Diabetologie. Nash Sinaia
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Transcript of Diabetologie. Nash Sinaia
NON-ALCOHOLIC FATTY LIVER NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN METABOLIC DISEASE (NAFLD) IN METABOLIC
SYNDROME&TYPE 2 D.M.SYNDROME&TYPE 2 D.M.
M.D., Ph.D., Prof.Dr.Amorin-Remus Popa,M.D., Ph.D., Prof.Dr.Amorin-Remus Popa,
University of Oradea,University of Oradea,
Emergency clinical hospitalEmergency clinical hospital
-Novel diseases, firstly recognized at the beginning of the second millenium
-Hepatic expression of the “so-called” metabolic syndrome
-Because of epidemic burden of O. , D.M. and metabolic diseases, NFALD and NASH -> probably the most common hepatic disease worldwide
Epidemiology and natural history of primary NAFLD
Current definition of non-alcoholic steatohepatitis
-histological leasons of steatohepatitis-risk factors of complications of I.R.-* a semiology cause of I.R.
(Prof.Vlad Ratziu, NASH, the liver and I.R. – 2009)
NAFLD-histological spectrum of liver damage-from simple steatosis -to advanced fibrosis and cirrhosis-individuals without a relevant alcohol
comsumption (<20g/day)
NAFLD – does not progress to end-stage liver dissease
NASH -is ↗ for hepatic fibrosis-20-30% of cases have histological signs of
fibrosis, inflammation and necrosis↓
high risk for -cirrhosis-terminal liver failure-hepatocellular carcinoma
Paloma Almeda-Valdes, Daniel Cuevas-Ramos, Carlos Alberto Aquilar-Salinas – Metabolic syndrome and non-acoholic fatty liver disease –
Annals of Hepatology 2009,8(1): Supplement: S18-S24
NAFLD – def. – condition of fat accumulation in the liver in the absence of excessive alcohol consumption (less than 20g/day)
-any other specific causes of hepatic steatosisa.Primary origin – aetiology not yet completely understood
• Related strictly to the presence of IR• Occurs as the initial part of the M.S.• Accompany O., D.M. type 2, DLP
b.Secondary • Nutritional - malnutrition, rapid weight loss• Metabolic - abetalipoproteinemia, lipodystrophy• Drug-induced-glucocorticoids, methotrexate,
chemotherapics, tamoxifene• Other conditions-jejunal diverticulitis with bacterial
overgrowth, inflammatory bowel disease, occupational exposure
(Bellentani S, Marino M. Epidemiology and Natural history of non-alcoholic fatty liver disease (NAFLD). Annals of Hepatology 2009)
Nonalcoholic
Fatty Liver
Disease
2. Etape diagnostique : distinction stéatose vs stéatohépatite
Excessive liver fatExcessive liver fat
SteatohepatitisBland steatosis
Diagnostic distinction based on hepatocyte cell injury(ballooning, necrosis /inflammation, Mallory bodies)
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Steatosis without other histological signs Steatosis without other histological signs
Bland steatosisBland steatosis
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
SteatosisSteatosis
SteatohepatitisSteatohepatitis
Hepatocyte cell injuryHepatocyte cell injuryBallooning, lobular Ballooning, lobular inflammation/necrosis,inflammation/necrosis,Mallory bodies, PMNMallory bodies, PMN
ballooningballooning
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
3. Etape pronostique : Évaluer le stade de fibrose
F0 (/F1 ?)F0
F4
Perisinusoïdal FibrosisPortal FibrosisPrognostic value
Nonalcoholic
Fatty Liver
Disease
Excessive liver fatExcessive liver fat
SteatohepatitisBland steatosis
Diagnostic distinction based on hepatocyte cell injury(ballooning, necrosis /inflammation, Mallory bodies)
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
• Pourquoi la stéatose ?Pourquoi la stéatose ?
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
NAFLD : a Model of Insulin NAFLD : a Model of Insulin Resistance-Induced Liver InjuryResistance-Induced Liver Injury
Normal liverNormal liver
STEATOSISSTEATOSIS
STEATOHEPATITISSTEATOHEPATITIS
CIRRHOSISCIRRHOSIS
??
HEMORRAGEHEMORRAGELIVERLIVER
FAILUREFAILURE CANCERCANCER
????
??
INSULININSULINSENSITIVITYSENSITIVITY
Insulin Insulin ResistanceResistance
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Physiologie de la répartition des substrats énergétiques :Physiologie de la répartition des substrats énergétiques :à distance des repas, le foie produit du glucose (PHG) et le tissu adipeux à distance des repas, le foie produit du glucose (PHG) et le tissu adipeux
produit les acides gras nécessaires au muscle et au foie (voies inhibées par produit les acides gras nécessaires au muscle et au foie (voies inhibées par l’insuline)l’insuline)
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Dpr.-ussualy-U.S.(ultrasonography)-moderate and severe steatosis
-only when fat on liver biopsy exceeds 33%-more sensitive techniques
-MR imaging and spectroscopy -expense and lack of feasibility in large
population
AASLD – diagnosis of NAFLD at fat accumulation in the liver of at least 5 to 10% by weight
→LIVER BIOPSY = gold standardDallas Heart Study / 30% of adult Americans \- NAFLDDionysos Study \ 25% of adult Italians /-
79% and 55% patients with NAFLD – normal aminotransferase levels – liver enzymes highly underestimate the prelevance of NAFLD
Prévalence de la stéatose Prévalence de la stéatose échographiqueéchographique
SujetNormal
Obésité DiabèteType 2
Sd métabolique
%
22
7470
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Prévalence de la stéatopathie Prévalence de la stéatopathie métabolique chez les patients avec métabolique chez les patients avec augmentation des transaminasesaugmentation des transaminases
AutresAutres
NormalNormal
StéatopathiesStéatopathiesmétabolqiuesmétabolqiues
StéatoseStéatose
26%26%
32%32%SteatohépatiteSteatohépatite
23%23%
19%19%
58 %58 %
Evaluation prospective multicentrique française (21 Evaluation prospective multicentrique française (21 centres) des 274 sujets avec augmentation inexpliquée centres) des 274 sujets avec augmentation inexpliquée des transaminasesdes transaminases
De Ledinghen, Ratziu, J Hepatol 2006De Ledinghen, Ratziu, J Hepatol 2006Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
TAKE HOME MESSAGESTAKE HOME MESSAGES
• Liver injury needs to be assessed in Liver injury needs to be assessed in patients with insulin resistancepatients with insulin resistance
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Steatosis Independently Induces Steatosis Independently Induces Hepatic IRHepatic IR
3 day high fat diet3 day high fat diet
STEATOSISSTEATOSIS
No increase visceral fatNo increase visceral fat
No increased portal FFANo increased portal FFA
No muscle adipose IRNo muscle adipose IR
MUSCLE:MUSCLE: normal normalglucose uptakeglucose uptake
ADIPOSE T :ADIPOSE T : normal normalinhibition of FFA inhibition of FFA release by insulinrelease by insulin
insulin suppressioninsulin suppressionof hepatic glucose of hepatic glucose
productionproduction
HEPATIC INSULIN RESISTANCEHEPATIC INSULIN RESISTANCE
Samuel, Shulman, JBC 2004Samuel, Shulman, JBC 2004
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Liver Fat is Associated with Liver Fat is Associated with Defects in Insulin Action Defects in Insulin Action
Independent of Obesity in Normal Independent of Obesity in Normal MenMen
30 Healthy controls differing in the 30 Healthy controls differing in the amount of liver fatamount of liver fat
Individuals with high liver fat content had :Individuals with high liver fat content had : Higher fasting hyperinsulinemia (7.3 vs 5.3)Higher fasting hyperinsulinemia (7.3 vs 5.3) Higher TG levels (1.4 vs 0.9)Higher TG levels (1.4 vs 0.9) Lower HDLc (1.4 vs 1.6)Lower HDLc (1.4 vs 1.6) Higher blood pressure (130 vs 122)Higher blood pressure (130 vs 122) Impaired insulin suppression of glucose and Impaired insulin suppression of glucose and
FFAFFASeppala-Lindroos, JCEM 2002Seppala-Lindroos, JCEM 2002
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Liver Fat Content : a Major Liver Fat Content : a Major Determinant of Insulin Determinant of Insulin
Requirements in DiabetesRequirements in Diabetes
60% of the variation of the daily insulin requirements was 60% of the variation of the daily insulin requirements was attributable to the variation of hepatic fat contentattributable to the variation of hepatic fat content
% fat liver was most closely correlated with reduced % fat liver was most closely correlated with reduced suppression of hepatic glucose production by insulinsuppression of hepatic glucose production by insulin
N=20 stable Type 2, Insulin treated diabetic Pts N=20 stable Type 2, Insulin treated diabetic Pts
Ryysy, Diabetes 2000Ryysy, Diabetes 2000Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
NAFLD patients present increased subclinical atherosclerosis compared to non-steatosis individuals
-CVD is the second most common cause of death in NAFLD
-hepatic steatosis alone -> triad: steatosis, hepatocellular necrosis, inflammation
-I.R. -> obesity, D.M. type 2, DLP
-NAFLD – component of M.S -> increase risk of coronary heart disease and C.V. complications
Competitive Risks : Heart vs LiverCompetitive Risks : Heart vs Liver
Early endothelial dysfunction in NAFLDEarly endothelial dysfunction in NAFLD• Independent of BMI, HOMA ?Independent of BMI, HOMA ?
Villanova, Hepatology 2005Villanova, Hepatology 2005ControlsControls
NAFLDNAFLD
Median 1.2%Median 1.2%
Median 3.7%Median 3.7%
*Framingham 10-year risk*Framingham 10-year risk
Ioannou, Gastroenterology 2006Ioannou, Gastroenterology 2006
Higher CV risk profile* in NAFLDHigher CV risk profile* in NAFLD
controlscontrols steatosissteatosis NASHNASH
Villanova, Hepatology 2005Villanova, Hepatology 2005
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
N=4222N=4222
100100
9090
8080
7070
6060
5050
4040
3030
2020
1010
00<50<50 50-5950-59 60-6960-69 70-7970-79
% p
atie
nts
wit
h p
laq
ue
% p
atie
nts
wit
h p
laq
ue
**
Age (yr)Age (yr)
No steatosisNo steatosis
****
SteatosisSteatosis
* p < 0.05* p < 0.05
Higher prevalence of carotid plaques in NAFLDHigher prevalence of carotid plaques in NAFLD• Independent of BMI, diabetes, smoking, lipid profileIndependent of BMI, diabetes, smoking, lipid profile
Higher carotid intima media thickness in NAFLDHigher carotid intima media thickness in NAFLD
• Mediated through visceral fat and serum TGMediated through visceral fat and serum TG
Volzke, W J Gastro 2005Volzke, W J Gastro 2005
Targher, Diabetes Care 2004Targher, Diabetes Care 2004
Competitive Risks : Heart vs LiverCompetitive Risks : Heart vs Liver
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
FFAs - increase in O. patient, D.M. type 2, H.S., C.V.D.
- myocardial dysfunction, proarrhythmic
M.S. -liver release pro-atherogenic factors–CRP,
fibrinogen, PAI-1, other inflammatory cytokines
I.R., DLP => CVD progression (Abdeen et al)
Liver Fat : Center Stage for Liver Fat : Center Stage for Metabolic Syndrome ?Metabolic Syndrome ?
STEATOSISSTEATOSIS
HypertensionHypertension
DiabetesDiabetes
AtherosclerosisAtherosclerosis
ALTALT
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
TAKE HOME MESSAGESTAKE HOME MESSAGES
• Liver injury needs to be assessed in Liver injury needs to be assessed in patients with insulin resistancepatients with insulin resistance
• Steatohepatitis worsens phenotypical Steatohepatitis worsens phenotypical complications of insulin resistance complications of insulin resistance
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
LIVER FATLIVER FAT
Chronic Chronic inflammatoryinflammatory
statestateHepatic IRHepatic IR
Systemic IRSystemic IR
Liver InjuryLiver Injury
• VulnerabilityVulnerability
•NASH/Cirrhosis/liver cancerNASH/Cirrhosis/liver cancer
• NecrosisNecrosis• Innate immune systemInnate immune system• ApoptosisApoptosis
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Marqueurs sériques non-Marqueurs sériques non-invasifs disponiblesinvasifs disponibles
FibroTestFibroTest ELF PanelELF Panel AnguloAngulo Fibromètre Fibromètre Ac Hyaluronique Ac Hyaluronique Score de LainéScore de Lainé
FIBROSE
SteatoTesSteatoTestt
STEATOSE
NASHTestNASHTest CK 18 ?CK 18 ?
STEATOHEPATITE
Wieckowska, Hepatology 2006Wieckowska, Hepatology 2006
Cales, Hepatology 2005Cales, Hepatology 2005
Angulo, Hepatology 2007Angulo, Hepatology 2007
Guha, Hepatology 2008 Guha, Hepatology 2008
Ratziu, BioMedCentral Gastro 2006Ratziu, BioMedCentral Gastro 2006
Poynard, BMC Gastro 2006Poynard, BMC Gastro 2006
Rosenberg, Gastroenterology 2004 Rosenberg, Gastroenterology 2004
Poynard, Comp Hepatol 2005 Poynard, Comp Hepatol 2005
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
TAKE HOME MESSAGESTAKE HOME MESSAGES
• Liver injury needs to be assessed in Liver injury needs to be assessed in patients with insulin resistancepatients with insulin resistance
• Steatohepatitis worsens phenotypical Steatohepatitis worsens phenotypical complications of insulin resistancecomplications of insulin resistance
• Steatohepatitis increases liver-Steatohepatitis increases liver-related morbidity/mortality (cirrhosis related morbidity/mortality (cirrhosis and hepatocellular cancer) and hepatocellular cancer)
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
No changeNo changeMuscle fatMuscle fat
Improvement Improvement in hepatic IRin hepatic IR
Liver fatLiver fat Body fatBody fat
ModestModestWeight lossWeight loss
Petersen, Diabetes 2005Petersen, Diabetes 2005
Tiikkainen, Diabetes 2003Tiikkainen, Diabetes 2003
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy
Cytokines play a pivotal role in pathogenesis and severity of NAFLD.-adipose tissue - endocrine organ - key role in energy homeostasis
- its metabolic products – adipokines- local- peripheral- central effects
Hypertrophied adipocytes -> release chemokines -> recruit macrophages -> releaseinflammatory cytokines
- stimulate inflammatory- suppress anti-inflammatory adipokines
Liver injury -> most adipokines are also produced and secreted by hepatocytes.I. Adipokines - leptin
- adiponectin- resistin- TNF-α - IL-6
new - visfatin - retinol-binding protein 4 (RBP4)
(Emmanuel A. Tsochatzis, George V. Papatheodoridis, and Athanasios J. Archimandritis: Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy, Mediators of
Inflammation, vol. 2009, pag. 831670, 8 pages)
The primary insult in NASH -> accumulation of triglycerides in the liver(as a result of IR)HyperIns. - ↗ glucose uptake \
- ↗ lipogenesis - inhibits lipolysis in the adipose tissue 1. ↗ synthesis of fatty acids in the liver -> lipid accumulation in the hepatocytes 2. ↗ oxidative stress within the hepatocytesII. Leptin - ↗ R.I. -> ↗ steatosis
- proinflammatory role -> mediator of liver fibrosisIII. Adiponectin - secreted by adipocytes = anti-inflammatory adipokine
- ↘ body fat- improves hepatic and peripheral insulin sensitivity- inversely associated with BMI and IR
Adiponectin induction -> protective action of saturated fat in liverIV. TNF-α - associated with obesity and IR
- TNF-α profibrotic action is mediated - Kupffer cells activationV. Resistin - recently discovered adipokine
- secreted by adipose tissue and macrophages- proinflammatory action- stimulates TNF-α and IL-12- regulates the secretion of IL-6 and IL-1BETA
(Emmanuel A. Tsochatzis, George V. Papatheodoridis, and Athanasios J. Archimandritis: Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy, Mediators of
Inflammation, vol.2009, pag. 831670, 8 pages)
VI. IL-6 – hepatoprotective action -> ↘ oxidative stress->preventing mitochondrial dysfunction
short-term action long-term action -> sensitize the liver to injury and apoptotic cell death
VII. Other Cytokines - RBP4 - secreted - adipose tissue ↗ I.R. state- Visfatin -> insulin-mimicking effects, by activating the insulin
receptor
Therapeutic Implications!!! Adipokines are key players in the pathogenesis and progression of NAFLDThe use of drugs directly targeting adipokines.a.Pentoxifylline - nonspecific TNF-α inhibitor - 1200 mg/day - ↘ of serum transaminases after 12 monthsb.Infliximab – selectively blocker of TNF-αc.Pioglitazone - improves NASH lesions - ↗ adiponectin levels – hepatoprotective action d.Tocilizumab - IL-6 receptor antibody
(Emmanuel A. Tsochatzis, George V. Papatheodoridis, and Athanasios J. Archimandritis: Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy, Mediators of
Inflammation, vol. 2009, pag. 831670, 8 pages)
Fatty liver (by US) -> predict the development
- IFG- T2DM
Irrespective of BMI
(T.Yamada, M.Fukatsu, S.Suzuki, T.Wada, T.Yoshida – Fatty liver predicts impaired fasting glucose and type 2 DM in Japanese Undergoing a healts
checkup, J.G.H.F, 25, 2010, 352-356)
Increased risk of liver cancer in Increased risk of liver cancer in diabetic personsdiabetic persons
Japan, General population, 40-69 yrsJapan, General population, 40-69 yrs
97,771 subjects 6,462 incident cancer cases
10.7 yrs mean f/u
MEN (n=3907, DM 366) WOMEN (n=2555, DM 104)
All cancers 1.27 (1.14-1.42) 1.21 (0.99-1.47)
Liver cancer 2.24 (1.64-3.04) 1.94 (1-3.73)Inoue, Arch Intern Med 2006Inoue, Arch Intern Med 2006
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Liver disorders in the elderlyThe prevalence of steatosis in the general population evaluated with ultrasound is approximately : 20 – 30 %.Its prevalence is increasing with advancing age ranging a peak of 62.8% in females and 59.5% in males between 46 - 75 years in a general population from Central Italy.Over 75 years: the prevalence of fatty liver ↘
=> effect of mortality due to M.S.10-15% patients -> advanced fibrosis, cirrhosis, HCCCohort study : Olmsted county (Minnesota)
NAFLD: - significantly higher mortality than expected- mortality was independently associated with:
- age- diabetes- cirrhosis
- increased risk for NAFLD- higher intake of soft drinks&meat- high fat / high calories diet
NAFLD treatment: as prevention rather than cure.prevention - children in primary school
- gradual weight loss – also to elderly(Annarosa Floreani: Liver disorders in the elderly, Best Practice & Research Clinical Gastroenterology, 2009)
Identification and treatment of metabolic complications in pediatric obesity
Pediatric population -> O. -> I.R., Type 2 D.M., Hyperlipidemia, HTA, PCOS, NASH.
-Pediatric obesity : tripled over the past 25 years- 16% girls- 18% boys
+ overweight: - 32% girls- 35% boys
-up 90% of children NAFLD are O.W. or O.- I.R. ↗- ↗ T.G., atherogenic lipid profile- HTA
Direct corelations - number of components of M.S.- higher transaminase levels with more fibrosis on biopsy.
(Ode KL, Frohnert BI, Nathan BM: Identification and treatment of metabolic complications in pediatric obesity, Rev. Endocr. Metab. Disord., 2009, 10: 167-188)
-> obese chinese school children with ↗ ALT & steatosis by liver u.s. – group control
↘ BMI, AST, ALT, I.R. -> - summer camp- vit. E
Dietary modifications may not equate to weight loss => ↘ BMI => ↘ NAFLD
Antioxidants : -> vit. E (α – tocopherol)study : NO. s.s. diference between vit.E, vit.C, placebo
- diet + 2 fold ↗ vit. E => ↘ ALT => larger scale studyInsulin sensitizers : - Pioglitazone
- MetforminOnly Metformin -> appropriate for use in children
Schwimmer et al. – 10 obese children with NAFLD by biopsy -> Met. 500mg x 2 -. S.s. ↘AST, ALT, liver fat, IRNobili et al. – 28 children NAFLD -> Met. 1,5g/day+lifestyle intervention lifestyle intervention
Both groups -> significantly↘ weight, improve ALT, AST, liver fatOther therapies : ursodeoxycolic acid – ineficient in monotherapy
- Pentoxyfilline – down regulates TNF-α production - promising
(Ode KL, Frohnert BI, Nathan BM: Identification and treatment of metabolic complications in pediatric obesity, Rev. Endocr. Metab. Disord., 2009, 10: 167 - 188)
NAFLD in pediatric O.Now: NAFLD – the most common cause of liver disease in childhood.
NHANES - 1999 – 2004 – 8% US children ages 12 – 19- ↗ liver enzymes in the absence of other causes- predilection - Mexican-American children
- male gender- 9,6% - 2 – 19 ages – autopsy
Obese youth – 14 – 24%Treatment – no conclusively proven effective for NAFLD
-Lifestyle interventions – weight loss, key components -> the greater the weight loss, the greater reductions in ALT levels
-Antioxidants vit.E) Metformin -> mixed results
Conclusions : weight reductions through lifestyle intervention.No extrem and rapid weight loss => worsening fibrosis
(Ode KL, Frohnert BI, Nathan BM: Identification and treatment of metabolic complications in pediatric obesity, Rev. Endocr. Metab. Disord., 2009, 10: 167 - 188)
Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis.
Aging -> strongest risk factor for A.D.T2DM, dyslipidemic conditions – cofactors for A.D.
- mild cognitive impairment (MCI)- dementia
- chronic hyperglicemia- IR- oxidative stress- accumulation of A.G.E.P.- ↗ proinflammatory cytokines- microvascular disease
Same insult : -> liver -> NASH, M.S.-> brain -> MCI, AD – type neurodegeneration
Peripheral I.R. Brain I.R. = link <= mediated by a liver-brain axis of neurodegenaration <= excessive neurotoxic lipids <= ceramides across blood-brain barrier(BBB)
(Warren Alpert Medical School of Brown University, Providence, RI 02912, USA: Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis., Current Opinion
in Investigational Drugs, 2009, 10 (10), 1049 - 1060)
Ceramides - I.R.- inflammatory- o. stress- cell death
S.H. (irrespective of etiology) -> ↗ hepatic& visceral ceramide production -> cognitive impairment and neurodegeneration
S.H. + peripheral I.R.-> liver brain axis of neuroinflammation&neurodegeneration by ceramides which can cross the BBB.
Insulin – senziting agents – dietary measures -> ↘ MCI, AD
(Warren Alpert Medical School of Brown University, Providence, RI 02912, USA: Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis., Current Opinion
in Investigational Drugs, 2009, 10 (10), 1049 - 1060)
Is exercise an effective treatment for NASH?
- weight loss is known to be effective as evident in several controlled trials and, in the extreme, with bariatric surgery.Today : skeletal muscle physiology is closely integrated with overall energy homeostasis => increased physical conditioning appears to be closely linked to improved hepatic metabolism !!! independent of changes in body weight
? effects of exercise on liver fat metabolism? how best to measure the degree of physical conditioning
The migratory palmipedes : (migratory geese and ducks)- don’t develop histological NASH- seasonal or pre-migratory steatosis -> carbohydrate loading ->foie gras farming.
Similar seasonal variation in liver fat -> non-hibernating animals.Causes : - changes in thyroid metabolism - altered lipoprotein metabolism
- skeletal muscle energy utilization - in animal : adaptative process preceding increased activity
(Caldwell S, Lazo M : Is exercise an effective treatment for NASH? Knowns and unknowns, Annals of Hepatology, 2009, 8(1). Suppl. – S60 – S66)
Little trials :Rector et al : simple addition of an exercise to an animal model of IR -> profound effects on the development of fatty liverYamauchi et al : Sumo wrestler of Japan
- BMI don’t accurately reflect the percentage of body fat - is due to increased muscle mass.- D.and other metabolic disorders are increased -> exercise training without
weight loss have significant limitations 3 months or less periods of exercise favorably change a number of parameters, without weight loss
- improvement of NASH ? -> more extended periods?Bonekamp et al. : 6-month intervention of 45 minutes exercise + weight lifting - 3 times per week, significant reduction of liver fat in the absence of significant weight loss.- visceral adiposity and steatosis -> correlate inversely with the degree of cardiorespiratory fitnessConclusions : NASH - diet
- exercise induced weight lossEvidence supports the role exercise, independent of weight loss:
- longer duration of physical activity- optimal intensity and amount - unknown- best method to measure?- basal health of the liver
(Caldwell S, Lazo M : Is exercise an effective treatment for NASH? Knowns and unknowns, 2009)
Protective Role of Coffee in NAFLDCofee drinking: - inverse & graded association with the risk of liver cancer
- greater comsumption -> ↘ risk of hepatocarcinomaex.: 2 cups of coffe per day -> ↘ 43% specific risk
Hypothesis: some ingredient in cofee could protect against cirrhosis & alcoholic cirrhosiscoffee, not other beverages with caffeine – inhibits the onset of alcoholic& non-alcoholic liver cirrhosis
↗ body weight -> ↗ γ-GTcoffee drinks ↘ the risk of ↗ γ-GTcoffee drinks ↘ R.I., ↘ risk of elevated ALT
Coffee drink in NAFLD is inversely associated with the degree of bright liver involvement and with overweightness.
Conclusion: a posible, favorable and/or preventive role of coffee use in the natural history of NAFLD, similar to that reported in hepatocarcinoma, cirrhosis and not mediated by I.R., is envisage.
(Daniela Catalano, Giuseppe Fabio Martines, Antonia Tonzuso, Clara Pirri, Francesca M. Trovato and Guglielmo M. Trovato, Protective Role of Coffee in NAFLD, Dig. Dis. Sci. ,2009)
Pharmacological Pharmacological treatmenttreatmentof NASHof NASH
Improve Improve Insulin Insulin
sensitivitysensitivity
Hepato-Hepato-protectantsprotectants
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Treatments:
10 – 15% NASH -> C.H. (cc)
Hussein&all.: 14 pac. = L.B. before and after treatment with 6 month of orlistat 120 mg tid
Results: 70% - reduced fatty infiltration22% - improve inflammation by two
grades50% - improve inflammation by one
gradeimprove in transaminases level, total
cholesterol, triglycerides, LDL, IR index
Weight loss by surgical measures
-bariatric surgery-Roux-en-Y gastric bypas, gastroplasty,
laparoscopic adjustable gastric banding
Review of 19 study of histological effects of gastric bypass of NAFLD. Verna and Berk: bariatric surgery
- usually improves steatosis- occasional reports of regressed cirrhosis
Some authors: the risk of liver disease progression due to rapid weight loss within the first few postoperative month – bariatric surgery in NAFLD and NASH.
Weight loss induced by bariatric procedures could be beneficial for NASH treatment.
The lack of randomised clinical trials to demonstrate the beneficial or harmful effects of bariatric surgery procedures for treatment of NASH could not enable us to reach any scientifically sustained conclusion.
(Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database of
Systematic Reviews 2010, The Cochrane Library)
Bariatric surgery for non-alcoholic steatohepatitis in obese patients
Insulin sensitizing agentsTZD: pioglitazone&rosiglitazone
- increase fatty acid oxidation- decrease fatty acid production within
the liver- improve R.I. - peripherall
- within the liver(Menon KVN, Angulo P, Lindor KD. Severe cjolestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus. Am J Gastroenterol 2001)
- improve transaminases&steatosis(Aithal GP, Thomas JA,Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, Freeman JG, Morgan L, Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008)
- improve in hepatocellular injury, mallory body and fibrosis(Ratziu V, Charlotte F, Jacqueminet S, et al. One year randomized placebo-controlled double-blind trial of rosiglitazone in nonalcoholic steatohepatitis: results of the Pilot trial. Hepatol 2006)
Side effects: - mild weight gain- lower extremity edema
Controversy over the increase cardiac risk of rosiglitazone
Metformin: significant decreases in steatosis,
necroinflammation and steatosislack of placebo controlled trials
Lipid lowering agents
Statins - concerns for hepatotoxicity-rare-use of statin in the setting of
compensated liver disease is safe.(Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatol 2006)(Gomez-Dominguez E, Gispert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemidic, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006)(Lewis JH, Mortensen ME, Zweig S. Efficacy and safety of highdose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatol 2006)
Fibrates: pio., a PPAR-γ agonist with peak PPAR-α activity, has shown some benefit in NAFLD-> it is possible fenofibrate may have some benefit as well
Antioxidants
Oxidative stress – “second hit” in the pathogenesis of NAFLDStudies: vitamin E, alpha-tocopherol
Cytoprotective agents
UDCA = used in primary biliary cirrhosisprimary sclerosing cholangitis
Some conditions: UDCA & dietary restriction were not superior to
dietary restriction alone
Benefits: UDCA + vitamin E
Others: lecithin, silymarin, beta-carotene, metadoxine – might be
examined
Anti-TNF agents
Agents improving necrosis, inflammation and fibrogenesis caused by pro-inflammatory adipocytokines (TNF-α)
Pentoxifylline - xanthine derivative that affects blood viscosity
- treatment of claudication- inhibit TNF-α- improvements in transaminases
(Satapathy SK, Garg S., Chauhan R, et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004)(Adam LA, Zein CO, Angulo P, et al. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004)
Novel treatments
ARB(losartan) - telmisartan \ -> stimulator PPAR-γ
- irbesartan / ↓insulin sensitizing
(Yokohama S, Yoneda M, Haneda M et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatol 2004)
Incretin analogues (exenatide and sitagliptin)(Ding X, Saxena NK, Lin S. Exendin-4, a glucagon-like protein 1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatol 2006)(Tushuizen ME, Brunck MC, Pouwels PJ. Incretin mimetics as a novel therapeutic option for hepatic steatosis. Liver Int. 2006)
Sulfonylureas second generation – repaglinide, nateglinide
Essais thérapeutiques en Essais thérapeutiques en courscours
Acide ursodesoxycholique forte dose, Acide ursodesoxycholique forte dose, multicentrique national , n=126multicentrique national , n=126
Trophos : essai pilote 30 pts en coursTrophos : essai pilote 30 pts en cours CB1 R blockers 2 essais interrompus CB1 R blockers 2 essais interrompus
(Sanofi, Pfizer)(Sanofi, Pfizer) Hépatoprotecteur (inhibiteur PDE4), Hépatoprotecteur (inhibiteur PDE4),
Astellas en coursAstellas en cours Antiapoptotique (anticaspase 3), Gilead en Antiapoptotique (anticaspase 3), Gilead en
courscours
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance
Conclusions: some certines- bariatric surgery- TZD- vitamin E
Focus on treating the comorbid conditions associated with metabolic syndrome.Life-style : diet + exercise
?? of physical activity is required to produce significant changes in hepatic fat(Kwon do Y, Jung YS, Kim SJ, Park HK, Kim YC. Impaired sulfur-amino acid metabolism and oxidative stress in nonalcoholic fatty liver are alleviated by betaine supplemention in rats. J. Nutr 2009)(Nugent C, Younossi ZM. Evaluation and management of obesity-related non-alcoholic fatty liver disease. Nature Clinical Practice Gastroenterology & Hepatology 2007)
TAKE HOME MESSAGESTAKE HOME MESSAGES
• Liver injury needs to be assessed in patients Liver injury needs to be assessed in patients with insulin resistancewith insulin resistance
• Steatohepatitis worsens phenotypical Steatohepatitis worsens phenotypical complications of insulin resistancecomplications of insulin resistance
• Steatohepatitis increases liver-related Steatohepatitis increases liver-related morbidity/mortality (cirrhosis and hepatocellular morbidity/mortality (cirrhosis and hepatocellular cancer) cancer)
• Set up collaborative networks with Set up collaborative networks with endocrinologistsendocrinologists
• The era of targeted therapies in NASH is starting The era of targeted therapies in NASH is starting and therefore therapeutic trials are essentialand therefore therapeutic trials are essential
Prof. Vlad Ratziu, Université Pierre et Marie Curie Hôpital Pitié Salpêtrière, Paris - NASH, the liver and insulin resistance