Hepatobilliary Flashcards
What is the largest parenchymal organ?
The liver
It is separated into two lobes (left and right lobes) by the falciform ligament.
What artery delivers oxygenated blood to the kidneys?
The hepatic artery
How does the liver metabolize, process, and detoxify nutrients?
Nutrients are absorbed in the small intestine, and the blood from the GI goes to the liver via the hepatic portal vein. This allows the blood to interact with liver lobules. The lobules contain all of the chemical and enzyme machinery to break down nutrients
Describe the anatomy of liver lobules?
They are hexagonal functional subunits of the liver. At each vertex of the hexagonal unit, contains three vessels. The first vessel is the portal vein (brings blood from GI), bile duct (contains digestive substances), hepatic artery (actually supplies hepatic tissue)
What is a common response to liver damage?
Fibrosis can develop, causing liver function to decrease
What are some functions of the liver?
Metabolism
Production of bile
Cholesterol metabolism
Glucose storage and release
Iron storage
Production of clotting factors, serum proteins, fat-soluble vitamins, and proteins reacting to infections
What are some strategies employed by the liver to clear drugs from the system?
Converts drug to inactive form
Prodrug to active form
Increased solubility or lipohillicity
The exact pathway depends on chemical structure
What is the function of bile?
Its function is to aid in the digestion of fats in the duodenum.
Bile is composed of bile acids and salts, phospholipids, cholesterol, pigments, water, and electrolytes
How much bile does the liver excrete in a day?
500-1000mL
What is the process of normal bilirubin metabolism?
- Hemoglobin release and breakdown (spleen, bone marrow)
- Heme enzymatically converted to bilirubin
- Bilirubin enters the liver through the circulation (unconjugated)
- Hepatocytes add additional functional groups to bilirubin to increase its solubility and excretion
- Most of the conjugated bilirubin then is excreted in the bile
- Bile enters the GI tract
- A small fraction of the bilirubin is reabsorbed and sent back to the liver
- Most of the bilirubin (90% is excreted in the faeces after being enzymatically reduced by colon bacteria)
- The breakdown products contribute to faecal colour
What are some genetic conditions associated with the liver?
Storage disorders and hyperlipidemia
What are some infections associated with the liver?
Hepatitis (A, B, C, D/E, Epstein-Barr, herpesviruses, adenovirus)
What are some acquired liver diseases?
The following two are responsible for the bulk of liver diseases in Canada:
Alcohol liver disease
Non-alcoholic fatty liver disease (NAFLD)
Other acquired liver diseases:
Liver involvement in systemic disease (TB, storage diseases)
Cholestatic syndromes (bile duct clotting)
Drug-induced liver injury
Vascular injury/disease
Mass lesions (tumour, abscess, cyst)
How many people in Canada have liver disease?
1 in 10 have liver disease (3M Canadians)
95% of deaths from chronic liver disease are due to:
Chronic hepatitis B or C
Alcoholic liver disease
Non-alcoholic fatty liver disease (NAFLD)
Liver cancer
What are some risk factors for liver disease?
Obesity/Diabetes (metabolic syndrome)
Exposure to certain chemicals or toxins including drugs, herbals, illegal drugs (ex. Acetaminophen overdose)
Alcohol abuse
Family history of liver disease
Hepatitis B or C
Is liver disease apparent in its early stages?
It can be asymptomatic
What are some symptoms associated with advanced liver disease?
Jaundice (yellowing of the skin and eyes due to elevated bilirubin in the blood)
Nausea (vomiting or loss of appetite)
Abdominal swelling (ascites) or tenderness in the area of the liver
Chronic fatigue
Itchy skin (pruritis)
Dark coloured urine
Pale stool
Dementia-like confusion
What is jaundice and why does it matter?
An elevation of serum bilirubin that gives a yellowish colour to skin, nails, and sclera
Jaundice indicates a problem with the liver’s processing of bile (could involve liver injury or liver disease, or more bilirubin is present)
What are the three types of jaundice?
Prehepatic
Hepatic
Posthepatic
What is the issue in prehepatic jaundice?
There is nothing wrong with liver or billiary function, just too many RBCs
(ex. Could be fetal jaundice)
What is the issue in hepatic jaundice?
It is an intrinsic issue with the liver. The liver is unable to transform unconjugated bilirubin into its conjugated form
What is the issue in posthepatic jaundice?
An obstruction (gallstone) of the bile duct causes bile to backup. This means that the liver is no longer able to process bilirubin, causing it to buildup in the blood
When the liver is damaged, does it retain the ability to regenerate a smooth organ surface?
No, it is lumpy
What is non-alcoholic fatty liver disease (NAFLD)?
Associated with obesity, Type 2 diabetes, hypertension, dyslipidemia, excess caloric intake with macronutrient imbalance
Can be silent or have perceptible symptoms (abdominal pain, fatigue, jaundice at more advanced stages)
It is reversible with weight loss and exercise, and dietary changes (cut out excess carbs, fast food, red meat)
What are some disorders that cause hepatic jaundice?
Viral hepatitis (A, B, C)
Drug-induced liver disease
Chronic hepatitis due to various causes
Cirrhosis (liver becomes fibrotic after some severe chronic injury)
Liver metastasis of cancer
Treatment of the underlying condition and avoidance of alcohol and hepatotoxic drugs is important
What are some disorders that cause post-hepatic jaundice?
Inflammation, scarring, gallstones block outflow of bile
Pancreatic or biliary disorders involving inflammation and obstruction
(RARE) Carcinoma
What is cholestasis?
Cholestasis can be due to functional impairment of the hepatocytes in the secretion of bile and/or due to an obstruction at any level of the excretory pathway of bile
What is the difference between intrahepatic and extrahepatic cholestasis?
Intrahepatic cholestasis: impairment of bile formation
Extrahepatic cholestasis: Impedance to bile flow occurs after it is formed
What are some causes of intrahepatic cholestasis?
Hepatocellular causes (viral or acute alcoholic hepatitis, parenteral nutrition)
Canalicular membrane changes (oral contraceptives, antibiotics, anti thyroid drugs, sulfonamides, and cholestasis in pregnancy)
How are gallstones formed (Cholelithiasis)?
- Solubility of cholesterol or bile is exceeded in the bile
- A nidus (nucleation site) of precipitated salts forms
- More precipitate is added and the stone grows larger
- Symptoms only manifest when they cause obstruction, irritation, or infection
What are the complications of gallstones?
These stones can be wearing away the inside of the gallbladder
Increased infection, inflammation, slightly higher risk of carcinomas
What is cirrhosis?
Chronic, progressive, irreversible, diffuse damage to the liver resulting in decreased liver function
What causes cirrhosis?
75% are caused by Hepatitis virus (B, C, and D), NAFLD, and alcohol
25% are caused by genetic metabolic diseases, autoimmune diseases, drugs, idiopathic
What is the pathogenesis of cirrhosis?
The following cause liver failure:
Liver cellular damage
Fibrosis
Nodule formation
Impaired blood flow
Bile formation
What happens to the visual appearance of a liver that is affected by alcoholic cirrhosis?
It is not smooth like a healthy liver, it is instead hard, lumpy, and shrunken
Who has non-alcoholic fatty liver disease?
30-90% of obese people
60-75% of Type 2 diabetics
What is the difference between NAFLD and non-alcoholic steatohepatitis (NASH)?
NASH is a more severe form of NAFLD that also involves inflammation
What is the treatment for NAFLD?
Weight reduction/dietary improvement, and blood lipid management
What is the progression of disease in alcoholic liver disease?
In order of least to most severe:
Fatty liver, Alcoholic hepatitis, alcoholic cirrhosis
Can you occasionally consume alcohol and not develop fatty deposits in the liver?
No, even moderate alcohol consumption creates fatty deposits in the liver
Why is alcohol toxic to the liver?
Ethanol in alcohol forms reactive oxygen species when oxidized by the microsomal ethanol oxidizing system.
The free radicals react with membrane and proteins. This reaction interferes with lipoprotein transport.
This disruption causes the accumulation of lipids in the liver
What are the clinical features seen in cirrhosis?
Jaundice
Ascites (fluid buildup in the abdomen)
Thin hair, Gynecomastia, and small testes (effects on the sex hormones)
Edema in the lower limbs (not enough albumin to keep fluid in the blood)
What are some complications of cirrhosis?
Increased bleeding (reduced clotting factors and thrombocytopenia)
Hematemesis and exsanguination from bleeding esophageal varices (portal hypertension-HTN in the the liver’s vascular system)
Reduced steroid hormones
Hepatic encephalopathy (buildup of toxins the blood cause brain damage)
Hepatorenal syndrome (toxic effects on the kidney)
What are some liver function tests?
ALT=alanine aminotrnasferase
AST=aspartate aminotransferasse
HIgh values usually indicate acute injury (ischemia, hepatitis)
Other values relevant to liver function:
Albumin, bilirubin, and prothrombin time
What is hepatocellular carcinoma?
It is a tumour that is relatively uncommon in North America, thought its incidence in rising due to the spread of hepatitis C
Is hepatocellular carcinoma curable?
Potentially curable by surgical resection, but surgery is the treatment of choice for only the small fraction of patients with localized disease
Other treatments:
Radiofrequency ablation
Transarterial chemoembolization
Terminal stages of hepatocellular carcinoma may need palliative care
What are the different types of liver tumours?
Benign liver tumours:
Hemangioma
Hepatocellular adenoma
Malignant liver tumours:
Hepatocellular carcinoma
Metastases (rare)
How is the prognosis of liver tumours determined?
TNM system (general tumour staging and grading system)
Child-Pugh score (specific to hepatobilliary)
Do benign tumours have an effect on liver function?
Yes, but due to the effect of the tumour compressing healthy tissue around it
What is entailed in drug induced liver injury (DILI)?
Hepatic inflammation, hepatocellular necrosis, or jaundice due to exposure to a medication or toxin
The most common cause of DILI is overdose of acetaminophen
Can therapeutic doses of drugs cause DILI?
Yes, it is called idiosyncratic drug metabolism
It is more likely to occur when a patient takes multiple drugs, especially is they are metabolized by the same enzyme systems
What types of drugs cause drug induced liver injury?
Almost half are caused by antimicrobials
Herbals and supplements account for 16%
The rest are CV, CNS, anti-neoplastic, analgesic agents
What factors increase the risk of DILI?
Many factors (review slide 60)
Drug properties (lipophilliciity, dose, exposure)
Host factors (race, sex, age, hormonal status, etc)
Genetic factors (polymorphisms)
Metabolic differences (individual variation of how body clears drugs)
Immune system
Can drug induced liver injury (DILI) be obviously differentiated from other types of liver injury?
No, DILI can mimic nearly any type of liver disease. Presentation is also variable (asymptomatic to acute liver failure)
Two different types (predictable and unpredictable)
What are the differences between the two types of drug induced liver injury (DILI)?
Predictable pattern: dose related (more drug=more injury, the damage is also closer to central blood vessels, always same kind of damage)
Unpredictable pattern: not related to dose or risk factors (idiosyncratic reaction)
Can we predict who will develop DILI?
No, there is no pre-test available. Maybe in the future tho (personalized medicine…)
What are the pathologies of DILI?
The histological patterns are very diverse:
Zonal hepatocellular necrosis (caused by acetaminophen, Amanita phalloides mushrooms)
Cholestasis (caused by estrogens, sulfamethoxazole)
Acute hepatitis (caused by isoniazid, antibiotics, and many others)
Chronic hepatitis
Fatty liver (caused by ethanols, poisonous mushrooms, corticosteroids, methotrexate)
Vascular disease (oral contraceptives, anabolic steroids, tamoxifen)
Neoplastic lesions (hepatic adenomas due to oral contraceptives and anabolic steroids)
What are some liver enzymes involved in drug breakdown?
Serum aminotransferases
ALT = alanine aminotransferase
AST= apartate aminotransferase
These enzymes get into the blood due to damage to hepatocytes
Do single measurements of serum liver enzymes reflect the extent of liver injury?
No, serial measurements better reflect severity and prognosis vs a single measurement
under 300u/L (mild, non-specific, viral hepatitis, NAFLD, cholestasis, etc.)
Over 500u/L (very high levels, acute hepatitis due to acetaminophen overdose)
What drugs can elevate serum liver enzymes?
Some antibiotics
Anabolic steroids
Oral contraceptives
NSAIDs
antihypertensives
Antiglycemics
Anticonvulsants
Statins + other lipid lowering agents
Psychotropic drugs
Can serum liver enzyme alone help HCPs come to a diagnosis?
No, it is a useful piece of information that is combined with clinical investigation to come up with an accurate diagnosis
Describe the role of albumin in liver function?
In low liver function, production of albumin is reduced
Albumin provides on oncotic pressure, pushes fluid into the blood and away from the tissues (prevents edema)
What is the difference between albumin and alpha-1 acid glycoproteins (AAG)?
Albumin will usually bind too acidic (negatively charged), neutral drugs, and steroids
alpha-1 glycoproteins (AAG) are carriers of basic (positively charged) and neutrally charged lipophillic compounds
What is the use of globulins?
Very diverse functions
Certain globulins bind with hemoglobin, transport metals (Fe) in the blood, and other globulins to help fight infection
What is direct bilirubin?
This is a conjugated form of bilirubin (bilirubin diglucoronide). This compound is water-soluble and can be easily excreted in the urine
What is indirect bilirubin?
It is free unconjugated bilirubin. It is a lose not water soluble
The conjugation process occurs in the liver. If indirect bilirubin is elevated, it is a proxy for liver function
What is the relevance of prothrombin time in liver dysfunction?
The liver makes clotting factors, due to liver dysfunction, the ability to clot should be reduced.
Prothrombin time is extended in patients with liver dysfunction
What is TwinRix effective against?
Hepatitis A and B (usually given to travellers)
What is a common therapy for acetaminophen overdose?
N-acetylcysteine
After determining plasma levels of acetaminophen, we can use the Acetaminophen Rumack Matthew nomogram to determine the appropriateness of starting overdose therapy.
Plasma concentration levels after 4 hours of ingestion are examined and it is determine either to give N-acetylcysteine or not
What are the four stages of acetaminophen poisoning?
STAGE 1 (Day 1): Nausea and vomiting, abdominal pain, sweating, general discomfort
STAGE 2 (Day 1-3): Liver injury develops, upper right quadrant pain, rise in liver function tests(ALT, AST, bilirubin, INR)
STAGE 3 (Days 3-5): Hepatoxicity peaks, rapid and severe hepatic failure
STAGE 4 (Days 5-8): Recovery stage for those who survive STAGE 3
