Pharmacology Renal and Hepatic Disease Flashcards
Describe the basic anatomy of the liver:
Left and right lobe
8 segments made up of lobules
Describe the lobules of the liver:
Each lobule made of central vein, radiating sinusoids (type of blood capillary) bile ducts, hepatocytes and other cells
What are the functions of bile ducts in the liver?
Join to form common bile ducts which drains bile into the duodenum after storage and concentration in the gall bladder
What is the function of the hepatic vein?
Deoxygenated blood from liver to heart from inferior vena cava
What is the function of the hepatic portal vein?
Carrying nutrient rich blood, oxygen poor, coming from GIT so can then travel to the body
Describe the vascular structure of the liver:
25% of resting CO in the liver (25% of bodies blood in liver at a time)
25% of blood is coming from the hepatic artery to liver (oxygen rich)
75% of blood is coming from the hepatic portal vein to liver (nutrient rich)
Blood leaves by hepatic vein to inferior vena cava to the heart
Name the structures in the hepatic lobules:
Portal triad
Sinusoidal capillaries
Central vein
Bile canaliculi
Hepatocytes
Name the features of the portal triad:
Bile duct
Portal vein
Artery
Name immune cells in the hepatic lobule:
Hepatic stellate cells (HSC)
Kupffer cells (KC)
Fibrocytes
What is the function of the HSC in the hepatic lobule?
Supporting hepatocyte
Perisinusoidal- very close to the blood capillaries
Antigen presenting role
Responsible for liver fibrosis (scarring) in liver disease
Important physiologically but bad in disease
What is the function of the KCs in the hepatic lobule?
They are macrophages attached to the endothelium
Phagocytosis of any foreign substances/ bacteria carried from the GIT in the portal vein
During disease can become inflammatory cells
Important physiologically but bad in disease
What are the functions of the liver?
Metabolism
Immunity
Storage
Detoxification
Synthesis
Catabolism
Activation
Transport
Excretion
How does the liver metabolically process carbohydrates?
Stores glucose as glycogen:
-up to 24 hrs worth
-not as good as not as energy dense and need water in there so lots of space taken up
Glycogenolysis in fasting
Gluconeogenesis in fasting:
-made from F.A and a.a
How does the liver metabolically process lipids?
Synthesis of cholesterol in liver
Lipoproteins
How does the liver metabolically process proteins?
Non-essential a.a synthesis
Breakdown of a.a to ammonia to urea for excretion
What is the difference between essential and non-essential a.a?
Non- essential= means we can synthesise it ourselves in the body
Essential= comes from the diet
Why does detoxification take place in the liver?
Conversion of harmful ammonia to urea- major elimination route of nitrogenous waste
Name and describe the different phases of drug detoxification and degradation in the liver:
Phase I reactions- by cyp450 enzymes
Phase II reactions- conjugation with other compounds to become more hydrophilic e.g gluconosyltransferase
What factors can affect metabolism?
Age, nutrition and genetics
What endocrine activities for modification of some hormones does the liver do?
Vit D3 to 25-OH vit D3 then in kidney 1,2 (OH2)D3
Thyroid hormone-> conversion of T4 to more potent T3
Insulin like GFs produced by hepatocytes modify action of growth hormone
What endocrine activities for major organ degredation of hormones does the liver do?
Insulin and glucagon
Oestrogens, glucocorticoids, growth hormones, PTH
Gastrin and other GI hormones
What does the liver store?
Fats- can be a problem during obesity, fatty liver
Glycogen
Trace elements- copper, iron
Vitamins A,D,K, some water soluble B vitamins for shorter periods
What does the liver synthesise?
Hormones
Plasma proteins
Iron transport and metabolism proteins
Acute phase proteins
Bile acids
Describe hormones synthesised by the liver:
Insulin like GF
Thrombopoietin- stimulates platelets
Describe plasma proteins synthesised by the liver:
Coagulation factors
Transport for cholesterol (lipoproteins)
Transport for steroid and thyroid hormones
Angiotensinogen- important for salt conversion
Describe iron transport and metabolism proteins synthesised by the liver:
Transferrin- transports iron in the blood
Hepatoglobin- bind free Hb blood
Hemopexin- bind free heme in blood
Hepcidin- inhibits iron uptake by gut
How is hemopexin involved in inflammation?
Important as can’t have free iron in the blood as its a pro-oxidant
During infection bacteria is attracted to this
Describe bile acids synthesised by the liver:
Primary:
-cholic acid
-chenodeoxycholic acid
Secondary:
-deoxycholic acid
-lithocholic acid
Where is bile secreted and stored?
Actively secreted by liver and actively diverted to gall bladder between meals
After a meal it enters the duodenum
Stored and concentrated in gall bladder
What is the composition of bile acids?
Aqueous alkaline fluid containing:
-bile salts
-cholesterol
-lecithin
-bilirubin
Describe excretion in the liver:
Excretion of cholesterol and bilirubin through bile secretion
Secreted bile salts consist of 95% of old recycled bile salts and 5% newly synthesised bile salts
How are bile salts recycled?
Re-absorbed in terminal ileum into the hepatic portal vein and into liver
Describe the first stages of removal of RBCs and heme breakdown until it enters the liver:
- senescent red cells are major source of heme proteins
- breakdown of heme into bilirubin, occurs in macrophages for the reticula-endothelial system
- the unconjugated bilirubin formed is transported through blood (complexed with albumin) to the liver
- then taken up via facilitated diffusion by the liver and conjugated with glucuronic acid
Describe the second stages of removal of RBCs and heme breakdown in the GIT:
- conjugated bilirubin is actively secreted into bile and then the intestine
- in the colon the part of the intestine, the glucuronic acid is removed by bacteria, the resulting bilirubin is converted to urobilinogen
- some of the urobilinogen is reabsorbed from the gut and enters the portal blood
- a portion of this urobilinogen participates in the enterohepatic urobilinogen cycle
Describe the third stages of removal of RBCs and heme breakdown in the kidney:
- the remainder of the urobilinogen is transported by the blood to the kidney, where it is converted to yellow urobilin and excreted, giving urine its colour
- urobilinogen which remains in the colon, is oxidised by intestinal bacteria to brown stercobilin
Name other immune cells involved in the immunological function of the liver:
NK cells
B cells
Dendritic cells
Neutrophils/ monocytes
Describe liver disease:
Over 200 types
Affects over 2 million people in the UK and is increasing
What are the main causes of increasing liver disease?
Alcohol
Obesity
Undiagnosed hepatitis infection
Drug or other chemical toxicity
Name types of liver diseases:
Alcohol related LD
Drug toxicity
Hepatitis
Non-alcoholic fatty LD (NAFLD)
Cirrhosis (late stage, fibrosis/ scarring )
Cancer (late stage)
Gall stones- stop bile secretion
Cholangitis
Hemochromatitis (Fe overload, inherited)
Wilson’s disease (Cu over load, inherited)
Gilbert’s disease (inability to metabolise bilirubin properly)
What is acute liver disease?
Usually self limiting
Results in hepatocyte inflammation/ damage
Occasionally severe resulting in liver failure
Generally caused by drugs/ viruses
What is chronic liver disease?
Inflammation present for longer than 6 months
Results in permeant damage with structural changes resulting in cirrhosis
Most common cause is alcohol abuse
What does the progression to early fibrosis involve from the normal liver?
Reversible
Inflammation
Fatty liver
Inflammatory damage
Matrix deposition
Parenchymal cell death
Angiogenesis
What does the progression to cirrhosis involve from early fibrosis?
Not reversible
Distrupted architechture
Loss of function
Aberrant hepatocyte region
Leads to hepatoceulluar carcinoma
Both needing a liver transplant
What is fatty liver?
A reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis (mainly due to obesity)
What is the fat composition in fatty liver?
Increase in TGs, LFTs and liver fat
What are the issues with Non-alcoholic fatty liver disease?
15-20% will develop from fatty liver
NASH liver:
steatosis
ballooning
inflammation
fibrosis
Describe the normal liver pathophysiology:
Hepatocytes
Sinusoidal endothelial cell- normal capillaries
Kupffer cells (normal)- few
Hepatic stellate cell- few
Sinusoid lumen with normal resistance to blood flow
Describe the liver pathophysiology in an advanced fibrosis liver:
Lots of hepatic stellate cells- causing lots of fibrosis and ECM proteins
Infiltrating lymphocytes
Activated kupffer cells- phagocytose any dead cells
Apoptotic hepatocytes
Sinusoid lumen with increased resistance to blood flow
Name the different types of hepatitis’:
A,B,C,D,E,G
Describe the route and symptoms of Hep A:
Faecal oral route
Acute inflammation that generally resolves spontaneously
Vaccine available to prevent
Describe the route and symptoms of Hep B:
Body fluids, mother to baby
Acute infection that progresses to chronic inflammation, cirrhosis and cancer
Vaccine available to prevent- normally in health care workers
Describe the route and symptoms of Hep C:
Body fluids, chronic and may progress to cirrhosis and cancer
No vaccine
Describe the route and symptoms of Hep D:
Body fluids, requires concomitant infection with Hep B to survive
Describe the route and symptoms of Hep E:
Contaminated food and water
Usually self limited
Describe the route and symptoms of Hep G:
Body fluids
Chronic infection
Similar to HCV
Describe how drugs can cause liver damage:
Hepatocytes become temporarily inflamed or permanently damaged by drugs/ medicines
Some drugs require overdose to cause damage e.g paracetamol
Other may cause damage even when appropriately prescribed e.g statins, Abs amoxicillin, tetracycline, MTX
Some natural products e.g Kava Kava, high doses of vit A
Describe how alcohol can cause liver damage:
Most common cause of liver disease/ cirrhosis
Directly toxic to liver cells
Alcohol causes inflammation which progress to fatty liver and eventually fibrosis
Fibrosis alters the structure and blood flow leading to back pressure in portal vein, leading to portal hypertension and eventual liver failure
How much alcohol needs to be consumed to cause liver damage?
More than 40g/d in men
More than 20g/d in women
How many grams of alcohol is 1 unit?
9g
How many units are in wine, beer and spirits?
Small glass of wine= 1.5 units
Standard glass of wine= 2.1 units
Large glass of wine= 3 units
Pint of beer= 2 units
Single spirit= 1 unit
What could cholestasis be due to?
It is due to lack of bile in the GIT either due to:
-hepatocytes
-bile duct
How can the hepatocytes contribute to cholestasis?
Failure of bile production and secretion
Causes include hepatitis from viruses, alcohol, drugs and pregnancy
How can the bile duct contribute to cholestasis?
Failure of outflow via able ducts due to obstruction
Gall stones, carcinoma, cholangitis (progressive scarring of bile ducts)
What are the symptoms of acute liver disease?
Possibly asymptomatic
Generalised malaise
Anorexia
Fever
Jaundice (later)
What are the symptoms of chronic liver disease?
Fatigue/ weakness
Loss of weight
N&V
Loss of appetite
Cachexia- wasting of muscle in arms and legs
Abdominal swelling
Right upper quadrant abdominal pain and tenderness
Jaundice
Bleeding from gums/nose and easy bruising
What are the progressive symptoms of patients with cirrhosis as the liver fails?
Inability to metabolise waste as liver fails- toxins lead to bilirubin in the skin
Failure to produce proteins require for body function e.g clotting
Symptoms include easy bruising, gynecomastia, impotence, confusion, ascites, portal hypertension, oesophageal varicies
What are the signs and complications of liver disease?
Jaundice
Skin changes
Ascites
Portal hypertension and oesophageal varicose
Circulatory changes
Hepatic encephalopathy
Haematological changes
Endocrine abnormliaties
Renal failure
Describe what jaundice is:
Yellow discolouration of the skin and mucous membranes (sclera)
Causes:
-haemolysis, RBCs breakdown, bilirubin buildup (haemolytic jaundice)
-hepatocellular damage (hepatic jaundice)
-cholestasis (obstructive jaundice)
Describe portal hypertension and oesophageal varicies:
Oesophageal varicies are swollen veins in the oesophagus
Blood flow decreases in liver when disease and therefore back pressure builds up in portal vein
High HP pushes blood into surrounding BVs including thin walled veins in oesophagus clot to surface
If pressure to high, they can rupture and bleed uncontrolled blooding leads to shock and death
Describe what ascites is:
Abnormal accumulation of fluid in the peritoneal cavity due to pressure inbalance between the circulation (high) and outside, in this case the peritoneal cavity (low)
What can ascites cause in liver disease?
Portal hypertension
Low plasma albumin
Salt and water retention by kidneys e.g secondary hyperaldosteronism
What is hepatic encephalopathy?
Neurological abnormality caused by build up of substances (mainly ammonia) normally metabolised by liver in blood and crosses BBB leading to neurological abnormalities due to ammonia and nitrogenous substances from gut by passing the liver
Can be associated with cirrhosis, or acute liver failure or portal systemic bypass of liver
How is ammonia produced?
Breakdown of a.a.
Bacteria in gut producing it
Kidney excretes urea
What are the symptoms of hepatic encephalopathy?
Altered mental state
Fetor hepaticus (musty breath)
Asterixis (hand tremor)
Drowsiness
Confusion
Coma
What can hepatic encephalopathy be precipitated by?
Dehydration
Hypovolaema
GI bleed
CNS drugs
Alcohol
Increase in dietary protein
Constipation
What is Wernicke encephalopathy?
Due to deficiency of thiamine, with decreased mental function
Occurs in chronic alcohol abuse
What are the haematological changes in liver disease?
Anaemia
Bleeding and bruising
What are the effects of anaemia in liver disease?
Effects on iron homeostasis
Splenomegaly from portal hypertension
Alcohol toxic to bone marrow
Decrease in clotting factor
What is the effect of bleeding and bruising in liver disease due to?
Results in decrease in clotting factor synthesis
What are circulatory changes in liver disease?
Palma erythema- like dermatitis but without the dryness, just redness
Spider naevi- clusters of little veins on skin surface
Finger clubbing- due to changes in interstitial fluid
What are the skin changes in liver disease?
Pruritus- toxic substances not broken down so get out into the skin
