Andrew Carlson, Grace Ryan, Jesus Cortes 05/08/2026
Case Study: Adam F.
Case Background
A 24-year-old man, AF, is brought to the ED at 02:47 by his guardian and personal physician, Dr. Victor F., MD, of the University of Ingolstadt. The patient is tall, with extensive surgical scarring of varying ages. Dr. F. is agitated. He refers to the patient as “the specimen,” then corrects himself.
When asked for a medical history, Dr. F. provides one. The dates do not align. The operations do not align. They appear to describe at least three different people. Asked about the patient’s mother, Dr. F. asks which one. The resident does not pursue it. Pharmacy notes that Dr. F. has previously attempted to write standing orders for “electricity, prn.”(pro re nata/as needed). These were declined. On examination, AF is jaundiced and edematous (excess fluid build-up). Last meal: ~14 hours ago. Family history: Dr. F. begins to list contributors. After the eleventh contributor, the resident asks him to stop.
After pointed questioning, Dr. F. notes that during construction “appropriate hepatic (liver) specimens had been in short supply,” and that he had used “what was at hand.” When asked what was at hand, he replies “mostly cat.” The remainder, he notes, is “miscellaneous.” CT shows heterogeneous tissue occupying the right upper quadrant. The radiologist reports “multiple discrete tissue domains of varying density, none consistent with adult human hepatic parenchyma.” A second reader, after viewing the images, declines to sign. The resident transcribes patient anatomically intact, hepatocytes absent or substituted with non-hepatic tissue and orders a metabolic panel.
Labs
| Test | Value | Flag | Test | Value | Flag |
|---|---|---|---|---|---|
| Glucose | 38 mg/dL | LOW | Free fatty acids | 2.4 mmol/L | HIGH |
| Lactate | 8.4 mmol/L | HIGH | β-hydroxybutyrate | <0.1 mmol/L | LOW |
| Pyruvate | 0.18 mmol/L | NORMAL | Acetoacetate | <0.1 mmol/L | LOW |
| Arterial pH | 7.21 | LOW | Triglycerides | 580 mg/dL | HIGH |
Biochemistry
The hepatocyte integrates carbohydrate and lipid metabolism. It is the dominant site of gluconeogenesis, the primary tissue that exports free glucose to blood (via glucose-6-phosphatase), the importer for the Cori cycle (lactate → glucose), and the site of ketogenesis (mitochondrial HMG-CoA synthase, HMGCS2). NADPH for reductive biosynthesis comes principally from the pentose phosphate pathway, which is highly active in the liver. Without functional hepatocytes, fasting fuel homeostasis collapses simultaneously: glucose cannot be made, lactate cannot be cleared, fatty acids cannot be converted to ketones, and a major site of NADPH-driven biosynthesis is gone.
Analysis
Q1. The patient’s lactate is 8.4 mM but pyruvate remains near normal. What does this lactate-to-pyruvate ratio reveal about the cytosolic NADH/NAD⁺ ratio in peripheral (outside liver) tissues, and why are these tissues producing more lactate, not less, when blood glucose is only 38 mg/dL?
Q2. The patient is hypoglycemic at 38 mg/dL despite carrying ~350 g of glycogen in skeletal muscle. What single enzyme separates a glucose donor tissue (liver, kidney cortex) from a glucose hoarder tissue (muscle), and without it, what happens to the glucose-6-phosphate that muscle generates from glycogenolysis?
Q3. Free fatty acids are 2.4 mM, indicating active lipolysis, but β-hydroxybutyrate is undetectable. β-oxidation occurs in muscle, heart, and many other tissues, so where is all the acetyl-CoA from extra-hepatic β-oxidation going, and why does it not become ketones?
Q4. NAD⁺/NADH and NADP⁺/NADPH differ by a single phosphate group, yet the cell holds them as separate pools, with one kept oxidized and the other reduced. Why must this separation be maintained for metabolism to function, and where does the cell’s NADPH primarily come from?
Epilogue
Patient transferred to ICU. Discharge planning is on hold pending clarification of the patient’s living arrangements. Dr. F. is last seen in the cafeteria, eating yogurt while reading an anatomy textbook open to the chapter on hepatic vasculature. He has been advised, in writing, to consult before a third construction. Numerous ethics reports have been filed. Animal control has forwarded a cluster of missing-cat reports to Dr. F’s attention. He has expressed concern about the supply.
References
- Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4(1):177–197. doi:10.1002/cphy.c130024
- Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25(2):262–284. doi:10.1016/j.cmet.2016.12.022
- Stincone A, Prigione A, Cramer T, et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev. 2015;90(3):927–963. doi:10.1111/brv.1214
ANSWER KEY
Q1 Lactate/pyruvate ratio
- High lactate/pyruvate ratio = high NADH/NAD⁺ in cytosol (LDH)
- Peripheral tissues run anaerobic glycolysis hard because no hepatic glucose is available
- Lactate is the exhaust of emergency ATP production, not sign of shutdown
Q2 Glucose-6-phosphatase
- G6Pase is the enzyme that releases free glucose from G6P for export to blood
- Expressed in liver and renal cortex, absent in muscle
- Without G6Pase, muscle G6P stay, trapped → glycolysis → lactate (Cori cycle), never free glucose
Q3 Acetyl-CoA fate
- Peripheral β-oxidation acetyl-CoA → local TCA cycle → ATP for that tissue
- Liver is the only tissue that diverts excess acetyl-CoA to ketones
- Liver-specific because HMGCS2 (mitochondrial HMG-CoA synthase) is restricted to hepatocytes
Q4 NAD⁺/NADH vs. NADP⁺/NADPH
- Cell holds NAD⁺/NADH oxidized (catabolism) and NADP⁺/NADPH reduced (anabolism)
- A single pool would prevent simultaneous catabolism and anabolism. Direction depends on ratio
- NADPH dominantly comes from the PPP oxidative phase (G6PD, 6PGD)