Non-alcoholic Fatty liver disease in children

Dr.S.Venkatesh Karthik

Consultant Paediatric Hepatologist

KTP-NUCMI, NUH, Singapore

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

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

Choice ? “Balanced diet ‘’

Definition

• No universal agreement- spectrum

• Liver biopsy evidence

• > 5% hepatocytes- fat infiltration

• Absence of other causes to explain this

• Alcohol- not relevant generally

Exclude

• Viral liver disease

• Drug-induced liver disease

• Autoimmune liver disorders

• Wilson’s disease

• Metabolic liver diseases

Spectrum

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

Spectrum and progression

IMPLICATIONS

• End-stage liver disease

• Insulin resistance, type 2 DM

• Hypertension

• Metabolic syndrome

• Cardiovascular morbidity

Prevalence

• 3- 10 % in children , Western hemisphere

• Ethnic and genetic factors

• 30- 40 % genetic influence- as a contributor

• Boys > Girls

• Overweight and obesity- single most relevant association

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

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

European data

• 35 specialist paediatric obesity centres in three countries

• 16390 children

• AST and/or ALT > 50 as cut-off

• 11% NAFLD

• Boys vs girls: 14.4% vs 7.4% (p < 0.001)

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

The “two- hit hypothesis”

• Model to explain aetio-pathogenesis

• First hit- Presence/Development of peripheral insulin resistance

• Hepatocyte fat accumulation

• Increased lipid peroxidation

The second hit

• Oxidative stress

• Free oxygen radicles

• Cytokines

• Hepatocyte inflammation

• Necrosis

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

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

Recognition

• Strict criterion- liver biopsy, as the gold standard

• Elevated liver transaminases – prompt US Liver

• High risk groups

• Further investigations

US

• Sensitivity- good only if > 30% liver fat • Cannot measure severity

• No information- NASH

• Sensitivity- 60-90%

• Specificity- 84-95%

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

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

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

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?

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

Management

• Increasing physical activity

• Diet

• Lifestyle changes

Pharmacotherapy

• Several pilot studies

• Even RCTs- Vitamin E, Metformin, UDCA

• No safe and effective drugs

• Similar picture with adults

Goals of treatment

• Normalisation of liver enzymes

• Ideally, histological resolution

• Weight loss

• Decrease peripheral insulin resistance

• Improve metabolic profile

• Cardiovascular benefits

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

Prevention- an ideal strategy

• Cost effective and overall benefit

• Health education

• Parental motivation

• Primary care

• Primordial prevention- Improving maternal nutrition, reducing SGA/IUGR incidence

Summary

• Increasing in incidence

• Worldwide- a challenge

• Low threshold for screening and early referral

• Specialist input- Dedicated NAFLD clinics

• Achievable results

• Research

Thank you