MODULE 9
Liver and GI and Anesthesia
KEY POINTS
KEY POINTS
Dr. Lori Tolson
Case Scenario
A 66-year-old woman with a history of alcoholic cirrhosis and portal hypertension is admitted to the intensive care unit with altered mental status and low urine output. She has ascites and encephalopathy. Her kidney injury is acute with a creatinine clearance of 30 mL per minute. Her international normalized ratio (INR) is 3.0. Her hemoglobin level is 10.2 g per dL. She has a model for end-stage liver disease (MELD) score of 28 points. Her respiratory rate is 30 breaths per minute. She is scheduled for orthotopic liver transplantation.
Hepatic portal circulation. In this unusual circulatory route, a vein is located between two capillary beds. The hepatic portal vein collects blood from capillaries in visceral structures located in the abdomen and empties into the liver for distribution to the hepatic capillaries. Hepatic veins return blood to the _______(1), I; _______(2), L; _______(3), R; _______(4), S, superior.
From Patton KT. Anatomy & Physiology. 10th ed. St. Louis: Elsevier, 2019:685.
Liver Review
- Largest Internal Organ
- 2% of the total body mass of adults
- Receives 25% of cardiac output
- Oxygenated blood from the hepatic artery; nutrient-rich blood from portal vein
- Each vessel provides _______(5) of the hepatic oxygen supply
The liver is the largest internal organ accounting for 2% of the total body mass of adults. It receives 25% of the cardiac output. The liver receives blood from two sources - oxygenated blood from the hepatic artery and nutrient-rich blood from the portal vein. And each vessel provides roughly _______(6) of the hepatic oxygen supply. Sympathetic innervation from _______(7) to _______(8) controls resistance in the hepatic venules. Changes in compliance in the hepatic venous system contribute to the regulation of cardiac output and blood volume. In the presence of reduced portal venous flow, the hepatic _______(9) can increase flow by as much as 100% to maintain hepatic oxygen delivery. The reciprocal relationship between flow in the two afferent vessels is termed the “hepatic arterial buffer” response.
Sources of blood and oxygen supply to the liver.
The liver receives blood from two sources - oxygenated blood from the _______(1) and nutrient-rich blood from the _______(2). And each vessel provides roughly _______(3) of the hepatic oxygen supply.
Anatomic and functional subdivisions of the liver. The _______(1) functional anatomic segments of the liver are demonstrated in this drawing. Each segment has its own _______(2) and _______(3).
Overall, the liver carries out essential metabolic, detoxifying, and regulatory functions to keep the body healthy. For a complete list of all the functions of the liver, please refer to Box 33.1 in Nagelhout. The liver metabolizes carbohydrates, proteins, fats, and vitamins and regulates energy balance. The liver plays a major role in the metabolism of nutrients such as glucose nitrogen and lipids and detoxifies chemicals, including lipophilic medications. Liver dysfunction affects the metabolism of nutrients and xenobiotics and negatively impacts nearly every other organ system. The liver is capable of _______(1) of amino acids, which is required for energy production or the conversion of amino acids to carbohydrates or fats. Deamination produces ammonia, which is toxic. Intestinal bacteria are an additional source of ammonia. The liver removes ammonia through the formation of _______(2).
Storage
The liver stores important nutrients like vitamin A, D, E, K, _______(1), iron, and minerals. It also stores glycogen which can be converted to glucose when the body needs energy. In patients with altered liver function, blood glucose concentration can rise several fold higher than the postprandial levels found in patients with normal hepatic function.
Regulation of Glucose levels must be a consideration in patients even if they aren’t Diabetic
Detoxification
The liver neutralizes chemicals and drugs in the blood and readies them for excretion.
Immune Function
The liver contains _______(2) cells which destroy bacteria and remove foreign particles from the blood. It produces immune factors and proteins that combat infections.
Filtration
The liver filters about _______(3) of blood per minute, removing toxins, waste products, bacteria, and old red blood cells.
Blood Clotting
The liver produces clotting factors and proteins that help the blood clot and prevent excessive bleeding.
All of the blood clotting factors, with the exception of factors _______(4) (tissue thromboplastin), _______(5) (calcium), and _______(6) (von Willebrand factor), are synthesized in the liver. Vitamin K is required for the synthesis of prothrombin (factor _______(7)) and factors _______(8), IX, and X.
BOX 33.1 NAGELHOUT
Selected Essential Physiologic Functions of the Liver
Bile Production
- _______(7) cells produce bile, which is stored in the gallbladder.
- Bile contains bile salts and phospholipids that emulsify fats and aid in their digestion and absorption.
- Think of bile as an _______(1) detergent for fats.
Plasma Protein Production
- Albumin - _______(2) pressure, transport, antioxidant
- Albumin is the _______(3) abundant plasma protein made by the liver.
- It maintains oncotic pressure, transports lipids and hormones, and has antioxidant properties.
- Serum albumin levels reflect liver function and nutritional status.
- Coagulation factors - hemostasis, anticoagulation
- The liver makes most coagulation factors involved in the clotting cascade including prothrombin, fibrinogen, factors _______(4), and it also makes anticoagulant proteins _______(5) and _______(6).
Plasma Protein Production
Immunoglobulins - humoral immunity and defense
- The liver synthesizes immunoglobulins including IgG, IgA, _______(1).
- It does not produce _______(2) or _______(3).
C-reactive protein - inflammation modulation
- C-reactive protein - This acute phase reactant produced by the liver _______(4) during inflammation and infection.
- It activates complement and phagocytosis.
Ceruloplasmin - copper and iron homeostasis
- Ceruloplasmin - This _______(5)-binding glycoprotein made in the liver carries 90% of plasma copper and has _______(6) activity.
Lipoproteins - lipid transport and metabolism
- Lipoproteins - The liver produces _______(7) low-density and _______(8) lipoproteins which transport lipids through the circulation.
Protease inhibitors - tissue protection
- Protease inhibitors - _______(9) made by the liver protects tissues from proteases like elastase.
- Low levels increase risk of _______(10).
Cruising in my AMG
Clinical Significance
- Levels indicate liver function and protein status
- Deficiencies cause edema, bleeding, lipid issues, infections
- The liver produces a wide range of vital plasma proteins involved in critical _______(1) processes.
- Dysfunction impairs _______(2), _______(3), _______(4).
Protein Metabolism
Plasma Protein Synthesis
- Albumin, clotting factors, complement, carriers like _______(5)
- Regulates blood _______(6) levels
- Acute phase proteins in _______(7)
Protein Metabolism
- Here are some key points about the liver’s role in protein metabolism:
- Synthesis of plasma proteins - The liver synthesizes and secretes many essential plasma proteins like albumin, coagulation factors, complement proteins, carriers like _______(1), and lipoproteins.
- Amino acid metabolism - The liver metabolizes amino acids and converts excess amino acids to _______(9). It detoxifies ammonia by converting it to _______(2).
- Regulation of blood amino acid levels - The liver takes up amino acids from the blood and regulates systemic amino acid levels.
- Synthesis of acute phase proteins - In response to inflammation or injury, the liver increases production of certain plasma proteins called _______(3) proteins.
- Examples are _______(4) protein and serum _______(5).
- Gluconeogenesis - The liver can synthesize glucose from amino acids through gluconeogenesis. This helps maintain blood glucose when glucose supply is _______(6).
- Protein storage - The liver stores amino acids in the form of proteins like albumin and stores excess amino nitrogen from protein breakdown as _______(7).
- Transport proteins - The liver makes carrier proteins that transport various compounds like bilirubin, hormones, metals, drugs.
- Coagulation factors - The liver synthesizes most of the coagulation factors and fibrinolytic proteins involved in blood clotting and thrombus dissolution.
In summary, the liver plays a major role in plasma protein synthesis, amino acid metabolism, storage and transport, and glucose _______(8) related to proteins.
Here is an improved 5-slide PowerPoint presentation on the liver’s vital role in protein metabolism:
Amino Acid Metabolism
- Detoxifies ammonia by _______(1) synthesis
- Converts excess amino acids to glucose or _______(2)
- Gluconeogenesis from amino acids
Protein Storage & Transport
- Stores amino acids and _______(3)
- Transport proteins like bilirubin and _______(4) carriers
- Coagulation factors for blood clotting
- Protein storage - The liver stores amino acids in the form of proteins like _______(5) and stores excess amino nitrogen from protein breakdown as _______(6).
- Transport proteins - The liver makes carrier proteins that transport various compounds like bilirubin, hormones, _______(7), drugs.
- Coagulation factors - The liver synthesizes most of the coagulation factors and _______(8) proteins involved in blood clotting and thrombus dissolution.
In summary, the liver plays a major role in plasma protein synthesis, amino acid metabolism, storage and transport, and glucose _______(9) related to proteins.
Fibrinogen
- Soluble plasma glycoprotein synthesized by the _______(1) and _______(2) (bone marrow cells)
- During coagulation, thrombin converts fibrinogen into fibrin forming the fibrin meshwork of a blood clot
- ~_______(3) is produced by megakaryocytes which helps maintain adequate fibrinogen level even in severe liver disease
Fibrinogen is a soluble plasma glycoprotein that is synthesized by the liver and megakaryocytes (bone marrow cells). During coagulation, thrombin converts fibrinogen into _______(4) which forms the fibrin meshwork of a blood clot.
Medication Metabolism
- Cytochrome P450 enzymes metabolize drugs through chemical reactions like oxidation, reduction, hydrolysis, etc.
- P450 system metabolizes ~_______(1) of all medications
- Phase I modifies drug with functionalization actions resulting in loss of pharmacologic activity
- Phase II conjugates the metabolite with a second molecule (glucuronic acid, sulfate, glutathione, amino acid, or acetate) forming a _______(2) link
- Leads to deactivation and transformation of substances into benign byproducts
- Medication Metabolism: The liver plays a major role in metabolizing medications and drugs that enter the body. Here are some key points about the liver and drug metabolism:
- Enzymes in liver cells called cytochrome P450 enzymes metabolize drugs through chemical reactions like oxidation, reduction, _______(3), etc. This makes drugs more water-soluble for easier excretion into the bile or urine.
- The cytochrome P450 system accounts for metabolizing about _______(4) of all medications. The enzymes transform drugs into metabolites that are more _______(5) and can be excreted more readily.
- Drug metabolism in the liver occurs in two phases - phase I modifies the drug by introducing or unmasking a functional group, phase II conjugates the drug or metabolite with compounds like _______(6) to increase water solubility.
- The liver can activate a prodrug into its active form through metabolism. It can also convert an active drug into an _______(7) metabolite, reducing its pharmacological effects.
- Liver impairment or disease like cirrhosis can significantly impact the metabolism and clearance of many drugs. Doses may need adjustment in such patients to avoid toxicity.
- Factors like age, genetics, drug interactions, and comorbidities affect hepatic metabolizing enzymes, altering the efficacy and side effects of medications.
- The liver helps detoxify and excrete drugs, but drug metabolites may also be more _______(8) than the parent drug in some cases.
In summary, the liver’s role in drug metabolism through specialized enzymes has a major influence on the pharmacological actions and side effects of medications.
Medication Metabolism
- _______(1)% of currently manufactured drugs are metabolized by a single CYP
- Rate of metabolism can be increased or decreased with coadministration of 2 drugs metabolized by the same enzyme system
- Enzyme induction hastens metabolism and promotes tolerance
Liver Function Tests
- Measure levels of enzymes, proteins, and bilirubin to assess liver function and identify liver injury
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
- ALP, 5’-NT, GGT
- Bilirubin: conjugated vs unconjugated
- Measure levels of _______(2), _______(3), and bilirubin to assess liver function and identify liver injury.
Liver Function Tests
1) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) - elevations indicate liver cell damage.
- Because A_______(5)T is also found in nonhepatic tissues (including the heart, skeletal muscle, kidney, and brain), elevations are not specific for hepatic disease.
- A_______(6)T is primarily localized to the liver. Fatty liver and chronic infections are associated with mild (several fold) elevations of AST and ALT.
- Acute hepatitis produces larger increases, but the highest concentrations, which can exceed 50 times normal, are seen with acute hepatic necrosis.
- The AST/ALT ratio may be helpful in differentiating alcoholic liver disease, in which the ratio is typically greater than _______(1),
- from viral hepatitis, which is associated with a ratio lower than _______(3).
2) Indices of bile flow obstruction include serum levels of alkaline phosphatase (ALP), 5’-nucleotidase (5’-NT), γ-glutamyl transferase (GGT). Alkaline phosphatase (ALP) - increases with bile duct obstruction.
3) Bilirubin - Elevated levels of unconjugated bilirubin indicate an excess production of bilirubin (hemolysis) or a decrease in the uptake and conjugation of bilirubin by hepatocytes.
- Conjugated bilirubin is _______(2) by impaired intrahepatic excretion or extrahepatic obstruction.
- Even with complete biliary tract obstruction, the bilirubin rarely exceeds _______(4) because of renal excretion of conjugated bilirubin.
normal ranges for common liver function tests:
4) Albumin - _______(1) in liver dysfunction.
- Prothrombin time (PT) - _______(2) in liver dysfunction.
- Tests of hepatic synthetic function focus on the measurement of serum albumin and coagulation testing.
- Although the liver is the primary site of albumin synthesis, excessive protein losses (enteropathy, burns, nephrotic syndrome) can also result in low albumin levels.
- Because of its 3-week half-life, serum albumin is not a reliable indicator of acute liver disease.
In contrast, the _______(4) and _______(5) are sensitive indicators of hepatic disease because of the short half-life of factor VII.
- The PT depends upon sufficient intake of vitamin K, which in turn depends upon adequate biliary secretion of bile salts. In patients with biliary obstruction, the PT can be prolonged despite preserved hepatic function.
- Other conditions that can affect the PT in the absence of liver disease include congenital coagulation factor deficiencies, consumptive coagulopathies such as disseminated intravascular coagulation (DIC), and warfarin therapy.
- ALT is more specific for liver injury than AST. _______(3) and GGT indicate cholestatic liver disease.
- Other specific tests check for liver diseases like iron overload, autoimmune hepatitis, metabolic disorders.
- In summary, _______(6) provide clinical chemistry evidence of liver injury and impaired function, but may not pinpoint exact etiology without biopsy. Still very useful for screening and monitoring.
QUIZ QUESTIONS:
1) Recall that the liver is divided into three separate zones. Which zone is affected most by hypoxia and reactive intermediates from biotransformation?
- _______(1) and reactive metabolic intermediates from biotransformation affect zone _______(2) more prominently than other zones.
2) Which liver cells have the greatest quantity of cytochrome P450 enzymes and are the site of anaerobic metabolism?
- _______(3) hepatocytes have a greater quantity of cytochrome P450 enzymes and are the site of _______(4) metabolism.
The liver is anatomically divided into three zones, each with distinct physiological and pathological roles: Chat GPT
Effects of Anesthesia on Liver Function
. dose
2. proportionally
3. vasodilation
4. reduced