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DISEASES OF THE LIVER 1 and 2

Dina C. Gonzales, MD, MHPEd, FPCP, FPSG


Department of Internal Medicine
De La Salle University Health Sciences Campus
LIVER

STRUCTURE AND FUNCTION

- weight: 1-1.5 kg  largest body organ


- represents 1.5-2.5% lean body mass
- held in place by ligamentous attachments
to diaphragm, peritoneum, great vessels
and upper GI organs
LIVER
STRUCTURE AND FUNCTION

- receives dual blood supply:


20% = hepatic artery: oxygen-rich
80% = portal vein: nutrient rich
- cell majority (2/3 of liver mass): hepatocytes
other cell types: Kupffer cells
stellate (Ito or fat-storing) cells
bile ductular structures
supporting structures
LIVER

STRUCTURE AND FUNCTION

acinus: physiologic unit of liver


Both hepatic arterial and portal venous
blood entering the acinus from portal areas -
flows through sinusoids to the terminal
hepatic veins
LIVER

FUNCTION OF HEPATOCYTES
1. synthesis of most essential serum proteins:
albumin, carrier proteins, coagulation factors,
hormonal and growth factors
2. Production of bile and its carriers: bile acids,
cholesterol, lecithin and phospholipids
3. Regulation of nutrients: glucose, glycogen, lipids,
cholesterol, amino acids
4. Conjugation of lipophilic compounds: bilirubin,
cations drugs for excretion in bile or urine
LIVER

Commonly used liver function tests:


1. Serum bilirubin
- measure of hepatic conjugation and excretion
2. Serum albumin
measures of
3. Prothrombin time protein synthesis
EVALUATION OF PATIENTS WITH
LIVER DISEASE

1. Establish etiologic diagnosis


- hepatocellular vs. cholestatic injury
- specific etiologic Dx
2. Estimate disease severity (GRADING)
- assess disease activity: active vs. inactive;
mild, moderate, severe
3. Establish disease state (STAGING)
- estimate place in the course of natural history
of disease: acute vs. chronic; early or late;
pre-cirrhotic,cirrhotic or end-stage
LIVER

Clinical History:

- focus on symptoms: nature, pattern of


onset, progression

- potential risk factors for liver disease


LIVER
SYMPTOMATOLOGY:
jaundice: hallmark
most reliable marker of severity
constitutional: fatigue, weakness, nausea,
anorexia, malaise
specific: dark urine, light stools, pruritus,
abdominal pain, bloating

* constellation of symptoms and their pattern of


onset rather than a specific symptom  points to
an etiology
LIVER
PHYSICAL EXAMINATION:

- rarely demonstrates evidence of liver


dysfunction in a patient without symptoms or
laboratory findings

- usually complements rather than replaces


need for diagnostic approaches
LIVER
PE findings:
typical : icterus
hepatomegaly
hepatic tenderness
splenomegaly
spider angiomata
excoriations
advanced disease : muscle wasting
edema
dilated abdominal veins
hepatic fetor
asterixis
mental confusion
stupor
coma
LIVER
Diagnostic Approaches

- Laboratory Tests
- Diagnostic Imaging
- Liver Biopsy : gold standard
LIVER
Biochemical Tests useful in evaluation and
management of patients with hepatic dysfunction:

- can be used to:


1. detect presence of liver disease
2. distinguish among different types of
liver disorders
3. Gauge extent of known liver damage
4. follow treatment response
Liver tests

Isolated elevation Cholestatic pattern Isolated elevation


of the bilirubin of the alkaline
phosphatase
Review drugs
Ultrasound Dilated
Fractionate ducts
bilirubin Ducts not
dilated
> 15% Direct < 15% Direct Check AMA CT/ERCP
AMA negative AMA positive
Dubin-Johnson or Evaluation for ERCP/Liver Bx Liver Bx
Rotor’s syndrome hemolysis
W/U
W/U negative positive
Hepatocellular Fractionate the alkaline
Gilbert’s Hemolysis pattern phosphatase or check GGT
Syndrome or 5’ nucleotidase to assess
origin of alkaline phosphatase
Review drug list Alkaline phos.
Hepatitis C antibody Alkaline
Ultrasound phos. of bone origin
Hepatitis B surface Ag Review drug list of liver
Iron, TIBC, ferritin Ducts not origin Bone Eval
W/U negative ANA, SPEP dialted,
Ceruloplasmin (if px < 40) but parenchyma Dialted ducts
Ultrasound to look abnormal and/or or W/U negative
W/U AMA positive
for fatty liver
R/O Celiac disease negative Consider Liver Biopsy Liver Biopsy ERCP
Liver Test Patterns in Hepatobiliary Disorders

Type of disorder Bilirubin Aminotransferases

Hemolysis/Gilbert’s Normal to 5 mg/dl Normal


Syndrome 85% due to indirect
fractions
No bilirubinuria

Acute Hepatocellular Both fractions may Elevated, often


necrosis (viral and be elevated > 500 IU
drug hepatitis , Peak usually follows ALT > AST
hepatotoxins, acute aminotransferase
heart failure) Bilirubinuria

Chronic hepatocellular Both fractions may Elevated, usually


disorders be elevated < 300 IU
Bilirubinuria
Liver Test Patterns in Hepatobiliary Disorders

Type of disorder Bilirubin Aminotransferases

Alcoholic hepatitis Both fractions may AST: ALT > 2 suggests


Cirrhosis be elevated alcoholic hepatitis or
Bilirubinuria cirrhosis

Intra-and extra- Both fractions may Normal to moderate elevation


hepatic cholestasis be elevated Rarely > 500 IU
(Obstructive jaundice) Bilirubinuria

Infiltrative diseases Usually Normal Normal to slight elevation


(tumor, granulomata);
partial bile duct
obstruction
Liver Test Patterns in Hepatobiliary Disorders

Type of disorder Alkaline Phosphatase Albumin Prothrombin


Time
Hemolysis/Gilbert’s Normal Normal Normal
Syndrome
Acute Hepatocellular Normal to < 3 times Normal Usually normal
necrosis (viral and normal elevation If > 5X above
drug hepatitis , control and
hepatotoxins, acute not corrected
heart failure) by parenteral
vitamin K,
suggests
poor
prognosis

Chronic hepatocellular Normal to < 3 times Often Often prolonged


disorders normal elevation decreased Fails to correct
with
parenteral
vitamin K
Liver Test Patterns in Hepatobiliary Disorders
Type of disorder Alkaline Albumin Prothrombin
Phosphatase Time

Alcoholic hepatitis Normal to < 3X Often Often prolonged


Cirrhosis normal decreased Fails to correct with
elevation parenteral Vit. K

Intra-and extra- Elevated, often Normal, Normal


hepatic cholestasis > 4X normal unless If prolonged, will
(Obstructive jaundice) elevation chronic correct with
parenteral Vit. K

Infiltrative diseases Elevated, often Normal Normal


(tumor, granulomata); > 4X normal
partial bile duct elevation
obstruction Fractionate, or
confirm liver
origin with 5’
nucleotidase or
gamma glutamyl
transpeptidase
DISEASES OF THE LIVER

ACUTE VIRAL HEPATITIS


• Systemic infection affecting the liver predominantly

Agents:
Hepatitis A virus - HAV
Hepatitis B virus - HBV
Hepatitis C virus - HCV
Hepatitis D virus - HDV or
HBV associated delta agent
Hepatitis E virus - HEV
Hepatitis G virus - HGV
ACUTE VIRAL HEPATITIS

• Agents produce clinically similar illness


• Agents can be distinguished by molecular and
antigenic properties

Clinically: asymptomatic and inapparent


 fulminant and fatal cases subclinical
persistent infection
 rapidly progressive chronic liver disease
with cirrhosis
Nomenclature and Features of
Hepatitis Viruses

HAV
Virus Particle : 27 nm
Morphology : Icosahedral
Genome : 7.5-kb RNA, linear, ss, +
Classification : Hepatovirus
Antigen(s) : HAV
Antibodies : anti-HAV
Features : Early fecal shedding
Diagnosis: IgM anti-HAV
Previous infection: IgG anti-HAV
Clinical and Epidemiologic Features
HAV
Incubation : 15-45, mean 30
Onset : Acute
Age preference : Children, young adults
Transmission
Fecal-oral : +++
Percutaneous : Unusual
Perinatal : -
Sexual : +
Clinical
Severity : Mild
Fulminant : 0.1%
Progression to
chronicity : None
Carrier : None
Cancer : None
Prognosis : Excellent
Prophylaxis : IG, Inactivated vaccine
Therapy : None
Scheme of typical clinical and laboratory
features of viral hepatitis A

Jaundice
 ALT IgG Anti-HAV
IgM Anti-HAV

Fecal HAV

0 4 8 12 16 20

Weeks after exposure


HEPATITIS A

Commonly = self-limited
Complications and Sequelae:
1. Relapsing Hepatitis
- weeks to months after recovery
- recurrence of symptoms, amino-transferase
elevations, jaundice, fecal excretion HAV
2. Cholestatic variant
- protracted cholestatic jaundice + pruritus
3. Rare fulminant cases: older adults, underlying
CLD
Nomenclature and Features of
Hepatitis Viruses

HBV
Virus Particle : 42 nm
Morphology : Double shelled virion (surface and
core spherical)
Genome : 3.2-Kb DNA, circular, ss/ds
Classification : Hepadna virus
Antigen(s) : HBsAg, HBcAg, HBeAg
Antibodies : anti-HBs, anti-HBc, anti-HBe
Features : Bloodborne virus, carrier state
Acute diagnosis: HBsAg, IgM anti-HBc
Markers of replication: HBeAg, HBV DNA
Liver, lymphocytes, other organs
Nomenclature and Features of
Hepatitis Viruses

HBV
Virus Particle : 27 nm
Morphology : Nucleocapsid core
Genome :
Classification :
Antigen(s) : HBcAg, HBeAg
Antibodies : anti-HBc, anti-HBe,
Features : Nucleocapsid contains DNA and DNA
polymerase; present in hepatocyte
nucleus’ HBcAg does not circulate,;
HBeAg (soluble, nonparticulate) and
HBV DNA circulate-correlate with
infectivity and complete virions
Nomenclature and Features of
Hepatitis Viruses

HBV
Virus Particle : 22 nm
Morphology : Spherical and filamentous; represents
excess virus coat material
Genome :
Classification :
Antigen(s) : HBsAg
Antibodies : anti-HBs
Features : HBsAg detectable in >95% of patients
with acute hepatitis B; found in serum,
body fluids, hepatocyte cytoplasm; anti-
HBs appears following infection-
protective antibody
HEPATITIS B VIRUS: HBV
Pre-S2

Pre-S1 S

GENOMIC STRUCTURE OF HBV


Clinical and Epidemiologic Features
HBV
Incubation : 30-180, mean 60-90,
Onset : Insidious or acute
Age preference : Young adults (sexual and percutaneous),
babies, toddlers
Transmission
Fecal-oral : -
Percutaneous : +++
Perinatal : +++
Sexual : ++
Clinical
Severity : Occasionally severe
Fulminant : 0.1-1%
Progression to
chronicity : Occasional (1-10%)
(90% of neonates)
Carrier : 0.1-30%
Cancer : + (neonatal infection)
Prognosis : Worse with age, debility
Prophylaxis : Recombinant vaccine
Therapy : Interferon, Lamivudine
Scheme of typical clinical and laboratory
features of viral hepatitis B

Jaundice
 ALT
HbeAg Anti-HBe
IgG Anti-
HBc

HBsAg

Anti-HBs
IgM
Anti-HBc

0 4 8 12 16 20 24 28 32 36 52 100

Weeks after exposure


HEPATITIS B VIRUS: HBV

COMPLICATIONS AND SEQUELAE


1. Serum - sickness like syndrome
- during prodromal phase
- Sx.: arthralgia/arthritis
rash
angioedema
hematuria
5-10%
proteinuria
2. Fulminant Hepatitis
3. Chronic Hepatitis
4.  Risk Hepatocellular carcinoma
HEPATITIS B VIRUS: HBV

Fulminant Hepatitis

- massive hepatic necrosis


- rare event
- signs and symptoms encephalopathy  coma
- small liver
- excessively prolonged prothrombin time (PT)
HEPATITIS B VIRUS: HBV

Hepatic Failure with Encephalopathy

- rapidly shrinking liver size


- rapidly rising bilirubin level
- markedly prolonged PT even as transaminases
fall
- clinical signs of confusion, disorientation,
somnolence, ascites and edema
FULMINANT HEPATIC FAILURE

- terminal events:
Cerebral edema - common
Brainstem compression
GIT bleeding
Sepsis
Respiratory Failure
Cardiovascular collapse
Renal Failure

Mortality rate: > 80%


Scheme of typical clinical and laboratory
features of chronic viral hepatitis B

ALT

HBeAg Anti-HBe
HBV DNA
HBsAg

Anti-HBc

IgM anti-HBc

0 1 2 3 4 5 6 12 24 36 48 60 120
CHRONIC HEPATITIS B

Clinical and laboratory features suggesting progression


Acute  Chronic Hepatitis B

1. Lack of complete resolution of clinical symptoms of


anorexia, weight loss, fatigue and persistence of
hepatomegaly

2. Presence of bridging or multilobular hepatic necrosis


on liver biopsy during protracted, severe acute viral
hepatitis
CHRONIC HEPATITIS B

Clinical and laboratory features suggesting progression


Acute  chronic Hepatitis B

3. Failure of serum transaminase, bilirubin and globulin


levels to return to normal within 6-12 months after acute
illness

4. Persistence of HBeAg beyond 3 months or HBsAg


beyond 6 months after acute hepatitis
Nomenclature and Features of
Hepatitis Viruses

HCV
Virus Particle : Approximately 40-60 nm
Morphology : Enveloped
Genome : 9.4-kb, RNA, linear, ss, +
Classification : Flavivirus-like
Antigen(s) : HCV, C100-3, C33c, C22-3, NS5
Antibodies : anti-HCV
Features : Bloodborne agent, formerly labeled
non-A, non-B hepatitis
Acute diagnosis: anti-HCV (C33c,
C22-3, NS5)
Chronic diagnosis: anti-HCV (C100-3,
C33c, C22-3, NS5) and HCV RNA;
cytoplasmic location in hepatocytes)
Clinical and Epidemiologic Features
HCV
Incubation : 15-160, mean 50
Onset : Insidious
Age preference : Any age, but more common in adults
Transmission
Fecal-oral : -
Percutaneous : +++
Perinatal : +
Sexual : +
Clinical
Severity : Moderate
Fulminant : 0.1%
Progression to
chronicity : Common (50-70% chronic hepatitis;
80-90% chronic infection)
Carrier : 1.5-3.2%
Cancer : +
Prognosis : Moderate
Prophylaxis : None
Therapy : Interferon plus ribavirin
HEPATITIS C VIRUS

COMPLICATIONS AND SEQUELAE

1. Rarely = Fulminant Hepatitis C

2. Chronic Hepatitis C
Scheme of typical clinical and laboratory features
during acute hepatitis C progressing to chronicity

Anti-C100
Anti-C22/C33
HCV RNA

ALT

0 1 2 3 4 5 6 12 24 36 48 60 120
Nomenclature and Features of
Hepatitis Viruses
HDV
Virus Particle : 35-37 nm
Morphology : Enveloped hybrid particle with HBsAg
coat and HDV core
Genome : 1.7-kb RNA, circular, ss, -
Classification : Resembles viroids and plant satellite
viruses
Antigen(s) : HBsAg, HDV antigen
Antibodies : anti-HBs, anti-HDV
Features : Defective RNA virus, requires helper
function of HVB (hepadnaviruses); HDV
antigen present in hepatocyte nucleus
Diagnosis: anti-HDV, HDV RNA;
HBV/HDV coinfection-IgM anti-HBc and
anti-HDV; HDV superinfection - IgG anti
HBc and anti HDV
Clinical and Epidemiologic Features
HDV
Incubation : 30-180, mean 60-90,
Onset : Insidious or acute
Age preference : Any age (similar to HBV)
Transmission
Fecal-oral : -
Percutaneous : +++
Perinatal : +
Sexual : ++
Clinical
Severity : Occasionally severe
Fulminant : 5-20%
Progression to
chronicity : Common
Carrier : Variable
Cancer : +
Prognosis : Acute, good
Chronic, poor
Prophylaxis : HBV vaccine (none for HBV carriers)
Therapy : Interferon +
HEPATITIS D VIRUS

COMPLICATIONS AND SEQUELAE

1. Fulminant Hepatitis

2. Mild disease

3. Asymptomatic carriers
Nomenclature and Features of
Hepatitis Viruses

HEV
Virus Particle : 32-34 nm
Morphology : Nonenveloped icosahedral
Genome : 7.6-kb RNA, linear, ss, +
Classification : Alphavirus-like
Antigen(s) : HEV antigen
Antibodies : anti-HEV
Features : Agent of enterically transmitted
hepatitis; rare in USA, occurs in Asia,
Mediterranean countries, Central
America
Diagnosis: IgM/IgG anti-HEV (assays
being developed) virus in stool,
bile, hepatocyte, cytoplasm
Clinical and Epidemiologic Features
HEV
Incubation : 14-60, mean 40
Onset : Acute
Age preference : Young adults, (20-40 years)
Transmission
Fecal-oral : +++
Percutaneous : -
Perinatal : -
Sexual : -
Clinical
Severity : Mild
Fulminant : 1-2%
Progression to
chronicity : None
Carrier : None
Cancer : None
Prognosis : Good
Prophylaxis : Unknown
Therapy : None
ACUTE VIRAL HEPATITIS
CLINICAL FEATURES

Prodromal Symptoms
- systemic and quite variable

- constitutional symptoms: anorexia, nausea, vomiting,


fatigue, malaise, arthralgia, myalgia, headache,
photophobia, pharyngitis, cough, coryza

- precedes jaundice 1-2 weeks

- dark urine and clay-colored stools 1-5 days before


jaundice
ACUTE VIRAL HEPATITIS
CLINICAL FEATURES

Clinical Jaundice:
- constitutional prodromal symptoms usually diminish
- mild weight loss ≈ 2.5-5 kg in some
- enlarged, tender liver + RUQ pain and discomfort
- cholestatic feature infrequently  extrahepatic biliary
obstruction
- 10-20%: (+) splenomegaly
cervical adenopathy
- few spider angiomas
ACUTE VIRAL HEPATITIS
CLINICAL FEATURES

Recovery Phase:
- constitutional symptoms disappear
- some liver enlargement and biochemical
abnormalities evident
- duration variable: 2-12 weeks
Complete biochemical and clinical recovery expected:
1-2 months: Hepatitis A and E
3-4 months: 3/4 uncomplicated cases
Hepatitis B and C
ACUTE VIRAL HEPATITIS
LABORATORY FEATURES

Serum Aminotransferases: AST, ALT


- variable  during prodrome
- precedes rise in bilirubin
- acute level does NOT correlate well with
degree of liver cell damage
- peak levels: 400-> 4,000 IU

Jaundice: (+) serum bilirubin > 43 umol/L (2.5 mg/dl)


ACUTE VIRAL HEPATITIS
LABORATORY FEATURES

Neutropenia transient followed by


Lymphopenia lymphocytosis
Atypical lymphocytes
Prothrombin time - if   worse prognosis
Hypoglycemia
Normal or mild  alkaline PO4tase
diffuse, mild  gamma globulin
Commonly Encountered Serologic Patterns of
Hepatitis B Infection

HBsAg Anti-HBs Anti-HBc HBeAg Anti-Hbe Interpretation

+ - IgM + - Acute HBV infection,


high infectivity

+ - IgG + - Chronic HBV infection,


high infectivity
+ - IgG - + Late-acute or chronic
HBV infection, low
infectivity

+ + + +/- +/- 1. HBsAg of one subtype


and heterotypic anti-
HBs (common)
2. Process of
seroconversion from
HBsAg to anti-HBs
(rare)
Commonly Encountered Serologic Patterns of
Hepatitis B Infection

HBsAg Anti-HBs Anti-HBc HBeAg Anti-Hbe Interpretation

- - IgM +/- +/- 1. Acute HVB infection


2. Anti-HBc window

- - IgG - +/- 1. Low-level HBsAg


carrier
2. Remote past infection
- + IgG - +/- Recovery from HBV
infection

- + - - - 1. Immunization with
HBsAg (after
vaccination)
2. Remote past
infection (?)
3. False-positive
ACUTE VIRAL HEPATITIS
Differential Diagnosis:
1. Viral diseases: Infectious Mononucleosis
CMV
Herpes simplex
Coxsackievirus
Toxoplasmosis
2. Drug hepatotoxicity
3. Alcoholic hepatitis
4. Biliary tract disease: acute cholecystitis, CBD stone,
cholangitis
5. Carcinoma: pancreas
metastatic
6. Pregnancy: HELLP syndrome
ACUTE VIRAL HEPATITIS

TREATMENT:

• Most cases: specific treatment generally NOT


necessary
• high calorie diet desirable
• forced, prolonged bed rest
• restricted physical activity beneficial
• withdraw hepatotoxic drugs
• intravenous feeding
• (+) pruritus = cholestyramine
ACUTE VIRAL HEPATITIS

Prophylaxis:

HEPATITIS A immunization
Passive - immune globulin
Active - killed vaccine

Pre-exposure prophylaxis of intimate contacts


(household, institutional): 0.02 ml/kg IG
as early as possible  2 weeks after exposure
HEPATITIS A PROPHYLAXIS

Pre-exposure immunoprophylaxis
- vaccine preferred

SKB: HAVRIX - > 18 years old


two 1.0 ml injections containing 1440 ELU
6-12 months apart
MERCK (VAQTA) - > 17 years old
two 1.0 ml injections
containing 50 units
6 months apart
HEPATITIS A PROPHYLAXIS

Prophylaxis not necessary for:

1. Casual contacts - office, factory, school, hospital

2. Most elderly persons - immune

3. (+) anti-HAV in serum


ACUTE VIRAL HEPATITIS

TREATMENT
HEPATITIS B PROPHYLAXIS

I. Pre-exposure prophylaxis in setting of frequent


exposure:

3 intramuscular injections (IM)


0,1,6 months

pregnancy NOT a contraindication to vaccination


ACUTE VIRAL HEPATITIS

HEPATITIS B PROPHYLAXIS

II. Post-exposure prophylaxis


- unvaccinated persons sustaining exposure to
HBV
- combination HBIG and Hepatitis B vaccine
a. Perinatal exposure: HbsAg mothers
- 0.5 ml IM immediately after birth, followed by
complete course of 3 Hepatitis B vaccine
injection within 1st 12 hours of life
HEPATITIS B POST-EXPOSURE PROPHYLAXIS

b. Direct percutaneous inoculation or transmucosal


exposure to HbsAg
(+) blood or body fluids
- accidental needle sticks, other mucosal
penetration/ingestion
- single IM dose HBIG 0.06 ml/kg as soon after
exposure as possible followed by complete
course Hepatitis B vaccine to begin within 1st
week
HEPATITIS B POST-EXPOSURE PROPHYLAXIS

c. Sexual Contact
- single IM dose HBIG 0.06 ml/kg within 14 days of
exposure followed by complete course Hepatitis
B vaccine
HEPATITIS B IMMUNIZATION

80-90% of immunocompetent vaccine retain


protective levels of anti-HBs for at least 5 years
60-80%: 10 years

booster immunizations: currently not


recommended except in immunosuppressed
persons
HEPATITIS D PROPHYLAXIS

- infection with Hepatitis D can be prevented by


Hepatitis B vaccination of susceptible persons

- NO product available for immunoprophylaxis to


prevent HDV superinfection in HbsAg carriers
HEPATITIS C PROPHYLAXIS

IG - ineffective in preventing Hepatitis C


- no longer recommended for post-exposure
prophylaxis in cases of perinatal, needle
stick or sexual exposure
Hepatitis C vaccination
- NOT feasible practically:
» genotype and quasispecies viral
heterogeneity
» rapid evasion of neutralizing antibodies by
rapidly mutating virus
HEPATITIS C PROPHYLAXIS

stable monogamous sexual partners


- transmission unlikely
multiple sexual partners or with
STD =  risk  barrier precautions recommended
Avoid sharing personal items re:
toothbrush, razors, nailclippers
No special precautions for babies born to
Hepatitis C (+) mothers
Breastfeeding - not restricted
HEPATITIS E PROPHYLAXIS

IG role - undetermined

vaccine - in progress
CHRONIC HEPATITIS

- represents a series of liver disorders of varying


causes and severity in which hepatic inflammation
and necrosis continue for at least 6 months:
- include: chronic viral hepatitis
drug induced chronic hepatitis
autoimmune chronic hepatitis
 clinical and laboratory features are insufficient to
allow assignment into 1 of these 3 categories
CHRONIC HEPATITIS

Classification - based upon:


1. Cause
2. Histologic activity - grade
3. Degree of progression - stage
Neither clinical features alone nor
histologic features - requiring liver biopsy - alone are
sufficient to characterize and distinguish among
categories of chronic hepatitis
CHRONIC HEPATITIS

Classification by cause:
Chronic Viral hepatitis caused by
Hepatitis B, B + D, C
Autoimmune hepatitis types 1,2,3 based on
serologic distinctions
Drug-associated chronic hepatitis
Cryptogenic chronic hepatitis = unknown cause
CHRONIC HEPATITIS

Classification by grade:
- based upon examination of liver biopsy
- include:
a. Degree of periportal necrosis
b. Disruption of limiting plate of periportal
hepatocytes by inflammatory cells:
piecemeal necrosis or interface
hepatitis
CHRONIC HEPATITIS

c. Bridging necrosis
- degree of confluent necrosis tract
links or form bridges between
vascular structure:
between portal tract and portal tract
between portal tract and central vein
d. Degree of hepatocyte degeneration and focal
necrosis within lobule
e. Degree of portal inflammation
Histologic Activity Index
Histologic Feature Severity Score

1. Periportal necrosis, including None 0


piecemeal necrosis (PN), and/or Mild PN 1
bridging necrosis (BN) Moderate PN 3
Marked PN 4
Moderate PN+BN 5
Marked PN+BN 6
Multilobular necrosis 10
2. Intralobular necrosis None 0
Mild 1
Moderate 3
Marked 4
3. Portal inflammation None 0
Mild 1
Moderate 3
Marked 4
4. Fibrosis None 0
Expanding portal tract 1
Bridging fibrosis 3
Cirrhosis 4_
Maximum Score 22
CHRONIC HEPATITIS

Classification by stage:
- reflects level of progression of disease
- based on degree of fibrosis
0 = no fibrosis
1 = mild fibrosis
2 = moderate fibrosis
3 = severe fibrosis, including
bridging fibrosis
4 = cirrhosis
CHRONIC VIRAL HEPATITIS B
Infection at birth  90% chance chronic Hepatitis B
Degree of Hepatitis B virus replication
- divided into 2 phases
a. Replicative phase
- (+) HBeAg
- (+) HBV DNA
- presence in liver of detectable intrahepatocyte
nucleocapsid antigens
- high infectivity
- accompanying liver injury
- HBV DNA detected in liver but extra
chromosomal
- more severe chronic hepatitis
CHRONIC VIRAL HEPATITIS B

b. Nonreplicative phase
- characterized by the absence of
conventional markers HBV
replication  (-) HBeAg
(+) anti-Hbe
- absence of intrahepatocytic HBcAg
- limited infectivity
- minimal liver injury
- HBV DNA detected in liver but integrated
in host genome
- minimal or mild chronic B or
asymptomatic carriers
- 10-15% conversion replicative to
nonreplicative
Diagnostic Criteria of HBV
Infection
• Chronic Hepatitis B
- HBsAg(+)>6 months
- Serum HBV DNA >20,000 IU/ml.
Lower values 2,000-20,000 IU/ml
are often seen HBeAg(-)chronic
hepatitis B
- Persistent or intermittent elevation in
AST/ALT levels
- Liver biopsy showing chronic hepatitis
with moderate or severe
necroinflammation
Diagnostic Criteria of HBV
Infection

• Inactive HBsAg carrier state


- HBsAg(+)>6 months
- HBeAg(-), anti-HBe(+)
- Serum HBV DNA <2000 IU/ml
- Persistently normal ALT/AST levels
- Liver biopsy confirms absence or significant
hepatitis
Diagnostic Criteria of HBV
Infection

• Resolved Hepatitis B
- Previous known history of acute or chronic
hepatitis B or the presence of
anti-HBC ± anti-HBs
- HBsAg(-)
- Undetectable serum level HBV DNA
- Normal ALT levels
Asian-Pacific Guidelines For
Treatment of Chronic Hepatitis B
Algorithm Management of
HBeAg(+) Carriers
Algorithm Management of
HBeAg(-) Carriers
Recommendations for Treatment
of Chronic HBeAg(-) Patients
Recommendations for Treatment of
Chronic Hepatitis B Patients with
Cirrhosis
CHRONIC HEPATITIS C

TREATMENT:
Two approaches to antiviral therapy:
1. Monotherapy with interferon
2. Combination therapy with interferon + ribavirin

Endtreatment responses: responses measured at end


of treatment

Sustained responses: responses sustained for at


least 6 months after discontinuation of therapy
Indications and Recommendations for Antiviral
Therapy of Chronic Hepatitis C

STANDARD INDICATIONS FOR THERAPY

Elevated ALT activity


Fibrosis or moderate to severe hepatitis on liver biopsy
Detectable HCV RNA

RETREATMENT RECOMMENDED

Relapsers after an initial course of interferon


A 6-month course of combination interferon-ribavirin or a
course of interferon monotherapy longer in duration
than the original course
TOXIC AND DRUG-INDUCED HEPATITIS

- liver injury that may follow inhalation,


ingestion or parenteral administration of
pharmacologic and chemical agents

history : elicit exposure


FEATURES: DILI ( DRUG INDUCED LIVER INJURY)
1. Direct Toxic Effect
- Acetaminophen

2. Idiosyncratic
- Halothane
- Isoniazid
- Chlorpromazine

3. Cholestatis
- Oral Contraceptives
Principal Alterations of Hepatic Morphology Produced
by Some Commonly Used Drugs and Chemicals
Principal
Morphologic
Change Class of Agent Example

Cholestasis Anabolic steroid Methyl testosterone


Anti-inflammatory Sulindac
Antithyroid Methimazole
Antibiotic Erythromycin estolate,
nitrofurantoin, rifampin,
amoxicillin-clavulanic
acid, oxacillin
Oral contraceptive Norethynodrel w/ mestranol
Oral hypoglycemic Chlorpropamide
Tranquilizer Chlorpropamide
Oncotherapeutic Anabolic steroids, busulfa,
tamoxifen
Immunosuppressive Cyclosporine
Anticonvulsant Carbamazepine
Calcium channel Nifedipine, verapamil
blocker
Principal Alterations of Hepatic Morphology Produced
by Some Commonly Used Drugs and Chemicals
Principal
Morphologic
Change Class of Agent Example

Fatty liver Antibiotic Tetracycline


Anticonvulsant Sodium valproate
Antiarrhythmic Amiodarone
Antiviral Dideoxynucleosides
(e.g. zidovudine) protease
inhibitors (e.g. indinavir,
ritonavir)
Oncotherapeutic Asparaginase, methotrexate
Principal Alterations of Hepatic Morphology Produced
by Some Commonly Used Drugs and Chemicals
Principal
Morphologic
Change Class of Agent Example

Hepatitis Anesthetic Halothane


Anticonvulsant Phenytoin, carbamazine
Antihypertensive Methyldopa, captopril,
enalapril
Antibiotic Isoniazid, rifampicin,
nitrofurantoin
Diuretic Chlorothiazide
Laxative Oxyphenisatin
Antidepressant Iproniazid, amitriptyline,
imipramine
Anti-inflammatory Ibuprofen, indomethacin,
diclofenac, sulindac
Antifungal Ketoconazole, fluconazole,
itraconazole
Antiviral Zidovudine, dideoxy inosine
Calcium channel Nifedipine, verapamil,
blocker diltiazem
Antiandrogen Flutamide
Principal Alterations of Hepatic Morphology Produced
by Some Commonly Used Drugs and Chemicals

Principal
Morphologic
Change Class of Agent Example

Mixed hepatitis/ Immunosuppressive Azathioprine


cholestatic Lipid-lowering Nicotinic acid, lovastatin
Toxic (necrosis) Hydrocarbon Carbontetrachloride
Metal Yellow phosphorus
Mushroom Amanita phalloides
Analgesic Acetaminophen
Solvent Dimethylformamide
Granulomas Anti-inflammatory Phenylbutazone
Antibiotic Sulfanomides
Xanthine oxidase Allopurinol
inhibitor
Antiarrhythmic Quinidine
Anticonvulsant Carbamazine
ACETAMINOPHEN HEPATOTOXICITY

- direct toxic effect (toxin)


single dose 10-15 g = produce clinical evidence of liver
injury

25 g or > = associated with fatal fulminant disease

blood levels: predictive or correlates with severity of


hepatic injury

> 300 ug/mL 4 hours post ingestion


 severe damage
< 150 ug/mL  hepatic injury unlikely
ACETAMINOPHEN TOXICITY

Clinical Symptomatology

4-12 H : nausea, vomiting, abdominal pain


after ingestion

24-48 H : apparent hepatic injury

4-6 days : maximal abnormalities


hepatic failure
aminotransferase ≈ 10,000 units
renal failure
myocardial injury may be (+)
TREATMENT: ACETAMINOPHEN TOXICITY

• Gastric lavage
• supportive measures
• oral administration of activated charcoal or cholestyramine to
prevent drug absorption
• N - acetylcysteine

5% solution orally: loading dose of 140 mg/kg


initially then 70 mg/kg
every 4 hours for 15-20 doses
POST-NECROTIC/POSTVIRAL
CIRRHOSIS
• Final common pathway of many types of
advanced fatty liver injury.
• Morphologic characteristics:
• extensive confluent loss of liver cells
• stromal collapse and fibrosis
• irregular nodules of regenerating
hepatocytes
ALCOHOLIC CIRRHOSIS
HISTOPATHOLOGY:

1. Alcoholic steatosis
(alcoholic fatty liver)
2. Alcoholic steatonecrosis
3. Alcoholic cirrhosis
ALCOHOLIC CIRRHOSIS
CLINICAL FEATURES:

Alcoholic fatty : Minimal or absent


liver Tender hepatomegaly

Alcoholic : asymptomatic or
hepatitis = viral/toxic hepatitis:
anorexia,vomiting, malaise,
weight loss, fever, jaundice,
tender hepatomegaly,
1/3 splenomegaly
ALCOHOLIC CIRRHOSIS
CLINICAL FEATURES:

Alcoholic Cirrhosis: clinically silent


easy bruising,
fatigue,
hepatocellular
dysfunction,
encephalopathy
ALCOHOLIC CIRRHOSIS
TREATMENT:

Supportive

Treat Encephalopathy
CARDIAC CIRRHOSIS
• Etiology: prolonged severe right sided
congestive heart failure
• Clinical features: tender enlarged liver
severe RUQ pain
AST
albumin and protime
• Diagnosis: usually clinical
(+) valvular heart disease
(+) cor pulmonale
• Treatment: treat underlying disorder
BILIARY CIRRHOSIS
PRIMARY BILIARY CIRRHOSIS

• Disease of unknown etiology


incidence : 40-60 years
90% women
• Pathogenesis : immunologic (?)
- inflammatory
destruction of
small intrahepatic
biliary ducts
PRIMARY BILIARY CIRRHOSIS

• Clinical Features
early: asymptomatic
marked alkaline P04tase
pruritus
jaundice
osteopenia 20%
xanthomas 10%
(+) association with Sjogren’s syndrome 75%
rheumatoid arthritis 5%
CREST syndrome 3%
PRIMARY BILIARY CIRRHOSIS
• Diagnosis:
serum cholesterol
4-6x elevation Alkaline P04tase
direct bilirubin
(+) antimitochondial antibodies 90%
• Treatment:
Supportive
Antipruritic = Cholestyramine
Vit. B/K supplements
Dietary supplements - MCT
SECONDARY BILIARY CIRRHOSIS

• Etiology: prolonged portal or total


obstruction CBD or its major
branches
• Adults : post operative stricture or
gallstones with superimposed
cholangitis, chronic pancreatitis
• Children : congenital biliary atresia
cystic fibrosis
SECONDARY BILIARY CIRRHOSIS

• Pathogenesis : Bile Stasis/cholangitis

Clinical features: jaundice


pruritus
fever
RUQ pain
Laboratory features: Alkaline P04tase
conjugated hyperbilirubinemia
leukocytosis
abnormal serum lipid
(+) antimitochondrial Ag
SECONDARY BILIARY CIRRHOSIS

• Diagnosis : clinical and lab features


cholangiography
liver biopsy
Treatment:
Relief of obstruction
- surgical
- endoscopic decompression
MAJOR SEQUELAE OF CIRRHOSIS

• Portal Hypertension
• Variceal bleeding
• Splenomegaly
• Spontaneous bacterial peritonitis
• Hepatorenal syndrome
• Coagulopathy
• Hepatocellular carcinoma
MAJOR COMPLICATION OF
CIRRHOSIS
PORTAL HYPERTENSION
results from increased resistance
to portal blood flow
(> 30 cm saline)
increased resistance can occur at
3 levels:
1. Presinusoidal
2. Sinusoidal
3. postsinusoidal
PORTAL HYPERTENSION
• Clinical Features:
- hemorrhage from : gastroesophageal
varices
- splenomegaly with hypersplenism
- ascites
- acute and chronic encephalopathy
• Diagnosis: clinical
endoscopic findings
• Treatment: directed toward a specific
complication
TIPS
Surgery
HEPATIC ENCEPHALOPATHY

- complex neuropsychiatric syndrome


characterized by disturbances in
consciousness and behavior, personality
changes, fluctuating neurologic signs,
asterixis or “flapping” tremor and
distinctive EEG changes
- maybe : acute and reversible
chronic and progressive
HEPATIC ENCEPHALOPATHY

Pathogenesis:
most important: severe hepatocellular
dysfunction and/or intrahepatic and
extrahepatic shunting of portal venous
blood into the systemic circulation
bypassing the liver

 failure to detoxify substances


HEPATIC ENCEPHALOPATHY

Incriminated substances:
1. Ammonia
2. Mercaptans
3. Short chain fatty acids
4. Phenol
5. False neurochemical
transmitters: octopamine
GABA
Common Precipitants of Hepatic Encephalopathy

Increased nitrogen load Drugs


Gastrointestinal bleeding Narcotics, tranquilizers,
sedatives
Excess dietary protein Diuretics
Azotemia
Constipation Miscellaneous
Electrolyte and metabolic Infection
imbalance Surgery
Hypokalemia Superimposed acute
Alkalosis liver disease
Hypoxia Progressive liver disease
Hyponatremia Portal-systemic shunts
Hypovolemia
Clinical Stages of Hepatic Encephalopathy

Stage Mental Status Asterixis EEG

I Euphoria or depression, +/- Triphasic


mild confusion, slurred waves
speech, disordered sleep

II Lethargy, moderate confusion + Triphasic


waves

III Marked confusion, incoherent + Triphasic


speech, sleeping but arousable waves

IV Coma; initially responsive to - Delta activity


noxious stimuli, later
unresponsive
HEPATIC ENCEPHALOPATHY
TREATMENT
Aims:
1. Eliminate or treat precipitating factors

2. Lower blood ammonia (and other toxins)


levels:
- decreases absorption of
proteins and nitrogenous
products from intestine
Approach to the patient with hepatic encephalopathy, BUN,
blood urea nitrogen
Initial Evaluation
– Exclude other causes of disordered mentation
– Identify precipitants and correct
– Determine electrolytes, BUN, creatinine, NH3 (optional), glucose

Protein restriction

Inadequate response?

Laxative, e.g., Lactulose 30-120 mL, 1 to 4 times daily


until 4 stools/day

Broad-spectrum antibiotics (e.g., neomycin 500-1000 mg qid, or


metronidazole 250 mg tid)

Inadequate response?

Consider liver transplantation


BENIGN TUMORS OF THE
LIVER
HEMANGIOMA:
- most common benign liver tumor
5-7% autopsy
women > men
- clinical features
usually absent
large lesions: thrombocytopenia
infants
hypofibrinogenemia
telangiectasia of other organs
BENIGN TUMORS OF THE LIVER
HEPATIC ADENOMA
- usually in women, childbearing age
- common in contraceptive pill use
- clinical features absent usually
- Symptoms: RUQ fullness
intraabdominal hemorrhage 25%
- Diagnosis: CT Scan: hepatic mass
cold spot
Abnormal liver function test
Abnormal alpha fetoprotein
Biopsy not suggested ---> hypervascularity
- Treatment : stop pill
surgery
HEPATIC CYST
SOLITARY CYST
- (R) liver lobe

- asymptomatic

- occasionally - pain 2º to bleeding,


fever infection or
rupture
HEPATIC CYST
POLYCYSTIC LIVER DISEASE
- multiple cysts
several mm ---> 10-15 cm
- asymptomatic
- Cx: hemorrhage
infection
rupture
- (+) cyst = pancreas, spleen, lungs
- liver function tests Normal
- mild alkaline P04tase
- Tx.: surgical aspiration/decompression
PRIMARY HEPATOCELLULAR
CARCINOMA

80-90% all primary liver CA


4x Men > Women
Peak: 5th-6th decade (Western)
1 year earlier = Asians
PRIMARY HEPATOCELLULAR
CARCINOMA
ETIOLOGIC FACTORS:
• Chronic Liver Disease
- Alpha-1 Antitrypsin deficiency
- tyrosinosis 40% risk
- hemochromatosis
- primary biliary cirrhosis
70-90% HCC = (+) cirrhosis
60-75% macronodular/
postnecrotic cirrhosis
PRIMARY HEPATOCELLULAR
CARCINOMA

ETIOLOGIC FACTORS:
• Previous HEPATITIS B infection
90-95% HCC: (+) HBV infection
60-70% Chronic hepatitis/cirrhosis
• Mycotoxins
• Humoral factors
androgen
• Schistosomiasis (?)
Clonorchiasis (?)
PRIMARY HEPATOCELLULAR
CARCINOMA

CLINICAL FEATURES:
• Hepatomegaly
• Hepatic bruit or friction rub
• ascites - bloody 50%
• nonspecific symptoms
- malaise - weight loss
- anorexia - abdominal pain
• clinical deterioration or sudden increase in
transaminases in a stable cirrhotic patient
PRIMARY HEPATOCELLULAR
CARCINOMA

DIAGNOSIS:

• Liver function test : Alkaline Po4tase


transaminases
• Gallium scan : focal filling defects
• Alpha fetoprotein elevation: 85-90%
• Angiography : hypervascularity
tumor blush
• Liver biopsy
PRIMARY HEPATOCELLULAR
CARCINOMA

TREATMENT:

• No effective treatment
Survival rate < 6 months
• Surgery : 5-year survival rate < 10%
• Radiotherapy
rare response
• Chemotherapy
METASTATIC HEPATIC
MALIGNANCY
• More common than primary
• Source:
GIT carcinomas
malignant melanoma
CA - pancreas
lung
breast
kidney
ovary
Lymphoma
METASTATIC HEPATIC
MALIGNANCY
• Clinical features:
fever
RUQ pain
hepatomegaly
friction rub
jaundice
• Diagnosis
liver biopsy; CT or UTS guided
aspiration biopsy
METASTATIC HEPATIC
MALIGNANCY

TREATMENT:

- depends on underlying primary


• Radiotherapy
• Chemotherapy
• Hepatic artery infusion
• Surgery
HEPATOBILIARY TUBERCULOSIS
• Presentation:
1. Miliary hepatic TB
2. Focal or nodular TB: single or
multiple conglomerate tubercles
3. TB of bile ducts or tubular TB

Incidence: rare - Western


35-65% : Phil. studies
HEPATOBILIARY TUBERCULOSIS
• Presenting Complaints
jaundice
abdominal pain
abdominal mass
fever
abdominal enlargement
weight loss
HEPATOBILIARY TUBERCULOSIS
PE findings
jaundice = all patients
abdominal tenderness
- RUQ
- epigastric
- RLQ
cervical lymphadenopathy
scrofuloderma
fluid wave
abdominal distention
normal PE
hepatosplenomegaly
HEPATOBILIARY TUBERCULOSIS
• Chest x-ray findings

Pulmonary TB
Normal
Pneumonia
Pulmonary Congestion
Elevated (R) hemidiaphragm
HEPATOBILIARY TUBERCULOSIS
• Sonographic findings
Biliary obstruction
intrahepatic duct
common bile duct
common hepatic duct
unspecified
Hepatomegaly
with calcification
without calcification
Contracted Gall Bladder
HEPATOBILIARY TUBERCULOSIS
• Sonographic findings
Cholecystitis
Choletithiasis
Choledocholithiasis
TB liver
Pancreatic head mass
Pancreatitis
Portal HPN
Splenomegaly
HEPATOBILIARY TUBERCULOSIS

TREATMENT:

Anti-TB therapy
12-18 months triple/
quadruple treatment

Surgery
LIVER ABSCESS

• Amoebic

• Pyogenic
AMOEBIC LIVER ABSCESS
• Etiology
Entamoeba histolytica
• Clinical features
RUQ pain
fever
chills
pleuritic pain
night sweats
intestinal amoebiasis 50%
AMOEBIC LIVER ABSCESS
• Laboratory
leukocytosis 50%
transaminases
serum bilirubin
alkaline Po4tase 80%
AMOEBIC LIVER ABSCESS
• Diagnosis
Ultrasound = complex mass
solitary
right lobe 90%
CT scan
Gallium scan - filling defect
Aspiration Biopsy
- “anchovy paste” fluid with trophozoites
Serologic test : (+) 95%
- indirect hemagglutination gel diffusion
AMOEBIC LIVER ABSCESS
• Therapy
Amoebicides : Metronidazole
Chloroquine
• Complications
cyst rupture pleural space
lung
bowel
retroperitoneum
PYOGENIC LIVER ABSCESS
70% mixed flora

commonly: Anaerobes
- E. coli
- Klebsiella
- Staphylococcus aureus
- Streptococcus
PYOGENIC LIVER ABSCESS
• ETIOLOGY:

Biliary tract disease : acute cholecystitis


cholangitis
Appendicitis
Diverticulitis
Intrinsic hepatic lesion
Undetermined = 10%
PYOGENIC LIVER ABSCESS

• CLINICAL FEATURES:

- fever
- chills
- RUQ pain
- anorexia
- nausea
- tender hepatomegaly 50%
PYOGENIC LIVER ABSCESS
• DIAGNOSIS:

Laboratory:
80% elevated Alkaline P04tase
33% jaundice = bilirubin
40% (+) Blood Culture
Diagnostic Procedures:
Ultrasound
CT Scan
UTS guided aspiration
PYOGENIC LIVER ABSCESS
• TREATMENT

- broad spectrum antibiotics:


gram (-) anaerobes

- aspiration:
percutaneous or surgical drainage