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)