Good Night, Sleep Tight … And Don't Let the Acid Bite!

June 2010

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tients with pancreatic adenocarcinoma were positive for the anti-PBP peptide antibody, making this an imperfect test. Despite the conclusion that this assay cannot absolutely prove the absence of pancreatic cancer, when one takes the entire clinical picture into account, the presence of anti-PBP peptide antibody should still be a helpful tool in distinguishing AIP from pancreatic cancer. Although not the primary aim of the study, the authors were able to demonstrate a possible mechanism of autoimmunity that carries biological plausibility. The homology between PBP peptide and UBR2, an antigen highly expressed in acinar cells of the pancreas, argues that pancreatic acinar cells may be the target of autoimmune attack in this disease entity. Additionally, the homology between PBP peptide and UBR2 supports the previously proposed theory that H pylori infection may play a role in the etiology of AIP (Gastroenterology 2007;133:368 –369). In this study, 83% of the patients in the initial AIP group and 81% of the patients in the validation group demonstrated H pylori–positive serologic status. Further research is necessary to investigate these linkages and the role of H pylori infection in the etiology of AIP. In summary, this study by Frulloni et al successfully identified a serologic marker that can be used to diagnose AIP and may prove to be a valuable complementary test in the differentiation of AIP from pancreatic adenocarcinoma. The clinical importance of this study cannot be overlooked; if validated in other studies, the antibody to PBP peptide may change the diagnostic algorithm in patients with suspected AIP. PARI SHAH, MD NUZHAT A. AHMAD, MD Division of Gastroenterology Department of Medicine Hospital of the University of Pennsylvania University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

GOOD NIGHT, SLEEP TIGHT . . . AND DON’T LET THE ACID BITE! Mody R, Bolge SC, Kannan H, et al. (Takeda Pharmaceutical North America, Inc, Deerfield, Illinois). Effects of gastroesophageal reflux disease on sleep and outcomes. Clin Gastroenterol Hepatol 2009;7:953–959. Jansson C, Nordenstedt H, Wallander MA, et al. (Unit of Esophageal and Gastric Research, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden). A population-based study showing an association between gastroesophageal reflux disease and sleep problems. Clin Gastroenterol Hepatol 2009;7:960 –965. Gastroesophageal reflux disease (GERD) affects approximately 40% of the US population on a monthly basis and 10% daily (Am J Dig Dis 1976;21:953–956). A

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majority of heartburn sufferers also report nocturnal GERD symptoms (Arch Intern Med 2001:45–52). Because the definition of nocturnal heartburn has not been standardized, this term has included the presence of heartburn symptoms occurring after dinner, GERD symptoms experienced when lying down to initiate sleep, heartburn causing nocturnal arousals, and waking up in the mornings with acid regurgitation (Clin Gastroenterol Hepatol 2009;7:372–378). The presence of nocturnal heartburn has been linked to impaired quality of life, more severe GERD symptoms, and reduction of work productivity (Value Health 2002;5:106 –113). Whether nocturnal GERD is associated with insomnia and other sleep disturbances deserves further study. Two articles were published in the September 2009 issue of Clinical Gastroenterology and Hepatology describing effects of GERD on sleep and associated outcomes (Clin Gastroenterol Hepatol 2009;7:953–959; Clin Gastroenterol Hepatol 2009;7:960 –965). In the first article by Mody et al, data were obtained from the 2006 US National Health and Wellness Survey, an annual cross-sectional study of a variety of health outcomes. Patients who reported GERD ⱖ2 times during the past month were classified as adults with GERD, whereas controls were adults not reporting GERD during the past month. Subjects were further classified as having daytime GERD, nighttime heartburn, or both. Sleep difficulties were defined independently from GERD symptoms and were characterized as either insomnia or sleep difficulty during the past 12 months. Patients reporting symptoms at least once a month were included and the response set included difficulty falling asleep, difficulty staying asleep, waking during the night and inability to get back to sleep, waking several times during the night, and waking up too early. Work productivity was assessed using the Work Productivity and Activity Impairment questionnaire. Separate logistic regression models were developed to determine the independent effects of GERD and time of symptoms on sleep difficulties. Demographics, physical and psychiatric comorbidity, body mass index (BMI), and smoking were included as potential confounders. Of the 62,833 respondents to the 2006 survey, 11,685 (19%) were classified as experiencing GERD, and 29,634 (47%) did not have GERD. Compared with patients without GERD, those patients with GERD were more likely to be female, Caucasian, married or living with a partner, not possessing a college degree, obese, with psychiatric comorbidity, and current smokers (P ⬍ .05 for all parameters). Eighty-nine percent of the GERD respondents experienced nocturnal GERD (with or without daytime symptoms); only 11% experienced daytime-only symptoms. Patients with nighttime GERD were significantly younger, less likely to have a college degree, and more likely to have an elevated BMI (30.3 vs 29; P ⬍ .001), psychiatric comorbidity, tobacco consumption, and use

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prescription and over-the-counter medications compared with patients with daytime-only GERD patients. Of the respondents with GERD, 7965 (68%) experienced sleep difficulties and those patients again were more likely to be obese, female, younger, non-white, and smokers. Descriptive analyses demonstrated that GERD subjects were significantly more likely to report sleep difficulties including induction and maintenance of sleep compared with subjects without GERD. Adjusting for differences in demographics and comorbid conditions, GERD patients were more than twice as likely to experience sleep difficulties (odds ratio [OR], 2.09) compared with controls, in addition to induction difficulties (OR, 1.75) and difficulties with sleep maintenance through the night (OR, 1.89). GERD patients with nocturnal symptoms were 1.53 times as likely to report sleep difficulties compared with patients with daytime-only GERD. Responders with GERD who reported sleep difficulties also had significantly greater health care resource usage including more emergency room visits, days hospitalized, and outpatient office visits. Associated work impairment included a 30% impairment as a result of presenteeism (reduced function at work) and a 24% work productivity loss overall attributable to GERD. In the second study by Jansson et al performed as a population-based, case-control study in Norway, data were collected via questionnaires and physical examinations as part of the HUNT 2 study, which included 65,333 participants. The presence of severe GERD symptoms was required to classify subjects with heartburn for the analysis. Of the 58,596 persons who responded to the questionnaire, 3153 (5%) reported severe GERD symptoms (of which 95% reported symptoms at least weekly) and were considered to be cases, and 40,210 (69%) reported no heartburn and were considered to be controls. The questionnaires used included items regarding insomnia, sleeplessness, and difficulty with sleep initiation. The ORs estimated from logistic regression were used to assess the association between sleep problems and risk of GERD. The age and gender distributions were similar between the 3,153 cases and 40,210 controls; however, tobacco intake, BMI, and prevalence of sleep problems (insomnia, sleeplessness, and difficulty initiating sleep) were higher among the cases compared with the controls. In the crude unadjusted models and the multivariable models adjusted for age, gender, tobacco intake, BMI, and socioeconomic status, there were positive associations noted between all studied sleep-related variables and severe GERD symptoms. For example, there was a 3.2-fold increased risk of GERD among patients with insomnia (95% confidence interval, 2.7–3.7), a 3.3-fold increased risk among patients reporting sleeplessness that occurred “very often,” and a 3.1-fold increased risk of GERD in patients who reported frequent problems falling asleep. The positive associations were attenuated when the models were adjusted for anxiety and depression (eg, the OR

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associated with insomnia decreased from 3.2 to 2.2) and further when adjusted for other comorbid conditions (including myocardial infarction, angina pectoris, stroke, nausea, diarrhea, and constipation), but remained significant nonetheless. Comment. The presence of abnormal esophageal pH exposure in the supine position has been associated with complications of GERD, including erosive esophagitis and Barrett’s esophagus (Aliment Pharmacol Ther 2003;18:1091–1098; J Gastroenterol Hepatol 2001;16:1191–1196; Aliment Pharmacol Ther 2004;20:637–643). It is now recognized that a majority of GERD patients experience nocturnal symptoms. In a 2003 study of 1000 GERD patients, 78% reported nocturnal heartburn, and two thirds of the patients experiencing heartburn ⱖ3 times per week reported associated sleep disturbances (Am J Gastroenterol 2003;98:1487–1493). The presence of nighttime heartburn has included the following terms per a recent systematic literature review: (1) Nighttime awakening by heartburn; (2) being awakened at night by coughing or choking because of fluid, an acid or bitter taste, or food in the throat; (3) heartburn that occurs when lying down to sleep at night; and (4) waking up in the morning with heartburn and/or acid regurgitation. Using these definitions, the prevalence of nocturnal GERD was found to be approximately 54% ⫾ 22% (range, 25%–79%; Clin Gastroenterol Hepatol 2009;7: 372–378). Both of these large, population-based, case-control studies confirm a relationship between severe GERD and sleep disturbances. Potential weaknesses of these studies include the fact that responses were based on self-reported severity of heartburn and/or acid regurgitation and not chart reviews, physicians’ diagnoses, or pH studies. There have been prior studies in the literature confirming this association. In a prospective study of 48 subjects with pathologic reflux documented by ambulatory pH monitoring, disorders of initiating and maintaining sleep were found to be positively associated with increasing severity of the heartburn symptom index. Patients with poorer sleep quality were found to have longer reflux events. More perceived awakenings correlated with the number and duration of supine reflux events (Aliment Pharmacol Ther 2007;26:41– 48). In another study of 1,002 GERD patients, patients reporting GERD symptoms ⱖ2 nights in the previous week had a significantly greater number of sleep disturbances and more severe GERD symptoms in addition to lower Short Form-36 scores and more work loss compared with GERD patients without nocturnal symptoms (Aliment Pharmacol Ther 2007;25:487–500). It is unclear whether the relationship between nighttime GERD and sleep problems is unidirectional or bidirectional. The state of sleep is associated with a decrease in swallowing, subsequent reduced amounts of salivary bicarbonate, and reduced esophageal peristalsis and gravity, all factors that can increase the severity and amount of refluxate. Sleep

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deprivation has been associated with increased perception and reported GERD symptoms (Gastroenterology 2007; 133:1787–1795). GERD events have been shown to be associated with multiple, brief arousals that lead to sleep fragmentation; in 1 study, the arousals usually lasted 30 seconds, occurred during stage 2 of sleep, and rarely during the rapid-eye movement period (Neurogastroenterol Motil 2007;19:709 –715). Patients who are awakened by nocturnal GERD events are able to mount defenses, including the usage of antireflux therapy, increased initiation of swallows, and increased peristalsis, whereas those patients who remain asleep during episodes may experience more mucosal injury (Curr Gastroenterol Rep 2009;11:202–208). The relationship between GERD and sleep disorders may be confounded by the presence of other commonly associated comorbid conditions, including obesity, and cardiovascular and pulmonary diseases, in addition to medications used to treat these disorders, such as calcium channel blockers or benzodiazepines, which can reduce lower esophageal sphincter pressure (Ann Intern Med 2000;133:165–175). However, the GERD–sleep relationship persisted in logistic regression models that adjusted for the presence of these comorbid conditions. In summary, although GERD has been linked to the presence of Barrett’s esophagus, esophageal adenocarcinoma, asthma, and other extra-esophageal disorders, we have evidence that sleep disorders and poor work performance should be added to the GERD associations list. To close with a modification of that famous nursery rhyme: “Good night, sleep tight, Don’t let the acid bite . . . . And if they do, take an antacid or 2, and see your MD to sleep the night thru!” LAUREN B. GERSON, MD, MSC Associate Professor of Medicine Stanford University School of Medicine Stanford, California

SWITCHING ON THE LIGHT TO SEE MORE DISEASE Urano Y, Asanuma D, Hama Y, et al. (Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan). Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes. Nat Med 2009;15:104 –109. In this paper, Urano et al demonstrate a new class of molecular probe based on a fluorescent small molecule that becomes “activated” after becoming internalized into cells for use in performing in vivo imaging. This probe is developed from an aniline moiety that reacts with protons to produce light-induced electron transfer in a boron-dipyrromethene (BODIPY) fluorophore. Spontaneous relaxation of delocalized electrons to lower energy levels results in fluorescence emission at wavelengths ⬎530 nm, a regime that can be distinguished

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from autofluorescence background in tissue. This small molecule produces undetectable fluorescence at a physiologic pH of 7.4. The probes are “switched on” inside the cell when they encounter an abrupt reduction in pH after being taken up by lysosomes. This novel imaging agent is used with a targeting agent, such as trastuzumab, an antibody to HER2, a growth factor receptor that is overexpressed on the cell surface of many cancers, including breast, esophagus, and lung. Targeting occurs when the Fab component of the probe binds to the HER2 receptor and initiates dimerization. The probe–receptor complex then becomes phosphorylated, internalized by endocytosis, and scavenged by lysosomes. The reduction in pH to a value between 5 and 6 results in the probe releasing an intense fluorescence signal. Furthermore, only live cancer cells are visualized because the low pH in lysosomes requires active proton pumps to maintain an acidic environment. This novel probe is shown to have high specificity for NIH3T3 cells and lung tumors that over-express HER2. In addition, activation of the probe after it reaches inside the cell rather than when it is in the extracellular space results in a very high target-to-background ratio. This targeted imaging concept can be generalized to the detection of other over-expressed cell surface receptors specific to cancer that results in cellular internalization. Comment. Molecular imaging represents a new frontier in medicine, and this shift in paradigm is making rapid inroads into the field of gastroenterology (Gastroenterology 2010;138:435– 446). Currently, diagnostic decisions are made during endoscopy based on observing structural changes and identifying anatomic landmarks. Instead, molecular imaging provides information about diseased tissue based on visualizing functional properties and protein expression, including important mechanisms that drive the progression of disease, such as the up-regulation of growth factors, activity of proteolytic enzymes, and expression of cell adhesion molecules. Although advances in technology have greatly improved the imaging performance of endoscopes over the past decade, the resolution of these instruments are limited by the optics and will never be sufficient to directly observe the molecular changes associated with a number of diseases. Thus, visualizing the molecular expression pattern of cells and tissues requires the use of exogenous probes. Most probes used in molecular imaging are attached to a label that is “always on,” and any nonspecific binding can result in a reduction in image contrast. In this paper, Urano et al describe the development of a novel class of molecular probe that binds to cancer-specific receptors, enters the cell, and becomes activated by a reduction in pH. In other words, this probe has a label that is “off” in the tissue microenvironment and becomes switched “on” only after entering a diseased cell to reveal its location. The release of fluorescence produces a high optical con-