Chapter 6 Liver PDF Lecture Series

Chapter 6 Liver Dr.-Ing. Sebastian Jansen Lecture Series: Künstliche Organe II Content 2 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Liver Artificial Organs - Liver Motivation „Aachener Weihnachtsmarkt“ 3 Artificial Organs - Liver Anatomy & Physiology Liver anatomy – Position & S...

Chapter 6 Liver Dr.-Ing. Sebastian Jansen Lecture Series: Künstliche Organe II Content 2 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Liver Artificial Organs - Liver Motivation „Aachener Weihnachtsmarkt“ 3 Artificial Organs - Liver Anatomy & Physiology Liver anatomy – Position & Shape Liver positioned directly under diaphragm (above the stomach) in the right upper abdominal cavity. It is divided into two lobes. The liver is the central organ of the entire metabolism and the largest gland in the body. It is of red-brown color. Liver – Weight 1500 – 2000 grams Position and schematic of liver 4 Artificial Organs - Liver Anatomy & Physiology Liver function – Synthesis of vital proteins & bile More than 3000 substances are produced by the liver. Most of the plasma proteins, for example the coagulation proteins. The liver produces the bile that supports detoxification and is important for digestion. – Metabolism of nutrients & storage Nutrients from the intestine are utilized in the liver. The liver stores blood, iron, fat, glycogen, and other substances (vitamins) Liver Position and schematic of liver 5 Artificial Organs - Liver Anatomy & Physiology Liver function – Regulation Blood-sugar level is mostly regulated by the interaction of pancreas and liver. The ability to store glycose as glycogen in the liver plays a vital role in this regulation – Detoxification & Degradation Hemoglobin is degraded to bilirubin (bound to albumin). The bilirubin is separated from albumin in the liver, modified to be watersoluble and excreted in the kidneys. The liver is able to make lipophilic toxins water-soluble and thus be able to be removed by the kidneys. Hence, the liver plays a vital part in detoxification Liver Position and schematic of liver 6 Artificial Organs - Liver Anatomy & Physiology Liver structure – Hepatic artery The liver is supported with oxygen-rich blood from the hepatic artery which branches from the aorta descendens (≈ 400 ml/min) – Hepatic portal vein The nutrient-rich blood from capillaries surrounding the intestine, the stomach, the spleen and the pancreas is first lead through the liver by the portal vein (≈ 1200 ml/min) – Venous return Through Vena Cave (≈ 1600 ml/min) – Hepatic duct The liver cells produce bile that is collected in the hepatic ducts and stored in the gallbladder. From there it is given into the intestine 7 Artificial Organs - Liver Right lobe Vena Cava Right hepatic duct Aorta desc. Left lobe Left hepatic duct Hepatic portal vein Spleen Common hepatic duct Hepatic artery Gallbladder Stomach Cystic duct Pancreas First pass of small intestine Common bile duct Structure of the liver Anatomy & Physiology Central Vein Liver structure Portal Field – Structure The liver is divided into two lobes; Each lobe consists of eight segments; Each segment consists of ca. 1000 lobules. – A Lobule A Lobule is the functional unit in the liver, hexagonal shaped with a vein in the center. The six corners are formed by the portal fields consisting of an arteriole, a portal venule, and a bile ductule One Lobule Portal venule Bile ductule Hepatic arteriole Structure of a lobules in the liver 8 Artificial Organs - Liver Anatomy & Physiology Liver structure – Structure The liver is divided into two lobes; Each lobe consists of eight segments; Each segment consists of ca. 1000 lobules. – A Lobule A Lobule is the functional unit in the liver, hexagonal shaped with a vein in the center. The six corners are formed by the portal fields consisting of an artery, a portal vein, and a bile duct – From the portal field, oxygen-rich blood (arteriole) and nutrient-rich blood (portal venule) is transported along the hepatocytes to the vein. Bile that is produced is transported backwards to the bile ductule. 9 Artificial Organs - Liver Portal venule Bile ductule Kupffer cells Sinusoid Portal field Central vein Hepatic arteriole Hepatocytes Endothelial cells Sinusoids from portal field to central vein Anatomy & Physiology Regulation of blood sugar level – High blood sugar triggers the discharge of insulin in the pancreas. Insulin induces the transition of glucose to glycogen in the liver. The glycogen remains stored in the liver. The transition of glucose reduces the blood sugar level. Insulin also impact tissue and muscles to increase their uptake of glucose from the blood, thus contribution to the reduction of blood sugar. – Low blood sugar Low blood sugar triggers the discharge of glucagon from the pancreas. It induces the transition from stored glycogen into glucose in the liver, which is then released into the blood stream and increases the blood sugar. It also increases the uptake of glucose in the intestines and induces a feeling of hunger. 10 Artificial Organs - Liver Regulation of blood sugar through pancreas and liver Anatomy & Physiology Detoxification RBC Hemoglobin Biliverdin Highly insoluble in water Unconjugated Bilirubin is highly insoluble and quickly binds to Albumin. Thus, it cannot be excreted by the kidneys. The hepatocytes in the liver separates the Albumin from the Bilirubin and converts into a watersoluble version that can be excreted through the kidneys. Heme Spleen Hepatocyte – Hemoglobin Erythrocytes are lysed in the spleen after about 120 days (physiological hemolysis). The free hemoglobin is processed in several steps into Heme, Biliverdin and unconjugated Bilirubin (of yellow color). Soluble in water Unconjugated Bilirubin Albumin Unconjugated Bilirubin Albumin Conjugated Bilirubin Excreted over kidneys Degradation and excretion of hemoglobin 11 Artificial Organs - Liver Return to blood Anatomy & Physiology Detoxification Alcohol is degraded to the toxic acetaldehyde by the alcohol dehydrogenase (ADH) and then further on to acetic acid via the enzyme acetaldehyde dehydrogenase (ALDH). It is then further metabolized to carbondioxid, water and fatty acids. Over consume of alcohol can thus contribute to a fatty liver. Stomach / Interstine => Portal vein Alcohol Hepatocyte – Alcohol Alcohol can be excreted via urine, but over 90% of the alcohol is directed via the stomach and the intestine to the liver by the portal vein. Alcohol ADH Acetaldehyde Hangover symptoms ALDH Acetic acid CO2 + H2O Fatty acids Return to blood Degradation of alcohol in the liver 12 Artificial Organs - Liver Ineffective in some people Anatomy & Physiology Drugs – First pass effect – Orally administered medicine Medicine that is administered orally will at first pass the liver until it is distributed into the blood stream. This first pass and a potential metabolism in the liver needs to be taken into account for the effect of the drugs. The effect of many drugs is significantly reduced by the metabolism in the liver. Other drugs rely on the metabolism in the liver and are only getting effective after the first pass Orally administered drugs 13 Artificial Organs - Liver Anatomy & Physiology Drugs – Enterohepatic circulation – Elimination via Bile Drugs and toxins are majorly eliminated in the liver via Bile that collects in the Gallbladder. From there it is discharged into the intestine. Substances in the intestine, however, are taken up by the blood and lead to the liver via the portal vein. Drugs that are taken up by the blood in the intestine may re-circulate multiple times through the liver (enterohepatic circulation) and may lead to liver damage 14 Artificial Organs - Liver Orally administered drugs Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Liver 15 Artificial Organs - Liver Pathophysiology Liver diseases – Multiple liver diseases: There a numerous diseases of the liver. Three major diseases are considers here: – Fatty liver (hepatic steatosis) Excessive fat is stored in the liver; too much fat can induce scarring and cirrhosis. Symptoms are mostly not noticeable (sometimes tired feeling). Causes are excessive alcohol, obesity or high blood sugar. – Hepatitis Inflammation of the liver (acute or chronic). Causes can range from detoxification over viruses, drugs, bacteria, parasites, …. Can lead to cirrhosis. Symptoms depends on cause 16 Artificial Organs - Liver Picture of a fatty liver (hepatic steatosis) Pathophysiology Liver diseases – Cirrhosis End-stadium of most chronic liver diseases. Cirrhosis describes the remodeling of the liver, especially of the lobules that are transformed into connective tissue and completely loose their function. A loss of liver function is mainly a loss of the synthesis performance (a lack of coagulation factors) and a loss of detoxification performance. Picture of end-stage liver cirrhosis 17 Artificial Organs - Liver Pathophysiology Liver diseases - Symptoms – Jaundice (Icterus) The loss of performance in detoxification can lead to an accumulation of unconjugated bilirubin. The yellow color of the bilirubin is accumulating in the tissue and is visible as a yellow tone in the skin color. Advanced jaundice (Icterus) in a patient 18 Artificial Organs - Liver Pathophysiology Liver diseases - Symptoms – Jaundice (Icterus) The loss of performance in detoxification can lead to an accumulation of unconjugated bilirubin. The yellow color of the bilirubin is accumulating in the tissue and is visible as a yellow tone in the skin color. – Hepatic encephalopathy (HE) The loss of performance in detoxification leads to an accumulation of toxins that induces neurological disturbances up to coma Stage Symptoms I Euphoria, depression, mild confusion, sleep disorder II Lethargy, moderate confusion III Clear confusion, awakening in dizziness IV Coma, initially still reaction to pain stimuli West-Haven classification of hepatic encephalopathy 19 Artificial Organs - Liver Pathophysiology Liver diseases - Symptoms – Jaundice (Icterus) The loss of performance in detoxification can lead to an accumulation of unconjugated bilirubin. The yellow color of the bilirubin is accumulating in the tissue and is visible as a yellow tone in the skin color. – Hepatic encephalopathy (HE) The loss of performance in detoxification leads to an accumulation of toxins that induces neurological disturbances up to coma – Coagulopathy The loss of performance in synthezising proteins can lead to a lack of coagulation proteins and thus bleeding complications 20 Artificial Organs - Liver Hematoma due to a coagulopathy Pathophysiology Liver diseases - Symptoms – Failing blood sugar regulation The failing liver does not respond to insulin and cannot store glycogen. Thus, elevated blood sugar (hyperglycemia) is common in failing liver patients, often resulting in diabetes. Also, mobilization of glycose stored in the liver is inhibited, thus acute hypoglycemia is also likely to occur. Failing blood sugar regulation with failing liver 21 Artificial Organs - Liver Pathophysiology Liver diseases – Treatment options – Liver regeneration The liver is exceptionally able to regenerate itself. 51% remaining liver tissue is able to regenerate back to full original size. Hence, change of behavior at early stages of liver failure is the best treatment – Symptoms treatment Advanced stages of cirrhosis cannot be cured today. Thus, only symptoms can be treated with medication and diets. Legend of Prometheus 22 Artificial Organs - Liver Pathophysiology Liver diseases – Treatment options – Liver regeneration The liver is exceptionally able to regenerate itself. 51% remaining liver tissue is able to regenerate back to full original size. Hence, change of behavior at early stages of liver failure is the best treatment – Symptoms treatment Advanced stages of cirrhosis cannot be cured today. Thus, only symptoms can be treated with medication and diets. – Liver transplantation Only treatment option for advanced liver cirrhosis. Due to the regeneration capacities of the liver, living donor transplantations are possible for nearest relatives. However, number of donors are not sufficient. 23 Artificial Organs - Liver Schematic of a living donor transplantation of the liver Pathophysiology Liver diseases – Treatment options – Artificial liver (liver-dialysis) as bridging The extracorporeal dialysis treatment to support liver detoxification is yet not a long-term treatment option. However, it might bridge the time on the waiting list. Especially, in acute liver failure, liverdialysis can bridge an otherwise lethal condition until regeneration of the liver. A variety of slightly different liver-dialysis techniques exist. Liver function 100% Liver-dialysis Lethality threshold Time Principle of bridging acute liver failure 24 Artificial Organs - Liver Pathophysiology Liver diseases – Numbers World (2011) Deaths 1.5 mio. Transplants 11.000 Germany (2011) Advanced liver failure 70.000 Deaths 20.000 Patients on waiting list 1.792 Transplantation 1.097 (80 living donor) Numbers of liver failure 25 Artificial Organs - Liver Content 1 Anatomy & Physiology 2 Pathophysiology 3 Design of Artificial Liver 26 Artificial Organs - Liver Design of Artificial Liver Liver-dialysis techniques – Artificial methods Purely synthetic methods (without involvement of biological cells). Only able to support detoxification (not the synthesis function of the liver) Classical Dialysis Methods AlbuminDialysis Hemodialysis SPAD Plasmapheresis Hemoperfusion MARS Whole Blood Exchange Exchange Transfusions FPSA Hepawash Artificial methods to support detoxification of the liver 27 Artificial Organs - Liver Design of Artificial Liver Liver-dialysis techniques – Artificial methods Purely synthetic methods (without involvement of biological cells). Only able to support detoxification (not the synthesis function of the liver) – Bio-artificial methods Involvement of cells. Tries also to support the synthesis functioning of the liver. Effect is yet to be proven. Bioreactor systems Extracorporeal liver perfusion Future concepts Cell Culture Xenogenic Liver Cell Therapy Porcine Hepatocytes Human Tissue Engineering Bioartificial methods to support detoxification and synthesis of the liver 28 Artificial Organs - Liver Design of Artificial Liver Basics of Albumin – Vital protein in the body Acts as a transport protein for several substances in the body (Bilirubin, Calcium, Magnesium,…) Also carrier for toxins – Synthesized by the liver Concentration is about 35 – 50 g/l in the plasma. The size is about 66.000 Da. Schematic of Albumin as a molecule (left) and bottled human albumin (right) 29 Artificial Organs - Liver Design of Artificial Liver Basics of adsorption – Clarification Common mixing of terms absorption and adsorption – Adsorption Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the adsorbate on the surface of the adsorbent. – Absorption Absorption is a physical or chemical phenomenon or a process in which atoms, molecules or ions enter some bulk phase – liquid or solid material. Wikipedia 30 Artificial Organs - Liver Adsorption Absorption Adsorption vs. Absorption Design of Artificial Liver Basics of adsorption – Adsorbent For example: Activated carbon. Also commonly used in non-medical fields (drinking water, …). Structure provides for exceptionally high surface area (≈ 106 m²/kg) => more than 200 football fields Also other, synthetic adsorbents (polymers, silicate) used for liver support Pore-size of the adsorbent defines the selectivity of the adsorber Activated carbon 31 Artificial Organs - Liver Design of Artificial Liver Basics of adsorption – Other influences Adsorption is also highly influenced by temperature, pH-value, flow rate (contact time) Adsorbed proteins – Vroman effect Proteins with the highest mobility are firstly adsorbed, but later displaced by proteins with a higher binding affinity. Protein I (Albumin) Protein III (Fibrinogen) Protein II Protein IV (Factor XII) Time Vroman effect 32 Artificial Organs - Liver Design of Artificial Liver Single Pass Albumin Dialysis (SPAD) Albumin – High Flux dialyzer (< 50 kDa) The SPAD uses a conventional high flux dialyzer that prevents albumin to pass the membrane. Substitute Patient – Dialysate with Albumin In SPAD, the Dialysate is enriched with Albumin. This allows the albumin bound toxins in the blood to jump over the membrane to bind to the Dialysatealbumin. The Dialysate is wasted after a single pass. The patient is given a substitute fluid to compensate for the substance loss during the dialysis. Substitute High Flux Dialyzer Waste Principle of Single Pass Albumin Dialysis 33 Artificial Organs - Liver Design of Artificial Liver Molecular Adsorbent Recirculation System (MARS®) (Gambro) – MARS® membrane The core of the MARS® system is the MARS® membrane. This membrane is highly permeable for albumin-bound toxins, but not for the albumin itself. The albumin-bound toxins switch through the membrane from the patient’s albumin to a dialysate’s-albumin. Hence, the patient’s albumin is not getting in contact with adsorbers. The membrane also let pass watersoluble toxins that can be removed via dialysis. – Adsorbers The MARS® adsorbers remove the toxins from the dialysate’s albumin similar to the Prometheus system. The dialysate’s albumin can thus recircle. 34 Artificial Organs - Liver Features of the MARS® membrane Design of Artificial Liver Molecular Adsorbent Recirculation System (MARS®) (Gambro) Blood – MARS® membrane The core of the MARS® system is the MARS® membrane. This membrane is highly permeable for albumin-bound toxins, but not for the albumin itself. The albumin-bound toxins switch through the membrane from the patient’s albumin to a dialysate’s-albumin. Hence, the patient’s albumin is not getting in contact with adsorbers. The membrane also let pass watersoluble toxins that can be removed via dialysis. – Adsorbers The MARS® adsorbers remove the toxins from the dialysate’s albumin similar to the Prometheus system. The dialysate’s albumin can thus recircle. 35 Artificial Organs - Liver circulation Albumin circulation Schematic of the MARS® circulation Dialysis circulation Design of Artificial Liver Molecular Adsorbent Recirculation System (MARS®) (Gambro) – MARS® membrane The core of the MARS® system is the MARS® membrane. This membrane is highly permeable for albumin-bound toxins, but not for the albumin itself. The albumin-bound toxins switch through the membrane from the patient’s albumin to a dialysate’s-albumin. Hence, the patient’s albumin is not getting in contact with adsorbers. The membrane also let pass watersoluble toxins that can be removed via dialysis. – Adsorbers The MARS® adsorbers remove the toxins from the dialysate’s albumin similar to the Prometheus system. The dialysate’s albumin can thus recircle. 36 Artificial Organs - Liver MARS® system Design of Artificial Liver Molecular Adsorbent Recirculation System (MARS®) (Gambro) – MARS® membrane The core of the MARS® system is the MARS® membrane. This membrane is highly permeable for albumin-bound toxins, but not for the albumin itself. The albumin-bound toxins switch through the membrane from the patient’s albumin to a dialysate’s-albumin. Hence, the patient’s albumin is not getting in contact with adsorbers. The membrane also let pass watersoluble toxins that can be removed via dialysis. – Adsorbers The MARS® adsorbers remove the toxins from the dialysate’s albumin similar to the Prometheus system. The dialysate’s albumin can thus recircle. 37 Artificial Organs - Liver Patients treated with MARS Design of Artificial Liver Fractionated Plasma Separation and Adsorbtion (FPSA) (Prometheus®, Fresenius) Special dialyzer (AlbuFlow®) Toxin-loaded albumin – AlbuFlow® The core of the FPSA is a dialyzer membrane with a higher cut-off so that the patient’s albumin which is loaded with toxins is separated from the blood (cut-off about 250 kDa). – Adsorbers The Prometheus® adsorbers remove the toxins from the patient‘s albumin. The first adsorber removes a variety of toxins, the second one is specialized for removing bilirubin. Adsorber Purified albumin Functioning principle of the FPSA 38 Artificial Organs - Liver Design of Artificial Liver Fractionated Plasma Separation and Adsorbtion (FPSA) (Prometheus®, Fresenius) – AlbuFlow® The core of the FPSA is a dialyzer membrane with a higher cut-off so that the patient’s albumin which is loaded with toxins is separated from the blood (cut-off about 250 kDa). – Adsorbers The Prometheus® adsorbers remove the toxins from the patient‘s albumin. The first adsorber removes a variety of toxins, the second one is specialized for removing bilirubin. High-Flow Dialyzer Sieving coefficient Molecular weight Selectivity of the AlbuFlow® Dialyzer 39 Artificial Organs - Liver Design of Artificial Liver Fractionated Plasma Separation and Adsorbtion (FPSA) (Prometheus®, Fresenius) – AlbuFlow® The core of the FPSA is a dialyzer membrane with a higher cut-off so that the patient’s albumin which is loaded with toxins is separated from the blood (cut-off about 250 kDa). – Adsorbers The Prometheus® adsorbers remove the toxins from the patient‘s albumin. The first adsorber removes a variety of toxins, the second one is specialized for removing bilirubin. Prometheus® circuit (left) and machine (right) 40 Artificial Organs - Liver Design of Artificial Liver Fractionated Plasma Separation and Adsorbtion (FPSA) (Prometheus®, Fresenius) – AlbuFlow® The core of the FPSA is a dialyzer membrane with a higher cut-off so that the patient’s albumin which is loaded with toxins is separated from the blood (cut-off about 250 kDa). – Adsorbers The Prometheus® adsorbers remove the toxins from the patient‘s albumin. The first adsorber removes a variety of toxins, the second one is specialized for removing bilirubin. Patient treated with the Prometheus® system 41 Artificial Organs - Liver Design of Artificial Liver ADVOS® formerly HepaWash® (ADVITOS GmbH formerly Hepa Wash GmbH) pH ≈ 7.4 – Effect of pH on albumin affinity In fluids that are shifted towards acid or base, the affinity of toxins to bind to albumin is decreased. The toxins are then solved in the fluid. Different pH-values affects different toxins. pH ≠ 7.4 Decreasing bonding strength of toxins (blue) to albumin (yellow) due to unphysiological pH-values 42 Artificial Organs - Liver Design of Artificial Liver ADVOS® formerly HepaWash® (ADVITOS GmbH formerly Hepa Wash GmbH) – High Flux Dialyzer The blood is treated with a albumin-rich dialysate through a high flux dialyzer membrane. 43 Artificial Organs - Liver Patient – Cleaning of albumin-dialysate The albumin in the dialysate is then cleaned not through adsorbers but by a change of pHvalue. The stream is divided and one is shifted towards higher, the other towards lower pH-values, thus affecting different toxins. The now water-soluble toxins are then removed by a dialyzers. Toxin-loaded Albumin dialysate Waste High Flux Dialyzer Waste High Flux Dialyzer Purified albumin dialysate Principle of HepaWash® albumin dialysis Acid pH Base pH Design of Artificial Liver ADVOS® formerly HepaWash® (ADVITOS GmbH formerly Hepa Wash GmbH) – High Flux Dialyzer The blood is treated with a albumin-rich dialysate through a high flux dialyzer membrane. – Cleaning of albumin-dialysate The albumin in the dialysate is then cleaned not through adsorbers but by a change of pHvalue. The stream is divided and one is shifted towards higher, the other towards lower pH-values, thus affecting different toxins. The now water-soluble toxins are then removed by a dialyzers. 44 Artificial Organs - Liver ADVOS system Take Home Message Take care of your liver – Advanced liver failure is incurable Liver-transplantation – up to now – is the only option! – Liver support Liver support systems are available but can only bridge to transplantation or to regeneration in case of acute liver failure.  Patient with cocaine poisoning. Regeneration of liver after 4 days of Prometheus® treatment.  Patient with mushroom poisoning waiting on transplant lists (Thus poisoning will usually lead to death within 3 – 4 days) is bridged 20 days until transplantation Take Home Message 45 Artificial Organs - Liver