Talk : Nash in children by Dr. Pramod Mistry


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Talk : Nash in children by Dr. Pramod Mistry

  1. 1. 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
  2. 2. 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
  3. 3. 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.
  4. 4. 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
  5. 5. 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
  6. 6. Example 1 of Steatosis Assoicated with Another Metabolic Disroders: Wilson Disease
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. Hepatic Triglyceride Content and Hepatic Steatosis in 3 Major Ethnic Groups Browning JD et al, Dallas Heart Study, Hepatology, 2004
  15. 15. Nature Genetics, Dec 2008
  16. 16. Pathophysiology of NASHVisceral Adipose Tissue is the Main Supplier of FFA to the Liver for TG Synthesis Day et al Gastroenterology 2006
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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%
  22. 22. 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)
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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%
  28. 28. 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
  29. 29. Two Main Histological Patterns of NAFLDType 1 NAFLD- commoner in adults Centrilobular steatosis, Inflammation, Mallory hyaline and sinusoidal fibrosis
  30. 30. Type 2 NAFLD-commoner in children Prominent steatosis and inflammation In portal track
  31. 31. 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%
  32. 32. 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)
  33. 33. 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.
  34. 34. 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
  35. 35. 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