approach to patient with deranged lft yuen-chun sze... · 2019-11-01 · rft normal • lft: tb 35,...
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Approach to patient with Impaired Liver Function
Dr Sze Yuen Chun
Specialist in Gastroenterology and Hepatology
Private Practice
Case
• F/58
• ADL-I
• PMHx:
• DM , on metformin
• No HBV vaccine before, not certain about hepatitis status
• Fhx: Father died of liver cirrhosis/ HCC, unknown cause
• Presented with epigastric pain and malaise for 2 weeks
• No fever or travel history
• No recent herbs, NSAID or OTC medication intake
• P/E:
• Afebrile, BP/P stable
• No P/J
• GCS 15/15
• Abdo: mild epigastric tenderness, no guarding
• AXR: no free gas
• ECG: SR, no ischaemic change
• Blood taken
• Given buscopan injection and Mg tri
• Pain improved after 2 hours
• Blood test:
• CBP normal
• RFT normal
• LFT: TB 35, ALP 130, ALT 125
• Glucose 8.5
• Bedside USG upper abdomen: No gallstone. Multiple liver cysts. CBD not dilated
• Blood for HBsAg, HCV taken
• Pain improved, discharged and referred medical SOPD
History
• Exposure to any potential hepatotoxins
• Alcohol
• Medications: OTC medications, herbal and dietary supplements, illicit drug use, paracetamol
• Wild mushroom picking
• Risk factors for viral hepatitis
• Intravenous drug use, tattoo
• Blood transfusion
• Family history
• Past medical history
• Chronic hepatitis carrier
• Heart failure, obesity, inflammatory bowel disease , thyroid disease
Physical examination
• Jaundice
• Stigmata of chronic liver disease
• Spider nevi, palmar erythema, gynaecomastia, caput medusa
• Feature of decompensation
• Hepatic encephalopathy
• Ascites
• Hepatomegaly, Murphy’s sign
Initial assessment
• Biochemical: bilirubin, ALT, AST, GGT, albumin, globulin
• CBP, clotting profile
• Anti-HCV Ab, HBsAg, IgM HAV/ HEV
• FBG, lipid
• USG abdomen
Patterns of abnormal liver function test
• Hepatocellular pattern:
• Disproportionate elevation in serum ALT compared with ALP
• Serum bilirubin may be elevated
• Common causes:
• Viral hepatitis
• Alcohol or Drug related
• NASH
• Thyroid disorder
• Autoimmune causes
• Cholestatic pattern:
• Disproportionate elevation in ALP compared to ALT
• Serum bilirubin may be elevated
• Common causes:
• Biliary obstruction ( intra-hepatic or extrahepatic)
• Drugs ( androgenic steroid, phenytoin)
• Non-hepatic causes: bone disease, thyroid or parathyroid disorder
• Hyperbilirubinaemia
• Unconjugated
• Conjugated
UpToDate
• Low serum albumin
• Suggest chronic process
• Cirrhosis or malignancy
• Prolong prothrombin time
• Vit K deficiency due to prolong jaundice or significant liver dysfunction
• AST to ALT ratio
• Ratio > 2:1 suggestive of alcoholic liver disease
• NASH
Indications for admission
• Hepatic encephalopathy
• New onset ascites
• ALT > 10 x ULN
• Prolong prothrombin time (INR > 1.6)
• Significant elevated bilirubin level
• Evidence of biliary obstruction
2 common liver diseases in HK
Chronic hepatitis B
Non-alcoholic fatty liver disease (NAFLD)
Chronic Hepatitis B
Estimated Global Prevalence of CHB in 2015: 257 Million
21mEastern
Mediterranean
15mEurope
7mAmericas
60mAfrica
39mSoutheast Asia
115mWestern Pacific
HBsAg
Positive, %
Taiwan 10.0-13.8
Vietnam 5.7-10.0
China 5.3-12.0
Africa 5.0-19.0
Philippines 5.0-16.0
Thailand 4.6-8.0
Japan 4.4-13.0
Indonesia 4.0
South Korea
2.6-5.1
India 2.4-4.7
Russia 1.4-8.0
US 0.2-0.5
• Data collected from general population in HK from 2015-2017
• Mean age: 50.4 (M) vs 52.3 (F)
• Overall HBsAg +ve 7.8%
• Risk factor for HBsAg +ve:
• Family history of hepatitis
• No history of vaccination
• Born in Mainland China
• If the overall prevalence is 7.8%, the total No of cases would be 576,000
Liu SH, et al. EASL 2017
Phase Immune Tolerant Immune Clearance Inactive Carrier State
Reactivation
LiverMinimal inflammation
and fibrosisChronic activeinflammation
Mild hepatitis and
minimal fibrosis
Active inflammation
Yim HJ, et al. Hepatology. 2006;43:S173-S181. Optimal treatment times
Anti-HBeAg
HBV DNA
ALT activity
4 Phases of Chronic HBV Infection
HBeAg
Initial Evaluation of Patients With Chronic HBV Infection
• Medical history and physical examination
• Family history of HBV infection and liver cancer
• Laboratory tests to assess liver disease
• CBC with platelets, hepatic panel, prothrombin time
• Serology
• HBeAg/anti-Hbe Ab
• Virology:
• HBV DNA
• Test for viral coinfection (HIV, HCV)
• Fibroscan to assess the degree of fibrosis
• Screen for HCC: AFP, Ultrasound of abdomen
Goals of HBV Therapy
Prevention of cirrhosis,
HCC, and death
Liver histology improves Serum HBV DNA declines
ALT normalizationSeroconversion (HBeAg loss, anti-HBe production, HBsAg loss)
For many patients, achieving these
goals may require lifelong therapy
When to start treatment ?
1. Sarin. Hepatol Int. 2016;10:1. 2. EASL. J Hepatol. 2017;67:370. 3. Martin. Clin Gastroenterol Hepatol. 2015;13:2071. 4. Terrault. Hepatology. 2018;67:1560.
Threshold for Treatment
APASL[1]
(2015)EASL[2]
(2017)US Algorithm[3]
(2015)AASLD[4]
(2018)
HBV DNA, IU/mL
▪ HBeAg positive > 20,000 > 2000 ≥ 2000 > 20,000
▪ HBeAg negative > 2000 > 2000 ≥ 2000 ≥ 2000
ALT > 2 x ULN > ULN > ULN ≥ 2 x ULN
▪ ULN for males 40 IU/mL 40 IU/L 30 IU/L 35 U/L
▪ ULN for females 40 IU/mL 40 IU/L 19 IU/L 25 U/L
• ALT > ULN but < 2 x ULN
• Consideration of liver disease severity by biopsy or noninvasive testing
• Other factors: Age, family history of HCC or cirrhosis, previous treatment history
• Compensated cirrhosis
• Patients with low-level viremia (HBV DNA < 2000 IU/mL) and should be treated, regardless of ALT
• Decompensated cirrhosis
• All patients with HBsAg positive should be treated, regardless of HBV DNA, HBeAg status, or ALT
Choice of treatment
Sarin. Hepatol Int. 2016;10:1-98.
Comparative Measure
Peginterferon Nucleos(t)ide Analogues
StrategySustained off-therapy response
(ie, immune control)Maintained on-treatment response
(ie, viral control)
Goal HBV DNA < 2000 IU/mL, normal ALT Undetectable HBV DNA, normal ALT
Duration Finite Prolonged or indefinite
Administration Subcutaneous injection QW Oral QD
ContraindicationsHepatic decompensation, pregnancy,
immunosuppression, uncontrolled severe depression or psychosis
None
Key considerations
▪ Frequent AEs (eg, influenzalike symptoms, headache, fatigue, myalgia, alopecia, ISRs)
▪ More appropriate for young patients, those who are HBeAg+ with best change of seroconversion
▪ High rate of viral relapse upon therapeutic cessation
AASLD Guidelines: Initial Treatment
Terrault NA, et al. Hepatology. 2016;63:261-283.
Treatment Preferred Notes
Entecavir Yes (unless previous history
of lamivudine resistance)
High potency, high genetic barrier to resistance
Tenofovir Yes High potency, high genetic barrier to resistance
PegIFN Yes Less safe in pts with cirrhosis
Adefovir No Low genetic barrier to resistance
Lamivudine No Low genetic barrier to resistance
Telbivudine No Low genetic barrier to resistance
▪ Treatment with antivirals does not eliminate the risk of HCC, and surveillance for HCC should continue in persons who are at risk
Preferred First-line Monotherapies for CHB
*Considered less safe than NA therapy; reserve for select patients (eg, mild to moderate CHB, well-compensated cirrhosis with no portal hypertension).
TAF, tenofovir alafenamide
TDF, tenofovir disoproxil fumarate
Decompensated Cirrhosis†
Entecavir 1 mg/day
Tenofovir DF
No Cirrhosis or Compensated Cirrhosis
Entecavir 0.5 mg/day
Tenofovir AF 25mg/day
Tenofovir DF 300mg/ day
PegIFN*
Terrault. Hepatology. 2018;67:1560. EASL. J Hepatol. 2017;67:370. Martin. Clin Gastroenterol Hepatol. 2015;13:2071. PI.
†PegIFN is contraindicated.
▪ If renal impairment and/or bone disease, ETV or TAF should be considered
Monitor Patients Receiving HBV Therapy
• LFT every 3-4 months in first year, then every 6 months thereafter
• Serum HBV DNA every 3-4 months in first year, then every 6-12 months
• HBeAg/anti-HBe in HBeAg-positive patients
• HBsAg every 12 mos in patients with persistently undetectable HBV DNA
• Those clearing HBsAg should be tested for anti-HBs
• Periodic renal monitoring in those treated with Tenofovir and those at risk of renal disease treated with any NA
EASL. J Hepatol. 2017;67:370.
When Can HBV Treatment Be Stopped?
• PegIFN: defined duration of 48 wks
• Nucleos(t)ide analogues: depends on cirrhosis and/or HBeAg status
• Cirrhosis: Indefinite antiviral therapy
• HBeAg positive:
• consider discontinuation following seroconversion to anti-HBe + consolidation therapy for ≥ 12 mos
• check HBV DNA, ALT, seroconversion every 3 months in first yr after cessation
• HBeAg seroconversion: ~ 50% after 5 yrs of treatment
• HBeAg negative:
• Indefinite antiviral therapy
• HBsAg loss: ~ 5% after 5 yrs of treatment
1. Terrault. Hepatology. 2018;67:1560. 2. Wong. Aliment Pharmacol Ther. 2018;47:114. 3. Broquetas. PLoS One. 2017;12:e0188303.
Risk of HBV reactivation with steroid
• High risk ( >10%)
• High dose steroid (prednisolone >20mg for > 4weeks)
• Moderate risk (1-10%)
• Moderate dose of steroid ( prednisolone <20mg for > 4 weeks)
• Low risk ( <1%)
• Prednisolone < 1 week, intraarticular steroid
Indications for sponsored treatment under the Hospital Authority
• ALT > 2x ULN & HBV DNA > 2000 IU/mL
• Cirrhosis & detectable HBV DNA
• Decompensated liver disease
• Hepatitis B reactivation during chemotherapy
• Transplant patient with hepatitis B infection
• Pre-emptive treatment for patient on anticancer chemotherapy or immunosuppressive therapy with moderate to high risk of hepatitis B reactivation
• Resistance to prior nucleoside analogues treatment (For Tenofovir)
Hong Kong Hospital Authority Drug Formulary
Non-alcoholic fatty liver disease
NAFLD• Most prevalent cause of chronic liver disease in Western world
• Accumulation of fat within hepatocyte
• Early stage: no inflammation or hepatocyte injury
• Later stage:lobular inflammation, hepatocyte ballooning, fibrosis →Non-alcoholic steatohepatitis (NASH)
NAFLD in Hong Kong
• Prevalence of 27.3% and annual incidence of 3.4% among Chinese adults
• High risk populations:
• Dyslipidaemia : Prevalence of NAFLD 50%
• Type 2 diabetes mellitus : Prevalence of NAFLD 69% by ultrasound
• Obese patients undergoing bariatric surgery: 96% had NAFLD and up to 25% had NASH
Gut 2012; 61(3):409-15
NAFLD is associated with multiple comorbidities
a: Hepatology 2019;69 (6) 2672 b: AASLD 2018 Abstract 0031
• Diagnosis by exclusion
• Excess alcohol intake
• Drugs ( including herbal medicine) known to cause raised ALT and GGT
• HBV/HCV
• Autoimmune disease, Wilson’s disease, malignancy, infection and biliary tract disease
• US, CT, MRI, Transcient Elastography (FibroScan)
• Liver biopsy
• In patient with unexplained ALT elevation, NAFLD if highly likely if hepatic imaging results are compatible with fatty liver and metabolic risk factors are present
Management
1. Lifestyle modification
• No pharmacologic therapy has conclusively proved to be effective
• Weight loss remains the standard of care
• Weight loss of 7-10% is associated with improvement in liver histology
• Diet: low carbohydrate ( carbohydrate intake correlate with inflammation ), increase fiber intake, low saturated fat
• Exercise improved insulin sensitivities, decrease visceral obesity
• Other intervention: enteric lipase inhibitor orlistat, bariatric surgery
2. Correct other metabolic risk factors
• Metabolic risk factors should be identified and treated
• BP, Lipid, glucose
3. Pharmacological therapy
• No FDA approved therapy for NASH
• New promising treatment ( Phase III trial)
• FXR agonist ( Farnesoid X receptor agonist) : Obetacholic acid
• REGENERATE trial
Bril & Cusi, Diabetes Care 2017 40:419-430
Treatment of NASH
Treatment of NASH
Pioglitazone if diabetes
Lifestyle Intervention
Weight reduction of 8-10%
Second-line therapies
Pharmacological treatment or
metabolic surgery
No response Not achieved
Control of other CV risk factors
Elevated A1C Elevated BP
Glucose controlMetformin
Blood pressure control
ARB or ACEI
Lipid-lowering therapyStatin
Add pioglitazone Add GLP-1RA or SGLT-2 inhibitors
Second-line therapies
Add fibrates to statins
Elevated TG and low HDL
Summary
• Impaired liver function is commonly encountered in our daily practice
• History taking, physical examination, blood and imaging
• Commonest caused deranged liver function in Hong Kong included Chronic hepatitis B and NASH
• Hepatitis B: Potent treatment with high efficacy and low resistant rate
• NASH: Lifestyle modification and weight reduction remain the most important part of management
• New emerging treatment for NASH
Thank You