# Clinical Cases: Glycolysis

## Case 1: Pyruvate Kinase Deficiency (Hemolytic Anemia)

### Clinical Image
![Pyruvate Kinase Deficiency Blood Smear](case_01_image.jpg)
*Source: [Wikipedia - Pyruvate kinase deficiency](https://en.wikipedia.org/wiki/Pyruvate_kinase_deficiency) - CC BY-SA 3.0*

### Case Presentation
A 4-year-old boy of Northern European descent is referred for evaluation of chronic anemia and intermittent jaundice. His parents report he has been pale since infancy and occasionally becomes more yellow during viral illnesses. Physical examination reveals pallor, mild scleral icterus, and splenomegaly. Laboratory studies show hemoglobin 8.5 g/dL, reticulocyte count 18%, total bilirubin 4.2 mg/dL (indirect predominant), LDH 450 U/L, and haptoglobin <10 mg/dL (low), consistent with chronic hemolysis. Direct Coombs test is negative. Peripheral blood smear shows polychromasia, echinocytes (spiculated cells), and rare spherocytes. Hemoglobin electrophoresis is normal. An erythrocyte enzyme panel reveals markedly reduced pyruvate kinase activity at 15% of normal. Genetic testing confirms compound heterozygous mutations in the PKLR gene. He is managed with folic acid supplementation and close monitoring. His elevated 2,3-BPG levels (a consequence of glycolytic intermediate accumulation) actually help compensate for his anemia by right-shifting the oxygen-hemoglobin dissociation curve.

### Key Learning Points
- Pyruvate kinase deficiency is the most common glycolytic enzyme defect causing hemolytic anemia; mature red blood cells depend entirely on glycolysis for ATP since they lack mitochondria
- Without adequate pyruvate kinase activity, RBCs cannot generate sufficient ATP to maintain membrane pumps and cellular integrity, leading to premature destruction (hemolysis)
- The accumulation of glycolytic intermediates upstream of the block leads to elevated 2,3-BPG, which paradoxically benefits patients by increasing oxygen delivery to tissues

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## Case 2: Type 2 Lactic Acidosis (Metformin Toxicity)

### Clinical Image
![Lactic Acidosis ABG](case_02_image.jpg)
*Source: [Radiopaedia - Lactic acidosis](https://radiopaedia.org/articles/lactic-acidosis) - CC BY-NC-SA 3.0*

### Case Presentation
A 68-year-old woman with type 2 diabetes and chronic kidney disease (baseline creatinine 2.1 mg/dL) presents with altered mental status, nausea, vomiting, and abdominal pain for 2 days. She recently had a CT scan with IV contrast for abdominal pain evaluation. Her medications include metformin 1000 mg twice daily. On examination, she is confused with Kussmaul respirations (deep, rapid breathing). Laboratory studies reveal pH 7.12, pCO2 15 mmHg, HCO3 5 mEq/L, anion gap 28 mEq/L, lactate 14 mmol/L (normal <2), creatinine 4.8 mg/dL (acute kidney injury), and metformin level markedly elevated. She has metformin-associated lactic acidosis (MALA) precipitated by acute kidney injury from contrast nephropathy. Metformin inhibits hepatic gluconeogenesis and complex I of the mitochondrial electron transport chain; when it accumulates due to reduced renal clearance, it shifts metabolism toward anaerobic glycolysis, causing lactate accumulation. She is treated with IV bicarbonate and emergent hemodialysis to remove metformin. She recovers over several days.

### Key Learning Points
- Lactic acidosis occurs when pyruvate is shunted to lactate production; this happens when the TCA cycle and oxidative phosphorylation are impaired and NAD+ must be regenerated anaerobically
- Metformin inhibits complex I of the electron transport chain and hepatic gluconeogenesis; it normally has a wide safety margin but accumulates dangerously with renal impairment
- Metformin should be held before and after IV contrast administration in patients with impaired kidney function to prevent metformin-associated lactic acidosis

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## Case 3: FDG-PET Positive Lung Mass (Warburg Effect)

### Clinical Image
![FDG-PET Lung Cancer](case_03_image.jpg)
*Source: [Radiopaedia - Lung cancer FDG PET](https://radiopaedia.org/cases/lung-cancer-fdg-pet) - CC BY-NC-SA 3.0*

### Case Presentation
A 62-year-old man with a 40 pack-year smoking history presents with a 3-month history of cough and unintentional 15-pound weight loss. Chest CT reveals a 4 cm spiculated mass in the right upper lobe with mediastinal lymphadenopathy. For staging, an FDG-PET scan is performed. The scan shows intense uptake (SUV max 12.5) in the primary lung mass and multiple mediastinal lymph nodes, but no distant metastases. CT-guided biopsy confirms non-small cell lung cancer (adenocarcinoma). The patient asks why the PET scan "lights up" cancer. He is explained that cancer cells preferentially use glycolysis even in the presence of oxygen (the Warburg effect), consuming glucose at high rates. The radiotracer 18F-fluorodeoxyglucose (FDG) is taken up by glucose transporters and phosphorylated by hexokinase but cannot proceed further in glycolysis, so it becomes trapped and accumulates in metabolically active cancer cells. He is referred to oncology for treatment of stage IIIA disease.

### Key Learning Points
- The Warburg effect describes the preference of cancer cells for glycolysis even when oxygen is available (aerobic glycolysis), producing lactate rather than fully oxidizing glucose
- While seemingly inefficient (2 ATP vs. 30-32 ATP per glucose), this metabolic reprogramming supports rapid proliferation by diverting glycolytic intermediates to biosynthetic pathways for nucleotides, amino acids, and lipids
- FDG-PET exploits the Warburg effect: FDG is trapped after hexokinase phosphorylation in cells with high glycolytic activity, allowing visualization of tumors, staging, and monitoring treatment response