GI Topic 5 - Liver Flashcards
What LFT results would suggest cholestasis?
High ALP and GGT
AST <3, ALP >2
High bilirubin
Describe the microanatomical organisation of the liver
- Arranged into lobules - structural units
- 1-2mm hexagonal lobules, centred on a central vein (terminal hepatic venule)
- At periphery of each - arteriole, venule + bile duct = portal triad
How are acini zones functionally distinct?
- Zone 1 - closest to blood supply, carries out processes which require oxygen e.g. synthesis of glycogen and plasma proteins
- Zone 2 - intermediate zone
- Zone 3 - vascular periphery, furthest from blood supply, hepatocytes sensitive to hypoxia
List the lobes of the liver
- R lobe (biggest)
- L lobe
- Quadrate lobe - next to gallbladder
- Caudate lobe - above quadrate, between right and left lobes
List the causes of hepatitis
- Alcohol
- Metabolic disease
- Viral infection
- Autoimmune disease
- Biliary disease
- Drugs/toxins
- Cryptogenic
What are AST/ALT levels used to indicate?
Hepatocellular injury markers - intermediates in gluconeogenesis
What test should be done if ALP and GGT are raised?
- Ultrasound or CT to visualise the biliary ducts
- Dilated ducts = stones/strictures
- Non-dilated ducts = primary biliary cholangitis
Describe the pathological changes which cause Reye-Like acute onset liver failure
Microvesicular steatosis
Describe the typical clinical history of fatty liver disease
- Usually asymptomatic
- Rarely, if severe - acute cholestasis and liver failure
What LFT results would suggest hepatocellular injury?
High AST and ALT
AST >3, ALP <2
High bilirubin
Describe the origins of the hepatic portal vein
HPV formed from the union of the superior mesenteric and splenic veins at the neck of the pancreas (splenic mesenteric confluence)
How is the biliary system of the liver organised?
- Bile canaliculi - between hepatocytes, direction of flow opposite to blood supply (towards bile duct)
- Bile ducts lined with columnar epithelium with thick nuclei
How does exchange of materials occur in the liver?
Hepatocytes arranged in plates and cords exchange material with blood at the sinusoidal surface
List the complications of liver cirrhosis
- Portal hypertension
- Liver failure
- Liver cancer
Describe the attachments of the coronary ligament
Attaches the liver to the inferior surface of the diaphragm
Describe the innervation of the liver
- Glisson’s capsule - branches of the lower intercostal nerves
- Parenchyma - hepatic plexus
- Sympathetic = coeliac plexus
- Parasympathetic = vagus nerve
- Enter liver at porta hepatis, follow branches of hepatic artery and portal vein
How are sinusoids specialised?
Fenestrated endothelium, lack complete basement membrane
Describe the microscopic pathological changes seen in alcoholic hepatitis
- Signs of fatty liver disease +
- Hepatocyte ballooning
- Mallory bodies in cytoplasm
- Hepatocyte death (necrosis)
- Neutrophil polymorph inflammation
- Fibrosis (scarring) - initially perivenular and pericellular - progresses to cirrhosis
What is the function of sinusoids?
- Specialised capillary
- Optimise exchange of material between blood and hepatocytes
Describethe functional organisation of the liver
- Acini = functional units
- Triangular structures, portal tracts at base and terminal hepatic venule at apex
- Divided into 3 zones
What does high conjugated bilirubin indicated?
Inherited/acquired defects in hepatic excretion
Describe the attachments and structure of the lesser omentum
- Attaches the liver to the lesser curvature of the stomach and the 1st part of the duodenum
- Hepatoduodenal ligament - duodenum to liver, surrounds the portal triad
- Hepatogastric ligament - lesser curvature of stomach to liver
What causes liver cirrhosis?
- Result of chronic inflammation (hepatitis) - injury causing agent present for a long time
- Can be reversed up to a certain point - if injury causing agent is removed, eventually irreversible
What is the role of accessory hepatic portal veins?
Drain directly into liver from the GI tract/spleen/pancreas without joining the hepatic portal vein
Describe the presentation of Reye-Like acute onset liver failure
- Neonatal to 3 years old
- History of episodic vomiting (since neonatal), failure to thrive, family history?
- Clinical features - encephalopathy, acidosis, hypoglycaemia, no ketosis, high transaminases, prolonged prothrombin time, low serum albumin, leukocytosis
How does the liver function in amino acid metabolism/disposal of urea?
- Nitrogen produced by amino acid metabolism is converted to urea in the liver and excreted by the kidneys
- Liver failure - encephalopathy due to increasing ammionia levels in the brain (drowsy, confused)
List the processes carried out in zone 1 of acini
- Respiratory chain
- Citric acid cycle
- Fatty acid oxidation
- Gluconeogenesis
- Urea synthesis - ammonia detoxification
- Production and excretion of bile
- Cholesterol synthesis
List the ligaments of the liver
- Falciform ligament
- Coronary ligament
- Triangular ligament
- Lesser omentum
Which areas are drained by the hepatic portal vein?
Drains from just below the gastroesophageal junction to the upper 2/3 of the rectum, as well as the spleen and pancreas
What is primary biliary cholangitis?
- Autoimmune disease of the liver
- Slow, progressive destruction of the bile ducts of the liver
- Symptoms - tiredness, pruritis, jaundice, cirrhotic symptoms in advanced disease
- Cholestatic LFTs, anti-mitochondrial antibodies
What should the patient be asked if their LFTs are abnormal
- Symptoms
- Weight loss?
- Anorexia?
- Vomiting?
- Pain?
- Myalgia?
- Jaundice?
- Pruritis?
- Urine/stool
- Exposure to hepatoxins? - alcohol, medication etc.
- Family history - viral hepatitis, heritable liver disease?
- Exposure to viruses - sexual transmission? Travel? Transfusion? IV drug use?
What causes liver cirrhosis?
- Long-term hepatitis, including viral
- Specifically - alcohol, non-alcoholic steatohepetitis (NASH), biliary disease
- Haemochromatosis
How is alcohol metabolised in the liver?
- 2 main pathways, both oxidise alcohol to acetaldehyde, which is converted to acetate then acetyl coA which is used in the tricarboxylic acid cycle to produce fatty acids
- Reduces the liver’s capacity to oxidise other molecules
- Pathways = cytoplasma alcohol dehydrogenase and microsomal ethanol oxidising system
List the external surfaces of the liver
- Diaphragmatic (has bare area)
- Visceral - in contact with right kidney, adrenal gland, colic flexure, transverse colon, 1st part of gallbladder, oesophagus and stomach)
What is Gilbert’s syndrome?
- Autosomal dominant disease
- Deficiency of UDP-glucuronyl transferase
- Test to confirm - unconjugated bilirubin
What does it mean if ALP is high without a corresponding rise in GGT?
Bone disease e.g. fractures, Paget’s disease, osteomalacia, bony metastasis
Where do vascular structures enter/exit the liver?
- R and L hepatic ducts, R and L branches of hepatic artery and portal vein enter/exit at the porta hepatitis
- From anterior to posterior - duct, artery, vein
What markers are tested in liver function tests?
- Bilirubin
- Albumin
- Alanin/aspartate aminotransferase (ALT/AST)
- Alkaline phosphatase
- Gamma glutamyl transferase (GGT)
- Total protein
- viral markers, serum autoantibodies, serum immunoglobulins?
When will total protein levels be high in LFTs?
Viral hepatitis
Describe the process of lipogenesis
- Acetyl choline (from steroids, amino acids or breakdown products of glucose) is converted to fatty acids (can then be converted to triglycerides or cholesterol / prostaglandins / phospholipids / glycolipids)
- Amino acids can be converted to pyruvate, which is converted to acetyl choline
- Glycerol from glucose breakdown can be converted to triglycerides
What causes fatty liver disease (steatosis)?
- Alcohol
- Obesity
- Type 2 diabetes
- Nutritional imbalance - after intestinal surgery or coeliac disease
- Drugs e.g. methotrexate, steroid-related drugs
Where do portosystemic shunts and varices typically form in portal hypertension?
- Gastroesophageal junction
- Rectum
- Left renal vein
- Diaphragm
- Retroperitoneum
- Anterior abdominal wall via the umbilical vein
Describe the cause of alcoholic hepatitis
- Related to volume and duration of alcohol excess
- Develops after 3-5 years of alcohol abuse but only occurs in 1/3 of alcoholics
- Females at greater risk
- Genetic susceptibility
Describe the path of blood through the liver
- Incoming from hepatic artery or hepatic portal vein
- Travels through liver parenchyma to reach hepatic veins
- Sinusoids (specialised capillaries in parenchyma) connect incoming and outgoing blood flow
Define cirrhosis
- Endstage liver disease
- Characterised by diffuse nodules and fibrosis
What are the potential complications of splenomegaly in liver cirrhosis?
Fewer clotting factors (liver dysfunction) and fewer platelets (splenomegaly) - portosystemic varices vulnerable to rupture and bleeding - causes haematemesis and malena/haematochezia
What are the consequences of hepatic detoxification?
Can generate toxic/carcinogenic metabolites
What causes centrilobular necrosis?
- Caused by sepsis, shock induced ischaemia, congestive heart failure, toxicity from drugs/poisons
- Made worse by malnutrition, infection, fasting and exercise
What function does the liver have in blood coagulation?
Formation of clotting factors - fibrinogen, prothrombin, accelerator globulin, factor VII (requires Vitamin K)
What causes metabolic liver disease?
- Congenital deficiencies of enzymes
- Nutritional deficiency/excess
- Toxic damage to organelles
- Hypoxic/ischaemic insult
- Secondary to metabolic effects of disease
Describe the epidemiology of hepatocellular carcinomas
- 85% of malignant primary liver tumours
- 80% in males
- 80% in cirrhotic livers
What is the portal triad?
Bile ducts, hepatic artery, portal vein
What does high unconjugated bilirubin indicate?
Increased bilirubin production or defects in hepatic uptake/conjugation
E.g. Gilbert’s disease (lack of UDP-glucuronyl transferase)
Describe the breakdown of fatty acids to produce ATP
- Fatty acids to fatty acyl coA to acyl carnitine
- Acyl carnitine transported into mitchondrial matrix by carnitine shuttle
- Acyl carnitine to fatty acyl coA, undergoes beta oxidation to acetyl coA
- Acetyl coA goes through citric acid cycle to produce NADH and FADH2, which produce ATP
How does alcohol consumption increase hepatic lipids?
- Alcohol changes hepatocyte fat metabolism - increases lipid synthesis, catabolism impaired, accummulation of cholesterol esters and fatty acids
- Raised peripheral fat metabolism
- Decreased lipoprotein synthesis
List the processes carried out in zone 3 of acini
- Glycolysis
- Glutamine synthesis
- Xenobiotic metabolism
- Lipogenesis
- Ketogenesis
What indicates hepatocellular carcinoma?
High serum alpha-fetoprotein
What causes Reye-Like acute onset liver failure?
Inherited metabolic disease - inborn errors of metabolism
How are lipids produced in the liver transported around the body?
- Initially transported as VLDL (very low density lipoprotein) in the bloodstream, lipoprotein lipase releases fatty acids and monoglycerides for uptake by tissues
- VLDL is converted to IDL (intermediate density lipoprotein) and LDL (low density lipoprotein) in the bloodstream
- LDL transports lipids in the bloodstream, lipids (cholesterol) move from high to low concentration through capillary walls into interstitial fluids
- Excess cholesterol diffuses out of cells back into the bloodstream, absorbed by HDL (high density lipoprotein)
- HDL transports lipids back to the liver, excess excreted in bile salts
List the types of parenchymal liver cells
- Hepatocytes (majority) - cuboidal epithelial cells, have microvilli
- Endothelial cells
- Kupffer cells (macrophages) - immune
- Perisinusoidal (fat-storing) cells - storage of fat-soluble vitamins A, D, E, K
- Liver associated lymphocytes - immune
Describe the functions of the liver involved in carbohydrate metabolism
- Stores glycogen, releases glucose (through glycogenolysis or gluconeogenesis)
- Uses glucose for energy in glycolysis, citric acid cycle and fatty acid/triglyceride synthesis
- Converts fructose/galactose to glucose phosphates (for use in respiration)
What is the effect of mitochondrial damage to the liver
- No beta oxidation of fatty acids - micro-vesicular steatosis
- No oxidative phosphorylation - insufficient ATP generation
- No respiratory chain - excess reactive oxygen species with lipid peroxidation
- Increased permeability transition - cell death
Describe the structural arrangement of the liver
Portal tracts and parenchyma
Describe the anatomical location of the liver
- R hypochondrium, epigastrum and L hypochondrium
- Just below diaphragm, lower edge at level of costal margin - usual not palpable unless hepatomegaly
- Inferior part passes xiphoid process
- Up to level of nipples
What is the treatment for Reye-Like acute onset liver failure
Correct hypoglycaemia, acidosis, bleeding tendency and hyperammonaemia
Describe the coverings of the liver
- Covered by fibrous membrane - Glission’s capsule
- Partially covered by peritoneum
What should be checked in a physical examination if LFTs are abnormal?
- BMI
- Nutritional status
- Jaundice
- Ascites, pleural effusion, ankle oedema
- Hepatomegaly, splenomegaly, other abdominal masses
- Spider naevi - swollen vessels under the skin surface, central red spot and red extensions
- Palmar erythema
How is the inferior vena cava secured to the liver?
By hepatic veins and fibrous tissue
Hepatic mitochondrial dysfunctions include inborn enzyme deficiencies involving…
- Fatty acid oxygenation
- Organic acids
- Lactate metabolism
- Oxidative phosphorylation
- Urea cycle
Where is alkaline phosphatase found?
Mostly liver and bone (+ intestines, placenta during pregnancy)
Describe the venous drainage of the liver
- Caudate lobe drains directly into the inferior vena cava
- Other lobes drain into central veins, which drain to collecting veins then hepatic veins, which then join the inferior vena cava
Describe the development and consequences of portal hypertension
- Increased resistance to blood flow due to fibrosis
- Blood escapes back to systemic circulation at portocaval anastomoses
- Leads to portosystemic shunts and varices, ascites and splenomegaly
What is the effect of metabolic disease of the liver?
Dysfunction of:
- Synthesis - plasma proteins etc.
- Detoxification/degradation e.g. ammonia
- Regulation e.g. blood glucose
How does the liver produce bile acids?
Bile acids are derivatives of cholesterol, which is recycled in the enterohepatic circulation
How is the liver involved in protein metabolism?
- Albumin and glycoprotein synthesis
- Glycation of proteins
Describe the conjugation of bilirubin in the liver
- Unconjugated bilirubin from the breakdown of haemoglobin is transported to the liver bound to albumin
- Ligandin presents unconjugated bilirubin to glucaronic acid
- Conjugated by UDP-glucuronyl transferase
Describe the blood supply of the liver
- Hepatic artery
- 30-40%
- Incoming blood supply - rich in oxygenated blood, high pressure
- Hepatic portal vein
- 60-70%
- Incoming blood supply - rich in nutrients from gut, low pressure
Describe the attachments of the triangular ligament
Left and right triangular ligaments attach the liver to the diaphragm
Compare the cytoplasma alcohol dehydrogenase pathway to the microsomal ethanol oxidising system
- CAD - main route, not inducible
- MEOS - in smooth endoplasmic reticulum, uses cytochrome P450, is inducible (increased by alcoholism), affects metabolism of drugs e.g. paracetamol
Describe the connective tissue of the liver
- Liver capsule
- Portal tracts
- Parenchymal reticulin - basement membrane, collagen type I + III
Describe the process of detoxification which occurs in the liver
- Phase 1 reactions
- In the smooth endoplasmic reticulum, mediated by cytochrome P450
- Produces hydroxylated or carboxylated compounds
- Phase 2 reactions
- Subsequent conjugation with glucaronic acid, acetyl or methyl radicals, glycine/taurine or sulphate
Why is GGT used as a marker for liver function?
- Microsomal
- Transfers glutamyl from alpha glutamyl pepides to other peptides/amino acids
- In liver, hepatobilliary tree, heart, kidneys, lungs, pancreas and seminal vescicles
- Poor specificity for liver disease - good for raised ALP of liver origin or chronic alcohol consumptions
- Rasied GGT may be due to liver damage/alcohol consumption - not definite
List the types of inherited metabolic diseases of the liver
- Essential product deficit e.g. glucose-6-phosphate deficiency (Glycogen storage 1)
- Precursor accummulation e.g. ornithine transcarbamylase deficiency (hyperammonaemia)
- Alternative pathway activation e.g. amino-acidopathy
- Or combination
List the functions of the liver
- Amino acid, carbohydrate and lipid metabolism
- Plasma protein and enzyme synthesis
- Bile production
- Detoxification - drugs etc.
- Storage of proteins, glycogen, vitamins and metals
- Immune function
Define ascites
Abnormal build-up of fluid in the abdominal cavity, sign of cirrhosis
Describe the pathogenesis of cirrhosis
- Hepatocyte injury
- Causes inflammation, which leads to fibrosis
- Also leads to hepatocyte regeneration, forming hyperplastic nodules
- Nodules and fibrosis cause architectural abnormality, leading to ischaemia which causes further hepatocyte injury
- Shunts form - allowing blood to flow between arteries and veins and reducing the oxygenation of tissues
How does the liver function in lipid metabolism?
- Mitochondrial beta oxidation of short chain fatty acids
- Synthesis of fatty acids, triglycerides, cholesterol, phospholipids and lipoproteins
Compare AST and ALT
- AST
- Cytosolic and mitochondrial
- In liver, cardiac/skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes and RBC
- Low sensitivity/specificity for the liver
- ALT
- Cytosolic
- More specific to liver
Describe the microscopic pathological changes seen in fatty liver disease
- Lipid droplets in hepatocytes
- Initially small - microvesicular
- Coalesce to form macrovesicular
- Seen after 2 days of alcohol excess
- Rapid reversal
Describe the blood pressure of the hepatic portal vein
Low pressure (below 10mmHg) already through the gut capillary bed
Describe the structure of the falciform ligament
- Attaches to the anterior abdominal wall, divides the left and right lobes
- Free edge = ligamentum teres, remnant of the umbilical cord
