patho accessory organs

normal functions of liver (summary)

1. synthesis: glucose, bile, plasma proteins, blood clotting factors

2. metabolism: steroids, drugs, carbs, fat, protein

3. storage: minerals,vitamins

4. filter blood, remove bacteria

what does the liver synthesize

glucose, bile, plasma proteins, blood clotting factors

describe the liver's role in estrogen/hormone metabolism

enterohepatic recycling: hormones (estrogen) are conjugated in the liver, secreted into bile->SI-> and reabsorbed

(increases half life)

normal function of endocrine and exocrine pancreas

endocrine: supply insulin and glucagon

exocrine: digestive enzymes

t/f: the liver's primary role in metabolism is to make substances more polar for excretion

true

what is evaluated in lab to establish proper liver function

1. enzymes: damaged proteins will be in lymph/blood (ASL,AST)

2. bilirubin (should be low in blood)

3. proteins (iron, transferrin, coags)

4. coagulation tests (liver secretes coag factors)

5. hepatitis virus markers

6. autoimmune antibodies (type 2)

why do we need to check liver enzymes during drug dosing

anything we take orally will come in contact with the liver. if a drug dose is too high, it will damage liver during metabolism

liver injuries usually result in which responses

1. inflammation (hepatitis)

2. degeneration (hydropic or lipid)

3. necrosis (cell death)

4. fibrosis (scarring/cirrhosis)

t/f: the liver is only capable of necrosis

false. hepatocytes are regenerable and can divide (apoptosis)

lipid degeneration of liver

lipids accumulate in liver (ex: during acute ethanol digestion)

cirrhosis

general term for fibrotic scarring of the liver

jaundice pathophys

yellow discoloration of skin and sclerae due to excess of blood bilirubin (iron protein breaks down and gives yellow color)

how does the liver normally function to prevent jaundice

uptakes and conjugates bilirubin compounds and places into bile for elimination

4 possible causes of jaundice

prehepatic:

1. excessive destruction of RBCs

intrahepatic:

2. impaired uptake of bilirubin by liver cells

3. decreased conjugation of bilirubin

intra/post:

4. cholestasis (obstruction of bile flow)

cholestasis

obstruction of bile flow in hepatic lobules or bile ducts

hematologic mechanism of jaundice (hemolytic jaundice)

excessive lysis of RBCs (ex: autoimmune) -> hepatocytes cannot conjugate bilirubin fast enough, it enters blood-> unconjugated hyperbilirubinemia= deposits in tissues= jaundice

a pt is diagnosed with unconjugated hyperbilirubinemia. possible mechanisms?

1. hemolysis (liver cannot conjugate so much bilirubin)

2. intrahepatic obstruction: bilirubin is in liver but is not conjugated (ex: liver damage)

intrahepatic obstructive jaundice mechanism

damage or obstruction within liver-> liver is not uptaking/conjugating bilirubin properly-> bilirubin enters lymph/blood= jaundice

t/f: if the intrahepatic bile ducts are blocked, jaundice may be a result of both conjugated and unconjugated bilirubin

true. functional areas of the liver will be able to conjugate but the blockage/damage will result in unconjugated bilirubin via cell damage

extrahepatic obstructive jaundice mechanism

cholestasis (bile duct obstruction)-> conjugated bilirubin in bile is not excreted into SI-> backflow into lymph/blood/tissue= jaundice, light stools, possible more in urine

t/f: extrahepatic obstructions will always result in conjugated hyperbilirubinemia

true. liver has done its job of conjugation. extrahepatic obstructions will cause a backleak into lymph-> blood

extrahepatic obstructions Sx in urine and feces

bile does not enter intestines= albino stools

increased excretion of bilirubin via urine= orange urine

causes of jaundice

pre-hepatic:

intra:

post:

pre: hemolysis of RBCs

intra: directly affect liver ability to remove bilirubin from blood or conjugate it [cancer, toxins, drugs, cirrhosis, neoplasms]

post: when bile flow is obstructed btwn liver and intestine [gallstones]

how does RBC breakdown lead to jaundice

RBCs contain hemoglobin which is broken down into bilirubin. large breakdown of RBCs lead to large bilirubin levels

liver blood flow abnormality: pre-hepatic

where is blockage?

Sx?

1. Hepatic artery damage (Ox): hypoxia, ischemia

2. Hepatic a. or Portal v. thrombosis/ obstruction

Effect:

- Esophageal varices

- Splenomegaly

- Intestinal congestion/ varicose

Bc blood is getting shunted back/ away from liver in portal v. obstruction

(note no hepatomegaly bc not reaching liver)

liver blood flow abnormality: intra-hepatic

where?

Sx?

1. Cirrhosis (poor blood movement)

2. Intrahepatic blood flow obstructions

3. Systemic circulatory compromise

Sx:

- Ascites (fluid is pushed out of liver bc of buildup)

- Esophageal varices (shunted)

- Hepatomegaly

- Elevated transaminases

Blood is not in all areas of liver; some back flow and some pooling in liver

liver blood flow abnormality: post-hepatic

where?

Sx?

1. Hepatic vein thrombosis

2. Obstructions

Sx:

- Ascites

- Hepatomegaly

- Abdominal pain

- Elevated transaminases

- Jaundice

Blood is not leaving liver-> backflow and leak into tissues

t/f: hepatomegaly is a common pathophysiology of portal vein obstruction

false. the portal vein brings blood from the GI tract to the liver. if it is obstructed then blood is not reaching the liver, therefore it will not enlarge

t/f: hepatomegaly is a common pathophysiology of hepatic vein obstruction

true. the hepatic vein carries deOx blood from the liver back to the heart. if it is obstructed then there is a backup of blood in the liver, causing enlargement

ascites

what is it?

when does it happen in impaired liver blood flow?

accumulation of fluid in the abdominal cavity

= occurs in intrahepatic and posthepatic obstructions (liver accumulates fluid-> ends up in tissue)

explain 2 ways how liver cirrhosis can lead to ascites

1. lymphatics/vessels are blocked from scarring= extra fluid ends up in tissue

2. low albumin production= edema

what does "congestion" mean in terms of blood flow

venous blood is pushed back into organs == dilates veins-> varicose

t/f: esophageal varices are common pathophysiologies of hepatic vein outflow obstructions

false. esophageal varices are pathophysiologies seen in impaired blood INflow and impaired INTRAhepatic blood flow. its usually due to the shunting of blood in the portal system back to organs.

t/f: ascites is a common pathophysiology of impaired blood inflow to the liver as a result of the blood being shunted to tissue

false. ascites is a common Sx of intrahepatic and posthepatic blood flow obstructions (NOT prehepatic). in prehepatic there is no hepatomegaly so the fluid isnt being pushed out into the tissues

pathologic conditions affecting the hepatobiliary system

1. injury from drugs and toxins (first pass, goes to liver first)

2. infection, inflammation, immune

3. metabolic disorders (ex: ethanol)

4. neoplasms (metastasis, not usually primary)

phase 1 vs phase 2 liver metabolism

P1: oxidations via cytochrome P450s

= make drug less active and more polar

P2: conjugation rxns

= caps free radicals

= makes molecule more water-soluble

which phase of metabolism often results in free radical production

P1 (momentarily; P2 usually caps the free radical)

t/f: phase 1 reactions are more abundant than phase 2

true. phase 2 reactions can get behind/ run out of conjugation molecules, leading to more free radicals= necrosis, inflammation

which phase of metabolism makes a drug more water soluble?

P2

which phase of metabolism makes a drug more polar?

P1

why is it important to monitor liver enzymes for certain medications

liver enzyme metabolism depends on genetics, could be diff for every patient

t/f: improper drug metabolism can lead to cirrhosis

true. production of free radicals will lead to damage= chronic inflammation= scarring

what can lead to an imbalance between phase 1/phase 2 rxns, leading to free radicals and liver damage

1. high drug concentrations

2. genetics

3. polypharmacy (more active drugs)

t/f: P1 reactions often give rise to free radicals and are inactivated by P2 reactions

true

host factors that contribute to drug-induced liver disease

1. genetics (missing CYPs)

2. age (very young and old= lower fxn)

3. underlying chronic liver disease (scarring= worse metabolism)

3. diet/alcohol (induce or suppress metabolism)

4. polypharmacy (higher affinity drug is metabolized before low affinity= more active drug)

4 drug-induced liver diseases

1. direct hepatotoxic injury: free-radical byproducts from metabolism

2. idiosyncratic rxns: genetic

3. cholestatic rxns: stasis; stuff isnt moving out of liver

4. chronic hepatitis: scarring, inflammation, poor function

what are idiosyncratic reactions of the liver

genetic; unpredictable response to drug

what does hepatocellular necrosis look like

pale, yellow scarring, coagulative necrosis, inflammation

Kupffer cell

resident macrophage in liver

liver fibrosis

Scar tissue forms, result of chronic inflammation

hemochromatosis

what is it?

stain?

excess iron deposits throughout the liver-> damage and dysfunction

prussian blue stain

nutmeg pattern of hemorrhagic necrosis

damage to liver vessels leads to mixing of extravasated RBCs with pale areas of the liver (necrotic cells)

causes of hepatitis

1. autoimmune

2. rxns to drugs/toxins

3. infectious (malaria, mono, salmonella...) (target bloodstream which goes through liver)

4. viruses

endogenous/aseptic hepatitis etiologies

1. autoimmune

2. liver is indirectly inflamed not bc its infected but bc theres inflammation in other areas of the body (changes in bloodstream)

hepatotropic viruses are?

examples?

viruses that need hepatocytes as host cell

= A,B,B-delta, C,E [virus mutated in different form]

2 mechanisms of cellular injury in viral hepatitis

1. direct cellular injury (virus uses cell as host)

2. induction of immune response against virus (collateral damage)

t/f: hepatotropic viruses always reside in the liver and often cannot survive in other environments

false, large blood flow in liver, viral particles can get into bloodstream

which WBCs are present in hepatitis

lymphocytes

t/f: hepatitis infections often trigger hepatocyte apoptosis, leading to a lower inflammation reaction

true

sequence of events in hepatitis infection (from incubation to recovery)

1. incubation phase (after exposure)

2. prodromal (preicteric phase): no specific symptoms, but feel sick

3. icteric phase: specific symptoms (jaundice, fever, inflammation)

4. recovery phase (complete/recovery or incomplete/healing)

in which phase of a hepatitis infection can you see specific symptoms such as jaundice

icteric phase

chronic active hepatitis

acute exacerbations of hepatitis have subsided, but there is no recovery-there is low level activity of virus

fulminant hepatitis

initially infected cell has ruptured next to non-infected neighbor cell-> release of intracellular enzymes-> digest non-infected neighbor-> more necrosis/inflammation

(indirect type of damage)

in which form of viral hepatitis is there indirect injury to hepatic cells that are not infected by a virus

fulminant hepatitis

HepA

-found where in infected individuals?

found in feces, bile, sera of infected individual

HepA

transmitted by?

fecal-oral route

=contaminated shellfish, unsanitary conditions, food/water contamination

t/f: hepatitis A recovery is usually spontaneous and highly resolvable

true. HepA is benign, self-limited, resolves spontaneously

Summarize the HepA chart

incubation/acute disease/recovery?

Incubation (4 weeks): viral particles appear in liver first (prodromal phase)

Acute (4-8w): viral particles in liver, feces (bile), blood = symptoms (icteric phase)

Recovery(8-12): no viral particles in feces/blood; levels slowly drop in liver

-not carrier, not chronic

which antibodies serve as memory cells for hepatitis A

IgG (but IgM made initially)

how is HepB transmitted

infected blood, sexual contact, body fluids, contaminated needles, maternal transmission (third trimester)

t/f: HBV is more serious than HAV

true

t/f: HAV can be transmitted to the fetus if the mother is infected during the third trimester

false. HBV can

Acute HepB with recovery

incubation period?

acute period?

transmission?

Incubation (2 months): virus is in blood first (that's how its transmitted)

Acute (2-4 months): virus enters liver

=no transmission after 4 months if recovered. possible transmission if carrier

what is different in chronic HepB chart compared to acute hep B with recovery

Acute disease in chronic is less intense, lasts longer, low level of inflammation

Virus remains in blood (unlike acute which is gone after 4 months)= possible transmission, symptomatic

HepB carrier state

Same as chronic but active acute disease is lower=no symptoms but they are infectious (virus is still in blood)

can patients with chronic hepatitis B transmit the virus if they do not have acute exacerbations

yes. virus is still in blood. same for carriers with no symptoms

in HepB infections, what is the most frequent outcome? least?

most= subclinical or acute-> recovery

least= carrier (5-10) or chronic (4%)

most people with CHRONIC HepB viruses develop which outcomes

cirrhosis, carcinoma, or recovery

Hep__ is responsible for most cases of post-transfusion hepatitis

HepC

t/f: most HepC cases result in chronic hepatitis

true (50-80%)

t/f: most HepB cases result in chronic hepatitis

false. only 4%

how is HepC transmitted

contaminated blood sources (IV drug use)

similarities in HepB and HepC incubation

both take about 2 months to incubate and virus begins in blood (unlike A, 4 weeks and starts in liver)

which Hep viral infection is marked by intense acute exacerbations during chronic inflammation

HepC

most HepC outcomes are? least?

most= chronic (85%)

=resolution (15%)

=fulminant (rare)

t/f: most pts with chronic HepC exhibit cirrhosis

false. 20% exhibit cirrhosis and 80% are stable (but majority of HepC pts do have chronic inflammation)

which form of hepatitis has the most risk for hepatocellular carcinoma

HepC

t/f: cirrhosis results in a smaller liver

true. collagen fibers contract the liver, but it is heavy and dense

t/f: most chronic hepatitis cases are autoimmune

FALSE. 20% of chronic hep cases are autoimmune

t/f: in most autoimmune hepatitis, another autoimmune disease is present

true. ex:UC, SLE, RA

primary biliary cirrhosis

-autoimmune: auto antibodies target bile ductal epithelial cells (not hepatocytes)

-inflammatory destruction of intrahepatic bile ducts

primary sclerosing cholangitis

Inflammation and fibrosis of intrahepatic and extrahepatic bile ducts that presents with obstructive jaundice

in which biliary disease is there hardening due to scarring

primary sclerosing cholangitis

symptoms of intrahepatic biliary disease

inflammation of bile ducts= disruption of bile flow-> backflow of bilirubin into lymph and blood

-pruritis/itching

-weight loss

-fatigue

-dark urine, pale stools

-jaundice

which type of hyperbilirubinemia do you expect to see in intrahepatic biliary diseases

conjugated, liver has conjugated the bilirubin but there is problem in bile duct flow

treatment of intrahepatic biliary disease

liver transplantation. you cannot separate out affected bile ducts

t/f: liver transplantations are considered a cure for intrahepatic biliary disease because you are removing the obstructed bile ducts

false. biliary disease is often auto immune, so the transplanted liver will be targeted by host's immune system

how is alcohol metabolized in the ADH system? where?

-via alcohol dehydrogenase

- in hepatocyte cytoplasm

EtOH-> acetaldehyde-> acetic acid