1. - Non-Alcoholic Fatty Liver Disease (NAFLD) - Hepatitis B
Hepatology Update
- Non-Alcoholic Fatty Liver Disease (NAFLD) - Hepatitis B
Dr Iain Ewing – Consultant Hepatologist
Dr Rob Palmer – GPwSI Gastro, CCG Gastro lead

2. Case
50y old man; known T2DM, hyperlipidaemia; DH: metformin, atorvastatin. BMI 31.
Attends nurse for routine bloods – results arrive in your inbox
HbA1c 6.7
Cholesterol 4.1
ALT 91
Bilirubin 12, ALP 90, AST 48, albumin 42, Plts 310

3. What would you do? Lifestyle advice and rpt in 3m Arrange USS
Arrange full liver screen
Stop statin
Other

5. NAFLD fatty liver  steatohepatitis  fibrosis  cirrhosis
Oxidative stress (imbalance between pro-oxidant and anti-oxidant chemicals that lead to liver cell damage)
Production and release of toxic inflammatory proteins (cytokines) by the patient’s own inflammatory cells, liver cells, or fat cells
Liver cell necrosis or death, called apoptosis
Adipose tissue (fat tissue) inflammation and infiltration by white blood cells
Gut microbiota (intestinal bacteria) which may play a role in liver inflammation

6. NAFLD - Epidemiology
Affects 20-30% of population (and the prevalence is increasing)
5-6% of these  fibrosis or cirrhosis.
5-10% of these will develop liver cancer
Predicted to become the leading cause of liver-related morbidity and mortality in the next 20yrs

7. Most of this is for alcohol, but NAFLD is catching up
Sheron 2010,

8. Projections for UK liver deaths
Lancet 2011

9. NAFLD - Diagnosis
Patients with ALL the following features can be reasonably diagnosed with NAFLD in primary care:
ALT 1-3 times upper limit normal (40 – 120)
Negative alcohol history
(<21units/week in men, <14units/week in women)
BMI >28 OR BMI<28 + any metabolic syndrome history (T2DM, hyperlipidaemia, hypertension)
Negative liver screen
(hepatitis B and C, autoimmune screen, ferritin)
Fatty liver on USS
Asymptomatic / otherwise well patient
Pathophysiology EtOH vs NAFLD

10. NAFLD - Diagnosis
The following are NOT typical – consider other diagnoses /specialist referral
ALT >3x Upper Limit Normal
BMI <28, no other metabolic syndrome history
Normal USS
ALP rise only abnormality
Any positivity on liver screen
Symptomatic patient
Hepatomegaly
The following can indicate advanced disease and specialist review is recommended:
Splenomegaly or presence of ascites on ultrasound
Low platelet count (even just below normal limits)
Low albumin (even just below normal limits)
Any features of chronic liver disease on examination

11. Is USS needed?
Definitive diagnosis of NAFLD requires evidence of excess fat in the liver, which may be seen on USS testing, or by liver biopsy.
BUT
The appearances of steatosis on U/S are operator-dependent and a normal ultrasound does not rule out NAFLD.
NICE does not recommend ultrasound routinely for patients who have evidence of the metabolic syndrome (T2DM, obesity, CVD, hypertension), and liver screening is otherwise normal, as there is a high probability of NAFLD.
Decision whether to perform USS on an individual case basis where there is concern about alternative diagnoses.
There’s another scan which I’ll come on to talk about in a moment

12. nafldscore.com NAFLD score (online tool): Low risk: < -1.455
predictor of absence of significant fibrosis. (negative predictive value of 88-93%) These patients can be managed in primary care
Intermediate risk: Score to 0.675:
High risk: Scores > 0.675
suggest a high risk of fibrosis (positive predictive value of 82%-90%).
(The result should be entered into EMIS Web using the term ‘NAFLD fibrosis score’)
Link on CEG template. Note need to request AST

13. NAFLD score Low score: manage in primary care
Intermediate score: elastography
Result to guide who needs referral
High score: refer to liver clinic

14. Elastography (Fibroscan)
Available on t-quest (NAFLD score mandatory)
refer to liver clinic if Mean Liver Stiffness >7.0kPa
Add-on to USS (USS liver will be done at the same time)

15. NAFLD Score examples
50y old man; known T2DM, hyperlipidaemia; DH: metformin, atorvastatin. BMI 31.
Attends nurse for routine bloods – results arrive in your inbox
HbA1c 6.7
Cholesterol 4.1
ALT 91
Bilirubin 12, ALP 90, AST 48, albumin 42, Plts 310

16. Other methods of assessing for fibrosis: ELF
NICE guidelines suggest to use Enhanced Liver Fibrosis (ELF) score
Includes : - hyaluronic acid (HA)
- amino-terminal propeptide of type III procollagen (PIIINP)
- tissue inhibitor of metalloproteinase 1 (TIMP-1)
Similar performance to NAFLD score
Not available at HUH lab (nearest = Royal Free/N.Midd)
Cost: £70-100
NAFLD score used by Barts Trust liver unit

17. CEG template – liver disease

18. NAFLD - Management Lifestyle measures Diet Weight loss Exercise
Manage metabolic syndrome

19. NAFLD - Management LIFESTYLE MEASURES 1. Diet Optimum diet unclear
Low in saturated fats, simple carbohydrates, sweetened drinks
600Kcal less than recommended intake/week
Aim for 0.5-1kg weight loss per week
Mediterranean diet (high in monounsaturates)
Mediterranean diet: 39% vs 7% reduction in steatosis (on MR spectroscopy), independent of weight
Eat: Vegetables, fruits, nuts, seeds, legumes, potatoes, whole grains, breads, herbs, spices, fish, seafood and extra virgin olive oil.
Eat in moderation: Poultry, eggs, cheese and yogurt.
Eat only rarely: Red meat.
Don't eat: Sugar-sweetened beverages, added sugars, processed meat, refined grains, refined oils and other highly processed foods.

20. NAFLD - Management LIFESTYLE MEASURES 2. Exercise 3. Weight loss
30mins moderate exercise 5x/week
3. Weight loss
0.6kg  20% remission in NAFLD
5.6kg  64% remission in NAFLD
Orlistat / Bariatric surgery: effective in treating NAFLD
Study: 12 week exercise programme – 45 mins per day - 48% reduction in ALT & AST

21. NAFLD - Management Optimal management of Metabolic syndrome T2DM:
assoc with faster progression to liver fibrosis
Hypertension
Hyperlipidaemia
Study: 12 week exercise programme – 45 mins per day - 48% reduction in ALT & AST

22. Should I stop statins? Continue…
UNLESS liver enzymes double within 3m of starting
(incl. in people with abnormal baseline LFTs)

23. NAFLD - Management Secondary care options 1) Pioglitazone 2) Vitamin E
in biopsy-proven NASH/fibrosis
Seldom used
1) Pioglitazone
47% vs 21% resolution of NASH vs placebo (1y)
But assoc with weight gain, ↑heart failure, bladder cancer, reduced bone density
2) Vitamin E
49% vs 19% improvement after 2y vs placebo
Increased risk of haemorrhagic stroke, Ca prostate
Study: 12 week exercise programme – 45 mins per day - 48% reduction in ALT & AST
DM: first line = metformin, 2nd line = pioglitazone

24. NAFLD – Following up / monitoring
EASL guidelines:
NAFLD (if no worsening of metabolic risk factors): follow-up every 2-3y (with NAFLD score)
Secondary care:
NASH +/- fibrosis: annually
NASH with cirrhosis: every 6m (with HCC surveillance

25. Hepatitis B
Global public health problem: significant morbidity and mortality
240 million chronic HBsAg carriers
Large regional variation in prevalence
UK considered low prevalence
Prevalence in Hackney elevated by migrant populations (West Africa, Turkey, Eastern Europe, South East Asia and China)

26. International guidelines
New information on pathogenesis and disease stages
Updated pan-European management guidelines EASL 2017
Contemporary guidelines differ from protocol used by Hackney GPs to monitor chronic hepatitis B

27. Hepatocellular carcinoma risk
Increased risk of HCC
Risk factors ethnicity, family history and stage of liver fibrosis
Six-monthly liver ultrasound and alfa-fetoprotein (AFP) in selected individuals
London Cancer (2014) identifies high risk groups requiring HCC surveillance
Current Hackney protocol of annual AFP without paired ultrasound not endorsed by any International Guideline or body
Exposing GPs to risk of late diagnosis of HBV-related HCC?

28. Hepatitis B:
Current pathway 2013

29. LTC LES 2017/18: L5 - Hep B Ann RV Liver disease template
Code in seen in liver clinic

30. LTC LES 2017/18: L5 - Hep B Ann RV
Develop accurate register of Hep B patients
search
Code as ‘43B4’ – Hepatitis B Surface Antig +ve
Invite for annual bloods (LFTs, aFP, HBV serology, DNA viral load)
Code annual rv
Telephone/ face-to-face rv/ letter)

31. Phases of HBV infection
Chronic HBV dynamic process of interaction between virus and immune response
Not all patients with chronic HBV infection have chronic hepatitis
Disease phases defined by HBeAg, HBV DNA levels, ALT and presence or absence of liver inflammation
Phases of infection are not necessarily sequential

32. eAg positive
eAg negative
Infection
Hepatitis
HBsAg
High
High/
intermediate
Low
Intermediate
HBeAg
Positive
Negative
HBV DNA
>10*7 iu/ml
10*4-10*7 iu/ml
<2000 iu/ml
>2000 iu/ml
ALT
Normal
Elevated
Fluctuant
Liver disease
None/minimal
Moderate/severe
Old terminology
Immune tolerant
Immune active
Inactive carrier
eAg negative chronic hepatitis

33. Initial assessment of HBV
History, examination, assessment of activity and severity
Markers of HBV infection
Test first degree relatives and sexual partners (HBsAg/anti-HBs/ anti-HBc): vaccinate if negative
Assessment of severity of liver disease (identify patients for treatment/HCC surveillance)
Biochemical and HBV markers/ultrasound/biopsy/elastography
Identify co-morbidities: alcohol, autoimmune, metabolic liver disease
Exclude co-infection HDV/HCV/HIV
Test anti-HAV: if negative vaccinate

34. Treatment of chronic HBV: goals
Prevent disease progression and HCC
Long-term suppression of HBV DNA current end point
+/- induction of HBeAg loss/anti-HBe seroconversion
ALT normalisation in most with viral suppression
HBsAg loss optimal: seldom achieved

35. Indications for treatment
HBeAg +/- chronic hepatitis B (HBV DNA >2000/ALT >upper limit normal/moderate liver inflammation or fibrosis)
Cirrhosis with detectable HBV DNA
HBV DNA >20,000 and ALT 2X ULN regardless of fibrosis
Consider in HBeAg positive chronic HBV infection with normal ALT and high HBV DNA if age >30
Consider in family history of HCC

36. Monitoring of treatment naïve
Periodic assessment of ALT/HBV DNA/fibrosis
Frequency depends upon disease stage
Many of these patients historically followed up annually in primary care in Hackney (HBV DNA <2000)
Role of secondary care virtual clinic with Consultant oversight?

37. Proposed virtual follow up
Disease stage
Quantative sAg
ALT check
HBV DNA check
Fibroscan
HBeAg + Infection
N/A
6 monthly
6-12 monthly
Annual
HBeAg –
DNA <2000
<1000
3 yearly
HBeAg neg
>1000
2 yearly
DNA >2000
Annual for 3 years then 2 yearly

38. HCC surveillance
High risk groups defined in London Cancer HCC guidelines 2014
African origin male and female >20
Asian males >40 years
Asian females >50 years
Cirrhotic HBV carrier
Family history HCC
Surveillance with six monthly paired US liver and AFP testing
AFP alone not recommended

39. Proposed structure of HBV services
HBV testing in primary care
HBV sAg and anti-HBc
HBV sAg neg
HBV sAg pos
Refer to liver clinic
Anti-HBc neg
No history HBV
Anti-HBc pos
No referral
(Rare reactivation risk)
No treatment indication
Treatment indication
Treatment and monitoring CNS/Cons clinic
Virtual/OPD surveillance according to phase

40. Questions