Long-Term Colorectal Cancer Mortality after Adenoma Removal

Posted by Daniela Lamas • August 27th, 2014

Your patient had thought it would be a relief to get the colonoscopy over with. “Not for another ten years,” she had vowed as she chugged that dreaded colonoscopy prep.

But then there was a polyp – low-risk, she was told – but with it, recommendations to return for another colonoscopy in as few as three years. She returned to your office, relieved that a potential malignancy had been caught early but very concerned by the recommendation to intensify her screening. Does the now-excised polyp place her at higher risk of dying from colon cancer?

In all that’s been written recently on colon cancer screening, her question – that is, whether or not polyp surveillance colonoscopies reduce colon cancer mortality – has remained unanswered. Our current screening guidelines aren’t based on data about mortality and colon cancer incidence after the removal of high and low-risk adenomas.

Now, results published in this week’s issue of the Journal offer new evidence about the outcomes of high and low-risk adenoma patients, that might ultimately change these recommendations.

Using population-based data from a cancer registry in Norway, Magnus Loberg and colleagues tracked colon cancer mortality of patients who’d had adenomas removed between 1993 and 2007.  They identified 40,826 such patients, and followed them for an average of 7.7 years. Of note, in Norway, guidelines recommend that patients who are found to have high-risk adenomas undergo repeat colonoscopy in 10 years, and in 5 years if they have multiple adenomas. In contrast to guidelines in the US, those with low-risk adenomas require no additional screening.  They compared the incidence of newly diagnosed colon cancer and mortality in these patients to the general population.

What they found was surprising, given our current screening recommendations.

Those who’d had what the authors defined as low-risk adenomas excised actually had a 25% lower risk of death than the general population. In contrast, those with high-risk adenomas experienced a higher rate of colon cancer mortality than the general population – despite these adenomas having been removed.

In an accompanying editorial, David Lieberman, who heads the Oregon Health and Science University’s division of gastroenterology, notes that there are many potential reasons for the colon cancer deaths seen in the high-risk adenoma patients. The polyps might have been incompletely removed. The patients might have had other adenomas that were missed at colonoscopy, or a genetic predisposition to develop such adenomas. He notes that the study doesn’t include information about the quality of these colonoscopies that could help to understand the reasons behind this difference – regardless, he writes, these findings “provide justification for surveillance in patients with high-risk adenomas.”
But what about those with low-risk adenomas, who didn’t receive any additional screening in Loberg’s study and experienced lower rates of colon cancer nonetheless? Leiberman notes that there might exist a low-risk group of patients for whom close surveillance is not necessary. While further study is needed before making this determination, Lieberman writes, “This would be an exciting development for patients and health care systems.”

For your patient, the results are reassuring, but they don’t change practice. She’ll still get that colonoscopy, while researchers continue to work to determine who does and who doesn’t benefit from surveillance colonos.

A 21-Month-Old Boy with Lethargy, Respiratory Distress, and Abdominal Distention

Posted by Sara Fazio • August 22nd, 2014

In the latest Case Record of the Massachusetts General Hospital, a 21-month-old boy presented to the emergency department because of lethargy, respiratory distress, and abdominal distention. Initial laboratory evaluation was notable for anion-gap metabolic acidosis. A diagnostic test result was received. The differential diagnosis of acutely altered mental status in a toddler includes trauma (accidental or abuse), intussusception, infection (encephalitis or meningitis), poisoning (toxin), shock, accidental alcohol intoxication, encephalopathy, epilepsy as subclinical seizures, inborn errors of metabolism, ingestion of opiates, and uremia.

Clinical Pearls

What is the differential diagnosis of an elevated anion-gap metabolic acidosis?

The differential diagnosis of an elevated anion-gap metabolic acidosis is detailed by the acronym “CAT MUDPILES” and includes cyanide, carbon monoxide, and congestive heart failure; aminoglycosides; theophylline; methanol; uremia; diabetic, alcoholic, or starvation ketoacidosis; paraldehyde, paracetamol (acetaminophen), and phenformin; iron, isoniazid, and inborn errors of metabolism; lactic acidosis; ethanol and ethylene glycol; and salicylate.

What is a unique feature of salicylate poisoning?

Multiple toxins that cause an elevated anion-gap metabolic acidosis can be responsible for changes in mental status, respiratory distress, and tachycardia, but only salicylate poisoning is independently capable of causing hyperthermia, through the uncoupling of oxidative phosphorylation. In fact, hyperthermia is more common in fatal than in nonfatal salicylate poisoning, making elevated body temperature an important indicator of severe toxicity.

Morning Report Questions

Q: What is the organ system most importantly affected by salicylate poisoning?

A: The organ system most importantly affected by salicylate poisoning is the central nervous system (CNS). Neurotoxicity due to impaired ATP formation (and possibly exacerbated by low glucose levels in the cerebrospinal fluid) may lead to agitation, combativeness, hallucinosis, lethargy, seizures, coma, cerebral edema, or death. It has been shown that levels of salicylate in the CNS correlate best with death in animals. Any neurotoxic effects are an indication of severe poisoning and should prompt aggressive management.

Q: What factors are important in the assessment of serum salicylate levels?

A: Owing to delayed gastric emptying and erratic absorption of oral salicylate, a single test that yields a normal salicylate level (generally considered to be 100 to 200 mg per liter) is insufficient to rule out serious poisoning. Since the volume of distribution of salicylate increases dramatically with a decrease in the serum pH, a falling salicylate level may actually indicate distribution into tissues, including the CNS, and may be associated with clinical worsening. Serum salicylate levels in persons who die from salicylate poisoning are similar to those in persons who recover, and thus absolute levels alone should never be used to guide management. That said, in most patients with serum salicylate levels of 1000 mg per liter (7.2 mmol per liter) or greater, an indication for hemodialysis usually develops during the course of their poisoning.

Aortic-Valve Stenosis — From Patients at Risk to Severe Valve Obstruction

Posted by Sara Fazio • August 22nd, 2014

A new review article on aortic-valve stenosis comes from Dr. Catherine Otto at the University of Washington School of Medicine in Seattle and Dr. Bernard Prendergast at John Radcliffe Hospital in Oxford, UK.

Valvular aortic stenosis is a progressive disease in which the end stage is characterized by obstruction of left ventricular outflow, resulting in inadequate cardiac output, decreased exercise capacity, heart failure, and death from cardiovascular causes.

Clinical Pearls

What is the epidemiology of aortic stenosis?

The prevalence of aortic stenosis is only about 0.2% among adults between the ages of 50 and 59 years but increases to 9.8% in octogenarians, with an overall prevalence of 2.8% in adults older than 75 years of age. Although mortality is not increased when aortic stenosis is asymptomatic, the rate of death is more than 50% at 2 years for patients with symptomatic disease unless aortic-valve replacement is performed promptly. A total of 65,000 aortic-valve replacements were performed in the United States in 2010, primarily for aortic stenosis; 70% of these procedures were performed in patients older than 65 years of age, contributing to the high cost of  health care in our aging population.

What clinical factors have been associated with calcific aortic valve disease?

Clinical factors associated with calcific valve disease mirror those associated with coronary atherosclerosis, and coronary artery disease is common among adults with aortic stenosis. Population-based studies have shown associations between calcific valve disease and older age, male sex, elevated serum levels of low-density lipoprotein (LDL) cholesterol and lipoprotein(a), hypertension, smoking, diabetes, and the metabolic syndrome. Specific opulations at increased risk for aortic stenosis include patients with a history of mediastinal irradiation, renal failure, familial hypercholesterolemia, or disorders of calcium metabolism.

Morning Report Questions

Q: Who should undergo an aortic-valve replacement?

A: Clinical outcomes in adults with aortic stenosis are determined primarily by clinical symptoms, the severity of valve obstruction, and the left ventricular response to pressure overload. Assessment of patients and management decisions should take all three of these factors into account. The presence or absence of symptoms is the key element in decision-making. There is robust evidence that aortic-valve replacement prolongs life in patients with symptomatic severe aortic stenosis, regardless of the type or severity of symptoms or the response to medical therapy. However, accurate measures of the severity of stenosis are needed to ensure that valve obstruction — rather than concurrent coronary, pulmonary, or systemic disease or other conditions — is the cause of symptoms. In a patient with typical symptoms, a maximum transvalvular velocity of 4 m per second or greater, in conjunction with calcified immobile valve leaflets, confirms the diagnosis of severe aortic stenosis. Intervention is not needed until symptoms supervene, because the risk of sudden death is less than the risk of intervention, even when valve obstruction is severe. With very severe aortic stenosis, the rate of symptom onset is so high that elective valve replacement may be reasonable in selected cases.

Figure 4. Diagnostic Approach to the Treatment of Suspected Aortic Stenosis.

Table 1. Disease Stages in Patients with Aortic-Valve Stenosis.

Q: What factors affect choice of valve type for replacement?

A: The primary consideration in the choice of valve type is the risk of reoperation when a bioprosthetic valve is used versus the risk associated with warfarin anticoagulation when a mechanical valve is used. Mechanical valves are appropriate for patients younger than 60 years of age who have no contraindication to anticoagulation, because of the long-term durability of these prostheses. An exception is women of childbearing age, in whom a bioprosthetic valve is preferred, given the risks of anticoagulation and thromboembolism during pregnancy. In patients older than 70 years of age, bioprostheses are favored because valve durability increases with age and the risks of anticoagulation are avoided. In patients between 60 and 70 years of age, the choice of valve is based on patients’ preferences and values after a shared discussion between the patient and the surgeon.

Learning to Modify the Chronic Neurologic Burden of Sickle Cell Anemia

Posted by Joshua Allen-Dicker • August 20th, 2014

The patient sitting in front of you is a smiling, well-adjusted 6-year old boy.  He has a supportive family, eats a healthy diet, and is physically active.  What if, despite all of this, you knew that he had more than a 30 percent chance of developing a condition that would hamper his educational attainment?  Every day, pediatricians caring for children with sickle cell anemia are faced with this reality: around 37% of patients with sickle cell disease develop silent cerebral infarcts during childhood, which place them at significantly increased risk for poor academic achievement, cognitive deficits and strokes.

In this week’s NEJM, the Silent Cerebral Infarct Transfusion (SIT) Trial examines whether regular blood transfusions in children with known silent cerebral infarcts can reduce recurrent cerebral infarcts.  This multi-center, randomized control trial recruited children aged 5 to 15 years with hemoglobin SS or hemoglobin Sβ0 thalassemia, and a silent infarct on screening head MRI.

Study participants were randomized to receive monthly transfusion to maintain target hemoglobin greater than 9g/dL and a percentage of hemoglobin S less than or equal to 30% of their total hemoglobin.  The primary endpoint was infarct recurrence, defined as presence of a new infarct or enlargement of a previously noted infarct on the brain MRI performed at study exit.  Additionally, SIT monitored cognitive outcomes and safety outcomes, including transfusion reaction occurrence, ferritin levels, development of alloantibodies, and need for permanent central venous catheter access.

Of the 196 children who met study entry criteria, 99 were assigned to the transfusion group and 97 were assigned to the observation group.  After a mean follow-up of about 3 years, the incidence rate of infarct recurrence was 4.8 per 100 person years in the observation group versus 2.0 per 100 person years in the transfusion group ( p=0.04).  The number needed to treat was 13.

There was no significant difference in measured cognitive outcomes between the two groups. Patients in the transfusion group had a five-fold higher rate of blood-transfusion reactions and fourteen-fold higher rate of elevated ferritin levels (greater than 1500ng/mL).  Additionally, 11 patients in the transfusion group required tunneled venous catheter placement, and 4 patients in the transfusion group developed alloantibodies, compared with 0 patients for both outcomes in the observation group.

So does the SIT trial prove that transfusion for secondary prevention of silent infarcts in children with sickle cell anemia is ready for prime time?  While they represent an important realization—the chronic neurologic burden of sickle cell anemia may be modifiable—SIT’s encouraging results should be viewed in the context of treatment risks and implementation uncertainties.

In his accompanying editorial, Dr. Martin Steinberg states, “The study raises important questions for pediatricians and especially for internists who see these patients after many years of treatment, when untoward consequences of chronic transfusion can be present.”  For patients undergoing transfusion for secondary prevention we will need long-term mitigation strategies for alloimmunization, complications of permanent central venous catheter access, and iron overload.  We also lack clarity on the most appropriate duration of transfusion therapy and on whether transfusion strategies can have meaningful effects on longitudinal neurocognitive function.

Despite these concerns, Dr. Steinberg’s commentary remains hopeful about the promise of future long-term implementation trials.  As NEJM Deputy Editor Dan Longo adds, “Other methods of suppressing sickle globin gene expression are on the horizon; however, for the time being, transfusion appears to be capable of halving the neurologic consequences of sickle cell disease.  The late effects of transfusion are either rare (alloimmunization) or treatable (iron overload).  The same cannot be said for strokes.”

Benefits and Risks of Salt Consumption

Posted by Karen Buckley • August 19th, 2014

Are we bartering our own good health for the seductive flavor of salt?  View the latest NEJM Quick Take, which looks at all current guidelines and statistics regarding what we know about salt and cardiovascular disease and death related to salt consumption.

NEJM Quick Takes are brief animations that summarize the key findings of an original research article and their broader implications, and are narrated by our Editor-in-Chief, Jeffrey Drazen. They are now gathered in one place for you to browse.

Watch all eight, and look for a new one in October.

Syndromes of Thrombotic Microangiopathy

Posted by Sara Fazio • August 15th, 2014

A new review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs. An interactive graphic shows the nine primary syndromes of thrombotic microangiopathy (TMA), and narrated animations describe the causes, clinical features, initial management, and underlying mechanisms for each syndrome.

The TMA syndromes are extraordinarily diverse. They may be hereditary or acquired. They occur in children and adults. The onset can be sudden or gradual. Despite their diversity, TMA syndromes are united by common, defining clinical and pathological features. The clinical features include microangiopathic hemolytic anemia, thrombocytopenia, and organ injury.

Clinical Pearls  

What are the features of ADAMTS 13 deficiency-mediated TMA?

Acquired TTP is an autoimmune disorder caused by autoantibody inhibition of ADAMTS13 activity. The incidence of acquired TTP is much greater in adults (2.9 cases per 1 million per year) than in children (0.1 cases per 1 million per year). Factors that are associated with an increased frequency of this disorder include an age of 18 to 50 years, black race, and female sex. Among the primary TMA syndromes, TTP is unique for rarely causing severe acute kidney injury. The clinical features of hereditary TTP are recurrent episodes of microangiopathic hemolytic anemia and thrombocytopenia, often with neurologic abnormalities or other signs of organ injury.

Figure 3. Algorithm for the Evaluation of Children and Adults Presenting with Microangiopathic Hemolytic Anemia and Thrombocytopenia.

Table 1. Primary Thrombotic Microangiopathy (TMA) Syndromes.  

What are the features of complement-mediated TMA?  

Complement-mediated TMA results from uncontrolled activation of the alternative pathway of complement. Unlike the other two pathways of complement activation, the alternative pathway is constitutively active as a result of spontaneous hydrolysis of C3 to C3b. In the absence of normal regulation, C3b deposition on tissues may increase markedly, resulting in increased formation of the C5b-9 terminal complement complex (also called the membrane-attack complex) and injury of normal cells. Acute kidney injury and hypertension are prominent abnormalities in complement-mediated TMA. Current diagnostic criteria are those that were used in clinical trials involving a total of 37 patients, which supported the approval of eculizumab (a humanized monoclonal antibody that blocks the generation of C5a and C5b) for the treatment of “atypical HUS” in 2011. These criteria include all of the following: a serum creatinine level at or above the upper limit of the normal range, microangiopathic hemolytic anemia, thrombocytopenia, ADAMTS13 activity of 5% or more, and negative stool tests for Shiga toxin-producing infection.

Morning Report Questions  

Q: What are the features of Shiga toxin-mediated TMA, also called hemolytic uremic syndrome?

A: Multiple E. coli strains produce Shiga toxin; E. coli O157:H7 is the most common pathogen associated with ST-HUS in Europe and the Americas. S. dysenteriae type 1 remains an endemic cause of ST-HUS in other countries. Although ST-HUS is popularized by large outbreaks, most occurrences are sporadic. ST-HUS is much more common among children (median age, 2 years), in whom mortality is 3%. ST-HUS in adults is more severe, with higher mortality. Severe abdominal pain and diarrhea, often bloody, begin several days after contaminated food is consumed. Thrombocytopenia and renal failure begin as gastrointestinal symptoms resolve. Shiga toxin is identified by means of stool analyses during the acute colitis phase but may not be identifiable when ST-HUS begins. Treatment remains supportive. Early, aggressive hydration has a renal protective role. Patients commonly require dialysis. The benefits of plasma exchange and anticomplement treatment are uncertain.

Q: What medications have been associated with TMA?        

A: Although many other drugs have been reported to be associated with TMA, only quinine-associated TMA has been supported by documentation of drug-dependent antibodies. Quetiapine and gemcitabine are the only other drugs for which association with acute episodes of TMA has been supported by recurrent acute episodes with repeated exposures.

37-Year-Old Man with Ulcerative Colitis and Bloody Diarrhea

Posted by Sara Fazio • August 15th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 37-year-old man with ulcerative colitis was admitted to the hospital because of abdominal cramping, diarrhea, hematochezia, fever to a peak temperature of 38.8°C, and drenching night sweats. Several weeks earlier, he had performed home fecal transplantation.

Bloody diarrhea is characteristic of infections caused by Escherichia coli O157:H7 and shigella. Patients with enterohemorrhagic E. coli often do not have fevers; the associated hemolytic-uremic syndrome is more common in children.

Clinical Pearls

What are the features of fecal microbiota transplantation (FMT)?

The purpose of FMT is to transfer normal intestinal flora from a healthy donor to a person with intestinal dysbiosis. The most common and now widely accepted indication for this novel therapy is recurrent C. difficile colitis. Many observational series and a few randomized, controlled trials have shown that this procedure is more than 90% effective in resolving relapsing and recurring C. difficile infection. A fecal slurry made from healthy donor stool can be administered by colonoscope, enema, nasogastric or nasoduodenal tube, or capsule. Although there are accepted standards for screening donors and donor stool, there is very limited information related to transmission of infections through FMT.

What percentage of adults in the United States are seropositive for CMV?

Fifty to 90% of adults in the United States who are older than 35 years of age are seropositive for CMV.

Morning Report Questions

Q: What are the most common infections in patients with ulcerative colitis?

A: The most common infections in patients with ulcerative colitis are those due to C. difficile or CMV. A varying but substantial fraction of C. difficile infections that occur in patients with IBD may occur in the absence of traditional risk factors. CMV colitis may complicate underlying ulcerative colitis; this occurs in up to one third of patients with glucocorticoid-refractory disease. The majority of cases represent reactivation of previous CMV infection. Primary CMV infection is infrequent and often manifested by systemic signs of fever, malaise, and sweats. Laboratory findings may include atypical lymphocytes and elevated aminotransferase levels.

Q: In a patient of inflammatory bowel disease, what is the best way to diagnosis CMV colitis?

A: In a patient with IBD, there are several assays that may aid in the diagnosis of CMV colitis. These include blood-based assays, such as those that detect CMV antigenemia or detect CMV DNA by polymerase chain reaction (PCR). However, detection of the viral protein or DNA does not definitively discriminate between CMV infection and CMV colitis; the latter diagnosis relies on the detection of colonic injury. Furthermore, a negative blood test does not rule out gastrointestinal disease. Several methods could be used to detect CMV in colonic biopsy specimens, including hematoxylin and eosin staining, immunohistochemical staining, and detection of viral nucleic acids by PCR. Among these, hematoxylin and eosin staining is the least sensitive. In addition, viral cytopathic changes are     generally subtle, and hence, immunohistochemical staining is a crucial ancillary test for the detection of CMV. A PCR-based assay offers the highest level of sensitivity; however, the clinical significance of the detection of CMV DNA in the absence of detectable colonic injury is uncertain.

Visit NEJM.org for the Latest on the Ebola Outbreak

Posted by Karen Buckley • August 14th, 2014

Be sure to visit the NEJM Infectious Disease page, which brings together new and recent articles on Ebola, and features a healthmap that tracks publicly-reported, confirmed and suspected cases of Ebola throughout the world. The map is automatically updated to provide up-to-the-minute data on the outbreak.

A new Perspective article from NIH’s Antony Fauci suggests we need sound public health practices, engagement with affected communities,  and considerable international assistance and global solidarity to defeat Ebola in West Africa.

Another Perspective article from NIAID’s Heinz Feldmann says the outbreak has demonstrated our public health systems’ limited ability to respond to rare, highly virulent communicable diseases.  A Brief Report looks at emergence of the outbreak of Ebola in Guinea back in March.

We’ll be posting more content in this space as it becomes available, so check back regularly.

A Salty Subject: Sodium Consumption and Cardiovascular Health

Posted by Rena Xu • August 13th, 2014

Salt has long been a staple of life.  Once upon a time, it was a form of currency; roads were built to transport it; cities arose to produce and trade it.  And, of course, people ate it.  Today, we continue to consume it the whole world over.

It’s hard to believe something so integral to the human experience, spanning centuries and civilizations, might be bad for the body.  But as the Mrs. Dashes of the world would have us know, salt consumption has been linked to high blood pressure, which in turn has been linked to heart disease — a reason, perhaps, to keep one’s salt intake in check.

Just how much salt are we consuming?  And how much damage can we attribute to the delicious granules that top our pretzels, coat our fries, and cure our meats?  A group of researchers from the Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NUTRICODE) used survey data and statistical models to estimate the sodium consumption of adults from 187 nations.  They also performed a meta-analysis of over a hundred randomized interventional studies to calculate the effects of sodium on blood pressure and analyzed pooled data from cohort studies to calculate the effects of high blood pressure, in turn, on cardiovascular mortality.

Their findings, published in this week’s NEJM, might make you think twice before reaching for the saltshaker.  In 2010, the average daily sodium consumption was 3.95 grams, well above the World Health Organization recommendation of 2 grams per day.  In fact, 181 out of the 187 nations — accounting for a whopping 99.2% of adults — exceeded the recommended intake level.  The consequence?  Nearly one in every ten deaths from cardiovascular causes in 2010, the authors estimated, could be attributed to excess sodium consumption.  That translated to 1.65 million deaths globally.  What’s worse, over 40% of these deaths occurred prematurely (i.e., in people younger than 70 years of age).

While no region of the world was spared, there was considerable variability across geographies in sodium-associated cardiovascular mortality rates.  The highest rates were in Central Asia and Eastern and Central Europe.  Among individual countries, Georgia had the highest rate (1967 deaths per 1 million adults per year), while Kenya had the lowest (4 deaths per 1 million adults per year).  Perhaps most striking, more than 80% of sodium-related cardiovascular deaths around the world — four out of every five — occurred in low- or middle-income countries.

There may be a silver lining.  The authors also found that reductions in sodium intake were linked proportionally to reductions in blood pressure (P<0.001 for a linear dose-response relationship).  For a white, normotensive 50-year-old, for instance, a reduction of 2.3 grams per day lowered systolic blood pressure by 3.74 mmHg (95% CI: 2.29 to 5.18).  The exact effect varied by age and race, with greater reductions in older people (vs. younger people), blacks (vs. whites), and people with hypertension (vs. without).

Does that mean low sodium intake translates to better health?  Not necessarily, according to two other articles published in this week’s NEJM.  The Prospective Urban Rural Epidemiology (PURE) study collected fasting morning urine specimens from over 100,000 adults, representing 18 different countries and a range of income levels, and calculated 24-hour urinary sodium excretion (a proxy of sorts for sodium consumption).  This was correlated with blood pressure.

The investigators found a non-linear relationship.  For people who excreted a lot of sodium (in this study, defined as over five grams per day), there was a strong association, meaning each additional gram of sodium was linked to a steep rise in blood pressure (2.58 mmHg per gram).  In contrast, for people with low sodium excretion (less than three grams per day), the association with blood pressure was not statistically significant (0.74 mmHg per gram; P=0.19).  Remarkably, only ten percent of study participants fell into this low-sodium category, and only four percent had sodium excretion levels consistent with the current U.S. guidelines for sodium intake.

Based on these results, Dr. Suzanne Oparil of the University of Alabama at Birmingham suggests in an accompanying editorial, a low-sodium diet might not be the most useful public health recommendation.  She writes, “The authors concluded from the findings that a very small proportion of the worldwide population consumes a low-sodium diet and that sodium intake is not related to blood pressure in these persons, calling into question the feasibility and usefulness of reducing dietary sodium as a population-based strategy for reducing blood pressure.”

The PURE study investigators also tested the correlation between sodium excretion and a composite outcome of death and major cardiovascular events (heart attacks, strokes, heart failure).  They observed that, compared to a reference sodium excretion range of four to six grams per day, a higher level of sodium excretion (seven or more grams per day) was linked to a greater risk of the composite outcome (odds ratio 1.15; 95% CI, 1.02 to 1.30).  But, when they looked at people with very low sodium excretion (below three grams per day), they found an increased risk as well (odds ratio, 1.27; 95% CI, 1.12 to 1.44).

Complicating matters further, the authors also looked at the urinary excretion of potassium.  Compared to a reference level of 1.5 grams per day, a higher potassium excretion level was linked to a reduced risk of the composite outcome.  “The alternative approach of recommending high-quality diets rich in potassium might achieve greater health benefits, including blood-pressure reduction, than aggressive sodium reduction alone,” Oparil writes.

To the scholars in us, these findings are an inspiration for further research.  But how should we apply this knowledge to our daily lives, when we’re sitting in diners wondering whether to shake or not to shake?  It may be presumptuous to read too much into the findings, to infer causality where it has yet to be established.  Still, as a species, we’re better equipped today than we’ve ever been to make smart choices about our diet.  And until more data become available, moderation may be the way to go.

The results of this new research are also summarized in a short animation.

View the latest NEJM Quick Take now.

A Gut Instinct

Posted by Sara Fazio • August 8th, 2014

In the latest Clinical Problem-Solving article, a 30-year-old female physician presented to the emergency department in mid-August, with a 4-day history of anorexia, nausea, vomiting, and diarrhea. She had no fever or respiratory symptoms but had mild abdominal discomfort.

Tuberculosis is a well-recognized occupational hazard for those involved in health care. In a systematic review that included 15 studies conducted in high-income countries, health care workers had a median annual risk of pulmonary tuberculosis infection of 1.1% (range, 0.2 to 12), as compared with a risk of 0.1 to 0.2% in the general population.

Clinical Pearls

How has the incidence of extrapulmonary tuberculosis changed in the United States?

There has been a steady decline in cases of tuberculosis in the United States, from 52.6 cases per 100,000 population in 1953 to 3.6 cases per 100,000 population in 2010. However, the proportion of cases of extrapulmonary tuberculosis per total cases of tuberculosis increased from 7.6% in 1962 to 20% or more since the late 1990s. The risk of extrapulmonary tuberculosis is reported to be increased among women, Asian and foreign-born persons, and health care workers.

What are the epidemiology and features of intraabdominal tuberculosis?

Intraabdominal tuberculosis, including peritoneal and mesenteric lymph-node involvement, is the sixth most common type of extrapulmonary tuberculosis reported in the United States. The diagnosis of intraabdominal tuberculosis is challenging, owing to its protean and nonspecific manifestations. In a large case series, up to two thirds of patients had negative tuberculin skin tests, and many did not have respiratory symptoms. Systemic and constitutional symptoms are frequent, as are abdominal pain and distention. The majority of patients with tuberculous peritonitis have ascites, which results from fluid exudation from peritoneal surfaces; only about 10% of patients present with the “dry type” of tuberculous peritonitis, characterized by a doughy abdomen, adhesions, fibrosis, and the absence of ascites. Often there is a long delay between symptom onset and diagnosis.

Morning Report Questions

Q: What is the reported sensitivity of tuberculin skin testing in cases of active tuberculosis?  

A: In the case of active tuberculosis, the reported sensitivity of tuberculin skin testing is highly variable and is generally estimated from culture-confirmed cases; false negative test results are reported in up to 25% of cases. Tuberculin skin tests should not be considered to be reliable tests for the diagnosis of active disease.

Q: What are the guidelines for treatment of extrapulmonary tuberculosis?        

A: Guidelines for the treatment of extrapulmonary tuberculosis closely mirror those for the treatment of pulmonary tuberculosis. Currently, for susceptible tuberculosis, four-drug therapy for 2 months is recommended, followed by two-drug therapy for 4 months or longer, depending on the extrapulmonary site (e.g., the meninges require longer therapy).