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Talk : Nash in children by Dr.  Pramod Mistry

Talk : Nash in children by Dr. Pramod Mistry






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    Talk : Nash in children by Dr.  Pramod Mistry Talk : Nash in children by Dr. Pramod Mistry Presentation Transcript

    • NAFLD in Children – Is it a reality in India? Learning from European-centric view Pramod K Mistry, MA, PhD, MD, FRCP Professor of Pediatrics and Medicine Chief, Pediatric Gastroenterology and Hepatology Indian Association for Study of the Liver: Metabolic Liver Disease Mumbai. January 13, 2012 SLIDE 1
    • Synopsis• Conditions that cause hepatic steatosis• Definition and natural history of NAFLD• Genes and environment in NAFLD• Pediatric NAFLD: size of the problem• Evaluation of NAFLD• Biomarkers of NAFLD• Treatment of NAFLD SLIDE 2
    • Case PresentationSimilar patient in New Haven, Connecticut (Hispanic)  Age 10  Sedentary, high carbohydrate, high fat, high sucrose diet  BMI 45  Acanthosis nigricans, T2DM, dyslipidemia, hypertension  Age 12; AST 110, ALT 70  Liver biopsy NASH  Age 18 Obstructive sleep apnea  Transient responses to diet  On metformin, ACE I, O2 therapy  Evaluated for bariatric surgery.
    • Fatty Liver in children Fatty liver: defined liver triglyceride >55 mg/g liver tissue – Secondary to inherited metabolic disorders – NAFLD usually associated with obesity and insulin resistance
    • Fatty Liver in Children Associations with other metabolic disorders Wilson’s Disease  Mitochondrial & Alpha – antitrypsin peroxisomal defects of deficiency fatty acid oxidation Galactosaemia  Citrin deficiency Fructosaemia Cholesterol ester storage  Lipodystrophies (Wolman) disease  Abetalipoproteinaemia Glycogen storage disease  Weber – Christian disease Cystic fibrosis  Schwachman syndrome
    • Example 1 of Steatosis Assoicated with Another Metabolic Disroders: Wilson Disease
    • Example 2: Early Onset Lysosomal Acid Lipase Deficiency (Wolman) Prominent hepatic and GI manifestations Weight-for-age percentiles: Boys, birth to 12 months – Hepatomegaly and liver failure 33.1 30.9 – Splenomegaly 28.7 26.5 97th 24.3 85th – Persistent vomiting Weight in 22.1 Pounds 50th 19.8 15th 17.6 3rd – Abdominal distension 15.4 13.2 11 – Profound growth failure 8.8 6.6 LAL Deficient 4.4 1 2 3 4 5 6 7 8 9 10 12 Age (months) Adrenal calcification Rapidly progressive and fatal 7
    • Lysosomal Acid Lipase (LAL) Biology LDL LDL receptors Liver lipid content in model of ENDOCYTOSIS LAL Deficiency coated Cholesteryl Ester vesicle lysosome LAL Deficient Normal LAL Deficient Normal FFA TriglycerideCholesterolesters & TG Free cholesterol and fatty acids are key Free regulators of lipid LAL Deficient Normal Cholesterol synthesis 8
    • Late Onset LAL Deficiency (CESD) Presents in adolescence and adults  Shortened lifespan and morbidity  Prominent hepatic manifestations – Fatty liver – Elevated transaminases Liver biopsy showing cirrhosis in CESD – Fibrosis – Liver failure  Other manifestations: splenomegaly, type II hyperlipidemia  Rare disease in a common phenotype  Incidence estimated at 1 in 40,0001 Affected liver removed during transplant surgery1Muntoni, etal 2007. Prevalence of Cholesteryl Ester Storage Disease, Arteriosclerosis, Thrombosis,and Vascular Biology, 27, p.1866 9
    • NAFLD In ChildrenUsual Presentations:- Incidental mildly elevated LFTs and/or echogenic liver- Obesity/positive FH of liver disease- Abdominal pain- GI co-morbidities: gallstones, functional GI disorders, dyslipidemia
    • DefinitionsNAFLD:– Exclusion criteria (known inherited causes of steatosis, other toxins)– Obesity and insulin resistance– >5% macrovesicular steatosisNASH ‘clinicopathological condition where liver biopsyconsistent with alcoholic hepatitis, but in whom alcoholic intakewas denied’ Ludwig et al. (1980), Mayo Clin Proc
    • Progressive Nature of NAFLDIn adults, 1/3 of patients with early NASH progress to cirrhosis in 5-10 yrs NASH leading cause of HCC (53%) Hobbs H et al, Science 2010
    • NAFLD in Children - Etiology GENES ENVIRONMENT/LIFE STYLEIndian Genomes Likely Display‘Thrifty Genotypes’PLUS Over-nutritionPNPLA3 polymorphisms prevalent Diet composition:in lean Indian men (Petersen K et al) fructose, sat fats, carbohydrates Sedentary life-style
    • Hepatic Triglyceride Content and Hepatic Steatosis in 3 Major Ethnic Groups Browning JD et al, Dallas Heart Study, Hepatology, 2004
    • Nature Genetics, Dec 2008
    • Pathophysiology of NASHVisceral Adipose Tissue is the Main Supplier of FFA to the Liver for TG Synthesis Day et al Gastroenterology 2006
    • NAFLD In Children Prevalence true prevalence elusiveProblems: • Selection bias • Lack of definitive Diagnosis - Radiological - Biochemistry - Histopathological NAFLD prevalence in India likely to be higher cf the West
    • NAFLDDionysis study NHANES III study Ultrasound based, n=257 Elevated liver tests as 16% healthy non obese surrogate markers in 15,000 nondrinkers subjects, healthy, no alcohol 46% heavy drinkers 2.8% elevated ALT 76% obese 65% of elevated ALT 95% obese heavy (overweight and obesity) drinkers
    • Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents -Strauss et al. J Pedaitr, 2000 N=2450 (12-18yrs)Obesity >95th centile for age and sexOverwieght>85th centile for age and sex 6% of overweight and 10% of obese adolescents had elevated ALT 50% of the obese adolescents with modest alcohol intake (4 times per month) had elevated ALT
    • The Population Prevalence of Fatty Liver Schwimmer et al, JPGN 2005Aim- Determine prevalence of fatty liver as diagnosed by histology (>5% fat) in a population based sample. (Year 1993-2002) n=954 (age 2-19)Died of external causes with in 48 hrs of injury and underwent autopsy
    • The Population Prevalence of Fatty Liver Schwimmer et al, JPGN 2005Results- Fatty liver –14% -1% age 2-4 -15% age 15-19Significant factors- Gender Boys >girls (67% more likely) Ethnicity Hispanic/Asians > non Hispanic white > African Americans Obesity 35%
    • Liver Involvement in Obese Children USS AND LIVER ENZYMES  MRI scanning Franzese et al DDS’ 97 Radetti et al Acta Ped 06 N=75, n=44Results- Results- -Age 9.5+/-2.9 yr -Age 10.9 +/-2.7 yr -38/72 (53%) fatty liver -14/44 (32%) fatty on USS liver on MR - 25% elevated ALT, -Elevated ALT in 50% (6 no USS abnormality) with abnormal MR (ALT normal in non NAFLD group)
    • The Utility of Radiological Imaging in Nonalcoholic Fatty Liver Disease Saadeh et al, Gastroenterology 2002 N=25 Liver biopsy proven NAFLD (NASH –17 Steatosis-8)Evaluated the value of USS CT MRI
    • The Utility of Radiological Imaging in Nonalcoholic Fatty Liver Disease Saadeh et al, Gastroenterology 2002Conclusions- The presence of >33% fat on liver biopsy was optimal for detecting steatosis on radiological imaging Differences between NASH and NAFLD were not apparent with any radiological modality
    • Investigations of suspected NAFLD/NASH Basic profile – full blood count, liver function tests, chemistry, INR Serum lactate, urate, ferritin Serum copper, ceruloplasmin, 24 hour urinary copper HBV, HCV serology CF (sweat test ) Alpha-1-antitrypsin phenotype Plasma fatty acids and acyl carnitine profile Lipid profile
    • Abnormal GTT should trigger assessment of Insulin Sensitivity (SI) HOMA QUICKI Homeostasis model  Quantitative insulin assessment of insulin sensitivity check index resistance (HOMA-IR) (QUICKI)  QUICKI=1/[(log[fasting HOAM-IR =(fasting insulin(uU/mL)+log(fasting insulin[uU/Ml])(fasting glucose[mg/Dl)] glucose[mmol/L]/22.5)  Impaired SI is defined as Insulin Resistance QUICKI < 0.339 – HOMA-IR>2
    • NAFLD in Children: A Prospective Clinical- Pathological Study and Effect of Lifestyle Advice - -Nobili et al Hepatology 2006 N=84 (3-18.8yrs;59 male) Elevated aminotransferase Liver biopsy- NAFLDRESULTS- Obese 41% (BMI>97TH centile) Overweight 51% (>85-97th centile) Normal 8%Insulin Resistance Abnormal GTT 12% Abnormal HOMA/ISI 80% (Including 7 with normal BMI)Liver Biopsy-Fibrosis 58%
    • Liver Biopsy Liver biopsy is the gold standard in establishing the diagnosis: clarifies Dx and gives prognosis Indicated in persistently elevated ALT concerning for NASH However, upto 59% with hepatic steatosis on USS and normal LFTs have NASH on biopsy
    • Two Main Histological Patterns of NAFLDType 1 NAFLD- commoner in adults Centrilobular steatosis, Inflammation, Mallory hyaline and sinusoidal fibrosis
    • Type 2 NAFLD-commoner in children Prominent steatosis and inflammation In portal track
    • Schwimmer et al Nobili et alSteatosis-16% Steatosis-17%Type 1-17% Type 1-2%Type 2-51% Type 2-29%Overlap-16% Overlap-52%
    • Noninvasive Markers of NASH - 1.675 + 0.037 x age (years) + 0.094 x BMI (kg/m2) + 1.13 x IFG/diabetes (yes=1; no=0) + 0.99 x AST/ALT ratio - 0.013 x platelet (x109/l) - 0.66 x albumin (g/dl) ______________________________ NAFLD Fibrosis score Low cutoff score= 1.45 = NPV93% (no fibrosis) High cutoff score=0676 = PPV 90% ( fibrosis)
    • TE versus fibrosis scoreDiagnostic performance of transient elastographyTE was a good discriminator of significant fibrosis ≥F2 from minimal / no fibrosis (<F2)(p<0.001), of severe fibrosis ≥F3 from <F3 (p<0.001) and cirrhosis (F4)(p=0.003).Though TE values were found to relate to bilirubin, AST and ALT (Spearman r values 0.25,p=0.04; 0.358, p=0.003 and 0.345 p=0.006 respectively), inflammation on biopsy did nothave a significant relationship to TE (Kruskall Wallis).BMI, sex and age did not correlate well with TE values.
    • TREATMENTWeight LossExerciseChange of life style - 5 servings of vegetables/fruit per day- TV/computer time to 2 hrs/d- aerobic exercise 1 hr/dMetforminVit EUrsodeoxycholic acidMetforminOthers: omega 3 PUFA
    • Conclusions Definition more descriptive Non invasive biomarkers do not differentiate between fat and fibrosis No classical clinical pattern in children as important to exclude other metabolic conditions Liver biopsy continues to be the GOLD STANDARD for research studies and high risk populations Non invasive markers of severity under investigation Life-style change is the only effective treatment