It is a presentation about cirrhosis of liver and its complications along with treatment of hepatitis B and C.

1. Complications and management of
cirrhosis of liver with special emphasis
on treatment of hepatitis B and C
DR. ADRIJA HAJRA, MD STUDENT, GENERAL MEDICINE SSKM AND IPGMER

3. Cirrhosis is defined as a diffuse process characterized by
fibrosis and the conversion of normal liver architecture into
structurally abnormal nodules.

4. Epidemiology
 Increasing cause of morbidity and mortality in more
developing countries
 14th most common cause of death in adults
worldwide
 Results in 1·03 million deaths per year worldwide
 Prevalence of cirrhosis is difficult to assess and
probably higher than reported,
 because initial stages are asymptomatic disorder is undiagnosed
Lozano RGlobal and regional mortality from 235 causes of death for 20 age groups in 1990
and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet

5. Etiology
 Conditions which may progress to cirrhosis of liver:
 Alcoholism
 Chronic viral hepatitis
 Autoimmune hepatitis
 Nonalcoholic steatohepatitis
 Biliary cirrhosis (primary biliary cirrhosis,primary
sclerosing cholangitis)
D’Amico GL. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;

6. Cardiac cirrhosis
Inherited metabolic liver
disease
Hemochromatosis
Wilsons disease
Alpha 1 antitrypsin deficiency
Cystic fibrosis

7. Three processes are central to
the pathogenesis of
cirrhosis.
1)Death of hepatocytes
2)Extracellular matrix
deposition.
3)Vascular reorganization.
Pathophysiology

9. HISTOPATHOLOGY

10. Clinical Features
 Onset is slow and may take years to develop symptoms
 Early Symptoms include:
 Fatigue
 Anorexia
 Vague right upper quadrant
pain
 Fever
 Nausea and vomiting
 Diarrhea
 Icterus
D’Amico GL. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;

11. Clinical Features
 Later
 Ascites
 Edema
 Upper GI bleeding
 Encephalopathy
D’Amico GL. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;

12. Clinical Examination
 Liver and spleen enlarged
 Scleral icterus
 Palmar erythema
 Spider angiomas
 Parotid gland enlargement
 Digital clubbing
 Muscle wasting

13. Development of edema and ascites.
Decreased body hair
Gynecomastia
Testicular atrophy
Menstrual irregularity

14. COMPLICATIONS

15. Portal hypertension:
gastroesophageal varices
portal hypertensive gastropathy
splenomegaly,hypersplenism
ascites
spontaneous bacterial peritonitis
Hepatorenal syndrome
Hepatic encephalopathy
Hepatopulmonary syndrome
Portopulmonary hypertension
Malnutrition
Coagulopathy
fator deficiency
fibrinolysis
thrombocytopenia
Bone disease
osteopenia
osteoporosis
osteomalacia
Hematologic abnormalities
anemia
hemolysis
thrombocytopenia
neutropenia

16. PORTAL HYPERTENSION:

19. TREATMENT OF VARICEAL HEMORRHAGE:
PRIMARY PROPHYLAXIS

20. APPROACH TO PATIENTS WITH VARICEAL BLEED:

21. RECURRENT BLEEDING:

22. SPLENOMEGALY ITSELF REQUIRES NO SPECIFIC TREATMENT,
ALTHOUGH SPLENECTOMY CAN BE PERFORMED UNDER VERY
SPECIAL CIRCUMSTANCES

24. ASCITES:

25. TREATMENT:
DIETARY SODIUM RESTRICTION
TO EAT FRESH OR FROZEN FOODS
AVOIDING CANNED OR PROCESSED FOODS
DIURETIC THERAPY
IN CASE OF REFRACTORY ASCITES:

26. SPONTANEOUS BACTERIAL PERITONITIS IS A COMMON AND SEVERE COMPLICATION
OF ASCITES CHARACTERIZED BY SPONTANEOUS INFECTION OF THE ASCITIC FLUID
WITHOUT AN INTRA ABDOMINAL SOURCE.
PATHOGENESIS: altered bowel flora bacteria in mesenteric lymph node
bacteria in abdominal lymphaticsthoracic duct lymphbacteremia
hepatic lymph ascites SBP
TREATMENT: Second generation cephalosporin,with cefotaxime being the most commonly
used.

27. PROPHYLAXIS:

28. HEPATIC ENCEPHALOPATHY:

29. HEPATIC ENCEPHALOPATHY ENCOMPASSES A WIDE ARRAY OF TRANSIENT AND
REVERSIBLE NEUROLOGIC AND PSYCHIATRIC MANIFESTATIONS USUALLY FOUND
IN PATIENTS WITH CHRONIC LIVER DISEASE AND PORTAL HYPERTENSION,BUT
ALSO SEEN IN PATIENTS WITH ACUTE LIVER FAILURE.
PATHOGENESIS:

30. CLINICAL FEATURE:
MILD CHANGES IN COGNITION TO PROFOUND COMA.
SUBTLE FINDINGS:
FORGETFULNESS
ALTERATION IN HANDWRITING
DIFFICULTY IN DRIVING
ALTERATION OF SLEEP WAKE CYCLE
OVERT FINDINGS:
ASTERIXIS
AGITATION
DISINHIBITED BEHAVIOR
SEIZURES
COMA

31. DIAGNOSIS: CLINICAL,BIOCHEMICAL,IMAGING
TREATMENT: ELIMINATION OF UNDERLYING CAUSE
ORAL LACTULOSE
ORAL ANTIBIOTICS
ACARBOSE
PROBIOTICS
SODIUM BENZOATE
ZINC
EXTRACORPOREAL ALBUMIN DIALYSIS
L ORNITHINE L ASPERTATE
FLUMAZENIL

32. HEPATORENAL SYNDROME

33. FUNCTIONAL KIDNEY FAILURE IN PATIENTS WITH END STAGE LIVER DISEASE.
RESULTS IN INTENSE RENAL VASOCONSTRICTION WITHOUT ANY OTHER
IDENTIFIABLE KIDNEY PATHOLOGY.
CLINICAL FEATURE:
OLIGURIA
DILUTIONAL HYPONATREMIA
PROGRSSIVE AZOTEMIA
HYPOTENSION
PRECIPITANTS:
GASTROINTESTINAL BLEEDING
SEPSIS
AGGRESSIVE DIURESIS
PARACENTESIS

34. TYPES:
TYPE 1- RAPID AND PROGRESSIVE IMPAIRMENT OF
RENAL FUNCTION DEFINED BY DOUBLING OF THE
INITIAL SERUM CREATININE LEVEL TO >2.5 mg/dl OR
50% REDUCTION OF THE INITIAL 24 HOUR
CREATININE CLEARANCE TO <20ml/min IN LESS
THAN 2 WEEKS
TYPE 2- MORE SLOWLY PROGRSSING ENTITY
CHARACTERISED BY SERUM CREATININE LEVEL < 2.5
mg/dl

35. PATHOGENESIS:

36. DIAGNOSIS:
TREATMENT:
PREVENTIVE
MEDICAL MANAGEMENT (ALBUMIN, VASOPRESSORS, ANTIBIOTICS)
LIVER TRANSPLANTATION

37. HEPATOPULMONARY SYNDROME:

38. HPS IS DEFINED AS A WIDENED AGE CORRECTED ALVEOLAR ARTERIAL
O2 GRADIENT (AaPo2) ON ROOM AIR IN THE PRESENCE OR ABSENCE OF
HYPOXEMIA.(AaPo2=15 mm of Hg or 20 mm of Hg in patients older than
64 yrs) AS A RESULT OF INTRAPULMONARY VASODILATION.
MILD- PaO2 more than or equal to 80 mm of Hg
MODERATE- PaO2 is equal to 61-80 mm of Hg
SEVERE- PaO2 50-60 mm of Hg
VERY SEVERE- PaO2 less than 50 mm of Hg

39. PATHOGENESIS:

40. CLINICAL FEATURE- PLATYPNEA
ORTHODEOXIA
CLUBBING
HYPOXEMIA
DIAGNOSIS:
CLINICAL SUSPICION
MEASUREMENT OF ARTERIAL BLOOD GASES
DETECTION OF INTRAPULMONARY SHUNTING
EXCLUSION OF INTRINSIC CARDIOPULMONARY DISEASE
TREATMENT:
MEDICAL MANAGEMENT
INTERVENTIONAL RADIOLOGIC THERAPY
LIVER TRANSPLANTATION

41. PORTOPULMONARY HYPERTENSION
DEVELOPMENT OF PULMONARY ARTERIAL HYPERTENSION IN THE SETTING OF
PORTAL HYPERTENSION
MECHANISMS POORLY UNDERSTOOD
OCCURS WHEN VASOCONSTRICTION AND REMODELING IN RESISTANCE VESSELS
INCREASE PULMONARY ARTERIAL PRESSURE
FOUND IN AS MANY AS 5% OF PATIENTS WITH CIRRHOSIS
EXERTIONAL DYSPNEA,ORTHOPNEA,FATIGUE,CHEST PRESSURE,SYNCOPE,EDEMA
LIGHTHEADEDNESS MAY BE THE COMPLAINTS.
CLINICAL SUSPICION LEADS TO FURTHER WORK UP TO ESTABLISH THE DIAGNOSIS
MEDICAL MANAGEMENT AND LIVER TRANSPLANTATION

42. CIRRHOTIC CARDIOMYOPATHY:
STRUCTURAL AND FUNCTIONAL VENTRICULAR ABNORMALITIES
LEFT VENTRICULAR HYPERTROPHY
DIASTOLIC DYSFUNCTION
AN ABNORMAL VENTRICULAR RESPONSE IN THE PRESENCE OF
PHARMACOLOGIC,PHYSIOLOGIC OR SURGICAL STRESS
MAY BE ATTRIBUTED TO IMPAIRED BETA ADRENERGIC
SIGNALING PATHWAYS THAT LEAD TO SUBNORMAL
CHRONOTROPIC AND CONTRACTILE RESPONSES.
CARDIAC ELECTROPHYSIOLOGIC ABNORMALITIES
PROLONGATION OF QT INTERVAL
TREATMENT: ALDOSTERONE ANTAGONISTS
NON CARDIOSELECTIVE BETA ADRENERGIC ANTAGONIST
LIVER TRANSPLANTATION: EFFECTS HAVE NOT BEEN FULLY CHARACTERIZED.

43. ENDOCRINE DYSFUNCTION:
ADRENAL INSUFFICIENCY
GONADAL DYSFUNCTION
THYROID DYSFUNCTION
BONE DISEASE (12-55% OF CIRRHOTIC PATIENTS)

44. COAGULATION DISORDERS:
PROLONGED PROTHROMBIN TIME.
PROGRESSIVE LOSS OF HEPATOCYTES LEADS TO DECREASED SYNTHESIS OF PROCOAGULANT FACTORS.
FFP,VIT K,OCCASIONALLY RECOMBINENT FACTOR VIIa CAN BE USED FOR TREATMENT
THROMBOCYTOPENIA
HYPERSPLENISM,DECREASED HEPATIC THROMBOPOIETIN SYNTHESIS,DIRECT BONE MARROW TOXICITY
DYSFIBRINOGENEMIA
INCREASED D DIMER AND FDP. PROLONGATION OF THE CLOT LYSIS TIME.
ALTERED PRODUCTION OF ACTIVITORS AND INHIBITORS OF FIBRINOLYSIS,
ACTIVATION OF THE COAGULATION CASCADE BY ENDOTOXEMIA AND
DECREASED CLEARANCE OF FIBRINOLYTIC PROTEINS IN THE SETTING OF
HEPATIC SYNTHETIC DYSFUNCTION.

45. HYPERCOAGULABLE STATE
CIRRHOSIS ALSO IMPAIRS THE PRODUCTION OF ENDOGENOUS ANTICOAGULANT PROTEINS,
INCLUDING PROTEIN C,PROTEIN S,ANTITHROMBIN,TISSUE PLASMINOGEN ACTIVATOR AND
THROMBOMODULIN.
THESE ABNORMALITIES MAY RESULT IN HYPERCOAGULABILITY AND A RISK OF THROMBOSIS.

46. TREATMENT OF HEPATITIS B AND C IN RELATION TO CIRRHOSIS

47. Hepatitis B is an infectious disease caused by
the hepatitis B virus (HBV) which affects
the liver, It can cause both acute and chronic
infections.

48. Chronic HBV infection is a serious clinical problem because of its worldwide
distribution and potential adverse outcomes, including cirrhosis, hepatic
decompensation, and hepatocellular carcinoma (HCC).
HBV infection is particularly important in the Asian-Pacific region, where it is
endemic, with the majority of infections being acquired perinatally or in early
childhood
Some patients may be superinfected with other viruses later in life, an event that
may adversely affect clinical outcomes.

49. GOALS OF TREATMENT FOR CHRONIC HBV
INFECTION
 It is now clear that active HBV replication is the key driver of liver injury and
disease progression, thus sustained viral suppression is of paramount
importance.
 Therefore, the primary aim of chronic hepatitis B treatment is to
permanently suppress HBV replication.
 This will decrease the infectivity and pathogenicity of the virus, thereby
reducing hepatic necroinflammation.
http://apasl.info/apasl/wp-content/uploads/2014/02/Guideline-HBV-2012-update.pdf
The ultimate long-term goal of therapy is to prevent hepatic decompensation,
reduce or prevent progression to cirrhosis and/or HCC, and prolong survival.

50. Clinical trials tend to focus on clinical endpoints achieved over 1-2
years
#suppression of HBV DNA to undetectable levels
#loss of HBeAg/HBsAg
#improvement in histology
#normalization of ALT

51. CURRENTLY AVAILABLE TREATMENTS
 Currently, interferon-alfa (IFN-a), lamivudine (LAM),
adefovir, entecavir, telbivudine, tenofovir, and pegylated
IFN (Peg-IFN)-a2a have been licensed globally.
 Peg-IFNa2b has been approved for the treatment of
chronic HBV infection in a few countries.
 Clevudine has been approved only in Korea and the
Philippines.
http://apasl.info/apasl/wp-content/uploads/2014/02/Guideline-HBV-2012-update.pdf

52. IFN alpha:
Increased level of HBV DNA,HBeAg positive patient and histologic
evidence of chronic hepatitis on liver biopsy
Dose: 16 week course of IFN given subcutaneously at a daily dose of 5 million
units or three times a week at a dose of 10 million units
But IFN has not been effective in patients with
cirrhosis.

54. Management of Patients With
Compensated Cirrhosis
Treatment is recommended regardless of HBeAg
status and ALT as long as HBV DNA is detectable at
>2000 IU/ml.
Monitoring without therapy is recommended for
those with HBV DNA <2000 IU/ml,unless ALT is
elevated.
Entecavir and Tenofovir ----- preferred
Lok AS, et al. Hepatology. 2009;50:661-662.

55. Management of Patients With
Decompensated Cirrhosis
Lok AS, et al. Hepatology. 2009;50:661-662.
Preferred therapies
(LAM or LdT) + (ADV or TDF); TDF or ETV monotherapy
–Treatment should be coordinated with transplantation
center
–IFNs should not be used in decompensated cirrhosis
Treatment duration
Lifelong treatment recommended
*Clinical data documenting safety and efficacy of TDF or ETV monotherapy in
decompensated cirrhosis are lacking.

56. Prevention and Monitoring of Resistance
Prevention
Avoid unnecessary treatment
Initiate potent antiviral that has low rate of drug resistance or use
combination therapy
Switch to alternative therapy in patients with primary nonresponse
Monitoring
Test for serum HBV DNA (PCR) every 3-6 mos during tx
Check for medication compliance in patients with virologic breakthrough
Confirm antiviral resistance with genotypic testing
Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF,
McMahon
BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver
Diseases. Reproduced with permission of the American Association for the Study of Liver
Diseases.

57. Hepatitis C

58.  HCV specifically infects hepatocytes, entering the
cells through endocytosis.
 After entry, the 9.6 kb viral genome undergoes
cytoplasmic translation into a single polypeptide,
which is further cleaved into 10 viral proteins—
three structural and seven non-structural
 Many of these non-structural viral proteins are the
target of newer “direct acting antivirals”.

59. About 20-30% of patients could develop a
progressive liver disease leading to cirrhosis
and HCC.
Subjects who achieve Sustained Virological
Response (SVR) have clear advantage at
histological and clinical levels compared to
those who do not achieve SVR.

60. Patients with chronic hepatitis c who have detectable HCV-RNA
in serum,whether or not aminotransferase levels are increased
and chonic hepatitis with portal or bridging fibrosis are candidates
for antiviral therapy.
Patients with cirrhosis—candidates for therapy
likelihood of sustained response is lower
survival improved after successful antiviral therapy
Decompensated cirrhosis—not candidate for IFN based therapy
liver transplantation

61. The current standard of care is the combination of long acting
PEG-IFN and ribavirin,which has increased responsiveness to
>40% in genotype 1 and 4 and to >80% in genotype 2 and 3
Patients with cirrhosis can respond but they are less likely to do
so.
Dose:PEG-IFN 2a 180 micro gram once weekly s.c plus 1000-
1200 mg ribavirin
PEG-IFN 2b 1.5 micro gram per kg body weight once weekly s.c.
plus 800 mg ribavirin
Duration:48 wk for genotype 1 & 4 , 24 wk for genotype 2 & 3
Interferon,combination interferon plus ribavirin and
peginterferon plus ribavirin increased SVR rate from
5% to 40-80% depending on the HCV genotype.

62. NEWER DRUGS

63. In 2011, telaprevir and boceprevir were the first approved
DAAs against HCV.
The triple combination therapy of telaprevir or boceprevir plus
ribavirin and peginterferon-alfa is a new treatment option for
chronic HCV genotype 1-infected patients.

64. SVR rates among treatment-naïve patients
were ~70% in telaprevir-included regimens.
The SVR rates among patients with no previous
response were 30~40% in these regimens
Boceprevir is a potent ketoamide inhibitor of HCV
NS3 serine protease.
The addition of Boceprevir results in higher SVR rates
in both treatment naïve and retreated patients infected
with HCV genotype 1.

65.  Simeprevir (TMC435) - investigational HCV NS3/4A protease
inhibitor administered orally once daily, currently in phase III
clinical development.
 Differs from first generation protease inhibitors in terms of its
once-daily administration.
 Superior efficacies of simeprevir and peginterferon plus
ribavirin were observed compared to those of peginterferon
plus ribavirin alone in treatment-naive and previously treated
patients
Tanwar S, Trembling PM, Dusheiko GM: TMC435 for the treatment of chronic hepatitis C. Expert Opin Investig Drugs 2012, 21:1193–1209

66. MK-5172, a novel P2-P4 quinoxaline macrocyclic peptide,
maintained potency across a genetically diverse panel of
genotype 1a and 1b sequences from plasma of HCV-
infected patients.
To be used in combination with peginterferon plus
ribavirin or with other DAAs
Daclatasvir potent NS5A replication complex inhibitor and increases the
antiviral potency of peginterferon and ribavirin.
Sofosbuvir is a nucleotide inhibitor of HCV NS5B polymerase.
Triple therapy including peginterferon plus ribavirin and sofosbuvir cures >90%
of patients treated for 12 or 24 weeks regardless of HCV genotype.
Asunaprevir, ledipasvir, inhibitor of cyclophilin A, antagonist of host liver expressed
Micro RNA 122

67. Conclusion:
Cirrhosis of liver has a variety of clinical manifestations and complications
some of which can be life threatening.
Preventive as well as defitine therapeutic measures have to be taken to reduce
the mortality and morbity of cirrohis and its complications.
Removal of underlying insult can cause reversal of fibrosis.
Newer diagnostic as well as therapeutic modalities will be helpful for management
of patients with cirrhosis.