Malnick Stephen, Abdullah Ali, Maor Yaacov, Neuman Manuela G
Department of Internal Medicine C, Kaplan Medical Center, Hebrew University, Rehovot 76100, Israel.
Institute of Gastroenterology and Liver Disease, Kaplan Medical Center, Rehovot 76100, Israel.
Curr Issues Mol Biol. 2024 Jul 16;46(7):7548-7557. doi: 10.3390/cimb46070448.
Herbal and complementary medicine are frequently integrated with conventional medicine. We aim to report a case of severe herbal-induced liver injury (HILI) due to chronic use of green tea and protein shake. We present both clinical and laboratory evidence implicating mitochondrial toxicity and an immune response leading to a hypersensitivity reaction to the products. We have recently treated a 39-year-old man with hepatotoxicity resulting from a combination of a green tea-containing powder and a branched-chain amino acid supplement that was commenced 2 months previously. The hepatotoxicity resolved by stopping the consumption of these products and no other cause was detected. We decided to perform a lymphocyte toxicity assay (LTA) to determine if there was laboratory support for this diagnosis. LTA (% toxicity) represents the response of the mitochondria to toxic injury. To determine the role of the proinflammatory and anti-inflammatory cytokines and chemokines in the patient's reaction, we measured the level of cytokines and chemokine in the media of growing cells, exposed to each product or to a combination of products. The increased cytokines and chemokines are presented as the x-fold elevations from the upper limit of normal (ULN) for matrix metalloproteinase (MMP) (pg/mL × 1.5 ULN) and interleukin (IL)-1β (pg/mL × 1.8 ULN). Higher elevations were found for interferon (IFN)-β, IFN-γ, IL-8, IL 13, IL-15 (pg/mL × 2 ULN), regulated upon activation, normal T cell expressed and presumably secreted (RANTES) (pg/mL × 2 ULN), and nuclear factor (NFκB) (pg/mL × 3 ULN). The highest increases were for vascular endothelial factor (VEGF) (pg/mL × 10 ULN), tumor necrosis factor (TNF)-α, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL × 13 ULN). An examination of cellular markers showed the difference between programmed cell death (apoptosis) and cell death due to necrosis. In our case, cytokeratin-ccK18 (M-30) U/L was within the normal limits, suggesting that apoptosis was normal, while ccK8(M65) U/L was elevated at 1.5 × ULN. This result implies that upon the treatment of the patient's lymphocytes with the products, the mechanism of toxicity is necrosis. In susceptible individuals, the combination of protein and herbal tea produces mitochondrial toxicity and a strong T-lymphocyte-1 response, leading to HILI. There is a need of international reporting of adverse drug reactions by clinicians, laboratories, and pharmaceutical manufacturers to drug regulatory authorities. This requires internationally accepted standard definitions of reactions, as well as criteria for assessment.
草药和辅助医学常常与传统医学相结合。我们旨在报告一例因长期饮用绿茶和蛋白奶昔导致的严重草药性肝损伤（HILI）病例。我们展示了临床和实验室证据，表明线粒体毒性和免疫反应导致了对这些产品的超敏反应。我们最近治疗了一名39岁的男性，其肝毒性由一种含绿茶的粉末和一种支链氨基酸补充剂联合引起，这两种产品在2个月前开始使用。停用这些产品后肝毒性消退，未检测到其他病因。我们决定进行淋巴细胞毒性试验（LTA），以确定该诊断是否有实验室依据。LTA（%毒性）代表线粒体对毒性损伤的反应。为了确定促炎和抗炎细胞因子及趋化因子在患者反应中的作用，我们测量了在生长细胞培养基中，暴露于每种产品或产品组合后的细胞因子和趋化因子水平。细胞因子和趋化因子升高以相对于基质金属蛋白酶（MMP）正常上限（ULN）的x倍升高表示（pg/mL×1.5 ULN）以及白细胞介素（IL）-1β（pg/mL×1.8 ULN）。干扰素（IFN）-β、IFN-γ、IL-8、IL-13、IL-15（pg/mL×2 ULN）、活化后正常T细胞表达并可能分泌的调节趋化因子（RANTES）（pg/mL×2 ULN）以及核因子（NFκB）（pg/mL×3 ULN）升高更为明显。升高最显著的是血管内皮生长因子（VEGF）（pg/mL×10 ULN）、肿瘤坏死因子（TNF）-α以及肿瘤坏死因子相关凋亡诱导配体（TRAIL）（pg/mL×13 ULN）。对细胞标志物的检查显示了程序性细胞死亡（凋亡）和坏死导致的细胞死亡之间的差异。在我们的病例中，细胞角蛋白-ccK18（M-30）U/L在正常范围内，表明凋亡正常，而ccK8（M65）U/L升高至1.5×ULN。这一结果表明，用这些产品处理患者淋巴细胞后，毒性机制是坏死。在易感个体中，蛋白质和花草茶的组合会产生线粒体毒性和强烈的T淋巴细胞1型反应，导致HILI。临床医生、实验室和制药制造商需要向药品监管机构进行国际药品不良反应报告。这需要国际上认可的反应标准定义以及评估标准。
