ALCOHOLIC FATTY LIVER DISEASE

Diana Alcantara-Payawal, MD
Histologic Spectrum NORMAL

90-100 %

FAT Fatty
Liver

10- 35 % 8-20%

Fat + Scar +
Nodules
Inflam
? 40% +/-
+/-
Fat
Fibrosis

Alcoholic Hepatitis Cirrhosis

Risk factors for alcoholic liver disease:

•Quantity
•Gender
•Hepatitis C: Accelerated disease
progression, more advanced
histology and decreased survival
rates
•Genetics: alcohol dehydrogenase,
acetaldehyde dehydrogenase
•Malnutrition:
 Major forms of alcoholic liver disease:
•Fatty liver
•Alcoholic hepatitis
•Cirrhosis

Time to develop liver disease = to amount of

alcohol consumed

One beer, 4 ounces of wine, one ounce of 80%

spirits = 12 grams of alcohol

Men:60-80 gm/day for 10 years

Women 20-40 gm/day for 10 years
Women’s Risk of ALD

Women alcoholics begin drinking

later, and drink less alcohol per day
than men

Women drink for fewer years than

men and have a lower cumulative
alcohol exposure at the time of
diagnosis of cirrhosis

Women die of ALD at a 10 year

earlier age than men.
Susceptibility of females to
hepatotoxicity of ethanol

More pronounced fatty liver

Less induction of fatty acid binding
protein (higher FFA)
Increased plasma endotoxin levels
Increased CD 13 and LBP
More severe pericentral hypoxia
More marked activation of NfkB
Enzymatic pathways of ethanol metabolism

ADH ALDH

NAD+ NADH NAD+ NADH

Ethanol Acetaldehyde Acetate

CYP2E1

Acetaminophen Toxic metabolites,

CCl4 reactive oxygen
species
 Update of the VA Twin Panel Study
15,924 twins followed until 1994
Concordance (%)

MZ DZ
Alcoholism 28.7 12.2
Psychosis 17.3 4.8
Cirrhosis 16.9 5.3

However, most of the genetic liability

to develop cirrhosis was the result of
shared genetic liability for alcoholism.
Traditional model of pathogenesis of fatty liver

Ethanol increases NADH level inhibiting

enzymes of fatty acid oxidation.

Ethanol increases synthesis of fatty

acids associated with induction of
lipogenic enzymes.
 New mechanism for control of lipid metabolism
+ + Induction of FFA
FFA oxidation,
transport and
PPAR/RXR export genes
Peroxisome proliferator activated receptor

- + Induction of
Sterol SREBP sterol/fat
synthesizing
genes
Sterol response element binding protein
New mechanism for control of lipid metabolism

+ + Induction of FFA
FFA oxidation,
- transport and
PPAR/RXR export genes
Ethanol

+
- + Induction of
Sterol SREBP sterol/fat
synthesizing
genes
 Hepatic Fatty Acid Metabolism
FFA
HOOC(CH2)NCH3
Triglycerides
Mitochondrial B Oxidation
PL,CE
CPT-1

L-FABP
FFA

Peroxismal B Oxidation Microsomal B Oxidation

AOX HOOC(CH2)NCH3 CYP4A1
 Hepatic Fatty Acid Metabolism
FFA
HOOC(CH2)NCH3
Triglycerides
Mitochondrial B Oxidation
PL,CE
CPT-1
LIPID PEROXIDATION
L-FABP
FFA
CYTOTOXICITY

Peroxismal B Oxidation Microsomal B Oxidation

AOX HOOC(CH2)NCH3 CYP4A1
 Hepatic Fatty Acid Metabolism
FFA
HOOC(CH2)NCH3

Triglycerides Mitochondrial B Oxidation

PL,CE CPT-1

L-FABP PPAR a
FFA
TRANSACTIVATION

Peroxismal B Oxidation Microsomal B Oxidation

AOX HOOC(CH2)NCH3 CYP4A1
 Effects of ethanol on protein metabolism

ETHANOL Acetaldehyde, HER + Protein adducts

Enzyme, cytoskeleton,
membrane protean
malfunction, neoantigen
formation

Inhibition of proteoasomal proteases,

protein accumulation, cell swelling
abnormal signaling
 Ethanol and acetaldehyde

ROS
ROS
TNFa
TNFa
TGFb
HC KC IL-6 HSC EC
IL-1
Injury Activating
TXA2
factors
Death
Fibrogenesis
(necrosis,
apoptosis) Inflammation; Adhesio
Hypoxia n
Molecul
e
cytokine
s
 Activation of HSC

Irreversible activation maybe mediated by HSC

products, retinoid depletion, and changes in the
matrix

ECM protein
collagen I,
fibronectin

TGFB
Activated HSC
 Sources of reactive oxygen species
in ethanol treated liver cells
Endoplasmic reticulum Mitochondria
NADPH + O2
CYP2E1 Ethanol
ADH
Acetaldehyde NADH

O2
ROS
E TC
ROS
H2O

Reductive stress
 Consequence of oxidant stress

Superoxide Hydrogen peroxide Hydroxyl radica

Attack of polyunsaturated fatty acids

Lipid hydroperoxide

Lipid radicals

Lipid decomposition
 Interactions of ethanol and endotoxin
FIRST HIT
Ethanol Kupffer cell
Activation of
Endotoxin Kupffer cell

Scavenger receptor
LBP
Endotoxin
CD14 Second Hit

Ethanol induces LBP and CD14

 Activation of Hepatic Stellate Cells

The very earliest event in HSC activation is unknown

Matrix changes ?
Activation of NF kB
Via degradation of IkB
Induction of PDGF-
Receptors present
R, TGFB-Rs, ICAM-1
TNFa, IL-1
Consequences of Kupffer cell activation by ethanol

Cytokines
TNFa
IL-1, IL-6
PDGF
Eicosanoids
ROS
MIP2, IL-8
Activated Kupffer Cell
 CHRONIC ETHANOL INGESTION

Lipid peroxidation

Acetaldehyde
Aldehydes

MAA adducts
Stellate cell

Autoantibodies Collagen
Autoimmun Fibrotic
e response response
 CHRONIC ETHANOL INGESTION

Lipid peroxidation
Protein
Intestine
Acetaldehyde adducts +
Aldehydes Endotoxin

Hepatocyte
PPARg/RXR
Kuppfer cells
MAA adducts TNF-a TGF-B
Stellate cell
IL-1 IL-6

Inflammatory
Autoantibodies Collagen
Response
Autoimmun Fibrotic
e response response
 Laboratory findings

Increased GGT :Not specific to alcohol, easily

inducible, elevated in all forms of fatty liver
Macrocytosis (Increased PMN). If >5500/uL
predictws asevere alcoholic hepatitis when
discriminatory index is >32
AST>ALT by 2 fold
High CDT
High gamma globulin (IgA)
High uric acid
High serum lactate
Low albumin
Low protime
High triglycerides
 Maddrey’s discriminatory function
4.6(protime- control in seconds) + bilirubin (umol/L)/17
>32 assess severity of AH
Alcoholic hepatitis has poor prognosis

Presence of ascites, variceal

hemmorrhage, deep encephalopathy or
hepatorenal syndrome has dismal
prognosis
Lifestyle modification

EtOH intake
Obesity
Smoking
 ABSTINENCE IMPROVES SURVIVAL
OF ALCOHOLIC CIRRHOSIS
SURVIVAL
120

100 ABSTINENCE

80

60

40

20

TIME OF OBSERVATION
Management of ALD

Abstinence and aggressive nutritional support

Traditional nutritional supplement

clearly improves nutritional status,
hepatic function, and outcome in
AH/ cirrhosis
Hepatology, 2000
Cigarette smoking is an
independent risk factor for cirrhosis
in ALD Am J Epidemiology, 1994
Eur J of EWpidemiology, 1994
Management of ALD

Propylthiouracil
Attenuates the hypermetabolic state to
have antioxidant properties and
improve portal blood flow.

No significant effects of PTU vs

placebo on mortality, complications
of liver disease or liver histology
Cochrane review of 6RCT
Management of ALD

Colchicine
Anti-fibrotic effects, inhibition of
collagenase activity and anti-
inflammatory functions.
No beneficial effect on with overall
mortality or liver related mortality.

Morgan, Gastroenterology, 2002

Management of ALD

Corticosteroid
Decrease the immune response and
proinflammatory cytokine response
They should be reserved for those
with severe liver disease (DF >31),
and hepatic encephalopathy.
Carithers, Ann Int Med, 1989
Mendenhall, NEJM, 1984
Management of ALD

Pentoxifylline (TRENTAL)

•Nonselective phosphodiesterase which

increases intracellular concentration of cAMP and
cGMP
•Decreases pro-inflammatory cytokines including
TNFa
•Improved vascular microcirculation
•Decreased leucocyte adhesion factor
•Antifibrotic
 Pentoxyfylline
vs placebo in
AH
PTX-Tx Placebo
PTX-tx
PTX 400 mg TID vs
vitamin B 12 for 4
weeks –improved
short term survival

Akriviadis, Gastroenterology, 2000

 Management of ALD
Vitamin E
Membrane stabilization, reduced NFkB activation
and TNF production, inhibition of stellate cell
activation and collagen production.
JCI, 1995

No benefit and likely due

to inadequate dose
J AM Nutrition, 1995
Management of ALD

SAMe
Precursor for the synthesis of polyamines, choline
and GSH
Obligatory intermediate in conversion of
methionine and cysteine in the hepatic
transulfuration pathway.
1200 mg daily for 2 years- showed
potential benefit

J Hepatology, 1999
JCI, 1995
 Management of ALD

GSH

Modulate proinflammatory
cytokine production with inhibition
of cytokines TNFa and IL-8.

Clin Biochem 1999

 ALOCHOLIC HEPATITIS

Alcoholic abstinence
Nutritional support

Discriminatory function >32

(with absence of comorbidity)

TREATMENT OPTIONS

Preferred Alternative

Prednisilone 32 mg Pentoxifylline 400 mg

PO PO TID for 4 weeks
Daily for 4 weeks
then taper for 4
 Proposed Pathophysiology
Insulin Resistance

Hyperinsulinemia

Liver Periphery

Resistant Sensitive Resistant

Glucose Lipid export

productio Lipid FFA
n peroxidation
B oxidation

Hepatic Steatosis
 LEAF PATHWAYS

Carnitine Acyl group

Carnitine Carnitine

Fatty acid
Carnitine Fatty Acid Carnitine
CPT1
FA+CoA

B oxidation

TRANSPORT AND Energy Production

OXIDATION OF FATTY ATP
ACID IN THE Protection of the Cell Membrane
MITOCHONDRIA
ALCOHOLIC FATTY
LIVER DISEASE

Diana Alcantara-Payawal, MD
 METABOLITES
Lipid peroxidation A-amino-N-Butyrate

Ethanol
Free radicals GSH A ketobutyrate

Microsomes
ADH (CYP2E)
cysteine

Acetaldehyde cystathionine

methionine
MAT homocysteine serine
S-adenosylmethionine
phosphatidylcholine

Phosphatidylethanolamine
 METABOLITES
Lipid peroxidation A-amino-N-Butyrate

Ethanol
Free radicals GSH
alpha ketobutyrate
Microsomes
ADH (CYP2E)
cysteine

Acetaldehyde cystathionine

methionine
homocysteine serine
S-adenosylmethionine
phosphatidylcholine

Phosphatidylethanolamine
cyp MITO

ROS Lipid peroxidation

FAT DEPOSITS
 Increased glucose/insulin

Sustained
lipolysis Increased Increased fat
FFA deposits
synthesis

Increased FFA Increased Increased

hepatic FFA triglyceride
pool pool

Increased B
oxidation

Increased triglyceride secretion

 Increased glucose/insulin

Sustained
lipolysis Increased Increased fat
FFA deposits
synthesis

Increased FFA Increased Increased

hepatic FFA triglyceride
pool pool

Increased B
oxidation

Increased triglyceride secretion

 Spectrum of alcoholic liver disease
death
8-20%
cirrhosis
Death >50%
SAH
SAH 40%
RECOVERY

Fatty liver
AH
RECOVERY

10-35%
 Social
Drinking
Alcohol Liver Disease
 FAT
Steatosis

Injury and inflammation

Steatohepatitis

fibrosis
0

cirrhosis HCC
+4
 Histologic Spectrum
Fatty
Liver
FAT
Steatosis

NASH Cirrhosis
Scar
Fat +
+
Inflam
Nodules
+/-
+/-
Fibrosis
Fat
 Mild Moderate Severe disease
Hepatocellular Normal Moderately impaired Hepatocellular failure
function
Histology Steatosis Marked SH, mallory Marked SH, mallory
bodies, advanced bodies, advanced
cirrhosis cirrhosis
Clinical Asymptomatic RUQ pain RUQ pain,fever
symptoms Hepatosplenomegaly Hepatosplenomegaly
Mild jaundice with PH Deep jaundice with PH

Fully reversible Potentially reversible Potentially

Outcome on alcohol abstinence improvement on alcohol
abstinence
 Innocent bystander
Steatosis

Guilty Party
 1st hit

Normal Steatosis
(vulnerable)

Oxidativ
2nd hit
e Stress

Steatohepatitis

Two-hit hypothesis of NASH

 Stasis
NAFLD
Insulin
Resistanc ETOH
e TNFa
TNFa
IkkB

Liver
Mesenteric Fat
Intestinal
Bacterial
Overgrowth
 FATTY
LIVER
Hepatic triglyceride Hepatic triglyceride
synthesis secretion
 Anti-viral agents
Abstinence from
alcohol
Removal of Iron,
Stellate cell Copper and toxic
salts
Anti-inflammatory
agents
INJURY
Quiescent Activated
Rich in retinoid Decreased retinoid acitivity
Few smooth muscle proteins Multiple smooth muscle protein
Little extracellular matrix Abundant extracellular matrix
Receptors Increased receptor density
Little proliferation Marked proliferation
Polyunsaturated soybean lecithin containing:
55%-60% phosphatidylcholine

Highly purified PC fraction with

an exceptionally high content of
essential fatty acids:
70% linoleic acid
10% linolenic acid
5% monounsaturated oleic
acid
15% saturated fatty acid
EPL reduces fibrogenesis:

direct effect on stellate cell activation

lipid peroxidation
Aleynik, 1997
Promotes breakdown of collagen
Gastroenterology, 1994
 PPC at 1.5 gm /day vs placebo
Decrease 4 plasma markers of oxidative stress
No change or presence of regression of fibrosis
on liver biopsy

Leiber, 2000
 METABOLITES
Lipid peroxidation A-amino-N-Butyrate

Ethanol
Free radicals GSH A ketobutyrate

Microsomes
ADH (CYP2E)
cysteine

Acetaldehyde cystathionine

methionine
homocysteine serine
S-adenosylmethionine
phosphatidylcholine

Phosphatidylethanolamine
Healthy liver Hepatic fibrosis

Cirrhosis Liver cancer

The basic purpose is to heal…and do no harm!!!
Anti-viral agents
Abstinence from Parenchyma inflammation
alcohol
Removal of Iron,
Copper and toxic salts Ischemic collapse of the liver tissue
Anti-inflammatory
agents Parenchymal Extinction

Progressive vascular occlusion

thrombosis

Anti-thrombotic agents Persistent fibrosis

Vasodilators
Cirrhosis
 Hepatic Cell membrane:

Represents vital morphological structure of

every organism
Essential components of cellular and
subcellular membranes:
65% hepatocells or liver parenchyma
80% of liver parenchyma is
membrane
60-65% of liver cell membrane is
phospholipids
70-90% is EPL
Phospholipids
serves as hinges
between cell-
breathing
enzymes and Choline
mitochondrial
crest Phosphate
glycerol

EPL:
Make membranes more fluid and
active enhancing permeability
Activates membrane located
phospholipids dependent
membranes