功能医学案例分析——银屑病性关节炎（下）---<功能医学医生>专业分享

DISCUSSION
MP was taking a powerful combination of commonly prescribed medications for autoimmune conditions, including etodolac, methotrexate and adalimumab. Unfortunately, MP's symptoms continued to worsen. Laboratory analysis helped to reveal the etiology of MP's condition, enabling an effective treatment plan to be designed.

讨论

针对自身免疫情况，患者MP曾坚持采取多种强有效的治疗方式相结合，包括：依托度酸、甲氨蝶呤和阿达木单抗。然而不幸的是，患者的症状仍在恶化。实验室分析可帮助阐明患者患病病因，并有助于治疗计划的制定。

In Figure 1, ELISA testing for total IgG response to 90 different foods demonstrated a strong positive reaction to eggs and yeast, and mild positive reactions ( 1 or 2) to 25 other foods, including gluten-containing wheat and barley. Food sensitivities generate significant inflammation, and as such are both a cause and effect of intestinal hyperpermeability. Other factors contributing to MP's intestinal hyperpermeability included alcohol and NSAID use. Intestinal hyperpermeability has been demonstrated to be a significant etiopathogenic mechanism in inflammatory arthritis and celiac disease.

在表格1中，鉴于免疫球蛋白G对90余种不同食物的反应，患者进行了酶联免疫吸附测定实验，这一结果表明患者对鸡蛋和酵母有着强烈的阳性反应，对其余25种食物有温和的阳性反应（ 1或 2），这些食物包括含谷蛋白的小麦和大麦。食物敏感性给患者造成了严重的炎症，并且与肠道渗透性过高形成恶性循环。其他造成患者肠道渗透性过高的因素还包括：酒精和非甾体抗炎药的使用。肠道通透性是炎症性关节炎和乳糜泄发病的重要的发病机制。

MP's genetic test for celiac disease demonstrated the presence of the DQ2 allele DQ.A1*0501 (Figure 1). Psoriatic arthritis is associated with celiac disease and subclinical gluten enteropathy. HLA DQ is a heterodimer cell surface type protein found on antigen-presenting cells. HLADQ2 is encoded by the DQAl*0501 and the DQ_B1*0201 alleles. Approximately 90% of celiac patients express the DQ2 heterodimer serotype. Interestingly, more than 3% of celiac patients present with only half the DQ2 heterodimer, as did MP. In one study looking at 1008 European celiac patients, 57 encoded only half of the DQ2 heterodimer. Because MP's test results demonstrated the presence of half the DQ2 heterodimer-specifically, the HLA DQA1*05 allele-celiac disease could not be ruled out. However, IgA tissue transglutaminase antibodies (tTG) were undetectable (Figure 1), which significantly reduced the likelihood of celiac disease.

患者乳糜泻的基因检测表明存在DQ2和等位基因DQ.A180501（表格1）。银屑病和乳糜泻与亚临床麸质肠病存在联系。人类白细胞抗原DQ是一种在抗原呈递细胞发现的细胞表面蛋白的异源二聚体类型。人类白细胞抗原DQ2是由DQAI*0501和DQ_B1*0201等位基因共同编码的。将近90%的乳糜泄患者呈现出DQ 2异源血清型。有趣的是，超过3%的乳糜泻患者呈现半数的DQ 2异质二聚体，正如同患者MP一样。在一项调查了1008名欧洲乳糜泻患者的报告中显示，其中57名患者只有DQ2异质二聚体的半数编码。由于患者MP的测试结果明显地表明半数的DQ2异质二聚体，因此排除因白细胞抗原DAQ1*05等位基因造成的乳糜泻可能。然而，未探测出免疫球蛋白A组织谷氨酰胺转移酶（表格1），但其很可能因乳糜泻而显著降低。

Despite positive the equivocal celiac panel, a gluten-free trial was suggested because of the IgG reaction to wheat and barley and the presence of the DQ2 allele. It was also recommended that he eliminate dairy and those foods with reactivity of 3 and above, and limit intake of the 2 foods.

尽管腹腔检查阳性结果不明确，但鉴于免疫球蛋白G对小麦的反应和耐受性以及DQ2等位基因的表现，仍建议患者实施无谷蛋白试验。同时建议患者停止食用乳制品及和 3及其以上产生反应的食品，并限制食用 2的食物。

Figure 2 showed reported levels of inflammatory markers, vitamin D and red blood cell magnesium.
With the exception of a high-normal ferritin and elevated hs-CRP, none of the inflammatory markers were abnormal. Methotrexate and adalimumab attenuate markers of inflammation, and may have been responsible for these negative findings.

表格2阐明了报告中感染指标的水平，维生素D和红细胞镁。患者除了高于正常的铁蛋白和较高的超敏C反应蛋白，没有异常炎症指标。甲氨蝶呤和阿达木单抗可缓解炎症指标，并可能在一定程度上是这些结果呈阴性的原因。

MP's vitamin D level of 21ng/mL (Figure 2) may have contributed to the severity of his symptoms. The pathophysiology of psoriatic arthritis includes up regulation of Th1-driven inflammation. Vitamin D specifically regulates T-helper and dendritic cell function while inducing regulatory T cells, causing a decrease in Th1 activity. The optimal serum vitamin D range is now thought to be 40 to 70 ng/mL. It is suggested that individuals with chronic disease maintain levels between 55 and 70 ng/mL. Hypovitaminosis D may have been a factor in MP's depression. Sub-optimal magnesium (Figure 2) is found in a large percentage of the population, and is a common finding in those with chronic disease.

患者的维生素D水平是21ng/ml（表格2），这可能是造成他严重的症状体征的原因之一。银屑病性关节炎的发病机制包括Th1细胞驱动感染的增量调节。维生素D在调节T细胞，降低Th1细胞活性时，对辅助细胞有特别作用。目前人们认为最理想的血清维生素D范围在40ng/ml至70ng/ml。建议有慢性疾病的患者将这一数值控制在55至70ng/ml范围内。维生素D缺乏症可能是造成患者MP抑郁的因素之一。在大量人群的体内发现了非最理想水平的镁元素（表格2），这一现象也同时存在于患有慢性疾病患者的体内。

In Figure 3, the omega-3 fatty acids (ALA, EPA and DHA) were all within normal limits, probably because MP was supplementing with them. However, the omega-6 fatty acid AA was high normal, supporting the production of pro-inflammatory cytokines. The 2- and 4-series eicosanoids, produced from AA, stimulate the up regulation of TNF-alpha, a Th1 cytokine strongly implicated in psoriatic arthritis pathogenesis. MP was taking the drug adalimumab, which binds TNF-alpha directly, blocking its ability to bind certain receptors. Reducing AA availability through diet and nutrients could similarly assist in modulating the inflammatory effects of psoriatic arthritis by reducing AA-derived eicosanoids.

表格3中，ω3脂肪酸（亚麻酸，二十碳五烯酸和二十二碳六烯酸）均在正常范围内，这一现象可能是患者有意补充的结果。然而，ω6脂肪酸丙烯酸高于正常值，这可能会增加促炎性细胞因子的数量。2-和4-类二十烷酸可从丙烯酸中获取，它们可对α肿瘤坏死因子产生增量调节的作用，而Th1细胞因子是银屑病性关节炎发病机制的明显标志。患者曾连续服用阿达木单抗药物，这可能会直接抑制α肿瘤坏死因子并阻止它抑制某些特定受体的能力。通过饮食和营养物的摄入来降低丙烯酸利用率，既降低来自丙烯酸的类二十烷酸，同样可以起到调节银屑病性关节炎的炎症影响的作用。

Figure 3 showed elevated saturated and monounsaturated fatty acids, which represent a pattern seen in metabolic syndrome with hypertriglyceridemia, where insulin stimulates the liver enzyme fatty acid synthase to produce saturated fatty acids. Insulin also stimulates delta-9 desaturase which converts saturated to monounsaturated fatty acids, primarily palmitoleic, vaccenic and oleic.

表格3表明，高饱和和单不饱和脂肪酸代表了伴有高甘油三酯血症的代谢综合症中一个模式，其中，胰岛素可调节脂肪酸合成酶从而产生饱和脂肪酸。胰岛素也会调节δ-9去饱和酶，这种酶将饱和脂肪转变为单不饱和脂肪，主要为棕榈油酸、反棕榈和亚油酸甘油三酯。

palmitoleic, vaccenic and oleic. Lipid peroxidation was also high, indicating increased oxidative damage to the lipid-rich cellular membranes.

脂质过氧化作用也强，表明增强的氧化作用损害富含脂质的细胞膜。

The metabolic assessment shown in Figure 4 demonstrated insulin resistance. It has been suggested that insulin stimulates the production of AA, and AA elevation has been associated with insulin resistance. These findings suggested a possible mechanistic link between psoriatic arthritis and metabolic syndrome through the common pathway of eicosanoid-driven inflammation. An elevated AA/EPA ratio has been shown to positively correlate with depression. MP had more than 7 times the amount of AA relative to EPA in his plasma, despite supplementation with omega-3 fatty acids.

表格4中的代谢评估显示了胰岛素抵抗。它说明胰岛素刺激氨基酸的产生，氨基酸的水平与胰岛素抵抗相关。这些结果显示银屑病关节炎和代谢综合征可能通过类花生酸驱动的炎症的常用通路存在某种机械关联。升高的氨基酸和二十碳五烯酸的比例已被证明与抑郁呈正相关。尽管补充了Omega-3脂肪酸，MP的血浆中氨基酸含量相对于二十碳五烯酸仍多了七倍有余。

MP's thyroid panel was within normal limits, including antibodies (Figure 5). Optimal TSH is now considered to be 2.5, but may be as low as 1.18 mIU/L. Free T3 and free T4 were low normal. These results suggested that the thyroid should be monitored, particularly given the association of hypothyroidism with rheumatologic conditions. Nutrients involved with thyroid function, including red blood cell zinc, whole blood selenium and plasma tyrosine, were within normal limits.

MP的甲状腺激素水平在正常范围内，其中包括抗体（表格5）。最理想的促甲状腺激素水平应该是2.5，但最低可以是1.8 mIU/L。游离T3和T4正常偏低。这些结果显示应该对甲状腺进行监测，尤其要考虑风湿性疾病情况下的甲状腺功能减退。营养物质与甲状腺功能有关，包括红细胞锌含量、全血硒含量和血浆酪氨酸含量均在正常值内。

As was suspected, DNA stool analysis demonstrated a significant quantity of Candida species in the gastrointestinal tract (Figure 6). Candida species in particular have been found in significant amounts relative to controls in the saliva, skin, and stool of psoriatic patients.

与猜测的一样，DNA粪便分析显示胃肠中有大量念珠菌类（表格6）。尤其大量念珠菌类与银屑病患者的唾液、皮肤、粪便有关。

As discussed above in the treatment rationale, a straightforward approach involving removing yeast and antigentic foods was used to address the imbalances found, reducing inflammation, restoring GI mucosa and providing the needed nutrients. It was expected that thyroid and metabolic imbalances would be normalized with these general interventions.

与上述讨论的治疗原理相同，用移除酵母菌和抗原食物这种直截了当的方法来处理失衡情况，减轻炎症，恢复胃肠粘膜，并提供需要的营养。希望甲状腺和代谢失衡能通过这些常规干预治疗恢复正常。

CONCLUSION
Autoimmune diseases are debilitating conditions that affect millions of individuals. Current standard-of-care therapies come with high risk profiles and may not slow the progression of the disease significantly. Despite the extensive categorization of autoimmune diseases into diagnoses such as lupus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, multiple sclerosis, nephritis, and scleroderma, the treatments are based on pathology, not etiology.

结论

自身免疫性疾病使人的身体处于虚弱的状态，这类疾病影响了上百万人。现有的标准疗法具有较高风险，且不一定能够明显减缓疾病的发展。虽然自身免疫性疾病的诊断法分类广泛，如红斑狼疮、类风湿性关节炎、银屑病性关节炎、炎性肠病、多发性硬化、肾炎和硬皮病，治疗一定是基于病理，而非病因。

Systems-based, or functional, medicine considers the diagnosis, of course, but also seeks to answer the question why. The etiology of a disease may vary among people with the same diagnosis or pathology. Conversely, the etiology maybe the same in patients with very different pathologies-for example, mercury toxicity is found in both multiple sclerosis and Crohn's disease. Approaches to treatment, therefore, will vary according to the particular upstream causes and downstream effects present in each patient. Treating only the downstream effects (such as nutrient deficiencies or food sensitivities due to malabsorption and intestinal hyperpermeability) without treating the upstream causes (such as gluten sensitivity, gastrointestinal yeast, or mercury toxicity) will often result in treatment failure.

基于系统的或功能性的医疗要考虑诊断，但也要找出病因。有相同诊断或病理现象的病人，其病因可能是不同的。相反地，有不同病理现象的病人可能存在相同病因。例如，在多发性硬化和克罗恩病中，汞中毒都可以作为病因。因此，治疗方法会根据每个病人各自独特的上游原因和下游结果而有所不同。只治疗下游的结果（如由于吸收不良和肠道渗透性过高引起的营养不良或食物过敏），而不治疗上游原因（如麸质过敏、胃肠道酵母菌或汞中毒）经常会导致治疗失败。

Focusing on the patient's individual etiology of autoimmune disease provides a personalized framework for diagnosis and treatment. Five primary etiologic factors have been identified that give rise to nearly all disease (including autoimmune disease) through their effects on gene expression: toxins, allergens, infections (or microbial imbalances), poor diet, and stress.

关注患者个人的自身免疫性疾病的病因为诊断和治疗提供了个性化框架。五个原发性病因已被证明能通过它们对基因表达的影响，如毒素、过敏原、感染（或微生物失衡）、不良饮食习惯和压力，从而导致几乎所有的疾病（包括自身免疫性疾病）。

MP, a highly successful, educated physician had access to the latest medications and technologies to address his psoriatic to deteriorate despite aggressive arthritis. Unfortunately, however, his condition continued interventions. He was in constant pain, with limited mobility and use of his hands. Using a systems approach with MP including laboratory analysis and thorough history allowed the variables involved in the etiopathogenesis of his illness to be successfully identified and addressed. His pain was alleviated, his movement restored and his quality of life immeasurably improved. Associated complaints such as reflux, constipation, migraines and depression were all resolved in the process, as they all shared pathogenic mechanisms with PA. He was able to reduce the dosage or eliminate all of his medications. As MP became versed in understanding the environmental role in his condition, he was able to identify and avoid his disease triggers, allowing him to take charge of his health.

MP是一位很成功并受过良好教育的医生，接触了最新的药物和技术来阻止他的银屑病恶化，虽然他还患有关节炎。然而不幸的是，他的病情要持续进行干预治疗，他感到持续疼痛，只能有限地活动和使用双手。用包括实验室分析和详查病史在内的系统方法检查MP，使得他疾病中的发病机理中的可变因素成功地得到确认和处理。他的疼痛得到缓解，恢复了活动能力，生活质量很大程度的提高了。相关的主诉如食管反流、便秘、偏头痛和抑郁都在过程中得到了解决，因为它们都与银屑病性关节炎有着相同的致病机制。他可以减少药物剂量，或者停止服药。MP很好地理解了环境在他疾病中的作用，他能够确认并避免疾病的触发因素。这使他能更好地管理健康。