Path- Liver Flashcards
Acinar zone with highest O2 content
Zone 1, closest to the portal triad
Cholestasis
disruption of bile flow
Important histologic structures of liver
Hepatocytes
Sinusoidal endothelial cells
Kupffer cells (attached macrophages, intrasinusoidal)
Stellate (Ito) cells (perisinusoidal, Space of Disse)
Stellate (Ito) cells
Located in Space of Disse.
Function in fat/vitamin/fibrous tissue metabolism and fat storage (Vitamin A).
If injured, can become activated and convert into highly fibrogenic myofibroblasts
Metabolic Functions of Liver
- Formation and excretion of bile during bilirubin metabolism
- Regulation of carbohydrate homeostasis
- Lipid synthesis and secretion of plasma lipoproteins
- Control of cholesterol metabolism
- Formation of urea, serum albumin, clotting factors, enzymes, etc
- Metabolism/detoxification of drugs and other foreign substances
Broad Etiologies of Liver Injury
Infectious Immune-Mediated Drug & Toxin Metabolic Genetic Autoimmune cholangiopathy
Defining characteristics of acute hepatic failure
coagulation abnormality (increased prothrombin time) encephalopathy (mental alteration)
MELD Score
Model for End-stage Liver disease. <15 not a candidate for transplantation
Manifestations of Acute Liver Failure
jaundice neurologic symptoms encephalopathy portal HTN hepatorenal syndrome (and hepatopulmonary syndrome)
Acute vs Chronic Hepatitis
Based on time course
Acute = <26wks
Steatosis
Accumulation of fat within hepatocytes, usually reversible
Causes of steatosis
Non-alcoholic fatty liver
Alcohol
Drugs
Viruses
Microvesicular steatosis
disruption of fat metabolism, usually irreversible
Causes of microvesicular steatosis
Reye syndrome
Tetracycline toxicity
Fatty change in pregnancy
Ballooning degeneration
Loss of water control, sign of early injury. Often seen with Mallory hyaline. Often associated with alcohol abuse.
Mallory hyaline
clumped/precipitated intermediate keratin filaments (complexed with proteins like ubiquitin). Often seen with ballooning degeneration. Often associated with alcohol abuse
Pathognomonic histologic finding of acute hepatitis
lobular disarray with mononuclear cell infiltrates
Histologic finding of cirrhosis
bridging fibrosis
Parenchymal extinction
feature of cirrhosis characterized by a loss of liver parenchyma d/t microscopic areas of ischemia
Characteristic finding of cirrhosis
Diffuse nodular regeneration…
surrounded by dense fibrotic septa…
with subsequent parenchymal extinction…
and collapse of liver structures…
causing pronounced distortion of hepatic vasculature…
which leads to increased resistance to portal blood flow…
and subsequent portal HTN
MCC of death in compensated cirrhosis
cardiovascular disease followed by stroke, malignancy, and renal disease
MCC of death in decompensated cirrhosis
Complications of portal HTN, hepatocellular carcinoma, sepsis
Pre-hepatic causes of portal HTN
portal vein thrombosis
narrowing of the portal vein
Intra-hepatic causes of portal HTN
cirrhosis (MCC)
sinusoidal obstruction
Post-hepatic causes of portal HTN
severe R CHF
constrictive pericarditis
hepatic vein outflow obstruction
Clinical consequences of portal HTN
- portosystemic venous shunts/portacaval anastomoses (esophageal varices, hemorrhoids, caput medusa)
- congestive splenomegaly
- ascites
- hepatic encephalopathy
Pathophysiology of ascites
sinusoidal HTN –> splanchnic vasodilation and hyperdynamic circulation –> decreased plasma oncotic pressure –> increased aldosterone
Hepatopulmonary syndrome
a complication of cirrhosis
intrapulmonary vascular dilation –> rapid blood flow –> poor Hb oxygenation –> hypoxia
unknown pathogenesis
Portopulmonary HTN
Related to portal HTN, possibly caused by excessive pulmonary vasoconstriction. Causes DOE and clubbing of digits
IgM as a test for hepatitis
measures initial response to acute infection
IgG as a test for hepatitis
long term response. signifies either ongoing chronic infection or past infection
Lobular disarray
histology of acute hepatitis
- ballooned hepatocytes and acidophilic bodies
- individual or confluent hepatocyte dropout
- zonal, bridging, or panlobular necrosis
- sinusoidal inflammatory cells
- prominent Kupffer cells
HAV transmission
fecal-oral route
person to person
contaminated water and foods
blood-borne is RARE
Risk factors for HAV
48% unknown 14% sexual or household contact 10% men who have sex with men 8% day-care 6% IVDA 5% international travel 4% food or waterborne outbreak 8% other
Pathobiology of HAV
HAV virus binds to an integral glycoprotein receptor on host cell
Virus serves as mRNA that is translated within the cytoplasm into a polyprotein
Polyprotein is later cleaved to mature viral proteins
Replication of membrane-bound complex generates new viral genomes that get exported out of cell and into bile
Pathophysiology of HAV
ingestion –> replication in GI tract –>transported to liver (major site of replication; immune response launched) –> shed in bile, transported to intestines –> shed in feces –> brief viremia –> cellular immune response: clinical disease and control
Hepatitis viruses that only cause acute self-limited disease
HAV
HEV
hepatitis viruses- RNA or DNA?
HAV = RNA (picoRNAvirus) HBV = DNA (hepaDNAviridae) HCV = RNA (flaviviradae, unstable genome) HDV = RNA (no classification, a virion) HEV = RNA (hepEviridae)
HEV transmission
enteric, water-borne infection
Population at great risk with HEV
pregnant women; mortality rate ~20%
Histology of HEV
lobular disarray
*Canalicular cholestasis and gland-like transformation of hepatocytes
HBV transmission
blood-borne, unprotected sex and IVDA
Clinical features of HBV
fatigue anorexia nausea jaundice/scleral icterus abdominal pain arthralgias
Dane Particle
intact HBV virion. Has an outer envelope and inner core
HBsAg
HBV infection (acute or chronic)
HBeAg
High viral load/infectivity
HBV DNA
High viral load/infectivity
Anti-HBs
immunity
Anti-HBc IgM
acute infection
Anti-HBc IgG
past or chronic infection
Anti-HBe
past or low infectivity chronic infection
Anti-HBc IgG and HBsAg
chronic infection
Anti-HBc and anti-HBs
resolved (past) infection
Distinctive histology of HBV
ground-glass hepatocyte containing abundant HBsAg
HDV transmission
follows that of HBV, primarily through parenteral exposure. Can either 1) be acquired at the same time as a primary HBV infection; or 2) later, superimposed on a pre-existent chronic HBV (worse prognosis)
Hepatitis viruses that may cause both acute and chronic disease
HBV
HBV + HDV
HCV
HDV Superinfection
HDV superimposed on a pre-existent chronic HBV. Most causes (50-70%) develop severe acute hepatitis, and 90% of them become chronic carriers
Histology of HDV
sanded nucleus d/t HDAg accumulation
MCC of chronic hepatitis worldwide
HCV
MCC of chronic hepatitis in the USA
HCV
Characteristic clinical feature of HCV
persistent elevation in serum aminotransferases
anti-HCV antibodies
In acute symptomatic HCV, Ab’s are only detected initially in 50-70% of pt’s. The remaining pt’s don’t have Ab’s for another 3-6wks
HCV transmission
parenteral, sex
Risk factors for HCV
54% IVDA
36% multiple sex partners
16% having had surgery w/i 6mths
10% needle stick injury
HCV IgG
past resolved or chronic infection
appears weeks after onset of new infection
occasional false positive
HCV RNA detected by PCR means…
virus is present in liver/blood
found in acute or chronic HCV
Histology of HCV
lobular disarray
steatosis
bile duct damage
Treatable hepatitis
HCV
$1000/pill
$100,000/course
Hepatitis viruses causing acute asymptomatic hepatitis
all hepatotropic viruses
Hepatitis viruses causing acute symptomatic hepatitis
all hepatotropic viruses
etiology of acute liver failure
viral hepatitis is responsible for ~10% of cases of acute liver failure
HAV, HEV and HBV, HDV
common causes of chronic viral hepatitis
HCV > 80%
HBV < 10% in adults (perinatal >90%)
Carrier state hepatitis
small number of HBV
No HCV
HIV and hepatitis
10% of HIV pt’s are co-infected with HBV
25% of HIV pt’s are co-infected with HCV
AIDS and hepatitis
liver disease is the 2nd MCC of death
When is HAV life-threatening?
in the presence of chronic HCV or chronic HBV
Autoimmune hepatitis
injury to normal hepatocytes by infiltrating T cells and plasma cells, leading to fibrosis/cirrhosis
Lab tests to detect AIH
Anti-nuclear Ab (ANA)
Anti-smooth (actin) muscle Ab (ASMA)
IgG
Outcome and prognosis of AIH
Can either develop with a rapidly progressive acute disease, or follow a more indolent path; if untreated, both are likely to lead to liver failure. Although a chronic disease, responds very well to immunosuppression with prednisone and azathioprine
Epidemiology of AIH
Most common in young women
Genetic predisposition (HLA-DR in Caucasians)
~50% of pt’s with AIH will have a concurrent autoimmune disorder
~20% of chronic hepatitis in Western Europe and North America
Type 1 AIH
middle-aged women
ANA, ASMA, pANCA
Type 2 AIH
children or teenagers
mostly female
associated with anti-liver kidney microsomal Ab (anti-LKM1)
Histology of AIH
extensive interface hepatitis
plasma cell predominance in the mononuclear inflammatory infiltrates
(*plasma cell = eccentric nucleus and Golgi huff)
Histologic patterns of drug-induced liver injury
bile duct injury
steatosis and steatohepatitis
vascular injury/veno-occlusive disease
neoplasms
steatosis vs steatohepatitis
steatosis: fat in cytoplasm of hepatocytes
steatohepatitis: neutrophils and fibrosis
Patterns of drug-/toxin-induced hepatic injury
Periportal region: gluconeogenesis, cholesterol and urea synthesis; high O2
Pericentral region: glycolysis, bile acid and glutamine synthesis, drug metabolism, p450-dependent bioactivation
Examples of drugs causing
- hepatocellular injury
- autoimmune hepatocellular injury
- cholestatic liver injury
- hepatocellular injury –> acetaminophen
- autoimmune hepatocellular injury –> halothane hepatitis
- cholestatic liver injury –> estrogen
MCC of acute liver failure necessitating transplantation in the USA
acetaminophen toxicity
acetaminophen toxicity
d/t metabolic by-product (NAPQI)
zone 3 necrosis (pericentral)
toxicity is enhanced by ETOH (up regulates CYP450
acetaminophen toxicity antidote
N-acetyl cysteine; must give w/i 8-12hrs; restores glutathione
drugs that induce CYP2E1 (increase acetaminophen toxicity)
ETOH
Isoniazid (INH)
Phenobarbital
Reye syndrome
associated with ASA
Seen in children
Mitochondrial dysfunction, mainly in liver and brain –> microvesicular steatosis (fat droplet accumulation)
Acute liver failure without extensive necrosis
Fatty liver
develops in all drinkers after moderate intake
completely reversible until there is fibrosis
have mild elevation of LFTs
Alcoholic hepatitis
ballooning (swelling) and necrosis of hepatocytes with formation of Mallory bodies
acute inflammation, especially around degenerating cells
centrilobular fibrosis
10% mortality acute phase, 70% develop cirrhosis
NAFLD
Non-alcoholic fatty liver disease
Hepatic steatosis (fatty liver) in pt’s who do not consumer alcohol or do so in very small quantities
Associated with metabolic syndrome (obesity, insulin resistance or DM, hyperlipidemia, and HTN)
NAFLD Presentation
Asx with elevated AST/ALT’s (<250IU/L)
Metabolic risk factors
Fatty infiltration on liver imaging
Patterns of NAFLD
- Fatty liver (NAFLD): >5% fatty change but no necroinflammatory change
- Non-alcoholic steatohepatitis (NASH): ballooning degeneration, necrosis, lobular inflammation, +/- fibrosis
Risk factors for alcoholic liver disease
- amount and duration of ETOH consumption
- F > M
- genetic factors
- protein-calorie malnutrition
Risk factors for non-alcoholic liver disease
- obesity
- DMII
- dyslipidemia
- metabolic syndrome
MCC’s of cirrhosis in the USA (3)
- chronic alcoholism
- chronic HCV
- Non-alcoholic steatohepatitis
Hepcidin regulation molecules
HFE (high iron gene)
HJV (hemojuvelin)
TfR2 (transferrin receptor)
Hepcidin synthesis is activated by
increased iron stores
infection or inflammation (IL-6)
Hepcidin synthesis is inhibited by
hypoxia
increased EPO
Pathogenesis of hemochromatosis
decreased hepcidin synthesis, caused by mutations in HFE protein plays a central role
Treatment of hemochromatosis
phlebotomy
Epidemiology of hemochromatosis
one of the most common genetic disorders in humans
complications of hemochromatosis
cirrhosis
cardiac disease
Classic tetrad of Hemochromatosis
hepatomegaly
skin pigmentation
destruction of pancreatic islets
cardiomyopathy
Diagnosing hemochromatosis
transferrin saturation
MRI of liver
Iron biopsy (not as useful)
HFE mutation (90% of pt’s are homozygous for C282Y mutations)
bronze diabetes
A complication of hemochromatosis; pigmentation d/t increased epidermal melanin.
Causes of secondary hemochromatosis
blood transfusions (for hereditary or acquired anemias) iron supplements or excess dietary iron (uncommon)
Etiology of Wilson’s disease
autosomal recessive disorder caused by mutation in copper transporting ATPase, leading to toxic levels of copper accumulation in liver, brain, and eye
Epidemiology of Wilson’s disease
5-15y/o
or neuropsychiatric pt’s in 20’s
treatment of Wilson’s disease
chelation with Pencillamine (or zinc, to competitively inhibit copper)
liver transplant for cirrhosis
no treatment can cure neurologic symptoms (Parkinsonian-like)
Where is dietary copper absorbed?
duodenum
ceruloplasmin
transporter protein for copper; usually low in Wilson’s disease, but not always
Diagnosing Wilson’s Disease
Biopsy to assess liver copper content (most sensitive, highest positive predictive value)
low serum ceruloplasmin (screening)
increased urine copper (specific)
Histologic preparation for Wilson’s disease
Copper (rhodamine) stain
Clinical Features of Wilson’s Disease
Kayser-Fleischer ring: Brown ring around iris of eye indicating copper accumulation; diagnostic of Wilson’s disease
Parkinson-like features
Alpha 1 antitrypsin deficiency
autosomal recessive disorder of protein folding marked by very low levels of circulation a1-antitrypsin
function of Alpha 1 antitrypsin
inhibition of proteases
Most common clinically significant mutation of Alpha 1 antitrypsin deficiency
PiZZ (a1AT levels are only 10% of normal)
Clinical features of Alpha 1 antitrypsin deficiency
neonatal hepatitis with cholestatic jaundice in 10-20%
HCC in 2-3% of PiZZ adults
Panlobular emphysema
Histologic findings of Alpha 1 antitrypsin deficiency
non-specific
globules
fibrosis
variable portal inflammation
Primary biliary cirrhosis
autoimmune cholangiopathy disease of unknown etiology which selectively affects the small intrahepatic bile ducts with progressive bile duct damage, chronic cholestasis, biliary fibrosis/cirrhosis leading to hepatic failure
Epidemiology of Primary biliary cirrhosis
middle-aged women 40-50y/o
F > M 9:1
Laboratory findings in Primary biliary cirrhosis
anti-mitochondrial Ab’s (AMA)
disproportionate elevation of serum Alk Phos
Histology of Primary biliary cirrhosis
Ductopenia (early ductal inflammation)
Epithelioid granulomas
Necroinflammatory and cholestatic process with fibrosis
portal-portal bridging septa
Gross findings of Primary biliary cirrhosis
yellow-green, cirrhotic liver
Primary Sclerosing Cholangitis
a progressive disease of the liver characterized by cholestasis with obliterative fibrosis of intra- and extra hepatic bile ducts with dilation of preserved segments
Common association with Primary Sclerosing Cholangitis
IBD in 70% of pt’s (90% Crohn’s, 10% ulcerative colitis)
Epidemiology of Primary Sclerosing Cholangitis
M > F 2:1
~40y/o
Prognosis of Primary Sclerosing Cholangitis
variable
some pt’s have severe recurrent cholangitis
others progress to biliary cirrhosis
Pathogenesis of Primary Sclerosing Cholangitis
unknown, features suggest T cell involvement
Treatment of Primary Sclerosing Cholangitis
no cure
cholestyramine for pruritis
liver transplant for liver failure
Diagnosing Primary Sclerosing Cholangitis
Pathologic and radiographic findings!
Elevated Alk phos in 90% of pt’s
pANCA in 90% of pt’s (non-specific finding)
strictures, beading, and dilation of large ducts
Liver Biopsy in Primary Sclerosing Cholangitis
obliterative cholangitis with inflammation
periductular onion ring fibrosis
ductopenia
secondary biliary cirrhosis
Histology of hepatic complications in GVHD
bile duct damage (lymphocytic infiltration of bile duct epithelium), modest mononuclear portal inflammatory infiltrate
Laboratory findings with GVHD
cholestatic liver biochemistry
mild elevations in serum transaminases
Diagnostic Triad of Cellular Liver Allograft Rejection
portal inflammation
bile duct damage
ventral endothelial inflammation
Humoral liver allograft rejection
endothelial cells in the graft are the main targets for humoral-mediated damage
Mechanisms of cholestasis
intrahepatic cholestasis
-decreased bile formation (sepsis, estrogen)
-destruction/compression of intrahepatic bile ducts/ductules (primary biliary cirrhosis, infiltration of liver with tumor/granuloma)
-any severe liver disease (viral hepatitis)
Extrahepatic/large bile duct obstruction (tumor, gallstone, duct strictures, primary sclerosing cholangitis)
Isolated disorders of uncongugated hyperbilirubinemia
Increased bilirubin production i.e. Hemolysis
Decreased hepatocellular uptake i.e. drugs
decreased conjugation:
-Gilbert’s syndrome
-Crigler-Najjar
-Neonatal jaundice
-Diffuse hepatocellular disease (virus, drugs, cirrhosis)
Isolated disorders of conjugated hyperbilirubinemia
decreased canalicular transport
- Dubin Johnson syndrome
- Rotor syndrome
- Autoimmune cholangiopathies
Sepsis-associated cholestasis
usually caused by gram (-) bacteria, leading to canalicular cholestasis with activated Kupffer cells, fatty change, and portal inflammation; typically conjugated
Lab findings with sepsis-associated cholestasis
increase in serum bilirubin out of proportion to Alk phase elevation
Prognosis of sepsis-associated cholestasis
poor, 60-90% mortality
causes of large duct obstruction in adults
gallstones (most common)
malignant neoplasms of biliary tree/head of pancreas
PSC
causes of large duct obstruction in peds
biliary atresia
choledochal cysts
CF
Complications of large bile duct obstruction
if prolonged –> secondary biliary cirrhosis
if intermittent –> ascending cholangitis
hepatolithiasis
intrahepatic gallstone formation, leading to progressive inflammatory destruction of parenchyma –> risk of cholangiocarcinoma
epidemiology of hepatolithiasis
East Asia
hepatolithiasis is frequently associated with
recurrent ascending cholangitis
etiology of ascending (suppurative) cholangitis
typically caused by bacteria within small bowel traveling through the Sphincter of Oddi to the liver and biliary tract
Clinical features of ascending cholangitis
fever
jaundice
abdominal pain
laboratory findings with ascending cholangitis
increased blood neutrophils, Alk phos, and bilirubin
Major causes of neonatal cholestasis
Extra-hepatic biliary atresia
infectious hepatitis
alpha 1 antitrypsin deficiency
idiopathic neonatal hepatitis (dx of exclusion)
Perinatal biliary atresia
absence of all or a portion of the extrahepatic bile ducts. most frequent cause of liver disease death in early childhood; congenital infections have been implicated in initiating autoimmune reaction
Hereditary fibropolycystic liver disease
group of genetic disorders with segmental dilatations of the intrahepatic bile ducts and associated fibrosis (CYSTS AND/OR FIBROSIS)
Pathogenesis of Hereditary fibropolycystic liver disease
primary cilia protein gene mutations leading to disruptions of portal tract embryogenesis
polycystic liver disease
most commonly associated with autosomal dominant polycystic kidney disease, also associated with autosomal recessive PCKD, and present with no renal cysts
Von Meyenburg Complexes
peripheral bile duct malformations (bile duct hamartoma)
Multiple complexes = polycystic liver disease
Congenital hepatic fibrosis is often associated with…
autosomal recessive polycystic kidney disease
Caroli syndrome
Congenitally dilated intrahepatic bile ducts often involving the entire liver + congenital hepatic fibrosis
Caroli disease is associated with…
recurrent bacterial cholangitis
Complication of Caroli disease
risk of cholangiocarcinoma
Choledochal cysts
congenital cystic dilation of extrahepatic and intrahepatic bile ducts; commonly leads to complete inflammatory obstruction of the terminal portion of the bile duct
Type V = Caroli disease
complications of choledochal cysts
stone formation
stenosis
pancreatitis
cholangiocarcinoma (age related, older = increased risk)
Intrahepatic cholestasis of pregnancy
mild cholestatic disease occurring in <2% of pregnancies
also seen with oral contraception use
may cause intrauterine fetal death
strong genetic component, 10-15% of first degree female relatives are affected
Clinical features of Intrahepatic cholestasis of pregnancy
onset in 3rd trimester
Pruritis!
occasional jaundice
resolves within a few days of delivery
Acute fatty liver of pregnancy
usually in 3rd trimester may present with acute failure with modest AST/ALT increase may occur in subsequent pregnancies maternal mortality 5-26% intrauterine fetal death 9-32%
Initial symptoms of acute fatty liver of pregnancy
N/V epigastric abdominal pain preeclampsia jaundice anorexia
lab tests for acute fatty liver of pregnancy
mildly elevated AST/ALT (<500)
hypoglycemia, abnormal coag studies
Characteristics of preeclampsia
HTN
proteinuria
peripheral edema
coagulation abnormalities
HELLP syndrome
hemolysis, elevated LFTs, low platelets
most common form of preeclampsia-related liver disease
Pathology of HEELP
periportal fibrin and hepatoceullular coagulative necrosis
Budd Chiari syndrome
hepatic vein thrombosis (2+ veins). Caused by
- polycythemia vera
- pregnancy
- postpartum state
Sinusoidal obstruction syndrome
obliteration of the terminal hepatic venules seen with chemotherapy and immunosuppressive agents
Causes of impaired blood flow through the liver
cirrhosis (MCC) sinusoid occlusion -sickle cell disease -R CHF -eclampsia -stellate cells
function of gallbladder
store and concentrate bile (~50mL)
Phyrigian Cap
inwardly folded fundus of gallbladder; mimics gallstones
congenital anomalies of gallbladder
shape (angulations/Pyrigian cap), separation
number (agenesis, duplication)
position (intrahepatic, falciform ligament location)
risk factors for cholelithiasis
obesity
female sex (2:1)
estrogens, oral contraception, pregnancy
age (middle age and older)
5 F's Female Fair Fat Flatulent Fertile
classes of gallstones
cholesterol stones (75%) pigment stones (25%)
pigment stones
calcium salts and unconjugated bilirubin
Complications of cholelithiasis
75% are asx
biliary pain (obstruction) cholecystitis pancreatitis ascending cholangitis fistula gallbladder carcinoma
indications for treatment of asymptomatic cholecystitis
surgery is generally discouraged, but may be indicated in pt’s
1) with gallstones >2cm in diameter
2) with nonfunctional of calcified (porcelain) gallbladder –> high risk of gallbladder carcinoma
3) with sickle sickle cell anemia in which the distinction between painful crisis and cholecystitis is difficult
Patients with risk factors for complications of gallstones
cirrhosis portal HTN children transplant candidates DM with minor symptoms
Outcomes of acute cholecystitis
Can present as…
- acute surgical emergency
- mildly symptomatic with spontaneous resolution
- gangrenous cholecystitis, can perforation (acalculous > calculous)
histologic hallmark of acute cholecystitis
neutrophils in the gallbladder mucosa and wall
mucosa may be ulcerated
signal void bubbles
MRI finding of acute cholecystitis (emphysematous)
Presentation of chronic cholecystitis
recurrent attacks of either steady epigastric or RUQ pain (INTERMITTENT PAIN!)
usually 50y/o
N/V, intolerance to fatty foods
Etiology of chronic cholecystitis
can be a sequel to acute cholecystitis, but often presents without a history of earlier attacks
Rokitansky-ashoff sinuses
outpouching of the mucosal epithelium into the gallbladder wall, seen with chronic cholecystitis
pathology of chronic cholecystitis
subserosal fibrosis –> fibrous adhesions –> chronic inflammation –> fibrosis –> metaplasia of gallbladder mucosa –> dystrophic calcification (porcelain gallbladder; associated with increased risk of carcinoma)
choledocholithiasis
common bile duct stones that may remain asx for years
Complications of choledocholithiasis
obstructive jaundice
gallstone pancreatitis
acute cholangitis
Charcot’s triad
fever
jaundice
abdominal pain
classic presentation of choledocholithiasis and/or ascending cholangitis
Carcinoma of the gallbladder
typically an adenocarcinoma (can also be SqCC, carcinoid, carcinosarcoma)
Associated with gallstones.
Presents with abdominal pain and elevated serum Alk Phos.
Infrequently diagnosed, usually pre-op for something else
Px of gallbladder carcinomas
terrible, 5-10% 5yr survival rate
papillary variant = best overall px
Congenital anomalies of the pancreas
pancreas divisor (2 duct system); most common anomaly
annular pancreas (wraps around duodenum, can cause obstruction)
ectopic pancreas
agenesis (rare)
acute pancreatitis
autodigestion of pancreas by its own enzymes (inappropriate activation of digestive proenzymes–> TRYPSIN)
causes of acute pancreatitis
ETOH pancreatic duct obstruction (calculi) drugs vascular injury infection hereditary factors hypercalcemia
etiology of acute pancreatitis
premature activation of trypsin is a likely cause; primarily a combination of genetic, environmental, and metabolic factors
markers of acute pancreatitis
serum amylase (elevates in 6-12hrs) and *lipase (elevates 4-8hrs)
Types of acute pancreatitis (based on histopathology)
Acute interstitial pancreatitis (interstitial edema, focal areas of fat necrosis in peri-pancreatic fat)
Acute necrotizing pancreatitis (necrosis of acinar and ductal tissues and islets of Langerhans)
Hemorrhagic pancreatitis (extensive parenchymal necrosis and hemorrhage within the pancreas)
Gross findings of acute pancreatitis
yellows specks
chalky white with calcium
Clinical findings of acute pancreatitis
flank ecchymoses
pathophysiology of chronic pancreatitis
can be initiated by recurrent acute pancreatitis –> myofibroblast stellate cell activation
irreversible destruction of exocrine parenchyma with fibrosis –> destruction of endocrine parenchyma –> IDDM
causes of chronic pancreatitis
ETOH
repeat episodes of acute pancreatitis
obstruction (calculi, neoplasm)
metabolic (primary hyperparathyroidism, hyperlipidemia, renal transplantation, CF)
diagnosing chronic pancreatitis
Histology (gold standard)
Reduction in bicarb in duodenal aspirate after secretin stimulation
ERCP
Intrapancreatic calcifications on plain films (rare)
histology of chronic pancreatitis
dense interlobular fibrosis with preserved (or atrophic) zones of acinar cells between septa
Autoimmune pancreatitis variant
Unique mass-forming inflammatory form of chronic pancreatitis
Elevated IgG4
Radiographs mimic pancreatic adenocarcinoma
Responds to corticosteroid therapy
Pancreatic pseudocyst
non-neoplastic
most common pancreatic cyst
associated with acute or chronic pancreatitis
usually does not require tx
can be associated with infection, bleeding, or rupture
serous cystadenoma
most common cystic neoplasm of pancreas most are benign F > M 2:1 ~66y/o lining: flat to cuboidal cells with clear cytoplasm and hyperchromatic nuclei
mucinous cystadenoma
>95% Females ~50y/o can be precursors to invasive carcinoma almost always in pancreas TAIL lining: tall columnar cells with abundant apical mucin
intraductal papillary mucinous neoplasm (IPMN)
Involves large ducts of pancreas, usually in the HEAD of the pancreas
M>F
Benign, borderline, and malignant variants
Mucinous cells with various degrees of dysplasia and papillary architecture line mystically dilated ducts
Tall, columnar mucinous epithelial cells
invasive ductal carcinoma of the pancreas
most common pancreatic neoplasm
5yr survival rate = 5%
9mths = medial survival
most are sporadic, 10% familial
Trousseau syndrome
migratory thrombophlebitis secondary to release of platelet activating factors and procoagulant factors
associated with 10% of invasive ductal carcinomas of the pancreas.
pathology of invasive ductal carcinoma of the pancreas
precursor lesion: pancreatic intraepithelial neoplasia (PanIN)
Tends to invade peri-pancreatic tissues and elicit desmoplastic tissue reaction
oncogene associated with invasive ductal carcinoma of the pancreas
KRAS
acinar cell carcinoma of the pancreas
uncommon (<2% of pancreatic CA)
>60y/o
15% develop lipase hypersecretion syndrome
metastasizes early
Px: poor, slightly better than invasive ductal carcinoma of the pancreas
Histology: trypsin in acinar cells
pancreaticoblastoma
uncommon, but most frequent pancreatic tumor in childhood ~4y/o
epithelial tumor
Histology: squamous nests, acinar pattern
Px: curable by surgery if detected early
Pancreatic neuroendocrine tumor (PanNET)
Most common in adults ~55y/o
most produce a peptide hormone (i.e. glucagon) but these are typically non-functional, so pt’s don’t have sx
preferentially metastasize to regional lymph nodes and liver
epidemiology of focal nodular hyperplasia
women 20-30y/o
gross findings of focal nodular hyperplasia
FOCAL! central scar, typically <5cm in diameter, but can be large; no true bile ducts or connection to the biliary outflow tract
composition of focal nodular hyperplasia
hyperplastic nodules of hepatocytes, separated by fibrous septa which form typical stellate scars
gross findings of nodular regenerative hyperplasia
liver is entirely transformed into nodules grossly similar to micro nodular cirrhosis, but without fibrosis
clinical findings of nodular regenerative hyperplasia
portal HTN (may be associated with disease development), most pt’s are asx
etiology of nodular regenerative hyperplasia
thought to be a regenerative response to vascular injury (small vessel vasculitis)
histology of nodular regenerative hyperplasia
sinusoidal dilation
no inflammatory infiltrates
no fibrosis
no necrosis
nodular regenerative hyperplasia also known as…
non-cirrhotic portal HTN
etiology of hepatic adenoma
oral contraceptives in females
anabolic steroids in males
gross findings of hepatic adenoma
subcapsular mass, prone to rupture, especially in pregnancy. no central scar, rounded, smooth borders.
Treatment for hepatic adenoma
resect if >5cm or symptomatic
cessation of sex hormones can lead to full regression
subtypes of hepatic adenoma
HNF1-alpha inactivated hepatocellullar adenoma
B-Catenin activated hepatocellular adenoma
inflammatory hepatocellular adenoma
epidemiology of HNF1-alpha inactivated hepatocellullar adenoma
most commonly found in women (low rate of malignancy)
B-Catenin activated hepatocellular adenoma
minority of adenomas
very high risk for malignant transformation
often have a high degree of cytologic or architectural dysplasia
inflammatory hepatocellular adenoma
found in men and women
associated with NAFLD
small but definite risk of malignant transformation
JAK/STAT (lots of inflammation)
complications of hepatocellular adenoma
can lead to fatal hemorrhage
epidemiology of cavernous hemangioma
most common benign liver tumor
diagnosing cavernous hemangioma
any imaging
epidemiology of hepatoblastoma
most common liver tumor of young childhood (90% before age of 5y/o)
prognosis of hepatoblastoma
fatal within the first few years if not treated
pathologic variants of hepatoblastoma
epithelial type - composed of polygonal epithelial cells or embryonal cells growing in patterns recapitulating liver development
mixed epithelial-mesenchymal - contains mesenchymal elements i.e. osteoid, cartilage, or striated muscle
epidemiology of HCC
most common primary hepatic malignancy of adults worldwide
M > F
etiology of HCC
hepatocellular carcinogenesis secondary to viral infections (HBV, HCV) and toxic injury.
Majority of cases in the world are d/t HBV
Number of HCV-associated cases are increasing in western world
toxins: aflatoxin (aspergillus mycotoxin) - moldy peanuts and grains
activation of B-catenin and inactivation of p53 are most common early mutational events
clinical features of HCC
clinically silent, most pt’s present with advanced dz –> upper abdominal pain, weight loss, signs of decompensated liver dz i.e jaundice, ascites
laboratory findings of HCC
elevated serum alpha-fetoprotein in 50% of pt’s
precursor lesions of HCC
- hepatocellular adenoma
- chronic liver disease (hepatocellular dysplasias - small cell change [more common] and large cell change)
- dysplastic nodules associated with cirrhosis
epidemiology of HCC- fibrolamellar variant
85% occur under 35y/o
M = F
no association with HBV, HCV, cirrhosis
prognosis of HCC- fibrolamellar variant
5yr survival rate: 30-75%
slow growing and surgically resectable frequently
histology of HCC- fibrolamellar variant
fibrous stroma
tumor cells larger than normal liver cells
deeply eosinophilic coarsely granular cytoplasm
lots of mitochondria in cytoplasm
cholangiocarcinomas arise from…
bile duct epithelium (a type of adenocarcinoma)
Klatskin tumor
a perihilar cholangiocarcinoma i.e. at the bifurcation (makes up 60% of all cholangiocarcinomas)
5yr survival: 15%
Risk factors for cholangiocarcinomas
primary sclerosing cholangitis
congenital biliary cystic diseases
thorotrast (radiographic contrast from 1930’s)
parasites (liver fluke- Opisthorchis and Clonorchis)
NOT CIRRHOSIS!
prognosis of cholangiocarcinomas
- undergoes hematogenous metastasis (~50%)
- often undergoes lymphovascular invasion and perineurial invasion
- lethal, median survival ~6mths
cholangiocarcinomas can look like…
metastatic carcinoma from breast of pancreas
premalignant lesions for cholangiocarcinomas
biliary intraepithelial neoplasia (low to high grade)
cholangiocarcinomas often produce…
mucin
epidemiology of angiosarcomas of the liver
older pt’s 60-70y/o
rare (10-20 cases/yr in US)
most common primary sarcoma of the liver
origin of angiosarcomas
vasculature
Angiosarcomas can be associated with
- vinyl chloride monomer
- thorotrast (radiographic contrast from 1930’s)
- arsenic
- anabolic steroids
metastatic tumors
most common tumors in the non-cirrhotic liver
uncommon in the cirrhotic liver
most common sites of metastatic tumors to the liver
lung
breast
colon
pancreas
markers for colon CA
CK7, CK20
CK = cytokeratin
clinical features of congenital hepatic fibrosis
complications of portal HTN i.e. splenomegaly and esophageal varices
(rarely see hepatic cystic lesions)
histology of congenital hepatic fibrosis
numerous residual biliary channels with widely patent lumens arranged around the periphery of the portal tract
Reynold pentad
Charcot’s triad (RUQ pain, jaundice, fever)
Hypotension
Sensorium/altered mentation
Sign of severe ascending cholangitis
markers for cholangiocarcinoma
CEA and/or CA 19-9
CCK EF <35% is diagnostic of
acalculous chronic cholecystitis
Serum-ascitic albumin gradient (SAAG) and Ascites total protein
- Cirrhosis
- Malignancy
- Cardiac disease
- Cirrhosis: high SAAG, low ascites total protein
- Malignancy: low SAAG, high ascites total protein
- Cardiac disease: high SAAG, high ascites total protein
Porcelain gallbladder
calcified gallbladder d/t chronic cholecystitis, usually found incidentally on imaging.
Tx: prophylactic cholecystectomy d/t high rates of gallbladder carcinoma
