1. HB Pathology Flashcards by J L

Well show you how the liver exists for clearing synthetic funct. And well show how the biliary system exists to clear some of the bile.

Now the systems of the liver and the biliary system are actually composed of both hepatocytes, arterial branches (bring blood in), they’re composed of venous flow (venous blood from portal system that drains gut into liver). They are composed of outflow venous systems from liver. So blood goes in, mixes around and goes out.

Then biliary system which drains bile (combo of bilirubin derived from Hemoglobin and bile salts from cholesterol metabolism). And they drain outward toward liver into lumen of duodenum.
Note that the arterial branches of hepatic artery to the liver feed not only ____ as they mix
w venous blood in liver, but actually directly feed another sole vascular nutrient source of ____.

hepacytes

biliary system

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Case 1- abnormal liver enzymes, on blood test, you think about diff processes that affect liver that give that presentation. Right off the bat its the vast ____ that have elevated or abnormal associated enzymes that truly have underlying liver disease. This is good news. Bad news: we have to figure out is that the case, if they do have liver disease, what is it?

Below: showing types of non neoplastic diseases well talk about. These may affect liver, txts may be very different. This is why knowing types of disease w in the liver esp for NON- neoplastic disease is v important cuz diff prognosis and therapeutic implications

Ex. Fatty liver disease. Whats the cause? ____ syndrome, altered diet, alcohol use. So consequences? W many chronic liver diseases may have ____, chriossis and impaired liver funct.

Ex. Viral Hep C. Chronic liver disease get fibrosis and chirroshis, treat w ____.
Ex. Autoimmune disease. May show similar liver enzymology and clinic presentation. You DONT treat w antivirals, use ____ suppression.
Point: figure out etiology of liver disease so you can understand prognosis and txt.

minority
metabolic
fibrosis
immune

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Bottom Line: Liver

Functions
____ (e.g. coagulation factors and albumin)
____/detoxify (e.g. bilirubin and drugs) Exogenous (drugs) and endogenous toxins (bilirubin)
Disease States
____ dictate treatment and outcomes
Acute (no risk fibrosis) versus Chronic (risk for fibrosis)

Rather than leave conclusion to end, shell start off w key points. reads bullets
In terms of inflammatory or non neoplastic states of liver make a point that we need to distinguish acute vs chronic!

Acute:
ALL acute liver injuries have no risk of ____ and no risk of subsequent going on to ____!
Cause NO problems long term, of synthetic and clearing; and no incr risk of ____.

Chronic:
have a risk for fibrosis, hence ____ hence can decrease funct. (both synthetic and learning)
All causes of cirrhosis increase risk of ____

synthetic
clearing
etiologies

fibrosis
cirrhosis
cirrhosis
hepatocellular carcinoma

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Lesions and Neoplastic processes

Inflammatory (e.g. abscess from bacteria)
Benign (e.g. hemagioma)
Malignant: the most likely tumor
____ (____ cancer) the most probable in a non-cirrhotic liver
____ the most probable in a cirrhotic liver

In terms of take away for neoplastic process in the liver aka mass lesions to be more inclusive, we can break down to these categories:
inflammatory
benign- no metastatic potential malignant
Most common malignant tumor in NON cirrhotic liver: is METASTATIC, COLON CANCER Most common malignant tumor in cirrhotic liver: hepatocllular carcinoma
Metastatic lesion to a chronic liver essentially doesn’t occur.

metastasis
colon
hepatocellular carcinoma

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Bottom Line Biliary System
• Functions:
• ____ for bile to GI lumen
• Bile helps in ____ absorption and clearing toxins and other agents

Diseases
Mechanical: e.g. ____
Developmental: e.g. Alagelieles
____: e.g. PBC, PSC
Neoplastic: ____

• Mechanical
• Developmental
• Inflammatory
◦ PBC- primary biliary colangitis (used to be called primary biliary chirossis)
◦ PSC (primary sclerosing colangitis)- which is highly associated w ulcerative colitis

• Neoplastic-cholangiocarcinoma
◦ Unlike hepatocellular carcinoma, which Is associated w ALL causes of cirrhosis. The risk factors for cholangiocarcinoma are 3. Most common: ____.
‣ Second most common in US is ulcerative colitis w associated ____.

‣ Worldwide- most common cause are ____ flukes that live in biliary tree that can injure biliary tree. So prevalence of diseases depends where you live

conduit
fat
stones
inflammatory
cholangiocarcinoma

bad luck
PSC
liver

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Liver: Functions
• \_\_\_\_
• Hormone converter 
• OH \_\_\_\_
• T4􏰍\_\_\_\_ 
• Storage
• Synthesizes

detoxification
VIT D
T3

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Liver: Clearing
• Glutamate + NH4+ > ____ + H2O; transaminases; transport to kidney where ammonia excreted
• Liver gets rid of 1000 mmol/day of ____ groups generated from catabolism of amino acids
• Liver makes ____ (95% of all ammonia)

glutamine
amino
urea

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Open abdomen. Liver composed of these things. Right lobe ____ in ____ abdominal quadrant.

larger

right upper

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Bile & Blood Flow

Nice ____ consistency.
Portal tracks is where venous blood flow goes from portal vein and hepatic artery. They exit thought ____ vein

Bile runs COUNTER to vascular flow in liver, exits thru ____to duodenum.

homogenous
hepatic
bile duct

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Liver histology

W closer power can see the liver actually has a CAPSULE. Capsule has nerve fibers. So if stretch liver quickly it ____to!

hurts

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Portal tract= portal triad (____, ____, ____)

* Sinusoids- where blood flows • Hepatocytes

vein
artery
bile duct

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• Hepatic sinusoids or hepatic CORDS.
◦ Structured well to achieve funct of synthesis and clearing
◦ Hepatocyte- which is main engine of the process, it wants to have optimal exposure to
blood flow
◦ As such its aligned in terms of ____ celled cords, so on ____ sides has access to
blood flow. Separated by actual blood by____ cell, so not in direct contact w many cell in the blood, but certainly in terms of the ____ theres great even exchange.

single
both
fenestrated endothelial

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The blood EXITS thru ____ aka central vein, which goes to the ____.

terminal venule

hepatic veins

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Compartmental analysis

Liver is series of repetitive units: portal triad > blood flows, mixes from the ____ and ____ into the sinusoids. Exchanges w the hepatocytes, each green hepatocyte here is called the ____. Whereas the bilirubin is excreted there and then ultimately travels to bile duct and out to duodenum.
Exits via ____.

artery
vein
bile caniculus
terminal venule

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Hepatocyte
􏰏Sub cellular compartments of ____ enzymes differs.
􏰏Elevated serum enzymes results from ____ post cellular injury.

• In terms of understanding elevated enzymes need to know what they are and how got elevated
• Liver associated enzymes are 3 fold
◦ AST- in ____
◦ ALT- ____ ONLY
◦ GGT- along ____
• Point: these have diff sub cellular compartments! So when have injury to hepatocyte can see patterns of elevation of enzymes based on subcellualr localization. Pattern and extent of elevation may give a clue of ____ of liver disease. When measure in blood liver ass. Enzymes, measuring blebs of hepatocytes that go into blood stream

enzymes
cytoplasmic blebbing

mitochondria
cytoplasm
canaliculus

etiology

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When we measure the enzymes, we can say if we have an elevation of:

• ALT- that its most likely from ____.
• GGT- this is liver but more importantly injury processes of ____ system!
• AST- from liver BUT alot in other ____
• LDH elevation- never only ____! Think about other ____, lymphomas or leukemia
Know the organ compartments important to understand how to evaluate elevations!

liver
biliary
organs
liver
organs

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Outline
• Acute versus chronic injury
• Patterns of injury and liver associated enzymes
 • Vascular
• Hepatitic
• Infiltrative 
• Cholestatic
All may give ACUTE or CHRONIC injury: KEY is \_\_\_\_

In terms of injury, wants to stress distinguish acute vs chronic
Given either you can talk about patterns of injury to give clues to etiology.
Doesnt read rest

etiology

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Approach

A. acute versus chronic & outcomes

B. compartments of injury

• In terms of distinguishing acute vs chronic, thats important first thing you do ◦ Acute- complete ____ or die or get liver transplant
◦ Chronic- percolates along and may go to ____ and cirrhosis
• When think in terms injury, think compartment injured
◦ ____, biliary system, ____ system, etc

recovery
fibrosis
hepatocytes
vascular

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Acute Injury May Result in Loss of Hepatocytes

􏰏Huge ____ capacity
􏰏Re-entry from ____ phase

• ACUTE
◦ Liver has yugeee regenerative capacity. Acute injury- the liver hepatocytes injured, die, but
cuz regenerative capability of hepatocytes that can re renter DNA syntheses-> regeneration. ◦ These no risk for more ____ disease assuming cause of acute injury gone.

regenerative
G0 into S
liver

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Chronic Injury May Result in Fibrosis

◦ In contrast, liver injuries like Hep C, B, autoimmune Hepatitis that are ____ liver injury have propensity to cause fibrosis–> cirrhosis (disruption of hepatocellular architecture by fibrosis w associated regenerative nodules)
◦ Gross liver- ____
◦ ____- see what cirrhosis looks like, biopsy gold standard to make dx of cirrhosis cuz
NOT all nodular livers are ____!
◦ why care about cirrhosis? .. next slide

chronic
nodular
histo
cirrhotic

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Consequences

Portal hypertension
Pressure = Flow X ____
Varices: bleeding
Ascites

• Increased risk of ____

Decreased function
Synthetic
____
Edema
Clearing
____
Altered drug metabolism

Portal hypertension
• Portal vein into liver, fibrosis increases ____ in liver! Therefore cuz portal flow maintained the pressure goes up in portal venous system
• Veins draining into portal system increase, like in lower esophagus. As a consequence of inc pressure–> expand aka ____
◦ Decrease the synthetic funct of the liver (coagulation factors) my have propensity to bleed–> death
◦ Cuz of fluid dynamics in the liver, one can have ____ (fluid in abdomen cuz of portal hypertension)
• Incr risk hepatocellular carcinoma
• Dec funct
◦ Synthetic factors: albumin synthesis
◦ Clearing- big issue cuz not cleaning endo.exogenous things–> ____ ◦ All of these can cause death.. and death is bad.. who knew.

resistance
HCC
coagulopathy
encephalopathy

resistance
varices
ascites
encephalopathy

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Stage

• How does cirrhosis occur? Very predictable pattern. Use trichrome stain.
• Normal- blue- mature collagen.
• Injuries:
◦ ____- of the portal Tracks in the collagen matrix
◦ 2 triads can connect and ____
◦ Ultimately get to cirrhosis
• Point- ____ incited by large variety of chimeric liver injuries

expansion
bridge
progressive

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Mechanisms and Results of Injury

When think about liver injury, this is is what she thinks.
• Series of ways injure the liver (A B C D). They can give set of presentations either lab data or
clinical (Y Z B)
• Sometime liver injury A only give Y presentation but alot of times the same injury may give
multiple ____ and vise versa
• It can be quite overlapping but are ways to think about in terms of consequences and set Y Z W
that we can classify in terms of patterns of injury
• Reason for classifying in this fashion is cuz it’ll narrow down possibilities of inciting agent. Even
given agent, also have to distinguish bet acute and chronic injury
• All these patterns can be acute OR chronic liver process

presentations

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• See again blood in and various flows inside
• Caudate lobe- has independent ____
drainage to Inferior vena cava
• Can drain out thru ____ veins

venous

hepatic

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Venous Outflow Obstruction: Acute * now bock blood flow OUT * Can happen from: clot in IVC, right sided heart failure (putting pressure on liver) * What happens? Liver ____. Blood in can't get out * Initial: increase ____ BUT..... * But... w increased mechanical pressure can start to incite ____ RESPONSE (shell show later what looks like) * After acute blockage get congestion in the liver here that show in histo * In gross section: ____ LIVER- sign ____ congestion in liver

``` swelling size fibrogenetic nutmeg passive ```

Venous Outflow Obstruction: Chronic “Cardiac Type Fibrosis” (NOT cirrhosis) as a response to that pressure alone, a ____ response may ensue. • Therefore see trichrome stain w increased collagen along the pressure gradient which will start fundamentally most increased pressure in the area of ____! Cuz if think about a stream w a damn, thats where the greatest pressure head is and eminates out from there. • Reticulin stain (A)- this is silver stain (name not important) just hilights some of size of ____. And what she shows in conjunction w the increases pressure w fibrogenetic response get ____ of hepatocytes. atrophy due to pressure alone. Overall- ____ response and ____.

``` fibrogenetic terminal venule hepatocellular cords thinning fibrogenetic atrophy ```

* Now fundamentally see this alot of times pt w ____ disease. * Interestingly cuz of livers tremendous ability and redundancy it RARELY leads to synthetic and clearing funct. BUT could get portal hypertension cuz reasons said before. * Over time get fibrosis and it'll affect whole liver

cardiac

* Here let's block the hepatic veins * What happens? Same thing. Initially liver ____ and if thats blocked acutely can swell acutely causing pain * But the right and left hepatic lobes are still blocked so they'll undergo same ____ like situation w cardiac disruption * BUT cuz of the CAUDATE LOBE w the INDEPENDENT ____ drainage directly to IVC can escape the increased pressure and therefore doesnt undergo ____ or increased pressure it, actually gets ____ * She loves liver cuz socially conscious system in sense of when it senses the loss of parenchyma of brothers and sisters it gets bigger and makes more hepatocytes to ____ for loss of other lobes

``` swells fibrosis venous fibrosis larger accomodate ```

Venous Outflow Obstruction: Chronic Budd-Chiari * The ____ globe can become very enlarged. When you get the atrophy and fibrosis of other lobes of liver * This state has a name: BUDD- CHIARI * initially= acute but over time w fibrosis its chronic * Caudate lobe enlarged and atrophy and fibrosis of rest of lobes * In contrast to what stressed before, it does NOT meet the histologic definition even tho theres fibrosis in these lobes and in the cardiac? situation, it does have ____ nodules so it does NOT see the definition of cirrhosis * Therefore in some ways accordingly, both the cardiac fibrotic state in these venous outflow and Budd- chair states do NOT have an increased risk of ____ * this is one ex. of fibrotic state without incr risk of carcinoma, and number 2, an amazingly interesting scenario where by shows us that ____ pressure alone in the liver--> fibrogeneic response NOT dependent on ____ mediators

``` caudate regenerative HCC mechanical inflammatory ```

Inflow Obstruction What I we blocked inflow? • Can get ____, looks like it would anywhere else in body • To have infaraction in liver which is just decrease blood flow in, takes work. Why? Just like lung, it has a ____ BLOOD SUPPLY (venous and arterial) • To get infarct need to disrupt ____ blood flows, but it can happen • You have ____ necrosis of hepatocytes, important feature! Cuz if see that means there was ischemic injury process.. seen on next slide

infarct dual both coagulative

What If use block venous inflow? Portal vein thrombosis • This is an autopsy, but it didn't die cuz of portal vein thrombus • Initially nothing may ____! You could be fine in terms of function cuz live off ____ artery • It wont cause infarction, shows dual blood supply

happen | hepatic

• However, over time the clot in the portal vein may ____ w in the portal tracks w in the liver and you can get the clot and then w organization of the clot may obliterate the____ branches w in the liver in its entirety

propagate | portal venous

Portal Tract Venopathy • And if that happens you get PORTAL TRACT ____ (said she doesnt care about the name...lies) • You dont see the vein here, you've obliterated the organize w the____ • think about it, what will happen to pressure in portal system? GO ____ ◦ Cuz increased resistance. Like taking a straw and decrease orfice of straw so harder to breathe through • So you'll have portal hypertension but it does NOT cause fibrosis in rest of the parenchyma, so NOT get ____ • this is ex. of how you have portal hypertension without cirrhosis! • Worldwide what else can have that will lodge in a portal vein? ◦ one of major causes of portal hypertension in world is NOT hep B C, cirrhosis, its ____ (are these parasites that live in portal vein and mate and shed eggs into system, as eggs go up to portal venous system it CLOGS the portal vein) • Portal hypertension is not a risk factor for ____ and doesnt cause ____ (google- A cancer in the slender tubes that carry the digestive fluid bile through the liver) cuz its not living in ____ tree (they have diff organisms)

venopathy clot up cirrhosis schistosomiasis hepatocellular carcinoma cholangiocarcinoma biliary

• What if block artery? Bile Duct Infarction • Because of dual blood supply the ____ will be fine! • However cuz bile duct nourished solely by hepatoarterial component, the ____ can have infarction if block some of hepatic arterial blood flow • Here infrarcted bile duct, it can get so infarcted that ____ oozes out

hepatocytes bile duct bile

``` “Hepatitis” • Definition: • Acute • Chronic • Etiologies: • Viral (e.g Hepatitis A ____, Hep C ____) • Autoimmune • Toxins • Other • Pathology and Mechanisms of Disease • Etiology dependent ``` • Hepatitis- when she says hepatitis patterns of injury, talking about those lier processes aimed at hepatocyteS, aimed at diff pathogenies and etiologies • Ex. Think about it in categories ◦ Viral- hep B and C are ____, hep A- affects hepatocytes and dmg but ALWAYS ACUTE NEVER CHRONIC ◦ Autoimmune ◦ Toxins

acute chronic chronic

``` Hepatitis C: Chronic Injury • ____ Virus • NOT incorporated into host ____ • 85% of people infected go on to chronic ____ • Cirrhosis may follow • ____ are relatively ineffective ``` • May mount antibodies to virus, unfortunately those ab are ineffective at clearing virus cuz of amazing high ____ role (envelope proteins help it escape immune surveillance) • Unfortunately theres NO ____ currently available to help hep C, unlike Hep B where vaccines v effective and hep B is DNA virus • Unlike hep B where minority get chronic liver injury, hep C for majority is ____ liver injury.. once you get it you have it. So may get fibrosis and cirrhosis

RNA genome hepatitis antibodies immunogenic vaccines chronic

• How does it give a hepatic pattern of injury? • Hep C and B actually infect and live in the hepatocytes themselves, they mount immune response and the response is ____ • B and T cells go to portal tracts • T cells go on to parenchyma, ID the infected hepatocyte and try to kill it to rid the body of the infection • It does it thru ____ • So see portal tract lymphocytic infiltrate • Enzymatically- enzymes rich in liver, and hepatocyte itself- ____ and ____ • Bile caniculus may have slight elevation But not too much cuz its not part of the liver cell thats injured w the viral hep C • To get increased GGT you need synthesis of GGT by the hepatocyte that occurs only in certain situation that occurs in some biliary types of injury

cell mediated apoptosis ALT AST

Terminology for Chronic Hepatitis 1. Limiting Plate 2. Interface hepatitis 3. Activity 4. Stage • Talk about nomenclature of chronic hep. • Applies to the Hep B, C, and autoimmune hep • Things we talk about are the activity, or how many lymphocytes there are limiting the hepatocyte, thats one feature and the other is ____ (something?) fibrosis • Why do we care? Care about fibrosis cuz of reasons said, but the activity is somewhat loosely associated w the probability and time course going onto fibrosis and cirrhosis

stage

``` Acetaminophen: Acute Injury • Metabolic product is ____ • ____ injury only • Zone three damage due to ____ metabolism • Dosage effect Acute injury etiologies NEVER result in ____ ``` * Actually cuz decreasing there 2 choices: either getting better or theres not enough liver left to make the enzymes * Many reasons for the presentation, but this is ex. Of acetaminophen toxicity- good ex of ____ liver injury, meaning that it causes dmgs hepatocytes, but if can get over it the liver can regenerate w no chronic issues * The way that this causes injury Is NOT by ____ directly, by ____ in ZONE 3 which is P450 rich * NEVER get ____!

toxic acute P450 fibrosis acute drug metabolism fibrosis

* the way that this happens is acetam. Is handled in matabolic pathways, but if it goes down the right sided panel and its can't be detoxified by ____ pathway, then ____ is TOXIC METABOLITE that injures hepatocytes * If too much overwhelme detoxifying pathways--> acute liver injury

glutathione | NAPQ1

Fulminant Hepatic Necrosis • Acute liver injury regardless of etiology can look like this • Surface of liver ____ DOWN WRINKLY • If cut looks ____, not cuz cirrhotic, BUT cuz alterations of complete compass and necrosis vs those that may have not been affect as much or even islands of hepatocytes trying to regenerate • So nodules NOT cuz cirrhosis but cuz of ____ of affect and or regernation

sunken cirrhotic heterogeneity

``` Steatosis & Steatohepatitis • “Fat” in hepatocytes • Macro vs. Micro • Zone three vs. zone one • Mechanisms • Associated conditions/etiologies • Implications ``` • Fatty liver.. • Hep C, risk --> liver disease going down now we can look at blood supply and w antivirals • However, w increase prevalence of ____ syndrome.. fatty liver disease on the rise and now becoming the #1 cause of liver disease in the US.. "lets all say a prayer for McDonalds" lol • Means you have fat in hepatocytes, how get there? Metabolic syndrome, alcohol are most common • Why do we care? Cuz fat in hepatocytes--> injury of cells, chronic injury of hepatocytes--> fibrogenetic response, ____ • Can present in hepatitis pattern w elevation of ____ and AST, sometimes increase ____ (cuz so much fat in there that can cause irritation to bile canaliculus

metabolic cirrhosis ALT GGT

Metabolic Syndrome (NAFLD) * Insulin resistance * 􏰍____ in peripheral tissues •􏰍increase circulating ____ •􏰍delivery to liver of ____ * 􏰍uptake and assembly into ____ * 􏰍increased lipid ____ and free radicals * How does metabolic syndrome, a "type 2 diabetes type of thing", cause fatty liver disease? Its not obvious * The mechanism that causes fatty liver disease is thru INSULIN RESISTANCE--> ____ IN PERIPHERAL ADIPOSE TISSUES--> increased Fatty acids in serum--> delivered to liver--> taken and converted to nutrolipids for storage * When you have all FFA in liver and nutrolipids--> inc lipid ____--> liver injury •

``` lipolysis FFAs FFAs lipid droplets oxidation ``` oxidation

• See in liver biopsy w fatty liver disease, doesnt equate w specific etiology be it alcohol or metabolic syndrome, you'll see the spaces in hepatocytes where lipid was • may undergo signs of injury called ____ DEGENERATION ◦ When see it gives term of ____ • STEATOSIS vs steto hepatitis (mean see balloning injury indicating further liver injury) • Sometimes see pink stuff fin hepatic nuclei which is ____, which is sign of metabolic syndrome • As a consequence of ballooning degeneration and ubiquitdation of intermediate filaments then hepatocyte may form the pink globules in ____ • Now none of these features are specific for the liver injury or etiology but DO tell theres ____

``` ballooning steatohepatitis glycogen mallorys hyaline steatohepatitis ```

“Fatty Liver Diseases” Non-alcoholic Alcohol * May lead to fibrosis and ____! * Therefore, increases risk ____. * Becoming the number ONE cause of cirrhosis in the USA. * ____ of fibrosis is most important predictor of outcomes. • Can talk about in terms of non alcoholic vs alcoholic • But regardless, both of these may--> fibrosis and cirrhosis and risks w them • Most important factor in terms of prediction of outcome: STAGE (degree of fibrosis within the live

cirrhosis HCC stage

Stage • Again just like w viral hepatitis, can go on w various progressive degrees of fibrosis which we term "the stage of liver" * End stage- ____ * Middle pic w blue is increased fibrosis BUT NOT YET CIRRHOSIS

cirrhosis

Metabolic Etiologies • ____ • ____ deficiency • ____ Disease

heochromatosis alpha-1 antitrypsin wilson

Hemochromatosis * Genetic disease that results in the abnormal regulation of ____ absorption from the small bowel, despite adequate iron stores the small bowel continually ____ iron * Mutations in gene hose protein product is ____ gene which --> some ____ mechanisms for shutting down iron absorption from lumen of small bowel

iron absorbs HFE sensing

• increased fe absorption from gut--> iron deposition w in parenchymal organs including liver • Here what look like, it can lead to cirrhosis • What see is ____ pigment w in hepatocyte • Have to do a special stain to highlight in blue the ____ w in hepatocyte itself • This doesnt say its hemochromatosis, what it tells is increased ____, hemosidern w in the hepatocyte • Why care? Cuz--> cirrhosis, increased ACC. If you have hemochromatosis, if you know and get phlebotomy and cure self and not get cirrhosis. • since genetic, you'd like to let them know so family can get tested • Why increased iron in hepatocyte cause problems? ◦ Iron--> increased ____ FORMATION when in free form and free radicals are bad--> cell dmg

brown hemosiderin iron free radical

HERIDITARY HEMOCHROMOTOSIS: HFE • HFE gene located on short arm chromosome ____ • Linked to ____ • Most mutations are C282Y: G A; cysteine tyrosine @ amino acid 282 . SnaBI restriction site. • Founder mutation 60-70 generations old; Celtic • H63D mutation • Details she said art important, just interesting in terms of founder mutation in ethnic group • Can test for mutation but most important takeaway: the genetic testing does NOT DEFINE THE ____ • If test and found homozygous for mutations, the probability of having iron deposition w in the liver to cause problems is less than ____% • So its a nice test but its not definitional of phenotype of disease process, so theres a ____ equation when one has to appreciate

``` 6 HLA class I ``` phenotype 50 penetrance

Compartments of Hemosiderin Deposition * You can have fe deposition in liver in ____ (means w inc absorption from gut thru various causes) or in ____ cells (red cell breakdown) * Luckily increased Fe or hemosiderin in kupffer cells does NOT lead to ____ injury ◦ So it wont cause any liver injury and not get fibrosis/irrosis * But in hepatocyte it CAN

hepatocytes kupffer liver

Alpha-1 Antitrypsin • Antiprotease important in lung • Predominant production in ____ • ____ mutations may lead to problems in secretion from hepatocyte • Neonatal jaundice • May lead to cirrhosis with a biliary pattern • Alpha 2 antitripsin- genetic disease • Mutation in the alpha 1 anti trysin, point mutation--> ____ so can't be exported out of hepatocyte • Why care? Cuz in baby its one of main differentials in terms of ____ ◦ Also certain group of people w it get fibrosis and cirrhosis • What can you do? NOTHIN • If you ____, and you'll get EMPHYSEMA early and bad

``` liver point misfolding neonatal jaundice smoke ```

AAT * see protein in pink globules in smooth ones in hepatocyte * NOT to be confused w ____ which looks different * Do immunohistochemistry in section to she AAT * But most important part of work up in terms of defining whether finding globules is AAT deficiency is NOT to do genetic test, look at ____ for Pi ____ or isoelectric focusing, lookin at ____

mallorys hilum serum phenotyping protein mobility

Normal Copper Metabolism Hepatocyte • Wilsons disease • Rare, but may present in adolescent or young adults • Defect in the ability of the liver to get rid of ____ • Liver is ____ place copper eliminated by body via exporting out thru ____ thru biliary system • Heres copper metabolism: copper is taken up by transporters--> Golgi where incorporated in terms of copper proteins in terms of cell function. In liver its located in bile canaliculus, to get rid of excess bile in canaliculus, into the biliary system--> excreted into lumen of gut and out through feces • Def safety valve to get rid of excess copper from body • If you dont have that, get too much copper in hepatocyte that can cause ____ dmg • Also get copper deposition in other ____, other imp one is in parts of brain gets increased deposition--> mild ____ disabilities

``` copper only bilie canaliculus hepatocellular organs cognitive ```

Etiologies of Biliary Injury and Cholestasis • Bile is combo of ____ (hemoglobin derived ) and ____ (from metabolism of cholesterol) ◦ So remember bilirubin is derived from breakdown of Hb from red cells and bilirubin itself is ____ soluble NOT water soluble, so non- covalently binds to ____ ◦ When gets to liver it can diffuse across membrane of liver and its bounded to various ligands that trap it and then undergoes glucogonation--> makes it ____ soluble, so secreted out to bile canaliculus into biliary system--> out thru bowel • Any impediment of flow= ____ (lots of causes)

bilirubin bile salts lipid albumin water cholestasis

• At a granular level, that bilirubin triangle is non covalently bound to albumin, diffuses across and binds to x and y ligands to have a sink in the liver ◦ Cuz it can diffuse across any membrane, but liver has a sink across ____ which are developmentally regulated so actually in neonates their development of lands may not be that great, esp in ____ infants, the ligands may not be mature enough. ◦ This is why premature infants may have elevated ____ aka unconjugated bilirubin, cuz of prematurity and cuz lipid soluble can diffuse in many cells like brain which can cause problems in brain development in ____ ◦ But after its in the liver it gets ____ so water soluble, excreted in bile canaliculus thru transporters ◦ Then cholesterol--> metabolized to bile salts and secreted, and that conglomeration is bile secreted out • Cartoon of bile caniculus and hepatocytes

``` x and y ligands premature bilirubin kernicterus glucuronidation ```

• This is unconjugated bilirubin and when the glucorinates are on its conjugated • So bilirubin can come in but no conjugation step, so what happens? Build up in blood ____ due to the lack of conjugation ◦ How happen? Happen in 2 ways!

unconjugated

``` Increased non-conjugated bilirubin • Complete loss: ____ (fatal) • ____ infant • In high school you periodically noticed your skin looked a bit yellowish. • Total Bilirubin elevated • All ____ bilirubin ``` ____ (no harm) • So the FIRST one is The case showed which doesnt harm liver or person, cuz developmental on and off thing called GILBERT • But there congenital one where complete lack of conjugation enzymes --> CRIGLER NIGER ◦ Can imagine if bilirubin unconjugated in your blood diffuses in brain and get kernicterus and you DIE. • Whereas in premature infant state? (Think she's referring to crippler niger? ) • in out case that showed= GILBERT where conjugation efficacy can be toggled based upon fasting or stress and that has no ____ to body or person whatsoever and in the blood its all ____ bilirubin. If at certain level cause yellow discoloration to sclera

crigler niger premature unconjugated gilbert harm unconjugated

• What if block bile duct OUT of liver • Think about like vascular things • the conjugated bilirubin regurgitate thru bile canaliculus that couple? In the hepatocyte into the blood • This is ____ bilirubin • Interestingly, when have unconjugated bilirubin in blood over time, for unknown reasons by NON enzymatic means --> ____ bound to albumin • Now this doesnt ____ anybody, nor does conjugated hyperbilirubemia hurt anyone (water soluble so excreted through kidneys, not diffuse thru membranes) • Reason for understanding can have this: ____ bilirubin ◦ Can explain when have inc bilirubin even after the abatement of cholestatic causes of disease cuz half like of conjugated form is ____

``` conjugated covalently hurt delta long ```

Which Blockage(s) will Result in Cholestasis? • Liver , r and l hepatic ducts--> common hepatic duct, gallbladder w cystic duct--> common bile duct--> pancreas--> duodenum • If block in each areas, which would cause INCREASED bile w in the liver and therefore blood? ◦ If do #1- no increased bilirubin in blood cuz rest of liver can serve as sink for it ◦ #2 alone wouldn't do it ◦ #1 and 2- it ____ do it cuz no other way out ◦ #3 would do it ◦ #4 cystic duct gallbladder- no big deal, it can still gets out ◦ "If block #5 then yeah".. idk what she means by that • Point- blocking 1 or 2 alone wont give complete ____ of biliary system • When does occur (blockage), can see histo evidence of cholestatis by ____ PLUGS and ____ and bile salts can accumulate in hepatocyte itself- see ____ DEGENERATION • Show this cuz lot of cholestatic liver injuries, based on blockage of flow, can cause rapid fibrosis w in the liver

``` would blockage bile cholesteral feathery ```

• Look as histo consequences of that • Bile- pigmented cuz bilirubin is pigmented • ____- washed out so pale leaving this feathery degeneration--> liver injury • Enzymology- ALT and AST (true hepatitis injury markers) a little elevated ◦ More important: ____- elevated more ◦ Maybe bilirubin elevated

cholesterol salts | ALK/GGT

Choledochal Cyst • If put stone or pancreases cancer (____ of pan)--> blockage of bile duct--> jaundice and cholestatic liver injury • Congenital injuries to bleary system • Pic shows that w anything you can have congenital issues, here is gallbladder and coming off bile duct near is is CYST in continuity w biliary system aka ____ CYST (congenital issue of biliary system) ◦ Contents of cyst is just like biliary system- ____ and ____ stoma around it. Why do we care? ‣ 1. If you have this big thing that can cause ____ by twisting around ‣ 2. Also cuz in conjunction w biliary system and bile is a v saturated solution, if you have stasis of super saturated solution--> precipitate causing ____ --> dislodge--> obstruction ◦ Cuz bile maybe carcinogenic process, choldochal cyst increased risk of ____ development of epithelial layer--> carcinoma and cuz from epithelial cells of biliary tract its called ____

``` head choledochal epithelium muscle obstruction stones neoplastic cholangiocarcinoma ```

Full Cross Section of Gallbladder • who cares about the gallbladder? "Oh you care? Ok thats good im glad you care" • From functional standpoint get rid of it and be happy, really a ____ organ. Take out and NO PROBLEMS. Some species that dont even have it ex. Rat • Stores bile and secretes under food stimulation, but dont need it.. • problems cause ◦ ____ of bile--> gallstones ◦ ____ there ◦ Find in xray if wall calcified (in this xray) aka ____. Pic cut open to see lumen ‣ Care about it cuz see on imaging and MAY be increased risk of cancers of gallbladder

stasis cancers porcelain gallbladder

“Klatskin Tumor”: ____ occurring at bifurcation hepatic ducts • Getting back to main biliary system here, things that block bile ducts are stones from bile stasis but any tumor can do too • If tumors of ____ system= CHOLANGIOCARCINOMAS (showed one in choledocal cyst, but epithelial cells ANYWHERE in tract can get neoplastic deformation, dysplasia and cancer) • If have cholangiocarcinoma here can block bifurcation so bile can't get out--> ____ ◦ when blocked specifically at. R and l ____ ducts= KLATSKIN TUMOR ◦ see cross section to see how cause huge desmoplastic response--> stricturing in that area

cholangiocarcinoma biliary jaundice hepatic

``` Cholangiocarcinoma 1. Non-cirrhotic liver 2. Peripheral vs. central 3. Extrahepatic vs. intrahepatic 4. Ulcerative colitis and cholangiocarcinoma 5. Other associations ``` Risk factors for cholangiocarcinoma? Occur within ____ tree or in ____ • Outside liver: liver ____, ____ luck (most common cause), choledocal cysts and primary sclerosing cholangitis • In liver- ____, may cause it but its more in the hilar or extra hepatic tree that it does, but in US most common cause of INTRAhepatic cholangiocarcinoma ie. Neoplastic transformation from bile duct cells is ____! NO known ____ factors

``` biliary liver flukes bad luck sclerosing cholangitis bad luck risk ```

Gallstones & Cholecystitis Transmural inflammation involving gallbladder bed and liver • Intrahepatic cholangio carcin. if peripheral liver would result in jaundice? ____ cuz no blocking main ducts! You'd have to block whole liver functionally and take care of everything • Galbladder ◦ Bile is ____ there and constrict to secrete bile into lumen ◦ But cuz of stasis and super saturated solution, may have ____ ◦ If that stone--> cystic duct and blocks it--> ____ ◦ But itself having gallstones NO problems unless ____ (biliary colic) cuz of stricture ◦ If just gallstone w no biliary pain DONT need to have gallbladder out UNLESS... the ____ given gallstones has HIGH RISK FACTOR FOR DEVELOPMENT OF CHOLANGIOCARCINMA OF GALBLADDER (dont know why).. this is the one exception ◦ Only take gallbladder out if pain

no ``` stored gallstones cholestasis pain native americans ```

• Gallstones • MOST material is ____ (predom component of bile, bilirubin gives color but minor) • This is rare pure cholesterol gallstone..."its beautiful.. she got this as a gift.. not to be sexist.. a diamond is not a girls best friend...sometimes its a gallstone... she cherishes it" uhhhhhh ok.

cholesterol

``` Bile Ducts • Extrahepatic • Biliary Atresia • Primary Sclerosing Cholangitis • Strictures/Stones • Intrahepatic • Primary Biliary Cirrhosis • Graft vs Host disease • Chronic Rejection • Idiopathic Adulthood ductopenia • Sarcoid/drugs/others ``` • "Don't get freaked out by this"... so everyone calm their ( . )( . ) • Think about biliary tree in several ways: 1. ____ the liver 2. ____ liver • Even w in the liver, not all bile ducts are the same: have larger, medium, small ones ◦ Why important? Cuz differing diseases may affect the differing types of intra extra hepatic bile ducts ◦ Really important to understand that not all bile ducts/systems are created the same, hence differing diseases affect different compartments! • give lists of some of diseases, NOT cuz she wants us to memorize list! Jsut to make point that there are ____!!

inside outside differences

``` Paucity of Intrahepatic Bile Ducts • Adult • Immune: PBC, PSC, Sarcoidosis, Rejection, GVH • Secondary: mechanical, drugs, others • Idiopathic • Pediatric • Syndromatic (Alagille’s) • Non-syndromatic • Metabolic • Secondary (biliary atresia) ``` * Some of diseases can result injury to bile ducts, or duct obliterated, portal tract.. there is no bile duct there * Once get rid of enough bile ducts w in liver at that point you may get ____, but if wipe off ____% of intrahepatic bile ducts.. you'll be fine * So loosing few bile ducts in liver alone is not sufficient, need ____ act of loss to have subsequent jaundice or cholestatic diseases.. this is the point

jaundice 50 certain

Causes of small-duct biliary diseases in 2,082 cases • "Again dont get freaked out" • Wants to point out that if you think about small bile ducts (intrahepatic bile ducts in liver).. what are diseases that can affect that? Tons of diseases can affect ◦ what are most common diseases of intrahepatic bile ducts: 1. ____ (primary biliary cholangitis) 2. ____ (associated w ulcerative colitis) .. says one is more common in men v woman but can't see where pointing ◦ She's go thru pathogenesis of each

PBC | PSC

``` Primary Biliary Cirrhosis: PBC • ____ • + ____ (anti-mitochondrail antibody) • Inflammatory destruction of ____ ducts • Pathogenesis, “____” • ____ bile duct disease • Pruritus • ____ pattern ``` * PBC now called primary biliary CHOLANGITIS (originally called cirrhosis but not everyone starts w cirrhosis, but many end up getting) * Inflammatory antibody and ____ meditated disease that attacked the intrahepatic biliary epithelium.. it sees it as foreign --> mount ab response and cellular response * Foreign cuz protein on apical aspect of the epithelium that mimics an ____ protein, MIMICRY not the protein itself * Can mount ab response, in serum can have anti Mt ab cuz of antigenic ____ * Where is mimicry coming from? They dont know, maybe retrovirus * Cuz of mimicry, body see biliary epithelium now INSIDE liver as FORIGEN --> attack * Also see some ____

``` female AMA intrahepatic autoimmune small LFT ``` cellular inter Mt mimicry granulomas

Pathogenesis of PBC 1. Normal biliaryepithelialcell 2. Abnormal expressionand/or antigenic mimickery of E2 component of pyruvate dehydrogenase 3. Cellular immunologic attack 4. Biliary epithelial cell death • View of bile duct epithelium Mt. • Protein- ____ in Mt envelope, its not the actual protein but its some antigenic mimicry that looks like protein thats now exposed on ____ aspect of biliary epithelium, viewed as forigen in ab and cellular medicated response have targeted the biliary epithelial cells --> destruction

pyruvate dehydrogenase | apical

Florid Duct Lesion of Primary Biliary Cirrhosis • What see is that bile ducts infiltrated by lymph, dmged and will then eventually become extinct w inflammatory response as well theres is ____ response in portal tracts --> posity? Of ____ and fibrosis in liver and cirrhosis • • Early on w dmg does not cause complete obstruction of biliary tree, so early on does not have ____ of bile flwocompletley so no elevation of bilirubin, but cuz injuring biliary system, should have elevation of ____ high and maybe ____. (GGT still higher cuz shows biliary injury)

fibrogenetic bile ducts obstruction bilirubin GGT AST

Primary Biliary Cirrhosis: Associated Diseases • Cuz it has some of ____ overtone • PBC people may have extraintestional manifestations ex. ____ disease, thyroiditis, hypothyroidism, sicca syndrome (cuz salivary glands) • Despite autoimmune issue DONT TREAT W ____ OR ANY IMMUNOSUPPRESSION (wont change anything) • ____ you can do about this, until once cirrhosis (then bilirubin elevated) then can do liver transplant

autoimmune thyroid steroids nothing

Primary Sclerosing Cholangitis: PSC * ____ Duct disease * Association with ____ & Crohn * ERCP diagnosis: “____ on a string” • In contrast PSC associated more w ____ • Happen by itself but highly associated w UC • Unlike PBC its NOT associated w any circulating ____ • NOT treat w ____ • Stricturing formation in liver of biliary tree • Unlike PBC affects ____ biliary system • Any time get structure--> bile ____ ◦ Cuz may affect extra hepatic biliary system and common bile duct, if stricture there--> bile spaces--> precipitation and sludge--> can get jaundice BEFORE ____ • Unlike PBC get JUANDICE BEFORE CIRRHOSIS and here they'll fix w ____ the biliary system • Txt- ____.. just try to keep biliary system clear of stricturing and of biliary sludge • May --> fibroiss and cirrhosis... liver transplant may be only cure

large ulcerative colitis beads ``` men autoab steroids extrahepatic stasis cirrhosis dilate nothing ```

PSC: Biliary Sludge • ____ and precipitate of bile • ____ cuz imflammatory •

stricturing | purulent

“Onion Skin” Fibrosis in Primary Sclerosing Cholangitis • ____ NOT know, but it may cause fibrosis around the bile duct • This fibrosis has been akin to "____ FIBROSIS"

pathogenesis | onion skinning

Primary Sclerosing Cholangitis • If does--> ____ where need liver transplant, here is cut section of liver • Reads labels • Normally bile duct size of hepatic a. But now dict thick cuz fibrosis • As w PBC can lead to posity of hepatic biliary system

cirrhosis

Tumors in Liver • Masses anywhere can be benign or malignant (primary or metastatic) • Most common malignant tumor in NON cirrhotic liver? ____ tumor at ____

metastatic | colon

``` Tumors in Liver • Cell type > Nomenclature • Hepatocyte • Benign: Adenoma • Malignant: Hepatocellular carcinoma ``` * Biliary epithelium * Benign: ____ * Malignant: Cholangiocarcinoma * Endothelial cells * Benign:e.g.____ * Malignant: Angiosarcoma • Take any cell type and make it benign or malignant counterpart • reads all • Lymph issue- lymphanginoma • Important: try to understand relative prevalence underlying risk factors, and when known what the pathogenies is

cysts | hemangioma

Metastatic Tumors: most common tumor in non cirrhotic liver GI: 45% Lung: 25% Urogenital: 10% Other 10% * Most common site is ____ tract! * age ____ get first colonoscopy! * Many things can metastasize to liver

GI | 50

Primary Liver Tumors • Primary tumors- benign or malignant ◦ Malignant most common ____ tumor ‣ Epithelial derived aka ____ • (Repeated this 2x)

primary | carcinomas

Age Adjusted Cancer Incidence (Events per 100,000) In USA • Look at liver malignancies in adult US population • Epidemiologicdata • See various cancer prevalence based upon sex and ethnicity • Anyone see liver or biliary tree? NOPE. They dont rank. • In THIS country liver tumors arnt as common as other HOWEVER ____ hepatocellular carcinoma is really common malignancy • Reason: worldwide HEP B is v prevalent, integrated to DNA of hepatocyte --> genomic issues,\ coupled w can cause chronic liver disease--> fibrosis, cirrhosis--> incr risk of hepatocellular car.

worldwide

Diagnosis: Hepatic Adenoma • This may bleed into itself, its histo is ____ • Care about this cuz can bleed--> intra-abdominal rupture and ____ (google- blood in peritoneal cavity)--> death • Alot of times dont know what is based on imaging • RISK of hepatic ademona transforming to hepatocellular carcinoma: ____. ◦ Some ppl say increased risk but NOT THE CASE.

normal hemoperiotenum none

• Show why saying its not increased risk. Make big distinction bet hepatic adenomas that are COMPLETLEY BENIGN vs class in black box thats alraeady hepatocellular carcinoma (HCC) • Black box- in men are clonal and have ____ mutations, called hepatic adenomas and incr risk of HCC cuz essentially already are. Not v common ◦ She doesnt think should be called adenomas • The 3 types of adenomas on top- ____ and mutational background have NO RISK FOR ____ POTENTIAL ◦ May go thru steatotic pathway, inactivation of HNF 1 alpha, telangiectatic form (mutations and inflamm mediators) and ◦ POINT= ALL BENIGN. Taken out to diagnose what are and be the risk of bleeding

beta catenin clonal neoplastic

Focal Nodular Hyperplasia * Higher power * Almost looks cirrhotic but its NOT * This is ____! Actually thought due to vascular inflow abnormality * If know what it is theres nothing wrong, leave it there!

benign

* Upon histo composed of liver w little fibrosis | * See hemangionoma- BENIGN NOT RISK FOR ____

angiosarcoma

``` Infections Forming Mass Lesions • Abscess • ____ • Fungal • ____ ``` * Parasites * ____

bacterial amoebic eichonicocus

EICHONICOCAL CYST * Tumor * Infection sue to ____ --> cyst * So caused by infection

eichonicoccus

Malignant, Epithelial, Primary, Liver Tumors ____ tumors are the most common malignant tumor in the ____ liver * Look at malignant epithelial tumors- most common primary malignant tumor * Most are ____ in a cirrhotic liver * Next is ____ * Little sliver- ____- pediatric, NO adults

metastatic non-cirrhotic HCC cholangiocarcinomas hepatoblastoma

``` Hepatocellular Carcinoma • Most occur in ____ damaged liver • Cirrhosis • Prognostic factors include • ____ invasion • ____ • Separate lesion shown by arrow ``` • Usually occur in some damaged liver usually cirrhosis, form this mass here • Can have vascular invasion, form a lesion or multiple lesion s • Chronically damaged liver is where occur, but NOT THE DAMAGE DUE TO ____ OBSTRUCTION *wants to really make this distinction ** • Ppl w cardiac fibrosis or ____ do NOT have increase risk of hepatocellular carcinoma .....Pple w ____ and C may

chronically vascular differentiation outflow budd chiari hep B

Macro-trabecular Architecture • It tries to do what normal liver does- form the chords but not v well • See hepatoceullar trabecular- thickened • Endothelial cells trying to make sinusoidal space, the endothelial cells are NOT malignant they're just trying to help make ____ .. make macro- trabeculae • Form of ____

endothelial space | HCC

The problem of the nodule in a cirrhotic liver * Benign or malignant? * How to tell? * What to do? • What do you do for hepatocellular carcinoma? Try ____ it out but cuz mostly arises in cirrhotic liver its hard to excise and also given cirrhotic liver, try to find hepatocullar carcinoma (imaging studies done) • Can imagine how hard to find a small nodule on a nodular liver • Finding early on is a ____ • See nodule here. Can someone tell if HCC? CANT ____ • Point is- even w looking wont know cuz need histo! So this makes screening difficult

taking struggle tell

See cirrhotic nodules and benign hepatocytes • But HCC just permeating through liver • So sometimes makes ____ and other times ____ tumor

mass | insidious

• Have hepatocytes and see bile • All throughout sinusoids see ugly cells which turns out that these cells are ____ • Point out as rare case, show angiosarcoma can be primary liver tumor • Risk factors- bad luck, toxins •

angiosarcoma