Thiazide類的利尿劑可以減少骨折機率

Do thiazide diuretics protect against fracture risk?

年紀大的病人，一不小心跌倒，很容易就骨折了。開刀加上復原休息，常常都要半年至一年才有機會回復至原先身體狀況，若有不幸的，甚至就產生更嚴重併發症。所以，看到這篇randomized clinical trial：thiazide可以減少骨折機率，就令我感到興趣了，因為之前有關thiazide降低骨折率只有observation study。

Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial (ALLHAT)

JAMA Intern Med. Published online November 21, 2016. 
http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2587085

研究族群是大約22,000位，55歲以上成年人，分別接受降血壓藥，1) thiazide (chlorthalidone), 2) the calcium-channel blocker amlodipine, 3) the ACE inhibitor lisinopril. 

在5年追蹤期，共有34位骨盆骨折，307位髖部骨折。分析結果：chlorthalidones組，有較低的骨折率 (hazard ratio, 0.79)

然而，這研究的Limitations 是
1) post hoc 事後檢定，因為ALLHAT研究一開始是設定為降血壓藥、降血脂藥和心臟病關係，不是和骨折的關係。所以，研究搜集的參數缺乏和骨折相關因子進來，例如： menstrual history (women), testosterone levels (men), history of falls (a proximate event in most hip and pelvic fractures), and bisphosphonate use.
2) ALLHAT研究排除了骨折高危險群病人進來 (active coronary artery disease and heart failure and chronic kidney disease)，所以這結論不能延申至以上這三族群病人。
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以前老師們說的：
Calcium excretion is increased by loop diuretics and diminished by thiazide-type diuretics and amiloride

所以，在選擇降血壓藥物時，這研究可以給我們一些用藥參考，特別是有骨折危險考量時。

紫質症 (Porphyria)

http://www.nytimes.com/2016/12/09/well/live/think-like-a-doctor-the-builders-blisters-solved.html

The New York Times 這期的病例是罕見疾病，又是常常耳聞的困難診斷疾病。吸引人從頭讀下去，讀起來真像偵探辦案一樣。

這是在美國榮民醫院的一位64歲男性患者，喜歡露營，是工程承包商，20年病史的偶發性手上手泡，不明原因。

The patient’s hands showed a blistering rash.

一次就診時，不經意的向實習醫生說起手上這些20年不間斷發作的水泡。一開始interns，和主治醫師認為可能是contact dermatitis, or allergic reaction。但是，了解病史後又被排除，只好把病人轉介給皮膚科。但是，這位認真主治醫師去查UpToDate: Rash chapter，發現這和porphyria cutanea tarda 皮疹很像。

Glowing Urine

The patient’s urine (right) glowed orange under a Wood’s lamp, while normal urine (left) glows blue.

於是經由尿液送檢，和用wood's lamp觀察尿液呈現orange (purple)，幾乎就要證實是這個疾病。然而，引發的原因是什麼(trigger)？測HCV也沒有，經過查閱過去的病歷，發現曾有很高的血液鐵質存在，但是之前醫師也沒有進一步處理。這時候，誘發原因：hemochromatosis，在抽血檢查後，就呼之欲出了。在這深秋的季節，患者的皮膚有點過度的tanned，原本以為是喜歡露營曬太陽所致，原來也是因為porphyria發作，導致皮下有Hb未分解產物過多造成。難怪患者說在夏天時，皮膚特別容易有水泡。

The rash was from: Porphyria cutanea tarda

Which was in turn caused by: Hereditary hemochromatosis (‘Bronze Diabetes’)

About the Diagnosis

The porphyrias are a group of diseases caused by a problem in the breakdown of hemoglobin, the oxygen-carrying part of red blood cells. The name comes from the Latin word for purple (porphyros), because with some forms of this disease, the unbroken-down parts of hemoglobin are eliminated from the body in the urine, and those chemicals can make the urine turn purple when exposed to sunlight.

The rest of the name highlights the disease’s most characteristic qualities: It affects the skin (cutanea) and it appears late in life (tarda). In P.C.T., the particular components of hemoglobin that are not fully broken down migrate to the skin, where they cause a blistering sore when exposed to sunlight.

結局：
患者開始看血液科，排除過多的鐵質。注意防曬，之前就是因為有習慣擦防曬乳所以porphyria發作得並不明顯。患者也想把過多的血捐給紅十字會，但是紅十字會不收有這樣疾病人的血液。

生活型態改變可以減輕基因導致的冠心症危險性

The “nature versus nurture”, which is more important?

美國心臟醫學會上的Breaking News，這篇文章真是令人覺得勵志，因為可以經由後天的生活形態改變，減輕因為基因導致的冠心症危險性。

對象是來自三個不同的大型研究（Women's Genome Health Study，Atherosclerosis Risk in Communities，Malmö Diet and Cancer Study），共51,425 個病人，找出和CAD有相關性的危險基因（polygenic scores of single nucleotide polymorphisms associated with CAD)

那一些生活形態呢？1) no current smoking 2) no obesity 3) regular physical activity 4) healthy diet.

結果發現，有較高冠心症危險基因者，若是有3個以上「好」的生活習慣，比有一個「壞」的習慣，下降了接近一半(46%)冠心症的風險。

For individuals at high genetic risk, unhealthy and healthy lifestyles were associated with the following standardized 10-year incidences of coronary events:

Women's Genome Health Study, 4.6% and 2.0%

Atherosclerosis Risk in Communities, 10.7% and 5.1%

Malmö Diet and Cancer Study, 8.2% and 5.3%

所以作者的結論是：
We need to get the message to our patients: A healthy lifestyle can mitigate one's inherited cardiac risk.

Ref.
Khera AV et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 2016 Nov 13; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1605086)

病風患者之降尿酸治療藥是不是一定要吃一輩子？

2016有新的gout guidelines出來，和大家分享。

是不是一旦開始了痛風患者的降尿酸藥物治療後(例如：allopurinol/febuxostat），就一定要吃一輩子？如果這患者這一輩子只發作那一次，也要吃藥一輩子嗎？或是一輩子痛風發作沒幾次？這就讓我想起以前在神經內科學習時，老師問的：dilantin是不是在有seizure發作過的患者，一定要吃一輩子的藥？

根據這2016新的準則，反對在只單一次發作或是不常發作的痛風患者，給予長期的降尿酸治療。也不再建議一定要把患者的尿酸值降至目標 6 mg/dl以下。

New ACP Gout Guidelines Exclude Treat-to-Target Recommendation
http://annals.org/aim/article/2578528/management-acute-recurrent-gout-clinical-practice-guideline-from-american-college

CLINICAL GUIDELINES |1 NOVEMBER 2016

Recommendation 1:

ACP recommends that clinicians choose corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine to treat patients with acute gout. (Grade: strong recommendation, high-quality evidence)

Recommendation 2:

ACP recommends that clinicians use low-dose colchicine when using colchicine to treat acute gout. (Grade: strong recommendation, moderate-quality evidence)

Recommendation 3:

ACP recommends against initiating long-term urate–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks. (Grade: strong recommendation, moderate-quality evidence)

Recommendation 4:

ACP recommends that clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence)

New gout guidelines from the American College of Physicians notably don't include a recommendation to lower serum uric acid levels below 357 µmol/L (6 mg/dL), in contrast with the American College of Rheumatology's 2012 guidelines.

美國心臟醫學會2016年建議：降血脂藥物和心臟藥的交互作用

雖然知道藥物吃多容易有令人想不到的交互作用，但是臨床上就是會遇到必需給多種藥物時，例如經過飲食和生活型態控制後，仍然TG超過600 mg/dl，Total cholesterol超過200 mg/dl的DM患者，這時候可能就需要合併使用fibrate和statin藥物，不然日久血管就狹窄發生心肌梗塞。過往的資料顯示，這樣合併藥物的副作用發生機會大，而且可能較嚴重，例如肝炎或是肌肉發炎。更令人頭痛的是，同類型藥物尤其是statin非常多種，到底要怎麼選擇？

AHA，2016提供最新的建議，告訴我們副作用發生的程度(magnitude)，以及給我們建議合併藥物的選擇。
Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease
http://circ.ahajournals.org/content/circulationaha/early/2016/10/17/CIR.0000000000000456.full.pdf
A Scientific Statement From the American Heart Association
Circulation. 2016;134:00-00.

例如，若是選擇gemfibrozil + simvastatin 呢？(avoid combination!)
若是，gemfibrozil + rosuvastatin (consider combination)

相當實用，提供大家參考。

重穩定同位素食物(Heavy Stable Isotope Food)可以延長壽命和保護腎臟嗎？

這一期的Acta Nephrologica，最令我注目的文章，討論重穩定同位素食物(Heavy Stable Isotope Food)的療效。文章的重點是，同位素(Isotope)是有相同數量的質子(proton)，但是有不同數量的中子(neutron)。而帶有不同數量電子的分子或是原子稱自由基(free radical)，自由基會破壞身體內的細胞或是基因。自由基破壞細胞脂質外壁的速度決定因子(rate-limiting step)是破壞碳和氫鍵結(C-H bond)。若是能經由外來補充重穩定同位素，例如13C, D, 15N, 18O，來取代原本身體內較輕的12C，13C，經由這些重隱定同位素形成較強的鍵結，以防止受到自由基的破壞，因而能保護身體內的細胞，延長壽命。

文章中引用的是細菌和老鼠實驗，尚未有人體試驗研究。內文中也寫到，活性氧化物質(Reactive oxygen species, ROS) 也是身體內必要的，例如：缺氧或是細菌感染時，或是細胞訊息傳遞時所必要的。所以，過度的抗氧化劑(anti-oxidant)也是有害的，會增加死亡率。例如，大量的vitamin E, carotene是有害的。所以，如何補到一個安全又有效的劑量，例如heavy stable isotope food，或是有機會應用在人體上否？還需進一步研究解答。

Acta Nephrologica 30(2): 96-106, 2016
Special Issue
Can “Heavy Stable Isotope Food” Increase Longevity and Protect Renal Function?
Yuan-Hau Lin1,2,3, Hsien-Saw Kuo1, Chun-Mao Lin1
1College of Medicine, Taipei Medical University, Taipei, Taiwan
2Yen-Lin Clinic, Taipei, Taiwan
3Taiwan Society of Nephrology, Taipei, Taiwan

止痛藥(NSAID)和心臟衰竭住院

常用的止痛藥(NSAID)又有壞消息了，除了常見胃腸、腎臟副作用和之前說過的MI住院外，可能會再導致病人因心臟衰竭(heart failure)而住院。

BMJ期刊在2000-2010年，收了820萬個病人使用NSAID，共有9.2萬人因心臟衰竭而住院，經過和對照組比較後發現以下結果：

Current  (use in preceding 14 days) use of any NSAID was associated with a 19% higher risk for heart failure hospitalization. The following individual, FDA-approved NSAIDs carried higher heart failure risk: ketorolac (odds ratio, 1.83), indomethacin (1.51), piroxicam (1.27), diclofenac (1.19), ibuprofen (1.18), and naproxen (1.16). The results were significant in patients regardless of their history of heart failure. Higher doses were associated with greater risk.

Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study
BMJ 2016; 354 doi: http://dx.doi.org/10.1136/bmj.i4857 (Published 28 September 2016)