1. COMPLICATIONS OF CIRRHOSIS Philip C. Delich MD

2. THE EPIDEMIC OF CIRRHOSIS  NAFLD/NASH  HCV  HBV  NAFLD/NASH  HCV  HBV

3. Cirrhosis  End stage of any chronic liver disease  Characterized histologically by regenerative nodules surrounded by fibrous tissue  Clinically there are two types of cirrhosis:  Compensated  Decompensated  End stage of any chronic liver disease  Characterized histologically by regenerative nodules surrounded by fibrous tissue  Clinically there are two types of cirrhosis:  Compensated  Decompensated DEFINITION OF CIRRHOSIS

4. Cirrhosis Normal Nodules Irregular surface GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER

5. Cirrhosis Normal Nodules surrounded by fibrous tissue HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER

6. Diagnosis of Cirrhosis  Gold standard=liver biopsy  Usually not necessary Physical exam findings (spiders, palmer erythema, gynecomastia, hepatosplenomegally) Labs- thrombocytopenia, AST>ALT Radiologic Evidence  Gold standard=liver biopsy  Usually not necessary Physical exam findings (spiders, palmer erythema, gynecomastia, hepatosplenomegally) Labs- thrombocytopenia, AST>ALT Radiologic Evidence

7. No Yes Diagnostic Algorithm Patient with chronic liver disease and any of the following:  Variceal hemorrhage  Ascites  Hepatic encephalopathy Patient with chronic liver disease and any of the following:  Variceal hemorrhage  Ascites  Hepatic encephalopathy Liver biopsy not necessary for the diagnosis of cirrhosis Physical findings: Enlarged left hepatic lobe Splenomegaly Stigmata of chronic liver disease Physical findings: Enlarged left hepatic lobe Splenomegaly Stigmata of chronic liver disease Laboratory findings: Thrombocytopenia Impaired hepatic synthetic function Laboratory findings: Thrombocytopenia Impaired hepatic synthetic function Radiological findings:  Small nodular liver  Intra-abdominal collaterals  Ascites  Splenomegaly  Colloid shift to spleen and/or bone marrow Radiological findings:  Small nodular liver  Intra-abdominal collaterals  Ascites  Splenomegaly  Colloid shift to spleen and/or bone marrow Yes No Yes No Liver biopsy DIAGNOSTIC ALGORITHM

8. Compensated vs Decompensated Cirrhosis Compensated Normal liver function Asymptomatic patient Diagnosis made incidentally Good prognosis Decompensated  Failing liver  Ill patient  Usually obvious diagnosis  Poor prognosis

9. 60 40 80 100 120 140 160 0 0 40 60 80 20 0 0 100 Months Probability of survival All patients with cirrhosis Decompensated cirrhosis 180 Decompensation Shortens Survival 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 SURVIVAL TIMES IN CIRRHOSIS

10. Cirrhosis-proposed new classification  Stage 1-compensated with no varices-1% mortality  Stage 2-compensated with varices- 3.4%mortality  Stage 3-ascites- 20% mortality  Stage 4- variceal bleeding- 57%mortality  Stage 1-compensated with no varices-1% mortality  Stage 2-compensated with varices- 3.4%mortality  Stage 3-ascites- 20% mortality  Stage 4- variceal bleeding- 57%mortality

11. MANAGEMENT OF WELL COMPENSATED CIRRHOSIS  Rx. Cause (HCV,HBV, wt. loss in NASH, phlebotomy in hemochromatosis etc)  Screen for esophageal varices  Screen for hepatocellular carcinoma  Vaccinate against Hepatitis A and B if not already protected.  Optimize transplant candidacy  Observe for signs of decompensation.

12.  Decompensated cirrhosis- cirrhosis with signs of liver failure (ascites, edema, hepatic encephalopathy etc)

13. Complications of cirrhosis  Ascites  refractory ascites  SBP  hepatorenal syndrome  Variceal Bleeding  Hepatic Encephalopathy  HCC  Ascites  refractory ascites  SBP  hepatorenal syndrome  Variceal Bleeding  Hepatic Encephalopathy  HCC

14. Uncomplicated Ascites  Low Na diet  Combination diuretics (spironolactone 100mg-400mg/day, furosamide 40mg-160mg/day)  Therapeutic Paracentesis  Low Na diet  Combination diuretics (spironolactone 100mg-400mg/day, furosamide 40mg-160mg/day)  Therapeutic Paracentesis

15. Refractory Ascites  Serial paracentesis with IV albumin infusion (8 grams/liter removed)  TIPSS (Transjugular Intrahepatic Porto-systemic Shunt) - contraindicated in patients with history of hepatic encephalopathy, advanced disease (bili >3 etc), elderly  Serial paracentesis with IV albumin infusion (8 grams/liter removed)  TIPSS (Transjugular Intrahepatic Porto-systemic Shunt) - contraindicated in patients with history of hepatic encephalopathy, advanced disease (bili >3 etc), elderly

16. Transjugular Intrahepatic Portosystemic Shunt Hepatic vein Hepatic vein Portal vein Splenic vein Splenic vein Superior mesenteric vein TIPS THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

17. Spontaneous Bacterial Peritonitis  Frequent complication  Approx. 30% in hospitalized patients  Diagnosed with paracentesis->250 PMNs per HPF  Rx-3 rd gen. cephalosporine x 5 days  70% recurrence in one year  prophylactic antibiotics  Frequent complication  Approx. 30% in hospitalized patients  Diagnosed with paracentesis->250 PMNs per HPF  Rx-3 rd gen. cephalosporine x 5 days  70% recurrence in one year  prophylactic antibiotics

18. Hepatorenal Syndrome  Rapidly progressive renal failure in setting of liver failure  Absence of other causal factors  No improvement with fluid challenge  oliguria  low urine Na  Rapidly progressive renal failure in setting of liver failure  Absence of other causal factors  No improvement with fluid challenge  oliguria  low urine Na

19. Rx. Of Hepatorenal syndrome  Vasoconstrictors (oral midodrine-5 mg TID)  Octreotide 100ug SQ TID  Volume expansion (IV albumin)  Vasoconstrictors (oral midodrine-5 mg TID)  Octreotide 100ug SQ TID  Volume expansion (IV albumin)

20. Variceal Bleeding  Frequent complication (33-50% lifetime risk in cirrhotics)  High mortality (20%)  Increased risk with progression of liver disease.  Preventable and treatable  Frequent complication (33-50% lifetime risk in cirrhotics)  High mortality (20%)  Increased risk with progression of liver disease.  Preventable and treatable

21. Prevalence of Esophageal Varices in Cirrhosis % % 100 60 40 20 0 0 Overall Child A Child B 80 Child C Pagliaro et al., In: Portal Hypertension: Pathophysiology and Management, 1994: 72 PREVALENCE OF ESOPHAGEAL VARICES IN CIRRHOSIS

22. Small varices Large varices No varices 7-8%/year Varices Increase in Diameter Progressively Merli et al. J Hepatol 2003;38:266 VARICES INCREASE IN DIAMETER PROGRESSIVELY

23. Prophylaxis of Variceal Hemorrhage Diagnosis of Cirrhosis Endoscopy No Varices Follow-up EGD in 2-3 years* Small Varices Follow-up EGD in 1-2 years* Medium/Large Varices Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No Contraindications Contraindications or Beta-blocker intolerance Contraindications or Beta-blocker intolerance Beta-blocker therapy Endoscopic Variceal Band Ligation *EGD every year in decompensated cirrhosis MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY

24. Management of Acute bleeding  Octreotide (50 ug bolus  50 ug/hr infusion  Prompt diagnosis with endoscopy  Band ligation if esophageal varices  TIPPS for gastric varices or salvage if not endoscopically managable  HIGH RISK OF SBP-NEED ANTIBIOTIC PROPHYLAXIS! (3 RD GEN. CEPHALOSPORINE)  Octreotide (50 ug bolus  50 ug/hr infusion  Prompt diagnosis with endoscopy  Band ligation if esophageal varices  TIPPS for gastric varices or salvage if not endoscopically managable  HIGH RISK OF SBP-NEED ANTIBIOTIC PROPHYLAXIS! (3 RD GEN. CEPHALOSPORINE)

25. Endoscopic Variceal Band Ligation  Bleeding controlled in 90%  Rebleeding rate 30%  Compared with sclerotherapy:  Less rebleeding  Lower mortality  Fewer complications  Fewer treatment sessions  Bleeding controlled in 90%  Rebleeding rate 30%  Compared with sclerotherapy:  Less rebleeding  Lower mortality  Fewer complications  Fewer treatment sessions ENDOSCOPIC VARICEAL BAND LIGATION

26. Transjugular Intrahepatic Portosystemic Shunt Hepatic vein Hepatic vein Portal vein Splenic vein Splenic vein Superior mesenteric vein TIPS THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

27. Secondary prophylaxis against variceal bleeding  Non-selective beta blockers (nadolol or propranolol-tritrate to pulse 60 and tolerance)  Serial endoscopic banding Q2-4 weeks until varices obliterated then yearly for surveillance.  Non-selective beta blockers (nadolol or propranolol-tritrate to pulse 60 and tolerance)  Serial endoscopic banding Q2-4 weeks until varices obliterated then yearly for surveillance.

28. Hepatic Encephalopathy  Neuro-psychological disorder resulting from inability of failing liver to remove nitrogenous waste products of protein metabolism from circulation.  CLINICAL DIAGNOSIS-ammonia levels do not correlate well with diagnosis or stage of encephalopathy.  Neuro-psychological disorder resulting from inability of failing liver to remove nitrogenous waste products of protein metabolism from circulation.  CLINICAL DIAGNOSIS-ammonia levels do not correlate well with diagnosis or stage of encephalopathy.

29. Hepatic Encephalopathy Is A Clinical Diagnosis  Clinical findings and history important  Ammonia levels are unreliable  Ammonia has poor correlation with diagnosis  Measurement of ammonia not necessary  Number connection test  Slow dominant rhythm on EEG  Clinical findings and history important  Ammonia levels are unreliable  Ammonia has poor correlation with diagnosis  Measurement of ammonia not necessary  Number connection test  Slow dominant rhythm on EEG HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS

30. Asterixis ASTERIXIS IS THE HALLMARK IN THE DIAGNOSIS OF HEPATIC ENCEPHALOPATHY

31. STAGES OF HEPATIC ENCEPHALOPATHY Confusion Drowsiness Somnolence Coma 1 1 2 2 3 3 4 4 Stage Stages of Hepatic Encephalopathy

32. Treatment of Hepatic Encephalopathy  Identify and treat precipitating factor  Infection  GI hemorrhage  Prerenal azotemia  Sedatives  Constipation  Lactulose (adjust to 2-3 bowel movements/day)  Protein restriction, short-term (if at all)  Identify and treat precipitating factor  Infection  GI hemorrhage  Prerenal azotemia  Sedatives  Constipation  Lactulose (adjust to 2-3 bowel movements/day)  Protein restriction, short-term (if at all) TREATMENT OF HEPATIC ENCEPHALOPATHY

33. Antibiotics for hepatic encephalopathy  Generally secondary agents in lactulose failures  Work through alteration of gut flora  decreased absorption of nitrogenous wastes.  Neomycin (500 mg TID)- cheap- theoretical risk of renal toxicity and deafness  Xifaxan (400 mg TID)-very expensive perhaps safer and more effective.  Generally secondary agents in lactulose failures  Work through alteration of gut flora  decreased absorption of nitrogenous wastes.  Neomycin (500 mg TID)- cheap- theoretical risk of renal toxicity and deafness  Xifaxan (400 mg TID)-very expensive perhaps safer and more effective.

34. “Natural benzodiazepines” and Hepatic Encephalopathy  Activated GABA-ergic tone in H.E.  Poorly delineated GABA receptor agonists with action similar to benzodiazepines activate GABA receptors.  Therefore, benzodiazepines ppt H.E. and are contraindicated in cirrhosis.  EXTREME CARE NECESSARY WHEN TREATING ALCOHOL WITHDRAWAL IN CIRRHOSIS!  Activated GABA-ergic tone in H.E.  Poorly delineated GABA receptor agonists with action similar to benzodiazepines activate GABA receptors.  Therefore, benzodiazepines ppt H.E. and are contraindicated in cirrhosis.  EXTREME CARE NECESSARY WHEN TREATING ALCOHOL WITHDRAWAL IN CIRRHOSIS!

35. Epidemic of Hepatocellular Carcinoma  Directly related to increased incidence of cirrhosis.  Cirrhosis “fertile ground” for HCC  HCV related cirrhosis carries 1- 4%/year risk of HCC  Hepatitis B even higher and virus alone without cirrhosis carries risk (oncogenic)  Directly related to increased incidence of cirrhosis.  Cirrhosis “fertile ground” for HCC  HCV related cirrhosis carries 1- 4%/year risk of HCC  Hepatitis B even higher and virus alone without cirrhosis carries risk (oncogenic)

36. HCC-Rationale for Screening  Early tumors potentially resectable (occasionally) and frequently curable with transplantation (Milan criteria).  Evolving treatments increasingly helpful even if “cure” not feasible (chemoembolization, radiofrequency ablation, cryotherapy)  Early tumors potentially resectable (occasionally) and frequently curable with transplantation (Milan criteria).  Evolving treatments increasingly helpful even if “cure” not feasible (chemoembolization, radiofrequency ablation, cryotherapy)

37. HCC Screening  Imaging modalities (US vs. CT vs. MRI)  AFP-probably not useful but still done.  Frequency needs to be Q 6 mo to be effective.  Screen stage 3 and 4 fibrosis patients.  In hepatitis B, all infected patients at risk and need to be screened.  Imaging modalities (US vs. CT vs. MRI)  AFP-probably not useful but still done.  Frequency needs to be Q 6 mo to be effective.  Screen stage 3 and 4 fibrosis patients.  In hepatitis B, all infected patients at risk and need to be screened.

38. Liver Transplantation  Only definitive treatment  Standard of care in 2014  Virtually all patients with ESLD should be considered- few absolute contraindications  Excellent short and long term survival  Only definitive treatment  Standard of care in 2014  Virtually all patients with ESLD should be considered- few absolute contraindications  Excellent short and long term survival

39. “Pearls” in management of cirrhosis  Cirrhosis is clinical diagnosis that rarely requires liver biopsy.  Low platelet count cirrhosis until proven otherwise.  AST>ALT =cirrhosis (or alcoholic liver disease)  Always consider SBP and when in doubt, rule it out  Avoid benzodiazepines and use extreme care in treatment of alcohol withdrawl in cirrhotics.  Cirrhosis is clinical diagnosis that rarely requires liver biopsy.  Low platelet count cirrhosis until proven otherwise.  AST>ALT =cirrhosis (or alcoholic liver disease)  Always consider SBP and when in doubt, rule it out  Avoid benzodiazepines and use extreme care in treatment of alcohol withdrawl in cirrhotics.

40. “Pearls” continued  Screen cirrhotics for varices and HCC regularly  Hepatic Encephalopathy is a clinical diagnosis-ammonia levels not useful.  Band esophageal varices to obliteration.  Remember low Na diets in management of ascites.  Cirrhosis is a catabolic state-low protein diets rarely useful and usually harmful.  Think about transplantation early in decompensation.  Screen cirrhotics for varices and HCC regularly  Hepatic Encephalopathy is a clinical diagnosis-ammonia levels not useful.  Band esophageal varices to obliteration.  Remember low Na diets in management of ascites.  Cirrhosis is a catabolic state-low protein diets rarely useful and usually harmful.  Think about transplantation early in decompensation.

41. SURGERY AND CIRRHOSIS  INCREASED RISK OF ANESTHESIA  INCREASED RISK OF HEPATIC ENCEPHALOPATHY WITH POST-OP PAIN MANAGEMENT  VERY HIGH RISK IN MAJOR CAVITIES (CHEST AND ABDOMEN)  CONTRAINDICATED IN DECOMPENSATED CIRRHOSIS UNLESS TRUE EMERGENCY!  INCREASED RISK OF ANESTHESIA  INCREASED RISK OF HEPATIC ENCEPHALOPATHY WITH POST-OP PAIN MANAGEMENT  VERY HIGH RISK IN MAJOR CAVITIES (CHEST AND ABDOMEN)  CONTRAINDICATED IN DECOMPENSATED CIRRHOSIS UNLESS TRUE EMERGENCY!

42. HOSPICE AND END STAGE LIVER DISEASE  APPROX. 50% MORTALITY OVER 2 YEARS  BENZODIAZEPINES AND OPIATES RELATIVELY CONTRAINDICATED IN CIRRHOSIS  HEPATIC COMA!  PAIN USUALLY NOT AN ISSUE EXCEPT ASCITES RELATED DISTENSION MANAGED BY TAP AND NOT OPIATES!  APPROX. 50% MORTALITY OVER 2 YEARS  BENZODIAZEPINES AND OPIATES RELATIVELY CONTRAINDICATED IN CIRRHOSIS  HEPATIC COMA!  PAIN USUALLY NOT AN ISSUE EXCEPT ASCITES RELATED DISTENSION MANAGED BY TAP AND NOT OPIATES!

43. PREVENTION BEST MEASURE  MOST CIRRHOSIS IN WESTERN COUNTRIES IS LIFESTYLE RELATED DISEASE (OBESITY/IVDA/ALCOHOL)  DIAGNOSE AND RX HCV  VACCINATION AGAINST HEPATITIS A AND B  EDUCATION AND LIFESTYLE MODIFICATION ESSENTIAL  MOST CIRRHOSIS IN WESTERN COUNTRIES IS LIFESTYLE RELATED DISEASE (OBESITY/IVDA/ALCOHOL)  DIAGNOSE AND RX HCV  VACCINATION AGAINST HEPATITIS A AND B  EDUCATION AND LIFESTYLE MODIFICATION ESSENTIAL