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LIVER

DR. MAGKASI
LIVER
1,400 1,600 gms
2.5% of body weight
Dual blood supply
o Portal vein: 60% - 70%
o Hepatic artery: 30% - 40%
General Features of Hepatic Disease
Vulnerable to metabolic, toxic, microbial, circulatory,
and neoplastic insults
Dominant primary diseases
o Viral hepatitis, alcoholic liver disease, NAFLD
o Hepatic damage maybe secondary
o Enormous functional reserve
o Insidious process
o May heal without clinical detection
Patterns of Hepatic Injury
1. Degeneration and intracellular accumulation
2. Necrosis and apoptosis
3. Inflammation
4. Regeneration
5. Fibrosis
Degeneration and Intracellular Accumulation
Degeneration
Ballooning degeneration toxic or immune
Feathery degeneration cholestatic injury
Accumulation
Iron and copper
Triglyceride droplets steatosis
o Microvesicular AFLP, valproic acid toxicity, Reye
Syndrome
o Macrovesicular obese, diabetic
Necrosis and Apoptosis
Coagulation necrosis
Lytic necrosis
Apoptosis
Zonal distribution
o Centrilobular, midzonal and periportal
Inflammation
Acute or chronic inflammatory cells
Necrosis incites inflammatory reactions
Inflammation may precede necrosis granulomatous
inflammation
Regeneration
Marked by mitosis, thickening of hepatocytes cords &
some disorganization of the parenchymal structures
Canal of Hering-bile ductile unit serves as reserve
compartment for restitution, ductular reaction
Even with submassive or massive necrosis, as long as
connective tissue framework in intact, perfect
restitution
Fibrosis
Response to inflammation or direct toxic insult
Irreversible

Affects patterns of blood flow and perfusion of


hepatocytes
Cirrhosis

Hepatic Failure
Most severe clinical consequence of liver disease
May be due to sudden, massive liver destruction
(fulminant hepatic failure)
Or due to insidious destruction of hepatocytes or by
repetitive waves of parenchymal damage
80-90% functional capacity destroyed
Liver transplantation only hope
80% mortality
Chronic liver disease
Most common route to hepatic failure
Endpoint of relentless chronic hepatitis leading to
cirrhosis
Hepatic dysfunction without overt necrosis
Hepatocytes are viable but unable to perform
functions
Tetracycline toxicity, acute fatty liver pregnancy
Hepatic Failure: Clinical Features
Jaundice
Hypoalbuminemia
Hyperammononemia
Fetor hepaticus
Impaired estrogen metabolism (palmar erythema,
spider angiomas, male hypogonadism and
gynecomastia)
Coagulopathy
Encephalopathy
Hepatorenal syndrome
o Drop in urine output
o Rising BUN, creatinine
o Poor prognosis
Hepatopulmonary syndrome
o Chronic liver disease
o Hypoxemia
o Intrapulmonary vascular dilations (IVPD)
Cirrhosis: Characteristics
Bridging fibrous septae
Parenchymal nodules
Disruption of liver architecture
Features to be understood:
Parenchymal and subsequent fibrosis are diffuse
Nodularity is part of diagnosis, resulting from repeated
cycles of regeneration and scarring
Vascular architecture reorganized forming bypass
channels
Fibrosis is a key feature of progressive liver damage
slow regression with cessation of injury; reversal is
rare
Pathogenesis
Death of hepatocytes
ECM deposition
Vascular reorganization

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o
o

Deposition of type I and II collagen is space of


Disse
Activation of stellate cells and Kupffer cells

Clinical Features
40% is asymptomatic
Nonspecific clinical manifestations
Incipient or overt hepatic failure
Hepatopulmonary syndrome
Death from:
o Progressive liver failure
o Complication of portal hypertension
o Hepatocellular carcinoma
Portal Hypertension
Increased resistance to portal blood flow
o Caused by contraction of vascular smooth muscle
cells and myofibroblasts and disruption of blood
flow, by scarring and formation of parenchymal
nodules
Increase in portal venous blood flow resulting from a
hyperdynamic circulation
o Caused by arterial vasodilation, primarily in
splanchninc circulation
Consequences:
1. Ascites
Detectable when at least 500ml
Generally serous
Pathogenesis
Sinusoidal hypertension
Percolation of hepatic lymph into the peritoneal
cavity
Splanchnic vasodilation and hyperdynamic
circulation
2. Splenomegaly
1000 gms wt
Induce hypersplenism with thrombocytopenia and
pancytopenia
3. Jaundice and Cholestasis
Causes of Jaundice:
o Bilirubin overproduction
o Hepatitis
Common Virus
Hepatitis A (HAV)
name
Common Disease
Infectious
Name
Virus
Picornavirus naked
capsid RNA

o Obstruction to the flow of bile


Function of Hepatic Bile:
o Emulsification of dietary fat
o Elimination of bilirubin, excess cholesterol,
xenobiotics and other waste products

Jaundice
Occurs when equilibrium between bilirubin production
and clearance is distributed by
1. Excessibe extrahepatic production of bilirubin
2. Reduced hepatocyte uptake
3. Impaired conjugation
4. Decreased hepatocellular excretion
5. Impaired bile flow
Cholestasis
Etiology: impaired bile formation and blood flow
Accumulation of bile in hepatic parenchyma
Morphology
Caused by:
o Intrahepatic or extrahepatic obstruction of bile
channels
o Defects in hepatocyte bile secretion
Treatment:
o Extrahepatic biliary obstruction surgery
o Intrahepatic cholestasis medical/transplant
Elevated ALP and GGT
Infectious Disorders
Viral foremost hepatic infection
Military tuberculosis
Malaria
Staphylococcal bacteremia
Salmonellosis
Candida
Amebiasis
Viral Hepatitis
Infectious Mononucleosis (EBV)
CMV in newborn or immunosuppressed
Yellow fever virus

Hepatitis B (HBV)

Hepatitis C (HCV)

Hepatitis D (HDV)

Hepatitis E (HEV)

Serum

Post-transfusion
or non-A, non-B
Flavivirus
enveloped RNA

Delta

enteric
Calcivirus naked
capsid RNA

Acute Hepatitis

Parenternal,
Sexual
Occasionally
severe

Parenternal,
sexual
Usually subclinical

No

Yes

Yes (high)

Defective
enveloped circular
RNA
Parenternal,
sexual
Co-infection with
HBV occasionally
superinfection
with HepB
Yes

Acute hepatitis

-Acute Hepa
-Chronic Hepa
-Cirrhosis
-Hepato-cellular
carcinoma (HCC)

-Acute Hepa
-Chronic Hepa
-Cirrhosis
-HCC

-Acute Hepa
-Chronic Hepa
-Cirrhosis
-HCC

Transmission

Fecal-oral

Severity

Mild

Chronicity or
carrier state
Clinical disease

Hepadnavirus
enveloped DNA

Fecal-oral
Normal patients:
mild, pregnant
patients: severe
No

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Laboratory
diagnosis

Symptoms and
anti-HAV IgM

Prevention

Vaccine, hygiene

Symptoms and
serum levels of
HBsAg, HBeAg,
and anti-Hbc IgM
Vaccine

HBV Infection 4-26 weeks incubation


HBV can produce:
1. Acute hepatitis with recovery and clearance of virus
2. Non-progressive chronic hepatitis
3. Progressive chronic disease ending in cirrhosis
4. Fulminant hepatitis with massive liver necrosis
5. Asymptomatic carrier state
Natural course of disease:
1. HBsAg- appears before onset of symptoms; declines in
6 months
2. Anti-HBs do not rise until acute is over; may persist for
life
3. IgM anti-HBc become detectable in serum before
onset of symptoms
HEPATITIS C VIRUS
Major cause of liver disease worldwide
Most common chronic blood borne infection
Progression to chronic disease occurs in majority of
infected individuals
20-30% develops to cirrhosis
Persistent infection and chronic hepatitis are
hallmarks of infection
A clinical feature that is quite characteristics of chronic
HCV infection is episodic elevation of serum
aminotransferases, with intervening normal or near
normal periods
Fulminant hepatic failure rarely occurs
HEPATITIS D VIRUS
Dependent for its cycle on HBV
Acute coinfeciton
Superinfection (30-50) days later
Helper independent latent infection in liver transplant
setting
Detectable in blood and liver just before and in early
days of acute asymptomatic disease
IgM and anti-HDV is the most reliable indicator of
recent HDV exposure
Vaccination for HBV can also prevent HDV infection
Clinicopathologic Syndromes of Viral Hepatitis
1. Acute asymptomatic infection with recovery: serologic
evidence only
2. Acute symptomatic infection with recovery
Incubation period
Symptomatic preicteric phase
Symptomatic icteric phase
Convalescence
1. Chronic Hepatitis
Continuing hepatic disease for more than 6
months
2. The carrier state
An individual who harbors and can transmit an
organism, but has no manifestations of symptoms

Symptoms and
anti-HCV ELISA

Anti-HCV
ELISA

Hygiene
Bacterial, Parasitic, and Helminthic Infections
Bacterial etiology
o S. aureus, S. typhi, & T. pallidum
o Bacterial gut flora in ascending cholangitis
Parasitic and helminthic
o Malaria, schitosomiasis, strongyloidiasis,
cryptosporidiosis,, leishmaniasis, echinococcosis,
liver flukes
Liver abscess
o Amebic, pyogenic
Liver Abscess
Solitary or multiple; echinococcal or amebic
Spread thru
portal vein
arterial supply
direct extension penetrating trauma
ascending infection
Rx: surgical drainage; antibiotics
MR: 30-90%;80% surgery with early dx
Autoimmune Hepatitis
A chronic and progressive hepatitis of unknown
etiology
Salient features
o Female predominance (78%)
o Absences of viral serologic markers
o Elevated serum IgG & gamma-globulin levels
o High serum titers of autoantibodies
Types I and II, based on the patterns of circulating
antibodies
Type I associated with HLA DR-3
o ANA, SMA, AAA, anti-SLA/LP antibodies
Type II
o ALKM-1, ACL-1
Lymphocyte and plasma cell infiltrates are prominent
May progress to cirrhosis without clinical diagnosis
Untreated, 40% die within 6 months, cirrhosis in at
least 40% of survivors
Responsive to immunosuppressive therapy
Liver transplantation for patients with severe disease
Drug and Toxin-induced Disease
Injury may result from:
o Direct toxicity to hepatocytes of biliary epithelial
cells
o Conversion of xenobiotic to active toxin, or
o Immune mechanisms
Maybe predictable (INTRINSIC) or unpredictable
(IDIOSYNCRATIC)
Predictable drug reactions:
Acetaminophen- leading cause of drug-induced acute
liver failure
Amanita phalloides toxin, CCl4, alcohol
Isoniazid, Nonsteroidal analgesics, antiseizure
medications prescription drugs with idiosyncratic
reactions
Reye syndrome

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Potentially fatal mitochondrial dysfunction of


liver, brain; exceedingly rare; microvesicular
steatosis
Exposure to toxin or therapeutic agent should always
be a differential dx in liver disease

Alcoholic Liver Disease


Excessive comsumption of alcohols is the most leading
cause of liver disease in most Western countries
Forms of alcoholic liver disease
o Hepatic steatosis
o Alcoholic hepatitis
o Cirrhosis
Pathogenesis:
o Up to 80gms, mild, reversible hepatic change
o 80gms or more, significant risk of severe hepatic
injury
o 160gms or more daily for 10 to 20 yrs, consistently
severe injury
o Only 10-15% of alcoholics develop cirrhosis
Factors for development and severity of alcoholic liver
disease
o Gender
o Ethnic differences
o Genetic factos
o Co-morbid conditions: HCV and HBV
Detrimal effects of alcohol & its byproducts on
hepatocellular functions:
o Excess NADH + H+ promotes lipid synthesis
o Impaired assembly & secretion of lipoproteins
o Increased peripheral fat catabolism
Alcohol can become sources of calories in diet,
displacing other nutrients and leading to malnutrition
and vitamin deficiency
Alcohol causes relased of bacterial endotoxin in gut
inducing inflammatory responses in the liver
Acetaldehyde induces lipid peroxidation disrupts
cytoskeletal and membrane function
Clinical Features:
Hepatic steatosis: hepatomegaly with mild increase in
billirubin and & ALF
Alcoholic hepatitis: acute following a bout of heavy
drinking; minimal Sx or fulminant hepatic failure;
nonspecific Sx; 10-20% risk of death
Alcoholic cirrhosis portal HPN

Most common cause of cryptogenic cirrhosis


10-30% eventually develop cirrhosis
Morphology: steatosis, steatohepatitis and cirrhosis

Hemochromatosis
Excessive accumulation of body iron especially in
parenchymal organs, e.g. liver and pancreas
Result from genetic defect causing excessive
absorption (hemochromatosis) or parenteral
administration of iron, (hemosiderosis) e.g.,
transfusion.
Total iron > 50 gm (NV=2-6 gm)
Adult form of hemochromatosis is almost always
caused by mutations of HFE
Characteristic features
1. Micronodular cirrhosis in all patients
2. Diabetes mellitus in 75- 80% of patients
3. Skin pigmentation 75- 80% of patients
Iron accumulation is lifelong manifest 5th or 6th
decades
Male prominence (5 to 7:1)
Mechanisms of direct tissue toxicity of excessive iron:
1. Lipid peroxidation via iron-catalyzed free rad
2. Stimulate collagen formation
3. Reactive O2 & iron interacting with DNA causing
lethal injury or predisposition to HCC
Hepcidin- main regulator of iron absorption encoded
by HAMP gene
Transcription of hepcidin is increased by inflammatory
cytokines and iron and decreased by iron deficiency,
hypoxia and ineffective erythropoiesis
Hepcidin lowers plasma iron levels; a deficiency in
hepcidin causes iron overload.
Hemochromatosis: Diagnosis and treatment
Very high serum iron and ferritin, exclude secondary
causes, liver biopsy
Screening of family members
Diagnosed in the subclinical, precirrhotic stage
Regular phlebotomy with normal life expectancy
Autosomal recessive, mutation of ATP7B gene
Impaired excretion of copper into bile and failure to
incorporate copper into ceruloplasmin
Marked by accumulation of toxic levels of copper in
many tissues or organs, principally liver, brain and eye.

Treatment:
Alcohol withdrawal and proper nutrition
Cause of death:
1. Hepatic coma
2. Massive GIT hemorrhage
3. Intercurrent infection
4. Hepatorenal syndrome
5. Hepatocellular carcinoma (1-6%)

Wilson disease: clinical features


Extremely variable at age onset
Most common presentation: acute or chronic liver
disease
Neuropsychiatric Sx, e.g., behavioral changes to frank
psychosis, Parkinson dse-like
Dx: decreased serum ceruloplasmin, increased in
hepatic Cu content, and increase in urinary excretion
of Cu; demo of Kayser-Fleischer rings

Nonalcoholic Fatty Liver Disease


In common with individuals who do not consume
alcohol or in those with very small quantities
Men & women equally affected
Strong association with obesity, dyslipidemia,
hyperinsulinemia & insulin resistance, and type 2
diabetes
Increased AST and ALT
Most common cause of chronic liver disease in US

Alpha-1-AT Deficiency
Autosomal recessive
Marked by abnormally low serum levels or A1AT
protease inhibitor (PI)
Inhibits proteases, elastase, cathepsin G, and
proteinase 3
Gene located in chromosome 14
PIMM, 90% genotype, normal A1AT

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Pi-null, no detectable serum A1AT, rare


PiZZ, 10% normal A1AT -> clinical disease

A1AT deficiency: pathogenesis


Mutant polypeptide (A1AT-Z) is abnormally folded and
polymerizes -> retention in the ER of Hepatocytes
A1AT not hepatotoxic
10% PiZZ develop clinical disease due to log in ER
protein degradation pathway->intense autophagocytic
response-> autophagocytosis of mitochondria
A1AT deficiency: clinical features
Remain silent until cirrhosis appears in middle to later
life; pulmonary emphysema
HCC in 2-3% of PiZZ
Rx; orthotopic liver transplant; avoidance of cigarette
smoking
Neonatal Cholestasis
Prolonged conjugated hyperbilirubinemia in the
neonates
Jaundice, dark urine, light or achcolic stools,
hepatomegaly, hypoprothrombinemia
Dx; liver biopsy
Neonatal Cholestasis: morphology
Lobular disarray w/ focal necrosis;
Panlobular giant cell transformation with rosette
formation;
Cholestasis
Mild portal mononuclear infiltrates;
Reactive kupffer cells;
Extramedullary hematopoiesis
Intrahepatic Billary Tract Disease
1. Secondary Billary cirrhosis
2. Primary Billary cirrhosis
3. Primary sclerosing cholangitis
4. Anomalies of the Biliary tree
Nodules and Tumors
Nodular hyperplasias
Focal nodular hyperplasia
Nodular regenerative hyperplasia
Benign neoplasms
Cavernous hemangioma
Liver cell adenoma
Malignant tumors
Hemangioblastoma
Hepatic cellular CA
Angiosarcoma
Cholangiosarcoma
Benign neoplasms
Cavernous hemangioma- most common benign tumor;
discrete red-blue, soft nodules, <2cm, beneath capsule
Significance: mistaken for metastatic tumors and
NOT for blind percutaneous biopsy
Liver cell adenoma young, oral contraceptive users
Significance:
1. Mistaken for HCC, if intrahepatic,
2. Subcapsular adenomas may rupture
during pregnancy, &
3. May transform into HCC

Malignant tumors
Can be primary or secondary
Primary liver CA, uncommon in N. America and w.
Europe (0.5-2%) but 20-40% other countries
Hepatocellular CA: arise from hepatocytes
Cholangiocarcinoma: from bile ducts
Hepatoblastoma: young childhood
Angiosarcoma: PVC arsenic, thorothrast
Hepatoblastoma
Most common liver tumor of young childhood
1-2 in 1 million births
Fatal if not treated
Two variants
Epithelial type
Mixed epithelial and mesenchymal type
Hepatocellular carcinoma
Third most common frequent cause of cancer death
Male predominance, 2,4:1
Four major etiologic factors associated with HCC
o Chronic viral infection (HBV, HCV)
o Chronic alcoholism
o Non alcoholic steatohepatitis (NASH)
o Food contaminants (aflatoxin)
HCC: Pathogenesis
Other conditions
Tyrosinemia- 40% develop HCC despite adequate
important but not requisite for HCC
HCC: clinical features
Masked by those related to cirrhosis of chronic
hepatitis
Ill-defined upper abdominal pain, malaise, fatigue,
weight loss, abdominal mass orr fullness
Jaundice, fever, GIT or esophageal bleed
Inc. AFP,
USG,
Hepatic angiography
CT, &MRI
Death from: cachexia, GIT or esophageal variceal
bleeding, liver failure with hepatic coma, & tumor
rupture.
Fibrolamellar Carcinoma
Young males and females
Patients do not have underlying chronic liver disease
Unknown etiology
Cholangiocarcinoma
Malignancy of the Biliary tree, arising from bile ducts
within and outside of the liver
Risk conditions: primary sclerosing cholangitis,
congenital fibropolycystic disease of biliary system,
previous exposure to thorotrast & previous infection
by liver fluke, O. sinensis
Morphology: adenocarcinoma
Mixed variants with HCC & cholangiocarcinoma may
occur
Hematogenous metastasis to lungs, bones (mainly
vertebra), adrenals, brain, etc present on autopsy in
50% of cases
Detected late in its course
Median time from Dx to death: 6 months

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Metastatic Tumors
More common than primary liver CA
Breast, lung & colon, pancreas
Any site, leukemias and lymphomas
Hepatomegaly + nodularity of free edge
Central necrosis and umbilication
Congenital Anomalies
Congenitally absent
Duplication
Aberrant locations
Folded fundus phrygian cup
Agenesis of hepatic or CBD
Hypoplastic narrowing of biliary channels
Disorders of the Gallbladder
1. Cholelithiasis (Gallstones)
2. Cholecystitis
Acute
Chronic
Risk Factors of Gallstones
Cholesterol Stones
Demorgraphy: N. Europe, N. and S. America, native
Americans, Mexican Americans
Advancing age
Female sex hormones
o Female gender
o Oral contraceptives
o Pregnancy
Obesity
Rapid weight reduction
Gallbladder stasis
Inborn disorders of bile acid metabolism
Hyperlipidemia syndromes

Acute Cholecystitis: Pathogenesis


Acute calculous cholecystitis: chemical irritation and
inflammation of obstructed gallbladder
Acute acalculous cholecystitis: ischemia
o Contributing factors: pigment load; gallbladder
stasis; accumulation of microcrystals of
cholesterol, viscous bile and mucus; inflammation
and edema; bacterial contamination
Clinical Features:
Acute: progressive RUQ or epigastric pain
Mild fever, anorexia, tachycardia, sweating N&V, no
jaundice
Mild-moderate leukocytosis, ALP
Acute calculous cholecystitis may appear with
remarkable suddenness acute surgical emergency
Acute acalculous cholecystitis: needs high index of
suspicion; may be fatal; high incidence of gangrene
and perforation
Chronic Cholecystitis
Sequal to repeated bouts of mild to severe acute
cholecystitis
>90% associated with cholelithiasis
Morphology: mononuclear cells, fibrosis, prominent
RA sinus, porcelain gallbladder
Xanthogranulomatous cholecystitis, hydrops of
gallbladder
Complications: bacterial superinfection, perforation &
abscess, rupture, fistula, aggravation of pre-existing
medical problems
***...eto un diniscuss na slides ni doc.
==============================================

Pigment Stones
Demography: Asian > Western, rural > urban
Chronic hemolytic syndromes
Biliary infection
GIT disorders: ileal disease (e.g. Crohn disease), ileal
resection or bypass, cystic fibrosis with pancreatic
insufficiency
Cholelithiasis: Clinical Features
80% are silent
90% - cholesterol stones: the rest are pigment stones
composed of bilirubin calcium salts
Sx: excruciating colicky or constant biliary pain
Complications: empyema, perforation, fistula,
cholangitis, and obstructive cholestasis or pancreatitis,
intestinal obstruction, risk for cholangiocarcinoma
Cholecystitis
Acute, chronic or acute superimposed on chronic
Almost always in association with gallstones
Most common indications for abdominal surgery
Acute calculous cholecystitis: 90% precipitated by
obstn of the ncek or cystic duct
Acute acalculous cholecystitis: severely ill patients
without gallstones
o Postoperative state after major nonbiliary surgery
o Severe trauma/burns, MOF, prolonged IV
hyperalimentation, postpartum state

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