NAFLD Update - Chronic Liver Disease · PDF fileBACKGROUND • Nonalcoholic fatty liver disease (NAFLD) including, nonalcoholic steatosis and steatohepatitis (NASH), is the most common
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NAFLD Update
Highlights from AASLD 2012
Nonalcoholic fatty liver disease without
cirrhosis is an emergent and independent risk
factor of hepatocellular carcinoma: A
population based study
Rubayat N. Rahman, Jamal A. Ibdah
Highlights of AASLD 2012
NAFLD
Abstract #97, AASLD 2012
BACKGROUND • Nonalcoholic fatty liver disease (NAFLD) including, nonalcoholic
steatosis and steatohepatitis (NASH), is the most common liver
disease with increasing incidence. NAFLD without cirrhosis is
rapidly evolving as a significant risk factor for primary
hepatocellular carcinoma (HCC) but the magnitude of this risk
has not been analyzed at a population level.
OBJECTIVE • Our goal is to analyze the association between HCC and NAFLD
with and without cirrhosis at national level.
Highlights from AASLD 2012
Nonalcoholic fatty liver disease without cirrhosis is an emergent
and independent risk factor of hepatocellular carcinoma
Rahman, R. M., et al. Abstract 97; AASLD 2012
Highlights from AASLD 2012
METHODS
• HCC cases reported between 1993-2007 in
Surveillance, Epidemiology, and End Results (SEER)-
Medicare database were identified. Demographics,
incidence, stage and grade of HCC due to
histopathologically confirmed NAFLD with and without
cirrhosis were compared with infection, alcohol and
other risk factors of HCC using SAS. Cases with more
than one risk factor were excluded. Logistic regression
for odds ratios adjusted for covariates and survival
analysis (age adjusted Kaplan Meier) were performed.
Nonalcoholic fatty liver disease without cirrhosis is an emergent
and independent risk factor of hepatocellular carcinoma
Rahman, R. M., et al. Abstract 97; AASLD 2012
Highlights from AASLD 2012
RESULTS SUMMARY
• A total of 17,895 cases of HCC were identified for analysis
• Among them 2,863 (16%) HCC were due to confirmed
NAFLD without evidence of other etiologies; 1,832 (64%)
with cirrhosis and 1,031 (36%) without cirrhosis.
• Among those without cirrhosis, 18% had steatosis without
NASH.
• Overall NAFLD was the third most common risk factor for
HCC after infection and alcohol etiologies.
• However, in US Asian/Pacific Islanders, it was the second
most common risk factor after infection.
Nonalcoholic fatty liver disease without cirrhosis is an emergent
and independent risk factor of hepatocellular carcinoma
Rahman, R. M., et al. Abstract 97; AASLD 2012
Highlights from AASLD 2012
RESULTS
* P value <0.01; NAFLD, Nonalcoholic fatty liver disease; HCC, Hepatocellular carcinoma; Fav., Favorable; USW, US Whites; Hisp, Hispanic; PI, Pacific Islander.
Comparison of cirrhotic and non-cirrhotic NAFLD HCC: SEER-
Medicare database1993-2007
Nonalcoholic fatty liver disease without cirrhosis is an emergent
and independent risk factor of hepatocellular carcinoma
Rahman, R. M., et al. Abstract 97; AASLD 2012
NAFLD HCC (2,863)
N (%)
Sex (M/F)
%
Race Early Stage (I/II)
Fav. Grade (I/II) USW Black Hisp Asian/
PI
With Cirrhosis 1,832 (64%)
68/32 65% 14% 6% 12% 44% 56%
Without Cirrhosis
Total 1,031 (36%)
61/39 63% 15% 7% 11% 62%* 76%*
Steatosis Only
186 (18%)
59/41 59% 20% 6% 11% 64% 77%
Highlights from AASLD 2012
RESULTS
a Includes only patients with ALT>ULN at baseline. b HBeAg-positive patients only. c No anti-HBs observed.
Trend of NAFLD Related HCC 1993-2007
Nonalcoholic fatty liver disease without cirrhosis is an emergent
and independent risk factor of hepatocellular carcinoma
Rahman, R. M., et al. Abstract 97; AASLD 2012
1993-2007 Average Cases
per Year (N=2,863)
1993-2000 Average Cases
per Year (N=1,393)
2001-2007 Average Cases
per Year (N=1,470)
P value
NAFLD HCC with cirrhosis without Cirrhosis
191 122 69
174 123 51
210 122 88
<0.01 NS
<0.01
Steatosis Only 12 4 22 <0.01
CONCLUSIONS
• NAFLD HCC is significantly increasing over time
• NAFLD is independently associated with HCC without cirrhosis
• NAFLD HCC without cirrhosis is increasing more than NAFLD
HCC with cirrhosis
• Simple steatosis may be a significant risk factor of HCC without
NASH or cirrhosis
• Our data suggest unique underlying pathophysiology for
development of HCC in non-cirrhotic NAFLD
Highlights from AASLD 2012
Nonalcoholic fatty liver disease without cirrhosis is an emergent
and independent risk factor of hepatocellular carcinoma
Rahman, R. M., et al. Abstract 97; AASLD 2012
Association between statin use and
Nonalcoholic Fatty Liver Disease in a
population-based study
Edith M. Koehler, Catherine E. de Keyser, Jeoffrey N. Schouten, Bettina E. Hansen, Harry L. Janssen, Bruno H. Stricker
Highlights of AASLD 2012
NAFLD
Abstract #825, AASLD 2012
AIM
• To study the association of statin therapy with presence of
NAFLD, and elevated alanine aminotransferase (ALT)
concentrations in a large cross-sectional population-based study,
accounting for dose and duration of statin therapy and history of
cardiovascular disease (CVD).
Highlights from AASLD 2012
Association between statin use and Nonalcoholic Fatty Liver
Disease in a population-based study
Koehler, E. M., et al. Abstract 825; AASLD 2012
METHODS • Data acquired from the Rotterdam Study, a population-based
cohort study of elderly persons.
• Nonalcoholic fatty liver disease (NAFLD) defined as presence of
fatty liver at ultrasonography (US) in the absence of known
secondary causes of fatty liver.
• Data on statin prescription was derived from automated
pharmacies.
• We used logistic regression analysis, adjusting for age, gender,
dose of statin therapy, alcohol consumption, presence of
metabolic syndrome (use of serum lipid reducing agents was
excluded in 2 criteria) and history of CVD, to investigate the
association of (duration of) current and past statin use with
NAFLD and elevated ALT.
Highlights from AASLD 2012
Association between statin use and Nonalcoholic Fatty Liver
Disease in a population-based study
Koehler, E. M., et al. Abstract 825; AASLD 2012
Highlights from AASLD 2012
RESULTS
Association between statin use and Nonalcoholic Fatty Liver
Disease in a population-based study
Koehler, E. M., et al. Abstract 825; AASLD 2012
Total (n=2,578)
Statin users (n=990)
Non-statin users (n=1,588)
Age (years) 76.5±5.9 76.8±5.5 76.2±6.2
Gender, female (%) 60.2 57.3 62.0
Drinks weekly 3.7±3.8 3.6±3.7 3.8±3.8
Metabolic syndrome (%) 40.1 52.5 33.8
Serum ALT (U/L) 20.3±10.7 21.6±11.3 19.5±10.2
History of CVD (%) 9.3 20.5 2.3
Baseline characteristics according to (ever) use of statin therapy
Highlights from AASLD 2012
RESULTS
Association between statin use and Nonalcoholic Fatty Liver
Disease in a population-based study
Koehler, E. M., et al. Abstract 825; AASLD 2012
OR (95% CI) P value
Full Model
Never Use ref -
>730 days past use 1.14 (0.81-1.59) 0.5
1-730 days past use 1.22 (0.85-1.73) 0.3
1-183 days current use 0.91 (0.61-1.35) 0.6
184-365 days current use 0.98 (0.62-1.55) 0.9
>365 days current use 0.77 (0.47-1.25) 0.2
Logistic regression: the association between use of statin
therapy and presence of NAFLD
Highlights from AASLD 2012
RESULTS
Association between statin use and Nonalcoholic Fatty Liver
Disease in a population-based study
Koehler, E. M., et al. Abstract 825; AASLD 2012
OR (95% CI) P value
Full Model
Never Use ref -
>730 days past use 1.28 (0.70-2.34) 0.4
1-730 days past use 1.68 (0.96-2.96) 0.1
1-183 days current use 1.51 (0.77-2.98) 0.2
184-365 days current use 1.16 (0.51-2.64) 0.7
>365 days current use 1.00 (0.41-2.43) 0.9
Logistic regression: the association between use of statin
therapy and elevation of ALT
CONCLUSIONS
• In this cross-sectional population-based study of elderly
persons, current use of statin therapy was associated with a
lower prevalence of NAFLD.
• Both past and current use of statin therapy was not
associated with elevated serum ALT concentrations.
• These findings suggest that statin therapy is safe in NAFLD,
and use of statins may have a beneficial effect on NAFLD.
Highlights from AASLD 2012
Association between statin use and Nonalcoholic Fatty Liver
Disease in a population-based study
Koehler, E. M., et al. Abstract 825; AASLD 2012
Long-Term Mortality Outcome of Metabolically
Normal Individuals with Non Alcoholic Fatty
Liver Disease (NAFLD)
Zobair M. Younossi, Munkhzul Otgonsuren, Chapy Venkatesan, Alita Mishra, Fatema Nader
Highlights of AASLD 2012
NAFLD
Abstract #1472, AASLD 2012
BACKGROUND • Non-alcoholic fatty liver disease (NAFLD) is an important cause
of chronic liver disease and is strongly associated with metabolic
syndrome (MetSynd).
• The long-term outcome for NAFLD patients remains
controversial
AIM • The goal of this study is to determine the long-term outcome of
NAFLD patients based on the presence or absence of
components of MetSynd in the U.S. population.
Highlights from AASLD 2012
Long-Term Mortality Outcome of Metabolically Normal Individuals
with Non Alcoholic Fatty Liver Disease (NAFLD)
Younossi, Z. M., et al. Abstract 1472; AASLD 2012
METHODS • Data were obtained from the National Health and Nutrition Survey
(NHANES) III; 6,709 participants, 64% males, 76% white, 8% black,
16% other ethnicities, ages 20-74.
• NAFLD was defined as significant steatosis on hepatic ultrasound and
exclusion of other chronic liver diseases (N=1,448). Patients were
classified as metabolically normal vs. abnormal. Mortality in this cohort
(N=377) was determined through December 31, 2006.
• Laboratory profiles, body measurement examinations, and mortality
data were linked to self-reported questionnaires of demographic and
health risk information.
• Cox models were used to estimate hazard ratios and 95% confidence
intervals for all-cause, cardiovascular and liver-specific mortality
differences between metabolically abnormal and metabolically normal
cohorts.
Highlights from AASLD 2012
Long-Term Mortality Outcome of Metabolically Normal Individuals
with Non Alcoholic Fatty Liver Disease (NAFLD)
Younossi, Z. M., et al. Abstract 1472; AASLD 2012
Highlights from AASLD 2012
Long-Term Mortality Outcome of Metabolically Normal Individuals
with Non Alcoholic Fatty Liver Disease (NAFLD)
Younossi, Z. M., et al. Abstract 1472; AASLD 2012
• The study cohort included 1,448 (22%) NAFLD participants: of those
1,243 (79%) had MetSynd, 305 (21%) did not have metabolic syndrome
(MetSynd).
• NAFLD patients with MetSynd were 10 yrs older, less likely to be black,
and more likely to have DM, IR, hypertension, and central obesity than
metabolically normal NAFLD patients.
• The risk for liver-specific mortality was independently associated with
obesity, having the diagnosis of MetSynd, and elevated liver enzymes.
• The risk of cardiovascular mortality was independently associated with
older age and the diagnosis of NAFLD with MetSynd.
• In comparison to individuals without liver disease, metabolically normal
NAFLD patients showed no difference in all-cause, liver-related, or
cardiovascular mortality.
RESULTS
Long-Term Mortality Outcome of Metabolically Normal Individuals
with Non Alcoholic Fatty Liver Disease (NAFLD)
Younossi, Z. M., et al. Abstract 1472; AASLD 2012
Factors Factors HR (95% CI)
OVERALL Age (years) 1.07 (1.06-1.09)
Metabolic syndrome 2.16 (1.15-4.03)
Race Black Other
1.42 (1.04-1.95) 0.37 (0.12-1.12)
Smoking status Never Current Former
Reference 54.66 (25.44-117.43)
1.24 (0.77-2.01)
WHITE Person-Years 19,728
Number of deaths 288
Age 1.08 (1.07-1.10)
Metabolic syndrome 2.57 (1.24-5.32)
BLACK Person-Years 8,382
Number of deaths 77
Age 1.07 (1.06-1.09)
Male 2.16 (1.15-4.03)
Factors associated with overall mortality in NAFLD
CONCLUSIONS • Diagnosis of having metabolic syndrome and NAFLD is an
independent predictor of all-cause, liver-specific, and
cardiovascular mortality.
• In contrast, mortality of metabolically normal NAFLD patients is
similar to the cohort without liver disease.
Highlights from AASLD 2012
Long-Term Mortality Outcome of Metabolically Normal Individuals
with Non Alcoholic Fatty Liver Disease (NAFLD)
Younossi, Z. M., et al. Abstract 1472; AASLD 2012
Dietary changes in patients with non-alcoholic
fatty liver disease are independently
associated with improvement in liver function
tests
Francisco Barrera, Jacob George, David van der Poorten, Alexis St. George
Highlights of AASLD 2012
NAFLD
Abstract #1484, AASLD 2012
BACKGROUND • Non-alcoholic fatty liver disease (NAFLD) is the hepatic
manifestation of the metabolic syndrome.
• Clinical and laboratory data support the role of dietary
interventions for treating NAFLD).
• However, the specific dietary modifications that benefit these
patients have not been thoroughly examined.
AIM • To investigate the relationship between changes in diet and
improvement in liver function tests in NAFLD subjects
participating in a lifestyle intervention program.
Highlights from AASLD 2012
Dietary changes in patients with NAFLD are independently
associated with improvement in liver function tests
Barrera, F., et al. Abstract 1484; AASLD 2012
METHODS
• Data was analyzed from 106 NAFLD patients with abnormal liver
enzymes who participated in a 3 month lifestyle intervention.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST),
gamma glutamyl transpeptidase (GGT), and 3 day food records at
baseline, 3 and 6 months were analyzed.
• Pearson correlation analysis between changes in diet and liver enzymes
were undertaken at 3 and 6 months adjusted for weight and total
physical activity change. Dietary changes with significant correlations at
p <0.1 were included in multi-linear regression analysis.
Highlights from AASLD 2012
Dietary changes in patients with NAFLD are independently
associated with improvement in liver function tests
Barrera, F., et al. Abstract 1484; AASLD 2012
Independent associations between changes in diet and liver
function tests
Dietary changes in patients with NAFLD are independently
associated with improvement in liver function tests
Barrera, F., et al. Abstract 1484; AASLD 2012
A
LT
at
6 M
(% r
esp
ect
of b
ase
line)
100
50
0
-50
-100-300 -200
Carbohydrate intake at 3 m (g/day)
-100
r = 0.25
p = 0.02
0 100
A
100
50
0
-50
-100-30 -20 -10
Carbohydrate intake at 6 m
(% of total kjle per day)
0
r = 0.39
p = 0.01
10 20 30
C
100
50
0
-50
-100-10 -5
PUFA intake at 3 m
(%of total kjle per day)
0 5
r = -0.24
p = 0.02
10 15
B
GG
T a
t 6 m
(%
)
100
50
0
-50
-100-60 -40 -20
MUFA Intake at 6 m (g/day)
0
r = -0.32
p = 0.01
20 40
D
AS
T a
t 6 M
(% o
f b
ase
line
)
200
150
100
50
0
-50
-100-30 -20 -10
Carbohydrate intake at 6m
(% of total kjle per day)
0
r = 0.26
p = 0.03
2010 30
E
% %
Highlights from AASLD 2012
Dietary changes in patients with NAFLD are independently
associated with improvement in liver function tests
Barrera, F., et al. Abstract 1484; AASLD 2012
β 95% CI P value
Change of GGT at 3 months follow up Carbohydrate intake (gr/d) PUFA intake (% of total kjle per day)
0.2
-0.19
0.03
0.006
0.03 0.04
Change of GGT at 6 month follow up Carbohydrate intake (% of total kjle per day)
0.42
0.347
0.001
Change of ALT at 6 month follow up Carbohydrate intake (% of total kjle per day)
0.31
0.531
0.01
Change of AST at 6 month follow up MUFA intake (gr/day)
-0.33
0.3
0.01
Multivariate analysis correlates dietary changes with
improvement in metabolic parameters and liver function tests.
GGT, gamma glutamyl transpeptidase, ALT, alanine aminotransferase , AST, aspartate aminotransferase (AST), MUFA, monounsaturated fatty acid.
CONCLUSIONS
• Specific dietary modifications were associated with
improvements in liver tests independent of physical activity and
weight loss changes.
• Decreases in carbohydrate intake and increases in PUFA intake
were independently associated with a reduction of GGT at 3
months.
• Decreases in carbohydrate and increases in MUFA intake were
independently associated with a decrease in ALT and AST
respectively at 6 months.
• These reports are important for the future development of
specific dietary recommendations for the treatment of NAFLD.
Highlights from AASLD 2012
Dietary changes in patients with NAFLD are independently
associated with improvement in liver function tests
Barrera, F., et al. Abstract 1484; AASLD 2012
Non-alcoholic fatty liver disease (NAFLD)
influences on cardiovascular disease:
Meta-analysis
Javier Ampuero, Rocío Gallego-Durán, Manuel Romero-Gómez
Highlights of AASLD 2012
NAFLD
Abstract #1485, AASLD 2012
AIM • To perform a meta-analysis to evaluate the influence of NAFLD in the
promotion of subclinical cardiovascular disease.
METHODS • We reviewed and identified studies in Pubmed and EMBASE to
September 2012. According to inclusion and exclusion criteria, we
selected 15 studies which were classified in 2 subgroups.
• NAFLD was evaluated by ultrasound in all studies. To assess subclinical
atherosclerosis, we selected studies (6) with carotid intima-media
thickness (CIMT), and to determine CVD, we selected studies (9) with
ischaemic heart disease.
• The random effect model of der Simonian and Laird method were used
for heterogeneous studies using the Meta-Disc 1.4 software, Madrid
Spain.
Highlights from AASLD 2012
Non-alcoholic fatty liver disease (NAFLD) influences on
cardiovascular disease: Meta-analysis
Ampuero, J., et al. Abstract 1485; AASLD 2012
Highlights from AASLD 2012
Non-alcoholic fatty liver disease (NAFLD) influences on
cardiovascular disease: Meta-analysis
Ampuero, J., et al. Abstract 1485; AASLD 2012
RESULTS
• In the subclinical atherosclerosis group (6 studies, 1599
patients), data analysis showed subjects with NAFLD presented
34% (282/832) of subclinical atherosclerosis; in patients without
NAFLD, it was detected in 19.3% (148/767), with odds ratio 2.15
(95% CI: 1.69-2.73).
• In the CVD subgroup (9 studies, 25,658 patients), subjects with
NAFLD presented 19.8% (1,594/8,065) of CVH, while in patients
without NAFLD, CVD was detected in 8.15% (1,433/17,593),
with odds ratio 2.99 (95% CI: 1.95-4.60).
CONCLUSIONS
• NAFLD increases the risk of subclinical atherosclerosis and
cardiovascular disease.
• This result provides a new dimension in clinical practice, as the
correct management of this kind of patients will enable to modify
the natural history both non-alcoholic fatty liver disease and
cardiovascular disease.
Highlights from AASLD 2012
Non-alcoholic fatty liver disease (NAFLD) influences on
cardiovascular disease: Meta-analysis
Ampuero, J., et al. Abstract 1485; AASLD 2012
Hypovitaminosis D associated with more
advanced non-alcoholic fatty liver disease
Jaividhya Dasarathy, Pranav Periyalwar, Sanath Allampati, Carol A. Hawkins, Patricia T. Brandt, Amer Khiyami, Arthur J. McCullough , Srinivasan Dasarathy
Highlights of AASLD 2012
NAFLD
Abstract #1486, AASLD 2012
BACKGROUND • Non Alcoholic Fatty Liver Disease (NAFLD) is the most common form of
liver disease. One of the nutritional abnormalities recognized in these
patients is hypovitaminosis D.
• Animal studies have suggested that hypovitaminosis D results in more
advanced forms of NAFLD.
• Hypovitaminosis D is also common in obesity and is believed to
contribute to insulin resistance: an important underlying factor in the
pathophysiology of NAFLD.
AIM • We therefore performed a prospective study to determine the
associations among plasma vitamin D concentration, severity of disease
in NAFLD and body composition
Highlights from AASLD 2012
Hypovitaminosis D associated with more advanced non-alcoholic
fatty liver disease
Dasarathy, J., et al. Abstract 1486; AASLD 2012
METHODS
• Plasma concentrations of vitamin D3 were quantified in 87
biopsy proven patients with NAFLD:51 patients with NASH and
36 subjects with hepatic steatosis alone.
• Healthy subjects (n=32) without disease formed the control
group.
• Body composition was quantified by bioelectrical impedance
analysis.
Highlights from AASLD 2012
Hypovitaminosis D associated with more advanced non-alcoholic
fatty liver disease
Dasarathy, J., et al. Abstract 1486; AASLD 2012
Highlights from AASLD 2012
RESULTS • Plasma vitamin D3 concentration were significantly lower in NAFLD
(24.0±10.7 ng/ml) compared to healthy controls (28.3±10.6 ng/ml).
• Higher NAFLD activity scores were associated with lower plasma
concentration of vitamin D3. Subgroup analysis amongst patients with
NAFLD showed that patients with NASH had significantly lower vitamin D3
levels than those with steatosis alone (21.9±9.0 vs. 26.9±12.2 ng/ml).
• Low concentrations of vitamin D were associated with greater severity of
steatosis, hepatocyte ballooning and fibrosis (p<0.05). Although body fat
mass was inversely correlated (p=0.008) with vitamin D concentration, on
multivariate regression analysis, severity of hepatic steatosis (p=0.01) and
inflammation (p=0.04) were independently associated with low vitamin D
concentrations.
• Plasma vitamin D (p=0.002) and insulin concentrations (p=0.048) were
independent predictors of the NAFLD activity score on biopsy.
Hypovitaminosis D associated with more advanced non-alcoholic
fatty liver disease
Dasarathy, J., et al. Abstract 1486; AASLD 2012
CONCLUSIONS
• Plasma vitamin D3 concentration were significantly lower in
NAFLD and correlated inversely with severity of liver disease.
• Subjects with NAFLD had significantly higher whole body fat
mass and fat/fat free mass ratios compared to controls.
• Whole body fat mass correlated inversely with plasma vitamin
D3 concentration in both NAFLD and control patients.
• Routine screening for hypovitaminosis D3 supplementation in
NAFLD and replacement therapy should form part of good
clinical practice and standard of care.
Highlights from AASLD 2012
Hypovitaminosis D associated with more advanced non-alcoholic
fatty liver disease
Dasarathy, J., et al. Abstract 1486; AASLD 2012
The natural history of nonalcoholic fatty liver
disease in children and adolescents assessed
in placebo recipients in the TONIC trial
Joel E. Lavine, Katherine P. Yates, Elizabeth M. Brunt, David E. Kleiner, Jeffrey B. Schwimmer, Karen F. Murray, Jean P. Molleston, Stephanie H. Abrams, Philip
Rosenthal, Rohit Loomba, Aynur Unalp, James Tonascia
Highlights of AASLD 2012
NAFLD
Abstract #1520, AASLD 2012
BACKGROUND • Nonalcoholic fatty liver disease is the most prevalent chronic pediatric
liver disease.
• Very little is published on the natural history of NAFLD in children and
adolescents. Given the increased genetic and environmental penetrance
likely associated with early onset, factors influencing consequence and
rate of progression need to be identified.
• The placebo arm of the NASK CRN TONIC trial offers a unique
opportunity to study the histological disease progression using repeat
biopsies in a cohort of children provided uniform standard of care (SOC).
AIM • This study characterizes placebo subjects in the “Treatment of NAFLD in
Children” (TONIC) trial, assessing factors associated with histological
and clinical improvement and worsening (JAMA 2011; 305:1659-68).
Highlights from AASLD 2012
The natural history of nonalcoholic fatty liver disease in children
and adolescents assessed in placebo recipients in the TONIC trial
Lavine, J., et al. Abstract 1520; AASLD 2012
METHODS
• The cohort consisted of 58 subjects ages 8-17 years with biopsy-proven
NAFLD.
• Assessments included changes in histology in relation to age, gender,
race, and changes in BMI z-score, insulin resistance, body composition,
diet, activity and routine laboratory assessments in children provided
uniform, standard-of-care advice on lifestyle.
• BMI z-scores were based on the sex-specific 2000 CDC population
reference curves.
Highlights from AASLD 2012
The natural history of nonalcoholic fatty liver disease in children
and adolescents assessed in placebo recipients in the TONIC trial
Lavine, J., et al. Abstract 1520; AASLD 2012
RESULTS
• Of 58 enrollees, 47 underwent repeat liver biopsy at 96 weeks. Of these
47, 8 initially had NAFLD without NASH, 22 borderline NASH and 17
definite NASH with a NAFLD Activity Score (NAS) mean of 4.6.
• Only 26% of children with NAFLD had a histological response (NAS
decrement of ≥2 with no worsening of fibrosis) after 96 weeks of SOC
treatment.
• Responders had greater decreases in ALT and AST levels and
improved insulin resistance as measured by HOMA-IR. The most
significant association with change in NAS was change in BMI z-score
(p=0.001).
Highlights from AASLD 2012
The natural history of nonalcoholic fatty liver disease in children
and adolescents assessed in placebo recipients in the TONIC trial
Lavine, J., et al. Abstract 1520; AASLD 2012
RESULTS (cont’d)
• Resolution of NASH was found in 28% and improvement in steatosis,
inflammation and ballooning in 40%, 43% and 21%, respectively.
Forty% had an improvement in fibrosis by at least one point and 26%
had worsening; none developed cirrhosis.
• Factors associated with improvement in fibrosis stage were non-white
race (white versus non-white, p=0.02), lower baseline BMI z-score (≥2.5
versus <2.5, p=0.06) and lower baseline serum LDL-cholesterol.
• Five of the 58 children developed diabetes and these 5 had significantly
higher baseline BMI z-scores (≥2.5 vs. <2.5, p=0.04), higher baseline
HbA1c levels (5.6% vs. 5.2%, p=0.01) and higher baseline ballooning
scores (1.7 vs. 0.7, p=0.02).
Highlights from AASLD 2012
The natural history of nonalcoholic fatty liver disease in children
and adolescents assessed in placebo recipients in the TONIC trial
Lavine, J., et al. Abstract 1520; AASLD 2012
CONCLUSIONS
• About one-quarter of children with NAFLD demonstrated histological
response and resolution of NASH with standard-of-care management.
Those with lower BMI z-score at baseline and decrease in scores during
follow-up were more likely to demonstrate “response” and diminished
fibrosis stage. Responders demonstrated larger decrements in serum
aminotransferases, HOMA-IR, alkaline phosphatase and BMI z-score
over the study interval. The incidence of diabetes in 10% of this cohort
suggests that children with NASH should be followed closely for this
problem.
Highlights from AASLD 2012
The natural history of nonalcoholic fatty liver disease in children
and adolescents assessed in placebo recipients in the TONIC trial
Lavine, J., et al. Abstract 1520; AASLD 2012
Factors Predict Normal Histology in Patients
at High Risk for Non-Alcoholic Fatty Liver
Disease
Kathleen E. Corey, Joseph Misdraji, Hui Zheng, Kyle Malecki, Jacob Kneeman, Louis G. Gelrud, Raymond T. Chung
Highlights of AASLD 2012
NAFLD
Abstract #1524, AASLD 2012
BACKGROUND
• Non-alcoholic fatty liver disease (NAFLD) is the most common cause of
liver disease in the United States.
• NAFLD is associated with increased all cause mortality.
• No screening guidelines for NAFLD exist.
AIM
• This study was designed to identify predictors of normal liver histology in
a high risk population to guide future screening.
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
METHODS
• Patients undergoing weight loss surgery at Bon Secours Healthcare in
Richmond, Virginia, from August 2009 through July 2011 were included.
• Exclusion criteria: patients with other chronic liver disease (assessed by
viral serologies, autoimmune markers, iron studies and liver biopsy),
with excess alcohol use (defined as >2 drinks per day for men and >1
drink per day for women).
• All subjects underwent liver biopsy at the time of weight loss surgery;
reviewed by a single blinded pathologist (JM) and scored according to
the NASH CRN scoring system.
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
• 159 patients were included in the study.
• Forty nine patients (30.8%) had normal liver histology, while 110
patients met criteria for NAFLD.
• Liver histology characteristics for NAFLD group:
Study Population Clinical Characteristics
NAFLD (n=110) n, (%)
Fibrosis stage 0 1 2 3 4
51 (46.8) 46 (42.4)
8 (7.3) 1 (0.9) 3 (2.8)
NASH Activity Score 0-2 3-4 5-8
45 (46.3) 35 (32.4) 28 (25.9)
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
Normal NAFLD P Value
Mean ALT, Units/mL (SD) 16.9 (7.9) 28.3 (27.1) 0.0042
Mean glucose, mg/dL (SD) 105.8 (35.3) 126.1 (41.1) 0.004
Mean insulin, µU/mL (SD) 20.8 (15.1) 32.4 (29.0) 0.01
HOMA-IR, (SD) 2.5 (1.6) 3.5 (1.7) 0.001
C Reactive Protein (SD) 1.1 (0.96) 1.0 (0.75) 0.64
Mean Total Cholesterol, mg/dL 170.6 (32.7) 161.3 (40.2) 0.16
Mean HDL, mg/dL 49.5 (14.5) 42.3 (11.1) 0.009
Mean LDL, mg/dL 98.2 (24.3) 94.2 (32.7) 0.45
Mean Triglycerides, mg/dL 114.6 (64.8) 133.4 (90.2) 0.19
Mean Non-HDL Cholesterol, mg/dL 121.1 (30.4) 119.0 (36.5) 0.73
Metabolic Characteristics of Patients with Normal
Histology and NAFLD
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
• Absence of obstructive sleep apnea - OR of 5.6 (95% CI 2.0-16.1)
• Black race - OR of 6.8 (95% CI 2.4-18.9)
• Low HOMA-IR – OR of 1.4 (95% CI 1.03-1.9)
• Low ALT – OR of 1.4 (95% CI 1.01-1.1)
• Low HDL was associated with decreased likelihood of normal liver
histology - OR of 0.38 (95% CI 0.05-0.83)
Factors that Predicted Absence of NAFLD
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
• Race, obstructive sleep apnea, HOMA-IR, and ALT predicted the presence of
normal histology with an area under the ROC curve of 0.85
• Addition of diabetes mellitus, glucose, insulin, age, gender, the presence of
hyperlipidemia or HDL did not improve this model.
• Our predictive score is: Healthy Liver Score=
1.8 (race) – 1.8 (sleep apnea) – 0.35 (HOMA-IR) – 0.05 (ALT) + 1.5
• The Healthy Liver Score ranged from -12 to 3 in our cohort
Score to Predict Normal Histology
NAFLD Histology Normal Histology -12 3 0
• A score of ≥0 maximized the combined sensitivity and specificity for predicting
normal liver histology (sensitivity 59.5%; specificity, 92.7%).
• High specificity minimizes the risk of falsely predicting normal liver histology,
suggesting it’s value as a tool to refer patients for NAFLD screening.
CONCLUSIONS
• Our study identified a new factor associated with normal histology in a
group at high risk for NAFLD: absence of OSA
• Our study confirmed previously identified factors protective against the
development of NAFLD, including: black race, low HOMA-IR, low ALT.
• The identification of protective factors offers a unique insight into the
forces that ameliorate or modulate the driving forces underlying NAFLD.
• Identification of the mediators of protection in time could lead to rational
approaches to prevention or treatment of patients at high risk for
NAFLD.
Highlights from AASLD 2012
Factors Predict Normal Histology in Patients at High Risk for Non-
Alcoholic Fatty Liver Disease
Corey, K.E., et al. Abstract 1524; AASLD 2012
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