Take the Case Challenge: A Man with Diarrhea, Nausea, and Weight Loss

Posted by Karen Buckley • September 11th, 2014

A 29-year-old man was seen in the walk-in clinic because of diarrhea of 1 year’s duration and weight loss. Initial laboratory values included elevated hepatic aminotransferase levels and a ferritin level of 1716 ng per milliliter. A diagnostic procedure was performed. What is the diagnosis? What diagnostic tests are indicated?

Read the case description. Then vote and comment about what the diagnosis may be and what diagnostic tests will prove useful. Find the answers in the full text of the case to be published on September 25.  Follow the conversation on Facebook and Twitter with #NEJMCases.



Posted by Sara Fazio • September 5th, 2014

Initial management for internal hemorrhoids includes adequate fiber and water intake and avoidance of straining. Office procedures (e.g., rubber-band ligation) are helpful when medical therapy fails; excisional therapies such as hemorrhoidectomy are used for severe disease.  Read the new Clinical Practice review article on this topic.

Symptoms related to hemorrhoids are very common in Western and other industrialized societies. Although published estimates of prevalence vary widely, millions of people in the United States are affected yearly.

Clinical Pearls

How are hemorrhoids categorized?

Hemorrhoids are categorized according to their origin relative to the dentate line, which is typically located about 3 to 4 cm proximal to the anal verge. The line represents the site where the squamous epithelial cells derived from the ectoderm interface with the columnar mucosa cells of endodermal origin. Besides being the basis for categorizing hemorrhoidal complexes as internal (if proximal to the dentate line), external (if distal to the dentate line), or mixed (both proximal and distal), the different embryonic origins lead to distinctly different vascular drainages, epithelialization, and innervation. Tissues that are distal to the dentate line are innervated by somatic nerves and are more sensitive to pain and irritation than those that are located more proximally, which receive sympathetic or parasympathetic visceral innervation.

Figure 1. Hemorrhoidal Disease. 

What are the typical clinical manifestations of symptomatic hemorrhoids?

The clinical manifestations of symptomatic hemorrhoids vary with the extent of the disease process. Patients who present for diagnosis and treatment typically report hematochezia (approximately 60%), itching (approximately 55%), perianal discomfort (approximately 20%), soiling (approximately 10%), or some combination of these symptoms. The rectal bleeding typically occurs with or immediately after defecation. Blood may be noticed on toilet paper, in toilet water, or, occasionally, staining the underwear. Patients should be queried about their fiber and fluid intake, bowel patterns (including stool frequency), bathroom habits (e.g., reading while seated on the toilet), the need for digital manipulation of prolapsed tissue, and whether there is a history of soiling or incontinence. Other disease processes must be considered. Substantial pain is rare in patients with uncomplicated internal or external hemorrhoids. The presence of severe pain raises the possibility of other conditions, including  anal fissure, perirectal or perivaginal infection, abscess, and other inflammatory processes, although severe pain may occur with  complications of hemorrhoids (e.g., prolapse with incarceration and ischemia or thrombosis).

Morning Report Questions

Q: What imaging is necessary in a patient with hemorrhoids?

A: Flexible endoscopy is not as successful as anoscopy for examining the anorectum. The decision to perform a more extensive colorectal evaluation should be informed by the patient’s age, presenting signs and symptoms and their duration, and the nature of bleeding. Evaluation of the entire colon is indicated for patients with any of the following: anemia; bleeding that is not typical of hemorrhoids; a change in bowel patterns; a personal history of rectal or colon polyps; a family history of inflammatory bowel disease, colorectal cancer, or other hereditary colorectal diseases in a first-degree relative; or other suspected pathologic pelvic changes that could contribute to the patient’s symptoms. For symptomatic patients younger than 50 years of age who have no risk factors for colonic disease and no evidence of other anorectal abnormalities and in whom examination confirms the presence of uncomplicated disease, hemorrhoid treatment can be administered in lieu of endoscopy or imaging studies. Persistent bleeding or other symptoms after successful local treatment of hemorrhoids is an indication for further evaluation.

Q: How should patients with symptomatic hemorrhoids be treated?

A: All patients should be encouraged to ingest a sufficient amount of insoluble fiber (typically 25 to 35 g per day) and sufficient water to avoid constipation and straining and to limit the time spent on the toilet. A meta-analysis of controlled trials showed that fiber supplementation was associated with significant reductions in the risk of persistent symptoms and the risk of rectal bleeding, although the effects of fiber supplementation on mucosal prolapse, pain, and itching were not significant. Clinical experience indicates that use of topical glucocorticoids, vasoconstrictors (e.g., phenylephrine-based creams or suppositories), or analgesics may provide temporary relief of some symptoms. For patients who do not respond to conservative treatment, a meta-analysis of 18 randomized trials comparing various treatment methods for grade I to III hemorrhoids concluded that rubber-band ligation was more effective than sclerotherapy and that patients who underwent ligation were less likely to need subsequent therapy. Rubber-band ligation was less effective than hemorrhoidectomy but had fewer complications and caused less pain. It therefore is considered appropriate as first-line therapy.

Influenza Vaccination in Pregnant Women

Posted by Sara Fazio • September 5th, 2014

In two trials of a trivalent inactivated influenza vaccine in pregnant women in South Africa, HIV-infected and HIV-uninfected vaccine recipients had increased influenza antibody titers and decreased influenza attack rates.

Pregnant women are designated as a priority group for seasonal influenza vaccination by the World Health Organization (WHO) because of their heightened susceptibility to severe influenza from the second trimester to the early postpartum period.

Clinical Pearls

What were the results of this study of trivalent inactivated influenza vaccine in the HIV-uninfected cohort?

The attack rates for confirmed influenza among placebo recipients and IIV3 recipients were 3.6% and 1.8%, respectively, indicating a vaccine efficacy of 50.4% (95% confidence interval [CI], 14.5 to 71.2). The vaccine efficacy was similar when determined according to the vaccine strain (46.1%; 95% CI, 6.4 to 69.0). For the 2 years of the study, the predominant strain of influenza virus circulating among placebo recipients was A/H3N2 (57.9%), for which an exploratory analysis identified a vaccine efficacy of 57.5% (95% CI, 7.6 to 80.4). The attack rate was lower among infants whose mothers were HIV-infected and HIV-uninfected  recipients (1.9%) than among those whose mothers were placebo recipients (3.6%), indicating a vaccine efficacy of 48.8% (95% CI, 11.6 to 70.4).

Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.

Figure 1. Kaplan-Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.

What were the results of this study in the HIV-infected cohort?

In the cohort of HIV-infected mothers, the attack rate was lower among IIV3 recipients than among placebo recipients (7.0% vs. 17.0%), indicating an adjusted vaccine efficacy of 57.7% (95% CI, 0.2 to 82.1). The attack rates were 5.0% and 6.8% among infants of IIV3 recipients and infants of placebo recipients, respectively (vaccine efficacy, 26.7%; P=0.60). In 6 of 11 infants of HIV-infected mothers with confirmed influenza (55%), including 2 infants whose mothers received IIV3, the mothers were infected with the same strain as their infants.

Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.

Figure 1. Kaplan-Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.  

Morning Report Questions

Q: What were adverse effects associated with vaccination?

A: Injection-site reactions (mainly mild to moderate) were more frequent among IIV3 recipients than among placebo recipients in both cohorts, but there were no other significant differences in solicited reactions between the two study groups in either cohort. There were no significant between-group differences with regard to rates of miscarriage, stillbirth, or premature birth or birth weight in the HIV-uninfected cohort and in the HIV-infected cohort. Among the HIV-infected cohort, IIV3 did not affect the plasma HIV-1 viral load, minimizing concern about the possibility of an increased risk of vertical transmission of HIV in vaccinees.

Table 1. Baseline Characteristics of HIV-Uninfected Pregnant Women, Fetal Outcomes, and Newborn Characteristics. 

Q: How did the influenza attack rate among HIV-infected and HIV-uninfected recipients who received placebo differ in this study, and what are the implications?

A: The authors note that the attack rate among HIV-infected placebo recipients in this study (17.0%) was greater than that observed among HIV-uninfected placebo recipients (3.6%), a finding that highlights the greater susceptibility of HIV-infected persons to influenza, even when the HIV infection is managed with antiretroviral treatment.

PARADIGM-HF: The Experts’ Discussion

Posted by Karen Buckley • September 4th, 2014

The PARADIGM-HF trial, presented last weekend at the European Society of Cardiology (ESC) Annual Congress and published in NEJM, suggests that neprilysin inhibition may replace ACE inhibition for the treatment of heart failure.  NEJM and ESC brought together the study co-chairs, John McMurray and Milton Packer, and cardiologists Mariell Jessup, Keith Fox, and Michel Komajda to discuss these practice-changing results in PARADIGM-HF- The Experts’ Discussion. View the video now on NEJM.org.

A new Perspective article includes an interactive timeline of select trials in heart-failure treatment since 1986. An accompanying editorial and concise video summary are also available on NEJM.org.

If you’re looking for further discussion on this topic, CardioExchange has an interview with the investigators, Will There Be a PARADIGM Shift in Treatment of Heart Failure?, and a critical assessment,  Let’s Take a Close Look at PARADIGM-HF, from Vinay Prasad.  NEJM JournalWatch Cardiology editor Harlan Krumholz also provides summary and comment.

Influenza Vaccination in Pregnancy

Posted by Rupa Kanapathipillai • September 3rd, 2014

As the days get shorter and cooler, you have an increasing sense of dread that Winter Is Coming – and with it comes flu season.   Once you stop daydreaming of the halcyon days of summer, you notice that in your waiting room are two pregnant patients, one HIV positive, one HIV negative.

You take a moment to reflect on how best to advise both patients regarding the approaching dreaded flu season. Do recommendations differ for the two women? What evidence are these recommendations based on?

Data on the efficacy and safety of vaccines in pregnant women are surprisingly limited, and they are even more limited in pregnant women who are HIV-infected.   Although pregnant women are at higher risk of severe influenza illness, especially from the second trimester of pregnancy until early post-partum, influenza vaccination rates in pregnancy were as low as 15%, but the rate has increased to about 50% since the 2009 H1N1 pandemic.   There may be tendency to feel that avoiding medical interventions, even vaccination, is safer for the developing fetus.  In this week’s NEJM, Dr. Madhi et al report the findings of two studies in HIV-infected and uninfected women in South Africa, seeking to provide some much-needed answers.

Two double-blind, randomized, placebo-controlled trials of trivalent inactivated influenza vaccines (IIV3) investigated the immunogenicity, safety and vaccine efficacy of IIV3 in pregnant HIV-infected and uninfected pregnant women and their infants in Soweto, South Africa.  The study included 2116 HIV uninfected and 194 HIV-infected pregnant women who were randomized to receive the IIV3 vaccine or placebo.  Outcomes of immunogenicity, safety, and vaccine efficacy were compared between the two arms.

The investigators found higher one-month seroconversion rates in HIV-infected and uninfected vaccine recipients and their newborns compared to placebo.  Significantly lower incidence of influenza illness was seen in HIV-uninfected vaccine recipients and their infants, with a vaccine efficacy of 50.4% [95%CI: 14.5% to 71.2%] and 48.8% [95%CI: 11.6% to 70.4%] respectively.  Among HIV-infected vaccine recipients, vaccine efficacy was 57.7% [95%CI: 0.2% to 82.1%].  Vaccine efficacy in HIV-exposed infants was 26.7% [p=0.60], but the study lacked sufficient power to detect a significant difference in HIV-exposed infants.  Higher proportions of HIV-infected and uninfected recipients experienced mild-moderate injection site reactions, but no other differences were found in rates of reactions or severe adverse events comparing vaccine recipients to non-recipients.

NEJM Deputy Editor Lindsey Baden states: ‘Protecting pregnant women and their infants from influenza infection and disease remains a high priority as these two groups are particularly vulnerable to severe complications from the flu. As the data from these studies show, influenza vaccination is a relatively simple way to achieve this.’

These data address key questions affecting this infrequently studied at-risk population and has significant public health implications.  Demonstration of vaccine efficacy and safety supports the recommendation of the World Health Organization, and should encourage clinicians to work for an increased uptake of influenza vaccination among pregnant women, including both HIV-infected and uninfected.

In your clinical practice, how do you counsel pregnant women regarding influenza vaccination?  What about HIV-infected pregnant women?  What questions do you have regarding vaccination during pregnancy in these populations? 

PARADIGM-HF Prompts a New Line of Thinking about Heart Failure

Posted by Chana Sacks • August 30th, 2014

Your patient – a 65-year-old man with an ischemic cardiomyopathy – presents to clinic one week after discharge from another hospitalization for a heart-failure exacerbation.

He is doing much better. He remains at his discharge weight and reports good adherence to a low-salt diet and to the extensive medication regimen that you have prescribed: he takes an aspirin, ACE inhibitor, beta-blocker, aldosterone antagonist, and a diuretic.  His ejection fraction is 30%, and he has NYHA class II heart-failure symptoms.

Doc, he asks you, are there any other medications I should be taking to keep me from getting hospitalized again or from dying from this?

His question has been the decades-long challenge facing physician-scientists working on heart failure.  Over the past quarter century, significant advances have been made. In 1987, the ACE-inhibitor enalapril was demonstrated to improve survival in patients with systolic heart failure [CONSENSUS].  In 1996, the mortality benefit of the alpha and beta-blocker carvedilol was shown [Packer], and in 1999, evidence of a mortality benefit with spironolactone added aldosterone antagonists [RALES] to heart-failure therapy.

With the PARADIGM-HF trial, published in this week’s NEJM, McMurray and colleagues report that a new drug can now be added to this list.  This study shows that the novel drug LCZ696 reduces mortality and decreases hospitalizations in patients with heart failure.

LCZ696 is a combination of the old angiotensin II receptor blocker (ARB) valsartan and the new neprilysin inhibitor sacubitril.   ARBs have long been used to replace ACE-inhibitors when patients cannot tolerate them, usually because of a cough.  Neprilysin is a neutral endopeptidase that degrades bradykinin, natriuretic peptides, and adrenomedullin.  Inhibition of neprilysin increases the circulating levels of those peptides.  According to the authors, these higher levels “counter the effects of neurohormonal overactivation that contributes to vasoconstriction, sodium retention and maladaptive remodeling.”

In this industry-funded, double-blind, randomized controlled trial of 8,000 patients, LCZ696 is compared with enalapril, a drug known to reduce mortality in heart failure. After a run-in period in which all screened participants received both drugs sequentially to ensure tolerance at target doses, patients were randomized to either LCZ696 at a dose of 200mg twice daily or enalapril 10mg twice daily.  Importantly, about 20% of screened participants were excluded during the run-in, most because of intolerance to one of the drugs.  Like your patient, all patients in the study had heart failure with an ejection fraction less than 40%.  Most were men, and they were well-managed medically at baseline, with more than 90% on a beta blocker, all on an ACE inhibitor (78%) or ARB (22%), and a majority on an aldosterone blocker.

The study was terminated early, after a median follow up of 27 months, because LCZ696 was found to be superior to enalapril, with a 20% reduction in the primary outcome of cardiovascular death or first hospitalization for heart failure (21.8% in the LCZ696 group compared with 26.5% in the enalapril group, P<0.0001).  All-cause mortality was also reduced, with 17% mortality in the LCZ696 group and 19.8% in the enalapril group (P <0.001). Overall, there was more symptomatic hypotension and non-serious angioedema in the LCZ696 arm, with more cough, renal failure, and hyperkalemia in the enalapril arm.

NEJM Executive Editor Greg Curfman describes the significance of this trial:  “Not only does this new treatment represent a significant advance, but it opens a new line of thinking about heart failure. Perhaps most exciting is the research it will stimulate in the future.”

In an accompanying editorial, Mariel Jessup, M.D., agrees, noting that the “PARADIGM–HF trial may well represent a new threshold of hope for heart failure patients.”

So to your patient – do you throw out his ACE inhibitor and start LCZ696?  Well, right now, you can’t.   LCZ696 is not FDA approved and is not commercially available.  Expect this study to form the basis of Novartis’ FDA application.  Perhaps by then it will have a catchier name.

Barrett’s Esophagus

Posted by Sara Fazio • August 29th, 2014

A new review article covers the epidemiology, pathogenesis, and natural history of Barrett’s esophagus and management options for the disorder.

It has been estimated that 5.6% of adults in the United States have Barrett’s esophagus, the condition in which a metaplastic columnar mucosa that confers a predisposition to cancer replaces an esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD). GERD and Barrett’s esophagus are major risk factors for esophageal adenocarcinoma, a deadly tumor whose frequency in the United States has increased by a factor of more than 7 during the past four decades. The metaplastic columnar mucosa of Barrett’s esophagus causes no symptoms, and the condition has clinical importance only because it confers a predisposition to cancer.

Clinical Pearls

How is the diagnosis of Barrett’s esophagus made?

The diagnosis of Barrett’s esophagus requires findings on endoscopy that columnar mucosa extends above the gastroesophageal junction, lining the distal esophagus, plus esophageal-biopsy results that confirm the presence of columnar metaplasia. Endoscopically, the gastroesophageal junction is identified as the most proximal extent of gastric folds, and the columnar mucosa is salmon-colored and coarse, in contrast to the pale, glossy esophageal squamous mucosa.

The extent of esophageal columnar metaplasia determines whether long-segment or short-segment Barrett’s esophagus (greater than or equal to 3 cm or <3 cm of columnar metaplasia, respectively) is diagnosed. However, authorities disagree on the histologic type of columnar mucosa that establishes a diagnosis of Barrett’s esophagus. U.S. gastroenterology societies require esophageal biopsies showing intestinal metaplasia with goblet cells (also called specialized intestinal metaplasia or specialized columnar epithelium) for a definitive diagnosis of Barrett’s esophagus. This intestinal metaplasia is a well-established risk factor for adenocarcinoma.

Figure 1. Diagnostic Features of Barrett’s Esophagus.

What are risk factors for Barrett’s esophagus as well as factors that may be protective?

Barrett’s esophagus is two to three times as common in men as in women, is uncommon in blacks and Asians, and is rare in children. Other important risk factors include obesity (with a predominantly intraabdominal fat distribution) and cigarette smoking, and there is a familial form of Barrett’s esophagus, which accounts for 7 to 11% of all cases. Most conditions associated with Barrett’s metaplasia are also risk factors for esophageal adenocarcinoma. Conversely, factors that might provide protection against Barrett’s esophagus include the use of nonsteroidal antiinflammatory drugs, gastric infection with Helicobacter pylori, and consumption of a diet high in fruits and vegetables.

Morning Report Questions

Q: What is the risk of esophageal adenocarcinoma in patients with nondysplastic Barrett’s esophagus?

A: Recent studies suggest that the risk of esophageal adenocarcinoma in the general population of patients with nondysplastic Barrett’s esophagus is only 0.1 to 0.3% per year. However, a number of factors influence the risk of cancer for individual patients. For example, cancer risk among men with Barrett’s esophagus is approximately twice that among women, the risk is greater with a longer segment of Barrett’s metaplasia, and the risk is especially high among persons with certain familial forms of Barrett’s esophagus. In addition, the risk appears to decrease with follow-up endoscopies showing no progression to dysplasia.

Q: How should Barrett’s esophagus be treated?

A: GERD should be treated aggressively in patients with Barrett’s esophagus, and there is indirect evidence to suggest that proton-pump inhibitors (PPIs) decrease the risk of cancer development. For example, a recent cohort study involving 540 patients with Barrett’s esophagus who were followed for a median of 5.2 years showed that PPI use was associated with a 75% reduction in the risk of neoplastic progression. Bile acids can also cause double-strand DNA breaks and might contribute to carcinogenesis in patients with Barrett’s metaplasia, and PPIs do not prevent bile reflux. Antireflux surgery can prevent reflux of all gastric contents (acid and bile), but the best available data suggest that surgery is not more effective than PPI therapy in preventing cancer. Thus, antireflux surgery is not advised solely for protection against cancer. Randomized, controlled trials have shown that endoscopic eradication of dysplasia in patients with Barrett’s esophagus with the use of photodynamic therapy or radiofrequency ablation (in which radiofrequency energy destroys the mucosa) significantly reduces the rate of progression to cancer. However, the efficacy of radiofrequency ablation for preventing cancer in patients with nondysplastic Barrett’s esophagus has not been established in long-term studies.

10-Month-Old Boy with Microcephaly and Episodic Cyanosis

Posted by Sara Fazio • August 29th, 2014

A 10-month-old boy with microcephaly and developmental delay was admitted to the hospital because of episodes of respiratory distress and cyanosis. Microcephaly was present at birth, and hypotonia was noted at 5 months. On admission, brain MRI revealed decreased myelination.

Microcephaly literally means “small head.” It is diagnosed when the head circumference is more than 2 SD below the mean for age and sex, although sometimes a stricter cutoff of 3 SD below the mean is used. The underlying causes of microcephaly can be divided into nongenetic and genetic causes.

Clinical Pearls

What are some examples of nongenetic and genetic causes of microcephaly?

Common nongenetic causes of microcephaly include intrauterine infections and in utero exposure to drugs, toxins, and ionizing radiation. Other nongenetic causes include disruptive brain injuries and systemic disorders. Genetic causes of microcephaly appear to be diverse; more than 200 genes are associated with microcephaly in the Online Mendelian Inheritance in Man database. MRI of the head can be helpful in guiding genetic testing, because many genetic disorders that occur in patients with microcephaly are associated with characteristic structural abnormalities. Microcephaly is a feature of various syndromes, such as the Rubinstein-Taybi syndrome (which iS characterized by intellectual disability, postnatal growth retardation, broad thumbs and halluces, and dysmorphic facial features) and the Cornelia de Lange syndrome (which is characterized by unique facial features, prenatal and postnatal growth retardation, and intellectual disability and often by upper-limb anomalies).

What is MTHFR deficiency and how is it diagnosed?

MTHFR is an inborn error of metabolism, in which deficiency of functional methionine synthase traps folates in the 5-methyltetrahydrofolate (5-MTHF) form, consequently causing a deficiency of other active forms of folate (including tetrahydrofolate [THF], 5,10-methenyl-THF, 5,10-methylene-THF, and 10-formyl-THF) and thereby resulting in megaloblastic anemia. In the severe form of MTHFR deficiency, the 5-MTHF level is reduced but anemia is not seen, because the 5,10-methylene-THF and other active forms of THF (including 10-formyl-THF) that are required for purine   and pyrimidine synthesis are not affected. The combination of homocysteinemia, low methionine levels, and absence of anemia indicated a diagnosis of severe MTHFR deficiency.

Morning Report Questions

Q: What are the manifestations of severe MTHFR deficiency?

A: Severe MTHFR deficiency is extremely rare but is the most common disorder of folate metabolism. Approximately 100 cases have been reported, and fewer than 15 have manifested before 6 weeks of age. The clinical presentation is nonspecific, with some age-related variations. In the newborn period and during early infancy, seizures and acute neurologic deterioration are the common initial manifestations, whereas in older infants and children, nonspecific psychomotor deterioration, acquired microcephaly, and abrupt deterioration (e.g., respiratory failure) can be seen. In older patients, isolated stroke, arterial or venous thromboembolic disease, and combined degeneration of the spinal cord have been reported as initial manifestations.

Q: How is MTHFR deficiency treated?

A: Treatment of the remethylation defects is directed toward reducing homocysteine levels (thereby lowering the risk of thromboembolism) and normalizing methionine levels (and normalizing the availabilitY of methionine in the central nervous system). These are achieved through betaine supplementation, which remethylates homocysteine to form methionine through an alternative pathway present in the liver and kidney. Additional treatment involves folate and cofactor supplementation for enzymes in the pathway; hydroxocobalamin (a cofactor for methionine synthase) and riboflavin (a cofactor for MTHFR) are administered to enhance residual activities and improve remethylation, and pyridoxine (a cofactor for cystathionine [beta]-synthase) is administered to enhance degradation of homocysteine through the degradation pathway.

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.