1 - 弗兰克的征兆

大家好，我是亚当·罗德曼，您正在收听《床边巡诊》，一档讲述临床医学中迷人故事的微型播客。本周的节目名为《弗兰克征》，是我为所有新听众准备的礼物——重新录制了本播客的首期内容。问题是：一位20世纪的医生如何仅凭体格检查就破解了一桩2000年前的死亡谜案？剧透警告，答案就在本期标题中。这个故事如同许多平装惊悚小说般，始于一场笼罩在迷雾中的死亡。

Hi, this is Adam Rodman and you're listening to Bedside Rounds, a tiny podcast about fascinating stories in clinical medicine. This week's episode it's called Frank's Sign and it is a re recording of my very first episode of this podcast as a gift for all my new listeners. And the question is, how did a twentieth century physician solve a 2,000 year old death using the physical exam alone. Spoiler alert, it's the title of the episode. So this story starts like so many paperback thrillers with a death shrouded in mystery.

但这并非普通死亡，死者是当时世界上最有权势的人物。天啊，我真该去写悬疑小说。这位主角名叫普布利乌斯·埃利乌斯·哈德良·奥古斯都，即哈德良皇帝。作为罗马帝国鼎盛时期的统治者，他的疆域北起英格兰南至埃及。这位希腊文化爱好者与人道主义者，如今最广为人知的身份是所谓'五贤帝'之一，当然还有他在不列颠修建的哈德良长城。史料记载，他二十年的统治期充满繁荣景象。

But not just any death, this was the death of the most powerful man in the world at the time. Man, I should really write mystery novels. The man in question was Publius Aelius Hadrianus Augustus or Hadrian and as the emperor of Rome at the height of its power he ruled a vast swath of territory that spanned from England in the North all the way to Egypt in the South. He was an admirer of the Greeks and a humanist and today he's most remembered for being one of the quote unquote good emperors and of course for building his eponymous wall in Britain. And by all accounts his twenty year rule was marked by prosperity.

这位皇帝几乎踏遍了庞大帝国的每个行省——考虑到公元二世纪主要交通工具是马匹，这堪称壮举。但刚过六十岁生日不久，哈德良就病倒了。多亏历史学家卡西乌斯·狄奥（事发约六十年后执笔）的记载，我们知晓其病情细节：长期困扰皇帝的鼻出血开始恶化。用狄奥的原话来说，'因严重失血导致消耗性疾病，进而引发水肿'（dropsy是浮肿的旧称）。

He managed to visit almost every province of his massive empire, a true feat given the fact that it was well the second century AD presumably was going by horse. But shortly after his sixtieth birthday Hadrian fell ill. We know all the details of his illness thanks to Cassius Dio who's a historian writing some sixty years after the fact. Hadrian had long been plagued by nosebleeds but this minor annoyance started to become more severe. Soon, and I am quoting Cassius here, became consumptive result of his great loss of blood and this led to dropsy and dropsy is an old fashioned word for edema or swelling.

他尝试用符咒和魔法仪式暂时缓解水肿，但积水总会复发。哈德良陷入抑郁并渴望死亡。最终他放弃严格养生，放纵饮食后临终高呼古罗马流行谚语——不得不说这句谚语让我着迷——'多少御医弑君王'。仅凭鼻出血（epistaxis的学名）和水肿的记载，现代学者能推断的线索有限，但这并未阻止近两百年的古病理学家们试图对哈德良进行死后诊断。

He tried charms and magic rites that would relieve the edema temporarily but inevitably he would fill up again with water. Hadrian became depressed and longed for death. Finally, he abandoned his careful regimen and by indulging in insuitable foods and drinks met his death shouting aloud the popular saying. And let me just say I absolutely love that this was a popular saying in ancient Rome, Many physicians have slain a king. Epistaxis, which is a fancy word for nosebleeds, and edema are not a whole lot of information to work off of, but that hasn't stopped paleopathologists from the last two hundred years from trying to diagnose Hadrian ex post facto.

顺便说，得知'古病理学家'是真实职业让我兴奋不已。学界对他的死因众说纷纭：肾衰竭（合理）、心衰（完全可能），还有我最爱的猜测——奥司勒-韦伯-朗迪综合征（鉴于全名太长，现称遗传性出血性毛细血管扩张症）。这种罕见遗传病会导致血管异常增生，引发严重鼻出血及全身多部位出血。由于动静脉血流混合，患者最终会出现高输出性心衰。老话说'病史能诊断八成病例'，但这可不适用于两千年前的二手记载。

I also just want to say that I'm jazzed that being a paleopathologist is a real job. So he has been diagnosed as alternatively having kidney failure, reasonable, heart failure, absolutely, or my favorite guess diagnosis, Osler Weber Rondeau syndrome, which is also known as since you know Osler Weber Rondeau is a little bit of a mouthful, hereditary hemorrhagic telangiectasia. Basically it's a rare genetic disorder of abnormal blood vessel proliferation that leads to, among other things, heavy nosebleeds and just generally bleeds all over the body. Its victims essentially get a high output heart failure because of the mixing of arterial and venous blood flow. The old aphorism is that history makes the diagnosis eighty percent of the time but they were not talking about second hand accounts from two thousand years ago.

所幸近年有位美国医生帕特拉基斯为哈德良的悬案增添了体格检查证据。在雅典国家博物馆观察哈德良半身像时，他意外发现一个显著的体征特征。激动之余，他又考证了希腊和意大利的三尊哈德良雕像，均呈现相同征象。

Fortunately, more recently, an American physician, Doctor. Patrakis, added a little bit of a physical exam to Emperor Hadrian's cold case. Doctor. Patrakis was observing a bust of Hadrian at the Athens National Museum and by chance saw a prominent physical exam finding. He excitedly sought out three additional busts of Hadrian in Greece and Italy, which all exhibited the exact same sign.

这个体征最终指向他的诊断结论。您或许要问：他究竟发现了什么？答案就在本期标题中。佩特拉基斯医生看到的，是双侧耳垂对角线皱褶——即'弗兰克征'。

And this physical exam finding led him to his diagnosis. What, you might ask, did he see? Well, the answer is in the title of the episode. What Doctor. Petrakas saw was bilateral diagonal earlobe creases otherwise known as Frank's sign.

想象一下这个场景：用拇指和食指轻轻揉捏你的耳垂。如果有弗兰克征，正中间会有一道深深的皱褶。这个皱褶最早由弗兰克医生在1973年注意到，他在20名年轻却患有心绞痛（心脏供血不足引发的胸痛）的患者身上发现了这一特征。此后，关于耳垂斜行皱褶的研究已发表了50多篇。

So to imagine what this looks like, the lower lobe of your ear and gently roll it between your thumb and your forefinger. If you have a Frank's sign, there will be a deep crease right in the middle. This crease was first noted by Doctor. Frank in 1973 in a group of 20 patients who were young but also had angina which is the chest pain that you get when your heart doesn't get enough blood. Since then, over 50 studies have been published on the diagonal earlobe crease.

所有这些研究共同表明，弗兰克征是心脏病的独立预测指标。也就是说，无论是否存在高胆固醇、高血压或吸烟等其他风险因素，有耳垂皱褶的人患心脏病的概率更高。当然科学就是科学，也有研究发现两者并无预测关联——弗兰克征可能只是正常衰老的标志，而老年人本就更容易患心脏病。那么弗兰克征对临床医生究竟有多大用处？

All these studies together suggest that Frank's sign is an independent predictor of heart disease. That is, if you have this earlobe crease you're more likely to have heart disease regardless of other risk factors such as high cholesterol, high blood pressure, or if you smoke. But of course, science being science, there are studies that have found that there is no predictive relationship. That is that Frank's sign might in fact just be a sign of normal aging and older people are more likely to have heart disease. So how useful is Frank's sign to clinicians?

2011年一项荟萃分析评估了所有将耳垂皱褶作为冠心病预测指标的研究，发现弗兰克征确实具有统计学意义。要理解其显著性需要简单了解生物统计学中的似然比概念。我的播客老听众（其实开播才五个月）都知道我有多痴迷生物统计学。对于统计爱好者来说，似然比等于灵敏度除以（1减特异度）。通俗地说，就是患者出现该体征的概率除以健康人出现相同体征的概率。

A 2011 meta analysis looked at all studies evaluating the earlobe crease as a predictor of coronary artery disease and it found that Frank's sign was in fact statistically significant. Now just how significant it is will take a brief foray into biostatistics, in particular likelihood ratios. And long time listeners of my podcast, long time being the five months I've been making it, should know just how much I love biostatistics. So, for our stats geeks out there, a likelihood ratio is the sensitivity divided by one minuteus the specificity. Or in normal people language, it's the probability of finding a clinical sign in patients with a disease divided by the probability of the very same finding in a patient without a disease.

举个虚构的例子更容易理解：假设80%的肝病患者会出现黄疸（胆红素升高导致的皮肤发黄），而健康人群中只有10%有黄疸。再次强调这些数据纯属虚构——现实中显然不会有10%的健康人皮肤发黄。

So this is easier to understand with a, well, example, though it is a made up example. So let's say that eighty percent of people with liver disease have jaundice, which is the yellow skin caused by elevated bilirubin. But only ten percent of people without liver disease have jaundice. Again, these are completely made up. Obviously, ten percent of people do not have yellow skin.

这种情况下，似然比就是80%除以10%等于8。似然比大于1支持诊断（本例中的肝病），小于1则否定诊断。如果等于1，那和抛硬币没区别——这个检查毫无意义。关键在于我们可以结合似然比和疾病验前概率，计算出体检发现能让实际患病概率提升多少。

But in that case, the likelihood ratio would be eighty percent divided by ten percent or eight. A likelihood ratio greater than one argues for the diagnosis, liver disease in this case. A likelihood ratio of less than one argues against it. And if the likelihood ratio is one, well you might as well flip a coin because the test tells you nothing. This is all important because we can combine the likelihood ratio with the pretest probability of a disease to find out how much more likely a physical exam finding makes it that someone actually has the disease.

实际诊疗时我并不会现场做这些计算。遇到疑问时我会查阅将似然比与概率变化关联的表格——这个神器叫法根诺模图，出门必备。前述荟萃分析发现耳垂斜行皱褶的似然比为2.4，意味着有弗兰克征的患者患冠心病的概率大约增加17%。

So in reality, I don't do all this math when I'm examining a patient and I see something. If I have a question, I use a table that correlates the likelihood ratio with this change in probability. It's called a Fagan's nomogram and it is awesome. Don't leave home without it. In the case of the diagonal earlobe crease, the meta analysis I mentioned found that the likelihood ratio was 2.4 which makes it roughly seventeen more percent that a patient with a Frank's sign has coronary artery disease.

举例来说：假设我诊所里一位中年男性通过风险计算器得出患心脏病概率是40%。如果检查时发现弗兰克征，可以推测其冠心病概率升至约60%。但这个数值足以改变诊疗方案吗？恐怕不行。坦白说，2.4的似然比实在不值得大惊小怪。

In other words, let's say that a middle aged man in my clinic has a forty percent chance of having heart disease which I can determine from any number of risk calculators. If when I examine him I notice Frank's sign, I can presume that his chance of having coronary artery disease has increased to roughly sixty percent. Now, is that enough to change my management? Probably not. Quite frankly, a likelihood ratio of two point four is nothing to get excited over.

确实，对大多数医生来说，这属于‘一般般’的范畴。但话说回来，通过吸烟、高血压和高胆固醇等传统风险因素预测心脏病的似然比仅为1.07，几乎和抛硬币差不多。这就让我们回到可怜的哈德良皇帝身上。如果要做一个总结性陈述——这是医生用来串联病情的经验法则——我可能会说：我们有一位60岁的罗马皇帝，有慢性鼻出血病史，现在出现鼻出血加重和进行性水肿。体格检查的显著发现是弗兰克征。

Really, it's in the meh range for most physicians. But then again, the likelihood ratio for predicting heart attacks from traditional risk factors such as smoking, high blood pressure and high cholesterol is only 1.07 which is barely better than a coin flip. So that takes us back to poor Emperor Hadrian. So if I were making a summary statement and a summary statement is a heuristic that physicians use to put a story together, I'd say something like We have a 60 year old Roman Emperor with a history of chronic nosebleeds now presenting with a worsened nosebleed and progressive edema. Physical exam was notable for Frank's side.

因此他的容量负荷提示心、肝或肾功能衰竭。当然，鼻出血可能导致本例中的罕见病——奥勒-韦伯-朗迪综合征伴高输出性心力衰竭。但弗兰克征额外带来的17%冠心病概率（包括哈德良年轻时乘公交车时的表现）将诊断推向心脏病杀手。虽然算不上板上钉钉，但如果我能成为皇帝的御医，而他汀类药物、β受体阻滞剂、ACE抑制剂和袢利尿剂都已问世，这足以让我为他启动一套完善的心脏治疗方案。以上就是本集全部内容。

So his volume overload suggests either heart, liver, or kidney failure. And sure, the nosebleeds might lead to the zebra in this case of Osler Weber Rendu syndrome with its high output heart failure. But that extra seventeen percent chance of having coronary heart disease from Frank's sign, including on bus when Hadrian was a much younger man, pushed the diagnosis towards heart disease killer. So a slam dunk it is not, but if I could be the personal physician to the emperor and statins, beta blockers, ACE inhibitors, and loop diuretics had all been invented, it would be enough for me to start him on a good cardiac package. Well that's it for the episode.

重录首期节目而非创作新内容，可能显得我有些偷懒。确实如此，但我有两个主要原因：首先，我刚从南意大利的美妙公路旅行归来——我知道你们都很羡慕——就像佩特拉克斯医生那样，我有幸亲眼见到了哈德良皇帝。

This might have seemed a little bit lazy of me re recording my first episode instead of creating new content. Sure, but I have two main reasons. So first of all, I just got back from an absolutely wonderful road trip across Southern Italy, I know you all feel very bad for me. And like Doctor. Doctor.

你们可以在我的网站上看到照片。在梵蒂冈博物馆入口处，游客罕至的走廊里，陈列着教皇们千年来收藏的无数古代半身像。这些展品几乎没有标签（与博物馆其他部分形成鲜明对比），只有些看起来像60年代的意大利语旧纸标签。

Petrachus, I had the pleasure of getting to see Emperor Hadrian firsthand. You can see the picture actually on my website. In the beginning of the Vatican Museum, hidden down a hallway where relatively few tourists venture, are shelves after shelves of heads essentially busts from antiquity that the popes have been collecting over I guess a thousand plus years. Now they're barely labeled especially compared to the rest of the museum. There's old paper labels that look like they're from the 60s written only in Italian.

但不知为何这让我异常兴奋，我拉着妻子开始寻找。很快我们就找到了他——‘哈德良’被标注为意大利语‘Adriano’，放在离地约两米的最高层架子上。但即便从这个距离，我也能清晰看到他的弗兰克征。我完全能理解佩特拉克斯医生初次见到哈德良时的激动心情。

But for whatever reason this made me really excited so I grabbed my wife and I went searching. And finally, and pretty quickly actually, we found him. So Hadrian was labeled in Italian Adriano and he was at the very, very top shelf, probably six, seven feet off the ground, way above my head. But of course, even from that distance I could see his Frank sign. And, well, I was very excited and I could totally understand how excited Doctor.

我重录的第二原因是：相比初创时只有几位医生朋友和父母听众，现在受众规模大了许多。而且我掌握了更多音频编辑技巧，还换了比旧Skype麦克风更专业的设备。鉴于第一期常被作为播客入坑起点，我想不妨借此机会试试新麦克风和音频编辑。

Patrakis must have felt when he saw Hadrian for the first time. Time. And my second reason for re recording this episode is that I have a lot more listeners than when I started, when my listeners were a few doctor friends and my parents. And I've learned a lot more about audio editing since then, and I bought a slightly fancier microphone instead of my old USB Skype mic. Since episode one seems to be a popular jumping off point for a podcast, go figure, I figured I might as well use it as an excuse to play around with my new microphone and some audio editing.

感谢收听，即便是第二次收听。请在iTunes或Stitcher等播客平台为我评分。我的网站是www.bedsiderounds.org。欢迎与我互动，我会尽力在Twitter和Facebook上与听众交流。

So, thank you for listening, even if it was for the second time. Please rate me on iTunes or Stitcher or however you get your podcasts. My website is at www.bedsiderounds.org. And please talk to me. I'm doing my best to talk to my listeners on Twitter and Facebook.

我在推特上的账号是adamrodmanmd，在Facebook上可以找到我，账号是bedsiderounds（一个词）。本期节目的参考资料包括《A型对角行为与哈德良皇帝之死》，作者是Patrakis医生，发表于1980年1月的《西方医学杂志》。我们还参考了Buckley医生发表在Clinical Correlations网站上的文章《对角耳垂折痕：历史趣闻还是冠状动脉疾病的有效征兆》。

I tweet adamrodmanmd and you can find me on Facebook at bedsiderounds, one word. My sources for this episode include Diagonal Type A Behavior and the Death of Emperor Hadrian, which is by Doctor. Patrakis, published in the Western Journal of Medicine in January 1980. We also have The Diagonal Earlobe Crease: Historical Trivia or Useful Sign of Coronary Artery Disease by Doctor. Buckley, which was published on the Clinical Correlations website.

最后，虽然我确实是一名医生，而不仅仅是在网上扮演医生，但如果您有任何健康问题，请咨询您的主治医生。

And finally, while I am actually a doctor and I don't just play one on the Internet, this If you have any medical concerns, please talk to your primary care provider.