Zinc
A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).30
Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.31 The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.32 Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.
Ranaldi et al33 exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.33
Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.34 A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.35
Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.36 The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.37
Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.38 A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.39 Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.40-42
Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.43 The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,42 the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.43 Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.44 However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.45
Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.46 It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.46 Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.47