5° Congreso Argentino de Gastroenterología, Hepatología y Nutrición Pediátricas

NAFLD: An overview NAFLD/NASH

(Esteatosis/Esteatohepatitis)

Eve A. Roberts, M.D., M.A., FRCPCDivision of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick ChildrenAdjunct Professor of Paediatrics, Medicine and Pharmacology, University of Toronto

Adjunct Scientist, Genetics and Genome Biology, Hospital for Sick Children Research InstituteDepartment of Philosophy, Dalhousie University

5° Congreso Argentino de Gastroenterología, Hepatología y Nutrición Pediátricas

• Conflict of interest: I have no conflicts of interest to declare.

• Acknowledgements:• Diana Mager, PhD, RD, University of Alberta• Jason Yap, MBBS, FRACP, University of Alberta• Metabolism Research Fund, Hospital for Sick

Children Research Institute

Key points—NAFLD• NAFLD (non-alcoholic fatty liver disease) is a

spectrum ranging from simple steatosis to steatohepatitis (NASH) to cirrhosis.

• Hyperinsulinemia↔insulin-resistance is the central feature of its pathophysiology.

• The disease mechanism involves genetic predisposition plus high-sugar/high-fat diet and lifestyle factors.

• Fatty liver is always abnormal in children and demands diagnostic evaluation.

• For children, prevention of NAFLD must be a key strategy; despite extensive clinical research, treatments are thus far ineffective.

NAFLD is a disease spectrum by definition

Simple steatosis >> NASH > cirrhosis

Hepatocellular carcinoma

Liver transplant

[80] [18] [2]*

*Based on Pediatrics 2006;118:1388 (9.6% adjusted for sex, age, race, ethnicity)

Mainly in adults, the other form of fatty liver disease is alcoholic. In children most other fatty liver disorders are genetic/metabolic.

Figure from Cohen et al. Science 2011;332:1519

[maybe 0.5]

Hepatocellular adenoma

Pathogenesis of NAFLD is complex!

FIBROSIS

↑ leptin, norepinephrine

CIRRHOSIS

hepaticvascular

injury

Based on (and extensively modified from) Day, Best Prac Res Clin Gastroenterol 2002;16:663

truncal

+ host genetic factors

Diet

Too littlephysicalInactivity

↑ FFA

↓ AdiponectinHyperinsulinemia

Acanthosis nigricans: cutaneous sign of insulin resistance

(From: Batch and Baur, Med J Aust 2005;182: 130)

30% in 1st Toronto study51% in 2nd Toronto study(irrespective of age)

50% in Dallas reportSignificant numbers in other reports

Disease mechanism: metabolic derangements in childhood NAFLD

HyperinsulinemiaInsulin resistance

Metabolic syndrome(not defined for children)

Insulin resistance syndrome(involves many of the metabolic effects associated with the metabolic syndrome)

Leptin resistance(feature of obesity)

Decreased adiponectin(modulates insulin action)(anti-inflammatory)

Hepatic inflammation↑ ↑ FFA↓ AdiponectinOther inflammatory cytokines↓ Antioxidants

Associated with cardiovascular risk factors (Schwimmer et al. Circulation 2008;118:277)Associated with cardiac dysfunction (Pacifico et al. Hepatology 2014;59:461)

Genetic factors• PNPLA3 Patatin-like phospholipase domain–containing

(PNPLA) 3 gene (also called adiponutrin)• Missense mutation [Ile148→Met148 (I148M)• nonsynonymous rs738409 C/G variant—G allele is the risk allele

(see work by Sookoian and colleagues)• Approximately 70% of difference in incidence of NAFLD in

Hispanics, African Americans and Caucasians• Extent of effect influenced by obesity and insulin

resistance• Associated with steatosis, NASH and cirrhosis— supports

notion of NAFLD as spectrum• Appears to be risk factor for development of severe liver

disease in children (Valenti et al. Hepatology 2010;52:1274–80)

• Genetic modifier of liver disease caused by various insults in the environment

• MTP (microsomal triglyceride transfer protein)

Pro-active definition for NAFLD• Problem: disease names which are negative are

not very good• “Non-alcoholic” vague• Makes it a diagnosis of exclusion

• What we need is a positive definition based on pathophysiology: NAFLD is a specific disease.

Yap et al. Clin Res Hepatol Gastroenterol 2011;35:500

Exclusion of competing diagnoses

NAFLD is a specific disease due to disordered insulin handling.

Fatty liver and

Central obesityand

Characteristic metabolic disturbance

↑ Waist Circumference

(>90th %ile)OR

WC/height > 1/2

Dyslipidemia Insulin resistance (HOMA-

IR > 2.0 in children) Fasting hyperinsulinemia

By some sort of imaging

(US, MR, MRS)

Exclude competing diagnoses!

Waist circumference: effective screen in children for possible NAFLD

Impact of Chronic LIver Diseaseon Waist Circumference (WC)

PSC NAFLD Viral Other0

25

50

75

100PSCNAFLDViralOther

a

b

a a

WC

(cm

)

Relationship between WCand BMI

10 15 20 25 30 35 40 45 500

100

200r2=0.89

BMI

WC

(cm

)

• Prospective cross-sectional study of all children aged 2-19 years (n=331) attending the Hospital for Sick Children Liver Clinic• Exclusions: patients with ascites• Waist defined as 2 cm above upper edge of umbilicus

b: p<0.001 compared to others

Waist circumference in children withchronic liver diseases

~ 20 cm

Hepatology 2006;44:434A

Relationship between waist circumference (WC) and body mass

index (BMI)

Obesity in early childhoodkey to childhood NAFLD

• Maternal-fetal environment• Postnatal factors

• Weight gain in first two years of life• Extent of rebound weight gain• Breast-feeding (lack of it, or not long enough)• Increased television or ‘screen’ time• Shortened sleep time• Parental obesity

• “Junk-food diet”• Environmental factors broadly speaking

• Built environment: no place to play• Cost of healthy food: when milk costs twice as much as

soft drink, who buys milk?

Dietary macronutrient distribution in children with NAFLD (Toronto)

Mean Age: 14.1 ± 3.3 (range 5.5-19.2 years)Gender distribution: 23M, 6F

Normal for age except that 33.% of carbohydrate intakeis sucrose.

0

10

20

30

40

50

60

Fat Carbohydrate Protein

32%

51%

18%

% to

tal e

nerg

y in

take

Eur J Clin Nutr 2010;64:628

0

10

20

30

Type of Fat

g/d

Sat

MUFA

PUFA

C-18:2 (n-6)

C:18:3 (n-3)

Analysis of dietary fat intake in children with NAFLD

↑ Omega-6/Omega-3 Ratio = 11:1

Eur J Clin Nutr 2010;64:628

(High-normal) intake of omega-6 fatty acids correlated with increased serum concentrations of TNF-a, C-reactive protein, and LDL(Low to subnormal) intake of omega-3 fatty acids correlated with increased ALT and increased HOMA-IR

Focus on postprandial hyperinsulinemia• Rationale: If hyperinsulinemia plays an important

initiating and/or perpetuating role in NAFLD, then the diet of choice is one which minimizes postprandial hyperinsulinemia.

• Low glycemic index foods—low glycemic load diet looks interesting:

• Developed by David Jenkins (University of Toronto) as dietary intervention for managing diabetes mellitus

• Reputation for being a difficult to diet follow• Simple-minded version: no white sugar; no white

bread; no white potatoes• Eliminates table sugar and sugary drinks; low-fibre

breadstuffs, pasta; French fries and potato chips• Caveat: do not substitute granulated fructose for

granulated sucrose!

Focus on fructose• Why fructose?• Circulating fructose taken up almost exclusively by

liver• Fructose cannot be made into glycogen—instead it

is converted to glyceraldehyde-3-phosphate, (→lipogenesis)

• Well-known that fructosemia (HFI) may show fatty fibrosis, even with excellent dietary compliance

• Sucrose = glucose + fructose• Numerous studies point to increased amounts of

added fructose in contemporary diets.

FRAGILE study(Mager et al. JPEN 2013;37:517)

• 12 children with NAFLD (8: simple steatosis, 4: NASH)

• Diet management: (Fructose and Glycemic Index/Glycemic Load Diet)

• Low glycemic index diet• Low glycemic load• (Almost) no fructose

• Results in NAFLD group:• No significant weight loss or smaller waist

circumference or decreased BMI• Significant changes: All had ↓body fat (including

abdominal); ↓systolic BP; HOMA-IR• No changes in inflammatory markers• 3 with simple steatosis did not finish the study.

Other treatment options• Lifestyle: lose 5-10% of initial body weight; get

enough sleep; exercise more• Drug treatments (selected):

• Vitamin E: TONIC study (vitamin R 400 IU BID; metformin 500 mg BID; placebo) did not outperform placebo for decreasing ALT but improved some histological features

• Metformin: possible benefit but TONIC failed to confirm

• Omega-3 fatty acids: ↓steatosis, insulin resistance and dyslipidemia in adults—recently in children (Nobili et al. NutrMetab Cardiovasc Dis 2013;23:1066; PLoS One 2014;9:e88005)

• Cysteamine (upregulates adiponectin): ↓AST/ALT, ↓CK-18 fragment levels, ↑serum adiponectine, no weight loss (Dohil et al. Aliment Pharmacol Ther 2011;33:1036-44)

• Probiotics

Updated differential diagnosis

• 1969—NASH was a disease based on histological abnormalities in a clinical setting discordant for alcohol abuse

• 2009—NAFLD is a disease process whose pathophysiology is fairly well sketched out

• Main differential diagnosis for adults: alcoholic liver disease

• Main differential diagnosis for children: genetic metabolic diseases resulting in fatty liver

• NAFLD is not a diagnosis of exclusion: we need to update the broad differential diagnosis

Revised disease classification(supersedes all others I have proposed)

NAFLD: primary hyperinsulinemia → deranged hepatic function

NAFLD-like:Bardet-Biedl syndrome, Alström syndrome Polycystic ovary diseaseLipodystrophiesChronic hepatitis C with fatty liver and insulin resistance

Fatty liver with or without inflammation and fibrosis but NOT NAFLD:Cystic fibrosisWilson diseaseCitrullinemia, type 2 Various types of drug hepatotoxicity: methotrexate (for example)Alcoholic liver disease

NOT NAFLD:Metabolic liver disorders with microvesicular steatosis

Liver biopsy findings in Toronto NAFLD clinical series

• Initial study: 24 of 36 children had biopsies and all showed macrovesicular steatosis

• 88% steatohepatitis• 75% fibrosis• 1 cirrhosis (maybe 2)

• Next study: 11 of 53 had biopsies• Steatosis: mild in 3, moderate to severe in 8• 45% steatohepatitis + 1 child had adult-pattern NASH• 73% fibrosis• NO cirrhosis

Formal and informal review of currently available literature:At least 20 cases of cirrhosis (sadly, an underestimate)

Childhood NAFLD: histology

Kindness of Glenn Taylor MD, Pathology, Hospital for Sick Children

Kindness of Glenn Taylor MD, Pathology, Hospital for Sick Children

Childhood NAFLD: histology

Most children with NASH have histological features which differ from

those of adult NASH• “Alcoholic hepatitis” picture uncommon

• Severe steatosis• Periportal inflammation or fibrosis• Chronic inflammatory cell infiltrate• Ballooning of hepatocytes• Mallory-Denk hyaline

• Intermediate between adult- and child- pattern more common than evident from initial Schwimmer et al. analysis

• Cirrhosis occurs• Toronto experience (2nd/3rd cases worldwide); Medical

Examiner’s case series from California• Familial; rapid weight gain associated with hypothalamic damage

Older, male, Caucasian

When to biopsy• Important question because NAFLD is classically a

histological diagnosis• Liver biopsy has noteworthy risks and cost.

• Too many NAFLD patients to biopsy everyone!• NAS (NAFLD activity score) is for interim change, not

diagnosis—developed for research purposes

• This is a good reason to develop and implement a pro-active diagnostic definition of NAFLD.

• Those who do not meet the criteria for NAFLD need an expedited work-up for other diseases in the differential diagnosis. Proposed pro-active diagnosis of NAFLD

Fatty liver by imaging ↑WC or WC/height >½ Serum triglycerides or cholesterol HOMA-IR >2.0 (child) or >3.15 (adult)

When to do liver biopsyin paediatric NAFLD? – no set rules

• Young age (<10 years-old)• Very severe insulin resistance (by HOMA-IR)• Hepatosplenomegaly• Very elevated serum AST or ALT• Detectable nonspecific autoantibodies• Inconclusive results from biochemical tests relating to Wilson

disease• Co-morbid liver diseases such as chronic viral hepatitis (e.g.,

due to HBV or HCV) or α1-antitrypsin deficiency• Hypothalamic disorder• Family history of severe NAFLD• Planned significant pharmacological intervention

At risk for rapidly progressive liver damage

Paediatric NAFLD contributed important observations to research about NAFLD

• NAFLD actually exists.• Hyperinsulinemia/insulin resistance key to disease

mechanism• Waist circumference is a critical datum.• We can formulate a positive definition of the disease

and a coherent disease classification. • Maternal-child developmental interactions are

important for how liver functions in adulthood.• Concurrent disease will be significant problem in the

future.

Summary—NAFLD• NAFLD (non-alcoholic fatty liver disease) is a spectrum

ranging from simple steatosis to steatohepatitis (NASH) to cirrhosis.

• Hyperinsulinemia/insulin-resistance is the central feature of its pathophysiology.

• Disease mechanism involves genetic predisposition plus high-sugar/high-fat “highly palatable” (and cheap) diet, and lifestyle factors—sedentary, screen-time. Sucrose? Fructose? Not enough sleep?

• Fatty liver is always abnormal in children and demands diagnostic evaluation. Long-term outcome is not benign.

• For children, prevention of NAFLD must be a key strategy; despite extensive clinical research, treatments are thus far ineffective. Treating NASH effectively is also important given the risk of cirrhosis and HCC.

Worn out Discarded vending machines

5° Congreso Argentino de Gastroenterología, Hepatología y Nutrición Pediátricas

Thank you!Muchas gracias!