Non-alcoholic Fatty liver disease in children. Dr.S.Venkatesh Karthik Consultant Paediatric Hepatologist KTP-NUCMI, NUH, Singapore

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1 Non-alcoholic Fatty liver disease in children Dr.S.Venkatesh Karthik Consultant Paediatric Hepatologist KTP-NUCMI, NUH, Singapore

2 Relevance Leading cause of chronic liver disease- both adults and children Under-recognised children are well Worldwide pandemic- obesity and excess body weight West- Almost 1 in 6 are overweight Two-thirds- varying degrees of NAFLD

3 Relevance Singapore- No data available Possibly increasing incidence Not a disease of the affluent Life style Diet Easy and relatively inexpensive access- Energy dense foods

4 Choice? Balanced diet

5 Definition No universal agreement- spectrum Liver biopsy evidence > 5% hepatocytes- fat infiltration Absence of other causes to explain this Alcohol- not relevant generally

6 Exclude Viral liver disease Drug-induced liver disease Autoimmune liver disorders Wilson s disease Metabolic liver diseases

7 Spectrum Simple steatosis Steato-hepatitis With or without minimal cholestasis Hepatocyte necrosis with mild fibrosis Advanced / Bridging fibrosis Cirrhosis HCC

8 Spectrum and progression

9 IMPLICATIONS End-stage liver disease Insulin resistance, type 2 DM Hypertension Metabolic syndrome Cardiovascular morbidity

10 Prevalence 3-10 % in children, Western hemisphere Ethnic and genetic factors % genetic influence- as a contributor Boys > Girls Overweight and obesity- single most relevant association

11 Population-based studies US NHANES 3 study Higher incidence in Hispanic children Lowest in blacks Intermediate- Caucasians and Asian children Japanese and Korean data- prevalence of between 2.5 and 4 % in adolescents

12 Other reports Huang et al- School children 6-12 yrs age group NAFLD rates 3% in normal weight group 25% in overweight children 76% in obese children

13 European data 35 specialist paediatric obesity centres in three countries children AST and/or ALT > 50 as cut-off 11% NAFLD Boys vs girls: 14.4% vs 7.4% (p < 0.001)

14 Dyslipidaemia Significant proportion Relatively less of an issue when compared to that in adults Italian study- biopsy proven NAFLD in children 45% dyslipidaemia 60% had high triglyceride levels Increased carotid artery intimal thickness

15 The two- hit hypothesis Model to explain aetio-pathogenesis First hit- Presence/Development of peripheral insulin resistance Hepatocyte fat accumulation Increased lipid peroxidation

16 The second hit Oxidative stress Free oxygen radicles Cytokines Hepatocyte inflammation Necrosis

17

18 Visceral fat and mediators Visceral fat especially relevant Leptin- satiety mediator Deficient- more prone to NAFLD Adiponectin in plasma and visceral fat Direct correlation Increased physical activity- reduces adiponectin activity

19 Recognition High risk groups Low threshold to investigate Typically recognised when ALT and/or AST levels are elevated But not always abnormal even with NAFLD No single reliable test in isolation

20 Recognition Strict criterion- liver biopsy, as the gold standard Elevated liver transaminases prompt US Liver High risk groups Further investigations

21 US Sensitivity- good only if > 30% liver fat Cannot measure severity No information- NASH Sensitivity % Specificity %

22 Further investigations Rule out other causes False positive auto-antibodies Check IgG levels Low threshold for liver biopsy, when in doubt Biopsy- ESPGHAN position paper CT, MRI- add to cost, not required

23 Avoiding a biopsy Invasive -Risks Fibro-scan and its modifications Compare favourably with biopsy findings, but not easily available Biomarkers- an area of research Hyaluronic acid, cytokeratin 18 fragment assay

24 A tool for primary care Paediatric NAFLD fibrosis index Age Waist circumference Triglyceride levels Low cost Useful to identify at risk patients Poor negative predictive value

25 Worsening LFT or diagnostic dilemma Percutaneous liver biopsy Still the gold standard Tertiary centres with expertise Distribution of steatosis differs in children Is paediatric NAFLD different?

26 Histology Children- steatosis starts in the periportal zone- Zone 1 Adults- Starts in zone 3 around the hepatic venules Ballooning of hepatocytes- Higher risk of progression Scoring systems Not validated- children Recent Paediatric NAFLD histology scoring system

27 Management Increasing physical activity Diet Lifestyle changes

28 Pharmacotherapy Several pilot studies Even RCTs- Vitamin E, Metformin, UDCA No safe and effective drugs Similar picture with adults

29 Goals of treatment Normalisation of liver enzymes Ideally, histological resolution Weight loss Decrease peripheral insulin resistance Improve metabolic profile Cardiovascular benefits

30 Current Research Long chain Omega-3- polyunsaturated fatty acids Probiotics normalise the gut microbiota (NIH) Recent trial- Docosa-hexanoic acid plus lifestyle intervention Improvement in ALT and histology

31 Prevention- an ideal strategy Cost effective and overall benefit Health education Parental motivation Primary care Primordial prevention- Improving maternal nutrition, reducing SGA/IUGR incidence

32 Summary Increasing in incidence Worldwide- a challenge Low threshold for screening and early referral Specialist input- Dedicated NAFLD clinics Achievable results Research

33 Thank you

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