Transcript diarrhoea-and-lft-presentation

LFT’s, tests of liver function &
Cirrhosis
Dr Kumudith Ekanayaka
12 September 2016
Normal Liver Anatomy
Hepatic Artery
Bile Duct
Portal Vein
Central Vein
Aetiology of Abnormal LFT’s
in my clinic (n= 672)
Liver Function Tests (LFT’s)
• Routinely ordered
• AST not routinely performed by the lab
• 1-4% of asymptomatic patients have
abnormal values
• Test results can fluctuate, 30% of
abnormal results can normalise (Lazo et al.)
• Diagnosis can be reached non invasively
LFT’s
Liver Enzymes
Cholestasis
ALP (<110 iU/L)
GGT (<60 iU/L)
Hepatitis
ALT (<55 iU/L)
AST (<45 iU/L)
Synthetic Function
Bilirubin (<24 umol/L)
Albumin (35-47 g/L)
Prothrombin Ratio (<1.2)
Patterns of raised LFT’s
A purely cholestatic or purely hepatitic picture uncommon
Cholestatic
ALT / ALP
<2
Mixed
ALT / ALP
2-5
Hepatitic
ALT / ALP
>5
[ Ratio = ALT (x ULN) / ALP (x ULN)]
Causes of Cholestasis
• Mechanical Bile duct obstruction
– Stones, tumour, surgery, parasites
• Medications
– Clavulanic acid, Flucloxacillin, Erythromycin
• Liver congestion / heart failure
• Sepsis / systemic inflammatory disorders
• Hormonal
– Pregnancy, OCP
• Chronic biliary disorders
– Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis
• Inherited conditions
– Biliary atresia, Cystic fibrosis
Choledocholithiasis (CBD Stones)
Normal
Stones & dilated CBD
Alkaline phosphatase (ALP)
• Produced in many tissues but raised levels usually
come from the biliary epithelium, bones, or
placenta.
• Raised in children and pregnancy
• Unlikely from liver if GGT normal
• Cholestasis causes increased synthesis of ALP
and “leakage” of ALP in to the circulation
Gammaglutamyl transpeptidase (GGT)
• Found in cell membranes throughout the body
including hepatocytes and biliary epithelium –
thought to have a role in AA transport
• Levels are not raised in bone disease or
pregnancy – unlike ALP
• Raised serum levels almost always have a liver
origin (usually relating to cholestasis or fatty liver)
• Serum levels can be elevated in the absence of
liver disease due to enzyme induction by
anticonvulsants (phenytoin) or EtOH
Causes of hepatocellular damage
( Hepatitis)
Acute
• Viral hepatitis
• EBV, HAV, HBV
• Drugs & herbal remedies
• Paracetamol OD
• Ischaemic / hypoxic
Rare: Autoimmune (AIH)
Wilson’s disease, BCS,
Acute Fatty Liver
Pregnancy
Chronic (>6 months)
• Viral hepatitis
• HBV,HCV
• Fatty Liver Disease
• NASH / NAFLD
• EtOH
• Medications
Rare: Haemochromatosis,
Wilsons Disease,
Autoimmune
Alanine Aminotransferase (ALT)
• Catalyses the formation of pyruvate in the
cytosol
• Found in many tissues but by far the highest
levels are in the liver (elevated levels are
relatively specific for liver disease)
• More sensitive marker of liver disease in
chronic viral hepatitis than the AST
Aspartate Aminotransferase (AST)
• Catalyses the formation of oxaloacetate in the cell
cytosol and mitochondria.
• Found in many tissues but high levels in liver and
muscle (cardiac & skeletal)
• Elevated levels are not as specific for liver disease
as an elevated ALT
• Less sensitive marker of hepatic inflammation than
ALT
Transaminases (ALT & AST)
• In chronic liver disease the ALT & AST are
usually only mildly elevated (typically 1.5 - 3 x
ULN). May be normal.
• In most causes of hepatitis the AST / ALT
ratio is < 1. Alcohol related hepatitis is the
exception where the ratio is usually > 2.
• Levels < 10x ULN are non-specific, but there
are only a few conditions that cause an ALT
or AST > 1000 IU/L
Transaminases > 1,000 iU/L
• Ischaemic hepatitis (shock)
• Acute viral hepatitis (HAV, HBV)
• Drugs (Paracetamol OD, halothane,
Carbemazepine)
[Alcoholic hepatitis ALT & AST < 300 IU/L]
Transaminases (ALT & AST)
• The degree of elevation of the does not
correlate well with the degree of histological
damage in the liver
• Levels may go in to the many thousands
acutely and the liver recover completely
• Falling levels usually denote recovery but are
an ominous sign if the liver synthetic function
is worsening.
Tests of Liver Synthetic
Function
Bilirubin
Albumin
Prothrombin Ratio (PR, INR)
Bilirubin
• 80% comes from breakdown of haemoglobin
• Taken up by hepatocytes and conjugated
with glucuronic acid and excreted in bile
• Normally > 95% of serum bilirubin is
unconjugated (indirect). Only conjugated
(direct) bilirubin can be excreted in the urine.
Hyperbilirubinaemia / Jaundice:
• In the absence of liver disease isolated
unconjugated hyperbilirubinaemia may occur
due to over production of bilirubin
(haemolysis) or inherited disorders of bilirubin
conjugation (Gilbert’s syndrome)
• Conjugated (direct)
hyperbilirubinaemia and
bilirubinuria occur only in
hepatobiliary diseases
Bilirubin - Prognosis
• Poor sensitivity for detecting liver dysfunction.
• Large reserve capacity of the liver to remove
bilirubin without the development of
hyperbilirubinaemia.
• In acute cholestatic disease (such as
choledocholithiasis) when the hepatocyte synthetic
function is normal and the degree of
hyperbilirubinaemia does not influence prognosis.
• In viral hepatitis, alcoholic hepatitis and PBC the
serum bilirubin does correlate with the degree of
injury on biopsy and the prognosis
Albumin
• Made in the liver. Quantitatively the most
important protein in the blood (500g in body
fluids), important role in maintaining colloid
osmotic pressure.
• Up to 30g / day can be synthesised in a normal
liver
• Serum albumin level is
determined by the rate of
synthesis, rate of loss /
degradation and the volume
of distribution.
Albumin
• A low serum albumin is a good indicator of
liver synthetic failure in the presence of
chronic liver disease, however other
causes of hypoalbuminaemia need to be
considered:
• Renal loss (Nephrotic syndrome)
• Protein-calorie malnutrition
• Haemodilution (raised)plasma volume
Prothrombin ratio (PR, INR)
• Most clotting factors are synthesised in the liver.
– Liver transplantation is a surgical cure for haemophilia !
• In the setting of both acute and chronic liver failure
the INR is a very useful indicator of liver synthetic
function and prognosis, however other causes of a
raised INR need to be excluded:
• Vitamin K deficiency (prolonged cholestasis)
• Increased clotting factor consumption (DIC)
• Warfarin therapy
Prothrombin ratio
• In chronic liver failure the INR rarely rises
above 2.0
• In acute or fulminant liver failure the INR may
rise rapidly to very high levels (>10), this is
associated with a very poor prognosis and
liver transplantation should be considered.
• Even an INR of 1.3 in the setting of an acute
severe hepatitis is of concern and should be
repeated after 6-8 hrs
Liver Failure
Acute (FHF)
Chronic (Cirrhosis)
• Patient unwell for hours
or days
• ALT & AST usually >
1,000
• INR & Bilirubin rise
rapidly
• Alb falls rapidly
• Patient unwell for months
or years
• ALT & AST usually < 200
• INR & Bilirubin rise slowly
• Alb falls slowly
• Death within days of
cerebral oedema, sepsis
or multi-organ failure
• Death from variceal
haemorrrhage, sepsis,
encephalopathy or other
complications
Cirrhosis
• May be the end result of chronic
cholestatic or hepatitic disease.
• Liver synthetic function may be impaired
or normal
• The enzymes may be of any pattern or
may be normal if the underlying aetiology
is inactive or no longer present.
Cirrhosis (histopathology)
Examination Findings
Asterixis
Examination Findings
Dupytrons Contracture
Examination Findings
Palmar Erythema
Examination Findings
Gynaecomastia
Examination Findings
Spider Naevi
Grading of ESLD
Child-Pugh Score
POINTS
1
2
3
Encephalopathy
None Grade 1, 2 Grade 3, 4
Ascites
None
Mild
Moderate
Bilirubin
< 35
35 - 50
> 50
Albumin
> 35
28 - 35
< 28
INR
< 1.3
1.3 – 1.5
> 1.5
Survival according to ChildPugh Score
Grade Score
1 year 5 year 10 year
A
0–6
84%
44%
27%
B
7–9
62%
20%
10%
C
10 - 15 42%
21%
0%
Cirrhosis - Importance
• Why Important?
– Hepatoma 1-2% per annum
– Variceal Bleeding
– Decompensation – Risk of Liver Failure
• Suggested By
– Bloods
• ↓Platelets, ↓Albumin, ↑INR, ↑Bilirubin
– Clinical Examination
• Liver Specific / Other Organ injury
– Imaging: USS / CT
• Irregular contour, ↑PV size, Splenomegaly, Varices
– Endoscopy
• Varices, Portal Hypertensive Gastropathy (PHG)
Middlemore Hospital Audit - Cirrhosis
New patients presenting each year
2010
2008
Number
Linear (Number)
2006
2004
2002
Before 2001
0
20
40
60
80
100
Gerred et al. 2012
Cirrhosis – New Case Aetiology
Y e a r o f p r e s e n t a t io n
2011
O th e r
2010
N AFLD
2009
2008
HCV
2007
HBV
2006
ALD
2005
2004
2003
2002
2001
0
50
100
N um ber of N ew C ases
150
Gerred et al. 2012
Liver Screen
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FBC
LFT’s, CK< TFT’s
Coagulation
AFP
Hepatitis Serology
• Auto Ab, ANA, Tissue
Antibodies, AMA, LKM,
SLA
• Alpha-1-AT
• Copper, Ceruloplasmin
– A, B, C, D, E
• Protein & Ig
• Ferritin
– Transferrin Sats, HFE
• AFP
Liver Cases
Dr Kumudith Ekanayaka
12 September 2016
Case 1
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42 year old Chinese female
No EtOH
BMI 21
No signs of Chronic Liver Disease
LFT’s Bil 18 (0-24)
AST 40 (0-45)
ALT 65 (0-55)
GGT 30 (0-60)
ALP 90 (40-110)
Case 1
• Other Bloods to check?
• INR
1.0 (<1.2)
• Alb
40 (35-47)
• Hepatitis BsAg +ve
• What is the cause?
• What would you do?
Case 1
• Who needs to be referred?
• Chronic Hepatitis B with
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Persistently raised ALT (e Ag +ve or –ve)
Fluctuating LFT’s (e Ag +ve or –ve)
E Ag –ve with high DNA levels
Rising AFP
Suspicion of Cirrhosis
Pregnant with HBsAg – Tenofovir
Immune tolerant patients >30yrs (e Ag +ve with
normal ALT
Case 2
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23 year old European female
Unwell 2 days
Abdominal pain, Jaundiced and drowsy
Depression otherwise well
OE: Jaundiced, No signs of CLD
LFTs
Bil 250
ALP 160
GGT 200
ALT 2380
AST 1960
Case 2
• Other Bloods:
– INR 2.3, Cr 85, pH 7.40, Paracetamol 120
• Liver Screen
– Negative (HAV and HBcoreIgM – Negative)
• Imaging
– USS: Normal
• Pattern of LFT Disturbance
– Hyperbilirubinaemia, Hepatitic Picture ALT>1000
• Diagnosis
– Paracetamol Overdose
Case 2
Case 2
• Liver Transplant Criteria (Kings College)
• Paracetamol
– Arterial pH < 7.3; or
– All three: INR>6.5, Cr>300, G3-4 Encephalopathy
• Non Paracetamol
– INR >6.5; or
– Three of the following five criteria
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Patient age <11 or >40;
Bilirubin >300;
Time from onset of jaundice to enceph. greater than 7 days;
INR >3.5; or,
Drug toxicity
Case 3
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Heavy alcohol consumption – Many years
Stopped 4 weeks ago
Gradual jaundice, confusion and lethargy
OE: Jaundiced, Spider Naevi, Small liver
LFTs
Bil 406
GGT 198
ALP 137
AST 126
ALT 52
Case 3
• Other Bloods:
– INR 1.8, Albumin 30
• Liver Screen
– Negative
• Imaging
– USS: Coarse Liver Echotexture
• Pattern of LFT Disturbance
– Mixed, significant hyperbilirubinaemia, AST>ALT
• Diagnosis
– Alcoholic Hepatitis
Case 3
Case 3
• Treatment
– Abstinence from Alcohol
– Monitor for withdrawal
– Vitamin K
– In Hospital 3 weeks
• Good improvement
– Prednisone 30mg Daily for 4 weeks
– Cirrhosis follow up