Chapter 27: Liver Diseases – Hepatitis & Cirrhosis Therapy

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Welcome to the Deep Dive.

Today we're tackling a really complex and frankly urgent area in advanced practice, managing complications from chronic liver disease, specifically cirrhosis.

That's a huge global health issue, cirrhosis.

And for providers, really getting the pharmacology right for these end stage conditions.

I mean, everything from bleeding varices to, you know, the confusion, the HEE, it's absolutely crucial.

Exactly.

So that's our mission today.

Cirrhosis is that end stage, right?

Where healthy liver cells, the hepatocytes, they get replaced by scar tissue.

That's it.

And that scarring creates physical blockages, which then triggers this whole cascade of really serious problems.

We often talk about the big five, portal hypertension, variceal bleeding, pandesics, hepatic encephalopathy or HESBP, that's spontaneous bacterial peritonitis, and then hepatic renal syndrome, HRS.

Okay.

So think of this deep dive as your kind of advanced shortcut to chapter 27's core pharmacology.

We'll slow it down, unpack the hows and whys, look at the drug choices and really focus on those clinical pearls you need to, turn theory into practice.

Let's start right at the beginning then, the core mechanics of how the liver decompensates.

Okay, let's unpack that.

So the shift from healthy to cirrhotic liver, it really boils down to these activated hepatic stellate cells causing fibrosis.

Exactly.

Once those stellate cells get activated, they just start pumping out extracellular matrix, that's the fibrosis, the scarring.

And that scarring physically increases resistance inside the issue.

Portal hypertension, pH.

And this is where it gets weird, right?

The body tries to fix it, but actually makes it worse, that physiological paradox?

Precisely.

You get this massive internal resistance in the portal vein.

The body senses this and releases a flood of potent vasodilators systemically.

Nitric oxide is a big one.

Trying to relieve the pressure.

Right, trying to open things up.

But because the liver structure is physically scarred and fixed, it doesn't work there.

Instead, you get widespread vasodilation all over the body.

Leading to systemic hypotension, low blood pressure everywhere else.

Yep.

So you've got high pressure locally in the portal system, but low pressure systemically.

And when the body detects that low systemic pressure, what does it do?

Hits the panic button.

Exactly.

Kicks in the renin -angiotensin -aldosterone system, RAAS.

Totally inappropriately.

And RAAS does what?

Constricts arteries, holds onto salt and water.

Massive sodium and water retention, hence the edema and ascites.

It increases the overall blood volume dramatically.

And all that extra volume gets dumped right back into the already high pressure portal circulation.

Worsening the portal hypertension.

Vicious cycle.

Totally.

Understanding that paradox, the local high pressure causing systemic low pressure, triggering RAAS, making the portal pressure even higher.

That's really the key to understanding why we use the drugs we do later on.

Okay, got it.

Before we jump into the drugs though, we need those assessment tools.

How do we gauge how bad it is?

Right.

We need objective measures.

Two main scoring systems.

The classic one is the child tricot Pew score, CTP.

Useful for staging, maybe some drug dosing adjustments.

But it's a bit subjective, right?

Judging ascites, encephalopathy.

Yeah, that's the limitation.

So we often rely more on the Meldie score model for end -stage liver disease and its buddy, Meldie now, which adds sodium.

Okay.

And Meldie is purely lab -based.

Purely bilirubin, INR and sodium.

It's designed to predict three month mortality very accurately and crucially, it's what we use to prioritize patients for liver transplant lists.

And those specific labs tell a story.

They really do.

INR reflects liver synthetic function making clotting factors.

Bilirubin reflects excretory function getting rid of waste.

Creatinine tells us about the kidneys.

A vital organ often hit hard.

And sodium gives us a handle on fluid status and severity of that RAAS activation.

It's a pretty powerful snapshot.

Okay, makes sense.

Let's move to tackling that portal hypertension directly and preventing the big catastrophe, variceal hemorrhage, bleeding from those swollen veins.

This is MSBB territory, right?

Non -selective beta blockers, first line.

Absolutely.

Cornerstone therapy.

We're talking propranolol, nodolol, and also carvetolol.

They're used for primary prophylaxis stopping the first bleed and secondary prophylaxis stopping another bleed.

And their effectiveness comes down to that dual action, beta 1 and beta 2 blocking.

Exactly.

The beta 1 blockade is pretty straightforward.

Slows the heart rate, reduces cardiac output.

Less blood pumped means less blood flowing into that high pressure portal system.

Simple enough.

But the beta 2 part is the real trick.

That's the key piece for portal hypertension.

Blocking beta 2 receptors specifically in the splaschnik circulation, the blood vessels supplying the gut leads to unopposed alpha receptor stimulation there.

Ah, so you get vasoconstriction just in the gut vessels feeding the portal vein.

Precisely.

It clamps down in the inflow, directly reducing blood flow and pressure entering the portal system.

It's quite elegant, really.

Now carvetolol, you mentioned it too.

It's newer, often preferred.

What's its advantage?

Yeah, carvetolol is interesting.

It's more potent generally, but it also has this additional alpha 1 receptor antagonism.

So besides the beta blockade effects, it adds another layer of vasodilation systemically, but seems to have particularly good effect on reducing portal pressure, maybe through intrahepatic effects.

So how do we dose these?

What are the targets?

With the traditional ones, natolol or propanolol, the goal is usually titrating the dose to achieve a resting heart rate of about 55 to 60 beats per minute.

Okay.

For carvetolol, it's often more about hitting a target dose, like 6 .25 milligram twice daily.

But with all of them, you absolutely have to monitor blood pressure.

Keep that systolic blood pressure up above 90 millimeter Hg.

We need to perfuse the kidneys.

Right.

Which brings up that clinical pearl.

If these drugs are so good at lowering portal pressure, why do we need to be careful or even stop them in patients with significant ascitis?

Seems counterintuitive.

It's a critical point, and it's all about balance.

And someone with bad ascites, who's already likely got that RAAS system cranked way up and is relying on every bit of systemic pressure to perfuse their kidneys, dropping their systemic blood pressure too much with an NSBB can kick them over the edge.

It can precipitate acute kidney injury or even full -blown hepatrion syndrome.

So in very decompensated patients, especially with refractory ascites, sometimes holding the NSBB is safer overall.

It's a judgment call.

Wow.

Okay.

A real balancing act.

Now shifting gears to the emergency,

acute variceal hemorrhage, 30 % mortality.

That's terrifying.

What's the immediate drug?

Octreotide.

It's a synthetic version of somatostatin.

Works incredibly fast.

How does it work so quickly?

It directly causes intense vasoconstriction in the splanchonic circulation,

clamps down those vessels, supplying the gut almost immediately, reducing blood flow into the portal vein, dropping the pressure and helping to stop the bleeding within minutes.

And dosing for that emergency.

Standard is an initial IV bolus, usually 50 micrograms.

Then you immediately start a continuous IV infusion at 25 to 50 micrograms per hour.

This typically runs for two to five days, always alongside getting endoscopy involved to band or sclerose the varices.

Any side effects to watch for short term?

Yeah.

Mainly hybrid glycemia can bump up blood sugar and potentially prolonging the QTC interval in the EKG.

So you monitor that.

Got it.

Okay.

Let's move downstream to ascites.

That massive fluid buildup signals a poor prognosis.

How do we diagnose it So you often need quite a bit of fluid, maybe 1500 millimiters or so, to detect it reliably on exam.

You know, listening for that tympanic dullness when you percuss the abdomen.

Right.

But the key diagnostic test, especially the confirm it's due to portal hypotension, is the SAG, the serumocytes albumin gradient.

You measure albumin in the blood and in the acidic fluid.

And a high gradient means?

A SAG of 1 .1 GDL or higher is really specific, like 97 percent accurate for a cause by portal hypertension.

It helps rule out other causes like infection or cancer.

Okay.

And treatment, since we know it's driven by that runaway RAAS and aldosterone.

Exactly.

You target the underlying problem.

Sporonolactone is the absolute gold standard initial diuretic.

It's an aldosterone antagonist.

So better than Lasix furosemide on its own.

Definitely preferred over furosemide monotherapy initially, because it directly hits that hyperaldosteronism.

Often you'll use them in combination later.

Typically a 100mg sporonolactone to 40mg furosemide ratio to maintain potassium balance.

And sporonolactone's main limiting side effect?

Tender or painful gynecomastia breast enlargement in men.

It's dose dependent and can be quite bothersome, sometimes forcing a switch to another drug like epirinone, though that's less common.

What about when diuretics aren't enough or you have to pull off huge volumes with paracentesis, like more than five liters?

That's a large volume paracentesis, LVP.

And when you take more than five liters, giving IV albumin is critical.

Not optional, really.

Why albumin?

What's it doing?

You're pulling off fluid that contains protein, including albumin.

Albumin in the bloodstream is what maintains oncotic pressure.

It holds fluid inside the blood vessels.

If you just drain off liters of fluid without replacing that oncotic pool, fluid shifts out of the vessels.

Hypotension.

Exactly.

You risk intravascular volume depletion, hypotension, and precipitating kidney injury or HRS.

So the standard is to give 25 % albumin, about six to eight grams, for every liter of fluid removed over five liters.

It's been shown to reduce mortality by about 35 % in this setting.

That's a huge impact.

Wow.

Okay.

So all that fluid's sitting there.

Big infection risk, right?

SPP.

Massive risk.

Spontaneous bacterial peritonitis.

It's an infection of the acidic fluid itself, usually by gut bacteria that translocate across the bowel wall.

Diagnosis is made by analyzing the acidic fluid from a paracentesis.

And the magic number.

A polymorphonuclear cell count PMNs, a type of white blood cell of 250 cells per cubic millimeter or more in the fluid.

That's the diagnostic threshold for SPP.

And empiric treatment.

Gotta cover those gut bugs.

Yep.

Think E.

coli clebsiella.

So third generation cephalosporins are first line.

Cifotaxin or ceftriaxone the fourth.

They give excellent coverage.

Is there a role for albumin here too, like with LVP?

Yes, absolutely.

For higher risk SPP patients, criteria usually include things like creatinine over one, BUN over 30, or bilirubin over four, giving AvV albumin.

Along with the antibiotics has been shown to improve outcomes, particularly reducing the risk of developing HRS.

Okay.

And once someone survives an episode of SPP, you have to prevent it from happening again.

Definitely.

Secondary prophylaxis is crucial and it's usually indefinite lifelong.

The preferred agent is generally sulfamethoxazole trimethoprim, like Bactrim, once daily.

Why that over, say, a fluoroquinolone like Cipro?

Fluoroquinolones can work, but there are growing concerns about resistance and also significant safety warnings.

Things like tendon rupture, CNS effects, and particularly in liver patients, they might increase the risk for C.

diff or further kidney injury.

So Bactrim is generally favored if the patient can tolerate it.

Makes sense.

Okay.

Let's pivot to the brain.

Hepatic encephalopathy, HE.

Ammonia is the bad guy, but the blood level isn't the whole story.

That trips people up all the time.

Ammonia builds up because the damaged liver can't convert it to urea for excretion.

It crosses the blood brain barrier and messes with neurotransmission, causing those mental status changes, confusion, lethargy, personality shifts, and that classic flapping tremor, asterixis.

But the ammonia level itself?

Doesn't correlate well with the severity of the HE.

You can have a high ammonia level, be fine, or a normal level, and be deeply encephalopathic.

So we treat the clinical signs and symptoms, not the number.

And the first line, workhorse treatment?

Laxulus.

Cheap, effective, still the standard of care, given orally, sometimes rectally in severe cases.

How does a laxative fix a brain problem though?

What's the mechanism?

It's clever actually.

Laxulus is a non -absorbable sugar.

Bacteria in the colon fermented, which acidifies the colon contents.

Ammonia, which is NH3 and easily absorbed, gets protonated in that acidic environment to become ammonium, NH4 plus do.

Ah, NH4 plus is charged, ionized.

Right, so it gets trapped in the colon.

It can't be reabsorbed into the bloodstream.

Then the laxative effect of laxulus just sweeps it out of the body.

So the goal is bowel movements.

Yep.

For chronic management, the goal is typically two to three soft, loose bowel movements per day.

For acute HE, you might push the dose higher initially to clear them out faster.

And if laxulus isn't cutting it, then you add rifaximin.

It's an antibiotic, but it's minimally absorbed, so it mostly stays in the gut.

It works by reducing the number of ammonia -producing bacteria in the colon, so less ammonia gets made in the first place.

It's used often as add -on therapy or for preventing recurrent HE episodes.

Okay, now the really late -stage kidney problem, hepatorenal syndrome, HRS, diagnosis of exclusion, right?

Absolutely.

It's a functional kidney failure.

The kidneys themselves look okay structurally, but they shut down because of the extreme circulatory dysfunction and end -stage liver disease, primarily that intense renal vasoconstriction driven by the systemic chaos.

You have to rule everything else out first.

And type 1 is the rapidly worsening kind.

Yes.

Type 1 HRS is an acute rapid decline in kidney function.

Very poor prognosis without transplant.

The treatment is really a bridge to transplant, trying to keep the kidneys perfused.

And the first -line therapy is

the classic triad, 5e -albumin, octreotide, and midadrine.

Albumin helps with volume expansion.

Octreotide might help counteract some vasodilation,

but midadrine is the key.

It's an oral alpha -1 agonist.

Its job is to cause systemic vasoconstriction,

raise the overall mean arterial pressure.

The idea is if you increase the systemic pressure, you can force more blood flow through those clamped -down renal arteries.

We often titrate up maybe to 15 mg three times a day, aiming for a specific MAP increase.

And if that doesn't work in the patients in the ICU, then you might escalate to IV norepinephrine.

A much more potent vasoconstrictor requires intensive monitoring.

Again, the goal is the same.

Titrated to raise the MAP, usually by about 10 mm Hg, trying to restore kidney perfusion.

It's a rescue therapy.

Okay.

We've hit the major complications.

Let's switch focus now to the viruses that often cause this downstream trouble.

Hepatitis B and C.

Right.

The major viral culprits leading to chronic liver disease and cirrhosis.

Both are blood -borne.

Quick definitions.

Chronic Hep B means the surface antigen, HBS ag, is positive for more than six months.

Chronic Hep C means the virus's RNA, HTV RNA, stays positive for more than six months.

And Hep C is much more likely to become chronic.

Way more likely.

If an adult gets Hep C, there's maybe an 85 % chance it So for Hep B, what are the treatment goals?

We can't always cure it, right?

Cure, meaning complete eradication and loss of HBS ag, is uncommon with current therapies, though it's the ultimate goal.

The more immediate goals are suppressing the virus, getting HPV DNA levels undetectable, preventing progression to cirrhosis or liver cancer, HCC, and ideally, eventually achieving HBS ag loss or cirrhoconversion.

And the preferred drugs have a high barrier to resistance.

Exactly.

We want drugs the virus is unlikely to easily mutate against.

First line choices are typically page interferon alpha, an injection, finite duration, or the oral antivirals and a caviar, ETV,

or tenofovir.

Tenofovir has two forms, TDF and TF.

Right.

TDF is tenofovir disaproxyl fumarate, the older form.

TF is tenofovir alaphenamide, newer form.

TF generally has a better safety profile, especially regarding kidney function and bone density, so it's often preferred.

But there's a kidney cutoff for TFF.

TF is usually contraindicated if the creatinine clearance is less than 15 melamine, whereas TDF might still be used carefully with dose adjustments, even in severe renal impairment or dialysis.

So you tailor the choice.

And how long is treatment?

Interferon is finite, usually 48 weeks.

But the oral agents, ETV or tenofovir, often indefinite, potentially lifelong, especially if the patient already has cirrhosis.

If you stop the meds, the virus usually comes roaring back.

Okay.

Now, Hep C, this is where the revolution happened with the DAAs,

direct acting antivirals.

Absolutely game changing.

We went from treatments that were poorly tolerated, long duration and had low cure rates, to therapies that are incredibly effective, short duration, often just 8 -12 weeks, well tolerated, and offer a cure for the vast majority.

How do they work?

They target the virus directly.

Exactly.

They target specific proteins the virus needs to replicate.

There are different classes, NS34A protease inhibitors, NS5A inhibitors, NS5B polymerase inhibitors.

We always use them in combination.

And treatment is recommended for pretty much everyone with chronic Hep C now.

Pretty much, yes.

Guidelines recommend treating all patients with chronic HCV, regardless of how long they've had it, or the stage of their liver disease, unless they have a very short life expectancy from other causes.

And the goal is simple.

Cure.

The goal is SVR -sustained virologic response.

That means the HCV RNA is undetectable in the blood 12 weeks after finishing treatment.

SVR12 is considered a virologic cure.

Fantastic.

But there's one huge safety warning with DAAs.

Something providers absolutely must check beforehand.

Critical point.

You must screen every patient for hepatitis B infection check, HBS ag and anti -HPC, before starting DAA therapy for Hep C.

Why?

What happens if they have both?

Treating the Hep C of the DAAs can cause the hepatitis B virus, which might have been dormant or suppressed, to suddenly reactivate and replicate rapidly.

This HBV reactivation, or flare, can be severe, sometimes causing fulminant hepatitis, liver failure, even death.

It's a black box warning.

Screen everyone.

Wow.

Okay, that is crucial.

So this deep dive, it's covered a huge amount of ground.

Precision pharmacology is definitely the name of the game here, from NSBBs and octreotide for pressure and bleeds, to diuretics and albumin for fluid, lactulase for the brain, DAAs for the cure.

It really is.

And we know we focused on the drugs, but we can't forget the foundation underneath it all.

The non -pharmacologic stuff is just as vital.

Absolute alcohol abstinence.

No debate there.

For sites, that strict sodium restriction 2000 milligrams a day or less.

That's tough, but essential.

And for HE, protein restriction used to be the thing, right?

Old thinking.

We now know protein restriction is harmful.

It leads to muscle breakdown, which actually worsens HE.

So current guidelines recommend adequate protein intake, about 1 .2 to 1 .5 grams per kilogram of ideal body weight per day to maintain muscle mass.

Good point.

And the one drug class to avoid across the board.

NSAIDs, ibuprofen, naproxen, declofenac, absolutely avoid them in patients with cirrhosis, especially those with the sites.

They inhibit prostaglandins, crucial for renal blood flow, and can easily cause acute kidney injury in these vulnerable patients.

Acetaminophen is generally safer at limited doses, assuming no active alcohol use.

Right.

Okay.

So here's a final thought to leave our listeners with.

Something to chew on.

Given all this complexity with the polypharmacy, the need for renal dosing with drugs like Natalol, managing CNS effects, potential drug interactions, especially when you get to things like HRS triple therapy,

how absolutely critical is that close collaboration between pharmacists and the advanced practice providers?

You know, simplifying regimens, watching interactions, constant monitoring.

Oh, it's indispensable.

It's probably one of the clearest examples in medicine where that tight multidisciplinary teamwork provider, pharmacist, nurse, dietitian is essential for keeping patients safe and optimizing these really complex therapies.

It's not optional.

It's core practice.

Well said.

Thanks for joining us for this deep dive today.

We really hope this summary helps you tackle this chapter and feel more confident managing these patients.

Yeah, absolutely.

Best of luck with your studies and thanks for being a part of our last minute lecture family.