Cirrhosis by Dr. Matt Deneke

Cirrhosis: clinical pearls for the practicing internist

ADR / Jun 2013

Matt Deneke

10/20/2014

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

General concepts about cirrhosis

ADR / Jun 2013

• Cirrhosis is the end result of chronic damage to the liver

General concepts about cirrhosis

ADR / Jun 2013

• Cirrhosis is the end result of chronic damage to the liver

Altamirano. Ann Hepatol 2012;11:426

General concepts about cirrhosis

ADR / Sep 2012

Hepatic Stellate Cell Activation

Mild Fibrosis (F1)

Clinically Relevant Fibrosis (F2)

Cirrhosis (F4)

Advanced Fibrosis(F3)

Liver Insult (chronic)

Altamirano. Ann Hepatol 2012;11:426

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Jun 2013

• There are other methods for diagnosing cirrhosis:– Clinical manifestations– Previous manifestations of portal hypertension– Routine biochemical parameters– Non invasive markers of cirrhosis: Fibrotest® and Fibroscan®

Do not forget that there is:

Pain in 80%, bleeding 3%; need for transfusion, pneumothorax, perforation of hollow viscous, death in <1%

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Jun 2013

• Clinical manifestations of cirrhosis

Heidelbaugh. Am Fam Physician 2006;74:756

AB wall vascular collaterals Splenomegaly

Ascites Temporal atrophy (sarcopenia)

Asterixis Testicular atrophy

Fetor hepaticus

Gynecomastia Other more cause-specific

Hepatomegaly Clubbing, hypertrophic osteoarthropathy

Jaundice Dupuytren

Nail changes: Muehrcke’s / Terry’s Kayser-Fleischer ring

Palmar erythema Parotid hypertrophy

Scleral icterus P2 increased

Vascular spiders

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Jun 2013

• Muehrckes’s and Terry’s nails

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Feb 2013

• Previous manifestations of portal hypertension– How do we define portal hypertension? What is HVPG?

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Feb 2013

• Previous manifestations of portal hypertension– HVPG

Bosch. Nat Rev Gastroenterol Hepatol 2009;6:573

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Jun 2013

• Previous manifestations of portal hypertension

Varices / variceal bleeding

Ascites, hepatic hydrothorax

Hyponatremia

Hepatic encephalopathy

SBP / SB Empyema

Hepatorenal syndrome

Portopulmonary hypertension

Hepatopulmonary syndrome

Portal vein thrombosis

Hepatocarcinoma

Cirrhotic cardiomyopathy

Other

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Jun 2013

• Noninvasive markers of fibrosis: transient elastography– Fibroscan®

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Oct 2012Castera. J Hepatol 2008;48:835

• Noninvasive markers of fibrosis: transient elastography– Vibrating probe with low frequency and amplitude– Mounted to an ultrasound transducer (3.5 MHz)

Total volume measured ≈3 cm3

100 times the area of liver biopsy

Do I need a liver biopsy to diagnose cirrhosis?

ADR / Oct 2012Castera. J Hepatol 2008;48:835

• Output: elastogram– Mathematic representation of propagation velocities– Limits 2.5 to 75 kPa

Do I need a liver biopsy to diagnose cirrhosis?

Mariappan et al. Clin Anat. Jul 2010; 23(5): 497–511

• Elastography can also be performed using MRI

• Sensitivity and specificity for detecting the presence of fibrosis are 98 and 99% using a cutoff of 2.93 kPa

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

Pros and cons of TIPS

ADR / Jun 2013

• TIPS: tranjugular intrahepatic portosystemic shunts

Pros and cons of TIPS

ADR / Jun 2013

• When to use a TIPS?

Boyer. Hepatology 2010;51:1

García-Pagán. N Engl J Med 2011;362:2370

Indications for TIPSEndoscopy refractory acute variceal bleeding

Acute variceal bleeding (CTP 7-13, after EGD)

Refractory ascites

Refractory hepatic hydrothorax

Hepatorenal syndrome (HRS type 2)

HRS type 1, after response to vasoconstrictors

Pros and cons of TIPS

ADR / Jun 2013

• Hepatic encephalopathy: the Achilles heel of TIPS

Author Indication FU PSE-TIPS PSE-Ctrl Severity

Gines 2002 RefAsc 10 mo 27 (77%) 23 (66%) TIPS > Ctrl

Sanyal 2003 RefAsc 17 mo 22 (42%) 13 (23%) TIPS > Ctrl

Salerno 2004 RefAsc 18 mo 20 (61%) 13 (39%) TIPS > Ctrl

Narahara 2011 RefAsc 27 mo 20 (66%) 5 (17%)* -----

Garcia-Pagan 2010 VB 16 mo (10%) (19%) -----

Exclusion criteria (RefAsc):- Age >70-75 yo, PSE > grade 1, TB >3-10 mg/dL, Cr >1.5-3.0 mg/dL, INR >2-2.5, CTP >11

OR: 2.26 (IC95%: 1.35-3.76)Relative increased risk (MA)

D´Amico. Gastroenterol 2005;129:1282

Pros and cons of TIPS

ADR / Jun 2013

• When not to use a TIPS (nor for acute bleeding)?

Contraindications Increased PSE RiskUncontrolled PSE Age >65

CTP ≥12 CTP ≥10

MELD ≥20 MELD ≥15

Bilirubin >5 mg/dL Bilirubin >3 mg/dL

Pulmonary HTN (>35 mmHg) Cr >1.3 mg/dL

Congestive HF Previous PSE

Hepatocarcinoma MAP <80 mmHg

Polycystic liver disease AbNL psychometric tests

Biliary obstruction Hyponatremia

Active infection Use of bare stents

INR >5 / Platelets <20,000 HVPG <12 mmHg (↓ 5 mmHg)

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

ADR / Jul 2012

Hepatorenal syndrome

• Hepatorenal syndrome– Definition

Francoz. J Hepatol 201052:605

ADR / Jul 2012

HRS algorithm

• Hepatorenal syndrome: treatment (up to 14 days)– Terlipressin = Norepinephrine > Midodrine

Stop diureticsStop nephrotoxics

Stop NSbB?

Albumin 1 g/kg(≤100 g/d), then,

25-50 mg/d

Check:Urine sedimentUrine sodium

ProteinuriaRenal US

Midodrine 7.5 mg tid(↑ to 12.5 tid) +

octreotide 100 mcg tid (↑ to 200 tid)

Transfer to ICUNorepinephrine

0.05-0.1 mcg/kg/min (↑ 0.05

mcg/kg/min)

Monitor:Daily SBP

CVP (10-15)UO (Foley’s)

Ischemia

How to adjust vasopressors:CVP: >15, albumin 20 mg/d; >18, stop albumin + furosemide IV bolusMAP ↑ <10 mmHg or UO <200 mL (4 h): ↑ NE; Cr ↓ <25% (72 h): ↑ NE/midodrine

No response

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

Pulmonary complications of cirrhosis

Pulmonary complications of cirrhosis

• Hepatopulmonary syndrome (HPS)– Effective shunting of

blood from pulmonary arteries to veins without oxygenation

• Capillary dilation• Collateral bypass channels• Hyperdynamic flow

J Gastro Hepatol 2013, 28(2)

Pulmonary complications of cirrhosis

• Portopulmonary Hypertension– Identical to primary pulmonary HTN in appearance

and behavior– Reversible with liver transplantation if arterial

hypertrophy and fibrosis have not developed

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

Hepatocellular Carcinoma

• Hepatic malignancies are the sixth most common cancer worldwide– The vast majority are hepatocellular carcinoma

• Over 90% of patients with HCC have cirrhosis• The risk of developing HCC in patients with cirrhosis varies

– Five-year risk varies from 4-30%– Risk varies with etiology of cirrhosis

• Higher in HBV and HCV– Annual risk from 1% to 8% in HCV cirrhosis

• Higher with multifactorial liver disease (e.g. HCV + EtOH)

Hepatocellular Carcinoma

• Prognosis for HCC is poor without definitive therapy• Surgical resection is ideal, but usually not an option for

patients with cirrhosis– Significant risk of decompensation– Significant risk of recurrent disease

• Liver transplantation is ideal therapy in cirrhosis, but only for selected patients – Early studies of patients transplanted with advanced HCC showed 5-

year survival of only 25% • Due to high risk of tumor recurrence

– For patients within Milan criteria, 5-year survival is excellent (>70%)• Similar to survival with nonmalignant indications

Hepatocellular Carcinoma

• Milan Criteria– single lesion less than 5 cm– up to 3 lesions all less than 3 cm– no macrovascular invasion– no extrahepatic spread

www.medscape.com

Hepatocellular Carcinoma

• Milan criteria require identification of HCC at an early stage• In order to accomplish this, screening of patients with

cirrhosis has been recommended– AASLD and EASL:

• Cross-sectional imaging with U/S every 6 months• Routine use of AFP is no longer recommended due to poor sensitivity and

specificity

• If lesion identified on screening, then contrast-enhanced CT or MRI along with AFP should be obtained– Diagnosis can be made without biopsy if typical imaging characteristics

are present or if AFP is very elevated

Hepatocellular Carcinoma

EASL HCC Guidelines, J Hepatol, 2012

Hepatocellular Carcinoma

• Treatment options for HCC not amenable to resection/OLT– Locoregional therapy

• Direct tumor ablation– Ethanol injection– Radiofrequency ablation– Very effective in small tumors

• Transarterial chemoembolization (TACE)– Often used in patients listed for transplant– Carries risk of causing hepatic decompensation

• Transarterial radioembolization (TARE, TheraSphere)– Used in large tumors or multifocal tumors

• Have been shown to prolong survival compared with no treatment

– Systemic therapy• Typical cytotoxic chemotherapy is not effective in HCC• Sorafenib is the only indicated agent for systemic therapy

– Prolongs survival by 3 months vs placebo– Tolerability is an issue– Patients with poor functional status usually do not tolerate it well

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute on chronic liver failure

Internal Medicine in cirrhosis

ADR / Jun 2013

• Presurgical evaluation– http://www.mayoclinic.org/meld/mayomodel9.html– Or Google search for “Mayo Clinic cirrhosis surgical risk”

• Use of common drugs in cirrhosis– Metformin and sulfonylureas

• Stop when patient reaches CTP B (8 points) switch to insulin

– Statins• Cirrhosis is NOT a contraindication to statin use• Some studies suggest statins may reduce rate of progression of disease

and reduce risk of HCC (Kumar et al, Dig Dis Sci, Aug 2014; El-Serag et al, Gastroenterology, May 2009)

Internal Medicine in cirrhosis

ADR / Jun 2013

• Never trust an HbA1c in advanced cirrhosis! – Anemia will decrease its predictive value

• Limit use of benzodiazepines– Favor propofol. If neuromuscular blockage cisatracurium

• Cirrhotics still have an increased risk for thromboembolism– Especially in those <45 year-old

• Hepatoadrenal syndrome (relative adrenal insufficiency)– Present in 33% of ALF and 65% of chronic liver disease and sepsis

ADR / Jul 2012

Internal Medicine in cirrhosis

• Pain treatment recommendations in cirrhosis:

Chandok. Mayo Clin Proceed 2010;85:451

ADR / Jul 2012

Internal Medicine in Cirrhosis

• Beware of Na in IV fluids & volume expansion with albumin

Osm mOsm/L

Na/Clmmol/L

Cl/K/Ca Max. Vol. Exp. (%)

Duration of Exp. (h)

Side Effects

NS 308 154/154 -/-/- 20-25 1-4 ↑ Cl

Ringer’s 275 130/110 4/3/28 20-25 1-4 ↑ K

DW5* 260 -/-/- -/-/- 20-25 <1-2 Edema

NS + DW5* 264 154/154 -/-/- 20-25 1-4 ↑Cl, edema

Albumin 5% 290 36/36# -/-/- 70-100 12-24 AllergyInfection

Albumin 25% 310 15/15$ -/-/- 300-500 12-24

*DW5 has 50 g of glucose = 200 kCal#In 250 mL; $in 100 mL

Rivers. Curr Opin Crit Care 2010;16:297

Objectives

ADR / Jun 2013

• General concepts about cirrhosis• Natural history of cirrhosis• Pros and cons of TIPS• HRS treatment algorithm• Pulmonary complications of cirrhosis• Hepatocellular carcinoma• Internal medicine and cirrhosis: miscellaneous• The cirrhotic in the ICU

– Acute-on chronic liver failure

Acute-on chronic liver failure (ACLF)

ADR / Jun 2013

• Acute deterioration of liver function in cirrhosis, either secondary to superimposed liver injury or due to extrahepatic precipitating factors such as infection, culminating in end-organ dysfunction

• Mortality 50-90% (single OF is reversible in 50% of cases)

Jalan. J Hepatol 2012;57:1336

Internal Medicine in cirrhosis

ADR / Jun 2013 Jalan. J Hepatol 2012;57:1336

Internal Medicine in cirrhosis

ADR / Jun 2013

• Mortality is defined by:– Degree of previous liver dysfunction & organ failure– It is difficult to estimate reversibility: immune paralysis?

Jalan. J Hepatol 2012;57:1336

Thanks…

ADR / Jun 2013