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NONALCOHOLIC NONALCOHOLIC STEATOHEPATITISSTEATOHEPATITIS
(NASH), NAFLD, ASH(NASH), NAFLD, ASH
J. HorákJ. Horák
Department od Medicine IDepartment od Medicine I Third Faculty of MedicineThird Faculty of Medicine
Charles UniversityCharles University
HEPATIC STEATOSISHEPATIC STEATOSIS
macrovesicular macrovesicular
in long-standing disorders of hepatic lipid in long-standing disorders of hepatic lipid metabolism (obesity, DM type II, alcohol)metabolism (obesity, DM type II, alcohol)
microvesicularmicrovesicular
impaired impaired ßß-oxidation of FA – abnormal -oxidation of FA – abnormal metabolism of VLCFA, LCFA, DCA and other metabolism of VLCFA, LCFA, DCA and other substrates for peroxisomal FA-CoA oxidase substrates for peroxisomal FA-CoA oxidase that activate PPAR-that activate PPAR-αα (peroxisome proliferator- (peroxisome proliferator-activated receptor)activated receptor)
NASHNASH
First described by Ludwig et al. (Mayo Clin. First described by Ludwig et al. (Mayo Clin. Proc. 55, 1980, 434 - 438)Proc. 55, 1980, 434 - 438)
NASH is a part of Nonalcoholic Fatty Liver NASH is a part of Nonalcoholic Fatty Liver Disease (NAFLD)Disease (NAFLD)
Defined clinically (alcohol intake Defined clinically (alcohol intake << 20 g/day) 20 g/day) and histologically; liver biopsy is necessary and histologically; liver biopsy is necessary for reliable diagnosis for reliable diagnosis
Predisposing factors: obesity, adult age, Predisposing factors: obesity, adult age, diabetes mellitus type II, female sex diabetes mellitus type II, female sex
Lab: AST Lab: AST >> ALT, ALT, hypertriacylglycerolemiahypertriacylglycerolemia
NAFLDNAFLD
Is a result of insulin resistance Is a result of insulin resistance
Histological findings:Histological findings:
1.1. Simple steatosis Simple steatosis
2.2. Steatosis plus inflammation Steatosis plus inflammation
3.3. Steatosis plus balloon degenerationSteatosis plus balloon degeneration
4.4. Steatosis, sinusoidal fibrosis and Steatosis, sinusoidal fibrosis and polymorphonuclear cell infiltrate, sometimes polymorphonuclear cell infiltrate, sometimes together with Malloryho hyalinetogether with Malloryho hyaline
Only stages 3 and 4 correspond with NASHOnly stages 3 and 4 correspond with NASH
PREVALENCEPREVALENCE
Whole population:Whole population:
NAFLD NAFLD ~~ 20% 20%
NASH NASH ~~ 2 – 3% 2 – 3%
The highest occurrence of NAFLD:The highest occurrence of NAFLD:
5th – 6th decade, females (65 – 83%), 5th – 6th decade, females (65 – 83%), diabetes mellitus type II (28 – 55%), obesity diabetes mellitus type II (28 – 55%), obesity (60 – 95%), hyperlipidemia (20 – 92%)(60 – 95%), hyperlipidemia (20 – 92%)
THE METABOLIC SYNDROME THE METABOLIC SYNDROME AND NAFLD AND NAFLD
67% patients with NAFLD and 88% with NASH 67% patients with NAFLD and 88% with NASH have MShave MS
MS increases risk of NASH (OR 3.2) and hepatic MS increases risk of NASH (OR 3.2) and hepatic fibrosis (OR 3.5)fibrosis (OR 3.5)
prevalence of MS in NAFLD increases with BMIprevalence of MS in NAFLD increases with BMI
in NAFLD prevalence of NASH increases with in NAFLD prevalence of NASH increases with BMIBMI
~~ 66% patients with NAFLD have 66% patients with NAFLD have hypertriacylglycerolemia hypertriacylglycerolemia
Marchesini et al, Hepatology 2003
CAUSES OF NAFLDCAUSES OF NAFLDMetabolic syndromeMetabolic syndrome– Insulin resistance is an important part of NAFLD Insulin resistance is an important part of NAFLD
and is found also in patients with normal weight and is found also in patients with normal weight and glucose tolerance and glucose tolerance
– NAFLD increases exponentially přibývá NAFLD increases exponentially přibývá exponenciálně with type II DM, hyperlipidemia, exponenciálně with type II DM, hyperlipidemia, visceral obesity and hypertensionvisceral obesity and hypertension
Drugs (steroids, amiodaron, diltiazem)Drugs (steroids, amiodaron, diltiazem)Chronic inflammation Chronic inflammation Total parenteral nutrition Total parenteral nutrition Short-bowel syndromeShort-bowel syndromeInborn errors of lipid metabolism Inborn errors of lipid metabolism (abetalipoproteinemia etc.)(abetalipoproteinemia etc.)
ETIOPATHOGENESIS OF NASH ETIOPATHOGENESIS OF NASH (1)(1)
Defined causesDefined causesThe initial lesion is simple steatosis; The initial lesion is simple steatosis; episodes of steatohepatitis lead to cirrhosis episodes of steatohepatitis lead to cirrhosis (cirrhosis prevalence up to 25%)(cirrhosis prevalence up to 25%)Insulin resistance of any cause Insulin resistance of any cause Rapid weight loss in obesity Rapid weight loss in obesity Total parenteral nutritionTotal parenteral nutritionDrugs and other toxins Drugs and other toxins Jejunoileal bypassJejunoileal bypassTNF-TNF-αα polymorfismspolymorfismsCopper intoxication Copper intoxication
ETIOPATHOGENESIS OF NASH ETIOPATHOGENESIS OF NASH (2)(2)
NASH might be due to liver lesion in NASH might be due to liver lesion in frame of a systemic disease frame of a systemic disease
Industrial toxins Industrial toxins – dimetylformamiddimetylformamid– toxic oil syndrometoxic oil syndrome
ETIOPATHOGENESIS OF NASH ETIOPATHOGENESIS OF NASH (3)(3)
DrugsDrugs
amiodaronamiodaron
perhexillinperhexillin
dilthiazem, niphedipindilthiazem, niphedipin
synthetic estrogens, tamoxiphensynthetic estrogens, tamoxiphen
chloroquinechloroquine
salicylatessalicylates
glucocorticoids (high doses)glucocorticoids (high doses)
tetracyclinetetracycline
ETIOPATHOGENESIS OF NASH ETIOPATHOGENESIS OF NASH (4)(4)
OthersOthers
Gluten-sensitive enteropathy Gluten-sensitive enteropathy
AbetalipoproteinemiaAbetalipoproteinemia
Wilson diseaseWilson disease
Colon diverticulosis Colon diverticulosis
PATHOGENESIS OF NASHPATHOGENESIS OF NASH
insulin resistanceinsulin resistance
simple hepatic steatosissimple hepatic steatosis
reactive oxygen speciesreactive oxygen species
lipid peroxidationlipid peroxidation
NASHNASH
?
HISTOLOGY OF NASHHISTOLOGY OF NASH
steatosis (100%)steatosis (100%)
balloon degeneration of hepatocytes (100%)balloon degeneration of hepatocytes (100%)
mild diffuse infiltration by PMNs (56 – 100%)mild diffuse infiltration by PMNs (56 – 100%)
perivenular and perisinusoidal collagen perivenular and perisinusoidal collagen deposition (41 – 100%)deposition (41 – 100%)
cirrhosis (0 – 26%)cirrhosis (0 – 26%)
Mallory hyaline (0 – 90%)Mallory hyaline (0 – 90%)
glycogen nuclei (35 – 100%)glycogen nuclei (35 – 100%)
focal necroses (25 – 57%)focal necroses (25 – 57%)
MINIMAL DEMANDS FOR MINIMAL DEMANDS FOR DIAGNOSISDIAGNOSIS
mainly macrovesicular steatosismainly macrovesicular steatosis
mild lobular infiltration by PMNs and mild lobular infiltration by PMNs and mononuclearsmononuclears
balloon degeneration of hepatocytes balloon degeneration of hepatocytes with a maximum around steatotic with a maximum around steatotic hepatocytes in zone 3hepatocytes in zone 3
CLINICAL AND LABORATORY CLINICAL AND LABORATORY FINDINGSFINDINGS
Asymptomatic course - in 45 – 100%Asymptomatic course - in 45 – 100%Symptomes: right epigastric pain, Symptomes: right epigastric pain,
abdominal dyscomfort, fatigue, malaiseabdominal dyscomfort, fatigue, malaiseObjective findings: hepatomegaly (12 – Objective findings: hepatomegaly (12 –
75%), abnormal liver fubction tests, 75%), abnormal liver fubction tests, precoccious atherosclerosis in NASH precoccious atherosclerosis in NASH
US, CT, NMR: hepatic steatosis US, CT, NMR: hepatic steatosis In advanced cases hepatic cirrhosis In advanced cases hepatic cirrhosis
(„cryptogenic“)(„cryptogenic“)
Adams et al, Gastroenterology, 2005, 129:113-121
NAFLD MORTALITY
TREATMENT OF NASH (1)TREATMENT OF NASH (1)
treatment of associated conditions treatment of associated conditions (metabolic syndrome, obesity, (metabolic syndrome, obesity, hyperglycemia, hyperlipidemia)hyperglycemia, hyperlipidemia)
aerobic exerciseaerobic exercise
avoid suspected drugs avoid suspected drugs
in terminal stage of cirrhosis liver in terminal stage of cirrhosis liver transplantation transplantation
TREATMENT OF NASH (2)TREATMENT OF NASH (2)
UDCA (Ursofalk), N-acetylcystein (ACC), UDCA (Ursofalk), N-acetylcystein (ACC), αα-tocoferol-tocoferol
statinesstatines
sibutramin (Meridia), orlistat (Xenical)sibutramin (Meridia), orlistat (Xenical)
metforminmetformin
thiazolidindiones – pioglitazone - Actos, thiazolidindiones – pioglitazone - Actos, rosiglitazone - Avandiarosiglitazone - Avandia
TREATMENT OF NASH (3)TREATMENT OF NASH (3)
anti-TNF drugs: pentoxiphyllin, anti-TNF drugs: pentoxiphyllin, adiponectineadiponectine
phenofibratephenofibrate
In extreme obesity (BMI In extreme obesity (BMI >> 40 or 40 or BMI BMI >> 35 + risk factors): bariatric 35 + risk factors): bariatric surgery surgery
NASH: NASH: before and after treatment with before and after treatment with pioglitazone + vitamin Epioglitazone + vitamin E
Sanyal et al, Clin Gastroenterol and Hepatol, Dec 2004Sanyal et al, Clin Gastroenterol and Hepatol, Dec 2004
Pre treatment (10 X) Post treatment (10 X)