Chapter 1. An Unexplained Death
1.1 Introduction
Case Study: The Runner's Experiment
By Justin Hines, Lafayette College and Marcy Osgood, University of New Mexico
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Instructor Notes for “An Unexplained Death”, Carbohydrate Metabolism Case Study
Topic Pre-requisites: Students should have exposure to the topics of Chapters 14 and 16 in Lehninger POB, 6th ed.
Overview
This case is designed to help students understand the importance of vitamins as precursors of coenzymes as well as to provide a context to review the reactions of glycolysis, the pentose phosphate pathway, the pyruvate dehydrogenase complex, and the citric acid cycle. As such, we have anticipated that students will have been exposed to material in the textbook through Chapter 16 of Lehninger POB, 6th ed.,before beginning the case (Chapters 14 and 16 are essential).
Students may work individually or in groups to complete this case study. Students are constantly encouraged to refer to their textbook throughout the case, and internet access is permitted, although it is not necessary for the completion of the case. Students are required to iteratively acquire, analyze, and integrate data as they progress through the case and answer assessment questions found throughout the case. All assessment questions are automatically scored.
The case will also keep track of the number of investigations that students conduct and report this number to the instructor; students are made aware of this fact as a means to encourage careful consideration of investigation options and discourage guessing. It is entirely up to the instructor what to do with this information; we suggest potentially rewarding students who solve the case efficiently and/or penalizing students who obviously used blanket guessing (evident by the use of all or nearly all investigative options). For reference: there are 29 total investigative options within the case and 8 are minimally required to complete the case. We anticipate that careful students will typically make use of 12 to 20 options in solving this case.
Finally, there is an optional section called “Extending your understanding beyond the case” that instructors may choose to include or exclude from the case. As the title implies, these questions extend to related information in the textbook but are not critical to the case itself. When assigning the case, you will be asked whether you would like to include this material.
Learning Objectives
This case is intended for remediating or extending student capabilities in these difficult topics:
- The real-world application of the study of human metabolism. Student will:
- utilize 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.
- explain why alcohol abuse can result in vitamin deficiency.
- Critical aspects of human central metabolism. Students will:
- review reactions of
- glycolysis
- the pentose phosphate pathway
- the pyruvate dehydrogenase complex (including cofactors involved)
- the citric acid cycle (with consideration of reversible vs. irreversible reactions)
- understand the role of vitamins as precursors of coenzymes.
- Appreciate the importance of coenzymes in enzyme function and human health.
- explain how vitamin deficiency can cause disease.
- explain the importance of thiamine, specifically in heart and brain function.
- review reactions of
- Practice critical thinking skills involving data. Students will:
- evaluate data provided by metabolite and enzyme tests.
- integrate multiple pieces of biochemical data.
Some questions are designed to show areas of difficulty for students
- The case connects a behavior (alcohol abuse) to specific organ failure. Students may find it challenging to connect all the dots. Our intention is to demonstrate how behavioral choices may lead to vitamin deficiency, how vitamin deficiency can lead to a loss of specific enzyme function (a connection to Chapter 6 of Lehninger POB, 6th ed.), and how tissue-specific differences in metabolic needs may then lead to specific organ failure.
- The reason why beriberi often leads to heart failure may be unclear to students.
- The description of Wernicke-Korsakoff syndrome in the textbook (page 580 in Lehninger POB, 6th ed.) provides an additional interesting perspective on vitamin deficiencies--specifically, that additional genetic polymorphisms influence the way different people respond to the same physical challenges. In this case, mild beriberi causes profound mental deficiencies in people with these polymorphisms. Some of the assessment questions in the optional “Extending your understanding beyond the case” section address this interesting but complex issue.
- Some of the assessment questions in the optional “Extending your understanding beyond the case” section present an opportunity to point out the physiological reversibility of some of the reactions of the citric acid cycle, an often overlooked aspect of the cycle.
- Author note: A common error is to jump immediately into testing a ‘pet’ hypothesis by conducting laboratory tests (metabolite assays or enzyme assays) before exploring “data gathering” options like visual inspections, an autopsy, or interviews with people who knew the victim. This is an excellent and intentionally designed opportunity to point out a common mistake about the scientific method--that is, it begins with making careful observations, rather than by immediately testing quickly formed hypotheses.
Suggested implementation
Below we describe two options for course implementation. The hybrid Online/In-class approach is recommended. Time required for students to complete the online case will vary by group depending on the level of discussion between each investigation. The case study can be started and stopped, and so it is recommended to give students a window of 2 to 3 days in which to complete the assignment.
Hybrid: Online/In-class: (recommended approach; ~30 minutes of class-time expected)
- Share the case study link with your students to work online outside of class, preferably in pairs or groups of three. Assign the case study to be due before your next class meeting. Students should be instructed to bring copies of notes and/or printed answers to assessment questions to the following class period.
- Review the online answers before the following class for difficult areas for students (see expected areas of difficulty above).
- Lead students in a discussion in pairs, groups, or as a class (depending upon class size and instructor preference) to address unresolved difficulties (~30 minutes in-class time).
- We recommend that you select questions from the supplied assessment questions to use on exams or as homework assignments to reinforce the difficult concepts covered. Please see document “Exam Questions for Case 2: Carbohydrate Metabolism.”
Online only approach: (minimal in-class time required)
- Share the case study link with your students to work online, preferably in pairs or groups of three. Assign the case study to be due before your next class meeting.
- Review the online answers for difficult areas for students (see expected areas of difficulty above).
- Mention or remediate tough points during a portion of lecture.
- We recommend that you select questions from the supplied assessment questions to use on exams or as homework assignments to reinforce the difficult concepts covered. Please see the document “Exam Questions for Case 2: Carbohydrate Metabolism.”
Suggestions for in-class discussions (these questions may also be used in summative assessments-- i.e., exams, scored quizzes, etc.):
- What were some of the most important facts about the case that were revealed without the use of specific enzyme tests?
- Students could be directed to brainstorm in groups or as a whole class.
- Why was it important to examine the activity of the three enzymes that make up the PDH complex individually and how did the information you acquired from this test help you solve the underlying problem?
- How does alcoholism relate to this case?
- Students could be directed to brainstorm in groups or as a whole class.
- What are the similarities between the pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase both in terms of the enzymes that catalyze the reactions and in terms of the types of reactions each catalyzes?
- Why does beriberi cause heart failure?
- Could be easily used as a think-pair-share exercise.
- Alternatively, students could first answer this question individually in writing, and then those responses could be collected or discussed in groups and revised.
Note: the final two discussion points refer to the optional questions at the end of the case that may be assigned and completed online at the discretion of the instructor.
- What is Wernicke-Korsakoff syndrome and how does it relate to this case? Is this syndrome the cause of the person’s death in this case? Why or why not?
- Could be easily used as a think-pair-share exercise.
- Alternatively, students could first answer this question individually in writing, and then those responses could be collected or discussed in groups and revised.
- The last assessment question of the case was particularly challenging. Form a group to discuss and answer this question. Why is it that when there are inborn errors in either α-ketoglutarate dehydrogenase, succinate dehydrogenase, or fumarase, the levels of α-ketoglutarate in the urine tends to rise no matter which of the three enzymes is defective?
- Group work is suggested here due to the difficulty of the question.
You are missing vital information
You are missing vital information to sufficiently explain this incident. You may be overlooking factors related to this man’s physiological state at the time of his death or your investigation may not be detailed enough. Review your options and try to select additional options to either discover new physiological abnormalities or to explore more deeply any that you have already uncovered. Try to think about what details you still cannot fully explain.
You are missing vital information
You are missing vital information to sufficiently explain this incident. You may be overlooking factors related to this man’s physiological state at the time of his death or your investigation may not be detailed enough. Review your options and try to select additional options to either discover new physiological abnormalities or to explore more deeply any that you have already uncovered. Try to think about what details you still cannot fully explain.
I have reviewed my options and I still need help. I would like to hire an outside consultant to review this case to provide guidance about what I might be missing.
The consultant reviews your notes and gives you this helpful advice: In this case, it is important to consider the details that would cause abnormalities in this man’s physiological (metabolic) state at the time of his death. You should completely examine the state of his body, his dietary habits, his medical history, and possible problems he might have had that are evident in his blood. For example, you may or may not have discovered that his blood is acidic… what are the possible causes for this? You should also make sure that you continue as in depth as possible in these lines of investigation as it is possible that there is a singular and specific reason for the failure of this man’s heart.
A 65-year-old man of Scandinavian descent was rushed to the Emergency Room of your local hospital after a family member discovered him unconscious in his home. The woman who dialed “911” told the dispatcher that the man, her brother, was the local librarian of the past 10 years and had no spouse or children. She reported that they had spoken the day before, and he had acted strangely on the phone. She says that she came by the house to check on him. Upon arriving at the hospital, he went into cardiac arrest and could not be resuscitated. Upon seeing the man, one of the physicians gasped, recognizing him as the winner of the state lottery a few years before. She had attended high school with the man and knew that he had a difficult time dealing with his new-found wealth; he preferred to keep to himself. You are shadowing the local coroner, who would like your assistance in determining what might have caused the man’s sudden health failure. Because a substantial inheritance will pass to the sister who reported discovering the man unconscious, the police have ruled the death “suspicious” and have asked you to be unusually thorough in your investigations to determine the specific cause of death.
1.2 Introduction (continued)
With the assistance of the coroner, you may conduct additional investigations to gather information about the case. The goal of this exercise is to correctly solve the case without conducting completely unnecessary investigations; hence, you are encouraged to carefully consider the information you receive with each investigation and avoid haphazardly guessing. You will be scored on this exercise based on your answers to assessment questions found throughout the case and so you are STRONGLY encouraged to use your textbook to complete this exercise; you may also use the internet as necessary.
Please note that there is a minimum set of investigations that must be conducted in order to have all the necessary information to fully understand the case. The number of investigations you select will be recorded and reported to your instructor, so randomly guessing could adversely affect your score. You should be both thorough and thoughtful in conducting your investigation. Hint: we recommend that you first thoroughly exhaust the use of broader initial investigation options, like interviewing someone, before proceeding to test specific hypotheses by performing more specific tests for particular enzyme activities, for example.
1.3 Investigation Options for Proceeding with the Case
RECOMMENDED INITIAL INVESTIGATIONS
Conduct an autopsy to evaluate the condition of major internal organs.
Results: An unusual amount of fluid was found throughout the body, causing swelling of tissues and lower extremities; excess fluid can be an indicator of cardiac malfunction.Nothing unusual was found in the man’s stomach; in fact, there was very little organic matter found within his digestive tract, indicating that he had not consumed much solid food in the past 24 hours. No blood or intestinal parasites were found. Mostmajor organs looked normal considering the age and overall health of the subject; however, considerable fat deposition in the liver and cirrhosis (scarring, indicative of liver damage) was observed. Notably, liver in this condition could be associated with undiagnosed diabetes. The coroner concludes, however, that liver failure (due to cirrhosis) was NOT the cause of death; cause of death is declared to be heart failure for unknown reasons.
Question 1.1
Which of the following molecules can the heart use for energy? (Select ALL that apply!) (Hint: Read the information about the heart on page 948 of Lehninger , 6th ed.)
| A. fatty acids | uS+xJY+rPntALoOB |
| B. glucose | uS+xJY+rPntALoOB |
| C. nucleic acids | Fd/yhwSeUQ6ZqQj4 |
| D. ketone bodies | uS+xJY+rPntALoOB |
| E. amino acids | Fd/yhwSeUQ6ZqQj4 |
Question 1.2
Under normal conditions—that is, in a well-fed, healthy individual--which of the following molecules would you expect to be primarily used by the heart for energy? (Mark "yes" for ALL that apply!)
| A. fatty acids | uS+xJY+rPntALoOB |
| B. glucose | uS+xJY+rPntALoOB |
| C. nucleic acids | Fd/yhwSeUQ6ZqQj4 |
| D. ketone bodies | Fd/yhwSeUQ6ZqQj4 |
| E. amino acids | Fd/yhwSeUQ6ZqQj4 |
Evaluate overall physical appearance, including the presence of insect bites or other injuries.
Results: The subjectdoes not appear to be particularly physically fit and shows a moderate to high amount of abdominal fat and low muscle tone; however, this is not uncommon for an American male of his age. Notably, the subject’s legs are swollen and spongy to the touch. Otherwise, the subject appears normal for a 65-year-old male.
Interview the patient’s co-workers to determine his dietary habits.
Results: Coworkers describe him as forgetful and perpetually late to work, both likely due to his suspected alcohol consumption habits; they report that he often smelled of alcohol and kept a flask of whisky in his desk. Nonetheless, he was rarely negligent in his work and otherwise appeared healthy, so everyone you speak to is shocked at his sudden death. As far as anyone knows, he ate a normal diet, although no one recalls seeing him eat much. He was never seen smoking and gave no indications that he used any illicit drugs. However, the night janitor noted that the man had had some trouble walking the last time he had seen him working in the library. When the janitor attempted to help him to a cab, he appeared confused as if he was unclear where he was and where he was going.
Investigate the patient’s medical history, including current medications.
Results: The man has a medical record on file. You find that he was negligent in getting annual physicals, having last been seen by a doctor 9 years and 5 years earlier. During both visits, the doctor made a note that he recommended the man reduce his alcohol consumption, increase his exercise regimen, and begin taking a multivitamin. The doctor noted that the man is likely an alcoholic, based on his answers to interview questions. Alcoholics often have nutritional deficiencies due to poor diet, low total food intake (consuming most calories in the form of ethanol), and the inhibition of vitamin absorption by the digestive system. High alcohol intake can also cause ketone body production because large quantities of ethanol are metabolized to acetyl groups present as acetyl-CoA. It is notable that the man must not have taken his doctor’s advice the first time it was given…it is unknown if he did anything differently after the second visit. No other relevant preexisting conditions were found and no medications were listed.
Test the blood and various tissues for common poisons.
Results: No common poisons were found in a toxicology test.
Test hair for common toxins (heavy metals and narcotics).
Results: No heavy metals or narcotics were detected.
SECONDARY INVESTIGATIONS
Determine Blood Serum Concentrations
common lipids: free fatty acids (FFAs) and triacylglycerols (TAGs)
Results: 450 mg/dL FFAs (normal range: 190–420 mg/dL); 200 mg/dL TAGs (normal range: 40–150 mg/dL)
galactose
Results: [Glc] = 75 mg/dL (normal range: 70–110 mg/dL)
H3O+ ions: blood pH
Results: pH = 7.0 (normal range: 7.35–7.45)
Question 1.3
A number of factors can lower blood pH. Which of the following are common reasons why someone might have metabolic acidosis? (Mark “yes” for ALL that apply!) Hint: Review pages 67, 79, 563–564, and 688 from Lehninger 6E as needed to answer this question.
| a. increased levels of CO2 in the blood | uS+xJY+rPntALoOB |
| b. increased levels of Na+ in the blood | Fd/yhwSeUQ6ZqQj4 |
| c. increased levels of lactic acid in the blood | uS+xJY+rPntALoOB |
| d. increased levels of lactic acid in the blood | Fd/yhwSeUQ6ZqQj4 |
| e. increased levels of O2 in the blood | Fd/yhwSeUQ6ZqQj4 |
| f. increased levels of ketone bodies in the blood | uS+xJY+rPntALoOB |
Determine blood levels of common electrolytes: Ca2+, K+, Na+, Cl-, PO43-
Results: All values are in normal ranges. (normal ranges: [Ca2+] = 8.5–10.5 mg/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)
Determine blood levels of ketone bodies: acetoacetate as a marker .
Results: detectable levels of acetoacetate were found; however, they do not indicate diabetic ketoacidosis (normal range: undetectable)
Determine blood levels of O2 and CO2 .
Results: pO2 = 88 mmHg (normal range: 75–100 mmHg); pCO2 = 41 mmHg (normal range: 35–45 mmHg)
Determine blood levels of lactate, pyruvate, and citric acid cycle intermediates.
Results: [lactate] = 5.5 meq/L (normal range: 0.5–2.2 meq/L); [pyruvate] = 0.32 meq/L (normal range: 0–0.11 meq/L). You also find elevated levels of alanine (most likely resulting from high pyruvate levels) and very high levels of α-ketoglutarate (αKG) and glutamate (most likely resulting from high αKG levels).
Question 1.4
Why might a person have elevated levels of pyruvate AND lactate? (Mark “yes” for ALL that apply!) Hint: Review pages 563–564, 568–575, 633–638, and 688 of Lehninger, 6th ed., as needed to answer this question.
| a. Because his/her body is doing lactic acid fermentation. | uS+xJY+rPntALoOB |
| b. Because he/she is hypoglycemic and is producing ketone bodies. | Fd/yhwSeUQ6ZqQj4 |
| c. Because he/she is in a fasted state and his/her liver is running gluconeogenesis to produce pyruvate for the brain. | Fd/yhwSeUQ6ZqQj4 |
| d. Because there might be a problem with the pyruvate dehydrogenase complex, resulting in a surplus of pyruvate in excess of what is needed for lactic acid fermentation. | uS+xJY+rPntALoOB |
Question 1.5
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Question 1.6
Which of the following cofactors/cosubstrates are essential for α-ketoglutarate dehydrogenase function? (Mark “yes” for ALL that apply!)
| a. biotin | Fd/yhwSeUQ6ZqQj4 |
| b. TPP | uS+xJY+rPntALoOB |
| c. FAD | uS+xJY+rPntALoOB |
| d. tetrahydrofolate | Fd/yhwSeUQ6ZqQj4 |
| e. NAD+ | Fd/yhwSeUQ6ZqQj4 |
| f. vitamin B12 | Fd/yhwSeUQ6ZqQj4 |
| g. lipoate | uS+xJY+rPntALoOB |
| h. GDP | Fd/yhwSeUQ6ZqQj4 |
| i. CoA | uS+xJY+rPntALoOB |
| j. O2 | Fd/yhwSeUQ6ZqQj4 |
Question 1.7
What are the similarities between the PDH complex and α-ketoglutarate dehydrogenase? (Mark “yes” for ALL that apply!)
| a. Both require the same cofactor(s). | uS+xJY+rPntALoOB |
| b. Both are part of the citric acid cycle. | Fd/yhwSeUQ6ZqQj4 |
| c. Both catalyze decarboxylation reactions. | uS+xJY+rPntALoOB |
| d. Both are part of glycolysis. | Fd/yhwSeUQ6ZqQj4 |
| e. Both catalyze oxidation reactions. | uS+xJY+rPntALoOB |
| f. Both catalyze reactions that proceed through a similar mechanism requiring three specific enzymatic activities catalyzed by distinct subunits. | uS+xJY+rPntALoOB |
Question 1.8
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
Results: [Insulin] = 10 mU/mL (normal range: 0–29 mU/mL)
phenylalanine
Results: [Phe] = 0.5 mg/dL (normal range: 0–2.0 mg/dL)
Determine Urine Concentrations
phenylpyruvate (a phenylketone)
Results: undetectable levels (normal range: undetectable)
Specific Enzyme Tests
aldolase
Results: [Aldolase] = 3.0 U/mL (normal range: 0–7 U/mL)
Conduct skin biopsy and send fibroblasts to center to test 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] = 270 U/L (normal range: 110–210 U/L)
pyruvate dehydrogenase (PDH)
Results: PDH complex activity= 0.6 nmol/min*mg (normal range: 2–2.5 nmol/min*mg)
Question 1.9
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Results:
| Enzyme component | Residual activity (% of normal) in cultured skin fibroblasts |
| PDH Complex Total | 28% |
| E1 (pyruvate dehydrogenase) | 26% |
| E2 (dihydrolipoyl transacetylase) | 100% |
| E3 (dihydrolipoyl dehydrogenase) | 100% |
Question 1.10
Which of the following molecules are cofactors/cosubstrates that are essential for function of the PDH complex? (Mark “yes” for ALL that apply!)
| a. biotin | Fd/yhwSeUQ6ZqQj4 |
| b. TPP | uS+xJY+rPntALoOB |
| c. FAD | uS+xJY+rPntALoOB |
| d. tetrahydrofolate | Fd/yhwSeUQ6ZqQj4 |
| e. NAD+ | uS+xJY+rPntALoOB |
| f. vitamin B12 | Fd/yhwSeUQ6ZqQj4 |
| g. lipoate | uS+xJY+rPntALoOB |
| h. GDP | Fd/yhwSeUQ6ZqQj4 |
| i. CoA | uS+xJY+rPntALoOB |
| j. O2 | Fd/yhwSeUQ6ZqQj4 |
The discovery that only E1 of the PDH complex has lower than normal activity has opened up five new investigation options! New options opened are:
Assay for the amount of riboflavin in various tissues.
Results: The amount of riboflavin was at the low end of the normal range.
Assay for the amount of niacin in various tissues.
Results: The amount of niacin was at the low end of the normal range.
Assay for the amount of thiamine in various tissues.
Results: The amount of thiamine was nearly undetectable; this indicates a severe deficiency.
Assay for the amount of lipoic acid in various tissues.
Results: The amount of lipoic acid was at the low end of the normal range.
Assay for the amount of pantothenic acid in various tissues.
Results: The amount of pantothenic acid was at the low end of the normal range.
1.4 Assessment
You have now completed the investigations and can go on to answer the following 11 questions, which will give you the opportunity to demonstrate your understanding of the cause of death.
Question 1.11
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 1.13
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Question 1.14
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 1.15
Note that fatty acids are catabolized to produce acetyl-CoA, which may then enter the citric acid cycle when oxygen is abundant. Considering this point and your answers to previous questions within this case as you proceed to answer the following question: Which biochemical pathways are utilized by cardiac muscle to oxidize organic carbon molecules and ultimately produce ATP? (Mark “yes” for ALL that apply!)
| a. glycolysis | uS+xJY+rPntALoOB |
| b. PDH complex | uS+xJY+rPntALoOB |
| c. citric acid cycle | uS+xJY+rPntALoOB |
| d. Oxidative phosphorylation | uS+xJY+rPntALoOB |
| e. gluconeogenesis | Fd/yhwSeUQ6ZqQj4 |
| f. glycogenolysis | Fd/yhwSeUQ6ZqQj4 |
Question 1.16
Which biochemical pathways would be severely hindered by a thiamine deficiency? (Mark “yes” for ALL that apply!) (Hint: which of these pathways include reactions catalyzed by enzymes that require thiamine as a cofactor?)
| a. citric acid cycle | uS+xJY+rPntALoOB |
| b. glycolysis | Fd/yhwSeUQ6ZqQj4 |
| c. PDH complex | Fd/yhwSeUQ6ZqQj4 |
| d. oxidative phosphorylation | Fd/yhwSeUQ6ZqQj4 |
| e. gluconeogenesis | Fd/yhwSeUQ6ZqQj4 |
| f. glycogenolysis | Fd/yhwSeUQ6ZqQj4 |
Question 1.17
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Question 1.18
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Question 1.19
Based on all the evidence you have gathered in this case, and your answers to previous questions, what do you think caused this man’s death? (Mark "yes" for ALL the relevant factors that should be included in a complete explanation of this man’s death!)
| a. murder | Fd/yhwSeUQ6ZqQj4 |
| b. vitamin deficiency due to alcoholism | uS+xJY+rPntALoOB |
| c. death due to acute alcohol intoxication | Fd/yhwSeUQ6ZqQj4 |
| d. thiamine deficiency | uS+xJY+rPntALoOB |
| e. inborn errors in the genes encoding the enzymes of the PDH complex | Fd/yhwSeUQ6ZqQj4 |
| f. diabetes mellitus (Type I or II) | Fd/yhwSeUQ6ZqQj4 |
| g. heavy metal exposure | Fd/yhwSeUQ6ZqQj4 |
| h. heart failure due to reduced activity of the PDH complex and citric acid cycle | uS+xJY+rPntALoOB |
| i. heart failure due to severe metabolic acidosis from lactic acid and ketone body accumulation | Fd/yhwSeUQ6ZqQj4 |
| j. heart failure due to diabetic ketoacidosis | Fd/yhwSeUQ6ZqQj4 |
Question 1.20
How did excessive alcohol consumption likely contribute to thiamine deficiency (beriberi) in this case? (Mark “yes” for ALL that apply!)
| a. Alcohol interferes with nutrient absorption in the intestine by damaging the intestinal lining, so this man could absorb very little thiamine from meals. | uS+xJY+rPntALoOB |
| b. Alcohol was the majority of this man’s caloric intake, so his diet was lacking in key nutrients such as thiamine. | uS+xJY+rPntALoOB |
| c. Alcohol can inhibit the ability of thiamine to act as a cofactor after it is absorbed, so very little of the already sparse dietary thiamine consumed by this man could bind to the enzyme. | Fd/yhwSeUQ6ZqQj4 |
| d. Alcohol can act directly as an inhibitor of key metabolic enzymes, so this man needed proportionately more thiamine than the average person. | Fd/yhwSeUQ6ZqQj4 |
| e. This man has a genetic disorder characterized by a mutation in the gene for transketolase, which results in a lowered affinity for TTP. | Fd/yhwSeUQ6ZqQj4 |
Question 1.21
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 results are being submitted...
1.5 Case Summary
Congratulations on completing this Case Study! The following Case Summary gives a full explanation of the two brothers’ conditions
Final Case Summary
The man died due to thiamine deficiency (“wet beriberi”) caused by his alcoholism. Without sufficient thiamine, E1 of the PDH complex and α-ketoglutarate dehydrogenase could not function well, so the mitochondria within the heart (where there is high energy demand) were unable to supply the needed energy to properly sustain a heartbeat. Energy sources of the heart (fatty acids, ketone bodies, and glucose) require functioning enzymes of the citric acid cycle such as α-ketoglutarate dehydrogenase. Oxidation of glucose also requires a functional PDH complex. Although this deficiency would presumably affect all tissues, small mishaps in the heart prove fatal. The heart does not store triglycerols or glycogen, and so it has only about 3-seconds worth of chemical energy stored as ATP and creatine monophosphate. After those are used up, cardiac muscle cells will cease to contract. The death would have been preventable if the man had reduced his alcohol consumption and been taking a multivitamin, or had changed his diet to include vitamin- and nutrient-containing food, rather than consuming mostly alcohol.
Proceed to the next page to extend your understanding of alcoholism and of the citric acid cycle.
1.6 Extending Your Understanding Beyond The Case
Question 1.22
Some people are much more sensitive than others to the effects of chronic alcoholism. The information found on page 580 (Section 14.5) of the Lehninger, 6th ed., helps explain why! Review that information and then answer the following question.
pUAhARUIuegYkLft1m2YxCt5+Kjr9aS3lpMCoxxHLNN0O391xl1kLkyYJzT96KvwF9kN89I6fyCWOFccxKknRmjtFSiqFcXzj2E42jVkZaQuY1fek/YGh59RJkcQ6NoXZzj474PivySPR1egEaxHA8rF9b87ZmpznT4H6tsX2P4+3cFfjDZzHj9DRWwNLaqjjwGlEzZI6uQFNXXx8c8hHYyIof4HBs2tInSrxQ0PMNmx/vvyAj34KGOy/TtA7RcLORVF85MzO+eHi4T9LWLCCq+YmPBlNs2ARy7j/DkWvFo7cVEgzeV1cxbq5eRHG3BtMfayShaHM0EGZjGNp7bIWlEIOK9SNvWTGXCKDD3JDE+TIXRu1CH5sNrPwkcLF5EPfkoZz8jYmag9acndWe80GXS362c=Explanation: Practicing physicians often notice that some patients seem to be far more sensitive to the detrimental effects of alcoholism than others. These patients have severe cognitive abnormalities; particularly notable are the defects in short-term memory. The doctor can introduce herself to the patient and then quickly turn around to face away, and turn back around again to face the patient and re-introduce herself, and the patient will act as if they are meeting for the first time. Page 580 (Section 14.5) of Lehninger, 6th ed., explains that some people have a genetic mutation in the enzyme transketolase that decreases the affinity of the enzyme for TPP by 10-fold. These people will experience the effects of a thiamine deficiency much sooner than others. Lack of transketolase activity results in neurological disorders, Wernicke’s encephalopathy, and Korsakoff syndrome, broadly called Wernicke-Korsakoff syndrome. Feel free to read more about these disorders online.
Explanation: Practicing physicians often notice that some patients seem to be far more sensitive to the detrimental effects of alcoholism than others. These patients have severe cognitive abnormalities; particularly notable are the defects in short-term memory. The doctor can introduce herself to the patient and then quickly turn around to face away, and turn back around again to face the patient and re-introduce herself, and the patient will act as if they are meeting for the first time. Page 580 (Section 14.5) of Lehninger, 6th ed., explains that some people have a genetic mutation in the enzyme transketolase that decreases the affinity of the enzyme for TPP by 10-fold. These people will experience the effects of a thiamine deficiency much sooner than others. Lack of transketolase activity results in neurological disorders, Wernicke’s encephalopathy, and Korsakoff syndrome, broadly called Wernicke-Korsakoff syndrome. Feel free to read more about these disorders online.
Question 1.23
Final Challenge Problem: Diseases caused by deficiencies in cofactors critical to the enzymes of the citric acid cycle are not all that uncommon, as illustrated by this case. However, genetic defects in an enzyme of the citric acid cycle are very rare; a 1997 review paper mentions fewer than 25 cases of defects in a citric acid enzyme in the literature. The cases mentioned all are due to defects in either α-ketoglutarate dehydrogenase, succinate dehydrogenase, or fumarase.
An abnormal urinary excretion of organic acids was frequently noticed in those patients with defects in citric acid cycle enzymes, with occasional peaks of α-ketoglutarate observed no matter which enzyme (of the three mentioned above) was defective. The excretion of α-ketoglutarate is easily understood in the cases of a defect in α-ketoglutarate dehydrogenase, but is less clear in the other defects.
Think about how you would COMPLETELY explain why α-ketoglutarate would be seen in high concentrations in the urine of patients with fumarase defects.
Answer the following series of four multiple choice questions to explain why α-ketoglutarate would be seen in high concentrations in the urine of patients with fumarase defects and complete this case study. Hint: Consider which reactions of the citric acid cycle are physiologically reversible and how they are regulated: Sections 16.2 and 16.3 of Lehninger 6E.
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