Transcript Slide 1

Points to consider
• When are LFTs indicated?
• How are isolated borderline LFT results managed?
• Is LFT monitoring necessary for people on statins?
• What are the best tests of liver failure?
• Who is at risk of chronic hepatitis?
• How is acute hepatitis managed in primary care?
• Is non-alcoholic liver disease a benign condition?
• What is the role of GGT?
Introduction
• Most liver problems are managed in primary care
• Testing and interpretation can be challenging
• Consider clinical findings, previous liver function
tests and other test results
Requesting LFTs
• Liver function testing is not indicated for
asymptomatic people without risk factors
Asymptomatic people at risk of
abnormal LFTs
• Diabetes or metabolic syndrome (increased risk of
NAFLD)
• Excessive alcohol intake
• Chronic hepatitis B
• Chronic hepatitis C
Excessive alcohol intake
• GGT, macrocytosis, triglycerides and uric acid are
both non-sensitive and non-specific to EtOH
• Screening questionnaires give better results
• GGT has better predictive value when there is
strong suspicion of alcohol excess
Diabetes or metabolic
syndrome
• Diabetes, metabolic syndrome, insulin resistance
and dyslipidaemia, increase the risk of NAFLD
• People with these conditions will benefit from
occasional measurement of LFTs at diagnosis, start
of antidiabetic therapy and any other time
indicated by clinical judgment
Chronic hepatitis B
• 50 - 90% neonates and children infected with hepatitis will
develop chronic hepatitis B infection, but < 5% of adults.
• Chronic hepatitis B carriers have ~ 25% risk of developing liver
damage, cirrhosis, liver failure and liver cancer.
• LFTs should be tested at least 6 monthly.
• Screening for hepatitis B infection, using HBsAg, is
recommended for all people of Maori, Pacific or Asian
ethnicity over the age of 15 years, who have not previously
been immunised.
Chronic hepatitis C
• Most people will not be symptomatic during the
acute infection but approximately 70% will remain
infected.
• Chronic infections carry a substantial risk of liver
damage, cirrhosis and liver cancer.
• Test people who had blood transfusions prior 1992,
inject street drugs or share needles.
People at risk of abnormal LFTs
because of other illnesses
Liver disease is associated with a wide range of other illnesses:
• Haemochromatosis
• Autoimmune diseases, including coeliac disease
• Chronic inflammatory bowel disease
• Metastatic cancer
• Clinically significant thyroid disease
• Right heart failure
People at risk of abnormal LFTs
because of drugs
Drugs which LFT monitoring is recommended in
primary care:
Valproic acid
Ketoconazole
Methrotrexate
Dantrolene
Amiodarone
Thiazolidinediones
Azathioprine
Synthetic retinoids
Anti-tuberculous drugs
Chemotherapy drugs
Routine monitoring of LFTs no longer
considered necessary for statin use
• Risk of liver damage from statin use has been overstated.
• Liver failure occurs with statins is similar to liver failure rate in
general population.
• Irreversible liver damage resulting from statin therapy is
exceedingly rare.
• Routine monitoring is not necessary.
• Statins should not be withheld in patients with baseline
abnormal LFTs.
People at risk of abnormal LFTs because
of other abnormal blood tests
In some situations LFTs may be indicated following abnormalities
in apparently unrelated tests. Examples are:
• Abnormal iron studies/elevated ferritin
• Abnormalities on blood film
– Macrocytosis
– Neutropenia
– Thrombocytopenia
Liver function testing when there are
clinical features of liver disease
Physical features of liver disease
Fatigue, pruritis, vague RUQ pain
Non-specific features
Jaundice
Acute hepatitis, biliary obstruction or
advanced chronic liver disease
Wasting
Protein-calorie malnutrition from cirrhosis or
hepatocellular carcinoma
Abdominal pain, fever
Acute cholangitis, cholecystitis or liver
abscess
Spider naevi
Testicular atrophy
Gynaecomastia
Palmar erythema
Cirrhosis
Encephalopathy
Acute GI bleeding
Ascites
Coagulopathy
Advanced liver disease (decompensated)
Interpretation of liver function
tests
Abnormal liver function tests must be interpreted with
regard to clinical context and results of previous tests:
• History of symptoms
• Medication history
• Occupational exposure
• Family history
• Social history
• Physical examination
Typical patterns of liver dysfunction
Liver dysfunction
Biochemical markers
Hepatocyte integrity
AST, ALT
Cholestasis
Alk Phos, GGT, Bilirubin
Liver function mass
Albumin, INR
Hepatocyte injury: usually results in
ALT and/or AST elevation
Most likely causes of hepatocyte injury are:
• Non-alcoholic fatty liver disease
• Viral hepatitis
• Alcohol, drugs, and herbal remedies
• Haemochromatosis
• Autoimmune disease
Cascade of testing following
abnormal LFTs
• Tests are requested in a
stepwise fashion
guided by presence of
risk factors and clinical
features
First tier tests
CBC, Fasting glucose &lipids,
Iron Studies, HBsAg, HCV
antibody
Second tier tests
Liver ultrasound,
autoantibodies, α-1-antitrypsin
Transaminases in general
• < 3 X ULN recheck in 1-3 months
• Two results elevated 3 months apart, investigate further
• > 3 X ULN, Investigate further
AST/ALT ratio
• < 1 in most hepatocellular injury
• >1 in alcholic liver diseae, drug induced, malignancy,
cirrohosis
Isolated GGT elevation
This has limited use as primary liver test and there is no clear
consensus on follow up. Suggestions are:
– Although non specfic, consider alcohol
– Review risk factors for non-alcoholic fatty liver
disease.
– Mild rises < 3 X ULN, test three monthly and consider
further investigation if elevation persists or rises.
– > 5 ULN or both GGT and alkaline phosphatase
raised without explanation - consider ultrasound
Cholestasis
Most likely causes of cholestasis include:
• Gall stones
• Abdominal masses
• Medications (erythromycin, phenytoin, flucloxacillin,
amoxicillin-clavulanic acid, combined oral contraceptive pill,
some antipsychotics)
• Pregnancy
• Primary biliary cirrhosis
• Paraneoplasia (especially lymphoma)
• Systemic sepsis
A cholestatic pattern of LFT disturbance
• ALP and bilirubin usually both elevated
Non-liver causes of ↑ ALP
• ALP is non-specific for liver. Other sources are bone, intestine,
and placenta.
• Bony causes include: bony metastases, hyperparathyroidism,
renal impairment, healing fractures and Paget’s disease.
• Other causes : CHF, hyperthyroidism, pregnancy, children
during bone growth, perimenopausal years.
Raised alkaline phosphatase plus raised
GGT makes liver problem more likely
• ↑ ALP / ↑ GGT = most likely a liver cause
• ↑ ALP / normal GGT = bony cause is more likely
Follow up of ↑ alkaline phosphatase
• Depends on the clinical context, other laboratory
abnormalities, and clinical review
• Liver ultrasound if cholestasis is suspected
Response to ↑ ALP
(when likelihood of disease is low)
ALP level
Followup
< 1.5 X ULN
•Recheck fasting level in 3 months.
> 1.5 X ULN
• 2 measurements taken 3 months apart
warrant further investigation
• exclude malignancy before waiting 3
months
> 3.0 X ULN
• Immediate investigation warranted
Causes of bilirubin elevation
• Liver disease: usually along with other LFTs
• Isolated ↑ bilirubin: familial hyperbilirubinaemias,
• Haemolysis: ↑ unconjugated bilirubin.
Haemolysis may be due to:
• Inherited haemolytic anaemias eg, spherocytosis, thalassaemia
• Immune reactions eg transfusion reaction or haemolytic disease of the
newborn
• Auto-immune disorders eg SLE, RA
• Renal or liver failure
• Drugs and chemicals eg, arsenic, sulphasalazine
• Infections eg, malaria, Clostridium perfringes
• Mechanical eg, valve prosthesis, march haemoglobinuria
• Hypersplenism
• Burns
Follow up of elevated bilirubin levels
(when no clinical indications of cause)
Bilirubin level
Follow up
Up to 1.5 X ULN
Retest when well in 3 months
> 1.5 X ULN
Test unconjugated portion.
Unconjugated >70% in a well patient with
otherwise normal LFTs, CBC and TSH = most
likely to be Gilberts Syndrome
> 3.0 X ULN
Unconjugated >70% consider haemolysis
Conjugated >50% consider ultrasound
Liver failure: reflected in serum
albumin and INR
• Failure of the liver to perform its synthetic functions is most often
related to loss of functioning liver mass. It is usually assessed by levels
of serum albumin and coagulation factors,
• Failure of the liver to synthesise albumin results in  albumin.
•  albumin may be due to: cachexia, catabolic states, such as sepsis
and cancer, nephrotic syndrome and protein-losing enteropathy.
• ↑ INR may be due to  synthesis of clotting factors
• Vitamin K malabsorption may ↑ INR
• Failure of liver synthetic function = severe liver disease
People who require specialist
referral for disturbed liver function
• HBsAg positive, ALT > ULN for at least 6. AFP is >100 =
should be seen urgently.
• Hepatitis C positive
• Evidence of acute or chronic failure of liver synthetic
function.
• Haemochromatosis positive with abnormal LFTs,
hepatomegaly or untreated ferritin > 1000 g/L.
• Anyone with persisting unexplained LFT abnormalities.
Management of acute hepatitis
Common causes of acute hepatitis are:
– Hepatitis A: contaminated food, men who have sex with men
• <1% develop chronic autoimmune hepatitis
– Hepatitis B: adult infection – sexual, intra-venous drug use
• Acute hepatitis B is unlikely in adults of Maori, Pacific or Asian ethnicity
(Likely to be immune or chronically infected due to infection at an
early age)
• < 5% of adults develop chronic infection
– Hepatitis C: adult infection, intra-venous drug use
• >80% develop chronic hepatitis
– Epstein-Barr viral hepatitis: usually adolescent (infectious mononucleosis)
• None develop chronic hepatitis
Monitoring in acute hepatitis
Monitoring for acute hepatitis managed at home
includes twice weekly testing of:
ALT, AST, INR, bilirubin, creatinine, glucose
Testing frequency is decreased as the results return
to normal.
Liver function testing not indicated in
infectious mononucleosis
• Liver function testing is rarely indicated in IM
• IM does not lead to chronic liver disease
• LFT results do not alter management
• Test LFTs only if patient becomes jaundice
Fatty liver (steatohepatitis)
• Fatty liver is associated with alcoholic liver disease but nonalcoholic causes are becoming increasingly common.
• NAFLD often has ↑AST/ALT.
• 10-15% of people with NAFLD will develop long term scarring.
• NAFLD associated with metabolic syndrome, insulin resistance,
diabetes, and hyperlipidaemia.
• LFTs especially indicated for people at risk of fibrosis or
progression.
Liver metastases
• Monitoring of LFTs is not routinely indicated for people with
cancer as it is rare to get liver failure from liver metastases.
Biliary obstruction may occur but leads rapidly to jaundice.
• Monitoring of LFTs is worthwhile for people on chemotherapy.
Gilbert’s syndrome
• Gilbert’s syndrome is asymptomatic and it is not a serious
disease.
• Occurs 2-10% of the population.
• Mostly unconjugated bilirubin and levels fluctuate, often
higher at times of illness and fasting.
• No proven association between tiredness and Gilbert’s
syndrome.
• No risk of kernicterus to the foetus.
Appendix 1 - Liver function tests
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•
•
•
•
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ALT
AST
GGT
ALP
Bilirubin
Total protein
Albumin
INR
Appendix 2 – Alcohol screening tests
1. The RAPS4 Alcohol Screening Test for dependent drinking
Please answer these 4 questions:
• During the last year have you had a feeling of guilt or remorse after
drinking?
• During the last year has a friend or a family member ever told you
about things you said or did while you were drinking that you could
not remember?
• During the last year have you failed to do what was normally
expected from you because of drinking?
• Do you sometime take a drink when you first get up in the morning?
Appendix 2 – Alcohol screening tests
…contd
2. Alcohol Advisory Council of New
Zealand ‘Drink Check’
The ALAC drinkcheck
questionnaire, based on the
AUDIT tool, is available online from
ALAC:
http://www.alac.org.nz/TestYourD
rinking.aspx
Appendix 3 - Screening for hepatitis B in
people not previously immune
HBsAg
Negative
No evidence of
Hepatitis B
infection
Positive
If positive for >
6 months,
consistent with
chronic
Hepatitis B
infection
Appendix 3 - Investigation for Evidence of
Previous Infection or Immunisation with
Hepatitis B – See footnote (a)
Anti-HBs
Negative
No evidence of
previous
infection or
immunization
See footnote(b)
a.
b.
Positive
Compatible
with previous
infection or
immunisation
A previous vaccination with documented immune response, the patient can then be
presumed to be protected long term unless they are immunosuppressed. If in doubt
revaccinate and recheck anti-HBs in 3 weeks.
A small number of patients may be positive for anti-HBc from a previous HBV infection in the
absence of anti-HBs. If there is a strong suspicion of previous infection or high risk, then order
an anti-HBc.
Appendix 4: Investigation for Evidence
of Chronic HCV Infection
Anti-HCV
Negative
No evidence of
chronic Hepatitis
C infection
See footnote (a)
a.
b.
Positive
Indicates possible
current, previous
or chronic
Hepatitis C
infection
See footnote (b)
A negative test does not exclude infection within the previous eight weeks.
Positive anti-HCV is followed up by HCV RNA tests. Persistently normal LFTs and two
negative HCV RNA tests 3 months apart indicate that active HCV is extremely unlikely.
Appendix 5 – Isoenzymes
Isoenzymes are different molecular forms of the same enzyme, which
all react in a similar manner with a laboratory test.
• ALP isoenzymes may originate from liver, bone, placenta, intestinal or
tumour cells.
• ALT is the most specific liver enzyme, but occasionally originates from
sources other than the liver.
• AST may originate from liver, heart or red blood cells.
• GGT isoenzymes have been identified in kidney, heart and pancreas but
these are not commonly encountered.
Appendix 6
Investigation for Evidence of Acute Viral Hepatitis8
ALT
Elevated > 5 x ULN
Hepatitis A
Hepatitis C
Hepatitis B
See footnote (a)
Anti-HAV IgM
Anti-HBc IgM
Negative
Positive
Positive
No evidence of
acute Hepatitis
A infection
a.
b.
HBsAg
Compatible
with acute
Hepatitis A
infection
Compatible
with acute
Hepatitis B
infection
Negative
No evidence of
acute Hepatitis
B infection
Positive
Positive
Compatible with
acute or chronic
hepatitis B
infection
See footnote (b)
Hepatitis C cannot reliably be diagnosed in the acute phase because of the prolonged period of sero-conversion.
Testing may be done for people with known risk factors. However, if HCV is negative and other causes of viral
hepatitis have been ruled out, a second sample should be specifically tested for HCV one to three months later.
If HBsAg is positive for a period of greater than six months, it is consistent with chronic Hepatitis B infection.
References
1. BPAC, Laboratory Testing in Diabetes, 2006
2. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease 8th ed, Chapter 83 pages
1807-1852 “Liver Disease Caused by Drugs”
3. Law M, Rudnicka AR. Am J Cardiol. 2006;97:52C-60C
4. Maddrey W. Drug-Induced Liver Disease: 2006 The risk profile of statins. Slide Show
Presentation: AASLD 2006
5. Evaluation and Interpretation of Abnormal Liver Chemistry in Adults, BC Health services
2004
6. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ
2005; 172:367-79.
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Path 2006;59:1229-37.
8. OAML Guidelines for Clinical Laboratory Practice. CLP 012: Guidelines for Testing for
Viral Hepatitis. Available from: http://www.oaml.ca/PDF/CLP012.pdf (accessed 21
June 2007)
9. Alcohol Advisory Council of New Zealand, ‘Drink Check’ Is your drinking OK?, Available
from: http://www.alac.org.nz/Documents/Campaigns/ALAC_DrinkCheck.pdf
(accessed 21 June 2007)