Tina Hepatic/Metabolic/endocrinology: 7 Flashcards
describe a hepatic lobule
describe a portal lobule
Hepatic lobule (emphasised blood flow): polygonal histologic unit composed of numerous plates of liver cells (hepatocytes), radiating centrifugally toward a central vein. Situated around the perimeter, at each “corner” of the hepatic lobule, are branches of the hepatic artery, hepatic portal vein, and bile duct (together called the hepatic triad), and lymphatics.
Portal lobule (emphasizes exocrine function/bile flow): triangular, three central veins centered around a portal tract.
Blood flow in the liver?
70% of blood flow to the liver is _deoxygenated blood from the hepatic portal vein._5
The hepatic portal vein receives blood from the stomach, spleen, pancreas, small
intestines, cecum, and large colon.
The other 30% of blood to the liver is oxygenated, provided by the accompanying
hepatic artery.
Approximately 10% of the total blood volume at any one time is found in the liver.
Macrophages of the liver?
Kupffer cells are tissue-fixed macrophages and are estimated to make up 20% of the mass of the liver
Histology of a bile duct
The bile canaliculi are formed solely by the cell membranes of the hepatocytes. The bile ductules and ducts are lined with cuboidal and columnar epithelial cells, respectively, that make up approximately 7% of the mass of the liver.
What is hepcidin?
Hepcidin is a peptide hormone synthesized mainly in the liver.
reduces dietary iron absorption by reducing iron transport across the gut mucosa (enterocytes) and
reduces iron exit from macrophages and the liver, the main sites of iron storage.
In horses and many other species, endotoxemia and systemic inflammation therefore cause a rapid decline in serum iron.
Proteins synthetized in the liver?
synthesizes 90% of the plasma proteins, including
albumin,
many factors involved in coagulation and fibrinolysis (fibrinogen and factors II, V, VII–XIII; antithrombin III; protein C; plasminogen; plasminogen activator inhibitor; α2-antiplasmin; α2-macroglobulin; and α1-antitrypsin),
transport proteins (haptoglobin, transferrin, ceruloplasmin, hormone transport proteins), and
acute phase reactant proteins (α- and β-globulins).
The liver is the only site of synthesis of albumin, fibrinogen, and C-reactive protein and is a predominant site for production of amyloid A and hepcidin.
Urea formation and metabolism?
The liver has sole responsibility for converting free ammonia or glutamine into urea, the principal form of amino group nitrogen excretion by mammals.
Urea is formed by the irreversible condensation of two ammonia molecules with carbon dioxide. The reaction takes place in the hepatocyte mitochondria via the Krebs-Henseleit cycle.
The newly formed urea is released from the hepatocyte, secreted into the
sinusoidal blood, and transported to the kidney as blood urea nitrogen (BUN) for excretion.
Effects of glucocorticoids and insulin on the liver
glucocorticoids
indirectly influence liver gluconeogenesis by promoting
peripheral protein catabolism, thus increasing the availability
of amino acids. Insulin inhibits gluconeogenesis in
the liver
Liver and ammonia
eliminating the major toxic
byproduct of amino acid catabolism, ammonia.12,16 Tissues
and intestinal microflora generate ammonia, which is subsequently
released into the circulation.
Role of glutamate
fundamental reaction in the synthesis of nonessential amino acids is the
formation of glutamate in the liver.
glutamate is used in
- transamination reactions to form other amino acids.
- participates in the conversion of ammonia into a nontoxic(except in neuronal glial cells) transport form: glutamine.
- may be delivered to the kidney, converted back to free ammonia and excreted, or delivered to the liver for urea synthesis.
Excessive glutamine in the brain, mostly as a result of glial cell metabolism of excessive ammonia, may cause cerebral edema.
Carbohydrate metabolism
The liver is responsible for the synthesis, storage, and release of glucose.
Most soluble carbohydrates such as starches and sugars are readily broken down to glucose or other monosaccharides in the small intestine, absorbed and delivered via portal blood to the liver.
In the hepatocyte the majority of glucose is phosphorylated to glucose-6-phosphate by the enzyme hexokinase. The remaining glucose is released into the systemic circulation.
=> majority of glucose-6-phosphate is converted to glycogen for storage. A small amount of glucose-6-phosphate is oxidized to form adenosine triphosphate, although the major source of adenosine triphosphate in the liver is amino acid and fatty acid oxidation.
=> 50% of glucose enters the phosphogluconate pathway for generation of nicotinamide adenine dinucleotide phosphate, which is required as a reducing agent in the biosynthesis of fatty acids and cholesterol.
From where does the liver derive fat?
majority of short-chain fatty acids are incorporated into phospholipid or triglyceride by the intestinal epithelium and transported to the liver via the portal blood.
The remaining small percentage of fatty acids are absorbed from the gastrointestinal tract and are transported as triglyceride in chylomicrons. After formation in the intestinal epithelial cells and absorption into lymphatics, chylomicrons enter the systemic circulation via the thoracic duct and subsequently
are delivered to the liver. The liver also may take up albuminbound fatty acids released from adipose tissue.
Fat metabolism in the liver
- esterify free fatty acids into triglycerides for export to other tissues
=> triglycerides are packaged with protein, carbohydrate, and cholesterol in the endoplasmic reticulum of the hepatocyte into
very low-density lipoproteins (VLDLs), which primarily contain triglyceride, and
_high-density lipoproteins (_HDLs), which primarily contain protein and phospholipid.
=> released into systemic circulation,
=> adipose tissue takes them up or endothelial cell lipases alter their composition by removing triglyceride, forming intermediate- and low-density lipoproteins.
- liver can oxidize free fatty acids for energy to acetyl coenzyme A (acetyl CoA), a fundamental compound in the tricarboxylic acid cycle => used in the synthesis of other fatty acids, cholesterol, steroids, and ketone bodies, acetoacetate, and β-hydroxybutyrate.
- through the synthesis of acetyl CoA from glucose and most amino acids, the liver is capable of converting carbohydrates and proteins into lipids.
What does bile consist of?
Purpose and metabolism of bile acids?
Bile consists of several components, including conjugated bilirubin, bile acids, cholesterol, lecithin, water, and electrolytes
Primary bile acids are produced in the liver, mostly from cholesterol, and compose 90% of the organic portion of bile.
=> Bile acids act as detergents, facilitating the excretion of cholesterol and phospholipid from the liver into bile and facilitate the digestion and absorption of lipids and lipid-soluble compounds (vitamins A, D, E, and K) from the intestinal tract.
in the horse: cholate and chenodeoxycholate => secreted into the lumen of
the intestinal tract => may be reabsorbed or degraded by bacteria, forming the secondary bile acids, deoxycholate or lithocholate, respectively.
More than 90% of the conjugated bile acids excreted in bile and released
into the intestinal lumen are reabsorbed by the jejunum and ileum and returned to the liver via the enterohepatic circulation.
Describe the bilirubin metabolism
majority of bilirubin formed from hemoglobin and myoglobin,
Macrophages in the spleen, bone marrow, and liver (Kupffer cells) engulf the pigments first, convert it to biliverdin, and then convert biliverdin to bilirubin and release it from the cell as free, insoluble bilirubin.
= indirect-reacting or unconjugated bilirubin in the circulation
Unconjugated bilirubin is bound with albumin in the plasma to decrease its hydrophobicity and is delivered to the liver. At the surface of the hepatocyte,
the bilirubin is transferred from albumin to ligandin,
Bilirubin metabolism (once arrived in the liver)
Within the hepatocyte, the bilirubin is conjugated with glucuronide in the endoplasmic reticulum.
=> Conjugated bilirubin/ direct-reacting bilirubin excreted into the bile canaliculi. Under normal circumstances, little conjugated bilirubin escapes into the general circulation. With severe liver disease increased amounts of conjugated bilirubin
will escape into circulation and be freely filtered in the urine.
Microflora in the intestinal tract reduce conjugated bilirubin to urobilinogen and stercobilin, which impart a yellow-brown color to feces.
Urobilinogen is absorbed by the intestinal mucosa and transported back to the liver via the enterohepatic circulation.
liver extracts most of the urobilinogen; however, a small amount spills over into the urine. Urobilinogen is concentrated in the normally alkaline urine of
horses and thus is detectable.
Kupfer cells and injured red blood cells
Kupfer cells help in recycling iron from senescent or injured red blood cells, and, as a result, Kupffer cells accumulate hemosiderin and this can be pronounced even in diseasefree horses
Liver stored which vitamines and trace minderals?
storage site for several vitamins and trace minerals, including vitamins A, D, and B12; copper; zinc; and iron.
Examples for diseases resulting in
- centrilobular injury
- periportal injury
centrilobular injury: severe acute anemia, passive congestion caused by congestive heart failure (nutmeg liver), and some toxic hepatopathies (e.g., pyrrolizidine alkaloids).
Periportal (zone I acinar lobular) injury: infarction of hepatic vessels, as may occur
during verminous arteritis, or exposure to gut-derived toxins that do not require metabolism by mixed function oxidases
Common clinical signs of hepatic injury
COMMON SIGNS
- Depression
- Anorexia
- Colic
- Hepatic encephalopathy (HE)
- Weight loss
- Icterus
- Pigmenturia (yellow-brown with bilirubinuria; red-brown with hemoglobinuria)
LESS COMMON SIGNS
Photosensitization
Diarrhea
Bilateral laryngeal paralysis
Bleeding
Ascites
Dependent edema
Icterus
Icterus, or jaundice, is caused by hyperbilirubinemia with subsequent deposition of the pigment in tissues causing yellow discoloration.
increased production
of bilirubin, impaired hepatic uptake or conjugation of bilirubin,
and impaired excretion of bilirubin.
how long does bilirubin stay stable in blood tubes?
The serum bilirubin concentration is stable for several
days if the sample is protected against sunlight
Bilirubin levels in anorexia?
Complete anorexia can cause an increase in the unconjugated bilirubin concentration within 12 hours;
however, it is _unlikely to rise greater than 6 to 8 mg/d_L (102.6–136.8 μmol/L) in horses suffering purely from anorexia.
How to make the difference between hepatocellular disease and cholestasis looking at bilirubin values?
increase in the conjugated bilirubin fraction
If the conjugated bilirubin concentration < 25% of the total bilirubin value => hepatocellular disease
If the conjugated bilirubin concentration > 30% of the total value => cholestasis
Serum bile acid concentrations in the blood
enterohepatic circulation normally removes greater than 90% of bile acids. Thus the blood concentration of bile acids may be increased with liver disease => functional test
Beware that fasting for longer than 3 days in mature horses caused an increase in the serum bile acid concentration of 3 times over baseline values.
serum bile acid concentrations are often higher in healthy neonatal foals during the first month of life and frequently exceed 20 μmol/L.
Bile acid concentrations are highest in biliary obstructive diseases and portosystemic shunts.
Why is albumin not a good indicator for liver function?
half-life of albumin in horses is long (19–20 days); thus a decrease in the albumin concentration is rarely detectable until greater than 80% of the liver mass is lost for more than 3 weeks
Influence of hepatic disease on blood clotting
The vitamin K–dependent factor with the shortest half-life is factor VII; thus
abnormalities are frequently first observed in the prothrombin time (PT). However, adequate evaluation of hemostatic function necessitates determination of the activated partial thromboplastin time (APTT), the fibrinogen and FDP concentrations, and a platelet count.
If the ratio of clotting time (PT or APTT) of the patient with possible hepatic disease to the normal horse’s value is greater than 1.3, the test may be interpreted as abnormal
liver insufficincy and blood glucose
Changes in the blood glucose concentration rarely occur in adult horses with liver insufficiency except maybe severe chronic disease OR WITH FOALS
hepatic viruses
nonprimate hepacivirus (NPHV; also called hepacivirus), Theiler’s disease–associated virus (TDAV), and equine pegivirus (EPgV),
Use of which sedation during hepatic insufficiency?
any medication should be used judiciously because most tranquilizers are metabolized
by the liver or potentiate the abnormal neural function of HE.
Xylazine or detomidine in small doses is safest and most effective in these instances. Use of diazepam is contraindicated because it enhances the effect of GABA on central inhibitory neurons and may exacerbate signs of HE.49
normal regulation of fat mobilisation
which hormone is responsible?
triglis mobilized from fat depots by hormone sensitive lipase to release free fatty acids and glycerol
-> in the liver either/or
- oxidized to acetyl coA -> ATP
- used for gluconeogensis (glycerol)
- reszynthetozed to trigli and stored in the liver
Calcium in the blood
In horses, serum ionized calcium represents 50% to 58% of the total serum calcium concentration.
Free, unbound, or ionized calcium (Ca2+) is the biologically active form of calcium. Of the protein-bound calcium, approximately 80% is associated with albumin and
20% with globulins.
What happens to Calcium blood levels during alkalosis and acidosis?
What during hypoalbulinemia
During acidosis, Ca2+ binding to albumin is reduced due to increased H+ concentrations, leading to higher Ca2+ concentrations;
during alkalosis, Ca2+ concentrations are lower.
Total calcium concentrations remain unchanged.
Hypoalbuminemia results in total hypocalcemia (pseudohypocalcemia), with Ca2+ concentrations remaining within the normal range
What happens during hypocalcemia and how are the clinical signs?
During hypocalcemia, fast Na+ channels open with small changes in the membrane potential, rendering nerve and muscle fibers very excitable.
This is associated with hyperexcitability, muscle fasciculations, and tetany.
How can blood Calcium help in cases of hyperkalemia?
Extracellular Ca2+ binds to Na+ channels to reduce Na+ entry, increasing the
depolarization threshold, thus stabilizing the cell membrane.
This is the mechanism by which Ca2+ antagonizes the effects of hyperkalemia.
Where is dopamine produced and what does it do?
in hypothalamus
then projected via dopaminergic neurons into pituitary gland to INHIBIT the pituitary peptide hormones
Describe the pituitary gland, what does it produce?
- Pars nervosa (post, neurohypoph): consists m_ainly of axons_ coming from the hypothalamus; => mainly Nucleus supraopticus and paraventricularis, axons store and release oxytocin and vasopressin/ADH (so produced in the hypothalamus!!!)
-
Pars distalis: (anterior, adenohypo): diff cell types:
- corticotrops: fe ACTH // melanotrops // lactotrops // thyrotrops (TSH) // gonado… POMC = precusor ==> production of mainly ACTH.
- Pars intermedia = junction between par distalis and nervosa; main cell: MELANOTROP: cleavage of POMC => mainly Alpha MSH, ACTH, Beta endorphin and -lipotropin, corticotropin like intermed peptide
GGT
gamma glutamyl transpeptidase
found in cell membranes of biliary epithelial cells
indicates presence of cholestasis
can also occur in large colon displacement
AST
aspartate transaminase
hepatic/muscular
slow half life : remains elevated 1-2 weeks after insiting cause
ALP
alkaline phophatase
=brush border enzyme
hepatobiliary/enteropathy
GLDH
glutamate dehydrogenase
only present in intact hepatocytes
Theiler’s disease
“serum hepatitis”
susp viral
What happens to free ionized Calcium during acidosis?
affinity to negatively charged molecules affected by pH:
Acidosis: more H+ ions in the blood so less binding of Ca to Protein - increased ionized Calcium
BUT total calcium levels remain stable
Cytosolic Calcium to plasma calcium
cytosolic concentrations are very low
high conc in (95% of Ca i) sequestered in endoplasm reticulu, and mitochondria
plasma and serum concentrations of calcium generally lower in foals
How is calcium antagonizing the effects of hyperkalemia?
Extracellular Ca2+ binds to Na+ channels to reduce Na+ entry, increasing the
depolarization threshold, thus stabilizing the cell membrane.
- hypocalcemia: fast Na+ channels open with small changes in the membrane potential, rendering nerve and muscle fibers very excitable. This is associated with hyperexcitability, muscle fasciculations, and tetany.
This is the mechanism by which Ca2+ antagonizes the effects of hyperkalemia.
Difference in Calcium metabolism in smooth muscle versus skeletal muscle?
- Smooth: Ca2+ channels (slow channels) are slightly permeable to Na+ and are abundant in cardiac and smooth muscle where they regulate action potentials. Because Ca2+ channel ion kinetics are slow, depolarization in smooth muscle cells is slow and Ca2+ dependent.
- Skeletal: Na+ channels (fast channels) are abundant in skeletal muscle and neurons where they regulate neurotransmitter release and rapid cell depolarization.also they have sarcoplasmatic reticulum full of Ca
Which type of muscle action does hypocalcemia influence and why?
skeletal muscle: almost all Ca2+ required for excitation and contraction comes from the SR.
smooth muscle cell: the SR is a rudimentary organelle, and most of the Ca2+ required for contraction comes from the extracellular fluid.
=> explains why hypocalcemia frequently results in ileus and hypotension and can contribute to conditions such as retained fetal membranes.
What happens to the coagulation times during changes in the Calcium plasma concentration?
amount of Calcium needed for coagulation is minimal so usually hypocalcemia doesnt interfere with coag times
however, prolonged severe hypercalcemia is reducing coag times
What is pica?
Horses do not have a nutritional drive to meet their calcium needs, which are highly dependent on dietary intake.
However, there appears to be a n_utritional drive for phosphorus_, as a_nimals with phosphorus deficiency will eat or lick foreign materials (dirt, rocks, and bones) in a condition known as pica._
Calcium demand of horses
Adult horses should receive approximately 40 mg of calcium/kg of body weight (BW) per day.
These requirements depend on the physiologic status of the animal.
Pregnant mares require around 50 to 60 g of calcium/day, and lactating mares and growing horses may require 50 to 75 g of calcium/day.
Required Calcium and phosphor content in horse feed?
HOw should the ratio be?
An acceptable diet for horses must have 0.15% to 1.5% of calcium and 0.15% to 0.6% of phosphorus in feed dry matter (DM)
A calcium:phosphorus ratio less than 1:1 may have negative effects on calcium absorption and skeletal development, whereas calcium:phosphorus ratios
as high as 6:1 for growing equids may not be detrimental.
=> Calcium need >> Phosphor need
Where is the intestinal site with the highest Calcium absorption in the horse?
Prox duodenum
Which effect does Dexamethason have on Calcium metabolism?
decrease in Calcium in the body:
- Dexamethasone decreases intestinal absorption of calcium,
- decreases bone resorption (so transfer from bone Ca to blood), and
- increases urinary excretion of calcium.
Phopshorous concentrations in acute and chronic renal failure
acute: HYPER
chronic: variable
Relationship between PTH and Vitamin D
1,25(OH)2D3 (=Calcitriol=Vit D) decreases PTH gene expression and secre-
tion.
In the chief cells, vitamin D binds to the vitamin D receptor, which acts as a transcription factor to decrease PTH gene transcription and secretion. Unlike vita-
min D, the effects of Ca2+ and phosphorus in the regulation of PTH secretion are not only mediated by gene transcription but also by altering PTH mRNA stability and translation.
Low Ca2+ concentrations increase PTH mRNA expression in equine parathyroid chief cells.
Hypercalcemia induces diureses in horses because…
- …the Na+/K+/2Cl cotransporter is blocked by Calcium (as by furosemide)
- …it diminishes insertion of Aquaporin channels mediated by Vasopressin.
Where does PTH act in the bone?
effects osteoblasts -> secret mediators that avtivate osteoclasts to dissolve bone matrix and liberate Ca
Who is stimulating osteoclast differentiation?
Vitamin D
TNF Alpha
IL1 and 6, 11
What is osteodystrophia fibrosa and how does it develop?
=> from hyperparathyreoidism
resulting in a “rubber jaw” (enlargement of facial bone mass with decreasing bone density)
Blood: hypercalcemia, hypophosphatemia and PTH up
Reasons can be:
- primary HPT
- secondary HPT bc of hypo Vitamin D (f.e. chronic kidney disease)
- nutritional hypocalc -> secondary HPT
Clinical signs of hyperphosphatemia and hypophosphatemia?
signs of acute hyperphosphatemia = those of acute hypocalcemia:
tetany, hyperexcitability, muscle fasciculation, colic, and dysrhythmias.
Signs of chronic;hyperphosphatemia = those of calcium deficiency:
lameness, orthopedic pathologies, fractures, and osteodystrophia fibrosa (nutritional secondary hyperparathyroidism).
Architecture and function of adrenal gland
MEDULLA: chromaffin cells that produce Epi/norepi/dopamine in response to symp
CORTEX: outer zona glomerulosa: producing aldosteron (incr Na reabs, incr pot exc
zona fasciculata: secrets glucocort (cortisol) after ACTH stim
