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Metabolic regulation. Carbohydrate metabolism Lipid metabolism Amino acid metabolism De-toxification and excretion Bilirubin metabolism Storage - vitamins [A, D, B 12 ], Cu, Fe. Haemotological regulation. Phagocytosis and antigen presentation Plasma protein synthesis

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liver function organ metabolism gland secretions

Metabolic regulation

Carbohydrate metabolism

Lipid metabolism

Amino acid metabolism

De-toxification and excretion

Bilirubin metabolism

Storage - vitamins [A, D, B12], Cu, Fe

Haemotological regulation

Phagocytosis and antigen presentation

Plasma protein synthesis

Removal of circulating hormones

Removal of antibodies

Removal /storage of toxins

Liver functionOrgan = metabolismGland = secretions

Bile production

slide2

Carbohydrate metabolism

Glycogenesis

Glycogenolysis

Gluconeogenesis

IMPAIRMENT

Hypoglycaemia

Glucose Intolerance

http://static.howstuffworks.com/gif/diabetes-glucose-regulation.gif

slide3

Lipid Metabolism

  • Lipoprotein synthesis
  • Oxidation of fats
  • Synthesis of cholesterol, phospholipids
  • Catabolism of steroids

IMPAIRMENT

Altered lipid profiles

2O Hyperaldosteronism →↑BP ↓K ↑pH

2O Hypercorticolism = Cushing’s disease

Gonadal dysfunction → ∆ oestrogen:testestorone

http://www.medscape.com/pi/editorial/clinupdates/2001/608/art-cu02.fig04.gif

slide4

Amino acid metabolism

  • Deamination and transamination of amino acids
  • Removal of ammonia
  • Synthesis of amino acids

Hepatic encephalopathy

Hypoproteinaemia

IMPAIRMENT

Source: seqcore.brcf.med.umich.edu/ mcb500/aametov.gif

slide5

Synthesis of hormones and plasma proteins…….

  • Insulin-like growth factor (IGF-1) → stimulated by pituitary growth hormone
  • Thrombopoietin → platelet production
  • Angiotensinogen (α-2-globulin) → hydrolysed by renin to angiotensin [renin-angiotensin-aldosterone system (RAAS)]
  • Heparin
  • Albumin
  • Extrinsic pathway clotting factors →I (fibrinogen), II (Prothrombin), IV, V, VI, and VII

Clotting disorders, ↓ osmotic pressure

IMPAIRMENT

http://www.biosbcc.net/doohan/sample/images/blood%2520cells/clottingcascade

slide6

Bile production ….

Water

Bile Acids e.g. taurocholic

and glycocholic acid

Electrolytes

Cholesterol

Phospholipids

Bilirubin

IMPAIRMENT

  • Malabsorption of fats and fat soluble vitamins
  • Jaundice

http://sbsweb.bangor.ac.uk/images/bsx1016/sm_liver_position

slide7

Detoxification – refer to Biochemistry and PK done in years 2/3.

Phase I = modify

Phase II = conjugate

Reduced drug metabolism, reduced protein binding of drugs

IMPAIRMENT

http://www.aspartame-detox.info/images/brain-01.jpg

slide8

Filtration – Reticuloendothelial system

Blood filtration, phagocytosis of bacteria and other particulate matter

IMPAIRMENT

Source :www.bu.edu/histology/ i/15204loa.jpg

Exposure to bacteria and other particles

symptoms of liver disease
Symptoms of liver disease
  • Most symptoms non specific - anorexia, malaise, fatigue, fever
  • ↓ general health
  • cirrhotic habitus = wasted extremities plus protuberant abdomen with ascites
  • Generalised pruritus (itchiness) – due to retention of bile salts
  • Xanthelasma (fat build up under skin surface), xanthomas
  • Pale stools – lack of bile
  • Which of these is most specific?

akimichi.homeunix.netXanthoma disappearance Document272 x 324 pixels - 55k - gif

disorders of coagulation circulation
Disorders of coagulation/circulation
  • ↑ bleeding and bruising
  • ↑ prothrombin time (PT) → extrinsic clotting pathway (Prothrombin ratio (PR) and international normalized ratio (INR) are derived measures of PT).
  • Thrombocytopaenia (↓platelets)
  • Dysfibrinogenaemia (altered fibrinogen function)
  • Portal hypertension → endothelial stretching and shear stress → ↑ NO → systemic vasodilation = hyperdynamic circulation
  • Hepatopulmonary syndrome = pulmonary vasodilation → ↑blood flow (ventilation-perfusion mismatch) → arterial desaturation
  • Cyanosis and clubbing → enlargement of distal fingers and toes. Due to vasodilation?

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/18127.jpg

liver disease
Liver disease?

http://upload.wikimedia.org/wikipedia/en/thumb/e/e0/Gollum.PNG/220px-Gollum.PNG

other changes
Other changes
  • ↑ parotid salivary gland → fatty infiltation
  • Gynecomastia (mammary gland development in males), testicular atrophy, impotence
  • Amenorrhoea (absence of menstrual period)
  • Erythema (redness of skin) – build up of unmetabolised wastes in body

http://www.sciencephoto.com/images/download_lo_res.html?id=771500153

jaundice
Jaundice
  • Icterus (icteric)
  • Accumulation of bilirubin = hyperbilirubinaemia
  • Skin, conjuctiva, mucous membranes
  • Dark urine from renal excretion of bilirubin

http://www.modulomedico.com/fotos/imgJaundiceBig.jpg

serum chemistry diagnostic testing
Serum chemistry/diagnostic testing
  • Breakdown product of haemoglobin
  • Globin = protein
  • Heme = iron containing → biliverdin (green bruising) → bilirubin → yellow (bruising/bile)
  • Bilirubin → conjugated with glucuronides in liver
  • Excreted in bile
  • Can be measured in the unconjugated (indirect) or conjugated (direct) form
  • Relatively insensitive indicator of liver disease

Bilirubin

Source:web.indstate.edu/thcme/ mwking/hemedegradation.jpg

slide15

From Swaminathan – Handbook of Clinical Biochemistry 2004

From Beckett - Lecture Notes : Clinical Biochemistry 7th ed 2005

aminotransferases alt and ast
Aminotransferases (ALT and AST)
  • Transaminase enzymes (aminotransferases) → reversible
  • transfer of an amino group between two a-keto acids.
  • Alanine aminotransferase = liver cytosol (ALT)
  • Aspartate aminotransferase = liver and other tissues (AST)
  • Reasonably sensitive indicators of liver disease, ALT >> AST

Source: http://www.np.edu.sg/~dept-bio/biochemistry/aab/topics/asptrans.gif

alterations in alt and ast
Alterations in ALT and AST

Mild elevations(<100U/L)

  • Fatty liver/non-alcoholic steatohepatitis (fatty degeneration)
  • Chronic viral hepatitis

Moderate elevations(100-300 U/L)

  • Acute or chronic hepatitis
  • Alcoholic hepatitis
  • Mild/moderate inflammation

High elevated(>300 U/L)

  • Acute viral hepatitis
  • Hepatic necrosis → drugs or toxins
  • Ischemic hepatitis /circulatory shock. VALUES CAN BE 500-1500 U/L
  • Values >3000 U/L- toxic necrosis, or severe hypoxia

AST/ALT ratio

  • Significant overlap between different conditions BUT
  • > 2 suggestive alcoholic liver disease (if ALT < 500 U/L)
  • < 1 viral hepatitis can ↑ratio as fibrosis and cirrhosis develop
alkaline phosphatases alp
Alkaline phosphatases (ALP)
  • ALP = hydrolase →removes phosphate groups
  • Present in bile canaliculi, bone and placenta
  • ↑ sensitivity for hepatobiliary disease
  • ↓ specificity for hepatobiliary disease
  • Due to its numerous isoenzymes, its presence in non-hepatic tissues, and its sensitivity to drug induction
increases in liver alp
Increases in liver ALP
  • Cholestasis, cholecystitis, cholangitis, cirrhosis, hepatitis, fatty liver, liver tumour, liver metastases, drug intoxication
  • Drugs e.g. verapamil, carbamazepine, phenytoin, erythromycin, allopurinol, ranitidine
  • ↑ → enhanced synthesis rather than hepatocytic leakage
  • ↓ ≠ clinically significant
  • If source ↑ ALP is not clear check other liver enzymes
gamma glutamyl transpeptidase ggt
Gamma glutamyl transpeptidase (GGT)
  • GGT → hydrolysis of gamma-glutamyl peptide bonds
  • Biliary enzyme → obstruction of biliary tract + damage to biliary capillaries
  • Easily induced (alcohol, drugs) → disproportionately ↑ in alcoholic liver disease
  • Can be elevated in other diseases e.g. CHD, MI, COPD, pancreatitis, renal disease
patterns of enzyme alterations
Patterns of enzyme alterations

Ramachandran and Kakar J Clin Pathol 2009;62;481-492 Histological patterns in drug-induced liver disease

slide22

ERCP = Endoscopic Retrograde Cholangiopancreatography From Beckett - Lecture Notes : Clinical Biochemistry 7th ed 2005

other tests
Other tests
  • Haematology (anaemia, RBC parameters)
  • Clotting tests (PT) NOTE – these are vitamin K-dependent clotting factors
  • Lipid tests (total cholesterol, HDL, LDL, triglycerides)
  • Biochemistry (albumin, glucose)
  • Serology

-Hepatitis virus

-Antimitochondrial antibody (present in >90% of biliary cirrhosis cases)

-Antinuclear factor- inflammatory marker

-Antismooth muscle antibody-inflammatory marker

-Alpha fetoprotein-hepatic carcinoma marker

  • Functional tests

-Clearance tests (caffeine, bromosulphthalein), Elimination tests (galactose)

  • Imaging procedures

-Abdominal radiographs

-US, NMR, CT

-Direct biliary visualisation → contrast studies

  • Liver Biopsy

-Percutaneous

-Surgical

drug induced liver disease dild
Drug Induced Liver Disease (DILD)
  • > 1000 drugs → DILD
  • ↑Hz drug withdrawal from the market

R

x

Reference Hughes et al. Use of laboratory test data: a process guide and reference for health care professionals. 2nd Ed, PSA, 2009.

drug induced liver disease dild1
Drug Induced Liver Disease (DILD)
  • Consider wherever altered liver function tests
  • However
    • Broad range of drugs
    • Wide variation in hepatic injury caused
drug induced liver disease dild2
Drug Induced Liver Disease (DILD)
  • Types of hepatic injury
    • Hepatitis
    • Cholestasis
    • Mixed
    • Fibrosis
    • Granulomatous lesions
    • Neoplasms

http://www.health-writings.com/img/mk/drug-induced-liver-disease/drugs_MIC062ML.jpg

drug induced hepatic failure
Drug induced hepatic failure

http://www.path.cam.ac.uk/Normal/AR_Alimentary/LV_Liver/N_AR_LV_02.jpg

http://mayoresearch.mayo.edu/mayo/research/nyberg_lab/images/histology.jpg

drug induced liver disease dild3
Drug Induced Liver Disease (DILD)
  • Other changes (functional)
  • Enzyme induction and inhibition
  • Dietary /other deficiencies e.g. cysteine, Vit K
  • Steatosis = fatty change
  • Phospholipidosis
drug induced liver disease dild4
Drug Induced Liver Disease (DILD)
  • Intrinsic
    • Dose related
    • Occurs within few days of use
    • Related to drug or toxic metabolite of drug
    • Known/reported/expected
  • Idiosyncratic
    • Unexpected
    • Variable latency
    • Not usually dose related
factors affecting dild
Factors affecting DILD
  • Age
  • Gender
  • Genetic factors
  • Nutritional status
  • Renal function
  • Dose and duration
  • Alcohol
  • Cigarette smoking
  • Other conditions- Hep C, HIV, RA
paracetamol toxicity
Paracetamol toxicity
  • Paracetamol = #1 drug → calls to poisons information centres in Australia and NZ. 1
  • Paracetamol = #1 drug overdose → hospital presentation and admission. 2,3
  • Hepatic failure and death → uncommon outcomes
  • #1 cause of acute fulminant hepatic failure in Western countries.4

Buckley N, Eddleston M. Paracetamol (acetaminophen) poisoning. Clin Evid 2005; (14): 1738-1744.

Dart RC, Erdman AR, Olson KR, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2006; 44: 1-18.

Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am 1984; 2: 103-119.

Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137: 947-954.

phases of paracetamol hepatotoxicity
Phases of paracetamol hepatotoxicity
  • PHASE 3 (72-96 H)
  • Centrilobular hepatic necrosis with continued abdominal pain
  • Jaundice
  • Coagulopathy
  • Hepatic encephalopathy
  • Nausea and vomiting
  • Renal failure
  • Fatality
  • PHASE 4 (4 D TO 3 WK)
  • Complete resolution of symptoms
  • Complete resolution of organ failure
  • PHASE 1 (0-24 H)
  • Asymptomatic
  • Anorexia
  • Nausea or vomiting
  • Malaise
  • Subclinical rise in serum transaminases levels begins at about 12 hours postingestion
  • PHASE 2 (18-72 H)
  • Right upper quadrant abdominal pain, anorexia, nausea, vomiting
  • Continued rise in serum transaminases levels
  • Admitted to hospital
paracetamol toxicity1
Paracetamol toxicity
  • Toxicity when GSH reserves overwhelmed by N-acetyl-p-benzoquinone imine (NAPQi)
  • ± gastric lavage and activated charcoal
  • Treatment → IV

N-acetylcysteine

http://drugdiscoveryopinion.com/images/paracetamol_metabolism.jpg

management plan dose thresholds for nac treatment
Management plan- dose thresholds for NAC treatment

≠ serum readings <4 hours of poisoning

Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas ABuckley(2008).Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. MJA 2008; 188 (5): 296-302.

management plan
Management Plan

Source- Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas ABuckley(2008).Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. MJA 2008; 188 (5): 296-302.

Source: Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas A Buckley(2008).Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. MJA 2008; 188 (5): 296-302.

management plan cont
Management Plan cont…

Source- Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas ABuckley(2008).Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. MJA 2008; 188 (5): 296-302.

Source: Frank F S Daly, John S Fountain, Lindsay Murray, Andis Graudins and Nicholas A Buckley(2008).Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. MJA 2008; 188 (5): 296-302.

management plan cont1
Management Plan cont…
  • Monitoring of liver function
  • Post –discharge patient education
  • Referral to Psychologist if needed
kava piper methysticum
Kava (Piper methysticum)
  • Kava = plant native to South Pacific Islands
  • Western society → herbal remedy anxiety
  • Kavalactones = active components

-6 KL ~ 95% of the activity

  • Anxiolytic effect ~ benzodiazepines

-few side effects

-limited cognitive and motor impairment

  • Kava → hepatotoxicity e.g. hepatitis, cirrhosis, fulminant liver failure, death
  • Banned in many countries
  • Australia → voluntary recall 2002
isolated perfused rat liver iprl
Isolated Perfused Rat Liver (IPRL)

PUMP

  • Perfusate
  • Kavalactone
  • 95% O2/5% CO2
  • Taurocholic acid
  • Krebs-Henseleit (KH) buffer

Inferior Vena Cava

Hepatic Portal Vein

37°C

10 g ml kavain for 2 hours is hepatotoxic in iprl studies
10 µg/mL Kavain for 2 hours is hepatotoxic in IPRL studies

Light Microscopy

Scanning Electron Microscopy

Control Liver

Following Kavain Treatment

Fu (2008) World J Gastroenterology 14: 541-546

slide45

Membranes and electron

dense structures

Distorted cell nuclei

Autophagosome

Whirled ER surrounding

mitochondrion

advice for case studies
Advice for case studies
  • Common things occur commonly.
  • Uncommon things don’t.
  • When you have eliminated the impossible, whatever remains, however improbable, must be the truth.

Sherlock Holmes - The Sign of the Four (1890)

case study 1 history and signalment
Case Study #1 – history and signalment
  • 68 YO male retired labourer
  • Lethargy but no pain
  • BW ↓19kg in the last 3 months
  • Eating normally up to last 3 weeks
  • Dark urine and pale stools
  • ‘Moderate’ drinker throughout lifetime
clinical findings
Clinical findings
  • Jaundice
  • Weakness
  • Palpable, non-tender mass in upper RHS abdominal quadrant
serum chemistry
Serum chemistry
  • Bilirubin predominantly conjugated
  • ↑↑ ALP and GGT
  • Predominantly cholestasis
  • Pancreatic tumour obstructing common bile duct
case study 2 history and signalment
Case Study #2 – history and signalment
  • 21 YO female student
  • Flu-like symptoms for 2 days
  • Condition deteriorating – dark urine, vomiting
  • Recently returned from long holiday in Asia
clinical findings1
Clinical findings
  • Jaundice
  • Temperature 38.6oC (36.5-37.5 oC)
  • Liver enlarged and tender
serum chemistry1
Serum chemistry
  • Bilirubin predominantly conjugated
  • ↑↑ ALT
  • Predominantly hepatocellular
  • Any other tests?
  • Serology - high Hepatitis A titre
case study 3 history and signalment
Case Study #3 – history and signalment
  • 48 YO male gardener
  • Fatigue
  • BW ↓8 kg over last 4 months
  • Denies any history of hepatitis, alcohol use, family history of liver disease, exposure to hepatotoxins
clinical findings2
Clinical findings
  • No abnormalities detected
serum chemistry2
Serum chemistry
  • Any other tests?
  • PT = 18 s (10-13 s)
  • IM dose 10 mg Vitamin K returned PT to 12 s < 48 hours
  • Serology and endoscopy → Coeliac disease → interfering with Vit K and protein absorption
case study 4 history and signalment
Case Study #4 – history and signalment
  • 13 YO male
  • Muscle pain and feeling hot for 2 days
  • Eaten little over this time
clinical findings3
Clinical findings
  • Jaundice
  • Temperature 38.3oC
  • No abdominal pain or swelling
serum chemistry3
Serum chemistry
  • Bilirubin 90% unconjugated
  • Any other tests?
  • Haematology – RBC and reticulocyte count normal
  • Gilbert’s syndrome = most common hereditary hyperbilirubinaemia
  • Familial autosomal dominant in 2-3% men
  • ↓ activity of the glucuronyltransferase → ↓ bilirubin conjugation
  • Exposed by caloric restriction while ill with cold
  • ↑ ALP but GGT normal ??
  • Raised ALP from bone turnover with onset of puberty
case study 5 history and signalment
Case Study #5 – history and signalment
  • 36 YO female lawyer
  • Very stressful job
  • Working 12 hour days striving for promotion
  • Feeling run down
  • Annual blood test
clinical findings4
Clinical findings
  • No abnormalities detected
serum chemistry4
Serum chemistry
  • Any other tests?
  • Haematology – leukopaenia (↓WBC), macrocytosis (↑MCV)
  • Toxic effects on bone marrow?
  • Finally admits drinking one bottle wine per day over lunch and after work
  • Quit job. Quit drinking
  • 3 months later – ALT 28 IU/L, GGT 50 IU/L, ALP 54 IU/L
case study 6 history and signalment
Case Study #6 – history and signalment
  • 26 YO male
  • Admitted to hospital with 5-day history of excruciating abdominal pain radiating up back
  • Patient reports persistent nausea and vomiting
clinical findings5
Clinical findings
  • Vital stable signs on admission
  • No fever
  • Extreme reaction to abdominal palpation
serum chemistry5
Serum chemistry
  • Any other tests?
  • Blood test normal
  • Serum amylase normal
  • US and CT normal
  • Requested ongoing opiates for pain control
  • Opiates withdrawn → patient checked out → continue search for opiates elsewhere
summary
Summary
  • Variable interspecies anatomy
  • Histological structure open to interpretation
  • Metabolic functions (glucose, protein, fat)
  • Glandular function (produces bile)
  • Jaundice = hyperbilirubinaemia
  • Bilirubin is a product of heme catabolism
  • Pre-hepatic (unconjugated)
  • Hepatic (unconjugated + conjugated – glucuronic acid)
  • Cholestatic/obstructive → intra/post-hepatic (conjugated)
  • Diagnosis – symptoms, laboratory, imaging, biopsy