Management of Hospitalized Patients with Cirrhosis Bilal Hameed, - - PDF document

10/26/2015 1

Management of Hospitalized Patients with Cirrhosis

Bilal Hameed, MD Division of Transplant Hepatology University of California, San Francisco

I have no financial relationships to disclose within the past 12 months relevant to my presentation My presentation does not include discussion of off-label or investigational use

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Outline

• Complications of cirrhosis

1.

Portal hypertension related variceal bleed

2.

Ascites, hyponatremia and hydrothorax

3.

Hepatic encephalopathy

4.

Renal failure and HRS

• Infections in cirrhosis
• Liver transplantation

Compensated cirrhosis Decompensated cirrhosis Death

Natural History of Cirrhosis

Development of complications:  Variceal hemorrhage  Ascites  Encephalopathy  Jaundice

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Question

• Most common decompensation in patient

with cirrhosis?

1.

Variceal bleed.

2.

Hepatic encephalopathy.

3.

Ascites.

4.

HCC.

5.

Jaundice.

Ascites (58%) Jaundice Encephalopathy GI hemorrhage Probability of developing event

20 60 80 100

60

40

20 40 80 100 120 140 160

Months

Gines et. al., Hepatology 1987.

Complications in Compensated Cirrhosis

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60 40 80 100 120 140 160 40 60 80 20 20 100

Months Probability of survival All patients with cirrhosis Decompensated cirrhosis

180

Median survival ~ 9 years Median survival ~ 1.6 years

Gines et. al., Hepatology 1987.

Decompensation Shortens Survival

Esophageal Varices

• Seen in 50% patients with cirrhosis
• 10-15% of all GI bleeds (~ 40,000 patients)
• $1.2 billion in health care expenditure

10/26/2015 5 Small varices Small varices Large varices Large varices No varices No varices

7-8%/year 7-8%/year 7-8%/year 7-8%/year

Merli et al. J Hepatol 2003;38:266 Merli et al. J Hepatol 2003;38:266

Varices Increase in Diameter Progressively

% Patients without bleeding % Patients without bleeding

100 100 50 50 25 25

12 12 24 24

75 75

36 36 12 12 24 24 36 36

Large Varices * * p<0.01 * p<0.01 *

2-year probability of first bleed:  Small varices: 7%  Large varices: 30% 2-year probability of first bleed:  Small varices: 7%  Large varices: 30% Time (months) Time (months)

No Varices Small Varices

*Merli et al., Hepatol 2003, **Conn et al., Hepatology 1991 *Merli et al., Hepatol 2003, **Conn et al., Hepatology 1991

Large Varices Are More Likely To Rupture

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What is the Risk of Mortality with Variceal Bleed?

1980 2013 2 months mortality 40% 6 weeks mortality 20%

• Pharmacotherapy
• Endoscopic

innovations

• IR Procedures
• Better ICU care

Better Bleeding Control Resulted in Decrease Mortality

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Case Presentation

• 60-year-old female with NASH cirrhosis is

brought to the ER because of melena. No prior endoscopy. Hgb is 8 (baseline 11).

• What is the best pharmacologic treatment
• ption?
• 1. IV PPI
• 2. IV PPI and IV octreotide
• 3. PO PPI, octreotide and antibiotics
• 4. IV PPI, octreotide and antibiotics

Case Presentation

• 60-year-old female with NASH cirrhosis is

brought to the ER because of melena. No prior endoscopy. Hgb is 8 (baseline 11).

• What is the best pharmacologic treatment
• ption?
• 1. IV PPI
• 2. IV PPI and IV octreotide
• 3. PO PPI, octreotide and antibiotics
• 4. IV PPI, octreotide and antibiotics

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Role of Endoscopy

• 40-50% have non variceal source of

bleeding like PUD, esophagitis, MW tear etc.

Dig Dis. 2005;23:11-7.

Case Presentation

• 50-year-old male with HCV related cirrhosis

is brought to the ER because of melena and hypotension (SBP 80 mmHg). What is the first priority in the management of this patient?

• Emergent upper endoscopy.
• Start antibiotics for SBP prophylaxis.
• Transfuse blood.
• Venous access and hemodynamic stability.

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Case Presentation

• 50-year-old male with HCV related cirrhosis

is brought to the ER because of melena and hypotension (SBP 80 mmHg). What is the first priority in the management of this patient?

• Emergent upper endoscopy.
• Start antibiotics for SBP prophylaxis.
• Transfuse blood.
• Venous access and hemodynamic stability.

Treatment of Acute Variceal Hemorrhage

• General Management:
• IV access and fluid resuscitation
• Airway protection
• Antibiotic prophylaxis
• Correct coagulopathy
• Specific therapy:
• Pharmacological therapy
• Early endoscopic therapy: band ligation
• Shunt therapy: TIPS, surgical shunt

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Transfusion Strategy: Too Much is Bad!

• 921 pts (277 with cirrhosis)
• Restrictive (Hgb <7) vs

liberal transfusion (Hgb <9)

• Liberal strategy had

increase portal pressure and rebleeding (11% vs 22%)

• Survival was improved

with restrictive transfusions

Villanueva et al, NEJM 2013 Control Antibiotic Absolute rate (n=270) (n=264) difference (95% CI) Infection 45% 14%

• 32%

(-42 to –23) SBP / Bacteremia 27% 8%

• 18%

(-26 to –11) Death 24% 15%

• 9%

(-15 to –3) Control Antibiotic Absolute rate (n=270) (n=264) difference (95% CI) Infection 45% 14%

• 32%

(-42 to –23) SBP / Bacteremia 27% 8%

• 18%

(-26 to –11) Death 24% 15%

• 9%

(-15 to –3)

Bernard et al., Hepatology 1999; 29:1655 Bernard et al., Hepatology 1999; 29:1655

Meta-analysis of 5 randomized trials

Prophylactic Antibiotics Improve Outcomes

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Hou M-C et al., Hepatology 2004 Hou M-C et al., Hepatology 2004

Prophylactic antibiotics (n=59) Prophylactic antibiotics (n=59) % free of variceal hemorrhage % free of variceal hemorrhage

1.0 1.0 0. 6 0. 6 0. 2 0. 2 0. 8 0. 8 1

No antibiotics (n=61) No antibiotics (n=61)

2 3 12 12 30 30

Follow-up (months) Follow-up (months)

18 18 24 24 0. 4 0. 4 Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days

Greatest benefit in first 7 days

Prophylactic Antibioics Reduce Probability of Recurrent Variceal Hemorrhage

Pharmacological Treatment for Acute Variceal Bleed

• Somatostatin
• Variable results in meta-analysis
• Octreotide
• Vasopressin
• Terlipressin (Not available in US)
• Vasopressin analogue
• Improve survival in some studies

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Pharmacologic therapy

Parameter Vasopressin Octreotide Dose 20 U bolus; 0.4- 0.6 U/min IV 50  bolus; 50 /hr IV Hemostasis ~ 50% > 80% Rebleed ~ 50% 14-30% Complications 32-64% 0-15% Mortality 5%

Gastroenterology 1995;109:1289-94 Aliment Pharmacol Ther. 2004;20:S18-22 Dig Liver Dis. 2004;36:S93-100

Endoscopic Band Ligation

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Refractory Variceal Bleeding

• Balloon tamponade
• TIPS
• Surgical shunt

Hepatic vein Hepatic vein Portal vein Portal vein Splenic vein Splenic vein Superior mesenteric vein Superior mesenteric vein

TIPS TIPS

Transjugular Intrahepatic Portosystemic Shunt

• 1. Second rebleed for

esophageal varices

• 2. First rebleed for gastric

varices

• 3. Rebleed on

combination endoscopic plus pharmacologic therapy (10-20%)

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Portal Hypertensive Bleed

Gastric Varices Portal HTN Gastropathy Typical GAVE “watermelon stomach

Case

 56 yr with acute variceal bleed (1st episode)  Bleeding controlled with band ligation  No bleeding for 5 days  Child score 10. MELD 15 MAP 90 mmHg

Which is the best discharge regimen? 1) Beta blockers and nitrates 2) Serial ligation alone 3) Ligation and beta blockers 4) TIPS 5) Portacaval shunt

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Case

 56 yr with acute variceal bleed (1st episode)  Bleeding controlled with band ligation  No bleeding for 5 days  Child score 10. MELD 15 MAP 90 mmHg

Which is the best discharge regimen? 1) Beta blockers and nitrates 2) Serial ligation alone 3) Ligation and beta blockers 4) TIPS 5) Portacaval shunt

(19 trials) (19 trials)(26 trials) (26 trials) (54 trials) (54 trials)

% Rebleeding Rebleeding

80 80 60 60 40 40 20 20 Untreated Untreated - blockers - blockers Sclero- therapy Sclero- therapy (18 trials) (18 trials) Ligation Ligation (6 trials) (6 trials) HVPG- Responder s* HVPG- Responder s* (6 trials) (6 trials)  -blockers + ISMN  -blockers + ISMN (2 trials) (2 trials) Ligation + -blockers Ligation + -blockers Bosch and García-Pagán, Lancet 2003; 361:952 Bosch and García-Pagán, Lancet 2003; 361:952

*  HVPG <12 mmHg

• r >20% from

baseline *  HVPG <12 mmHg

• r >20% from

baseline

Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation + -Blockers

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Acute Variceal Bleed Key Points

Ascites

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Causes of Ascites

Cause Proportion

Cirrhosis 80% Malignancy 10% Heart Failure 4% Nephrotic Syndrome 2% Tuberculosis 2% Pancreatitis 1% Others (Budd Chiari) 1%

Case

• 47 yr old male with hepatitis C cirrhosis now

presented with new onset abdominal distention and leg swelling.

• Ultrasound showed large ascites. No evidence
• f portal vein thrombosis.

INR 2.2 5 30 62 50 66 7.0 140

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Which Statement is correct?

1.

Need correction of INR before paracentesis.

2.

No need to send cell count as no abdominal pain and fever.

3.

SAAG of > 1.1 is only seen in portal hypertension.

4.

Direct inoculation into blood culture bottles at the bedside improves yield.

Which Statement is correct?

1.

Need correction of INR before paracentesis.

2.

No need to send cell count as no abdominal pain and fever.

3.

SAAG of > 1.1 is only seen in portal hypertension.

4.

Direct inoculation into blood culture bottles at the bedside improves yield.

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SAAG

• Serum-ascites albumin gradient
• SAAG = serum albumin – ascites albumin
• SAAG ≥1.1 g/dL is 97% accurate at diagnosing

ascites due to portal hypertension

• High SAAG and high total protein (>2.5 g/dL)

suggests cardiac cause

Probability of Survival is Poor After Developing Ascites

56% 5 year survival

Planas et al. Clin Gastroenterol Hepatol. 2006

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When to Perform Paracentesis

• Rule out SBP
• Any new onset ascites
• Any admission to hospital
• Worsening of controlled ascites
• Any change in clinical status
• - Encephalopathy
• - Unexplained renal failure

Ascitic Fluid Analysis

Runyon, Hepatology 2004

Routine Optional

(Suspicion for Infection)

Unusual

Cell count & differential Culture (bedside) AFB Albumin Glucose Bilirubin Total Protein LDH Triglyceride Amylase Cytology Gram stain

10/26/2015 21 First-Line Therapy Tense ascites Paracentesis

Sodium restriction (<2 Gm/24 Hrs) and diuretics*

Non-tense ascites

*Diuretics: Spironolactone 100 mg/day, furosemide 40 mg/day or bumetanide 1 mg/day; uptitrate stepwise to spironolactone 400 mg/day, furosemide 160 mg/day or bumetanide 4 mg/day as tolerated

Refractory Ascites 10 % Second-Line Therapy

• Repeated large

volume paracentesis

• TIPS
• Liver

Transplantation

Management of Ascites

Adapted from Runyon BA. Hepatology. 2009; 49:2087-2107.

Treatment of Refractory Ascites

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2 4 6 8 10 12 14 16 18 Bleeding Ascites Pre-op Decompression

71% 25% 4%

Courtesy Dr.Jeanne M. LaBerge

TIPS Indications:UCSF Treatment: Serial LVP

• Colloid replacement is important
• Patients receiving albumin had less

hemodynamic deterioration, renal failure and hyponatremia

• Recommendation to administer 6-8 gm

albumin per L of ascites removed if more than 5 L removed

• Recent meta-analysis of 17 studies have

shown improved survival in the albumin group

Bernardi M, Carceni P et al. Hepatology 2012 Gines et al, Gastro 1988

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Routine prophylactic use of fresh frozen plasma or platelets before paracentesis?

• Not recommended
• Complications were reported in only about 1% of

patients

• Bleeding conditions occur in less than 1 per 1,000

patients who require paracentesis

• Coagulopathy should preclude paracentesis only

when there is clinically evident hyperfibrinolysis

• r DIC

Pache I et al. Aliment Pharmacol Ther 2005. Caldwell SH et al. Hepatology 2006.

Ascitic Fluid Analysis: cell count

• Normal ascites
• Total WBC upper limit 500 cells/mm3
• Total count can concentrate with diuresis, but

not PMN count

• PMNs normally account for 25-30%
• SBP definition PMNs >250 cells/mm3
• Culture: Direct inoculation into blood culture

bottles at the bedside to improve yield

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SBP

• Start broad spectrum antibiotics immediately
• Community acquired SBP
• Causes: Gram negative (E.Coli)
• 3rd generation cephalosporin (cefotaxime for 5-7 days)
• Hospital acquired SBP
• High risk of ESBL E.coli
• Treatment Failure
• Secondary bacterial peritonitis
• Resistant organism

Treatment Trials for SBP

Study N Results p Hospital Mortality

Cefotaxime vs ampicillin/ tobramycin 73 Cure 85% vs 56% <0.02 33% vs 43% Cefotaxime 5 vs 10 days 100 Cure 93% vs 91% Recurrence 12% vs 13% NS 33% vs 43% Oral ofloxacin vs cefotaxime 123 Resolution 84% vs 85% NS 19% vs 19% Cefotaxime with or without Albumin 126 Resolution 98% vs 94% Renal failure 10 vs 33% NS 0.002 10% vs 29%

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Probability of SBP recurrence Months

1.0 .8 .4 .2 .6 3 6 12 24 36

Recurrence of Spontaneous Bacterial Peritonitis is Common

Titó et al., Hepatology 1988; 8:27

70%

Case

• 47 yr old male with hepatitis C cirrhosis with
• ascites. He is on lasix and aldactone which

was recently increased.

• Exam showed large ascites.
• Now fatigue and worsening encephalopathy.

116 5.0 20 1.00 103

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Which statement is NOT True

• Need to stop diuretics.
• Start hypertonic saline.
• Fluid restriction.
• Associated with increase mortality.

Potential Consequences of Hyponatremia

• Hepatic encephalopathy
• Reduced quality of life
• Neurologic consequences after liver

transplantation

• Central Pontine Myelinolysis
• High incidence in patients with Na<127 prior

to OLT

• Associated with rapid correction of sodium
• May not be reversible
• Increased risk of hepatorenal syndrome and death

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Types of Hyponatremia in Cirrhosis

Hypovolemic Hyponatremia Hypervolemic Hyponatremia

Definition Na<130 in setting of intense sodium loss and contraction of intravascular volume Na<130 in setting of solute free water retention and expansion of ECF volume Clinical Findings Develops in a few days Signs of dehydration No ascites/edema Encephalopathy present May be transient Ascites/edema present Encephalopathy variable Causes Over diuresis Sodium loss Diarrhea Excess of solute-free water (spontaneous, fluid induced, drug induced, infections) Management Stop diuretics Treat diarrhea Give sodium cautiously Reduce fluid intake: free water restriction Increase free-water excretion

Types of Hyponatremia in Cirrhosis

Hypovolemic Hyponatremia Hypervolemic Hyponatremia

Definition Na<130 in setting of intense sodium loss and contraction of intravascular volume Na<130 in setting of solute free water retention and expansion

• f ECF volume

Clinical Findings Develops in a few days Signs of dehydration No ascites/edema Encephalopathy present May be transient Ascites/edema present Encephalopathy variable Causes Over diuresis Sodium loss Diarrhea Excess of solute-free water (spontaneous, fluid induced, drug induced, infections) Management Stop diuretics Treat diarrhea IV albumin Give sodium cautiously Reduce fluid intake: free water restriction Increase free-water excretion

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Conclusions

• Ascites is very common in cirrhosis
• Should be tapped whenever new, different, or

admitted to the hospital

• Low index of suspicion for SBP
• Need IV albumin for LVP
• Hyponatremia should be managed

according to overall volume status of the patient

Case

• 47 yr old male with NASH cirrhosis. History of hepatic
• hydrothorax. Now with worsening SOB.
• He had 2 thoracentesis last month.
• Best long term treatment for him?

1.

Chest tube placement

2.

Pleurodesis

3.

TIPS procedure

4.

Liver transplant

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Hepatic Hydrothorax

• Occurs in 5-10% with decompensated

cirrhosis

• Passage of ascites through diaphragmatic

defect

• Risk of spontaneous bacterial pleuritis
• Mainstay is control of ascites
• Chest tube is not indicated

Hepatic Hydrothorax: Treatment Options

• Repeated thoracentesis
• TIPS (50% patient may not be candidate)
• VATS and diaphragmatic repair (low

success rate and high mortality)

• Denver shunt (pleuro-venous shunt)
• PleurX Catheter
• Liver Transplantation

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Hepatic Encephalopathy

Case

• 47 yr old male with hepatitis C cirrhosis. Wife brought

him to ER with 3rd episode of hepatic encephalopathy.

• On exam he is sleepy and has asterixis.
• What is not needed in the work up?

1.

Infectious work up

2.

Rectal exam/melena

3.

Diagnostic paracentesis

4.

Ammonia level

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Prevalence of Hepatic Encephalopathy

• Two forms of HE are recognized: Overt and Minimal

based on the nature and severity of clinical manifestations

• Overt hepatic encephalopathy (OHE) occurs in:

‒ 30 to 45% of cirrhotic patients ‒ 10 to 50% of patients with TIPS

• Poor Survival
• 42% at 1 year
• 23% at 3 years

Mullen KD et al. Semin Liver Dis. 2007. Poordad FF. Aliment Pharmacol Ther 2006. Bustamante J et al. J Hepatol. 1999.

Blood Ammonia and Diagnosis of HE

• Accuracy is Technique-Dependant
• Efficient venous draw, rapid transport on ice to

reliable lab, quick analysis, pH controlled

• Not Specific
• Elevated in TPN, GI hemorrhage, intense

muscular activity, and urosepsis

• Limited Reliability
• Overt HE is not always accompanied by a very

high ammonia

• Not a Guide to Treatment
• Not a useful clinical endpoint for HE treatment in

practice

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Case

• A 63-year-old woman with NASH cirrhosis in the ER.
• She had slurring of her speech and was “confused,”

according to her husband that worsened overnight

• It was difficult for her to maintain her balance and fell

while in the bathroom and hit her head

• First step in management is?

1.

Blood cultures

2.

Ultrasound

3.

Head CT

4.

Diagnostic paracentesis

Precipitating Factors Involved in Overt HE

GI hemorrhage Constipation Portosystemic shunt Deterioration in liver function Psychoactive Medications

Benzodiazepines Narcotics, sedatives

Dietary protein Noncompliance

Blei AT et al. Am J Gastroenterol. 2001;96:1968-1976. Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.

Infection Shock Anemia Surgery Renal/electrolyte disturbances:

Renal failure Metabolic alkalosis Hypovolemia Hypokalemia Hyponatremia

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HE Treatment Goals

Blei AT et al. Am J Gastroenterol. 2001.

Provide supportive care Identify and remove precipitating factors Reduce nitrogenous load from gut Assess need for long-term therapy

1 2 3 4

• Reduction of nitrogenous load from gut
• Bowel cleansing
• Non-absorbable disaccharides (lactulose)
• Antibiotics (rifaximin, metronidazole)*
• Agents that bind NH3 in the gut
• Na benzoate
• Na phenylacetate
• Na hydroxybutyrate
• Glycerol phenyl butyrate
• Drugs that affect neurotransmission (flumazenil)
• Manipulation of splanchnic circulation (occlusion of portal-

systemic collaterals)

• Occlude TIPS shunt if present

* Neomycin (historical interest).

Adapted from Blei AT et al. Am J Gastroenterol. 2001;96(7):1968-1976.

Treatment Options for HE

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Current Therapy Options for HE

Drug Name Drug Class Indication Lactulose Poorly absorbed disaccharide

• Decrease blood ammonia

concentration

• Prevention and treatment of

portal-systemic encephalopathy Rifaximin Non-aminoglycoside semi-synthetic, nonsystemic antibiotic Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age. Neomycin Aminoglycoside antibiotic Adjuvant therapy in hepatic coma Metronidazole Synthetic antiprotozoal and antibacterial agent Not approved for HE Vancomycin Aminoglycoside antibiotic Not approved for HE

Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugs AdvisoryCommittee/UCM203247.pdf, accessed 02/17/11

• Mechanism of action:

– A non-absorbable dissacharide – Bacterial flora metabolizes in the colon to lactic acid lowers the colonic pH

• Administered orally, by mouth or through a nasogastric tube or

via retention enemas

• Start 25 mL every 1-2 hours until at least two soft or loose bowel
• movements. Subsequently, the dosing is titrated to 3-4 soft

stools per day

• Monitor stool output and side effects

Lactulose

Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. Ferenci P. Semin Liver Dis. 2007;27(suppl 2):10-17. Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547.

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Bass NM. Semin Liver Dis. 2007.. Mullen KD et al. Semin Liver Dis. 2007.

• Minimally absorbed (<0.4%) oral antibiotic
• No clinical drug interactions reported
• No dosing adjustment required in patients with

liver disease or renal insufficiency

• Approved for overt recurrent HE risk reduction in

patients ≥18 years of age

Rifaximin

0.2 0.4 0.6 0.8 1 28 56 84 112 140 168

Rifaximin: Time to Breakthrough HE Episode (Primary Endpoint)

Rifaximin Placebo Proportion Without HE Breakthrough

0.77 0.53

Days Post-Randomization

58%  in risk

• f HE

breakthrough (P<.0001)

Bass et al. N Engl J Med. 2010.

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Nutritional Management in HE

 Importance of preserving muscle mass  Avoidance of protein restriction

• Protein generally well-tolerated at 1.0-1.5 g/kg/d
• More vegetable, less animal sources

 Branch-chain amino acids (BCAA):

• Many studies, analyses - remains controversial

HE Summary

• HE is very common in the cirrhotic patient
• Ammonia is not useful for clinical endpoint

in HE treatment

• Look for precipitating factors of HE
• Minimize narcotics and sedatives
• Lactulose and rifaximin are the main

treatment options

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Renal Dysfunction in Cirrhosis

The Kidneys are also important?

• Renal dysfunction is one of the most important risk

factors for adverse outcomes in patients with cirrhosis

• Found in 20% of cirrhotics admitted to the hospital
• The average cirrhotic will experience ~2 episodes per

year

• Acute kidney injury (AKI) in cirrhosis is associated with:
• 7-fold increase in overall mortality

Fede, J Hep 2012. Martin-Llahi, Gastro 2011. Tsien, Gut 2013.

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Case

• 50 yr old female with hepatitis C cirrhosis

complicated by ascites. He is on diuretics.

• No new medications. Normal creatinine last

week.

125 5 16 2.5

Case

• What is the most likely etiology his AKI?

1.

Hepatorenal syndrome (HRS).

2.

Obstructive (post-renal).

3.

Pre-renal azotemia.

4.

ATN.

5.

Cryoglobulinemia.

10/26/2015 39

Case

• What is the most likely etiology his AKI?

1.

Hepatorenal syndrome (HRS).

2.

Obstructive (post-renal).

3.

Pre-renal azotemia.

4.

ATN.

5.

Cryoglobulinemia.

Differential Diagnosis of Renal Dysfunction in Cirrhotics

• Pre-renal azotemia
• Hepatorenal

syndrome

• Intrinsic renal

disease

• Post-renal disease

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Intrinsic Renal Disease

Type Typical clinical setting

Acute tubular necrosis (ATN) Hypotension, IV contrast, prolonged hepatorenal syndrome Acute interstitial nephritis (AIN) Beta-lactam antibiotics (Zosyn, Augmentin), cephalosporins (ceftriaxone), NSAIDs IgA nephropathy* Cirrhosis, especially alcoholic Membranous nephropathy* Hepatitis B / C Membranoproliferative glomerulonephritis (MPGN) / cryoglobulinemia* Hepatitis B / C

* Renal biopsy is needed to make the diagnosis.

Pre-Renal Azotemia

• The most common

cause of AKI in cirrhosis

• Diagnostic evaluation:
• Urine studies

(fractional excretion

• f sodium)
• R/o obstruction
• Management:

Diuretics Diuretics Diarrhea (lactulose) Diarrhea (lactulose) Acute GI bleed Acute GI bleed LVP w/o albumin LVP w/o albumin NSAIDs, ACE-I NSAIDs, ACE-I

Common causes of renal hypo- perfusion in cirrhotics:

Poor PO intake Poor PO intake

• IV hydration with IV albumin 1g/kg
• Treat the underlying cause
• Remove the offending agent

10/26/2015 41

Hepatorenal syndrome (HRS)

• Functional pre-renal azotemia
• 85% have an identifying stressor

Tsien, Gut 2013. Arroyo, J Hep 2013.

Type 1 Type 2

Rapid (<2 weeks) Speed Slower course 2x baseline and >2.5 mg/dL Creatinine >1.5 mg/dL Typically SBP Associated with Refractory ascites Reversible Response to treatment May be reversible but usually recurs Extremely poor (days-weeks) Prognosis Poor (months)

Diagnostic Criteria of Hepatorenal Syndrome

International Ascites Club Guidelines.

• Presence of cirrhosis with ascites
• Serum creatinine >1.5 mg/dL
• No improvement in creatinine after:
• Withdrawal of diuretics, and
• 1 g/kg IV albumin per day (up to

100g/day max) for 2 days

• Absence of circulatory shock
• No recent administration of nephrotoxic

medications

• Absence of intrinsic renal disease
• Normal renal ultrasound
• Bland urinalysis (no blood; <0.5 g/day

protein)

10/26/2015 42

HRS management: vasoconstrictors

• Vasoconstrictors:
• V1 agonists
• Vasopressin and its analogues (terlipressin)
• A1-adrenergic agonists
• Norepinephrine
• Midodrine
• Glucagon release inhibitor
• Octreotide

Gines and Schrier, NEJM 2009

Management of Hepatorenal Syndrome

STEP 1 STEP 2 STEP 3

• IV Albumin 1g/kg per day

x 2 days (max 100g/day)

• Treat precipitating factors

Manage what you can

• Midodrine 7.5 mg PO TID
• Octreotide 100 mcg SQ TID
• Continue IV albumin 25-50

g/day)

Start vasoconstrictors

• Raise mean arterial

pressure (MAP) by >15 mmHg

• Max midrodine 15 mg

TID, octreotide 200 mcg TID

Titrate

10/26/2015 43

Key Points

• Acute kidney injury is an important

prognostic marker in cirrhotics

• 50% risk of death in the first month
• Causes can be categorized as:
• Hepatorenal syndrome is diagnosed after an IV albumin

challenge and ruling out other causes of AKI

• Managed with midodrine, octreotide, and albumin

Pre-renal (most common) Intrinsic renal Post-renal

Case

59 yr old male with HCV cirrhosis, complicated by ascites and HE. His meld score is 18. Admitted to the ICU with hypotention and sepsis.

1.

What is his mortality?

2.

Most likely source of infection?

10/26/2015 44

Infections in Cirrhosis

• Bacterial infections are the leading cause of

mortality in cirrhosis

• One third patients have at least one infection
• Increase in MDR organisms (40% in some latest

studies)

Fernandez J et al. Hepatology 2011; Arvaniti V et al. Gastroenterology 2010

Bacterial Infections in Cirrhosis

Site Percentage SBP 30 % UTI 25 % Pneumonia 20 % Soft Tissue infection 10 % Sepsis 5 % Other 10 %

10/26/2015 45

Infections: Hospitalized Cirrhotic patients

• 207 patients studied
• Most first infections

were HCA (71%), then nosocomial (15%)

• Second infections

were seen in 24%

• 30 day mortality: 23%

Bajaj J et al. Hepatology 2012 CA: community acquired (blue) HCA: hospital acquired (brown) Noso: nosocomial (green)

Septic Shock in cirrhotic patients

• Retrospective, 635 pt’s with sepsis
• Mortality 75%
• Fungal infections seen in 10% patients
• Septic shock but Culture negative: 25%

Arabi YM et al. Hepatology 2012

10/26/2015 46

Does Timing and choice of antibiotics makes a difference?

• Inappropriate initial empiric antimicrobial

therapy was administered in 25%

• The median time to appropriate

antimicrobial was 7.3 hours

• In bacterial septic shock, a single rather

than 2 or more appropriate antimicrobials was used in 73%

Arabi YM et al. Hepatology 2012

Timing of Antibiotics by onset

• f hypotension and mortality

Hours

Arabi YM et al. Hepatology 2012

10/26/2015 47

Key Points

• Sepsis mortality is high in cirrhosis (60-

80%)

• Bacterial infections are the most common

infections

• Low threshold for starting the antibiotics
• Increase in resistant organisms

Liver Transplantation

10/26/2015 48

Liver Transplantation Timing of Referral

• Early referral is the key
• Complications of Cirrhosis (Child’s B or C)
• Ascites
• Portal hypertensive bleeding
• Hepatic encephalopathy
• Spontaneous bacterial peritonitis
• Synthetic function abnormalities
• Waiting list priority is based on liver disease

severity (=MELD), not waiting time

Deceased Donor Liver Allocation

February 2002 Changes:

Child-Turcotte-Pugh Score MELD Score ■ Ascites ▬ Creatinine ■ Encephalopathy ▬ Bilirubin ■ Bilirubin ▬ Protime INR ■ Protime INR ■ Albumin MELD Score = 0.957 x Loge (creatinine mg/dL) + 0.378 x Loge(bilirubin mg.dL) + 1.120 x Loge(INR) + 0.643

10/26/2015 49

Meld Score Predicts 90 Day Mortality

Patient/Graft Survival Among U.S. Liver Transplant Recipients.

69% 74% 85% 87% 54% 60%

10/26/2015 50

• 53 yo male patient with HCV/HIV and

alcholic cirrhosis, current MELD score of 20.

• BMI is 39.5
• History of renal cancer s/p resection 3

yrs (3 cm)

• Portal vein thrombosis on ultrasound
• Last alcohol use 5 months back (heavy

use)

Question Which is the factor will limit his transplant listing?

• 1. Obesity, BMI 39.5.
• 2. HIV.
• 3. Hx of renal cell cancer.
• 4. PVT.
• 5. Alcohol use.

10/26/2015 51

Which is the factor will limit his transplant listing?

• 1. Obesity, BMI 39.5 (BMI 40-50 need eval)
• 2. HIV (HIV/HCV high risk)
• 3. Cancer (need to see 5 yr survival and

recurrence)

• 4. PVT (Not a contra-indication)
• 5. Alcohol use (6 months sober)

Key Points

• Avoid narcotics, sedatives and NSAID’s
• Tylenol is safe (max dose 2 grams per day)
• Avoid IV fluids (NS). If needed use IV

albumin

• Low threshold of starting antibiotics
• Any change in clinical status need

infectious work up and paracentesis

• Please monitor stool output on lactulose
• Early referral to transplant center

10/26/2015 52

THANK YOU

“Is life worth living? It all depends on the liver.” William James, American philosopher (1842)

Acute Liver Failure

10/26/2015 53

Case Presentation

• 18-year-old woman
• Binge-drinking on New Year Eve
• 1/1: Tired, “hungover”
• 1/2: Nausea, vomiting, abd pain, moody, sleepy
• 1/3: Confused, disoriented, agitated, calling

people by wrong names, talking to objects

Past History

• PMH: asthma, binge drinking
• Meds: beclamethasone, albuterol, ranitidine,

minocycline

• SH: Lives with parents

10/26/2015 54

Initial Labs

130 4.5 20 1.18 103 15.4 37.7 362 10,299 10,651 3.7 199 7.42/35/52 Lactate 5.8 NH3 150 INR 7.2 APAP 30

Coagulopathy INR > 1.5 Encephalopathy No pre-existing liver disease Duration < 26 weeks

10/26/2015 55

Acute Liver Failure

Hep B Autoimmune HELLP HSV Wilson Disease DILI Acetaminophen Hep A Coagulopathy Coma Infection Renal failure Bleeding CAUSE EFFECT Indeterminate Budd- Chiari Shock

Etiology of Acute Liver Failure Adult Registry (n = 2,224)

ALF Study Group, Jan 2015

46% 11% 12%

10/26/2015 56

Acetaminophen cases as % of all ALF per year Prognosis in ALF: Etiology is a Main Determinant

Good prognosis:

• APAP

66%

• Ischemia66%
• Pregnancy

55%

• Hepatitis A

56% Transplant free survival rates differ greatly

(Age is NOT an important determinant)*

*Schiødt FV, et al., Liver Transplant 2009

10/26/2015 57

Prognosis in ALF: Etiology is a Main Determinant Good prognosis:

• APAP

66%

• Ischemia

66%

• Pregnancy

55%

• Hepatitis A

56% Transplant free survival rates differ greatly Bad prognosis:

• Drugs

27%

• Indeterminate 25%
• Autoimmune

26%

• Hepatitis B

26%

• Wilson Disease 0%

(Age is NOT an important determinant)*

*Schiødt FV, et al., Liver Transplant 2009

Specific Therapies

• 1. Acetaminophen
• 2. Autoimmune
• 3. HBV
• 4. HSV
• 5. Amanita
• 6. Pregnancy
• A. NAC/ Charcoal
• B. Corticosteroids

C.Entecavir/tenofovir D.Acyclovir

• E. Silibinin/Penicillin
• F. Delivery

10/26/2015 58

Initial Management

 Must have high index of suspicion at time

• f admission

 Condition progresses rapidly  Changes in consciousness occur hour-by-

hour

 Admission or early transfer to ICU

warranted

Principles of care

 Intensive care management of severe, rapidly

progressive multi-organ system failure

 Only effective treatment: emergent liver

transplant

Rapid psycho-social evaluation critical

 Order sets and daily checklists can be used  No substitute for experience

10/26/2015 59

Treatment for APAP Overdose

N-acetylcysteine (NAC) is an effective antidote!

• IV NAC will totally prevent toxicity if given < 12 hrs
• Uncertain benefit after 30 hours
• Supportive care in ICU: may develop fatal

complications: brain edema.

• Initial evaluation: is it ALF? If so, is he/she a LT

candidate? If so, consider early transfer to OSU.

Acute Liver Failure: An Orphan Disease Still very rare but interesting!

• Requires specialty care
• Outcomes improved in recent era
• Transplantation still the centerpiece of care
• Treatment trials underway; use NAC for all (?)
• Recognize the hallmarks of ALF: coma/high INR
• Refer early

10/26/2015 60

10/26/2015 61 ≥6 mmHg Sinusoidal PHT

Portal Hypertension: HVPG measurement

≥ 12 mmHg Varices & Ascites

Reduction of HVPG to <12 or at least by 20% reduces the risk of rebleeding from 46-65% to 0-13%

Variceal Hemorrhage Suspected Variceal Hemorrhage Suspected Initial Management Initial Management

NO

Rescue TIPS/Shunt surgery Rescue TIPS/Shunt surgery

Balloon Tamponade Balloon Tamponade

YES

Early rebleeding? Early rebleeding? Acute Hemorrhage Controlled? Acute Hemorrhage Controlled?

YES

2nd Endoscopy 2nd Endoscopy

Further bleeding NO

Prophylaxis against recurrent hemorrhag Prophylaxis against recurrent hemorrhag

Management of Acute Variceal Hemorrhage

10/26/2015 62 Control of Acute Variceal Hemorrhage Control of Acute Variceal Hemorrhage

NO

Surveillance Endoscopy and/or Life-long Pharmacotherapy Surveillance Endoscopy and/or Life-long Pharmacotherapy

Prophylactic Pharmacotherapy and/or Endoscopic Variceal Band Ligation Prophylactic Pharmacotherapy and/or Endoscopic Variceal Band Ligation Recurrent Hemorrhage Recurrent Hemorrhage

YES NO YES

Initiate combination Rx Initiate combination Rx TIPS/Shunt Surgery TIPS/Shunt Surgery

Further bleeding

Is patient on EVL + Pharmacotherapy? Is patient on EVL + Pharmacotherapy?

Prophylaxis of Recurrent Variceal Hemorrhage

Infections:Hospitalized Cirrhotic patients

Distribution of 1st Infection’s % of first & second infection (body sites)

CA: community acquired HCA: hospital acquired Noso: nosocomial Bajaj J et al. Hepatology 2012

10/26/2015 63

Secondary Prevention Variceal Bleeding

• The combination of endoscopic therapy

with medical therapy is the initial approach to prevent variceal re-bleeding.

Curr Treat Options Gastroenterol. 2002;5(6):471

Liberal vs Restrictive Transfusion Strategy

Villanueva et al, NEJM 2013

10/26/2015 64

Medical therapy Acute resuscitation IV Vasoactive drugs Antibiotic prophylaxis Endoscopic therapy Banding Injection therapy TIPS Covered stent

Garcia-Tsao G. NEJM 2010; 362: 823-832

Therapy for Variceal Bleeding Epidemiology

• Most common complication of cirrhosis
• Within 10 years of diagnosis of

compensated cirrhosis, 50% of patient with develop ascites

Development of ascites = 50% two year mortality Diuretic refractory ascites = 50% one year mortality Development of SBP = 30% one year mortality

10/26/2015 65

Pharmacologic therapy

• Octreotide is superior and safer compared

to vasopressin

• Octreotide infusion for 5 days prevent

early re-bleeding

Endoscopic Variceal Band Ligation

• Bleeding controlled in 90%
• Rebleeding rate 30%
• Compared with

sclerotherapy:

• Less rebleeding
• Lower mortality
• Fewer complications
• Fewer treatment sessions

10/26/2015 66

TIPS in the Treatment of Variceal Hemorrhage

• Recurrent variceal hemorrhage (at second

rebleed for esophageal varices, at first rebleed for gastric varices)

• Rebleed on combination endoscopic plus

pharmacologic therapy (10-20%)

• In patients with Child A/B cirrhosis, the

distal spleno-renal shunt is as effective as TIPS (dependent on local expertise)

Treatment: Diuretics

• Monotherapy spironolactone more successful

than use of furosemide alone

• Loop diuretics depend on secretion into the tubule

for action. Secretion is impaired in cirrhosis

• Monotherapy spironolactone can cause

hyperkalemia

• Optimal regimen: spironolactone 100 mg/d and

furosemide 40 mg/d single daily dose

• Increases should be made every 3-5 days as

needed, maintaining ratio

• Ratio may need to be < 100/40 in patients with

parenchymal renal disease

• Maximum doses: 400 mg/d spironolactone, 160

mg/d furosemide

10/26/2015 67

Natural History of Hepatorenal Syndrome (HRS)

Arroyo et al., Gastroenterology 2002; 122:1658

5 3 1

Months Creatinine (mg/dL)

6

• 4

1 3 4 2

• 6
• 2

2

Weeks

Type 2 HRS Type 1 HRS SBP Cefotaxime Cefotaxime

Therapeutic paracenteses Therapeutic paracenteses

Ascites and Hyponatremia are Always Present in HRS

 Besides renal failure, patients with HRS have sodium and water retention  Ascites is universal in patients with HRS. If ascites is absent, renal failure is more likely due to other causes  Hyponatremia is almost universal in HRS. If serum sodium is normal, diagnosis of HRS is unlikely

10/26/2015 68

Overt Hepatic Encephalopathy

• Associated with a poor prognosis
• Retrospective review of 111 cirrhotic patients for

12±17 months following first episode of acute OHE:

• 82 (74%) died during follow-up period
• Survival probability
• 42% at 1 year
• 23% at 3 years

Bustamante J et al. J Hepatol. 1999;30(5):890-895.

The Acute Episode of HE

• Supportive care, airway protection
• Head imaging
• Precipitating causes
• Dehydration - lactulose overtreatment?
• Missed medication dose(s)
• Infection (SBP, UTI)
• Specific medical therapy
• Transplant candidacy

10/26/2015 69

RFHE3001 Trial: Rifaximin for Maintaining Remission in Hepatic Encephalopathy

• Multicenter, randomized, double-blind, placebo-

controlled, phase III trial of efficacy and safety of rifaximin 550 mg BID for 6 months in maintenance of remission in patients with recurrent, overt HE

• Cirrhosis and /or portal hypertension
• Two or more episodes of HE (Conn score ≥2) within

6 months of screening

• Conn score 0 or 1 at screening

NM Bass, KD Mullen, S Sigal, A Sanyal, F Poordad, K Merchant, S Huang, A Shaw, E Bortey, WP Forbes Presented at: 44th Annual Meeting of the European Association for the Study of the Liver; April 25, 2009; Copenhagen, Denmark.

Sepsis Mortality Cirrhosis v/s Non cirrhosis

10 20 30 40 50 60 70 80 90 Cirrhosis Non cirrhosis

30 day mortality %

Mortality in Sepsis

60-80% 50%

Fernandez et al. Hepatology 2006; Plessier et al. Liver Int 2003

10/26/2015 70 Predictors of hemorrhage:  Variceal size  Red signs  Child B/C

• NIEC. N Engl J Med 1988; 319:983

Variceal hemorrhage Varix with red signs

10/26/2015 71 Liver insufficiency Variceal hemorrhage

Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency

Cirrhosis

Ascites Encephalopathy Jaundice Portal hypertension

Spontaneous bacterial peritonitis Hepatorenal syndrome

HE Clinical Diagnosis

 Knowledge of existing liver disease/portosystemic

shunting

 Precipitating factors  Altered mental state, hypertonicity, asterixis, fetor

hepaticus

 Reversibility with treatment  Testing to exclude other causes of altered mental

state (brain imaging, EEG, lumbar puncture)

 No consensus on diagnostic criteria

Mullen et al. Semin Liver Dis. 2007 Blei et al. Am J Gastroenterol. 2001

10/26/2015 72

Number Needed to Treat

1 of 4 cases of breakthrough

HE can be avoided with 6 months

• f rifaximin (NNT=4)

1 of 9 cases of hospitalization-

related HE can be avoided with 6 months of rifaximin (NNT=9)

Bass et al. N Engl J Med. 2010;362:1071-1081.

Routine prophylactic use of fresh frozen plasma or platelets before paracentesis?

• In a study of 1100 large volume

paracenteses there were no hemorrhagic complications despite a) no prophylactic transfusions, b) platelet counts as low as 19,000 cells/mm3 (19 x 106 /L)(54% <50,000) and c) international normalized ratios for prothrombin time as high as 8.7 (75% >1.5 and 26.5% >2.0)

Grabau CM et al. Hepatology 2004

10/26/2015 73

• One controlled trial randomized patients with SBP to receive

cefotaxime alone versus cefotaxime plus 1.5 g albumin per kg body weight within 6 hours of enrollment and 1.0 g/kg on day 3. A decrease in mortality from 29% to 10% was reported

• A more recent study has shown that albumin should be

given when the serum creatinine is >1 mg/dL, blood urea nitrogen >30 mg/dL, or total bilirubin >4 mg/dL but is not necessary in patients who do not meet these criteria.

MELD

0% 20% 40% 60% 80% 100% 5 10 15 20 25 30 35 40

90-day Survival MELD

90% 7%

e INR Bilirubin Creatinine

10/26/2015 74 147

• Bacterial Infections in Hospitalized

Cirrhotic Patients

10 20 30 40 50 60

1980’s Non- cirrhotics Deschenes (1999) n=140

%

Fernandez (2002) n=1,567 32% 34% 20% 6% ~46% 41% Dupeyron (2001) n=589 Borzio (2001) n=405

Cirrhosis: ICU admissions

ICU admissions related to cirrhosis in the US is about 26,000 per year with an estimated cost of $3 billion

Olson JC, Kamath PS. Curr Opin Crit Care 2011

10/26/2015 75

Non-Pharmacologic Treatment of Acute Variceal Hemorrhage

• Endoscopic Band Ligation
• Transjugular Intrahepatic Portal-systemic

Shunting (TIPS)

• Mostly Historical Interest
• Embolization of varices
• Injection Sclerotherapy

Questions

• What is the risk of variceal bleed in

cirrhosis?

• What is your goal Hgb/HCT?
• Use of IV octreotide? Other medications?
• Use of IV antibiotics?
• Control of bleeding? Banding vs.

medications?

10/26/2015 76

Acute Variceal Hemorrhage Labs

130 4.5 20 1.18 103 102 120 4.5 199 INR 1.6 12 19 62

10/26/2015 77

Treatment: Serial LVP

• If patient compliant with diet, should need no

more than 8.4 L every two weeks

• LVP does result in protein and complement

depletion, may indirectly predispose to ascitic fluid infection

• Every tap should be tested for cell count and

differential

• Prevalence of occult infection low

Evans et al, Hepatology 2003: 3.5%

Lactulose Therapy in HE

 Standard of care  Poorly tolerated

• Unpalatable
• Flatulence and abdominal pain
• Diarrhea
• Nausea/ Ileus in large doses
• Hypernatremia

Gerber T, Schomerus H. Drugs. 2000;60:1353-1370; Mullen KD, Dasarathy S. In: Schiff ER, et al, eds. Schiff’s Disease of the Liver, ed 8. Philadelphia, PA: Lippincott-Raven; 1999, pp 545-581; Williams R, et al. Eur J Gastroenterol Hepatol. 2000;12:203-208.

10/26/2015 78

 140 consecutive

cirrhotic patients recovering from a bout

• f HE

 Randomized to

lactulose (30-60 ml/day)

• r placebo (non-blinded)

 Primary endpoint = an

episode of overt HE

 Follow-up 1-20 months

(median = 14 mo.)

Lactulose resulted in a 58% reduction in the incidence of

• vert HE (p=0.001)
• Gastroenterology. 2009;137:885-891

Prevention of Overt Episodic HE: Is Drug Therapy Effective?

10/26/2015 79

• 52 year-old man with cirrhosis due to HCV,

listed for LT. Complications include ascites and encephalopathy

• Labs at time of listing: MELD 17
• Which of the following changes in lab

parameters will increase his MELD score the most?

INR Bilirubin Creatinine Baseline 1.5 3.0 1.2 Change in Labs 3 months later #1 3.0 3.0 1.2 #2 1.5 6.0 1.2 #3 1.5 3.0 2.4

MELD 17 25 19 24

Question

Ascites

10/26/2015 80

Pathophysiology of HRS

Portal hypertension Splanchnic vasodilation Low effective arterial blood volume  BP, no ascites, no edema

Disease progression Refractory ascites, anasarca, severe  BP Decompensated Cirrhosis Renal Failure (HRS) Renal Failure (HRS) Compensated Cirrhosis

Adapted from Gines, NEJM 2009.

SBP: Emergence of enterococci

• 170 episodes of culture positive ascites
• Gram +ve infections in 50% cases
• Enterococcus spp: 28% cases
• Poor survival in enterococcus group

Reuken PA et al. Aliment Pharmacol Ther 2012