NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IN METABOLIC SYNDROME&TYPE 2 D.M.

M.D., Ph.D., Prof.Dr.Amorin-Remus Popa, University of Oradea, Emergency 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)

NASH
-intermediate stage in the progression from steatosis to cirrhosis -histological -Steatosis -Mixed inflammatory cell infiltration -Necrosis -Progresive fibrosis -Cirrhosis and end-stage liver disease
Similar to alcoholicinduced hepatics

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 steatosis a. 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)

2. Etape diagnostique : distinction statose vs statohpatite

Nonalcoholic Fatty Liver Disease

Excessive liver fat

Bland steatosis

Steatohepatitis

Diagnostic distinction based on hepatocyte cell injury

(ballooning, necrosis / inflammation, Mallory bodies)

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Bland steatosis

Steatosis without other histological signs

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Steatohepatitis
Steatosis Hepatocyte cell injury Ballooning, lobular inflammation/necrosis, Mallory bodies, PMN

ballooning

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

3. Etape pronostique : valuer le stade de fibrose

Nonalcoholic Fatty Liver Disease

Excessive liver fat

Bland steatosis

Steatohepatitis

Diagnostic distinction based on hepatocyte cell injury

(ballooning, necrosis / inflammation, Mallory bodies)

F0 (/F1 ?)

F0

F4

Perisinusodal Fibrosis Portal Fibrosis Prognostic value

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

 Pourquoi la statose ?

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

NAFLD : a Model of Insulin Resistance-Induced Liver Injury

Normal liver INSULIN SENSITIVITY

STEATOSIS
Insulin Resistance

STEATOHEPATITIS
?

CIRRHOSIS
?

?
LIVER FAILURE

? CANCER

HEMORRAGE

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Physiologie de la rpartition des substrats nergtiques :

distance des repas, le foie produit du glucose (PHG) et le tissu adipeux produit les acides gras ncessaires au muscle et au foie (voies inhibes par linsuline)

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, 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 standard Dallas Heart Study / 30% of adult Americans \- NAFLD Dionysos Study \ 25% of adult Italians /-

79% and 55% patients with NAFLD normal aminotransferase levels liver enzymes highly underestimate the prelevance of NAFLD

Prvalence de la statose chographique

% 74 70

22

Sujet Normal

Obsit

Diabte Type 2

Sd mtabo lique

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Prvalence de la statopathie mtabolique chez les patients avec augmentation des transaminases
Evaluation prospective multicentrique franaise (21 centres) des 274 sujets avec augmentation inexplique des transaminases
Autres 23% Statose

26%

Statopathies mtabolqiues

Normal

Steatohpatite
32%

58 %

19%

De Ledinghen, Ratziu, J Hepatol 2006

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

TAKE HOME MESSAGES

Liver injury needs to be assessed in

patients with insulin resistance

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Steatosis Independently Induces Hepatic IR

3 day high fat diet
Samuel, Shulman, JBC 2004

No increase visceral fat No increased portal FFA

No muscle adipose IR

STEATOSIS
MUSCLE: normal glucose uptake ADIPOSE T : normal inhibition of FFA release by insulin

insulin suppression of hepatic glucose production

HEPATIC INSULIN RESISTANCE

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Liver Fat is Associated with Defects in Insulin Action Independent of Obesity in Normal Men

30 Healthy controls differing in the amount of liver fat Individuals with high liver fat content had :

Higher fasting hyperinsulinemia (7.3 vs 5.3) Higher TG levels (1.4 vs 0.9) Lower HDLc (1.4 vs 1.6) Higher blood pressure (130 vs 122) Impaired insulin suppression of glucose and FFA
Seppala-Lindroos, JCEM 2002

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Liver Fat Content : a Major Determinant of Insulin Requirements in Diabetes

N=20 stable Type 2, Insulin treated diabetic Pts

60% of the variation of the daily insulin requirements was attributable to the variation of hepatic fat content % fat liver was most closely correlated with reduced suppression of hepatic glucose production by insulin
Ryysy, Diabetes 2000

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

NAFLD patients present increased subclinical atherosclerosis compared to non-steatosis individuals NAFLD

-CVD is the second most common cause of death in

triad: steatosis,

-hepatic steatosis alone -> 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 Liver

Early endothelial dysfunction in NAFLD
Independent of BMI, HOMA ? Villanova, Hepatology 2005

controls

steatosis

NASH

Higher CV risk profile* in NAFLD

NAFLD

Median 3.7%
Median 1.2%

Villanova, Hepatology 2005 Ioannou, Gastroenterology 2006

Controls

*Framingham 10-year risk

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Competitive Risks : Heart vs Liver

Higher carotid intima media thickness in NAFLD

Mediated through visceral fat and serum TG

Higher prevalence of carotid plaques in NAFLD
Targher, Diabetes Care 2004

Independent of BMI, diabetes, smoking, lipid profile

No steatosis
100

Steatosis *

% patients with plaque

90 80 70 60 50 40 30 20 10 0 <50 50-59

* * * p < 0.05

Volzke, W J Gastro 2005

60-69

70-79

Age (yr)

N=4222

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

FFAs C.V.D.

- increase in O. patient, D.M. type 2, H.S., - myocardial dysfunction, proarrhythmic

M.S.

-liver release pro-atherogenic factorsCRP, fibrinogen, PAI-1, other inflammatory cytokines

I.R., DLP => CVD progression (Abdeen et al)

Liver Fat : Center Stage for Metabolic Syndrome ?

Hypertension Atherosclerosis

STEATOSIS

ALT

Diabetes
Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

TAKE HOME MESSAGES

Liver injury needs to be assessed in

patients with insulin resistance Steatohepatitis worsens phenotypical complications of insulin resistance

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

LIVER FAT
Chronic inflammatory state Hepatic IR

Liver Injury
Vulnerability
Necrosis Innate immune system Apoptosis NASH/Cirrhosis/liver cancer

Systemic IR

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Marqueurs sriques non-invasifs disponibles

FIBROSE STEATOSE STEATOHEPATITE

FibroTest SteatoTest NASHTest ELF Panel CK 18 ? Angulo Ratziu, BioMedCentral Gastro 2006 Fibromtre Guha, Hepatology 2008 Angulo, Hepatology 2007 Ac Hyaluronique Cales, Hepatology 2005 Score de Lain Rosenberg, Gastroenterology 2004
Poynard, Comp Hepatol 2005 Poynard, BMC Gastro 2006 Wieckowska, Hepatology 2006

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

TAKE HOME MESSAGES

Liver injury needs to be assessed in

patients with insulin resistance Steatohepatitis worsens phenotypical complications of insulin resistance Steatohepatitis increases liver-related morbidity/mortality (cirrhosis and hepatocellular cancer)

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Modest Weight loss

Liver fat

No change Muscle fat

Body fat

Tiikkainen, Diabetes 2003 Petersen, Diabetes 2005

Improvement in hepatic IR
Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, 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 -> release inflammatory cytokines - stimulate inflammatory - suppress anti-inflammatory adipokines Liver injury -> most adipokines are also produced and secreted by hepatocytes. I. Adipokines - leptin - adiponectin - resistin - TNF- - 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

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 hepatocytes II. Leptin - R.I. -> steatosis - proinflammatory role -> mediator of liver fibrosis III. 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 liver IV. TNF- - associated with obesity and IR - TNF- profibrotic action is mediated - Kupffer cells activation V. Resistin - recently discovered adipokine - secreted by adipose tissue and macrophages - proinflammatory action - stimulates TNF- 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 NAFLD The use of drugs directly targeting adipokines. a.Pentoxifylline - nonspecific TNF- inhibitor - 1200 mg/day - of serum transaminases after 12 months b.Infliximab selectively blocker of TNF- c.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 diabetic persons

Japan, General population, 40-69 yrs

97,771 subjects

10.7 yrs mean f/u

6,462 incident cancer cases WOMEN (n=2555, DM 104)

MEN (n=3907, DM 366)

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 2006

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Liver disorders in the elderly

The 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, HCC Cohort 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 ( tocopherol) study : NO. s.s. diference between vit.E, vit.C, placebo - diet + 2 fold vit. E => ALT => larger scale study Insulin sensitizers : - Pioglitazone - Metformin Only 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, IR Nobili et al. 28 children NAFLD -> Met. 1,5g/day+lifestyle intervention lifestyle intervention Both groups -> significantly weight, improve ALT, AST, liver fat Other therapies : ursodeoxycolic acid ineficient in monotherapy - Pentoxyfilline down regulates TNF- 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) - dont 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 liver Yamauchi et al : Sumo wrestler of Japan - BMI dont 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 fitness Conclusions : NASH - diet - exercise induced weight loss Evidence 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 NAFLD

Cofee drinking: - inverse & graded association with the risk of liver cancer - greater comsumption -> risk of hepatocarcinoma ex.: 2 cups of coffe per day -> 43% specific risk Hypothesis: some ingredient in cofee could protect against cirrhosis & alcoholic cirrhosis coffee, not other beverages with caffeine inhibits the onset of alcoholic& nonalcoholic liver cirrhosis body weight -> -GT coffee drinks the risk of -GT coffee 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 treatment of NASH

Improve Insulin sensitivity

Hepatoprotectants

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance

Treatments: 10 15% NASH -> C.H. (cc) Hussein&all.: 14 pac. = L.B. before treatment with 6 month of orlistat 120 mg tid and after

Results:

70% - reduced fatty infiltration 22% - improve inflammation by two grades 50% - improve inflammation by one grade improve 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.

Bariatric surgery for non-alcoholic steatohepatitis in obese patients

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)

Insulin sensitizing agents TZD: 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)

(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 transaminases&steatosis

and fibrosis

- improve in hepatocellular injury, mallory body

(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 rosiglitazone

cardiac

risk

of

Metformin: significant decreases in steatosis, necroinflammation and steatosis lack 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- agonist with peak PPAR- 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 NAFLD Studies: vitamin E, alpha-tocopherol Cytoprotective agents UDCA = used in primary biliary cirrhosis primary 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-) Pentoxifylline viscosity - xanthine derivative that affects blood

- treatment of claudication - inhibit TNF- - 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- - irbesartan / insulin sensitizing Incretin analogues (exenatide and sitagliptin)

(Yokohama S, Yoneda M, Haneda M et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatol 2004)

(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 thrapeutiques en cours

Acide ursodesoxycholique forte dose, multicentrique national , n=126 Trophos : essai pilote 30 pts en cours CB1 R blockers 2 essais interrompus (Sanofi, Pfizer) Hpatoprotecteur (inhibiteur PDE4), Astellas en cours Antiapoptotique (anticaspase 3), Gilead en cours

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, 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 MESSAGES

Liver injury needs to be assessed in patients with

insulin resistance Steatohepatitis worsens phenotypical complications of insulin resistance Steatohepatitis increases liver-related morbidity/mortality (cirrhosis and hepatocellular cancer) Set up collaborative networks with endocrinologists The era of targeted therapies in NASH is starting and therefore therapeutic trials are essential

Prof. Vlad Ratziu, Universit Pierre et Marie Curie Hpital Piti Salptrire, Paris - NASH, the liver and insulin resistance