A 32-year-old man with hereditary fructose intolerance presents with hypoglycemia and hepatomegaly after consuming fruit juice. Which enzyme deficiency is the most common cause of this condition?

Explanation

## Hereditary Fructose Intolerance (HFI) **Key Point:** Hereditary fructose intolerance is caused by deficiency of **aldolase B** (fructose-1-phosphate aldolase), the most common form of fructose metabolism disorder. This enzyme normally cleaves fructose-1-phosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde. ## Pathophysiology of Aldolase B Deficiency ```mermaid flowchart TD A[Fructose ingestion]:::outcome --> B[Fructokinase converts fructose to F-1-P]:::action B --> C{Aldolase B present?}:::decision C -->|No - HFI| D[F-1-P accumulates]:::urgent C -->|Yes - Normal| E[F-1-P cleaved to DHAP + glyceraldehyde]:::action D --> F[Depletes free phosphate pool]:::urgent D --> G[Inhibits glucose-6-phosphatase]:::urgent D --> H[Inhibits aldolase A]:::urgent F --> I[Decreased ATP synthesis]:::urgent G --> J[Hypoglycemia]:::urgent H --> K[Blocks glycolysis]:::urgent I --> L[Hepatocellular necrosis]:::urgent ``` ## Clinical Features of HFI | Feature | Mechanism | |---------|----------| | **Hypoglycemia** | F-1-P accumulation inhibits glucose-6-phosphatase and depletes ATP | | **Hepatomegaly** | Hepatocellular necrosis and cirrhosis from F-1-P toxicity | | **Lactic acidosis** | Impaired gluconeogenesis and glycolysis | | **Hyperuricemia** | Increased purine degradation from ATP depletion | | **Renal tubular dysfunction** | Fanconi syndrome from F-1-P accumulation | | **Failure to thrive** | Chronic malnutrition from fructose avoidance | **High-Yield:** HFI is the **most common fructose metabolism disorder** and presents with acute symptoms (vomiting, hypoglycemia) within 30 minutes of fructose ingestion. Chronic exposure leads to cirrhosis. **Clinical Pearl:** The key distinguishing feature is that patients develop an **aversion to sweet foods** because they associate them with illness — a protective mechanism. **Mnemonic:** **HFI = Hepatic Fructose Intolerance** — aldolase B deficiency causes hepatic toxicity from F-1-P accumulation, NOT a simple inability to metabolize fructose. ## Differential Diagnosis of Fructose Disorders | Disorder | Enzyme Deficiency | Severity | Clinical Presentation | |----------|-------------------|----------|----------------------| | **Hereditary Fructose Intolerance (HFI)** | **Aldolase B** | **Severe** | **Hypoglycemia, hepatomegaly, cirrhosis** | | Essential Fructosuria | Fructokinase | Benign | Asymptomatic; fructose in urine | | Galactosemia | Galactose-1-phosphate uridyltransferase | Severe | Cataracts, intellectual disability, hepatomegaly | **Warning:** Do not confuse HFI with essential fructosuria (fructokinase deficiency), which is benign and asymptomatic. HFI is clinically significant and life-threatening if fructose is not avoided.