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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

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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.

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

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Case Intro

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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

Physical Exam/ROS today:

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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

Diagnostics/Labs

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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)

Cirrhosis

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Cirrhosis: Risk Factors

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Cirrhosis: Pathophysiology

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Cirrhosis: Pathophysiology

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Cirrhosis: Pathophysiology

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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

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Cirrhosis: Major Complications

• Ascites

• Spontaneous Bacterial Peritonitis

• Varices & Variceal Bleeding

• Hepatic Encephalopathy

• Coagulation Defects, Hepatorenal syndrome, Hepatopulmonary syndrome, Endocrine dysfunction

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Cirrhosis: Presentation

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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/Lytes

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

Liver Dysfunction Test Interpretation for our patient

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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

Cirrhosis: Classification Scores

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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.

Ascites

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Ascites: Pathophysiology

Dipiro 19

Ascites: Physical Findings

• Test for distended abdomen

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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

Paracentesis

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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)

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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

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Ascites: Treatment

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Ascites: Treatment

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• 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

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

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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?

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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

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8g Albumin/ L ascitic fluid removed; prevent PCD

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?

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Fluid WBC 95 M/L Fluid RBC 10000 M/L Fluid Neut 3% Fluid Albumin 8 g/L

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 ?

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Other DRP Management

• What are some additional plans for JF’s other DRPs?

– Pain

– Gout

– Alcohol withdrawal

– Hypercholesterolemia

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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.

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Case Part B: SBP

Peritoneal Fluid Cell Count

• The medical team’s provisional diagnosis is spontaneous bacterial peritonitis (SBP).

•

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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

SBP: Pathophysiology

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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

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SBP: Diagnosis questions

Peritoneal Fluid Cell Count

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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.

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.

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SBP: Acute Treatment

• What would you recommend for JF’s empiric treatment?

– How long would you treat for?

• Provide alternative recommendations.

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SBP: Acute Treatment

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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?

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)

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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

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SBP 2o Prophylaxis: Options

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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

10-minute Intermission

Variceal Bleeding, Hepatic Encephalopathy

M Legal, PharmD March 7th, 2014

Thanks to Krystin Boyce and Claudia Ho for sharing some of

their slides/diagrams.

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

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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

Why do esophageal varices form and what danger(s) do they pose?

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Case Question

Varices and Portal Hypertension

• Portal pressure ↑ due to:

– ↑ resistance to flow in fibrous nodular liver

– active intra-hepatic vasoconstriction

– Splanchnic vasodilation

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Esophageal varices

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

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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

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Case Question

What are the goals of therapy for JF?

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

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Case Question

Outline a pharmacotherapeutic plan for JF’s variceal bleeding.

– Include pharmacologic and non-pharmacologic measures

Non-Pharmacologic

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• 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

Endoscopic band ligation

Pharmacologic Alternatives

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• 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

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)

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

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?

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Types of Prevention

Pre-Primary:

Preventing the development of varices

Primary:

Preventing bleed when varices present

Secondary:

Preventing recurrence of hemorrhage

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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

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)

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ARR NNT

Preventing Recurrence

21% 5 over 1-2 yrs

Mortality 7% 14 over 1-2 yrs

Transjugular intrahepatic portosystemic shunt (TIPS)

What should we order for JF?

• NSBB + Banding

– Dose?

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).

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Hepatic Encephalopathy

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

What risk factors does JF have for developing hepatic encephalopathy?

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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)

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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

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Goals of Therapy

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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

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)

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• Evidence is limited or conflicting for most therapies

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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

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

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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

What should we order for JF?

• Avoid triggers (electrolyte abnormalities, benzos)

• Abstinence from alcohol, avoid NSAIDs

• Start Lactulose- dose??

Questions?

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