Provided to the Lower Mainland Pharmacy Services residents at St Paul's Hospital, Vancouver, British Columbia on March 7, 2014.

1. 1
Cirrhosis, Portal Hypertension,
and Complications
LMPS Residency Academic Half-day - March 7, 2014
Presenters: Joan Ng, LMPS Pharmacy Resident 2013-2014
Dr. Michael Legal, Pharm D

2. 2
Learning Objectives
1. To describe the pathophysiology and etiology of
cirrhosis and its associated complications (ascites,
spontaneous bacterial peritonitis, portal
hypertension, variceal bleeding, hepatic
encephalopathy).
2. To assess a patient who presents with clinical signs
and symptoms, as well as laboratory findings,
indicative of complication(s) of liver disease, and
make appropriate treatment recommendations and
monitoring plans to resolve drug-related problems.

3. Outline
• Case Intro (HPI, PMHx, MPTA, Sx, ROS, Diagnostics, Labs)
• Introduction to Cirrhosis
• Case Part A: Ascites
• Case Part B: Spontaneous Bacterial Peritonitis
• Intermission (10 minutes)
• Case Part C: Variceal Bleeding
• Case Part D: Acute Hepatic Encephalopathy
3

4. Case Intro
4
JF, 65 y.o. male, presented to ER. NKDA
CC Increased abdominal girth and pain
HPI •Noticed increasing abdominal girth and pain over last several weeks
•has not affected his ADLs, but he has been uncomfortable
PMHx Cirrhosis, diverticulitis (not active issue), gout, hypercholesterolemia
SHx Smokes 6-8 cigarettes/day
Drinks 6-8 beers/day x40 years
Retired mechanic
MPTA Rosuvastatin 20mg/day
Indomethacin 50mg po tid prn (last took 3 months ago – gout)
Ibuprofen 400mg po tid prn (for knee and belly pain)
No herbals

5. Physical Exam/ROS today:
5
Vitals T = 37.1 C, BP = 120/70, HR = 82, RR = 22, O2Sats 99% RA
General Not in acute distress. Historical weight: 65kg; currently: 72kg
CNS/Neuro A+O x3, asterixis
HEENT Mild scleral icterus
Resp Chest clear, equal air entry to bases bilaterally
CVS JVP 3cm ASA, Normal S1 S2
Abdo/GI Protuberant abdomen, bulging flanks, shifting dullness, positive
fluid wave, prominent abdominal veins, caput medusae
GU N/C
MSK/EXT Palmar erythema, spider angiomata
Skin Pale, mild jaundice

6. Diagnostics/Labs
6
CXR No consolidation or opacity
Abdominal
U/S
Enlarged cirrhotic liver, evidence of portal hypertension with
recanalized periumbilical vein, abdominal wall varices,
splenomegaly, and ascites. No stones observed.
Na+ 135 (135-148) WBC 5.6 (4-11)
K+ 3.6 (3.6-4.7) Neut 3.2 (2-8)
Cr 84 (60-100) Hg 125 (135-170)
Urea 6.3 (2.5-8) Plts 70 (150-400)
ALT 78 (15-55) T BILI 50 (<20)
AST 277 (15-45) Alb 28 (35-48)
GGT 959 (<50) INR 1.3 (0.9-1.2)
ALK 264 (30-105)

7. Cirrhosis
7

8. Cirrhosis: Risk Factors
8

9. Cirrhosis: Pathophysiology
9

10. Cirrhosis: Pathophysiology
10

11. Cirrhosis: Pathophysiology
11

12. Cirrhosis: Pathophysiology
• Resistance to portal blood flow
• Intrahepatic
– Decreased nitric oxide, increased vasoconstrictors
• Splanchnic
– Increased nitric oxide vasodilation, decreased
responsiveness to vasoconstrictors
• Further increased portal blood pressure
• = portal hypertension
12

13. Cirrhosis: Major Complications
• Ascites
• Spontaneous Bacterial Peritonitis
• Varices & Variceal Bleeding
• Hepatic Encephalopathy
• Coagulation Defects, Hepatorenal syndrome,
Hepatopulmonary syndrome, Endocrine
dysfunction
13

14. Cirrhosis: Presentation
14
Physical Exam/ Laboratory /Screening
CNS Malaise, encephalopathy, asterixis
HEENT Scleral icterus
CVS
Resp Pleural effusion, respiratory distress
GI/GU Anorexia, abdominal pain, enlarged abdomen
(with shifting dullness, positive fluid wave test)
Upper GI endoscopy:
esophageal or gastric varices
Liver/Renal/Lyte
s
CT abdo: hepatomegaly, splenomegaly, hepatic
metastases
U/S: gallstones, biliary duct abnormalities,
recanalized paraumbilical vein, abdominal wall
varices
Liver dysfunction tests:
-Elevated AST, ALT, GGT, ALP
Liver enzymes:
-↓Alb, ↑bili, ↑INR/PTT
-Thrombocytopenia (Plts <150)
Endo Gynecomastia
MSK/Derm Pruritis, jaundice, palmar erythema, spider
angiomata, caput medusae

15. Liver Dysfunction Test
Interpretation for our patient
16
ALT 78 (15-55)
AST 277 (15-45)
GGT 959 (<50)
ALK 264 (30-105)
Alcoholic liver disease
AST 6-7x ULN, AST:ALT ratio 2:1

16. Cirrhosis: Classification Scores
17
Child-Pugh Classification Mayo End-Stage Liver Disease (MELD)
Score
- Used widely for quantifying myriad
effects of cirrhotic process on lab and
clinical manifestations of disease
- Basis for recommended dose
adjustments for patients
- Accepted classification scheme used
by United Network for Organ Sharing
(UNOS)
- to quantify end-stage liver disease for
transplant planning
Components:
- bilirubin, albumin, ascites,
encephalopathy, PTT
- Total score from 5-15
- A (5-6), B (7-9), C (≥10)
Components:
- SrCr, bilirubin, INR, and etiology of
liver disease
- Does not incorporate subjective
reports of ascites or encephalopathy
Controversy: Child-Pugh highly subjective. Should MELD replace it? Ongoing.

17. Ascites
18

18. Ascites: Pathophysiology
Dipiro 19

19. Ascites: Physical Findings
• Test for distended abdomen
20
Flank Dullness Set-up: patient is supine
(+) if percussion is tympanic over umbilicus,
dull over lateral abdomen and flank
Shifting Dullness Set-up: patient is lying on one side
(+) suggesting ascites when area of
tympany shifts towards the side of the
patient facing up
Fluid
Thrill/Wave
Set-up: patient is supine; pressure applied
by patient/assistant on mid-abdomen,
examiner has one hand on either flank
(+) if shock-wave of fluid detected with
fingertips on one side of flank when a sharp
tap is applied to opposite flank

20. Paracentesis
21

21. Ascites: Diagnosis
• Abdominal paracentesis with ascitic fluid analysis
– Efficient, effective, and safe
– Appearance (clear/turbid/milky/bloody)
– Serum ascites albumin gradient: Serum Alb – fluid Alb
• If > 11g/L, portal hypertension is present with 97% accuracy
– CBC-Differential
• If WBC ≥500/mm^3 or ANC ≥250/mm^3, consider antibiotics (SBP)
22

22. Case Questions
• What are all of JF’s drug-related problems?
• What are the goals of therapy regarding his
ascites DRP?
– Improve patient’s QoL
– Minimize risks of electrolyte disturbances, acid-
base abnormalities, hepatic encephalopathy,
hypovolemia, renal insufficiency
– Little effect on survival expected
23

23. Ascites: Treatment
24

24. Ascites: Treatment
25
• Non-pharmacological:
– Avoid hepatotoxins
– Alcohol abstinence
– Sodium restriction to 2000mg/d
• Pharmacological:
– Spironolactone 100mg + Furosemide 40mg
• Increase q3-5 days, goal = 0.5kg daily weight loss
(1kg/day if peripheral edema present)
– Alternatives: amiloride, eplerenone

25. Ascites: Monitoring
• Efficacy:
– Pain, decrease over time; monitor daily
– Weight loss, 0.5kg/day goal; weigh daily
– Abdominal girth, decrease; monitor daily
• Safety:
– Hyperkalemia/hypokalemia; monitor daily
– Hyponatremia (Na<120mEq/L); monitor daily
– Gynecomastia, presence; long-term
26

26. Ascites: Tense or Refractory
• How would your management change if the
patient has large-volume or tense ascites?
• What if he has ascites refractory to diuresis?
27

27. Ascites: Tense or Refractory
• Tense Ascites (Grade 3 Ascites)
– Large volume paracentesis (usually >5L) before
diuresis and salt restriction
– Albumin?
• Refractory Ascites
– Serial paracentesis (5-10L q1-2 weeks)
– Diuretics
– TIPS, liver transplant
28
8g Albumin/ L ascitic fluid removed; prevent PCD

28. More Info Case Part A: Ascites
• As part of management for JF’s ascites the medical
team does paracentesis. The fluid is sent for analysis
and yields the following:
• Peritoneal Fluid Cell Count
• Gram stain shows +3 RBC (otherwise negative).
• How would you interpret this result?
29
Fluid WBC 95 M/L
Fluid RBC 10000 M/L
Fluid Neut 3%
Fluid Albumin 8 g/L

29. Ascitic Fluid Interpretation
• Appearance
• SAAG
– 28 – 8 = 20g/L (>11g/L)
– Patient has portal hypertension
• CBC-D
– Corrected WBC = 95 – 13 = 82 <500
– No infection
• Fluid albumin <10g/L ?
30

30. Other DRP Management
• What are some additional plans for JF’s other
DRPs?
– Pain
– Gout
– Alcohol withdrawal
– Hypercholesterolemia
31

31. Case Part B: SBP
• JF was successfully managed for his ascites
and was sent home on an appropriate diuretic
regimen (mostly due to the excellent work of
his pharmacist).
• About a month later JF returns to your
hospital complaining of worsening belly pain
again, however this time he looks more
unwell. He is febrile, and slightly confused.
32

32. Case Part B: SBP
Peritoneal Fluid Cell Count
• The medical team’s provisional diagnosis is
spontaneous bacterial peritonitis (SBP).
•
33
Vitals T = 38.3 C, BP = 100/60, HR = 94, RR = 22 O2Sats 99% RA
WBC 15.6 (4-11)
Neut 11.2 (2-8)
Fluid WBC 1000 M/L
Fluid RBC 250 M/L
Fluid Neut 60%
Fluid Albumin 8 g/L

33. SBP: Pathophysiology
34

34. SBP: Etiology
• Most common pathogens:
– Gram-negative Enterobactericeae (E. coli,
Klebsiella pneumoniae)
– Also Gram-positive Strep pneumoniae is common
• Risk factors:
– Low ascitic fluid albumin concentration (fluid
albumin <10g/L)
– Coexisting GIB
– Severe hepatic insufficiency
35

35. SBP: Diagnosis questions
Peritoneal Fluid Cell Count
36
Vitals T = 38.3 C, BP = 100/60, HR = 94, RR = 22 O2Sats 99% RA
WBC 15.6 (4-11)
Neut 11.2 (2-8)
Fluid WBC 1000 M/L
Fluid RBC 250 M/L
Fluid Neut 60%
Fluid Albumin 8 g/L
• What findings are
consistent with
SBP?
• Provide an
interpretation of
the Peritoneal
Fluid Cell Count.

36. SBP: More Questions
• When should treatment be initiated?
• What is this patient’s current main DTP?
– JF is experiencing worsening belly pain, fever, and
malaise secondary to untreated SBP, and would
benefit from initiation of appropriate antibiotic
drug therapy.
37

37. SBP: Acute Treatment
• What would you recommend for JF’s empiric
treatment?
– How long would you treat for?
• Provide alternative recommendations.
38

38. SBP: Acute Treatment
39
Drug Dosing Regimen Cost SE/Monitoring
Cefotaxime* 2g IV q8h x5d $37.50/day Anaphylaxis during
first dose, SCr
Ciprofloxacin 400mg IV q12h x5d
500mg PO q12h x5d
$5.08/day
$0.14/day
Dizziness, rash, QTc
prolongation
Amoxi-Clav 500/125mg PO q8h $1.32/day Diarrhea
*any 3rd generation cephalosporin okay; e.g. ceftriaxone
Piperacillin/tazobactam?

39. SBP: Acute - Monitoring
• How would you monitor the patient, in terms
of efficacy and safety?
• Efficacy:
– Fever, malaise, pain; resolution within 5 days
– Infection; resolution within 5 days
• Safety:
– SE of antibiotic (anaphylaxis, GI symptoms)
40

40. SBP: Prophylaxis
• What is the proposed theory behind
prophylaxis?
– Selective intestinal decontamination
• Would you recommend secondary prophylaxis
for this patient?
– 40-70% risk of repeat infection per year
41

41. SBP 2o Prophylaxis: Options
42
Drug Dosage Regimen Cost SE/Monitoring
Norfloxacin 400mg PO daily $17.08/month LFT increase,
Eosinophilia, Qtc
Ciprofloxacin 750mg PO once
weekly
$5.52/month GI, ALT/AST
increase, QTc
prolongation
TMP/SMX 160/800mg PO 5
days/wk
$2.6/month Hematologic
toxicity, rash (SJS)
Cochrane review, N=674 total
• Mixture of primary and secondary prophylaxis
• SBP: RR=0.2, ARR=0.168, NNT=5.9
• Mortality: RR=0.91, NNT=11

42. 10-minute Intermission

43. Variceal Bleeding,
Hepatic Encephalopathy
M Legal, PharmD
March 7th, 2014
Thanks to Krystin Boyce and
Claudia Ho for sharing some of
their slides/diagrams.

44. Case Part C: Variceal Bleeding
• Two months after JF was discharged (post-SBP), he is
brought back to the hospital by EMS. He called 911 after
several episodes of bloody vomit (hematemesis).
• Initial findings on admission to the ER are: BP 90/60, HR 110.
• I/P: UGIB- Probable variceal bleeding
45
Na+ 138 (135-148) WBC 10.6 (4-11)
K+ 3.6 (3.6-4.7) Neut 8.2 (2-8)
Cr 95 (60-100) Hg 65 (135-170)
Urea 8.3 (2.5-8) Plts 65 (150-400)
INR 1.4

45. Why do esophageal varices form
and what danger(s) do they pose?
46
Case Question

46. Varices and Portal Hypertension
• Portal pressure ↑ due to:
– ↑ resistance to flow in
fibrous nodular liver
– active intra-hepatic
vasoconstriction
– Splanchnic vasodilation
47

47. Esophageal
varices

48. Variceal Bleeding
• Overall incidence 25-40% in patients with cirrhosis
• High mortality rate
– 30- 50% with first bleed
– Higher mortality with more advanced liver disease
• Rebleeding common following intitial hemorrhage,
especially within first 72 hours
• >50% recurrent occur w/in first 10 days of initial
bleed and risk returns to baseline after 6 weeks
49

49. Risk Factors for Bleeding
• Risk Factors for bleeding: HVPG > 12 mm Hg
• Varix size and location
– Large esophageal varices (highest risk for first hemorrhage)
– Small varices in patients with advanced liver failure
– Isolated cluster of varices in fundus of stomach
• Variceal appearance on endoscopy
– Red wale marks - longitudinal streaks on varices
– Cherry-red spots - discrete red flat spots on varices
– Hematocystic spots - discrete, red, raised spots
• Degree of liver failure - Child-Pugh class C cirrhosis
50

50. Case Question
What are the goals of therapy for JF?

51. Goals of Therapy- Variceal Bleeding
Prevent mortality associated with the variceal bleed
Maintain support of- (ABC’s)
Airway, breathing, circulation
Achieve hemostasis (stop the bleed)
Prevent infection
Avoid adverse effects of drug therapy
Prevent recurrent bleeds in the future
52

52. Case Question
Outline a pharmacotherapeutic
plan for JF’s variceal bleeding.
– Include pharmacologic and non-pharmacologic
measures

53. Non-Pharmacologic
54
• Fluid and blood products
–If hemodynamically compromised
–Bolus of 0.9% Sodium Chloride IV
–PRBCs (Blood) transfusions- goal hemoglobin 80 g/L
–Platelets, fresh frozen plasma to control bleeding
• Endoscopic Therapies
–Endoscopy used for diagnostic and for therapeutic purposes
–Endoscopic band ligation
–Sclerotherapy
• Rescue therapies
–Early rescue (severe uncontrolled bleeding)
• Balloon Tamponade
–Late rescue (recurrent bleeding, despite repeated endoscopic measures)
• Transjugular intraheptic portosystemic shunt

54. Endoscopic band
ligation

56. Pharmacologic Alternatives
57
• Presumptive antibiotic therapy- beneficial
Norfloxacin 400 mg po bid, IV cipro, IV ceftriaxone (2g iv q24h x 7/7 if sick)
• Vaso-active drug therapy
–Terlipressin alone- not available in Canada
–Octreotide/ Somatostatin + EBL used in combo (1st line)
–No clear benefit seen if used as monotherapy (mixed evidence)
Doses: O: 50mcg IV bolus, then continuous infusion 50mcg/hour
S: 250 mcg IV bolus, then continuous infusion 250 mcg/hour
 Infection RR 0.32
Mortality RR 0.39
Initial Bleeding Control NNT = 8
5 Day Hemostasis NNT = 5

57. What would you order?
• Stop NSAIDS (if not done already)
• NS 1L Bolus X 1
• PRBCs, +/- plts
• Ceftriaxone 2g IV daily X 7 days
• Banding of bleeding varices (EBL) AND
• Octreotide 50 mcg bolus then 50 mcg/hr infusion X
72 hours (continue up to 5 days until bleed free X 24
hours)

58. What would you monitor?
• Vitals- BP, HR, volume status q1h (or more frequently)
• LOC
• Hg, obvious signs of bleeding (hopefully stopping),
rebleeding
• Octreotide, somatostatin- N/V, hyperglycemia (BG tid)
• Infection (WBC, T)
• Complications of EVL- esophageal ulcers, re-bleeding

59. Case Questions
• What options are available to reduce the
risk of re-bleeding?
• In a patient with cirrhosis but no history of
variceal bleeding are any strategies
available to mitigate the risk of future
variceal bleeding?

60. 61
Types of Prevention
Pre-Primary:
Preventing the development of varices
Primary:
Preventing bleed when varices present
Secondary:
Preventing recurrence of hemorrhage

61. 62
Evidence Summary
Prevention of Variceal Bleeds
• Pre-Primary (none present)
– No benefit of drug therapy or EBL if no varices
• Primary (Varices, no hx bleed)
– NSBB + EBL not superior to beta-blocker mono-therapy
– NSBB = EBL
– Beta-blockers:
– ↓ risk of 1st variceal bleed: ARR 9%, NNT=11 for 2yrs
• Propranolol 20mg bid
• Nadolol 20-40 mg daily
• Carvedilol 6.25-12.5 mg/day ($)
– Nitrates may  bleeding
– Nitrates + NSBB not more effective than NSBB
Aim: Titrate BB to 25% ↓ in
HR or 55-60bpm

62. Evidence Summary
Prevention of Variceal Bleeding
• Secondary Prevention (Hx bleed)
– NSBB + EBL (1st line) better than either alone
• Titrate HR 50-60 bpm or  25%
• Nitrates + BB = NSBB (mortality & bleeding)
63
ARR NNT
Preventing
Recurrence
21% 5 over 1-2 yrs
Mortality 7% 14 over 1-2 yrs

63. Transjugular intrahepatic portosystemic shunt
(TIPS)

64. What should we order for JF?
• NSBB + Banding
– Dose?

65. Case Part D: Hepatic Encephalopathy
• Despite recovering from his bleed, JF becomes
increasingly confused during the admission.
The team suspects that he is suffering from
acute hepatic encephalopathy (HE).
66

66. 67
Hepatic Encephalopathy
The Int Journ Biochem & Cell Biol. 2003:35(8) p.1175-1181

67. What risk factors does JF have for developing
hepatic encephalopathy?
68

68. Risk Factors
• ↑ dietary protein
• Constipation
• GI bleed
• med noncompliance
• Infection
• azotemia
• ↓ K
• Change in volume/water
• Hypoxia
• portosystemic shunt
• portal vein thrombosis
• Medications (e.g. CNS depressants)
69

69. Labs & Diagnostics
Hepatic Encephalopathy
• Signs & Symptoms
– Mental status changes
– Flapping tremor “asterixis”
– Mood/behaviour changes
– Other signs indicative of hepatic failure
– Stages (1) confusion; (2) drowsiness; (3) stupor; (4) coma
• Diagnostics “Diagnosis of Exclusion”
– LFTs, Lytes, BUN, SCr, Glu
– **Blood ammonia level
– Head CT/MRI
70

70. Goals of Therapy
71
Normalize Level of consciousness
Remove reversible causes and avoid precipitants
Prevent worsening
Prevent recurrence
Improve or maintain quality of life
Limit adverse effects of drug therapy

71. Non-pharmacologic Measures
Non-Drug Measures:
• Aim to avoid HE/correct triggers
– Avoid constipation, electrolyte abnormalities (Na+, K+),
hypovolemia, CNS depressants
– Routine protein restriction NOT supported by evidence.
May restrict dietary protein acutely (60–80 g/d)
72

72. • Evidence is limited or conflicting for most therapies
73
Pharmacologic Measures
Medication
Lactulose
30-45ml po q1h until catharsis.
Then ↓ 15-30mL po 2-4x/day
“titrate to 3-4 loose BMs/day”
• MOA: acidification of colon:NH3  NH4+
• drug of choice, based on anecdotal/clinical experience
•Cochrane Review: lactulose/disaccharides is inconclusive. Overall
RR of no improvement in HE=0.4 (lactulose vs. no therapy)
•2 prevention: lactulose ± rifaximin 550 bid (Gastro
2009;137:885 NEJM 2010;362:1071)
Oral neomycin
(not available in Canada)
• probably “as good as” lactulose
• ototoxity/ nephrotoxicity concern in long-term
Rifaximin 400mg po tid • MOA: ↓ gut bacteria ↓ NH3 prod
•Rifaximin “at least as effective” as other abx or lactulose and may
be better tolerated (World J Gastro 2012; 18: 767-77)
•Cost $$$, availability can be an issue

73. Am J Gastroenterol 2013; 108:1458–63
For overt hepatic encephalopathy in ICU patients in India
combination of lactulose + rifaximin was superior to lactulose alone
(up to 10 days of Rx)
Primary outcome: reversal of hepatic encephalopathy (76% vs 44%)
Decreased mortality, decreased hospital stay

74. 75
Other Pharmacologic Measures
Medication
Other antibiotics •MOA: ↓ gut bacteria ↓ NH3 prod
•Almost no evidence for these
•Vancomycin po (costly)
•Metronidazole po (risk of toxicity long-term)
Multiple other agents Flumazenil, zinc, acarbose (in patients with DM)
•Limited/conflicting evidence

75. What should we order for JF?
• Avoid triggers (electrolyte abnormalities, benzos)
• Abstinence from alcohol, avoid NSAIDs
• Start Lactulose- dose??

76. Questions?
77

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