5070: Liver Disease

which type of capillaries have larger lumens than other types of capillaries?

what do these also have between endothelial cells? x 2 things

what is able to pass through these? x 2 things

sinusoids

fenestrations and large intracellular clefts

large molecules and some cells

what are the 2 functions of the fenestrations in the sinusoids?

1. unimpeded blood flow bathing hepatocyctes

2. allow products to leave the liver

how does bile flow out of the liver?

where does it go after that?

bile canaliculi

bile ducts

what is essential to normal liver function?

free flow of blood in and out of liver

what is one cell type in the lumen of the sinusoids called?

what type of cell are they?

what do they do? x 3 things

Kupffer cells

macrophages

phagocytosis of bacteria, activating, sending cytokines

what type of cell is activated by Kupffer cells?

where are these located?

what is their function?

hepatic stellate cells

outside the sinusoids

store vitamin A

when hepatic stellate cells are activated, what do they have a key role in? x 2 things

liver scarring and fibrosis

what is the space of disse?

space between sinusoidal endothelium and hepatocytes

what is bilirubin a waste product of ?

in what form is it toxic to the brain?

heme metabolism from breakdown of RBCs

unconjugated form

what are the steps of bilirubin formation? x6 things

1. heme → biliverdin → bilirubin (uncjd/indirect)

2. bilirubin binds to album

3. this goes to liver

4. in liver, attaches with glucuronides (cjd/direct/soluble)

5. cjd bilirubin → bile through gut

6. bacteria dcjd → urobilinogen → stercobilin

after glucuronides are attached to bilirubin, what is it called? x 3 things

conjugated, hydrophilic (from OH groups) and direct

conjugation _______ water solubility of bilirubin.

increases

how does unconjugated bilirubin travel bound to albumin?

conjugated?

tightly-bound

most loosely-bound, can separate

which bilirubin is toxic?

is this direct/indirect ?

unconjugated

indirect

what does jaundice result from?

what are the 3 causes of jaundice?

too much bilirubin

prehepatic, hepatic, posthepatic

what is the cause of prehepatic jaundice? x3 things

hemolysis (G6PD), some anemias, reabsorption of large hematomas

what are causes of hepatic jaundice?

1. liver disease

2. hepatocyte dysfunction

3. physiologic newborn jaundice

4. dysf of metabolism enzymes

what are some posthepatic cuases of jaundice?

what is a common reason this occurs?

obstruction of bile ducts (cholestasis)

gallstones block bile duct, bilirubin reabsorbed into blood

how does G6PD def cause prehepatic jaundice? x 4 steps

1. oxidative stress → acute hemolytic anemia

2. destruction of RBCs

3. heme release

4. bilirubin production

why do newborns have hepatic jaundice?

1. bilirubin is 2-3 x higher than adults

2. bilirubin clearance decreased (low UGT1A1)

3. insufficient gut bacteria to convert to stercobilin

4. beta-glucuronidase that dcjd bilirubin →reabsorbed through intestinal wall, recyled into circulation

what is the serum level result of newborn physiologic jaundice?

incr unconjugated (indirect) bilirubin

why is bilirubin production higher in neonates? x 3 reasons

more RBCs

fetal RBCs have shorter lifespan

increased turnover of RBCs

w excess unconjugated bilirubin, what happens? x 3 things

why are neonates at incr risk w this?

1. exceeds albumin binding capacity

2. leaks into CNS

3. damage/death - kernicterus

BBB less developed

what population is more at risk for kernicterus than other races?

black neonates

what is viral hepatitis?

inflammation of the liver parenchyma

what are some s/sx of acute viral hepatitis?

gray/light BMs

dark urine

joint pain, jaundice

pruritis

what type of virus is HAV?

how is it spread?

what is the incubation period?

SS, non-enveloped RNA

fecal-oral route, contaminated food/water

15-50 days

for HAV, does it become chronic?

is there a vax available?

what causes the most damage to hepatocytes during this disease?

no

yes

body’s inflammation/immune response

what type of virus is HBV?

what is the viral polymerase enzyme?

how long can this live outside the body?

double stranded DNA virus

reverse transcriptase

7 days

how is HBV spread? x 3 ways

IV use

infected mother

sexual contact

who are at highest risk for developing a chronic HBV infection?

is a vax available?

what is most damage to hepatocytes from?

infants + young children

yes

cytotoxic T cells

Neonates born to a non-HBV-infected mother will get the first dose of HBV vaccine within how many hrs?

24 or at d/c, whichever is sooner

Neonates born to an HBV-infected mother will get what 2 vaccines?

how quickly?

HBV vax and HBV immune globulin

w/in 12 hrs of birth

what type of virus is HCV?

how is it primarily spread?

ss, enveloped RNA

IV drug use, blood exposures

the risk for infection from needlestick is greatest in what disease?

hep B if unvaccinated (compared to HIV, HCV)

how many people with acute HCV infection develop to chronic infection?

is a vax available?

75-85%

no

are HCV infections usually sx?

no, acute is asx

chronic is asx until advanced liver disease

what is the course of HCV to cancer?

1. HCV infection

2. fibrosis activated from immune response

3. compensated cirrhosis

4. decomp cirrhosis/liver cancer

for pts with acute or chronic liver disease, what should pts avoid? x 4

what vax should they get ? x 2

1. alcohol

2. acetaminophen

3. hepatotoxic drugs

4. aspirin/nsaids

vax’ed for HAV, HBV

what is steatosis?

fat accumulated in the liver

what does MASLD stand for?

what happens during this disease?

metabolic dysfunction-associated steatotic liver disease

fat droplets (TGs) accumulate in the liver cells, cause swelling and damage to the liver

what does MASH stand for?

What happens during this?

metabolic dysfunction-associated steatohepatitis

steatosis and inflammation (incr cytokine signaling, liver chronically inflamed)

an enlarged, fatty liver is often incidentally found when ?

ultrasound or other imaging

is MASLD sx?

it is the #1 cause of what in children?

asx normally

chronic liver disease

MASLD is an _____ related disease

what population of people are more vulnerable to this and why?

obesity

latinos, PNPLA3 gene- fatty liver

what is the progression of MASLD?

1. MASLD

2. MASH

3. FIBROSIS/CIRRHOSIS

4. hepatocyte carcinoma

during which two stages is steatotic liver reversible?

MASLD and MASH

WHAT IS CIRRHOSIS?

what does the liver look like?

what is the resulting function of the liver? x 3 things

irreversible end stage of hepatic injuries

fibrotic, scarred, nodular

permanent alteration in hepatic blood and bile flow and liver function

what is compensated cirrhosis?

what sx do they have?

liver is scarred/fibrotic but can still perform many important functions

FEW OR NO SX, possible ASX esophageal varices

what is decompensated cirrhosis?

what are some sx of this? x 6 things

liver is extensively fibrotic/scarred, can’t perform functions

jaundice, portal htn, ascites, edema, varices w bleeding, encephalopathy

how does cirrhosis occur? x

1. liver macrophages (kupffer cells) generate cytokines/mediators

2. activation of stellate cells by kupffer cytokines, increases ECM/collagen deposition → fibrosis

3. subendothelial collagen disrupts blood flow, impairs movement of solutes

4. hepatic microvilli are lost/flattened

5. fenestrations narrowed/closed

6. disruption of hepatic blood flow

what are 5 clinical manifestations of hepatocellular failure due to cirrhosis? x 9

1. jaundice

2. muscle wasting

3. ascites

4. impaired ADEK absorption

5. altered lipoprotein processing (dyslipidemia)

6. impaired processing of estrogen

7. impaired clearance of drugs/toxins

8. abnormal storage/release of glucose

9. inadequate protein synthesis (clotting factors and albumin)

what is oncotic pressure?

what is hydrostatic pressure?

fluid pulled into vessels due to albumin protein

fluid pushed into tissues

what is portal hypertension?

it causes congested venous drainage of the ____ TRACT

obstructed hepatic blood flow from inflammation/fibrosis of sinusoids, pressure in portal vein

GI

what is hepatic encephalopathy?

why does it happen?

neuropsychiatric syndrome from much ammonia

blood doesn’t pass through liver for removal of toxic substances → enter circulation

what is the normal pressure of the portal vein?

why is this

what are 5 results of portal HTN?

low pressure

lacks valves we see in other veins

1. esophageal, GI varices

2. caput medusae

3. splenomegaly

4. hepatic encephalopathy

5. ascites

what are easily ruptured?

esophageal varices

why do ascites occur?

what are three contributing reasons for this?

shift in starling forces, filtration/move out of the capillaries > moving in

1. incr sinusoid/capillary hydrostatic bc of incr lymph

2. decr capillary oncotic pressure bc decr albumin in capillary

3. incr oncotic pressure in extravascular/tissue bc of protiens there

what do hemodynamic changes that result from portal HTN signal to the body?

what does this activate? x3 things

does this help or hurt the ascites?

hypovolemia

compensatory mechs like RAAS, vasopressin/ADH and aldosterone release

worsens it (incr sodium/water retention)

liver plays a role in converting ammonia to what?

can ammonia cross the BBB?

urea

yes and its toxic

what is ammonia a byproduct of ?

what does each molecule of urea remove?

what are 2 side effects of hepatic encephalopathy?

catabolism of proteins/AAs

2 ammonias

cognitive changes, asterixis (liver flap)

what causes metal storage diseases ?

genetic disorders which excessive minerals are absorbed and deposited in the liver

GSH binds to acetaldehyde, but is unable to counter oxidative stress, what is released in response to this?

what is the reason for kupffer activation?

activated kupffer cells, release cytokines that recruit inflammation cells and activate stellate cells

gut-derived endotoxin release

what is hereditary hemochromatosis (HH) genetic pattern, what is the mutant Gene?

what is disproportionately absorbed ?

where is this deposited?

what can this progress to?

autosomal recessive, HFE

sequestering iron

liver, pancreas, heart

hepatocellular carcinoma

what are 4 clinical manifestations of HH?

what is the first organ to show involvement?

hepatomegaly, heart failure, hyperpigmentation, DM

liver

what is a treatment mainstay for HH? x 3 things

routine phlebotomy, avoid iron supplements, minimize iron-rich foods

what are intracellular liver enzymes?

what do these indicate?

when do they resolve

AST and ALT

current liver injury, or chronic injury

2 weeks after acute injury ends

what is ALP stand for?

what does this point to?

how do they do this?

alkaline phosphatase

elevated levels show cholestasis

bile salts are detergent on hepatocyte membranes and release ALP into the bloodstream

what is direct serum bilirubin measuring?

total?

what does elevated urinary bilirubin signal?

how are these measured?

conjugated

both types

liver dysfunction

URINEEEEEE DIPSTICK

are there any cures for HBV?

newer DAAs for HCV are considered what?

no

“cures”

what does SVR stand for?

what does this mean?

is it possible to become reinfected ?

sustained virologic response (SVR)

undetectable HCV RNA 12 wks after completing treatment

yes