Liver Damage Flashcards
Reminder: what are the different zones of the liver? How do they differ in function?
Zone 1 (nearest portal vein) = synthesis and export
Zone 3 (adjacent central vein) = metabolism
Difference in function possibly due to microenvironments in different zones e.g. pO2
Reminder: how does the liver buffer blood glucose?
Increased blood glucose —> glycogenesis
Reduced blood glucose
- –> glycogenolysis (75%)
- –> gluconeogenesis (25%)
note: when liver function is poor, blood glucose conc. can rises 2-3 times normal after a meal
What proteins are produced by the liver? What are the functions of the proteins?
90% of plasma proteins
- albumin = oncotic pressure, transport of bilirubin, transport of drugs
- coagulation factors = vitamin K dependent factors, prothrombin, fibrinogen (therefore check clotting function before doing liver biopsy - risk of catastrophic bleeding)
- lipoproteins
- acute phase proteins
Reminder: outline the cycle of bile
Haemoglobin broken down into haem, biliverdin, and bilirubin (breakdown products bound to albumin)
Bilirubin conjugated to glucuronide or sulfate
Conjugated bilirubin converted to urobilinogen in gut —> converted to urobilin and stercobilin —> excreted
Reabsorbed bilirubin
- –> 5% excreted by kidneys
- –> 95% re-excreted in bile
85%+ total recycled via enterophepatic circulation
Give some examples of causes of haemolytic jaundice.
Pre-hepatic jaundice
- haemolysis
- reduced bilirubin-albumin binding
- reduced conjugation of bilirubin to glucuronide or sulfate
Increased conc. of unconjugated bilirubin in the blood
How does liver damage cause jaundice?
Hepatocyte injury —> reduced bilirubin conjugation —> increased conc. of unconjugated bilirubin in the blood
Give some examples of causes of obstructive jaundice.
Post-hepatic jaundice
- bilirubin or urobilinogen excreted instead of recycled (lack of reabsorption) e.g. obstruction of biliary tree (choleliathisis, pancreatic cancer) —> steatorrhoea
- conjugated bilirubin escapes into blood to be excreted —> “coca-cola” coloured urine
Give some examples of causes of liver damage.
Toxic injury:
- drug-induced
- industrial/environmental toxin
- alcohol
Immune:
- autoimmune
- primary biliary cirrhosis
Infection:
- viral hepatitis
- bacterial
- parasitic
Tumours:
- primary benign
- primary malignant
- metastatic malignant
Inherited:
- haemochromatosis
- alpha-1-antitrypsin deficiency
- Wilson’s disease
- hereditary fructose intolerance
- glycogen storage disease
- cystic fibrosis
- congenital hepatic fibrosis
Reminder: how does the liver change as liver damage progresses?
Acute liver disease/failure = acute loss of liver parenchyma
Acute on chronic liver disease/failure = acute liver cell damage in an abnormal liver
End-stage liver disease/failure = systemic consequences of altered liver architecture
Acute injury —> necrosis —> regeneration —> recovery
Chronic/repeated injury —> ongoing cell damage —> regeneration with scarring —> architectural changes/cirrhosis
Cirrhosis = nodular regeneration surrounding by scarring (deforms shape of nodules)
Alcoholic liver disease = steatosis —> hepatocyte injury/inflammation —> stellate cell activation —> cirrhosis
Give some examples of causes of cirrhosis.
Toxins:
- alcoholic liver disease
- non-alcoholic fatty liver disease e.g. diabetes, hypercholesterolaemia, obesity
Infection:
- chronic hepatitis C —> hepatocellular carcinoma (rapid regeneration —> cirrhosis)
Autoimmune
Hereditary
What is seen on histology in hepatitis C? How does this condition progress?
Histology:
- +++lymphocytes
- cirrhosis (regenerative nodules surrounded by fibrous bands)
85% progress to chronic infection after 10-30yrs
- –> 80% of those have stable disease
- –> 20% develop cirrhosis (some subsequently develop hepatocellular carcinoma)
15% resolve
Rarely it causes acute fulminant hepatitis
Give some examples of autoimmune disorders affecting the gallbladder. What is seen on histology?
Primary biliary cirrhosis = chronic destructive cholangitis
- autoimmune, but immunosuppressants ineffective
- 90% of cases in females over 40yrs
- positive for anti-mitochondrial antibodies (AMA) in 95% of cases
- infiltrate (lymphocytes and macrophages)
- bile ducts eventually disappear (“vanishing bile ducts”)
Primary sclerosis cholangitis = cholangitis characterised by periductal fibrosis
- unknown pathogenesis
- 75% male
- 89% have ulcerative colitis
- positive for perinuclear anti-neutrophil cytoplasmic antibodies (PANCA) in 80% of cases
- 8% develop cholangiocarcinoma
- concentric scarring (“onion-ring scarring”) on histology
- develop biliary strictures
What is hereditary haemochromatosis? What is seen on histology?
Most common autosomal recessive disorder (CYP mutation)
20% become symptomatic
- –> 100% of those develop cirrhosis
- –> 75% develop diabetes
- –> 75%-80% develop hyperpigmentation
80% of cases are males between 50yrs-70yrs
Diagnosis: transferrin saturation > 50%, genetic testing
Iron deposition seen on histology (should be none)
Outline the cells of the liver and their functions.
Hepatocytes (~60%) = perform majority of liver function
Endothelial cells = sinusoidal circulation
Kupffer cells (macrophages) = filter portal blood
Stellate cells = extracellular matrix (+++ activity —> cirrhosis)
Biliary epithelium = line bile ducts (prevent tissue damage due to bile leakage)
NK cells = immune function
Why might ALT increase and then decrease in liver damage?
Initially increases due to damaged hepatocytes
Subsequently reduces due to necrotic liver damage (worsening function)
Contrast the liver function tests and in what disease states they are altered.
AST = released in cellular damage (non-specific)
- acute cellular necrosis
- cardiac necrosis
- skeletal necrosis
ALT = Krebs cycle (liver-specific)
- hepatocellular damage (AST:ALT can help determine cause)
ALP = isoenzymes
- biliary obstruction
- cholestasis
- viral hepatitis
Albumin
- changes in synthetic function of liver
INR
- changes in synthetic function of liver
GGT = released by hepatocellular damage, more sensitive than ALP, less specific than AST, sensitive to alcohol
- obstructive jaundice
What are the symptoms of hepatic encephalopathy?
Increased ammonia
Stage I = altered mood, sleep, and behaviour
Stage 2 =
- drowsy
- hepatic flap
- confusion
- slurred speech
Stage 3 =
- incoherent speech
- hepatic flap
- stupor
- restless
Stage 4 = coma
What is fetor hepaticus?
Occurs in end-stage liver failure
Faeces + ketones —> “stench of death”
What are the most common causes of chronic liver disease in the UK?
- alcohol
- viral hepatitis e.g. B, C
- non-alcohol related fatty liver disease
- autoimmune
- genetic e.g. haemochromatosis
- drugs e.g. co-amoxiclav, isoniazid, nitrofurantoin
What are some signs of chronic liver disease?
- jaundice
- spider Naevi (reduced oestrogen)
- gynaecomastia (reduced oestrogen)
- hepatic flap
- clubbing
- palmar erythema (increased lipolysis —> oestrogen release)
- parotitis
- raised JVP
- “water hammer” pulse
- umbilical hernia
What are some signs of decompensated liver disease?
- confusion
- hepatic flap
- fluid thrill/shifting dullness
- caput medusae
How is primary biliary cirrhosis diagnosed? How is it treated?
S&S:
- jaundice
- pruritis
Investigations:
- raised ALP and bilirubin (obstructive jaundice)
- presence of anti-mitochondrial antibodies
- raised IgM
- hypercholesterolaemia
Histology:
- inflammatory infiltrate (granulomas, lymphocytes, macrophages)
- vanishing bile ducts
- fibrosis —> cirrhosis
Treatment:
- ursodeoxycholic acid (increase aminotransferases)
- ADK vitamin supplements
- bisphosphonates
- cholestyramine/opioid antagonists (for pruritus)
What organs are affected in haemochromatosis?
Excess iron deposition in liver
Pancreas —> diabetes mellitus
Endocrine glands —> hypogonadism
Heart
- –> arrhythmias
- –> heart failure
Skin —> bronze skin pigmentation
Joints —> chondrocalcinosis —> arthropathy
What is the treatment for haemachromatosis?
Venesection (to reduce [Fe2+]blood) 3-4/yr
Monitor serum iron, ferritin, and MCV
Cannot tolerate venesection —> chelation therapy
Treatment of complications (diabetes, hypogonadism, and chondrocalcinosis cannot be treated by reduction in serum iron)
How does excessive alcohol cause liver damage?
Aldehyde toxicity —> formation of Schiff base adducts
Increased NADH:NAD+ —> inhibition of fatty acid and triglyceride synthesis —> hepatic steatosis
Reduced NAD+ —> reduced oxidation of lactate to pyruvate (lactic acidosis and hypoglycaemia)
Reduced ubiquitin activity
- –> increased apoptosis
- –> reduced hepatic repair
- –> increased oxidative stress
Increased collagen synthesis in liver —> fibrosis
