Enfermedad por Hígado Graso y Obesidad Infantil

Dr. José Luis Gonzáles

Gastroenterología

Noviembre 2009

SteatosisSteatosis

SteatohepatitisSteatohepatitis

CirrhosisCirrhosis

Hepatocellular carcinoma

Hepatocellular carcinoma

Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology

Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology

The Hypothalamic-Leptin AxisThe Hypothalamic-Leptin AxisHow it works: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

What blocks leptin?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

Insulin excess blocks leptinInsulin excess blocks leptin

Lustig, Ped Annals, 35:12 Dec 2006

INSULIN RESISTANCE AND FAT DEPOSITION

Insulin resistance

Free Fatty AcidsInsulin resistance

Insulin resistance

insulin

Liver

Muscle

HispanicsHispanics WhitesWhites BlacksBlacks

45%45%42%42%

24%24%

FLDFLD

24%24%M M

M

F

F F

Hepatic SteatosisGender Disparities in Whites

TV + Food = OverweightTV + Food = Overweight

Enfermedad de Hígado Graso No Alcohólico

Esteatohepatitis no Alcohólica

NAFLD

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.

• 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

•

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

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

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).

Elevated Alanine Aminotransferase Among US Adolescents

Elevated Alanine Aminotransferase Among US Adolescents

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

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)

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

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.

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.

Fatty Liver: Macrovescicular steatosis with nucleus positioning at cell periphery

NASH: Mallory bodies, ballooning degeneration,lobular neutrophil inflammationand perisinusoidal fibrosis

AGA Technical Review on Nonalcoholic Fatty Liver DiseaseGastroenterology 2002;123:1705-1725

NAFLD

NAFLD

• 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>28Centipetal (apple)Bright liver on USSInsulin ResistanceNormal ALT

NASH

Obese BMI>28Bright liver on USSAbnormal ALTFeatures of metabolic syndrome Dyslipidaemia DM HBP

Cirrhosis

Bright/ small liver on USS + splenomegalyAbnormal ALTThrombocytopeniaObesityPoorly controlled DMPoorly controlled lipidsHypertension

2nd hit

NASH

Steatosis Cirrhosis

NASH- Peri-sinusiodal fibrosis

Grading NAFLD

1.Macrovescicular steatosis

Grade 0: NoneGrade 1: Up to 33%Grade 2: 33%-66%Grade 3: >66%

2. Necroinflammatory activity

Mild, Mod, Severe

Grading and Staging of NAFLDBrunt et al Am J Gastro 1999

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

FFA oxidationLipogenesisLipid Export

Hepatic Steatosis

High Fat/CHO DietLack of Exercise

Insulin Insulin ResistanceResistance

White Adipose Tissue

Adipokines- adiponectinCytokines- TNF

IL-6

Oxidative Stress

EndotoxinCytokinesROSToxins

NASHPeroxidation of

hepatocyte membraneCytokine release

Stellate cell activation

2nd Hit

Pathogenesis of NASH

FFA oxidationLipogenesisLipid Export

Hepatic Steatosis

High Fat/CHO DietLack of Exercise Pathogenesis of NASH

CellularFFA

Insulin Insulin ResistanceResistance

IB and NFBactivation

IL6 &TNFα

FFA oxidationLipogenesisLipid Export

Hepatic Steatosis

High Fat/CHO DietLack of Exercise Pathogenesis of NASH

CellularFFA

Insulin Insulin ResistanceResistance

GLUT 4 activity

Reduced glucose entry into cells

FFA oxidationLipogenesisLipid Export

Hepatic Steatosis

High Fat/CHO DietLack of Exercise

Insulin Insulin ResistanceResistance

White Adipose Tissue

Adipokines- adiponectinCytokines- TNF

IL-6

Oxidative Stress

EndotoxinCytokinesROSToxins

NASHPeroxidation of

hepatocyte membraneCytokine release

Stellate cell activation

2nd Hit

Treatment StrategiesIn NASH

Diet &Exercise

OrlistatSibutramineRimonabant

StatinsGemfibrozil

MetforminPioglitazoneRosiglitazone

Diet &Exercise

ProbioticsAntioxidants

Bariatric Surgery

SINTOMAS DE NAFLD/NASH

• La mayoría de pacientes con NAFLD no tienen síntomas y el exámen puede resultar normal.

• Puede hallarse un hígado crecido.

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..

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.

• 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.

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

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.

NASHAffects 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.

Non-alcoholic fatty liverNon-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

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Schwimmer, Pediatrics, 118(4):1388, Oct 2006