OOC #2 Due: Friday, March 2, 2018, 5pm Overview CASE: A Day at the Beach, Lipid
ID: 203870 • Letter: O
Question
OOC #2 Due: Friday, March 2, 2018, 5pm
Overview
CASE: A Day at the Beach, Lipid Metabolism Case Study
This case is designed to help students understand the importance of fatty acid transport into mitochondria, the role of carnitine in this process, and the interconnections between carbohydrate and lipid metabolism in humans. You may work individually or in groups to complete this case study, but you must submit your own work in Canvas (“Enter your ooc #2 answers here”). You are encouraged to refer to your textbook throughout the case, and internet access is permitted, although it is not necessary for the completion of the case. You will need to iteratively acquire, analyze, and integrate data as you progress through the case and answer assessment questions found throughout the case. You are encouraged to carefully consider investigation options; guessing is discouraged. Your score on this assignment will reflect correct answers.
Learning Objectives
1) The real-world application of the study of human metabolism. You will:
• Use real biochemical tests to evaluate and ‘solve’ a metabolic disorder case
• Consider the importance of factors like personal and family history, diet, medications taken, and symptoms in solving a biochemical case
2) Connections between carbohydrate and fat metabolism in humans. You should be able to:
• Outline and explain the importance of carnitine-mediated fatty acid transport into mitochondria • Review fatty acid metabolism pathways and regulation
• Explain the importance of ketone body formation in human metabolism
3) Practice critical thinking skills involving data. Students will:
• Evaluate data provided by metabolite and enzyme tests • Integrate multiple pieces of biochemical data
“A Day at the Beach”, Lipid Metabolism Case Study
Introduction: =
Jessie knew she was late for the family reunion, probably too late for the big picnic lunch at Forest Lake Beach, but too early for the barbecue dinner. “Too bad” she thought, because she had skipped breakfast as well, trying to get out of the city and on the road to the lake. Perhaps there would be some leftovers; she hoped so, because she was beginning to get that slightly dizzy feeling that meant she was pushing her limits.
No leftovers, but the whole extended family was there: sitting and talking on the beach, playing Frisbee golf, and throwing a football. Some of the younger cousins were having swimming contests out from the floating platform at the edge of the swimming area. Jessie watched the kids swimming, and smiled sadly. She had been a competitive swimmer as a teenager and still missed it. As she watched the group of splashing children, Jessie began to think that something wasn’t right about a little boy off to the right of all the others. She put her hand up to shade her eyes from the sun and squinted; the kid was in trouble! He was throwing his arms around randomly, and thrashing the water into froth. None of the other children were close enough to notice, and there didn’t seem to be any other adults near enough to raise the alarm.
Without any further thought, Jessie ran into the lake, and after the first few lunges through the water, dove shallowly and began swimming towards the now sinking child. Her muscle memory kicked in and her strokes became fast, efficient, and powerful. With each stroke she raised her head enough to keep the small head in sight; she was making progress, but he was going down! She pushed harder, picked up speed, and then she saw him, underwater, sinking quickly despite his frenzied paddling. Jessie took a breath and dove; she grabbed the little guy’s surfer swim shorts, and kicked hard back toward the surface. She began the one-sided stroke that allowed her to keep his head above the water, and swam toward the beach, which seemed, strangely, to be disappearing into a haze. Jessie felt exhausted, but kept swimming, breathing in short gasps. Her vision narrowed, and she barely felt the sand under her knees as reached the shallow water. As the little boy was taken from her arms, Jessie lost consciousness.
Jessie woke up in the hospital emergency room, very weak and confused. She tried to sit up, but her arms and legs felt heavy, completely without strength. She was dizzy, disoriented, and exhausted. A gray-haired woman in a short white coat came into view, as well as a younger person dressed in scrubs.
“Hello, Jessie. Glad to see you’re finally awake. You were out for a pretty long time. I understand you are a hero; saved the day and your little cousin. Can you tell me what happened to make you faint? Did you hit your head, or swallow too much water? Everyone said that you were a really good swimmer, and so no one understood why you fainted.”
Jessie took a deep and unsteady breath. “I haven’t tried to swim that hard since I had a head injury, 5 years ago.” When the ER doctor asked Jessie if anything like this had happened to before, she looked sheepish and said “yes”. She recalled similar episodes, all under similar circumstances—“pushing herself too hard”.
Gathering Additional Information:
You are a biochemistry student who is shadowing the ER doctor. With the assistance of the physician, you may conduct additional investigations to determine the cause of Jessie’s incident. The goal of this exercise is to correctly solve the biochemical case without carrying out completely unnecessary investigations; hence, you are encouraged to carefully consider the information you receive with each investigation and avoid haphazard guessing. You will be scored on this exercise based on your answers to assessment questions found throughout the case so you are STRONGLY encouraged to use your textbook to complete this exercise; you may also use the internet as necessary.
RECOMMENDED INITIAL INVESTIGATIONS:
Evaluate overall physical appearance, including the presence of insect bites or other injuries Results: Subject is a young, adult female with a slim, athletic frame but otherwise appears normal.
Fecal analysis – Look for blood, intestinal parasites, high levels of fat in stool
Results:No blood or intestinal parasites were found. Levels of fat in the stool were normal considering the subject’s recent food intake.
Interview patient to determine dietary habits and look for neurological problems
Results:No abnormalities in cognitive function were found. Jessie reported being a strict vegan for many years; however, she claims to get a large amount of protein from plant sources. She also reports eating a high calorie diet and occasional, moderate alcohol consumption. She says that she is a non-smoker, does not use illegal drugs, and does not recall eating anything unusual recently; in fact, she had not eaten anything yet on the day of the fainting episode because she was in a rush. You ask whether she knows if she might be diabetic or has had any trouble in the past controlling her blood sugar levels and she responds by saying “I really don’t know.”
Investigate past medical history
Results:Jessie explained that she was on the verge of gaining a swimming scholarship to college when she injured her head in a rock climbing accident. Her head injury led to epileptic episodes that were now controlled by regularly taking anticonvulsant drugs. Swimming was one of the activities she gave up because of the fear of seizures. She reports that, since the accident, she has had less endurance, which she had always ascribed to the fact that she was no longer working out regularly. She sighed and said longingly, “I don’t swim anymore... don’t really do much of anything in terms of hard exercise. I am just miserably out of shape, I guess.” You ask whether she has had a blood test to look at her blood lipid profile recently and she responds that she has not had a full physical since she was dismissed from the hospital five years ago.
SECONDARY INVESTIGATIONS:
DETERMINE BLOOD SERUM CONCENTRATIONS OF: Common electrolytes: Ca2+, K+, Na+, Cl–, PO43-
Results: All values are in normal ranges. (normal ranges: [Ca2+] = 8.5–10.5 gm/dL; [K+] = 3.5–5.0 meq/L; [Na+] = 135–145 meq/L; [Cl–] = 100–106 meq/L; total phosphorus = 2.6–4.5 mg/dL)
2
Common lipids: free fatty acids (FFAs), triacylglycerides (TAGs), total cholesterol, and ketone bodies (acetoacetate as a marker)
Results: [FFAs] = 500 mg/dL (normal range: 190–420 mg/dL); [TAGs] = 175mg/dL (normal range: 40–150 mg/dL); [Total cholesterol] = 140 mg/dL (normal range: 120–200 mg/dL); acetoacetate was undetectable
1. Dietary fat is absorbed through the intestinal endothelial cells and then transported in the blood in the form of _______________ bound to or part of ________________?
Fatty acids; albumin
Fatty acids; chylomicrons
Fatty acids; apolipoproteins
Triacylglycerides; albumin
Triacylglycerides; chylomicrons
Acetyl-CoA; albumin
Acetyl-CoA; apolipoproteins
2. Lipids stored in adipose cells are released into the blood in the form of _______________ and transported in the blood bound to or part of ________________?
Fatty acids; albumin
Fatty acids; chylomicrons
Fatty acids; apolipoproteins
Triacylglycerides; albumin
Triacylglycerides; chylomicrons
Acetyl-CoA; albumin
Acetyl-CoA; apolipoproteins
3. Which of the following would you expect to be elevated in the blood of a person who has been fasting for 12 hours, compared to a person who has recently eaten a large meal with carbohydrate, protein, and fat? (Select ALL that apply!)
Free fatty acids (FFAs)
Ketone bodies
Glucose
Insulin
Glucagon
4. Jessie has elevated levels of TAGs and FFAs but normal cholesterol and no ketone body production. Elevated TAGs and FFAs would be expected in a person who is overweight or a person who has just eaten a large meal. If a person is fasting, then FFAs would likely be elevated but ketone body production would be expected as well.
Which of the following best explains why Jessie has these results? (Note: Depending on what investigations you have or have not conducted, you may not know, for example, whether Jessie is obese, ate recently, or what her diet consists of. You may want to conduct more investigations before attempting to answer this question.)
Jessie is obese.
Jessie recently ate a large meal.
People who are athletic like Jessie don’t produce ketone bodies, even when fasting.
Jessie is not producing ketone bodies solely because of her vegan diet.
All of the above.
None of the above.
The discovery that Jessie has elevated levels of TAGs and FFAs, but no ketone bodies has opened up a new investigation option! All of the blood-level data comes from just a single moment in time. It might be more informative to see how Jessie’s lipid levels respond to fasting. The new option is: Conduct a fasting metabolism study to monitor subject’s FFAs and ketone bodies in response to fasting
Glucose
Results:[Glc] = 60 mg/dL (normal range: 70–110 mg/dL)
Jessie is hypoglycemic. It is unclear from this test, however, whether she is just hypoglycemic right now, or has some longer-term issue with regulating her blood glucose levels, like Type I or Type II diabetes.
5. How might you test whether a person has had abnormally high or abnormally low blood glucose levels over a longer period of time (say, over a two-week period)? Hint: Review pages 321-322 of Stryer 8E before attempting this question.
Ask her to come in and submit to a blood test every day for two weeks.
Keep her confined to a hospital bed for two weeks and monitor her blood glucose.
Look at % body fat.
Measure insulin levels now.
Measure total hemoglobin levels now.
Measure glycosylated hemoglobin levels now.
The discovery that Jessie is hypoglycemic has opened up a new investigation option! The new option is: Measure blood levels of glycosylated Hb (HbA1c as a marker)
H3O+ ions: blood pH
Results:pH = 7.41 (normal range: 7.35–7.45)
Lactate and pyruvate
Results:[lactate] = 1.0 meq/L (normal range: 0.5–2.2 meq/L); [pyruvate] = 0.05 meq/L (normal range: 0– 0.11 meq/L)
NH4+ (total ammonia)
Results:[NH4+] = 45 mmol/L (normal range: 12–48 mmol/L)
O2 and CO2
Results: PO2 = 88 mmHg (normal range: 75–100 mmHg); PCO2 = 41 mmHg (normal range: 35–45 mmHg)
Total protein (mostly albumin)
Results:[total protein] = 4.9 g/dL (normal range: 6.0–8.0 g/dL)
SPECIFIC ENZYME TESTS
Asp amino-transaminases (AST) and Ala amino-transferase (ALT)
Results: Both enzymes are within normal range (normal range: 7–55 U/L) Aldolase
Results: [Aldolase] = 1.0 U/mL (normal range: 0–7 U/mL) Carnitine acyltransferases I & II (CAT I & CAT II)
Results: The activity of both transporters was found to be well below normal. Expression levels of both
proteins were actually slightly elevated, however.
Test cells for Electron Transport Chain enzyme activities Results: ETC enzyme activities were normal
Creatine kinase (CK)
Results:[CK] = 100 U/L (normal range: 40–150 U/L)
Glucose 6-phosphate dehydrogenase (G6PD)
Results:[G6PD] = 8 U/g Hb (normal range: 5–13 U/g Hb)
Lactate dehydrogenase (LDH)
Results:[LDH] = 150 U/L (normal range: 110–210 U/L)
Pyruvate dehydrogenase (PDH)
Results:PDH complex activity= 2.5 nmol/min•mg (normal range: 2–2.5 nmol/min•mg)
SPECIAL INVESTIGATIONS
Measure blood levels of glycosylated Hb (HbA1c as a marker)
Results: HbA1c = 3.2 % (normal range: 4–6.5%)
6. What relevant new information does this result provide?
Jessie is hyperglycemic right now.
Jessie has had abnormally elevated glucose levels in the blood over the past two weeks.
Jessie is hypoglycemic right now.
Jessie has had lower-than-normal glucose levels in the blood over the past two weeks.
7. Which of the following factors can affect the concentration of glucose in the blood? (Select ALL that apply!)
Ability to release insulin
Ability to respond to insulin (insulin sensitivity)
Ability to release and respond to glucagon
The availability of glycogen in the liver
The availability of gluconeogenic (also called glucogenic) substrates to fuel gluconeogenesis and glucose
export in the liver
The ability of the liver to produce ketone bodies when necessary
The discovery that Jessie has chronic, not just temporary, hypoglycemia indicates that she might have some problems with hormonal regulation of glucose metabolism (and/or another problem). To test the hypothesis that her hypoglycemia is due to a hormonal issue, you could have her take a glucose tolerance test and examine how her body responds to glucose in her diet. In this test, a person fasts and then swallows a solution of glucose. Changes in blood glucose as well as insulin and glucagon are followed over time. The following is now a new investigation that you may conduct: Conduct an oral glucose tolerance test to measure changes in insulin, glucagon, and blood glucose when oral glucose is administered.
Conduct an oral glucose tolerance test to measure changes in insulin, glucagon, and blood glucose when oral glucose is administered.
Results: Jessie fasted for 12 hours prior to the test, and her glucose, glucagon, and insulin levels were measured just before the test began. She was then given 75 grams of glucose in water to drink, and her blood was drawn and tested every 60 minutes for 5 hours. Results were as follows: She was hypoglycemic when the test began but otherwise showed completely normal responses to the glucose challenge (to be explained in greater detail in the following assessment questions!). In the very last hour, her blood glucose slowly decreased to below normal levels (hypoglycemia).
8. When a person has fasted for 12 hours before a test like this, blood glucose is still being used by the brain and other tissues. How is that glucose being replenished? (Select ALL that apply!)
Muscles run gluconeogenesis and export glucose into the blood.
Muscles run glycogenolysis and export glucose into the blood.
Large amounts of dietary glucose are still being absorbed from the digestive tract.
The liver runs gluconeogenesis and exports glucose into the blood.
The liver runs glycogenolysis and exports glucose into the blood.
The brain makes its own glucose from large amounts of glycogen stored in the brain.
Adipocytes breakdown TAGs to fatty acids and then convert those fatty acids to glucose, which is then
exported by the adipocyte.
9. A healthy individual who has fasted for 12 hours is expected to have glucose levels that are at the low end of the normal range. Their liver maintains glucose homeostasis through gluconeogenesis and glycogenolysis. What should this healthy person’s hormone levels look like at the start of the test (before glucose is administered orally)?
High insulin, high glucagon
Low insulin, low glucagon
Low insulin, high glucagon
High insulin, low glucagon
Low insulin, low glucagon
10. Within the first 30 minutes after glucose is administered orally, what should happen to the levels of insulin, glucagon, and glucose in the blood of a healthy individual?
Insulin rises, glucagon rises, glucose rises
Insulin falls, glucagon falls, glucose falls
Insulin rises, glucagon falls, glucose rises
Insulin falls, glucagon rises, glucose rises
Insulin rises, glucagon falls, glucose falls
Insulin falls, glucagon rises, glucose falls
11. What is happening in a healthy individual about an hour into a glucose tolerance test? (Note: At this early time- point, blood glucose levels are still high. Also, remember that a person who is taking a glucose tolerance test was fasting for 12 hours prior to the test!) (Select ALL that apply!)
Glucose is being exported by the liver.
Glucose is being taken up by the liver.
Glucose is being taken up by adipocytes.
Glycogen is being synthesized by adipocytes.
Triacylglycerides are being synthesized by adipose cells.
Glycogen is being synthesized by the liver.
Glucose is being taken up by muscle cells that are deficient in glycogen.
Glycogen is being synthesized by muscle cells where it is needed.
Glucose is being taken up by the brain.
Large amounts of glycogen are being synthesized by the brain.
12. In a healthy individual, glucose concentrations will spike but then return to normal levels during a glucose tolerance test. In a Type I diabetic, they will spike dramatically, due to a lack of insulin release and remain high. In a Type II diabetic, they will also spike dramatically, but due to a lack of insulin response (reduced sensitivity to insulin) and remain high. Jessie had normal glucose levels throughout the glucose tolerance test except that she was more hypoglycemic than normal at the beginning and the end of the test. Which of the following could explain her test results? (Select ALL that apply!)
Jessie is a Type I diabetic.
Jessie is a Type II diabetic.
Jessie may have a problem with gluconeogenesis in the liver resulting in lower than normal glucose
production during fasting.
Jessie may have a problem with the production of ATP from other sources, i.e., -oxidation of fatty acids,
which results in increased glucose uptake by tissues from the blood to compensate.
Jessie may have glucagon levels that are too high when fasting.
Jessie may have glucagon levels that are too low when fasting.
Jessie’s hormone levels were also examined during the glucose tolerance test: her insulin and glucagon levels responded normally to the test and returned to normal levels at the end (i.e., her glucagon levels are elevated but not abnormally high, as should be expected when she is fasted, and her insulin levels are low under those same conditions). She obviously has some other issue affecting her ability to maintain glucose homeostasis. Depending upon the other investigations you have already conducted, you may need to continue to conduct additional investigations to determine what is specifically wrong with Jessie to complete this case.
Conduct a fasting metabolism study to monitor subject’s FFAs and ketone bodies in response to fasting Results: A 40-hr fasting study was performed. Refer to the figure below to see how Jessie’s blood FFAs, and ketone body (acetoacetate and -hydroxybutyrate) levels changed during the fasting study. (Note that at the beginning of the study, she had just eaten!)
The physician who oversaw the study noted two things that were abnormal compared to a normal person who participates in the same fasting study:
1. Healthy individuals produce significant levels of ketone bodies by the end of the 36-hour fast whereas Jessie produced barely any.
2. The study was abruptly halted after only 36 hours because Jessie fainted again! Fasting for 36 hours is clearly not safe for Jessie! Depending on what other investigations you have already conducted, it may or may not be clear why Jessie would faint during this study but her glucose levels are something that would be important to investigate if you have not already...
13. Consider how the carbon from fatty acids is ultimately converted into ketone bodies. The build-up of fatty acids and the lack of significant ketone body formation could be explained by a deficiency in only a single biochemical pathway. What is it?
Glycolysis
Gluconeogenesis
The reactions catalyzed by the PDH complex
The citric acid cycle
-oxidation
The pentose phosphate pathway
14. In what organ or tissue are fatty acids broken down into acetyl-CoA to be turned into ketone bodies?
The brain
Adipose tissue
Muscle
The liver
The skin
The pancreas
The discovery that Jessie has very low levels of ketone body formation and a build-up of free fatty acids could be explained if -oxidation is somehow blocked, but how it is blocked is unclear. Consider that Jessie did not always have these problems. Consult your textbook to review the reactions and processes necessary to convert palmitate (from a TAG) all the way to acetoacetate (Pages 648-652 and 657-660, Figures 22.22 and 22.24 of Stryer 8E). Review the text and continue with the case.
15. There are multiple possible explanations for how and why -oxidation might be blocked. Consider that there could be an inborn error in metabolism (a polymorphism in a gene coding for an enzyme in the pathway), a vitamin deficiency leading to the lack of enzyme action, or a problem with the transport of fatty acids into the mitochondria among other possibilities. You call your biochemistry professor up to ask for any ideas about how to proceed and she/he suggests that you consider looking at whether Jessie can metabolize short-chain fatty acids (12 or fewer carbons). When you ask why, your professor tells you to consult your book if you are unclear about what this might accomplish. What is different about the metabolism of short-chain fatty acids compared to long-chain fatty acids? Hint: Review pages 649-650 of Stryer 8E to answer the question. Note: the relevant section on these pages of this textbook refers specifically to “medium-chain (C8-C10) fatty acids”. In this case study, we will simply consider any fatty acid 12 carbons or shorter to be “short-chain”.
Short-chain fatty acids are not catabolized by -oxidation.
Short-chain fatty acids do not require the carnitine-shuttle to enter the mitochondria.
Short-chain fatty acids are catabolized by humans and used to produce pyruvate for gluconeogenesis.
Short-chain fatty acids are not catabolized in the mitochondria.
All of the above.
None of the above.
The fatty acid chains in TAGs and phospholipids are generally 14 carbons long or longer. Because the majority of dietary lipids come from TAGs and phospholipids of other organisms, short-chain fatty acids are neither prevalent in the human diet (with a few exceptions like coconuts!) nor are they produced by lipolysis of TAGs stored within the body. As such, the lipid metabolism we have studied in Jessie’s body has been primarily long-chain fatty acid metabolism. Because short-chain fatty acids do not require special transport, it might be informative to see how Jessie’s body responds to short-chain fatty acids. You have opened up a new investigation option! The new option is: Investigate short-chain (12 carbons or less) fatty acid metabolism: Monitor ketone body formation in the blood
Investigate short-chain (12 carbons or less) fatty acid metabolism: Monitor ketone body formation in the blood
Results: Interestingly, when Jessie was fed a solution containing short-chain fatty acids and again fasted, plasma acetoacetate and -hydroxybutyrate concentrations increased.
16. What does this result tell you about Jessie?
Nothing
Something, but not clear what
One of the enzymes of the -oxidation pathway must be deficient.
There must be a problem with long-chain fatty acid transport, not with -oxidation.
There must be a problem with lipolysis of TAGs to produce FFAs.
17. If Jessie has a problem transporting fatty acids into the mitochondria for -oxidation, then there may be another consequence that we have not yet uncovered! Consider this question: what do you think would happen to fatty acids that arrive at the liver for -oxidation but then cannot be metabolized because they cannot enter the mitochondria? (Hint: They are not transported back to adipose tissue or excreted in the urine!)
They are stored as TAGs in the liver.
They are exported back into the blood and used by the brain.
They are used by the liver to make glucose.
They are used by the liver to make ketone bodies.
If the hypothesis that ‘long-chain fatty acid transport into the mitochondria is deficient’ is correct, then we might expect Jessie to have unusual fat deposition in the liver. This is common in people suffering from obesity or diabetes, but uncommon in a fit, young person. Excessive fat accumulation in the liver may lead to loss of liver function. You have opened up a new possible investigation! It used to be necessary to actually remove a piece of the liver (biopsy) to measure fat content, which can be dangerous. In the last few years it has become possible to measure liver fat with a Magnetic Resonance Imaging (MRI) scan. The new investigation option is: Conduct an MRI to determine liver fat levels.
Conduct an MRI to determine liver fat levels.
Results:Concentrations of liver fat were found to be 12%. (normal range = 3–5.5%)
18. These results confirm that fat is indeed being deposited in Jessie’s liver, a health hazard that Jessie was completely unaware of! Jessie’s liver fat concentration supports the hypothesis that fatty acid oxidation is impaired. Jessie is very grateful for your help so far. In a previous investigation you also found evidence that the specific problem is likely to be the inability to transport long-chain fatty acids into the mitochondria, since short- chain acids are processed normally. The exact problem and cause still remain to be determined, so you must continue with your investigations. Consider this question before returning to additional investigations: Which of the following proteins are involved in the transport of long-chain fatty acids into the mitochondria? (Select ALL that apply!)
Pyruvate dehydrogenase
Carnitine acyltransferase I (CAT I)
Citrate synthase
Carnitine acyltransferase II (CAT II)
Aldolase
Acyl-CoA dehydrogenase
You have uncovered a number of important clues, but depending upon which other investigations you have already conducted, you may need to continue to conduct additional investigations to determine what is specifically wrong with Jessie to complete this case.
“Conduct an MRI to determine liver fat levels”
“Conduct an oral glucose tolerance test to measure changes in insulin, glucagon, and blood glucose when oral glucose is administered”
“Specific Enzyme Test: Carnitine acyltransferases I & II (CAT I & CAT II)”
You have uncovered almost all the information necessary to explain Jessie’s health issues, but something still does not add up: specifically, why is she having these problems now and not all of her life? For example, if she has an inborn error of one of the genes encoding for CAT I or CAT II, you would expect that she would have always suffered from bouts of hypoglycemia. You discuss all the results with the physician you are working with and she suggests that you never actually asked Jessie what medication she was taking for the seizures she was having! It may be nothing, but what an oversight! The following new investigation is now available:
Ask again about past medical history including a list of current medications
Results: She reported, “I take an anticonvulsant drug, valproic acid, to control the seizures. Why, what does that have to do with anything?”
You have a new instigation option: "Investigate the physiological side effects of valproic acid"
Investigate the physiological side effects of valproic acid
Results:You quickly look up the side effects of valproic acid on your smart phone; it can cause nausea and vomiting, anorexia, carnitine deficiency, and abnormal bleeding, in patients on certain diets. You ask Jessie, and she says that she has experienced none of these—as far as she knows...
The investigation into the potential side effects of valproic acid has opened up seven new investigation options! Review your previous results so far in this case and consider whether this new information provides any logical explanation for Jessie’s odd metabolic limitations. What would you like to investigate next? The new options opened are:
Ask Jessie to think hard about whether she has been vomiting recently
Ask Jessie to think hard about whether she might have a carnitine deficiency Look for abnormal bleeding in the GI tract
Measure blood levels of carnitine
Measure blood levels of CoA
Measure blood levels of valproic acid
Send Jessie to a counselor to discuss the possibility that she might be anorexic
Ask Jessie to think hard about whether she has been vomiting recently
Result:Jessie restates that she has not had any bouts of nausea or vomiting recently. She is mildly annoyed by this question.
Ask Jessie to think hard about whether she might have a carnitine deficiency
Result:Jessie responds with a puzzled look and says: “Umm... I don’t think so...but what is carnitine anyway?” The physician you are shadowing steps in and clarifies that Jessie would not know whether she has a carnitine deficiency or not.
Look for abnormal bleeding in the GI tract
Result:You request that Jessie submit to an endoscopy and a colonoscopy. However, the physician you are shadowing disagrees with you - this is not a necessary set of procedures since Jessie does not report any bleeding and does not have any other apparent symptoms that would justify doing these procedures. She also notes that bleeding in the GI tract, even if it is found, does not explain the symptoms that Jessie is exhibiting.
Send Jessie to a counselor to discuss the possibility that she might be anorexic
Result:Jessie is deeply insulted by the insinuation; she has already stated that she eats a high calorie, but vegan, diet and takes your suggestion as an insinuation that she has been lying to you. She restates that she eats regularly and abundantly.
Measure blood levels of carnitine
Result:[Carnitine] = 5 mol/L (normal range: 24–64 mol/L)
Jessie has a severe carnitine deficiency! Carnitine is synthesized in humans from the amino acids methionine and lysine, but it is also acquired in the diet. As the name implies, carnitine is especially abundant in meat and dairy products. Because a typical omnivorous diet provides ~75% of a person’s carnitine, carnitine is sometimes considered a vitamin. However, since it can be synthesized de novo means that it is not a true vitamin. Valproic acid depletes carnitine stores in the body by multiple mechanisms but rarely results in true carnitine deficiency in most people. Something to consider: Why is Jessie experiencing carnitine deficiency? Is there any other aspect about her that might make her particularly sensitive to this side-effect of valproic acid?
Measure blood levels of CoA
Result:Levels of Coenzyme A are normal
Measure blood levels of valproic acid
Result:Valproic acid and its metabolites are detected in the blood. Levels are normal and appropriate for the dose that Jessie is taking to control her seizures
ENDING THE CASE AND THE ASSESSMENT QUESTIONS:
You have finished gathering information for this investigation, should be able to fully explain the reason(s) for Jesse’s incident in biochemical and physiological terms, and be able to fully justify and completely explain your reasoning based on the evidence gathered.
Interview patient to determine dietary habits and look for neurological problems Investigate past medical history
Measure blood levels of carnitine
If all of the criteria are not met, you are missing vital information to sufficiently explain this incident. You may be overlooking factors related to Jesse’s physiological state at the time of the accident or your investigation may not be detailed enough. Review your options and try to select options that would provide more information relevant to Jess’s condition. Try to think about what details you still cannot fully explain.
If you have reviewed your options and still need help, you may hire an outside consultant to review this case to provide guidance about what you might be missing. This person reviews your notes and gives you this helpful advice: In this case, it is important to consider the details that would cause abnormalities in Jesse’s physiological (metabolic) state at the time of the accident. You should completely examine her regular dietary habits, her past medical history, and her blood glucose and lipid levels. You should also make sure that you continue as in depth as possible in these lines of investigation.
Final Assessment Questions for “A Day at the Beach”:
19. Which of the following metabolic changes will occur in a typical human after a meal balanced in carbohydrates, protein, and fat is consumed? (Select ALL that apply!)
Liver glycogen synthesis increases.
Muscle glycogenolysis increases.
Liver gluconeogenesis decreases.
Insulin levels in the blood decrease.
Ketone body production in the liver is increased.
20. Which of the following metabolic changes will occur in a typical human during 12 hours of fasting? (Select ALL that apply.)
Liver glycogen synthesis decreases.
Liver glycogenolysis decreases.
Liver gluconeogenesis increases.
Liver fatty acid oxidation increases.
Ketone body formation increases.
21. Fatty acids in the bloodstream that are NOT part of TAGs or phospholipids: (Select ALL that apply!)
Are present at levels that are independent of epinephrine, glucagon, or insulin levels
Are carried by the protein albumin
Are soluble in the aqueous phase of the blood in free form
Are nonexistent; the blood only carries ketone bodies
Are carried as part of the lipid bilayer of LDLs and chylomicrons
Originate primarily from stored TAGs in adipose tissue
Originate primarily from dietary fats that have just been released into the bloodstream from intestinal cells
22. Which of the following statements about ketone bodies is/are true? (Select ALL that are true.)
One cause of ketone body formation can be that oxaloacetate is being used up by continuous gluconeogenesis during starvation, slowing the TCA cycle.
The production of ketone bodies frees up molecules of CoA so that -oxidation can continue.
Ketone bodies are produced only during vigorous exercise.
Ketone bodies provide an alternate substrate for glycolysis in the brain.
Ketone bodies are formed in the brain when -oxidation is interrupted.
23. Marasmus is the medical term for the condition that results from overall calorie starvation. In developed countries like the US, it is relatively uncommon. However, there is a common psychological illness, anorexia nervosa that results in the same symptoms and problems as marasmus. Both conditions result in high ratios of glucagon to insulin. Having a high ratio of glucagon to insulin would do which of the following in most healthy people? (Select ALL that apply!)
Promote mobilization of fatty acids from adipose tissue
Result in increased glycogen storage by the liver
Stimulate -oxidation by inhibiting the production of malonyl-CoA
Lead to increased concentrations of ketone bodies in the blood
24. What single problem in metabolism best explains Jessie's condition?
Jessie suffered from hypoglycemia due to anorexia.
Jessie was suffering from a deficiency of carnitine.
Jessie has a genetic disorder of CAT I or CAT II.
Jessie’s has a vitamin deficiency.
Jessie has a shortage of long-chain fatty acids.
Jessie has late-onset diabetes.
25. What are some of the expected physiological consequences of a carnitine deficiency? (Select ALL that apply!)
Depletion of stored fat in adipocytes
Inability to metabolize short-chain fatty acids
High levels of circulating fatty acids
Chronic hypoglycemia when fasted
Impaired ability to produce ketone bodies
Inability to catabolize glucose to pyruvate
26. At the biochemical level, why does a carnitine deficiency lead to impaired ketone body formation?
Loss of -oxidation in the liver results in an inability of the brain to transport fatty acids from the blood into the cells to make ketone bodies.
Ketone bodies are made directly from carnitine in humans.
Ketone bodies are primarily produced from the acetyl-CoA produced from -oxidation of the fatty acids of
stored triglycerides, but -oxidation cannot occur without carnitine-mediated fatty acid transport.
Carnitine is necessary for fatty acid transport into liver cells, so deficiency prevents -oxidation and the
absence of -oxidation prevents ketone body formation.
Carnitine deficiency does not impair ketone body formation.
27. At the biochemical level, why does a carnitine deficiency lead to increased fat deposition in the liver?
In the absence of carnitine, the liver stores large amounts of glycogen, which is converted into fatty acids and stored as TAGs within the liver.
Carnitine is an activator of hepatocellular TAG lipases; as a result, in the absence of carnitine, lipase activity is turned off, favoring TAG synthesis.
Because -oxidation is blocked, fatty acids arriving to the liver from the blood cannot be oxidized and are instead stored in intracellular lipid droplets.
Carnitine is an inhibitor of fatty acid synthesis; as a result, in the absence of carnitine, fatty acid synthesis is stimulated, leading to an increase in stored TAGs in the liver.
28. Why did Jessie’s carnitine deficiency cause her to have abnormally low plasma glucose levels at the end of a fasting study, when compared to a healthy person who has fasted for the same length of time?
In the absence of carnitine, the liver stores large amounts of glycogen; absorption of glucose to create these stores depletes blood glucose.
Carnitine acts as a hormone and stimulates glucose release from the liver; lack of carnitine results in loss of hepatic glucose production, which leads to hypoglycemia.
In the absence of carnitine, fatty acids cannot be used for energy nor can ketone bodies be produced in large quantities; tissues like the muscle, heart, and brain can only use glucose under these conditions. This drives excessive glucose uptake from the blood, depleting glycogen stores in the liver and resulting in hypoglycemia.
In the absence of carnitine, fatty acid transport into the mitochondria requires a large amount of ATP; to produce the additional ATP required the liver must oxidize glucose, which depletes glycogen stores, causing hypoglycemia.
In the absence of carnitine, Jessie’s muscles could not use fatty acids as substrates for glycolysis.
29. A deficiency of a particular protein in the liver causes the liver to become enlarged and fatty and causes a reduction of ketone bodies in the blood. In the muscle, deficiency of this same protein causes recurrent muscle weakness, especially during fasting or exercise. This protein is normally found on the outside surface of the outer mitochondrial membrane. It normally releases free CoA-SH as one of its products. People with this deficiency would be particularly sensitive to some of the side effects of valproic acid. What is this protein?
Citrate synthase
Carnitine acyltransferase I
Carnitine acyltransferase II
Fatty-acyl-CoA synthetase
Hormone-sensitive lipase
30. Is there anything about Jessie that would make her particularly sensitive to the side effects of valproic acid or was her carnitine deficiency just a rare and accidental occurrence?
No, Jessie is just unlucky but there is nothing else about her that contributed to this problem.
Yes, Jessie is not likely getting adequate carnitine in her diet.
Yes, Jessie is a Type II diabetic.
Yes, Jessie has an inborn error of metabolism that affects lipid transport.
31. Based on all the evidence you have gathered in this case, and your answers to previous questions, what do you think caused Jessie’s fainting episode? (Select ALL the relevant factors that should be included in a complete explanation of her biochemical/medical issues!)
Jessie’s medication
Jessie’s diet in the days leading up to the episode
Jessie is a Type II diabetic
Jessie’s diet the day of the episode
Jessie has an inborn error of metabolism that affects lipid transport
Jessie is a type I diabetic
Jessie has chronic hypoglycemia as a result her inability to adequately metabolize most fatty acids Jessie lost consciousness due to severe hypoglycemia because the overexertion from her swim further depleted her blood glucose
32. she does not deal with her carnitine deficiency, what future health problems do you predict for Jessie?
An increase in ketones during any fasting periods
The development of type-II diabetes as she ages
Increased levels of -oxidation, leading to fat deposits in the muscle and liver cells.
Low levels of free fatty acids in the blood due to Jessie’s inability to mobilize fatty acids from adipose tissue. Because of a build-up of fatty acids in the blood, she may have pathological deposits of fat in liver and muscle tissues.
33. In your personal investigation of the case, you may or may not have discovered that Jessie had decreased levels of total blood protein and elevated levels of ammonia. Considering the metabolic consequences of her carnitine deficiency, why might this be? (Select ALL answers that would be part of a complete explanation!)
Ammonia is produced from short-chain fatty acid oxidation and inhibits protein synthesis
Because Jessie has reduced glycogen stores and hypoglycemia, her liver must run gluconeogenesis to
provide glucose for the brain.
Deamination of amino acids produces ammonia
Because Jessie cannot produce ketone bodies, her brain must rely solely on blood glucose as its source of
energy
Normally, ketone bodies may be converted into glucose to feed the brain, but Jessie cannot make ketone
bodies, so she cannot make glucose from this source and has to degrade proteins in order to do so.
Under starvation conditions, non-essential proteins are catabolized to release glucogenic amino acids
which can be deaminated to provide carbon skeletons that serve as gluconeogenic substrates
Explanation / Answer
Fats have a different mechanism of absorbtion compared to other compounds because of thier nature .All the dietary fats are incorporated in triglyceride which is transported as chylomicrons .
All the fas stored in adipose tissue is broken in fatty acids .since fatty acids are insoluble in water Therefore they are transported bound to albumin.
In case of fasting ,glucagon level in the blood increases ,it causes the breakdown of fats stored in adipose tissue and therefore the level of fatty acids increases ,plus in order to supply ketones to brqin ,liver also start making increasing amount of ketones .
4)none of the above because for ketone body production has nothing to do with being obese .athletic etc
The most probable reason is that ketone body production requires alltleast 12-24 hours fasting before that gluconeogenesis can maintain the blood glucose for the brain .
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