WBR0773

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Will Gibson)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Immunology
Sub Category	SubCategory::Gastrointestinal, SubCategory::General Principles
Prompt	[[Prompt::A 57-year-old Japanese man presents to the physician's office for abdominal fullness, weight loss, and excessive belching. Following appropriate work-up, he is diagnosed with advanced gastric cancer. The patient undergoes treatment with 5-fluorouracil and leucovorin rescue, but his tumor failed to show an objective response and therapy is discontinued. Several months later, he returns to the office appearing pale and asthenic. He suffers from dyspnea and weakness on minimal exertion. On physical examination, he has marked skeletal muscle atrophy and fat loss. Which of the following proteins most likely mediates the patient's condition?]]
Answer A	AnswerA::Interleukin-2 (IL-2)
Answer A Explanation	AnswerAExp::IL-2 is not a main mediator of cachexia syndrome. IL-2 is secreted by T cells and helps to activate other T cells.
Answer B	AnswerB::Tumor growth factor - beta (TGF-beta)
Answer B Explanation	AnswerBExp::TGF-beta is not a main mediator of cachexia syndrome. TGF-beta is a cytokine whose physiologic functions are varied and complex. Generally, TGF-beta is thought to reduce inflammation by inhibiting cell proliferation.
Answer C	AnswerC::IL-4
Answer C Explanation	AnswerCExp::IL-4 is not a main mediator of cachexia syndrome. IL-4 normally functions to induce the differentiation of naive T-helper cells in lymph nodes.
Answer D	AnswerD::Tumor necrosis factor - alpha (TNF-alpha)
Answer D Explanation	AnswerDExp::TNF-alpha is also known as cachectin because it is the main mediator of the syndrome of cachexia.
Answer E	AnswerE::Interferon-alpha (INF-alpha)
Answer E Explanation	[[AnswerEExp::INF-alpha is not a main mediator of cachexia syndrome. Nonetheless, IFN-gamma is frequently activated in cachexia. IFN-gamma is normally secreted by CD4+ Th1 cells and serves to activate nearby macrophages in the presence of a viral infection. The interferons as a family have direct antiviral activity and help to induce the expression of MHC-class II in virally infected cells.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation:: This patient presents displays signs and symptoms consistent with cachexia, a syndrome that is characterized by the presence of anorexia, fat loss, skeletal muscle wasting, severe asthenia, and fatigue. An unintentional loss of greater than 10% loss of body weight over a 12 month period that is associated with an underlying disease constitutes the technical definition of cachexia. Affected patients have dyspnea and severe weakness on minimal exertion or even at rest. Cachexia typically arises in the setting of cancer and other chronic inflammatory conditions such as AIDs, tuberculosis and COPD. The weight loss in cachectic patients is caused by both a decrease in appetite and a hypermetabolic state caused by higher resting energy expenditure. The precise reasons that cancers evolve to consistently induce cachexia are unknown. One hypothesis is that cancers induce cachexia to generate more bioavailable nutrients (glucose and amino acids) to sustain rapid tumor growth. Another hypothesis is that cancers maintain a complex relationship with stromal and immune cells in which inflammatory cytokines play an essential role. In this model, a systemic side-effect of high levels of these cytokines in the bloodstream is cachexia. There is no scientific consensus on the specific cytokines responsible for inducing cachexia, but one of the prevailing candidates is TNF-alpha. TNF-alpha is sufficient to inhibit myocyte differentiation and induce myocyte atrophy in-vitro. Other mediators such as IL-6 and IFN-gamma may collaborate with TNF-alpha to promote cachexia. The only anti-cachexia drugs to date that have demonstrated benefit in phase III clinical trials are ghrelin analogues. Note: While TNF-alpha is firmly entrenched in the USMLE canon as the mediator of cachexia, evidence in favor of TNF-alpha has weakened over time. There is no strong evidence that levels of TNF-alpha are increased in the circulation of cancer patients with weight loss. Trials of anti-TNF-alpha antibodies (infliximab) in cancer patients have also failed to show any clinical benefit. On the other hand, evidence in favor of IL-6 as a cachexia mediator is mounting. Circulating levels of IL-6 correlate with weight loss and reduced survival in cancer patients. Still, for the purposes of USMLE Step 1, remember that cachexia is caused by TNF-alpha. Educational Objective: TNF-alpha (cachectin) is the main mediator of cachexia. References: Gordon JN, Green SR, Goggin PM. Cancer cachexia. Q J Med. 2005; 98:779-788. Fearon, Kenneth CH, David J. Glass, and Denis C. Guttridge. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell metabolism 16.2 (2012): 153-166. Oliff, Allen, et al. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50.4 (1987): 555-563. First Aid 2014 page 231]]
Approved	Approved::Yes
Keyword	WBRKeyword::TNF-alpha, WBRKeyword::TNF, WBRKeyword::Alpha, WBRKeyword::Cachexia, WBRKeyword::Cachectin, WBRKeyword::Anorexia, WBRKeyword::Asthenia, WBRKeyword::Fatigue, WBRKeyword::Weakness, WBRKeyword::Dyspnea, WBRKeyword::Cancer, WBRKeyword::Gastric, WBRKeyword::Tumor, WBRKeyword::Tumor necrosis factor, WBRKeyword::IL-6, WBRKeyword::IL
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