NAFLD, NASH
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Transcript of NAFLD, NASH
DR. Shatdal Chaudhary MDDR. Shatdal Chaudhary MD
NAFLD
NNon-on-AAlcoholic lcoholic FFatty atty LLiver iver DDisease isease (NAFLD) (NAFLD)
• An epidemic of new milleniumAn epidemic of new millenium..• A new consequence of A new consequence of the obesity epidemicthe obesity epidemic..• Represents a spectrum of conditions
characterized by macrovesicular hepatic steatosis in the absence of significant alcohol intake.
• Includes histological pattern:– Simple steatosis( without inflammation)– Steatohepatitis(NASH) with inflammation fibrosis &
cirrhosis
NNon-on-AAlcoholic lcoholic FFatty atty LLiver iver DDiseaseisease(NAFLD) (NAFLD)
Fatty liver (Steatosis)
SteatohepatitisSteatohepatitis - inflammation- inflammation - fibrosis - fibrosis
Cirrhosis Cirrhosis
Normal liver Normal liver
The Brief History of NAFLD The Brief History of NAFLD
Fatty Liver Disease: NASH and Related DisordersFatty Liver Disease: NASH and Related DisordersBlackwell Publishing, 2005 Blackwell Publishing, 2005
19791979 ~8 papers published~8 papers published19981998 First NIH conferenceFirst NIH conference19991999 First Clinical Trials First Clinical Trials20022002 ~60 papers published~60 papers published20042004 Release of first book on NAFLD/NASHRelease of first book on NAFLD/NASH20052005 ~354 papers published~354 papers published
Prevalence of fatty liverPrevalence of fatty liver
• “Estimated” prevalence is 2.8 - 25 % of population
• 20 to 30 % adults in western countries have NAFLD of which 2 to 3 % are NASH
(Imaging & autopsy study)
• Steatosis seen in 80 % obese patients
• NASH seen in 9 - 30 % obese Hepatology 2003
NAFLD NAFLD
1. 1. Most commonMost common of all liver disorders. of all liver disorders.2. Frequent cause of chronic liver disease.2. Frequent cause of chronic liver disease.3. Present in 3% of children and >50% of 3. Present in 3% of children and >50% of obese children.obese children.
Fatty Liver Disease: NASH and Related DisordersFatty Liver Disease: NASH and Related DisordersBlackwell Publishing, 2005 Blackwell Publishing, 2005
Prevalence of NAFLD In General Prevalence of NAFLD In General Population In Asian Pacific RegionPopulation In Asian Pacific Region
Name of the Percentage NAFLD inCountry AdultsJapan 9 – 30%China 5 – 18%Korea 18 %India 5 – 28%Indonesia 30%Malaysia 17 %Singapore 5%
Prevalence of NAFLD In High Risk Prevalence of NAFLD In High Risk Population In Asian Pacific RegionPopulation In Asian Pacific Region
Name of the Diabetes Obesity Dyslipidemia country
Japan 40-50% 50-80% 42-58%China 35% 70-80% 57% Korea 35% 10-50% 26-35%India 30-90% 15-20% NAIndonesia 52% 47% 56%
Aetiological ClassificationAetiological Classification
• Primary NAFLD: associated with metabolic syndrome.
• Secondary NAFLD: includes fatty liver diseases with a proximate causes.
Types of NAFLDTypes of NAFLD Primary Secondary 1 Insulin resistance 1 severe weight loss
Obesity jejunoileal bypass
Diabetes gastric bypass
Hypertriglyceridemia severe starvation
Hypertension 2 total parenteral nutrition
3 Iatrogenic
Amiodarone
Diltiazem
Tamoxifen
Steroids
HAART
3 Refeeding syndrome
4 Toxic exposure
Hydrocarbon , yellow phosphorus
5 Disorders of lipid metabolism
Abetalipoproteinemia
Hypobetalipoproteinemia
Andersen’s disease
Weber –christian syndrome
Morbid ObesityMorbid Obesity• Four studies evaluating > 600 morbidly
obese patients undergoing gastric bypass – All patients underwent intraoperative liver
biopsies– Prevalence of NAFL ranged from 30-90% and
NASH was documented in 33-42%. – > 2/3 of morbidly obese patients
undergoing gastric bypass surgery have NAFL/NASH
Abrams GA, et al. Hepatology 2004;40:475-483; Frantzides CT, et al. J Gastrointest Surg 2004;8:849-855; Dallal RM, et al. Obes Surg 2004;14:47-53; Beymer C, et al. Arch Surg 2003;138:1240-1244.
Type 2 Diabetes MellitusType 2 Diabetes Mellitus
• Recent study surveyed 100 patients with type 2 DM and used U/S to screen for NAFLD– Detected fatty liver in 50% of patients – Performed subsequent liver biopsy in those
with NAFLD:• NAFL: 13%
• NASH: 86%
• Fibrosis: 22%
Gupte, et al. J Gastro Hepatol 2004;19:854-858.
DyslipidemiaDyslipidemia
• Canadian study used U/S to screen 95 adults with dyslipidemia– Detected fatty liver in 50%– Steatosis was particularly common in
individuals with moderate to severe hypertriglyceridemia or mixed dyslipidemia
– Hypertriglyceridemia and mixed dyslipidemia increased the risk for hepatic steatosis by ~5-fold
Assy N, et al. Dig Dis Sci 2000;45:1929-1934.
PathophysiologyPathophysiology
Salgado W, et al. Acta Cir. Bras. 2006; 21.
Two-hit HypothesisTwo-hit Hypothesis
Fatty Liver11stst Hit Hit
Damaged Liver
22ndnd Hit HitOxidative StressOxidative Stress
ToxinsToxinsInflammatoryInflammatoryMoleculesMolecules
SusceptibilitySusceptibility
Donnelly et al. J. Clin. Invest. 113: 1343, 2005Day and James. Gastroenterol. 114: 842, 1998
DietDietFFAFFA
BurnedBurnedVLDL-TGVLDL-TG
Liver DamageLiver Damage
22ndnd Hit Hit
Liver DamageLiver DamageSat FASat FA
22ndnd Hit Hit
ApoptosisApoptosis
Hepatocyte Mass Hepatocyte Mass
Fatty Liver Fatty Liver
PathophysiologyPathophysiology
• Other factors involved in NASH pathogenesis– Bacterial overgrowth
• Increased hepatic oxidative stress• Production of ethanol and TNF-α• Direct activation of inflammatory cytokines and
liver macrophages via release of lipopolysaccarides
– Leptin – Obesity gene
• Regulates food intake and body composition• Leads to hepatic steotosis by promoting insulin
resistance or by modulating insulin signalling in hepatocytes
Pathophysiology: othersPathophysiology: others
• Serum and liver iron– Mitochondrial β oxidation leads to generation
of hydrogen peroxide– In presence of increased iron hydrogen
peroxide converted to hydroxyl free radicles– This leads to oxidative stress and
hepatocellular injury
Pathophysiology: othersPathophysiology: others
• TNF- α– Corelates with obesity– Derives from adipose tissue– Decrease phosphorylation of insulin receptor– Reduce expression of GLUT-4– Contributes toward insulin resistence– Also causes chemotaxis, activation of stellate
cells, Mallory hyaline formation, collagen synthesis
Clinical PresentationClinical Presentation
• Variable clinical presentation • Typically asymptomatic, but may have
hepatomegaly and abdominal discomfort• Liver enzymes may be normal in >75% of
cases, making them insensitive in detecting NAFLD– When increased, usually only modestly and
limited to aminotransferases– ALT upper limits of normal: <30 in M, <20 in F
Natural history and clinical Natural history and clinical outcomes of NASHoutcomes of NASH
20% 30—40%
NASH CIRRHOSIS Liver related Death
Sub acute HCC Post-OLTX
Failure recurrance
DiagnosisDiagnosis
• Cf• h/o • Disturbed liver enzymes
• Radioimaging• Biopsy
Lab StudiesLab Studies
• No laboratory studies can help definitively establish a diagnosis of fatty liver or NASH.
• Aminotransferases– Elevated AST or ALT– As much as 10-fold– In the absence of cirrhosis, an AST-to-ALT ratio of
greater than 2 suggests alcohol use, whereas a ratio of less than 1 may occur in patients with NASH.
• Alkaline phosphatase– Can be elevated– Usually less than 2 to 3 times normal
DiagnosisDiagnosis
• Diagnosis of NAFLD can often be made by imaging studies, including U/S, CT or MRI – detects presence of fat
Diagnosis (cont.)Diagnosis (cont.)
• MR spectroscopy accurately measures hepatic triglyceride content– Has advantage over U/S, CT and MRI as it is
quantitative rather than qualitative
Diagnosis (cont.)Diagnosis (cont.)
• No imaging studies can differentiate between the histological subtypes of benign steatosis or aggressive NASH, or stage the degree of fibrosis– Need tissue for staging
and to make diagnosis of NASH
• Liver biopsy– A liver biopsy and histopathological
examination are required to establish the diagnosis.
– The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use).
• Doing liver biopsy is controversial– Arguments favoring
• Exclusion of other cause• To distinguish steatosis from NASH • Estimation of prognosis• Determination of progression
– Arguments against biopsy• Good prognosis• Lack of effective therapy• Risk & cost associated with biopsy
HistologyHistology
• Histologic diagnosis of NAFL requires presence of ≥ 5% steatosis– Indistinguishable
from alcoholic fatty liver
HistologyHistology
• NASH involves presence of steatosis with evidence of inflammation and hepatocyte injury: – Ballooning – Mallory bodies
HistologyHistology
• Histologic evidence of steatohepatitis may disappear with progression to cirrhosis – Thus, significant
proportion of cryptogenic cirrhosis is likely related to unrecognized NASH
COMPLICATIONCOMPLICATION
• Cirrosis – Risk- 8 to 15%
• Hepatocellular carcinoma– Risk: 1-2%
NASH Criteria (AGA guidelines)NASH Criteria (AGA guidelines)
• Characteristic liver biopsy that shows fatty change with inflammation– Indistinguishable from alcoholic hepatitis
• Convincing evidence of negligible alcohol consumption (less than 20g alcohol per day)– Detailed history obtained independently by 3
physicians, interrogation of family members
• Absence of serologic evidence of Hep B or Hep C infection – Should not exclude those with evidence of past Hep B
infection, but should exclude patients with positive HBs Ag or HCV Ab
• Clues for severe NASH– Old age(>50 yrs)– Presence of diabetes– Pesence of obesity– AST/ALT > 1– ALT >2 times of normal– TG >1.7m mol/L
Prognosis Prognosis
• Patients with bland steatosis (NAFL) have a benign liver-related prognosis– 1.5% develop cirrhosis– 1% die from liver-related causes over 10-20 years
• Almost 30% of patients with NASH and fibrosis become cirrhotic within 5-10 years– Those with biopsy-proven NASH have a liver-related
death rate of ~10%
• NASH cirrhosis may develop into HCC– ~13% of cases of all HCC are related to NASH cirrhosis– Endstage NAFLD accounts for ~5-10% of liver
transplantsMatteoni C, et al. Gastroenterology 1999;116:1413-1419.
TreatmentTreatment
• Aim to improve insulin sensitivity and modify underlying metabolic risk factors– Diet and exercise– Insulin Sensitizing Agents (metformin, TZD)– Lipid lowering medications (statins, fibrates)
• L-Carnitine supplementation
McCullough AJ. N Engl J Med 2006; 355: 2361-3.
TreatmentTreatment• Lifestyle modification
– Diet and exercise• Weight reduction• Insulin sensitizers
– Metformin– Troglitazone– Rosiglitazone– Pioglitazone
• Lipid Lowering agents• Antioxidants
– Vitamin E– Vitamin C
• Hepatoprotective agents– Betaine– Ursodeoxycholic acid– Pentoxyfylline
• Angiotensin-converting enzyme inhibitors• Probucol
Treatment (cont.)Treatment (cont.)
• Beneficial according to preliminary studies:– Insulin sensitizers: TZD > metformin
• Benefit unproven by preliminary studies– Lipid lowering agents– Antioxidants– Probiotics (animal models only)
• Not beneficial– Ursodiol
BetaineBetaine• Metabolite of Choline
• increases S-adenosylmethionine levels (SAM)
• protect against steatosis and decrease oxidative stress.
PentoxifyllinePentoxifylline
• Production of tumour necrosis factor-alpha is one of the primary events in many types of liver injury
• Patients with NASH have been shown to have higher levels of TNF-alpha.
• Biochemical improvement was demonstrated in certain study
ProbucolProbucol
• Probucol is a lipid-lowering drug with potent antioxidant properties that tends to accumulate in fatty tissues
• Significant improvement in ALT levels with normalization of aminotranferases