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STEATOHEPATITIS
Richard K. Sterling, MD, MSc, FACP, FACGVCU Hepatology Professor of Medicine
Chief, Section of HepatologyVirginia Commonwealth University
Richmond, VA
Conflicts of Interest in the last 12 months
• Advisory Board – Roche/Genentech, Merck, Vertex, Bayer, Salix, BMS,
Abbott
• Research support – Roche/Genentech, Merck, Bayer, Boehringer
Ingelheim, Vertex, BMS, Abbott
• Speaker – None
• Stock/Financial interest– None
Objectives
• Definitions• Histology• Types of steatohepatitis
– Alcoholic – Non-alcoholic– Drugs
• Pathophysiology• Presentation• Therapy
Definitions
• Steatosis = fatty liver (>5%)– Microvesicular– Macrovesicular– Mixed
• Steatohepatitis = fatty liver with inflammation and cytologic ballooning– Grade
• Degree of inflammation• Pattern
– Fibrosis• Degree• Pattern
Conditions Associated with Steatosis
• Alcohol • Microvesicular• Insulin resistance (NAFLD) TCN• Lipid disorders Valproate• Drugs AFLP
– Amiodarone Rye’s syndrome– Diltiazem HELLP syndrome– Steroids Inborn errors – Tamoxifen– HAART (NRTI/PI)
• HCV (genotype 3)• Weight loss• TPN• Wilson Disease• Idiopathic
• Macrovesicular
Steatohepatitis
• Fatty change (>5%)• Ballooning degeneration• Lobular inflammation• Mallory bodies• Perisinusoidal fibrosis
Steatohepatitis
Macrovesicular
Cytologicballooning
Mallory bodies
Alcoholic Liver Disease
• Fermented beverages have been around since 10,000 B.C.
• In the US:– 7.4% of adults abuse alcohol– 44% of all liver related deaths are attributed to
alcohol
Alcoholic Steatohepatitis
• Alcohol metabolism
EtOH Small bowelStomach ADH- gender ethnicity
LIVER
Microsomal ethanolOxidizing system (MEOS)- CYP 2E1 - Inducible by chronic alcohol
Acetaldehyde
ADHNAD
NADHAcetateALDH
Mitochondria
Liver toxicityLiver toxicity
Pathogenesis of ASH in the Liver
Kupffer Cell
TNF-
LPSOther stimuli
Hepatocyte
TGF- matrix
Hepatic stellate cells
KV Kowdley, MD
Leaky gutPV endotoxemia
Fibrosis
Mechanisms of Alcoholic Liver Injury
LIVER
AcetaldehydeInhibition of mitochondrialbeta-oxidation of fatty acidsOxygen-free radicalsGlutathione depletionAcetaldehyde Adducts
Oxidative StressOxygen-free radicalsDecreased Anti-oxidants
Redox StatusNAD depletionFat accumulation
Cytokines TNFα TGFβ
Hepatitis C
Natural History of Alcoholic Hepatitis
Normal liver
Steatosis
Steatohepatitis
Fibrosis
Cirrhosis
Alcohol (90-100%)
reverse
20% progress
50% progress, 38% with abstinence
~20% of alcoholics
50% reverse
80%
Factors Associated with Liver Injury
• Dose• Duration• Gender• Ethnicity• Other factors
– Obesity– Iron Overload– Viral hepatitis (HCV, HBV) – Genetic (PNPLA3)
Alcohol Threshold
• Men 80 grams (6-pack/day)• Women 40-60 grams (4 drinks/day)
• 12 oz beer• 4 oz drink• Glass of wine
10-12 grams
Alcoholic Liver Disease: Natural History
• Alcoholic hepatitis:– Women more likely to develop cirrhosis– Those with clinically severe hepatitis more
likely to progress to cirrhosis– Perivenular lesions, degree of necrosis
predictors of development of cirrhosis– Acute mortality 10-20% (related to severity,
complications and renal failure)• 50-80% if DF > 32
Alcoholic Liver DiseaseClinical Features
• Symptoms/signs of intoxication• Symptoms/signs of withdrawal• Hepatomegaly• Jaundice• Features of chronic liver disease
– Spiders, dypuytrens contractures• Extrahepatic manifestations: pancreatitis, neurologic disease, etc• Fevers• Leukocytosis (leukemoid reaction)• AST:ALT > 2• Hemolysis: Zieve’s syndrome
• Both AST and ALT are elevated but rarely exceed 300 IU/L (never above 500)• If > 300, think acetaminophen
• AST / ALT ratio > 2 : 1 Cytoplasmic isoenzymes for both cAST and
cALT but mitochondrial isoenzyme only for mAST.
ALT requires pyridoxal phosphate (vit-B6), which is consumed for the metabolism of alcohol.
Alcohol and AST:ALT ratio
Alcoholic Liver Disease Management
• Management of intoxication• Management of withdrawal• Nutrition (key and often overlooked)• Management of metabolic derangements:
– electrolytes: Mg, PO4, K,– thiamine, glucose, folate– vitamin K
Alcoholic liver disease: Steroid treatment
Discriminant function (DF) = 4.6 x (PT-control) + bilirubin (mg)
• Indications for steroids– DF > 32– Encephalopathy
• Contraindications for steroids– Sepsis– GI bleeding– If contraindications, treat and reassess
Comparison of Diagnostic Indiceson Survival
Author N MELD DF Sensitivity % Specificity % AUROC
Sheth 34 >11 86 81 0.82
>32 86 48 0.86
Srikureja 202 >18 85 84 0.89
>32 83 60 0.81
Dunn 73 >21 75 75 0.83
>41 75 69 0.83
Soultati 34 >30 100 94 0.97
>108 100 97 0.98
Adapted from O’Shea et al. Hepatology 2010;51:307-328
Both MELD and DF have similar sensitivity (75-85%) while MELD has higher specificity
Effects of steroids on survival in alcoholic steatohepatitis
Author n Severity
assessment
F/U % Survival
Pred vs placebo
Carithers
Ramond
Mathurin
66
61
122
DF
DF + Bx
DF + Bx
4 wks
8 wks
1 yr
94:65
88:45
70:41
Meta-analysis of 11 randomized studies (Imperiale and McCullough, AIM 1990)• 37% reduction in mortality (95% CI 20-50%)• In those with HE, 34% protective efficacy (95% CI 15-48%)• Minimal protective effect in those without HE• More effective in studies that excluded active GI bleeding
A few more things
• MELD may be better than DF in predicting survival– No threshold for use of steroids (~18)
• Pentoxifylline (400 mg tid)– Not compared to steroids– Seems to be a safe alternative– Not helpful if steroids fail
• If no improvement after 1 week, steroids unlikely to be of benefit (Lily criteria)
• Liver transplantation not an option
Used with Permission: O’Shea et al. Hepatology 2010;51:307-328
Used with Permission: O’Shea et al. Hepatology 2010;51:307-328
1.2-1.5 g/kg protein35-40 kcal/kg energy
Consider transplant
Non-alcoholic Fatty Liver (NAFLD)
• Spectrum of conditions– Simple steatosis (NAFL) NASH
• Most common cause of elevated liver enzymes– 14-34% (NAFLD)– 3% (NASH)
• Associated with insulin resistance (IR)• Decreased adiponectin (and adiponectin resistance)• Increased FFA, leptin and TNF-α• Fat may not be present once cirrhosis develops
– Cryptogenic cirrhosis• Remember
– Non-alcohol = < 21 alcohol drinks/week in men (<3/d) and <14 drinks/week (<2/d) in women
Natural History of NAFLD
NAFLD
Isolated fatty liver
NASH
Cirrhosis
HCC
Decompensation
No increased morbidityor mortality
Increased morbidityand mortality• CVD• Liver-related• Malignancy
>80%
<20%
2-3%/yr
3-5%/yr
1-3%/yr
Adapted from Torres et al. CGH 2012;10:837-858
Nonalcoholic fatty liver disease
H&E stain 20X Masson’s trichrome
SteatohepatitisHepatocyte ballooning (large arrow)Mallory bodies (small arrow)
Perisinusoidal fibrosis
Causes of NAFLD
• The metabolic syndrome• Drugs (steroids, diltiazem, amiodarone, NRTI, PI)• Lipodystrophy (HIV vs others)• Congenital lipid disorders (abetalipoproteinemia)• TPN• Short bowel• Chronic inflammatory disorders• Wilson Disease• HCV (genotype 3)• Hypothyroid
Metabolic Syndrome
Obesity
Diabetes Hypertension
NAFLD
Dyslipidemia
The metabolic syndrome (syndrome-x) ATP III criteria: 3 or more of the following
• Abdominal obesity – (waist > 102 cm for men, > 88 cm for women)
• Triglycerides > 150mg/dl• HDL < 40 mg/dl for men, < 50 mg/dl for women• BP > or = 130/85• Fasting blood glucose > or = 110 mg/dl
Prevalence of the metabolic syndrome in the US
Adapted from Ford et al, JAMA, 287:356-359, 2002
Based on 2000 censusN= 47 million in US
20-29 30-39 40-49 50-59 60-69 >700
10
20
30
40
50malesfemales
Age range (yrs)
Prevalence of NAFLDEthnic Variation
0
10
20
30
40
50
60
Overall Hispanic White AA NASH NASHamongNAFLD
San Antonio (1)
Dallas (2)
1. Gastroenterology 2011;140:124-131 2. Hepatology 2004;40:1387-1395 Adapted from Torres et al. CGH 2012;10:837-858
%
Associations with NAFLD
Author Obesity Diabetes Lipid HTN
Ludwig 90% 25% 67% 15%
Powell 95% 36% 62% ND
Bacon 39% 21% 21% 18%
Angulo 60% 28% 27% ND
Harrison 75% 45% ND 68%
Chitturi 57% 29% ND ND
Adapted from Stengel and Harrison Gastroenterology and Hepatology 2006;2:440-449
Can you predict NASH in those with steatosis?
Adapted from: Hepatology 2010;52:913-924
No NASH NASH p
N 291 404
% Male 45 34 .006
T2DM 17 26 .007
MS 56 66 .01
AST (U/L) 37 55 <.0001
ALT (U/L) 56 74 <.0001
AST/ALT 0.68 0.74 0.03
gGGT (U/L) 40 56 <.0001
HOMA-IR 3.8 5.0 <.0001
Model including labs, demographics AUROC = 0.79
NAFLD: sonographic evidence
• Bright liver• echotexture increased
compared to kidney• vascular blurring
Courtesy of KV Kowdley
NASH and normal ALTAdapted from Mofrad et al, Hepatology, 2003
none portal bridging cirrhosis0
30
60
90
upper limitof normal
stage of fibrosis
ALT
(I.U
./L)
Pathophysiology of NASHThe Players
• Insulin resistance• FFA -> lipotoxicity• Leptin• Adiponectin• Oxidative stress• Cytokines
– TNF-α– IL-6
The “two hit” hypothesis
Insulin Resistance
Lipid accumulation
Reactive oxygen species production
FibrosisNASH
1st hit
Increased MitochondrialOxidative stress 2nd hit
Lipid peroxidationCytokine inductionFAS ligand induction
Mostly TG from excess FFA influx fromhigher rates of lipolysis with increasedleptin and decreased adiponectin withdecreased in FA oxidation
Reduced ability of insulin to suppress endogenous glucoseproduction and increase glucose uptake by fat and muscle.Blunted insulin-mediated suppression of FFA release fromadipocytes and reduced FA oxidation
Clinical Conditions Associated with NAFLD
Cardiovascular Disease
DiabetesPCOS
Increased Ferritin
Adenomatous Colon Polyps
Obstructive SleepApnea
Vitamin DDeficiency
Hypothyroidism
Hyperuricemia
Pancreatic Steatosis
Cirrhosis
HepatocellularCarcinoma
Adapted from Torres et al. CGH 2012;10:837-858
NAFLD
Risk factors for severe fibrosis
Study Risk factors
Angulo (1999) Age, obesity, DM, AST/ALT ratio
Marceau (1999) Age, steatosis, WHR, BMI, DM
Garcia-Monson (2000) Age, steatosis, inflammation
Ratziu (2000) Age, BMI, ALT, TG, inflammation
Dixon (2001) HTN, ALT, c-peptide, IR
Chitturi (2002) Female, DM, inflammation
Harrison (2003) Age, DM, female, AST/ALT ratio
Adapted from Stengel and Harrison Gastroenterology and Hepatology 2006;2:440-449
Non-Invasive Assessment of NAFLD
Model Components Cutoffs AUROC PPV NPV
APRI AST, PLT <0.5 & >1.5 0.73
FIB-4 AST, ALT, Age, PLT <1.3 & >2.67 0.80 80 90
BAAT ALT, BMI, age, TG <2 47 100
BARD AST/ALT>.8, BMI>28, DM
2-4 0.70-0.82 35 96
NAFLDscore* AST, ALT, Age, PLT, BMI, Albumin
<-1.45 & >0.67
0.76-0.88 90 93
European Liver Fibrosis
Age, TIMP1, PIIINP, HA 0.37 80 98-82
Fibrosure Α2macroglobulin, apolipoprotein A1, haptoblobi9n, bilirubin, GGT
0.3 54 90
* >50% will have intermediate range
Weapons of mass destruction
Courtesy of AJ Sanyal
Therapy for NAFLD
• Weight loss (10% may be all it takes)• Diet (low carbohydrates)• Exercise (>30 min/day or 150 min/wk)• Pharmacotherapy
– Insulin sensitizing drugs (no longer recommended)• Thiazolidinediones (TDZ)• Metformin
– Antioxidants• Vitamin E, SAM-E, Betaine
– Anti-TNF• Pentoxyfylline
• Bariatric surgery
TDZ for NAFLD
• Peroxisome proliferator-activator receptor γ (PPAR) agonist
• Improves insulin sensitivity• Decrease hepatic glucose production• Enhance glucose disposal in muscle• Improves steatosis• But
– Weight gain– Increased cardiovascular events long term– No better than vitamin E
Pioglitazone (30 mg/d), Vitamin E (800 IU/d) or Placebo for NASH
Sanyal et al. NEJM 2010
0
10
20
30
40
50
60
70
Steatosis Lob Inflam Ballooning Fibrosis Resolution ofNASH
Placebo
Vit E
Pioglit% I
mpr
ovem
ent
N=83
N=84
N=80
* * * *
* = p<.05
Although the study was not designed or powered to compare vit E toPioglitazone, vit E did as well (or better) with less side effects
Treatments for NASHDietary Effect Comments
Weight loss (7-10%)
Reduce daily calories by 500-750 kcal
Improves histology <50% able to comply
No data on improvement in fibrosis
Reduce high fructose from diet
Increases lipogenesis No prospective data
High Fructose risk for NAFLD
Omega 3 FA Improves TG, may reduce steatosis
Need about 1g/d
Reduced CVD
Coffee (2-3 cups/d) Decrease risk of fibrosis I like coffee
Exercise
30-40 min 4-5 x week Improves LFTs and steatosis Need to combine with diet
Pharmacology
Vitamin E (800-1000 IU/d) Improves fat and inflammation Long term risks
Pioglitazone (30-45mg/d) Improves fat and inflammation Wt gain, long term risks
Pentoxifylline (400 mg tid) Improves NASH and fibrosis Small studies
Surgery
RYGB, Sleeve, other Improves NASH and fibrosis
Caution in cirrhosis
PNPLA3Patatin-Like Phospholipase Domain-Containing Protein 3
• Polymorphism of adiponutrin• Present in 12-14% of NAFLD compared to 3% controls• Acyl-CoA independent pathway of TG synthesis
– MG + MG -> DG + glycerol– MG + DG -> TG + glycerol
• In NAFLD, it is independently associated with– Steatosis– Inflammation– NASH and fibrosis
• Also a risk of developing alcoholic liver injury
Practice Guidelines for NAFLDAASLD, ACG, AGA (AJG 2012)
• NAFLD = <21 drinks/wk in men and 14/wk in women.
• Alcohol use should be minimized.• If NAFLD is detected on imaging without signs or
symptoms and normal enzymes, evaluate for other causes (ETOH, MS), but biopsy is not recommended.
• If NAFLD is detected on imaging with signs or symptoms and abnormal enzymes, evaluate for other causes (ETOH, MS) and consider biopsy.
Practice Guidelines for NAFLDAASLD, ACG, AGA (AJG 2012)
• Screening for NAFLD in high risk groups is not recommended.
• Systematic screening family members is not recommended.
• When evaluating NAFLD, exclude other common liver diseases (HHC, HCV, ETOH, AIH, Wilson).
• Presence of MS may help target those for biopsy.
• NAFLD Fibrosis Score (http://nafldscore.com) may help identify those with NASH.
Practice Guidelines for NAFLDAASLD, ACG, AGA (AJG 2012)
• Weight loss (3-5%) may reduce steatosis.• Weight loss (10%) may improve inflammation.• Exercise (even without weight loss) may improve
steatosis.• Metformin, Urso, omega-3 fatty acids are not
recommended.• Pioglitazone can be used to treat NASH in non-
DM, but safety for long term use a concern.• Vitamin E (800 IU/d) is non-DM can be
considered, but long term safety a concern.
Practice Guidelines for NAFLDAASLD, ACG, AGA (AJG 2012)
• Statins use is safe, but not recommended to treat NASH.
• Bariatric surgery is not recommended as a treatment for NASH, but is not contraindicated as a treatment of obesity in those without cirrhosis.
• Those with cirrhosis should undergo periodic US for HCC and endoscopy for varices.
Case Study 1
1. A 45 year old man is admitted with nausea and jaundice. There is no history of fever. He reports consuming a fifth of vodka per day for the past 15 years. Physical examination reveals tender hepatomegaly and grade 2 PSE. Laboratory tests reveal a serum bilirubin of 6 mg/dl, albumin 3 gm/dl. AST 250 IU/L, ALT 110 IU/L, Alk phos 155 IU/L, PT 20/INR 2.3 and serum creatinine 1.5 mg/dl. The most appropriate for this patient is:
Case Study 1-contd
A. Rifaxamin 400 mg tid
B. prednisolone 32 mg/day
C. Pentoxfylline
D. Referral to a liver transplant center
Case Study 1-contd
A. Rifaxamin 400 mg tid
B. prednisolone 32 mg/day
C. Pentoxfylline
D. Referral to a liver transplant center
The DF is 43 and the MELD is 26. Given PSE, pt should benefit from steroids.
Case 2
A 46 year old man is admitted to the hospital after being found unconscious by his family. He is known to consume more than a fifth of vodka a day for at least two decades. Physical examination reveals no fever. Tender hepatomegaly and splenomegaly are present. Laboratory tests reveal a serum bilirubin of 3 mg/dl, albumin 3 gm/dl. AST 1,550 IU/L, ALT 1210 IU/L, Alk phos 155 IU/L, PT 14 secs and serum creatinine 2.1 mg/dl. There is no leukocytosis.
Case 2 continued
The next appropriate test for this patient is:
a. Doppler ultrasound of the liver
b. ERCP
c. Acetaminophen level
d. CPK level
e. Blood cultures
Case 2 continued
The next appropriate test for this patient is:
a. Doppler ultrasound of the liver
b. ERCP
c. Acetaminophen level
d. CPK level
e. Blood cultures
Case 3
A 40 yo obese male (BMI 35) is found to have NASH. He has tried weight loss and exercise but his liver enzymes remain elevated and he has only lost 10 lbs. Which of the following do you recommend?
a. Start pioglitazone.
b. Start metformin
c. Bariatric surgery
d. Vitamin E
Case 3
A 40 yo obese male (BMI 35) is found to have NASH. He has tried weight loss and exercise but his liver enzymes remain elevated and he has only lost 10 lbs. Which of the following do you recommend?
a. Start pioglitazone.
b. Start metformin
c. Bariatric surgery
d. Vitamin E
Case 4
A 52 yo male with excessive alcohol presents with abdominal pain. Labs show AST 250, ALT 150. Which of the following reasons may explain the AST:ALT ratio?
1. AST requires B6 which is depleted
2. ALT is a mitochondrial enzyme affected more that AST
3. AST is a mitochondrial enzyme affected more that ALT
4. AST is a cytosolic enzyme affected more that ALT
Case 4
A 52 yo male with excessive alcohol presents with abdominal pain. Labs show AST 250, ALT 150. Which of the following reasons may explain the AST:ALT ratio?
1. AST requires B6 which is depleted
2. ALT is a mitochondrial enzyme affected more that AST
3. AST is a mitochondrial enzyme affected more that ALT
4. AST is a cytosolic enzyme affected more that ALT
Case 5
The pathogenesis of alcohol induced liver injury includes:
1. Reduced oxidative stress
2. Increased acetaldehyde
3. Reduced TNF
4. Reduced bacterial translocation
Case 5
The pathogenesis of alcohol induced liver injury includes:
1. Reduced oxidative stress
2. Increased acetaldehyde
3. Reduced TNF
4. NADH depletion