1. Management of Liver Failure and Cirrhosis Hesham Elgouhari, MD, FACP Associate Professor of Medicine Hepatologist and Medical Director, Avera Center for Liver Disease

2. Management of Cirrhosis: How are we doing?
Large body of high-quality evidence
Many randomized trials and guidelines
Despite all of that, Not doing very well:
Cirrhotics received Hepatitis A/ B vaccines: 7%-62%
EV/GV grade II-III on NSBB: 6%-22%
Cirrhotic ascites on recommended therapy: 33%
HCC surveillance: 16%-28%
One month readmission of cirrhotics: > 30%

3. Improving Cirrhosis Care The Need for Coordination
Generalist and subspecialist
Bini et al: GI/Hepatology consultation was associated with improved outcome for patients hospitalized with decompensated cirrhosis
Limited access
Fragmentation between inpatients& outpatient settings and between PCPs& Subspecialists
Limited application of Multidisciplinary team approach

4. Team Work…

5. Practical Approach of Cirrhosis Management

6. Characters of inpatient cirrhotics
Very sick
Crash easily and quickly
Multiorgan dysfunction
Multidisciplinary management
Atypical presentations of common acute illnesses (Infections and kidney diseases)
Malnourished

7. Characters of inpatient cirrhotics
Medications are sometimes very dangerous
Surgeons
Elective procedures
Discharge plan
Only one Backup: Liver Transplantation which is complicated and not easily available

8. Five Questions Does the patient have cirrhosis?
What is (are) the cause(s)?
What stage of Cirrhosis is present?
What is (are) the complication(s) present?
What is the status of Liver Transplantation?

9. Question # 1: Does the patient have cirrhosis?

10. Terminology in Hepatology What are you dealing with?
Transaminitis
Hepatitis
Liver Failure
Liver fibrosis
Liver cirrhosis
Acute Liver Disease
Chronic Liver Disease
Acute on top of Chronic Liver Disease
ESLD

11. Cirrhosis, Relevant Facts
The word cirrhosis comes from the Greek word “kirrhos”, the name for a yellowish-brown color
The definition of cirrhosis remains pathological, described by “WHO” in 1978 as: “a diffuse process characterized by fibrosis and the conversion of normal liver architectures into structurally abnormal nodules”

12. Cirrhosis, Relevant Facts
The prevalence is not well known
About two Million outpatients visits and 750,000 hospitalizations per year for CLD
About 40,000 per year progress to ESLD, Liver failure and death

13. Cirrhosis, Relevant Facts
The 12th most common cause of death in USA
In 2007, more than 29,000 patients died from it
In August 2010, About 16,000 were listed for Liver transplant, only about 6000 got it
About 5%-10% listed for LT died while waiting

14. Natural history of chronic liver disease
Jaundice
Encephalopathy
Variceal bleeding
Ascites
Increasing
liver fibrosis
5%-7%/Y
Chronic
Liver Disease
Compensated
Cirrhosis
Decompensated
Cirrhosis
Death
2%- 7%/Y
-Steatohepatitis
-HBV& HCV Hepatitis
-Autoimmune Hepatitis
-Biliary liver disease
-Metabolic/Hereditary
Liver Disease
-Others
Liver
Transplantation
HCC
Death

15. When should you look for Liver disease?
Positive RISK FACTOR and/or Positive “Others”
Unlike heart or lung or even Kidney…
All “others” ALONE are NOT 100% sensitive
What are the “others”?
History and Physical
Liver chemistry tests
Abdominal imaging
EGD findings: Varices or PHG

16. Liver Cirrhosis… When should we think of it
History:
Positive for a cause of CLD as HCV, ETOH,...
Symptoms of hepatic decompensation
Remember it in diabetic and/or obese patients
Up to 40 % of cirrhotic patients are asymptomatic

17. Liver Cirrhosis, When should we think of it
Physical examination:
General appearance
Temporal wasting
Skin signs
Ascites/leg edema
Splenomegaly (It is OK…)
Asterixis in patients with AMS

18. Liver Cirrhosis, When should we think of it
Lab:
Low plat. Count! It is not ITP yet…
AST:ALT > 1 in non alcoholic CLD
Hyperbilirubinemia
Hypoalbuminemia

19. Abnormal Abdominal Imaging
Hepatomegaly
Splenomegaly
Fatty liver (coarse echogenicity): ALD& NAFLD
Lobulated liver margin, shrunken Liver, or nodular Liver, large left lobe with small /low normal right one Cirrhosis
Varices
Ascites

20. Liver Biopsy

21. Question # 2: What is (are) the cause(s)?

22. What is the cause Alcoholic Liver Disease (ALD)
Non Alcoholic Fatty Liver Disease (NAFLD)
Chronic Hepatitis C
Chronic Hepatitis B
AIH
Hemochromatosis
PBC/PSC
Wilson disease
Alpha one Antitrypsin Deficiency

23. Diagnosis of ALD The Diagnosis is based on: Not that easy
History of significant ETOH intake
Clinical evidence of liver disease
Supporting Laboratory abnormalities
Not that easy
Have a low threshold to suspect ALD, but in a gentle way
Four tools:
History (Questionnaires)
Physical Examination
Laboratory studies
Liver Biopsy

24. What is our performance?
McQuade et al*:
300 random patients were interviewed
Use Questionnaires to assess
DSM-IV for diagnosis
Compare to physicians’ diagnosis
*McQuade WH et al. Detecting symptoms of alcohol abuse in primary care settings. Arch Fam Med 2000 Sep;9(9):

25. Risk factors for NAFLD A common disease
Linked to Metabolic Syndrome& IR
Could show up with manifestations of decompensated cirrhosis
In diabetics, NAFLD is present in 63%
In morbidly obese patients undergoing bariatric surgery, NAFLD is present in 96%

26. The features of the MS are commonly seen in subjects with NAFLD
METABOLIC SYNDROME
Feature
Prevalence
Obesity
Diabetes
Hypertension
Dyslipidemia
50-90%
20-50%
25-70%
35-75%
Still, Patients without any component of MS but with Insulin Resistance can have NAFLD

27. The Suggested Natural History of NAFLD
Majority
Stable
Simple Steatosis
Liver cancer ?
10%/7 yrs
9%-20%
Fibrosis
Progression ?
25%-35%
Cirrhosis
NASH
50%/7 yrs
65%-75%
Liver failure
Stable or with
Regression
22%-33%
Death or OLT

28. NAFLD Rapidly growing cause of CLD/Cirrhosis
Expected to be the most common cause of liver failure and liver cancer (HCC)
Add “Liver” to your diabetic patients check list beside heart, kidney, eye,….
NASH could be presented with biopsy proven cirrhosis even with normal LFTs
NASH could be presented with liver failure/HCC

29. HCV Risk factors: Screen regardless LCT
BABY BOOMERS (DOB between )
IVDU: In the recent or remote past even once
Hemophiliacs who received clotting factor concentrates before 1987
Blood transfusion/ organ transplant before July 1992
Patients on HD
HIV patients
Children born to HCV-infected mothers
Sexual partners of HCV-infected patients
Elevated liver enzymes
Others: Occupational exposure, Tattoo, Cocaine abuse

31. HBV Risk Factors: Screen regardless LCT
Immigrants and adopted children
Households of HBs Ag positive patients
Sexual contacts of HBs Ag positive patients
Persons who have ever injected drug
Persons with multiple sexual partners or Hx of STD
Before Immunosuppressive therapy
Men who have sex with men
Inmates of correctional facilities
Individuals with chronically elevated ALT or AST
Individuals infected with HCV or HIV
Patients undergoing renal dialysis
All pregnant women

32. Risk Factors for Autoimmune Liver Disease
Other Autoimmune Diseases:
About 35%-60% of patients with AIH
RA, SLE, HT, DM-2, …
IBD:
Among IBD patients (UC>CD), 4% have PSC
Among PSC patients, 2/3 have IBD
Family history of PBC

33. Hereditary Liver Disease
All are AR
Hereditary Hemochromatosis:
Relatively common (1:300)
Get Iron studies in patients with abnormal LCT
Alpha one Antitrypsin deficiency
Wilson Disease
If you have an index case Screen first degree relatives

34. Treatment of the cause Very helpful
Achieves variable degrees of reversibility
CHC, CHB, ETOH, and AIH are the prominent examples in compensated cirrhosis
CHB and ETOH are the prominent examples in decompensated cirrhosis
Risk: Benefit Ratio

35. Question # 3: What stage of Cirrhosis is present?

36. Natural history of chronic liver disease
Jaundice
Encephalopathy
Variceal bleeding
Ascites
Increasing
liver fibrosis
5%-7%/Y
Chronic
Liver Disease
Compensated
Cirrhosis
Decompensated
Cirrhosis
Death
2%- 7%/Y
-Steatohepatitis
-HBV& HCV Hepatitis
-Autoimmune Hepatitis
-Biliary liver disease
-Metabolic/Hereditary
Liver Disease
-Others
Liver
Transplantation
HCC
Death

37. Child-Turcotte-Pugh Score

38. Model for End stage Liver Disease (MELD)
Designed first to assess Candidacy for TIPS
Shown to be very good (Not perfect) in predicting short term mortality
Based on Creatinine, T. Bilirubin, and INR
Objective and immune to behavioral biases
MELD exception (HCC, HPS, others)
The initial concern of ‘Sickest first” system would decrease post LT survival faded
MELD < 15 carries more risks with surgery

40. MELD Modifications MESO index: MLED and S. Sodium
Mortality of patients with low MELD +Na <125 = that of those with MELD of 20 points higher
iMELD: Age, S. Sodium, and MELD
The United Kingdom End Stage Liver Disease Score (UKELD)
Liver INR
MELD-XI (patients on AC therapy)
MELD Modified-by-Gender score

41. Variceal bleeding +/- Ascites
Cirrhosis Stages
Characters
1-Year mortality
Stage I
No varices or ascites 1%
Stage II
Non-bleeding Varices 3%
Stage III
Ascites
20%
Stage IV
Variceal bleeding +/- Ascites
57%

42. Question # 4:
What is (are) the complication(s) present?

43. Complications of Cirrhosis
Portal Hypertension
Ascites
Esophageal and Gastric Varices
Hepatorenal Syndrome
Pulmonary Complications (HH, HPS, PPHTN)
Hypersplenism
Coagulopathy
Encephalopathy
? Cardiomyopathy
Hepatocellular Carcinoma
Malnutrition

44. Ascites The most common complication of cirrhosis
About 50% of patients with compensated cirrhosis will develop ascites over a 10-year period
After 2 years of ascites, the mortality rate is 50%
With refractory ascites, one-year survival is 57%
Be careful about the kidneys!

45. Ascites
The most common cause of ascites in the US is cirrhosis (about 85%), then heart disease, cancer& TB
The old theory is the “Backward” theory with cirrhosisPHTNBackward Pressure in the splanchenic capillariesFluid leak from the capillaries
The new theory is “Forward” theory in which splanchnic art. vasodilatation (SAVD) is the key word:
Forward increase in the capillary pressure in the liver with subsequent increase in lymph formation > lymph absorption
Arterial underfilling in the systemic circulation (blood stagnation in the spalnchnic area) ++ of hypovolemic hormones (RAAS), SNS, and ADH

46. Approach to Ascites...Easy!
Do Paracentesis
Get Cell count with diff always to rule out SBP
Get ascitic albumin and protein
Get Serum Ascitic Albumin Gradient (SAAG)
If ≥ 1.1 Portal Hypertension:
If Protein > 2.5Think more of cardiac ascites
If protein < 2.5gm/dlThink more of cirrhotic ascites
If <1.1 Others (Cancer, TB, Renal, Thyroid…)

47. Ascites Management Salt not fluid restriction NO NSAIDs
Diuretics especially Spironolactone and maximize with monitoring
Paracentesis:
Always for any inpatient if feasible
Get Cell count in a purple-top tube
No limit but give Albumin if ≥ 5 Liters or even less with renal insufficiency
Transjugular Intrahepatic Portosystemic Shunt (TIPS)

48. Spontaneous Bacterial Peritonitis
No specific or sensitive symptom or sign
Ascitic fluid analysis is the only way
PMNLs > 250 cells/cc and/or Positive Culture
Ascitic fluid culture in BC tubes (80% Vs 50%)
The usual MOs are E. coli (43%), Klebsiella (11%), Pneumococci (9%), and others
Treat with 3rd GCS and add Albumin if TB > 4, Creatinine > 1, or BUN > 30 ↓ HRS & short term Mortality
Indefinite secondary prophylaxis if ascites exists

49. EV, GV, and PHG Any patient with cirrhosis should get EGD:
Present in 30% of patients compensated cirrhosis
Present in 60% of patients with decompensated cirrhosis
Risk of Bleeding increases with large varices, CPS of B or C, and red wheel sign
Use Nonselective BB or EVL for 1ry prophylaxis
In a large meta-analysis, the risk of the first variceal bleeding was 14% in those on BB compared to 30% in those on placebo
BB acts by:
↓ COP (via β1 receptor)
Inducing splanchnic vasoconstriction (via β2 receptor) ↓ splanchnic blood flow ↓ Portal flow and PV pressure.

50. Variceal Bleeding
Despite every thing we have, the current mortality of EV bleeding is at least 20% at 6 weeks and the immediate mortality from uncontrolled bleeding is 50%
Variceal bleeding ceases spontaneously in 40-50% of cases& in 80% by active therapy if done in the 1st 24h
With acute variceal bleeding:
ICU + Air way protection + good IV lineSSS with IVF
Octreotide IV (50 ug loading dose then 50 ug/hour for 3-5 d)
Keep Hb around 8 gm/dL and do not replace all lost blood (increase rebleeding risk and the mortality if you give more)
Ceftriaxone 1 gm IV daily for ≤ 7 days
EGD within 12 hours
Platelet and/or FFP transfusion if needed
Alert IR for possible TIPS

51. Hepatic Encephalopathy (HE)
HE-A for ALF-related; B for Bypass (shunt) without intrinsic liver disease; and C for cirrhosis-related HE
Regarding B and C:
Minimal HE: with 2 or more abnormal psychomotor tests (Digit symbol test, Block design test, Number connection test A and B)
Episodic HE: Spontaneous, precipitated, or recurrent (2 or more within 1 year)
Persistent HE (> 28 days): Mild (grade I and II), Severe (grade III and IV), and treatment-dependent

52. HE, Lines of Management
Make sure of Diagnosis (No alternatives or Concomitant problems)
Look for and treat the Predisposing Factors
Specific Therapy

53. Make sure of Diagnosis
Cirrhotic patients are not immune to other causes of AMS
Gradual Onset
Presence of precipitating factors
Asterixis
Non focal Neuro exam
Ammonia level is not helpful
Get CT head in the following scenarios:
Severe HE (grade III or IV)
Focal Neurological examination
Head trauma is suspected or confirmed
Absence of recovery/improvement with standard treatment

54. Predisposing Factors
Increased NH3 level (↑ production or ↓consumption):
GIB, constipation, and high protein diet ↑ NH3 production
Portosystemic shunt Decreased hepatic consumption
HypoKIncreased NH3 production by the kidney
Azotemia and Dehydration (overuse lactulose with hyperNa) Decreased NH3 renal excretion
Diureticsdehyration, azotemia, and sometimes, hypoK
Increased sensitivity of CNS to toxins:
Metabolic alkalosis increased BBB permeability to NH3
Psychoactive medications
Hponatremia cerebral edema
Increased hepatic dysfunction:
Acute AH
Surgery with hepatic hypoperfusion
Infections: By all of the above 3 mechanisms

55. Specific Therapy Lactulose//Krystalose: Rifaximin: Neomycin: Flagyl:
Still first line and cheap
Has side effects as Diarrhea that may ↑ Serum Na and Ileus
Get 3-4 semisolid BM daily
Rifaximin:
Has less side effects
Decreases breakthrough by 58%& HE-related hospitalization by 50%
Neomycin:
Rarely used now
4% get absorbed may lead to renal or Oto toxicity
Flagyl:
Do not give it for long dutration as it may lead to neuropathy
Others:
Do not restrict protein intake completely
Compliance

56. HRS
A clinical syndrome of renal and cardiovascular disturbance that occurs usually in patients with advanced cirrhosis with portal HTN
HRS-I (Progressive) and HRS-II (Less progressive)
Cirrhosis Portal HTN ↑ NO Splanchnic VD ++ Vasoconstrictor system (RAS and Sympathetic NS) VC of cerebral, UE, LE and renal BV the latter leads to ↓ RBF↓GFR with normal tubular function at least initially
The PFs are Infections (SBP), LVP without albumin, and Acute AH
The median Survival for patients with HRS-I is 1 month and 7 months for those with HRS-II

57. Diagnosis of HRS: 4 Elements
Cirrhosis
Ascites
Creatinine > 1.5 mg/dL
No other cause of AKI like:
1-Sepsis with onset before not after AKI (usually not that clear in practice)
2-Volume depletion (not better with Albumin and being off diuretics for at least 2 days
3-No Nephrotoxic drugs for the last 2 weeks
4-No parenchymal renal disease as suspected by:
-Proteinuria > 500 mg/day
-Microscopic hematuria (< 50 RBCs/HPF)
-Abnormal kidney imaging

58. Management of HRS Avoid Nephrotoxic drugs and diuretics
Liver Transplantation Evaluation
HRS-I:
Albumin
Vasoconstrictors (Octreotide& Midodrine)
Terlipressin/Noradrenaline
RRT if OLT candidate
HRS-II
LVP with Albumin
? TIPS
? Vasoconstrictors (Octreotide& Midodrine)

59. Cirrhotics and Infections
Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis
Overall median mortality of infected patients was 30.3%, 44% and 63% at 1-, 3- and 12 months, respectively.
The main factor independently associated with death was the occurrence of renal failure
Age, severity of cirrhosis, shock, HE and nosocomial infections were other independent predictors.
Obtaining BC in cirrhotics is almost always needed
Empiric Antibiotic use is often needed

60. Cirrhotics and Nutrition
Protein-calorie malnutrition (PCM) in cirrhotics is multifactorial
PCM is progressive and parallels the severity of liver insufficiency:
20% of Child’s Class A patients
65%–90% of patients with more advanced liver disease
Nearly 100% of liver transplant candidates
frequent meals, daily weights, and nutrition consultation on all hospitalized patients
Protein intake grams/Kg/Day

61. Question # 5 What is the status of Liver Transplantation?

62. A Mandatory Question… Too early…Rare Not interested….Uncommon
With a clear obvious contraindication
Under evaluation
Not a candidate
Actively Listed
On Hold

63. Thank you….