Muscle wasting disease：筋消耗性疾患

Muscle wasting disease(筋消耗性疾患)という新しい疾患概念の提言に関する論文を紹介します。

Stefan D. Anker, et al. Muscle wasting disease: a proposal for a new disease. Journal of Cachexia, Sarcopenia and Muscle, doi:10.1007/s13539-014-0135-0

定義としては従来のミオペニアや広義のサルコペニアに近いです。急性疾患、慢性疾患どちらにも使用できますし、サルコペニア、悪液質、消耗性疾患どれにも使用できます。まず急性か慢性かで分類し、慢性の場合には次に原因疾患と重症度で分類します。

原因疾患には、がん、慢性腎不全、慢性心不全、慢性閉塞性肺疾患、神経筋疾患、慢性感染、加齢（サルコペニア）、多疾患の合併、代謝性疾患関連疾患があります。重症度には軽度、中等度（前悪液質）、重度（悪液質）があります。

まずはMuscle wasting disease(筋消耗性疾患)と診断して、その原因を何かと考えるスタンスのようです。ただ診断基準の記載はなく、今後の会議で修正、変更して行くそうです。こういった用語ができたことだけ知っておけばよいかなと思います。

Muscle wasting and cachexia are the ultimate consequence of aging and a variety of acute and chronic illnesses. Significant efforts are made by many stakeholders to develop effective therapies. An important aspect of successful therapeutic development research is a common nomenclature for effective communication between researchers and clinicians, to the public, and also with regulatory bodies. Despite several efforts to develop consensus definitions for cachexia and sarcopenia, including such new terms for muscle wasting as myopenia, a common conceptual approach and acceptable vocabulary and classification system are yet to be established. Notwithstanding the potential need to translate such disease definitions and terminologies into different languages, we advocate the use of the term “muscle wasting” as the unifying entity that represents the single most common disease process across a large spectrum of cachexia and in sarcopenia-associated disorders. In this paper, we outline a first proposal for the disease nomenclature and classification of “Muscle Wasting Diseases.” This concept can be applied in acute and chronic disease settings. It is pertinent for wasting diseases, cachexia, and sarcopenia of any severity and due to any underlying illness. The concept of muscle wasting disease underscores the most common denominator of the underlying wasting processes, i.e., muscle wasting, without ignoring the advanced disease states that are also accompanied by fat tissue wasting. The term muscle wasting disease is easily understood by both the scientific community and the lay public. This may promote its general use and efforts to heighten education and awareness in the field.

がん悪液質とGlasgow Prognostic Score

がん悪液質とGlasgow Prognostic Scoreのレビュー論文を紹介します。

Euan Douglas, Donald C McMillan. Towards a simple objective framework for the investigation and treatment of cancer cachexia: The Glasgow Prognostic Score. Cancer Treatment Reviews.

http://www.sciencedirect.com/science/article/pii/S0305737213002600

Glasgow Prognostic Scoreのスコアで悪液質の有無とステージを評価して、どんな介入をするかを表で示しています。主観的な項目がないので、簡単な診断基準といえます。個人的にはCRPが1mg/dl以上でないと悪液質と判断できないのは気になります。

Abstract

Progress in the treatment of progressive involuntary weight loss in patients with cancer (cancer cachexia) remains dismally slow. Cancer cachexia and its associated clinical symptoms, including weight loss, altered body composition, poor functional status, poor food intake, and poorer quality of life, have long been recognised as indicators of poorer prognosis in the patient with cancer. In order to make some progress a starting point is to have general agreement on what constitutes cancer cachexia. In recent years a plethora of different definitions and consensus statements have been proposed as a framework for investigation and treatment of this debilitating and terminal condition. However, there are significant differences in the criteria used in these and all include poorly defined or subjective criteria and their prognostic value has not been established.

The aim of the present review was to examine the hypothesis that a systemic inflammatory response accounts for most of the effect of cancer cachexia and its associated clinical symptoms on poor outcome in patients with cancer. Furthermore, to put forward the case for the Glasgow Prognostic Score to act a simple objective framework for the investigation and treatment of cancer cachexia.

悪液質に対する酢酸メゲステロール：コクラン

悪液質に対する酢酸メゲステロールのコクランレビューを紹介します。

Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Marti S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2013 Mar 28;3:CD004310. doi: 10.1002/14651858.CD004310.pub3.

前回2005年のバージョンからアップデートされたものです。結果ですが、エイズやがんによる悪液質に対する酢酸メゲステロール投与で、プラセボと比較すると食欲増進や体重増加が得られました。一方、他の薬との比較では有意な改善は認めませんでした。

投与量に関しては量が多いほうが体重増加が多いです。QOLはプラセボとの比較では改善しましたが、他の薬との比較では有意差を認めませんでした。酢酸メゲステロールの副作用として、浮腫、血栓塞栓症、死亡が有意に増加しました。

以上より、エイズやがんによる悪液質に対する酢酸メゲステロール投与で、食欲改善とわずかな体重増加を認めるという結論です。ただし、緩和ケアを受けている患者であっても、リスクについて十分に伝えることが必要です。

コクランレビューで有効というのは意味がありますが、体重増加の一因は浮腫かもしれません。また死亡が有意に増加するようでは、食欲改善や体重増加より問題が大きいです。日本では使用できない薬剤ですが、使用できたとしても適応は少ない気がします。

Abstract

BACKGROUND:

This is an updated version of a previously published review in The Cochrane Library (2005, Issue 2) on 'Megestrol acetate for the treatment of anorexia-cachexia syndrome'. Megestrol acetate (MA) is currently used to improve appetite and to increase weight in cancer-associated anorexia. In 1993, MA was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia or unexplained weight loss in patients with AIDS. The mechanism by which MA increases appetite is unknown and its effectiveness for anorexia and cachexia in neoplastic and AIDS (acquired immunodeficiency syndrome) patients is under investigation.

OBJECTIVES:

To evaluate the efficacy, effectiveness and safety of MA in palliating anorexia-cachexia syndrome in patients with cancer, AIDS and other underlying pathologies.

SEARCH METHODS:

We sought studies through an extensive search of electronic databases, journals, reference lists, contact with investigators and other search strategies outlined in the methods. The most recent search for this update was carried out in May 2012.

SELECTION CRITERIA:

Studies were included in the review if they assessed MA compared to placebo or other drug treatments in randomised controlled trials of patients with a clinical diagnosis of anorexia-cachexia syndrome related to cancer, AIDS or any other underlying pathology.

DATA COLLECTION AND ANALYSIS:

Two independent review authors conducted data extraction and evaluated methodological quality. We performed quantitative analyses using appetite and quality of life as a dichotomous variable, and analysed weight gain as continuous and dichotomous variables.

MAIN RESULTS:

We included 35 trials in this update, the same number but not the same trials as in the previous version of the review. The trials comprised 3963 patients for effectiveness and 3180 for safety. Sixteen trials compared MA at different doses with placebo, seven trials compared different doses of MA with other drug treatments and 10 trials compared different doses of MA. Meta-analysis showed a benefit of MA compared with placebo, particularly with regard to appetite improvement and weight gain in cancer, AIDS and other underlying conditions, and lack of benefit in the same patients when MA was compared to other drugs. There was insufficient information to define the optimal dose of MA, but higher doses were more related to weight improvement than lower doses. Quality of life improvement in patients was seen only when comparing MA versus placebo but not other drugs in both subcategories: cancer and AIDS. Oedema, thromboembolic phenomena and deaths were more frequent in the patients treated with MA. More than 40 side effects were studied.

AUTHORS' CONCLUSIONS:

This review shows that MA improves appetite and is associated with slight weight gain in cancer, AIDS and in patients with other underlying pathology. Despite the fact that these patients are receiving palliative care they should be informed of the risks involved in taking MA.

がんの筋肉量減少と筋肉の質低下は予後不良

肥満時代のがん悪液質：がん患者の筋肉量減少はBMIと独立した強力な予後予測因子であるという論文を紹介します。

Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, Murphy R, Ghosh S, Sawyer MB, Baracos VE. Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index. J Clin Oncol. 2013 Mar 25. [Epub ahead of print]

対象はがん患者（肺がんもしくは消化器がん）1473人です。筋肉量はCTでL3レベルの筋面積（腹筋、大腰筋、傍脊柱筋）を身長で2回割った骨格筋指数SMIで評価しています。同時に筋肉減衰muscle attenuation（筋肉内に脂肪が多いとCTで薄い）も評価しています。

結果ですが、生存期間に独立して関連があったのは、高度の体重減少、骨格筋指数低値、筋肉減衰低値（筋肉内に脂肪が多い）の3項目でした。3項目とも該当すると生存期間は8.4カ月でまったく該当しないと生存期間は28.4ヶ月でした。

以上より、CTによる筋肉量と筋肉の質（muscle quality）の評価は有用であり、現体重が肥満かるいそうかに関わらず、高度の体重減少、骨格筋指数低値、筋肉減衰低値で生存期間を予測できるという結論です。

図のように同じ骨格筋指数でもBMIが15.3と40.2の方がいたり、同じBMIでも骨格筋指数が33.7から58.3の方がいたり、同じBMIや骨格筋指数でも筋肉減衰が大きく異なったりしますので、身体計測だけでなく、画像による筋肉量と筋肉の質の評価は有用と言えます。

Abstract

PURPOSE
Emerging evidence suggests muscle depletion predicts survival of patients with cancer.
PATIENTS AND METHODS
At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models.
Results
Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001).
CONCLUSION
CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.

悪液質のLカルニチンレビュー

悪液質に対するLカルニチンのレビュー論文を紹介します。

Robert Ringseis, Janine Keller, Klaus Eder. Mechanisms underlying the anti-wasting effect of l-carnitine supplementation under pathologic conditions: evidence from experimental and clinical studies. European Journal of Nutrition, DOI10.1007/s00394-013-0511-0

Lカルニチンの投与による窒素バランスの改善（蛋白合成増加もそくは蛋白分解減少）、アポトーシスの阻害、悪液質下での炎症反応の改善は、動物実験、ヒトでの臨床試験ともエビデンスがあります。酸化ストレスの緩和やミトコンドリア機能の改善は動物実験でのみ認めています。

Lカルニチン投与が悪液質に有効かどうかは、より大規模なRCTで検証されることが必要です。現時点では悪液質に対して試しに投与してもよいというところでしょうか。もちろん栄養療法や運動療法を併用した包括的対応の一環としてということになりますが。

Abstract

Purpose

Loss of skeletal muscle mass, also known as muscle wasting or muscle atrophy, is a common symptom of several chronic diseases, such as cancer and infectious diseases. Due to the strong negative impact of muscle loss on patient’s prognosis and quality of life, the development of efficacious treatment approaches to combat muscle wasting are of great importance. In order to evaluate the suitability of l-carnitine (LC) as an anti-wasting agent for clinical purposes the present review comprehensively summarizes the results from animal and clinical studies showing the effects of supplementation with LC or LC derivatives (acetyl-LC, propionyl-LC) on critical mechanisms involved in skeletal muscle loss under pathologic conditions, such as increased proteolysis, impaired protein synthesis, myonuclear apoptosis, inflammation, oxidative stress, and mitochondrial dysfunction.

Results

Evidence from both animal and clinical studies exists that LC supplementation causes an improved nitrogen balance either due to increased protein synthesis or reduced protein degradation, an inhibition of apoptosis and an abrogation of inflammatory processes under pathologic conditions. Furthermore, strong evidence has been provided, at least from animal studies, that LC supplementation prevents oxidative stress and ameliorates mitochondrial function, whereas results from a very low number of available clinical studies in this regard are inconclusive.

Conclusion

In conclusion, LC supplementation beneficially influences several critical mechanisms involved in pathologic skeletal muscle loss that may at least partially explain the anti-catabolic effects and the improvement of fatigue-related parameters following LC supplementation in patients with chronic diseases. However, more suitable clinical trials (double-blinded, randomized, placebo-controlled, large-scale) are necessary in order to establish LC supplementation as strategy for anti-wasting therapy.

がん悪液質に対するenobosarm

選択的アンドロゲン受容体モジュレーターenobosarmのがん悪液質と身体機能に対する効果をみたフェーズ2のRCTを紹介します。

Adrian S Dobs, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. The Lancet Oncology, http://dx.doi.org/10.1016/S1470-2045(13)70055-X

リサーチクエスチョンは以下の通りです。

P：肥満がなく過去6ヶ月間に2％以上の体重減少をみとめたがん患者に
I：enobosarm（1mg、3mg）を113日間投与すると
C：プラセボと比較して
O：除脂肪体重（DEXAで測定）が増加する
D：RCT

結果ですが、プラセボ群では中央値0·02 kgの変化でしたが、1mg投与群では中央値1·5 kg, 幅−2·1 to 12·6、3mgでは中央値1·0 kg,幅 −4·8 to 11·5と前後比較で有意に除脂肪体重が増加しました。プラセボとの比較では1mg群がp=0.066、3mg群がp=0.041でした。

主な有害事象はがんの進行、肺炎、発熱性好中球減少症でしたが、プラセボ群とenobosarm（1mg、3mg）で著明な差はなく、enobosarmによるものではないと思われました。以上よりがん悪液質に対してenobosarmは除脂肪体重を増加させる可能性があるという結論です。

今回の研究では除脂肪体重が一次アウトカムでしたが、今後は身体機能・ADL・QOL・生存期間を一次アウトカムとした研究も行われるとよいですね。選択的アンドロゲン受容体モジュレーターenobosarmのフェーズ3の臨床研究も行われているようですので、その結果にも期待したいところです。

Summary

Background

Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer.

Methods

We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844.

Findings

Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range −2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, −4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range −5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6% vs one [2%] vs none). None of these events were deemed related to study drug.

Interpretation

Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents.

CKDのPEWコンセンサス論文

慢性腎臓病（CKD）のProtein-Energy Wasting（PEW）に関する国際腎臓栄養代謝学会（ISRNM）コンセンサス論文を紹介します。

Juan Jesús Carrero, et al. Etiology of the Protein-Energy Wasting Syndrome in Chronic Kidney Disease: A Consensus Statement From the International Society of Renal Nutrition and Metabolism (ISRNM). Journal of Renal Nutrition, Volume 23, Issue 2, March 2013, Pages 77–90

下記HPで全文無料で見れますし、PDFをダウンロードすることも可能です。

http://www.sciencedirect.com/science/article/pii/S105122761300006X

今回のJSPEN金沢でも腎不全患者の栄養管理：Protein-Energy Wastingへの対応を考えるというパネルがありました。この論文は、腎不全の栄養管理に関わるすべての方に読んでほしい重要論文ですね。英語ですが。

食欲不振や食事制限による不十分な食事摂取（true undernutrition、飢餓）もPEWの原因の1つですが、他の要素も関わっています。尿毒症によって引き起こされるエネルギー消費量増加、慢性炎症、アシドーシス、筋肉や脂肪の代謝（分解）を亢進させる内分泌障害などです。

それに加えて、CKDに関連する併存疾患、身体活動性低下、虚弱、人工透析そのものがPEWに影響しています。

私はざっくり慢性腎不全は悪液質の原因疾患の1つと言っていますが、他の臓器不全と異なる要素（人工透析による蛋白喪失など）もありますね。その分、人工透析中の栄養療法や運動療法といった、他の悪液質の原因疾患とは異なるリハ栄養の対応も可能です。

以前は人工透析中まで運動しなくてもよいのでは、と思っていました。人工透析以外の時間で十分な運動・リハ栄養をできる方であれば構いません。でも実際には疲労などの理由で人工透析以外の時間でも安静臥床している方もいます。透析中のリハ栄養プログラムが必要だと考えます。

Abstract
Protein-energy wasting (PEW), a term proposed by the International Society of Renal Nutrition and Metabolism (ISRNM), refers to the multiple nutritional and catabolic alterations that occur in chronic kidney disease (CKD) and associate with morbidity and mortality. To increase awareness, identify research needs, and provide the basis for future work to understand therapies and consequences of PEW, ISRNM provides this consensus statement of current knowledge on the etiology of PEW syndrome in CKD. Although insufficient food intake (true undernutrition) due to poor appetite and dietary restrictions contribute, other highly prevalent factors are required for the full syndrome to develop. These include uremia-induced alterations such as increased energy expenditure, persistent inflammation, acidosis, and multiple endocrine disorders that render a state of hypermetabolism leading to excess catabolism of muscle and fat. In addition, comorbid conditions associated with CKD, poor physical activity, frailty, and the dialysis procedure per se further contribute to PEW.

がん悪液質に酢酸メゲストロール＋サリドマイド

酢酸メゲストロールとサリドマイド併用によるがん悪液質の治療のRCTを紹介します。

Wen HS, Li X, Cao YZ, Zhang CC, Yang F, Shi YM, Peng LM. Clinical Studies on the Treatment of Cancer Cachexia with Megestrol Acetate plus Thalidomide. Chemotherapy. 2013 Feb 7;58(6):461-467. [Epub ahead of print]

リサーチクエスチョンは以下の通りです。

P：がん悪液質・食欲不振患者102人に
I：酢酸メゲストロール160mg1日2回＋サリドマイド50mg1日2回を8週間経口投与すると
C：酢酸メゲストロール160mg1日2回のみと比較して
O：がん悪液質が改善する
D：RCT

結果ですが両群で比較すると、一次アウトカムでは体重、疲労、QOLが介入群で有意に改善しました。二次アウトカムでは握力、Glasgow Prognostic Score、機能状態、IL-6、TNF-αが有意に改善しました。

毒性は両群とも比較的少なかったです。以上より酢酸メゲストロール単独でも前後比較では体重と食欲が改善しますが、酢酸メゲストロールとサリドマイドを併用するほうがよりがん悪液質が改善するという結論です。

酢酸メゲストロール、サリドマイドとも日本では通常の臨床で使用できない薬剤です。がん悪液質に対しては薬物療法だけでなく、栄養療法や抗炎症作用としての運動療法も重要ですが、副作用に配慮しながらより多くの薬物療法を臨床現場で使えるようになるといいですね。

Abstract

Background: The management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge in clinical practice. To date, practice guidelines for the prevention and treatment of CACS are lacking. The authors conducted a randomized study to confirm the effectiveness and safety of treatment of CACS utilizing megestrol acetate (MA) plus thalidomide. Methods: One hundred and two candidates with CACS were randomly assigned to two treatment groups (trial group and control group): the trial group received MA (160 mg po, bid) plus thalidomide (50 mg po, bid), while the control group received MA (160 mg po, bid) alone. Treatment duration was 8 weeks. Results: Analysis of the trial group demonstrated a significant increase from baseline in body weight, quality of life (p = 0.02), appetite (p = 0.01), and grip strength (p = 0.01), and a significant decrease in fatigue, Glasgow Prognostic Score (p = 0.05), Eastern Cooperative Oncology Group performance status (p = 0.03), IL-6, and tumor necrosis factor-α (p = 0.02). In contrast, in the control group, endpoints with a significant improvement from baseline included body weight and appetite (p = 0.02). The mean changes in the endpoints from baseline in the trial group were significantly greater compared with the control group: in the primary endpoints, body weight (p = 0.05), fatigue and quality of life (p = 0.01), and in the secondary endpoints, grip strength (p = 0.05), Glasgow Prognostic Score (p = 0.02), Eastern Cooperative Oncology Group performance status (p = 0.02), IL-6  and tumor necrosis factor-α (p = 0.01). Toxicity was found to be relatively negligible in both groups. Conclusion: A combination regimen of MA and thalidomide is more effective than MA alone in the treatment of CACS.

サルコペニアと悪液質と心不全

高齢者のサルコペニアと悪液質とうっ血性心不全のレビュー論文を紹介します。

Zamboni M, Rossi A, Corzato F, Bambace C, Mazzali G, Fantin F. Sarcopenia, Cachexia and Congestive Heart Failure in the Elderly. Endocr Metab Immune Disord Drug Targets. 2013 Jan 15. [Epub ahead of print]

軽中度の慢性心不全患者に骨格筋異常や骨格筋減少はよく認め、疲労や呼吸困難に影響している可能性があります。骨格筋異常としてサルコペニア（原発性）と心臓悪液質が考えられます。悪液質では筋肉量減少が特徴的ですが、サルコペニアの方の多くは悪液質ではありません。

体重減少、食欲不振、全身炎症反応がない場合には、サルコペニアが疑われます。容易ではありませんが、慢性心不全患者でサルコペニアと悪液質を区別することは治療上、重要です。悪液質の特異的な治療方法はありませんが、サルコペニアなら治療の選択肢があります。

原発性サルコペニアと悪液質を区別することは、リハ栄養的には広義のサルコペニアの原因検索と対応につながりますので、重要だと同感します。ただ、悪液質に対しては決定的な治療方法がないとはいえ、栄養・運動・薬物などの包括的対応はすべきだと考えます。

Abstract

Skeletal muscle abnormalities and loss are frequently present in patients with mild or moderate cardiac heart failure (CHF) and may contribute to fatigue and dyspnea. These muscle abnormalities may be associated with age related body composition changes, such as sarcopenia. Muscle damage has also been observed in subjects with cardiac cahexia, a serious CHF complication, associated with poor prognosis independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Loss of muscle mass is a feature of cachexia, whereas most sarcopenic subjects are not cachectic. Individuals with no weight loss, no anorexia, and no measurable systemic inflammatory response may be sarcopenic. Patients with severe CHF show multiple marked histological abnormalities of skeletal muscle, such as muscle fiber atrophy. These abnormalities are different in sarcopenia and cachexia. The majority of mechanisms involved in sarcopenia play a role even in the determination of cachexia and they are amplified in cachexia where they may induce both muscle damage as well as other abnormalities, such as fat and weight loss, through activation of lypolisis or anorexia. To distinguish cachexia and sarcopenia in CHF patients, even if not easy, should be clinically relevant, because no specific treatment is available for cachectic patients whereas treatment options are possible for sarcopenia.

終末期肝疾患のCT身体組成評価

腹部CTで終末期肝疾患の身体組成を評価した論文を紹介します。

Cruz RJ Jr, Dew MA, Myaskovsky L, Goodpaster B, Fox K, Fontes P, Dimartini A. Objective Radiologic Assessment of Body Composition in Patients with End-Stage Liver Disease: Going Beyond the BMI. Transplantation. 2013 Jan 23. [Epub ahead of print]

対象は肝移植を希望している234人の終末期肝疾患患者です。結果ですが、BMIは皮下脂肪、内臓脂肪と高い相関を認めました。しかし、筋肉量で評価した悪液質を肥満患者でもよく認めました。BMI30以上の患者の56%が悪液質でした。

非アルコール性脂肪肝炎では他の肝疾患と比較して、内臓脂肪がより多く筋肉量がより少なかったです。探索的解析では、身長で補正した筋肉量は、肝移植後の生存期間の有意な予測因子でした。腹部CTは肥満と筋肉減少の評価に有用で、予後予測にはさらなる研究が必要という結論です。

肝疾患患者で筋肉量が少ないことは、臨床的に十分納得できます。BMIでの評価だけでは不十分で、検査機器で体組成を評価すべきです。重症な肝疾患であれば必ず腹部CTを行っているでしょうから、腹部CTによる評価がルーチンとなればいいなあと思います。

Abstract

BACKGROUND:

Body mass index (BMI) is a commonly used but likely inexact measure of body composition for patients with end-stage liver disease. For this reason, we examined whether body composition measurements from direct visualization on computed tomography (CT) scans provide new insights in both the degree of malnutrition and the discordant combinations such as obesity with muscle mass loss. This technology is widely used in other medically ill populations but not yet in liver transplantation.

METHODS:

We examined actual body composition using abdominal CT scan data and software designed to measure fat and muscle compartments.

RESULTS:

In 234 liver transplant candidates, we found that BMI was highly and significantly correlated to subcutaneous and visceral fat. However, we additionally found that, even among obese patients, cachexia, as defined by muscle mass, was common, with 56% of those with BMI above 30 being cachexic. We also found that patients with nonalcoholic steatohepatitis, compared with other types of liver diseases, were significantly more likely to have larger amounts of visceral fat while also having less muscle. In an exploratory analysis, muscle mass corrected for height was a significant predictor of posttransplantation survival.

CONCLUSIONS:

Body composition by CT scan data provides a specific method to identify obesity and muscle wasting for end-stage liver disease patients. Whether these data can aid in the prognostication of outcomes and survival requires further investigation.

がん悪液質の診断基準とQOL・予後

がん悪液質の診断基準と、QOL、運動能力、生命予後との関連を緩和けあ患者で調査した論文を紹介します。

Wallengren O, Lundholm K, Bosaeus I. Diagnostic criteria of cancer cachexia: relation to quality of life, exercise capacity and survival in unselected palliative care patients. Support Care Cancer. 2013 Jan 13. [Epub ahead of print]

悪液質の診断基準は3つ使用しています（Fearonら2006年：10%以上の体重減少、1日エネルギー摂取量1500kcal以下、CRP1mg/dl以上、Enansら2008年、Fearonら2011年）。

結果ですが、2%以上の体重減少、BMI20未満、CRP1mg/dl以上はQOL低下と関連していました。疲労、握力低下、全身炎症は歩行距離低下と関連を認めました。2%以上の体重減少、疲労、CRP1mg/dl以上、アルブミン3.2g/dl未満は生命予後不良と関連していました。

悪液質の有病割合は12～85％と診断基準によって大きく異なりました。以上より、体重減少、疲労、全身炎症がもっともQOL低下、運動能力低下、生命予後と関連していました。悪液質の有病割合は診断基準で大きく異なり、さらなる研究が必要という結論です。

ただ、現状では前悪液質、悪液質不応性、悪液質というステージ分類を導入したのは、Fearonらの2011年の診断基準だけですので、現状ではこれを用いるのがベストではと感じています。

Abstract

PURPOSE:

Cachexia is associated with adverse outcomes. There is limited information on the impact of different diagnostic criteria of cachexia on patient centered outcomes.

METHODS:

We compared the prevalence of reduced quality of life (QoL), physical function and survival in palliative care cancer patients classified by different cachexia criteria. Four hundred and five patients with advanced cancer were included. Cachexia criteria were BMI, weight loss, fatigue, Karnofsky performance score, low handgrip strength, lean tissue depletion (DXA or arm muscle circumference) and abnormal biochemistry (inflammation, anemia or low serum albumin). QoL was assessed with a cancer specific questionnaire (EORTC QLQ-C30) and classified by cluster analysis. Dietary intake was obtained from a 4-day food record. Physical function was measured on a treadmill.

RESULTS:

Weight loss >2 %, BMI <20 and="and" crp="crp" fatigue="fatigue">10 mg/L were associated with adverse QoL, function and symptoms (odds ratios: 2.1, 2.9, 4.0 and 3.1 respectively, P < 0.05 for all). Fatigue, low grip strength and markers of systemic inflammation were associated with short walking distance (P < 0.05). Weight loss > 2 %, fatigue, CRP > 10 mg/L and S-albumin < 32 g/L were associated with shorter survival (hazard ratios: 1.4, 1.6, 2.2 and 2.0 respectively, P < 0.05 for all). The prevalence of cachexia diagnosis varied from 12 to 85 % using different definitions.

CONCLUSIONS:

Weight loss, fatigue and markers of systemic inflammation were most strongly and consistently associated with adverse QoL, reduced functional abilities, more symptoms and shorter survival. The prevalence of cachexia using different definitions varied widely; indicating a need to further explore and validate diagnostic criteria for cancer cachexia.

悪液質診断の検査値の違い

血液腫瘍とその他の腫瘍・心不全で悪液質診断に使用する検査値が異なるという論文を紹介します。

Letilovic T, Perkov S, Mestric ZF, Vrhovac R. Differences in routine laboratory parameters related to cachexia between patients with hematological diseases and patients with solid tumors or heart failure -- is there only one cachexia? Nutr J. 2013 Jan 7;12(1):6. [Epub ahead of print]

対象は血液腫瘍（悪性リンパ腫）55人とその他の腫瘍・心不全の患者64人です。悪液質の診断基準にはEvansらの基準を用いています。Evansらの基準には検査値異常としてCRP0.5mg/dl以上、Hb12g/dl未満、Alb3.2g/dl未満が含まれています。

119人のCRP、Hb、Albを評価して、血液腫瘍とその他の腫瘍・心不全で検査値に違いがないかを評価しました。結果ですが、疾患の違いにかかわらず、悪液質群ではCRPが有意に高く、HbとAlbが有意に低かったです。

疾患の違いで、血液腫瘍群ではCRPが有意に低く（1.598 vs. 2.871）mg/dl、Albが有意に高いという結果でした（4.095 vs. 3.601）g/dl。Evansの定義で検査値以上を判断すると、感度と陰性的中率が低かったです。以上より疾患群で検査値が異なり、カットオフ値のさらなる研究が必要という結論です。

CRPだけカットオフ値が0.5mg/dl以上に対して、今回の症例では血液疾患で非悪液質というもっともCRPの低い群でも平均が0.975±1.29mg/dlと高かったです。標準偏差が大きいので、CRPを平均値で表すことは不適切かもしれません。中央値も知りたいですね。

Abstract

ABSTRACT:

BACKGROUND: Cachexia is a state of involuntary weight loss common to many chronic diseases. Experimental data, showing that cachexia is related to the enhancement of acute phase response reaction, led to the new definition of cachexia that included, aside from the principal criterion of weight loss, other "minor criteria", Amongst them are levels of C-reactive protein (CRP), albumin and hemoglobin. However, there is paucity of data regarding possible differences of these laboratory parameters in patients with various diseases known to be related to cachexia.

METHODS:

CRP, albumin and hemoglobin were evaluated in 119 patients, divided into two disease groups, hematological (ones with diagnosis of non-Hodgkin lymphoma or Hodgkin disease) and non-hematological (solid tumor patients and patients with chronic heart failure). Patients were further subdivided into two nutritional groups, cachectic and non-cachectic ones according to the principal criterion for cacxehia i.e. loss of body weight.

RESULTS:

We found that cachectic patients had higher levels of CRP, and lower levels of both hemoglobin and albumin compared to non-cachectic patients, regardless of the disease group they fitted. On the other hand, the group of hematological patients had lower levels of CRP primarily due to the differences found in the non-cachectic group. Higher levels of albumin were also found in the hematological group regardless of the nutritional group they fitted. Limitations of cut-off values, proposed by definition, were found, mostly regarding their relatively low sensitivity and low negative predictive value.

CONCLUSIONS:

As expected, differences in values of routine laboratory parameters used in definition of cachexia were found between cachectic and non-cachectic patients. Their values differed between hematological and non-hematological patients both in cachectic and non-cachectic group. Cut-off levels currently used in definition of cachexia have limitations and should be further evaluated.

終末期がんへの栄養サポート

緩和ケア病棟における終末期がん患者への栄養サポートの効果に関する日本からの論文を紹介します。

Koji Amano, et al. Effect of Nutritional Support on Terminally Ill Patients With Cancer in a Palliative Care Unit. AM J HOSP PALLIAT CARE, Published online before print December 12, 2012, doi: 10.1177/1049909112469273

個別の栄養サポートを行った患者22人とその他の患者41人を、後ろ向きコホート研究（かな？）で比較検討しています。結果ですが、栄養サポート群で褥瘡が有意に少なく、浮腫と抗生剤使用が少ない傾向にありました。栄養サポートが有用な終末期がん患者もいる可能性があるという結論です。

リハよりも栄養サポートの効果を出しにくいセッティングで、こうして論文をまとめるのは素晴らしいと思います。ただ、対照群で褥瘡が多かったのは、対照群にPSが3の方がより多かったせいかもしれません。リハ栄養でもこうして成果を出していければと感じます。

Abstract
The role of nutritional support on terminally ill patients with cancer in a palliative care unit has not been clarified. A total of 63 patients were retrospectively investigated; the patients receiving individualized nutritional support (intervention group [n = 22]) were compared to the others (control group [n = 41]). The intervention group received individualized nutritional support. There were no significant differences in the characteristics of patients between the groups. The prevalence of bedsores was significantly lower in the intervention group (14% vs 46%, P = .012). The prevalence of edema and the use of antibiotic therapies tended to be lower in the intervention group than in the control group (36% vs 54%, P = .19; 14% vs 27%, P = .34, respectively). Some terminally ill patients with cancer in a palliative care unit might benefit from nutritional support.

がん悪液質のメカニズムと治療

がん悪液質のメカニズムと治療のレビュー論文を紹介します。

Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol. 2012 Dec 4. doi: 10.1038/nrclinonc.2012.209. [Epub ahead of print]

悪液質の早期治療（＝早期診断）の重要性が指摘されています。その上で、食欲不振（痛み、吐気）に対して、栄養サポート、抗炎症作用のある薬物もしくは栄養素、レジスタンス運動を組み合わせた包括的治療に、新たな治療方法を開発・実践することで、QOLやがん治療耐性の改善を期待できます。

エビデンスは十分とはいえませんが、がん悪液質に対して栄養・薬物・運動（レジスタンス運動だけでなく有酸素運動もよいと思います）を組み合わせた包括的治療は、もはや標準的なパッケージとあります。がん以外の慢性臓器不全も含めた悪液質に対するリハ栄養＋薬物療法の重要性を早く広めたいです。

Abstract

Cancer cachexia is a metabolic syndrome that can be present even in the absence of weight loss ('precachexia'). Cachexia is often compounded by pre-existing muscle loss, and is exacerbated by cancer therapy. Furthermore, cachexia is frequently obscured by obesity, leading to under-diagnosis and excess mortality. Muscle wasting (the signal event in cachexia) is associated not only with reduced quality of life, but also markedly increased toxicity from chemotherapy. Many of the primary events driving cachexia are likely mediated via the central nervous system and include inflammation-related anorexia and hypoanabolism or hypercatabolism. Treatment of cachexia should be initiated early. In addition to active management of secondary causes of anorexia (such as pain and nausea), therapy should target reduced food intake (nutritional support), inflammation-related metabolic change (anti-inflammatory drugs or nutrients) and reduced physical activity (resistance exercise). Advances in the understanding of the molecular biology of the brain, immune system and skeletal muscle have provided novel targets for the treatment of cachexia. The combination of therapies into a standard multimodal package coupled with the development of novel therapeutics promises a new era in supportive oncology whereby quality of life and tolerance to cancer therapy could be improved considerably.

悪液質に対する運動仮説モデルEACH

悪液質に対する運動仮説モデルEACHの論文を紹介します。

Claudio L. Battaglini, Anthony C. Hackney, and Matthew L. Goodwin. Cancer Cachexia: Muscle Physiology and Exercise Training. Cancers 2012, 4(4), 1247-1251; doi:10.3390/cancers4041247

下記のHPから全文PDFで入手できます。

http://www.mdpi.com/2072-6694/4/4/1247

EACHモデルを図に示します。悪液質に対する運動療法は、抗炎症性サイトカインの増加、アンドロゲンの増加、炎症性サイトカインの減少によって、筋蛋白質の合成増加・分解減少を期待できるという仮説モデルです。いくつかの研究で検証されていますが、今後さらなる研究での検証が必要です。

日本ではまず前悪液質や悪液質を早期に発見、診断する体制作りが必要だと考えます。不応性悪液質になってから診断しても、このモデルのような運動療法の効果を期待することは困難です。「悪液質＝ターミナル」という過去の考え方を早くアップデートしたいですね。そして悪液質のリハ・運動療法は、重要な研究テーマです。

Abstract:
Cachexia in cancer patients is a condition marked by severe tissue wasting and a myriad of quality of life and health consequences. Cachexia is also directly linked to the issues of morbidity and survivability in cancer patients. Therapeutic means of mitigating cachexia and its effects are thus critical in cancer patient treatment. We present a discussion on the use of physical exercise activities in the context of such treatment as a means to disruption the tissue wasting effects (i.e., muscle tissue losses via anorexigenic pro-inflammatory cytokines) of cachexia. In addition we propose a theoretical model (Exercise Anti-Cachectic Hypothetical—“EACH” model) as to how exercise training may promote a disruption in the cycle of events leading to advancing cachexia and in turn promote an enhanced functionality and thus improved quality of life in cancer patients.

心臓悪液質とサルコペニア

心臓悪液質とサルコペニアの2010-2012年の研究をまとめたレビュー論文を紹介します。

Anker MS, von Haehling S, Springer J, Banach M, Anker SD. Highlights of the mechanistic and therapeutic cachexia and sarcopenia research 2010 to 2012 and their relevance for cardiology. Int J Cardiol. 2012 Nov 19. pii: S0167-5273(12)01393-9. doi: 10.1016/j.ijcard.2012.10.018. [Epub ahead of print]

2012年10月までの心臓悪液質とサルコペニアの文献のレビューです。選択的アンドロゲン受容体調節剤（enobosarm）とグレリン（anamorelin）は、phase IIIの研究が行われています。多くの医療人に関心をもってほしい領域ですね。

ただ、Journal of Cachexia, Sarcopenia and Muscleからの引用論文が多すぎるという印象です。この雑誌のImpact Factorを高めるためのレビュー論文ではないかという見方もできます。確かに悪液質とサルコペニアの研究は、この雑誌の掲載が多いですが…。

Abstract

Sarcopenia and cachexia are significant medical problems with a high disease related burden in cardiovascular illness. Muscle wasting and weight loss are very frequent particularly in chronic heart failure and they relate to poor prognosis. Although clinically largely underestimated, the fields of cachexia and sarcopenia are of great relevance to cardiologists. In cachexia and sarcopenia a significant number of research publications related to basic science questions of muscle wasting and lipolysis were published between 2010 and 2012. Recently, the two processes of muscle wasting and lipolysis were found to be closely linked. Treatment research in pre-clinical models involves studies on a number of different therapeutic entities, including ghrelin, selective androgen receptor modulators (SARMs), as well as drugs targeting myostatin or melanocortin-4. In the human setting, studies using enobosarm (a SARM) and anamorelin (ghrelin) are in phase III. The last 3years has seen significant efforts to define the field using consensus statements. In the future, these definitions should also be considered for guidelines and treatment trials in cardiovascular medicine. The current review aims to summarize important information and development in the fields of muscle wasting, sarcopenia and cachexia focussing on findings in cardiovascular research, in order for cardiologists to have a better understanding of the progress in the still not well enough known field.

心臓領域の悪液質とサルコペニア

心臓領域の悪液質とサルコペニアの研究のミニレビュー論文を紹介します。

Coats AJ. Research on cachexia, sarcopenia and skeletal muscle in cardiology. J Cachexia Sarcopenia Muscle. 2012 Nov 16. [Epub ahead of print]

抄録しか読めていませんが、過去3年間の肥満パラドックス、原因、治療に関するミニレビュー論文のようです。がん、COPD、慢性腎不全、慢性肝不全の悪液質でも研究が進んでいるようです。心筋のサルコペニアに関する研究も増えてほしいですね。

Abstract

BACKGROUND:

The awareness of cardiac cachexia, i.e. involuntary weight loss in patients with underlying cardiovascular disease, has increased over the last two decades.

METHODS AND RESULTS:

This mini-review looks at recent research in the cardiovascular literature that is relevant to the areas of interest of the Journal of Cachexia, Sarcopenia and Muscle. It identifies significant research in the last 3 years on the obesity paradox, the causes and effects of skeletal muscle wasting, animal models of cachexia and emerging treatment ideas in cardiac cachexia.

CONCLUSIONS:

Assuming a similar literature in the fields of cancer, chronic obstructive pulmonary disease, chronic renal failure and chronic liver failure, the emergence of cachexia as a vibrant area of clinical and experimental research seems assured.

非小細胞肺がんの前悪液質と悪液質

StageⅢの非小細胞肺がんの前悪液質と悪液質の有病割合をみた論文を紹介します。

van der Meij BS, Schoonbeek CP, Smit EF, Muscaritoli M, van Leeuwen PA, Langius JA. Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: an exploratory study comparing two consensus-based frameworks. Br J Nutr. 2012 Nov 16:1-9. [Epub ahead of print]

対象はStageⅢの非小細胞肺がん患者40人です。悪液質の診断方法は以下の2つを用いています。

１．ESPENの定義と国際コンセンサスの定義をミックスした「がん悪液質」
Muscaritoli M, Anker SD, Argiles J, et al. (2010) Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr 29, 154–159.

Fearon K, Strasser F, Anker SD, et al. (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12, 489–495.

がん前悪液質は、6か月で5％以下の体重減少、食欲不振、全身炎症（CRP0.8mg/dl以上）に該当で診断しています。

がん悪液質は、6か月で5％以上の体重減少（BMI20未満もしくはサルコペニアなら2％以上の体重減少）、食欲不振、全身炎症（CRP0.8mg/dl以上）に該当で診断しています。

がん不応性悪液質は、がん悪液質に該当、がんは異化期で抗がん治療が無効、身体機能低下（Karnofsky Performance Scoreが50未満）、生命予後3カ月未満に該当で診断しています。

２．疾患非特異的な「悪液質」
Evans WJ, Morley JE, Argiles J, et al. (2008) Cachexia: a new definition. Clin Nutr 27, 793–799.

6か月で5％以上の体重減少（またはBMI20未満）に加えて以下の3 つ以上に該当。
①筋力の低下（最低3分位数）
②疲労
③食欲低下（通常の摂取の70％以下）
④除脂肪体重が10パーセンタイル以下
⑤生化学検査の異常：a）炎症マーカーの増加（CRP＞0.5mg/dl ，IL-6＞4.0pg/ml ），b）貧血（＜12 g/dl），c）血清アルブミン＜3.2g/dl」
どちらも元の論文と比較して若干、診断基準をアレンジしています。前者では本来、食欲不振や全身炎症は診断基準に含まれていませんし、後者では本来、12カ月で5％以上の体重減少となっています。

結果ですが、①ではがん前悪液質を9人(23%)、がん悪液質を7人(18%)に認めました。がん悪液質はQOL低下と生命予後に有意に関連していました。②では疾患非特異的な悪液質を11人(28%)に認めました。QOL低下、生命予後に有意に関連していました。

どちらの悪液質の診断基準でもQOL低下や生命予後と有意に関連していましたので、どちらの診断基準を用いてもよいのかもしれません。いずれにしても前悪液質、悪液質を早期に発見して早期からリハ栄養介入することが重要だと考えます。

Abstract

Despite the development of consensus-based frameworks to define cancer cachexia, the validity and usefulness of these frameworks are relatively unknown. The aim of the present study was to study the presence of pre-cachexia and cachexia in patients with stage III non-small-cell lung carcinoma (NSCLC) by using a cancer-specific framework and a general framework for cachexia, and to explore the prognostic value of pre-cachexia and cachexia. In forty patients at diagnosis of stage III NSCLC, weight loss, fat-free mass, handgrip strength, anorexia and serum biochemistry, assessed before the first chemotherapy, were used to define 'cancer cachexia' or 'cachexia'. The cancer-specific framework also classified for pre-cachexia and refractory cachexia. Additionally, quality of life was assessed by the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire C30. Groups were compared using independent t tests, ANOVA, Kaplan-Meier and Cox survival analyses. Based on the cancer-specific framework, pre-cachexia was present in nine patients (23 %) and cancer cachexia was present in seven patients (18 %). Cancer cachexia was associated with a reduced quality of life (P = 0·03) and shorter survival (hazard ratio (HR) = 2·9; P = 0·04). When using the general framework, cachexia was present in eleven patients (28 %), and was associated with a reduced quality of life (P = 0·08) and shorter survival (HR = 4·4; P = 0·001). In conclusion, pre-cachexia and cachexia are prevalent in this small population of patients at diagnosis of stage III NSCLC. For both frameworks, cachexia appears to be associated with a reduced quality of life and shorter survival. Further studies are warranted to more extensively explore the validity and prognostic value of these new frameworks in cancer patients.

がん悪液質のNSAID：系統的レビュー

がん悪液質に対するNSAID（非ステロイド性抗炎症薬）の系統的レビュー論文を紹介します。

Solheim TS, Fearon KC, Blum D, Kaasa S. Non-steroidal anti-inflammatory treatment in cancer cachexia: A systematic literature review. Acta Oncol. 2012 Oct 1. [Epub ahead of print]

リサーチクエスチョンは以下の通りです。

P：がん悪液質患者に
I：NSAIDを使用すると
C：NSAIDを使用しない場合と比較して
O：体重と筋肉量が改善する
D：系統的レビュー

結果ですが、13論文中2論文のみ、体重もしくは除脂肪体重の改善・維持を認めました。7論文は比較対照群がありませんでした。サンプルサイズが小さく、方法論的に欠点のある研究が多かったです。そのため、がん悪液質に対するNSAID使用のエビデンスは脆弱という結論です。

がん（以外も含めて）悪液質で治療に難渋する場合には、NSAIDの使用を考慮してもよいかと思います。ただ現時点では、副作用の問題もありますし、悪液質に対してルーチンでNSAIDを使用することは推奨できません。

Abstract

Background. There are no established treatments for cachexia. Recently it has been suggested that the evidence for non-steroidal anti-inflammatory (NSAID) treatment is sufficient to support its regular clinical use. Primary objective in this systematic review was to assess efficacy and safety of NSAID treatment in improving body weight and muscle mass in patients with cancer cachexia. Secondary objectives were to assess whether this treatment could improve other cachexia domains such as anorexia and food intake, catabolic drive and function. Material and methods. A systematic literature review of PubMed, EMBASE and Cochrane Central register of controlled trials database was carried out using both text words and MeSH/EMTREE terms. Results. Thirteen studies were included; all but two trials showed either improvement or stabilization in weight or lean body mass. Seven studies were without a comparator. Studies are generally small and a few are methodologically flawed, often due to multiple outcomes with excess risk of false positives. Conclusion. NSAIDs may improve weight in cancer patients with cachexia, and there is some evidence on effect on physical performance, self-reported quality of life and inflammatory parameters. Evidence is too frail to recommend NSAID for cachexia outside clinical trials. This is supported by the known side effects of NSAIDs, even though the reviewed literature report almost negligible toxicity.

COPDの筋異常と悪液質

COPDの筋異常の原因である悪液質のメカニズムに関するレビュー論文を紹介します。

Remels AH, Gosker HR, Langen RC, Schols AM. The mechanisms of cachexia underlying muscle dysfunction in COPD. J Appl Physiol. 2012 Sep 27. [Epub ahead of print]

肺悪液質（Pulmonary cachexia）はCOPDでの死亡率増加と、末梢筋および呼吸筋の機能障害と関連しています。悪液質のメカニズムの詳細は不明ですが、細胞内での筋肉量維持のメカニズム（蛋白や筋核のターンオーバー）の病的変化が関与しているというエビデンスが増えています。

病的変化の要因として、酸化ストレス、ミオスタチン、炎症が考えられています。筋肉減少に加え、末梢筋では筋線維がⅡ型（速筋）にシフトして酸化能に障害が出やすくなります。一方、呼吸筋の筋線維は筋萎縮を認めるとともにⅠ型（遅筋）にシフトして酸化能が増強されます。

下肢筋肉の筋線維の変化は、悪液質や体重減少の影響を受けやすい肺気腫でより顕著であり、筋肉量減少と下肢筋肉の筋線維変化にはつながりがありそうです。

仮説ですが、下肢筋肉の筋線維変化が悪液質を加速させる可能性があります。十分な食事摂取が確保されていない場合、よりエネルギー不足や体重減少になりやすいためです。下肢筋肉の筋線維が変化することで、より炎症や酸化ストレスの影響を受けやすくなっている可能性があります。

悪液質のメカニズムが複雑であるために、その治療も栄養療法単独、運動療法単独、薬物療法単独では十分な効果が期待しにくいのだと思います。食事・運動・薬物のどれが欠けても悪液質が進行しやすいので、やはりCOPDには包括的な治療・対応が求められます。

Abstract

Pulmonary cachexia is a prevalent, debilitating and well-recognized feature of COPD associated with increased mortality and loss of peripheral and respiratory muscle function. The exact cause and underlying mechanisms of cachexia in COPD are still poorly understood. Increasing evidence however shows that pathological changes in intra-cellular mechanisms of muscle mass maintenance (i.e. protein turn-over and myonuclear turn-over) are likely involved. Potential factors triggering alterations in these mechanisms in COPD include oxidative stress, myostatin and inflammation. In addition to muscle wasting, peripheral muscle in COPD is characterized by a fiber-type shift towards a more type II, glycolytic phenotype and an impaired oxidative capacity (collectively referred to as an impaired oxidative phenotype). Atrophied diaphragm muscle in COPD, however, displays an enhanced oxidative phenotype. Interestingly, intrinsic abnormalities in (lower limb) peripheral muscle seem more pronounced in either cachectic patients or weight-loss susceptible emphysema patients, suggesting that muscle wasting and intrinsic changes in peripheral muscle's oxidative phenotype are somehow intertwined. In this manuscript, we will review alterations in mechanisms of muscle mass maintenance in COPD and discuss the involvement of oxidative stress, inflammation and myostatin as potential triggers of cachexia. Moreover, we postulate that an impaired muscle oxidative phenotype in COPD can accelerate the process of cachexia, as it renders muscle in COPD less energy-efficient thereby contributing to an energy-deficit and weight loss when not dietary compensated. Furthermore, loss of peripheral muscle oxidative phenotype may increase the muscle's susceptibility to inflammation- and oxidative stress-induced muscle damage and wasting.