Liver Flashcards
Where is the liver located?
Right upper qaudrant of the abdomen
How many lobes are in the liver
2
What are the lobes of the liver made up of?
Lobules
Describe the lobules
centered on a branch of the hepatic vein
inerconnected by small ducts
What is the portal triad?
at corners of adjacent lobules; branches of bile duct, portal vein, and hepatic artery
What are hepatocytes separated by?
sinusoids
What does the hepatic duct do?
transports bile produced by liver cells to the gallblader and duodenum
What % of liver tissue needs to be destroyed before the body is unable to eliminate drugs and toxins?
~70%
Can liver cells regenerate?
Yes
what % of CO does the liver take?
~25%
What kind of blood supply does the liver have?
a dual lood supply; venous flow in from portal vein, arterial flow in from hepatic artery
What does the venous flow from the portal vein do?
blood comes from small intestine directly to liver, pancreatic venous drainage
What does the arterial flow from the hepatic artery do?
oxygenates the liver
What does the venous flow out through the hepatic vein do?
mixes blood from portal vein and hepatic artery in sinusoids and exits liver
Major functions of the liver?
Excretion
Metbolism
Storage
Synthesis
What does the gallbladder do?
stores and concentrates bile
What does bile do?
emulsification of dietary fat, cholesterol, and vitamins
elimination of waste: excess cholesterol, xenobiotics, bilirubin
What % of bile acids are reabsorbed due to enterohepatic recirculation?
95%
How is bilirubin metabolized?
Glucuronidated in liver and excreted in bile
What is indirect bilirubin?
bilirubin bound to albumin
What is direct bilirubin?
bilirubin glucuronidated in liver
What parameters are needed for the reversal of liver damage?
That there isnt destuction of the liver’s capacity to regenerate
What is the pattern of hepatocellular injury?
necrosis –> degeneration -> inflammation –> regeneration or
necrosis –> degeneration -> inflammation –>fibrosis –> cirrhosis
What can cause hepatic injury?
viruses
Drugs
Environmental toxins
Alcohol
What are the 2 main types of hepatic injury?
cholestasis
Hepatocellular
Define cholestasis
a failure of normal amounts of bile to reach the duodenum leading to accumulation of bile in liver cells and biliary passages.
What causes cholestasis?
Gall stones (cholelithiasis) - most common
tumor
viral hepatitis
alcohol-related liver disease
drugs
primary biliary cholangitis
primary sclerosing cholangitis
What is priamry biliary cholangitis?
slow, immune-mediated destruction of small bile ducts within the liver
What is the leading cause of liver transplant for women in Canada?
Primary biliary cholangitis
What is primary sclerosing cholangitis?
progressive inflammation and fibrosis affecting any part of the biliary tree
Leads to progressive destruction of bile ducts
Commonly associated with IBD
Cholestatic syndrome symptoms?
Pruritis
Jaundice
Dark Urine
Light coloured stools
Steatorrhea
Xanthoma and xanthelasma
Hepatomegaly
What is ursodiol used for?
Management of cholelithiasis
How does ursodiol work?
unknown MOA but, gradualy dissolves stones in 30-40% of pts
What drug can be used alternatively to ursodiol in PBC?
Obeticholic acid
Does ursodiol prevent progression of PSC?
Limited efficacy
Treatment of pruritis?
Cholestyramine (benefits seen in 90% of pts must be used as long as pruritis is present)
Antihistamines: hydroxyzine; no proven benefit but, their sedative propeties may help
Naltrexone, rifampin or sertraline: may be tried if refractory
Describe hepatocellular damage.
Direct damage to hepatocytes, can be acute or chronic
Causes of hepatocellular damage?
Toxic agents: alcohol, drugs, toxins
Infections (hepatitis)
Longstanding cholestasis
Ischemic injury (thrombosis)
other diseases (autoimmune, iron overload)
what happens when hepatocytes are destroyed?
Contents of cell are released into the circulation, can compromise function of liver.
Liver enzyme increases that indicate cholestatic injury?
ALP and GGT
Liver enzyme increases that indicate hepatocellular injury?
AST and ALT
LDH to LDH5 but very nonspecific
What happens to albumin level after a sustained assault on the liver?
Reduced
What tests the synthetic capability of the liver?
Albumin Levels
Bilirubin retention signs?
Yellow tinge to skin, dark urine, pale stools
What happens to prothrombin time if the liver is damaged?
Increases
Big 7 lab tests liver?
AST
ALT
ALP
GGT
Bilirubin
Albumin
INR/PTT
Cirrhosis?
Fibrosis and nodular formation of liver
What is ALD?
Alcohol-related liver disease
NAFLD?
non-alcoholic fatty liver disease
MASH?
metabolic dysfunction associated steatohepatitis
NASH?
non-alcoholic steatohepatitis
MASLD?
metabolic disfunction-assocaited steatotic liver disease
MeALD?
MASLD and increased alcohol intake
Alcohol recomendations (2023)
low risk: <= 2 drinks/week
Moderate risk: 3-6 drinks/week
High risk: > 6 drinks/week
Tests done to diagnose cirrhosis?
biochemical markers
AST to platlet ratio index
Abdominal ultrasound
elastography
Liver biopsy(rare)
Compensated cirrhosis characteristics?
body function well despite scaring
may be asymptomatic
anorexia, wt loss, wekaness, NV, GI upset, muscle wasting
Decompensated cirrhosis characteristics?
severe scarring and disrupted function
confusion, edema, fatigue, bleeding
Abnormal INR, albumin, bilirubin
Signs of portal HTN, ascites, varices, encephalopathy
what occurs if blood flow is obstructed in the liver?
portal HTN
Describe the portal system?
self-contained, low pressure venous system
What can cause portal HTN?
splanchnic dilation
increased NO
RAAS activation
what happens to the blood flow in portal HTN?
increased resistance to portal flow, increased portal venous inflow
backflow of blood widens the venous channels
portal HTN causing Splenomegaly? symptoms?
Enlargement of spleen, uncomfortable/painful
- increased sequestering and destruction of RBCs
- anemia (Very common in cirrhosis)
- thrombocytopenia
Consequences of protal to systemic shunting?
metabolites and toxins not processed by liver
increased sensitivity to noxious substances
malabsorption of fat in the stool
decreased bile flow
Contributes to complications like ascites, varices, hepatorenal syndrome
What is ascites?
collection of fluid in peritoneal cavity
How can ascites form?
hydrostatic pressure
hypoalbuminemia (reduced oncotic pressure)
RAAS activation –> salt and water retention
What should acites patients be evaluated for?
liver transplant b/c poor prognosis
what is SAAG?
serum-ascites albumin gradient
what does a SAAG of >11g/L indicate?
portal HTN
Is ascites responsive to diureses?
typically no
SAAG of >25g/L indication?
cardiac dysfunction
Treatment for ascites?
Salt restriction of 2g/day
Spironolactone + furosemide (usually)
Large volume paracentesis, TIPS, or transplant
what is sometimes given with paracentesis to help maintain oncotic pressure?
albumin
Risks of paracentesis?
abdominal perforation
INFECTION!!!!!!
What is TIPS?
transjugular intrahepatic portosystemic shunt;
stent to bypass liver to decrease portal pressure
When is fluid restriction recommended in ascites?
if Na is <120-125 mEq/L
Cure for ascites?
transplant only
Spironolactone dosing and MOA? for ascites
100mg max 400mg
inhibition of aldosterone
Onset 3-5 days
Spironolactone monitoring?
hyperkalemia!!!!
dehydration (not common in monotherapy though)
Gynecomastia + other estrogen-like SE’s
Can increase digoxin levels
Furosemide dosing and MOA? for ascites
40mg OD Max: 160mg
loop-diuretic
Cautions with furosemide use in ascites?
over diuresis
hypovolemia
Combo dosing titration of spironolactone and furosemide
100:40 to max of 400:160 mg
Major important monitoring for ascites diuretic therapy?
K, Na, SCr, wt, BP
What is refractory ascites?
unresponsive to Na restriction and high dose diuretics , reoccurence is rapid after paracentesis
Treatment of refractory ascites?
serial therapeutic paracentesis +/- albumin
TIPS
Transplant
What should be avoided in refractory ascites?
NSAIDs
What is the goal of a pts wt with ascites therapy?
gradual wt loss; ~05kg/d if no edema (higher with edema)
assumption is that 1 kg body wt = 1L of fluid
What to do if urinary Na is low? high?
Low: more diuresis
High: check for non-adherence to low Na diet
What other treatment should be consider w/ ascites?
SBP prophylaxis treatment
What is spontaneous bacterial peritonitis? cause?
infection in ascitic fluid without obvious cause
bacteria translocation from gut to blood stream
Symptoms of spontaneous bacterial peritonitis?
fever, chills, abdominal pain –> can be asymptomatic
3 most common pathogens for spontaneous bacterial peritonitis?
E. coli
Kleb pneumoniae
Strep pneumoniae
Diagnosis of spontaneous bacterial peritonitis?
daignostic paracentesis
Treatment of community acquired SBP?
Cefotaxime or ceftriaxone x 5 d
Treatment of nosocomial acquired SBP?
Piperacillin/tazobactam
meropenem +/- vancomycin
Albumin infusions if needed
when should a second ascitic fluid collection be done? why?
q48h after intitation of therapy
Decrease in PMN count by 25% to ensure clincal response
Prophylaxis drugs for SBP?
norfloxacin, septra, cipro
What is hepatorenal syndrome?
renal failure in pts with severe liver disease
Characterization of hepatorenal syndrome?
sever vasoconstriction of renal circulation
Is the identifiable pathological changes in the kidneys in hepatorenal syndrome?
No
When is hepatorenal system more often seen?
in pts with massive, tense ascites
What to do for hepatorenal syndrome?
STOP diuretics, nephrotoxic drugs
Transplant; usually see improvement with transplant
What occures for vaices to form?
high pressure in portal vein causing bypasses or shunts that causes small veins to become engorged with an excess of blood
Normal portal pressure? at what pressure do varices have a high risk of bleeding?
5-8 mmHg
12mmHg
Do we take portal pressure often?
No, very invasive
what % of advanced cirrhosis pts have esophageal varices?q
65%
What can happen with esophageal varices?
easily rupture and cause massive bleeding
Why are esophageal varice ruptures one of the most feared complications of cirrhosis?
hard to stop the bleeding
high risk of recurrent hemorrhage
Acute management of a variceal bleed?
packed RBCs: resuscitate blood volume : hgb target of 70-90 g/L
antibiotic prophylaxis of SBP: ceftriaxone, cirpo, septra, or norfloxacin
Octreotide or somatostatin IV: to slow/ stop bleeding, d/c once free of bleeding for q24h
Treatment strategies of variceal bleeds?
band ligation –> > control of hemorrhage and less risk of rebleeding, decreased AE’s chance
Sclerotherapy via injecting sclerosing agents
TIPS for pts unable to maintain hemostasis despite combined endoscopic and pharmacological therapy
When should prophylaxis of variceal bleeding be given?
smal varice + increased risk of bleeding (child pugh C, alcohol use, portal pressure >12mmHg)
medium/ large varices
Why use propranolol and nadolol?
unopposed alpha constriction leading to arteriolar splanchnic vasoconstriction
reduces bleeding incidences by up to 50%
Precautions with non-selective beta blockers?
asthma
diabetes
refractory ascites (hypotension risk)
beta blocker SE’s
Dosing of nadolol?
20mg OD max of 240mg/d or 120mg if ascites
titrate every 3-4 days
primarily renally eliminated
Dosing for propranolol?
20mg BID max of 320mg/d or 160mg/d with ascites
CYP 1A2 substrate
What do you base the titration of beta blockers on?
25% decrease in resting HR or a bpm of 55
What other beta-blocker can be used sometimes instead of nadolol and propranolol?
Carvadilol
Primary variceal bleeding prophylaxis treatment?
non-selective beta blocker
Endoscopic variceal ligation
Secondary varieal bleeding prophylaxis treatment?
non-selective beta blocker
Endoscopic variceal ligation
TIPS if re-bleeding w/ therapy
Primary treatment target of hepatic encephalopathy?
Ammonia
Grade 1 descriptions of encephalopathy?
changes in behaviour, mild confusion, slurred speech, disordered sleep, mild tremor, anxiety, impaired handwritting
Grade 2 descriptions of encephalopathy?
lethargy, moderate confusion, ataxia, asterixis (flapping hand tremor), personality change
Grade 3 descriptions of encephalopathy?
marked confusion, incoherent speech, sleeping but arousable, seizures, muscle twitching, delirium, bizarre behaviour
Grade 4 descriptions of encephalopathy?
Coma, unresponsive to pain
Potential factors of hepatic encephalopathy?
protein intake or GI bleeding
drugs
surgery
alcohol use
infection/sepsis
renal failure
metabolic alkalosis
Management of encephalopathy?
correct precipitant factor
restirct dietary protein
avoid CNS depressants
DOC for encephalopathy?
lactulose
how does lactulose work for encephalopathy?
reduces pH, reducing ammonia absorption and prodcution of urease-producing bacteria
Dosing of lactulose?
15-45mL TID-QID
Onset of 12-48hrs
Maintenance dose based on mental state improvement and 2-3 soft stools/day
Can be d/c after improvement but usually on long term (prophylaxis)
Tolerance issues w/ lactulose?
Very sweet
GI: gas, bloating, nausea, diarrhea
ALternative choices to lactulose for encephalopathy?
Metronidazole: limited b/c AE’s
Rifaximin: costly but, EDS now in Sask but, second line and can be used in combo w/ lactulose
What is associated with long term use of metronidazole?
neuropathy
General approach to cirrhosis management?
D/c alcohol
dont use NSAIDs, ASA
avoid sedatives/narcotics
ADequate nutrition
What nutritional defeciencies are common in liver disease?
protein and micronutrients b/c of decreased dietary itnake, malabsorption and digestion
What deficiency do advanced alcohol related liver disease/ cholestatic disease often have?
Fat soluble vitamins (ADEK)
Prevention dose of Thiamine?
200mg/d orally
What can thiamine deficiency cause?
Wernicke’s encephalopathy
suggested supplementation of Vit B6?
2mg od
Suggested supplementation of folate?
400 ug od
What is an overall suggestion to made about vitamins with a pt who has liver disease?
Consider a multivitamin to help reduce deficiencies
What is elevated in asymptomatic hepatitis?
AST and ALT
Hepatitis A virus type? transmission?
RNA virus
fecal-oral transmission –> more likely to occur in countries with poor hygiene and overcrowding
Hep A vaccines?
Harvix
Avaxim
Vaqta
Twinrex both A and B
Symptoms of Hep A?
fever, jaundice, sceral icterus, symptoms last approximately 3 months
Hep A Time from exposure to clinical manifestation?
30 days
Is hep A chronic?
no, fulminant very rare
Antivirals for Hep A?
None, no clear role of pharmacologics for treatment
Post-exposure prophylaxis timing?
within 14 days of exposure, Ig given ASAP if vaccine is not available
CI with Ig in Hep A?
under 1
What type of immunity does Ig give?
passive immunity
Idication of + total anti-HAV?
acute, resolved infection or immunity
Indication of + anti-HAV IgG?
immunity via previous exposure or vaccination
Indication of + anti-HAV IgM?
acute HAV infection
Hep B virus type?
DNA virus
Hep B transmission?
perinatal, sexual, blood
Vaccines for Hep B?
Engerix B
REcombivax HB
Twinrix (A and B)
When does revaccination need to reoccur in Hep B?
in hyperresponders, antibody resposne decreases with age in general so may need another booster in elderly
Symptoms of Hep B?
most pts subclincal or asymptomatic
jaundice dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, and pruitus
Chance of Hep B being chronic?
90% in neonatal
25-50% in 1-5 years old
10% in adults
What other conditions can hep B cause?
fulminant Hep, cirrhosis, hepatic carcinoma
HBsAg indication?
+ indicates Hep B infection –> acute or chronic
Anti-HBs indication?
marker of immunity if HBsAg also present then Hep B infection persists
HBV-DNA indication?
marker of viral replication/infectiity –> used to assess and monitor treatment of chronic Hep B infection
Screening for Hep B?
at leas once for over 18
PWID
immunocompromised
incarceration
WHen is Hep B treated?
during immune active Hep B (increased Hep B DNA and ALT)
Treatment of Hep B?
Interferon (peginterferon alfa-2a) or
Nucleoside analogues ( lamivudine, tenofovir, entecavir, adefovir) suffix: ovir
goals of Hep B treatment?
permanent suppression/ elimination of virus
prevent cirrhosis, liver failure, and hepatocellular carcinoma
“cure of Hep B” in regards to HBsAg?
defined as HBsAg loss w/ or w/o appearance of antibodies to HBsAg
interferon therapy length and success rate?
16-48 weeks, 30% success
When is interferons used? advantages?
in pts w/ lower HBV DNA levels an elevated serum aminotransferase values
Advantages:
- shorter course of therapy
- absence of resistance
- a chance at full seroconversion
Disadvantages of interferon therapy?
Lots of SEs
contraindicated in decompensated cirrhosis
increased risk of life-threatening infection and possible worsening of hepatic decompensation
SQ injection
influenza like illness, emotional liability, myleosuppressive effects, hyper/hypothyroidism
Success rate with nucleoside analogues?
90% respond
10-15% develop immunity
40-50% seroconversion in 5yrs depending on agent
Advantages of nucleoside analogues?
Safer
fewer SEs
oral pill
Disadvantages of nucleoside analogues?
chronic therapy
can take years and may require therapy indefinetly
drug resistance possible
main use for lamivudine (heptovir)?
in pregnancy and for prophylaxis for those on immunosuppression
Use for adefovir (hepsera)?
less potent, used as add on in lamivudine resistance
SEs of adefovir?
nephrotoxicity
hypophosphatemia
what is the DOC for Hep B nucleoside analogues?
Tenofovir
- TDF
- TAF
Why is tenofovir the DOC? what kind of drug is it?
most potent and low chance of resistance
Both TDF and TAF are prodrugs (purine nucleotide reverse transcriptase)
What type of drug is entecavir (baraclude)?
selecive guanosine analogue
When should you NOT use entecavir?
to rescue lamivudine as it may confer resistance
When is a combo therapy used for Hep B w/ nucleoside analogues
ppl w/ cirrhosis and who have resistance and could have fatal flares
generally add on such as:
- lamivudine and tenofovir or tenofovir and entecavir
Hep C virus type?
ssRNA
transmission of Hep C?
perinatal, sexual, blood
perinatal is seen the most
Prevalence of Hep C in canada?
0.8% in 2007
Symptoms of Hep C?
lots asymptomatic
jaundice, dark urine, white stool, abdominal pain, fatigue, fever, chills, loss of appetite, pruitus
what can hep C cause?
chronic hep C (75%)
cirrhosis
hepatocellular cancer
Genotypes of hep C?
1-6
Anti-HCV indication?
infection, acute or chronic
Remains positive for life despite clearance of infection
Why is an additional HCVRNA needed to confirm acute infection?
b/c anti-HCV can be negative within first 6 weeks after exposure
HCV RNA by PCR indication?
virus replication activity
How should pts be screened?
high risk anti-HCV but, if previously infected and cleared use HCV RNA test instead
Harvoni drugs? genotype treatment?
ledipasvir and sofosbuvir
g 1,4,5,6
SEs of harvoni?
fatigue, headache, insomnia, nausea
DI w/ harvoni?
PPI’s
Drugs in zepatier? genotypes?
grazoprevir and elbasavir
g1,4
What needs to be added to zepatier if genotype 3?
sofosbuvir
What needs to be monitored with zepatier?
ALT, transient increase seen around week 8
drugs in epclusa?
sofosbuvir and velpatasvir
genotypes fro epclusa?
all, some activity against g3 but not always
Cure rate of epclusa?
99-100%
What might cirrhosis pts require with epclusa?
ribavirin
duration of therapy w/ sofosbuvir?
12-24 weeks
Disadvantage of sofosbuvir?
accumulation in renal disease, still not great results with g3
Maviret drugs?
glecaprevir and pibrentasvir
maviret genotype activity?
all 1-6
benefits of maviret?
can take w/ food
may be used in severe kidney disease
DI w/ epclusa?
acid suppressing drugs
Drugs in vosevi?
sofosbuvir, velpatasvir, and voxilaprevir
role for vosevi?
treatment failure
benefits of vosevi?
all genotypes
can take w/ food
when to avoid vosevi use?
in decompensated cirrhosis
Usual treatment length for Hep C? (epclusa and maviret used most now)
8-12 weeks
who to screen for Hep C?
people born between 1945-75
PWIDs
incarceration
remote blood transfusions
immigrants from endemic countries
Hep C screening test procedure?
Hep C antibody
if + Hep C antigen
if + Hep C RNA PCR
Suffix of the NS3/4A protease inhibitors?
previr
suffix of the NS5B inhibitors?
buvir
suffis of the NS5A inhibitors?
asvir
Hep D virus type?
RNA virus
what does Hep D occur with?
HBV
What vaccine covers Hep D?
Hep B vaccines
what can Hep D cause?
chronic infection
hepatic carcinoma
cirrhosis
Treatment of Hep D?
Peg interferons at standard dosing for minimum 12 months
Hep E virus type?
RNA
Hep E transmission?
fecal-oral
who has a high mortalilty rate w/ Hep E?
pregnant women
who is more affected by drug-induced hepatotoxicity?
women
Hepatocellular DILI characteristics?
Increased AST and ALT
usually occurs within 1 year of starting drug
Ex: aluperinol
What can result from a hepatocellula DILI?
fulminant hepatitis
Steatonecrosis DILI characteristics?
increased FA synthesis, hepatocytes become engorged and burst open causing inflammation
Ex: alcohol, tetracycline
Fibrosis DILI characteristics?
mild, chronic hepatitis leads to fibrosis which can lead to cirrhosis if drug not d/c
Ex: methotrexate
Cholestatic DILI characteristics?
PRevents proper elimination of bile by liver leading to accumulation
increase in ALP
Ex: carbamazepine, erythomycin
Clinically significant ALT increase?
> 3x upper limit of normal
Clinically significance of bilirubin?
> 2x upper limit of normal
R value equation?
(ALT / upper limit normal ALT) /
(ALP / upper limit normal ALP)
R value of > 5?
hepatocellular injury
R value between 2 and 5?
mixed
R value of < 2?
cholestatic injury
Intrinsic DILI mechanism?
predictable, direct hepatotoxin where a drug has ability to induce injury in all individuals –> dose dependant or time dependant and reproducable
Idiosyncratic DILI mechanism?
unpredictable, variable, further classified into allergic and non-allergic
Most common intrinsic DILI drug?
general AST/ALT levels?
Acetaminophen
>3500 5x upper limit usually
Acetaminophen liver metabolism?
90% glucuronidated or sulfated
2% CYP450
How does acetaminophen toxicity occur?
glucuronidated or sulfated pathway saturated
CYP elimination produces toxic metabolite that is detoxified by glutathione but glutathione becomes quickly depeleted
Toxic Acetaminphen produt?
NAPQI
4 stages of acetaminophen toxicity?
stage 1: GI symptoms within 24hrs
stage 2: 24-72 hrs, resolution of stage 1 symptoms, onset of RUQ pain, increased bilirubin PT and transaminases
stage 3: 72-96hrs, asymptomatic to fulminant hepatic failure, AST and ALT peak (100x normal), death if it occurs at 3-5 days after ingestion
stage 4: recovery stage, symptoms subside, and levels normalize. no chronic hepatic dysfunction in survivors
Acetaminophen toxic doses?
ADults: > 7.5g
children: >150mg/kg
What does the rumack-mathew nomogram predict?
likelihood of AST/ALT > 1000
Gut decontamination options?
Syrup of Ipecac
Activated Charcoal
Antidote for acet toxicity?
Acetylcysteine
How does acetylcysteine work?
enhances glutathione stores
What is the likely cause of non-allergic DILI?
likely caused by toxic metabolites
onset is 1 week- 1 year
Reoccurence can take days to weeks possibly accumulation lag time?
Allergic DILI drug examples?
phenytoin, phenobarb, carbamazepine
allopurinol
dapsone, minocycline, propythiourocil
sulfa antibiotics
non-allergic DILI examples?
isoniazid
valproic acid
ketoconazole
methyldopa
Approach to suspected DILI?
take med history
examin labs and identify type of liver injury
symptoms presented?
assess if alternate cause
consider onset and drug timing
Se’s go away after rug d/c
Steps to manage suspected DILI?
d/c all potential hepatotoxic drugs
provide supportive care
monitor liver enzymes to ensure the return to normal
How does the severity of the child pugh rank?
A least, C worst
Is there a risk increase for DILI in pts w/ liver disease?
No, but likelihood for recovery is lower
