Acute Liver Failure
Definition
 The
development of prolonged
prothrombin time and
encephalopathy within 8 weeks of
symptom onset in patient with no
previous liver disease
 U.S. annual incidence about 2,000
cases per year (1)
 High mortality
Causes of Acute Liver Failure
 Varies
by geographic region
 In the U.S., acetaminophen
hepatotoxicity most common
 Indeterminate cause
 Idiosyncratic drug reactions –
Isoniazid most common
Causes of ALF
 Hepatitis
B – U.S. 4th most common
cause; world wide # 1 cause
 Hepatitis A – endemic areas
 Autoimmune hepatitis
 Ischemia
 Wilson’s Disease
Causes of ALF
 Budd
Chiari Syndrome
 Pregnancy – acute fatty liver of
pregnancy and the HELP syndrome
(hemolysis, elevated liver
chemistries, low platelets)
Transplant-free Survival
 Highest
in APAP hepatotoxicity
 Followed by drug reaction
 Followed by indeterminate cause
 Best when ALF develops hyper
acutely i.e., within seven days
The Phenomenon
 Highly
unpredictable
 Dramatic
 Requires aggressive intensive care
management, anticipation of
complications, and evaluation/listing
for liver transplantation
Survival
 Correlates
with degree of
encephalopathy and coagulopathy
 Encephalopathy may be abrupt and
rapidly progressive
– Subtle mood change - > seizures - >
obtunded - > decorticate posture
– Associated with cerebral edema rather
than portosystemic shunting of toxins
seen in cirrhosis
Acetaminophen Overdose
 Accidental
 Suicide
gesture/attempt
 Emergency Room administration of
antidote: p.o. NAC or I.V. Acetadote
(contraindicated in sulfa allergy)
Accidental Overdose
 High
dose APAP for an extended
period
 Inadvertent simultaneous
administration of APAP w/
combination drugs:
– OTC Sinus and cold preparations
– OTC Narcotic pain relievers
– OTC Sleep preparations
– In combination w/ alcohol
Pathophysiology
 Dose
dependent; known liver toxin
 Also influenced by the presence of
malnutrition, concomitant ethanol,
co-administered drugs, and CYP 384
polymorphisms
 Centrilobular necrosis without
inflammation
Signs and Symptoms
 Anorexia,
nausea, vomiting, malaise,
right upper quadrant discomfort
 Dark urine, pale stool, icterus
 Transaminases rise within 10 – 12
hours, often to dramatic levels AST >
ALT, peak at day three and rapidly
improve
 Jaundice develops quickly, total
bilirubin not as high as that seen in
other causes of ALF
Case Study
Questions and Answers
Cirrhosis and Portal
Hypertension
The Final Stage of Chronic
Liver Disease Due to Any
Cause
Cirrhosis
 Excess
extracellular matrix/fibrosis in
liver
 Fibrosis spans portal-central areas
– portal-portal or central-central also seen
 Fibrosis
encases groups of
hepatocytes
 Results in distorted architecture and
vasculature
Normal
Cirrhosis
Nodules surrounded
by fibrous tissue
GROSS IMAGE OF A CIRRHOTIC LIVER
Cirrhotic liver
Nodular, irregular surface
Nodules
Portal Hypertension

•
•
•
•
Cirrhosis - > increased resistance to flow
of blood in sinuosoids and in liver
Increased resistance = increased portal
pressure = portal hypertension
Pressure in PV causes release of
vasodilators, i.e., nitric oxide (NO)
NO causes splanchnic arteriolar
vasodilation and increased splanchnic
inflow of blood
This increased flow maintains portal
hypertension in spite of development of
low resistance collaterals
SINUSOIDAL PORTAL HYPERTENSION
Sinusoidal Portal Hypertension
Cirrhotic
liver
Portal
vein
Portal
systemic
collaterals
Consequences of
Portal Hypertension

Splenomegaly
– Thrombocytopenia
– Palpable spleen; splenectomy harmful

Varices
– On imaging may be peri-gastric, esophageal,
or splenic
– On gastroscopy of variable size
– Risk for bleed increases w/ advancing liver
failure
– Treat w/ nonselective beta blocker, banding
Consequences of
Portal Hypertension
 Ascites:
The accumulation of fluid in
the peritoneal cavity
– An important clue to the presence of
advanced cirrhosis
– Result of sinusoidal HTN caused by
blocked hepatic venous outflow 2/2
regenerative nodules and fibrosis
– Result of plasma volume expansion,
sodium, and water retention
Serum to Ascites Albumin Gradient
“SAAG”
 The
concentration of ascitic fluid
protein is much lower than the
concentration of serum protein
 This is due to sinusoidal
capillarization, decreased
permeability to plasma proteins
 Protein concentration in ascitic fluid
in cirrhosis correlates inversely w/
the degree of portal hypertension
Ascites
 Associated
conditions:
– Hyponatremia
– Umbilical hernia
– Hepatic hydrothorax
 Complication
of ascites:
– Spontaneous bacterial peritonitis
– Pneumococus common etiology
– Gram negative bacteria
Ascites
 Treatment:
– Sodium restriction, diuretics,
paracentesis
– Transjugular intrahepatic portosystemic
shunt
 TIPS
often worsens encephalopathy
 Prognosis:
continuum of
uncomplicated ascites - > refractory
ascites - > hepatorenal syndrome
 Mortality approximately 20%/year
THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT
Hepatic
vein
TIP
S
Portal vein
Splenic
vein
Superior
mesenteric vein
Consequences of
Portal Hypertension
 Hepatic
encephalopathy
 Episodic vs persistent
 Usually precipitated by events such
as:
– Bleeding
– Infection
– Use of sedatives or hypnotics
– Dehydration
Hepatic Encephalopathy
Pathogenesis: failure of the liver to
detoxify portal blood toxins in the setting
of decreased hepatic function and/or
diminished hepatic perfusion by portal
blood. Cerebral edema, ammonia, and
disturbances in cell function, esp.
astrocytes
 Diagnosis: don’t assume it is HE until
other potential causes of altered mental
status have been considered

Encephalopathy
Alternative Explanations
 Metabolic:
hypoxia, hypoglycemia,
hypo/hypernatremia, thyroid
disease, hypercalcemia
 Central Nervous System: CVA,
Subdural hematoma, post ictal state,
metastatic cancer
 Toxins: alcohol, CNS depressants
 Infection: sepsis, meningitis,
encephalitis, delerium tremens
Staging
West Haven Criteria
 Stage
0: No abnormality
 Stage 1: Trivial lack of awareness
– Shortened attention span
– Euphoria or anxiety
– Impairment of addition and subtraction
 Stage
2: Lethargy
– Time disorientation
– Personality change
– Inappropriate behavior
Staging Hepatic Encephalopathy
West Haven Criteria
 Stage
3: Somnolence to semistupor
– Response to stimuli
– Confusion
– Disorientation
– Bizarre behavior
 Stage
4: Coma
 Generalized motor abnormalities
common: hyperreflexia, asterixis,
Babinski +
Hepatic Encephalopathy
 Blood
ammonia testing has little role
in the diagnosis of HE
 Clinical suspicion is the main guide
 Treatment:
– Supportive care for altered mental state
– Identify and treat the precipitating
cause
– Exclude and/or treat other medical
illnesses
– Begin empirical therapy: lactulose,
nonabsorbable antibiotics,
metronidazole
Complications of Cirrhosis
 Osteoporosis
 Increased
risk of infections
 Muscle cramps
 Increased risk for hepatocellular
carcinoma
 Malnutrition
 Depression
 Pruritis
Standard Recommendations
for All Cirrhotics
 Vaccinate
against viral hepatitis,
pneumococcal pneumonia, influenza
 Baseline bone density test – treat
osteopenia or osteoporosis as
indicated
 Baseline ultrasound and AFP and
repeat semi-annually for HCC
surveillance if cirrhotic
 Esophageal varix surveillance – treat
as indicated
Standard Recommendations
for All Cirrhotics
 Refer
for liver transplantation
 Monitor for signs of advancing liver
failure
 Avoid alcohol
 Avoid NSAIDs
 Acetaminophen is analgesic of choice
 If significant ascites, cane, walker
 If Grade II or higher encephalopathy
take the car keys, protect from harm
Case Study
Hepatitis C
Prototype Chronic Liver
Disease
History of Viral Hepatitis
 2000
B.C. 1st recorded hepatitis
epidemic
 1963 Australia antigen AKA Hepatitis
B surface antigen (Blumberg & Alter)
 1970 Hepatitis B
 1972 National Blood Policy requires
testing of blood donors for HBsAg
History of Viral Hepatitis
 1973
Hepatitis A (Feinstone, Kapikian
& Purcell)
 1975 “Non-A Non-B Hepatitis”
 1977 Hepatitis D (Rizzetto & Gerin)
 1983 Hepatitis E (Balayan)
 1989 Hepatitis C (Alter, et al. &
Chiron Corp)
Disease Burden Estimates
Center for Hepatitis C, Cornell University
HIV
US
Chronic Infection
HBV
HCV
1.0 million
1-1.25 million
3-4 million*
New Infection/year
40,000
50,000*
20-30,000
Deaths/year
16,000*
3,000-5,000
10,000 – 12,000
40 million
350 million*
1/3 world population
170 million
New Infection/year
4 million
65 million*
3-4 million
Deaths/year
3 million*
0.5 – 1.2 million
>250,000
Worldwide
Chronic Infection
Hepatitis C Prevalence Estimates



Affects both genders, all ages, races and regions
of the world: 170 million or 3% world population
40% of all chronic liver disease in U.S.
Most common blood-borne infection in the U.S.:
1.8% of population
– 5.2 million HCV antibody positive, 4.1 million HCV
RNA+
– 1.1 million = homeless, incarcerated,
institutionalized, undocumented, and military
– U.S. prisons estimates: 600,000 HCV RNA+


25% - 40% of prison population
30% released each year (high risk behavior perpetuates
transmission)
– Born between 1945 and 1964, now age 55-64, have
highest mortality
Estimated Incidence of Acute HCV Infection
United States, 1960-2001
New Infections/100,000
140
120
100
80
60
40
20
0
1960 1965 1970 1975 1980 1985 1989 1992 1995 1998 2001
Year
Hepatitis C Facts

HCV related deaths increased 123%
between 1995-2004 (Wise, et al.)
– 1.09 deaths per 100,000 in 1995
– 2.44 deaths per 100,000 in 2004
– In 2004: 7,427 deaths, male 2.5 x >
female
– Middle-aged cohort 45 y/o to 64 y/o

Male Hispanic, AA, NA, Alaska natives
– African American males 9% w/ HCV-1
Hepatitis C Facts
Less than 10% of infected are being
treated
 Most do not know they are infected
 85% of HCV positive individuals can be
identified by testing 20-59 year olds with
elevated ALT and history of IDU or blood
transfusion before 1992
 Those infected for 20 – 30 years

– 10% - 20% -> cirrhosis
– 1% - 5% -> hepatocellular carcinoma
Who to Screen
 Ever
injected drugs
 Clotting factors before 1972
 Received organ before 1992
 Ever on dialysis
 Children of infected mothers
 Evidence of liver disease
 Workers after needle stick injury
Who Not to Screen
 Non-sexual
household contacts
 Healthcare workers, emergency
medical workers, public safety
workers
 Pregnant women
 If have contraindication to treatment
 If have limited life expectancy
Hepatitis C Virus
 An
enveloped, single-stranded, RNA
virus with a genome of about 9,600
nucleotides (1 pentose sugar, 1 base
+ phosphoric acid = structural unit of
nucleic acids i.e., RNA and DNA)
 Flaviviridae family; other viruses in
the family include West Nile virus;
others cause yellow fever, dengue
Hepatitis C Virus
 Viral
replication 1011 to 1012
virion/day (trillions!)
 No proof reading ability -> high rate
of mutation helps it to escape the
immune system -> difficult to
eradicate
Genotype: Genetic Sequence
 Used
to project response to
treatment
 Six types, multiple subtypes
Hepatitis C Around the World
1: 60% U.S. cases; (Europe, Turkey,
Japan)
2: 10% - 15% U.S. cases; wide
distribution
3: 4% to 6% U.S. cases (India,
Pakistan, Australia, Scotland)
4: < 5% (Middle East, Africa)
5: < 5% (South America)
6: < 5% (Hong Kong, Morocco)
Following Exposure
 Two
weeks: HCV RNA detectable
 Between weeks 2-4: ALT elevated
with spike by week 6
 6-7 weeks: Anti-HCV/HCV Antibody
detectable
Routes of Transmission
Percutaneous
Permucosal
Household
Percutaneous Exposure
 Highest
users
rate is among injecting drug
– 80%-90% of cases
 Recipients
of clotting factors prior to
1987 (before virus inactivation)
 Hemophiliacs
 Blood transfusion, transplant prior to
1992
Percutaneous Exposure
 Contaminated
equipment, unsafe
injection practices
– Hemodialysis, plasmapheresis,
phlebotomy
– Multiple dose injection vials – Las
Vegas, NV 2008
– Therapeutic injections
 Treatment
of schistosomiasis in Egypt
Percutaneous Exposure
 Occupational
Exposure
– Needle stick with hollow bore needles
– Incidence 1.8% with exposure to HCV+
source
– 10 X lower than from HBV + source
– Case reports: transmission from blood
splash to eye
– Prevalence 1-2% among health care
workers (same as general population)
Peter Gulick D.O., Rule of Three’s
 Risk
of viral transmission following
occupational needle stick injury:
– 30% hepatitis B
– 3% hepatitis C
– .3% HIV
Post-Hepatitis C Exposure
Test source for HCV Antibody (anti-HCV)
 If positive, test worker

– No post exposure IgG or anti-viral Rx
– ALT and anti-HCV at baseline and 4 – 6
months
– For earlier diagnosis, HCV RNA by PCR 4 – 6
weeks
– Confirm all anti-HCV + result w/ RIBA
– Refer infected worker to specialist for medical
evaluation and management
Route of Transmission
Permucosal Inefficient

Perinatally: 5% risk
– Higher if woman co-infected with HIV
– No association with delivery method/breast
feeding
– Infected infants: If test for anti-HCV at
birth will be positive due to placental
transfer; best to test for HCV RNA 3rd or 4th
month; often clear by two years, others
develop CHC; refer to pediatric specialist
Permucosal - Inefficient
Sexual: 1.5% in monogamous relationships
 Accounts for 15% - 20% of acute and
chronic infections in U.S.
 Factors that facilitate transmission
unknown

 Infected
partner, multiple partners, early sex, non
use of condoms, other STDs, sex with trauma
 MSM no higher risk than heterosexuals
 Partner studies report low prevalence (1.5%)
among long term partners
Route of Transmission
Household Contact

Rare
– Could occur through percutaneous or
mucosal exposures to blood
 Sharing
personal hygiene items
 Contaminated equipment used for home
injections, folk remedies, cultural practices
such as scarification, circumcision, tattooing
Natural History
 Clinical
spectrum is variable and
disease progression is unpredictable.
 Majority develop chronic hepatitis C:
HCV Ab+, RNA by PCR+
– Mild - majority
– Moderate
– Severe
Natural History
Acute Hepatitis C
Frequently asymptomatic
 Symptoms: malaise, asthenia, anorexia,
right upper quadrant discomfort, pruritis,
less common jaundice (25%), intermittent
nausea, vomiting. 1/6 seek medical
attention
 Usually resolves in 12 weeks
 Rates of spontaneous clearance between
15% to 45%
 Loss of virus between 6 and 24 months

Factors Influencing Progression
 Host
 Virus
Factors
Factors
 Environment
Factors Influencing Progression
 Host
Factors
– Age at infection: 40 y/o and older, more
severe disease
– Male gender: less likely to clear virus
– Obesity/Non Alcoholic Fatty Liver
Disease
– Immune system status
– ? Genetic susceptibility
Factors Influencing Progression
 Viral
Factors
– Co-infection with HBV, HIV
– Duration
 Transfusion
related CHC leads to more
aggressive disease (CABG age 50, time to
cirrhosis 14.7 years)
 IDU age 40: 16 years to cirrhosis
 Less than age 50: 29.2 years to cirrhosis
 IDU age 21-30: 33 years to cirrhosis
Factors Influencing Progression
 Environmental
Factors
– Alcohol consumption
 suppresses
immune response
 hepatotoxic
 promotes
fibrogenesis
 50g/day men, 20g/day women
– Antiviral Therapy
– Iron – Genetic Hemochromatosis
Natural History
Chronic Hepatitis C
 Mild
– infection 40 years or more
with no or mild fibrosis
 Moderate – Severe cases progress
to:
– Cirrhosis
– End Stage Liver Disease
– Hepatocellular carcinoma
– Liver transplantation
– Death
Chronic Hepatitis C
 Frequently
no symptoms until
development of advanced liver
disease
 Fatigue, depression, cognitive
changes (difficulty concentrating,
memory impairment)
 Extra hepatic manifestations
As Soon as Diagnosis Confirmed
 Immunize
against hepatitis A and
hepatitis B
 Advise patient to avoid alcohol
 Review all medications, including
over the counter, vitamins, herbal
remedies, and nutritional
supplements for potential
hepatotoxicity
 Teach transmission risk reduction
strategies
Barriers to Treatment
Stigma – people unwilling to discuss
 Treatment options: toxic, costly, overall
sustained virological response (SVR) 55%
 Access to care: collaborative approach
should include PCP, specialist, case
manager, qualified mental health provider,
substance abuse trained provider
 No public funds for screening,
surveillance, prevention programs,
treatment, community- based needle
exchange programs

Barriers to Treatment
Substance abusers mistrust authorities,
unpredictable follow through, lack of
experience w/ the healthcare system
 Provider:

–
–
–
–
–
–
Inexperience, ignorance
Unrealistic expectations, resource intense
Negative attitude
Frustration
Moralize
Patient blame
History of HCV Treatments
1991: 1st generation was interferon alpha
 1998: 2nd generation ribavirin added to
interferon alpha (increased SVR from 16%
to 41%*)

– Virazole developed 1972 for influenza
– Viramidine the pro-drug of ribavirin
– RVN is a nucleoside analog

2001: 3rd generation pegylated interferon
replaces interferon alpha
Factors Influencing Response to
Treatment

Host Factors
–
–
–
–

Race
Steatosis, obesity
Cirrhosis 10% to 12% lower rate of SVR
Immunocompromised
Virus Factors
– Genotype
– Viral load
– Early viral kinetics

Therapeutic
– Presence of rapid virological response
– Inadequate dosing
– Non-compliance
Goals of Therapy
 Viral
Eradication: sustained
virological response
– Genotypes 1,4,6 45% SVR
– Genotypes 2 & 3 70% to 85% SVR
 Improve
Histology
– Prevent decompensation
– Reduce rates of HCC
– Reduce need for transplantation
– Prevent liver-related death
Treatment Considerations
 Stage
of liver disease
 Likelihood of SVR
 Co-morbidities
 Social support
 Presence of extra-hepatic
manifestations
 Age, motivation
Who is Eligible for Treatment?
 Any
person infected with hepatitis C
is a potential candidate
 The majority will not progress to
cirrhosis and its complications: 20%
will progress to cirrhosis in 20 years
 If no contraindications, treat
genotypes 2 and 3 without liver
biopsy
 Perform biopsy on genotype 1
Who is Eligible for Treatment?
(cont’d)
 If
no fibrosis may choose to delay
 Treatment often not urgent
 Patient should determine timing
Contraindications to Treatment
 Uncontrolled
or severe depression
 Active alcohol/substance abuse
 Decompensated liver disease
 Renal transplant
Liver Biopsy
Liver biopsy is to hepatitis C as CD4 count
is to HIV
 Grade indicates the extent of necroinflammatory damage
 Stage indicates the cumulative fibrosis
damage
 Confirm clinical diagnosis
 Evaluate possible concomitant disease
 Assess therapeutic response

Liver Biopsy
 20%
sampling error
 Tendency to under stage fibrosis
 Pathologist inter-individual
variability, experience
 Not without risk
– Pain
– Bleed
– Perforated viscous
Treatment
Pegylated interferon SQ weekly with
ribavirin PO twice daily for 24 to 48 wks
 Difficult. Fatigue universal
 Common adverse effects:

– Flu like symptoms fever, myalgia, cephalgia
– Nausea, diarrhea, weight loss – 1/3
– Irritability, anxiety, anger, insomnia, impaired
concentration 1/3
– Depression – severe in < 1:1,000
– Rash, pruritis, alopecia
Treatment—Adverse Effects
 Neutropenia,
anemia,
thrombocytopenia – growth factors
and/or dose reduction may be
required
 Retinopathy - rare
 Immune mediated disorders < 1%
– Thyroid, diabetes, psoriasis, neuropathy
 Teratogenic
– protection against
pregnancy required
Monitoring While on Treatment
Significant other/caregiver to help pick up
changes in mood that require treatment
 Frequent phlebotomy, office visits
 Look for side effects and treat
 Some side effects diminish w/ time
 Hydration, healthy diet important
 Medication compliance crucial
 Sleep hygiene

Future of Hepatitis C Treatments
 Protease
inhibitor:
– VX-950/Telepravir
– SCH-503034/Boceprevir
 Polymerase
inhibitor: R 1626
complicated by ADE i.e., StevensJohnson’s syndrome, neutropenia
 These agents will be add-on to
overcome mutations and subsequent
resistance
Summary
Hepatitis C is epidemic
 Most don’t know they are infected
 Treatment is difficult, but most can handle
it with appropriate support systems in
place and careful monitoring
 Hepatitis C is the driving force behind the
rise in cases of HCC
 New treatments on the horizon purport to
shorten treatment duration

References
 Wise
M, Bialek S, Finelli L, Sorvillo F.
Changing trends in hepatitis Cmortality in the United States. 19952004. Hepatology; 47,4:1128-1135.
Extrahepatic Manifestations of
Hepatitis C
 Cryoglobulinemia
– Clinical triad of purpura, arthralgias,
weakness
– May affect kidneys, peripheral nerves,
or brain
 Membranoproliferative
Glomerulonephritis
 Porphyria cutanea tarda
 Leukocytoclastic vasculitis
Extrahepatic Manifestations of
Hepatitis C
 Sicca
syndrome/Sjogren’s syndrome
 Sero negative arthritis
 Autoimmune thyroiditis
 Idiopathic pulmonary fibrosis
(Hamman-Rich syndrome)
 Polyarteritis nodosa
 Lichen planus
Extrahepatic Manifestations of
Hepatitis C
 Mooren’s
corneal ulcer
 Aplastic anemia
 Overt B-cell lymphomas
 Psychological disorders, including
depression
 Osteosclerosis
 Higher incidence of non-Hodgkin’s
lymphoma, thyroiditis, diabetes
mellitus
Nonalcoholic Fatty
Liver Disease
A Growing Epidemic
NAFLD
A Continuum
 Simple
 May
steatosis – a benign condition
progress to steatohepatitis – >
fibrosis - > cirrhosis - > hepatic
decompensation - > liver failure - >
premature death without liver
transplantation
Natural History of NAFLD
Simple
steatosis affects 60%
of the obese
These individuals will not
progress to steatohepatitis
and cirrhosis
Where is the fat in fatty liver?
Obesity
An Epidemic
Obesity

NHANES data 2003-2004 shows:
– 32% of U.S. adults aged > 20 are obese
– 17% U.S. children and teens are overweight
Becoming one of the most important
chronic liver diseases in children and
adolescents
 Affects 2.6% to 9.8% of this young
population, up to 77% of the obese. 1
 Rapid progression to cirrhosis in some
children and young adults

Obesity Defined
 “Just
right”: Adult w/ body mass
index (BMI) 20 to 25 kg/m2
 Overweight: BMI 25 to 29.9 kg/m2
 Obese: BMI > 30 kg/m2
 Morbid obesity greater than 35
Natural History of NAFLD
20 – 25% will develop the progressive
form of NAFLD, called “Nonalcoholic
steatohepatitis” (NASH)
 One of the most common liver diseases in
the developed world
 15% will progress over five years to
cirrhosis
 Cirrhosis increases risk of Hepatocellular
Carcinoma

– Greater w/ increasing BMI
– Male > Female
Risk Factors for NAFLD
 Waist
: hip ratio > .9 in males, > .85
in females (apple shape), BMI > 30
 Medications: amiodarone, tamoxifen,
corticosteroids, estrogens, agents
used in treatment of AIDS indinavir
 Severe weight loss, i.e., jejunoileal
bypass
 Metabolic syndrome
The Metabolic Syndrome
 About
47 million U.S. adults affected
 1 million 12 to 19 year old
adolescents
 World Health Organization definition
of the metabolic syndrome:
– BP: > 140/90, hyperglycemia, high
waist to hip ratio, triglyceride > 150
and/or low HDL
 NAFLD,
NASH are the hepatic
manifestation of the metabolic
syndrome
Epidemiology
 NAFLD
prevalence 3-6
– 17% to 33% of U.S. adults
– Bariatric surgical candidates 84% to
96%
 NASH
prevalence:
– 5% to 17%
– Bariatric surgical candidates 25% to
55%
 CIRRHOSIS
prevalence:
– 0.8% to 4.3%
– Bariatric surgery patients 2% to 12%
Pathophysiology
Obesity and fatty liver are often
accompanied by a chronic, low grade
inflammatory state mediated by the
immune system
 The pro inflammatory cytokines tumor
necrosis factor alpha, interferon beta,
interleukin-6, C reactive protein, and other
acute phase proteins are released by
adipocytes and macrophages
 Evidence suggests that the inflammatory
response itself may be responsible for
insulin resistance and cardiovascular
disease

Pathophysiology
 In
the liver, Kupffer cells release
cytokines that activate stellate cells
to begin forming scar tissue
(fibrogenesis)
 Oxidative stress enhances insulin
resistance; however, antioxidants,
i.e., vitamin C and vitamin E have
not been shown to improve hepatic
histology
Diagnosis of NAFLD
 In
the U.S. NAFLD is the most
common cause of elevated
transaminases. ALT usually > AST
 Persistent elevation of AST and/or
ALT @ least 1.5 x ULN for six months
 Exclusion of other causes of liver
disease
 Ethanol consumption < 140g/wk in
men, < 70 g/wk in women
Diagnosis of NASH
NASH is a tissue diagnosis
 Liver biopsy required (unless
“cryptogenic” cirrhosis already present)
 Biopsy can accurately diagnose NASH,
exclude other causes of liver disease,
stage, and determine prognosis
 Consider when age > 45, need to gain
commitment to treatment
 If cirrhosis, consider referral to
hepatologist

Histology
Features of NAFLD include:
 Steatosis (0-3)
 Hepatocyte ballooning (0-3)
 Lobular inflammation (0-2)
 Fibrosis (0-4)
 Grade of necroinflammatory change
is scored from 0–8
 Stage of fibrosis is scored 0-4
Management
No approved pharmacotherapy at this
time, though active research is ongoing
 Control diabetes, hypertension,
dyslipidemia. Therapeutic lifestyle changes
are the cornerstone of management
 Extremely resistant to treatment; dietician
consultation critical
 Discourage rapid weight loss (can worsen
liver disease)

Case Study
Middle-aged female BMI 31.4
95
-----------------------------< .9
104 220
 Non-drinker
 DM-2 on oral agents
 Viral hepatitis panel negative, normal
platelet count and albumin
 Right Upper Quadrant Ultrasound suggests
fatty infiltration of liver

Case Study
 30
y/o M
 BMI 34
 Alcohol consumption about 24g/day
 No previous hepatitis B immunization
 Family history of diabetes, coronary
artery disease
 Takes no regular medications or
supplements
Case Study (cont.)
54
--------------/------< .8
79 120
 Ultrasound normal
 Stops all alcohol and repeat LFTs
show:
49
--------------/------< .7
38 120
References
1.
2.
3.
Nobili V, Manco M, Devito R, et al.
Lifestyle intervention and antioxidant
therapy in children with non alcoholic
fatty liver disease: A randomized
controlled trial. Hepatology 2008;48:119128.
Fortson J, Howe L, Harmon C, & Sherrill
WW. Targeting cardiovascular risk: Early
identification of insulin resistance.
Journal of the American Academy of
Nurse Practitioners 2008;319-325.
Diehl AM. Hepatic complications of
obesity. Gastroenterology Clinics of
North America 2005;34:45-62.
References
4. Clark JM. The epidemiology of
nonalcoholic fatty liver disease in adults.
Journal of Clinical Gastroenterology
2006;40(3 suppl 1):S5-S10.
5. Sanyal AJ. Gastroenterological
Association technical review on
nonalcoholic fatty liver disease.
Gastroenterology 2002;123:1705-1725.
6. MCullough AJ. Pathophysiology of
nonalcoholic steatohepatitis. Journal of
Clinical Gastroenterology 2006;40 (3
suppl 1):S17-S29.
References
7. Jonson JR, Barrie HD, O’Rourke P,
Clouston AD and Powell EE. Obesity and
steatosis influence serum and hepatic
inflammatory markers in chronic
hepatitis C. Hepatology 2008;48:80-87.