Liver Overview
Injury patterns:
1.
ballooning degeneration
hepatocyte damage à intracellular edema (balloon cells)
2.
intracellular accumulations
a.
fatty change
- etiology: alcohol,
CCl4 ,
inorganic phosphorus, pregnancy, nutritional deficiencies, severe obesity
- liver is swollen, yellow, greasy
- distinct clear vacuoles are evident à macrovesicular steatosis
- some conditions à microvesicular steatosis (tetracycline use, Reye’s syndrome)
- uncomplicated fatty change is reversible
mechanisms of fat accumulation
i.
increased
mobilization of fat
ii.
increased
synthesis of fat within liver
iii.
decreased ability
of liver to release fat
b.
glycogen
enlarged
pale liver
etiology:
glycogen storage diseases, administration of intravenous glucose with DM
c.
pigment
d.
lipofuscin (recovery from serious liver disease)
e.
iron (hemosiderin, reddish-brown rusty liver)
f.
bile (may
accumulate in ducts, canaliculi, hepatocytes)
g.
protein
i.
Mallory’s hyaline (cytokeratin, alcoholic liver disease)
ii.
alpha-1-antitrypsin (most abundant protease inhibitor produced, PAS stain, hereditary)
iii.
Hepatitis B surface antigen (“ground glass” cytoplasm)
3.
hepatocyte necrosis (à release of enzymes, transaminases – ALT, AST, GGT)
a.
types
i.
coagulative (ischemia)
ii.
apoptosis
(toxic or immunologic injury, round opaque hypereosinophilic
body w/o nucleus)
iii.
lytic (injured cells swell and rupture)
b.
distribution
i.
focal
(apoptosis or lytic: viral hepatitis and toxic
injury)
ii.
zonal (zone 3 – central portion,
circulatory failure)
iii.
diffuse
(overwhelming viral, toxic)
4.
inflammation = hepatitis
may be
portal, lobular or both
5.
regeneration
increased
numbers of binucleated cells
6.
fibrosis
irreversible
chronic
persistent injury (alcoholism, chronic viral hepatitis)
Functional Patterns of Injury
1.
Jaundice
visible
increase in bilirubin (breakdown product of hemoglobin, small
component of bile)
skin,
sclera, urine
etiologies:
increased production (hemolysis), defect in uptake or
excretion of bilirubin from hepatocyte,
obstruction to flow of bile
metabolism of bilirubin
a.
bilirubin is carried to liver by albumin
b.
taken up by liver
cells à glucuronic
acid (water soluble)
c.
actively excreted
into biliary canaliculi à bile ducts à intestine
2.
Cholestasis
manifestations: jaundice, pruritis (bile deposition
in skin), skin xanthomas (cholesterol accumulation), intestinal malabsorption
elevation of alkaline phosphatase
3.
Hepatic (Liver) Failure
etiology:
cirrhosis or sudden massive liver injury (toxic – tetracycline, Reye’s, fatty
liver of pregnancy, viral infection, acetaminophen)
reflects
80-90% loss
transplantation is only survival option
major
manifestations
a.
jaundice
b.
hypoalbuminemia
c.
coagulopathy
d.
hyperammonemia
e.
hyperestrogenemia
f.
fetor hepaticus
g.
hepatic
encephalopathy
h.
hepatorenal syndrome
I.
Cellular
elements and other Features
1.
Hepatocytes
- liver parenchymal cells
- synthesis
of protein, lipids, carbohydrates
- detoxification
of hormones and other substances
- production of bile
- there is a large hepatic reserve
- function affected by: 1) large loss of parenchyma (fibrosis,
necrosis); 2) change in circulation (bypassing of normal contact of blood with
hepatocytes)
2.
Kupffer cells
- phagocytic system;
- decreased circulation à decreased Kupffer
functioning à infection
3.
Stellate (Ito) cells
- perisinusoidal distribution (space
of Disse)
- normally store Vitamin A
4.
Bile ducts
-
carry bile exreted by the liver to the intestine
-
become visible during bile stasis (cholestasis)
5.
Portal tracts
6.
Circulation
i.
Portal vein
-
carries blood from the alimentary canal, pancreas, spleen à liver
- blood from the portal vein is carried to the sinusoids between
the hepatocyte cords
ii.
Hepatic artery
- supplies oxygenated blood to liver
- blood mixes with portal vein blood (this gives some
protection, but lower oxygen tension can damage cells farthest from hepatic
artery branches)
iii.
Central veins
- hepatic venules
- empty into IVC
-
RHF à dilation of central
veins and sinusoids à atrophy, necrosis
iv.
Lymphatics
- lymph vessels are present (ascites formation)
II.
Hepatitis
1.
Viral Hepatitis
necrosis
(apoptosis, lysis) of hepatocytes with an associated inflammatory response
inflammatory
response may be minimal
Yellow fever primarily affects liver
description of clinicopathologic syndromes
a.
b.
Asymptomatic
infection
c.
Acute hepatitis
- resolution in weeks-months
- preicteric
phase: malaise, fatigue, nausea, anorexia, fever
- icteric
phase: jaundice, cholestasis
- hepatocyte
necrosis and mononuclear
inflammation
- ballooning
degeneration
- bridging
necrosis
- steatosis
(HCV)
d.
Fulminant
hepatitis
- hepatic failure within 2-3 weeks of symptoms onset
- necrosis of entire lobules or
parts of lobules
e.
Chronic hepatitis
- hepatitis of at least 6 months duration based on biochemical or clinical
findings
- portal inflammation (lobule at limiting plate = interface hepatitis) with
periportal hepatocyte
necrosis
- initially: portal fibrosis (may develop portal-portal and/or
portal-central bridging fibrosis)
chronic hepatitis C
- portal: lymphoid aggregates +/-
bile duct injury
- lobular:
acidophilic bodies, sinusoidal lymphocytosis +/- steatosis
i.
Hepatitis A
RNA
fecal-oral
2-6 week incubation
injury: immunologic response (not
cytopathic effect)
usually complete
recover
never produces
chronic hepatitis
diagnosis:
antibody titers
ii.
Hepatitis B
DNA
(hepadenovirus)
core, e and
surface antigens
parenteral transmission, close contact
4-26 week incubation
injury: immunologic response
(primarily cytotoxic T cells)
extrahepatic manifestations: arthiritis,
membranous nephropathy
clinical outcomes
a.
subclinical disease à recovery
b.
acute hepatitis à recovery or (fulminant hepatitis à death)
c.
healthy carrier
d.
persistent
infection à recovery or (chronic
hepatitis à cirrhosis à hepatocellular
carcinoma, death)
iii.
Hepatitis C
RNA
(flavivirus)
parenteral transmission, rarely sexual
2-26
week incubation
direct cytopathic and immune-mediated hepatocyte injury
no
effective vaccine
45% of alcoholics with liver disease
have Hepatitis C
à chronic hepatitis > 70%
diagnosis:
PCR
clinical outcomes
a.
resolution
b.
chronic hepatitis à stable disease or (cirrhosis à hepatocellular
carcinoma, stable cirrhosis, death)
c.
fulminant
hepatitis
iv.
Hepatitis D
RNA
superinfection of cells only already infected with hepatitis B
direct cytopathic effect
incubation:
3-7 weeks
if coinfected with Hep B à acute hepatitis à recovery
if superinfected after Hep B à chronic hepatitis (80%)
v.
Hepatitis E
RNA
transmitted
enterically; water-borne
incubation:
6 weeks
high
mortality in pregnant
women (20%)
diagnosis:
serology
2.
Autoimmune Hepatitis
- female predominance
- histology indistinguishable from chronic viral hepatitis (plasma cells may be more
prominent)
- diagnosis: serological testing (circulating autoantibodies), ANA, anti-smooth muscle (ASMA),
anti-liver/kidney microsomal (ALKM)
- HLA-B8 and DRw3
3.
Toxic and Drug-induced Hepatitis
- symptoms parallel viral hepatitis
- necrosis: carbon
tetrachloride, mushrooms, aflatoxins,
halothane
- steatosis: alcohol, tetracycline, salicylates
(Reye syndrome), amiodarone, methotrexate
- cholestasis: anabolic steroids,
contraceptive steroids, cholorpromazine
- hepatic venous occlusion: Vitamin A (toxic doses)
Two
categories
a.
predictable toxins
- direct liver injury in proportion to the dose of the agent
in most or all subjects
- physiochemical effect: carbon tetrachloride
- metabolic pathway effect: chemotherapy, alcohol,
tetracycline
b.
idiosyncratic
agents
- hypersensitivity
- halothane
(anesthetic), isoniazid (Tb treatment)
III.
Cirrhosis
definition:
hepatic fibrosis with regeneration of hepatocytes that create nodules of liver
parenchyma
alteration of circulation
1. shunting of blood away from liver
2. shunting of blood within liver away from sinusoids
clinical manifestations (most problems
attributable to circulatory
changes)
1. loss of liver parenchyma
2. active parenchymal disease
Pathologic
Classification (have little
correlation with clinical findings)
1. Micronodular cirrhosis
2. Macronodular cirrhosis
Etiology
1.
Alcoholic liver disease (60-70%)
2.
Viral hepatitis
3.
Biliary disease
4.
Primary Hemochromatosis
5.
Wilson’s disease
6.
alpha-1-antitrypsin deficiency
7. cryptogenic cirrhosis (cirrhosis of unknown etiology)
1.
Clinical Manifestations and Pathophysiology
of Cirrhosis
i.
Portal hypertension
-
etiology: anastomoses between portal venous and
hepatic arterial, fibrosis, compression of hepatic veins by nodules,
thrombosis/obstruction of hepatic or portal veins, severe RHF, constrictive pericarditis
1.
Ascites
- fluid accumulation within peritoneal cavity
- increase in hydrostatic pressure within portal circulation
- hypoalbuminemia
- sodium retention
- flow of lymph through liver capsule into peritoneal cavity
2.
Varices
- anastomoses
- locations: hemorrhoidal plexus, gastroesophageal junction, umbilical vein
(à varicosities on
abdominal wall = caput
medusa)
- complications: massive bleeding from esophageal varices,
shunting of blood from liver
clinical outcome of anastomoses
-
circulating endogenous estrogens (à gynecomastia and testicular atrophy in men, palmar erythema, spider angiomas)
-
increased levels of ammonia
(hepatic encephalopathy
à rigidity, hyperreflexia, asterixis)
- fetor hepaticus:
musty body odor from increased mercaptans
-
decreased drug clearance
-
decreased enteric bacteria clearance (normally cleared by Kupffer
cells)
3.
Hypersplenism
etiology:
chronic congestion of spleen
increased
enlargement à increased
destruction of erythrocytes, leukocytes, platelets
symptoms:
anemia, leukopenia, thrombocytopenia
ii.
Decreased synthesis of proteins
albumin (à edema, ascites), clotting factors (à coagulopathy)
iii.
Susceptibility to further (ischemic) liver damage
iv.
Hepatorenal syndrome
v.
Hemorrhage
etiology:
decreased clotting factors, thrombocytopenia, varices
2.
Pathogenesis of Cirrhosis by Etiology
i.
Alcoholic liver disease
1.
steatosis
occurs in
anyone who consumes alcohol (reversible)
macrovesicular fatty change
2.
alcoholic hepatitis
seen with
chronic abuse (not dose related)
reversible
but often à cirrhosis
compounding
factors: viral hepatitis, poor nutrition
hallmarks:
steatosis,
mallory’s hyaline, banquet
pattern, inflammation (neutrophils), hepatocytes necrosis, centrilobular
fibrosis
3.
cirrhosis
irreversible
10-15%
of alcoholics
women have
a higher risk
<
80g/day: reversible
>160g/day:
severe injury/cirrhosis
ii.
Viral hepatitis à cirrhosis
vast
majority are HCV
usually
after chronic hepatitis (sometimes after severe fulminant, post-necrotic
hepatitis)
iii.
Metabolic causes (all autosomal recessive)
1.
Primary hemochromatosis
autosomal recessive (chromosome 6, HFE gene)
HLA-A3
excessive
absorption of iron à deposition of hemosidirin in
various organs (liver, pancreas, spleen, heart)
symptoms: bronzing, cirrhosis, DM, cardiomyopathy, arrhythmias, 200X risk of hepatocellular carcinoma
menstruation:
protective
pathology:
liver is enlarged and brown, micronodular cirrhosis, Prussian blue stain
pathogenesis:
20g iron accumulation à directly toxic (free radicals, collagen production, interacts with DNA)
diagnosis: high serum iron
(other causes
of iron overload: Sickle cell, blood transfusions, etc.)
2.
Wilson’s disease
autosomal recessive disorder of copper metabolism (defective excretion in bile)
chromosome
13 (ATP7B gene)
copper
accumulates in liver (adolescent
cirrhosis), brain (atrophy
of basal ganglia – lentiform nucleus à Parkinson’s like movement disorder and psychiatric
disturbances), eye (Kayser Fleischner rings:
cornea deposits)
diagnosis:
low levels of ceruloplasmin (protein carrier of
copper), increased copper in urine
3.
alpha-1-antitrypsin deficiency
autosomal
recessive (A1AT is synthesized by liver but not released)
90%:
liver AND lung disease (10%: both)
ineffective
transport from ER à Golgi
clinical
manifestations: neonatal cholestasis, hepatitis, cirrhosis, symptomatic emphysema (10%), increased risk of HCC
diagnosis:
low A1AT in serum, PAS positive cytoplasmic inclusions in hepatocytes
iv.
Biliary cirrhosis
clinical
features: edema of portal tracts, bile ductular
proliferation, bile accumulation (initially in zone 3)
1.
Extrahepatic biliary
obstruction
gallstones,
neoplasms of biliary tract, inflammatory and traumatic strictures of major
ducts, fibrotic pancreas
cholestasis
correction
of obstruction à arrest progress of liver disease
2.
Primary biliary cirrhosis (PBC)
destruction
of intrahepatic bile ducts à chronic progressive cholestatic
liver disease
epidemiology:
middle aged women
unknown etiology (autoimmune?)
granulomas à complete cirrhotic nodules
diagnosis: elevation of anti-mitochondrial
antibodies (M2 antigen of pyruvate
dehydrogenation complex), elevated serum lipids, elevated ALT, AST, alkaline
phosphatase
hypergammaglobulinemia, abnormal cell immunity
symptoms:
jaundice, pruritis, fatigue
3.
Primary sclerosing cholangitis
(PSC)
diffuse
inflammatory disorder of extrahepatic and large intrahepatic
bile ducts
epidemiology:
young men, 3-5th
decades
unknown etiology (autoimmune?)
diagnosis:
p-ANCA (80%)
4%
of patients with ulcerative
colitis
70%
of PSC have inflammatory bowel disease
cholangiogram: strictures,
beading, dilation
symptoms:
fatigue, cholestasis, jaundice, pruritis à cirrhosis, biliary stones
bile ducts
have periductal « onion-skin »
pattern
increased
risk for cholangiocarcinoma
|
PBC |
PSC |
Epidemiology |
middle aged women |
young men, UC 70% |
Diagnosis |
biopsy |
cholangiogram |
Pathology |
granulomatous destruction of
small intrahepatic bile ducts |
strictures and onion-skin
fibrosis of large and extrahepatic ducts |
Serology |
AMA |
ANA, p-ANCA ;
gold-standard : cholangiogram |
Natural
History |
liver transplantation 10-15 years after |
major complication: cholangiocarcinoma |
IV.
Neoplasms of the Liver
1.
Focal nodular hyperplasia
epidemiology:
any age
nodular
overgrowth of hepatocytes around an AV malformation
characteristic central stellate
scar
contains
bile ducts
2.
Hepatic adenoma
young
women, oral contraceptives
risk for
rupture and bleeding
no bile ducts as part of portal triad in lesion (otherwise, look
normal)
presentation:
hemorrhage within or around adenoma à massive bleeding
3.
Hepatocellular Carcinoma
risk
factors: cirrhosis
from any cause, Hepatitis
B, C (with cirrhosis), Aflatoxin, hemochromatosis
most common
liver cancer in trans-Saharan
epidemiology:
older, male, alcohol, nutrition
histology:
tend to form cords, with thick cell plates
lesion
usually surrounded by abnormal (cirrhotic) tissue
other
factors: age, gender, chemicals, alcohol, nutrition, iron accumulation
symptoms:
non-specific upper abdominal pain, weight loss, fatigue, elevated AFP
invasion of
large veins, hepatic veins, portal veins
metastasizes
to lungs, regional lymph nodes, bones
median
survival: 7 months
treatment:
resistant to radiation, difficult to resect
only hepatic tumor
that makes bile
elevated AFP (alpha fetoprotein)
i.
Fibrolamellar
Hepatocellular Carcinoma
less than 5% of HCC
teenagers and young adults
more indolent growth
younger, otherwise healthy patients
central stellate scar (but larger than focal nodular hyperplasia)
histology: well-diffentiated
4.
Cholangiocarcinoma
resembles
bile duct epithelium
primary
adenocarcinoma of bile duct epithelium
second most
common primary malignant liver tumor
etiology: bile stasis/bile inflammatory
disorders (PSC=primary sclerosing cholangitis,
parasitic infections – clonorchis sinensis), thorotrast, anabolic steroids
route of
spread: perineural
very poor
prognosis
Klatskin
tumor
5.
Metastases
most common
cancer of the liver in the
6.
Vascular neoplasms
i.
Hemangioma
most common
benign liver tumor; usually incidental
ii.
Angiosarcoma
etiology: vinyl choloride,
thorotrast, aresenic
7.
Hepatoblastoma
hepatic
analog of Wilm’s tumor
resembles
fetal liver tissue
aggressive,
rapidly growing
V.
Biliary Calculi (Cholelithiasis)
10-20%
of adults in developed countries
two major
types: 1) cholesterol [80%]; 2) bilirubin [20%]; 3)
calcium
epidemiology:
native Americans,
age, female sex,
pregnancy, obesity,
disorders of bile acid metabolism, hyperlipidemia
biliary
lipid à supersaturation
with cholesterol à multilamellar vesicles à gallbladder hypermotility
and cholesterol nucleation à gallstones
composition
of bile: bile salts, lecithin, cholesterol, bilirubin,
electrolytes, protein
more likely
to occur in gallbladder than ducts (stasis, concentration)
symptoms:
biliary colic, RUQ pain radiates to right scapula, colicky
pathologic findings
1. “Rokitansky-Aschoff sinuses”: microscopic diverticula of
mucosa
2. mild infiltration by
lymphocytes and plasma cells
3. muscular thickening of gallbladder wall
composition of calculi
1. cholesterol (85%) [etiology: decrease in bile salts]
2. bilirubin
[etiology: increase in bilirubin (chronic hemolytic
disease, infection by specific organisms)]
3. calcium calculi
complications
of calculi
1. acute cholecystitis (see below)
2. extrahepatic bile duct obstruction
(biliary colic, nidus, ascending cholangitis à secondary biliary cirrhosis)
3. gallstone ileus (rare; obstruction
of intestine)
4. adenocarcinoma (gallstones, porcelain gallbladder is associated)
VI.
Acute Cholecystitis
etiology:
obstruction of cystic duct, chemical irritation from bile, enteric bacteria
15%
do not have gallstones (= acalculus acute cholecystitis;
etiology: bacterial infection, regurgitation of pancreatic juice, ischemia)
lack of
treatment à necrosis, bile
peritonitis
VII.
Cholesterolosis
macrophages
ingest cholesterol, yellow streaks within the mucosa
VIII.
Biliary Stricture
[not emphasized – not on test]
progressive
destruction/fibrosis of biliary tree à jaundice
may be
auto-immune (associated with Hashimoto’s) or post-operative
IX.
Neoplasms of the Biliary Tract
risk
factors: occurs in very elderly patients, associated with gallstones (most
cases), calcification
locations: common bile duct, ampulla
of vater, hepatic ducts (mimics inflammatory
strictures = “Klatskin” tumor)