rowbottom - liver function assessment [2]

8/12/2019 Rowbottom - Liver Function Assessment [2]

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Overview of liver structure andfunction

&Assessment of liver function

Lynn Rowbottom

Department of Clinical Biochemistry & Metabolic Medicine

Royal Liverpool & Broadgreen University Hospitals Trust


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22g/kg body weight

70kg man=1.5kg


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Blood supply to liver

Via hepatic vein

which drains into inferior vena cava

Blood from liver

2/3 from portal vein (i.e from gut =

nutrients/substances for metabolism)

1/3 from hepatic artery (supplies O2)


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Liver lobule


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Liver acinifunctional unit


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Major functions of the liver

Carbohydrate metabolism

Fat metabolism

Protein metabolism

Hormone metabolism

Drug/toxin metabolism & excretion

Storage

Metabolism and excretion of bilirubin

Synthesis of proteins


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Carbohydrate metabolism

Glycogenesis

Excess glucose glycogen

Glycogenolysis Glycogen glucose

Gluconeogenesis

Amino acids/lactate/glycerol glucose


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Fat metabolism

Triglyceride oxidation energy

Lipoprotein synthesis

Excess carbohydrate & fat fatty acids &trigs stored in adipose tissue

Cholesterol (& phospholipid) synthesis &

excretion


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Protein metabolism

Deamination and transaminationof amino

acids

Non-nitrogenous part glucose or lipid

Nitrogenous part ammonia urea


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Hormone metabolism

Insulin-like Growth Factor-1 (IGF-1)

Angiotensinogen

Thrombopoeitin Hepcidin


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Drug/toxin metabolism

Phase I reactions: Intro/unmask functional group Oxidation (Cytochrome P450)

Reduction

Hydrolysis

Phase II reactions: Glucuronide/Acetyl/Methyl

Glutathione

Glycine/Sulphate

Usually necessary to achieve renal excretion


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Storage

Glycogen

Vitamins A, D & B12

Iron & Copper


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Metabolism & Excretion of Bilirubin

Senescentred cells

(80%)

Haem

Biliverdin

Bilirubin

Bilirubin glucuronide

(H2O sol)

Haem proteins

(15%)

Ineffective

erthyropoiesis

(5%)

Renal

excretionBiliary

excretion


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Synthesis of proteins

Plasma protein synthesis

Albumin

Fibrinogen/Prothrombin (& other clotting

factors)

Lipoproteins/Caeruloplasmin/Transferrin/

CRP/1AT/FP/

Synthesis of non-essential amino acids


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Assessment of liver function

Clinical assessment

Imaging - level of expertise

Biopsyinvasive & level of expertise Time to prep and stain histology slide

Analysis & interpretation

Biochemical tests Blood (plasma/serum) & urine


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Clinical signs associated with liver

disease

Dupuytrens contracturePalmar erthyema Spider Naevi

Male gynaecomastiaAscites

Jaundice
http://en.wikipedia.org/wiki/File:Morbus_dupuytren_fcm.jpg


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Clinical signs associated with liver

disease

Oesophageal varices

PALE STOOLS&DARK URINE

Hepatic encephalopathy


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The Liver Function Test (LFT)

Albumin

Total Protein

Bilirubin Alkaline Phosphatase (ALP)

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST) Gamma glutamyl transferase (GGT)


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What does the LFT actual show?

Albumin

Crude indicator of synthetic capacity of liver

Liver synthesises 12g albumin per day

Half-life ~20 days

Maintains plasma oncotic pressure

Binds several hormones, drugs, anions and

fatty acids

Decreases in the acute phase response

(APR)


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Total Protein

Very little utility in liver function assessment

Reflects balance between synthesis &

degradation

Often allows calculation of globulin fraction

Globulin = Total Protein - Albumin


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Bilirubin Total Bilirubin

Direct/Conjugated Bilirubin

Differentiate between intra-hepatic and extra

obstruction

Intrahepatic

E.g Liver metastases, Hepatitis

Extrahepatic

E.g Gall stones,carcinoma of head of pancreas


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Alkaline Phosphatase

Maximum activity in pH 9-10.5

Removes phosphate from molecules incl

proteins & nucleic acids

Isoenzymes (Liver, Bone, Intestinal &

Placenta)

Age dependent reference range Liver: sinusoids & endothelium of central &

periportal veins


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Alanine aminotransferase

Catalyses transfer of amino group from

alanine residues

Present in wide range/All tissues

Cytosolic


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Aspartate aminotransferase

Catalyses transfer of amino group from

aspartate residues

Present in wide range/All tissues

Cytosolic and mitochondrial

High levels in heart, liver, skeletal muscle,

kidney, lung & red blood cells.Also found in significant amounts in brain,

gastric mucosa & adipose tissue


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Gamma glutamyl transferase

Catalyses transfer of gamma glutamyl group

from peptides to appropriate acceptors

Located in cell membrane of various tissues;mainly kidney, liver, biliary tract & pancreas

Found in hepatocytes & biliary epithelial cells

Kidney contains largest amount but is notreleased into plasma


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The LFT

Pattern rather than single analyte result

Abnormal LFT not just in primary hepatic

disorders

Heart failure

Sepsis

Infection/inflammation


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Bilirubin

Jaundice Visible at ~3XULN (50mol/L)

*Unconjugated bilirubin crosses blood-brain barrier

in neonates= brain damage kernicterus*
http://www.amazon.com/gp/reader/1441965548/ref=sib_dp_pt/189-8131619-3903360


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Conjugated

Bilirubin Water soluble Filtered at the glomerulus

Hence reaches the urine=

bilirubinuria

Pathological

Intra or extra hepatic

obstruction

Unconjugated

Bilirubin Not water soluble=protein bound Not filtered at the glomerulus

Hence does not reach the urine

Haemolytic states

Gilberts (inherited defect inUDP glucuronyl transferase)

Mixed: Hepatocellular diseases

Direct:Total

20-40%

>50%


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Urobilinogen

When bilirubin reaches the gut

Converted to urobilinogen by gut bacteria

Gets absorbed from the small intestine

Excreted in the urine

If urobilinogen present in urine, shows that

bilirubin is reaching the gut High plasma bilirubin & No urobilinogen in urine

= bilirubin is not reaching the gut (cholestasis)


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ALP

Secreted by cells lining biliary tract

Enhanced synthesis/inducible enzyme

Raised in bone disease (osteoblastactivity)

Raised during growth, pregnancy (different

reference ranges apply)

ALP electrophoresis to determine source


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GGT

Indicator of obstruction

(intrahepatic/biliary)

Enhanced synthesis/inducible enzyme

Alcohol & anticonvulsants

Useful in conjunction with ALP

e.g ALP - ?liver/bone/other

ALP & GGT suggests hepatic cause

GGT & N ALP alcohol intake


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ALT & AST

Indicators of hepatocellular damage ALT more specific for liver than AST

AST 80% mitochondrial, 20% cytosolic

High AST also seen in MI, muscle injury & CCF
http://micro.magnet.fsu.edu/cells/animals/animalmodel.html


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ALT:AST ratio

ALT:AST 2 Viral hepatitis

Infectious hepatitis

Drugs/toxins NASH

Intra/extrahepaticobstruction


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LFT at RLUH

Analyte Ref range

Albumin 35-50 g/LTotal Protein 60-80 g/L

Globulin 19-35 g/L

Total Bilirubin 2-17 mol/L

ALP 35-125 U/L

ALT


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Other tests Prothrombin

Clotting

Alphafetoprotein (AFP) Raised in liver disease (hep, cirrhosis, biliary tract obstruction, ALD)

Tumour marker (liver, germ cell tumours, pregnancy)

Alpha-1 antitrypsin (1AT)

Protease inhibitor. Deficiency can produce cirrhosis Raised in APR= may mask deficiency

Caeruloplasmin Copper transport protein (low in liver disease/Wilsons)

Bile acids Cholestasis in pregnancy

N-terminal pro-collagen 3 peptide (P3NP) Marker of fibrosis (esp dermatology patients Rx methotrexate)

Immunoglobulins IgG : immune hepatitis, IgA : ?alcohol, IgM : PBC

Ferritin


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Function tests

BSP clearance

Indocyanine green

14C aminopyrine breath test Ammonia


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Further investigations

Ultrasound/CT/MRI/PET imaging

Endoscopic retrograde

cholangiopancreatography (ERCP)

Percutaneous Transhepatic

Cholangiography (PTC)

Liver biopsy


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rowbottom - liver function assessment [2]

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