLD were matched with an equal number of
subjects of the same age and sex but without SLD, randomly selected
among the remaining 2832 subjects. After exclusion of subjects with
HBV or HCV infection, the original analysis was performed on 224
subjects with and 287 without SLD [1]. The present analysis is
performed on 216 (96%) subjects with and 280 (97%) without SLD,
based on the availability of skinfold measurements.
Methods
•
Besides a clinical and laboratory evaluation, each subject underwent a liver
ultrasonography, an anthropometric assessment and a 7-day diary of food intake
(7DD) [1]. HBsAg and anti-HCV antibodies were assessed and subjects with anti-HCV
antibodies underwent an HCV-RNA assessment to confirm HCV infection [1,14]. ALT,
aspartate transaminase (AST), GGT, glucose, triglycerides and cholesterol were
measured by standard laboratory methods after 8-hr fasting. Insulin was measured by
radio-immuno-assay (ADVIA Insulin Ready Pack 100, Bayer Diagnostics, Milan, Italy),
with intra- and inter-assay coefficients of variation < 5%. FL was diagnosed by the same
operator at ultrasonography [6]. Weight, stature, circumferences (waist and hip) and
skinfolds (triceps, biceps, subscapular and suprailiac) were measured by two trained
dietitians who had been standardized before and during the study according to standard
procedures [15]. Body mass index (BMI) was calculated as weight (kg)/stature (m)2 and
the sum of 4 skinfolds by summing triceps, biceps, subscapular and suprailiac
skinfolds [16,17]. The 7DD was administered to the subjects by two trained dietitians,
who discussed it with the subject when she/he returned it one week later [18]. To avoid
the confounding effect of seasonality on food intake, the 7DD diary was administered to
a similar number of patients with and without SLD each month [19]. Mean daily ethanol
intake was calculated as the mean value of ethanol intake as assessed by the 7DD[20].
The study protocol was approved and supervised by the Scientific Committee of the
Fondo per lo Studio delle Malattie del Fegato (Trieste, Italy), and all subjects gave their
written informed consent to participate.
Statistical analysis
•
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Continuous variables are given as medians and interquartile ranges (IQR) because of
skewed distributions. Comparisons of continuous variables between subjects with and
without FL were performed with the Mann-Whitney test and those of nominal variables
with the Fisher's exact test. To identify candidate predictors of FL, we performed a
stepwise logistic regression analysis on 1000 bootstrap samples of 496 subjects
(probability to enter = 0.05 and probability to remove = 0.1) [21]. All variables besides
gender were evaluated as continuous predictors. Linearity of logits was ascertained
using the Box-Tidwell procedure [22]. To obtain a linear logit, we transformed age
using the coefficient suggested by the Box-Tidwell procedure [(age/10) 4.9255] and ALT,
AST, GGT, insulin and triglycerides using natural logarithms (loge). The logits of the
other predictors (BMI, waist circumference, glucose, cholesterol, ethanol and the sum of
4 skinfolds) were linear.
Candidate predictors identified at bootstrap analysis were evaluated using three stepwise
logistic models before obtaining a final prediction model (probability to enter = 0.01 and
probability to remove = 0.02; these more stringent levels were used to protect against
type I errors). The goodness of fit of the models was evaluated using the HosmerLemeshow statistic and their accuracy was assessed by calculating the non-parametric
area (AUC) under the receiver-operating curve (ROC) with 95% confidence intervals
(95%CI) [23,24]. The standard errors of the regression coefficients of the final model
were calculated using 1000 bootstrap samples of 496 subjects. The probabilities
obtained from the final model were multiplied by 100 to obtain the fatty liver index
(FLI). The sensitivity (SN), specificity (SP), positive likelihood ratio (LR+) and
negative likelihood ratio (LR-) of 10-value intervals of FLI were calculated [23].
Statistical analysis was performed using STATA 9.2 (StataCorp, College Station, Texas,
USA).
Results
• Table 1 gives the characteristics of the subjects with and without FL.
FL was more frequent among males than females (54 vs. 34%). Age,
ethanol intake and cholesterol did not differ between subjects with and
without FL. On the contrary, ALT, AST, GGT, BMI, waist
circumference, the sum of 4 skinfolds, glucose, insulin and
triglycerides were significantly higher in subjects with than in those
without FL.
• Table 1. Measurements of subjects with and without fatty liver.
• Figure 1 (Model 1) gives the number of times each of the 13 variables
of interest was selected by bootstrapped stepwise logistic regression.
The predictors identified most frequently were insulin (93%),
triglycerides (91%), BMI (78%), gender (77%), GGT (77%) and age
(64%). When these 6 predictors were entered into the stepwise model,
age did not remain in the model (p = 0.0766; model not shown). The
model based on the remaining 5 predictors fitted well (p = 0.9976,
Hosmer-Lemeshow statistic) and had a ROC-AUC of 0.85 (95%CI
0.82–0.89; model not shown).
Table 1: Measurements of subjects
with and without fatty liver.
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FL (n = 228) No FL (n = 268) p
Gender (male/female, n) 164/64 141/127 <0.0001
Age (years) 58 (17) 57 (26) 0.9535
Ethanol (g*day-1) 13 (35) 11 (28) 0.1272
ALT (U*L-1) 27 (21) 19 (16) <0.0001
AST (U*L-1) 22 (10) 20 (8) 0.0004
GGT (U*L-1) 31 (35) 19 (14) <0.0001
BMI (kg*m-1) 29.5 (5.8) 25.7 (4.1) <0.0001
Waist circumference (cm) 98 (16) 86 (14) <0.0001
Sum of 4 skinfolds (mm) 74.1 (37.4) 59.6 (26.8) <0.0001
Glucose (mg*dL-1) 96 (18) 89 (13) <0.0001
Insulin (mU*L-1) 9 (8) 5 (4) <0.0001
Triglycerides (mg*dL-1) 141 (102) 91 (60) <0.0001
Cholesterol (mg*dL-1) 219 (57) 212 (52) 0.1547
Values are medians and interquartile ranges for continous variables and number of
subjects for categorical variables.
Abbreviations: FL = fatty liver; p = p-value (Mann-Whitney U-test for continuous
variables and Fisher's Exact test for categorical variables); ALT =
alanine transaminase; AST = aspartate transaminase; GGT = gamma-glutamyltransferase; BMI = body mass index.
Figure 1 Selection of candidate predictors at bootstrapped stepwise logistic regression
Selection of candidate predictors at bootstrapped stepwise logistic regression. Bars indicate
the number of times out of 1000
that the variables were selected for inclusion in 3 models. Model 1 is the starting model,
Model 2 removes insulin and Model 3
removes skinfolds. Data are sorted using Model 3. Abbreviations: * = transformed using
natural logarithm; ** = transformed
using Box-Tidwell transformation (see text for details); other abbreviations as in Table 1.
Table 2: The parameters of the
fatty liver index (FLI).
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•
β SE (β) STD (β) p
Loge (triglycerides, mg*dL-1) 0.953 0.211 0.308 <0.0001
BMI (kg*m2-1) 0.139 0.050 0.353 0.006
Loge (GGT, U*L-1) 0.718 0.202 0.278 <0.0001
Waist circumference (cm) 0.053 0.019 0.356 0.005
Constant -15.745 1.631 - <0.0001
Abbreviations: β = regression coefficient; SE = standard
error; STD = standardized value; loge = nathural
logarithm. Other abbreviations as in Table
• 1. FLI is calculated by multiplying the predicted
probabilities per 100 (see text for the formula).
Results
•
•
•
Since insulin is not routinely measured, we tested whether its removal from the model
would decrease the accuracy of the estimate. After exclusion of insulin, the predictors
most frequently identified were triglycerides (100%), GGT (80%), BMI (79%), ALT
(70%), the sum of 4 skinfolds (68%) and gender (67%) (Figure 1, Model 2). When these
6 predictors were entered into the stepwise model, ALT did not enter it (p = 0.0780;
model not shown). The model based on the 5 remaining predictors fitted well (p =
0.9704, Hosmer-Lemeshow statistic) and had a ROC-AUC of 0.85 (95%CI 0.81–0.88;
model not shown).
Since skinfolds are not routinely measured, we tested whether their removal from the
model would decrease the accuracy of the estimate. After exclusion of the sum of 4
skinfolds, the predictors identified most frequently were triglycerides (100%), BMI
(95%), ALT (77%), GGT (73%) and waist circumference (58%) (Figure 1, Model 3).
When these 5 predictors were entered into the stepwise model, ALT did not enter it (p =
0.0241; p to remove = 0.0200; model not shown). The model based on the remaining 4
predictors fitted well (p = 0.9704, Hosmer-Lemeshow statistic) and had a ROC-AUC of
0.85 (95%CI 0.81–0.88; model not shown).
A comparison of the ROC-AUCs of Models 2 (p = 0.6320; Bonferroni's correction) and
3 (p = 0.1038)vs. Model 1 revealed no difference so that we choose Model 3 for further
analysis. The bootstrapped regression coefficients of Model 3 are given in Table 2. We
multiplied the probabilities generated by Model 3 per 100 to obtain a score comprised
between 0 and 100, which we call the "fatty liver index" (FLI). FLI is thus calculated as:
Fatty Liver Index
• FLI = (e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) +
0.053*waist circumference - 15.745) / (1 + e 0.953*loge (triglycerides)
+ 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) *
100
• As shown by the standardized regression
coefficients, the greatest contribution to the
prediction of FL came from waist circumference,
followed by BMI, triglycerides and GGT.
Table 3 gives the SN, SP, LR+ and LR- for 10unit intervals of FLI. A FLI < 30 can be used to
rule out (SN = 87%; LR- = 0.2) and a FLI ≥ 60 to
rule in hepatic steatosis (SP = 86%; LR+ = 4.3).
Table 3: Diagnostic accuracy of
the fatty liver index.
•
•
•
•
•
•
•
•
•
•
•
FLI cut-point % SN SP LR+ LR≥10 90 98 17 1.2 0.1
≥20 74 94 44 1.7 0.1
≥30 60 87 64 2.4 0.2
≥40 53 82 72 2.9 0.3
≥50 43 70 80 3.5 0.4
≥60 36 61 86 4.3 0.5
≥70 28 49 91 5.2 0.6
≥80 18 35 96 9.3 0.7
≥90 9 18 99 15.6 0.8
Abbreviations: FLI = fatty liver index; % = number of patients with
FLI
• ≥ cut-point; SN = sensitivity; SP = specificity; LR+ = positive
likelihood
Discussion
•
•
•
•
•
We used data from the Dionysos Nutrition & Liver Study to develop a simple algorithm for the prediction of FL. Age
was not associated with FL in any of the multivariable models while gender lost its association with FL after
exclusion of insulin and skinfolds. Ethanol intake was not associated with FL in any of the models. Thus, at least at
the values of intake observed in the Dionysos Nutrition & Liver Study, ethanol is not a risk factor for FL in the
general population of Northern Italy.
Waist circumference and BMI were the strongest predictors of FL in the final model. Together with the lack of
association of FL with ethanol intake, this finding strongly supports the hypothesis that obesity is the main
responsible of the current epidemic of FL [1,4,6]. It is of some interest that waist circumference did not add to the
prediction of FL when skinfolds were in the model but, from a practical viewpoint, there is no need to measure
skinfolds for predicting FL.
Among liver enzymes, only GGT was an independent predictor of FL while AST was not associated with FL in any
of the models and ALT was not an independent predictor of FL. We have previously shown that ALT is not a
surrogate marker of NAFLD and the present study extends this consideration to the entire spectrum of FL disease [1].
Insulin was the predictor most frequently selected for inclusion in Model 1 and was the second most important
predictor after BMI in the same model (data not shown). Thus, we confirm that insulin is an independent risk factor
for FL in the general population [12]. It is of some interest that waist circumference did not add to the prediction of
FL when insulin was in the model but that it was the strongest predictor of FL in the final model. This cannot be
easily explained by the known association between waist and insulin (resistance) because BMI is similarly correlated
with this latter [25,26] as also observed in this study (data not shown). Triglycerides were independent predictors of
FL in all models, confirming our previous findings [16]. Glucose and cholesterol were not predictors of FL even if it
may be noticed that the selection of glucose as potential predictor increased after exclusion of insulin from the model.
The main limitations of the Dionysos Nutrition & Liver Study are the suboptimal respondent rate (58%) and the fact
that ultrasonography cannot detect steatohepatitis (SH) [1]. This latter diagnosis can be obtained only by biopsy and,
because of obvious ethical reasons, a SH score will never be available in a representative sample of the general
population [3]. Scores developed in clinical series may be used for this purpose but they have not been tested in the
general population [27,28].
Conclusion
• The "fatty Liver index" (FLI) we developed is accurate and
easy to employ as BMI, waist circumference, triglycerides
and GGT are routine measurements in clinical
practice [7,29,30]. In our population, a FLI < 30 ruled out
and a FLI ≥ 60 ruled in hepatic steatosis as detected by
ultrasonography. Potential clinical uses of FLI include the
selection of subjects to be referred for ultrasonography and
the identification of patients for intensified lifestyle
counseling [30,31]. On the research side, FLI may be used
to select subjects at greater risk of FL for planning
observational or interventional studies [30,32]. Even
though, for reasons of biological plausibility and coherence
with previous studies [5,6,8], we expect that the
parameters employed by FLI will be predictors of FL in
Western countries besides Italy, it is very important that
FLI be validated in external populations before it is
employed in practice.
References
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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•
•
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•
•
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•
•
•
Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S: Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and
liver study.
Hepatology 2005, 42:44-52. PubMed Abstract | Publisher Full Text
Bellentani S, Bedogni G, Miglioli L, Tiribelli C: The epidemiology of fatty liver.
Eur J Gastroenterol Hepatol 2004, 16:1087-1093. PubMed Abstract | Publisher Full Text
Bedogni G, Bellentani S: Fatty liver: how frequent is it and why?
Ann Hepatol 2004, 3:63-65. PubMed Abstract
Neuschwander-Tetri BA, Caldwell SH: Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.
Hepatology 2003, 37:1202-1219. PubMed Abstract | Publisher Full Text
Angulo P: Nonalcoholic fatty liver disease.
N Engl J Med 2002, 346:1221-1231. PubMed Abstract | Publisher Full Text
Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristanini G, Tiribelli C:Prevalence of and risk factors for hepatic steatosis in Northern Italy.
Ann Intern Med 2000, 132:112-117. PubMed Abstract | Publisher Full Text
Bellentani S, Tiribelli C: The spectrum of liver disease in the general population: lesson from the Dionysos study.
J Hepatol 2001, 35:531-537. PubMed Abstract | Publisher Full Text
Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY: Prevalence of and risk factors for fatty liver in a general population of Shanghai, China.
J Hepatol 2005, 43:508-514. PubMed Abstract | Publisher Full Text
Bedogni G, Pietrobelli A, Heymsfield SB, Borghi A, Manzieri AM, Morini P, Battistini N, Salvioli G: Is body mass index a measure of adiposity in elderly women?
Obes Res 2001, 9:17-20. PubMed Abstract | Publisher Full Text
Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP, Yaffe K: Obesity in middle age and future risk of dementia: a 27 year longitudinal population based
study.
BMJ 2005, 330:1360. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Twisk JW, Kemper HC, van Mechelen W, Post GB, van Lenthe FJ: Body fatness: longitudinal relationship of body mass index and the sum of skinfolds with other risk
factors for coronary heart disease.
Int J Obes Relat Metab Disord 1998, 22:915-922. PubMed Abstract | Publisher Full Text
Bugianesi E, McCullough AJ, Marchesini G: Insulin resistance: a metabolic pathway to chronic liver disease.
Hepatology 2005, 42:987-1000. PubMed Abstract | Publisher Full Text
Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, Cristianini G:Prevalence of chronic liver disease in the general population of northern Italy: the
Dionysos Study.
Hepatology 1994, 20:1442-1449. PubMed Abstract
Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Crocè LS, Mazzoran L, Masutti F, Cristianini G, Tiribelli C: Clinical course and risk factors of hepatitis C virus related
liver disease in the general population: report from the Dionysos study.
Gut 1999, 44:874-880. PubMed Abstract | Publisher Full Text
Lohman , Roche , Martorell : Anthropometric standardization reference manual. Champaign, IL: Human Kinetics Books; 1988.
Durnin JV, Womersley J: Total body fat, calculated from body density, and its relationship to skinfold thickness in 571 people aged 12–72 years.
Proc Nutr Soc 1973, 32:45A. PubMed Abstract | Publisher Full Text
Fiori G, Facchini F, Pettener D, Rimondi A, Battistini N, Bedogni G: Relationships between blood pressure, anthropometric characteristics and blood lipids in high- and
low-altitude populations from Central Asia.
Ann Hum Biol 2000, 27:19-28. PubMed Abstract | Publisher Full Text
References
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Thompson FE, Byers T: Dietary assessment resource manual.
J Nutr 1994, 124:2245S-2317S. PubMed Abstract
Willett W: Nutritional epidemiology. New York: Oxford University Press; 1998.
MacDonald I: Health issues related to alcohol consumption. ILSI Press; 1993.
Steyerberg EW, Harrell FE, Borsboom GJ, Eijkemans MJ, Vergouwe Y, Habbema JD:Internal validation of predictive models: efficiency
of some procedures for logistic regression analysis.
J Clin Epidemiol 2001, 54:774-781. PubMed Abstract | Publisher Full Text
Box GEP, Tidwell PW: Transformation of the Independent Variables.
Technometrics 1962, 4:531-550. Publisher Full Text
Zhou , Obuchowski , McClish : Statistical methods in diagnostic medicine. New York: Wiley; 2002.
Hosmer DW, Lemeshow S: Applied logistic regression. New York: Wiley; 2000.
Farin HM, Abbasi F, Reaven GM: Body mass index and waist circumference correlate to the same degree with insulin-mediated
glucose uptake.
Metabolism 2005, 54:1323-1328. PubMed Abstract | Publisher Full Text
Reaven GM: The metabolic syndrome: is this diagnosis necessary?
Am J Clin Nutr 2006, 83:1237-1247. PubMed Abstract | Publisher Full Text
Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L, Tahiri M, Munteanu M, Thabut D, Cadranel JF, Le Bail B, de
Ledinghen V, Poynard T, LIDO Study Group, CYTOL study group: Diagnostic value of biochemical markers (FibroTest-FibroSURE) for
the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease.
BMC Gastroenterol 2006, 6:6. PubMed Abstract | BioMed Central Full Text |PubMed Central Full Text
Poynard T, Ratziu V, Naveau S, Thabut D, Charlotte F, Messous D, Capron D, Abella A, Massard J, Ngo Y, Munteanu M, Mercadier A,
Manns M, Albrecht J: The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis.
Comp Hepatol 2005, 4:10. PubMed Abstract | BioMed Central Full Text |PubMed Central Full Text
Kushner RF, Blatner DJ: Risk assessment of the overweight and obese patient.
J Am Diet Assoc 2005, 105:S53-S62. PubMed Abstract | Publisher Full Text
Bayard M, Holt J, Boroughs E: Nonalcoholic fatty liver disease.
Am Fam Physician 2006, 73:1961-1968. PubMed Abstract
Marchesini G, Natale S, Manini R, Agostini F: Review article: the treatment of fatty liver disease associated with the metabolic
syndrome.
Aliment Pharmacol Ther 2005, 22(Suppl 2):37-39. PubMed Abstract | Publisher Full Text
Comar KM, Sterling RK: Review article: Drug therapy for non-alcoholic fatty liver disease.
Aliment Pharmacol Ther 2006, 23:207-215. PubMed Abstract | Publisher Full Text
45th Annual Meeting of the European
Association for the Study of Diabetes
• High levels of fatty liver index (FLI) were associated with increased
insulin resistance, carotid intima-media thickness and coronary heart
disease risk in middle-aged people without diabetes, according to new
data presented here.
• Using data from the European RISC study (n=1,308), researchers in
Italy evaluated a variety of cardiometabolic risk factors, including fatty
liver index, metabolic profile, glucose tolerance, peripheral insulin
sensitivity, hepatic insulin resistance, beta cell function, physical
activity, CHD risk and early carotid atherosclerosis.
• FLI is a new index recently proposed as a predictor of the presence of
fatty liver, which includes in its formula waist circumference, BMI and
triglycerides, Amalia Gastaldelli, PhD, metabolism unit, Fondazione
Toscana G. Monasterio and CNR Institute of Clinical Physiology, Pisa,
Italy, told Endocrine Today. FLI >60 is equal to a greater than 78%
presence of fatty liver whereas FLI <20 is equal to a greater than 91%
absence of fatty liver, she said.
45th Annual Meeting of the European
Association for the Study of Diabetes
•
•
•
•
•
•
The first goal was to validate FLI as a predictor of hepatic steatosis, and the second goal was to
determine if FLI score .60 could predict metabolic alterations and presence of atherosclerosis. In a
separate group of people (n=37), hepatic fat content was measured using magnetic resonance
spectroscopy.
Comparison revealed that FLI and hepatic fat percentage were well correlated, according to the
researchers. People with FLI <20 had no hepatic fat (range, 0.4% to 4.2%; n=6) whereas those with
FLI >60 had steatosis (range, 8.6% to 24%; n=10).
In the RISC cohort, people with FLI scores >60 had higher fasting concentrations of glucose, insulin
and LDL, and reduced concentrations of HDL, compared with those with index scores <20.
Moreover, they had higher blood pressure, were more insulin resistant at the whole body level and in
the liver, and had impaired beta cell glucose sensitivity, Gastaldelli said.
Overall, the RISC cohort was at low risk for CHD — 9% were at medium-to-high risk and 83% were
at below average risk. The 10-year CHD score was positively associated with BMI and waist
circumference, but negatively associated with physical activity and peripheral insulin sensitivity. The
researchers reported a strong association between FLI and CHD.
Intima-media thickness was low, on average, in the cohort (0.60 mm), and was positively associated
with age, BMI, waist circumference, systolic BP, LDL and fasting plasma glucose; it was negatively
associated with HDL, physical activity, peripheral insulin sensitivity and FLI (P<.0001) for all.
Higher values of intima-media thickness were also associated with increased CHD and fatty liver
scores. Independent predictors of intima-media thickness included peripheral insulin sensitivity, age,
systolic BP, LDL and gender, according to multivariate analysis. When FLI was added to the
multivariate model, it replaced peripheral insulin resistance (P=.0001).
“Calculation of FLI from simple metabolic and anthropometric data can be a useful parameter to
assess cardiometabolic risk,” Gastaldelli said. – by Katie Kalvaitis
Simple Index Helps Identify Fatty Liver
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•
•
May 5, 2006 (Vienna) — A score derived from 5 easy-to-measure parameters can be used clinically to help identify patients with fatty
liver disease, according to Italian researchers. The tool should help general practitioners and other physicians diagnose this
underreported condition, which otherwise requires ultrasound for its identification.
According to senior investigator Giorgio Bedogni, MD, "Fatty liver is the most [common] liver disease in Western countries" and is
often seen in combination with metabolic syndrome. "A diagnostic algorithm developed in the general population may help general
practitioners to diagnose [it]." Dr. Bedogni is an internist and coordinator of the Clinical Epidemiology Unit at the Liver Research
Center, University of Trieste, Italy. He is also an adjunct professor of statistics in medicine at the School of Nephrology & Dialysis,
Modena and Reggio Emilia University, Italy.
Elisabetta Bugianesi, MD, PhD, who was not involved in the study, agrees that nonalcoholic fatty liver disease (NAFLD) in particular
is an important clinical entity that can be difficult to identify. "NAFLD constitutes a special challenge for physicians for several
reasons: any distinction between nonprogressive (fatty liver) and progressive disease (nonalcoholic steatohepatitis [NASH]) is only
based on liver histology, but NAFLD patients are generally asymptomatic [so] invasive procedures are not easy to propose [or] to
accept," she told Medscape via email.
"Surrogate markers (mainly alanine aminotransferase) are not universally accepted, and a large body of evidence indicates that
progressive liver disease may also be present in subjects with normal enzyme levels," Dr. Bugianesi pointed out. "Hence, identification
of scientifically compelling noninvasive markers is eagerly awaited." Long-term complications of NAFLD include cirrhosis and
hepatocellular carcinoma. Dr. Bugianesi is a professor of gastroenterology and an expert in NAFLD from the Division of Gastrohepatology, University of Torino, Italy.
In an effort to develop a simple method for identifying patients who may have fatty liver disease, Dr. Bedogni and colleagues used data
from the Dionysos Nutrition and Liver Study to determine the degree to which drinking habits, anthropometry, and metabolic
parameters contribute to the risk for the condition in 216 patients with suspected liver disease but no hepatitis B and C infection as well
as in 280 age- and sex-matched controls. All participants were from the same town in northern Italy. The presence of fatty liver disease
was confirmed via ultrasonography. Results were presented here by Vittorio di Maso, MD, another researcher at the Liver Research
Center, at the 41st annual meeting of the European Association for the Study of the Liver (EASL).
"Body mass index and waist circumference are independent predictors of fatty liver in the general population, while ethanol intake and
alanine transaminase [levels] are not," Dr. Bedogni told Medscape in an email. "A [Fatty Liver Index or FLI] score obtained from 5
parameters — gender, gamma-glutamyl-transferase, body mass index, waist circumference, and triglycerides — may be used to rule out
fatty liver when 1.0 [or less, negative likelihood ratio = 0.2] and rule it in when [the score is at least] 3.0 [positive likelihood ratio =
4.4].... This score was developed on a representative sample of the general population of a town of Northern Italy and as such is ideal
for use by general practitioners."
The authors conclude that patients' FLI could be used to determine who requires a confirmatory ultrasound and/or counseling to reduce
weight or improve other clinical risk factors for complications.
According to Dr. Bugianesi, "This index may help primary care physicians to identify NAFLD, especially in high-risk subjects, and
may help to increase the public awareness of NAFLD." Its only major limitation is that it cannot determine the type of fatty liver
disease present. To date, she says, only liver biopsy can reliably do so.
EASL 2006: Abstract 676. Presented April 27, 2006.
Nonalcoholic fatty liver
disease (NAFLD)
•
•
•
INTRODUCTION — Nonalcoholic fatty liver disease (NAFLD) is a clinicohistopathological entity with histological features that resemble alcohol-induced liver
injury, but by definition, occurs in patients with little or no history of alcohol
consumption. It encompasses a histological spectrum that ranges from fat accumulation
in hepatocytes without concomitant inflammation or fibrosis (simple hepatic steatosis)
to hepatic steatosis with a necroinflammatory component (steatohepatitis) that may or
may not have associated fibrosis. The latter condition, referred to as nonalcoholic
steatohepatitis (NASH), may progress to cirrhosis in up to 20 percent of patients [1].
NASH is now recognized to be a leading cause of cryptogenic cirrhosis [2].
The pathogenesis of nonalcoholic fatty liver disease has not been fully elucidated. The
most widely supported theory implicates insulin resistance as the key mechanism
leading to hepatic steatosis, and perhaps also to steatohepatitis. Others have proposed
that a "second hit," or additional oxidative injury, is required to manifest the
necroinflammatory component of steatohepatitis. Hepatic iron, leptin, anti-oxidant
deficiencies, and intestinal bacteria have all been suggested as potential oxidative
stressors.
This topic review will focus on the pathogenesis of NAFLD. An approach to such
patients is presented separately.
CAUSES OF TRIGLYCERIDE
ACCUMULATION
•
•
•
•
— Hepatic steatosis is a manifestation of excessive triglyceride accumulation in the liver. This can occur from the
excessive importation of free fatty acids (FFA) from adipose tissue, from diminished hepatic export of FFA
(secondary to reduced synthesis or secretion of VLDL), or from impaired beta-oxidation of FFA (figure 1). The major
sources of triglycerides are from fatty acids stored in adipose tissue and fatty acids newly made within the liver
through de novo lipogenesis [3].
Excessive importation of FFA can result from either increased delivery of triglycerides to the liver (as seen with
obesity and rapid weight loss), or from excessive conversion of carbohydrates and proteins to triglycerides (eg,
secondary to overfeeding or use of total parenteral nutrition).
Impaired VLDL synthesis and secretion can result from abetalipoproteinemia, protein malnutrition, or choline
deficiency. Patients with NASH may have a defect in postprandial Apo B secretion, leading to triglyceride
accumulation [4]. In addition a defect in the lipidation of Apo B, caused by an inhibition of microsomal triglyceride
transfer protein (MTP), may be a key mechanism in drug-induced NAFLD, such as seen
with amiodarone and tetracycline [5]. Depletion of the orphan receptor small heterodimer partner (SHP) results in
increased VLDL secretion, elevated MTP levels, and increased insulin sensitivity, whereas induction of SHP results
in the rapid accumulation of hepatocyte lipids [6].
Impaired beta-oxidation of FFA to ATP may be seen with vitamin B5 (pantothenic acid) deficiency, excessive alcohol
consumption, or coenzyme A deficiency (as can occur with valproic acid or chronicaspirin use). Activation of
peroxisome proliferator-activated receptor alpha appears to have a central role in stimulating beta-oxidation and
disposing hepatic fatty acids in NASH [7]. The ability to recover from hepatic ATP depletion is severely impaired in
patients with obesity-related NASH [8]. Compromised hepatic ATP homeostasis may predispose to injury from other
insults. Adiponectin, a fat derived hormone, appears to have a pivotal role in improving fatty acid oxidation and
decreasing fatty acid synthesis [9]. Administration of adiponectin improved hepatomegaly, steatosis, and ALT levels
in obese, leptin deficient mice. Also implicated in the steatosis pathway is the cannabinoid receptor type 1 (CB1).
Administration of a CB1 receptor antagonist rapidly abolished hepatic steatosis, improved aminotransferase levels,
reduced the levels of proinflammatory cytokines, and increased adiponectin levels in leptin-deficient mice
SUMMARY AND RECOMMENDATIONS
•
•
•
•
•
Nonalcoholic fatty liver disease is a spectrum of disorders that range from
simple hepatic steatosis without significant inflammation or fibrosis to
nonalcoholic steatohepatitis with varying degrees of inflammation and fibrosis.
Strong epidemiological, biochemical, and therapeutic evidence supports the
premise that the primary pathophysiological derangement, in most patients
with NAFLD, is insulin resistance. Insulin resistance leads to increased
lipolysis, triglyceride synthesis, increased hepatic uptake of free fatty fatty
acids, and accumulation of hepatic triglyceride. (See 'Insulin
resistance' above.)
Several fat derived hormones, such as adiponectin, leptin, and resistin, are
important regulators of hepatic insulin sensitivity. At the cellular level, these
effects appear to be modulated through altered activation of numerous
receptors, membrane glycoproteins, and cytokines.
Factors that determine the presence and extent of necroinflammation are not
yet well understood. Several possible mechanisms have been theorized,
including host factors, such as defects in mitochondrial structure and function,
impaired freeoxygen radical scavengering, increased hepatic iron, and
hepatotoxic byproducts of intestinal bacteria.
The factors involved in hepatic fibrogenesis are slowly becoming understood.
Activation of both lobular stellate cells and hepatic progenitor cells have been
observed in NAFLD. (See 'Fibrosis' above.)
TREATMENT
•
— There is no proven effective therapy for NASH, although
modification of risk factors, such as obesity, hyperlipidemia, and poor
diabetic control is generally recommended.
• Weight loss — Weight reduction should be gradual, since rapid
weight loss has been associated with worsening of liver disease [65].
One report suggested that weight loss should not exceed approximately
1.6 kg per week in adults [65]. Weight loss and increased physical
activity can lead to sustained improvement in liver enzymes, histology,
serum insulin levels, and quality of life [66-68]. Improvement in
steatosis (but not inflammation and fibrosis) and a decrease in hepatic
factors involved in regulating fibrogenesis has been observed one-year
following bariatric surgery [26]. In another report, baseline steatosis
and insulin resistance were associated with the degree of steatosis oneyear after bariatric surgery [27].
SUMMARY AND
RECOMMENDATIONS
• There is no proven effective therapy for NASH. Attempts
should be made to modify potential risk factors such as
obesity, hyperlipidemia, and poor diabetic control. Weight
reduction should be gradual, since rapid weight loss has
been associated with worsening of liver disease.
• Some hepatologists are already using insulin sensitizing
drugs (metformin or pioglitazone) based upon the
preliminary data presented above. Further controlled data
concerning the efficacy and safety of these approaches
should be available in the next few years. Given the slow
rate of progression in most patients with NASH, we
currently emphasize control of risk factors rather than
medical therapy in most patients.
•
•
•
•
•
FOLLOW-UP
— How patients with NAFLD should be followed is unsettled. Our approach is as
follows:
For patients with fatty liver without inflammation or fibrosis, we check liver
biochemical tests, a complete blood count, platelet count, and prothrombin time
annually and request that they be seen by a hepatologist yearly during which a careful
search should be performed for physical findings consistent with liver disease. In
addition, serial laboratory values should be reviewed to examine for concerning trends,
such as a declining platelet count or worsening liver biochemical tests. We repeat a liver
biopsy five to six years after the initial biopsy. We do not routinely repeat imaging tests
such as an ultrasound.
For patients with NASH, we check liver biochemical tests, a complete blood count,
platelet count, and prothrombin time every six months and request that they be seen by a
hepatologist every six months. We repeat a liver biopsy two to three years after the
initial biopsy. We do not routinely repeat imaging tests such as an ultrasound.
For patients found to have fatty liver on an imaging test and who either declined to
undergo a liver biopsy or in whom a liver biopsy was not immediately indicated (as
described above), we check liver biochemical tests, a complete blood count, platelet
count, and prothrombin time annually. We also request that they be seen yearly by a
hepatologist as described above. We do not routinely repeat imaging tests such as an
ultrasound.
The above recommendations will change if noninvasive markers of hepatic fibrosis are
validated in patients with NAFLD.
Why gastric bypass surgery
works
• small pouch restricts amount of food eaten
• 20 ft of small intestine acts as common limb with
bile acid (does not cause malabsorption)
• negative aversion—eg, when candy bar (with1000
osmol/L) eaten, it does not pass through pylorus
(candy bar goes directly to small intestine where
osmolarity 280-290 osmol/ L)
• fluid rushes into small intestine and causes
expansion
• vagal reaction causes patients to feel unwell
• “they don’t eat candy anymore”
Brain and weight control
• brain programmed to eat continuously
• body weight controlled by, eg, hormonal or
vagal messages that shut off eating for
about 2 hr
• within 2 hr, drive to forage for food returns
• after reaching higher weight, body defends
that weight
• hormones—ghrelin from stomach stimulates
appetite
• peptide YY (PYY) and glucagon-like
peptide 1 (GLP-1) turn off hunger
Procedures
• gastric bypass—causes 37% to 38% weight loss, but weight gradually
regained due to lowered metabolism
• (eg, if 10% of body weight lost, metabolism lowers by 25%)
• results in 25% weight loss
• gastric banding—band placed at top of stomach
• does not alter hormones, so amount of weight loss 50% less than that
of other procedures
• restricts eating
• slippage—occurs after band placement causes vomiting of fluids
• one side of band breaks loose from sutures, slips, and rotates around
one side and results in obstruction and herniation; surgical emergency
• gastric pouch—part of stomach removed and stapled
• Tubularized stomach restricts eating; pylorus intact
• Lowers ghrelin and increases GLP-1
• weight loss results better than with banding (almost as good as gastric
bypass)
DM and Gastric Bypass
• Adjustment of medications for type 2
diabetic with gastric bypass surgery
• serum glucose likely to drop and
normalize normalize due to reduced eating
and increased GLP-1
• recommend discontinuing agents that
reduce serum glucose
• below normal (eg, glipizide [Glucotrol] and
insulin)
Thiamine deficiency
• Thiamine deficiency: case—6 wk after
gastric bypass
• 50-lb weight loss
• patient presents with vomiting, vision
problems, and symptoms of ataxia
• often missed
• Restore thiamine urgently
• worsens with carbohydrate intake
Pain after gastric bypass
• case—1 yr after surgery and 100• lb weight loss, patient presents with
epigastric pain of 3-wk duration
• no nausea or vomiting
• normal stools
• ask about use of over-the-counter (OTC)
drugs
• when drug (eg, aspirin) taken, it bypasses
stomach, goes directly to small intestine and
causes pain
Osteoporosis after gastric bypass
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case—woman 52 yr of age presents 7 yr after surgery
lost 90 lb, but regained 25 lb
menopausal for 4 yr
dual energy x-ray absorptiometry (DEXA) shows moderate
osteoporosis
work-up—check parathyroid hormone (PTH) and 25-hydroxyvitamin
D levels chemistry panel
hyperparathyroidism secondary to vitamin D deficiency—consider if
PTH elevated and vitamin D low
patients cannot absorb vitamin D or calcium
Replace calcium and vitamin D (start with ergocalciferol, 50,000 U/wk
recheck level in 2 wk)
give intravenous (IV) bisphosphonates
patients cannot acidify calcium bicarbonate (give calcium citrate,
1000-1500 mg/day)
seen in up to 30% of patients; usually occurs 7 to 10 yr after surgery
Iron deficiency
• common (60%-90% of patients especially
in menstruating women)
• presents as pica (eg, chewing ice or dirt)
• since patients in slow metabolic state,
inflammatory markers drop (ferritin
accurate for measuring iron
• total ironbinding capacity and serum iron
acceptable)
• due to inability to absorb iron, patients may
need IV iron, eg, iron sucrose, 200 mg
(reaction [eg, fever, joint aches] rate, 1%-
Vitamin B12 deficiency
• treat with sublingual form (effective 80%
of time)
• must be taken regularly
• monitor regularly
• some patients require monthly vitamin B12
injection
Supplements
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multivitamin with iron for all patients
Calcium citrate
potassium and magnesium early on
zinc and copper—enter through same
transport system; as zinc replaced, copper
malabsorbed
• necessary to stop one, then start other (“it’s
a game, but you have to hang in there with
it”)
• check levels regularly
Conclusions
• bariatric surgery beneficial (especially to
seriously overweight patients with type 2
diabetes)
• be prepared to withdraw diabetic medications
• follow nutritional problems
• check hemoglobin A1C yearly
• diabetes recurs in some patients as they regain
weight
• 15% of patients who undergo gastric bypass fail
(ie, do not lose >20 lb, and regain weight)
Major cause of weight regain
• metabolic slowdown
• Body lowers metabolic rate more than needed
• weight gain seen in patients who consume 1500 to 1700
calories/day
• Absorption of medications
• thyroid replacement therapy— follow thyroid-stimulating
hormone levels after gastric bypass every 6 mo to 1 yr
• 20% to 25% of patients may need increased doses (from,
eg, 125 μg/day to 200-300 μg/day)
• oral contraceptives (OCs)—after surgery, estrogen levels
drop as body fat drops, resulting in heavy menstrual
periods maintain patients on standard dosage
• Celecoxib (Celebrex)—not studied in gastric bypass
patients
• Cannot guarantee use will not result in ulcer
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Carotene deficiency
common; good general nutritional marker for fat-soluble vitamins
check levels 18 mo after surgery
can be replaced with OTC Beta-carotene
difficult to absorb from fruits and vegetables
recommend B complex vitamin
Vitamin D monitoring
patients require vitamin D supplementation for life
PTH levels change after a bout6 wk of vitamin D supplementation
check every 6 to 8 wk
Thiamine deficiency: rarely seen later than 6 mo after surgery
usually occurs within 2 to 3 mo
Iron deficiency: cannot be treated with interferon; treat with iron
dextrose, iron sucrose, or iron gluconate
• Criteria for gastric bypass: morbid obesity (2 times normal weight)
• body mass index (BMI) cutoff, 40 (35 if patient has diabetes or
hypertension)
anorexia and bulimia
• Introduction: 40% of anorexics develop
bulimic symptoms
• patients with BMI <20 to 25 at as high risk for
health issues as patients with BMI of 40 to 55
• 90% of patients with anorexia or bulimia women
• survey found 7% of white, 7% of Hispanic, and
4% of black students said they took laxatives or
vomited to lose weight or to avoid gaining weight
• normal weight for woman 5'4”—125 lb, BMI 21.5
• BMI calculator available online
Constitutional thinness
vs anorexia
• BMI similar, but percentage of body fat differs
• leptin related to amount of body fat
• leptin responds more acutely when body fat
reduced due to anorexia, compared to
constitutional thinness
• Anorexic patients amenorrheic (>16% to 17% of
body fat required for menstruation)
• constitutionally thin women menstruate
• check estradiol levels (should be 30 pg/mL) to
verify
General considerations
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eating disorders becoming increasingly more common in adults
average age of onset for anorexia nervosa (AN) is 15 yr of age
bulimia nervosa (BN) 18 yr of age
binge eating disorder (BED) 25 yr of age
BED more prevalent than AN or BN
BED lasts longer, so clinician more likely to see patients with BED than AN or
BN
embarrassment and difficulty acknowledging problem inhibits initiation of specific
eating-disorder therapy
Older women—tend to have more comorbidities; longer duration of eating
disorder
prognosis inversely related to duration of illness BED—falls under Diagnostic
and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-1V)
classification of eating disorder not otherwise specified (EDNOS)
majority of eating disorder patients classified under BED, as patients not
meeting criteria for AN or BN included in this diagnosis
similar to BN, but without compensatory purging; affects older patients
have fewer dietary restraints
many patients overweight
prevalence— data (10,000 patients) show AN 1.0%; BN 1.5%; BED 3.5%
all 3 diagnoses have long duration (average 6 yr for patient with AN)
Common themes
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intense fear of gaining weight
body image distortion can progress to body dysmorphic disorder
Selfperception not based on reality
self-esteem totally dependent on weight
decreased stigma associated with treatment of mental health conditions and
improved access to eating disorder specific therapies
likely reasons for increase in older women seeking treatment
treatment for BN available since 1990s;
epidemiology—incidence of BN and BED increasing
since 1960s (era of very thin fashion models [eg, Twiggy] as ideal of female
beauty)
studies show slow increase in AN throughout last century, although currently at
plateau
data show patients with eating disorders most likely to seek care from primary
care provider; psychiatry and other mental health professionals seen
as well as complementary and alternative medicine (CAM) practitioners
Onlly 30% of patients with AN seek treatment
patients with BN and BED much more likely to do so
AN considered egosyntonic illness it does not contradict person’s goals or view
of self
patients not interested in cure
often, patient’s family initiates treatment
patient who binges and purges more likely to seek treatment because behaviors
cause them distress
Characteristics of older
patients
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high scores on Beck Depression Inventory
significant anxiety measured by State-Trait Anxiety Inventory
compromised self-worth
elevated scores on all eating disorder assessments; ie, increased dietary
restraint
eating concerns, weight and shape concerns (compared to normal population)
data show 94% of eating disorder patients >30 yr of age have had illness since
adolescence or experiencing relapse of preexisting illness
de novo illness unusual (6%)
older patient more likely to engage in risky behaviors,
eg, abuse of over-the-counter (OTC) laxatives and diuretics
purchase of prescription diuretics via Internet (can
lead to hypokalemia)
over-exercise
contributing factors— inability to make life transitions or accept losses (eg,
death, divorce, empty-nest syndrome, aging, changing appearance)
data show majority of older patients struggle with eating issues for 10 yr
drive for thinness as strong as in younger patients
body image dissatisfaction increases as women age (normative discontent), and
more prevalent than in past
Evaluation
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Scoff questionnaire: mnemonic for sick, control, one, fat and food
do you make yourself sick because you feel uncomfortably full?
do you worry that you have lost control over your eating? (universally
reported in BN and BED)
have you lost >14 lb (one stone) in past 3 mo?
Do you believe yourself to be fat when others say you are too thin?
would you say food dominates your life?
2 positive answers 100% sensitive for AN, BN, and binge eating
behavior (not BED)
87.5% specificity
Physical examination: temperature (hypothermia common);
height, weight and body mass index (BMI); orthostatic blood pressure
(BP) and pulse (changes related to increased parasympathetic tone)
oropharynx—loss of dental enamel (amalgam islands) and translucent
appearance
related to vomiting
skin and hair—acrocyanosis, lanugo hair, and Russell’s sign (abrasions
on knuckles)
muscle wasting—BMI <19 (Asians excepted)
Laboratory Values
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complete blood cell count (CBC) with differential—bone marrow
sensitive to malnutrition, so abnormal values seen in
white blood cells
Hemoglobin
platelets (in that order) with eating disorders;
Chemistry battery—hypokalemia
liver function tests (LFTs)— elevated liver enzymes common (resolve
with weight gain); phosphorous and magnesium—levels tend to be low
Thyroid function—euthyroid sick syndrome (with abnormal thyroidstimulating hormone [TSH] levels) common with significant weight loss;
repeat TSH testing after weight gain, rather than immediate treatment
with thyroid medication
pregnancy—urine test
electrocardiography—prolonged QT interval
dual-energy x-ray absorptiometry (DEXA)—decrease in bone mineral
density (BMD) with 6 mo of amenorrhea
female athlete triad (amenorrhea, osteoporosis and disordered eating)
common among female cross-country runners
elevated cholesterol related to cortisol (stress hormone)
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Worldwide epidemic of
obesity
25% of industrialized world
64% of United States population overweight
definitions—overweight defined BMI >25;
obesity, BMI >30 (good predictor of
development of health risks)
Obesity considered lifelong
Progressive
life-threatening
Genetically related
multifactorial disease of excess fat storage
multiple comorbidities
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Physiologic impact of
obesity
obstructive sleep apnea
Hypoventilation syndrome
nonalcoholic fatty liver disease (steatohepatitis
leading to cirrhosis)
Cholelithiasis
Gynecologic abnormalities
phlebitis and venous stasis (increases risk for deep venous thrombosis)
increased risk for cancer
pancreatitis,
heart disease
direct relationship between weight and diabetes
women develop type 2 diabetes with smaller increases in BMI than men
obesity and pregnancy
spontaneous abortion
congenital abnormalities
Gestational diabetes
Preeclampsia
delivery complications
postterm onset of labor
failed induction
shoulder dystocia (increased incidence of third- and fourth-degree tears)
neonatal macrosomia (with possible early neonatal death)
also precursor for childhood obesity
Mortality
higher risk for death with increasing weight
years of life lost believed greater when weight increases early in life
data show bariatric surgery for severe obesity associated with decreased overall mortality
Treatment options
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estimated only 1% of patients qualifying for bariatric surgery undergo surgery
alternatives to surgery
diet, exercise, behavior modification
antiobesity medications orlistat, sibutramine [Meridia], phentermine
challenge is sustaining weight loss
data show only 7 of 102 participants maintained weight loss at 9 yr
qualifications for surgery
BMI >40
BMI >35 with significant comorbidities (diabetes, hypertension, and sleep apnea
most important)
documented attempts at nonsurgical weight loss
why patients choose surgery
sustainable weight loss
desire to feel healthier
improvement in self-esteem
increased ability to “keep up” with children
Increased fertility
bariatric surgery trends
number of bariatric procedures projected to continue increasing
80% of bariatric surgery patients women
many in childbearing years
Gastric bypass (Roux-en-Y
procedure)
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restrictive and malabsorptive procedure
small stomach pouch stapled and divided from main stomach
2 variations, proximal and distal
Malabsorption of fats
dumping syndrome—normally, pyloric valve releases food into intestine slowly
physiologic reaction to food rapidly leaving stomach
small bowel distention, flushing, and Headache remind patients to avoid eating sweets or foods high in fat
patients can forget to eat because of changes in ghrelin levels
mortality and complication
mortality 0.3%
Increase with male sex, age, and BMI
pulmonary embolism after surgery
leak (staple line disconnects or does not heal) 2 most frequent causes of death
hemorrhage and stricture technical complications
late complications—anastomotic ulcer
5% of patients (may present with epigastric pain)
treated with proton pump inhibitor and sucralfate (Carafate)
internal hernia in pregnancy serious complication
expected outcomes from surgery
loss of two-thirds to three-quarters of excess body
weight 12 to 18 mo after surgery
60% of weight loss maintained at 14 yr
resolution of comorbidities—diabetes in 83% of patients
hypertension improved in 87% of patients and
eliminated in 75%
sleep apnea in 85%
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Laparoscopic adjustable gastric band
(lap band)
Second most common bariatric surgery performed in United States;
restrictive procedure
silastic band around stomach connected to subcutaneous port
no hormonal changes
no dumping syndrome
no malabsorption
follow-up band adjustments recommended for optimal results
if band too tight, patient unable to enjoy healthy foods and likely to resort to eating foods that
“slide down” more easily (eg, ice cream, sweets) or may develop reflux disease
over time, hunger may increase because ghrelin not as well suppressed as with other types
of surgery
mortality and complications—mortality approaches zero
Obstruction and perforation of stomach unlikely
band slip—as patient eats food
stomach distends and is pulled underneath band
this cuts off blood supply to stomach, leading to necrosis
resection required
band erosion—erosion seen from inside stomach
rare complication
port-related problems
rate of reoperation (because of complications) higher than gastric bypass;
weight loss at 1 yr averages 40%, 52% at 3 yr
Longterm weight loss unknown in United States Europe and Australia report loss of 50%
excess weight long-term
Comorbidities improve
not as effective as gastric bypass
Ghrelin
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Ghrelin is a hormone produced mainly by P/D1 cells lining
the fundus of the humanstomach and epsilon cells of the pancreas that
stimulates hunger.[1] Ghrelin levels increase before meals and decrease
after meals.
It is considered the counterpart of the hormone leptin, produced
by adipose tissue, which induces satiation when present at higher
levels.
In some bariatric procedures, the level of ghrelin is reduced in patients,
thus causing satiation before it would normally occur.
Ghrelin is also produced in the hypothalamic arcuate nucleus, where it
stimulates the secretion of growth hormone from the anterior pituitary
gland.[2]. Receptors for ghrelin are expressed by neurons in the arcuate
nucleus and the ventromedial hypothalamus. The ghrelin receptor is
a G protein-coupled receptor, formerly known as the GHS receptor
(growth hormone secretagogue receptor).
Ghrelin plays a significant role in neurotrophy, particularly in
the hippocampus, and is essential for cognitive adaptation to changing
environments and the process oflearning.[3] Recently, ghrelin has been
shown to activate the endothelial isoform of nitric oxide synthase in a
pathway that depends on various kinases includingAkt.[citation needed]
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Ghrelin
Mechanism of action
Ghrelin has emerged as the first circulating hunger hormone. Ghrelin and synthetic ghrelin mimetics (the
growth hormone secretagogues) increase food intake and increase fat mass [4][5] by an action exerted at the
level of the hypothalamus.
They activate cells in the arcuate nucleus[6][7] that include the orexigenic neuropeptide Y (NPY)
neurons.[8] Ghrelin-responsiveness of these neurones is both leptin- and insulin-sensitive.[9]
Ghrelin also activates the mesolimbic cholinergic-dopaminergic reward link, a circuit that communicates the
hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as
ethanol.[10][11] [12]
[edit]Roles of Ghrelin
Lung Development
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In fetuses, it seems that ghrelin is early produced by the lung and promotes its growth. [13]
Learning and Memory
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Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, enhancing
learning and memory.[14] It is suggested that learning may be best during the day and when the
stomach is empty, since ghrelin levels are higher at these times. In rodents, X/A-like cells produce
ghrelin.
Stress-Induced Depression
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A study appearing in the journal Nature Neuroscience (June 15, 2008 online) suggests that the
hormone might help defend against symptoms of stress-induced depression and anxiety.[15] To test
whether ghrelin could regulate depressive symptoms brought on bychronic stress, the researchers
subjected mice to daily bouts of social stress, using a standard laboratory technique that induces
stress by exposing normal mice to very aggressive “bully” mice. Such animals have been shown to be
good models for studying depression in humans.
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The researchers stressed both wild-type mice and altered mice that were unable to respond to
ghrelin. They found that, after experiencing stress, both types of mice had significantly elevated levels
of ghrelin that persisted at least four weeks after their last defeat encounter. The altered mice,
however, displayed significantly greater social avoidance than their wild-type counterparts, indicating
an exacerbation of depression-like symptoms. They also ate less than the wild-type mice.[16]
Sleep-Duration
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A study [17] appearing in the journal PLoS Medicine suggests that short sleep duration is associated
with high levels of ghrelin and obesity; ghrelin appears to be a factor contributing to the short sleep
duration and obesity. Scientists have uncovered an inverse relationship between the hours of sleep
and blood plasma concentrations of ghrelin; as the hours of sleep increase, ghrelin concentrations
were considerably lower, thereby potentially reducing appetite and avoiding potential obesity.
Ghrelin
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[edit]Role in Disease
Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals[18] except in the
case of Prader-Willi syndrome-induced obesity.
Those suffering from the eating disorder anorexia nervosa have high plasma levels of ghrelin compared to
both the constitutionally thin and normal-weight controls.[19]
These findings suggest that ghrelin plays a role in both anorexia and obesity.
Yildiz and colleagues found that the level of ghrelin increases during the time of day from midnight to dawn
in thinner people, suggesting a flaw in the circadian system of obese individuals.[20]
Professor Cappuccio of the University of Warwick has recently discovered that shortsleep duration may
also lead to obesity, through an increase of appetite via hormonal changes.
Lack of sleep produces ghrelin, which stimulates appetite and creates less leptin, which, among its many
other effects, suppresses appetite.
Ghrelin levels are also high in patients that have cancer-induced cachexia.[21]
Prader-Willi syndrome is also characterized by high fasting levels of ghrelin; here the ghrelin levels are
associated with high food intake.[22]
At least one study found that gastric bypass surgery not only reduces the gut's capacity for food but also
dramatically lowers ghrelin levels compared to both lean controls and those that lost weight through dieting
alone.[23]
[edit]Relation to obestatin
Obestatin is a putative hormone that was described, in late 2005, to decrease appetite. Both obestatin and
ghrelin are encoded by the same gene; the gene's product breaks apart to yield the two peptide
hormones.[24] The purpose of this mechanism is unknown.
[edit]History and name
The discovery of ghrelin was reported by Masayasu Kojima and colleagues in 1999.[25] The name is based
on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root ghre,
meaning to grow. The name can also be viewed as an interesting (and incidental) pun, too, as the initial
letters of the phrase growth hormone-releasing give us "ghre" with "lin" as a usual suffix for some
hormones.
[edit]Anti-obesity vaccine
Recently, Scripps research scientists have developed an anti-obesity vaccine, which is directed against the
hormone ghrelin.[26][27] The vaccine uses the immune system, specifically antibodies, to bind to selected
targets, directing the body's own immune response against them. This prevents ghrelin from reaching the
central nervous system, thus producing a desired reduction in weight gain.
Sleeve gastrectomy
• stomach excised
• leaving only narrow area
• Complications include leak or hemorrhage
because of long staple line
• stricture (treated by balloon dilation)
• Mortality 0.39% (should improve with
experience)
• Stenosis
• Vitamin B12 deficiency
• resolution of comorbidities—diabetes 72%;
• hypertension 57%
• sleep apnea 85%
• gaining in popularity
Micronutrients at risk with
bypass surgery
• iron—lack of stomach acid compromises conversion of ferrous
iron to ferric iron
• intolerance to red meat because of narrow opening
• leads to less bioavailable heme
• iron and ascorbic acid prescribed to make up for decreased acid
• calcium— cells that absorb calcium in jejunum bypassed
• BMD evaluated with DEXA scan at first and second year after
surgery
• Calcium supplementation prescribed
• vitamin B12—decreased binding with intrinsic factor
• replacement can be oral, sublingual, nasal,or intramuscular
• vitamin D—fat-soluble
• Requires aggressive replacement to improve calcium absorption
• Folate and thiamine—deficiencies less common
Pregnancy after weight-loss
surgery
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data show pregnancy after lap-band surgery as safe as in women with
normal BMIs
Australian study of 79 patients with lap band showed gestational
diabetes rates not significantly different from community
less pregnancy-induced hypertension seen relative to pre-lap band
pregnancies
no significant difference in premature delivery, macrosomia or perinatal
mortality, compared
to community controls
gastrointestinal (GI) complications during antepartum period
Cholelithiasis (ursodeoxycholic acid given at time of surgery)
Marginal ulcer
internal hernia (potentially fatal complication); patient presenting with
bowel obstruction who had gastric bypass should be treated as surgical
emergency
computed tomography (CT) recommended during pregnancy (minimal
risk to fetus) to diagnose internal hernia
CT insensitive in less severe cases
diagnostic laparoscopy should be considered for patients with recurrent
symptoms
Nutritional goals
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determine baseline nutritional status early in pregnancy
deficiencies best corrected early or in preconception phase
multivitamin plus iron, in addition to prenatal
Vitamin
recommended (liquid or chewable form because of small opening
between stomach and small intestine)
Vitamin A >5000 IU/day should be avoided
beta carotene can be given at higher dose
iron —requirement increases in second half of pregnancy, due to
expansion of red blood cell mass and transfer of iron to fetus and
placenta
Postoperative dose of iron 40 to 100 mg of essential iron per day
During pregnancy, 30 to 60 mg per day
180 to 220 mg with maternal anemia (should be given with vitamin C or
ascorbic
acid)
folic acid—400 μg
800 to 1000 μg in typical prenatal vitamin and 400 μg in multivitamin
adequate
calcium—1200 to 1500 mg with 800 IU of vitamin D
Other pregnancy
considerations
• oral glucose tolerance test (50-100 g)
• typically performed at 28 wk gestation
• Causes dumping syndrome in patients with history of gastric
bypass
• sweating, nausea, flushing, tachycardia, diarrhea, crampy
abdominal pain, and hypoglycemia
• fasting and 2-hr postprandial glucose level, hemoglobin A1C
and continuous glucose sensor for 3 days other options
• pregnant women with history of lap-band surgery should not
have electrolyte imbalances or vitamin or iron deficiencies if
supplements taken
• pregnancy should be delayed 12 to 18 mo after weight-loss
surgery period of most rapid weight loss
• Concern baby may become malnourished
• pregnancy may reduce long-term weight loss (controversial)
Weight gain during
pregnancy
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gastric bypass requires dietary counseling
lap banding requires active management
key elements of band management
close cooperation with obstetrician
fluid removed from band to minimize band restriction
determine optimal weight gain for pregnancy
recommended 15-20 lb)
• fluid added after 14 wk if weight gain excessive
• fluid removed from band at 36 wk to minimize impact
on delivery and establish lactation
• removal of fluid whenever patient having abdominal
surgery
General recommendations
• instruct women to use contraception
postoperatively
• fertility issues often resolved after surgical
weight loss
• patient presenting with GI complaints should
be assessed for internal hernia
• multidisciplinary approach to prenatal care of
bariatric patients important
• Determine baseline nutritional status early in
course of pregnancy