Points to consider

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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?

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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

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Requesting LFTs

• Liver function testing is not indicated for
  asymptomatic people without risk factors

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Asymptomatic people at risk of abnormal LFTs

• Diabetes or metabolic syndrome (increased risk of
  NAFLD)
• Excessive alcohol intake
• Chronic hepatitis B
• Chronic hepatitis C

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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

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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

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Chronic hepatitis B

• 50 - 90 neonates and children infected with
  hepatitis will develop chronic hepatitis B
  infection, but lt 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.

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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.

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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

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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
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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.

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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

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Liver function testing when there are clinical
features of liver disease
Physical 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 Gynaecomastia Testicular atrophy Palmar erythema Cirrhosis
Encephalopathy Ascites Acute GI bleeding Coagulopathy Advanced liver disease (decompensated)
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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

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Typical patterns of liver dysfunction
Liver dysfunction Biochemical markers
Hepatocyte integrity AST, ALT
Cholestasis Alk Phos, GGT, Bilirubin
Liver function mass Albumin, INR
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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

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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, a-1-antitrypsin
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Transaminases in general

• lt 3 X ULN recheck in 1-3 months
• Two results elevated 3 months apart, investigate
  further
• gt 3 X ULN, Investigate further
• AST/ALT ratio
• lt 1 in most hepatocellular injury
• gt1 in alcholic liver diseae, drug induced,
  malignancy, cirrohosis

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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 lt 3 X ULN, test three monthly and
  consider further investigation if elevation
  persists or rises.
• gt 5 ULN or both GGT and alkaline phosphatase
  raised without explanation - consider ultrasound

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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

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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 Pagets disease.
• Other causes CHF, hyperthyroidism, pregnancy,
  children during bone growth, perimenopausal
  years.

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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

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Response to ? ALP (when likelihood of disease is
low)
ALP level Followup
lt 1.5 X ULN Recheck fasting level in 3 months.
gt 1.5 X ULN 2 measurements taken 3 months apart warrant further investigation exclude malignancy before waiting 3 months
gt 3.0 X ULN Immediate investigation warranted
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Causes of bilirubin elevation

• Liver disease usually along with other LFTs
• Isolated ? bilirubin familial hyperbilirubinaemia
  s,
• Haemolysis ? unconjugated bilirubin.

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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

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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
gt 1.5 X ULN Test unconjugated portion. Unconjugated gt70 in a well patient with otherwise normal LFTs, CBC and TSH most likely to be Gilberts Syndrome
gt 3.0 X ULN Unconjugated gt70 consider haemolysis Conjugated gt50 consider ultrasound
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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

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People who require specialist referral for
disturbed liver function

• HBsAg positive, ALT gt ULN for at least 6. AFP is
  gt100 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 gt 1000 ?g/L.
• Anyone with persisting unexplained LFT
  abnormalities.

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Management of acute hepatitis

• Common causes of acute hepatitis are
• Hepatitis A contaminated food, men who have sex
  with men
• lt1 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)
• lt 5 of adults develop chronic infection
• Hepatitis C adult infection, intra-venous drug
  use
• gt80 develop chronic hepatitis
• Epstein-Barr viral hepatitis usually adolescent
  (infectious mononucleosis)
• None develop chronic hepatitis

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Monitoring in acute hepatitis

• Monitoring for acute hepatitis managed at home
  includes twice weekly testing ofALT, AST, INR,
  bilirubin, creatinine, glucoseTesting frequency
  is decreased as the results return to normal.

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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

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Fatty liver (steatohepatitis)

• Fatty liver is associated with alcoholic liver
  disease but non-alcoholic 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.

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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.

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Gilberts syndrome

• Gilberts 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
  Gilberts syndrome.
• No risk of kernicterus to the foetus.

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Appendix 1 - Liver function tests

• ALT
• AST
• GGT
• ALP
• Bilirubin
• Total protein
• Albumin
• INR

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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?

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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/TestYourDrinking.aspx

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Appendix 3 - Screening for hepatitis B in people
not previously immune
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Appendix 3 - Investigation for Evidence of
Previous Infection or Immunisation with Hepatitis
B See footnote (a)

1. 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.
2. 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.

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Appendix 4 Investigation for Evidence of Chronic
HCV Infection

1. A negative test does not exclude infection within
   the previous eight weeks.
2. 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.

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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.

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Appendix 6Investigation for Evidence of Acute
Viral Hepatitis8
ALT Elevated gt 5 x ULN
Hepatitis A
Hepatitis C See footnote (a)
Hepatitis B
Anti-HAV IgM
HBsAg
Anti-HBc IgM
Negative
Positive
Negative
Positive
Positive
No evidence of acute Hepatitis A infection
Compatible with acute Hepatitis A infection
Positive Compatible with acute or chronic
hepatitis B infection See footnote (b)
Compatible with acute Hepatitis B infection
No evidence of acute Hepatitis B infection

1. 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.
2. If HBsAg is positive for a period of greater than
   six months, it is consistent with chronic
   Hepatitis B infection.

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   Liver Disease Caused by Drugs
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   Presentation AASLD 2006
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