A 3-month-old male infant presents with chronic diarrhea, failure to thrive, and hypoproteinemia despite adequate milk intake. Laboratory studies show normal pancreatic enzyme levels in serum and normal stool chymotrypsin. Genetic testing reveals a homozygous loss-of-function mutation in the gene encoding the brush-border enzyme marked **B** in the diagram. Which of the following best explains the pathophysiology of this infant's presentation?

Explanation

## Why option 1 is correct The structure marked **B** is enterokinase (enteropeptidase), a duodenal brush-border enzyme that catalyzes the FIRST AND CRUCIAL STEP in pancreatic enzyme activation: cleavage of trypsinogen to active trypsin. Once trypsin is generated in the duodenum, it acts as the "master activator," cleaving all other pancreatic zymogens (chymotrypsinogen, proelastase, procarboxypeptidases) into their active forms. Loss of enterokinase function means trypsinogen cannot be activated, preventing the cascade of pancreatic enzyme activation. This results in severe protein maldigestion and malabsorption, manifesting as diarrhea, failure to thrive, and hypoproteinemia in infants. The normal serum pancreatic enzymes and normal stool chymotrypsin in this case are misleading distractors — the enzymes are synthesized normally but cannot be activated without the enterokinase-mediated first step. This is a rare but well-documented condition (enterokinase deficiency) described in Harper 32e Ch 28. ## Why each distractor is wrong - **Option 2**: Defective pancreatic secretory trypsin inhibitor (SPINK1) is a protective mechanism against premature trypsin activation within the pancreas, leading to hereditary pancreatitis, NOT malabsorption in infancy. The clinical presentation here is malabsorption, not pancreatitis. Moreover, the question states normal serum pancreatic enzymes, inconsistent with pancreatitis. - **Option 3**: Impaired di-/tripeptide absorption via PepT1 (marked **D**) would cause malabsorption, but the question specifically identifies a defect in the enzyme marked **B** (enterokinase), not the transporter. Additionally, PepT1 deficiency alone would not prevent the normal activation of pancreatic enzymes or explain the complete failure of protein digestion. - **Option 4**: Reduced gastric pepsin secretion would affect the stomach phase of proteolysis, but pepsin (marked **A**) is not the defective enzyme in this case. The question identifies a brush-border enzyme defect, and pepsin is a gastric enzyme. Pepsin deficiency alone would not prevent pancreatic enzyme activation in the duodenum. **High-Yield:** Enterokinase is the rate-limiting, non-redundant first step in pancreatic enzyme activation; its deficiency causes protein malabsorption and failure to thrive, not pancreatitis. [cite: Harper 32e Ch 28; Robbins 10e Ch 19]