Section: IntroductionOverall Progress: 14%

Chapter 1. An Unexplained Death

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A 65-year-old man of Scandinavian descent was rushed to the Emergency Room of your local hospital after he was discovered unconscious by a family member 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 from a few years prior. 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.

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.

Recommended Initial Investigations

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Evaluate overall physical appearance including the presence of insect bites or other injuries

Results: The subject does 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.

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Investigate past medical history including current medications

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, though 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 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.

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Conduct autopsy to evaluate 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. Most major 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.

1.

Which of the following molecules can the heart use for energy? (Select ALL that apply!)

Hint: Read the information on the heart on page 948 of Lehninger 6E and try again.
Hint: Read the information on the heart on page 948 of Lehninger 6E and try again.
A. Fatty acids TrueFalse
B. Glucose TrueFalse
C. Nucleic acids TrueFalse
D. Ketone bodies TrueFalse
E. Amino acids TrueFalse
Hint: Read the information on the heart on page 948 of Lehninger 6E and try again.
Hint: Read the information on the heart on page 948 of Lehninger 6E and try again.

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true

Test hair for common toxins (heavy metals and narcotics)

Results: No heavy metals or narcotics were detected.

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Investigate 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.

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Test the blood and various tissues for common poisons

Results: No common poisons were found in a toxicology test.

Secondary Investigations

Determine blood serum concentrations of:

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Common lipids: free fatty acids (FFAs) and triacylglycerides (TAGs)

Results: 450 mg/dL FFAs (normal range: 190-420 mg/dL); 200 mg/dL TAGs (normal range: 40-150 mg/dL)

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Galactose

Results: [Gal] = 1.5 mg/dL (normal range: 0-6.0 mg/dL)

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Glucose

Results: [Glc] = 75 mg/dL (normal range: 70-110 mg/dL)

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H3O+ ions: blood pH

Results: pH = 7.0 (normal range: 7.35–7.45)

3.

A number of factors can lower blood pH. Which of the following are common reasons why someone might have metabolic acidosis? (Select ALL that apply!)

Hint: Na+ ions are neither significantly acidic nor basic. Review pages 67, 79, 563-564, and 688 of Lehninger 6E and try again.
Hint: Alanine exists as a zwitterion at neutral pH and its concentration has little effect on blood pH. Review pages 67, 79, 563-564, and 688 of Lehninger 6E and try again.
Hint: Molecular oxygen is neither significantly acidic nor basic. Review pages 67, 79, 563-564, and 688 of Lehninger 6E and try again.
A. Increased levels of CO2 in the blood TrueFalse
B. Increased levels of Na+ in the blood TrueFalse
C. Increased levels of lactic acid in the blood TrueFalse
D. Increased levels of alanine in the blood TrueFalse
E. Increased levels of O2 in the blood TrueFalse
F. Increased levels of ketone bodies in the blood TrueFalse
Hint: Na+ ions are neither significantly acidic nor basic. Review pages 67, 79, 563-564, and 688 of Lehninger 6E and try again.
Hint: Alanine exists as a zwitterion at neutral pH and its concentration has little effect on blood pH. Review pages 67, 79, 563-564, and 688 of Lehninger 6E and try again.
Hint: Molecular oxygen is neither significantly acidic nor basic. Review pages 67, 79, 563-564, and 688 of Lehninger 6E and try again.

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true

Insulin

Results: [Insulin] = 10 mU/mL (normal range: 0-29 mU/mL)

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Phenylalanine

Results: [Phe] = 0.5 mg/dL (normal range: 0-2.0 mg/dL)

Determine urine concentrations of:

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phenyl-pyruvate (a phenylketone)

Results: undetectable levels (normal range: undetectable)

Specific enzyme tests:

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Aldolase

Results: [Aldolase] = 3.0 U/mL (normal range: 0-7 U/mL)

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Creatine kinase (CK)

Results: [CK] = 100 U/L (normal range: 40-150 U/L)

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Conduct skin biopsy and send fibroblasts to center to test for Electron Transport Chain enzyme activities

Results: ETC enzyme activities were normal.

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Glucose 6-phosphate dehydrogenase (G6PD)

Results: [G6PD] = 8 U/g Hb (normal range: 5-13 U/g Hb)

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Lactate dehydrogenase (LDH)

Results: [LDH] = 270 U/L (normal range: 110-210 U/L)

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Pyruvate dehydrogenase (PDH)

Results: PDH complex activity= 0.6 nmol/minmg (normal range: 2-2.5 nmol/minmg)

4.

The PDH complex is a complex of how many distinct enzymes that must function sequentially to convert pyruvate into acetyl-CoA? (Hint You may wish to review pages 634 and 635 of Lehninger 6E before attempting this question.)

A.
B.
C.
D.
E.
F.

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Correct.
Incorrect.
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Culture fibroblasts and send to a lab to investigate which enzymes of the Pyruvate Dehydrogenase Complex are defective

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%

5.

Which of the following molecules are cofactors/cosubstrates that are essential for function of the PDH complex? (Select ALL that apply!)

Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
A. Biotin TrueFalse
B. TPP TrueFalse
C. FAD TrueFalse
D. Tetrahydrofolate TrueFalse
E. NAD+ TrueFalse
F. Vitamin B12 TrueFalse
G. Lipoate TrueFalse
H. GDP TrueFalse
I. CoA TrueFalse
J. O2 TrueFalse
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.
Hint: Review pages 634-637of Lehninger 6E for information on the relevant biochemical reactions and try again.

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true

Assay for the amount of riboflavin in various tissues

Results: The amount of riboflavin was at the low end of the normal range.

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true

Assay for the amount of niacin in various tissues

Results: The amount of niacin was at the low end of the normal range.

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true

Assay for the amount of thiamine in various tissues

Results: The amount of thiamine was nearly undetectable; this indicates a severe deficiency.

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true

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.

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true

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.

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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)

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true

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)

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true

Determine blood levels of O2 and CO2

Results: PO2 = 88 mmHg (normal range: 75-100mmHg); PCO2 = 41 mmHg (normal range: 35-45 mmHg)

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true

Determine blood levels of lactate, pyruvate, and TCA 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 -ketoglutarate (aKG) and glutamate (most likely resulting from high aKG levels).

6.

Why might a person have elevated levels of pyruvate AND lactate? (Select ALL that apply!) hint: Review pages 563-564, 568-575, 633-638, and 688 of Lehninger 6E as needed to answer this question.

Hint: This answer does not necessarily explain why the concentrations of pyruvate and lactate would both be elevated. Review pages 563-564, 568-575, 633-638, and 688 of Lehninger 6E and try again.
Hint: Hepatic gluconeogenesis produces glucose, not pyruvate, for the brain. Review pages 563-564, 568-575, 633-638, and 688 of Lehninger 6E and try again.
A. Because his/her body is doing lactic acid fermentation. TrueFalse
B. Because he/she is hypoglycemic and is producing ketone bodies TrueFalse
C. Because he/she is in a fasted state and his/her liver is running gluconeogenesis to produce pyruvate for the brain TrueFalse
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. TrueFalse
Hint: This answer does not necessarily explain why the concentrations of pyruvate and lactate would both be elevated. Review pages 563-564, 568-575, 633-638, and 688 of Lehninger 6E and try again.
Hint: Hepatic gluconeogenesis produces glucose, not pyruvate, for the brain. Review pages 563-564, 568-575, 633-638, and 688 of Lehninger 6E and try again.

Assesment

11.

Blood tests found elevated levels of lactate and pyruvate. You may or may not have also discovered that enzyme tests found elevated levels of lactate dehydrogenase (LDH) as well. What is a possible explanation for the elevated levels of all three molecules?

A.
B.
C.

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Correct.
Incorrect.
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The man died due to thiamine deficiency (“wet beriberi”) caused by his alcoholism. Thiamine deficiency resulted in minimal functionality of E1 of the PDH complex and AKG DH, 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 AKG DH. 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 triglycerides 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 changed his diet to include vitamin- and nutrient-containing food, rather than consuming mostly alcohol.

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Case Summary