18.1

Question 1

when is hepatocyte destruction reversible vs irreversible

Answer 1

reversible - accumulate fat, cholestasis

irreversible - apoptosis & necrosis

Question 2

describe the mechanism of necrosis

Answer 2

part of oxidative stress & predominant mode of death in ischemic/hypoxic injury

Blebs (cytosolic content) into extracell compartments

Irregular osmotic flow → cell swell & rupture. & Mo cluster at the site of necrosis

Confluent necrosis (Coagulative necrosis: (widespread parenchymal loss) = loss of zonal hepatocytes (acute/ischemic injury or severe viral/AI hepatitis. Fill the space of lost cells w/ debris, Mo and reticulin meshwork. ⇒ bridge necrosis- this space links central V to portal tracts or bridge next to portal tracts

Question 3

describe apoptosis

Answer 3

programmed cell death (DNA damage, accumulation of misfolded proteins, certain infxns) = round/oval mass of intensely eosinophilic cytoplasm w/ fragments of dense nuclear chromatin (pyknosis)

Apoptotic bodies are cleared by phagocytes W/O INFLAM→ shrinkage, condensation (pyknosis) & fragmentation (karyorrhexis)

Acidophil bodies seen freq in acute/chronic hepatitis

Question 4

describe regeneration

Answer 4

hepatocytes are stem-cell like and continue to regenerate even with chronic injury. For this reason stem cells are not seen often in parenchymal repair

after chronic state the cells reach senescence and stop regenerating; –> increase stem cells in the form of ductal reaction. “Ductular” stem cells can give rise to cholangiocytes. Regeneration occurs by 2 major mechanisms= prolif of remaining hepatocytes or repopulation of progenitor cells.

Question 5

what are the 2 mechanisms of of regeneration by ductal stem cells

Answer 5

Proliferation is triggered by 1. Priming phase = cytokines made by kupffer cells act on hepatocytes to make parenchymal cells compete to get GF signals; 2. Growth Factor phase = GF (HGF & TGF-a) stimulate cell metabolism - takes several hrs to get from G0→ G1→ S phase of cell cycle; 3. Replication; 4. Termination and return to quiescence.

Regeneration from progenitor cells reside in special niches called canal of Hering, where bile canaliculi connect w/ larger bile duct

Question 6

what are hepatic stellate cells and what is the fxn

how are they stimulated

Answer 6

Scar formation/regression: primarily by hepatic stellate cells. With injury they can be activated and converted to myofibroblasts.

normally store Vit A

stimuli for stellate cell activation include: direct toxin stimulation/ROS, chronic inflam→ inflam cytokines (THF, lymphotoxins, IL-1B and lipid peroxidase), and ECM disruption/altered interaction

Question 7

what happens to stelate cells in chronic liver dz

Answer 7

Zonal loss of parenchyma (Chronic liver dz) can lead to dense fibrous septa by collapse of reticulin and activation of stellate cells→ deposition of myofibroblasts. Cirrhosis can occur if fibrous septa surround surviving and regenerating hepatocytes. In chronic liver dz, surviving hepatocytes replicate in an effort to restore parenchyma → regenerative nodules = *predom feature in most cirrhotic livers*

Question 8

what tests measure hepatic integrity

Answer 8

cytosolic hepatocellular enzymes

AST, ALT, LDH

Question 9

what tests give info about bile excretory fxn

Answer 9

substances normally secreted in bile :

serum bili- total (both); direct (conjugated); (calculate indirect)

urine bili

serum bile acids

plasma membrane enzymes : ALP, GGT

Question 10

what tests will help determine hepatic synthetic fxn

Answer 10

serum albumin

coagulation factors: PT, PTT

hepatocyte metabolism: serum ammonia; aminopyrine breath test (hepatic demethylation)

Question 11

how much liver fxn must be lost for sxs to show

Answer 11

80-90 %

Question 12

what is acute liver failure (ALF)

Answer 12

sudden & massive hepatic destruction. Acute liver failure is encephalopathy and coagulopathy w/i 26 wl of initial liver injury.

Knowing the interval between onset of symptoms and liver failure can help with figuring out etiology.

Question 13

what is the pathogenesis of ALF

Answer 13

diffuse poisoning of cells w/o obvious cell death and parenchymal collapse. This is due to mitochondrial dysfxn. If pt is immunodeficient, pt may have acute liver failure from the underlying cause of immunodeficiency.

Rarely widespread dysfxn like diffuse microvesicular steatosis (pregnancy or idiopathic reaction to toxins-valproate/tetracycline)

Question 14

what is the clinical presentation of ALF

Answer 14

N/V, jaundice/icterus followed by encephalopathy and coagulation defects

increase in AST/ALT

Question 15

what is the etiology of chronic liver Dz (CLD)

what is the prevalence of each

Answer 15

: years/decades of insidious progressive liver injury

Leading causes:

chronic hepatitis B (SE Asia/Africa)

hepatitis C (USA

NFLD (USA)

alc liver dz (USA/Europe).

Question 16

what is cirrhosis

Answer 16

associated w/ CLD

diffuse transformation of the liver into regenerative parenchymal nodules surrounded by fibrous bands and varying vascular shunting

_Child-Pugh classificatio_n of cirrhosis: correlate w/ diff morphology/histology features and help monitor decline in pt’s liver.

Question 17

what are sxs of CLF

Answer 17

begin w/ nonspecific signs

40% asymptomatic until advanced stage; N/V, icterus/jaundice, aspects seen in acute liver dz (hepatic encephalopathy-asterixis, jaundice → pruritus bc cholestasis, coagulopathy)

or HCC, variceal bleeding or bacterial infxn

Men- hyperestrogenemia (palmar erythema and spider angioma) → hypogonadism and gynecomastia

Women- hyperestrogenemia

Question 18

what can give rise to cirrhosis

Answer 18

untreated viral hepatitis, alc liver dz, NFLD, metabolic dz

Question 19

what will NOT fully give rise to cirrhosis

Answer 19

primary biliary cirrhosis,

primary sclerosing cholangitis,

nodular regenerative liver dz,

chronic schistosomiasis

fibropolycystic liver dz

Question 20

what can give rise to ALF

Answer 20

ABCDEF

A- acetaminophen, hep A, AI hep

B = hep B

C= hep C;

D= drugs/toxins

E= Hep E, esoteric causes (wilson dz, budd-chiari)

F= fatty changes of microvesicular type (fatty liver of preg, valproate, tetracycline, reye syndrome)

Question 21

what is the reaction that takes place w/ acetaminophen OD

Answer 21

(accidental or intentional) for almost 50% of US cases

caused by massive hepatic necrosis in zone 3 (direct damage) which is broad regions of parenchymal loss surrounding islands of regenerating hepatocytes

Failure occurs within a week of symp onset

Toxicity only lasts a couple hours-days so no time for scarring or regeneration

Question 22

how is HBV & HEV ALD different from acetaminophen OD

Answer 22

takes _longer t_o develop than OD

caused by direct and immune mediated damage

Hepatic injury can last for weeks to months, scarring and regeneration possible.

Question 23

what is the sequalae of ALD

Answer 23

Jaundice and icterus

cholestasis –> Increase risk of life-threatening bacterial infxn

hepatic encephalopathy (elevated ammonia, CNS - impaired neural fxn and cerebral edema)

characterisitic : asterixis, nonrhythmic, rapid extension/flexion of head/extremities when arms in extension w/ dorsiflexed wrists.

Coagulopathy (life-threatening) –> easy bruising and DIC

Portal HTN - if this developed w/i days-weeks (rare) = ascites and hepatic encephalopathy

Hepatorenal syndrome ( renal failure )

Question 24

what is the sequalae of CLD

Answer 24

Portal HTN- due to prehepatic (thrombosis, narrowing of portal V), intrahepatic (MC= cirrhosis) or post hepatic (severe R-HF, constrictive pericarditis and hepatic V obstruction) conditions

Ascites is fluid in peritoneal cavity w/ albumin and possible mesothelial cells and mononuclear leukocytes (>=500 ml = clinically detectable).

Portosystemic shunts - Principal sites = rectum (hemorrhoids), esophagogastritis jxn (varices), retroperitoneum and falciform L of liver (involve periumbilical and abd wall collaterals)

Long standing congestion → congestive splenomegaly - degree varies and could reach to 1000 gm (nl = 150-200 gm), BUT NOT correlated w/ other features of portal HTN. May induce hematologic abnormalities (thrombocytopenia or pancytopenia)

Question 25

what can cause portal HTN

Answer 25