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