Download - DR. UMESH KHANNA MUMBAI NASH and nonalcoholic liver disease NASH – NonAlcoholic SteatoHepatitis

DR. UMESH KHANNAMUMBAI

NASH and nonalcoholic liver disease

NASH – NonAlcoholic SteatoHepatitis

Introduction

Non-alcoholic fatty liver diseases [NAFLD] represents a spectrum of diseases ranging from

“simple steatosis,” which is considered relatively benign, to

Non alcoholic steatohepatitis (NASH) and NAFLD-associated cirrhosis and end-stage liver disease

Has become a common cause of liver transplant Also been identified as an important risk factor for

development of primary liver cancer , mostly due to NAFLD-associated cirrhosis

J Lipid Res. 2009 April; 50: S412–6.

NAFLD : Natural history over 8–13 years

HCC, hepatocellular carcinoma; OLTx, liver transplantation.

Journal of Hepatology 2008;48: S104–12

NonAlcoholic Fatty Liver Disease

Histopathologic Spectrum Steatosis

Steatohepatitis

Fibrosis CirrhosisCancer

Progression to cirrhosis and cancer have been documented from few studies in the Asian Pacific Region but still exact magnitude of the problem is not known.

Introduction

NAFLD Health dilemma for the recent 3 decades provoking

quite less concerns in the past However,

Nowadays, its prevalence has grew to 30% in the United States general population and like other gastrointestinal disorders it also grew in developing countries

NAFLD is rapidly becoming a worldwide public health problem* It is the most common liver disease in the United

States and, indeed, worldwide

Hepat Mon. 2011;11(2):74-85 ;* J Lipid Res. 2009 April; 50: S412–6.

Non-Alcoholic Steatohepatitis [NASH]

NASH Represents only a part of wide spectrum of non

alcoholic fatty liver One of the leading causes of chronic liver disease

[CLD] 3rd most common cause of CLD in North America after

alcoholic liver disease & Hepatitis C The most common cause of raised transaminases > 6

months

Introduction

NASH was coined by Ludwig et al in 1980 while describing a

Series of patients of non-alcoholic, diabetic patients, mostly females, in whom

Liver histology was consistent with alcoholic liver disease but

did not have a history of alcohol consumption

Epidemiology: NALFD, NASH

Problems In Studying Epidemiology Of NAFLD And NASH Lack of definitive laboratory test Studies dependence on different definitions Published series with biopsy confirmation are

selected cases that have presented to medical attention

Values of alcohol consumption in published series ranged from < 20 gm/week to <140 gm/week


Prevalence of NAFLD Appears to be increasing, in part due to the increasing

numbers of adult and pediatric individuals who are obese or overweight or have metabolic syndrome or type 2 diabetes, all major risk factors for development of NAFLD


Problems in Assessing NAFLD In Asian Pacific Region Inaccurate evaluation of alcohol abuse Infrequent use of liver test in general practice Lack of presentation of asymptomatic individual Burden of viral hepatitis Reluctance to do liver biopsy Lack of awareness of the severity Pursued slowly progressive nature Considered as a disease of affluence

Chitturi S, Farrell G, George J JGH 2004



Steatosis Most common cause of raised transaminases & affects

10-24 % of gen.population while only 2-3 % of gen.population have steatohepatitis

In pts undergoing liver biopsy, the prevalence ranges NAFLD [NonAlcoholic Fatty Liver Disease] - 15-39% Steatohepatitis - 1.2-4.8%


Name of the Percentage NAFLD inCountry AdultsJapan9 – 30%China5 – 18%Korea18 %India 5 – 28%Indonesia 30%Malaysia 17 %Singapore 5%

Prevalence of NAFLD In General Population In Asian Pacific Region


Western EasternPopulation Population

Age at Presentation 4th – 8th decade 4th – 8th decadePrevalence 20-30% -10%Obesity 71% (30-100) 44% (12-89)T2DM 28% (2-55) 34% (11-39)Hyperlipidemia 38% (15-81) 41% (28-81)Natural History Worse with Limited data

severe firbosisChitturi Et al JGH 2004

NASH In Asia Pacific – Future Shock!!

NASH in India

India Many diabetics but very few studies on NASH

Among pts from India, 50 – 70% had one of the 3 risk factors – diabetes,

obesity, hyperlipidemiaMean age of pts is 35 – 55 yrsPredominant in menNASH constitute 6% of all chr.hepatitis

cases

NAFLD: Risk factors

ObesityDiabetes HyperlipidemiaFemale sex

NALFD: Etiology

To date, major gaps remain in our understanding of the etiology of NAFLD and why it progresses Generally agreed that dysregulation of lipid

metabolism is involved Furthermore, it seems likely that dysregulation of the

immune response plays an important role, particularly in progression


NAFLD: Factors that may impact

Any or all metabolic pathways may play a role in NAFLD and its progression dependent on an individual's cohort of genes and genetic and epigenetic interactions. The question mark indicates that little evidence is available supporting an influence, but that, hypothetically, one may exist J Lipid Res. 2009 April; 50: S412–6.

NASH: Potential etiologies

Hepat Mon. 2011;11(2):74-85

NASH: Pathogenesis

Increased delivery of fatty acids to liver Obesity StarvationIncreased synthesis of fatty acids in liver excess carbohydrate ( TPN )Decreased mitochondrial beta oxidation of

fatty acids Carnitine deficiency Mitochondrial dysfunctionDecreased incorporation of triglycerides into

functional VLDL Impaired apolipoprotein synthesis

NASH: Pathogenesis

Impaired cholesterol esterification Choline deficiency Protein malnutritionImpaired export of VLDL from hepatocyteInsulin resistance increased lipolysis hyperinsulinemia

NASH: Pathology

Diagnosis of NASH depends on Histopathological features & Exclusion of alcohol as the cause of disease

Liver biopsy features : Steatosis polymorphonuclear and / mononuclear

hepatocyte ballooning and necrosi, mallory hyaline,glycogenated nuclei,metamitochondria and fibrosis indistinguishable from alcoholic liver disease

NASH: Pathology

Steatosis in NASH – macrovesicularInflammation of steatohepatitis is predominantly

lobular, [whereas intense portal inflammation with interface activity is

seen in chronic viral, autoimmune & drug indued hepatitis] But in children , NASH may have portal infiltrate

Neutrophilic cells in lobular inflammatory infiltrate Balloon degeneration – recognized form &

characteristic finding in NASHMallory hyaline may be +/-

Characteristic of alcoholic hepatitis

NASH: Pathology

Pattern of fibrosis Initial collagen deposition in perivenular & peri

sinusoidal spaces of Zone 3 . Chicken wire fibrosis Fibrosis – in 66% pts

While 25% have severe fibrosis And 14% have well established cirrhosis

JAPI 2005;53: 195-99

Histological Differential Diagnosis

Hepatitis CPrimary Biliary CirrhosisAutoimmune hepatitisAlpha 1 anti trypsin deficiencyHemochromatosis

NALFD: Clinical features

NAFLD Largely asymptomatic condition that may reach an

advanced stage before it is suspected or diagnosed Symptoms such as right upper quadrant discomfort,

fatigue and lethargy have been reported in up to 50% of patients but are uncommon modes of presentation

Most patients with NAFLD are diagnosed after they are found to have hepatomegaly, or more commonly, unexplained abnormalities of liver blood tests performed as part of routine health checks or during drug monitoring (e.g., statin therapy)


NALFD: Clinical features

On examination Most patients are centrally obese and dorsocervical

lipohypertrophy (a ‘‘buffalo hump”) appears to be a particular feature of the fat distribution in patients with advanced NAFLD

Features of PCOS (hyperandrogenism) should be sought in young women with suspected NAFLD


NASH: Clinical features

Most of the patients are asymptomatic 1/3rd present with

Nonspecific constitutional symptoms like weakness, fatigue & malaise

Rapid onset of Fulminant hepatic failure NASH d//t drugs like nucleoside analogues,

tetracyclinesHepatomegaly , splenomegalyPresence of ascites, spider angiomata –

indicate development of cirrhosis

Laboratory findings

Mild – moderate elevations of S.Transaminases, typically <4 times the upper normal limit

ALT level > AST in absence of cirrhosisLiver biopsy

Diagnosis

Clinical historyExclusion of significant alcohol intakePursue dietary history, medication,

occupational exposure to organic solventsFamily history of liver diseaseOther causes of CLD – infections, metabolic

heriditary & autoimmune causes to be ruled out

Liver biopsy – confirm diagnosis & for prognostic information

Difference between NASH and alcoholic hepatitis

JAPI 2005;53: 195-99

Natural course

SteatosisSteatohepatitisCirrhosisSteatosis – good prognosisSteatohepatitis , cirrhosis – bad prognosis

NALFD: Treatment

Currently, the only accepted treatment for NAFLD regardless of stage is lifestyle modifications These include weight loss by a combination of decreased

caloric intake and increased physical activity Of potential importance is choice of diet, for example, low

fat/high carbohydrate versus high fat/low carbohydrateAnother option, generally available only for the

morbidly obese, is bariatric surgeryAn important caveat for both treatment

approaches Rapid weight loss by any means is to be avoided because it

can cause NAFLD progression


NASH: Treatment

Treatment options are limitedWeight Reduction: • wt loss – normalization of s.aminotransferases.• Means of wt loss is important not the amount of wt

loss• Recommended wt loss – 230 g/day or 1.6 kg/week• Diet : 45 -100 g high quality animal protein

<100g carbohydrates <10 g fat per day providing 600 -800 kcal

NASH: Treatment

Ursodeoxycholic acid : • Has membrane stabilizing / cytoprotective /

immunological effect• 10-15 mg/kg/day for 6-12 months

• Significant improvement in transaminases levels and degree of steatohepatitis

NASH: Treatment

Liver Transplantation :• NASH – A relative contraindication• Many of pts with NASH with CLD who

underwent Liver Transplant – redeveloped NASH in the new donor liver ( 2/3 cases ) &

• 1/3rd cases – liver transplantation is unsuccessful

Newer treatment modalities

Inhibition of macrophage activation:

Anti oxidant ( Vit E ) glutathione prodrugsAntibiotics, preprobioticsAnti cytokines ( anti TNF alpha antibodies,

pentoxiphylline )

Newer treatment modalities

Protect hepatocyte ATP storesPARP inhibitorsMinimize CYP2F activityDietary modification ( avoid fats )Insulin sensitizers : pioglitazoneAntiobesity drugs : sibutramine, orlistatAntilipid drugs : Simvastatin, Procusol

Thank You!

Download - DR. UMESH KHANNA MUMBAI NASH and nonalcoholic liver disease NASH – NonAlcoholic SteatoHepatitis

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