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G30 Gastroenterology
Liver Toronto Notes 2019
DDx for Hepatomegaly
• Congestive (right heart failure, Budd-Chiari syndrome)
• Infiltrative
• Malignant (primary, secondary,
lymphoproliferative, leukemia)
• Benign (fatty liver, cysts,
hemochromatosis, extramedullary
hematopoiesis, amyloid) • Proliferative
• Infectious (viral, tuberculosis, abscess, echinococcus)
• Inflammatory (granulomas [sarcoid], histiocytosis X)
From Description to Cure in One Generation
Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection
NEJM 2014;370:1889-1898
If you ever need an example to demonstrate the miraculous advances of modern medicine, consider usingchronichepatitisC. Itinflictsabout6per 1000 of Canadians and is the commonest reason for liver transplant in most studies. Yet until 1989, when the virus was first cloned, this condition was so poorly understood that it was labelled as what
it wasn’t - it was called hepatitis non-A, non-B because there was insufficient evidence to even appreciate that it was one disease, let alone an infection. Today it can be cured by taking a safe drug regimen for 6-24 wk, depending on the virus strain, previous treatments, and the degree of liver damage. This recent study showed that sofosbuvir (nucleoside polymerase inhibitor) and ledispavir (NS5A inhibitor) led to a 99% cure rate in genotype 1 (the most common) infection with only minimal side-effects. These antiviral drugs are designer drugs: specifically tailored in the laboratory to combat pathogenic features of the hepatitis C virus.
Treatment of Hepatitis C: A Systematic Review
JAMA 2014;312(6):631-40
Purpose: To evaluate the evidence for the safety, efficacy, and tolerability of interferon and non- interferon based, oral therapies in the treatment of Hepatitis C virus (HCV).
Study: Literature review of phase 2, 3, and 4 studies published from January 1, 2009 – May 30, 2014, with data graded according to Oxford Centre for Evidence-Based Medicine criteria.
Population: 19, 063 adult patients infected with HCV genotype 1, 2, or 3 with or without HIV coinfection.
Outcome: Sustained virologic response (SVR) of undetectable plasma HCV RNA at 12 or 24 wk post-therapy.
Results: Achievement of SVR was more difficult
in HCV genotype 1 patients. Treatment of HCV genotype 1 patients with sofosvubir with pegylated interferon and ribavirin yielded high rates of SVR (89-90%) and shorter duration of therapy. HCV genotype 2 or 3 patients treated with sofosbuvir and ribavirin alone achieved SVR of 82-93% and 80-95% for genotype 2 at 12 wk and genotype 3 at 24 wk, respectively. Patients with HCV and HIV coinfection with compensated cirrhosis should be treated in the same manner as HCV-monoinfected patients. Conclusions: High SVR rates can be achieved
for HCV patients with or without HIV coinfection using shorter durations of non-interferon therapies. HCV genotype 1 patients are likely to benefit from co-treatment with interferon and non-interferon therapies.
Treatment
• counselling:40%ofmenand10%ofwomenwithperinatalinfectionwithouttreatmentwilldiefrom HBV-related complications
• prolongedimmune-mediateddamageleadstohigherriskofliverfibrosis
• hepatocellular carcinoma screening with ultrasound q6mo, especially if high serum HBV-DNA levels,
cirrhosis, men, (age >40 in Asian men, >50 in Asian women, and >20 in African descent) • considerpharmacologicaltherapyif:
1. HBeAg positive + HBV-DNA >20,000 IU/mL + elevated ALT; or
2. HBeAg negative + HBV-DNA >2,000 IU/mL + elevated ALT ± stage ≥2 fibrosis on liver biopsy 3. treat to prevent flare when placed on immunosuppressive therapy such as prednisone,
chemotherapy, biologics, etc.
• treatmentgoal:reduceserumHBV-DNAtoundetectablelevel
• treatmentoptions:interferon,tenofovir,entecavir,lamivudine
• vaccinateagainstHAVifserologynegative(topreventfurtherliverdamage) • followbloodandsexualprecautions
Hepatitis D Virus
• defectiveRNAvirusrequiringHBsAgforentryintohepatocyte,thereforeinfectsonlypatientswith HBV; causes more aggressive disease than hepatitis B virus alone
• coinfection: acquire HDV and HBV at the same time
• HDVcanpresentasALFand/oraccelerateprogressiontocirrhosis
• treatment:low-doseinterferon(20%response)andlivertransplantforend-stagedisease
Hepatitis C Virus
• RNA virus (7 genotypes; genotype 1 is most common in North America)
• blood-bornetransmission;sexualtransmissionis“inefficient”
• majorriskfactor:injectiondruguse
• otherriskfactors:bloodtransfusionreceivedbefore1992(orreceivedindevelopingworld),tattoos,
intranasal cocaine use
• clinical manifestation develops 6-8 wk after exposure
■ symptoms mild and vague (fatigue, malaise, nausea) therefore not commonly diagnosed in acute stage
Diagnosis
• suspectedonbasisofelevatedALT/ASTandpositiveserumanti-HCV • diagnosisestablishedbydetectableHCV-RNAinserum
• virusgenotypecorrelateswithresponsetotreatmentbutnotprognosis
■ serumHCV-RNAinverselycorrelateswithresponsetotreatment
• normaltransaminasescanhaveunderlyingcirrhosisonbiopsy,butotherwiseexcellentprognosis
Treatment
• blood-borneprecautions;vaccinateforhepatitisAandBifserologynegative;avoidalcohol
• clearestindicationfortreatmentisinsubgrouplikelytodevelopclinicallysignificantliverdisease,i.e.,
persistently elevated transaminases, liver biopsy showing fibrosis/cirrhosis, and at least moderately
severe necrosis/inflammation
• treatment depends partly on genotype; length of treatment depends on degree of fibrosis, level of serum
HCV-RNA, comorbidities, and previous treatment
• oralinterferon-freeregimens(forallgenotypes)(e.g.sofosbuvir/ledipasvir,ombitasvir/paritaprevir/
ritonavir+dasabuvir, or elbasvir/grazoprevir and sofosbuvir/velpatasvir) are now the standard of care with >90% success rate without significant side-effects including those who failed previous interferon- based treatment
Prognosis
• 80%ofacutehepatitisCbecomechronic(ofthese20%evolvetocirrhosis)
• riskofhepatocellularcarcinomaincreasesifcirrhotic
• cancausecryoglobulinemia;associatedwithmembranoproliferativeglomerulonephritis,lymph