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

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

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 2012; 380: 2095–128

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; 44: 217–31.

Cardiac cirrhosis

Inherited metabolic liver disease

HemochromatosisWilsons diseaseAlpha 1 antitrypsin deficiency Cystic fibrosis

Three processes are central to the pathogenesis ofcirrhosis.1)Death of hepatocytes2)Extracellular matrix deposition.3)Vascular reorganization.

Pathophysiology

HISTOPATHOLOGY

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; 44: 217–31.

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; 44: 217–31.

Clinical Examination Liver and spleen enlarged Scleral icterus Palmar erythema Spider angiomas Parotid gland enlargement

Digital clubbing Muscle wasting

Development of edema and ascites.

Decreased body hair Gynecomastia

Testicular atrophy

Menstrual irregularity

COMPLICATIONS

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

PORTAL HYPERTENSION:

TREATMENT OF VARICEAL HEMORRHAGE:

PRIMARY PROPHYLAXIS

APPROACH TO PATIENTS WITH VARICEAL BLEED:

RECURRENT BLEEDING:

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

ASCITES:

TREATMENT: DIETARY SODIUM RESTRICTION TO EAT FRESH OR FROZEN FOODS AVOIDING CANNED OR PROCESSED FOODS DIURETIC THERAPY

IN CASE OF REFRACTORY ASCITES:

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 lymphatics thoracic duct lymphbacteremia

hepatic lymph ascites SBP

TREATMENT: Second generation cephalosporin,with cefotaxime being the most commonly used.

PROPHYLAXIS:

HEPATIC ENCEPHALOPATHY:

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,BUTALSO SEEN IN PATIENTS WITH ACUTE LIVER FAILURE.

PATHOGENESIS:

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

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

HEPATORENAL SYNDROME

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 HYPOTENSIONPRECIPITANTS: GASTROINTESTINAL BLEEDING SEPSIS AGGRESSIVE DIURESIS PARACENTESIS

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

PATHOGENESIS:

DIAGNOSIS:

TREATMENT:PREVENTIVE

MEDICAL MANAGEMENT (ALBUMIN, VASOPRESSORS, ANTIBIOTICS)

LIVER TRANSPLANTATION

HEPATOPULMONARY SYNDROME:

HPS IS DEFINED AS A WIDENED AGE CORRECTED ALVEOLAR ARTERIALO2 GRADIENT (AaPo2) ON ROOM AIR IN THE PRESENCE OR ABSENCE OFHYPOXEMIA.(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 HgMODERATE- PaO2 is equal to 61-80 mm of HgSEVERE- PaO2 50-60 mm of HgVERY SEVERE- PaO2 less than 50 mm of Hg

PATHOGENESIS:

CLINICAL FEATURE- PLATYPNEA ORTHODEOXIA CLUBBING HYPOXEMIA

DIAGNOSIS:

CLINICAL SUSPICIONMEASUREMENT OF ARTERIAL BLOOD GASESDETECTION OF INTRAPULMONARY SHUNTINGEXCLUSION OF INTRINSIC CARDIOPULMONARY DISEASE

TREATMENT:

MEDICAL MANAGEMENT

INTERVENTIONAL RADIOLOGIC THERAPY

LIVER TRANSPLANTATION

PORTOPULMONARY HYPERTENSION

DEVELOPMENT OF PULMONARY ARTERIAL HYPERTENSION IN THE SETTING OF PORTAL HYPERTENSION

MECHANISMS POORLY UNDERSTOOD

OCCURS WHEN VASOCONSTRICTION AND REMODELING IN RESISTANCE VESSELSINCREASE PULMONARY ARTERIAL PRESSURE

FOUND IN AS MANY AS 5% OF PATIENTS WITH CIRRHOSIS

EXERTIONAL DYSPNEA,ORTHOPNEA,FATIGUE,CHEST PRESSURE,SYNCOPE,EDEMALIGHTHEADEDNESS MAY BE THE COMPLAINTS.

CLINICAL SUSPICION LEADS TO FURTHER WORK UP TO ESTABLISH THE DIAGNOSIS

MEDICAL MANAGEMENT AND LIVER TRANSPLANTATION

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 ANTAGONISTSNON CARDIOSELECTIVE BETA ADRENERGIC ANTAGONIST

LIVER TRANSPLANTATION: EFFECTS HAVE NOT BEEN FULLY CHARACTERIZED.

ENDOCRINE DYSFUNCTION:

ADRENAL INSUFFICIENCY

GONADAL DYSFUNCTION

THYROID DYSFUNCTION

BONE DISEASE (12-55% OF CIRRHOTIC PATIENTS)

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

THROMBOCYTOPENIAHYPERSPLENISM,DECREASED HEPATIC THROMBOPOIETIN SYNTHESIS,DIRECT BONE MARROW TOXICITY

DYSFIBRINOGENEMIAINCREASED 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.

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.

TREATMENT OF HEPATITIS B AND C IN RELATION TO CIRRHOSIS

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.

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.

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.

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

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

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 withcirrhosis.

Management of Patients With Compensated CirrhosisTreatment 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.

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.

Prevention and Monitoring of Resistance

PreventionAvoid 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

MonitoringTest 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.

Hepatitis C

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”.

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.

Patients with chronic hepatitis c who have detectable HCV-RNA in serum,whether or not aminotransferase levels are increasedand 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

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 from5% to 40-80% depending on the HCV genotype.

NEWER DRUGS

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.

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 HCVNS3 serine protease.The addition of Boceprevir results in higher SVR ratesin both treatment naïve and retreated patients infected with HCV genotype 1.

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

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

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.