3. HB Therapeutics Flashcards
(71 cards)
1
Q
Normal > chronic hepatitis w/ ____ > cirrhosis»_space;
Decomp cirrhosis
- ____
- hepatic encephalopathy
- variceal ____
OR
____
> >
liver transplant
A
fibrosis
ascites
bleeding
HCC
2
Q
HCV- Viral life cycle
• Evnvelope \_\_\_\_ virus ○ Intiially found incidentally, but then mech of rep was figured out > breaktkthrough in therapeutics ○ Virus binds reeptors hepato > viral enveolpe > relaese viral capsid protein > contains viral genome > polyprotein > broken down into indiviudal compoentn s> protease activity ○ **component of the virl polyportien > \_\_\_\_; the host cell will not have an RNAdependent polymerase § In order to rplicated viral genome need \_\_\_\_ > viral genoe is replicated > genoe and stuctural components are rpelciated
A
ss RNA
viral polymerase
viral polymerase
3
Q
HCV genotypes
• Viral replication rate is very ____: 1012 virions /day
• The viral RNA-dep RNA polymerase lacks ____ activity
High ____ rate
• Clusters of HCV with sequence similarities >60% remain ____ within the individual patient: “genotype”
* High mutation rate > how the virus evades the immune response * Virus within an patient tht has a sequence that's protected from the mutation rate in the viral genotype > remains constant
A
elevated
proofreading
mutation
constant
4
Q
HCV Genotypes in the US • - \_\_\_\_ ~ 75% - Genotype 2 ~ 15% - Genotype 3 ~ 7% - Genotype 4, 5, 6 < 5% • Clinical significance of HCV genotypes: - No impact on the \_\_\_\_ of liver injury - Major impact on the likelihood of \_\_\_\_ to HCV therapy
• 6 genotypes ○ 1,2 3 are most common in the US ○ 456 common in other parts • Genotype has impact on which drug you will use ○ The viral compositino may differ among genotypes
A
genotype 1
severity
response
5
Q
Chronic Hepatitis C – Natural History
• Majority of patients w HCV > chonic infection > \_\_\_\_ in 20%; once develops > 5%/ear dev \_\_\_\_ or decomp cirrhosis
A
cirrhosis
HCC
6
Q
Gold standard for response to HCV treatment: Sustained Viral Response (SVR)
- Defined as the absence of detectable ____ in blood ____ wks (SVR 24) or ____ wks (SVR 12) after the end of the course of therapy
- < 1% chance of detecting HCV after ____• How to measure success of treating HCV
• SVR
○ Absence of detectable HCV after therapy
○ Can be in 12 or 24 weeks
○ Important: important virological endpoint
§ Achieve the response milestone > cahnce of ever seeing the virus again in blood is <1% > ____ of virus
A
HCV
24
12
SVR
erradication
7
Q
Effect of SVR on patients with advanced fibrosis/cirrhosis
• Not just virological endpoint, orrelates in reduction in risk of complications as well (clinically!) • Sutyd of patiets who were treated ○ Patients who respond w SVR > lower \_\_\_\_ over long term follow up ○ Liver specific mortality is even bigger; mortality is driven by liver disease so it's low ○ Patients were selected who were undegroing cirrhosis ○ Don't treat successfully > risk of dying from liver dx at 10 years > \_\_\_\_% • SVR is important bc it prevents serious \_\_\_\_ of iver dsisae ○ Prevent \_\_\_\_ of dx down spectrum, and prvenets liver cancer and failure
A
mortality
20-22
complications
progression
8
Q
General Principles in HCV Treatment
* Expose pt to a drug > produce a response > \_\_\_\_ level drops * Then continue to treat beyond the \_\_\_\_ where virus isn't detected > virus is mostly in liver > treat for longer than the time where the virus isn't in blood > clear the resoirvori from the \_\_\_\_ (\_\_\_\_ treatment) > then stop > virus load 10-24 weeks later > is the response sustained?
A
virus
phase
liver
maintenance
9
Q
Interferon and Ribavirin in hepatitis C treatment (1990s to 2011)
• Interferon (IFN) is a ____ that activates the anti-viral immune response
• Ribavirin (RBV) is a ____ analogue that inhibits viral replication
• (____) x 6-12 mos was the first treatment for HCV:
- Limited efficacy (~50% SVR in geno 1)
- Many ____
• First xtnebt available > interferon > cytokine ○ \_\_\_\_ injections ○ Activates antiviral immune response • Combination of the two were tested in anumber of infections ○ Soe patients got an improvement in liver tests • Problem: needed xment that was injection based for 6-12 mo > even in patients who could \_\_\_\_ (a lot of SE from the cytokines) > the chance of an SVR was only 50% in the ost common genotype (1)
A
cytokine
guanosine
IFN+RBV
side effects
tolerate
10
Q
HCV - viral life cycle
• Treamtnet was dveloepd before we knew how the virus replicated • Was based on non-specific replication of virus • Can now target specific areas to prevent the replication of virus ○ Three targets: § \_\_\_\_ (NST34A) § NS5B (\_\_\_\_) § \_\_\_\_ (helps in the viral replciation) § Inhibit any > virus cannot replicated
A
viral protease
viral dependent RNA polymerase
helicase
11
Q
The new era in HCV therapy: Directly Acting Antivirals
• Development of new drugs in HCV therapy targeting specific components of the ____
• Goals :
1. Improving ____
2. Reducing adverse effects of ____ therapy
A
viral replication cycle
SVR
HCV
12
Q
Conceptual Evolution of Mutations on Monotherapy
• Cannot use as \_\_\_\_ > virus has high mutation rate > develop resistant mutants • Drugs that are specific to one component > have to use them in \_\_\_\_ ○ At east \_\_\_\_ steps in order to not develop mutations
A
monotherapy
combination
two
13
Q
• Don’t need to know • Target at least two components of viral rep process • Viral protease inhib have easy identifier ○ -\_\_\_\_ • NS5B inhibit ○ -\_\_\_\_ • Viral polymerase inhib ○ -\_\_\_\_
A
previr
asvir
buvir
14
Q
Current HCV treatment
• All ____
~ 90- 95% chance of SVR with 1st line
~ Vast majority of failures to first line therapy can be treated ____ with second line agents
- Treatment well tolerated with little adverse effects
• Likelihood of clearing HCV has gotten so good ○ 90-95% success rate w oral drugs and little SE • Patients who fail first line therapy > have second line therapy that will clear the virus • No patient w HCV that you cannot treat properly
A
genotypes
successfully
15
Q
Remaining challenges in HCV therapy
• ____ patients with HCV
• ____ of decompensated cirrhosis
• ____ of therapy / access to care
• Silent infection until they develop serious complications ○ Screening anyone bron bt 45-65 > 80% of infected patients in the US § \_\_\_\_ epidemics > new wave of HCV infections • Treat pt w decomp cirrhosis > cannot get them recompensated ○ Too late to prevent from iver transplant • Cost of therapy is getting better ○ Inusrance had a hard time covering high cost of therapy
A
identifying
reversibility
cost
opiates
16
Q
Virology • \_\_\_\_ family • 44 nm virion: - Host-derived lipoprotein envelope expressing \_\_\_\_ - \_\_\_\_ protein (HB core Ag) - \_\_\_\_ - Partially ds \_\_\_\_
* HBV has a vaccine bc of a neutralizing ab * DNA virus * Virological diff bt HCV and HBV > big diff in treatment
A
hepadnaviridae HBsurfaceAg core capsid DNA polymerase DNA
17
Q
HBV Replication
• HBV is DNA virus that has ability to target nucleus of cell where it's used as repair machinery > closed circuarl DNA > genomic form of virus that \_\_\_\_ in cell for as long as its alive • All targets are at the \_\_\_\_ which is needed for replication ○ None of them target the stable \_\_\_\_ form ○ C is an RNA virus > cytoplasm of cell > desn't rep it's gone ○ B can sit and not replciated and persist for a long tiem
A
survive
viral polymerase
DNA
18
Q
Immune Response to HBV
Replication of the virus does little direct damage to ____
The hepatic injury is mostly due to the ____ to the virus
The degree of immune tolerance to ____ will determine whether a chronic infection will develop (HBsAg positive > 6 months)
• The rep of the virus can induce an immune response > results in tissue injury • Most patients exposed to HBV as adult > clear the \_\_\_\_ ○ The hepatitis > the symptoms > function of immune response to virus ○ Children w underdeveloped immune > less likely to clear, and less likely to get \_\_\_\_ § All depends on the immune response!
A
hepatocytes immune response hepatitis B virus sick
19
Q
Key Hepatitis B tests and their significance
• ____: indicates the presence of the virus in an individual
• ____: indicates immunity to the virus, acquired by vaccination or naturally by immune clearance
• ____: core antibody persists in any individual exposed to the virus (current or past infection)
• ____: e-antigen secreted with active replication of the ‘wild-type’ virus
• ____: antibody to eAg becomes positive when eAg titers decrease
• ____: presence of viral DNA in the blood
• HBsAb > neutralizing ab • WT virus secretes e antigen > virus is actively replicating ○ If e antigen goes down, the antibody will appear ○ Immune complex phenomenon § Both are typically present; but no replication you will detect ab, and vice-versa
A
HBsAg HBsAb HBcAb HBeAg HBeAb HBV DNA
20
Q
Phases of Chronic Hepatitis B
• Role of immune system in rlationship to hepB infection • Acquire inf perinatally (mother to child) > immune system of the infant is \_\_\_\_ > tolerates the viral inf > high levels of \_\_\_\_, normal ALT (immune system isn't attacking) Eant \_\_\_\_ and Eab - • Adults acquire acute inf > most clear bc of the \_\_\_\_ > if don't > chronic hepatitis > ongoing immune respnose but not clearing it > high \_\_\_\_, high DNA, Eant \_\_\_\_ (eant+ chronic hep b) • Some patients, bc itnerplay w immue system > atsome point it controls replciation > low or undet DNA > Eant \_\_\_\_ and Eab + > ALT normal ○ Inactive carriers for HepB • Can hav virus develop mutation > replciate w/o \_\_\_\_ (core mutantI9 > not as effective at rep as WT (not as high DNA), there is an immune response > ALT is high, but cannot control ○ Eant-chronci hepB • L is youngr; R is older • Virus can persist for decades, over the history of dx > you have the whole spectrum • Stages are not \_\_\_\_, can go from one to the other • Hard time clearing the virus > hard time making them surface ant negative bc of the stable genomic form of virus > persist • Good at prveenting viral rep and preventing liver injury ○ Turning everyoe into an ainactive carrier, that's what we want
A
immature
DNA
+
immune response
ALT
+
-
Eant
static
21
Q
Indications for HBV treatment
• Elevated ____
• Elevated ____
• Patients with cirrhosis and any detectable HBV DNA
• Don’t treat \_\_\_\_ carriers, bc all treatment is bc of target rep • ALT > injury • If having cirrhosis, even if ALT is not elevated> ptwent torugh cycles of swithces bt phases several times ○ Can look inactive, but not really that ○ Liver damage in these patients • Cirrhosis, any detectable virus > reason to treat
A
ALT
HBV DNA
inactive
22
Q
Endpoints of chronic hepatitis B therapy
• ____ seroconversion (in eAg + patients)
• HBV viral DNA ____
• Normalization of ALT
• Improvement in ____ and fibrosis on liver histology
• ____ loss: rarely achieved
• W C it's SVR • HBV ○ Doesn't happen, rarely ever lose the surface antigen • eAg + > make them - • Try to bring the DNA down • Patients who respond well > lower number of red box > less LF, less decomp, less ascites, less encephalopathy and HCC
A
eAg
suppression
inflammation
HBsAg
23
Q
Pharamcological agents for chronic hepatitis B
• \_\_\_\_ • Telvibudine • \_\_\_\_ • Adefovir • \_\_\_\_ - Viral polymerase inhibitors Oral agents
• Pegylated interferon alpha 2a
• All are viral pol inhibit • Entecavir and tenofovir ○ Used most often ○ They are the most potent ○ Trying to suppress viral replication > target one comp of the virus > must suppress it hard § Most potent = lowest \_\_\_\_ risk § Allowing virus to replicate in presence of drug > tends to casue mutations • Pegylated interferon ○ Option for HBV ○ \_\_\_\_ antiviral effect ○ Used when oral drugs were not as effective
A
lamivudine
entecavir
tenofovir
mutation
nonspecific
24
Q
Treatment of eAg positive chronic HBV
• Goal: ____ seroconversion (eAg negative, eAb positive)
• Oral agents: 20 - 50% (increased with longer duration of therapy)
• Pegylated Interferon for ____ months: 30%
A
eAg
12
25
```
Treatment of eAg negative chronic HBV
• Goal: Long term ____ suppression
• Oral agents: 50-90%
• PEGIFN: 20%
• eAg negative patients have a high ____ rate off therapy: PEGIFN is generally avoided
```
DNA
| relapse
26
Alcohol-mediated liver injury
• Alcohol-mediated liver injury results in ____ accumulation: increased synthesis and inhibition of fat export from the liver
• Oxidative stress within the liver due to depletion of ____
• Immune response to altered cellular proteins results in liver ____ and fibrosis
• The alcohol injury > inc fat synthesis
○ Typical > hepatic steatosis is the common injury
○ Most common > ____ fatty liver > obesity, diabetes, etc.
• Glutathione
○ Used in alcohol metabolism
• Steatosis > presence of fat
• Steahepatitis > fat and an ____ response from altered proteins due to alc exposure
• Can be on either end of things dpeneding on the amount of alcohol drank
```
fat
glutathione
inflammation
non-alcoholic
inflam
```
27
Threshold of alcohol intake for alcoholic liver disease
• ____ drinks per week for women
• ____ drinks per week for men
• Based on epi studies looking at the risk of liver injury in people self-reporting their drink
○ Can be an underestimate of what it actually is
• No increased risk when drink less than this when compared to non-drinkers
• ____ oz of beer, 5 oz of wine, ____ oz for liquor
7
14
12
1.5-2
28
```
Clinical manifestations of alcoholic liver disease
• Alcoholic Fatty Liver
* asyx, ____,liver test mildly abnl
* present in 90% of heavy ____
* ____ with discontinuation
```
• Alcoholic Hepatitis
* acute on chronic liver injury with moderate to severe liver test abnl
* signs of liver dysfunction, liver failure
May be life threatening
• Alcoholic Cirrhosis
Manifests with complications of decompensated ____
• Number of ways where ALD
○ Simplest > AFL
§ Biopsy > ____ (less inflam)
§ Asymptomatic
§ Fat acum > liver larger > hepatomegaly
§ ____ manifestation of drinking too much
• AH
○ Chronic liver injury > acute on chronic injury
§ Liver test can be mild or sever
○ In the sever form: liver dysfxn and failure > can be life threatening
• AC
○ Chronic manifestations
○ Without an ____ component
hepatomegaly
drinkers
reversible
cirrhosis
steatosis
earliest
acute
29
Alcohol abstinence
• Cornerstone of all therapy of alcoholic liver disease
– results in improvement in liver function.
• Physical and psychological alcohol ____ is commonly associated, complicated by withdrawal symptoms and high risk of relapse of alcoholism
• Specialized counseling recommended to promote long term abstinence.
• Withdrawal syndrome from alcohol is serious
○ Physical
• Also a psychological dependance > at risk of relapse
• Talk to patients ab not drinking
○ Need specialized counseling
dependence
30
Nutrition and vitamin deficiency
* ____ is common in patients who abuse alcohol
* A ____ is associated with poor outcome in alcoholic hepatitis
* Nutritional ____ is considered an important element of therapy that promotes liver recovery
* Vitamin deficiencies common in alcohol abuse and supplementation is needed: ____, Folic acid, vitamin D, ...
• Have nutritional deficiencies
○ In protein-calorie and nutritional deficiencies in vitamins and nutrients
• Protein calorie malnutriton > negative nitogen balance (catabolic) > poorly if have hepatitis
○ Focus on quitting alcohol and nutrition > impt component of recovery
• Vitamin def is common > alcoholics get most calories from alcohol
○ ____ can lead to chronic neuotoxicity
malnutrition
negative nitrogen balance
supplementation
thiamine
thiamine
31
Specific therapy of alcoholic hepatitis: corticosteroids
* Patients with severe alcoholic hepatitis may benefit from ____ (Prednisolone 40mg/d x 28 days)
* Lack of improvement within ____ week of initiation of corticosteroid therapy is reason to stop early to reduce the risk of subsequent infection
• Group who has the most severe > corticos
• If don't improve within a week > stop treatment
• If respond > continue for ____ weeks
• Main issue: patients who don't respond and even those who do > develop severe infections and you're adding an immunosupp on top of hepatitis
○ Don't continue to treat if not improving
corticosteroids
1
4
32
Liver transplant for alcoholic liver disease
• Main concern is risk of ____ recidivism
• A period of ____ along with therapy/counseling to prevent alcohol relapse is generally required
• 10-15% of transplant recipients due to alcoholic liver disease have problem drinking after transplant
• A very select group of patients with ____ may be considered for liver transplant, based on an assessment of low risk of recidivism
• If alcoholism is persistence > damage the transplant
alcohol
absitnence
alcoholic hepatitis
33
• ____ is the histological end stage of liver disease, putting pt at clinical complications
○ What really affects pt and their outcome > complications of liver dx
○ How severe is the cirrhosis?
§ There's a scale - ____ score
□ Assign pt a score based on severity of their laboratory dysnfunction
® ____ is higher if liver isn't working properly
® Albumin is ____ bc it's synth by the liver
® PT and INR are ____ > liver makes blood clotting factors
® Two clinical parameters: presence of ____, and ____
□ Class A, B, or C depending on the severity
```
cirrhosis
child
bilirubin
lower
prolonged
ascites
hepatic encephalopathy
```
34
Child score correlates with prognosis (1 and 2 y survival probability)
• Likelihood of survival
○ Child A
§ Long term survival is good - ____% range
○ Child B
§ One year survival is down to ____%, 70% for 2 years
○ Child C
§ Most severe patients
§ One year survival is ____%, and 2 year survival below 40%
§ Outcome is as bad as some of the worst ____
§ May need transplants
90
80
40
cancers
35
Measuring the severity of decompensated cirrhosis: MELD Score
* MELD =(0.957 x ln(____) + 0.378 x ln(____) +1.12 x ln(____) +0.643) x 10
* Better predictor of ____ (3 month) survival than the Child score
* Used to prioritize patients on the liver transplant waiting list
• MELD score
○ Doesn't include clinical parameters
○ Includes four parameters
§ ____
§ ____
§ ____
§ Serum ____
§ Predict the likelihood of survival
○ Best predictor of short-term survival (3 month)
§ Child is 1-2 years
□ Number can vary from 5-15
§ MELD score can spread from 15-40
○ Prioritize patients on the transplant list
§ Higher MELD > higher on the list; lower MELD > lower on the list
§ The sickest patient gets the next liver
creatinine
bilirubin
INR
short term
creatinine
bilirubin
INR
sodium
36
Ascites
Accumulation of fluid in the peritoneal cavity
• Syx: abdominal pain/bloating, early ____/poor nutrition, shortness of breath
• 50% of pts with ____ cirrhosis develop ascites in 10 years
• 50% 2-year mortality
* Most common complication of cirrhosis
* Don't eat as well > nutritional status gets worse
* Comp cirrhosis > no complications > 50% develop ascites
* Once develop ascites > 2 year mortality is ____%
* Will need a liver transplant
* Once ascites develops > patient is ____
pain
compensated
50
decompensated
37
Ascites in Cirrhosis - Pathogenesis
• Mechanism of ascites formation in cirrhosis
• Patients w/ cirrhosis and portal HTN > have ____ that's NO mediated
○ Vasodila response due to ____ of flow at liver bc of fiubrosis obliteration at capillaries due to the fibrotic process; flow goes up > compensatory mech undergoes vasodilation > keeps the pressure from increasing
○ At some point > overflow > vasodilation stimulus to the GI tract
§ Common manifestation of cirrhosis
§ Inc c____, and inc lymph productino
§ Most important: response to vasodilation > stim components that keep BP from falling > RAT, epinephrine > kidneys hold onto ____ > patients develop ascites
□ In addition to ____ production
§ Activates renal vasoconstriction > ____ goes down > hepatorenal syndrome
○ In the int phase > hyponatremia > system secretes ____ > kidneys retains more free water > patient has low serum ____
§ Is why it's a predictor of survivor in pt w cirrhosis
§ More severe cirrhosis > hyponatremic bc of the underfilling going on
```
vasodilation
obstruction
cap pressure
salt and water
lymph
GFR
sodium
```
38
Management of Cirrhotic Ascites
• ____ restriction (2 g Na)
• Treat underlying etiology of liver disease
• Diuretics:
- ____ 100mg:____ 40mg
• Avoid/discontinue drugs that can cause renal vasoconstriction – especially ____. ____ is the preferred analgesic.
• Any patient w fluid overload problems > salt restriction
○ Foods today have a lot of sodium in > obvious and hidden
• Kidneys are holding onto Na and water > force kidneys to not do that
○ Use diuretics to achieve
○ Use spirnolactone (____ blocker) and a ____ (furosemide - inhibits salt reabsorption)
• Whole process is triggered by arterial underfilling and renal ____
○ Avoid NSAIDS - they're renal vasoconstrictors
§ Renal failure and worsened fluid retention
§ Prescribe acetaminophen if need an analgesic
□ At high doses > can develop liver failure
□ ____mg is safest thing you can give to patients who have cirrhosis
```
salt
spironolactone
furosemide
NSAIDs
acetaminophen
```
aldo receptor
loop
vasoconstriction
2000
39
Refractory Ascites
• Failure of ____ therapy (400mg ald/160mg lasix) or complications of ____ (renal failure, severe hyponatremia, encephalopathy)
• Exclude:
- non ____ w salt restriction (UNa)
- ____ use
- Other causes of renal dysfunction
• Develop symptoms despite you're restricting salt, not taking drugs that make it worse, escalating the diuretic doses
• Urine sodium cxn
○ Very vasoconstrictive holding onto a lot of salt > tough to get significant salt excretion even on diuretics
○ If high > underlying physiology of renal vasocon is not that severe > overwhelming by taking in a lot of salt
• Cannot manage the ascites to keep the pt comf w medication and dietary restriction
○ Use ____
§ Drainage of fluid from perioteneal cavity
§ Should not have to remove more than ____L of fluid 1-2
□ More than that > not on a 2g sodium diet > can improve on their diet
```
diuretic
diuretics
adherence
NSAID
paracentesis
10
```
40
Treatment of Refractory Ascites (1)
• Serial large volume paracentesis
Removing up to ____ L of ascitic fluid every 1- 2 weeks
10
41
Treatment of Refractory Ascites (2)
• Transjugular Intrahepatic Portosystemic Shunt (TIPS):
- reducing ____ pressure
• Possible adverse effects: -
Worsening ____ function
- Worsening ____
• Does not reduce ____ – only liver transplant does
• TIPS
○ Connecting liver inflow via ____ vein to the liver outflow through the ____ vein
○ High resistance flow through the liver driving the ascites
§ Drop pressure within portal vein > can resolve the process
○ Shunting blood away from the liver > lower perfusion > liver injury
○ Blood going through the liver > clear toxins > can accum toxins > ammonium > more hepatic encephalopathy
○ More effective relieving the ascites than draining it every two weeks, but no impact on the history of the liver dx; does not reduce mortality
§ Only treatment is a liver transplant
```
portal
liver
hepatic encephalopathy
mortality
portal
hepatic
```
42
Ascitic fluid infection: SBP
• Normal ascites cell count: < ____ WBC, < ____ neutrophils
• Spontaneous Bacterial Peritonitis (SBP)
Neutrophils > ____, Positive culture in the peritoneal fluid
• Can happen bc the pt's ascitic fluid has a composition that's low in ____ (component that you need to fight inf, particularly globulin levels) > fluids can be infected > no ____ in internal organ, etc, happens bc the ____ can seed it (poor immune response)
500
250
250
protein
inflammation
bacteria
43
Treatment of SBP
* 5 days of therapy with IV 3rd generation ____ (cefotaxime)
* Addition of IV ____: reduction in renal dysfunction and mortality
* ____ detection and treatment of SBP crucial: mortality is ~ 80% once septic shock ensues
• IV antibiotics is the treatment
• IV albumin
• Insidious in its onset > present w symptoms of things other than inf > confusion, jaundice, not clear fever
○ Detect early, if patient develops sepsis > mortality is very high
cephalosporin
albumin
early
44
Prevention of SBP
• Secondary prophylaxis: up to ____% recurrence rate at 1 yr
• ____ prophylaxis in patients with ascites and severe liver or renal dysfunction and low ascites protein (<1.5)
• 7 days of abx prophylaxis in cirrhotic patients presenting with gi bleed
• If someone develops inf > high risk of second infection > 70%
○ Remain on ____ until liver function improves or transplant
○ Sign of advanced liver disease > ____ infected fluid > need a transplant
• Can be primary prophylaxis
○ Prevent an initial infection
• Cirrhosis + ascites + GI bleeding > inc risk of inf tremendously
70
primary
antibiotics
spontaneous
45
Hepatic encephalopathy
• Syndrome encompassing the neuropsychiatric manifestations of portosystemic ____ and/or hepatocellular ____
Neurotoxic compounds (____) normally metabolized by the liver gain access to the CNS
• Manifestations of HE can be neurologic, can be behavioral as well
○ Due to either portosystemic shunting (PV > into liver > systemic)
§ GI tract feeds the liver; if shunting the liver (can be natural, complication of elevated portal pressure - formation of collateral veins, or artificially [TIPS]) or the liver isn’t doing it's job detoxifying (hepatocellular failure)
§ Have a little bit of both in patients with HE
shunting
failure
ammonia
46
Pathogenesis: ammonia hypothesis
• Reduced clearance of NH3 > ____ of brain have high ammonia levels that are dealt with > convert glutamate to ____, as the glutamine exceeds what the cell needs > osmolol load > draws water behind it > brain ____
○ In chronic liver disease - the edema is compensated, pumps solute out
§ Chronic low grade brain edema > not detected on clinical imaging
§ Don't see on ____
§ But do w SPEC scan > see how much water is in the brain
○ In a different condition > acute liver failure > compensatory mechanism doesn't ____ > intracranial swelling and HTN > brain edema that is detectable on imaging > can see on ____ > brain ____
§ One of the ways ____ liver failure pts die
§ Never seen in ____ patients bc of the comp mechanisms
astrocytes
glutamine
edema
```
MRI
exist
MRI
herniation
acute
cirrhotic
```
47
Pathogenesis
• Way pts develop HE > pt has chronic brain injury
○ Either something that inc ammonia
§ ____ (blood has a lot of proteins > metabolized > gut bacteria makes ammonia > overwhelming the comp system)
§ ____ a lot of protein
§ ____
□ Things don't move in the GI tract > more time for ammonia to be absorbed
§ Renal source
□ Volume depletion > kdineys ____ a lot of thing
□ Hypokalemia and metabolic alkalosis
§ Dec hepatic ____
□ Stable chronic dx > acute on chronic insult > ____ drops > HE
□ Create a ____ (TIPS) > inc ammonia load in brain suddenly
○ ____ can trigger > form a catabolic state increasing ammonia load, patient w chronic injury to brain > manifestation of severe sepsis is confusion
○ ____ > pts are more susceptible to sedatives > easily confused
○ ____ disturbances
§ Pts are very susceptible
§ Compensated state can fall apart
```
GI bleeding
eat
constipation
reabsorb
clearance
clearance
portosystemic shunt
infection
sedatives
metabolic
```
48
Clinical manifestations
• ____ dysfunction
• Sleep-wake cycle disturbance
• Decline in level of ____
• Motor dysfunction / Parkinson-like syndrome
• ____ changes: Depression, mania, psychosis
• Focal neurological signs
• Cognitive dysfunction > earliest sign
○ If require analytical skill, it's detected sooner
• Sleep-wake cycle
○ Happens early
• Pt heading to ER > confused, not knowing where they are, going into coma
• Focal neurological signs
○ Things that make you think of a stroke
§ Weakness on one side
cognitive
consciousness
behavioral
49
1. Treat the precipitating factor
• What is the trigger?
○ Underlying chronic brain injury, but why did it happen?
• Important not to miss ____
○ If you miss infection > patient can be ____ a few hours later
infection
| septic
50
2. Non-absorbable Disaccharides: Lactulose
• Colonic acidification: NH3 > ____decreased colonic absorption
• Increased bulk of stool > increased stool ____ excretion
First line of therapy in ____
```
• Drug monst commonly used: lactulose
○ Non-absorb ____
○ Fermented in gut by bacteria
• NH4+ is less ____
• Main mechanism: fact that you have more bowel ____ > clearing the gut of its contents > reducing the amount of nitrogen that the bacteria has to work with
```
```
NH4+
nitrogen
hepatic encephalopathy
disacch
absorbable
movement
```
51
3. Antibiotics in HE
• Reduction in colonic ____ producing organisms > reduction in ____ production
Considered ____ line therapy in HE
urease
ammonia
second
52
Rifaximin in HE
• Non-____ antibiotic = rifaximin
○ Reduce rate of ____ to hospital once HE occurs
absorb
| readmission
53
4. Liver Transplantation
| • Hepatic Encephalopathy is form of hepatic ____ and is an indication for ____
decompensation
| liver transplant evaluation
54
Esophageal varices
• As ____ pressure increases due to increased resistance to flow in the liver, venous channels connecting the portal vein to the ____ veins develop
• Portosystemic shunt at the level of the ____
○ Communicating the portal/systemic veins in the esophagus
portal
systemic
esophagus
55
Natural history of varices in cirrhosis
Initial ____ for variceal screening is recommended in patients with cirrhosis
• Can put the pt at risk of GI bleeds
endoscopy
56
Prevalence and Size of Esophageal Varices in Patients with Newly-Diagnosed Cirrhosis
• More likely to occur as ____ of liver disease increases
• Child B have more than A, and C has more than B
○ ____ as well
severity
| larger
57
Primary prophylaxis for varices
• If large varices are found: 30% risk of rupture/bleeding > primary prophylaxis indicated:
* ____ (propranolol, nadolol, carvedilol)
OR
* serial ____ band
ligation
• If varices are found > concern is with large ones > sig risk for bleeds (30%)
○ Pharmacological therapy (____) > reduce flow through the GI tract > vasoconstriction (through the portal vein and varices); and B1 reduce ____ and reduce flow through varices > reduce pressure so it doesn't bleed
○ Endoscopic ligation
§ Inserted into esophagus > use ____ to bring vein into cup, and release the ____ on it > ties up the vein
non selective beta blockers
endoscopic
B1 and B2 antagonists
CO
suction
band
58
Rupture of esophageal varices can cause massive bleeding
* ~ 20 % mortality due to ____ rupture
* Requires emergency care, ressucitation and urgent endoscopy to control the bleeding
* ____ can be helpful in cases where endoscopy fails to control bleeding.
• The bleeding is massive > can ____ blood, or pass large amount of blood into the stool
• TIPS > reduces pressure in the portal vein
○ Drop the pressure > can prevent bleeding
variceal
TIPS
vomit
59
Secondary Prophylaxis in variceal bleeding
• Once bleeding happens from varices > ____ prophylaxis
○ Primary prophylaxis: use ____ or endo ligation
○ Secondary prophylaxis: use a ____ of the two
secondary
non-sel beta blocker
combination
60
Hepatocellular Carcinoma (HCC)
* Risk ~ 1-3% per year in cirrhosis
* Large/symptomatic HCC associated with poor ____ (~10-15% 5y survival)
* Early stage HCC is potentially ____ with > 50% 5 y survival
• Primary care of cirrhotic patients must be screened for early liver cancer that is curable
outcome
| curable
61
HCC Screening
- Cirrhosis
- Select pts with ____ chronic HBV
* ____ Hx of HCC
* ____ pts with HBV, age > 20
* Asian pts with HBV, males age > 40,
females age > 50
> ____ of the liver Q 6 months
• Everyone w cirrhosis is screened for HCC
• HBV is assoc w a risk of HCC (more than ____)
○ May be because of ____ into the genome and induce cellular replication > inducing HCC even without cirrhosis
• New ____ that are under clinical trials that can detect the cancer early
non-cirrhotic
family
african
ultrasound
HCV
integrating
biomarkers
62
```
Therapeutic options for HCC
• ____ Resection
• Percutenaous ablation
• ____ Transplant
• Chemo- or Radioembolization
• ____ therapy
```
• Three treatments that are curative
○ ____ resection
○ ____ ablation
§ Placing a needle into the tumor and delivering heat, or freezing it to treat the tumor
□ Burning the tumor and the tissue around it
○ Liver ____
• If cannot cut or ablate > do an ____ transplant
• The others are not curative
○ Chemo/radioembolization
○ Sytemic therapy
surgical
liver
systemic
surgical
percutaneous
transplant
entire
63
Surgical resection for HCC
```
____ Candidate
Single lesion
Small tumor < 5cm
Intact liver ____
No portal hypertension
No ____ invasion
```
```
Contraindicated
____ lesions involving both lobes
Poor liver function
____ disease
Invasion of adjacent organs
Involvement of the confluence of the portal or hepatic veins
```
```
• Ideal patient
○ Single lesion
○ Small
○ Intact liver function
§ Usually happens in cirrhotic cases
○ No portal HTN
○ No vascular invasion
• Can spread from one side of the liver to another
```
single
function
vascular
multiple
metastatic
64
Percutaneous Ablation for HCC
• Tumor takes ____ on the CT scan
• After ablation > doesn't take up contrast > dead tissue and the margin surrounding
• TL: radiofrequency ablation device
• Small tumor > can achieve a result w ____ that's close to surgery
○ ____ is still slightly better
contrast
ablation
surgery
65
Liver Transplantation for HCC
• Only ____ option in patients with (____) multifocal disease, or liver dysfunction precluding resection
• 5y survival of ____% in a select group of patients
• If patient has multifocal cancer
○ The entire liver is at risk bc it has spread within the liver
• If there is a lot of tumor > tend to ____ after transplant > microscopic cells that escaped the liver
○ Keep the tumor within certain limits
○ Some ____ therapy to keep the cancer within the liver > make sure it's not spreading
```
curative
limited
70
recur
bridging
```
66
Liver Transplant Evaluation
• Candidates for liver transplant undergo a thorough evaluation
* Indication for ____
* General health/medical comorbidities
* ____ health
* Nutritional status / physical condition
* ____ assessment
* Surgical / anatomic considerations
transplant
cardiovascular
psycho-social
67
Waiting list
• Candidates who successfully complete the evaluation are registered on a deceased donor waiting list
• Rank on the list depends on MELD score
MELD =[0.957 x ln(____) + 0.378 x ln(____) +1.12 x ln(____) +0.643] x 10
• Waiting list supply - demand mismatch:
~6,500 liver transplants yearly in the US
~12,000 patients on the waiting list (20% of whom subsequently removed for being ‘too sick’)
• MELD - best predictor of ____ term mortality
○ Higher MELD > higher on list; vice-versa
• Liver transplants has been stagnant over the past few years
• More need for transplants than ____ livers
creatinine
bilirubin
INR
short
available
68
Liver Transplant Complications
```
Early
____ / infections
Biliary strictures
____ artery thrombosis
Acute Rejection
____ disease
```
Late
Recurrence of the original ____ disease
Late/chronic ____
Complications of ____ therapy
• Early
• Livers are reattached w/ anastomoses that can have problems
○ Small anastomosis of the bile duct is a common problem
§ Stump of ____ coming from recipient and the liver and trying to connect > can have biliary ____
○ Not as many problems w the ____ vein > it's very large
§ Hepatic artery > can have thrombosis
○ GvHD
§ Lymphocytes from ____ attacking the immune system and tissues of the ____
• Late complications
○ Whatever caused the original liver disease
○ Gone with modern therapy
○ Most emphasis we have in post-liver transplant clinic > ____ of immunosuppressive therapy
§ Liver has a ____ rejection rate
§ Rejection of it is easy to treat
□ Can tolerate little immunosuppression
□ Talk more ab the complications of immunosuppressants, less about the rejection itself
bleeding
hepatic
GvHD
liver
rejection
immunosuppressive
```
bile duct
strictures
portal
donor
recipient
```
treatment
low
69
```
Liver Transplant Immunosuppression
• Classes :
- Calcineurin Inhibitors: ____, Cyclosporine
- Anti-metabolites: ____, Azathioprine
- mTOR inhibitors: ____, Everolimus
- Corticosteroids: ____
```
* Highly effective in preventing and treating ____ in liver transplant
* Rejection is an ____ cause of liver graft loss
• Changed the outlook of transplantation
○ Rejection used to be a huge problem
§ W advent of cyclosporine > transplanting bc much more effective
□ Balance of preventing rejection and infection
□ Achieved through calcineurin inhibitors
• Corticos are used earlier in the transplant (3 months)
○ Not ____
tacrolius
mycophenolate
sirolimus
prednisone
rejection
uncommon
long-term
70
Complications of immunosuppression
• Metabolic complications:
____ gain, hypertension, diabetes, hyperlipidemia
• Malignancy:
____ Cancer, Lymphoma (PTLD), ____ cancer in women
• Infections: e.g. ____, TB, ..
• Chronic kidney disease (____ inhibitors)
• Osteoporosis
• Side effects from long term use is significant
• Use corticosteroids > ____ complications
• Calcineurin inhibitors > ____
○ Skin cancer is common
§ Cancers that are normally controlled through the immune system
○ Lymphoma that is due to lack of immune surveillance
○ Cervical cancer
• Risk of infection is lower but it's not eliminated
○ CMV
○ TB
• Calcineurin inhibitors > renal ____ > can cause CKD directly
○ Can develop renal failure and dialsysis
○ The main problem with ____ inhibitors
• ____ due to the use of steroids and calcineurin inhibitors
```
weight
skin
cervical
CMV
calcineurin
```
metabolic
malignancy
vasoconstriction
calcineurin
osteoporosis
71
• Patient and graft survival is about ____%
70
