Non-alchoholic Steatohepatitis Non-alchoholic Steatohepatitis ( NASH ) ; Advances in ( NASH ) ; Advances in

evaluation and managementevaluation and management

Presenter : Vivek AgarwalaPresenter : Vivek Agarwala

Moderator : Dr B.P. PriyadarshiModerator : Dr B.P. Priyadarshi

Dr Prem SinghDr Prem Singh

ReferencesReferences1. Feldman: Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 7th ed.

2. Harrison’s Principles of Internal Medicine, 17th ed.

3. Hepatology, 2009 jan; 49(1); 209-217- Raj vuppalanchi & Naga Chalasani

4. Expert Rev Gastroenterol Hepatol.2010;4(5):623-635–LA Adams,AFeldstein

5. South Med J. 2010;103(6):547-550.- Lakshmi Pasumarthy, James srour.

6. Various internet references.

Non Alchoholic Steatohepatitis (NASH)Non Alchoholic Steatohepatitis (NASH) is a form of chronic hepatits with histologic features of hepatic is a form of chronic hepatits with histologic features of hepatic

steatosis, inflammation & hepatocellular damage occuring in steatosis, inflammation & hepatocellular damage occuring in persons who donot consume significant amount of alchohol. persons who donot consume significant amount of alchohol.

Other terms: Pseudoalchoholic liver disease, Alchohol like Other terms: Pseudoalchoholic liver disease, Alchohol like hepatitis, Fatty liver hepatits, Diabetic hepatitis, Non alchoholic hepatitis, Fatty liver hepatits, Diabetic hepatitis, Non alchoholic Laennec’s dis, Steatonecrosis and Non Alchoholic fatty liver Laennec’s dis, Steatonecrosis and Non Alchoholic fatty liver disease (NAFLD).disease (NAFLD).

Associated with Metabolic syndrome.Associated with Metabolic syndrome.

NAFLD— SpectrumNAFLD— Spectrum

Macrovesicular Steatosis(Fatty liver)

Lobular inflamm (NASH)

Fibrosis

Cirrhosis

Tim

e P

rogr

essi

on

EpidemiologyEpidemiology NAFLD – m/c cause of CLD all around the NAFLD – m/c cause of CLD all around the

world, m/c liver condition, m/c cause of world, m/c liver condition, m/c cause of elevated liver enzymes in the U.Selevated liver enzymes in the U.S

Prevalence of NAFLD – 10-20% , U.S – 14-Prevalence of NAFLD – 10-20% , U.S – 14-20% , East Asia- 17%, West Asia- 9%.20% , East Asia- 17%, West Asia- 9%.

NASH – 3.5-5%, 30-40% develop advanced NASH – 3.5-5%, 30-40% develop advanced fibrosis while upto 15% of proven NASH fibrosis while upto 15% of proven NASH progress to Cirrohsis & its complications progress to Cirrohsis & its complications including cancer.including cancer.

Previously Cryptogenic cirrhosis – now NASHPreviously Cryptogenic cirrhosis – now NASH

Ethnicity : African Americans have 30% lower Ethnicity : African Americans have 30% lower prevalence of NASH than Caucasians & prevalence of NASH than Caucasians & Hispanic population.Hispanic population.

Typical pt of NAFLD is a middle aged female Typical pt of NAFLD is a middle aged female but overall more prevalent in men.but overall more prevalent in men.

Disease prevalence is underestimated as Disease prevalence is underestimated as May be present in nonobese-nondiabeticsMay be present in nonobese-nondiabetics Increasingly diagnosed in children-adolescentsIncreasingly diagnosed in children-adolescents Requires liver biopsy for dx.Requires liver biopsy for dx.

NAFLD—DemographicsNAFLD—Demographics

0 10 20 30 40 50 60 70

Prevalence (%)

Obesity

High TG

Diabetes

Yu et al.. Nonalcoholic Fatty Liver Disease. Reviews in Gastroenterological Disorders. 2002; 2 (1):11-19

Epidemiologic risk factors & Epidemiologic risk factors & Comorbidities Comorbidities

ObesityObesity – found in 30-100% of pts of NAFLD, – found in 30-100% of pts of NAFLD, while 57.5-74% obese have NAFLDwhile 57.5-74% obese have NAFLD

• NAFLD in lean people with normal BMI with NAFLD in lean people with normal BMI with truncal obesity , more common in asian truncal obesity , more common in asian population.population.

• Each unit increase in BMI increases the chance Each unit increase in BMI increases the chance of fatty liver by 5%.of fatty liver by 5%.

• NASH – prevalence is 3% in lean population NASH – prevalence is 3% in lean population but 19% in obese.but 19% in obese.

Diabetes Mellitus – type II Diabetes Mellitus – type II Found in 10-75% of NAFLD pts. Some children with Found in 10-75% of NAFLD pts. Some children with

Type I DM have also been found to have NAFLD.Type I DM have also been found to have NAFLD.

Hyperlipidemia Hyperlipidemia Found in 20-92% of pts of NAFLD.Found in 20-92% of pts of NAFLD. Hypertriglyceridemia is more commonly found than Hypertriglyceridemia is more commonly found than

hypercholesterolemia.hypercholesterolemia.

Coronary artery diseaseCoronary artery disease Account for death in NAFLD in 25-45%.Account for death in NAFLD in 25-45%.

Secondary causes of Fatty liverSecondary causes of Fatty liver Toxins & drugsToxins & drugs

MetallicMetallic – Antimony, Barium salts, Carbon – Antimony, Barium salts, Carbon disulphide, Borates, Chromates, Phosphorous, disulphide, Borates, Chromates, Phosphorous, Thallium & Uranium compounds.Thallium & Uranium compounds.

Cytotoxic drugsCytotoxic drugs – L-asparginase, azacytidine, – L-asparginase, azacytidine, azauridine, methotrexate, azaserine, bleomycin.azauridine, methotrexate, azaserine, bleomycin.

Antibiotics Antibiotics – puromomycin , tetracyclin.– puromomycin , tetracyclin. OthersOthers – amiodarone, coumadin, tamoxifen, – amiodarone, coumadin, tamoxifen,

estrogens, glucocorticoids, hydrazine.estrogens, glucocorticoids, hydrazine.

Cont..Cont..

Inborn errors of metabolismInborn errors of metabolism Abetalipoproteinemia, Refsum’s disease, Abetalipoproteinemia, Refsum’s disease,

Homocystinuria, Glycogen storage ds, tyrosinemia, Homocystinuria, Glycogen storage ds, tyrosinemia, hereditary fructose intolerance, galactosemia, hereditary fructose intolerance, galactosemia, systemic carnitine def, Shwachman syndrome, systemic carnitine def, Shwachman syndrome, Weber- christian syndrome, Wilson’s disease.Weber- christian syndrome, Wilson’s disease.

Acquired metabolic disordersAcquired metabolic disorders Diabetes, jejuno-illeal bypass, starvation, obesity, Diabetes, jejuno-illeal bypass, starvation, obesity,

kwashiorkor, inflammotory bowel disease, severe kwashiorkor, inflammotory bowel disease, severe anaemia, TPN, choline defanaemia, TPN, choline def

Liver dis - Indian Childhood Cirrhosis , Chronic Liver dis - Indian Childhood Cirrhosis , Chronic Hepatitis C- genotype3Hepatitis C- genotype3

Insulin resistance

Fatty acids

SteatosisLipid peroxidation

NASH

NAFLD—PathogenesisNAFLD—Pathogenesis

First Hit

Second Hit

PathogenesisPathogenesis

GeneticsGenetics

PolymorphismsPolymorphisms (genetic variations) in the  (genetic variations) in the single-nucleotide polymorphismssingle-nucleotide polymorphisms (SNPs)  (SNPs) T455C and C482T in T455C and C482T in APOC3APOC3 which are  which are associated with fatty liver disease, insulin associated with fatty liver disease, insulin resistance, and possibly hypertriglyceremia. resistance, and possibly hypertriglyceremia. These mutations have high prevalence in These mutations have high prevalence in Indian men.Indian men.

NAFLD—SymptomsNAFLD—Symptoms

0 10 20 30 40 50 60 70

Prevalence (%)

Asymptomatic

Fatigue

RUQ pain

Edema

Pruritus

GI bleeding

Ascites

Sanyal et al., 2003

NAFLD—Exam FindingsNAFLD—Exam Findings

0 5 10 15 20 25 30 35 40

Prevalence (%)

Normal

Hepatomegaly

Edema

Jaundice

Splenomegaly

Ascites

Sanyal et al., 2003

Lab findingsLab findings

Increased aminotransferases ( 1.5-2 times), Increased aminotransferases ( 1.5-2 times), Usually ALT>AST . Ratio decreases as fibrosis Usually ALT>AST . Ratio decreases as fibrosis advances leading to loss of its diagnostic advances leading to loss of its diagnostic accuracy in cirrhotic NAFLD.accuracy in cirrhotic NAFLD.

Occasionally Increased ALP & GGT. May also Occasionally Increased ALP & GGT. May also be seen in ALDbe seen in ALD

Increased S. cholesterol & more commonly Increased S. cholesterol & more commonly increased TGs.increased TGs.

Increased glucose levels is commonIncreased glucose levels is common

CONT..CONT.. Absence of viral markers and autoantibodiesAbsence of viral markers and autoantibodies Abnormal iron study values in 50% - increased Abnormal iron study values in 50% - increased

ferritin , serum iron and transferrin saturation. ferritin , serum iron and transferrin saturation. Increased ferritin may be a marker of insulin Increased ferritin may be a marker of insulin resistance in NASH. 33% pts may be homozygous or resistance in NASH. 33% pts may be homozygous or heterozygous for HFE gene.heterozygous for HFE gene.

Imaging studies – USG, CT, MRI detect fatty liver but Imaging studies – USG, CT, MRI detect fatty liver but cannot reliably differentiate fibrosis and detect cannot reliably differentiate fibrosis and detect inflammation.inflammation.

Liver biopsy is the best diagnostic tool for confirming Liver biopsy is the best diagnostic tool for confirming the clinical suspicion of NAFLD & staging the severity the clinical suspicion of NAFLD & staging the severity liver injury & fibrosis.liver injury & fibrosis.

Histologic featuresHistologic features Hallmark of NAFLD is characteristic macrovescicular Hallmark of NAFLD is characteristic macrovescicular

steatosis with occasional microvescicular fat being steatosis with occasional microvescicular fat being identified, more in Zone 3 or perivenular area.identified, more in Zone 3 or perivenular area.

In NASH, there is a characteristically mild mixed In NASH, there is a characteristically mild mixed mononuclear/neutrophillic lobular infiltrate which may mononuclear/neutrophillic lobular infiltrate which may be associated with hepatocyte ballooning and less be associated with hepatocyte ballooning and less commonly Mallory’s hyaline generally in perivenular commonly Mallory’s hyaline generally in perivenular area.area.

Fibrosis is characteristically pericellular & perisiusoidal Fibrosis is characteristically pericellular & perisiusoidal giving a chicken wire appearance.giving a chicken wire appearance.

Eventually fibrotic septa form between the hepatic vein Eventually fibrotic septa form between the hepatic vein & the portal tract and nodules may form with cirrhosis.& the portal tract and nodules may form with cirrhosis.

Normal liver histologyNormal liver histology

NAFLD—SteatosisNAFLD—Steatosis

Source: Ibdah 2003

NAFLD—NASH (without fibrosis)NAFLD—NASH (without fibrosis)

Source: Ibdah 2003

NAFLD—NASH (with fibrosis)NAFLD—NASH (with fibrosis)

Source: Ibdah 2003

CONT..CONT..

Portal tracts are relatively spared from inflammation Portal tracts are relatively spared from inflammation but they may be involved with some children with but they may be involved with some children with NAFLD.NAFLD.

Histologic distinction between NASH & simple Histologic distinction between NASH & simple steatosis – a composite score of steatosis(1-3) , steatosis – a composite score of steatosis(1-3) , lobular inflammation(0-2) and ballooning(0-2) is taken.lobular inflammation(0-2) and ballooning(0-2) is taken.

<= 2 excludes NASH<= 2 excludes NASH 3-4 borderline3-4 borderline >= 5 definitely NASH>= 5 definitely NASH Brunt classification is another system for grading Brunt classification is another system for grading

severity of NASHseverity of NASH

Diagnosis & Evaluation of newly Diagnosis & Evaluation of newly suspected NAFLD: recent advancessuspected NAFLD: recent advances

No h/o previous or ongoing significant alchohol No h/o previous or ongoing significant alchohol consumption (20g/day in males and 10g/day in consumption (20g/day in males and 10g/day in females)females)

When h/o insufficient alchohol intake positive , When h/o insufficient alchohol intake positive , specially in presence of metabolic risk factors – specially in presence of metabolic risk factors – difficult to distinguish Alchoholic and Nonalchoholic difficult to distinguish Alchoholic and Nonalchoholic fatty liver.fatty liver.

Conventional markers of alchohol abuse like GGT, Conventional markers of alchohol abuse like GGT, MCV, AST/ALT not useful. Specific markers of limited MCV, AST/ALT not useful. Specific markers of limited utility.utility.

Specific markers of chr. Alchohol abuse - CDT( 81% Specific markers of chr. Alchohol abuse - CDT( 81% sens & 98% spec) & mitochondrial AST/ALT – not sens & 98% spec) & mitochondrial AST/ALT – not readily available.readily available.

““ALD/NAFLD Index” (ANI)ALD/NAFLD Index” (ANI) that consisted of five easily that consisted of five easily available variables: mean corpuscular volume, AST and ALT available variables: mean corpuscular volume, AST and ALT values, height and weight and gender.values, height and weight and gender.

Score > 0 incrementally favors ALD whereas value < 0 favors Score > 0 incrementally favors ALD whereas value < 0 favors NAFLD in decrement. E.g ANI of 8.95 would correspond to NAFLD in decrement. E.g ANI of 8.95 would correspond to greater than 99% probability of alcoholic liver disease whereas greater than 99% probability of alcoholic liver disease whereas a value of -5.04 would correspond to greater than 99% a value of -5.04 would correspond to greater than 99% probability of NAFLD.probability of NAFLD.

As the majority with alcoholic liver disease in this study had As the majority with alcoholic liver disease in this study had high MELD scores, this tool is more likely applicable to patients high MELD scores, this tool is more likely applicable to patients with decompensated cirrhosis presenting for liver transplant with decompensated cirrhosis presenting for liver transplant evaluation rather than outpatients with fatty liver.evaluation rather than outpatients with fatty liver.

Elevated serum auto-antibodies are Elevated serum auto-antibodies are common in patients with NAFLD , although common in patients with NAFLD , although in low titer – upto 33%in low titer – upto 33%

  In patients with suspected NAFLD and In patients with suspected NAFLD and ANA positivity at titers greater than 1:160 ANA positivity at titers greater than 1:160 or ASMA positivity at titers greater 1:40, a or ASMA positivity at titers greater 1:40, a liver biopsy may be considered.liver biopsy may be considered.

Elevated ferritin should prompt testing for Elevated ferritin should prompt testing for HFE gene. Relevance of this association HFE gene. Relevance of this association remains largely unknown but it justifies a remains largely unknown but it justifies a liver biopsy in pts of suspected NAFLD.liver biopsy in pts of suspected NAFLD.

R/o Chr Hepatitis B & C, alpha 1- AT def, R/o Chr Hepatitis B & C, alpha 1- AT def, Wilson’s dis & other secondary causes like Wilson’s dis & other secondary causes like drugs and toxins.drugs and toxins.

Evaluation for co-morbiditiesEvaluation for co-morbidities The body mass index and waist circumference should The body mass index and waist circumference should

be measured to better characterize the degree (mild, be measured to better characterize the degree (mild, moderate and severe) and the nature (central versus moderate and severe) and the nature (central versus peripheral) of obesity. peripheral) of obesity.

Fasting blood glucose and insulin levels and Fasting blood glucose and insulin levels and hemoglobin A1c. hemoglobin A1c.

Insulin resistance should be assessed by calculating Insulin resistance should be assessed by calculating HOMA-IR (homeostasis model assessment-insulin HOMA-IR (homeostasis model assessment-insulin resistance) or QUICKI (quantitative insulin-sensitivity resistance) or QUICKI (quantitative insulin-sensitivity check index) – mathematical translation of FBS and check index) – mathematical translation of FBS and insulin levels.insulin levels.

HOMA-IR ([fasting insulin (μU/ml) * fasting glucose HOMA-IR ([fasting insulin (μU/ml) * fasting glucose (mmol/L)]/22.5). HOMA-IR value > 3 considered to be (mmol/L)]/22.5). HOMA-IR value > 3 considered to be clinically significant .clinically significant .

Cont…Cont…

Fasting lipid profile should be obtained as dyslipidemia Fasting lipid profile should be obtained as dyslipidemia is nearly universal. Typically, fasting serum TG levels is nearly universal. Typically, fasting serum TG levels are high with low HDL values. are high with low HDL values. 

Recent data suggest that high-sensitivity CRP (hs-Recent data suggest that high-sensitivity CRP (hs-CRP) is frequently elevated in patients with NAFLD CRP) is frequently elevated in patients with NAFLD and should be measured along with fasting lipid profile and should be measured along with fasting lipid profile to assess cardiovascular risk .to assess cardiovascular risk .

Other co-morbidities - obstructive sleep Other co-morbidities - obstructive sleep apnea, hypopituitarism, hypothyroidism, polycystic apnea, hypopituitarism, hypothyroidism, polycystic ovary syndrome. ovary syndrome.

Identification of NASH in NAFLDIdentification of NASH in NAFLD

Liver biopsy is the current gold standard to Liver biopsy is the current gold standard to identify steatohepatitis but it is not without identify steatohepatitis but it is not without controversies and practical difficulties. controversies and practical difficulties.

Over the recent past, there has been significant Over the recent past, there has been significant interest & research to non-invasively predict interest & research to non-invasively predict liver histology in patients with NAFLD using liver histology in patients with NAFLD using several biomarkers and prediction models.several biomarkers and prediction models.

Non-invasive biomarkersNon-invasive biomarkersSerum biomarkersSerum biomarkers Imaging testsImaging tests Breath testsBreath tests

FibrosisFibrosis BARD scoreBARD score

NAFLD fibrosis scNAFLD fibrosis sc

OELF/ELFOELF/ELF

FibrotestFibrotest

Hyaluronic acidHyaluronic acid

Transient Transient elastographyelastography

MR elastographyMR elastography

MR spectroscopyMR spectroscopy

MethacinMethacin

KetoisocaproateKetoisocaproate

EthanolEthanol

AcetoneAcetone

Oxidative stressOxidative stress TBARSTBARS

Oxidised-LDLOxidised-LDL

Total AOx Total AOx responsrespons

Total lipid Total lipid peroxide levelsperoxide levels

Hepatocyte Hepatocyte apoptosisapoptosis

CK-18 fragmentsCK-18 fragments

InflammationInflammation TNFTNFαα/adiponectin/adiponectin

Hs-CRPHs-CRP

IL-6IL-6

CCchemokine lig2 CCchemokine lig2

CK-18CK-18

Wieckowska et al. measured plasma CK-18 fragment Wieckowska et al. measured plasma CK-18 fragment levels in 44 consecutive individuals with suspected levels in 44 consecutive individuals with suspected NAFLD undergoing liver biopsy. NAFLD undergoing liver biopsy. 

CK-18 is a major intermediate filament protein in CK-18 is a major intermediate filament protein in hepatocytes and it is cleaved by the effector caspases hepatocytes and it is cleaved by the effector caspases (mainly caspase 3) upon the activation of the (mainly caspase 3) upon the activation of the apoptosis cascade.apoptosis cascade.

It was suggested that CK-18 fragment levels > 380.2 It was suggested that CK-18 fragment levels > 380.2 U/L can predict definite NASH in a very precise U/L can predict definite NASH in a very precise fashion.fashion.

A puzzling and unexplained aspect of this small cross-A puzzling and unexplained aspect of this small cross-sectional study is that nearly 25% of patients with sectional study is that nearly 25% of patients with suspected NAFLD supposedly had normal hepatic suspected NAFLD supposedly had normal hepatic histology on liver biopsy. histology on liver biopsy.

Charlton et al. have shown that serum Charlton et al. have shown that serum DHEADHEA levels levels had a consistent and stepwise inverse relationship had a consistent and stepwise inverse relationship with the degree of hepatic fibrosis that persisted after with the degree of hepatic fibrosis that persisted after adjusting for age. adjusting for age.

SteatoTestSteatoTest for the diagnosis of hepatic steatosis and for the diagnosis of hepatic steatosis and NashTestNashTest for the diagnosis of NASH. These tests for the diagnosis of NASH. These tests utilize noninvasive biomarkers such as gamma utilize noninvasive biomarkers such as gamma glutamyl-transferase (GGTP), total bilirubin, AST, ALT, glutamyl-transferase (GGTP), total bilirubin, AST, ALT, haptoglobin, α2-macroglobulin, apolipoprotein A1, haptoglobin, α2-macroglobulin, apolipoprotein A1, serum TG & cholesterol with age, gender, height & serum TG & cholesterol with age, gender, height & weight.weight.

Angulo et al. have shown that Angulo et al. have shown that NAFLD fibrosisNAFLD fibrosis score consisting of 6 variables (age, BMI, score consisting of 6 variables (age, BMI, AST/ALT ratio, hyperglycemia, platelet count AST/ALT ratio, hyperglycemia, platelet count and albumin) can reliably predict advanced and albumin) can reliably predict advanced fibrosis. A low cutoff point (score < -1.455) fibrosis. A low cutoff point (score < -1.455) signified the absence of advanced fibrosis signified the absence of advanced fibrosis whereas a high cutoff point (score > 0.676) whereas a high cutoff point (score > 0.676) identified advanced fibrosis. It was concluded identified advanced fibrosis. It was concluded that NAFLD fibrosis score can be utilized as a that NAFLD fibrosis score can be utilized as a triaging tool for optimizing liver biopsy yield in triaging tool for optimizing liver biopsy yield in terms of identifying or excluding advanced terms of identifying or excluding advanced fibrosis.  fibrosis. 

Original European Liver Fibrosis” Original European Liver Fibrosis” (OELF)(OELF) test, a test, a model consisting of age and three serum markers of model consisting of age and three serum markers of matrix turnover (TIMP 1, hyaluronic acid and P3NP), & matrix turnover (TIMP 1, hyaluronic acid and P3NP), & “Enhanced Liver Fibrosis” “Enhanced Liver Fibrosis” (ELF)(ELF) score predicted score predicted different levels of fibrosis in a variety of liver disorders different levels of fibrosis in a variety of liver disorders inc NAFLD.inc NAFLD.

Harrison et al. have recently developed Harrison et al. have recently developed BARDBARD score score to predict advanced fibrosis in patients with NAFLD. to predict advanced fibrosis in patients with NAFLD. BARD score is a weighted sum of three easily BARD score is a weighted sum of three easily available variables [BMI > 28 kg/m2 (1 point), available variables [BMI > 28 kg/m2 (1 point), AST/ALT ≥ 0.8 (2 points) and diabetes (1 point)] and AST/ALT ≥ 0.8 (2 points) and diabetes (1 point)] and authors have shown that a score of 2-4 was authors have shown that a score of 2-4 was associated with an odds ratio 17 (95% CI) for associated with an odds ratio 17 (95% CI) for predicting advanced fibrosis.predicting advanced fibrosis.

One French study tested One French study tested “Fibrotest”“Fibrotest” for predicting for predicting advanced fibrosis in NAFLD , an already popular advanced fibrosis in NAFLD , an already popular serum test for predicting advanced fibrosis in Chr serum test for predicting advanced fibrosis in Chr Hepatitis C.Hepatitis C.

Liver stiffness measured by transient elastography Liver stiffness measured by transient elastography (FibroScan(FibroScan) may have some role in predicting the ) may have some role in predicting the degree of fibrosis. degree of fibrosis.

New technologies including proteomics, genomics and New technologies including proteomics, genomics and lipidomics are likely to identify novel markers of lipidomics are likely to identify novel markers of histology in individuals with NAFLD. One study of 80 histology in individuals with NAFLD. One study of 80 bariatric surgery patients found free hemoglobin bariatric surgery patients found free hemoglobin subunits to be associated with NASH by using a subunits to be associated with NASH by using a proteomic approach proteomic approach

Future is around the corner for non-invasively Future is around the corner for non-invasively diagnosing progressive NASH. While this may diagnosing progressive NASH. While this may be the case for advanced fibrosis, insufficient be the case for advanced fibrosis, insufficient attention has been paid to developing markers attention has been paid to developing markers for non-invasively identifying steatohepatitis in for non-invasively identifying steatohepatitis in patients with NAFLD. patients with NAFLD.

These promising models will need to be These promising models will need to be validated by external investigators before they validated by external investigators before they are recommended for wide clinical use. are recommended for wide clinical use.

Liver BiopsyLiver Biopsy The decision to pursue a liver biopsy to definitively diagnose The decision to pursue a liver biopsy to definitively diagnose

NASH needs to be weighed against the small but definite risks NASH needs to be weighed against the small but definite risks of harm, which include bleeding and rarely death. of harm, which include bleeding and rarely death.

The European Association for the Study of the Liver suggests The European Association for the Study of the Liver suggests performing a biopsy in subjects in whom advanced fibrosis is performing a biopsy in subjects in whom advanced fibrosis is suspected and avoid biopsying patients who are undergoing suspected and avoid biopsying patients who are undergoing lifestyle modification with the potential for weight loss and an lifestyle modification with the potential for weight loss and an improvement in underlying insulin resistance, ALT and improvement in underlying insulin resistance, ALT and noninvasive markers. noninvasive markers.

In the absence of robust noninvasive predictors of NASH, In the absence of robust noninvasive predictors of NASH, current clinical practice guidelines recommend  liver biopsy to current clinical practice guidelines recommend  liver biopsy to selected patients with suspected NAFLD based on the selected patients with suspected NAFLD based on the presence of certain risk factors such as older age, diabetes, presence of certain risk factors such as older age, diabetes, severe obesity and metabolic syndrome.  severe obesity and metabolic syndrome.  

Insulin resistance

Fatty acids

Steatosis

Lipid peroxidation

NASH

CytoprotectantsInsulin SensitizersAntihyperlipidemics

First HitSecond Hit

Weight Loss

Diet/Exercise

Antioxidants

NAFLD—How to Treat?

TreatmentTreatment

Non pharmacologicNon pharmacologic Avoidance of alchoholAvoidance of alchohol Low fat dietLow fat diet ExerciseExercise Tight glycaemic control of diabetesTight glycaemic control of diabetes Weight lossWeight loss Bariatric surgeryBariatric surgery

Weight loss ??Weight loss ?? Overweight and obese patients with NAFLD should Overweight and obese patients with NAFLD should

lose weight no more than 2lbs per week & 7-10% of lose weight no more than 2lbs per week & 7-10% of their body weight over the course of 6-12 months, by their body weight over the course of 6-12 months, by dietary modification and exercise. Gradual weight loss dietary modification and exercise. Gradual weight loss of this magnitude improves insulin resistance and of this magnitude improves insulin resistance and hepatic histology.hepatic histology.

Recommend low glycemic food with decreased Recommend low glycemic food with decreased saturated and trans-fat intake but increased mono and saturated and trans-fat intake but increased mono and polyunsaturated fatty acid intake.polyunsaturated fatty acid intake.

High fructose should be avoided.High fructose should be avoided. Popular weight-loss diets such as Atkins, Ornish and Popular weight-loss diets such as Atkins, Ornish and

South Beach diets should not be recommended. South Beach diets should not be recommended. Ideally recommend diminished portions of balanced Ideally recommend diminished portions of balanced

diet with 5-7 sessions per week of aerobic exercises diet with 5-7 sessions per week of aerobic exercises with each session lasting for 30-45mins.with each session lasting for 30-45mins.

Bariatric surgeryBariatric surgery Though weight loss is rapid, bariatric surgery for morbid obesity Though weight loss is rapid, bariatric surgery for morbid obesity

does help NASH significantly with improvement in liver does help NASH significantly with improvement in liver histology & metabolic syndrome.histology & metabolic syndrome.

Dixon et al showed that NASH resolved in 82% of patients Dixon et al showed that NASH resolved in 82% of patients undergoing laparoscopic adjustable gastric banding after losing undergoing laparoscopic adjustable gastric banding after losing approximately 40 kg. approximately 40 kg.

In a recent meta-analysis consisting of 15 studies and 766 In a recent meta-analysis consisting of 15 studies and 766 paired liver biopsies, Mummadi et al. have shown that all paired liver biopsies, Mummadi et al. have shown that all components of NAFLD show significant improvement following components of NAFLD show significant improvement following foregut bariatric surgery. Pooled proportion of patients with foregut bariatric surgery. Pooled proportion of patients with improvement or resolution in steatosis was 93%, with improvement or resolution in steatosis was 93%, with improvement or resolution of steatohepatitis was 82%, with improvement or resolution of steatohepatitis was 82%, with improvement in fibrosis when assessed using needle biopsies improvement in fibrosis when assessed using needle biopsies was 73% . was 73% .

Liver disease is unlikely to worsen in association with rapid and Liver disease is unlikely to worsen in association with rapid and profound weight loss after bariatiric surgery unless there are profound weight loss after bariatiric surgery unless there are additional risks such as bacterial overgrowth (e.g., jejunoileal additional risks such as bacterial overgrowth (e.g., jejunoileal bypass) or nutrient depletion (e.g., kwashiorkor). bypass) or nutrient depletion (e.g., kwashiorkor). 

Compensated cirrhosis is not a contraindication for foregut Compensated cirrhosis is not a contraindication for foregut bariatric surgery provided it is performed by an experienced bariatric surgery provided it is performed by an experienced surgeon and clinically evident portal hypertension is absent (no surgeon and clinically evident portal hypertension is absent (no esophageal or abdominal varices). There are reports that esophageal or abdominal varices). There are reports that cirrhosis may reverse following bariatric surgery.cirrhosis may reverse following bariatric surgery.

  Foregut bariatric surgery may be recommended as a Foregut bariatric surgery may be recommended as a therapeutic possibility for the severely obese NAFLD patients therapeutic possibility for the severely obese NAFLD patients with advanced fibrosis who failed to lose weight despite with advanced fibrosis who failed to lose weight despite repeated nutritional counseling. repeated nutritional counseling.

Bariatric surgery may be particular attractive for carefully Bariatric surgery may be particular attractive for carefully selected patients with Child’s A cirrhosis not only because it selected patients with Child’s A cirrhosis not only because it may stabilize or improve the liver disease but it also may may stabilize or improve the liver disease but it also may enhance their future suitability for liver transplantation. enhance their future suitability for liver transplantation.

Pharmacologic treatmentPharmacologic treatment Weight reducing drugsWeight reducing drugs

OrlistatOrlistat, , a reversible inhibitor of gastric and pancreatic a reversible inhibitor of gastric and pancreatic lipase, may be effective in promoting limited weight loss in lipase, may be effective in promoting limited weight loss in selected patients, but side effects such as diarrhea and selected patients, but side effects such as diarrhea and bloating make it less desirable. A clinical trial using orlistat bloating make it less desirable. A clinical trial using orlistat showed a mean decrease in body weight of 10.3 kg and showed a mean decrease in body weight of 10.3 kg and significant reductions in serum transaminase levels in obese significant reductions in serum transaminase levels in obese patients with NASH. In a randomized study, Harrison et al. patients with NASH. In a randomized study, Harrison et al. have shown that orlistat does not cause weight loss or have shown that orlistat does not cause weight loss or histological improvement above and beyond that is histological improvement above and beyond that is accomplished with calorie restriction alone. accomplished with calorie restriction alone.

SibutramineSibutramine, centrally acting SSNRI, an oral , centrally acting SSNRI, an oral anorexiant, showed weight loss and improved anorexiant, showed weight loss and improved insulin resistance and biochemical profile in a insulin resistance and biochemical profile in a recent 6 month pilot study.recent 6 month pilot study.

Rimonabant Rimonabant (endocannabinoid receptor 1 (endocannabinoid receptor 1 antagonist) is approved in Europe for promoting antagonist) is approved in Europe for promoting weight loss, and it may have favorable anti-steatotic weight loss, and it may have favorable anti-steatotic and anti-fibrotic properties. Neuropsychiatric side-and anti-fibrotic properties. Neuropsychiatric side-effects are a concern. Large multicenter trials are effects are a concern. Large multicenter trials are underwayunderway

Insulin sensitisersInsulin sensitisers MetforminMetformin causes causes decreased hepatic gluconeogenesis, decreased hepatic gluconeogenesis,

decreased glucose absorption and increased insulin sensitivity decreased glucose absorption and increased insulin sensitivity by facilitating glucose uptake and utilization. Metformin can also by facilitating glucose uptake and utilization. Metformin can also increase fatty acid oxidation and suppress lipogenesis. In increase fatty acid oxidation and suppress lipogenesis. In addition, its stimulatory effect on AMP activated protein kinase addition, its stimulatory effect on AMP activated protein kinase or modulation of hepatic TNFα expression may be benefit or modulation of hepatic TNFα expression may be benefit favorably.favorably.

A recent meta-analysis published in Cochrane database A recent meta-analysis published in Cochrane database

showed that metformin leads to normalization of serum showed that metformin leads to normalization of serum aminotransferases in a significantly greater proportion of aminotransferases in a significantly greater proportion of patients compared to dietary modification and improved patients compared to dietary modification and improved steatosis by imaging. It also decreased insulin and C-peptide steatosis by imaging. It also decreased insulin and C-peptide levels significantly.levels significantly.

Favoured in nondiabetics with NASH, role in diabetics not Favoured in nondiabetics with NASH, role in diabetics not known. Biochemical improvement shown but histological data known. Biochemical improvement shown but histological data insufficient. Avoided in renal insufficiency and CHF.insufficient. Avoided in renal insufficiency and CHF.

ThiazolidinedionesThiazolidinediones reduce insulin resistance reduce insulin resistance byby acting on acting on (PPAR)—gamma in adipose tissue. They redistribute fat from (PPAR)—gamma in adipose tissue. They redistribute fat from muscle and liver to adipose tissue and thereby improving muscle and liver to adipose tissue and thereby improving peripheral (skeletal muscle) and hepatic insulin sensitivity. In peripheral (skeletal muscle) and hepatic insulin sensitivity. In addition, they increase circulating levels of adiponectin which is addition, they increase circulating levels of adiponectin which is produced exclusively by the adipose tissue and has insulin produced exclusively by the adipose tissue and has insulin sensitizing properties.sensitizing properties.

Both pioglitazone and rosiglitazone have been studied and Both pioglitazone and rosiglitazone have been studied and demonsrated improvements in transaminases and liver demonsrated improvements in transaminases and liver histology in multiple studies although their favorable effect on histology in multiple studies although their favorable effect on steatosis is more striking than on other histological variables steatosis is more striking than on other histological variables such as inflammation, ballooning or fibrosis. The favorable such as inflammation, ballooning or fibrosis. The favorable effect on liver histology and liver biochemistries disappears effect on liver histology and liver biochemistries disappears upon their discontinuation, suggesting that long term treatment upon their discontinuation, suggesting that long term treatment is needed to maintain their therapeutic benefits.is needed to maintain their therapeutic benefits.

Concern for cardiovascular side effects and weight gain limit Concern for cardiovascular side effects and weight gain limit long term use . Role in diabetics with NASH doubtful.long term use . Role in diabetics with NASH doubtful.

Lipid lowering drugsLipid lowering drugs

  Fibrates decrease TG and increase HDL. Gemfibrozil Fibrates decrease TG and increase HDL. Gemfibrozil has shown an improvement in aminotransferases in a has shown an improvement in aminotransferases in a trial, though no other fibrate has replicated this result.trial, though no other fibrate has replicated this result.

Statins showed an improvement in aminotransferases Statins showed an improvement in aminotransferases

and, as expected, in the lipid panels. Atorvastatin and and, as expected, in the lipid panels. Atorvastatin and Pravastatin have been studied.The use of statins Pravastatin have been studied.The use of statins raises concerns for hepatotoxicity, but this was not raises concerns for hepatotoxicity, but this was not seen with standard doses used in the study.seen with standard doses used in the study.

AntioxidantsAntioxidants Vitamin E & CVitamin E & C - - hepatologists utilize vitamin E based hepatologists utilize vitamin E based

on trials in which decrements in ALT were on trials in which decrements in ALT were demonstrated either with vitamin E alone or in demonstrated either with vitamin E alone or in combination with pioglitazone or with vitamin C. combination with pioglitazone or with vitamin C.

BetaineBetaine is a metabolite of choline that assists with the is a metabolite of choline that assists with the synthesis of S-adenosylmethionine, which is a synthesis of S-adenosylmethionine, which is a powerful antioxidant. It has been studied in a small powerful antioxidant. It has been studied in a small trial and showed improvements in liver biochemistries trial and showed improvements in liver biochemistries and histology.and histology.

PentoxifyllinePentoxifylline, a TNF-α inhibitor has shown , a TNF-α inhibitor has shown improvement in transaminases and insulin resistance; improvement in transaminases and insulin resistance; nausea was also a significant concern. nausea was also a significant concern.

PIVENS trialPIVENS trial In the In the PioglitazonePioglitazone versus Vitamin E versus Placebo  versus Vitamin E versus Placebo

for the Treatment of Nondiabetic Patients with for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, for Nonalcoholic Steatohepatitis (PIVENS) trial, for patients with NASH but without diabetes mellitus, the patients with NASH but without diabetes mellitus, the use of very high dosages of vitamin E (800 IU/day) for use of very high dosages of vitamin E (800 IU/day) for four years was associated with a significantly higher four years was associated with a significantly higher rate of improvement than placebo (43% vs. 19%) in rate of improvement than placebo (43% vs. 19%) in the primary outcome. The primary outcome was an the primary outcome. The primary outcome was an improvement in certain histological features as improvement in certain histological features as measured by biopsy—but it did not improve fibrosis. measured by biopsy—but it did not improve fibrosis. Pioglitazone improved some features of NASH but not Pioglitazone improved some features of NASH but not the primary outcome, and resulted in a significant the primary outcome, and resulted in a significant weight gain (mean 4.7 kilograms) which persisted after weight gain (mean 4.7 kilograms) which persisted after pioglitazone was discontinued.pioglitazone was discontinued.

OthersOthers Ursodeoxycholic acid (UDCA) is a cytoprotective Ursodeoxycholic acid (UDCA) is a cytoprotective

medication tried by Lindor and coworkers and did not medication tried by Lindor and coworkers and did not reveal any significant benefits in a double-blind, reveal any significant benefits in a double-blind, placebo-controlled trial. placebo-controlled trial.

Animal studies have demonstrated a marked decrease Animal studies have demonstrated a marked decrease in hepatic fibrosis and stellate cell activation with in hepatic fibrosis and stellate cell activation with inhibition of renin-angiotensin system . Losartan has inhibition of renin-angiotensin system . Losartan has been studied in patients with NASH and hypertension been studied in patients with NASH and hypertension and has shown improvements in markers of fibrosis.and has shown improvements in markers of fibrosis.

Liver transplantationLiver transplantation is a therapeutic alternative for is a therapeutic alternative for some p'ts with decompensated, end-stage NAFLD, but some p'ts with decompensated, end-stage NAFLD, but NAFLD may recur after liver transplantation.NAFLD may recur after liver transplantation.