COMPLICATIONS OF CIRRHOSIS

Arjmand Mufti

UTSW

Outline

• Portal hypertension

• Ascites

• Hepatic encephalopathy

• Hepatorenal syndrome

• Hypoalbuminemia and coagulopathy

• Hepatocellular carcinoma

• Prognostic Tools

CirrhosisNormal

Nodules

Irregular surface

Cirrhosis

Definition• Diffuse fibrosis following hepatocyte

destruction and nodular regeneration• Multiple causes

– All may lead to cirrhosis

• Asymptomatic (compensated)• Symptomatic (decompensated)

– portal hypertension– hepatic failure

The Natural History of cirrhosis

Decompensation:•Variceal hemorrhage

•Ascites•Encephalopathy

•Jaundice

D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-231.

Liver insufficiency

Variceal hemorrhage

Decompensated Cirrhosis

Ascites

Encephalopathy

Jaundice

Portal hypertension SBP

HRS

Compensated Cirrhosis

5- 7%per year

Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency

Natural History of Cirrhosis

Stage Definition 1-year mortality

Median Survival

1 Compensated without varices

1% >12 years

2 Compensated with varices 3%

3 Decompensated with ascites without variceal hemorrhage

20% ~2 years

4 Decompensated with/out ascites with variceal hemorrhage

57%

D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-231.

Clinical Presentation

• Symptoms– Anorexia– Weight loss– Generalized

weakness

– Easy fatigability

– Nausea

– Vomiting– Diarrhea

• Exam Findings– Spider angiomatas– Palmar erythema– Gynecomastia– Testicular atrophy– Leuconychia– Parotid gland

hypertrophy– Dupuytren’s contractures– Clubbing– Jaundice

Asymptomatic

Portal Hypertension

Arroyo, V. & Fernández, J. Nat. Rev. Nephrol. 2011

Mechanisms Leading to Circulatory & Renal Dysfunction in Cirrhosis

6040 80 100 120 140 1600

40

60

80

20

200

100

Months

Probability of survival

All patients with cirrhosis

Decompensated cirrhosis

180

Gines et. al., Hepatology 1987;7:122

Median survival~ 9 years

Median survival~ 9 years

Median survival~ 1.6 years

Median survival~ 1.6 years

Decompensation shortens survival

Venous Anatomy

Cirrhotic Liver

Pressure Measurements

Portal Venous Pressure (PVP)

Normal = 5-10 mm Hg

Hepatic Venous Pressure Gradient (HVPG)

= portal venous pressure - hepatic venous pressure or RA pressure

Normal = 1-5 mm Hg

PORTAL HTN

• HVPG ≥6 mm Hg• HVPG ≥10mm Hg – clinically significant• HVPG ≥12 mmHg, risk of variceal

bleeding and the development of ascites• HVPG >20 mmHg – bleeding unlikely to

respond to conventional therapy

Definition of Portal Hypertension

PathophysiologyPortal Hypertension

• Increased intrahepatic vascular resistance– Fixed component

• Sinusoidal fibrosis• Compression by regenerative nodules

– Functional component• Vasoconstriction

– Deficiency in intrahepatic NO– Enhanced activity of vasoconstrictors

Classification Type Examples

• Prehepatic Portal or splenic vein thrombosis

Presinusoidal Schistosomiasis• Intrahepatic Sinusoidal Cirrhosis

Postsinusoidal Veno-occlusive disease

• Posthepatic Hepatic vein thrombosisConstrictive pericarditis

Varices: Portosystemic Collateral Formation

• Esophageal varices

• Gastric varices

• Intraabdominal varices

• Caput medusa

• Rectal varices

Variceal Bleeding

35-80% 25-40%

50-70%

Survival Death

Rebleed

30-50%

70%

Varices

• Common lethal complication

• ~ 50% of patients with cirrhosis

• More likely to bleed in more decompensated disease– 40% of Child A – 85% of Child C

Practice Guidelines: Am J Gastroenterol. 2007;102:2086-2102

%Patients with

varices

100

60

40

20

0

Overalln=494

Child A

n=346

Child B

n=114

80

Child C

n=34

Large

Medium

Small

Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72

Prevalence and Size of Esophageal Varices in Patients with Newly-Diagnosed Cirrhosis

LaPlace’s Law

T = wall tension

P1 = intravariceal pressure

P2 = esophageal lumen pressure

r = vessel radius

W = wall thickness

T = (P1-P2) x (r/W)

Variceal Bleed: Risk Factors

• High Gradient• Large esophageal varices• Endoscopic features

– red wale markings– cherry red signs

Varices

• All patients with new dx of cirrhosis should undergo EGD to screen for varices

• High risk for bleeding:– Childs B/C (more

evidence of decompensation)

– Large varices– Red wale markings

Varices

• Primary prophylaxis (never bled)– If no varices: no need for nonselective B

blocker– If small varices: no long term evidence to use B

blocker unless red signs present– If large varices:

• High risk patient (red wale, childs B/C): B blocker (nadolol/ propranolol) or prophylactic banding

• Low risk patients: B blocker

– Titrate B blocker to max tolerated dose

Got one for you…Variceal Bleed

• Blood transfusion: Target Hgb=8• Antibiotics: norfloxacin, IV cipro, ceftriaxone

(probably best)• Vasopressin, telipressin, octreotide, vapreotide x

3-5 days– Splanchnic vasoconstriction, reduced portal flow

• EGD within 12 hours– Banding(almost always) or sclerotherapy (rare)

Variceal Bleed: When Banding Fails

• Balloon Tamponade (Blakemore / Minnesota tube) temporizing measure for up to 24 hours

• TIPS

After the Bleed

• Secondary prophylaxis– All patients who have has a variceal bleed– Combination of B Blocker and serial banding– Continue banding (usually outpt) until varices

are eradicated

Take Home: Varices

• All patients with cirrhosis should be screened with EGD

• Primary prophylaxis– Large varices / decompensated patients : usually

nonselective B blocker– Banding and “sicker” patients

• Variceal bleed: abx, octreotide, Hgb 8,scope with banding– Blakemore/TIPS when in trouble

• Secondary prophylaxis– Combination B blocker / banding to eradication

Ascites

ASCITES

Definition

• Fluid within the peritoneal cavity

• Occurs in 50-60% of patients with cirrhosis over 10-15 years

• Mixture of liver and intestinal lymph

Cirrhosis Heart failure

Peritoneal tuberculosis

Cirrhosis is the Most Common Cause of Ascites

Others•Pancreatic •Budd-Chiari syndrome•Nephrogenic ascites

Peritoneal malignancy

CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES

85%

33

Ultrasound

Pathophysiology

Elevated Hydrostatic Pressure

•Cirrhosis•Congestive heart failure•Constrictive pericarditis•Hepatic outflow block

Decreased Oncotic Pressure

•Nephrotic syndrome•Protein-losing enteropathy•Malnutrition•Cirrhosis

Peritoneal Fluid Production > Resorption

•Infections (bacterial, tuberculosis, fungal)•Neoplasms

Hepatic Sinusoid• Unlike other capillaries, normal hepatic sinusoids

lack a basement membrane. • The sinusoidal endothelial cells themselves

contain large fenestrae (200-400 nm in diameter)

• These two features make the normal hepatic sinusoid very permeable with movement of fluid depending mostly on hydrostatic pressure

• Normal portal sinusoid pressure is 3-4 mmHg

36

THE PERMEABILITY OF THE HEPATIC SINUSOID VARIES IN HEALTH AND DISEASE

In cirrhosis, the hepatic sinusoid is LESS leaky

The Permeability of the Hepatic Sinusoid Varies in Health and Disease

Hepatocytes

The normal sinusoid is “leaky”

Sinusoid

Sinusoid

fibrous tissue deposition “capillarization” of

sinusoid

no basement membrane

37

Clinical Presentation

• Abdominal distention

• Bulging flanks

• Shifting dullness

• Fluid wave

• Fluid detected on US or CT scan

Total Protein

(SAAG = serum albumin - ascitic albumin)

≥1.1 <1.1

<2.5 -Cirrhosis-Acute Liver Failure-Alcoholic Hepatitis-Massive Hepatic Mets

-Nephrotic syndrome-Myxedema

≥2.5 -CHF-Constrictive Pericarditis-Budd-Chiari-Venoocclusive Disease

-Peritoneal Carcinomatosis-TB Peritonitis-Pancreatic Ascites-Chylous Ascites-Serositis 39

Serum-Ascites Albumin Gradient

Treatment of Ascites

• Usually responds to Na restriction and diuretics– When SAAG >1.1

• Dual diuretics:– Furosemide AND Spirololactone

• Single daily dosing (40/ 100)

• Na restriction– <2000mg/day

• Fluid restriction is usually NOT necessary

Patients with Refractory Ascites Have Worse Survival than Patients with Diuretic-Responsive Ascites

Survival probability

1.0

.8

.6

.4

.2

0120 24 4836 60 8472

Refractory ascites

Non refractory ascites

p<0.001

Months

Salerno et al., Am J Gastroenterol 1993; 88:514

In refractory ascites…

• AVOID– ACE inhibitors / angiotensin receptor blockers

• Blood pressure / adverse renal effects

– Propranolol• Blood pressure / circulatory dysfunction during

LVP• Renal function

– Consider risks benefits

– NSAIDS

With Large / Tense ascites

• Therapeutic paracentesis followed by diuretics / Na restriction

• 6-8 g/of albumin per liter of ascites removed

• Midodrine may be helpful– Shown to increase BP, survival benefit

• Consideration of liver transplantation referral

Complications of Ascites

• Hepatorenal syndrome– “The HRS Cocktail”

• Albumin + Octreotide + Midodrine

– In ICU: • Albumin + Norepineprhine

• Hepatic Hydrothorax– NO CHEST TUBE!!– Same as acsites (Na restrict / diuretics)

Spontaneous Bacterial Peritonitis (SBP)

Infectious complications of cirrhosis1. Spontaneous bacterial peritonitis (SBP)2. Urinary tract infection3. Pneumonia4. Bacteremia

SBP 7-25% of hospitalized cirrhotics– In-hospital mortality 20-50%

Recurrence of SBP 30-70%

Borzio M Dig Liver Dis 2001;33(1):41-8Runyon Hepatology 2004

Infecting Agents

Eschericia coli 43%

Klebsiella pneumoniae 8%

Streptococcus pneumoniae 8%

Alpha-hemolytic streptococcus 5%

Group D stretocococcus 8%

Miscellaneous Enterobacteriaceae 3%

Miscellaneous 20%

ASCITES

Spontaneous Bacterial Peritonitis (SBP)

• Tap all patients admitted to hospital or for any reason rub you the wrong way…

• Diagnosis:– Culture NOT needed (but send it anyways)– PMN >250cells/mm3

• Treatment:– 3rd gen cephalpsporin ie cefotaxime 2g q8– Albumin 1.5g/kg day 1 and 1.0 g/kg day 3

• Cr >1, BUN >30, or bili >4

SBP : prevention

• GI bleed and cirrhosis– Ceftriaxone or norflox x 7 days

• If prior episode of SBP, long term prophylaxis– Daily norfloxacin or bactrim

Hepatic Encephalopathy

Definition

• Reversible alteration in the neuropsychiatric function

• Due to shunting of neurotoxic nitrogenous products

• Lack of hepatic detoxification

Hepatic Encephalopathy Pathogenesis

Bacterial actionProtein load

Failure to metabolize

NH3

NH3 Shunting

GABA-BD receptors

Toxins

1 2 3 4

Coma

Somnolence

Confusion

Drowsiness

????

? ?

StagesHE

Adapted from AGA Teaching Slides.

Hepatic Encephalopathy (HE)

• 10-50% of cirrhotics

• 40% survival 1 year after 1st episode

• 15% survival 3 years after 1st episode

• Disturbance in diurnal sleep pattern precedes neurologic signs

Minimal Encephalopathy

• 15-30% have abnormal NCT or abnormal EEG without overt encephalopathy

• Significance unclear– impaired health-related quality of life

(HRQOL) compared to patients with cirrhosis without minimal HE

– impairs driving capacity and poor insight into their driving skills

• Not replicated in real life conditionsMetab Brain Dis 1998 Jun;13(2):159-72

Hepatology 1998 Jul;28(1):45-9

Metab Brain Dis 1995 Sep;10(3):239-48

Kappus et al Clinical Gastroenterology and Hepatology, Volume 10, Issue 11, 2012, 1208 - 1219

Classification of Hepatic Encephalopathy

Management of HE

• Identify / treat precipitating factors

• Empiric treatment – Rifaximin – Lactulose

GI bleedingExcess protein

Sedatives / hypnotics

TIPSDiuretics

Serum K+

Plasma volume

Azotemia

Temp

Infections

Precipitating Factors of HE

Ammonia Levels in HE

• May be correlation of ammonia levels and severity of HE

• Diagnosis and treatment is clinical– Should not change management– No utility in following levels

Treatment of HE

• Lactulose– First line– 2-3 soft BM/ day

• Rifaximin– 550 BID– Reduced ammonia

producing bacteria

Long Term Management of HE

• After initial HE event– Usually on therapy indefinitely or until liver

transplant

– Long term use of lactulose and or rifaximin

• High protein diet is OK (and preferred in cirrhosis)

• Patients with HE should NOT undergo TIPS if possible

Hepatorenal Syndrome

Pathophysiology

• Occurs in setting of cirrhosis and ascites

• Severe renal arterial vasoconstriction

• Compromised glomerular filtration rate

• Normal kidney structure

1.0

0.8

0.6

0.4

0.2

0.0

Su

rviv

al

Type 1 hepatorenal syndrome

Months

Gines et al. NEJM 2004;350:1646-1654.

P<0.001

Creatinine <1.2 mg/dL

Creatinine 1.2-1.5mg/dL

Creatinine >1.5mg/dL

1.0

0.8

0.4

0.2

0.0

1 2 3 4 5

Years

Su

rviv

al

Refractory ascites

Survival in Cirrhosis Based on Level

of Renal Dysfunction

Survival Among Patients With Cirrhosis and HRS

1 2 3 4 500 6

0.6

00

Survival is Decreased with Renal Dysfunction

Setting

•Advanced liver disease: cirrhosis, alcoholic hepatitits, fulminant hepatitis

•Sometimes precipitated by overdiuresis, GI bleed, use of nephrotoxic agents

Clinical Features•Ascites • Oliguria•Hypotension • Jaundice

Course•Typically death within weeks

Hepatorenal Syndrome

Splanchnic/systemic vasodilatation

Intrahepatic resistance

Portal (sinusoidal) hypertension

Activation of neurohumoral systems

Cirrhosis

Effective arterial blood volume

Renal vasoconstriction

HEPATORENAL SYNDROME

Type 1 and Type 2 HRS

• HRS Type 1– Rapidly progressive– Precipitating event frequent, esp SBP– Very short survival

• HRS Type 2– Slow onset of moderate renal insufficiency– Poor response to diuretics (refractory ascites)– Longer survival

0 2 4 6 8 1210

Months

1

0.2

0.4

0.6

0.8

Survival probability

0

Type 2

p = 0.001

Gines et al., Lancet 2003; 362:1819

Type 1

Prognosis in Type 1 and 2 HRS

Precipitants of Type 1 HRS

• Infection– Spontaneous bacterial peritonitis (SBP)– Urinary tract infection– Cellulitis

• Gastrointestinal hemorrhage• NSAID use• Large volume paracentesis without albumin• Adrenal insufficiency

Salerno et al. Gut 2007

HRS Diagnostic Criteria

1. Cirrhosis with ascites

2. Serum CR >1.5 mg/dL

3. No improvement in serum CR after at least 2 days of diuretic withdrawal & volume expansion with albumin (max 100g/day)

4. Absence of shock

5. No current or recent nephrotoxic drugs

6. Absence of parenchymal kidney disease

Clinical Characteristics of HRSAscites

Advanced liver disease

Low mean arterial pressure (median 74 mmHg)

Low serum Na (median 127 mEq/L)

Low urinary output

Do not rely on urine Na or urine sediment to differentiate HRS from ATN

Garcia-Tsao et al. Hepatology 2008

Prevention of AKI in cirrhotics Careful use of diuretics & lactulose Albumin after large volume paracentesis Avoid NSAIDs & aminoglycosides Albumin & antibiotics for treatment of SBP Primary prophylaxis of SBP with

antibiotics Antibiotics for 5-7 days at time of GI bleed

Precipitants

• Treatment principles• Treat the underlying precipitant promptly

• More quickly addressed the more likely to have improvement in HRS

• Have a high suspicion for an occult precipitating event in any liver patient who has ARF

• Even with removal of the precipitant, HRS may be irreversible

72

Treatments

• Precipitating events

• Renal vasodilators

• Systemic vasoconstrictors

• TIPS

• Dialysis

• Transplantation

73

Hepatocellular Carcinoma

Hepatocellular Carcinoma

• Seen in cirrhosis– Exception: HBV (can be noncirrhotic)

• Diagnosis by US, CT scan, MRI– Histology is not essential

• Alpha-fetal protein level may be elevated

Hepatocellular Carcinoma (HCC)

• Surveillance– Screen all patients with cirrhosis for HCC

• Up to 8% risk of HCC/year

– Also male HBV carriers >40 and female HBV >50 (even if they don’t have cirrhosis)

• Up to 0.6% risk of HCC/year

• For boards…screen with ultrasound q 6 months– No benefit to shorten interval– No benefit to screen with AFP– In practice many still use cross sectional imaging and

AFP to screen as well

Diagnosis of HCC

• Usually with imaging, histology used less often

• If lesion seen on u/s> 1cm then follow up with CT or MR– If hypervascular lesion that washes out on

portal venous phase then dx with HCC– No bx needed

CT appearance of HCC

Arterial Phase

Arterial Phase Washout

Treatment of HCC

• Resection

• Local-Regional therapy– TACE– RFA– Ethanol ablation

• Liver transpantation

• Systemic– Sorafenib

Treatment of HCC

• Resection– Less commonly used– Noncirrhotic or very well compensated

• Well preserved synthetic function (INR near normal)

• Normal bili• Low portal pressure

– Possibly for noncirrhotic HBV patient..– No role for adjuvant chemotherapy

Treatment of HCC

• Local ablation– Alcohol injection

• Only in smaller tumors

• Not used very often

– Radiofrequency ablation• Better for larger tumors

– May use as a bridge to liver transplantation

Treatment of HCC

• Transarterial Chemoebolization (TACE)– Non curative– Nonsurgical patients

– Large multifocal HCC– No vascular invasion– No extrahepatic spread

Treatment of HCC

• Liver transplantation– Curative approach– Milan Criteria

• 1 tumor <5cm• Up to 3 tumors <3cm• No vascular / extrahepatic spread

– Tumor exception points• MELD=22

Treatment of HCC

• Sorafenib– Last resort– Cannot benefit from resection, transplantation,

ablation or TACE– Multifocal disease with well preserved hepatic

function– SHARP trial median survival 10.7 months vs

7.9 months average survival

Take Home: HCC

• Screen patients with u/s q6 months if they have cirrhosis / older patients with HBV

• Usually radiographic diagnosis– Biopsy rarely needed– Cross sectional imaging look for “arterial

enhancement” and “washout”

• Treatment:– Possibly “curative”: ablation, resection,

transplant– Palliative: TACE, sorafenib

Prognostic Tools

Prognostic Models

• Tools for predicting disease severity and death– Child-Turcotte-Pugh (CTP) score– Model or End-Stage Liver Disease (MELD)

Child-Pugh-Turcotte Classification

1 2 3

Albumin (g/dl) >3.5 2.8-3.5 <2.8

Total bilirubin (mg/dl) <2 2-3 >3

Prothrombin time (INR) <1.7 1.7-2.3 >2.3

Ascites None Medically Uncontrolled

controlled

Encephalopathy (grade) 0 I-II III-IV

Class: A = 5-6 points, B = 7-9 points, C = 10-15 points

MELD Score

• Model for Endstage Liver Disease

• MELD = INR, Creatinine, Bilirubin

• Higher scores (6 to 40) indicate worse prognosis

• MELD >15 would benefit from liver transplant

Conclusions

• The transition from compensated cirrhosis to decompensated cirrhosis carries a significant change in mortality

• Clinical diagnosis is important

• Simultaneous compications may (and usually arise)