Acute and Chronic Liver Disease

Acute– < 6 months duration– No permanent damage– Often resolves spontaneously

Chronic– > 6 months– May progress to cirrhosis after many years– Must look for treatable causes

Diagnosis of Acute hepatitis

Nausea, anorexia, Mild RUQ discomfort Rarely jaundice, dark urine Occas low grade fever ALT in 100’s or 1000’s (N<40) Cannot usually differentiate cause by clinical

presentation

Causes of “acute hepatitis”

Hepatitis A,B,C,D,E Other viruses eg CMV (cytomegalovirus),

EBV (mono), HSV (herpes simplex virus) Medications Wilson's Disease Autoimmune Hepatitis Common Bile Duct Stone

Hepatitis A Virus (HAV) Fecal-oral spread

Never cause chronic infection

More severe illness in adults

Only 20% of Canadian army recruits immune to HAV compared with 70% of 60 year-olds

Outbreaks world-wide from imported Infected shell-fish, berries

Travel to endemic area eg Mexico

Occupations at risk of Hepatitis A

Military personnel

Food handlers

Health care workers

Child care workers

Sanitation workers

Acute Type A Hepatitis

Complications of Hepatitis A

Cholestatic Jaundice

Relapsing Hepatitis

Fulminant Hepatitis

Hepatitis A vaccine

Available alone (Havrix)or combined with Hepatitis B (Twinrix)

Almost 100% effective Recommended in individuals travelling to

high risk countries, patients with cirrhosis, MSM, sanitation workers

Hepatitis B HBV is a DNA virus, discovered in

1966

350 million people worldwide infected

A leading cause of cirrhosis and hepatocellular (HCC) carcinoma

1 million deaths yearly

Geographic Distribution of Chronic HBV Infection

HBsAg Prevalence

≥ 8% (high)2% to 7% (intermediate)

< 2% (low)

Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Outcome of neonatal InfectionAcute Infection (< 10%)

Neonatal Infection ( from infectious mother)

Chronic Carrier(90%)

Normal Histolo

gy

Mild hepatiti

s

Active hepatiti

sCirrhosis

Hepatocellular

Carcinoma

Consequences of Acute HBV infection- in an adult

CLINICAL INFECTION(icteric or anicteric)

FULMINANTHEPATITIS (<

1%)

RECOVERY AND

IMMUNITY (95%)

CHRONIC CARRIER (5%)

DEATH

Outcome of Acute HBV Infection

Transmission of HBV InfectionTransfusion

(Blood, blood products)

Fluids(blood, semen)

Organs and tissue

transplantation

Mother to baby

Contaminated needles and

syringes

Child to child

HEPATITIS B

Impact of Immigration on US HBV Prevalence

HBsAg Prevalence[2]

≥ 8% (high)2% to 7% (intermediate)

< 2% (low)

Immigration Numbers by Continent: 2000-2009[1]

~ 3.6 million Asians

~ 875,000South Americans

~ 804,000 Africans

~ 1.3 million

Europeans

1. US Department of Homeland Security. Yearbook of Immigration Statistics: 2009. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Hepatitis B in Ottawa 90 % are Immigrants from high-

risk countries eg. SE Asia, Viet Nam, Africa

IV drug users

Hemodialysis patients ( rare now)

MSM (rare now)

Multiply-transfused patients (rare now)

Consequences of HBV infectionCLINICAL

INFECTION

CHRONIC CARRIER

CHRONIC Mild HEPATITIS

Reactivation

Liver Cancer

DEATH

CIRRHOSIS

SUBCLINICALINFECTION

CHRONIC ACTIVE

HEPATITIS

Mild inflammation

Mild Hepatitis B

Active hepatitis B- moderate inflammation

The structure of the Hepatitis B Virus (HBV

HBV-DNA Integration in HepatocytesEpisomal HBV-

DNA

Chromosomal HBV-DNA(Integrated into host cell chromosome)

Cytoplasm

Acute Hep B infection

Treatment of Acute Hepatitis B- No specific treatment

- Avoid alcohol and hepatotoxic drugs

- Hospitalization if protracted vomiting or PT > 3 seconds prolonged

- Immunization (active and passive) of contacts

Immunization against HBVPassive

Hepatitis B Immune Globulin(Anti-HBS Titer > 1:1 000 000) Needle-stick Acute sexual contact Perinatal transmission

ActiveHepatitis B vaccine

Chronic Hepatitis B

clinicaloptions.com/hep

HBV Core Curriculum 2008: Treatment and Management

Phase Immune Tolerant

Immune Clearance

Inactive Carrier State

Reactivation

LiverMinimal

inflammation and fibrosis

Chronic activeinflammation

Mild hepatitis and minimal

fibrosis

Active inflammation

Yim HJ, et al. Hepatology. 2006;43:S173-S181.Optimal treatment times

Anti-HBeAg

HBV DNA

ALT activity

Current Understanding of HBV Infection

4 Phases of Chronic HBV Infection

HBeAg

Indications for Treatment of

Chronic Hepatitis B Infection

• HBsAg positive, HBV DNA positive

• Persistent elevation of ALT

• Significant liver fibrosis (Liver Biopsy/ fibroscan)

• Other factors eg infectivity in healthcare worker

Antivirals in Chronic Hepatitis B

• Generally well-tolerated oral agents

• Effectively ( 90%) suppress HBV DNA – but need ?life-long Rx

• Resistance a potential problem with Lamivudine- so not used in high level viral DNA

• Tenofovir ( Reverse transcriptase inhibitor) or Entecavir (DNA polymerase inhibitor) are indicated in patients with high viral DNA levels

Hepatocellular Carcinoma (HCC) = Hepatoma

HBsAg As a Risk Factor for primary hepatocellular carcinoma (P.H.C.) - Taiwan

22,708subjects

19,254HBsAg Negative

Controls

3,454HBsAg Positive

Carriers

9 P.H.C. 152 P.H.C.

Risk = 5/100,000/Year Risk = 495/100,000/YearRelative Risk - 94

Morphologic Forms of HBsAg

HBcAg

HBsAg

Who should receive hepatitis B vaccine?

• Infants of Infected Mothers (plus HBIg

• MSM

• IV Drug users

• Heterosexual and household Contacts of Hepatitis B carrier

• Travelers to Endemic Areas

• Hemodialysis Patients

• Health Care Workers

• Universal Vaccination?

Hepatitis C

Hepatitis CSpectrum of

DiseaseAcute HCV Infection

Recovery

15%-30%

Chronic HCV Infection

70%-85%

Chronic Hepatitis C

Mild Moderate Severe

End-stage Liver Disease

Cirrhosis

Hepatocellular carcinoma

Liver Transplantation Death

Acute Hepatitis C

Estimated Incidence,United States, 1982-1996

Prevalence of anti-HCV in

various Study populations

Population NAnti-HCV

Reactivity

IV Drug users 41475.6%

Hemophiliacs 18459.8%

Renal Dialysis Pt 697 20.0%

MSM 3884.4%

Random Population 2432.1%

Blood Donors 9,9980.6%

HCV Infection

Risk FactorsKnown Risk

• Injection-drug use(i.e., shared paraphenalia)

• Receipt of clotting factor before 1987

• Immigration from areaswithout universal precaution

Unproved/Low Risk

• Perinatal transmission

• Transfusion after 1992

• Body piercing/scarification

• Long-term hemodialysis

• Occupational exposure (eg. Healthcare worker)

• Intranasal cocaine use

• Sex with multiple partners

Risk Factors

Pull out, pull out, you’ve hit an artery!!!

How to diagnose Hepatitis C: (HCV)

1. HCV Antibody positive

2. Confirm with HCV RNA-pcr based assay

3. 6 Genotypes world-wide: influences RX regimen

4. Liver biopsy or fibroscan to determine degree of fibrosis

1a, 1b 2a,

2b, 3a

1a, 1b 2a, 2b,

2c, 3a

4

5a

1b

1b, 6

1b, 3a

1b, 3a

3b

4

Fang et al. Clin Liver Dis. 1997.

HCV Infection: Worldwide Genotype Distribution

1a, 1b, 2b, 3a

2a

Relationship Between ALT, HCV RNA, and Anti-HCV

During Acute and Chronic HCV Infection

Hepatitis C and cryoglobulinemia/ leukocytoclastic vasculitis

Hepatitis C and Porphyria Cutanea Tarda

Treatment of HCV: indications• Transaminases (ALT) > 1.5 X normal

• ? Symptoms

• Significant fibrosis on biopsy/fibroscan

• Age

• Presence of associated conditions

• No current alcohol or drug abuse

Rapidly evolving Rx of Hepatitis C

Pegylated Interferon plus Ribavirin: overall 55% success rate ie. “cured” but major side-effects

New antivirals ( Protease and Reverse Transcriptase Inhibitors) : about to be licensed: 97% cure rate with 12- 24 weeks of Rx (Sofosbuvir/ Ledipasvir)

Cost ? > $70,000 for 12 weeks

Hepatitis C

Epidemic in baby boomers secondary to use of IV drugs in 60’s/70’s

Virtually no newly acquired Hepatitis C except current drug users

Aggravated by alcohol and fatty liver Cause of 50% of liver transplants in Canada Spectrum of disease from minimal fibrosis to

cirrhosis at 20 years New treatments > 70% successful

Delta Agent

Delta Hepatitis

Rare in Canada Delta is incomplete virus which requires

HBsAg to enter hepatocytes Causes more aggressive liver damage No effective treatment

Hepatitis E

• Epidemic form of Non-A Non-B hepatitis

• Similarities to Hepatitis A

• Waterborne, Outbreaks

• High morality in pregnant women

• Rarely found in North America- ?sausage

Etiology Agents of Chronic Viral Hepatitis

Alcoholic Liver Disease (ALD)

“To a Liver, they are all the same!” Each unit = 14 gm Etoh.

Alcoholic Liver Disease:

Causes 40% of cirrhosis deaths in UK: 27% of men and 13% of women drink > recommended (30 gm/day for men, 20 gm/day for women)

Increasing prevalence in last 2 decades < 20% of very heavy drinkers (>120gm/day)

develop Cirrhosis after 20 years: genetic factors??

Alcoholic Liver Disease: Pathology

Spectrum of Liver Damage from Fatty liver to Alcoholic Hepatitis to Cirrhosis

Fatty liver:>50%of liver cells contain large droplet fat Alcoholic Hepatitis: fat and inflammatory infiltrate

with lymphocytes and PMN’s/ ballooned cells and variable degrees of fibrosis: ?TNF/cytokine mediated

Cirrhosis: micronodular or mixed micro/macronodular cirrhosis

Acute Alcoholic Hepatitis

Often presents with sudden jaundice, RUQ pain, nausea, fever: after years of drinking

Spider nevi, palmar erythema, frequent edema and ascites. Patient looks sick, malnourished.

Elevated Total Bilirubin, Macrocytosis, elevated WBC (PMN’s), low platelet ct, low albumin.

AST>ALT but usually only mild to moderately elevated (<5XN)

Treatment of Alcoholic Hepatitis:

Admit to hospital. Stop alcohol/ nutritional support/ thiamine/ vitamins

Look for infection Alcoholic Hepatitis Score: Maddrey

Discriminant Function: (Bili and INR);>32 have 6 month mortality of 50%

Prednisilone 40 mg/day for 1 month: still controversial. ? Pentoxifyline

?Liver Transplant

Risk factors for NAFLD (Non-alcoholic fatty liver disease) 69-100% obese 34-75% Diabetic 20-80% hyperlipidemic Central obesity more important than total

weight Insulin resistance invariable

NAFLD:Non Alcoholic Fatty Liver Disease:Spectrum

Benign steatosis- large droplet fat found in most patients with significant central obesity

NASH- found in 8.5% of morbidly obese at Surgery and in 18.5% of obese at autopsy; resembles ALD pathologically: Mechanisms unkown: genetic factors/ cytokines/ TNF?

NASH: Non-Alcoholic Steatohepatitis

% of patients with fatty liver who develop NASH/ cirrhosis unknown

Reason? Genetic,” second hit”? Recent association with various SNP’s

Natural history: 3-15% of patients with NASH have cirrhosis on Bx. ? Commonest cause of cirrhosis in Canada

Third most common cause of liver transplant and increasing in frequency

Rx: gradual weight loss

Other causes of Cirrhosis:

Genetic eg. Wilson's Disease, Hemochromatosis

Autoimmune eg. Autoimmune Hepatitis, Primary Biliary Cirrhosis, Primary Sclerosing cholangitis

Alcoholic Liver Disease NASH (Non-Alcoholic Steatohepatitis) Misc: eg Budd-Chiari Syndrome

Wilson’s Disease•Autosomal recessive

•Abnormality in handling of copper

•Copper deposits in liver and basal ganglia

•Presentation age 5-30 years with either neurologic or hepatic disease

•Liver disease can vary from acute hepatitis to cirrhosis

Wilson’s Disease•Must be ruled out in all patients < age 30 with liver disease

•May present as 1) ABN LFT’s 2) Fulminant Hepatic Failure 3) Chronic Active Hepatitis 4) Cirrhosis

•CNS Features

Wilson’s Disease•Decreased ceruloplasmin (a copper binding protein)

• Increased Urinary Copper

•Kayser-Fleisher Rings

•Neurologic manifestations esp tremor and psychiatric abnormalities

Presentation of Wilson’s Disease

Wilson’s DiseaseTreatment

•D-Penicillamine- binds copper so not absorbed from diet and copper deposits gradually decline

Hereditary hemochromatosis

0.4-1.0% of N European One of the most common inherited

disorders Autosomal recessive Leads to excess iron absorption in gut

and deposition in liver,heart,joints,pancreas and other endocrine organs

HFe

HFe

Hemochromatosis genes:

85% of HFe patients are Homozygous for C282Y mutation

5% are C282Y/H63D heterozygote C282Y predominantly northern Europe

(1/300) H63D common in all ethnic groups-

14% allelic frequency, low penetrance

Management of Hemochromatosis:

Gene testing Phlebotomy/ Become Blood Donor Family screening ?MRI Screening for hepatoma in Cirrhotics

Other causes of iron overload: Metabolic syndrome

Obesitas Hypertension Insulin resistance

Chronic Liver Disease Hepatitis Alcohol use NASH Porphyria Cutanea Tarda

Iron overload in sub-Saharan Africa

α-1 Antitrypsin Deficiency•Hereditary deficiency of α-1 antitrypsin

•Often presents as neonatal Jaundice EG: - 5/28 infants with neonatal hepatitis ultimately diagnosed as α-1 at deficiency. - 9/13 patients with α-1

antitrypsin deficiency presented as jaundice < age 1 year.

•Liver disease associated with Pizz Phenotype

Autoimmune Chronic Active Hepatitis

• Disease of young women and menopausal women

• C/O fatigue

• AST, ALT

• High IgG levels

• ANA +VE in 80%

• Anti-smooth muscle antibody most specific test (80%)

• Liver biopsy shows chronic hepatitis with plasma cells and more damage than anticipated

• Treatment = Corticosteroids

Primary Biliary Cirrhosis (PBC)

•Disease of Middle-aged women

•Presents with fatigue, hepatomegaly, +- pruritus (itch)

• Increased Alkaline phosphate

•Cell-mediated damage to intrahepatic ductules

•+ve antimitochondrial antibodiesin 95%

Primary Biliary Cirrhosis

Was major cause of liver transplant URSO (Ursodeoxycholic Acid)

treatment since 1986 .. Few progress Itch can be debilitating: Rx

cholystyramine which binds bile salts in GI tract

Primary Sclerosing Cholangitis: PSC

70% have Ulcerative colitis Either can present first PSC can develop after colectomy Autoimmune damage of medium size

intra and extra- hepatic bile ducts Presents as abnormal cholestatic liver

enzymes and occasionally recurrent cholangitis

Primary Sclerosing Cholangitis

• Frequently progresses to Liver transplant- but age varies

• No Known treatment• ERCP dilatation of tight strictures• Risk of cholangiocarcinoma ( and

hepatoma)

Budd-Chiari Syndrome:

Blockage of Hepatic veins Usually secondary to Hypercoagulable state Often presents with ascites Diagnosed with US/doppler of hepatic veins Rx: anticoagulation +/- Tipps +/- Liver

transplant Rare

Medication Induced Liver Disease

Several medications/herbal products can cause severe liver disease

Nitrofurantoin and Minocycline –Autoimmune hepatitis

Methotrexate and Amiodarone- NASH/cirrhosis

Hydroxycut/Tylenol –fulminant liver failure