acute liver failure. definition the development of prolonged prothrombin time and encephalopathy...

Acute Liver FailureAcute Liver Failure

DefinitionDefinition

The development of prolonged The development of prolonged prothrombin time and prothrombin time and encephalopathy within 8 weeks of encephalopathy within 8 weeks of symptom onset in patient with no symptom onset in patient with no previous liver diseaseprevious liver disease

U.S. annual incidence about 2,000 U.S. annual incidence about 2,000 cases per year (1)cases per year (1)

High mortalityHigh mortality

Causes of Acute Liver FailureCauses of Acute Liver Failure

Varies by geographic regionVaries by geographic region In the U.S., acetaminophen In the U.S., acetaminophen

hepatotoxicity most commonhepatotoxicity most common Indeterminate causeIndeterminate cause Idiosyncratic drug reactions – Idiosyncratic drug reactions –

Isoniazid most commonIsoniazid most common

Causes of ALFCauses of ALF

Hepatitis B – U.S. 4Hepatitis B – U.S. 4thth most common most common cause; world wide # 1 causecause; world wide # 1 cause

Hepatitis A – endemic areasHepatitis A – endemic areas Autoimmune hepatitisAutoimmune hepatitis IschemiaIschemia Wilson’s DiseaseWilson’s Disease

Causes of ALFCauses of ALF

Budd Chiari SyndromeBudd Chiari Syndrome Pregnancy – acute fatty liver of Pregnancy – acute fatty liver of

pregnancy and the HELP syndrome pregnancy and the HELP syndrome ((hhemolysis, emolysis, eelevated liver levated liver chemistries, chemistries, llow ow pplatelets)latelets)

Transplant-free SurvivalTransplant-free Survival

Highest in APAP hepatotoxicity Highest in APAP hepatotoxicity Followed by drug reactionFollowed by drug reaction Followed by indeterminate causeFollowed by indeterminate cause Best when ALF develops hyper Best when ALF develops hyper

acutely i.e., within seven daysacutely i.e., within seven days

The PhenomenonThe Phenomenon

Highly unpredictableHighly unpredictable DramaticDramatic Requires aggressive intensive care Requires aggressive intensive care

management, anticipation of management, anticipation of complications, and evaluation/listing complications, and evaluation/listing for liver transplantationfor liver transplantation

SurvivalSurvival

Correlates with degree of Correlates with degree of encephalopathy and coagulopathyencephalopathy and coagulopathy

Encephalopathy may be abrupt and Encephalopathy may be abrupt and rapidly progressiverapidly progressive– Subtle mood change - > seizures - > Subtle mood change - > seizures - >

obtunded - > decorticate postureobtunded - > decorticate posture– Associated with cerebral edema rather Associated with cerebral edema rather

than portosystemic shunting of toxins than portosystemic shunting of toxins seen in cirrhosisseen in cirrhosis

Acetaminophen OverdoseAcetaminophen Overdose

AccidentalAccidental Suicide gesture/attemptSuicide gesture/attempt Emergency Room administration of Emergency Room administration of

antidote: p.o. NAC or I.V. Acetadote antidote: p.o. NAC or I.V. Acetadote (contraindicated in sulfa allergy)(contraindicated in sulfa allergy)

Accidental OverdoseAccidental Overdose

High dose APAP for an extended High dose APAP for an extended periodperiod

Inadvertent simultaneous Inadvertent simultaneous administration of APAP w/ administration of APAP w/ combination drugs:combination drugs:– OTC Sinus and cold preparationsOTC Sinus and cold preparations– OTC Narcotic pain relieversOTC Narcotic pain relievers– OTC Sleep preparationsOTC Sleep preparations– In combination w/ alcoholIn combination w/ alcohol

PathophysiologyPathophysiology

Dose dependent; known liver toxinDose dependent; known liver toxin Also influenced by the presence of Also influenced by the presence of

malnutrition, concomitant ethanol, malnutrition, concomitant ethanol, co-administered drugs, and CYP 384 co-administered drugs, and CYP 384 polymorphisms polymorphisms

Centrilobular necrosis without Centrilobular necrosis without inflammationinflammation

Signs and SymptomsSigns and Symptoms

Anorexia, nausea, vomiting, malaise, Anorexia, nausea, vomiting, malaise, right upper quadrant discomfortright upper quadrant discomfort

Dark urine, pale stool, icterusDark urine, pale stool, icterus Transaminases rise within 10 – 12 Transaminases rise within 10 – 12

hours, often to dramatic levels AST > hours, often to dramatic levels AST > ALT, peak at day three and rapidly ALT, peak at day three and rapidly improveimprove

Jaundice develops quickly, total Jaundice develops quickly, total bilirubin not as high as that seen in bilirubin not as high as that seen in other causes of ALFother causes of ALF

Case StudyCase Study

Questions and AnswersQuestions and Answers

Cirrhosis and Portal Cirrhosis and Portal HypertensionHypertension

The Final Stage of Chronic The Final Stage of Chronic Liver Disease Due to Any Liver Disease Due to Any

CauseCause

CirrhosisCirrhosis Excess extracellular matrix/fibrosis in Excess extracellular matrix/fibrosis in

liverliver Fibrosis spans portal-central areasFibrosis spans portal-central areas

– portal-portal or central-central also seenportal-portal or central-central also seen Fibrosis encases groups of Fibrosis encases groups of

hepatocyteshepatocytes Results in distorted architecture and Results in distorted architecture and

vasculaturevasculature

CirrhosisCirrhosisNormalNormal

Nodules surrounded by fibrous tissue

Nodules surrounded by fibrous tissue

Cirrhotic liverCirrhotic liverNodular, irregular

surfaceNodular, irregular

surface

NodulesNodules

GROSS IMAGE OF A CIRRHOTIC LIVERGROSS IMAGE OF A CIRRHOTIC LIVER

Portal HypertensionPortal Hypertension

Cirrhosis - > increased resistance to flow Cirrhosis - > increased resistance to flow of blood in sinuosoids and in liverof blood in sinuosoids and in liver

• Increased resistance = increased portal Increased resistance = increased portal pressure = portal hypertensionpressure = portal hypertension

• Pressure in PV causes release of Pressure in PV causes release of vasodilators, i.e., nitric oxide (NO)vasodilators, i.e., nitric oxide (NO)

• NO causes splanchnic arteriolar NO causes splanchnic arteriolar vasodilation and increased splanchnic vasodilation and increased splanchnic inflow of bloodinflow of blood

• This increased flow maintains portal This increased flow maintains portal hypertension in spite of development of hypertension in spite of development of low resistance collateralslow resistance collaterals

SINUSOIDAL PORTAL HYPERTENSIONSINUSOIDAL PORTAL HYPERTENSION

Cirrhotic liver

Cirrhotic liver

Portal vein

Portal vein

Sinusoidal Portal HypertensionPortal systemic collaterals

Portal systemic collaterals

Consequences ofConsequences ofPortal HypertensionPortal Hypertension

SplenomegalySplenomegaly– ThrombocytopeniaThrombocytopenia– Palpable spleen; splenectomy harmfulPalpable spleen; splenectomy harmful

VaricesVarices– On imaging may be peri-gastric, esophageal, or On imaging may be peri-gastric, esophageal, or

splenicsplenic– On gastroscopy of variable sizeOn gastroscopy of variable size– Risk for bleed increases w/ advancing liver Risk for bleed increases w/ advancing liver

failurefailure– Treat w/ nonselective beta blocker, bandingTreat w/ nonselective beta blocker, banding


Ascites: The accumulation of fluid in Ascites: The accumulation of fluid in the peritoneal cavitythe peritoneal cavity– An important clue to the presence of An important clue to the presence of

advanced cirrhosisadvanced cirrhosis– Result of sinusoidal HTN caused by Result of sinusoidal HTN caused by

blocked hepatic venous outflow 2/2 blocked hepatic venous outflow 2/2 regenerative nodules and fibrosisregenerative nodules and fibrosis

– Result of plasma volume expansion, Result of plasma volume expansion, sodium, and water retention sodium, and water retention

Serum to Ascites Albumin GradientSerum to Ascites Albumin Gradient“SAAG” “SAAG”

The concentration of ascitic fluid The concentration of ascitic fluid protein is much lower than the protein is much lower than the concentration of serum proteinconcentration of serum protein

This is due to sinusoidal This is due to sinusoidal capillarization, decreased capillarization, decreased permeability to plasma proteins permeability to plasma proteins

Protein concentration in ascitic fluid Protein concentration in ascitic fluid in cirrhosisin cirrhosis correlates inversely w/ correlates inversely w/ the degree of portal hypertensionthe degree of portal hypertension

AscitesAscites

Associated conditions:Associated conditions:– HyponatremiaHyponatremia– Umbilical herniaUmbilical hernia– Hepatic hydrothoraxHepatic hydrothorax

Complication of ascites:Complication of ascites:– Spontaneous bacterial peritonitisSpontaneous bacterial peritonitis– Pneumococus common etiologyPneumococus common etiology– Gram negative bacteria Gram negative bacteria

AscitesAscites Treatment:Treatment:

– Sodium restriction, diuretics, paracentesisSodium restriction, diuretics, paracentesis– Transjugular intrahepatic portosystemic Transjugular intrahepatic portosystemic

shunt shunt TIPS often worsens encephalopathyTIPS often worsens encephalopathy

Prognosis: continuum of Prognosis: continuum of uncomplicated ascites - > refractory uncomplicated ascites - > refractory ascites - > hepatorenal syndromeascites - > hepatorenal syndrome

Mortality approximately 20%/yearMortality approximately 20%/year

Hepatic Hepatic veinveinHepatic Hepatic veinvein

Portal veinPortal veinPortal veinPortal veinSplenic Splenic veinveinSplenic Splenic veinvein

Superior Superior mesenteric veinmesenteric veinSuperior Superior mesenteric veinmesenteric vein

TIPSTIPSTIPSTIPS

THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTTHE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT


Hepatic encephalopathyHepatic encephalopathy Episodic vs persistentEpisodic vs persistent Usually precipitated by events such Usually precipitated by events such

as:as:– BleedingBleeding– InfectionInfection– Use of sedatives or hypnoticsUse of sedatives or hypnotics– DehydrationDehydration

Hepatic EncephalopathyHepatic Encephalopathy

Pathogenesis: failure of the liver to Pathogenesis: failure of the liver to detoxify portal blood toxins in the setting detoxify portal blood toxins in the setting of decreased hepatic function and/or of decreased hepatic function and/or diminished hepatic perfusion by portal diminished hepatic perfusion by portal blood. Cerebral edema, ammonia, and blood. Cerebral edema, ammonia, and disturbances in cell function, esp. disturbances in cell function, esp. astrocytesastrocytes

Diagnosis: don’t assume it is HE until other Diagnosis: don’t assume it is HE until other potential causes of altered mental status potential causes of altered mental status have been consideredhave been considered

EncephalopathyEncephalopathyAlternative ExplanationsAlternative Explanations

Metabolic: hypoxia, hypoglycemia, Metabolic: hypoxia, hypoglycemia, hypo/hypernatremia, thyroid disease, hypo/hypernatremia, thyroid disease, hypercalcemiahypercalcemia

Central Nervous System: CVA, Central Nervous System: CVA, Subdural hematoma, post ictal state, Subdural hematoma, post ictal state, metastatic cancermetastatic cancer

Toxins: alcohol, CNS depressantsToxins: alcohol, CNS depressants Infection: sepsis, meningitis, Infection: sepsis, meningitis,

encephalitis, delerium tremensencephalitis, delerium tremens

StagingStagingWest Haven CriteriaWest Haven Criteria

Stage 0: No abnormalityStage 0: No abnormality Stage 1: Trivial lack of awarenessStage 1: Trivial lack of awareness

– Shortened attention spanShortened attention span– Euphoria or anxietyEuphoria or anxiety– Impairment of addition and subtractionImpairment of addition and subtraction

Stage 2: LethargyStage 2: Lethargy– Time disorientationTime disorientation– Personality changePersonality change– Inappropriate behaviorInappropriate behavior

Staging Hepatic Encephalopathy Staging Hepatic Encephalopathy West Haven CriteriaWest Haven Criteria

Stage 3: Somnolence to semistuporStage 3: Somnolence to semistupor– Response to stimuliResponse to stimuli– ConfusionConfusion– Disorientation Disorientation – Bizarre behaviorBizarre behavior

Stage 4: Coma Stage 4: Coma Generalized motor abnormalities Generalized motor abnormalities

common: hyperreflexia, asterixis, common: hyperreflexia, asterixis, Babinski +Babinski +

Hepatic EncephalopathyHepatic Encephalopathy Blood ammonia testing has little role Blood ammonia testing has little role

in the diagnosis of HEin the diagnosis of HE Clinical suspicion is the main guideClinical suspicion is the main guide Treatment:Treatment:

– Supportive care for altered mental stateSupportive care for altered mental state– Identify and treat the precipitating causeIdentify and treat the precipitating cause– Exclude and/or treat other medical Exclude and/or treat other medical

illnessesillnesses– Begin empirical therapy: lactulose, Begin empirical therapy: lactulose,

nonabsorbable antibiotics, metronidazolenonabsorbable antibiotics, metronidazole

Complications of CirrhosisComplications of Cirrhosis

OsteoporosisOsteoporosis Increased risk of infectionsIncreased risk of infections Muscle crampsMuscle cramps Increased risk for hepatocellular Increased risk for hepatocellular

carcinomacarcinoma MalnutritionMalnutrition DepressionDepression PruritisPruritis

Standard RecommendationsStandard Recommendationsfor All Cirrhoticsfor All Cirrhotics

Vaccinate against viral hepatitis, Vaccinate against viral hepatitis, pneumococcal pneumonia, influenzapneumococcal pneumonia, influenza

Baseline bone density test – treat Baseline bone density test – treat osteopenia or osteoporosis as osteopenia or osteoporosis as indicatedindicated

Baseline ultrasound and AFP and Baseline ultrasound and AFP and repeat semi-annually for HCC repeat semi-annually for HCC surveillance if cirrhoticsurveillance if cirrhotic

Esophageal varix surveillance – treat Esophageal varix surveillance – treat as indicatedas indicated

Standard RecommendationsStandard Recommendationsfor All Cirrhoticsfor All Cirrhotics

Refer for liver transplantationRefer for liver transplantation Monitor for signs of advancing liver Monitor for signs of advancing liver

failurefailure Avoid alcoholAvoid alcohol Avoid NSAIDsAvoid NSAIDs Acetaminophen is analgesic of choiceAcetaminophen is analgesic of choice If significant ascites, cane, walker If significant ascites, cane, walker If Grade II or higher encephalopathy If Grade II or higher encephalopathy

take the car keys, protect from harmtake the car keys, protect from harm

Hepatitis CHepatitis C

Prototype Chronic Liver Prototype Chronic Liver DiseaseDisease

History of Viral Hepatitis History of Viral Hepatitis

2000 B.C. 12000 B.C. 1stst recorded hepatitis recorded hepatitis epidemicepidemic

1963 Australia antigen AKA Hepatitis 1963 Australia antigen AKA Hepatitis B surface antigen (Blumberg & Alter)B surface antigen (Blumberg & Alter)

1970 Hepatitis B 1970 Hepatitis B 1972 National Blood Policy requires 1972 National Blood Policy requires

testing of blood donors for HBsAgtesting of blood donors for HBsAg

History of Viral HepatitisHistory of Viral Hepatitis

1973 Hepatitis A (Feinstone, Kapikian 1973 Hepatitis A (Feinstone, Kapikian & Purcell)& Purcell)

1975 “Non-A Non-B Hepatitis”1975 “Non-A Non-B Hepatitis” 1977 Hepatitis D (Rizzetto & Gerin)1977 Hepatitis D (Rizzetto & Gerin) 1983 Hepatitis E (Balayan)1983 Hepatitis E (Balayan) 1989 Hepatitis C (Alter, et al. & 1989 Hepatitis C (Alter, et al. &

Chiron Corp)Chiron Corp)

Disease Burden EstimatesDisease Burden EstimatesCenter for Hepatitis C, Cornell UniversityCenter for Hepatitis C, Cornell University

HIVHIV HBVHBV HCVHCVUSUS

Chronic InfectionChronic Infection 1.0 million1.0 million 1-1.25 million1-1.25 million 3-4 million*3-4 million*

New Infection/yearNew Infection/year 40,00040,000 50,000*50,000* 20-30,00020-30,000

Deaths/yearDeaths/year 16,000*16,000* 3,000-5,0003,000-5,000 10,000 – 12,00010,000 – 12,000

WorldwideWorldwide

Chronic InfectionChronic Infection 40 million40 million 350 million*350 million*

1/3 world population1/3 world population170 million170 million

New Infection/yearNew Infection/year 4 million4 million 65 million*65 million* 3-4 million3-4 million

Deaths/yearDeaths/year 3 million*3 million* 0.5 – 1.2 million0.5 – 1.2 million >250,000>250,000

Hepatitis C Prevalence EstimatesHepatitis C Prevalence Estimates Affects both genders, all ages, races and regions Affects both genders, all ages, races and regions

of the world: 170 million or 3% world populationof the world: 170 million or 3% world population 40% of all chronic liver disease in U.S.40% of all chronic liver disease in U.S. Most common blood-borne infection in the U.S.: Most common blood-borne infection in the U.S.:

1.8% of population1.8% of population– 5.2 million HCV antibody positive, 4.1 million HCV 5.2 million HCV antibody positive, 4.1 million HCV

RNA+RNA+– 1.1 million = homeless, incarcerated, 1.1 million = homeless, incarcerated,

institutionalized, undocumented, and military institutionalized, undocumented, and military – U.S. prisons estimates: 600,000 HCV RNA+U.S. prisons estimates: 600,000 HCV RNA+

25% - 40% of prison population25% - 40% of prison population 30% released each year (high risk behavior perpetuates 30% released each year (high risk behavior perpetuates

transmission)transmission)– Born between 1945 and 1964, now age 55-64, have Born between 1945 and 1964, now age 55-64, have

highest mortalityhighest mortality

Estimated Incidence of Acute HCV InfectionEstimated Incidence of Acute HCV InfectionUnited States, 1960-2001United States, 1960-2001

0

20

40

60

80

100

120

140

1960 1965 1970 1975 1980 1985 1989 1992 1995 1998 2001

Year

New

In

fect

ion

s/10

0,00

0

Hepatitis C FactsHepatitis C Facts

HCV related deaths increased 123% HCV related deaths increased 123% between 1995-2004 (Wise, et al.)between 1995-2004 (Wise, et al.)– 1.09 deaths per 100,000 in 19951.09 deaths per 100,000 in 1995– 2.44 deaths per 100,000 in 20042.44 deaths per 100,000 in 2004– In 2004: 7,427 deaths, male 2.5 x > In 2004: 7,427 deaths, male 2.5 x >

femalefemale– Middle-aged cohort 45 y/o to 64 y/oMiddle-aged cohort 45 y/o to 64 y/o

Male Hispanic, AA, NA, Alaska nativesMale Hispanic, AA, NA, Alaska natives

– African American males 9% w/ HCV-1African American males 9% w/ HCV-1

Hepatitis C FactsHepatitis C Facts

Less than 10% of infected are being Less than 10% of infected are being treatedtreated

Most do not know they are infectedMost do not know they are infected 85% of HCV positive individuals can be 85% of HCV positive individuals can be

identified by testing 20-59 year olds with identified by testing 20-59 year olds with elevated ALT and history of IDU or blood elevated ALT and history of IDU or blood transfusion before 1992transfusion before 1992

Those infected for 20 – 30 yearsThose infected for 20 – 30 years– 10% - 20% -> cirrhosis10% - 20% -> cirrhosis– 1% - 5% -> hepatocellular carcinoma1% - 5% -> hepatocellular carcinoma

Who to ScreenWho to Screen

Ever injected drugsEver injected drugs Clotting factors before 1972Clotting factors before 1972 Received organ before 1992Received organ before 1992 Ever on dialysisEver on dialysis Children of infected mothersChildren of infected mothers Evidence of liver diseaseEvidence of liver disease Workers after needle stick injuryWorkers after needle stick injury

Who Not to ScreenWho Not to Screen

Non-sexual household contactsNon-sexual household contacts Healthcare workers, emergency Healthcare workers, emergency

medical workers, public safety medical workers, public safety workersworkers

Pregnant womenPregnant women If have contraindication to treatmentIf have contraindication to treatment If have limited life expectancyIf have limited life expectancy

Hepatitis C VirusHepatitis C Virus

An enveloped, single-stranded, RNA An enveloped, single-stranded, RNA virus with a genome of about 9,600 virus with a genome of about 9,600 nucleotides (1 pentose sugar, 1 base nucleotides (1 pentose sugar, 1 base + phosphoric acid = structural unit of + phosphoric acid = structural unit of nucleic acids i.e., RNA and DNA)nucleic acids i.e., RNA and DNA)

Flaviviridae family; other viruses in Flaviviridae family; other viruses in the family include West Nile virus; the family include West Nile virus; others cause yellow fever, dengueothers cause yellow fever, dengue

Hepatitis C VirusHepatitis C Virus

Viral replication 10Viral replication 101111 to 10 to 101212 virion/day (trillions!)virion/day (trillions!)

No proof reading ability -> high rate No proof reading ability -> high rate of mutation helps it to escape the of mutation helps it to escape the immune system -> difficult to immune system -> difficult to eradicateeradicate

Genotype: Genetic SequenceGenotype: Genetic Sequence

Used to project response to Used to project response to treatmenttreatment

Six types, multiple subtypesSix types, multiple subtypes

Hepatitis C Around the WorldHepatitis C Around the World

1: 60% U.S. cases; (Europe, Turkey, 1: 60% U.S. cases; (Europe, Turkey, Japan)Japan)

2: 10% - 15% U.S. cases; wide 2: 10% - 15% U.S. cases; wide distributiondistribution

3: 4% to 6% U.S. cases (India, 3: 4% to 6% U.S. cases (India, Pakistan, Australia, Scotland)Pakistan, Australia, Scotland)

4: < 5% (Middle East, Africa)4: < 5% (Middle East, Africa)

5: < 5% (South America)5: < 5% (South America)

6: < 5% (Hong Kong, Morocco)6: < 5% (Hong Kong, Morocco)

Following ExposureFollowing Exposure

Two weeks: HCV RNA detectable Two weeks: HCV RNA detectable Between weeks 2-4: ALT elevated Between weeks 2-4: ALT elevated

with spike by week 6with spike by week 6 6-7 weeks: Anti-HCV/HCV Antibody 6-7 weeks: Anti-HCV/HCV Antibody

detectabledetectable

Routes of TransmissionRoutes of Transmission

PercutaneousPercutaneousPermucosalPermucosalHouseholdHousehold

Percutaneous ExposurePercutaneous Exposure

Highest rate is among injecting drug Highest rate is among injecting drug usersusers– 80%-90% of cases 80%-90% of cases

Recipients of clotting factors prior to Recipients of clotting factors prior to 1987 (before virus inactivation)1987 (before virus inactivation)

HemophiliacsHemophiliacs Blood transfusion, transplant prior to Blood transfusion, transplant prior to

1992 1992

Percutaneous ExposurePercutaneous Exposure Contaminated equipment, unsafe Contaminated equipment, unsafe

injection practicesinjection practices– Hemodialysis, plasmapheresis, Hemodialysis, plasmapheresis,

phlebotomyphlebotomy– Multiple dose injection vials – Las Vegas, Multiple dose injection vials – Las Vegas,

NV 2008NV 2008– Therapeutic injections Therapeutic injections

Treatment of schistosomiasis in EgyptTreatment of schistosomiasis in Egypt

Percutaneous ExposurePercutaneous Exposure

Occupational Exposure Occupational Exposure – Needle stick with hollow bore needlesNeedle stick with hollow bore needles– Incidence 1.8% with exposure to HCV+ Incidence 1.8% with exposure to HCV+

sourcesource– 10 X lower than from HBV + source 10 X lower than from HBV + source – Case reports: transmission from blood Case reports: transmission from blood

splash to eyesplash to eye– Prevalence 1-2% among health care Prevalence 1-2% among health care

workers (same as general population)workers (same as general population)

Peter Gulick D.O., Rule of Three’s Peter Gulick D.O., Rule of Three’s

Risk of viral transmission following Risk of viral transmission following occupational needle stick injury:occupational needle stick injury:– 30% hepatitis B30% hepatitis B– 3% hepatitis C3% hepatitis C– .3% HIV.3% HIV

Post-Hepatitis C ExposurePost-Hepatitis C Exposure

Test source for HCV Antibody (anti-HCV)Test source for HCV Antibody (anti-HCV) If positive, test workerIf positive, test worker

– No post exposure IgG or anti-viral RxNo post exposure IgG or anti-viral Rx– ALT and anti-HCV at baseline and 4 – 6 monthsALT and anti-HCV at baseline and 4 – 6 months– For earlier diagnosis, HCV RNA by PCR 4 – 6 For earlier diagnosis, HCV RNA by PCR 4 – 6

weeksweeks– Confirm all anti-HCV + result w/ RIBAConfirm all anti-HCV + result w/ RIBA– Refer infected worker to specialist for medical Refer infected worker to specialist for medical

evaluation and managementevaluation and management

Route of Transmission Route of Transmission Permucosal InefficientPermucosal Inefficient

Perinatally: 5% riskPerinatally: 5% risk– Higher if woman co-infected with HIVHigher if woman co-infected with HIV– No association with delivery method/breast No association with delivery method/breast

feedingfeeding– Infected infants: If test for anti-HCV at birth Infected infants: If test for anti-HCV at birth

will be positive due to placental transfer; will be positive due to placental transfer; best to test for HCV RNA 3best to test for HCV RNA 3rdrd or 4 or 4thth month; month; often clear by two years, others develop often clear by two years, others develop CHC; refer to pediatric specialistCHC; refer to pediatric specialist

Permucosal - InefficientPermucosal - Inefficient Sexual: 1.5% in monogamous relationshipsSexual: 1.5% in monogamous relationships Accounts for 15% - 20% of acute and Accounts for 15% - 20% of acute and

chronic infections in U.S. chronic infections in U.S. Factors that facilitate transmission Factors that facilitate transmission

unknownunknown Infected partner, multiple partners, early sex, non Infected partner, multiple partners, early sex, non

use of condoms, other STDs, sex with traumause of condoms, other STDs, sex with trauma MSM no higher risk than heterosexualsMSM no higher risk than heterosexuals Partner studies report low prevalence (1.5%) Partner studies report low prevalence (1.5%)

among long term partnersamong long term partners

Route of TransmissionRoute of Transmission Household Contact Household Contact

RareRare– Could occur through percutaneous or Could occur through percutaneous or

mucosal exposures to bloodmucosal exposures to bloodSharing personal hygiene itemsSharing personal hygiene itemsContaminated equipment used for home Contaminated equipment used for home

injections, folk remedies, cultural practices injections, folk remedies, cultural practices such as scarification, circumcision, tattooingsuch as scarification, circumcision, tattooing

Natural HistoryNatural History

Clinical spectrum is variable and Clinical spectrum is variable and disease progression is unpredictable. disease progression is unpredictable.

Majority develop chronic hepatitis C: Majority develop chronic hepatitis C: HCV Ab+, RNA by PCR+HCV Ab+, RNA by PCR+– Mild - majorityMild - majority– ModerateModerate– SevereSevere

Natural HistoryNatural HistoryAcute Hepatitis CAcute Hepatitis C

Frequently asymptomaticFrequently asymptomatic Symptoms: malaise, asthenia, anorexia, Symptoms: malaise, asthenia, anorexia,

right upper quadrant discomfort, pruritis, right upper quadrant discomfort, pruritis, less common jaundice (25%), intermittent less common jaundice (25%), intermittent nausea, vomiting. 1/6 seek medical nausea, vomiting. 1/6 seek medical attentionattention

Usually resolves in 12 weeksUsually resolves in 12 weeks Rates of spontaneous clearance between Rates of spontaneous clearance between

15% to 45% 15% to 45% Loss of virus between 6 and 24 monthsLoss of virus between 6 and 24 months

Factors Influencing ProgressionFactors Influencing Progression

Host FactorsHost Factors

Virus FactorsVirus Factors

EnvironmentEnvironment


Host FactorsHost Factors– Age at infection: 40 y/o and older, more Age at infection: 40 y/o and older, more

severe diseasesevere disease– Male gender: less likely to clear virusMale gender: less likely to clear virus– Obesity/Non Alcoholic Fatty Liver Obesity/Non Alcoholic Fatty Liver

DiseaseDisease– Immune system statusImmune system status– ? Genetic susceptibility? Genetic susceptibility


Viral FactorsViral Factors– Co-infection with HBV, HIVCo-infection with HBV, HIV– DurationDuration

Transfusion related CHC leads to more Transfusion related CHC leads to more aggressive disease (CABG age 50, time to aggressive disease (CABG age 50, time to cirrhosis 14.7 years)cirrhosis 14.7 years)

IDU age 40: 16 years to cirrhosis IDU age 40: 16 years to cirrhosis Less than age 50: 29.2 years to cirrhosisLess than age 50: 29.2 years to cirrhosis IDU age 21-30: 33 years to cirrhosisIDU age 21-30: 33 years to cirrhosis


Environmental FactorsEnvironmental Factors– Alcohol consumption Alcohol consumption

suppresses immune responsesuppresses immune responsehepatotoxic hepatotoxic promotes fibrogenesispromotes fibrogenesis50g/day men, 20g/day women50g/day men, 20g/day women

– Antiviral TherapyAntiviral Therapy– Iron – Genetic HemochromatosisIron – Genetic Hemochromatosis

Natural HistoryNatural HistoryChronic Hepatitis CChronic Hepatitis C

Mild – infection 40 years or more with Mild – infection 40 years or more with no or mild fibrosisno or mild fibrosis

Moderate – Severe cases progress to:Moderate – Severe cases progress to:– CirrhosisCirrhosis– End Stage Liver DiseaseEnd Stage Liver Disease– Hepatocellular carcinomaHepatocellular carcinoma– Liver transplantationLiver transplantation– DeathDeath

Chronic Hepatitis CChronic Hepatitis C

Frequently no symptoms until Frequently no symptoms until development of advanced liver development of advanced liver diseasedisease

Fatigue, depression, cognitive Fatigue, depression, cognitive changes (difficulty concentrating, changes (difficulty concentrating, memory impairment)memory impairment)

Extra hepatic manifestationsExtra hepatic manifestations

As Soon as Diagnosis ConfirmedAs Soon as Diagnosis Confirmed

Immunize against hepatitis A and Immunize against hepatitis A and hepatitis B hepatitis B

Advise patient to avoid alcoholAdvise patient to avoid alcohol Review all medications, including over Review all medications, including over

the counter, vitamins, herbal the counter, vitamins, herbal remedies, and nutritional supplements remedies, and nutritional supplements for potential hepatotoxicity for potential hepatotoxicity

Teach transmission risk reduction Teach transmission risk reduction strategiesstrategies

Barriers to TreatmentBarriers to Treatment

Stigma – people unwilling to discussStigma – people unwilling to discuss Treatment options: toxic, costly, overall Treatment options: toxic, costly, overall

sustained virological response (SVR) 55%sustained virological response (SVR) 55% Access to care: collaborative approach Access to care: collaborative approach

should include PCP, specialist, case should include PCP, specialist, case manager, qualified mental health provider, manager, qualified mental health provider, substance abuse trained providersubstance abuse trained provider

No public funds for screening, surveillance, No public funds for screening, surveillance, prevention programs, treatment, prevention programs, treatment, community- based needle exchange community- based needle exchange programsprograms

Barriers to TreatmentBarriers to Treatment

Substance abusers mistrust authorities, Substance abusers mistrust authorities, unpredictable follow through, lack of unpredictable follow through, lack of experience w/ the healthcare systemexperience w/ the healthcare system

Provider:Provider:– Inexperience, ignoranceInexperience, ignorance– Unrealistic expectations, resource intenseUnrealistic expectations, resource intense– Negative attitudeNegative attitude– FrustrationFrustration– MoralizeMoralize– Patient blamePatient blame

History of HCV TreatmentsHistory of HCV Treatments

1991: 11991: 1stst generation was interferon alpha generation was interferon alpha 1998: 21998: 2ndnd generation ribavirin added to generation ribavirin added to

interferon alpha (increased SVR from 16% interferon alpha (increased SVR from 16% to 41%*)to 41%*)– Virazole developed 1972 for influenzaVirazole developed 1972 for influenza– Viramidine the pro-drug of ribavirinViramidine the pro-drug of ribavirin– RVN is a nucleoside analogRVN is a nucleoside analog

2001: 32001: 3rdrd generation pegylated interferon generation pegylated interferon replaces interferon alphareplaces interferon alpha

Factors Influencing Response to Factors Influencing Response to TreatmentTreatment

Host FactorsHost Factors– RaceRace– Steatosis, obesitySteatosis, obesity– Cirrhosis 10% to 12% lower rate of SVRCirrhosis 10% to 12% lower rate of SVR– ImmunocompromisedImmunocompromised

Virus FactorsVirus Factors– GenotypeGenotype– Viral loadViral load– Early viral kineticsEarly viral kinetics

TherapeuticTherapeutic– Presence of rapid virological responsePresence of rapid virological response– Inadequate dosingInadequate dosing– Non-complianceNon-compliance

Goals of TherapyGoals of Therapy

Viral Eradication: sustained Viral Eradication: sustained virological responsevirological response– Genotypes 1,4,6 45% SVRGenotypes 1,4,6 45% SVR– Genotypes 2 & 3 70% to 85% SVRGenotypes 2 & 3 70% to 85% SVR

Improve HistologyImprove Histology– Prevent decompensationPrevent decompensation– Reduce rates of HCCReduce rates of HCC– Reduce need for transplantationReduce need for transplantation– Prevent liver-related deathPrevent liver-related death

Treatment ConsiderationsTreatment Considerations

Stage of liver diseaseStage of liver disease Likelihood of SVRLikelihood of SVR Co-morbiditiesCo-morbidities Social supportSocial support Presence of extra-hepatic Presence of extra-hepatic

manifestationsmanifestations Age, motivationAge, motivation

Who is Eligible for Treatment?Who is Eligible for Treatment? Any person infected with hepatitis C Any person infected with hepatitis C

is a potential candidateis a potential candidate The majority will not progress to The majority will not progress to

cirrhosis and its complications: 20% cirrhosis and its complications: 20% will progress to cirrhosis in 20 yearswill progress to cirrhosis in 20 years

If no contraindications, treat If no contraindications, treat genotypes 2 and 3 without liver genotypes 2 and 3 without liver biopsybiopsy

Perform biopsy on genotype 1 Perform biopsy on genotype 1

Who is Eligible for Treatment? Who is Eligible for Treatment? (cont’d)(cont’d)

If no fibrosis may choose to delayIf no fibrosis may choose to delay Treatment often not urgent Treatment often not urgent Patient should determine timingPatient should determine timing

Contraindications to TreatmentContraindications to Treatment

Uncontrolled or severe depressionUncontrolled or severe depression Active alcohol/substance abuseActive alcohol/substance abuse Decompensated liver diseaseDecompensated liver disease Renal transplantRenal transplant

Liver BiopsyLiver Biopsy

Liver biopsy is to hepatitis C as CD4 count Liver biopsy is to hepatitis C as CD4 count is to HIVis to HIV

Grade indicates the extent of necro-Grade indicates the extent of necro-inflammatory damageinflammatory damage

Stage indicates the cumulative fibrosis Stage indicates the cumulative fibrosis damagedamage

Confirm clinical diagnosisConfirm clinical diagnosis Evaluate possible concomitant diseaseEvaluate possible concomitant disease Assess therapeutic responseAssess therapeutic response

Liver BiopsyLiver Biopsy

20% sampling error20% sampling error Tendency to under stage fibrosisTendency to under stage fibrosis Pathologist inter-individual Pathologist inter-individual

variability, experiencevariability, experience Not without riskNot without risk

– PainPain– BleedBleed– Perforated viscousPerforated viscous

TreatmentTreatment

Pegylated interferon SQ weekly with Pegylated interferon SQ weekly with ribavirin PO twice daily for 24 to 48 wksribavirin PO twice daily for 24 to 48 wks

Difficult. Fatigue universalDifficult. Fatigue universal Common adverse effects:Common adverse effects:

– Flu like symptoms fever, myalgia, cephalgiaFlu like symptoms fever, myalgia, cephalgia– Nausea, diarrhea, weight loss – 1/3Nausea, diarrhea, weight loss – 1/3– Irritability, anxiety, anger, insomnia, impaired Irritability, anxiety, anger, insomnia, impaired

concentration 1/3concentration 1/3– Depression – severe in < 1:1,000Depression – severe in < 1:1,000– Rash, pruritis, alopeciaRash, pruritis, alopecia

Treatment—Adverse Effects Treatment—Adverse Effects

Neutropenia, anemia, Neutropenia, anemia, thrombocytopenia – growth factors thrombocytopenia – growth factors and/or dose reduction may be and/or dose reduction may be requiredrequired

Retinopathy - rareRetinopathy - rare Immune mediated disorders < 1%Immune mediated disorders < 1%

– Thyroid, diabetes, psoriasis, neuropathyThyroid, diabetes, psoriasis, neuropathy Teratogenic – protection against Teratogenic – protection against

pregnancy requiredpregnancy required

Monitoring While on TreatmentMonitoring While on Treatment

Significant other/caregiver to help pick up Significant other/caregiver to help pick up changes in mood that require treatmentchanges in mood that require treatment

Frequent phlebotomy, office visitsFrequent phlebotomy, office visits Look for side effects and treat Look for side effects and treat Some side effects diminish w/ timeSome side effects diminish w/ time Hydration, healthy diet importantHydration, healthy diet important Medication compliance crucialMedication compliance crucial Sleep hygieneSleep hygiene

Future of Hepatitis C TreatmentsFuture of Hepatitis C Treatments

Protease inhibitor: Protease inhibitor: – VX-950/TelepravirVX-950/Telepravir– SCH-503034/Boceprevir SCH-503034/Boceprevir

Polymerase inhibitor: R 1626 Polymerase inhibitor: R 1626 complicated by ADE i.e., Stevens-complicated by ADE i.e., Stevens-Johnson’s syndrome, neutropenia Johnson’s syndrome, neutropenia

These agents will be add-on to These agents will be add-on to overcome mutations and subsequent overcome mutations and subsequent resistanceresistance

SummarySummary

Hepatitis C is epidemicHepatitis C is epidemic Most don’t know they are infectedMost don’t know they are infected Treatment is difficult, but most can handle Treatment is difficult, but most can handle

it with appropriate support systems in it with appropriate support systems in place and careful monitoringplace and careful monitoring

Hepatitis C is the driving force behind the Hepatitis C is the driving force behind the rise in cases of HCCrise in cases of HCC

New treatments on the horizon purport to New treatments on the horizon purport to shorten treatment duration shorten treatment duration

ReferencesReferences

Wise M, Bialek S, Finelli L, Sorvillo F. Wise M, Bialek S, Finelli L, Sorvillo F. Changing trends in hepatitis C-Changing trends in hepatitis C-mortality in the United States. 1995-mortality in the United States. 1995-2004. 2004. Hepatology; Hepatology; 47,4:1128-1135.47,4:1128-1135.

Extrahepatic Manifestations of Extrahepatic Manifestations of Hepatitis CHepatitis C

CryoglobulinemiaCryoglobulinemia– Clinical triad of purpura, arthralgias, Clinical triad of purpura, arthralgias,

weaknessweakness– May affect kidneys, peripheral nerves, or May affect kidneys, peripheral nerves, or

brainbrain Membranoproliferative Membranoproliferative

GlomerulonephritisGlomerulonephritis Porphyria cutanea tardaPorphyria cutanea tarda Leukocytoclastic vasculitisLeukocytoclastic vasculitis


Sicca syndrome/Sjogren’s syndromeSicca syndrome/Sjogren’s syndrome Sero negative arthritisSero negative arthritis Autoimmune thyroiditisAutoimmune thyroiditis Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis

(Hamman-Rich syndrome)(Hamman-Rich syndrome) Polyarteritis nodosaPolyarteritis nodosa Lichen planusLichen planus


Mooren’s corneal ulcerMooren’s corneal ulcer Aplastic anemiaAplastic anemia Overt B-cell lymphomasOvert B-cell lymphomas Psychological disorders, including Psychological disorders, including

depressiondepression OsteosclerosisOsteosclerosis Higher incidence of non-Hodgkin’s Higher incidence of non-Hodgkin’s

lymphoma, thyroiditis, diabetes mellituslymphoma, thyroiditis, diabetes mellitus

Nonalcoholic Fatty Nonalcoholic Fatty Liver DiseaseLiver Disease

A Growing EpidemicA Growing Epidemic

NAFLDNAFLDA ContinuumA Continuum

Simple steatosis – a benign conditionSimple steatosis – a benign condition

May progress to steatohepatitis – > May progress to steatohepatitis – > fibrosis - > cirrhosis - > hepatic fibrosis - > cirrhosis - > hepatic decompensation - > liver failure - > decompensation - > liver failure - > premature death without liver premature death without liver transplantationtransplantation

Natural History of NAFLDNatural History of NAFLD

Simple steatosis affects 60% Simple steatosis affects 60% of the obese of the obese

These individuals will not These individuals will not progress to steatohepatitis progress to steatohepatitis and cirrhosisand cirrhosis

Where is the fat in fatty liver?Where is the fat in fatty liver?

ObesityObesity

An EpidemicAn Epidemic

ObesityObesity

NHANES data 2003-2004 shows:NHANES data 2003-2004 shows:– 32% of U.S. adults aged 32% of U.S. adults aged >> 20 are obese 20 are obese– 17% U.S. children and teens are overweight17% U.S. children and teens are overweight

Becoming one of the most important Becoming one of the most important chronic liver diseases in children and chronic liver diseases in children and adolescents adolescents

Affects 2.6% to 9.8% of this young Affects 2.6% to 9.8% of this young population, up to 77% of the obese. population, up to 77% of the obese. 11

Rapid progression to cirrhosis in some Rapid progression to cirrhosis in some children and young adultschildren and young adults

Obesity DefinedObesity Defined

““Just right”: Adult w/ body mass Just right”: Adult w/ body mass index (BMI) 20 to 25 kg/mindex (BMI) 20 to 25 kg/m22

Overweight: BMI 25 to 29.9 kg/mOverweight: BMI 25 to 29.9 kg/m2 2

Obese: BMI Obese: BMI >> 30 kg/m 30 kg/m22

Morbid obesity greater than 35Morbid obesity greater than 35

Natural History of NAFLDNatural History of NAFLD

20 – 25% will develop the progressive form 20 – 25% will develop the progressive form of NAFLD, called “Nonalcoholic of NAFLD, called “Nonalcoholic steatohepatitis” (NASH)steatohepatitis” (NASH)

One of the most common liver diseases in One of the most common liver diseases in the developed worldthe developed world

15% will progress over five years to 15% will progress over five years to cirrhosiscirrhosis

Cirrhosis increases risk of Hepatocellular Cirrhosis increases risk of Hepatocellular Carcinoma Carcinoma – Greater w/ increasing BMIGreater w/ increasing BMI– Male > FemaleMale > Female

Risk Factors for NAFLDRisk Factors for NAFLD

Waist : hip ratio > .9 in males, > .85 Waist : hip ratio > .9 in males, > .85 in females (apple shape), BMI > 30in females (apple shape), BMI > 30

Medications: amiodarone, tamoxifen, Medications: amiodarone, tamoxifen, corticosteroids, estrogens, agents corticosteroids, estrogens, agents used in treatment of AIDS indinavir used in treatment of AIDS indinavir

Severe weight loss, i.e., jejunoileal Severe weight loss, i.e., jejunoileal bypassbypass

Metabolic syndromeMetabolic syndrome

The Metabolic SyndromeThe Metabolic Syndrome About 47 million U.S. adults affectedAbout 47 million U.S. adults affected 1 million 12 to 19 year old adolescents 1 million 12 to 19 year old adolescents World Health Organization definition of World Health Organization definition of

the metabolic syndrome:the metabolic syndrome:– BP: BP: >> 140/90, hyperglycemia, high waist to 140/90, hyperglycemia, high waist to

hip ratio, triglyceride hip ratio, triglyceride >> 150 and/or low HDL 150 and/or low HDL NAFLD, NASH are the hepatic NAFLD, NASH are the hepatic

manifestation of the metabolic manifestation of the metabolic syndromesyndrome

EpidemiologyEpidemiology

NAFLD prevalenceNAFLD prevalence 3-6 3-6 – 17% to 33% of U.S. adults17% to 33% of U.S. adults– Bariatric surgical candidates 84% to 96%Bariatric surgical candidates 84% to 96%

NASH prevalence:NASH prevalence:– 5% to 17%5% to 17%– Bariatric surgical candidates 25% to 55%Bariatric surgical candidates 25% to 55%

CIRRHOSISCIRRHOSIS prevalence: prevalence:– 0.8% to 4.3%0.8% to 4.3%– Bariatric surgery patients 2% to 12%Bariatric surgery patients 2% to 12%

PathophysiologyPathophysiology Obesity and fatty liver are often Obesity and fatty liver are often

accompanied by a chronic, low grade accompanied by a chronic, low grade inflammatory state mediated by the immune inflammatory state mediated by the immune systemsystem

The pro inflammatory cytokines tumor The pro inflammatory cytokines tumor necrosis factor alpha, interferon beta, necrosis factor alpha, interferon beta, interleukin-6, C reactive protein, and other interleukin-6, C reactive protein, and other acute phase proteins are released by acute phase proteins are released by adipocytes and macrophages adipocytes and macrophages

Evidence suggests that the inflammatory Evidence suggests that the inflammatory response itself may be responsible for insulin response itself may be responsible for insulin resistance and cardiovascular diseaseresistance and cardiovascular disease

PathophysiologyPathophysiology

In the liver, Kupffer cells release In the liver, Kupffer cells release cytokines that activate stellate cells cytokines that activate stellate cells to begin forming scar tissue to begin forming scar tissue (fibrogenesis)(fibrogenesis)

Oxidative stress enhances insulin Oxidative stress enhances insulin resistance; however, antioxidants, resistance; however, antioxidants, i.e., vitamin C and vitamin E have not i.e., vitamin C and vitamin E have not been shown to improve hepatic been shown to improve hepatic histologyhistology

Diagnosis of NAFLDDiagnosis of NAFLD

In the U.S. NAFLD is the most common In the U.S. NAFLD is the most common cause of elevated transaminases. ALT cause of elevated transaminases. ALT usually > ASTusually > AST

Persistent elevation of AST and/or ALT Persistent elevation of AST and/or ALT @ least 1.5 x ULN for six months@ least 1.5 x ULN for six months

Exclusion of other causes of liver Exclusion of other causes of liver diseasedisease

Ethanol consumption < 140g/wk in Ethanol consumption < 140g/wk in men, < 70 g/wk in women men, < 70 g/wk in women

Diagnosis of NASHDiagnosis of NASH

NASH is a tissue diagnosisNASH is a tissue diagnosis Liver biopsy required (unless Liver biopsy required (unless

“cryptogenic” cirrhosis already present)“cryptogenic” cirrhosis already present) Biopsy can accurately diagnose NASH, Biopsy can accurately diagnose NASH,

exclude other causes of liver disease, exclude other causes of liver disease, stage, and determine prognosisstage, and determine prognosis

Consider when age > 45, need to gain Consider when age > 45, need to gain commitment to treatmentcommitment to treatment

If cirrhosis, consider referral to If cirrhosis, consider referral to hepatologisthepatologist

HistologyHistology

Features of NAFLD include:Features of NAFLD include: Steatosis (0-3)Steatosis (0-3) Hepatocyte ballooning (0-3)Hepatocyte ballooning (0-3) Lobular inflammation (0-2)Lobular inflammation (0-2) Fibrosis (0-4)Fibrosis (0-4) GradeGrade of necroinflammatory change of necroinflammatory change

is scored from 0–8is scored from 0–8 StageStage of fibrosis is scored 0-4 of fibrosis is scored 0-4

ManagementManagement

No approved pharmacotherapy at this No approved pharmacotherapy at this time, though active research is ongoingtime, though active research is ongoing

Control diabetes, hypertension, Control diabetes, hypertension, dyslipidemia. Therapeutic lifestyle dyslipidemia. Therapeutic lifestyle changes are the cornerstone of changes are the cornerstone of managementmanagement

Extremely resistant to treatment; dietician Extremely resistant to treatment; dietician consultation criticalconsultation critical

Discourage rapid weight loss (can worsen Discourage rapid weight loss (can worsen liver disease)liver disease)

Case StudyCase Study Middle-aged female BMI 31.4 Middle-aged female BMI 31.4 95 95 -----------------------------< .9-----------------------------< .9 104 220104 220 Non-drinkerNon-drinker DM-2 on oral agentsDM-2 on oral agents Viral hepatitis panel negative, normal Viral hepatitis panel negative, normal

platelet count and albuminplatelet count and albumin Right Upper Quadrant Ultrasound suggests Right Upper Quadrant Ultrasound suggests

fatty infiltration of liverfatty infiltration of liver


30 y/o M30 y/o M BMI 34BMI 34 Alcohol consumption about 24g/dayAlcohol consumption about 24g/day No previous hepatitis B immunizationNo previous hepatitis B immunization Family history of diabetes, coronary Family history of diabetes, coronary

artery diseaseartery disease Takes no regular medications or Takes no regular medications or

supplementssupplements

Case Study (cont.)Case Study (cont.)

54 54 --------------/------< .8--------------/------< .8 79 12079 120 Ultrasound normalUltrasound normal Stops all alcohol and repeat LFTs Stops all alcohol and repeat LFTs

show:show: 49 49 --------------/------< .7--------------/------< .7 38 12038 120


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2.2. Fortson J, Howe L, Harmon C, & Sherrill Fortson J, Howe L, Harmon C, & Sherrill WW. Targeting cardiovascular risk: Early WW. Targeting cardiovascular risk: Early identification of insulin resistance. identification of insulin resistance. Journal Journal of the American Academy of Nurse of the American Academy of Nurse Practitioners 2008;319-325.Practitioners 2008;319-325.

3.3. Diehl AM. Hepatic complications of obesity. Diehl AM. Hepatic complications of obesity. Gastroenterology Clinics of North America Gastroenterology Clinics of North America 2005;34:45-62. 2005;34:45-62.


4. Clark JM. The epidemiology of nonalcoholic 4. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. fatty liver disease in adults. Journal of Journal of Clinical Gastroenterology Clinical Gastroenterology 2006;40(3 suppl 2006;40(3 suppl 1):S5-S10.1):S5-S10.

5. Sanyal AJ. Gastroenterological Association 5. Sanyal AJ. Gastroenterological Association technical review on nonalcoholic fatty liver technical review on nonalcoholic fatty liver disease. disease. GastroenterologyGastroenterology 2002;123:1705- 2002;123:1705-1725.1725.

6. MCullough AJ. Pathophysiology of 6. MCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. nonalcoholic steatohepatitis. Journal of Journal of Clinical Gastroenterology Clinical Gastroenterology 2006;40 (3 suppl 2006;40 (3 suppl 1):S17-S29. 1):S17-S29.


7.7. Jonson JR, Barrie HD, O’Rourke P, Jonson JR, Barrie HD, O’Rourke P, Clouston AD and Powell EE. Obesity and Clouston AD and Powell EE. Obesity and steatosis influence serum and hepatic steatosis influence serum and hepatic inflammatory markers in chronic inflammatory markers in chronic hepatitis C. hepatitis C. HepatologyHepatology 2008;48:80-87. 2008;48:80-87.

acute liver failure. definition the development of prolonged prothrombin time and encephalopathy...

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