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64 Cards in this Set

  • Front
  • Back
Anatomy
Acinus/lobule
defined by peripheral portal triads and a terminal hepatic venule/central vein.
Anatomy
Portal triad
contains a branch of the hepatic artery, the portal vein, bile duct and a lymphatic channel supported by connective tissue
Anatomy
limiting plate
the boundry between the connective tissue matrix of triad and the liver parenchyma
Anatomy
hepatic cords
Liver laminae as seen in sections.
Anatomy
Space of Disse
The small space between the endothelium and the hepatocytes
Anatomy
stellate (Ito) cells
small numbers of specialized connective tissue cells in the Space of Disse
Anatomy
Kupffer cells
the phagocytes of the liver
Anatomy

Lymphatic
canal of Hering (location; cell types)
most proximal cells around the limiting plate

bridge between hepatocytes and bile duct
Anatomy

dual blood supply - hepatic and portal circulations
Portal venous and Hepatic arterial

Inflow:
Portal Vein: Low pressure, 40% O2
Hepatic Artery: Systemic pressure, 60% O2
Anatomy

acinus vs. classical lobule
Classic Lobule:
Centered on portal vein, forms a hexagon along portal septa (lining between lobules)

Acinus:
Centered on portal triad and extends to terminal hepatic venule (central vein)
Anatomy

zones 1, 2, and 3
Zone 1
Periportal hepatocytes at the periphery of the acinus/lobule

Zone 2 Mid-zonal hepatocyes between zones 1 and 3

Zone 3 Centrilobular hepatocytes closest to the central vein
Patterns of Injury and Repair
interface vs. bridging
Interface is used to describe changes at or near the interface between the limiting plate of the portal triad and the periportal hepatocytes (e.g., interface hepatitis or necrosis)

Bridging is used to describe the interconnection of portal areas or central veins by a pathologic process such as inflammation, fibrosis, or necrosis (e.g., central-central, portal-portal, or central-portal bridging fibrosis).
Patterns of Injury and Repair
ductular reaction (where is it coming from?)
When parenchymal loss is extensive, the Canal of Hering (terminal bile ductule) is the major source of hepatic progenitor cells (oval cells)

Extensive parenchymal loss is often associated with an increase in ductular structures (termed “ductular reaction”; the DR includes not only the epithelial component, but also a fibro-inflammatory component)
Patterns of Injury and Repair
ballooning degeneration and lytic necrosis
- Ballooning (hydropic) degeneration refers to clearing of the hepatocyte cytoplasm due to intracellular edema. The cell appears swollen and enlarged and the cytoplasm is clumped. These changes are common features of many types of severe hepatic injury, including acute viral hepatitis.

- Lytic necrosis refers to the rupture or dissolution of single cells or groups of cells, usually in the context of osmotic swelling and ballooning degeneration.
This is sometimes referred to as drop-out.
Patterns of Injury and Repair
acidophil body
Apoptosis accompanies many types of hepatocellular injury, particularly with immune-mediated or toxic insults. The apoptotic bodies were described as acidophil or Councilman bodies.

Although this terminology is still widely used, acidophil bodies resemble other types of apoptotic cells.
Patterns of Injury and Repair
cholestasis (intrahepatic vs. extrahepatic)
categorized as obstructive or non-obstructive.

Pathologically, both forms are characterized by abnormal accumulation of bile within distended bile canaliculi. In the setting of severe _________ the cytoplasm of the hepatocytes often acquires a foamy, reticular appearance described as feathery (or foamy) degeneration.

With prolonged obstructive _________, bile stasis and back pressure can lead to the detergent-mediated dissolution of hepatocytes and the extravasation of bile with the formation of extracellular bile lakes or bile infarcts

extrahepatic:
obstruction characterized by portal edema and bile lakes, a portal ductular proliferation, and periductular infiltrates of neutrophils. It can also be complicated by secondary ascending infections.
Patterns of Injury and Repair
cholate stasis (chronic cholestatic liver disease)
Inhomogenous involvement of liver parenchyma
- Destruction, loss of intralobular ducts
+/- Inflammation

Characteristic pattern of “biliary” and/or incomplete septal fibrosis

- Biliary interface, feathery degeneration
- Ductular reaction
- Mallory-Denk bodies in periportal/periseptal hepatocytes
- Copper in periportal/periseptal hepatocytes
- Foam/pseudoxanthoma cell collections
- Cholestatic rosettes
Patterns of Injury and Repair

portal vs. lobular vs. interface hepatitis
"portal hepatitis" indicates infiltration of the portal space by inflammatory cells.

"Lobular hepatitis" is the term used to indicate the presence of necroinflammatory lesions in the acinus and hepatic cords.

"Interface hepatitis" describes the presence of mixed chronic inflammation that involves and “crosses” the limiting plate.

Interface hepatitis used to be referred to as "piecemeal necrosis" to acknowledge the fact that ongoing hepatocellular death and dropout are also present.
Patterns of Injury and Repair

Steatosis (2 types)
Intracytoplasmic accumulations

- fatty change

- Accumulation of lipids in the cytoplasm of hepatocytes is seen in a wide variety of diseases, usually reflecting abnormalities in lipid transport, degradation, oxidation, and/or apo-lipoprotein production.

Can be:
Microvesicular __________ (many small fat vacuoles - indicative of mitochondrial dysfunction, and the related disease processes are usually quite severe

Macrovesicular ________ (one large fat vacuole - less injurious than micro) - seen in alcoholic liver disease, non-alcoholic steatohepatitis (NASH), hepatitis C, and Wilson disease
Patterns of Injury and Repair

Types of Necrosis
Cell loss - regardless of cause - is ultimately accompanied by local collapse of the associated reticulin network.

1. Ischemic coagulative necrosisis is associated with loss of cytoplasmic detail and nuclear staining.

2. Lytic necrosis refers to the rupture or dissolution of single cells or groups of cells, usually in the context of osmotic swelling and ballooning degeneration. This is sometimes referred to as drop-out.

3. Apoptosis accompanies many types of hepatocellular injury, particularly with immune-mediated or toxic insults. The characteristic nuclear fragmentation may not be evident on a given section, and cellular debris can be rapidly cleared by Kupffer cells. Usually, there is no significant inflammatory response; however, lymphocytes involved in immune-mediated apoptosis can occasionally cluster around apoptotic bodies, resulting in “spotty necrosis”.

Spotty necrosis refers to the necrosis of single or small groups of hepatocytes. For our purposes, that is all you need to know.

An aside. Because lytic necrosis is usually spotty, the two terms are sometimes used interchangeably.

Confluent necrosis refers to loss of a large number of hepatocytes, typically in Zone 3. There is associated reticulin network collapse. This type of necrosis may occur with some viral infections (but usually NOT hepatitis C) and with autoimmune hepatitis.

Submassive (bridging necrosis) and massive necrosis (self-explanatory) are the terms used when large confluent areas of the liver undergo necrosis (multiacinar or panacinar necrosis). These patterns are seen with certain drug or toxic reactions and in some forms of acute viral hepatitis. Grossly, massive necrosis is often suggested by decreased organ weight and wrinkling of the capsule.
Patterns of Injury and Repair

Cirrhosis
Stereotyped response to injury that is characterized by many severe infectious, inflammatory, immune-mediated or metabolic disorders that lead to complete and irreversible, gross remodeling of liver parenchymal structure with regenerative nodules surrounded by scar which contains aberrant vascular channels and ductules

- Alcoholism is the most common cause

- increases the risk of hepatocellular carcinoma.

- requires both fibrosis AND nodules

- septa often accompanied by a ductular reaction as a manifestation of the regenerative process

- accompanied by mechanical effects on blood flow and vascular remodeling (can lead to portal hypertension with resulting ascites, and congestive splenomegaly)
Patterns of Injury and Repair

patterns of vascular compromise:
artery
portal vein
outflow veins
Cirrhosis: there is increased flow resistance at the level of the sinusoids, and compression of terminal hepatic veins by fibrosis and regenerative nodules.

In addition, anastomoses can form between the high pressure hepatic and low pressure portal systems.

Together, these changes contribute to portal hypertension with resulting ascites, and congestive splenomegaly.

Portal-systemic shunting also allows substances delivered via the portal circulation to bypass metabolism by hepatocytes, thereby contributing to clinical signs and symptoms of hepatic failure.
Patterns of Injury and Repair

heart failure: right-sided; left-sided; both
The malfunctioning heart can affect the liver either by low arterial flow (left-sided or shock) or right-sided failure with back pressure (congestion)

1. Passive congestion occurs in cases of right-sided cardiac decompensation or right heart failure. Central sinusoidal congestion and hepatocyte atrophy (Zone 3) are usually seen.
2. Left sided decompensation or hemodynamic shock can precipitate centrilobular (Zone 3) ischemic necrosis.
Patterns of Injury and Repair

ischemic necrosis
Is similar to coagulative necrosis in other tissues.

It is associated with loss of cytoplasmic detail and nuclear staining.
Patterns of Injury and Repair

Zahn's infarct (just because it seems to show up on Boards)
- A sharp to mottled area of red or red-blue discoloration produced by a recent thrombosis of an intrahepatic branch of the portal vein

- It is not a true infarct because there is no necrosis.

- It results from congestion secondary to diversion of blood flow proximal to the obstructed branch.

- Histologically, the only finding is congestion and atrophy.

It has no clinical significance
Patterns of Injury and Repair

Budd-Chiari syndrome
Thrombotic occlusion of the hepatic veins can be acute or chronic and presents with hepatomegaly, ascites with weight gain, and abdominal pain (syndrome)

- associated with polycythemia vera (hyperviscosity secondary to overproduction of red cells), inherited disorders of coagulation, pregnancy, oral contraceptives, paroxysmal nocturnal hemoglobinuria and hepatocellular carcinoma. However, nearly a third are idiopathic.

- the liver is grossly swollen and red and the capsule is tense, contributing to the clinical symptom of pain

- With the more common subacute presentation, there is centrilobular congestion, centrilobular fibrosis, and fresh or organized thrombi involving central veins. Chronic obstruction can lead to "reverse lobulation" cirrhosis resembling that seen with cardiac dysfunction. The vena cava frequently exhibits intraluminal membranes reflecting reorganized thrombi.
Patterns of Injury and Repair

Patterns of fibrosis
There are three major, sometimes overlapping patterns:

1. Portal and periportal fibrosis are particularly common after the chronic hepatitides.

2. Fibrosis surrounding the central vein is common in alcoholism and circulatory disorders associated with venous obstruction or heart failure.

3. Fibrosis of the space of Disse is seen in alcoholism and in nonalcoholic fatty liver disease, and contributes to remodeling following other types of injury. This pattern is referred to as perisinusoidal, pericellular or chickenwire fibrosis.

4. Fibrosis in the liver is currently thought to be due to transformation of stellate cells into myofibroblasts with subsequent production of matrix materials. Portal myofibroblasts may or may not be derived from these cells.

Bridging fibrosis refers to complete or partial fibrous bridging between portal triads and/or central veins, is usually a consequence of bridging necrosis, and contributes to the development of cirrhosis. Collagen deposition occurring as a consequence of an inflammatory process or zonal necrosis is usually an irreversible phenomenon.
Veno-occlusive disease
aka (Sinusoidal Obstruction Syndrome)

- Patients with allogeneic bone marrow transplants develop ___________ in the first few weeks following transplantation.

The mortality is quite high (approximately 30%).

HIstopathology:
characterized by obliteration of central veins by subendothelial swelling accompanied by centrilobular congestion and necrosis.

Chronic or healed disease is characterized by perivenular fibrosis

- Believed to result from the toxic injury to sinusoidal endothelial cells, which embolize toward the vein and obstuct sinusoidal blood flow, hence the name.

Similar pathologic changes are seen after ingestion of specific alkaloids that injure the veins.
Chronic passive congestion
Central hemorrhagic necrosis

Classical gross appearance:
The combination of marked passive congestion and hypoperfusion can lead to centrilobular hemorrhagic necrosis and a margin viable periportal hepatocytes.

This results in the classical gross appearance of nutmeg liver.
Cardiac or "reverse lobulation" cirrhosis
The term cardiac sclerosis/cirrhosis has been used to describe central fibrosis resulting from severe passive congestion with central venous necrosis.

However, overall lobular architecture is maintained, and cardiac sclerosis/fibrosis would be a better term.

Along with the severe venocentric fibrosis that bridges between central veins, the pattern of "reverse lobulation cirrhosis" occurs (central venous areas are linked together in a manner resembling normal portal triads).
Acute pancreatitis:

Definition:
Clinical condition characterized by abdominal pain

Caused by pancreatic inflammation and necrosis
Acute pancreatitis:


Causes:
Primarily due to:

Biliary tract disease + Alcohol abuse = 80%

Other causes: trauma, ulcer disease, drugs, bacterial or viral infection, hyperlipoproteinemia, hypercalcemic states, familial disease
Acute pancreatitis

General Pathogenesis
Digestive enzymes are released and activated within the pancreatic parenchyma

This results in tissue “autodigestion.”
The mechanism(s) operable in these circumstances are a matter of debate
Acute pancreatitis

Pathogenesis: Initiating insults
Causes:
Alcohol, Viruses, Drugs, Ischemia, Trauma --> Acinar Cell Injury

Cholelithiasis, chronic alcoholism, obstruction lesions --> Duct obstruction

Nutritional Deficiency --> Deranged intracellular transport of pancreatic enzymes
Acute pancreatitis

Pathogenesis: Observed Lesions that lead to Acute Pancreatitis
- Inflammation

- Proteolysis (active proteases)

- Fat Necrosis (active lipase)

- Hemorrhage (active elastase)
Pathologic findings:
Acute pancreatitis

Gross and Microscopic Findings:
Gross Findings --> due to Microscopic findings:
- Grey/white areas --> Enzymatic autodigestion

- Hemorrhage --> Blood vessel damage, red blood cell extravsation

- Chalky white areas --> Fat necrosis, with adipocyte granular debris
Acute pancreatitis

Clinical course:
Acute abdominal pain: very severe

Jaundice develops

Differential diagnosis includes gut emergencies: appendicitis, perforated ulcer, bowel infarcts, gallbladder disease

Systemic problems: shock, ARDS, acute renal failure

Complications include abscesses, duodenal obstruction, hemorrhage, pseudocysts

Mortality rate: in the range of 5%
Chronic Pancreatitis

Definition
A condition characterized by repeated episodes of mild or subacute acute pancreatitis

Results in progressive parenchymal destruction
Chronic Pancreatitis

Clinical settings:
Alcohol abuse and biliary tract disease are the most important causes

Alcohol>>>biliary tract disease

Other rarer causes include hypercalcemia, hyperlipidemia, and familial disease
Chronic Pancreatitis

Pathogenesis:
Process is that of repeated flares of acute pancreatitis

Alcoholic disease:
- Ducts contain proteinaceous plugs
- Also metaplasia of the ductal epithelium
- Diffuse obstruction and destruction

Biliary disease:
- Gallstone and tumors
- More localized inflammation and destruction
Chronic calcifying pancreatitis (alcoholic type)

Gross and Microscopic Findings:
Gross:
- lobular architecture largely intact, with fibrosis and calcification

Microscopic:
- Acinar atropy, with intra- and inter-lobular fibrosis

- Mixed inflammation: lymphocytes, plasma cells, neutrophils

- Dilated ducts with luminal proteinaceous plugs; ductal epithelium may be hyperplastic, atrophic, or have squamous metaplasia

- Damage to the islets is variable
Obstructive chronic pancreatitis

Characteristic features:
- Localized obstruction with localized involvement

- Inflammatory infiltrate similar to calcifying pancreatitis, but involvement not clearly as lobular in nature

- Ductal calculi not common
Chronic pancreatitis

Clinical course:
Repeated bouts of:
Fever, jaundice, and abdominal pain

Elevations of amylase and alkaline phospahatase

Pancreatic pseudocysts eventually occur - walled off collections of necrotic material

Malabsorption, steatorrhea, diabetes
Pancreatic Endocrine Tumors
Classically called “islet cell tumors”

Less common than carcinomas that arise from the ducts or exocrine glands

Mostly occur in adults

More islets in the tail and body; more islet cell tumors there, as well

Syndromes related to specific hormone excess
Can be a component of MEN I
Islet cell tumors

Distinguishing Features
Most are “functional” (hormone-producing), and so present with hormonal syndromes

Diagnosis is then confirmed by CT or MRI scans, may also include needle biopsies

Can be seen by nuclear medicine scans (octreatide), as well

Treatment is surgical resection

ambiguous in regard to malignant potential, we don’t always know

Mitotic rate, necrosis, hemorrhage and local infiltration are worrisome features

Best indicator of malignancy is still metastasis, to lymph nodes or liver

Usually long survival, even with metastatic disease, in most cases

Small cell carcinoma is a very aggressive variant
Insulinoma
Insulin secreting tumor

Present with Whipple’s triad: - CNS symptoms of confusion, fatigue, weakness,
- glucose less than 50 mg%,
- Prompt relief of symptoms with glucose adminstration

• about 3/4 of the tumors are solitary

• Often times small lesions

• Only rarely malignant (10% or less)
Glucagonoma
Clinical manifestations include diabetes, necrotizing migratory skin rash, chelitis, and anemia, but more often clinically silent than insulin-producing tumors

Solitary tumors are often very large
Gastrinoma
• Presentation includes the Zollinger-Ellison syndrome, of a gastrinoma, gastric hyperacidity, and recalcitrant gastric ulcers

• Multiple tumors are often seen in MEN I

• More than half (60%) are malignant

• Identical tumors can occur in the pancreas, duodenum, or nearby sites (gastrinoma triangle)
T/F

Insulinoma has a greater propensity for malignant behavior than glucagonoma
False

Glucagonoma has a greater propensity for malignant behavior than insulinomas
Pancreatic Exocrine Carcinomas

Epidemiology
Common cancer: 5th most common cause of cancer deaths (behind lung, colon, breast, prostate)

28,000 new cases per year

Dismal outcome; less than 5% survival at 5 years

Disease mainly of older individuals; 60-80 years

Associations:
Most well-established link is with cigarette smoking; claims of linkage to alcohol use or coffee drinking are not supported in large studies
Pancreatic Exocrine Carcinomas

Genetic features
Most common mutations are seen in K-RAS and CDKN2A (p16)

At least 1/2 of cases have loss of tumor suppressor genes p53 or DPC4 (deleted)

Miscellaneous: MLH1, BRCA2, her2/neu
Pancreatic Exocrine Carcinomas

Pathologic features
About 3/4 arise in the head of the pancreas

Great majority are adenocarcinomas of ductal origin

Head of pancreas lesions: typical impinge on the ampulla or common bile duct, obstruct bile flow, and cause biliary tract distention; will also invade the duodenum

Body/tail lesions: Do not impinge on major structures in the head/ampulla, so they can be present for longer period of time before detection; will be large and disseminated at the time of discovery, with tumor invasion of adjacent structures
Pancreatic Exocrine Carcinomas

Metastases

Clinical features

Migratory thrombophlebitis (inflammation of veins with thrombosis): known as what sign?
Metastases: will involve peripancreatic, gastric, omental or porta hepatis lymph nodes; many cases will spread to peritoneum and cause “carcinomatosis,” liver, lungs and bone are also favorite sites for metastatic disease

Clinical features: Pain is most common presenting complaint
Obstructive jaundice noted in cases in the head

Migratory thrombophlebitis (inflammation of veins with thrombosis): Trousseau’s sign
Other rare pancreatic tumor types
Acinar cell carcinoma

Intraductal papillary mucinous tumors (“IPMT)

Serous and mucinous cystadenomas
Other rare pancreatic tumor types

Acinar cell carcinoma:
tumor resembles the acinar cells (with enzyme production)

Tend to be in the body or tail, and to present as large bulky tumors, with invasion of adjacent local structures.

Poor outcome also
Other rare tumor types

Intraductal papillary mucinous tumors (“IPMT)
These are tumors that are limited to growth within the ducts, in analogy to intraductal breast carcinoma.

They may diffusely involve the ducts throughout the pancreas, and would require total pancreatectomy for therapy in those cases.

May be eventually associated with development of invasive ductal adenocarcinomas
Other rare tumor types

Serous and mucinous cystadenomas
Multicystic lesions, most with benign outcome.

May present as incidental findings.
Chronic Pancreatitis

Chronic calcifying (alcohol-related)

vs.

Obstructive (stones or neoplasia)
Chronic calcifying (alcohol-related)
- All areas of pancreas may be
involved

- Calcifications along the duct and in affected parenchyma


Obstructive (stones or neoplasia)
- Lesions are proximal, near the ampulla

- Calcification usually absent, unless obstructing lesion calcifies
Chronic Pancreatitis

T/F

Diabetes is a complication of chronic pancreatitis that can be predicted from the severity of the acinar injury.
False

Damage to islets is variable. In some cases, extensive acinar loss and fibrosis is not accompanied by islet injury, while in other patients, islet loss may coincide with acinar injury.

Therefore, diabetes is a complication of chronic pancreatitis, but NOT one that can be predicted from the severity of the acinar injury.
Complications of pancreatitis

Localized destruction may result in the formation of a fluid filled cavity that is lined by chronically-inflamed fibrous tissue called __________ (they do not have an epithelial lining, and do not communicate with the pancreatic ducts)

They may enlarge over time to sizes in excess of 10 cm; compression of adjacent structures (including the stomach) may occur.

Because these _________ are filled with tissue debris, they are fertile soil for bacterial infection.

However, because they usually present as a mass, the differential diagnosis always includes neoplasia
pseudocysts
The typical islet in the body and tail contains three primary endocrine cell populations:
+ alpha cells (peripheral location) produce glucagon

+ beta cells (central location) produce insulin

+ delta cells (few, scattered throughout the islet) produce somatostatin

+ other cell populations are considerably smaller - produce gastrin, VIP, others
The electron microscopic morphology of the secretory vesicle is characteristic for a given hormone peptide:

glucagon granules:

insulin granules:

somatostatin granules:
+ glucagon granules: targetoid with a central electron dense zone and clear halo; the limiting membrane is sharply defined

+ insulin granules: angular paracrystalline deposits in vesicle somewhat larger than that of alpha cells

+ somatostatin granules: homogeneous electron density in a large vesicle; the limiting membrane is not always clearly visible.
T/F

Lymph node or distant (often liver) metastases are still the most reliable indicators that a given pancreatic tumor is in fact malignant.
True
T/F

Except for small cell carcinoma-like tumor, most malignant islet cell tumors have a relatively fast pace of disease; patients may only live for a few months or more with metastatic disease
False

Except for small cell carcinoma-like tumor, most malignant islet cell tumors have a relatively SLOW pace of disease; patients may live for a DECADE or more with metastatic disease