ARTIFICIAL ORGANS. The Liver. Sarah Waller Nathan De Jong

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1 1 ARTIFICIAL ORGANS The Liver Sarah Waller Nathan De Jong

2 WHAT IS THE LIVER? The largest internal organ, weighing around 3 lbs in an adult male Forms a key part in metabolism and digestion Also filters and regulates blood Works closely with the kidneys and pancreas 2

3 LOCATION At the top of the abdominal cavity Inferior to the diaphragm Divided into two lobes by the falciform ligament Connects it to the diaphragm Each lobe consists of many lobules 3

4 LOBULES Hexagonal in shape Consist of: Hepatocytes around a central vein (leads to hepatic vein) Sinusoids (highly permeable capillaries) also contain Kupffer cells Branches of the hepatic artery and the hepatic portal vein Bile ducts 4

5 LOBULES 5

6 HEPATOCYTES Hepato = Liver, cytes = cells The main functional cell of the liver Protein synthesis, filtration, etc. Arranged in plates one cell thick next to sinusoids contact with blood 6

7 KUPFFER CELLS Also known as stellate reticuloendothelial cells Filter the blood Phagocytes Destroy: Worn out blood cells Bacteria Other foreign matter 7

8 WHAT DOES THE LIVER DO? Metabolism Carbohydrates, lipids and proteins Drug and hormone processing Bile production Storage Phagocytosis (Kupffer cells) Activation of Vitamin D 8

9 METABOLISM Carbohydrates Regulates blood sugar levels by converting glucose to glycogen or vice versa Stores glycogen or releases glucose into blood Can also convert fructose, galactose, some amino acids and lactic acid to glucose 9

10 METABOLISM Lipids Breaks down fatty acid into ATP Synthesizes lipoproteins to transport lipids and cholesterol Stores lipids if necessary Proteins Remove the NH 2 from amino acids for ATP production or conversion to carbohydrates or fats NH 3 that results is converted into urea 10

11 METABOLISM 11

12 PROCESSING Drugs and hormones Detoxifies blood and excretes waste into bile Alters or excretes certain hormones when necessary Bilirubin and bile salts Absorbs bilirubin from old blood cells Work of the Kupffer cells Synthesizes bile salts Bilirubin and bile salts are components of bile Used in the small intestine for digestion 12

13 STORAGE Hepatocytes are used as storage for Glycogen (when blood sugar is high) Vitamins A, B 12, D, E and K Minerals iron and copper Helps with the synthesis of Vitamin D as well as storing it 13

14 LIVER FAILURE General symptom is jaundice Yellow colouring to eyes and skin due to build-up of bilirubin Acute Liver Failure Rapid progression into worse symptoms E.g. confusion, stupor or coma Chronic Liver Failure Slow, gradual, consistent decay of the liver Usually leads to cirrhosis or cancer of the liver Cirrhosis: distorted or scarred liver; hepatocytes are replaced by fibrous or adipose connective tissue 14

15 LIVER FAILURE Hepatitis: inflammation of the liver caused by Viruses Drugs and chemicals Genetic disorders 15

16 VIRUSES Five strains of the Hepatitis virus (A-E) Hep A Infectious, caused by fecal contamination Fairly mild, no lasting damage Hep B and C Transmitted through bodily fluids (sexual contact, contaminated needles, saliva) Lasts for many years, and can eventually cause cirrhosis or liver cancer Vaccines are available through recombinant DNA technology 16

17 VIRUSES Hep D Transmitted like Hep B and C Person must already have Hep B to contract Hep D Causes severe liver damage, essentially intensifies Hep B Hep E Transmitted like Hep A No chronic effect on the liver High mortality rate in pregnant women 17

18 DRUGS AND CHEMICALS Metabolized by the liver Alcohol is the most common chemical abuse Long-term abuse leads to cirrhosis or cancer Also commonly caused by allergic reactions to medication Tends to have acute effects, rather than chronic 18

19 GENETIC DISORDERS Commonly is a failure to excrete specific ions Ex. Wilson s Disease The liver retains Cu+ ions, instead of excreting them via bile, which damages it Eventually re-releases the Cu into the bloodstream, poisoning the body 19

20 WHAT ARE THE TYPES OF LIVER SUPPORT? Liver Transplants Liver Dialysis Bio-Artificial Liver Stem Cell grown liver Fully Artificial Liver? 20

first human liver transplant in 1963 Successfully completed first human liver

21 HISTORY OF LIVER TRANSPLANTS Main figure was Dr. Thomas Starzl Performed hundreds of canine liver transplants in the 50 s Attempted first human liver transplant in 1963 Successfully completed first human liver transplant in 1967 (first one-year survival) Limited success for next decade One-year survival rate never exceeded 50% 21

22 CYCLOSPORINE 1979 Cyclosporine is approved by the FDA Immunosuppressive agent Vastly decreases rejection rate and with it, mortality rate 1983 Liver transplantation is accepted as a viable treatment option for End Stage Liver Disease 1989 Tacrolimus is approved Success rates continue to improve Today 5-10 year survival rate is 80% 22

23 LIVER TRANSPLANTS Supply and demand Over 17,000 individuals on waiting list ,000 donated yearly Need for a more available resource Types of transplants o Deceased-donor grafts Whole organ Reduced-size Split-liver o Live-donor grafts o Xenografts 23

LIVER TRANSPLANTS Reduced-size grafts Developed for pediatric cases Left lobe (segments 2 and 3) or segments 2-4 are transplanted into children

24 LIVER TRANSPLANTS Reduced-size grafts Developed for pediatric cases Left lobe (segments 2 and 3) or segments 2-4 are transplanted into children from an adult liver. This technique can also be used in live-donor transplants. If successful the liver will grow to full size in 6-8 weeks. 24

LIVER TRANSPLANTS Split-liver transplants o Developed in order to increase the number of transplants per donation Right side to an adult patient Left

25 LIVER TRANSPLANTS Split-liver transplants o Developed in order to increase the number of transplants per donation Right side to an adult patient Left side to a pediatric patient More success with left lobe transplants. Is it fair to give a patient the right lobe knowing there is less chance of survival? 25

26 LIVER TRANSPLANTS Reasons why an individual may not qualify o Chronic liver disease o HIV Infected o Types of cancer o Uncontrolled sepsis o Cardiac/Pulmonary Disease o Active alcoholism or substance abuse o Advanced age o Severe Obesity 26

27 LIVER DIALYSIS What is it? o Extracorporeal device o Similar to kidney dialysis o Detoxifies blood from hydrophilic and hydrophobic toxins How it works o Makes use of the properties of albumin in the blood Hydrophobic toxins are attracted to the hydrophobic areas of albumin. It acts as an adsorber 27

LIVER DIALYSIS Blood runs through the hollow fibres Human albumin is contained outside of the fibres Water soluble toxins diffuse through semi-permeable membrane Non water

28 LIVER DIALYSIS Blood runs through the hollow fibres Human albumin is contained outside of the fibres Water soluble toxins diffuse through semi-permeable membrane Non water soluble toxins bond to the membrane proteins an get picked up by the internal albumin Meanwhile, the albumin is filtered in a series of adsorbers and a separate dialysis circuit. 28

29 LIVER DIALYSIS 29

30 LIVER DIALYSIS Benefits o Reduces plasma toxicity in blood o Allows for liver regeneration Drawbacks o Only for detoxification o Only one function of the liver is replicated o Does not produce albumin 30

31 BIO-ARTIFICIAL LIVER What is it? o An artificial device that uses biological materials in order to produce a desired function o Devices vary in structure and cell line between suppliers Invention of the year by TIME Magazine in

32 BIO-ARTIFICIAL LIVER How it works 32

33 BIO-ARTIFICIAL LIVER How it works Bioreactor Animation 33

34 BIO-ARTIFICIAL LIVER Types of design o Main areas of variation are in the bioreactor shape and method of cementing used The hepatocytes in each bioreactor are different but most are differentiated from either porcine (pig) or human liver cells 34

35 PORCINE CELLS Very similar in structure to human hepatocytes Porcine Liver cells Pigs metabolize hormones, chemicals and toxins nearly the same as homo sapiens 35

36 IMMORTALIZED HUMAN CELLS Normal Liver Cells Immortalized Cells are immortalized by SV40 virus large T-antigen which binds to the DNA of the cells and promotes transcription and in turn replication. 36

37 PROS AND CONS Pros Cons Immortalized Human Cells Biochemicals produced are the same Less chance of immunogenic response Not an abundant resource Difficult to grow in culture Outperformed by porcine cells Porcine Hepatocytes Readily available Easily reproduced May transfer porcine retroviruses May lack a speciesspecific response 37

liver size of a penny A full-sized liver has not been grown yet

38 STEM CELL LIVER British scientists stimulated umbilical cord stem cells in a Bioreactor to form liver cells Essentially created a mini liver size of a penny A full-sized liver has not been grown yet Within the next 15 years, livers could be grown and transplanted into humans 38

39 FULLY ARTIFICIAL LIVER One science journalist speculated that the equipment needed to simulate the functions of a single human liver would occupy a large office building With over 500 essential functions, a fully artificial liver seems impractical and near impossible 39

40 FUTURE? Research is being done to see which bioreactor shape and cell line is most beneficial and cost effective Promising progress with stem cell research in this area We will always be dependant on liver transplants but maybe not so heavily in the future 40

41 QUESTIONS? 41

42 SOURCES bpage/intro.html am/liver.html vol2n1/transplant.xml

Liver. Harminder Sandhu Magy Salib

Liver. Harminder Sandhu Magy Salib Liver Harminder Sandhu Magy Salib Structure [1] 2 nd largest organ 1 st largest gland Weighs 3 pounds Contains: Hepatocytes Bile Canaliculi Hepatic sinusoids Figure 1: The liver [1] 2 Hepatocytes [2] Hepatocytes