Cirrhosis Case Discussion

Pratima Sharma, MD, MS

Associate Professor of Medicine
Interim Medical Director of Liver Transplant Program
Michigan Medicine, University of Michigan
Ann Arbor, MI 48109
pratimas@med.umich.edu
Objective
• Diagnosis of Cirrhosis and quality of care
• Management of esophageal varices bleeding
• Management of Ascites
• Management of Acute Kidney Injury (AKI)
 Cirrhosis
• 8th leading cause of death in 2010
• 49,500 total deaths
• 19,500 HCC related deaths
• Incidence expected to increase in coming decades:
• Alcohol Use Disorder and Liver Disease
• Obesity epidemic and NAFLD-related cirrhosis
• Direct medical costs for HCV-related disease: $11 billion for
period of 2010-2019
 Case Scenario 1
58-year-old male with BMI 34, diabetes and hypertension had his
yearly labs that showed mildly elevated liver enzymes (AST=40,
ALT=55) Hb 14.5, WBC 4.8, platelet count 120. His exam stable
vital signs with a BMI of 32, protuberant belly, no icterus, asterixis
or lower extremity swelling.
• Does this patient have cirrhosis?
• What is the quality-of-care management?
 Cirrhotic Liver
Portal systemic
collaterals

Distorted sinusoidal
architecture leads to
increased resistance

Portal
vein
Etiology of liver diseases
Viral hepatitis, Alcohol-related liver
diseases, NAFLD, Autoimmune & cholestatic
liver diseases, Inherited and metabolic Splenomegaly
disease, Others
When to suspect cirrhosis?
• Stigmata of chronic liver disease found on physical exam
• Subtle clues based on lab and radiological findings
• Low platelet counts
• Imaging showing enlarged caudate lobe of liver
• Splenomegaly
• Collaterals
Overt Decompensation of Cirrhosis

• Esophageal varices
• Ascites
• Hepatic encephalopathy
• Hepatorenal syndrome
• Hepatocellular carcinoma
Non-invasive Assessment of Liver Fibrosis.

Tapper EB, Lok AS--F. N Engl J Med ;377:756-768

Vibration controlled elastography (VCTE)

Magnetic resonance elastography (MRE)
Tapper and Lok, 2017
Tapper and Lok, NEJM, 2017
Risk Index to Prognosticate Cirrhosis
• Child-Turcotte-Pugh (CTP) score: 5-15
• Ascites, hepatic encephalopathy,
• Serum Albumin, Bilirubin and Pro-time
• MELD/MELD-Na Score: 6-40
• Creatinine, bilirubin, INR and Sodium
 Stages and Sub-stages of Cirrhosis
Child A Child B Child C
5-6 7-9 10-15

Mild portal hypertension

(PH): HVPG 6-9 mm hg

Clinically significant PH Referral for Liver transplantation

(CSPH): ≥10 mm hg
Garcia-Tsao et al. Hepatology 2017 65(1): 310-336
Quality of Care: Compensated Cirrhosis
• EGD to screen for EV
• Screening for HCC with every 6 months of ultrasound
• No varices: 2-3 years
• varices: 1-2 years
• Vaccination for hepatitis A and B if not immune
• Treatment of underlying disease and
• Life-style modification and weight loss (7-10%)
• Alcohol cessation
• Referral for liver transplantation if there is any decompensation
 Case Scenario 2
58-year-old male with BMI 34, diabetes and hypertension had his
yearly labs that showed mildly elevated liver enzymes diagnosed
with cirrhosis recently. (AST=40, ALT=55) Hb 14.5, WBC 4.8,
platelet count 120. You saw him in clinic and ordered quality of
care investigations. His lab work did not reveal any other etiology
of liver disease. He was vaccinated for hepatitis B and C. His
ultrasound showed shrunken liver with splenomegaly, no ascites.
His EGD was scheduled. Two days later he went to ER with
hematemesis. He was A+OX3 and BP was 110/70 and HR 112.
• What is the differential diagnosis?
• What are the next management steps?
 Management of Acute Gastrointestinal Bleed
• Initial assessment:
• Assessment of severity
• Resuscitation
• Airway protection
• Pharmacologic therapy
• IV Octreotide
• PPI
• IV antibiotics for 7 days
• Endoscopy for diagnosis and therapy within 12 hours
Varices

• Liver disease
severity
• Size
• Red wale sign

Video Courtesy: Dr. Neehar Parikh

 Varices Increase in Diameter Progressively

No varices Small varices Large varices

7-8%/year 7-8%/year
Rate of hemorrhage per year: 10-15%
12-month rate of recurrent hemorrhage: 60%
6-week mortality for every episode of hemorrhage: 15-20%
Garcia-Tsao et al. Hepatology 2017 65(1): 310-336
Primary Prophylaxis

Small varices without high- Small varices with high-risk

risk features: observation features (red wale): non-
selective beta blockers (NSBB)
NSBB
• Carvedilol vs. propranolol: equally efficacious in reducing portal
pressure
• Tolerability may be an issue in some patients
• Titrated to a HR of 55-60
• Reduce bleeding episodes and overall hepatic decompensation
• One prospective study has shown an increase in mortality in patients
with refractory ascites

Reilberger et al. Gut. 2013.

Management of Non-bleeding Moderate/Large Esophageal Varices
 Secondary Prophylaxis
• Nonselective beta blockers and/or
band ligation recommended
• Banding: within short intervals
(q2-6 weeks) until complete
eradication
• Salvage TIPS in cases refractory to
endoscopic therapy
 Varices Increase in Diameter Progressively

No varices Small varices Large varices

7-8%/year 7-8%/year
Rate of hemorrhage per year: 10-15%
12-month rate of recurrent hemorrhage: 60%
6-week mortality for every episode of hemorrhage: 15-20%
Garcia-Tsao et al. Hepatology 2017 65(1): 310-336
Quality of Care for Acute Variceal Bleeding
• Adequate resuscitation
• IV Antibiotics for 5 days to prevent AKI
• Endoscopic therapy within 12 hours of presentation
• Secondary prophylaxis
Case Scenario 3
• 48-year-old male with h/o alcohol related cirrhosis c/w ascites
presented to ED with abdominal pain. Pain started one day back and
initially gelt like he has pulled a muscle and now become diffuse, not
associated with nausea, vomiting or diarrhea. On exam: His BP 90/60,
HR 110, RR 20, T max 99.6. Labs revealed WBC of 8.4, Hb 12, Plt 62,
Na 135, Cl 88, HCO3 20, BUN 10, Cr. 0.7.
• Diagnostic paracentesis was performed. SAAG was 1.2 and T protein
was 1.8, WBC 500, %PMNs 80%
• What is the diagnosis?
• What is the management?
Natural History of Cirrhosis: Risk of Developing
Ascites
 Classification

Post Sinusoidal

Sinusoidal
High HVPG

Pre- Sinusoidal

Hepatic Venous Pressure Gradient (HVPG)= HV wedge pressure (WHVP) - free HV pressure
WHVP = sinusoidal pressure (1-5 mm of Hg); lower than free HV pressure in normal subjects
SAAG and Classification
SAAG = Serum albumin to ascites albumin gradient (SA-AG)

SAAG

≥ 1.1 <1.1

Ascitic fluid Total Protein Ascitic fluid Total Protein

< 2.5 g/dl ≥ 2.5g/dl

<2.5 g/dl ≥ 2.5g/dl
Nephrogenic Tuberculosis
Portal Hypertension Cardiac Carcinomatosis
Serositis
Pancreatitis
Chylous
Management of Ascites
• Sodium restriction
• 2g/day (88 mmol/day) increases the urinary Na excretion to >78 mmol/day
• Spot urine Na: urine K >1.0- correlates with >78mmol sodium excretion/day with
90% accuracy
• Diuretic therapy
• Single-agent spironolactone can be used with minimal fluid overload
• Single-agent furosemide less efficacious than spironolactone
• Single morning doses of oral spironolactone and furosemide
• Large volume paracentesis
• Reserved for refractory ascites
• TIPS
• Liver transplantation
 Take Home Points in the Management of Ascites

• Sodium restriction to 2000 mg/day

• Diuretics: furosemide + spironolactone in the ratio of 40 mg to 100
mg to maintain normokalemia
• Fluid restriction is not necessary unless serum sodium <125 mmol/L
• Monitor electrolytes and kidney functions
• Referral for liver transplantation

Biggins et al. 2021, Hepatology

Management of Refractory Ascites

• Refractory ascites: Unresponsive to Na-restricted diet and diuretics

• Diuretic resistant:
• Diuretic intractable
• Management:
• TAPS:
• Large volume paracentesis
• Albumin replacement
• No contraindication
• TIPS
• Shunt between portal and systemic circulation
• MELD score
Splenic V
• Pre-TIPS: get an ECHO
• Educate patient regarding side effects
SMV
• Liver Transplantation
Portal Vein
Comparison of TIPS vs. TAPS

Runyon et al. 2009, Hepatology

Quality of Care for SBP
• Diagnostic paracentesis: Send for cell count and bed side culture
• IV Abx within 6 hours
• IV albumin on day 1 and day 3 to prevent AKI
• Secondary prophylaxis
• Referral for liver transplantation
Spontaneous Bacterial Peritonitis
• Diagnosis: PMN’s > 250
• Patients with PMN’s <250 but with signs of SBP i.e., fever,
abdominal pain
• IV antibiotics: 2nd/ 3rd generation cephalosporin
• Albumin 1.5 g/kg on Day 1 (within first 6 hours) and 1
g/kg body weight on Day 3
• Consider holding NSBB if patient is hypotensive
• Secondary SBP prophylaxis
SBP and AKI
• SBP and AKI:
• At onset: 20%-40% have AKI without shock
• Septic shock and subsequent AKI: 10% of patients
• HRS-AKI: Spontaneous or precipitating factors
• Spontaneous bacterial peritonitis (30%)
• Large volume paracentesis (10%)
• Severe alcoholic hepatitis (25%)
Case Scenario 4
• 48-year-old male with h/o alcohol related cirrhosis c/w ascites
presented to ED with abdominal pain. Pain started one day back and
initially gelt like he has pulled a muscle and now become diffuse, not
associated with nausea, vomiting or diarrhea. On exam: His BP 90/60,
HR 110, RR 20, T max 99.6. Labs revealed WBC of 8.4, Hb 12, Plt 62,
Na 135, Cl 88, HCO3 20, BUN 10, Cr. 0.7. Diagnostic paracentesis
showed SBP. Next day his BUN increased to 40 and Creatinine was
1.5.
• What are the next diagnostic and management steps?
SBP and AKI
• SBP and AKI:
• At onset: 20%-40% have AKI without shock
• Septic shock and subsequent AKI: 10% of patients
• HRS-AKI: Spontaneous or precipitating factors
• Spontaneous bacterial peritonitis (30%)
• Large volume paracentesis (10%)
• Severe alcoholic hepatitis (25%)
 AKI in Hospitalized Patients with Cirrhosis

Adapted from Garcia-Tsao et al. 2008, Hepatology

Peron et al., 2005, AJG; du Cheyron et al., 2005, Intensive Care Med; Moreau et al. 2002, Gastro, Fang et al., 2008, Nephrol Dial Transpl
Previous Criteria for Hepatorenal syndrome
(HRS)

Salerno et al. 2007, Gut

New Classification of HRS
Old New Criteria
classificati Classification
on
HRS-1 HRS-AKI • Absolute increase in sCr≥ 0.3mg/dl within 48 hrs - Urinary
output≤ 0.5ml/kg body weight≥ 6 hr
• % increase in sCr≥50% based on last outpatient sCr as
baseline value
HRS-2 HRS- HRS-AKD • eGFR<60ml/min <3 months no other structural causes
NAKI • % increase in sCr<50% using the last available value of
outpatient sCr within 3 months at baseline value
HRS-CKD • eGFR<60 ml/min for ≥ 3 months without structural causes

Angeli et al., 2019, J Hep

 Definition and AKI stages
Definition of AKI Increase in sCr ≥0.3 mg/dL within 48 h; or a percentage increase sCr ≥50% from baseline which is known, or presumed, to
have occurred within the prior 7 days
Staging of AKI Stage 1: increase in sCr ≥0.3 mg/dL; increase in sCr ≥1.5-2 X from baseline
Stage 2: increase in sCr >2-3 Xfrom baseline
Stage 3: increase of sCr >3X or sCr ≥4.0 mg/dL with acute rise ≥0.3 mg/dL or RRT
Baseline serum sCr obtained in the previous 3 months, when available
creatinine >1 value within last 3 months, baseline should be the value closest to the admission
No previous sCr value, the sCr on admission should be used as baseline
HRS-AKI  Diagnosis of cirrhosis and ascites
(previously HRS-1)  Diagnosis of AKI according (as defined above)
 No response to 2 consecutive days of diuretic withdrawal or plasma vol expansion with albumin 1 g/kg bodyweight
 Absence of shock
 No current or recent use of nephrotoxic drugs
 No macroscopic signs of structural kidney injury, defined as:
– No proteinuria (>500 mg/day); No microhematuria (>50 RBCs per HPF)
– normal findings on renal ultrasonography
HRS-AKD (HRS-2) a) estimated GFR <60 ml/min per 1.73 m2 for <3 months and no (structural) causes
b) % increase in sCr <50% last value of outpatient sCr within 3 months as baseline
HRS-CKD (HRS-2) a) estimated GFR <60 ml/min/1.73 m2 for ≥3 months no other (structural) causes
 Diagnosis
Clinical feature Diagnosis
History and physical
❖ Refractory ascites, chronic hypotension, hyponatremia, recent Favors HRS-AKI
(within 1 week) large volume paracentesis, active infection
❖ Use of potential nephrotoxic agents (NSAIDs, iodinated contrast Favors ATN-AKI
etc.), sepsis, renal ischemia, prolonged prerenal azotemia diagnosis
Routine testing
❖ FeNa < 1%, Urine sodium < 10 meq/L Favors HRS diagnosis
❖ FeNa > 2-3%, Urine RBC > 50 cells per HPF(when no urinary
catheter is in place), proteinuria > 500 mg/day, casts Favors ATN diagnosis
Novel biomarkers Favors ATN-AKI
 NGAL > 220 µg/g creatinine diagnosis
Renal ultrasonography Favors HRS-AKI
 No urinary obstruction or renal parenchymal disease diagnosis
Renal histology Favors ATN-AKI
 Normal renal tubules and glomeruli
Response to treatment Favors HRS-AKI
 Good response to vasoconstrictors plus intravenous albumin diagnosis
Survival of Patients with Cirrhosis after Diagnosis
of HRS

Rodes J, Postgrad Med J, 1975

Therapeutic Options and Aim of Therapy for
HRS

Cárdenas A and Ginès P, 2006 Nat Clin Pract Gastroenterol Hepatol

Splanchnic Vasoconstrictors and Albumin
• Vasopressin analog
• Terlipressin
• Somatostatin analog +/- α-1 adrenergic agonist
• Octreotide +/- midodrine
• α-1 adrenergic agonist
• Noradrenaline
• In combination with albumin
• Hold diuretics
• Hold NSBB
 Midodrine and Octreotide
• Combination: Midodrine (7.5 to 12.5 mg tid) and octreotide (100-
200 µg sq TID) titrated to increase MAP at 15 mmHg
• Both groups received IV albumin

13 patients with HRS 1

Dopamine
Combination
N=8
N=5

D/C from Hospital Not D/C Not D/C

N=3 N=2 N=7
1=LT 1=LT All died within 12 days
1=alive at 472 days 1=Died
1=died after 2.5 mths

Angeli et al. Hepatology 1999

 Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal
syndrome: A randomized trial

Complete/partial
Complete

Endpoints:
Complete response: decrease in serum creatinine to ≤1.5 mg/dL
Partial response: ≥50% serum creatinine decrease from baseline to >1.5 mg/dL)
No response: serum creatinine decrease of <50% from baseline
Hepatology Volume 62, Issue 2, pages 567-574, 13 FEB 2015 DOI: 10.1002/hep.27709
 P=0.01
2

35% 32.0%
30%
Verified HRS Reversal

P=0.006 Terlipressin
25% (n=199)
20% 17.0% Placebo (n=101)
15% Z score =
2.52618
10%
5%
0%
The CONFIRM Study: HRS Response by SCr
Category

Terlipressin Placebo
SCr Category
(n=199) (n=101)
<3 mg/dL 39/79 (49.4%) 14/40 (35.0%)
≥3 to <5 mg/dL 31/97 (32.0%) 3/53 (5.7%)
≥5 mg/dL 2/23 (8.7%) 0/8 (0%)

Wong et al., NEJM 2021

Noradrenalin
• Pilot study of 12 patients with type 1 HRS
• Treated with noradrenalin (0.5-3 mg/dl) to achieve an
increase in MAP of 10 mm Hg or urine output to 200 ml
in 4 hours until reveral of HRS or 15 days
• Endpoint: Serum creatinine < 1.5 mg/dl or creatinine
clearance > 40 ml/min
• Reversal of HRS: 10/12 patients after a median of 7 days
• Improvement in renal function was associated with
increase in MAP and decrease in serum renin and
aldosterone levels
Prevention of AKI in Cirrhosis
• Spontaneous bacterial peritonitis (SBP)
• use of albumin with antibiotics
• 1.5 g/kg BW on day 1 and 1g/kg BW on day 3
• Secondary prophylaxis
• Norfloxacin
• Large volume paracentesis ≥ 5 liter of fluids
• AASLD guideline: 8-10 g of albumin for every liter of fluid removed
• Close monitoring of renal functions while on diuretic therapy for
ascites
• Avoidance of NSAIDS
MOC Questions
Which one of the following lab finding is suggestive of cirrhosis?
A. Thrombocytopenia
B. Neutropenia
C. AST to ALT ratio >2
D. Anemia

Answer: A
Patients with cirrhosis have portal hypertension that results in splenomegaly.
Patients with cirrhosis are more likely to have thrombocytopenia because of
hypersplenism.
MOC Question 2:
• Which of the following provide evidence-based recommendation provide survival
benefit in patients with acute variceal bleeding?

A. IV octreotide for 2-5 days

B. PPI drip for first 24 hours
C. IV antibiotics for 5 days
D. Correction of coagulopathy

Answer: C
IV antibiotics for 5 days provide survival benefit by preventing SBP and AKI which
are associated with high mortality in patients with acute variceal bleeding
 MOC question 3
• Which one of the following patients should be referred for liver transplantation?
A. 50-year-old male with a new diagnosis of NAFLD cirrhosis with non bleeding
esophageal varices
B. 50-year-old male with new diagnosis of cirrhosis, platelet count of 140, no
ascites and no varices
C. 50-year-old male with cirrhosis who had an episode of GI bleeding one year ago
underwent band ligation with complete eradication and now on NSBB with
normal albumin and INR
D. 50-year-old with cirrhosis and difficult to control ascites and H/o SBP
Answer: D
Patients with decompensation of liver disease such as ascites should be referred for
liver transplantation because it is the only therapeutic option for decompensated
liver disease.