A 6-month-old girl from Delhi is brought to the pediatric emergency with a history of vomiting, abdominal pain, and hypoglycemia (blood glucose 38 mg/dL) that developed 2 hours after her mother fed her honey and fruit juice. On examination, she is irritable with hepatomegaly. Serum fructose is markedly elevated. Liver function tests show elevated transaminases (AST 320 U/L, ALT 280 U/L) and hyperbilirubinemia. Which enzyme deficiency best explains this acute presentation?

Explanation

## Clinical Diagnosis: Aldolase B Deficiency (Hereditary Fructose Intolerance) ### Key Clinical Trigger: Fructose Ingestion **Key Point:** Aldolase B deficiency causes hereditary fructose intolerance (HFI), an autosomal recessive disorder where fructose metabolism is blocked at the aldolase B step, leading to toxic accumulation of fructose-1-phosphate in hepatocytes. ### Pathophysiology of HFI 1. **Fructose enters hepatocytes** → phosphorylated by fructokinase to **fructose-1-phosphate (F1P)** 2. **Aldolase B deficiency** → F1P cannot be cleaved → **toxic accumulation** 3. **F1P traps inorganic phosphate (Pi)** → depletes ATP in hepatocytes 4. **ATP depletion consequences:** - Inhibits gluconeogenesis → severe hypoglycemia - Inhibits protein synthesis → hepatic dysfunction - Triggers hepatocyte necrosis → elevated transaminases - Inhibits uric acid excretion → hyperuricemia ### Distinguishing HFI from Other Fructose Disorders | Feature | HFI (Aldolase B) | Essential Fructosuria (Fructokinase) | Sorbitol Intolerance (Sorbitol DH) | |---------|------------------|--------------------------------------|-----------------------------------| | **Enzyme defect** | Aldolase B | Fructokinase | Sorbitol dehydrogenase | | **Trigger** | Fructose ingestion | Fructose ingestion | Sorbitol ingestion | | **Toxic metabolite** | Fructose-1-phosphate | Fructose (excreted in urine) | Sorbitol | | **Hypoglycemia** | **Severe, acute** | None | Mild | | **Hepatotoxicity** | **Yes (cirrhosis risk)** | No | Mild | | **Hyperuricemia** | **Yes** | No | No | | **Elevated transaminases** | **Yes** | No | No | | **Urine finding** | Normal | **Fructose in urine** | Sorbitol in urine | | **Clinical severity** | **Severe** | Benign | Mild | | **Management** | Strict fructose avoidance | None needed | Sorbitol avoidance | ### Clinical Pearl **Clinical Pearl:** HFI is a **medical emergency** when fructose is ingested. The combination of **acute hypoglycemia + hepatomegaly + elevated transaminases + hyperuricemia triggered by fructose/sucrose/honey ingestion** is diagnostic. Repeated exposure leads to cirrhosis. ### High-Yield Biochemistry **High-Yield:** Fructokinase is the **rate-limiting enzyme** of fructose metabolism. Its deficiency (essential fructosuria) is **benign**—fructose is simply excreted in urine and causes no harm. In contrast, aldolase B deficiency is **life-threatening** because F1P accumulates and depletes hepatocyte ATP. **Mnemonic:** **HFI = Hepatic Fructose Intolerance** - **H**epatomegaly (acute) - **F**ructose trigger (honey, fruit, sucrose) - **I**njury to liver (transaminitis, cirrhosis risk) ### Mechanism of Hypoglycemia in HFI ```mermaid flowchart TD A[Fructose ingestion]:::outcome --> B[Fructokinase: Fructose → F1P]:::action B --> C[Aldolase B deficiency]:::urgent C --> D[F1P accumulation]:::urgent D --> E[Traps inorganic phosphate Pi]:::action E --> F[ATP depletion in hepatocytes]:::urgent F --> G1[Inhibits gluconeogenesis]:::action F --> G2[Inhibits protein synthesis]:::action F --> G3[Hepatocyte necrosis]:::action G1 --> H1[Severe hypoglycemia]:::urgent G2 --> H2[Hepatic dysfunction]:::outcome G3 --> H3[↑ Transaminases]:::outcome F --> I[Inhibits uric acid excretion]:::action I --> J[Hyperuricemia]:::outcome ``` ### Management - **Acute:** IV glucose, avoid fructose-containing foods - **Chronic:** Strict avoidance of fructose, sucrose, sorbitol - **Foods to avoid:** Honey, fruits, table sugar, soft drinks, fruit juices - **Safe foods:** Glucose, lactose, starch [cite:Robbins 10e Ch 7; KD Tripathi 8e Ch 12]