Transcript Slide 1

Dr Jonathan Stenner
Alcoholic fatty liver
Non Alcoholic fatty liver
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Primary
 Associated with metabolic syndrome
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Secondary
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Drugs – Steroids, Amiodarone, Tamoxifen
Metabolic/ Genetic – Lipodystrophies
Nutritional – TPN, Rapid weight loss
Small bowel disease- IBD, Bacterial overgrowth
Environmental - petrochemicals
What is fatty liver?
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Histopathological
 Accumulation of fat in the liver > 5-10% of total liver weight
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In clinical practice
 Abnormal LFTS
 Fatty liver on USS (not present if steatosis < 33%)
What does Non- alcoholic mean?
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Daily alcohol consumption of < 20g/day
 1 unit alcohol = 8g
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Type of Study
Country
Prevalence NAFLD%
Prevalence of NASH%
Autopsy
Sweden
24
NR
Hospital LB
Sweden
Spain
39
NR
NR
16
Hospital Imaging
Romania
20
NR
Outpatients Imaging
Italy
Italy
53
20
NR
NR
General Population
Imaging
Italy
Germany
Spain
23
36
23
NR
NR
NR
Bariatric Surgery
Belgium
Italy
France
74
78
NR
NR
27
14
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Largely benign
Few good studies
Largest study of paired liver biopsies (n=103 mean
follow up 3.2 ±3 years)
37% progressed fibrosis stage
34% remained stable
29% regressed
Mean rate of fibrosis progression 0.09 stages/year
Adams et al J. Hep 2005
Fibrosis progression rate was highly variable
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Extrapolation of data in autopsy and liver biopsy
studies
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20-30 % of general public have NAFLD
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Of whom 10-25% may have NASH
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2-10% of these patients may be at risk of progressive
liver fibrosis, cirrhosis and HCC
Data from Mediplus practices
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Prevalence of NAFLD is similar in adults with
(25%) and WITHOUT abnormalities of liver
enzymes)
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50% of NAFLD cases will be missed if abnormal
LFTS are considered as a selection criteria
Bedogni et al Hepatology 2005
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Obese (36-78%)
Diabetes Mellitus (43-62%)
Patients with hyperlipidaemia (50%)
Hypertension (30%)
Metabolic Syndrome (50-83%)
Insulin Resistance (80%)
Suspect the diagnosis
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Diabetic
 Metabolic syndrome
 BMI > 30
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Incidental finding of “bright liver on USS”
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> 33% steatosis
Abnormal LFTs
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Mildly elevated ALT
 GGT often isolated elevation
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Patients at risk to develop NASH with fibrosis:
A. Age > 45
B. Obesity (BMI > 31-32)
C. Diabetes
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Angulo et al. Independent predictors of liver fibrosis in patients with NASH. Hepatology. 2000; 30: 1356-1362.
Risk factors for advanced fibrosis at baseline
 ALT > 100 IU/ml
 AST:ALT ratio > 1.0
 Platelet count < 150 x 109/ml
Faster progression to advanced fibrosis
 BMI > 30
 Type 2 Diabetes Mellitus
Matteoni et al 1999
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Peripheral stigmata of chronic liver disease
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Splenomegaly
3.
Cytopaenia
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Abnormal iron studies
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Diabetes and/or significant obesity in an individual
over the age of 45
Argo CK, J Hepatol 2009
Abn LFTs
LIVER OPD 1
LIVER OPD 2
Suspicion of NAFLD
History and exam
Diagnosis NAFLD
Fatty liver on USS
Bloods
Risk Factor assessed
USS
? Screening bloods
and USS organised
prior to referral
LOW RISK OF FIBROSIS
HIGH RISK OF FIBROSIS
No risk factors
Age>45 DM or Obese
PRIMARY CARE
Age < 45
AST:ALT > 1
Management of BP
BMI <30
Platelets < 150
Rx Hyperlipidaemia
With AST:ALT < 1
Yearly screening
AST/ALT
ALT>100
Abnormal
LIVER BIOPSY
Ferritin > 400
2 occasions 3 months
apart
Platelets
Standard Follow up
Bland Steatosis
NASH
Cirrhosis
Mild fibrosis
Bridging fibrosis
Secondary Care HCC screening
varices follow up etc
How to Treat?
Antioxidants
Cytoprotectants
Insulin Sensitizers
Antihyperlipidemics
First Hit
Steatosis
Insulin
resistance
↑ Fatty acids
Second
Hit
Lipid
peroxidation
Weight Loss
Diet/Exercise
NASH
348 male subjects with abn
ALT (other causes excluded)
Followed for 1 year after
health advice re exercise and
weight loss
Patients who normalised ALT
were followed for a further 2
years
Weight loss of 5% improved
ALT with OR 3.6 for ALT
normalisation
Maintainance of weight loss
OR 4.6 for ALT normalisation
Suzuki et al 2005
Palmer et al. Gastroenterology 1990
--39 obese patients, no primary liver disease
--Retrospective analysis after weight loss
--Lower ALT seen in patients with >10% weight loss
Anderson et al. Journal Hepatology 1991
--41 obese patients with biopsy-proven NAFLD
--Low calorie diet (~400 kcal/d)
--Most improved, but 24% worse fibrosis/inflammation
--Histological worsening associated with rapid weight loss
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Can lead to sustained improvement in liver
enzymes, histology, serum insulin levels, and
quality of life.
Improvement in steatosis following bariatric
surgery
Should not exceed approximately 1.6 kg per
week in adults .
Metformin
Marchesini et al. Lancet 2001
--20 patients, biopsy-proven NASH
--14 metformin (500 tid) x 4 months; 6 controls
--ALT & OGTT improved in metformin
Nair et al. AP& T 2004
--22 patients, biopsy-proven NASH
--Received metformin 20 mg/kg/d x 12 months
--Improvement in ALT & insulin sensitivity
--No improvement in liver histology
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Non significant improvement in inflammatory
markers
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No improvement in histological scoring
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?transient in effect.
Rosiglitazone (FLIRT-1 and FLIRT-2)
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1 year RCT
47% in Rosi group improved steatosis, 16% placebo
38% normalised ALT in Rosi group vs 7% placebo
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Concerns about long term effects especilaly weight
gain
Laurin et al. Hepatology 1996- Clofibrate
-No significant improvement in ALT or histology
Basaranoglu et al. J.Heptol 1999- Gemfibrozil
--74% patients in gemfibrozil group had lower ALT
--30% patients no treatment group had lower ALT
Naserimoghadam SSO - J Hepatol 2003
Probucol was associated with a significant reduction in
serum aminotransferases
No conclusive evidence of benefit
Statins
BASELINE ALT
POSTBASELINE ALT (week 12)
<ULN
<Upper limit normal
56
>x1
58
6
>x2
8
1
1
P=0.78
>x1
14
12
33
38
9
7
>x2
1
1
9
9
5
9
Patients with Pravastatin
Patients with Placebo
No differences in baseline ALT values between groups
Lewis 2007
Moderate
elevation
Cohort 2 (normal LFT + statins)
Severe
elevation
1.9%
0.2%
P=0.002
Cohort 1 (elevated baseline LFT + statins)
Cohort 3 (elevated LFT without statins)
4.7%
6.4%
NS
0.6%
NS
NS
0.4%
In summary, individuals with elevated LFT do not appear to have
increased susceptibility to hepatotoxicity from statins.
Measure baseline ALT/AST
Start statin if AST/ALT < 3 xULN
 Monitor AST/ALT at 6 and 12 weeks
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If AST/ALT < 3 x ULN continue or dose advance
 If AST/ALT > 3 x ULN recheck in 1 week if still
elevated then dose reduce or stop
 If AST/ALT return to baseline then continue lower
dose
 If stopped then rechallenge with lower dose of
another statin
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How to Treat?
Antioxidants
Cytoprotectants
Insulin Sensitizers
Antihyperlipidemics
First Hit
Steatosis
Insulin
resistance
↑ Fatty acids
Second
Hit
Lipid
peroxidation
Weight Loss
Diet/Exercise
NASH
Laurin et al. Hepatology 1996
--63% had improved ALT and steatosis
--No significant improvement in inflammation/fibrosis
Lindor et al. Hepatology 2004
--Randomized controlled double-blind study
--168 patients with biopsy-proven NASH
--No significant improvement in ALT or histology
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Betaine
Losartan
Pentoxifylline
Orlistat
Vitamin E
Hasegawa et al. Aliment Pharmacol Ther 2001
--22 patients, 10 steatosis and 12 biopsy-proven NASH
--6/12 standard diet followed by Vitamin E 100 IU tid x 12/12
--Steatosis group showed improvement in ALT after diet
--Improvement in ALT after Vitamin E
--40% NASH patients had histological improvement
Kugelmas et al. Hepatology 2003
--16 patients with biopsy-proven NASH followed for 3 mo
--9 received diet/exercise and Vitamin E 800 IU qd
--7 diet/exercise only
--Vitamin E conferred no significant improvement in ALT
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247 non diabetic patients RCT for 96 weeks
80
Pioglitazone 30 mg daily
84
Vitamin E 800 IU daily
83
Placebo
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No difference in adverse events amongst groups
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Sanyal et al NEJM 2010
Sanyal et al NEJM 2010
Sanyal et al NEJM 2010
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NAFLD is common, may be clinically silent, and
is likely to increase
NAFLD is a marker of metabolic syndrome and
increased risk of CV disease
Weight loss / exercise are the only proven
treatments-?role of bariatric surgery
Emerging evidence for antioxidants
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Other causes must be excluded!!!
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Alcohol-use disorders:
preventing harmful drinking
Workshop on putting NICE guidance
into practice
June 2010
NICE public health guidance 24
Background
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Alcohol is attributable for:
• 14,982 deaths in England (2005)
• 500,000 recorded crimes (England)
• up to 35% of attendances at hospital
emergency departments (2003)
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24% of adults drink a hazardous or harmful
amount
Screening
AUDIT – C
For people aged 16 years and over
• Scoring: A total of 5+ indicates increasing or higher risk drinking.
Summary
• Addresses recognising alcohol dependency
• Advice on “brief intervention”
• Criteria for specialist referral
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show signs of moderate or severe alcohol-dependence
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have failed to benefit from structured brief advice and
an extended brief intervention and still want help
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show signs of severe alcohol-related impairment
or have a related co-morbid condition
Alcohol-use disorders:
physical complications
Implementing NICE guidance
June 2010
NICE clinical guideline 100
Acute alcohol
withdrawal: 1
For people in acute alcohol withdrawal with,
or who are assessed to be at high risk of
developing, alcohol withdrawal seizures or
delirium tremens, offer admission to hospital
for medically assisted alcohol withdrawal.
Alcohol-use disorders:
diagnosis, assessment and
management of harmful drinking
and alcohol dependence
Implementing NICE guidance
February 2011
NICE clinical guideline 115
Epidemiology
Weekly alcohol consumption of more than 50 units (men) or more than
35 units (women) by age (years) and gender – Great Britain, 2009
Source: General Lifestyle Survey, Office for National Statistics
Background
• Current practice and service provision
across the country is varied
• Only 6% per year of people aged 16–65 years
who are alcohol dependent receive treatment
• Comorbid mental and physical disorders are
common.
Assisted alcohol withdrawal
Person who drinks > 15 units alcohol per
day or scores > 20 on AUDIT
Assessment
 Consider offering:
– assessment for and delivery of a community-based assisted withdrawal, or
– assessment and management in specialist alcohol services if there are safety
concerns about a community-based assisted withdrawal.
Community base assisted
withdrawal
Inpatient and residential
withdrawal
Intensive community programmes
after assisted withdrawal for severe
or mild to moderate dependence
with complex needs
Thank you