Cirrosis of liver and its complication and traetment of hep b and c
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Transcript of Cirrosis of liver and its complication and traetment of hep b and c
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.