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Common liver Disease in Primary Care Setting
1. Common liver problems in
primary care- what should we be
doing differently?
Speaker:
Dr Chong Chern Hao
2. Objectives
• Walk Through the common liver problem encounter in
primary care such as abnormal liver function test,
abnormal liver ultrasound findings, viral hepatitis serology
interpretations and vaccinations.
• Improve understanding on pathophysiology of each
common scenarios.
• Discuss about investigation and management plan for each
condition and when to escalate for specialist care.
4. Liver Function Tests and Mortality
4
Increase risk of mortality in patients
with abnormal LFT
5. Interpretation of altered LFT
• ALT reflects hepatocyte damage – reversible or irreversible
• AST less specific for liver, and may be raised in damage to
muscle, myocardium
• Bilirubin unconjugated suggests haem overload, or enzyme deficiency
or drugs, conjugated reflects either cholestasis or liver disease
• ALP typically seen in cholestasis but may also be due to liver
space occupying lesions or infiltrative disease of liver
• GGT raised in most liver disease and all cases of cholestasis but
poor diagnostic marker for liver disease.
• Albumin can reflect liver function but very sensitive to weight loss
and poor diet. Also reduced in nephrotic syndrome and
protein losing enteropathy
6. Factors affecting Liver Enzymes
• Day to day variation
• Race
• Gender
• BMI
• Exercise
• Pregnancy
• Smoking
• Hemolysis (transaminase)
• Muscle injury
• Food (bilirubin, ALP)
• Variations range from 4% to
40%
• Laboratory variations can
be 4-9% and ranged from
39-85 IU/ml for same
specimen for ALT
measurement
• Using ULN may be a better
method to compare
between labs
Dufour, Clin Chem 2000
7. Significance of abnormal LFTs
• Abnormal LFTs is NOT a “disease”
• Abnormal LFTs are surrogate markers of disease
• Abnormal LFTs may have prognostic significance
9. Studies on Abnormal LFTs
BALLETS study (Lilford, BMJ Open
2013)
• Prospective UK GP study of abn
LFTs (n=1290) with 2y FU in pts
with no obvious liver disease
• Results:
– Only 32 cases (2.5%) had liver
disease
– No cause assigned to the
remainder
– Pt with hx of HBV, HCV, AICAH,
alcohol, NASH, biliary disease,
tumours in liver all excluded
• ALFIE study (Donnan, HTA 2009)
• Retrospective UK GP study of abn
LFTs (n=95,977) with median FU
3.7y of which 21.7% (n=20,827) had
one abn LFT, Results:
– Overall 1090 (5.2%) had liver
disease
– HBV(3%), HCV (9.6%), AICAH
(10%), ALD (30.6%),cirrhosis
(16.7%), PBC (12.3%), HCC (6.2%),
NAFLD (7.2%), iron overload
(1.4%), others (4.4%)
10. Prognosis: 1 year mortality of abn
LFT
Causes Number %
Neoplasms 1027 39.3%
- Digestive tract or peritoneum 314 12%
- Resp or Thorax 305 11.7%
- Unspecified sites 138 5.3%
- Genitourinary organs 125 4.8%
- Bone, connective tissue or breast 72 2.8%
Diseases of circulatory system 907 34.7%
Diseases of respiratory system 258 9.9%
-pneumonia and influenza 119 4.6%
-COPD 103 3.9%
-other respiratory disease 26 1%
McLernon, PLOS One 2012;7(12): e50965
11. New considerations in approach
to abn LFTs
Search for
disease
Exclude
Liver
disease
Exclude
Cancer
Exclude
systemic
disease* 40%
5-10%
40%
Respiratory Disease
Circulatory Disease (IHD)
Diabetes
*
Abn LFTs
12. Summary
• Abn LFTs represent liver damage and are surrogate markers
• Studies show that only a small minority of abn LFTs are due to
liver disease
• The vast majority of abn LFTs are due to cancer, and systemic
disease esp IHD, stroke, metabolic and respiratory disease
• Nonetheless, an stepwise algorithm to exclude liver disease is
prudent, based on hepatitic, cholestatic or mixed pattern of
abn LFTs
• Role of Specialist to risk stratify(Cancer, risk of fibrosis
progression, metabolic ds work up) with advanced/specialized
tests that may not readily available in primary care settings.
14. Mr H with Fatty Liver:
• Mr H 69 Male, security officer
• BMI 35 BP 140/90
• Occasional Alcohol consumption, rarely exercise
• Fatty Liver noted in US HBS
• FBC Hb 14 Plt 150 Tw 7.6
• AST 79 ALT 89 ALP 95 GGT 150 Alb 38
• Lipid profile : Total Chol : 5.5 Tg : 2.4 HDL 1.1 LDL 2
• HbA1c 6%
15. Sample report
The liver is normal in size with a liver span of 13 cm. Its surface appears
smooth. The liver parenchyma shows increased echogenicity consistent with
fatty infiltration. No focal hepatic lesion is detected. The portal vein is normal in
capacity, it shows hepatopetal flow.
Absence of the gallbladder is in keeping with cholecystectomy. The biliary tree
is normal and the common duct measures 0.4 cm.
The spleen is normal with a length of 7.5 cm. The imaged pancreas is
unremarkable.
COMMENT:
Fatty liver.
S/p cholecystectomy.
16. 1) How common is NAFLD in Asia
Vs West?Western Asian countries
Prevalence of NAFLD 25% 25%
Proportion of NAFLD w NASH 20-30% 10-20%
NAFLD w F3-4 Fibrosis ~10% 3-5%
Prevalence of NAFLD in Subject
with BMI < 25
~10% 7-19%
Risk factors Obesity, Metabolic
syndrome, Genetic
Obesity, Metabolic
syndrome, stronger
genetic component
Fan JG, et al. J Hepatol 2017;67:862-73
17. NAFLD/NASH
• Total 362 patients referred to Fatty liver clinic between 2015- 2016 (
either US findings of fatty liver/abnormal LFT after ruling out hep
B/C/AIH)
• 67 patients age < 40 , 139 patients < 50 yo
• Significant Fibrosis > F3 118/362 ( 32.5%)
• Suspected NASH ( ALT > 2x ULN) 113/362 , 31.2% , only 26 biopsies
done.
• Among those patient with DM(n = 94, 26%), 70% with severe steatosis
S3, 63% patients with >= F3 fibrosis.
18. 2) NAFLD: The liver manifestation
of metabolic syndrome
19. Metabolic Associated Fatty Liver
Disease (MAFLD)
• New Diagnosis published in Journal of hepatology in May
2020.
• Diagnostic Criteria:
• > 5% steatosis of hepatocytes in the absence of excessive alcohol
consumption/other chronic liver ds +
• One of 3 following
• Overweight/obesity
• Type 2 DM or
• Evidence of metabolic dysregulation (High Waist
Circumference,HTN, HL, Pre-DM)
20. Leung JC et al. Hepatology 2017
Kuwamura Y et al. Am J
Gastroenterol 2012
21. Q1 : WHO SHOULD BE SCREENED
21
(1) NAFLD in a common cause of chronic liver disease in general
population but cause severe liver disease in a small proportion of
affected people
(2) Type Ⅱ diabetes patients have higher prevalence of NAFLD,
NASH and advanced fibrosis
(3) There is a current lack of effective drug treatment;
(4) Liver biopsy is a procedure with related risks;
(5) Few cost-effective analysis are available
ISSUES WITH SCREENING
22. Hepatic Steatosis
Quantification/Measurement
Gold Standard : Liver Biopsy
Non invasive Method : US HBS, MRI, Fibroscan
Fibroelastography and Controlled Attenuation
Parameter(CAP) measurement
Steatosis Cut off ( dB/m) AUC
S0 Vs S1-3 ( < 5% steatosis) <248 0.823
S0-S1 Vs S2-3 ( 5-33%
steatosis)
268 0.865
S0-2 Vs S3 ( 34-66%
steatosis)
280 0.882
Fibrosis Cut off ( KPA) AUC Sn Sp PPV NPV
> = F2 7 0.84 79.2 75.9 69.6 84
> = F3 8.7 0.93 83.9 83.2 59.5 94.6
> = F4 10.3 0.95 92 87.8 46 99
Karlas et al Hepatology 2017
VW et al Hepatology 2013
23. “I DON’T HAVE FIBROSCAN MACHINE, HOW DO I KNOW IF
PATIENT HAS ADVANCE FIBROSIS /EARLY CIRRHOSIS?
Non invasive predictors markers for advance Fibrosis
No Markers Validated
Population
AUC,Sensitivity and Specificity
1 NAFLD Fibrosis score*(NFS) (age,
BMI,hyperglycaemia,platelet
count,albumin,AST/ALT ratio)
NASH/NAFLD < -1.455 exclude advanced fibrosis
NPV 93%
>0.676 presence of advanced fibrosis
PPV 90%
2 FIB-4 NASH/NAFLD
Fibrosis
Hep C
AUC 0.86
AUC 0.87 * Japanese Cohort
< 1.45 NPV 90% for advance fibrosis
> 3.25 PPV 65%, 97% sp
3 AST to Platelet Ratio indec ( APRI) Hep C >0.7 Cirrhosis Sn 76% Sp 72%
25. Selection of patient for Liver
biopsy
When to consider Liver
biopsy
1)Suspected NAFLD in
whom competing
aetiologies for
steatohepatitis and co-
existing Chronic liver
disease cannot be
excluded without liver
biopsy
27. What are we treating in NAFLD?
• Overweight
• Insulin resistance/ Metabolic syndrome
• Hepatic steatosis/inflammation
• Fibrosis
• Liver complication
• Metabolic complications : cardiovascular ds and cancer
28. WHOM TO TREAT?
Those with NASH and significant Fibrosis
Metaanalysis of 1495 patients in 5 adult cohort studies.
Increase all cause and liver related mortality in patient with significant
fibrosis.
Dulai et al Hepatology 2017
32. Follow up
• All Patients with NAFLD should have non invasive
evaluation to exclude advanced fibrosis/cirrhosis.
• HCC Surveillance
• NASH/F3 fibrosis – 12 months
• F4/Cirrhosis – 6 months
• Follow up Non invasive monitoring Fibrosis for low
risk patient – 2 years
32
EASL-EASD-EASO Clinical Practice
Guidelines for the management of non-
alcoholic fatty liver disease. 2017
33. Summary
• Prevalence NAFLD increase in Asia pacific region
• Screen, manage and follow up other metabolic
complications when NASH/NAFLD is found.
• Assess for significant liver fibrosis/cirrhosis for high
risk patient
• Exercise, dietry manipulation remain the 1st line
treatment for patient with NASH/NAFLD
• More exciting phase 3 trials results and new drugs to
be announce in 2021
36. Failed First Course ?
• Repeat Vaccination Series(1-2m after last dose) or Single Dose
Booster (10ug)
36 Gastroenterol Hepatol (N Y). 2019 Feb
37. Failed 2 courses?
• Increase dose: 40ug – 0,1,6m
• Intradermal administration
• Switch to other Vaccine : HEPLISAVE-B 0,1m– approved in US.
Higher Response rate
37
Double-dose hepatitis B vaccination in cirrhotic patients
on a liver transplant waiting list. Bonazzi et al 2008
Intradermal versus intramuscular hepatitis B
vaccination in hemodialysis patients: a prospective
open-label randomized controlled trial in nonresponders
to primary vaccination. 2009
Hepatitis B surface antigen-1018 ISS adjuvant-
containing vaccine: a review of HEPLISAV™ safety and
efficacy. 2011
40. 40
Epidemiology and public health burden1
1. EASL CPG HBV. J Hepatol 2017;67:370–98; 2. Schweitzer A, et al. Lancet 2015;386:1546–55;
3. Ott JJ, et al. Vaccine 2012;30:2212–9; 4. GBD 2013 Mortality and Causes of Death Collaborators. Lancet 2015;385:117–71;
5. Coppola N, et al. Euro Surveill 2015;20:30009; 6. Hampel A, et al. Bundesgesundheitsblatt Gesundheitsforschung
Gesundheitsschutz 2016;59:578–83; 7. Chen C-L, et al. J Hepatol 2015;63:354–63.
• Worldwide ≈250 million chronic HBsAg carriers2,3
• 686,000 deaths from HBV-related liver disease and HCC in 20134
Increasing prevalence in
some European countries:5,6
• Migration from high
endemic countries
HBsAg prevalence, adults (1949 years), 20053
<2%
24%
57%
≥8%
Not applicable
Decreasing prevalence
in some endemic
countries, e.g. Taiwan7
Possible reasons:
• Improved
socioeconomic
status
• Vaccination
• Effective treatments
41. How serious in Singapore
• Seroprevalence rate is 3.6%
• Chinese 4.2%, Malays 2.2%, Indian 0.6%.
• Overall seroprevalence surveys shows decreasing
trend.
42. 42
HBeAg positive HBeAg negative
Phase 1 Phase 2 Phase 3 Phase 4 Phase 5
Chronic HBV
infection
Chronic hepatitis
B
Chronic HBV
infection
Chronic hepatitis
B
Resolved HBV
infection
Old
terminology
Immune tolerant
Immune reactive
HBeAg positive
Inactive carrier
HBeAg negative
chronic hepatitis
HBsAg negative
/anti-HBc positive
HBsAg High
High/
intermediate
Low Intermediate Negative
HBeAg Positive Positive Negative Negative Negative
HBV DNA >107 IU/mL 104–107 IU/mL <2,000 IU/mL* >2,000 IU/mL <10 IU/mL‡
ALT Normal Elevated Normal Elevated† Normal
Liver disease None/minimal
Moderate/
severe
None
Moderate/
severe
None§
New nomenclature for chronic phases
*HBV DNA levels can be between 2,000 and 20,000 IU/mL in some patients without signs of chronic hepatitis;
†Persisitently or intermittently, based on traditional ULN (~40 IU/L). ‡cccDNA can frequently be detected in the liver;
§Residual HCC risk only if cirrhosis has developed before HBsAg loss.
EASL CPG HBV. J Hepatol 2017;67:370–98
• The natural history of chronic HBV infection has been schematically divided into five phases
Chronic HBV
infection
Chronic
hepatitis B
43. CHB follow up?
• All Patients with Chronic hepatitis B infection
• When HCC screening starts?
• > 40 years old
• Younger patients w Strong family hx of liver cancer
• Hep B with evidence of advanced fibrosis ( >F3)
Recommendations
Follow-up at least every 3–6 months
• HBeAg-positive chronic HBV infection, <30 years old
Follow-up at least every 6–12 months
• HBeAg-negative chronic HBV infection and serum HBV DNA
<2,000 IU/ml
44. US interval and AFP cut-off?
44
6 monthly US
surveillance shows a
better sensitivity
compared to 6-12 months
surveillance
AFP cut off at 20ng/mL
has a good sensitivity in
predicting HCC
45. All CHB should have Fibrosis Assessment
• Ultrasound HBS : look for coarsened echotexture,
splenomegaly, portal HTN, portal vein thrombosis,
ascites
• Fibroelastography : non invasive Liver stiffness
measurement
• *Liver biopsy : indicated in grey zone area ( usually
F2-3) with abnormal LFT to verify cause before
starting treatment.
46. Risk Stratification
Low
Regular
surveillance
ALT< ULN
Monitor ALT 6
months
Medium
Close
surveillance
ALT 1-2x ULN
No Fibrosis
HBV DNA<20000
IU/ml
Repeat ALT 3
months
High
Consider
Treatment
ALT > 2x ULN
HBV DNA >
20000IU/ml
Monitor 1-3
months,
Cirrhosis/Advance
fibrosis
47. Treatment options
Drugs Dose Side effects Monitoring
Peg IFN 2a 180 ug weekly x
48
Flu like symptoms,
depression, fatigue, mood,
cytopenias, anorexia, weight
loss
FBC , TSH, monitong
autoimmune, ischaemic,
neuropsy symptoms
Lamivudine 100mg OD Pancreatitis, Lactic Acidosis Abdominal pain
Telbivudine 600 mg OD CK, myelopathies, lactic
acidosis
Muscle pain/weakness
Entecavir 0.5mg/1mg OD Lactic acidosis Lactic acidosis if concerned
Tenofovir
Disoproxil
Fumarate/Tenofovir
Alafenamide
300mg OD/25mg
OD
Neuropathy, fanconi
syndrome, lactic acidosis,
osteomalacia
CK, phosphate, urine glucose,
proteinuria(yearly), bone density
imaging
Adefovir 10mg OD AKI, Fanconi syndorme,
Diabetes insipidus, lactic
acidosis
AASLD CHB Practice
Guideline 2016
49. 49
Indications for selecting ETV or TAF
over TDF*
*TAF should be preferred to ETV in patients with previous exposure to NAs; †ETV dose needs to be adjusted
if
eGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged ≥12 years and ≥35
kg body weight) with estimated CrCl ≥15 ml/min or in patients with CrCl <15 ml/min who are receiving
haemodialysis
EASL CPG HBV. J Hepatol 2017;67:370–98
• In some circumstances ETV or TAF may be a more
appropriate treatment choice than TDF
Age • >60 years
Bone disease
• Chronic steroid use or use of other medications that
worsen bone density
• History of fragility fracture
• Osteoporosis
Renal alteration†
• eGFR <60 ml/min/1.73 m2
• Albuminuria >30 mg/24 h or moderate dipstick proteinuria
• Low phosphate (<2.5 mg/dl)
• Haemodialysis
50. Treatment end point
• HBeAg +ve without cirrhosis- seroconverted to
anti-Hbe + HBeAg -ve
• 12 months of normal ALT, undetectable HBV DNA
• Discuss risk and benefit : virological relapse, hepatic
decompensation, liver cancer, death Vs financial
burden, monitoring, drug resistance
• Monitor every 3 months HBV DNA, ALT flares,
seroreversion, decompensation
• HBeAg –ve flare – not recommended unless
achieve HbsAg loss
• Patient with Cirrhosis : not recommended
51. 51
Chronic HBV infection*
(no signs of chronic hepatitis)
Monitor
(includes HBsAg, HBeAg, HBV
DNA, ALT, fibrosis assessment)
Consider
Risk of HCC, risk of HBV
reactivation, extrahepatic
manifestations, risk of
HBV transmission
HBsAg positive
Chronic hepatitis B
± cirrhosis*
Start antiviral treatment
HBsAg negative, anti-HBc positive
No specialist follow-up
but inform patient and general
practitioner about the potential
risk of HBV reactivation
In case of immunosuppression,
start oral antiviral prophylaxis
or monitor
Suspected chronic HBV infection
NO
YES
Algorithm for the management of chronic
HBV infection
52. 52
Special patient groups: pregnant women
EASL CPG HBV. J Hepatol 2017;67:370–98
• Management may depend on severity of liver disease and timing of a future
pregnancy
Recommendations
Screening for HBsAg in the first trimester is strongly recommended I 1
In women of childbearing age without advanced fibrosis planning a
pregnancy in the near future, it may be prudent to delay therapy until
the child is born
II-2 2
In pregnant women with chronic hepatitis B and advanced fibrosis or
cirrhosis, therapy with TDF is recommended
II-2 1
In pregnant women already on NA therapy, TDF should be
continued while ETV or other NA should be switched to TDF
II-2 1
In all pregnant women with HBV DNA >200,000 IU/ml or HBsAg
>4 log10 IU/ml, antiviral prophylaxis with TDF should start at Week
24–28 of gestation and continue for up to 12 weeks after delivery
I 1
Breast feeding is not contraindicated in HBsAg-positive untreated
women or those on TDF-based treatment or prophylaxis
III 2
Grade of evidence Grade of recommendation
54. 54
Epidemiology of HCV
1. Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol 2017;2:161–76; 2. World Health Organization. Global
Hepatitis Report 2017. Available at: http://apps.who.int/iris/bitstream/handle/10665/255016/9789241565455-
eng.pdf?sequence=1;
EASL CPG HCV. J Hepatol 2018;69:461–511.
• Estimated global prevalence of HCV in 2015: 1.0% (95% uncertainty interval 0.8–1.1)1
• Corresponds to 71.1 million (62.5–79.4) viraemic infections1,2
• ~399,000 deaths each year, mostly from cirrhosis and HCC2
• GT 1 and 3 are the most common causes of infection (44% and 25%, respectively)1
Incidence of HCV infection and new HCV infections in the general population, by WHO region, 20152
WHO region
Map
key
HCV incidence rate per
100,000:
Best estimate
(uncertainty level)
New HCV infections
(x 1,000):
Best estimate
(uncertainty level)
African 31.0 (22.5–54.4) 309 (222–544)
Americas 6.4 (5.9–7.0) 63 (59–69)
Eastern
Mediterranean
62.5 (55.6–65.2) 409 (363–426)
European 61.8 (50.3–66.0) 565 (460–603)
South-East Asia 14.8 (12.5–26.9) 287 (243–524)
Western Pacific 6.0 (5.6–6.6) 111 (104–124)
Global 23.7 (21.3–28.7)
1,751
(1,572–2,120)
55. 55
IFN-free, RBV-free combination regimens
recommended for each genotype
*Triple combination therapy efficacious but not useful due to the efficacy of double combination regimens;
†TN patients without cirrhosis or with compensated (Child–Pugh A) cirrhosis;
‡TN and TE patients without cirrhosis or with compensated (Child-Pugh A) cirrhosis with HCV RNA ≤800,000 IU/mL (5.9 Log10
IU/mL);
§TN and TE patients without cirrhosis;
‖TN and TE patients with compensated (Child–Pugh A) cirrhosis;
¶TN patients without cirrhosis or with compensated (Child–Pugh A) cirrhosis with HCV RNA ≤800,000 IU/mL (5.9 Log10 IU/mL)
EASL CPG HCV. J Hepatol 2018;69:461–511.
Genotype Pangenotypic regimens Genotype-specific regimens
SOF/VEL GLE/PIB
SOF/VEL/
VOX SOF/LDV GZR/EBR
OBV/PTV/r
+ DSV
1a Yes Yes No* Yes† Yes‡ No
1b Yes Yes No* Yes Yes Yes
2 Yes Yes No* No No No
3 Yes§ Yes Yes‖
No No No
4 Yes Yes No* Yes† Yes¶
No
5 Yes Yes No* Yes† No No
6 Yes Yes No* Yes† No No
56. 56
Indications for treatment: who should be treated?
*Individuals who failed to achieve SVR after prior treatment; †Symptomatic vasculitis associated with HCV-related
mixed cryoglobulinaemia, HCV immune complex-related nephropathy and non-Hodgkin B-cell lymphoma; ‡Non-liver
solid organ or stem cell transplant recipients, HBV coinfection, diabetes
EASL CPG HCV. J Hepatol 2018;69:461–511.
Recommendations
All patients with HCV infection must be considered for therapy, including
treatment-naïve and treatment-experienced* patients
A 1
Patients who should be treated without delay
• Significant fibrosis or cirrhosis (METAVIR score ≥F2): including compensated
(Child–Pugh A) and decompensated (Child–Pugh B or C) cirrhosis
• Clinically significant extra-hepatic manifestations†
• HCV recurrence after liver transplantation
• Patients at risk of rapid evolution of liver disease due to concurrent comorbidities‡
• Individuals at risk of transmitting HCV
– PWID
– MSM with high-risk sexual practices
– Women of child-bearing age who wish to get pregnant
– Haemodialysis patients
– Incarcerated individuals
A 1
• In patients with decompensated cirrhosis and an indication for liver transplantation (MELD
score ≥18–20), transplant first and treat after transplantation
• For waiting time >6 months, treat before transplant (clinical benefit not well established)
B
B
1
2
• Treatment is generally not recommended in patients with limited life expectancy due to non-
liver-related comorbidities
B 2
Grade of evidence Grade of recommendation
57. 57
HCV DAAs approved in Sg in 2018
SG ACE GUIDELINE 2019 JAN.
Product Presentation Posology
Pangenotypic drugs or drug combinations
Sofosbuvir/velpatasvir Tablets containing: 400 mg SOF, 100 mg VEL 1 tablet Daily x 12w
1
COST : 7-8k for Sg Citizen
(MAF)
58. Summary
• If you found any Chronic Hep C patient, check HCV
RNA, if positiveplease refer them for treatment!
58