Lecture 14 - Liver Diseases Part 2

do all patients with NAFLD develop severe disease

vast majority will not

80% of patients are low risk and managed with lifestyle interventions aimed at addressing risk factors

what is nonalcoholic steatohepatitis (NASH)

severe form of NAFLD (20%)

what are the benefits of GLP-1 agonists for liver disease

appear to improve liver damage, reduce steatosis and inflammation when used to treat NASH

what are manifestations of ESLD

Jaundice

Cholestasis

Hepatomegaly (liver enlargement)

Portal hypertension

Ascites (accumulation of fluid in the abdominal cavity)

Hepatic encephalopathy (deterioration of brain function due to buildup of toxic substances normally removed by the liver)

Coagulapathy

Liver failure

Malignancy

what is cholestasis

reduction or stoppage of bile flow

Occurs when flow impaired from the hepatic cells into duodenum

• Impaired secretion from hepatocytes

• Obstruction due to scar tissue

Bile accumulates in the liver → absorbed into blood

what are symptoms of hepatic cholestasis

Yellowing of skin and eyes- deposition of bilirubin

Pruritus- irritation of peripheral nervous system due to bile salts

Dark urine- excess bilirubin excretion in urine

Light-coloured stool- reduced bilirubin excretion through stool

what is cholestatic pruritus

Itch typically not accompanied with rash

Intensity is not associated with severity of liver disease

Usually worse at night

what is the treatment for cholestatis pruritus

Cholestyramine resin 4g PO up to 4 times daily

Alternatives: naltrexone, rifampin or sertraline

(No role for antihistamines)

what are adverse effects of Cholestyramine

constipation, diarrhea, bloating, rarely hyperchloremic metabolic acidosis

what is portal hypertension

Defined as abnormally high blood pressure in the portal venous system

Diagnosed as hepatic venous pressure gradient (HVPG) > 5 mm Hg

• (Gradient between portal vein and hepatic vein or inferior vena cava)

classified as: Prehepatic, Intrahepatic, Posthepatic

what is the mechanism of intrahepatic portal HTN in cirrhosis

Increased resistance to the blood flow in liver due to distorted architecture of liver in cirrhosis

Imbalance of vasoconstrictors and vasodilators

Reduced production of albumin by hepatocytes

what are consequences of intrehepatic portal HTN

Collateral blood vessel formation= portosystemic shunts

Ascites

Hepatic Encephalopathy- portosystemic shunts

Splenomegaly

what are consequences of portosystemic shunts

Caput medusae

Rectal hemorrhoids

Varices

what is caput medusae

Appearance of large and swollen veins on the surface of the abdomen

Occurs due to collateral vessel formation

As blood flows through, the vessels cannot withstand the pressure of the increased blood flow so they become distorted

what are varices

Collateral vessels that form at esophagus and stomach

As blood flows through these vessels, they become enlargednot built to withstand high pressure and volume of flow

Once developed, varices may remain stable, increase in size(if liver disease worsens) or decrease in size (if liver disease improves)

Ruptures can be life threatening- medical emergency!

what does the risk of variceal bleeding depend on

Severity of liver disease

Size and thickness of varices

History of bleeding- rebleeding occurs at rate of ~60%

Varices and variceal bleeding can occur once portal venous pressure >10mmHg

who should be screened for ascites

All patients diagnosed with cirrhosis should be screened upon diagnosis for varices with endoscopy

Upper endoscopy: insertion of a thin, light flexible tube with a camera to view esophageal and gastric lining

how often should varices be screened for if screening shows no varices

every 1-3 years

what is the presentation of acute variceal bleeding

Varices are asymptomatic until they rupture and bleed

Gastrointestinal bleeding: hematemesis, melena, hematochezia

Lightheadedness,bloating, tachycardia, decreased blood pressure

what are the goals of therapy of varices

Primary prevention - Prevent variceal rupture and bleeding

Treatment of acute episode - Provide supportive management for patient with an acute variceal bleed

Secondary prophylaxis - Reduce risk of recurrent variceal rupture and bleed

what are surgical interventions for varices

Endoscopic variceal ligation(EVL), endoscopic injection sclerotherapy(EIS)

Transjugular intrahepatic portosystemic shunt (TIPS)

what is acute treatment for varices

Supportive management

Pharmacological: Octreotide, vasopressin, antibiotic prophylaxis

Surgical/endoscopic

what is the role of beta blockers in non-bleeding varices

reduce portal blood flow

primary prevention of a bleed and secondary prevention

why are non-selective beta blockers preferred for non-bleeding varices

Beta-1 blockade: decreased cardiac output → decreased portal perfusion

Beta-2 blockade: unopposed alpha-adrenergic vasconstriction → decreased sphlachnic perfusion

what are examples of non-selective beta blockers

propranolol

nadolol

carvedilol

how should beta blockers be titrated

Decreased resting heart (by 25% or 55-60 bpm) while maintaining BP >90mmHg

what should be monitored with beta blockers

Efficacy: HR, absence of bleeding

Safety: bradycardia, hypotension (<90mmHg), hyponatremia, AKI

what is Endoscopic variceal ligation (EVL)

Using an endoscope, provider uses suction to pull varices into the scope

Rubber bands are deployed from scopethese wrap the vein and prevent further bleeding

what is Endoscopic injection sclerotherapy (EIS)

More complications than EVL

Not as effective as Betablocker+EVL

what is supportive management of acutely bleeding varices

ABC- protecting airway, supplementing O2

Blood transfusions

Fresh frozen plasma, Vitamin K, platelets

Fluids to maintain intravascular volume

what is pharmacologic management for acutely bleeding varices

Prophylactic Antibiotics

Octreotide IV infusion (somatostatin analogue)

Somatostatin

Vasopression

what is endoscopic management of acutely bleeding varices

Endoscopic variceal ligation

Endoscopic injection sclerotherapy

what is surgical management of acutely bleeding varices

Transjugular intrahepatic portosystemic shunt

what is secondary prevention of variceal bleeding

Non-selective beta-blockers and endoscopic variceal ligation(EVL) if eligible

Start as soon as hemodynamically stable from acute bleeding episode

Can consider transjugular intrahepatic portosystemic shunt if patient has recurrent bleeding on betablocker+EVL

what is ascites

Accumulation of protein containing fluid in abdomen

Fluid leaks from the surface of the liver and intestine and accumulates in peritoneal cavity due to activation of the RAAS system

Reduced hepatic synthetic function leads to hypoalbuminemia which can further exacerbate fluid accumulation

what are presenting symptoms of ascites

Abdominal distention

Weight gain

Dyspnea

Early Satiety

what are the goals of therapy of ascites management

Reduce volume of ascitic fluid in abdomen

Reduce risk of recurrence

Resolve symptoms

what are non-pharm treatments for ascites

Low sodium diet- <2g per day

Fluid Restriction <1.5L/day

Removal of fluid (therapeutic paracentesis)

what are pharmacological treatments for ascites

Diuretics → Spironolactone, Furosemide

what are surgical interventions for ascites

Surgery to reroute blood flow. Creation of a transjugular intrahepatic portosystemic shunt

Liver transplantation

what order are diuretics added for ascites

spironolactone → furosemide → metolazone → amiloride

what is the target ratio of spironolactone:furosemide

40:100 to prevent electrolyte derangements

what are efficacy monitoring parameters for ascites

Weight

• Aiming for weight loss of 1–1.5 kg/day in patients with peripheral edema, and 0.5–1 kg/day in patients without edema.

Abdominal girth

Urine output → In relation to input. Should be about ~500mL/day

what are safety monitoring parameters for ascites

Electrolyte abnormalities (K, Na, Mg), SCr, BUN

Blood pressure

Furosemide, metolazone → Uric acid, Volume depletion

Spironolactone-specific: Gynecomastia, Hyperkalemia

what is spontaneous bacterial peritonitis

Infection of the ascitic fluid

Unclear mechanism, suspected source is bacterial translocation from GI tract to ascites

Serious infection- can be life threatening!

what are presenting symptoms of spontaneous bacterial peritonitis

Presence of ascites

Fever

Abdominal tenderness

what are causative organisms in spontaneous bacterial peritonitis

Enterobacterales, less commonly streptococcus species

what is empiric treatment for spontaneous bacterial peritonitis

Third generation cephalosporin or ciprofloxacin for 5-7 days

Nosocomially acquired infection may require broader coverage

Tailor based on fluid culture results

what are prophylactic options for spontaneous bacterial peritonitis

TMP-SMX, norfloxacin, ciprofloxacin

Only recommended in high risk patients due to risk of contributing to development of resistant organisms

Primary: consider use in patients with GI bleed

Secondary: CP score ≥9; but may not have much benefit per a recent meta-analysis

how should PPIs be managed in spontaneous bacterial peritonitis

consider deprescribing

what is hepatic encephalopathy

Deterioration of brain function due to liver insufficiency or portosystemic shunting

Occurs because of accumulation of gut-derived nitrogenous substances such as ammonia

Due to poor hepatic function, these substances are not removed by the liver, reach the systemic circulation and can enter the CNS

Alters neurotransmission

what are symptoms of hepatic encephalopathy

Changes in cognition, behaviour, level of consciousness

Presentation can range from mild confusion to coma

is hepatic encephalopathy reversible

yes

what is type A hepatic encephalopathy

Associated with Acute liver failure.

Has the potential for cerebral edema and herniations.

what is type B hepatic encephalopathy

Due to portal-systemic Bypass without associated intrinsic liver disease

what is type C hepatic encephalopathy

Occurs in patients with Cirrhosis

Episodic, which may be precipitated, spontaneous, or recurrent

Persistent, which may be mild, severe, or treatment-dependent

Minimal

what is asterixis

seen in hepatic encephalopathy

involuntary flapping of hands

very characteristic of disease

what are major risk factors for hepatic encephalopathy

constipation

portosystemic shunts (including surgical)

CNS active drugs

infections

AKI, electrolyte derangements

GI bleed

excess dietary protein

hypoxemia, hypercapnia

what are general principles for hepatic encephalopathy management

1. Supportive care for patients with altered consciousness

2. Identify and treat precipitating factors

3. Identify and treat other potential causes for altered mental status

4. Begin empiric treatment for HE

what is the focus of empiric treatment for hepatic encephalopathy

improving neurological status by reducing concentrations of gut-derived nitrogenous substances

what is first line treatment for hepatic encephalopathy

lactulose

Nonabsorbable disaccharide

Mechanism of Action: Removes nitrogenous waste products from the GI tract through laxative action

what is the dosing of lactulose for hepatic encephalopathy

Start at 45 mL Q1H PO until patient has a bowel movement and clinical improvement is noted. Then maintain with 15–45 mL 1–4 times daily PO-titrate to produce 2–3 loose bowel movements per day

what should be monitored with lactulose

neurological status, # of BMs

what are adverse effects of lactulose

Bloating, flatulence, cramps, diarrhea.

what is rifaximin

Antibiotic

Mechanism of Action: reduces urease producing bacteria in the intestines which decreases the level of ammonia in the blood

what is the dosing of rifamixin

550mg PO BID without food

what are adverse effects of rifaximin

Not significantly absorbed from the GI tract

what are the benefits of combining rifaximin with lactulose

maintain remission better than lactulose alone

what should be monitored with rifaximin

neurological status

GI upset, edema, headache

what is the preferred tool for drug dosing in hepatic impairment

Child-Pugh Score