1 Enfermedad por Hígado Graso y Obesidad Infantil Dr. José Luis Gonzáles Gastroenterología Noviembre 2009

2 Steatosis Steatohepatitis Cirrhosis Hepatocellular carcinoma Non Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology Non Alcoholic Fatty Liver Disease (NAFLD) Spectrum of Hepatic Pathology

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5 The Hypothalamic-Leptin Axis How it works: When excess fat builds up in the fat cell, leptin is produced and enters the bloodstream. Leptin receptors in the hypothalamus are triggered. This shifts the hypothalamus into “Spend Energy” mode. Leptin changes SLOWLY (days to weeks) Lustig, Ped Annals, 35:12 Dec 2006

6 What blocks leptin? Brain damage to the leptin receptor area: hypothalamic obesity syndrome Insulin excess blocks leptin receptors (Fructose is what leads to insulin excess) Lustig, Ped Annals, 35:12 Dec 2006

7 Insulin excess blocks leptin Lustig, Ped Annals, 35:12 Dec 2006

8 INSULIN RESISTANCE AND FAT DEPOSITION Insulin resistance Free Fatty Acids Insulin resistance insulin Liver Muscle

9 Hispanics Whites Blacks 45% 42% 24% FLD 24% MM M F F F Hepatic Steatosis Gender Disparities in Whites

10 TV + Food = Overweight

11 Enfermedad de Hígado Graso No Alcohólico Esteatohepatitis no Alcohólica NAFLD

12 Enfermedad de Hígado Graso No Alcohólico Se refiere a un grupo de condiciones en donde existe acumulación de exceso de grasa en el hígado de personas en el hígado de personas que no beben alcohol. La condición mas común de NAFLD es una condición conocida como Hígado Graso (Fatty Liver). En esta última condición la grasa se acumula en las células hepáticas. Aunque tener grasa en el hígado no es normal su presencia, probablemente, en forma mayoritaria no haga daño.

13 Un pequeño grupo de gente con NAFLD puede tener una condición mas seria llamada Esteatohepatitis no-alcohólica (NASH). En esta última condición existe inflamación de las células hepáticas y diferentes grados de cicatrización. El NASH es una condición potencialmente severa que puede llevar a cicatrización y cirrosis. Esta última condición se produce cuando existe una condición de daño hepático y el tejido hepático es reemplazado por tejido cicatrizal, lo cual resta capacidad funcional del hígado

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15 NON-ALCOHOLIC FATTY LIVER DISEASE Hepatic steatosis –Grasa incrementada en el hígado –Steatohepatitis associated with liver inflammation and elevated liver enzymes –20%-25% obese children have evidence of steatohepatitis Tazawa Acta Paeditr 1997;86:238-241

16 NON-ALCOHOLIC FATTY LIVER DISEASE Liver disease can progress to fibrosis or frank cirrhosis Obesity and type 2 diabetes are the strongest predictors of progression of fibrosis Age is also a risk factor for cirrhosis which may reflect increased duration of risk for the “second hit” thought to initiate fibrosis. »Angulo P, Keach JC, Batts KP, Lindor KD. Hepatology 1999;30(6):1356-62

17 Prevalence of Elevated Alanine Aminotransferase Among US Adolescents and Associated Factors: NHANES 1999–2004 NAFLD es una causa común de enfermedad hepática en niños y adolescentes. data of adolescent participants (aged 12– 19 years; N= 5586) in NHANES study identify leading risk factors for ALT elevation (>30 U/L).

18 Elevated Alanine Aminotransferase Among US Adolescents

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20 ALT level is associated with waist circumference and insulin resistance even in a young population Primary care MDs, Pediatricians, NPs, Gastroenterolgists, Hepatologists all will play a role in trying to reduce morbidity in adolescents with NAFLD using ALT as screening test GASTROENTEROLOGY 2007;133:1814–1820

21 The Problem: Non-alcoholic Fatty Liver Disease in Your Practice and Interpretation of ALT Levels NAFLD is probably the most common cause of abnormal ALT values among US adults –may affect up to 3% of the US population Clearly linked to obesity and metabolic syndrome/insulin resistance Elevated ALT may be a component of the metabolic syndrome, the hallmark of which is insulin resistance, manifested by hyperglycemia, hyperlipidemia, abdominal obesity and hypertension ALT related to mortality in cohort of participants of a large health insurance program in Korea (142,055 participants)

22 Elevated Alanine Aminotransferase Among US Adolescents ALT level is associated with waist circumference and insulin resistance even in a young population Primary care MDs, Pediatricians, NPs, Gastroenterolgists, Hepatologists all will play a role in trying to reduce morbidity in adolescents with NAFLD using ALT as screening test GASTROENTEROLOGY 2007;133:1814–1820

23 NAFLD Condición muy común. NAFLD afecta al 20% de adultos y 5% de niños. Obesidad es la condición mas frecuente. Algunos expertos consideran que 2/3 de los obesos adultos y ½ de los niños obesos pueden tenr hígado graso. 2 al 5% de adultos americanos y 20% de aquellos que son obesos pueden sufrir de la condición mas severa NASH. El número de niños con NASH no es conocido. El incremento del sobrepeso y obesidad en el mundo genera un incremento del NAFLD y del NASH.

24 Causa NAFLD es parte del síndrome metabólico caracterizado por diabetes, resistencia de insulina, sobrepeso y obesidad, incremento de los lípidos así como incremento de la PA. – Estress Oxidativo stress (disbalance entre pro-oxidantes y anti-oxidantes que dañan las células del tejido – Producción y liberación de proteínas inflamatorias (citoquinas) por las propias células inflamatorias, células hepáticas o células adiposas. – Necrosis de células hepáticas o muerte, llamada apoptosis.

25 Fatty Liver: Macrovescicular steatosis with nucleus positioning at cell periphery NASH: Mallory bodies, ballooning degeneration, lobular neutrophil inflammation and perisinusoidal fibrosis AGA Technical Review on Nonalcoholic Fatty Liver Disease Gastroenterology 2002;123:1705-1725 NAFLD

26 NAFLD is a spectrum of disease which includes Fatty liver disease and NASH, but only NASH is known to progress to cirrhosis. Fatty Liver Obese BMI>28 Centipetal (apple) Bright liver on USS Insulin Resistance Normal ALT NASH Obese BMI>28 Bright liver on USS Abnormal ALT Features of metabolic syndrome Dyslipidaemia DM HBP Cirrhosis Bright/ small liver on USS + splenomegaly Abnormal ALT Thrombocytopenia Obesity Poorly controlled DM Poorly controlled lipids Hypertension 2 nd hit

27 NASH Steatosis Cirrhosis

28 NASH- Peri-sinusiodal fibrosis

29 Grading NAFLD 1.Macrovescicular steatosis Grade 0: None Grade 1: Up to 33% Grade 2: 33%-66% Grade 3: >66% 2. Necroinflammatory activity Mild, Mod, Severe Grading and Staging of NAFLD Brunt et al Am J Gastro 1999

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31 Diseases associated with Steatohepatitis 1.Alcoholism 2.Insulin resistance a.Metabolic Syndrome i.Obesity ii.Diabetes iii.Hypertriglyceridemia iv.Hypertension b.Lipoatrophy c.Mauriac Syndrome d.PCOS 3.Disorders of lipid metabolism a.Abetalipoproteinemia b.Hypobetalipoproteinemia c.Andersen’s disease d.Weber-Christian syndrome 4.Total parenteral nutrition 5. HCV 6.Severe weight loss a.Jejuno-ileal bypass b.Gastric bypass c.Severe starvation 7.Iatrogenic a.Amiodarone b.Diltiazem c.Tamoxifen d.Steroids e.HAART f. tetracycline g.glucosamine 8.Refeeding syndrome 9.Exposure to toxic agents a.Environment b.Workplace – Sb,Th,Ba

32  FFA oxidation  Lipogenesis  Lipid Export Hepatic Steatosi s High Fat/CHO Diet Lack of Exercise Insulin Resistan ce White Adipose Tissue Adipokines- adiponectin Cytokines- TNF IL-6 Oxidative Stress Endotoxin Cytokines ROS Toxins NASH Peroxidation of hepatocyte membrane Cytokine release Stellate cell activation 2 nd Hit Pathogenesis of NASH

33  FFA oxidation  Lipogenesis  Lipid Export Hepatic Steatosi s High Fat/CHO Diet Lack of Exercise Pathogenesis of NASH  CellularFFA Insulin Resistan ce I  B and NF  B activation  IL6 &TNFα

34  FFA oxidation  Lipogenesis  Lipid Export Hepatic Steatosi s High Fat/CHO Diet Lack of Exercise Pathogenesis of NASH  CellularFFA Insulin Resistan ce  GLUT 4 activity Reduced glucose entry into cells

35  FFA oxidation  Lipogenesis  Lipid Export Hepatic Steatosi s High Fat/CHO Diet Lack of Exercise Insulin Resistan ce White Adipose Tissue Adipokines- adiponectin Cytokines- TNF IL-6 Oxidative Stress Endotoxin Cytokines ROS Toxins NASH Peroxidation of hepatocyte membrane Cytokine release Stellate cell activation 2 nd Hit Treatment Strategies In NASH Diet &Exercise Orlistat Sibutramine Rimonabant Statins Gemfibrozil Metformin Pioglitazone Rosiglitazone Diet &Exercise Probiotics Antioxidants Bariatric Surgery

36 SINTOMAS DE NAFLD/NASH La mayoría de pacientes con NAFLD no tienen síntomas y el exámen puede resultar normal. Puede hallarse un hígado crecido.

37 NAFLD NASH DIAGNOSIS Puede encontrarse el diagnóstico en niños con sobrepeso y obesidad en niños con elevaciones leves de transaminasas. El NAFLD puede darse sin incremento de TGP/TGO. El Dx de NAFLD puede diagnosticarse mediante Eco hepático en donde se aprecia el depósito de grasa en el hígado. Nuestro paciente tiene NASH o tiene FL Algunos medicamentos, hepatits viral, enf hepática autoinmune, enfermedades metabólicas o enfmedades hepáticas heredadas pueden causar FL. Biopsia hepática cuando requiere diferenciar el NASH del FL.Infiltración grasa del hígado y presncia de inflamación y diferentes grados de cicatrización..

38 NAFLD NASH: Tx NAFLD / NASH: IGUAL MANEJO No existe tratamiento médico que revierta el FL. Baja de peso en algunos estudios demuestran regresión de la grasa dentro del Hígado. Reducir el peso. Medicamentos que disminuyan los lípidos. Sensibilizadores a Insulina Disminuir la cantidad de inflamación hepática. Emplear antioxidantes, medicación contra apoptosis y medicación anticitoxina.

39 What are the risks of having NAFLD / NASH? Most people with NAFLD, especially those with simple fatty liver with no inflammation, have little or no problems from the condition. In contrast, about a quarter of people with NASH may have scarring of the liver that gets worse with time. In general, the progression of scarring is slow and can take years and even decades to occur. In some patients the scarring can stabilize and in persons who have lost significant amounts of weight there are cases where scarring has been shown to reverse. In others, the progression continues with scar tissue accumulating in the liver, leading to cirrhosis. NASH is an increasingly common reason for liver transplantation in the United States.

40 Current Management of |NAFLD and NASH. APT. Younossi Z: 2008

41 Natural history Simple steatosis: relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%. NASH and fibrosis: risk of progress to cirrhosis between 0% at 5 years to 12% over 8 years. Cirrhotic: high risk of developing hepatic decompensation and of dying from a liver- related cause including HCC.

42 NASH Affects 3.5-5% of the population The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years. There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.

43 Non-alcoholic fatty liver Rare until recently Can cause death from cirrhosis Found in 9% of children autopsied in LA Increased with BMI to 38% in obese kids Linear correlation with their BMI Cause? excess fructose increasing hepatic lipid content Schwimmer, Pediatrics, 118(4):1388, Oct 2006