Zinc and liver disease

Abstract

Zinc is an essential trace element required for normal cell growth, development, and differentiation. It is involved in DNA synthesis, RNA transcription, and cell division and activation. It is a critical component in many zinc protein/enzymes, including critical zinc transcription factors. Zinc deficiency/altered metabolism is observed in many types of liver disease, including alcoholic liver disease (ALD) and viral liver disease. Some of the mechanisms for zinc deficiency/altered metabolism include decreased dietary intake, increased urinary excretion, activation of certain zinc transporters, and induction of hepatic metallothionein. Zinc deficiency may manifest itself in many ways in liver disease, including skin lesions, poor wound healing/liver regeneration, altered mental status, or altered immune function. Zinc supplementation has been documented to block/attenuate experimental ALD through multiple processes, including stabilization of gut-barrier function, decreasing endotoxemia, decreasing proinflammatory cytokine production, decreasing oxidative stress, and attenuating apoptotic hepatocyte death. Clinical trials in human liver disease are limited in size and quality, but it is clear that zinc supplementation reverses clinical signs of zinc deficiency in patients with liver disease. Some studies suggest improvement in liver function in both ALD and hepatitis C following zinc supplementation, and 1 study suggested improved fibrosis markers in hepatitis C patients. The dose of zinc used for treatment of liver disease is usually 50 mg of elemental zinc taken with a meal to decrease the potential side effect of nausea.

Figure 1

Classic skin lesions around the eyes, nose, and mouth in 2 alcoholics with extremely low serum zinc levels (a, b). Skin lesions rapidly resolved in both patients with zinc supplementation. Patient 1b had encephalopathy that was initially believed to be hepatic encephalopathy. However, this resolved with zinc supplementation, documenting how zinc deficiency can cause mental disturbances. From McClain et al and McClain.

Figure 2

Healthy volunteers were injected intravenously with low-dose endotoxin or lipopolysaccharide (LPS). There was a marked reduction in the serum zinc level, which nearly normalized by 24 hours. A second dose of LPS caused a similar reduction in serum zinc. Injection of vehicle caused no significant reduction in zinc. Importantly, this very low dose of endotoxin caused no changes in the serum albumin. Thus, the hypozincemia was not secondary to a drop in the serum albumin level.

Figure 3

This graph depicts the gut-liver axis in alcoholic liver disease (ALD), beginning with altered gut flora and gut leakiness, leading to endotoxin-stimulated cytokine production, and, ultimately, liver injury and systemic inflammation. LPS, lipopolysaccharide; TLR, toll-like receptor; TNF, tumor necrosis factor.

Figure 4

Zinc deficiency can disrupt intestinal-barrier function in vitro (a), and zinc deficiency can enhance alcohol-induced intestinal-barrier dysfunction (b). (a) Effect of zinc deprivation on the epithelial barrier of Caco-2 cells. Caco-2 cells were cultured on inserts and treated with N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) at 2, 3, and 4 µM or 4 µM TPEN plus 100 µM zinc for 24 hours. The epithelial barrier function was assessed by measuring transepithelial electrical resistance (TEER) and FD-4 permeability. Results are means ± SD (n = 8). Significant differences (P < .05, analysis of variance [ANOVA]) are identified by different letters, a–e. T, TPEN. (b) Sensitizing effect of zinc deprivation on alcohol-induced epithelial barrier dysfunction. Caco-2 cells were cultured on inserts and treated with TPEN at 2 µM for 24 hours, followed by treatment with 5% (vol/vol) ethanol for 5 hours. The epithelial barrier function assessed by measuring TEER and FD-4 permeability. Results are means ± SD (n = 8). Significant differences (P < .05, ANOVA) are identified by different letters, a–c. From Zhong et al.