Transcript STEATOHEPATITIS - Old Dominion Medical Society

STEATOHEPATITIS
Richard K. Sterling, MD, MSc, FACP, FACG
VCU Hepatology Professor of Medicine
Chief, Section of Hepatology
Virginia 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
• Macrovesicular
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Alcohol
Insulin resistance (NAFLD)
Lipid disorders
Drugs
– Amiodarone
– Diltiazem
– Steroids
– Tamoxifen
– HAART (NRTI/PI)
HCV (genotype 3)
Weight loss
TPN
Wilson Disease
Idiopathic
• Microvesicular
TCN
Valproate
AFLP
Rye’s syndrome
HELLP syndrome
Inborn errors
Steatohepatitis
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Fatty change (>5%)
Ballooning degeneration
Lobular inflammation
Mallory bodies
Perisinusoidal fibrosis
Steatohepatitis
Macrovesicular
Cytologic
ballooning
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
Stomach
ADH- gender
ethnicity
EtOH
Small bowel
LIVER
ADH
ALDH
Acetate
NAD
Acetaldehyde
Mitochondria
Liver toxicity
NADH
Microsomal ethanol
Oxidizing system (MEOS)
- CYP 2E1
- Inducible by chronic alcohol
Pathogenesis of ASH in the Liver
Hepatic stellate cells
Leaky gut
PV endotoxemia
TGF-
matrix
LPS
Kupffer Cell
Other stimuli
Fibrosis
TNF-
KV Kowdley, MD
Hepatocyte
Mechanisms of Alcoholic Liver Injury
Acetaldehyde
Oxidative Stress
Inhibition of mitochondrial
beta-oxidation of fatty acids
Oxygen-free radicals
Glutathione depletion
Acetaldehyde Adducts
Oxygen-free radicals
Decreased Anti-oxidants
LIVER
TNFα
TGFβ
Redox Status
NAD depletion
Fat accumulation
Cytokines
Hepatitis C
Natural History of Alcoholic Hepatitis
Normal liver
Alcohol (90-100%)
reverse
80%
Steatosis
20% progress
50% reverse
Steatohepatitis
50% progress, 38% with abstinence
Fibrosis
~20% of alcoholics
Cirrhosis
Factors Associated with Liver Injury
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•
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•
•
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 Disease
Clinical Features
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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
Alcohol and AST:ALT ratio
• 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.
Alcoholic Liver Disease
Management
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•
•
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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 Indices
on Survival
Author
Sheth
N
MELD
34
>11
DF
>32
Srikureja
202
>18
>32
Dunn
73
>21
>41
Soultati
34
>30
>108
Sensitivity %
Specificity %
AUROC
86
81
0.82
86
48
0.86
85
84
0.89
83
60
0.81
75
75
0.83
75
69
0.83
100
94
0.97
100
97
0.98
Both MELD and DF have similar sensitivity (75-85%)
while MELD has higher specificity
Adapted from O’Shea et al. Hepatology 2010;51:307-328
Effects of steroids on survival in alcoholic
steatohepatitis
Author
Carithers
Ramond
Mathurin
n
Severity
assessment
F/U
% Survival
Pred vs
placebo
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
1.2-1.5 g/kg protein
35-40 kcal/kg energy
Consider transplant
Used with Permission: O’Shea et al. Hepatology 2010;51:307-328
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
Isolated fatty liver
No increased morbidity
or mortality
>80%
NAFLD
<20%
HCC
NASH
Increased morbidity
and mortality
• CVD
• Liver-related
• Malignancy
Adapted from Torres et al. CGH 2012;10:837-858
2-3%/yr
Cirrhosis
1-3%/yr
Decompensation
3-5%/yr
Nonalcoholic fatty liver disease
H&E stain 20X
Steatohepatitis
Hepatocyte ballooning (large arrow)
Mallory bodies (small arrow)
Masson’s trichrome
Perisinusoidal fibrosis
Causes of NAFLD
• The metabolic syndrome
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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
Dyslipidemia
NAFLD
Diabetes
Hypertension
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
50
Based on 2000 census
N= 47 million in US
males
females
40
30
20
10
0
20-29 30-39 40-49 50-59 60-69
Age range (yrs)
>70
Prevalence of NAFLD
Ethnic Variation
60
50
40
%
30
San Antonio (1)
Dallas (2)
20
10
0
Overall
Hispanic
White
AA
NASH
NASH
among
NAFLD
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?
N
% Male
T2DM
MS
AST (U/L)
ALT (U/L)
AST/ALT
gGGT (U/L)
HOMA-IR
No NASH
291
NASH
404
p
45
17
56
34
26
66
.006
.007
.01
37
56
0.68
40
55
74
0.74
56
<.0001
<.0001
0.03
<.0001
3.8
5.0
<.0001
Model including labs, demographics AUROC = 0.79
Adapted from: Hepatology 2010;52:913-924
NAFLD: sonographic evidence
• Bright liver
• echotexture increased
compared to kidney
• vascular blurring
Courtesy of KV Kowdley
NASH and normal ALT
Adapted from Mofrad et al, Hepatology, 2003
90
ALT (I.U./L)
upper limit
of normal
60
30
0
none
portal
bridging cirrhosis
stage of fibrosis
Pathophysiology of NASH
The Players
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Insulin resistance
FFA -> lipotoxicity
Leptin
Adiponectin
Oxidative stress
Cytokines
– TNF-α
– IL-6
The “two hit” hypothesis
Insulin Resistance
1st hit
Reduced ability of insulin to suppress endogenous glucose
production and increase glucose uptake by fat and muscle.
Blunted insulin-mediated suppression of FFA release from
adipocytes and reduced FA oxidation
Lipid accumulation
Increased
Mitochondrial
Oxidative stress
Mostly TG from excess FFA influx from
higher rates of lipolysis with increased
leptin and decreased adiponectin with
decreased in FA oxidation
Reactive oxygen
species production
Lipid peroxidation
Cytokine induction
FAS ligand induction
2nd hit
Fibrosis
NASH
Clinical Conditions Associated with NAFLD
Cardiovascular
Disease
Diabetes
PCOS
Pancreatic
Steatosis
Increased Ferritin
NAFLD
Hyperuricemia
Adenomatous
Colon Polyps
Hepatocellular
Carcinoma
Obstructive Sleep
Apnea
Cirrhosis
Hypothyroidism
Adapted from Torres et al. CGH 2012;10:837-858
Vitamin D
Deficiency
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
80
90
47
100
APRI
AST, PLT
<0.5 & >1.5
0.73
FIB-4
AST, ALT, Age, PLT
<1.3 & >2.67
0.80
BAAT
ALT, BMI, age, TG
<2
BARD
AST/ALT>.8, BMI>28,
DM
2-4
0.70-0.82
35
96
<-1.45 &
>0.67
0.76-0.88
90
93
NAFLDscore* AST, ALT, Age, PLT, BMI,
Albumin
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
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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
70
*
*
*
*
% Improvement
60
50
40
Placebo N=83
Vit E N=84
Pioglit N=80
30
20
* = p<.05
10
0
Steatosis
Lob Inflam
Ballooning
Fibrosis
Resolution of
NASH
Although the study was not designed or powered to compare vit E to
Pioglitazone, vit E did as well (or better) with less side effects
Treatments for NASH
Dietary
Effect
Comments
Weight loss (7-10%)
Reduce daily calories by 500750 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
Improves LFTs and steatosis
Need to combine with diet
Exercise
30-40 min 4-5 x week
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
Improves NASH and
fibrosis
Caution in cirrhosis
Surgery
RYGB, Sleeve, other
PNPLA3
Patatin-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 NAFLD
AASLD, 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 NAFLD
AASLD, 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 NAFLD
AASLD, 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 nonDM, 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 NAFLD
AASLD, 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