Complications of cirrhosis review

conference

1. COMPLICATIONS OF
CIRRHOSIS
Arjmand Mufti
UTSW

2. Outline
•Portal hypertension
•Ascites
•Hepatic encephalopathy
•Hepatorenal syndrome
•Hypoalbuminemia and coagulopathy
•Hepatocellular carcinoma
•Prognostic Tools

3. CirrhosisNormal
Nodules
Irregular surface
Cirrhosis

4. Definition
•Diffuse fibrosis following hepatocyte
destruction and nodular regeneration
•Multiple causes
–All may lead to cirrhosis
•Asymptomatic (compensated)
•Symptomatic (decompensated)
–portal hypertension
–hepatic failure

5. 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.

6. 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

7. Natural History of Cirrhosis
StageDefinition 1-year
mortality
Median
Survival
1 Compensated without
varices
1% >12 years
2 Compensated with varices3%
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.

8. 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

9. Portal Hypertension

10. Arroyo, V. & Fernández, J. Nat. Rev. Nephrol. 2011
Mechanisms Leading to Circulatory &
Renal Dysfunction in Cirrhosis

11. 6040 80 100120140160
0
40
60
80
20
200
100
Months
Probability of
survival
All patients with
cirrhosis
Decompensated
cirrhosis
180
Gines et. al., Hepatology 1987;7:122rntpcwd6vgMpMcF
7dDd1ncg6
Median survival
~ 9 yearsrntpcwd6vgMpMcF
7d0EBd1ncg6
Median survival
~ 1.6 years
Decompensation shortens survival

12. Venous Anatomy

13. Cirrhotic Liver

14. 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

15. •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

16. Pathophysiology
Portal Hypertension
•Increased intrahepatic vascular
resistance
–Fixed component
•Sinusoidal fibrosis
•Compression by regenerative nodules
–Functional component
•Vasoconstriction
–Deficiency in intrahepatic NO
–Enhanced activity of vasoconstrictors

17. Classification
Type Examples
•Prehepatic Portal or splenic vein
thrombosis
PresinusoidalSchistosomiasis
•Intrahepatic Sinusoidal Cirrhosis
Postsinusoidal Veno-occlusive disease
•Posthepatic Hepatic vein thrombosis
Constrictive pericarditis

18. Varices: Portosystemic Collateral
Formation
•Esophageal varices
•Gastric varices
•Intraabdominal varices
•Caput medusa
•Rectal varices

19. Variceal Bleeding
35-80% 25-40%
50-70%
Survival Death
Rebleed
30-50%
70%

20. 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

21. %
Patients with
varices
100
60
40
20
0
Overall
n=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

22. LaPlace’s Law
T = wall tension
P
1
= intravariceal pressure
P
2
= esophageal lumen pressure
r = vessel radius
W = wall thickness
T = (P
1
-P
2
) x (r/W)

23. Variceal Bleed: Risk Factors
•High Gradient
•Large esophageal varices
•Endoscopic features
–red wale markings
–cherry red signs

24. 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

25. 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

26. 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)

27. Variceal Bleed: When Banding Fails
•Balloon Tamponade
(Blakemore /
Minnesota tube)
temporizing measure
for up to 24 hours
•TIPS

28. 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

29. 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

30. Ascites

31. ASCITES

32. Definition
•Fluid within the
peritoneal cavity
•Occurs in 50-60% of
patients with
cirrhosis over 10-15
years
•Mixture of liver and
intestinal lymph

33. 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

34. Ultrasound

35. 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

36. 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

37. 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
Hepatocyt
es
The normal
sinusoid is
“leaky”
Sinusoid
Sinusoid
fibrous tissue deposition
“capillarization” of
sinusoid
no basement
membrane
37

38. Clinical Presentation
•Abdominal distention
•Bulging flanks
•Shifting dullness
•Fluid wave
•Fluid detected on US or CT scan

39. Total
Protei
n
(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

40. 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

41. Patients with Refractory Ascites Have Worse
Survival than Patients with Diuretic-Responsive Ascites
Survival
probability
1.0
.8
.6
.4
.2
0
120 24 4836 60 8472
Refractory ascites
Non refractory ascites
p<0.00
1
Months
Salerno et al., Am J Gastroenterol 1993; 88:514

42. 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

43. 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

44. 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)

45. Spontaneous Bacterial
Peritonitis (SBP)
Infectious complications of cirrhosis
1.Spontaneous bacterial peritonitis (SBP)
2.Urinary tract infection
3.Pneumonia
4.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):41-8
Runyon Hepatology 2004

46. 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

47. 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:
–3
rd
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

48. SBP : prevention
•GI bleed and cirrhosis
–Ceftriaxone or norflox x 7 days
•If prior episode of SBP, long term
prophylaxis
–Daily norfloxacin or bactrim

49. Hepatic Encephalopathy

50. Definition
•Reversible alteration in the
neuropsychiatric function
•Due to shunting of neurotoxic
nitrogenous products
•Lack of hepatic detoxification

51. Hepatic Encephalopathy
Pathogenesis
Bacterial action
Protein load
Failure to
metabolize
NH
3
NH
3

Shunting
GABA-BD
receptors
Toxins

52. 1 2 3 4
Coma
Somnolence
Confusion
Drowsiness
??
?
?
? ?
Stages
HE
Adapted from AGA Teaching Slides.

53. Hepatic Encephalopathy (HE)
•10-50% of cirrhotics
•40% survival 1 year after 1
st
episode
•15% survival 3 years after 1
st
episode
•Disturbance in diurnal sleep pattern
precedes neurologic signs

54. 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 conditions
Metab Brain Dis 1998 Jun;13(2):159-72
Hepatology 1998 Jul;28(1):45-9
Metab Brain Dis 1995 Sep;10(3):239-48

55. Kappus et al Clinical Gastroenterology and Hepatology, Volume 10, Issue 11, 2012, 1208 - 1219
Classification of Hepatic
Encephalopathy

56. Management of HE
•Identify / treat precipitating factors
•Empiric treatment
–Rifaximin
–Lactulose

57. GI bleeding
Excess protein
Sedatives /
hypnotics
TIPS
Diuretics
Serum K
+
Plasma volume
Azotemia
Temp
Infections
Precipitating Factors of HE

58. 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

59. Treatment of HE
•Lactulose
–First line
–2-3 soft BM/ day
•Rifaximin
–550 BID
–Reduced ammonia
producing bacteria

60. 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

61. Hepatorenal Syndrome

62. Pathophysiology
•Occurs in setting of cirrhosis and
ascites
•Severe renal arterial vasoconstriction
•Compromised glomerular filtration rate
•Normal kidney structure

63. 1.0
0.8
0.6
0.4
0.2
0.0

S
u
r
v
i
v
a
l
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
S
u
r
v
i
v
a
l
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

64. 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

65. Splanchnic/systemic vasodilatation
Intrahepatic resistance
Portal (sinusoidal) hypertension
Activation of neurohumoral systems
Cirrhosis
Effective arterial blood volume
Renal vasoconstriction
HEPATORENAL SYNDROME

66. 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

67. 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

68. 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

69. 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

70. Clinical Characteristics of HRS
Ascites
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

71. 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

72. 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

73. Treatments
·Precipitating events
·Renal vasodilators
·Systemic vasoconstrictors
·TIPS
·Dialysis
·Transplantation
73

74. Hepatocellular Carcinoma

75. 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

76. 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

77. 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

78. CT appearance of HCC
Arterial Phase
Arterial Phase Washout

79. Treatment of HCC
•Resection
•Local-Regional therapy
–TACE
–RFA
–Ethanol ablation
•Liver transpantation
•Systemic
–Sorafenib

80. 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

81. 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

82. Treatment of HCC
•Transarterial
Chemoebolization
(TACE)
–Non curative
–Nonsurgical patients
–Large multifocal HCC
–No vascular invasion
–No extrahepatic spread

83. 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

84. 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

85. 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

86. Prognostic Tools

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

88. 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

89. 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

90. 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)