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Pathology of pancreas, liver, biliary tract and gall bladder

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Trauma injury to the liver
-what makes it vulnerable to it?
-which lobe is usually injured?
The large size of the liver, its friable parenchyma, its thin capsule, and its relatively fixed position in relation to the spine make the liver particularly prone to blunt injury.

As a result of its larger size and proximity to the ribs, the right lobe is injured more commonly than the left.
Which visceral organ is the largest size in the body?
liver
Which lobe is often enlarged in imaging studies in a pt with cirrhosis?
caudate lobe
Gallbladder is next to the
quadrate lobe
What is the acinus? What are the zones? Which is most prone to injury when bile flow is obstructed? from drugs and toxic metabolites?
Acinus= Functional Unit of the liver
* Blood flows from portal triads to central veins
* Bile flows from the central vein region toward the portal triads.

Zone 1 (periportal)
o periportal = next to the portal triad
o receives the most richly oxygenated blood directly from the hepatic arteries
o zone 1 suffers greatest damage when bile flow is obstructed

Zone 2 (midzonal)

Zone 3 (centrilobular)
o next to the central vein
o receives the least oxygenated blood, and thus is most prone to ischemia
o toxic metabolites of drugs also collect in Zone 3 hepatocytes and damage them
Which cells are the most richly bathed in blood in the whole body?
hepatocytes
Space of disse
-stellate ito cells
-Kupffer cells
+ lymphatic drainage of the liver

+ Stellate (Ito) cells
# stimulated in liver disease to become myofibroblast
# once stimulated, deposit collagen pathologically

+ activated Kupffer cells release cytokines that lead to hepatocyte dysfunction and death (apoptosis)

+ this forms the diffuse array of nodules of hepatocytes that are classically seen in cirrhosis
What is true of complexity of the hepatocyte?
What are its functions?
THE HEPATOCYTE IS UNRIVALED BY ANY OTHER PARENCHYMAL CELL TYPE IN FUNCTIONAL COMPLEXITY

Metabolic: glucose and lipid metabolism
Synthetic: albumin, coagulation factors
Storage: glycogen, triglycerides, fe, copper, lipid soluble vitamins
Catabolic: ammonia to urea, certain proteins and hormones, detoxifying drugs and chemical
Excretory: bile excretion
Patterns of hepatic injury
Degeneration and intracellular accumulation
Necrosis and apoptosis
Inflammation
Regeneration
Fibrosis
Degeneration and intracellular accumulation in damaged hepatocytes
* Ballooning Degeneration: swelling of hepatocytes with fatty accumulation --> leakage of ALT/AST
+ hepatitis
+ alcohol
+ non-alcohol liver injury

* Feathery Degeneration
o retained biliary material in swollen hepatocytes
o Bile cause cytoplasm to take on a "feathery"
o Bile plugs seen in other areas of the liver
+ Chronic cholestasis

* Macrovesicular Steatosis
- accumulation of large fat droplets in hepatocytes that displace the nucleus
+ Alcohol
+ Fatty liver disease (related to obesity)
+ Hepatitis C

* Microvesicular Steatosis
o accumulation of small fat droplets in hepatocytes that do NOT displace the nucleus
o Ominous prognosis in its pure form
+ Acute fatty liver pregnancy
+ Valproic acid
+ Cocaine toxicity
+ Reye's Syndrome
microvesicular steatosis in its pure form has a good or bad prognosis?
poor if alone, OK if in mixed form
Ballooning degeneration of hepatocytes
swelling of hepatocytes with fatty accumulation --> leakage of ALT/AST
+ hepatitis
+ alcohol
+ non-alcohol liver injury
Feather degeneration of hepatocytes
o retained biliary material in swollen hepatocytes
o Bile cause cytoplasm to take on a "feathery"
o Bile plugs seen in other areas of the liver
+ Chronic cholestasis
macrovesicular steatosis
- accumulation of large fat droplets in hepatocytes that displace the nucleus
+ Alcohol
+ Fatty liver disease (related to obesity)
+ Hepatitis C
Microvesicular steatosis
o accumulation of small fat droplets in hepatocytes that do NOT displace the nucleus
o Ominous prognosis in its pure form
+ Acute fatty liver pregnancy
+ Valproic acid
+ Cocaine toxicity
+ Reye's Syndrome

HEPATIC DYSFUNCTION WITHOUT OVERT NECROSIS
hepatocyte necrosis types
* focal/spotty necrosis
* inferface hepatitis (piecmeal necrosis)
* bridging necrosis - bridges from one lobule to the next
* submassive necrosis - involves an entire lobe
* massive necrosis - most of the liver
* ie centrilobular Zone 3 necrosis --> associated with acetominophen overdose)
interface hepatitis
piecemeal necrosis
ex. hepatitis/inflammation of hepatocyte
bridging hepatitis
bridges from one lobule to the next
submassive necrosis
involves an entire lobe of the liver
massive necrosis
involves most of liver
centrilobular zone 3 necrosis
associated with acetaminophen overdose
hepatocyte regeneration
Hepatocytes proliferate in response to tissue resection or cell death, can occur as long as framework is there, cords of hepatocytes usually become thicker but no more than 2-3 layers thick
inflammation of hepatocytes
hepatitis
Viral, some toxins, infections, drugs, autoimmune, wilsons, A1At,
Piecemeal necrosis, involving lobular parenchyma as well
hepatocyte fibrosis
RESPONSE TO INFLAMMATION OR DIRECT TOXIC INSULT. Sinister ITO cells change into myofibroblasts and lay down collagen
important synthetic factors of liver
* albumin
* clotting factors (II, VII, IX, X)
* Alkaline phosphatase (also made in bone)
* ALT & AST
serum transaminases
-what are they?
-leakage suggests what?
-pattern with alcohol injury?
* ALT (Alanine Aminotransferase) and AST (Asparate Aminotransferase)

* leakage/elevation in serum indicates hepatocyte injury
* If AST is twice as high as ALT, that indicates alcohol-related-injury... "AST=Scotch & Tonic"
* Note: AST is also found in erythrocytes and myocytes, so if AST>>ALT, this can indicate hemolysis, myocardial infarction, or skeletal muscle diseases
If AST 2x as high as ALT, it indicates what?
If AST >>ALT, what else can it indicate?
indicates alcohol-related-injury... "AST=Scotch & Tonic"

AST is also found in erythrocytes and myocytes, so if AST>>ALT, this can indicate hemolysis, myocardial infarction, or skeletal muscle diseases
Lab assessment of the liver includes what?
Serum Transaminases
-ALT (Alanine aminotransferase)
-AST (Asparate aminotransferase)

Alkaline Phosphatase
Gamma Glutamyl Transpeptidase
Bilirubin

Function
-Prothrombin time
-Albumin
-ammonia
Liver function tests
Prothrombin time (liver synthesis of clotting factors)
Albumin (synthesis by liver)
ammonia (breakdown to urea)
Elevation of Alkaline phosphatase
# Alkaline Phosphatase (AP) - in bone and liver

* elevated in bile cannaliculi epithelium Injury OR bone injury
* bile injury because alkaline phosphate is found in high levels in cells lining the bile canaliculi
Why is Alk Phos elevated in bile injury?
alkaline phosphate is found in high levels in cells lining the bile canaliculi
Hepatic failure
80-90% LOSS OF FUNCTION
80% MORTALITY
TRANSPLANT
SUDDEN AND MASSIVE
END STAGE OF CHRONIC INJURY
Elevation in Gamma Glutamyl Transpeptidase (GGT)
-elevation means what?
* elevation confirms that AP elevation is due to bile cannaliculi epithelial damage (not bone but more likely liver damage)
Elevation in bilirubin
* Elevated in liver failure
* Not being conjugated or excreted in stool
Hepatic failure
-what loss of function?
-mortality?
-What are the 4 main types?
-clinico-pathologic correlate?
-what are the most grave stages?
80-90% LOSS OF FUNCTION
80% MORTALITY
Treatment: TRANSPLANT
SUDDEN AND MASSIVE
END STAGE OF CHRONIC INJURY

Types:
-acute (fulminant vs. subfulminant)
-massive hepatic necrosis
-non-necrotic liver failure
-chronic liver disease

Clinico-pathologic correlate:
Jaundice: elevated bilirubin, can't process/excrete it
Hepatic encephalopathy: elevated ammonia levels affect neutoransmission
Coagulopathy: lack of clotting factors
Hepatorenal syndrome
Hypoalbuminemia
Fetor hepaticus
Endocrine related problems: gynecomastia

Most grave stages:
HEPATIC ENCEPHALOPATHY
Confusion, coma, convulsions
Asterixis
Disorder of neurotransmission in CNS and neuromuscular system

HEPATORENAL SYNDROME
HEPTOPULMONARY SYNDROME: Orthodeoxia and platypnea (SOB when they stand up)
Acute liver failure
-the 2 types and time frame?
-etiology? Almost 50% due to what?
-FULMINANT (ENCEPHALOPATHY WITHIN 2 WEEKS OF JAUNDICE)
-SUBFULMINANT (ENCEPHALOPATHY WITHIN 3 MONTHS OF JAUNDICE)

etiology:
Usually secondary to drugs and toxins
Also viral hepatitis, autoimmune hepatitis and unknown causes
Almost 50% of US cases are from accidental of suicidal ingestion of acetaminophen
Most common route to hepatic failure
cirrhosis
end stage liver disease
cirrhosis
Cirrhosis
-2 types based on size?
-etiologies?
-pathogenesis?
-clinical sx? advanced ones?
A DIFFUSE PROCESS CHARACTERIZED BY FIBROSIS AND A CONVERSION OF NORMAL ARCHITECTURE INTO STRUCTURALLY ABNORMAL NODULES.

2 types based on size: Macronodular > 3 mm and micronodular cirrhosis

Etiologies:
Main etiologies of cirrhosis
-Alcohol abuse
-Viral hepatitis
-Non-alcoholic steatohepatitis (NASH- NEW!! Seen in obesity)
-Biliary Diseases
-Iron overload/primary hemochromatosis
(others: Wilson's disease, a-1 antitrypsin deficiency, metabolic disorders, drug rxns, cryptogenic, infection)

Pathogenesis: Pathogenesis: Kupffer cell activated and activates stellate ITO cells to become myofibroblasts that lay down collagen and also secretes cytokines that promote proliferation, contraction, fibrogenesis and chemotaxis --> space of disse collagenized with fibrous tissue --> hepatic dysfunction

Clinical symptoms:
can be SILENT
can be NONSPECIFIC: ANOREXIA, WEIGHT LOSS, WEAKNESS

ADVANCED sx:
1) PROGRESSIVE LIVER FAILURE
2) PORTAL HYPERTENSION
3) HEPATIC ENCEPHALOPATHY
4) Hepatopulmonary syndrome
5) Development of hepatocellular carcinoma
Portal hypertension
-types?
-pathology?
-symptoms?
+ Types: prehepatic, intrahepatic, posthepatic

# Prehepatic (before blood enters liver)
* Obstructive thrombosis
* Narrowing of portal vein
* Massive splenomegaly

# Intrahepatic (most common, within liver)
* Cirrhosis Cirrhosis Cirrhosis!!
* Schistosomiasis
* Massive fatty change
* Diffuse fibrosing granulomatous disease: sarcoidosis
* Disease of portal microcirculation: nodular regenerative hyperplasia

# Posthepatic
* Severe right sided heart failure
* Constrictive pericarditis
* Hepatic vein outflow obstruction

Pathogenesis:
Blockage in liver/portal vein disrupts normal liver blood flow:
Blood flow in L gastric vein reverts and now travels in the opposite direction toward the IVC to return to the heart --> esophageal varices
Blood flow in the splenic vein also reverts and is not getting drained through the liver and then IVC like it normally does --> hepatosplenomegaly
Blood flow not going through liver effectively --> loss of detox, build up of ammonia --> dumping of these into systemic system

Pathologic findings: liver is hardened, splenomegaly, liver is weeping lymph, esophageal varices

Symptoms
# Ascites (from liver weeping lymph)
# portosystemic venous shunts (ie. esophageal varicies)
# encephalopathy
# congestive splenomegaly
Jaundice and cholestasis
RETENTION OF PIGMENTED BILIRUBIN

Jaundice = yellow skin
Icterus = yellow sclerra
Cholestasis = retention of bile
Retention of bilirubin?
Retention of bile?
1) bilirubin: jaundice = yellow skin, icterus = yellow sclera
2) bile: cholestasis
Explain metabolism of RBCs/Bilirubin
Heme from sescent erythrocytes gets converted to biliverdin and then combined with albumin to become the bilirubin-albumin complex, which is unconjugated. It enters the blood stream and once in the liver, gets conjugated in the hepatocyte and then released into the biliary tract as part of the bile --> enters duodenum --> degraded into urobiligin in the GI tract
Hepatic bile formation
EMULSIFICATION OF DIETARY FAT IN THE GUT LUMEN

ELIMINATION OF SYSTEMIC WASTE PRODUCTS THAT ARE NOT WATER SOLUBLE ENOUGH TO BE EXCRETED IN URINE

BILE: BILIRUBIN, BILE SALTS, CHOLESTEROL
If someone has jaundice do they have to also have cholestasis?
No - example is sickle cell anemia - jaundiced but not cholestasis because bile is still flowing
Cholestasis
-definition
-symptoms
-lab findings
-etiology
-Types
DEFINITION: Decreased bile flow; denotes impaired bile formation and flow leading to accumulation in hepatic parenchyma

SYMPTOMS:
-JAUNDICE
-PRUITITS
-STEATORRHEA
-HEMORRHAGIC DISORDERS
-XANTHOMAS

Lab findings: elevated conjugated bilirubin, elevated alk phos, GGT

Etiology
EXTRAHEPATIC: Surgical Team vs. INTRAHEPATIC: Medical Team

Types:
1) Acute intrahepatic: drug induced, cholestasis of pregnancy, benign recurrent cholestasis, sepsis, stress (post-op)
2) Acute extrahepatic: biliary obstruction
3) Chronic intrahepatic: PBC, PSC, sacroidsosis, drug induced, congenital/metabolic, GVHD/transplant
4) Chronic extrahepatic: prolonged biliary obstruction
Progressive familial intrahepatic cholestasis
What viruses cause viral hepatitis?
Hep A-E, infectious mononucleosis, CMV, yellow fever, in immunosuppressed: adenovirus, herpes virus, hemorrhagic fevers: ebola
Hepatitis A
-Route?
-incubation
-clinical picture
-epi
-diagnosis?
"ATE"
1) FECAL - ORAL
2) INCUBATION: 3 TO 6 WEEKS
Clinically: mild or asymptomatic
FULMINANT <1%
NO CHRONIC STATE
US: 50% of people over 50 show previous exposure (seropositivity)
-Diagnosis: IgM indicates infection, IgG indicates recovery/vaccination
Hepatitis B
1) what's unique about it relative to the others?
2) Incubation
3) increased risk of?
4) people at risk?
5) Diagnosis?
6) Liver injury
7) Potential outcomes
"BAD BLOOD"
Only DNA virus in the bunch

Incubation 4-26 weeks
Fulminant 0.1 - 0.5 %

Chronic hepatitis with risk of cirrhosis
* liver transaminases fluctuate
* viral DNA load stays steady

Increased risk of Hepatocellular Cancer

Primary risk categories:
-Transfusions (markedly decreased)
-Dialysis
-Needle stick accidents
-IV drug abuse
-Sexual intercourse
-Perinatal transmission

diagnosis
-HBsAg: first to appear (2-8 weeks up until 4 months), first marker of infection. If > 6 months --> chronic infection
-HBeAg: 2nd marker for infection to appear but disappears before HbsAg
-AntiHBV core antibody IgM: non protective Ab that remains + in actue infections, PERSISTS DURING WINDOW PHASE/SEROLOGIC GAP (4-6 months post innoculation) but converts entirely to IgG by 6 months
-Anti HBs (surface antibody): protective, marker of immunity

Liver injury
NOT DIRECTLY CYTOTOXIC TO LIVER CELLS
LIVER INJURY IS CAUSED BY THE IMMUNE RESPONSE (CYTOTOXIC T CELLS)

Outcomes:
Acute infection --> acute hepatitis --> subclinical (70%) or icteric disease --> recovery (>90%!), fulminant hepatitis or chronic hepatitis (which can progress to recovery, healthy carrier state or cirrhosis and hepatocellular carcinoma)
Difference between acute vs. chronic hepatitis
fibrosis only present in chronic hepatitis
Which hepatitis is a risk factor for hepatocellular cancer?
Heb B and C
E has unlikely risk of hepatocellular carincoma!
Which hep is transmitted fecal: oral? via blood?
1) A - fecal oral (ATE)
2) B - Blood
How do you diagnose someone with Hep B if they are in the "window"
Heb B core antigen (Yong also said HbE but RR did not)
What causes liver injury in hep B?
Liver injury
NOT DIRECTLY CYTOTOXIC TO LIVER CELLS
LIVER INJURY IS CAUSED BY THE IMMUNE RESPONSE (CYTOTOXIC T CELLS)
Hepatitis C
-Incubation
-route?
-symptoms
-progression to chronic?
-increased risk of?
-etiology/RF?
"CHRONIC AND CLANDESTINE"
-Incubation 2 - 26 weeks
-Route: parenteral, sexual
-85% of patients asymptomatic with acute infection
-Fulminant: rare
-Chronic 80 - 85% (20-30% progress to cirrhosis)
Increased risk of Hepatocellular Cancer and cholangiosarcoma

Most common risk factors: IVDA***, Multiple sex partners , surgery < 6 months, needle stick injury, multiple contact with infected person, employment in dental or medical field, unk
Which hep viruses are transmitted parenterally
B,C, D
Hepatitis D
1) incubation
2) Relationship to Hep B
3) Epidemiology?
4) Prognosis and labs for coinfection vs. superinfection
"DEFECTIVE AND DEVIOUS"
Incubation: same as HBV

Requires Hep B for infection b/c uses HBsAg to replicate!
-->HDV in ~ 5% of HBV infected persons

Fulminant: 3-4%
Chronic < 5% coinfection, 80% superinfection
Same risk of HCC as HBV infection

Epi:
-->20-40% OF HBsAg CARRIERS IN Amazon basin, AFRICA, MIDDLE EAST AND SOUTHERN ITALY ARE +HDV
-->1-10% OF DRUG ADDICTS AND HEMOPHILIACS IN United States ARE +HDV (HDV now disappearing from hemophiliacs and other blood transfusion recipients)

Prognosis:
1) HDV AND HBV COINFECTION: Most people with coinfection of HDV and HBV recover with immunity, but rarely develop fulminanet hepatitis/death and even more rarely chronic hepatitis and cirrhosis
Labs: IgM anti-HDAg and IgM anti HBcAg (VERY FEW PROGRESS TO CHRONIC)

2) SUPERINFECTION: HepD exposure in a HepB carrier --> much higher % of fulminant hepititis/severe disease. 80% progress to chronic hepatitis and cirrhosis!
Labs: -IgM & IgG anti-HDV, HBsAG
Which 2 hepatitises are usually seen together
Hep B and D - Hep D requires HbAsAg to replicate
Hep E
1) Incubation
2) Risk of carcinoma?
"EXPECTANT"
Incubation 6 weeks
Fulminant: 0.2-3%, 20% in pregnancy
NO CARRIER STATE
Unlikely risk of Hepatocellular carcinoma
Which hepatitis virus has no carrier state?
Hepatitis E
Chronic hepatitis
1) criteria
2) etiologies
3) biopsied?
4) Pathologic findings
5) Grading
Citeria: Need to have biochemical or serologic studies/sx > 6 months

Etiologies:
-Hepatitis B, C, or D
-Autoimmune hepatitis
-Drugs
-Wilson's Disease
-Alpha-1 Antitrypsin Deficiency

OFTEN BIOPSIED (unlike acute)

Pathologic findings: Fibrosis
-enlarges portal tract
-can spill out (periportal fibrosis)
-can bridge portal tract and central vein ("bridging fibrosis")
-periportal necrosis
-Ground glass-cells (hep B)
-apoptosos
-lymphocytes
-fatty change (hep C)
-maccrophage aggregate

From niopsy, Grading of inflammation (minimal - grade 1, mild -2, moderate - 3, severe -4) and fibrosis (minimal - stage 1, mild - stage 2, moderate - stage 3, severe - stage 4)
Ex Diagnosis: Chronic hepatitis with mild inflammatory activity, Grade 2 and bridging fibrosis, Stage 3
Hepatitis carrier state
Important reservoir for infection
Individuals who carry one the viruses but has no liver disease
Individuals who harbor one of the viruses and have nonprogressive liver disease but is free of symptoms
Acute viralhepatitis
1) how commonly biopsied?
2) pathogenesis?
Acute hepatitis is rarely biopsied - easier to do serologic/blood tests

Acute viral hepatitis:
1) Hepatocyte injury / necrosis: inflammation in portal tract --> reaches parenchyma --> piece meal necrosis + dead hepatocytes + cholestasis + fatty change in hep C + apoptosis + ballooning degeneration
2) Cholestasis: bile plugs
3) Fatty change (HCV)
4) Bile duct reaction/jaundice: /jaundice: bile cannicular spaces become distoreted and can rupture when cells balloon, causing leakage of bile into sinusoids and hyperbilirubinemia
5) Kupffer cell hypertrophy
6) Inflammatory cells: lymphocytes and plasma cells, NOT neutrophils
In which viral hep might you see fatty change?
Hepatitis C
Why do pts with acute viral hepatitis develop jaundice?
Bile duct reaction/jaundice: /jaundice: bile cannicular spaces become distoreted and can rupture when cells balloon, causing leakage of bile into sinusoids and hyperbilirubinemia
What histopathologic findings are seen in acute viral hepatitis?
1) Hepatocyte injury / necrosis: inflammation in portal tract --> reaches parenchyma --> piece meal necrosis + dead hepatocytes + cholestasis + fatty change in hep C + apoptosis + ballooning degeneration
2) Cholestasis: bile plugs
3) Fatty change (HCV)
4) Bile duct reaction/jaundice:
5) Kupffer cell hypertrophy
6) Inflammatory cells: lymphocytes and plasma cells, NOT neutrophils
Which types of inflammatory cells are seen in viral hepatitis?
lymphocytes and plasma cells, NOT neutrophils
Is acute hepatitis often biopsied? Is chronic?
Acute is not b/c serologic/blood studies are usually sufficient, chronic IS biopsied to assess fibrosis
Whch hep virus causes "ground glass cells" in chronic hepatitis?
Hep B - Homogenization and smoothing of the cytoplasm due to surface antigen
Fulminant viral hepatitis etiologies
DRUGS & CHEMICAL TOXICITY
RARE CAUSES
UNKNOWN
Acute fatty liver of pregnancy
-cause
-prognosis
Mitochondrial problem - abnormality in B-oxidation of fatty acids/lipid metabolism, fatal to mom and fetu sunless baby is delivered
See microvesicular damage, but not necrosis
Drug and toxin damage to liver
1) types of damage
2) pathologic findings
3) vs. chronic liver disease
4) Area most affected
Can do almost ANY kind of damage to the liver!
-INJURY MAY BE IMMEDIATE OR MAY TAKE WEEKS TO MONTHS

Pathologic findings: HEPATOCYTE NECROSIS, CHOLESTASIS, INSIDIOUS ONSET OF LIVER DYSFUNCTION

CAN BE INDISTIGUISHABLE FROM CHRONIC LIVER DISEASE --> Therefore negative serologic viral markers are important for diagnosis

--INJURY MAY BE IMMEDIATE OR MAY TAKE WEEKS TO MONTHS
--HEPATOCYTE NECROSIS, CHOLESTASIS, INSIDIOUS ONSET OF LIVER DYSFUNCTION
--CAN BE INDISTIGUISHABLE FROM CHRONIC LIVER DISEASE
**Therefore negative serologic viral markers are important for diagnosis

Tends to cause CENTRILOUBLAR (zone 3) liver damage
Why should serologic viral markers be ordered on someone with suspected drug/toxin damage to liver?
CAN BE INDISTIGUISHABLE FROM CHRONIC LIVER DISEASE --> Therefore negative serologic viral markers are important for diagnosis
injury commonly seen following an acetaminophen averdose
-zone?
-pathogenesis?
centrilobular damage (zone 3)


Acetaminophen gets converted into an active metabolite in the liver, and neutralized via the p450 system with glutathione. However, when glutathione is consumed, or in alcoholics who have less glutathione, the active metabolite can be converted to a toxic metabolite that causes necrosis
Autoimmune hepatitis
1) description - what cells are prominent
2) affects mostly males or females?
3) Lab findings?
4) other processes that may be present?
Chronic hepatitis with prominent plasma cells

Females > Males

Labs:
-Negative viral markers
-Elevated IgG and gamma globulins
Positive autoantibodies
+ANA, +Anti SMA, +AAA, +SLA/LP and +ALKM-1
Negative AMA

Other autoimmune processes may be present
autoimmune hepatitis is associated with prominent infiltrate of what type of cells?
plasma cells
Alcoholic liver disease
-3 forms?
HEPATIC STEATOSIS
ALCOHOLIC HEPATITIS
ALCOHOLIC CIRRHOSIS
HEPATIC STEATOSIS
-what 3 things are going on that contribute to it?
ALCOHOL FATTY LIVER DISEASE
most common type of alcohol disease of liver
tender hepatomegaly without fever or neutrophilic leukocytosis
microvesicular steatossis

HEPATOCELLUAR STEATTOSIS:
-LIPID BIOSYNTHESIS
-IMPAIRED ASSEMBLY AND SECRETION OF LIPOPROTEINS
-INCREASED PERIPHERAL CATABOLISM OF FAT
alcoholic hepatitis
Pathogenesis: acetaldehyde damages hepatocytes
ACETALDEHYDE --> INDUCTION OF CYTOCHROME P450 AND GENERATION OF REACTIVE OXYGEN SPECIES
1) DECREASE GLUTATHIONE LEVELS
2) MALNUTRITION AND VITAMIN DEFICIENCIES
3) BACTERIAL ENDOTOXINS FROM GUT

Pathologic changes: Fatty liver, inflammation , hepatocelluar injury (hepatocyte swelling, apoptotic bodies) Mallory hyaline with NEUTROPHILIC ASSOCIATION
Mallory Hyaline/"mallory dank bodies"
used to be called Alcoholic hyaline
-damaged cytokeratin intermediate filaments in hepatocytes --> lumps together and looks like worm like inclusions
-Evidence of major hepatocellular injury and damage
-can also be seen in nonalcoholic steatitis

It's an indication that the cytoskeleton in the hepatocyte has "gone amuck" and is not wokring
How does alcohol lead to temporary and chronic damage?
Normal liver with exposure can lead to steatosis, with sever exposure can lead to hepatitis. Abstinence can lead back to normal liver, but continued exposure in both cases leads to cirrhosis
NONALCOHOLIC FATTY LIVER DISEASE "NAFLD"
-histology
-etiology
-sx
-most common cause of what?
HISTOLOGICALLY IDENTICAL TO ETOH INDUCED LIVER DISEASE
1) HEPATIC STEATOSIS
2) STEATOSIS WITH MINOR NONSPECIFIC
3) INFLAMMATION
--> NON ALCOHOLIC STEATOHEPATITIS "NASH"
--> HEPATOCYTE INJURY CAN PROGRESS TO CIRRHOSIS

INDIVIDUALS DO NOT CONSUME ETOH OR VERY SMALL QUANTITIES (<20GRAMS/WEEK)

OBESITY, AND METABOLIC SYNDROME: DYSPLIPIDEMIAN, HYPERINSULINEMIA, AND INSULIN RESISTANCE

NONSPECIFIC SYMPTOMS

**MOST COMMON CAUSE OF CHRONIC LIVER DISEASE AND CRYTOGENIC CIRRHOSIS
ESTIMATED;~30% OF US POPULATION, 70% OF OBESE INDIVIDUALS
MOST COMMON CAUSE OF CHRONIC LIVER DISEASE AND CRYTOGENIC CIRRHOSIS
Nonalcoholic fatty liver disease
ESTIMATED;~30% OF US POPULATION, 70% OF OBESE INDIVIDUALS
HEMOCHROMATOSIS
-definition
-hereditary vs. secondary
-diagnosis (labs?)
-finding on liver biopsy?
IRON STORAGE DISEASE

HERIDITARY HEMOCHROMATOSIS: homozygous recessive (chromsome 6 short arm, C282Y mutation)
-one of the most common genetic disorders
-H63D
-excessive absorption of dietary iron

SECONDARY HEMOCHROMATOSIS
-IRON DEPOSITION IN PARENCHYMAL TISSUES
-"BRONZE DIABETES"
-TREATMENT AVAILABLE
-RISK OF HCC

DIAGNOSIS
-ELEVATED Serum iron & Ferritin
-Genetic testing for the HFE gene mutation
-Liver biopsy for quantitative iron studies and histologic examination

Biopsy findings:
1) Liver: See BROWN pigmented hepatocytes + Iron stain with positive BLUE staining of all the hepatocytes demonstrating severe increased iron stores
2) Gross pancreas may appear brown from liver deposition
3) Myocardium: Iron stain shows + blue staining due to iron deposition
"bronze diabetes"
secondary hemochromatosis
WILSON'S DISEASE
-Definition/pathogenesis
-inheritence
-symptoms
-treatment available?
-diagnosis
-biopsy findings
"HEPATOLENTICULAR DEGENERATION"
-IMPAIRED COPPER EXCRECTION AND FAILURE TO INCORPORATE INTO Cu IN TO CERULOPLASMIN
-DEPOSITION OF COPPER IN A VARIETY OF ORGANS

AUTOSOMAL RECESSIVE DISORDER - CHROMOSOME 13


VARIABLE SYMPTOMS - DIFFICULT DIAGNOSIS TO MAKE

TREATMENT AVAILABLE - copper chelation

DIAGNOSIS
-LOW CERULOPLASMIN
-INCREASED URINARY COPPER
-LIVER BIOPSY FOR QUANTITIATIVE COPPER ANALYSIS
-KAYSER-FLEISCHER RINGS IN EYES

Biopsy:
Chameleon of liver disease. It resembles chronic hepatitis in this image. Can also look like an acute hepatitis, steatosis, cirrhosis or massive liver necrosis
chameolion of liver disease
Wilson's disease - It resembles chronic hepatitis in this image. Can also look like an acute hepatitis, steatosis, cirrhosis or massive liver necrosis
Kayser Fleischer ring
due to copper deposits in Descemet's membrane in the cornea
-can be due to Wilson's disease but not pathognomonic of it because also seen in primary biliary cirrhosis
ALPHA-1 ANTITRYPSIN DEFICIENCY
-definition/pathogenesis
-consequences
-genetics (worst variant?)
-diagnosis
LOW LEVELS OF ALPHA-1 ANTITRYPSIN : alpha-1 antitrypsin inhibits proteases

-PULMONARY EMPHYSEMA
-HEPATIC DAMAGE due to accumulation in hepatocytes

Autosomal recessive disorder; CHROMOSOME 14
-Many allelic variants
-PiZZ has only 10% of normal circulating levels

Dx:
-PERIPORTAL PAS POSITIVE CYTOPLASMIC GLOBULES
-IMMUNOHISTOCHEMICAL STAIN , POSITIVE BROWN STAINING
PERIPORTAL PAS POSITIVE CYTOPLASMIC GLOBULES
alpha-1 antitrypsin deficiency
Hepatic circulatory disorders (pre, intra and post-hepatic)
Prehepatic/impaired blood inflow: hepatic artery compromise, portal vein obstruciton, intra or extrahepatic thrombosis
-esophageal varices, splenomegaly, intestinal congestion (NO HEPATOMEGALY!)

Intrahepatic: cirrhosis, sinusoid occlusion, systemic circulatory compromise
-ascites (cirrhosis) esophageal varices (cirrhosis), hepatomegaly, elevated transaminases

Post-hepatic: Hepatic outflow obstruction: hepatic vein thrombosis or veno-occlusive disease
-Ex. Budd Chiari, Sinusoidal obstructive syndrome/veno-occlusive disease
-ascites, hepatomegaly, abdominal pain, elevated transaminases, jaundice
BUDD-CHIARI SYNDROME
-pathogenesis?
-sx?
HEPATIC VEIN OBSTRUCTION / THROMBOSIS
-Primary myeloproliferative disorders
-Inherited disorders of coagulation
-Antiphospholipid syndrome
-Paroxysmal nocturnal hemoglobinuria
-Intra-abdominal cancers

See CENTRILOBULAR CONGESTION

symptoms: HEPATOMEGAL, ASCITIES, ABDOMINAL PAIN AND HEPATIC DYSFUNCTION

Note: form of POSTHEPATIC circulatory disorder
SINUSOIDAL OBSTRUCTIVE SYNDROME OR VENO-OCCLUSIVE DISEASE
Jamaican drinkers of PYRROLIZINE ALKALOID containing bush tea

complication of BONE MARROW TRANSPLANTS (collagen develops around central veins)
-First 3 weeks
-25% of recipients of allogeneic BMT

Chemotherapy patients

(form of post-hepatic circulatory disorder)
Primary Biliary Cirrhosis (PBC)
-other term?
-pathogenesis?
-who does it mostly affect?
-pathologic changes?
-diagnosis?
-treatment?

**IMPORTANT - IN A LEARNING OBJECTIVE!
Summary: Middle age women, +AMA, periductal inflammation with granulomas

"Chronic nonsuppurative destructive cholangitis" term hasn't caught on yet

DESTRUCTION OF SMALL / MEDIUM SIZED INTRAHEPATIC BILE DUCTS
-PROGRESSIVE OFTEN FATAL CHOLESTATIC LIVER DISEASE
-CONSIDERED TO BE OF AUTOIMMUNE ETIOLOGY

MILDDLE AGE WOMEN. may see xanthomas due to inc cholesterol

Pathologic changes: FLORID DUCT LESION
-PERIDUCTAL INFLAMMATION WITH GRANULOMA -FORMATION AND DUCT DESTRUCTION
-PORTAL TRACTS WITH LYMPHOCYTES, PLASMA CELLS, EOSINOPHILS, MACROPHAGES AND GRANULOMAS.
-BILE DUCT INJURY AND BILE DUCTS ARE INFILTRATED BY LYMPHOCYTES

DIAGNOSIS: Rule out obstruction
-Cholestatic symptoms: Pruritis, xanthomas, jaundice late
-LABS: Elevated alkaline phosphatase, cholesterol and bilirubin (late), Positive AMA (90-95%) + anti-mitochondrial antibody
-Liver biopsy: intrahepatic bile duct destruction with granulomas

Treatment: first medically, then transplantation
PRIMARY SCLEROSING CHOLANGITIS
-definition
-clinical
-prognosis/tx
-histology
-diagnosis

LO - IMPORTANT!
Summary: Younger people with ulcerative colitis, "Beading" pattern on ERCP, periductal fibrosis

-OBLITERATIVE FIBROSIS OF INTRAHEPATIC AND EXTRAHEPATIC BILE DUCTS WITH INFLAMMATION AND DILATION OF PRESERVED SEGMENTS

-ERCP SHOWS "BEADING"

Clinical:
-ASSOCIATED WITH INFLAMMATORY BOWEL DISEASE
-CHOLESTATIC SYMPTOMS

Prognosis/Treatment:
GO ON TO END STAGE LIVER DISEASE
LIVER TRANSPLANTATION
**RISK OF CHOLANGIOCARCINOMA!!!

Histology
Bile duct undergoing degeneration and is surrounded by dense fibrosis with a "onion skin" pattern
--NOTE: DO NOT SEE GRANULOMAS

diagnosis:
-Cholestatic: Elevated alkaline phosphatase +/- elevated bilirubin
-ERCP: shows "BEADING" of the bile ducts
Liver biopsy
FOCAL NODULAR HYPERPLASIA
SOLITARY mass with CENTRAL STELLATE SCAR, thought to be an AV malformation with hypertrophy of hepatocytes
20-40 YEAR OLD ADULTS, more common in women
NO MALIGNANT POTENTIAL
-usually biopsied to differentiate from malignancy or left alone unless it causes pain

Gross appearance:
Well demarcated nodule, generally lighter than the surrounding parenchyma and usually contains a central stellate scar.
NODULAR REGENERATIVE HYPERPLASIA
-partial or diffuse?
-pathology?
-dx?
PARTIAL OR DIFFUSE

Pathology
1) LIVER TRANSFORMED INTO NODULES IN THE ****ABSENCE OF FIBROSIS!!!
2) NON CIRRHOTIC PORTAL HYPERTENSION

DIFFICULT DIAGNOSIS TO MAKE ON LIVER BIOPSY
Is there fibrosis in focal nodular hyperplasia? is there in nodular regenerative hyperplasia?
1) Yes - central stellate scar
2) NO
LIVER CELL ADENOMA
-YOUNG WOMEN, ASSOCIATED WITH ORAL CONTRACEPTIVES
-USUALLY SOLITARY

Histology:
-CORDS OF NORMAL HEPATOCYTES WITH ABSENT PORTAL TRACTS

PROBLEM: INTRAHEPATIC MASS WHICH CAN NOT BE DISTINGUISHED FROM CANCER, CAN POSSIBLY RUPTURE (ex. during pregnancy) & RARELY TRANSFORMS TO HEPATOCELLULAR CARCINOMA
benign liver tumor associated with oral contraceptives
liver cell adenoma
hemangioma
-gross and microscopic appearance/histology
MOST COMMON BENIGN TUMOR

Gross appearance: DISCRETE RED-BLUE NODULES
MICROSCOPICALLY: BENIGN VASCULAR CHANNELS AND FIBROSIS TISSUE. See VASCULAR ENDOTHELIAL LINED SPACES
1 Most common benign tumor of liver
2 Most common primary sarcoma of the liver
3 most common primary malignant tumor of childhood
4 Most common liver cancer
5 most common malignancy of bile ducts
6 Most common mets in adults and kids
1-Hemangioma
2-Angiosarcoma (says Yong - RR says Hepatocellular carcinoma)
3-HEPATOBLASTOMA
4-Mets
5-cholangiosarcoma
6- ADULTS: Breast, lung, colon and pancreas
Children: Neuroblastoma, Wilms tumor and rhabdomyosarcoma
Angiosarcoma
-MOST COMMON PRIMARY SARCOMA OF THE LIVER (according to Yong - RR says HCC)

-MALIGNANT VASCULAR TUMOR: vesse
ls lined with malignant endothelial cells

-ASSOCIATED WITH EXPOSURE TO VINYL CHLORIDE, ARSENIC, THOROTRAST
Exposure to vinyl chloride can cause what liver cancer
angiosarcoma
HEPATOBLASTOMA
1) common in?
2) clinical presentation
PRIMARY HEPTOCELLULAR MALIGNANCY

Epi: MOST COMMON PRIMARY MALIGNANT LIVER TUMOR OF CHILDHOOD, M>F

Clinical:
-ABDOMINAL ENLARGMENT NOTED BY PARENT, RUQ -MASS FOUND ON PHYSICAL EXAM
-ELEVATED ALPHA FETOPROTEIN (AFP)

Pathological:
-EPITHELIAL TYPE ; FETAL AND EMBRYONAL HEPATOCYTES
-MIXED EPITHELIAL AND MESENCHYMAL; FETAL AND EMBRYONAL HEPATOCYTES WITH FOCI OF MESENCHYMAL DIFFERENTIATION
Tumors of the liver
Benign
-focal nodular hyperplasia, hemangioma, hepatic cell adenoma
Malignant
-met (most common liver cancer)
-Hepatocellular carcinoma
-angiosarcoma
-hepatoblastoma
-FIBROLAMELLAR VARIANT OF HCC
Malignancy of bile duct: cholangiocarcinoma (intra and extrahepatic)

Liver Mets
ADULTS: Breast, lung, colon and pancreas
Children: Neuroblastoma, Wilms tumor and rhabdomyosarcoma
Kids with hepatoblastoma have elevated what?
AFP (alpha fetoprotein)
HEPATOCELLULAR CARCINOMA
-how common?
-symptoms?
-etiologies?
-gross/microscopic features?
-pathogenesis
-clinically
-treatment
-diagnosis
-treatment
GLOBALLY ONE OF THE MORE COMMON VISERAL MALIGNANT TUMOR
-THIRD MOST COMMON CANCER DEATH
-Increase in US over last decade rapidly due to HCV infection

VAGUE SYMPTOMS (rapid enlargement of liver in pt with cirrhosis - Abd pain, ascites, fever), VARIETY OF PATHOLGIC FEATURES

MULTIPLE ETIOLOGIES: usually pts have preexisting cirrhosis
1) CHRONIC VIRAL INFECTION: HEPATITIS B & C
2) CHRONIC ALCOHOLISM
3) NASH (NON ALCOHOLIC STEATOHEPATITIS)
4) FOOD CONTAMINANTS: AFLATOXINS (from aspergillus mold in grains and peanuts)
5) OTHER: HEREDITARY TYROSINEMIA (HIGHEST RISK - 40%)

GROSS: SINGLE LESION vs. MULTIFOCAL vs. DIFFUSELY INFILTRATIVE

MICROSCOPIC: TRABECULAR, ACINAR / PSEUDOGLANDUAR, AND UNDIFFERENTIATED
*BILE in neoplastic cells** = characteristic finding
Thickened hepatic cords >3 cell layers
CLEAR CELL FEATURES

Pathogenesis
-Accumulation of mutations because of repeated cycles on cell death and regeneration (chronic hepatitis)
-Integration of viral DNA (HBV)
-**Presence of bile in neoplastic CELLS***

Diagnosis:
-50% elevated alpha fetoprotein (AFP)
-Detected on imaging studies: CAT SCAN AND U/S to localize it

Treatment
-Surgery
-Radiofrequency ablation
-chemoembolization
presence of bile in neoplastic cells
HCC!
Pts with HCC usually have preexisting what?
cirrhosis
FIBROLAMELLAR VARIANT OF HCC
-seen in what type of pts
-associated with cirrhosis/HBV?
-histological features
-prognosis
YOUNGER PERSON
-NOT ASSOCIATED WITH CIRRHOSIS OR HBV

CHARACTERIZED BY AREAS OF DENSE COLLAGENOUS FIBROSIS AND LARGE POLYGONAL TUMOR CELLS

Thought to have a better prognosis than regular HCC
CHOLANGIOCARCINOMA:
-intra vs. extrahepatic: which is more common, clinical presentation
-Risk factors
Malignancy of the bile ducts (within or outside the liver)

Intra vs. extrahepatic: MOST are extra
1) 10% INTRAHEPATIC: ARISING FORM BILE DUCTS WITHIN THE LIVER
2) CLINICAL: Bile flow obstruction, symptomatic mass
*Not detected until late!
3) GROSS: SINGLE, MULTIPLE, OR DIFFUSE
4) MICROSCOPIC: ADENOCARCINOMA with malignant glaundar cells + FIBROUS STROMA
***CAN BE ALMOST IMPOSSIBLE TO DISTINGUISH FROM A METASTATIC ADENOCARCINOMA!!!

2) 90% EXTRAHEPATIC: ARISING FROM BILE DUCTS OUTSIDE THE LIVER, usually very small!!
Can involve ANY portion of the bile duct:
-Perihilar (hilar) 50-60%: most common
-Distal bile duct 20-30%
-Periampullary
**CLINICAL: Biliary obstruction leading to obstructive jaundice, cholangitis, RUQ pain, clay-colored stools

ALMOST ALL ARE ADENOCARCINOMAS
SPECIAL VARIANT: KLASKIN TUMOR (PERIHILAR /HILAR: junction if right/left hepatic duct)


Risk factors:
-Primary sclerosing cholangitis**
-Congenital fibropolycystic disease of the biliary system
-HCV infection
-Exposure to Thorotrast
-Liver fluke; Clonorchis sinensis
Main risk factor for cholangiocarcinoma
primary sclerosing cholangitis
Infections with liver fluke, clonorchis sinensis and exposure to thorotrast are associated with what cancer?
cholangiocarcinoma
INTRAHEPATIC CHOLANGIOCARCINOMA can be almost impossible to distinguish from what?
CAN BE ALMOST IMPOSSIBLE TO DISTINGUISH FROM A METASTATIC ADENOCARCINOMA - need to scan head to toe to look for primary tumors elsewhere before confirming dx!
Klaskin tumor
special variant of cholangiosarcoma found at the junction of the R and L hepatic duct
Liver metastasis
-most common in kids and adults
ADULTS: Breast, lung, colon and pancreas
Children: Neuroblastoma, Wilms tumor and rhabdomyosarcoma
CHOLELITHIASIS
-how common
-Types
-complications
-acute vs. chronic
Very common ( 10-20% of population),
gallstones - variable # and size
commonly associated with cholecystitis

2 Types
-90% Cholesterol stones (Female, Obesity, Older, pregnancy)
-10% Pigmented stones (Chronic hemolytic disorders, biliary infection, GI disorders)

Clinical symptoms: Asymptomatic 70-80%
"Colicky" pain

Complications:
-Cholecystitis
-Perforation, Empyema, fistula
-CBD Obstruction; cholestasis, cholangitis and pancreatitis
*Increased risk for carcinoma*
RF for cholesterol gall stones
Female, Obesity, Older, pregnancy)
RF for pigmented gal stones
Chronic hemolytic disorders, biliary infection, GI disorders
black gallstones
sign of chronic extravascular hemolytic anemia
brown gallstones
sign of infection of CBD, commonly seen in Asians
white stones
calcium
CHOLEDOCHOLITHIASIS
PRESENCE OF STONES WITHIN THE BILIARY TREE

More common in Asia

Stones usually pigmented and associated with biliary tract infections
Cholecystitis
-acute vs. chronic
95% associated to gallstones

ACUTE: DIFFUSE INFLAMMATION
-RELATED TO OBSTRUCTION OF THE GALLBLADDER OUTLET
-STONES
-Clinical picture: RUQ PAIN, FEVER, N/V, LEUKOCYTOSIS, radiation of pain to R scapula/shoulder, Murphy sign, possibly jaundice, palpable gallbladder
-Other causes: BURNS, SURGERY, TRAUMA, SEPSIS, PROLONGED HYPERAL, POSTPARTUM STATE, OTHER INFECTIONS

CHRONIC : REPEATED BOUTS OF ACUTE CHOLECYSTITIS
-FIBROSIS OF THE WALL
-STONES
-severe persistent COLICKY RUQ PAIN postprandially in the evening, N/V, INTOLERANCE FOR FATTY FOODS, recurrent epigastric distress, blenching, bloating, pain radiating to R scapular area
CARCINOMA OF THE GALLBLADDER
-type of tumor

ADENOCARCINOMA
STEALTH TUMOR
-Stones present in 95% of cases SYMPTOMS SIMILAR TO CHOLECYSTITIS / CHOLELITHIASIS
-Exophytic or infiltrating mass
-Most are adenocarcinomas
-Mean 5 year survival 5-12% despite surgery
LO: Know the histologic findings classically seen in alcoholic hepatitis.
Steatosis (fatty change), Balloon cell changes, Mallory hyaline bodies, neutrophils
LO: Know the vascular disorder that is a complication of bone marrow transplant
VENO-OCCLUSIVE DISEASE
LO: Know the clinical , laboratory and pathologic findings seen in primary biliary cirrhosis.
Middle age women, +AMA, periductal inflammation with granulomas
LO Know the clinical, radiographic and pathologic findings in primary sclerosing cholangitis.
Younger people with ulcerative colitis, "Beading" pattern on ERCP, periductal fibrosis
LO: Know the common non malignant hepatic nodules
(focal nodular hyperplasia, hepatic adenoma, Hemangioma)
Know the clinical and pathologic findings for primary malignant tumors of the liver; hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma and cholangiocarcinoma.
HCC: risk factors-cirrhosis, HBV, HCV ect, malignant hepatocytes

FIBROLAMELLAR: younger person, no cirrhosis or other risk factors, big malignant hepatocytes with
lamellar fibrosis, thought to have a better prognosis

CHOLANGIOCARCINOMA: various risk factors (PSC), adenocarcioma
LO: Know the risk factors for cholelithiasis.
Female, fat, fertile, forties
LO: Know the clinical, common histologic pattern and risk factors for gallbladder cancer.
ADENOCARCINOMA, gallstones
LO: Know the vascular relationship of cirrhosis to portal hypertension and esophageal varicies.
Blood is re-routed through the left gastric vein to collateral is the esopagus and then into the azygos vein
LO: Know the common etiologies of chronic hepatitis
Viral, drug, A1AT, autoimmune, Wilsons
Be aware of Hemochromatosis, Wilsons disease and Alpha-1 antitrypsin disease and the associated pathologic finding in the liver.
Hemochromatosis (increased iron), Wilson's (increased copper) and A1AT globules in hepatocytes (+PASD) in A1AT deficiency
OVerview of pancreas pathology
Inflammation
-Acute with necrosis
-Chronic with fibrosis
Malignant
-Adenocarcinoma
-Endocrine tumor
Mucinous
IPMNS
Head of pancreas lies where?
uncinate process is what?
Superior mesenteric arery and vein cross what?
What part touches the splenic hilum?
1) in duodenum
2) a prolongation of the head. The superior
3) uncinate process
4) tail
Parts of the pancreas
Head (includes uncinate process): lies within the curve of the duodenum

uncinate process : the part of the head that wraps behind the superior mesenteric artery and vein and comes to lie adjacent to the ascending part of the duodenum.

Neck: a constricted portion to the left of the head. It abuts the pylorus above and the beginning of the portal vein behind.

Body: anterior surface separated from the stomach by the omental bursa , posteriorly related to the aorta, splenic vein, left kidney and renal vessels, left suprarenal, origin of superior mesenteric artery and crura of diaphragm.

Tail: extends into the lienorenal ligament and abuts the spleen. Touches splenic hilum
Know the congenital condition associated with an abnormality of the main pancreatic duct
Pancreas Divisum
+ failure of fetal duct system (main pancreatic and common bile duct) to fuse
+ 3-10% of the population
+ Can cause acute/chronic pancreatitis:
--> # much smaller "minor" sphincter has to accomodate a heavy flow
--># can lead to back up into major pancreatic duct --> bile activates pancreatic proenzymes causing acute pancreatitis
Embryologic abnormalities of the pancreas
1) Annular pancreas: dorsal and ventral buds form a RING AROUND THE DUODENUM, associated with small bowel obstruction

2) Ectopic pancreas/Aberrant pancreatic tissue

3) Major pancreatic duct abnormality (Pancreas divisum): blockage of flow/reflux associated with acute pancreatitis

4) Agenesis
Variations of the Common Bile Duct and Pancreatic duct
Wirsung won! (Main pancreatic duct)
Santorini second (Accessory pancreatic duct)
2 main types of cells in the pancreas
endocrine vs. exocrine functions
Islet cells (endocrine) and acinar cells (exocrine)

Exocrine: (85% - vast majority): produces and delivers digestive enzymes and proenzymes necessary for digestion
-->Acinar cells secrete digestive granules (bicarb, mucin, digestive enzymes)
(small ducts - bicarb, large ducts - mucin)

Endocrine pancreas: secretes insulin which controls the blood sugar and it also secretes other hormones
--> Islets of langerhans: insulin/monitoring of blood glucose (insulin, glucagon, somatostatin, PP, VIP, serotonin)
small acinar ductules secrete what? Large?
small - bicarb
large- mucin
How much pancreatic juice is released a day?
2-2.5 liters/day of bicarbonate rich fluid containing digestive enzymes and proenzymes
What prevents self-digestion of the pancreas?
1) Inactive proenzymes are synthesized (exception; amylase and lipase)
2) Enzymes are in membrane bound zymogen granules
3) Activation of proenzymes requires activation of trypsinogen to trypsin
4) Trypsin inhibitors are present
5) Trypsin can inactivate itself
6) Resistance of acinar cells
Which proenzymes secreted by the pancreas are active?
amylase and lipase
Exocrine pancreas pathology - 4 main thigns
Cystic fibrosis
Congenital anomalies
Acute and chronic pancreatitis
Neoplasms
Ectopic pancreas
-where is it found?
-what part of the wall does it develop in?
-what does it contain histologically?
-symptoms?
congenital anomoly

-2% of autopsies
-Stomach and duodenum, jejunum, Meckel diverticulum, ileum
-Usually develops in SUBMUCOSA
-Few millimeters to centimeters
-Glands and Islets of Langerhans
-Asymptomatic or pain, mucosal bleeding
-2% of islet cell neoplasms
Annular pancreas
congenital anomoly

dorsal and ventral buds form a RING AROUND THE DUODENUM, associated with small bowel obstruction
Pancreatitis
Definition - Inflammation of the pancreas
Usually associated with acinar cell injury

Acute pancreatitis vs. Chronic

Range from mild self limited disease to a life threatening acute inflammatory process
Acute pancreatitis
-definition
-epi
-etiologies
-pathology & histopathologic findings
-mechanisms
-clinicopathologic correlation
-treatment
-sequelae
-Characterized by acute onset of boring knife-like midepigastric abdominal pain with radiation into back (Due to retroperitoneal location) resulting from enzymatic necrosis and inflammation of the pancreas, also may see fever, nausea, vomiting and severe,
-Majority of cases associated with biliary tract disease or alcohol(ism)

Epi: 3x More common in females due to biliary tract disease, 6x more common in males due to alocoholism

Etiologic factors
-**Obstruction of pancreatic ductal system: GALLSTONES, Periampullary neoplasms, Other (choledochoceles, divisum, parasites)
-**Alcohol
-Drugs (azothioprine, etrogens, furosemide, etc.)
-Trauma
-Metabolic: hyperlipoproteinemia, hypercalcemia
-Vascular (Ischemia): Shock, emboli, vasculitis
-Infectious: Mumps,
-Genetic , PRSS1 and SPINK1

Pathology: Anatomic changes of acute pancreatitis suggest autodigestion of pancreatic substance by inappropriately activated pancreatic enzymes
1) Microvascular leakage causing edema
2) Necrosis of the fat by lipolytic enzymes
3) Acute inflammation
4) Proteolytic destruction of pancreatic parenchyma
5) Destruction of blood vessels and subsequent interstitial hemorrhage

Mechanisms of pancreatic enzyme initiation (Sometimes unknown)
-Pancreatic duct obstruction: gallstones, ductal concretions
-Acinar cell injury: alcohol, drugs, trauma, ischemia, viruses
-Defective intracellular transport: Alcohol, duct obstruction

Clinicopathologic correlation
-Abdominal pain
-Elevated plasma amylase and lipase
-Diffuse fat necrosis (hypocalcemia)
-Other systemic problems: ARDS (circulating pancreatic phospholipase destroys surfactant), Acute renal failure, DIC (trypsin activates prothrombin), Fluid sequestration
Full blown acute pancreatitis is a medical emergency!!!

Treatment
1) "resting" the pancreas: Total restriction of oral intake (NPO)
2) Supportive: analgesia, IV fluids

Sequelae: 5% death, Pancreatic abscess, Pancreatic pseudocyst, Infected necrotic debris
Drugs that can cause acute pancreatitis
Azothioprine
Estrogens
Furosemide
Many more
3 main mechanisms of pancreatic enzyme initiation
-Pancreatic duct obstruction: gallstones, ductal concretions
-Acinar cell injury: alcohol, drugs, trauma, ischemia, viruses
-Defective intracellular transport: Alcohol, duct obstruction
2 main causes of acute pancreatitis
-Alcohol is MOST common cause
-**Obstruction of pancreatic ductal system, usually by gallstones
Mechanism of acute pancreatitis
Why do pts with acute pancreatitis become hypocalcemic?
Fat necrosis precipitates calcium into pancreas --> takes it out of blood so they become hypocalcemic
Chronic pancreaittis
-definition
-predisposing factors
Repeated bouts of mild to moderate pancreatic inflammation with continued loss of pancreatic parenchyma and replacement by fibrous tissue

Irreversible impairment in pancreatic function!!

Predisposing factors: up to 40% are idiopathic, but most common known cause is LONG TERM ALCOHOL ABUSE!!!!!
-Long standing obstruction: Biliary tract disease/calculi, Pancreas divisum, Neoplasms, pseudocysts
-Tropical pancreatitis - Africa and Asia
-Hereditary pancreatitis- PRSS1 and SPINK1
-Cystic fibrosis transmembrane conductance regulator gene mutation

Proposed pathogenetic mechanisms
-Ductal obstruction by precipitated protein/cellular debris plugs (concretions)
-TOXIC EFFECT: Metabolic, direct toxic effect
-OXIDATIVE EFFECT: generation of free radicals in acinar cells

Pathology:
-Tons of FIBROSIS!
-Reduced number and size of acini (exocrine pancreas)
-Obstruction and dilatation of pancreatic ducts: Protein plugs
-Late stage loss of Islets of Langerhans (endocrine pancreas)
-Pseudocyst formation
-Calcified concretion

Clinico-pathologic correlation
-Recurrent attacks of abdominal pain
-Radiation of pain to back
-Triggers= putting demands on pancreas= ETOH, overeating, opiates
-Recurrent attacks of jaundice or vague indigestion
-Exocrine pancreatic insufficiency: Steatorrhea
-Diabetes mellitus
-Pancreatic calcifications on CT or ultrasound
Which pancreatic cells are the most resistance?
islets are most resistant -- acinar cells will go first. once islets go, there will be glucose impairment
How does acute pancreatitis progress to acute?
What might be seen on CT that would suggest chronic pancreatitis?
dystrophic calcification
Pancreatic pseudocyst
-Localized collections of pancreatic secretions in pancreatic interstitium as a result of damaged ducts, Lacks a true epithelial lining!
(essentially granulation tissue with no epithelial lining)

Etiology: Acute or Chronic Pancreatitis or Trauma

Symptoms: Abdominal mass, abdominal pain

Complications: May become infected/hemorrhage

(persistence of serum amylase > 10 days)
Pancreatic Cystic Neoplasms
Serous Cystadenoma

Mucinous Cystic Neoplasms: Benign (mucinous cystadeonoma), Borderline, Malignant (mucinous cystadenocarcinoma)

Intraductal Papillary Mucinous Neoplasms: Benign, Borderline, Malignant

Solid-Pseudopapillary Tumor
Serous cystadenoma
Benign cyst composed of glycogen rich cells
Women > men
Nonspecific symptoms
Mucinous cystic tumor of the pancreas
-men or women most commonly?
-what part of the pancreas?
-which is benign and which is malignant
-how is the distinction made?
Most commonly in women

Tail of the pancreas and not connected to the main pancreatic duct! HAS NOTHING TO DO WITH PANCREATIC DUCT

Mucinous Cystadenoma - benign
1) Mucinous epithelial lining
2) Ovarian like stroma
3) Invasion = cystadenocarcinoma

Mucinous Cystadenocarcinoma - malignant (invasive adenocarcinom arising in a mucinous cystic neoplasm)

Only way to distinguish benign from malignant is by pathologic examination after complete surgical removal of the lesion
1) Do mucinous cystic tumors of the pancreas arise from the pancreatic duct?
2) Intraductal papillary mucinous neoplasms?
3) Cancers arising from the head usually
4) Cancers arising from the tail usually
1) NO! Tail of the pancreas and not connected to the main pancreatic duct!
2) Yes - arise in main pancreatic duct system
3) head
-intraductal papillary mucinous neoplasms
-pancreatic carcinoma
4) tail
-Mucinous cystic tumor
Mucinous cystadenoma
-lining?
-stroma?
-name for invasion?
Mucinous epithelial lining
Ovarian like stroma
Invasion = cystadenocarcinoma
Intraductal Papillary Mucinous Neoplasms (IPMNs)
-more common in men or women?
-arise where?
-stroma?
-name for invasion?
Men>Female
Head>tail
Arise in the main pancreatic duct system
Intraductal papillary mucinous neoplasm
Intraductal papillary mucinous adenocarcinoma (invasive adenocarcinoma arising in an IPMN)

1) Involve pancreatic ductal system (IPMN)
2) NO OVARIAN LIKE STROMA
3) Mucinous epithelial cells
4) Invasion = malignant adenocarcinoma
Pancreatic Carcinoma AKA Infiltrating ductal adenocarcinoma of the pancreas
-What # cause of death in US?
-pathogenetic factors?
-mutations?
-location?
-gross?
4th most frequent cause of cancer death in US

Pathogenetic factors
-Pancreatic intraepithelial neoplasia (PanIN) (Precursor lesions)
-Smoking
-Familial clustering has been reported
-May be cause or effect:
Chronic pancreatitis
Diabetes mellitus

Cytogenetics: begins with KRAS**, CDKN2A (p16), SMAD4. P53
Other genes, Methylation abnormalites and Gene Expression

Location: Head of Pancreas (60%), Body (15%), Tail (5%), Diffuse (20%)
Gross: Gritty gray-white solid firm masses
Histology:
--Adenocarcinoma, Majority of ductal origin
--see Dense stromal fibrosis "desmoplastic response"

Local invasion
-Adjacent nerves
-Spleen, adrenals, transverse colon, stomach, -vertebral column
-Regional lymph nodes involved: Peripancreatic, gastric, mesenteric, omental, portahepatic
-Distant metastases: Liver, lungs, bones

Clinico-pathologic correlation
-Remain clinically silent until tumor impinges on other structures
-Obstructive jaundice
-Pain is usually first symptom, then weight loss, anorexia, malaise, weakness signs of advanced disease
-Elevated CA19-9 in some cases

IF IN HEAD OF PANCREAS (MAJORITY): "Obstructive jaundice"
-Tumor obstructs ampullary region/common bile duct --> Obstruction prevents conjugated bile from entering duodenum, bile pressure increases in the biliary tract, and conjugated bile enters the vascular space --> Distention of biliary tree

IF IN BODY AND TAIL OF PANCREAS: Do not impinge on biliary tract, "Silent" for a long time. Large, locally invasive, disseminated at time of diagnosis

"Trousseau Sign" (10% of pts)
-Migratory thrombophlebitis
-Spontaneously appearing and disappearing venous thromboses
Attributed to elaboration of platelet-aggregating factors and procoagulants from tumor

Prognosis:
Symptomatic course of disease brief/progressive
Less than 20% of tumors are resectable at time of diagnosis
< 5% 5 year survival

Treatment: If resectable, can do Whipple procedure
Desmoplastic response
dense stromal fibrosis seen in pancreatic carcinoma
Which pancreatic cancer "loves nerves"
Perineural invasion
What marker may be elevated in pancreatic cancer?
CA19-9
Trousseau Sign
-Migratory thrombophlebitis seen in 10% of pts with pancreatic carcinoma
-Spontaneously appearing and disappearing venous thromboses
Attributed to elaboration of platelet-aggregating factors and procoagulants from tumor
Whipple Procedure
Surgical opreation performed to performed to treat cancerous tumours on the head of the pancreas,

consists of removal of the distal half of the stomach (antrectomy), the gall bladder and its cystic duct (cholecystectomy), the common bile duct (choledochectomy), the head of the pancreas, duodenum, proximal jejunum, and regional lymph nodes. Reconstruction consists of attaching the pancreas to the jejunum (pancreaticojejunostomy) and attaching the hepatic duct to the jejunum (hepaticojejunostomy) to allow digestive juices and bile respectively to flow into the gastrointestinal tract and attaching the stomach to the jejunum (gastrojejunostomy) to allow food to pass through.