Acute Liver Failure - Michigan State University
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Transcript Acute Liver Failure - Michigan State University
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
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