• Inability of liver cells to conjugate and excrete bilirubin leads to build-up of bilirubin in the blood

• Hepatocellular injury progresses -> fibrous material develops within the hepatic lobules -> disrupts normal blood flow through the liver
• Fibrous tissue accumulates -> resistance to portal blood flow increases -> persistent and progressive elevations in portal blood pressure
• Also increases endothelin (vasoconstrictor) and decreases in nitric oxide (vasodilator) attenuate increases in portal venous pressure

• Blood "backs up" from portal HTN and finds an alternative route back to the systemic circulation
• Most clinically significant route is the gastric vein and development of esophageal varices
• Risk of variceal bleeding begins when portal venous pressure reaches 12 mmHg > inferior vena cava pressure

• Upper GI Bleed -- variceal hemorrhage
• Hemorrhoids
• Caput medusa -- abdominal veins that "stick out"

1.  Non-Selective Beta-Blocker (first line)

• Beta1 receptor inhibition leads to decreased CO
• Beta2 receptor inhibition leads to decreased splanchnic blood flow
• The combined effects produce a decreased portal pressure

2.  Endoscopic Band Ligation (EBL)

• For patients with contraindications or intolerance to non-selective beta-blockers
• Superior to both beta-blockers and nitrates for preventing first bleed -- BUT since not proven to improve survival and long-term benefits are still uncertain
• Therapy is reserved for those intolerant to beta-blockade

3.  Nitrates

• Smooth muscle vasodilation -> decreased portal pressure
• Used as add-on therapy to patients that have inadequate response to beta-blockers as monotherapy
• Isosorbide mononitrate

• Rupture of varices into the GI tract leading to blood loss -> can progress to hypovolemic shock
• Hemorrhage is complicated by the hypocoagulable state that accompanies liver disease

• Hematemesis or melena
• Decrease in hemoglobin and hematocrit
• Possible hypotension, dizziness, etc.

1.  Supportive Measures

• Adequate fluid resuscitation -- PRBCs, crystalloids
• Correction of coagulopathies and thrombocytopenia -- fresh frozen plasma, platelets, vitamin K

2. Vasoactive Therapy

• Octreotide -- preferred agent

-Naturally occurring somatostatin analog

-Inhibits vasoactive intestinal peptide  -> mesenteric vasoconstriction

-Decreases splanchnic blood flow -> decreased portal and variceal pressure

• Vasopressin

-Non-selective vasoconstrictor with the vasoconstricting effects not restricted to the splanchnic vessels

-ADRs: coronary ischemia, AMI, arrhythmias

• Terlipressin

Analog of vasopressin with longer t1/2

Allows for q 4hr dosing rather than continuous infusion

Not available in US

3.  Antibiotics

• All patients with variceal hemorrhage get antibiotics
• Increased risk due to: aspiration, placement of multiple IV access devices, sclerotherapy, translocation, defects in immune system
• Reduces the risk of sepsis --> reduces the risk of rebleeding and increase short-term survival
• Screen for infection

4.  Endoscopic Interventions

• Guidelines recommend as primary diagnostic and treatment strategy for upper GI tract hemorrhage secondary to portal HTN and varices
• Sclerotherapy
• Band Ligation

5.  Surgical Interventions

• If standard therapy fails, use this
• Transjugular Intrahepatic Portosystemic Shunt (TIPS) -- placement of one or more stents between the hepatic vein and portal vein -> decompresses portal system by shunting blood around the liver

6.  Secondary Prophylaxis

• Endoscopic Management (EBL, Endoscopic Injection Sclerotherapy)
• Non-Selective Beta-Blockers
• Non-Selective Beta-Blockers + nitrates
• TIPS procedure

• Likely a result from seeding of ascitic fluid via the blood, lymph, or bacteria crossing the gut wall

• Low protein levels in the ascitic fluid
• High bilirubin
• Variceal hemorrhage
• Prior SBP

• Fever
• Increase WBC count
• Abdominal pain
• Guarding
• Hypoactive/absent bowel sounds
• Rebound tenderness
• Some pts are asymptomatic

• Low ascitic protein levels (< 1 g/dL)
• Variceal hemorrhage
• Prior SBP

Antibiotics and Albumin

Antibiotics

• 3rd Gen Cephalosporins (Cefotaxime, Ceftriaxone)
• Fluoroquinolones (Cipro, Levo)

Duration of therapy:

5 days if repeat paracentesis @ 48 hrs reveals sterile ascitic fluid

10-14 days in no follow-up paracentesis performed

Primary prophylaxis x 7 days

• Accumulation of gut-derived nitrogenous substances (ammonia) bypass the liver via portal-to-systemic shunting --> enter the CNS and alter neurotransmitter
• Elevated arterial ammonia levels are the most commonly cited causative agent although there is poor correlation with ammonia levels and severity of HE
• Clinical symptoms range from subtle mental status changes to deep coma

1.  Cognitive

• confusion
• agitation
• euphoria
• restlessness, insomnia
• reversal of day-night sleep pattern
• somnolence, coma

2.  Motor

• fine tremor
• slowed coordination
• asterixis
• posturing and flaccidity

3.  Increased serum ammonia levels

1.  Lactulose

• Removes nitrogen-containing compounds from GI tract
• Lowers GI pH -- bacteriostatic effect reduces the number of ammonia-producing bacteria
• Decreasing ammonia content in GI tract leading to diffusion of additional ammonia into the GI tract from the serum and then subsequent GI removal
• ADR: flatulence, diarrhea, abdominal pain

2.  Antibiotics

• Inhibits activity of urease-producing bacteria
• Place in therapy: patients refractory to lactulose, can use in combo w/ lactulose or substitution
• Neomycin -- ADR: ototoxicity, nephrotoxicity
• Metronidazole -- ADR: Disulfiram-Like Rxn
• Rifaximin -- ADR: GI

• Reduces synthesis of clotting factors
• Decrease absorption of vitamin K

• Bleeding
• Increased PT/INR

• Vitamin K
• Fresh Frozen Plasma -- give if pt. is actively bleeding or before invasive procedure to decrease bleeding