Dr Jonathan Stenner

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

What is fatty liver? Histopathological

Accumulation of fat in the liver > 5-10% of total liver weight In clinical practice

Abnormal LFTS Fatty liver on USS (not present if steatosis < 33%)

What does Non- alcoholic mean? Daily alcohol consumption of < 20g/day 1 unit alcohol = 8g

Type of Study Country Prevalence NAFLD% Prevalence of NASH%

Autopsy Sweden 24 NR

Hospital LB SwedenSpain

39NR

NR16

Hospital Imaging Romania 20 NR

Outpatients Imaging ItalyItaly

5320

NRNR

General Population Imaging

ItalyGermany

Spain

233623

NRNRNR

Bariatric Surgery BelgiumItaly

France

7478NR

NR2714

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

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

Data from Mediplus practices

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

Obese (36-78%) Diabetes Mellitus (43-62%) Patients with hyperlipidaemia (50%) Hypertension (30%) Metabolic Syndrome (50-83%) Insulin Resistance (80%)

Suspect the diagnosis Diabetic Metabolic syndrome BMI > 30

Incidental finding of “bright liver on USS” > 33% steatosis

Abnormal LFTs Mildly elevated ALT GGT often isolated elevation

Patients at risk to develop NASH with fibrosis:

A. Age > 45

B. Obesity (BMI > 31-32)

C. Diabetes

1. 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/mlFaster progression to advanced fibrosis BMI > 30 Type 2 Diabetes Mellitus

Matteoni et al 1999

1. Peripheral stigmata of chronic liver disease

2. Splenomegaly

3. Cytopaenia

4. Abnormal iron studies

5. Diabetes and/or significant obesity in an individual over the age of 45

Argo CK, J Hepatol 2009

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

HIGH RISK OF FIBROSIS

Age>45 DM or Obese

AST:ALT > 1

Platelets < 150

LOW RISK OF FIBROSIS

No risk factors

Age < 45

BMI <30

With AST:ALT < 1

LIVER BIOPSY

Cirrhosis

Bridging fibrosis

NASH

Mild fibrosis

Bland Steatosis

PRIMARY CARE

Management of BP

Rx Hyperlipidaemia

Yearly screening AST/ALT

ALT>100

Ferritin > 400

2 occasions 3 months apart

Platelets

Standard Follow up Secondary Care HCC screening varices follow up etc

Abnormal

? Screening bloods and USS organised prior to referral

Insulin resistance

↑ Fatty acids

Steatosis

Lipid peroxidation

NASH

CytoprotectantsInsulin Sensitizers

Antihyperlipidemics

First HitSecond Hit

Weight Loss

Diet/Exercise

Antioxidants

How to Treat?

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

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 .

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

Metformin

Non significant improvement in inflammatory markers

No improvement in histological scoring

?transient in effect.

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

Laurin et al. Hepatology 1996- Clofibrate-No significant improvement in ALT or histologyBasaranoglu 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

Lewis 2007

<Upper limit normal

>x1

>x2

>x1 >x2<ULN

BASELINE ALT POSTBASELINE ALT (week 12)

56 6 1

14 33 9

1 9 5

P=0.78

No differences in baseline ALT values between groups

58

12

1

8

38

9

1

7

9

Patients with Pravastatin

Patients with Placebo

Cohort 1 (elevated baseline LFT + statins)

Cohort 2 (normal LFT + statins)

Cohort 3 (elevated LFT without statins)

4.7%

Moderate elevation

Severe elevation

0.6%

1.9% 0.2%

6.4% 0.4%NS

NS

NS

P=0.002

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

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

Insulin resistance

↑ Fatty acids

Steatosis

Lipid peroxidation

NASH

CytoprotectantsInsulin Sensitizers

Antihyperlipidemics

First HitSecond Hit

Weight Loss

Diet/Exercise

Antioxidants

How to Treat?

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

Betaine Losartan Pentoxifylline Orlistat

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

Vitamin E

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

Sanyal et al NEJM 2010

Sanyal et al NEJM 2010

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!!!

Alcohol-use disorders: preventing harmful

drinkingWorkshop on putting NICE guidance

into practice

June 2010

NICE public health guidance 24

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

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

ScreeningAUDIT – C

For people aged 16 years and over

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

Alcohol-use disorders: physical complications

Implementing NICE guidance

June 2010

NICE clinical guideline 100

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.

Acute alcohol withdrawal: 1

Alcohol-use disorders: diagnosis, assessment and

management of harmful drinking and alcohol dependence

Implementing NICE guidance

February 2011

NICE clinical guideline 115

EpidemiologyWeekly 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