Dr Jonathan Stenner

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• Dr Jonathan Stenner

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• Alcoholic fatty liver
• Non Alcoholic fatty liver
• Primary
• Associated with metabolic syndrome
• Secondary
• Drugs Steroids, Amiodarone, Tamoxifen
• Metabolic/ Genetic Lipodystrophies
• Nutritional TPN, Rapid weight loss
• Small bowel disease- IBD, Bacterial overgrowth
• Environmental - petrochemicals

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• What is fatty liver?
• Histopathological
• Accumulation of fat in the liver gt 5-10 of total
  liver weight
• In clinical practice
• Abnormal LFTS
• Fatty liver on USS (not present if steatosis lt
  33)
• What does Non- alcoholic mean?
• Daily alcohol consumption of lt 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 (n103
  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
• 20-30 of general public have NAFLD
• Of whom 10-25 may have NASH
• 2-10 of these patients may be at risk of
  progressive liver fibrosis, cirrhosis and HCC

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Data from Mediplus practices
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• Prevalence of NAFLD is similar in adults with
  (25) and WITHOUT abnormalities of liver enzymes)
• 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)

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• Suspect the diagnosis
• Diabetic
• Metabolic syndrome
• BMI gt 30
• Incidental finding of bright liver on USS
• gt 33 steatosis
• Abnormal LFTs
• Mildly elevated ALT
• GGT often isolated elevation

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• Patients at risk to develop NASH with fibrosis
• A. Age gt 45
• B. Obesity (BMI gt 31-32)
• C. Diabetes

1. Angulo et al. Independent predictors of liver
   fibrosis in patients with NASH. Hepatology.
   2000 30 1356-1362.

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• Risk factors for advanced fibrosis at baseline
• ALT gt 100 IU/ml
• ASTALT ratio gt 1.0
• Platelet count lt 150 x 109/ml
• Faster progression to advanced fibrosis
• BMI gt 30
• Type 2 Diabetes Mellitus

Matteoni et al 1999
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• Peripheral stigmata of chronic liver disease
• Splenomegaly
• Cytopaenia
• Abnormal iron studies
• Diabetes and/or significant obesity in an
  individual over the age of 45

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Argo CK, J Hepatol 2009
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Abn LFTs Suspicion of NAFLD Fatty liver on USS
LIVER OPD 1 History and exam Bloods USS
LIVER OPD 2 Diagnosis NAFLD Risk Factor assessed
? Screening bloods and USS organised prior to
referral
HIGH RISK OF FIBROSIS Agegt45 DM or Obese ASTALT
gt 1 Platelets lt 150
LOW RISK OF FIBROSIS No risk factors Age lt 45 BMI
lt30 With ASTALT lt 1
PRIMARY CARE Management of BP Rx
Hyperlipidaemia Yearly screening
AST/ALT ALTgt100 Ferritin gt 400 2 occasions 3
months apart Platelets
Abnormal
LIVER BIOPSY
NASH Mild fibrosis
Cirrhosis Bridging fibrosis
Bland Steatosis
Standard Follow up
Secondary Care HCC screening varices follow up etc
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How to Treat?
Antioxidants
Insulin Sensitizers
Cytoprotectants
Antihyperlipidemics
Second Hit
First Hit
Steatosis
NASH
Insulin resistance ? Fatty acids
Lipid peroxidation
Weight Loss Diet/Exercise
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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
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• Palmer et al. Gastroenterology 1990
• --39 obese patients, no primary liver disease
• --Retrospective analysis after weight loss
• --Lower ALT seen in patients with gt10 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 .

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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
• No improvement in histological scoring
• ?transient in effect.

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• Rosiglitazone (FLIRT-1 and FLIRT-2)
• 1 year RCT
• 47 in Rosi group improved steatosis, 16 placebo
• 38 normalised ALT in Rosi group vs 7 placebo
• Concerns about long term effects especilaly
  weight gain

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• 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

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Statins
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BASELINE ALT
POSTBASELINE ALT (week 12)
gtx1
gtx2
ltULN
ltUpper limit normal
56
6
1
58
8
1
P0.78
gtx1
14
33
9
12
38
7
gtx2
1
9
5
1
9
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Patients with Pravastatin Patients with Placebo
No differences in baseline ALT values between
groups
Lewis 2007
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Moderate elevation
Severe elevation
1.9
0.2
Cohort 2 (normal LFT statins)
NS
P0.002
Cohort 1 (elevated baseline LFT statins)
4.7
0.6
NS
NS
Cohort 3 (elevated LFT without statins)
6.4
0.4
In summary, individuals with elevated LFT do not
appear to have increased susceptibility to
hepatotoxicity from statins.
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• Measure baseline ALT/AST
• Start statin if AST/ALT lt 3 xULN
• Monitor AST/ALT at 6 and 12 weeks
• If AST/ALT lt 3 x ULN continue or dose advance
• If AST/ALT gt 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
Insulin Sensitizers
Cytoprotectants
Antihyperlipidemics
Second Hit
First Hit
Steatosis
NASH
Insulin resistance ? Fatty acids
Lipid peroxidation
Weight Loss Diet/Exercise
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• 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

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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
• No difference in adverse events amongst groups

Sanyal et al NEJM 2010
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Sanyal et al NEJM 2010
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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
• 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
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Background

• 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)
• 24 of adults drink a hazardous or harmful
  amount

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Screening
AUDIT CFor people aged 16 years and over

• Scoring A total of 5 indicates increasing or
  higher risk drinking.

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Summary

• Addresses recognising alcohol dependency
• Advice on brief intervention
• Criteria for specialist referral
• show signs of moderate or severe
  alcohol-dependence
• have failed to benefit from structured brief
  advice and an extended brief intervention and
  still want help
• show signs of severe alcohol-related impairment
  or have a related co-morbid condition

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Alcohol-use disorders physical complications
Implementing NICE guidance
June 2010
NICE clinical guideline 100
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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.

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Alcohol-use disorders diagnosis, assessment and
management of harmful drinking and alcohol
dependence
Implementing NICE guidance
February 2011
NICE clinical guideline 115
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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
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Background

• Current practice and service provision
  across the country is varied
• Only 6 per year of people aged 1665 years who
  are alcohol dependent receive treatment
• Comorbid mental and physical disorders are
  common.

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Assisted alcohol withdrawal
Person who drinks gt 15 units alcohol per day or
scores gt 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
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Thank you