Lecture 22 Flashcards
What are the 2x sources of inflow into the liver?
Hepatic artery (bringing fresh blood from the heart) Portal Vein (bringing blood from the intestines)
What are the 2x sources of outflow out of the liver?
Bile Duct (drains into intestines) Hepatic Vein (returning blood to the heart (IVC))
What is the function of Hepatocytes/mass of liver cells within the Liver lobule structure?
Good filtration structure
-removes unwanted things
- provides needed things
all before gets to systemic circulation
What are the 3x functional tests of the liver?
- Albumin- liver produces
- Prothrombin ratio/INR (international normalised ratio)- liver produces coagulation factors
- Glucose- liver produces between meals
Change in Bilirubin
- Portal triad injury
2. Manner of Liver lobule processes bilirubin
Enzyme patterns of an Inflammatory Pathology of the liver
AST and ALT enzymes increased release into blood stream
- Hepatocellular (injures liver diffusely
- Viral hepatitis
- Liver toxins/drugs (toxic dose of paracetamol or magic mushrooms)
Enzyme patterns of an Extraheaptic Pathology of the liver
GGT and ALP enzymes increased release into blood stream
Potential for Bilirubin increased release in blood stream (if problem involves processing of bilirubin)
- Obstructive process, causing dilation of biliary system
- Gallstones (effects flow of bile through bile canaliculi and portal tract)
- Some drugs (effect biliary system)
Liver Enzyme patterns
Pathology of liver almost always has a degree of overlap
-different pattens of enzyme patterns (seen in lab)
Bilirubin metabolism
- Bilirubin= chicken wire molecule, product of heme(carries iron)
- Released Bilirubin = Insoluble
- Bilirubin + Albumin (unconjugated/unprocessed >-85% (of total bilirubin blood stream of av. healthy patient)) INdirect
- Albumin is required as a large molecule which shields Bilirubin from water. - Bilirubin then taken up by liver and processed to be made soluble
- Bilirubin-Glucuronide (conjugated Intestine reabsorption) - Urobilinogen small enough to get back into blood stream
- Urobilinogen can get into urine
What happens if there is a blockage during the process of bilirubin?
Bilirubin blockage
1. -increase in small bilirubin-glucuronide conjugated
Bilirubin metabolism - Heamolysis
Heamolysis = increase rate of RBC breakdown
- Increased Heme release
- Increased unconjugated Bilirubin
- Increased load on liver, (has to work harder, and the normal liver has a good processing capacity to deal with this)
- Increased Bilirubin-glucuronide
- if has easy flow into gut, liver will be able to process - Increased Urobilinogen
- will be reabsorbed, as increase urobilingoen in plasma
- Increased Urobilinogen in urine
- urinary urobilinogen can be an indirect measure of rate of RBC turnover (can indicate haemolysis if rate is increased) - If no bile blockage, amount of bilirubin in blood would be low
- If bile blockage, No bilirubin getting into gut, Decreased Urobilinogen - therefore hardly any in urine
- Bilirubin-glucuronide increased (sugar conjugated fraction) - can be directly measured in blood stream
Hameolysis differentiating factors if with blockage
If bile blockage, No bilirubin getting into gut, Decreased Urobilinogen - therefore hardly any in urine
-Bilirubin-glucuronide increased (sugar conjugated fraction) - can be directly measured in blood stream
(If no bile blockage, Increased Urobilinogen in urine
-urinary urobilinogen can be an indirect measure of rate of RBC turnover (can indicate haemolysis if rate is increased). And amount of bilirubin in blood would be low)
Indirect measure of Haemolysis
No-blockage
Increased Urobilinogen in urine
-urinary urobilinogen can be an indirect measure of rate of RBC turnover (can indicate haemolysis if rate is increased)
Direct measure of Haemolysis
If bile blockage, No bilirubin getting into gut, Decreased Urobilinogen - therefore hardly any in urine
-Bilirubin-glucuronide increased (sugar conjugated fraction) - can be directly measured in blood stream
Causes of Jaundice
Haemolysis (increased load of bilirubin precursor(heme))
Gilbert’s Syndrome (Slower conjugation problem with UDP enzyme. Genetic variability. Slightly higher bilirubin- especially when system is stressed)
Intrahepatic:
1. Cholestasis - drugs, pregnancy, thyroid disease. Hard to get bilirubin into bile canaliculi
2. Obstruction inside liver- (obstruction to portal tract flow inside liver)
-hepatitis, cirrhosis (diffuse or local), biliary cirrhosis, large/many liver masses(metastatic)
Extrahepatic:
1. gallstones (common bile duct)
2. biliary/pancreatic cancer
3. pancreatitis (diffuse inflammation- obstruction)
Gilbert’s Syndrome
Genetic variability
Conjugation problem (sugar glucuronide attachment)
-slower
-problem with UDP enzyme
Result: Slightly higher Bilirubin especially when system is stressed
Intrahepatic causes of Jaundice
Intrahepatic:
- Cholestasis - drugs, pregnancy, thyroid disease. Hard to get bilirubin into bile canaliculi
- primary process effect AST ALT - Obstruction inside liver- (obstruction to portal tract flow inside liver)
- hepatitis, cirrhosis, biliary cirrhosis, large/many liver masses
- -secondary process effect/increase AST ALT, due to pressure on portal ducts/passage of substances through portal system
Hepatitis and Jaundice
Liver inflammation
Inflammation = enlagerment
-but liver has tight capsule around it, increased pressure, less room for things that usually pass unhindered (bile through canaliculi)- pressure on portal ducts in liver
-secondary process effect AST ALT/passage of substances through portal system
Extrahepatic causes of Jaundice
Extrahepatic:
- gallstones (common bile duct)
- biliary/pancreatic cancer
- pancreatitis (diffuse inflammation- obstruction)
ALP
Alkaline Phosphatase
-Transfers/hydrolyses phosphate groups (amongst small molecules/proteins)
-Wide age-related variation (bone turnover) (2x main sources of ALP are liver and bone, liver amount is steady, but bone conc. changes with age (puberty, (peri) menopausal bones are actively remodelling rapidly) ALP involved with osteoblasts will be released into blood stream in greater amounts)
-average blood ALP level does increase in these 2x types in life/ages
Main sources:
1. Liver: mainly biliary system (obstruction, inflammation)
2. Bone: osteoblasts (growing, remodelling)
3. Intestine: Inflammation (e.g. Chron’s disease)
4. Placenta: late pregnancy (ALP enzyme made by placenta)
5. Tumours: bone, lung (some cancers can reduce ALP)
Wide age related variation of ALP
Wide age-related variation (bone turnover)
2x main sources of ALP are liver and bone, liver amount is steady, but bone conc. changes with age (puberty, (peri) menopausal bones are actively remodelling rapidly)
-ALP involved with osteoblasts will be released into blood stream in greater amounts
-average blood ALP level does increase in these 2x types in life/ages
Placenta Enzyme
ALP increase during late pregnancy
ALP enzyme made by placenta
Serum Alkaline Phosphatase in different Liver diseases
ALP enzyme doesn’t have individual situation where levels are absolutely unique pathonamonic profile of lab result
ALP upper limit =~100 U/L
-all assoc. with an elevation, but others are relatively more elevated
1. Gallstones
2. Ca head pancreas
3. Malignant Obstruction
4. Primary Biliary Cirrhosis
5. Matastases (diffuse metasteses largest average higher levels)
-Hepatitis does cuase ALP increase, increased liver pressure, therefore increases the tendency for bile obstruction (within canaliculi) ALP can increase(bile) aswell to a smaller degree
-ALP is associated with biliary tree/system. any blockage or structural problem will cause it to raise
GGT
Gamma-Glutamyl
-Most biliary origin
-transfers 2x Carbon units around
-Largest single tissue source Liver
-also various others: heart, pancreas, lung (therefore cant automatically assume is liver pathology)
Causes of elevation:
-inflammation/obstruction of biliary system
Inducible
(even if dont have structural problem, therefore will be an increase in GGT as involved in processing of that substance)
–alcohol
–drugs: phenytoin(anti-epileptic)/Dilantin, rifampicin(anti-TB drug)
GGT and alcohol intake
=~2/3 of heavy drinkers have high GGT (1-3x)
-sort of patient specific due re sensitivity to alcohol intake
-(1/3 wont have high GGT - sensitivity not that great)
(inducible)
Weekend drinking (5x drinks+ x 2-3 nights) (rise and fall time sensitive/recent consumption)
-mean rise= 25% (1/2 had -> 50% rise)
-peaks 2-3 days; falls over 56 days
-ALT rises only about 10-15%
Takes 6 weeks+ to return to normal with abstinence (1/2 fall in 2 week)
-prolonged exposure to alcohol/toxin will scar liver- cirrhosis- chronic obstruction of flow- GGT chronically deranged
GGT doesnt correlate well with liver biopsy (microscopy not good diagnosis-other things that give you noise in the background)
-mild increase GGT is common, due to alcohol and fatty liver(common due to diabetes and obesity common problems)
Fatty liver rise of GGT
common due to diabetes and obesity common problems
GGT sensitivity
- GGT sensitivity not that good
- there are other causes of GTT elevation, therefore if dont have patient which you really suspect the GGT rise is due to their alcohol, -the likelihood of alcohol being the cause is less than 1/3
ALT
Alanine Aminotransferase
-involved in a/acid processing and glucogenesis
-“normal” plasma concentration Glutamate + Pyruvate (A/amino) (glucogenesis)
-blood stream is just marker of amount of release
Main tissue sources:
-Liver-hepatocytes (cytosol: hepatitis) - specific test to liver (normally require pretty serious damage to one of the other organs do elevate the ALT levels up)
-ALT is restricted to liver Cytoplasm
Most liver specific
Other tissues (minor)- muscle, heart, RBC
Pyruvate
Key 3x carbon molecule converted into Gluconeagenesis: oxaloacitate Before Kreb cycle: Acetyl Co-A -central molecule -ALT is important for the processing pathway
ALT and AST restrictions
ALT- Liver cytoplasm restriction
AST- Liver cytoplasm and mitochondria
-if serious liver damage which breaks through all cell membranes, will get release of both cytosolic and mitochondria component and AST will be elevated more than ALT
AST
Aspartate Transaminase AST
Asp + a-ketoglutarate Glutamate + Oxaloacetate (also involved in kreb cycle) (gluconeogenesis)
Main tissue sources:
Liver- hepatocytes (cytosol, mitochondria); hepatitis
Other tissues (minor)- muscles, heart, RBC
Less liver specific than ALT
Shorter T1/2 than ALT (8hr vs 48 hr in circulation) (S=short, L=long)
Serum ALT and AST levels in Liver diseases
ALT elevation: 1. Early hepatitis 2. Later hepatitis- longer half life -these 2x give elvation in the 1000s, reflecting diffuse damage across liver lobules resulting in enzyme release -lots of others still related with elevation AST elevation: 1. Early hepatitis - shorter half life 2. Chronic Acute Hepatitis
Albumin
Liver is only real source of albumin production
Embryonic life Yolk sac produced Albumin (not in adults)
Normal concentration 35-47 g/L
Liver is only source in adults
Falls with:
-decreased synthesis (cirrhosis)
-increased loss (kidney) - necrotic levels of proteinuria- liver has to try keep up with loss of protein. Loss through gut w. enteropathies
-illness (non-specific) (not to a great degree 2-3gram. some cytokines tell liver cells to switch off albumin production- esp. in sick hospitalised patients
-redistribution (odematis, albumin normally restricted to intravascular blood stream as is big molecule, but could also get out into interstitial fluid IF is increased permeability assoc. w. edema)
Globulins
Reflect inflammation (subacute, chronic)
Very high levels with chronic hepatitis, cirrhosis
(Immunoglobulin A, G, M - immune cells against chronic stimulus)
Prothrombin Ratio (PR) (INR)
International Normalized Ratio
-commonly done on patients with blood thinners e.g. Wolferin (monitor dose closesly)
Reflects clotting factor synthesis 2,7,9,10
-if canNOT make the clotting factors= increase ratio
Rise indicates vit K deficiency or liver failure
-Vit K is an important precurosor in clotting factor synthesis
-Vit K also in leafy greens- so need to consume greens otherwise INR will increase
Glucose
Liver maintains fasting blood glucose (between meals)
Inability to maintain glucose is ominous(as you have gone through all liver reserve to get through this)
Signs of Scarring and Declining Function
- Persistent GGT, ALP elevation (biliary)
- increased AST/ALT ratio (>1)
- increased globulins (immunoglobulins)- due to chronic inflammation
- decreased albumins
- increased bilirubin
- increased prothrombin ratio (low vit K)
- decreased glucose, increased NH3 (ammonia - have constant production, liver converts it to urea(anocuous), ammonia is highly toxic, esp. to brain)- if patient has acute liver failure/inability to remove ammonia encephalopathy/loss of mental status is serious marker reflecting ammonia increase
23 year old man. Strong family history of bowel cancer Symtoms: -rectal bleeding -right upper abdominal discomfort -previously well Examination: Normal ALP and GGT sig raised Marginal increase in Albumin CEA hugely risen
History: Bowel cancer? Liver Secondaries?
Marginal increase in Albumin - may just reflect that he isnt very well. Mild fall. Sickness?
Increase GGt and ALP/Normal Bilirubin: bile duct block
-stones?
-space occupying lesions (e.g. cancer)
Normal bilirubin- remainder of tree distal to obstruction still patent, enough bile goes through and still able to process bilrubin and keep within normal range
Normal AST-minimal liver cell inflammation
CEA= Carcino Embryonic Antigen (primary cancer marker - Metastatic bowel cancer??
Final diagnosis: Metastatic Cancer
What is a key point about assumptions
never jump to conclusion
- always ask about clinical background
- and family history
CEA
Carcinoembryonic Antigen
Cancer: Colon, breast, lung, pancreas, thyroid
Benign: hepatitis, cirrhosis, ulcerative colitis, renal failure, smoking
3-5ng/ml: 99% non-smokers, 95% smokers
5-10ng/ml: smokers and most with benign disease
10-20ng/ml: 20ng/ml: almost always malignant
-can get some mild elevation with benign causes. (not 100% cancer specific)
-above 20(4x normal) increasing concern
CEA monitoring of Bowel cancer
Surgery causes fall
- Possible cure (initially falls little then rises)
- Recurrence (fall then residual cancer rises progressively)
- Failed Primary therapy
20 year old male medical student Intermittent Jaundice -yellow sclerae -worse when tired sick or after alcohol No change in colour of urine/faeces Otherwise well Examination normal
Same urine/feces colour- urinobilinogen escape
Bilirubin mildly raised- mild bilirubin is the only abnormality - probably unconjugated (urine not dark)
Normal enzymes - no bile duct obstruction. - no liver cell injury
Typical of Gilbert’s syndrome (carrier of polymorphism in enzyme involved in bilirubin conjugation/processing w sugar sticking)
Diagnosis: Clinical/laboratory pattern (overall picture and excluding other cuases of elevation)
Treatment: None needed
Final diagnosis: Gilbert’s Syndrome
Intermittent Jaundice common
illness in the whites of his eyes
-had a hard weekend
bilirubin (40-50 yellow eyes) 2x normal (normal 20)
Change in colour of urine/faeces
suggests no bilirubin getting out as urobilinogen into bowel
Features of Gilbert’s Syndrome
Common (3-5% population) (usually only mild) Genetic- usually unhelpful Variant in bilrubin conjugation Other liver function tests normal Bilirubin conjugated (indirect); 2x) Well patient, persistent mild jaundice (
Exclusion in order to diagnose Gilbert’s syndrome
-seen with blood tests
Haemolysis (CBC, haptoglobins, reticulocytes)
Hypo-/hyperthyroidism
Iron overload (patient with mild hepatitis, bilirubin can just hang around and be midly raised for a while)
Recent Hepatitis
Drugs
35 year old woman History of excessive alcohol intake Symptoms: nausea, vomiting, weakness Intake high over last few weeks Highly Raised AST and ALT GGT and ALP also raised but rel less. Albumin severely dropped. Bilirubin raised. INR higher
History: possible alcoholic liver disease
Highly Raised AST and ALT (inflammation- alcohol)- recent liver damage
GGT and ALP also (mildly) raised but rel less - due to general swelling and slight structural damage (due to long term drinking). GGT is also inducable- recent alcohol drinking (secondary)
Albumin severely dropped- liver function 10g less, (unless losing through kidneys)
Bilirubin raised- liver function process, or damage to bile flow through liver architecture
INR= higher ratio - longer to clot- liver not producing clotting factors
-Exclude viral hepatitis (alcoholic patients more predisposed to get heaptitis)
Liver both: acutely inflamed, degree of background/longterm scarring, function impaired
Final diagnosis:
-Hepatitis (?alcoholic)
-Long standing liver disease
Common Causes of Viral Hepatitis
Virus - Freq. - Test Infectious mono 50% VCA-IgM (most common) Hepatitis A 25% HAV-IgM Hepatitis B 15% Hep B Ag + HepBcIgM Hepatitis C 5% Hep C Ab Cytomegalovirus 2% CMV-IgM Other 3%
52 year old man Long history of excess alcohol Symptoms: vomited blood Gastroscopy: oesophageal varices Largest rise in GGT and ALP mild rise in AST and ALT inflammatory enzymes INR mildly increase Raised bilirubin Decreased Albumin
History: ? alcoholic cirrhosis (liver scarring). ?2 secondary portal hypertension
Main LFT changes: Increased bilirubin, ALP, GGT - scarring
Increase ALT and AST- ongoing inflammation
Decreased Albumin, Increased PR impaired function
Scan: shrunken, scarred liver, No bie duct dilation
GGT and ALP - carrying/ had alot of chronic damage to liver, or gall stones, or (alcohol–>fibrosis) cirrhosis predisposing to liver cancer (hepatocellular 1 carcinoma)
Final Diagnosis: Alcoholic liver disease. Cirrhosis and Portal hypertension
Scarred liver indicators
vomiting blood
portal hypertension
=serious chronic problem
-raised bilirubin, ALP and GGt
43 year old man presents acutely Large overdose of paracetamol (30gm) O/E: alert, tender enlarged liver 3 days later- unconscious 5 days later- demise SEVERE AST and ALT mild GGT and ALP
Serious acute posioning by a toxin or viral hepatitis
-only thing that could result in elevation of liver enzymes >10,000 (severe liver cell injury)
Mild GGT and ALP elevation- liver is really inflammed, therefore dont get passage of things (bile) through liver architecture (Canaliculi) like normally
Liver failure:
-Synthesis: Decreased Glucose - hypoglycemia. Decreased clotting factors - increase PR. (albumin normal- recent onset)
Metabolism- Increased bilirubin
Unconscious= ? ammonia
Bilirubin- same concept or pressure + liver isnt functioning well (liver isnt functioning to conjugated sugar sticking liver enzyme)
Glucose decreased- cant maintain blood sugar- ominous feature
INR- severely raised- cant clot AT ALL
NH3= severely raised- can travel through blood-brain barrier readily and toxic effecting health status
Final: Paracetamol poisoning, liver failure
Liver failure but normal albumin
Due to recent onset
Albumin has half life of 3 weeks
-therefore if sudden acute insult (paracetamol insult/poisoning overdose) have time (3 weeks) for albumin to fall- if patient lives long enough
-therefore in first few days, even if albumin synthesis may have been stopped abruptly, albumin levels may not have changed much
Hypoxic and Ischaemic liver
Yellow
Hardly any blood
Causes of LFT abnormlities
Fatty Liver 45% Viral heaptitis 27% Alcohol 8% Haemochromatosis 3% Other 16% (drugs, autoimmune, porphyria, Wilsons's disease, granulomatous, malignancy, coeliac disease, heart failure, antitrypsin deficiency, rare metabolic)
