Page 72 – Practical Gastro

Lisa B. Malter

The incidence of pediatric-onset inflammatory bowel disease is rising. As this growing population nears adulthood, they are faced with transition of care (TOC) to adult gastroenterologists. This critical transition period has been studied in pediatric patients with chronic medical conditions and several core conditions for successful transition have been identified. In this paper we apply Lugasi’s conditions for successful transition of care specifically to patients with inflammatory bowel disease and suggest a blueprint for a successful TOC process.

Joseph Kingsbery1 Martin J. Wolff¹,² Nancy McGreal³ Lisa B. Malter^1,2 ¹New York University School of Medicine, Department of Internal Medicine, ²New York University School of Medicine, Division of Gastroenterology, New York, NY; ³Duke University Medical Center, Divisions of Adult and Pediatric Gastroenterology, Durham, NC

INTRODUCTION

Transition of care, recently defined as the lengthy process of preparing the adolescent for a life as an adult and receiving care from adult health care providers, is a pivotal point in an adolescent’s life.¹ It is essential that this process result in uninterrupted care, but frequently there are barriers to a successful transition. Patients and their families are often hesitant to leave their pediatric caregivers, and do not fully understand the meaning of – and reason for – transitioning to adult-centered care (ACC). Despite the increasing emphasis placed on this process, transitioning care often remains a stressful time for pediatric patients and their families.^2,3,4 To address these concerns, in 2010 Lugasi et al. performed a metasummary of 46 qualitative and descriptive quantitative studies involving adolescents with chronic medical illness before and/or after their transfer to ACC. This comprehensive metasummary which included adolescents with cystic fibrosis, congenital heart disease, sickle cell disease, solid organ transplant and diabetes identified 5 core conditions for a successful transition process. In this article we have adapted these “core” conditions to the adolescent population with inflammatory bowel disease (IBD).

Core Conditions

I. Meaning of transition
II. Expectations
III. Level of patient’s knowledge/skills
IV. Planning/Timing
V. Environment

I. Meaning of Transition

Transitioning from child-centered care (CCC) to ACC is an understandably stressful time for pediatric patients and their families. Often when the subject of transitioning care is broached, the initial fear of patients and parents is that of abandonment.^2,3,4,5,6,7 It is important to elicit the main concerns that patients and families have about transitioning to ACC, gauge their understanding of the reason for transitioning care, and to highlight the benefits of transitioning care (Table I).

For parents transition from CCC to ACC reduces their authority in their young adult’s health care. Parents who have been involved in all treatment decisions must relinquish these responsibilities to their children and trust that they make well-informed long term decisions.³ This new onus is daunting to the patient, who must now assume responsibility for all aspects of their own healthcare, inform themselves of a new healthcare system and redefine their role in the self-management of their condition.⁸

This shift in responsibility may be anxiety- provoking for the parent and patient. The literature has identified certain aspects of transitioning care that pediatric patients are particularly interested in, which affords an opportunity to advocate for ACC.

Perhaps the most consistent theme among transition- aged patients is their preference for being treated like adults.^4,5,9 Transition aged patients described CCC as patronizing.⁴ They prefer the medical staff to address them as opposed to their parents. Despite their initial anxiety, adolescents appreciate taking responsibility for their own care and gain self-esteem and confidence from the transition.⁴ In the “patronizing” setting of CCC it is easy to forget the patient’s social environment and the decisions they are making without the assistance of their parents on a daily basis. In CCC, pediatric gastroenterologists do address the impact of tobacco use, drug use, and sex – as well as less hot-button topics such as sun exposure and stress – on their disease. Adult gastroenterologists reported that their newly transitioned patients were not sufficiently privy to these topics and transition-aged patients reported that they would like more information on these topics.^6,9

In counseling patients and families about transitioning to ACC, it is important to acknowledge and validate their concerns to ensure that transitioning care is not construed as abandonment by their pediatric care team. Instead, the pediatric provider should convey that transitioning care is an involved and lengthy process in which they will be educated and ushered toward ACC, as well as highlight the benefits of transitioning: engendering autonomy, responsibility and self-management skills.

II. Expectations

Pediatric patients and their families frequently have preconceptions about ACC (table II). This section describes the preconceptions that pediatric patients and their families have toward ACC and provides a general outline of the important differences between CCC and ACC that patients should be informed of in advance of initiating the transition process.

Lugasi et al. describe that pediatric patients and family members generally think of ACC as cold, impersonal, and business-like, whereas CCC is familiar and friendly. Escher et al. describes the perceived differences between pediatric and adult gastroenterologists similarly.^2,3 Though these differences are subjective and difficult to investigate, pediatric care for IBD tends to be provided at tertiary care centers with a multidisciplinary team in a family- focused arena, whereas adult care is often provided by a single doctor at a local hospital and is patient focused.¹¹ Newly transitioned patients in a flare of their disease usually will be admitted to a general medicine floor at a local hospital, as opposed to the familiar setting of a pediatric unit.

Pediatric practitioners focus on physical, developmental, and psychosocial milestones of their patients with IBD. The dynamic nature of IBD as well as medication side effects during critical stages of growth and development often result in failure to meet these milestones, and pediatric practitioners are keenly aware of this.¹³ Puberty is sometimes delayed due to malnutrition, and psychosocially patients suffer as they miss school during flares and commonly struggle with self-esteem and identity issues.¹³ Pediatric practitioners aim to alter the early disease course in their patients to minimize long-term sequelae. Adult practitioners also aim to minimize disease flares, but the focus of care begins to shift toward malignancy surveillance, new drugs/treatments, and long-term effects of IBD and IBD treatment, as well as family planning.³

Patients and families develop expectations of endoscopy, radiation exposure and treatment of IBD based on the care they have received in CCC, though they should be made aware of potential changes to expect. Frequent endoscopic surveillance is an important aspect of ACC. Endoscopy is a means of monitoring for malignancy, evaluate response to therapy and predict future risk of recurrence. Endoscopies are more frequent in ACC and performed under moderate sedation, whereas in CCC endoscopy is usually performed under deep sedation or monitored anesthesia care. This change alone may cause anxiety in a transition-aged patient, and therefore it is important for patients to be aware of this difference.

Children are considerably more sensitive to radiation than adults. A study from Columbia University in 2008 showed that earlier exposure to radiation was associated with a higher risk of developing cancer later in life. A study from Great Britain in 2012 showed a positive association between radiation dose from childhood CT scans and the subsequent development of leukemia.^16,17 At the University of Michigan in 2013, pediatric patients with IBD had undergone 1.08 CT scans in their lifetime.¹⁸ In contrast, radiation exposure amongst all-comers with IBD in Ireland between 1999 and 2009 showed a trend toward more radiation exposure on over a ten-year period in adult compared with pediatric populations.¹⁹ These trends have been reproduced in studies of adult patients with IBD in Alberta, Canada,²⁰ as well as a study of lifetime radiation exposure in adult IBD patients in the UK.²¹ There is significant variation in resource utilization depending on the local patterns of practice, but there is an overall trend toward significantly more diagnostic radiation in adult patients with IBD. Transition-aged patients must be made aware of the long-term risks associated with exposure to radiation during CCC and also of the trend toward more radiation in ACC.

Patients who are stable on certain drug regimens in CCC may be asked to change medications by their adult gastroenterologist, potentially adding uncertainty while transitioning care. Newly transitioned patients, when compared with their pre-transition counterparts, have poorer rates of medicine compliance, which may be an indication of discomfort and unfamiliarity with new treatment regimens.12 Adult gastroenterologists treating IBD typically present several therapeutic options to the patient in the hopes at arriving at a shared decision. In CCC the patient’s parent or guardian is much more likely to be the decision-making party regarding a particular therapeutic venture. Additionally, pre-conceptive counseling and more aggressive medical or surgical management of longstanding disease are more common in ACC. In ACC patients are expected to play a more active role in their management and often require re-education on the nature of their disease, the risks and benefits of their therapy, and counseling as to the possible consequences of medical non-compliance.

Pediatric patients and family members often have preconceived notions about ACC and the changes to expect. It is important to address these notions about the general environment of ACC, and to acknowledge that there are significant changes to be expected simply by transitioning from CCC to ACC. Speaking openly with patients and family members about these changes will help to reduce uncertainty during and after transition as well as to ensure that their expectations of transitioning care are realistic.

III. Level of Patient’s Knowledge/Skill

In a joint study published by the Journal of Pediatric Gastroenterology and Nutrition (JPGN) in 2008, adult gastroenterologists affiliated with the Crohn’s and Colitis Foundation of America (CCFA) were asked what they expected from young adult patients with IBD entering their care in terms of patient knowledge about their disease.⁶ Among the most important expectations were knowledge of the name, dose and major side effects of the medications at the time of transition, their medical condition, and an understanding of their disease course and prognosis. Adult gastroenterologists routinely reported that these expectations were often unmet upon patient transition into their care.

The JPGN and adult gastroenterologists affiliated with the CCFA recommend early and repetitive teaching of these basic concepts. There are checklists based on chronological age of their patients for age-appropriate knowledge of their disease.²³ Readiness assessments based on disease knowledge such as “IBD yourself” ,¹⁴ and “MyHealth Passport for IBD”¹⁸ have been devised but have not yet been validated for assessing readiness for transition. The Social-Ecological Model of Adolescent and Young Adult Readiness to Transition (SMART) is a more comprehensive readiness assessment tool that highlights the importance of patient, parent and provider components to a successful transition.^24,25

These assessment tools are limited and knowledge alone is not sufficient. Fishman et al. suggest that self- efficacy – an individual’s mental or cognitive state based on past or present experience determines his/her ability to organize and implement a pattern of behavior necessary for health promotion – which correlates better than knowledge alone.^14,15 Similarly, in a recent study, healthcare providers caring for adolescents with IBD identified the patient’s developmental maturity as one of the greatest predictors of transition success, and identified difficulties with abstract reasoning as predictive of a failed transition. Patients have difficulty understanding that absence of symptoms may not correlate to disease activity emphasizing the need to take medications despite feeling “well”. ²²

A patient’s knowledge of their disease and medications, as well as evaluation of a patient’s social understanding and self-advocacy would best predict a patient’s readiness for transition and determining the proper timing for transition.

IV. Planning/Timing

Transitioning to ACC must be broached early in the course of a young patient’s chronic illness. However, there is no consensus on the exact timing of transfer of care.⁹

The age at which transfer must occur has varied from country to country based upon age. In the UK and France, the legal age limit for pediatric medical care is 18 years of age, whereas in the USA it is 21 years. In the UK, patients with cystic fibrosis and their parents reported frustration at the inflexibility of the legislatively determined age of transition.¹ Since the legal age of transfer in the USA is 21, the transition timeline must not follow as “rigid” of a protocol as elsewhere.

The exact timing of transfer must be tailored to the emotional and cognitive competency level of the patient during a time of medical stability.⁶ Transfer should occur at a time of relative disease quiescence; active flares are contraindications to transitioning care. However, there is debate about the timing of transfer with regards to social stability.

Many patients that are “transition-aged” or otherwise deemed “ready” for transition are commonly 16 to 19 years old. Transferring medical care in the setting of other major life changes creates undue stress and be deleterious to the patient’s health.¹¹ On the other hand, pediatric and adult gastroenterologists in the UK agreed that the age of 18 was an ideal time for transfer since 18 marks the end of secondary school and entry into university education or employment.²⁶ Transfer therefore should occur not reflexively at a specified chronological age, but rather be assessed on a case-by- case basis (Figure 2).

V. Environment

Appropriate resources are integral to a successful transition environment. Currently there is no standardized transition of care protocol in the US since transition programs are highly variable. Transition preparation ranges from brief educational sessions to more extensive visits with adult and pediatric gastroenterologists and a dedicated nurse or social worker to facilitate transition.⁸ Most important in transitioning care is the joint visit with the pediatric and adult gastroenterologist.⁷ These joint visits engender a sense of continuity and security with their new provider. Patients and family members surveyed after a joint meeting with their former and future provider felt that the visit was useful in terms of establishing confidence in the new physician.⁷

As awareness of this critical transition period becomes more widespread, programs have helped ease the psychosocial stress that accompanies growing up with a chronic medical illness. At Duke University, the Adolescents Transitioning to Leadership and Success program (ATLAS) pairs college students living with a chronic disease with children also coping with an illness. The children and their mentors discuss issues pertinent to living with a chronic disease, how it may influence relationships with their family, their peers, as well as illness-related experiences.²⁷ Children are paired with an empathetic friend and are equipped with a strong support system. Doctors, nurses and social workers help assist them in navigating a complex medical system.

In many pediatric practices it is not feasible to orchestrate a multidisciplinary transition process incorporating transition nurses, psychologists/ psychiatrists and social workers. However, providing patients and families with information about available support programs and arranging joint meetings between pediatric and adult gastroenterologists positively impact the transition experience.^15,21,28

CONCLUSION

Transitioning from CCC to ACC is a critical event in a young person’s life. Pediatric practitioners have recognized the importance of this process but this process is not as yet optimized. The discussion about transitioning care must begin early in the pre-adolescent course of disease. The healthcare provider should validate and address the patient’s and family’s concerns about transition while highlighting the benefits of this transition. The pediatric care provider must educate the patient about their disease, the natural history of their illness and what to expect during and after the
transition process. Joint meetings among pediatric and adult gastroenterologists, family and patient builds trust between patient and providers. By satisfying the 5 core conditions of TOC set forth by Lugasi, a
potentially tumultuous time in a young patient’s life can be translated into an empowering event guiding their future health care.

LIVER DISORDERS, SERIES #2

An Overview of Hepatic Fibrogenesis

George Tan,

Duminda Suraweera,

Gaurav Singhvi

Hepatic fibrosis is a dynamic process that results from chronic liver injury. While the common mechanism involves hepatocyte injury, inflammation and eventual distortion of hepatic architecture, each etiology has a unique pathway. In this review we discuss major causes such as alcoholic liver disease, non-alcoholic fatty liver disease, chronic viral hepatitis and cholestatic liver disease. In addition we review current diagnostic modalities and provide general management principles.

George Tan MD, MBA, Kaiser Permanente, Daly City, Duminda Suraweera, MD, Olive View-UCLA Medical Center, Gaurav Singhvi, MD, UCLA, David Geffen School of Medicine

Hepatic fibrosis is a dynamic process that results from chronic liver injury. It kills over one million people a year worldwide and has many etiologies. While the common mechanism involves hepatocyte injury, inflammation and eventual distortion of hepatic architecture, each etiology has a unique pathway. In this review we discuss major causes such as alcoholic liver disease, non-alcoholic fatty liver disease, chronic viral hepatitis and cholestatic liver disease. In addition we review current diagnostic modalities and provide general management principles.

Hepatic fibrosis is a major public health problem that carries with it a high morbidity and mortality. It results from the wound-healing response to chronic liver injury and can result in cirrhosis and hepatocellular carcinoma (HCC).^1,2 Common causes include alcoholic liver disease, non-alcoholic liver disease (NAFLD), chronic viral hepatitis, and cholestatic liver disease. Other less common etiologies include autoimmune hepatitis, Wilson’s disease, hemochromatosis, and schistosomiasis (See Table 1).^2-7 Regardless of etiology, the end result of chronic hepatic injury is a fibrotic liver with hepatic stellate cells playing a pivotal role in the formation of hepatic fibrosis.^8-10

Fibrogenesis begins with hepatocyte injury and inflammation that activates hepatic stellate cells (HSC). These activated HSCs then transdifferentiate into myofibroblasts, which results in an increased extracellular matrix (ECM) deposition in the liver leading to fibrosis.^2,11-13 This is shown pictorially in Figure 1. Bone marrow derived fibrocytes and epithelial- mesenchymal transition (EMT) from hepatocytes and cholangiocytes also contribute to fibrosis. Several fibrogenic mediators get recruited in the inflammatory cascade including transforming growth factor (TGF- beta), platelet derived growth factor (PDGF), insulin- like growth factor I (IGF-I), endothelin-I (ET-I), and reactive oxygen species (ROS).^13,14 Repeated hepatic injury results in this proinflammatory microenvironment and leads to liver fibrosis, cirrhosis, and the development of HCC. Early intervention can lead to the reversal of hepatic fibrogenesis.¹⁴

Alcoholic Liver Disease

Alcoholic liver disease (ALD) is due to chronic and excessive alcohol consumption and is a leading cause of liver disease worldwide.¹⁵ In fact, ALD is the third highest risk factor for disease and disability globally with nearly 4% of the world’s deaths attributed to alcohol consumption.^16,17 Per the National Institute on Alcohol Abuse and Alcoholism, the 12th leading cause of death in the United States is cirrhosis with 48% of those deaths due to alcohol.¹⁸ Not only is there a high mortality associated with alcohol abuse, but it leads to increased social problems including violence, child neglect and abuse, and absenteeism in the workplace.¹⁶

By definition, ALD can occur when daily alcohol ingestion exceeds 20g in women or 30g in men. This number should not be taken as an absolute threshold as patients vary based on differences in genetic susceptibility and other risk factors.^19,20 Indeed, the spectrum of alcoholic liver disease is vast and includes simple steatosis or fatty liver, alcoholic hepatitis, end- stage cirrhosis, and HCC.²¹ Of note, nearly 100% of heavy drinkers have fatty liver, but only 10-20% of them advance to alcoholic hepatitis or obtain the final pathologic changes of ALD associated fibrosis and cirrhosis.^15,22,23 In ALD-associated fibrosis, the major cell type that contributes to fibrogenesis is the activated hepatic stellate cell. While the underlying mechanism of fibrosis in ALD is very similar to the mechanisms seen in other chronic liver diseases, methionine metabolism abnormalities, hepatocyte apoptosis, oxidative stress, and endotoxin lipopolysaccharides which activate Kupffer cells may play special roles in ALD fibrosis.^16,22 In addition, emerging mechanisms underlying hepatic fibrogenesis in ALD include lipogenesis, cannabinoid receptor activation, and IL-1 signaling.^11,16

Non-alcoholic Fatty Liver Disease (NAFLD)

As opposed to ALD, non-alcoholic fatty liver disease (NAFLD) occurs in the absence of chronic alcohol consumption (less than 20g of pure alcohol/day for women and less than 30g of pure alcohol/day for men) or other liver diseases and has emerged as the most common chronic liver disease in Western countries.^24-26 Obesity, unhealthy diet, sedentary lifestyle and genetic predisposition are all risk factors associated with the development of NAFLD. Higher rates of insulin resistance, diabetes mellitus, hypertension, dyslipidemia and the metabolic syndrome are associated with this disorder.²⁷ In fact, excessive food intake, especially high fructose corn syrup and saturated fats have been shown in numerous studies to contribute to the development of NAFLD.²⁸ NAFLD is thought to affect 30% of the general adult population and 70-80% of patients that are diabetic or obese.²⁹ Furthermore, the impact of NAFLD on society is significant since it is estimated that NAFLD increases healthcare costs by 26% and will be the leading cause of liver transplantation by 2020.²⁵

NAFLD encompasses two clinicopathological entities that range from simple steatosis to non-alcoholic steatohepatitis (NASH). Simple steatosis accounts for 80-90% of NAFLD cases and is characterized by an excessive amount of fat in the liver, and is mostly benign and non-progressive. NASH constitutes the remaining 10-20% of NAFLD cases and is characterized by steatosis coupled with inflammation and fibrosis, and can progress to cirrhosis and HCC.¹⁹ The development of NASH is often described by the “two-hit” mechanism with the “first hit” being the development of steatosis and the “second-hit” involving environmental factors such as oxidative stress and proinflammatory cytokines coupled with genetic factors leading to hepatic injury.^29-31 Once patients develop NASH, approximately one-third go on to develop hepatic fibrosis.³² In addition to obesity and sedentary lifestyle, NAFLD increases with age, central obesity, and has a strong genetic predisposition with several affiliated gene polymorphisms.³³ The renin- angiotensin system (RAS) seems to play an important role in the development of NASH, as does the bacterial endotoxin within the gut-liver axis.^34-36

Chronic Viral Hepatitis

Hepatitis B (HBV) and Hepatitis C (HCV) viruses are leading causes of chronic liver disease. It is estimated that over two billion people have been infected with HBV, of which over 300 million are chronic carriers.³⁷ On average only about 10% of patients with HBV progress to chronic disease.³⁸ Of the chronic HBV patients, about 20% will develop liver cirrhosis.³⁹ The risk of HCC is about 100 times greater than the general population.⁴⁰ HBV promotes liver fibrosis via expression of the hepatitis B virus X (HBx) protein. This particular protein increases the expression of type 1 collagen, TGF-beta and increases the cell proliferation rate.⁴¹ Studies have also shown that the HBx protein accelerates proliferation of HSC cells thereby facilitating liver fibrosis.⁴²

It is estimated that over 185 million people worldwide are infected with HCV. Eighty percent of those infected progress to chronic infection.⁴⁴ Furthermore 20% of patients with chronic HCV will develop cirrhosis within 25 years and 25% of these patients develop HCC or decompensated liver disease.⁴⁵ HCV is the primary cause of liver transplantation in the United States.⁴⁶ There are a total of 6 identified genotypes of HCV. In the United States, 97% of all infections are from genotype 1, genotype 2 and genotype 3.⁴⁷ The inflammatory cascade that leads to cirrhosis is likely initiated by HCV core and NS3 proteins.⁴⁸ The subsequent cytokine and chemokines generated lead to increased recruitment of inflammatory cells such as macrophages, dendritic cells, natural killer cells and cytotoxic T cells. HCV activated Kupffer cells release ROS and other proinflammatory mediators thus leading to the common hepatic fibrosis pathway.

Cholestatic Liver Disease

Cholestatic liver disease primarily results from an impairment of hepatobiliary production and excretion of bile. Cholangiocytes and hepatocytes proliferate in response to injury leading to biliary damage, periductular fibrosis and cirrhosis.⁴⁹ The two most common causes of chronic cholestatic liver disease are primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). PBC is a progressive autoimmune condition with an incidence of approximately 100 cases per million people.⁵⁰ It primarily affects women in the fifth decade of life and is associated with an increased incidence of HCC.^51,52 The pathogenesis of PBC is an autoimmune mediated process and can be divided into several stages. The initial stage involves infiltration of the portal triad by lymphocytes, plasma cells and eosinophil granulocytes.⁵³ As PBC progresses fibrotic septa extend from the portal tracts and link them together. This is called “bridging fibrosis” and is the characteristic finding in PBC.⁵³ Eventually the hepatic architecture becomes distorted leading to cirrhosis and the formation of regenerative nodules. Diagnosis of PBC is made when 2 of the following 3 criteria are met: presence of anti-mitochondrial antibodies, elevation serum alkaline phosphatese > 1.5 times the upper limit of normal and consistent histologic findings on liver biopsy.⁵¹

Primary sclerosing cholangitis (PSC) is a progressive inflammation and fibrosis of the intra and extra hepatic bile ducts. It is estimated that 1 in 100,000 people will be affected. Most are males and the median age of diagnosis is 40.⁵⁴ Of note, 75% of patients with PSC have inflammatory bowel disease (IBD).⁵⁵ PSC leads to cholestasis, progressive hepatic fibrosis and decompensated cirrhosis over the course of 10-15 years.⁵⁶ PSC increases the risk for hepatobiliary and colorectal cancer.⁵⁷ The pathogenesis of PSC is poorly understood. It is believed to be a complex immune mediated disease. There is likely a genetic predisposition that is subsequently triggered by an environmental component.⁵⁸ Diagnosis is primarily made through liver tests and imaging. ⁵⁹ No auto-antibody has been found that is specific to PSC.⁶⁰ Cholangiography shows short, multifocal, annular strictures alternating with normal and slightly dilated intervening segments leading to the classic “beads-on-a-string” appearance.⁶¹

Diagnosis of Hepatic Fibrogenesis

Liver biopsy with histologic examination has been the gold standard for diagnosis and staging of hepatic fibrogenesis. However several non-invasive methods also are available to assist in diagnosis. Ultrasound (US) is the first modality as it is non-invasive, cost-effective and does not expose patients to radiation. Characteristic findings of cirrhosis on US include a coarse nodular appearance of hepatic parenchyma, hepatomegaly, ascites and caudate lobe atrophy.⁶² Computer tomography (CT) is also a commonly used modality in the evaluation and diagnosis of liver fibrogenesis. CT is believed to have sensitivity of 77.1% and specificity of 67.6%.⁶³ Magnetic resonance imaging (MRI) has been used to quantify fibrosis with a sensitivity of 85% and specificity of 100%.⁶⁴ More recently a new method called transient elastography (TE) has been developed. It relies on the principle of shear waves. A transducer emits a 50MHz pressure wave through the liver and the resulting shear wave is measured by US. The shear wave velocity is correlated with liver stiffness, which in turn estimates liver fibrosis. For the diagnosis of cirrhosis, TE has a sensitivity of 83% and a specificity of 89%.⁶⁵ Several serum biomarkers are also available in the non-invasive diagnosis of liver fibrogenesis. Often these biomarkers are described as direct, which reflect extracellular turnover, or indirect, which reflect overall liver function. AST-Platelet Ratio Index (APRI) is a common biomarker used in the estimation of fibrosis. A higher APRI value is indicative of worsening fibrosis. APRI score of 1.0 had a sensitivity and specificity of 76% and 72% respectively for the prediction of cirrhosis.⁶⁶ Fibrotest is a another biomarker panel that uses alpha-2 macroglobulin, haptoglobin, total bilirubin, apolipoprotein-A, GGT, age and gender to calculate score between 0.0 to 1.0, with 1.0 meaning significant fibrosis.⁶⁷ Direct biomarkers include hyaluronic acid (HA), amino terminal of serum procollagen III peptide (PIIINP), tissue inhibitors of metallopreinase-1 (TIMP- 1). HA is a glycosaminoglycan found in the extracellular matrix. It enters circulation during matrix turnover and is degraded in the liver through hepatic endothelial cells. High levels of HA can be due to increased matrix turnover or reduced clearance. PIINP is a marker of collagen turnover with increased levels correlated with tissue repair and fibrosis. PIINP has been found to accurately predict fibrosis in the setting of PBC, NAFLD and viral hepatitis.^68-71 TIMP-1 is an enzyme that inactivates chollagenase with levels found to be higher in patients with liver fibrogenesis.⁷² Enhanced liver fibrosis (ELF) test uses a combination of PIIINP, HA and TIMP-1. It has been found to have a sensitivity and specificity of 90% and 69% respectively in those with chronic liver disease.⁷³

Recommendations for the Primary Care Provider

From this overview on the basics of hepatic fibrogenesis, several recommendations can be made for the primary care physician when co-managing these patients (see table 2). First should be the removal of any liver injury- causing factors such as viral agents, alcohol, toxins and medications. This not only halts the progression of hepatic fibrosis, but it often leads to its regression.³ Alcohol abstinence is the most effective treatment for ALD, and this should be enforced at every encounter as it may completely reverse steatosis.^16,17 Viral hepatitis screening, vaccination, and treatment is paramount since even cirrhosis has been reversed in several patients, when HBV and HCV have been treated.⁹

When it comes to NAFLD, generalists can screen for risk factors of the metabolic syndrome by measuring waist circumference, obtaining body mass index (BMI), and screening for insulin resistance and dyslipidemia.³³ Obesity, especially central obesity, is a major risk factor for NASH and BMI is a good marker for predicting NAFLD.^74,75 Counseling on regular moderate physical activity for 3 to 5 days per week should be recommended.^27,76,77 In addition, high calorie diets that are rich in trans/saturated fat and high fructose-sweetened beverages should be avoided, while low calorie diets supplemented with monounsaturated fatty acids, omega-3 fatty acids, and probiotics should be encouraged.⁷⁸ 6-gingerol, a key component of ginger, and curcumin, a bioactive component in turmeric have both been shown to have anti-inflammatory and antioxidant properties that may be hepatoprotective.^79,80 Pharmacotherapy should include an angiotenstin receptor blocker (ARB) for hypertension, statin therapy, with close monitoring of liver tests, for dyslipidemia, and metformin or pioglitazone for diabetes.^24,25,34 Vitamin E and pentoxifylline may have a role for NASH, but need further study.²⁰

The advent of antiviral therapy has revolutionized the management of viral hepatitis. In managing HBV there is now strong evidence that antiretroviral therapy lowers disease progression and the incidence of HCC in patients with high serum HBV DNA levels and advanced liver disease.⁸¹ Recently several oral direct acting antiviral medications that target different stages of the HCV life cycle have become available. Treatment using these agents is genotype specific. Treatment of HCV in HIV coinfected patients can be a challenge as there are extensive drug interactions with HIV antiretrovirals.^82,83

Treatment of PBC and PSC are limited. For patients with PBC, treatment with ursodeoxycholic acid (ursodiol) has been shown to delay progression of hepatic fibrosis.⁸⁴ Other medications such as colchicine and methotrexate may be effective.^85,86 There are no medical therapies that alter the natural course of PSC. Liver transplant is the only definitive treatment for patients with advanced disease. Overall prognosis in PSC remains poor with a 12 year median time from diagnosis to death or liver transplant.87 Acute decompensation can occur in patients with PSC due to sudden obstruction of the hepatobiliary system. Relieving obstruction can improve outcomes.

CONCLUSION

Hepatic fibrogenesis is a dynamic process with a multitude of etiologies. In the United States there are over 100,000 hospitalization and 36,000 deaths from liver disease.88 Etiologies include ALD, NAFLD, viral hepatitis and cholestatic liver disease. Diagnostic modalities ranging from invasive liver biopsy to non- invasive imaging and serum markers provide physicians with an array of options for further evaluation of suspected liver disease. In addition to the etiology specific treatments available, general measures can be taken to prevent and arrest the progression of hepatic fibrogenesis.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #140

Guide to Front Line Drugs Used in the Treatment of Short Bowel Syndrome

Lingtak-Neander Chan,

John K. DiBaise,

Carol Rees Parrish

In patients with short bowel syndrome (SBS), malabsorption of drugs is an important consideration, particularly if the expected clinical response to a medication is not attained. Factors include length, location and health of the remaining bowel, the form of the medication administered and the site of action of the drug. Part 4B of this 5-part series will focus on conventional pharmacological agents used in the treatment of SBS.

As you may recall from Part IV-A of this series, a 64-year-old woman is hospitalized with hypotension, chronic diarrhea (6-10 per day in the last 4 weeks), fatigue and general malaise. Seven weeks ago, she was hospitalized with acute abdominal pain and severe nausea. Further work-up revealed acutemesenteric infarction due to a superior mesenteric artery thrombus and she underwent extensive resection of the ischemic bowel leaving her with about 100 cm of small bowel from the ligament of Treitz anastomosed to the proximal transverse colon. She was discharged from the hospital 2 weeks later on home parenteral nutrition (PN). Her weight is down 6 kg since hospital discharge 5 weeks ago. In addition to PN, she also takes loperamide 2 mg TID as needed (she has not been using it because “it doesn’t help”), cholestyramine 4g BID, mirtazapine 15 mg daily, levothyroxine 0.075 mg daily and oral glutamine 30g daily. Famotidine, 40 mg, has been added to her PN. Stool output, which is watery and without blood, ranges from 2500 to 3000 mL daily. She is not eating much as she is so depressed and uncomfortable and “it just comes right out anyway”. She is afraid to leave her house for fear of “having an accident”. Part 4B of this 5-part series on SBS focuses on conventional anti-motility agents used in the treatment of short bowel syndrome that will allow you to help this woman control her diarrhea and improve her quality of life.

Lingtak-Neander Chan, PharmD, BCNSP, Associate Professor of Pharmacy and Nutritional Sciences, University of Washington, Seattle, WA. John K. DiBaise, MD, Professor of Medicine, Mayo Clinic, Scottsdale, AZ. Carol Rees Parrish MS, RD, Nutrition Support Specialist, University of Virginia Health System Digestive Health Center of Excellence, Charlottesville, VA

INTRODUCTION
Chronic Diarrhea

While gastric hypersecretion is a transient complication in SBS, chronic diarrhea is often a long-term and sometimes quite disabling complication experienced by most patients and requires continued intervention and monitoring. A recent study involving patients with SBS found that chronic, uncontrolled diarrhea has a more negative impact on quality of life than home PN therapy.¹ Therefore, optimizing the antidiarrheal regimen is a critical component in the care for patients with SBS. Established antidiarrheal regimens in the management of SBS are summarized in Table 1.

Antimotility Agents

Since opioid receptors are widely distributed in the GI tract and play a key role in the regulation of GI tract motility, secretion, and sensation,² opioids should be considered the first-line antimotility therapy in the treatment of chronic diarrhea in patients with SBS. Additionally, opioid receptors also regulate chloride secretion and luminal water movement in the colon. Opioid agonists therefore also exert an antisecretory effect on the colon. High-level clinical evidence supporting their use is unavailable in the literature. This absence of evidence, however, is not evidence of lack of clinical utility. The lack of high-level published data can be explained by the fact that these compounds have been available for use for decades and their role in clinical management has generally been accepted. There is also a lack of more established alternative therapy in managing patient’s symptoms. Additionally, there is no financial incentive for drug manufacturers to conduct such clinical trials. Opioid derivatives used as antimotility agents can be loosely categorized as locally-acting agents with low systemic effects (e.g., loperamide, diphenoxylate) and systemic agents (e.g., codeine, morphine).

Loperamide (e.g., Imodium A-D)

Loperamide is one of the most widely used over-the- counter anti-diarrheal drugs. It is a synthetic opioid. With low systemic absorption and poor penetration across the blood-brain barrier, loperamide is a safe antidiarrheal agent with minimal systemic side effects. Its antimotility action is mediated by both binding to opioid receptors in the intestine as well as inhibiting calcium channels and calmodulin in intestinal smooth muscle.3 It also has an antisecretory effect on the colonic epithelial cells.⁴ Since the oral bioavailability is negligible, loperamide is usually well-tolerated; however, factors that alter the pharmacokinetics and pharmacodynamics of loperamide may potentially exacerbate the untoward effects.

In SBS, an initial dose of 4 mg (2 capsules or tablets, or 30 mL) every 6 to 8 hours is recommended. Loperamide should be taken 30 to 60 minutes prior to a meal and again at bedtime. While the maximal recommended daily dose is 16 mg in generally healthy individuals, in the SBS patient, a dose up to 8 mg every 6 hours (32 mg total) may be needed. In patients with inadequate response (continued watery diarrhea in spite of taking 8 to 16 mg per dose; total dose at 32 mg/day or higher), other pharmacotherapeutic approaches, such as narcotics, etc., should be considered.

Diphenoxylate (e.g., Lomotil®) and Difenoxin (Motofen®)

Diphenoxylate is also a synthetic opioid and likely exerts its antimotility effect by binding to the opioid receptors in the intestine. At low doses, diphenoxylate primarily has antimotility effects; however, at high doses (e.g., over 40 mg daily), it produces typical opioid systemic effects such as euphoria and sedation suggesting an increased systemic effect. Difenoxin is an active metabolite of diphenoxylate. It is rapidly and extensively absorbed after oral administration with peak effects occurring within 40 to 60 minutes in most patients. Although commercially available in the U.S., it is less commonly used than diphenoxylate.² To reduce the abuse potential for these drugs, they are formulated with the anticholinergic agent atropine. Excessive use of diphenoxylate/difenoxen-atropine combination can lead to symptoms ranging from unpleasant sensations similar to those with cholinergic discharge, to serious cardiovascular symptoms such as palpitation and tachycardia.

The typical dose for diphenoxylate is two tablets (or 10 mL) four times daily as needed; generally before meals and at bedtime. Although atropine is an anticholinergic agent and may decrease GI secretion, the amount in the combination is too low to cause clinically significant side effects other than acting as a deterrent for opioid abuse.

Given the extensive clinical experience, both loperamide and diphenoxylate can be considered as first-line antimotility agents in SBS. Based upon both the pharmacokinetic and side effect profile, loperamide is usually considered the preferred agent for initial therapy.

Paregoric

Paregoric, USP, also known as camphorated tincture of opium, is an oral liquid that contains 0.4 mg/mL of anhydrous morphine as its main active ingredient. Paregoric also contains glycerin, benzoic acid, and generally 45% alcohol. Although paregoric elixir has been used to manage pain, GI discomfort, and other ailments since the early eighteenth century, its role in the treatment of chronic diarrhea has diminished considerably because of its high potential for addiction and abuse. Drugs with more limited effect on the brain such as loperamide and diphenoxylate are preferred. According to one study, 4 mL of paregoric solution is approximately equipotent to one diphenoxylate/atropine tablet in controlling diarrhea.⁵

Opium tincture

Opium tincture, USP or deodorized tincture of opium typically contains 10 mg/mL of morphine. One of the most dangerous medication errors is the confusion between paregoric (especially if labelled as camphorated tincture of opium) and opium tincture. Given the same volume, there is a 25-fold difference in the amount of opiate extract between these products. If prescribed incorrectly, serious overdosing and fatalities can result. To minimize the risk of medication error, it is helpful to remember that opium tincture should be dispensed and administered with small droppers or oral syringes and each dose should not exceed 1-2 mL, every 6-8 hours when treating diarrhea. Because safer and possibly more effective alternatives such as loperamide are available, both paregoric and opium tincture have very limited role in the management of SBS. See Tables 1 and 2 for clinical considerations and cost when prescribing opium tincture.

Codeine and Morphine

Both codeine and morphine can be used as antimotility and antisecretory agents in patients with SBS as both compounds bind to the opioid receptors in the GI tract leading to decreased GI secretion and increased orocecal transit time. Although codeine has an antidiarrheal effect, about 10% of an administered dose is metabolized by the enzyme CYP2D6 to morphine, a more potent metabolite.^6,7 In patients with decreased CYP2D6 enzyme activity (i.e., poor metabolizers), either from genetics or drug interactions (e.g., CYP2D6 inhibitors such as citalopram, fluoxetine, paroxetine), the antidiarrheal effect of codeine could be reduced compared with patients having normal CYP2D6 activity.⁸ Conversely, DNA variations also occurs in a subgroup of patients resulting in more active CYP2D6 enzyme activities. These “ultra-rapid metabolizers” convert codeine to morphine faster and more completely than in other people and are more likely to have higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in respiratory depression and failure, which may be fatal.

Data from an international clinical pharmacogenetics databank show that 77-92% of the population are phenotypically “normal” CYP2D6 metabolizers. The allele frequency for poor-metabolizer is about 5-10% and ultra-rapid metabolizer between 1-2%.9 Therefore, codeine is generally a safe and effective treatment option for a majority of the patients as long as the dose is initiated cautiously and patient-specific side effects are carefully monitored (e.g., sedation, rash, nausea, respiratory depression). In at-risk patients, such as children, patients with adverse reactions or unpredictable response to codeine previously, or if there is concern about a particular patient’s CYP2D6 phenotype based on his/her clinical response/drug dosing to other CYP2D6 substrates (e.g., tricyclic antidepressants), CYP2D6 genotyping should be performed before drug initiation to optimize the patient’s codeine regimen and minimize serious adverse events.⁷ Genotyping can be performed using tissue samples obtained from either buccal swabs or whole blood samples. Before ordering the test, clinicians should discuss with the laboratory personnel in their institution to ensure that samples are properly collected so the test results can be accurately documented in the patient’s medical record. Pharmacogenetic testing is now covered by most insurance companies.

Since both codeine and morphine are well-absorbed, systemic side effects are the primary concerns when used as antimotility agents. Renal failure can increase the accumulation of morphine and its active metabolites and potentially increases the risk of experiencing systemic side effects; in this situation, start at one-half the usual dose.

Considerations when Using Opioid-based Antidiarrheal Agents

When a patient with SBS (or non-SBS high ostomy output) is showing inadequate response to aggressive dosing of loperamide or diphenoxylate, clinicians often find themselves in a clinical conundrum µ When should a systemic opioid be used? Should I add it to the other antidiarrheal or should I stop the other drug first? Does the bowel anatomy determine whether or which opioid to use? What is the treatment endpoint? Would the use of opioid be in violation of federal regulations? Could drug addiction become a problem for the patient? How much opioid can I prescribe? In the following, we attempt to provide some guidance and clarification on these points.

Threshold to Start Systemic Opioid

There is no established threshold and high quality research is sorely needed to guide practice decisions. Based on the pharmacology and physiology, it is our opinion that starting a systemic opioid drug is reasonable when the following criteria are met:

The patient has received the maximal
recommended doses of the first-line
antimotility agents and:
- Stool output remains over 1500 mL per day, OR
- Recurrent admissions for dehydration with stool/ostomy output < 1500mL, OR
- The reduction of stool output from baseline is less than 50%, OR
- The patient remains dehydrated with persistent orthostatic hypotension, OR
- The patient develops intolerable side effects from the first-line agent(s) that are unrelated to the systemic side effects of narcotics (e.g., bloating), OR
- The total pill count reveals that it is unreasonable to ask the patient to take 16-24 pills to slow their gut, when potentially a single 30 mg tablet of codeine QID will be as effective, or even more so.
The patient cannot tolerate or has developed adverse events from the first-line antimotility agents;
There are no clinical contraindications to using systemic narcotics (e.g., allergic reactions, delirium, underlying respiratory problem such as obstructive sleep apnea); and
The patient has no known history of drug abuse (although this should not be an absolute contraindication; 1-2 septic episodes on PN/IV fluids and the potential for recurrent abuse may be the lesser of evils).

Is there benefit to use both loperamide and systemic narcotics at the same time? What if a patient does not have an ileum µ can loperamide still be utilized?

Opioids interact and regulate the enteric nervous system primarily through 3 different opioid receptors µ, δ, and k receptors. Binding of opioids to these receptors results in a decrease in intestinal motility and secretion. Loperamide is only selective to m opioid receptors. Therefore, the addition of the non-selective agonist, such as morphine, may provide a synergistic effect in reducing GI motility and secretion, especially in patients with insufficient response to loperamide alone. The combined use of loperamide and codeine was demonstrated in a randomized, controlled study to be safe and exert a synergistic effect on ileostomy output.¹⁰ Although animal data have shown that loperamide has a more profound effect in the small intestine than in the colon, it can still be used in patients with a significant portion of the ileum removed because opioid receptors are also present in the colon.^3,11 Loperamide will provide some antisecretory effect and can reduce the frequency and severity of diarrhea.

What is the treatment endpoint and duration of therapy?

The treatment endpoint is patient-specific but should be directed to improving the frequency and severity of diarrhea and preventing dehydration. The patient should be assessed regularly for treatment response and side effects. The goal when using a narcotic agent as an anti-diarrheal is to use the lowest effective dose to achieve the overall therapeutic endpoint. It is reasonable to titrate the narcotic down every few weeks as long as the patient is clinically stable.

What are some of the reasons clinicians give for not using narcotics in the treatment of patients with short bowel syndrome?

Risk of narcotic addiction
- This begs the question, is this risk higher than the risks involved with keeping a patient on PN or IV fluids requiring a central venous catheter? The goal of using any narcotic drug is to use the minimal effective dose and continually reassess the need for this therapy. The risk of causing narcotic addiction in a patient with no history of substance abuse is minimal.

Drug abuse potential
- There is no doubt that a clinician should carefully select the “best” patients to receive narcotic therapy. Patients with active drug seeking or narcotic abuse behavior should generally not be considered appropriate candidates to receive prescription narcotic drugs as antimotility, antidiarrheal agents. At the same time, clinicians must carefully assess whether it is appropriate to discharge a patient with a documented history of narcotic abuse with a central catheter in place even though the intention of the catheter is for IV fluids or PN.
Narcotics require a monthly prescription to be handed directly to the patient. Prescriptions cannot be faxed/mailed directly to the pharmacy.
There are concerns that using high doses of narcotics may result in an audit from the Drug Enforcement Agency (DEA). While it may be easy to support this practice from a busy physician’s office that sees a fair number of SBS patients, it may require the office to be closed down while the audit is completed.

Overall, there is much misconception and lack of understanding among healthcare providers about the use of narcotic agents in the management of chronic diarrhea. Although this indication is an off-label use of narcotic drugs, the rationale is well-supported by science and the efficacy is supported by clinical literature. In the process of evaluating the appropriateness of narcotic therapy, clinicians should follow federal and state regulations, exercise good clinical judgment in patient selection, and implement a patient-specific monitoring plan. Our experience suggests that a carefully executed management plan with low-dose narcotic therapy can reduce PN use and unnecessary hospitalizations.

SUMMARY

Anti-diarrheal agents are part of the cornerstone of
therapy in the treatment of short bowel syndrome. If
not well controlled, not only are hydration and nutrient
utilization at risk, but also overall quality of life is
seriously threatened. It is of particular importance in
the SBS population to consider the site of absorption,
formulation, frequency, and timing of each drug, as well
as cost and availability before it is ordered. Setting and
monitoring endpoints for each intervention (i.e., how
long you will give each intervention time to achieve
efficacy or not), is also fundamental. Keep in mind that
there are only so many hours in the day, and patients
need to fit “life” in between all their medications,
meals/snacks and fluids. When the “Total Pill Count”
of the lesser gut slowing medications exceeds a certain
number, it is time to use stronger agents that will not
only be more effective, but also require fewer pills per
day.

FRONTIERS IN ENDOSCOPY, SERIES #17

Evaluation and Therapy of Pancreatic Cysts

Serge A. Sorser,

Ali Siddiqui,

Douglas G. Adler

Multiple societal guidelines have been established to assist clinicians in directing the care of patients with pancreatic cysts, but the natural history and malignant potential of all cystic lesions is not entirely understood. In this article, we aim to describe the common types of pancreatic cysts, their natural history, means of follow up, and possible modes of endoscopic and non-endoscopic intervention.

Serge Sorser, MD,¹ Ali Siddiqui, MD² and Douglas G. Adler, MD, MD, FACG, AGAF, FASGE, Associate Professor of Medicine, Director of Therapeutic Endoscopy, Director, GI Fellowship Program, Gastroenterology and Hepatology3 ¹Providence Hospital, Southfield Michigan ²Jefferson University School of Medicine 3University of Utah School of Medicine, Huntsman Cancer Center, Salt Lake City, UT

Pancreatic cysts are a common incidental finding as a result of increased use of diagnostic cross sectional imaging. They run the gamut from benign disease processes to pre-cancerous entities to frank malignant lesions. Much has been written in regards to the natural history of pancreatic cysts, their presentation, diagnostic evaluation, endoscopic and surgical intervention and surveillance. In this article, we aim to summarize the natural history/epidemiology of cysts, their evaluation, and future endeavors in the management of pancreatic cysts.

INTRODUCTION

The increased use of cross-sectional imaging in recent years has led to more incidental findings being noted.¹ The prevalence of pancreatic cysts has been documented to range from 2.6% to 13.5%.^2,3 The majority of these cysts are asymptomatic, but further work-up is often warranted once they are noted.⁴

Subsequent evaluation may be performed in the form of further imaging, but fluid acquisition/analysis helps delineate the nature of the cyst, its potential for malignant transformation, possible need for surgical intervention and further surveillance. Endoscopic Ultrasound guided fine Needle Aspiration (EUS- FNA) plays a crucial role in cyst evaluation.^5,6 Multiple societal guidelines have been established to assist clinicians in directing the care of these patients, but the natural history and malignant potential of all cystic lesions is not entirely understood.^7,8,9 In this article, we aim to describe the common types of pancreatic cysts, their natural history, means of follow up, and possible modes of endoscopic and non-endoscopic intervention.

Serous Cystadenoma (SCA)

SCA, previously known as a microcystic adenomas, are benign entities and the second most common cystic tumors of the pancreas, accounting for up to 30% of pancreatic cysts.^10,11 These tumors occur most commonly in the body and tail of the pancreas and are often seen in middle-aged women, but can occur in both sexes and at any age.^12,13 Patients are commonly asymptomatic, but may present with abdominal pain and a palpable mass, depending on the size of the tumor.¹⁴

Cross sectional imaging may help make the diagnosis, as the tumor appears as a multi-septated cyst with so-called “honeycombing.”¹⁵ A central, spiculated (“sunburst”) calcification may also be seen.¹⁶ EUS FNA is commonly performed if the diagnosis of SCA is less than certain, but some advocate that if a lesion is classic for SCA, an EUS guided-FNA may not be needed.^17,18 (Figure 1) When fluid for analysis is obtained, it is often noted to be clear with cuboidal cells lining the cyst cavity, although acellular fluid is also commonly obtained.¹⁹ A low cyst fluid CEA and bland cytology are frequently noted on fluid analysis.

Due to the benign nature of SCA, no surveillance is generally felt to be warranted. SCA have a low rate of malignant transformation, quoted as less than 3%.²⁰ Surgical intervention is not indicated for serous cystadenomas, unless they are symptomatic. However, recent literature recommends consideration of surgical intervention if the patient has symptoms that can be attributed to the lesion and if the cyst in aggregate is greater than 4 cm.^21,22 It should be stated that many lesions that are, in fact, SCAs do not have all of the classic findings of these lesions and it can sometimes be hard to distinguish SCA from other, more ominous lesions.

Mucinous Cystic Neoplasm (MCN)

MCNs are the most common type of pancreatic cysts. They constitute up to one half of all known cystic lesions of the pancreas. They range in size from 5 to 35 cm and are predominantly found in females.^23,24 The age of onset is usually in the fifth or sixth decade of life and the tumor tends to localize in the body or tail of the pancreas.^{25, 26, 27} These cysts are defined strictly by the presence of ovarian type stroma within the tumor.^28,29 On cross sectional imaging, no communication with the main pancreatic duct is typically noted. On fluid analysis, thick and mucoid material is typically found, with a low amylase and an elevated cyst fluid CEA level.^30,31 Histologically, these cysts are mostly benign. An adenoma was noted in 72% of the cases, borderline neoplasm in 10.5%, carcinoma in situ in 5.5% and invasive cancer in 12% of patients in a series of 163 patients.³² Given that malignant transformation may occur via K-ras and p53 mutations, surgical resection should be considered for MCNs in patients who are suitable operative candidates.^33,34,35,36 The cysts are typically unifocal and when the lesion is resected and is noted to be non-invasive, no surveillance is typically required although in practice many patients undergo post-treatment imaging periodically.⁸

Pancreatic Pseudocysts

Pancreatic pseudocysts are most commonly a complication of acute or chronic pancreatitis, although they can also occur following trauma to the pancreas. Pseudocysts are rich in amylase and are not lined by an epithelium.³⁷ The underlying etiology is multifactorial, but ultimately leads to ductal disruption and an increase in pancreatic ductal pressure.³⁸ Patients tend to present with ongoing abdominal pain and anorexia weeks after their initial presentation, with rare complications such as jaundice or sepsis also noted.³⁹ Jaundice can result from extrinsic compression of the bile ducts, and sepsis from secondary infection of the cyst itself can be seen. Large cysts frequently compress the stomach and/or duodenum and can cause gastric outlet obstruction. Pseudocysts are usually distinguished from other pancreatic fluid collections by the lack of significant solid debris (as is more commonly seen in walled off pancreatic necrosis (WOPN). The diagnosis of a pseudocyst is made by cross-sectional imaging. CT scans will, in general, underestimate the amount of solid debris within a lesion.⁴⁰ Other modes of evaluation, including MRI or EUS may be considered.⁴¹ MRI and EUS will give a more accurate assessment of the amount of solid debris with in a pancreatic fluid collection.

Numerous studies have been published regarding cyst fluid analysis to help distinguish pseudocysts from mucinous cystic neoplasms.^42,43,44 In general, pancreatic pseudocysts will have a high cyst fluid amylase with a low cyst fluid CEA. Pancreatic cyst fluid is often laden with debris and macrophages and often has a “dirty” chocolate brown color. Endoscopic, surgical and interventional radiology approaches may be offered for treatment/drainage of the cysts.⁴⁵

Symptoms from pseudocysts that require treatment include pain, infection, hemorrhage into the cyst, and compression of the stomach, bowel, and/or bile duct. Many symptomatic pancreatic pseudocysts can be treated endoscopically with transampullary drainage via pancreatic duct stent placement. In some patients the cyst decompresses through the pancreatic duct via the stent, while in other patients the pancreatic stent simply relieves pressure on the pancreatic duct; this stops the backfilling of the cyst, allowing it to resolve over time.⁴⁶ A recent paper by Lin et al. showed that transpapillary drainage may be an adequate approach in up to 79.5% of patients.⁴⁷

If transmural drainage is desired, technique usually involves puncturing the stomach or the duodenum to gain access to the cyst via EUS under fluoroscopic guidance, delineating the cyst cavity, dilating the tract and placing multiple plastic double pigtail stents or single metal stents. ^48,49,50,51 (Figure 2) Some patients warrant both transmural and transampullary drainage simultaneously.⁵² Surgical management involves creation of a cyst-enterostomy in the most dependent part of the cyst cavity.^53,54 The percutaneous approach involves finding the most appropriate window (transperitoneal, retroperitoneal, transgastric, transduodenal or transhepatic) and placement of a Percutaneous External Drain.^55,56 Percutaneous approaches are the least invasive and can be favored in patients who are poor candidates for other interventions, although they result in external drainage and there is a risk of chronic cutaneous fistula development.

Walled-off Pancreatic Necrosis (WOPN)

WOPN, a complication of necrotizing pancreatitis, is defined as a collection of fluid and solid components that tends to develop 3 to 6 weeks after an episode of pancreatitis, although some patients can develop an immature form of this lesion in a shorter timeframe.⁵⁷ WOPN is seen in 1 to 9% of cases of acute pancreatitis and occurs most commonly after biliary pancreatitis.⁵⁸

Patients typically present with ongoing abdominal pain as well as fever and leukocytosis.⁵⁹ Fever and leukocytosis can be present even in the absence of infection. The diagnosis of WOPN is typically made on cross-sectional imaging by visualizing a non-enhancing pancreatic fluid collection, which may contain solid and liquid debris, correlated with the age of the fluid collection and the presence of a surrounding capsule.⁶⁰ Indications for intervention include clinical suspicion of, or documented, infected necrotizing pancreatitis with clinical deterioration, gastric outlet, intestinal, or biliary obstruction due to mass effect of walled-off necrosis or persistent symptoms in patients with walled- off necrosis without signs of infection.⁶¹

While many therapeutic modalities for WOPN exist, not all infected pancreatic necrosis requires intervention. Multiple case series have reported good clinical outcome in patients treated conservatively with a prolonged course of antibiotics and supportive care.^62,63 This was later supported by a meta-analysis of eight studies, including 324 patients, which noted that conservative management without necrosectomy is a successful approach in 64% of patients.⁶⁴

In patients who are deemed candidates for intervention, multiple treatment modalities are available. In stable patients, therapy should be delayed a suitable amount of time (usually 4 weeks or more) to allow liquefaction of the contents and the development of a fibrous wall around the necrosis.⁶⁵ This timeframe also allows the fibrous wall to adhere to the stomach or duodenum if endoscopic approaches are to be undertaken.

Multiple endoscopic drainage methods are available for patients with WOPN. One option is endoscopic transmural drainage, in which one or more transmural tracts are created with EUS guidance between the necrotic cavity and the GI lumen. These tracts can be flushed with saline or a mixture of saline and hydrogen peroxide via endoscopic means or via a nasocystic catheter. The tracts can be held open via plastic or metal stents per physician preference.⁶⁶ In the combined percutaneous/endoscopic techniques, a large caliber percutaneous catheter can be used for irrigation of a cavity that has been accessed endoscopically to provide multiple routes for irrigation and drainage.⁶⁷

Recently, the use of dedicated, covered, transmural self-expanding metal stents has been described, in which a short, barbell shaped metal stent is deployed and apposes the pancreatic cyst to the gastric cavity.⁶⁸ (Figure 3) The use of fully covered esophageal and biliary stents has also been noted for these purposes.⁶⁹ A tailored endoscopic approach has also been proposed, which is based on size and extent of the walled-off necrosis and stepwise response to intervention.⁷⁰

Patients undergoing necrosectomy by any route constitute a high risk population; procedure related complications are as high as 25%. These complications include bleeding, sepsis and perforation and the procedure has an overall success rate of 82-93%.^71,72 It should be noted that some patients will fail endoscopic approaches and still require a traditional surgical necrosectomy and/or percutaneous drains.

The radiologic approach has been noted to be safe and feasible. This technique is minimally invasive and has an overall success rate of 33-56% in resolving the WOPN.^73,74 Complications of the percutaneous approach include internal and external pancreatic fistulas, with an overall mortality rate of 17.4%.⁷⁵

Surgical approaches to patients with WOPN are well described and are now often performed through minimally invasive/laparoscopic techniques, although some patients still require an open necrosectomy. With the laparoscopic approach, a transgastric endolumenal cystogastrostomy is created.⁷⁶ Common adverse events include pancreatic fistulae (28.6%), debris recollection (10.7%) and wound infection (10.7%).⁷⁷

While each individual approach has its advantages and disadvantages, a combined/multidisciplinary approach may be needed. A 2012 study by Gluck et al. showed that dual modality (endoscopic and percutaneous) drainage reduced length of stay, number of radiological procedures and number of ERCPs with a durable long-term outcome (100/103 patients did not require surgery at two years).^78,79 A multidisciplinary approach should be undertaken and the treatment modalities selected should rely on individual center expertise, but also depend on the anatomical position, the ratio of solid to fluid components within the collection, and the degree of systemic organ dysfunction.^80,81

Intraductal Papillary Mucinous Neoplasm (IPMN)

IPMNs are mucin producing lesions of the exocrine pancreas. They account for up to one third of pancreatic cysts, but are felt to be responsible for only one percent of pancreatic cancers.⁸² They may be subcategorized in terms of their ductal involvement: main duct (16-30%), side branch (40-65%) or mixed type (15-23%).^83,84 Most IPMN are solitary and are located in the pancreatic head, but 20-40% may be multifocal.⁸⁵ Histologically, the tumors are graded as having low-grade dysplasia, intermediate grade dysplasia and high-grade dysplasia. IMPN are also sub-classified into four different types: gastric, intestinal, pancreaticobiliary and oncocytic. This classification is descriptive and indicative of different pathways of differentiation and progression to carcinoma.^58,86

While IPMN are usually incidentally found on imaging, diagnostic evaluation with EUS is commonly undertaken for a more detailed evaluation and for cyst fluid aspiration and analysis.⁸⁷ (Figure 4) The cyst content may be analyzed in a number of ways, including mucin stain and viscosity, and cyst fluid CEA level, although all of these tests can be limited when attempting to identify malignancy.^88,89 DNA studies of cyst fluid are also available but are not in widespread use. IPMN may be malignant at presentation, but they carry a better prognosis than pancreatic adenocarcinoma in this setting.⁹⁰ Worrisome features of IPMN lesions include size greater than 3 cm, presence of mural nodules, dilation and/or involvement of the main pancreatic duct and cyst location (main duct versus side branch).⁹¹ Surgical intervention includes pancreaticodeuodenectomy, distal pancreatectomy, total pancreatectomy, segmental resection, enucleations and duodenum preserving resections.^92,93,94 For patients who are not surgical candidates, endoscopic ablation of the cyst cavity with ethanol has been described but can only be considered experimental at this time.^95,96,97 Surveillance strategies after definitive therapy are guided by the Sendai Criteria, and are based on clean surgical margins, extent of dysplasia and whether known cystic lesions remain in the pancreas.⁸

Rare Pancreatic Cystic Lesions

There are a number of relatively rare cystic lesions of the pancreas or solid lesions with cystic degeneration or solid lesions with cystic components that are also worthy of brief discussion.

Cystic lymphangioma of the pancreas arise from lymphatic vessels, and this is thought to be developmental aberrancies. They account for 0.2% of all pancreatic cysts and are most often noted incidentally.⁹⁸ These tumors are benign, but may be locally invasive, and are more commonly found in women.⁹⁹ Symptomatic lymphangioma patients usually present with epigastric pain and a palpable mass although they can be asymptomatic as well.¹⁰⁰ Review of histology yields interconnecting cysts separated by septa, lined by epithelial cells, and contain serous, serosanguineous, or chylous fluid (elevated triglyceride level).¹⁰¹ Given their benign nature, no further work-up is needed and lesions can be resected based on symptoms as needed.¹⁰²

Lymphoepithelial cysts are also benign cystic entities, most commonly seen in men and also typically discovered incidentally.¹⁰³ The diagnosis is made by EUS/FNA showing abundant anucleated squamous cells, multinucleated giant cells, mature lymphocytes in a background of keratinaceous debris and a lack of neoplastic cells.¹⁰⁴ Surgery is not recommended in most patients unless they are symptomatic.¹⁰⁵

Other rare cystic tumors include cystic degeneration of ductal adenocarcinoma¹⁰⁶ and solid pseudo-papillary tumors of the pancreas^107,108 and other mesenchymal origin cysts.¹⁰⁹

CONCLUSION

Cystic lesions of the pancreas are more commonly
encountered with increased use of cross sectional
imaging for evaluation of gastrointestinal and other
symptoms. These lesions have a wide range of presenting
symptoms, while most are asymptomatic. EUS/FNA
plays a key role in the diagnostic work-up, and offers
prognostic value, with surveillance recommendations
made based on the cyst size and fluid characteristics.
Depending on the type of cyst, endoscopic, radiologic
and/or surgical modalities may be employed in treating
the underlying pathology. No definitive guidelines
exist for surveillance of all the known cyst types, and
a tailored approach is recommended in many cases. In
the future, genetic profiles and tumor markers may play
a role in improving treatment strategies.

A CASE REPORT

Acquired Heterotopic Gastric Mucosa after Gastrojejunostomy Tube Placement Causing Intermittent Obstruction

Sameer Lapsia,Anupama Chawla,Juan Carlos Bucobo,Rupinder Gill

Sameer Lapsia, M.D., Clinical Fellow in Pediatric Gastroenterology. Anupama Chawla, M.D., Chief, Division of Pediatric Gastroenterology. Juan Carlos Bucobo, M.D., Assistant Professor of Medicine/ Gastroenterology. Rupinder Gill, M.D., Assistant Professor of Pediatric Gastroenterology. SUNY at Stony Brook, Health Science Center, Stony Brook, NY

CASE PRESENTATION

An otherwise healthy 14 year-old obese male presented after suffering second- and third- degree burns to over 40% of his body surface area including his face, arms and chest while attempting to light a tiki torch. His hospital course was complicated by acute respiratory distress syndrome, acute kidney injury and sepsis.

Due to an anoxic brain injury resulting in disturbed oral-motor function, the patient had a percutaneous gastrostomy tube (G-tube) placed to provide enteral feeding. Despite radiographic studies showing patency of the G-tube he began to have episodes of non-bilious vomiting after feeds. An upper gastrointestinal (UGI) series as well as a computed tomography (CT) scan of his abdomen showed no signs of obstruction or dilated loops of bowel. After a successful trial with nasojejunostomy (NJ) tube feeds, a gastrojejunostomy (GJ) tube was placed endoscopically to provide post- pyloric feeds. At that time, no mucosal abnormalities of the duodenum or proximal jejunum were appreciated.

Approximately 6 weeks later, he again presented with intermittent emesis, now occasionally bilious. An UGI series showed the tip of the jejunostomy tube had migrated back into the stomach. No obstructive bowel gas pattern was noted. Repeat endoscopy to reposition the jejunal portion of the GJ tube was performed. A 2.5 cm semi-pedunculated salmon-red colored polyp was noted in the distal duodenum/proximal jejunum (Figure 1) causing partial obstruction of the lumen. Biopsies revealed heterotopic gastric tissue with predominantly antral type gastric mucosa and occasional oxyntic cells (Figure 2). A distinct zone of demarcation was present between the heterotopic gastric mucosa and normal intestinal mucosa. There was no evidence of metaplasia, dysplasia or malignancy.

Due to the patient’s recurrent episodes of emesis, a repeat esophagogastroduodenoscopy was performed and the polyp was removed using snare cauterization. After polyp removal, the patient slowly started to tolerate feeds and was transferred to a long-term care facility.

Discussion

Heterotopic gastric mucosa (HGM) was first reported in the literature in 1912 by Poindecker. Since then there have been numerous articles describing its occurrence.¹ HGM is most commonly found along the gastrointestinal tract, but has been reported in extraintestinal sites such as the umbilicus, bronchi, spinal column, urinary bladder, gall bladder, biliary tree and scrotum.^2,3 Composed of ectopic gastric tissue, its presence distal to the ligament of Treitz is rare except in Meckel’s diverticulum and intestinal duplication.⁴ HGM has a male predominance and is usually an incidental finding. However, it can present with symptoms of vomiting secondary to obstruction or intussusception. Although rare, anemia, gastrointestinal (GI) bleeding and perforation have also been reported secondary to ulceration from the ectopic gastric mucosa.^2,5-6

In the small intestine, heterotopic gastric mucosa can clinically resemble a polyp, ulcer, adenomas, angiomas, lipomas, lymphomas or carcinoma. The frequency of HGM is 0.5-2% in the duodenum and in this portion of the GI tract it often appears as a nodular mass.^2,4 In the small intestine, the size of these masses can range from 1.0 cm-2.5 cm.⁷ There are two types of heterotopic gastric mucosa: congenital and acquired. As our patient previously had numerous UGI series, a CT scan, as well as an initial endoscopy for GJ tube placement, which did not show any evidence of a lesion, he most likely had acquired heterotopic gastric mucosa. This signifies replacement of his native small intestinal mucosa by gastric epithelial tissue, which has been described in adult patients after gastrojejunostomy. It is suspected that HGM occurs due to infiltration of mucosa through defects in the muscularis mucosa by repeated erosion.⁸ It has also been described in patients with inflammatory bowel disease, intestinal tuberculosis, celiac disease, intestinal cancers and post-irradiation enteritis.² These lesions are almost always incidental findings and little data exists on their rate of growth, though they may grow briskly.⁸

The pathology of the lesion in our patient showed only pyloric type of mucosa with rare oxyntic cells characteristic of an acquired heterotopic gastric mucosa. Most jejunal lesions are polypoid in shape as seen in our patient.² Additionally, congenital HGM is rare distal to the ligament of Treitz and includes a mixture of both fundic and pyloric-type of epithelium without any associated conditions that can cause inflammatory changes. Histopathology remains the gold standard for diagnosis of these lesions.

To avoid complications from HGM, endoscopic resection is suggested. For large masses, a surgical approach with excision followed by anastomosis to reestablish intestinal continuity may be necessary. In addition to the complications of having ectopic gastric tissue, adenocarcinomas and adenomas may rarely stem from these lesions.⁹

Our patient had occasional episodes of bilious emesis that improved after the mass was resected. We hypothesize two possible mechanisms for the patient’s symptoms: a) the size of the HGM causing partial obstruction and resulting in intermittent episodes of vomiting and/or b) the lesion acting as a lead point causing intermittent small bowel-to-small bowel intussusception.

CONCLUSION

To our knowledge, heterotopic gastric mucosa appearing after gastrojejunostomy placement and causing intermittent obstruction in a pediatric patient has not been described in the literature.

Although there are many causes of emesis after GJ tube placement, this case illustrates the importance of repeat endoscopy to evaluate for rare acquired anatomic causes like heterotopic gastric mucosa, especially if contrast studies do not yield a diagnosis.

A SPECIAL ARTICLE

Effectiveness of a Personal and Family History Questionnaire When Assessing Colorectal Cancer Risk

Seper Dezfoli,

Thomas J. McGarrity,

S. Devi Rampertab

Background: Few studies have evaluated whether a personal and family history questionnaire (PFHQ) administered at the initial patient encounter improves the provider’s ability to appropriately risk stratify patients for colorectal cancer (CRC) screening. The objective of this study was to determine if a PFHQ completed by the patient prior to the initial encounter improved the provider’s ability to extract pertinent information relating to CRC risk.

Methods: This was a prospective intervention study conducted in the adult outpatient gastroenterology clinic at Penn State Hershey Medical Center. A PFHQ was created based on expert opinion and current screening guidelines. 199 patients evaluated as new encounters between February 2009 and June 2009 completed the questionnaire. We also retrospectively evaluated 186 randomly chosen charts of new patient encounters that had not utilized a questionnaire. A point system was created to score all charts in both the retrospective (without the questionnaire) group as well as the prospective group (with the questionnaire) based on quantity and quality of information documented in the consultation reports relating to CRC risk. Results between the two groups were compared using Wilcoxon Rank Sum test.

Results: Both patient and family history scores were significantly lower in the prospective study group that completed the questionnaire (p=0.05, p<0.01, respectively) when compared to the group that did not utilize a questionnaire. Composite scores (personal & family history) were significantly lower in the study group that completed the questionnaire (p=0.01).

Conclusion: Our study demonstrated that clinician-led history taking was superior to a questionnaire in obtaining quality history that can be used to appropriately risk stratify patients for CRC screening.

Seper Dezfoli, M.D.¹ Thomas J. McGarrity, M.D.² S. Devi Rampertab, M.D.³ ¹Department of Gastroenterology, Medstar Washington Hospital Center, Washington, DC ²Division of Gastroenterology and Hepatology, Penn State Medical Center, Hershey, PA ³Division of Gastroenterology and Hepatology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ

INTRODUCTION

Colorectal cancer (CRC) remains the third leading cause of cancer in the United States in both men and women. It is also the third leading cause of cancer-related deaths.^1,2 Evidence supports that mortality from CRC is reduced by screening asymptomatic persons.^3-8 Patients who gain the most benefit from current screening modalities are those at increased risk for developing CRC. Thus, it becomes essential to appropriately identify these individuals and refer them for screening measures accordingly.^9-13 Obtaining a personal and family history helps identify risk factors for development of sporadic cancers and potentially identify single-gene disorders such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC).

Questionnaires have been utilized to assist in gathering this type of detailed history. Several modalities have been developed, including paper-based and web- based questionnaires.¹⁴ In fact, Qureshi and colleagues state in their review on family history collection in primary care that it may be logical to have a “disease- specific risk assessment tool, rather than a stand-alone tool,” so that the history can be assessed in the context of disease-specific guidelines, such as CRC screening guidelines.¹⁵ However, little is known about the clinical utility of these tools.

Few studies have attempted to ascertain whether a personal and family history questionnaire (PFHQ) enriches the ability to appropriately risk stratify patients for CRC. The objective of this study was to evaluate if a PFHQ completed by the patient prior to the initial encounter enhances a provider’s ability to extract pertinent information related to CRC risk.

METHODS
Design and Setting

This was a prospective intervention study that was conducted in the Gastroenterology adult outpatient clinic at the Milton S. Hershey Medical Center in Hershey, Pennsylvania. This institution is a large, academic referral medical center. The study was approved by the departmental scientific review committee and by the institutional review board.

A retrospective review of two hundred randomly chosen charts of patients seen as new consultations between July 2008 and November 2008, herein referred to as the “control group”, was conducted to measure outcome parameters prior to intervention. Of these, fourteen charts were excluded due to incomplete charting. The consultation reports for all the charts were evaluated for information relating to CRC risk. This allowed the investigators to establish a baseline indicator of clinicians’ ability to elicit details pertinent to determining CRC risk.

The prospective portion of the study involved patients evaluated as an initial consultation at the Gastroenterology outpatient clinic between February 2009 and June 2009 (herein referred to as the “intervention group”). One hundred ninety-nine patients were recruited for the study. Subjects were approached and consented at time of check-in. Consented participants were asked to complete a PFHQ before their physician encounter. Completed questionnaires were attached to the patient’s chart and given to the practitioners to use at their discretion. Practitioners included attending physicians, gastroenterology fellows and physician assistants. The primary investigator of this study was excluded.

A point system was created as a surrogate marker to measure the amount of useful information gathered and documented from the PFHQ. Only information that could potentially risk stratify a patient’s CRC risk was included. All charts in both the control group (without the questionnaire) as well as the intervention group (with the questionnaire) were scored based on quantity and quality of information documented in the consultation reports relating to CRC risk. We compared the results between the two groups using Wilcoxon Rank Sum test.

Development of the Questionnaire

Content of the questionnaire was solely determined by the most current CRC screening guidelines set forth in 2008 by the American Cancer Society and American Gastroenterological Association.16 The first section gathered information regarding personal history. Questions in this section surrounded a personal history of polyps, including histology, CRC, inflammatory bowel disease (IBD), and suspected diagnosis of HNPCC or familial adenomatous polyposis (FAP)

With regard to a history of polyps, the number identified and histology are important determinants of risk. In addition to pathologic terms such as “hyperplastic” and “villous”, layman terms such as “benign” and “pre-cancer” were included as an approach to increase user recall. The final question in this section was aimed to identify patients at risk for hereditary syndromes as it addressed the presence of extra-colonic tumors associated with HNPCC and FAP.

The second section of the questionnaire gathered information regarding family history. It was divided into two subsections: first-degree and second-degree relatives. Patients were asked about family history of CRC, polyps, and any extra-colonic cancers. Histology of polyps (e.g. hyperplastic versus adenomatous) is an important determinant of risk. A majority of patients are unaware of polyp histology, especially with regard to family members. Thus we incorporated time-lines as a way to extrapolate pathology of family members who may have had polyps. For example, if a patient marked that his or her father has had polyps, he or she was asked, “When were they asked to return for testing?” A response of “0-5 years” implied the patient’s father had a pre-malignant polyp whereas a response of “10 years” implied normal tissue or polyps with benign histology (i.e. hyperplastic)

Validity of the questionnaire was determined through discussion with gastroenterologists with expertise in CRC, screening guidelines, and survey design.

Development of Point-System

A novel point system was created by the investigators to assign points to pertinent information recorded in the initial consultation reports for both the retrospective charts as well as the prospective charts, which utilized the questionnaire (Table 1). Pertinent information was defined as any information that could potentially be useful in determining a patient’s risk for development of CRC in the context of current screening guidelines. That is, any piece of information that could be cross referenced with current screening CRC guidelines and lead to a decision regarding patient risk: average risk versus increased risk.

Specific information (i.e. personal history of polyps) received a full point. General information that could be helpful, but not necessarily help a practitioner risk- stratify a patient in the context of CRC (e.g. “personal history of cancer” versus “personal history of colorectal cancer”) received 0.5 points.

Qualifying statements with regard to age of onset, family relationship, histology, etc. received an additional 0.5 points each. Non-cancer history with the exception of IBD received zero points, as this information does not help risk stratify patients with regard to CRC. As there is no finite amount of information that can potentially help stratify an individual’s risk, there was no set maximum point value or range.

Thirty randomly chosen patient charts were reviewed prior to the study to obtain a general overview of practitioner language and to gain experience in applying the point system. An independent third-party also reviewed the charts and was asked to apply the point system to each chart. There was no significant difference in the average score given to the pre-study charts between the investigators and the third-party.

RESULTS

The retrospective arm of the study (control group) was comprised of 186 patients whose initial consultation reports were reviewed and scored. One hundred ninety- nine patients participated in the prospective arm of the study (intervention group) by completing the questionnaire. The demographics of the two groups are shown in Table 2. There was no significant difference in age or gender between the two study groups.

Patient and family history scores were analyzed across both groups with the non-parametric Wilcoxon rank sum test, as data were not found to follow a normal distribution as determined by the Kolmogorov-Smirnov test.

Patient history and family history scores are outlined in Table 3. Mean scores were compared. Both patient and family history scores were significantly lower in the intervention group, the prospective study group that completed the questionnaire (p=0.5 and plt;0.01, respectively). Composite scores (sum of personal and family history scores) were also significantly lower in the intervention group (p=0.01).

DISCUSSION

This study evaluated the impact a PFHQ has on the ability of a provider to extract pertinent information related to CRC risk stratification, and demonstrated two important findings. First, implementation of a PFHQ did not enhance the ability to extract information that could potentially help stratify a patient’s risk of developing CRC. Second, using a PFHQ led to significantly lower rates of documentation related to CRC risk-stratification. That is, practitioners extracted and documented more pertinent information that could potentially risk stratify a patient in the control group, the group that did not utilize the questionnaire.

Although many primary care physicians recognize the importance of gathering a family history, studies suggest that most lack the history-taking skills required to risk stratify patients appropriately while also implementing current guidelines.^17-23 One study revealed that only 50% of primary care physicians updated family histories during routine or annual examinations and only 28% routinely obtained history information beyond first-degree relatives; less than half of practitioners inquired about specific cancer types.¹⁷ A recent study surveying 285 primary-case based physicians in Germany, found that less than 75% of physicians routinely inquired about family history. Seventeen percent of the physicians utilized a standardized assessment tool to gather information, only 35% of which stating they routinely update it.²⁴ Furthermore, although several questionnaires have been formally evaluated, only a few claim to have been clinically validated.²⁵ The questionnaire in our study was created to extract information that can be cross referenced with current CRC screening guidelines and that can be used easily by clinicians. By using a standard questionnaire, we hoped to eliminate the variation between practitioner assessments of risk that results from unawareness of current guidelines.

One systematic review reporting the use and outcome of questionnaires identified only four studies that aimed to validate their questionnaire against a reference standard.²⁶ In all cases, the reference standard was a genetic interview conducted by a trained geneticist. Although geneticists do gather patient histories, typical encounters involve a clinician gathering personal and family history from a patient. Thus, the outcomes of these studies cannot be practically applied to common practice. A recent outcomes study by Vogel and co- workers evaluated the rate at which patients were referred for genetic counseling based on information gathered from a self-administered questionnaire versus a review of the patient’s electronic medical record.27 Similar to other previous studies, results were compared to a structured, genetic interview. The authors did conclude that the questionnaire led to a higher capture rates than a review of the medical record, however the study did not include physician-led interviews. In fact, no study has aimed to determine whether a questionnaire is superior to physician-led history-taking in the assessment of colorectal cancer risk in patients being seen in an outpatient setting. We provide a novel study that aimed to assess if a questionnaire is superior to physician-led history. In our study, significantly less information was extracted from patients when a questionnaire was utilized with respect to personal and family history

Lack of time is the most notable barrier to obtaining personal and family history. As questionnaires are meant to be a time-saving tool, we hypothesize that practitioners do not repeat questions pertaining to history when the patient has completed a questionnaire. The questionnaire is only as valuable as the practitioner who reads it. It must be read, and pertinent positive and negative information should be documented in the patient’s chart. This, in turn, would then lead to proper assignment of the patient into the “high risk for CRC” category and appropriate screening could then be recommended and implemented.

Our study provides a novel examination of current practices in a large outpatient gastroenterology clinic. It also examines the behavior and documentation patterns of gastroenterologists when implementing a questionnaire as compared to practices when such a tool is not utilized. Clinicians may be more inclined to remember information they asked themselves rather than information visualized on a questionnaire.

Clinician-led history taking was superior to questionnaires in obtaining quality history that can be used to appropriately risk stratify patients. This suggests that practitioners may neglect to elicit important details in the history pertaining to establishing CRC risk when a questionnaire is available. Therefore, although current studies show that physicians have suboptimal rates of assessing personal and family history, implementation of a questionnaire may be even more detrimental and possible even impede the process of gathering information. Thus, we do not recommend the implementation of questionnaires for the use to history-taking, especially in the context of CRC risk assessment.

There are limitations to this study. The questionnaire created by the study investigators was not validated. However, its content was derived from the most current CRC screening guidelines set forth by the American Cancer Society and America Gastroenterological Association in 2008. Moreover, investigators collaborated with experts in CRC screening guidelines when developing the questionnaire. Second, the point system used to analyze the primary outcome was developed and implemented by the study investigators, thus leading to potential bias. However, a subset of randomly chosen charts was analyzed by a third- party and there was no significant difference in the points assigned by investigators and the third-party analyst. Lastly, there were significant differences in the type of provider (e.g. attending versus fellow trainee) conducting the patient interviews between the two groups, which could play a confounding factor. Interestingly however, it was the intervention group, the group evaluated by significantly more attending Gastroenterologists, that scored significantly lower. Thus it appears that less formal training did not influence the negative result.

CONCLUSION

Clinician-led history-taking was superior to the utilization of a questionnaire as clinicians documented significantly lower rates of information regarding CRC risk when the questionnaire was utilized. This suggests that clinicians may rely too heavily on information- gathering tools such as questionnaires, and that implementation of a questionnaire may negatively impact information gathering and risk stratification.

Questionnaires should not be used as a sole tool to gather personal and family history in the context of CRC risk unless the practitioner actually has time to review, interpret and document what is stated on the questionnaire.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #139

Short Bowel Syndrome in Adults – Part 4A A Guide to Front Line Drugs Used in the Treatment of Short Bowel Syndrome

Lingtak-Neander Chan,

John K. DiBaise,

Carol Rees Parrish

In patients with short bowel syndrome (SBS), malabsorption of drugs is an important consideration, particularly if the expected clinical response to a medication is not attained. Factors include length, location and health of the remaining bowel, the form of the medication administered and the site of action of the drug. Part 4A & B of this 5-part series will focus on conventional pharmacological agents used in the treatment of SBS.

A 64-year-old woman is hospitalized with hypotension, chronic diarrhea (6-10 per day over the past 4 weeks), fatigue and general malaise. Seven weeks ago, she was hospitalized with acute abdominal pain and severe nausea. Further work-up revealed acute mesenteric infarction due to a superior mesenteric artery thrombus and she underwent extensive resection of the ischemic bowel leaving her with about 100 cm of small bowel from the ligament of Treitz anastomosed to the proximal transverse colon. She was discharged from the hospital 2 weeks later on home parenteral nutrition (PN). Her weight is down 6 kg since hospital discharge 5 weeks ago. In addition to PN, she also takes loperamide 2 mg TID as needed (she has not been using it because “it doesn’t help”), cholestyramine 4 g BID, mirtazapine 15 mg daily, levothyroxine 0.075 mg daily and oral glutamine 30 g daily. Famotidine, 40 mg, has been added to her PN. Stool output, which is watery and without blood, ranges from 2500 to 3000 mL daily. She is not eating much as she is so depressed and uncomfortable and “it just comes right out anyway”; she is afraid to leave her house for fear of “having an accident.” Part 4A & B of this 5-part series on SBS will focus on conventional pharmacological agents used in the treatment of short bowel syndrome that will allow you to help this woman control her diarrhea and improve her quality of life.

INTRODUCTION

The intestine is a vital organ for the absorption of nutrients, fluids, and drugs. In patients with short bowel syndrome (SBS), malabsorption of drugs is an important consideration, particularly if the expected clinical response to a medication is not attained. In assessing the cause of lack of clinical response, a number of factors should be considered (Table 1).¹ The extent of a patient’s malabsorptive potential will depend on the length, location and health of the remaining bowel, the form of the medication administered and, in some cases, the site of action of the drug.² Although the proximal small bowel is the primary site of drug absorption, many drugs can be sufficiently absorbed along the entire length of small intestine. There is even strong evidence that some drugs can be efficiently absorbed in the colon.^3-6 The solution in response to a lack of clinical response of a drug will vary and may include escalating the dose, changing to a different dosing schedule or frequency, and/or changing to a different drug formulation (e.g., crushed tablet, capsule, liquid) or route of administration (e.g., intravenous, subcutaneous, transdermal).

Understanding the Implications of Drug Formulations

Medications in solid dosage forms, such as a tablet, need to undergo disintegration and dissolution before absorption can take place. Disintegration, whereby the tablet is broken down into small particles, takes place efficiently in the stomach in the presence of gastric acid along with the help of the churning and grinding action of the distal stomach. Dissolution is the process by which the active ingredient is dissolved into a liquid medium7 and is the final process to allow the active ingredient to be absorbed in the small intestine. Dissolution may take place in the stomach, the duodenum or the proximal jejunum. The dissolution rate is specific to the active ingredient and is pH-dependent. Regular tablets, capsules, and caplets undergo a similar process of disintegration and dissolution. Delayed-release tablets and enteric-coated tablets are formulated with a chemical coating to delay disintegration and dissolution until the tablet has passed through the stomach to prevent the active ingredient from being destroyed or inactivated by gastric secretions or where it may irritate the gastric mucosa.⁷ Time-release formulations, such as extended-release or controlled-release tablets are formulated to make the active ingredient(s) available for absorption over an extended period of time following ingestion, especially in the small intestine.^8,9

Based on these principles, impaired disintegration and dissolution of a regular tablet can occur in the setting of gastric, duodenal or proximal jejunal resection or achlorhydria, and may result in decreased oral drug absorption (i.e., bioavailability). Fortunately, SBS patients rarely have had resections of the upper gut. In these patients, improved absorption of medication can be achieved by using liquid dosage forms, such as oral solutions or suspensions (be watchful for sugar alcohols such as sorbitol and xylitol that can exacerbate diarrhea), or crushed tablets. In patients with only partial resection of the jejunum or proximal ileum, although the rate of drug absorption may be altered, the overall extent of drug absorption appears to be preserved.^10-13

Drug malabsorption is more likely in patients with extensive resection of the distal jejunum and ileum, especially with the loss of the terminal ileum and ileocecal valve,^2,12 the most common area resected in SBS patients. In these patients, if the desired clinical responses cannot be achieved by orally administered medications, use of an alternate route of drug administration such as the use of transdermal patches, subcutaneous injections or even intravenous administrations should be considered. In patients with extensive GI tract resection, sustained- release or extended-release products should generally be avoided, as the extent of drug absorption can be erratic or severely impaired.

Assessment of Drug Response

When evaluating suboptimal clinical responses to medications in SBS, a clinician should evaluate factors related to the patient and the specific medication involved. Table 2 outlines a process to aid clinicians in critically assessing the potential cause(s) of inadequate drug response.

Management of GI Hypersecretion and Chronic Diarrhea in SBS

The most commonly used medications in the SBS patient, particularly during the period of greatest intestinal adaptation, are antisecretory and antimotility agents. They are frequently necessary to control gastric hypersecretion and chronic diarrhea. Antimotility agents will be discussed in Part 4B of this series.

Gastric Hypersecretion

The link between gastric acid hypersecretion after resection of a large segment of small intestine has been known for decades and has been attributed to the development of parietal cell hyperplasia and hypergastrinemia. This process generally lasts up to 12 months after a single massive resection with more than 50% of the small intestine removed.^14,15 If additional resections are performed, the duration of gastric hypersecretion may be more prolonged. Hypersecretion results in an increase in fluid volume entering the small bowel contributing to diarrhea; it also lowers the pH of the proximal small intestine and may result in peptic injury and inactivation of pancreatic digestive enzymes further aggravating fat maldigestion.^16,17 Fortunately, with the availability of potent and safe acid reducing drugs, gastric hypersecretion in most patients can be effectively managed using histamine-2 receptor blockers (h3RB) and proton pump inhibitors (PPI). Table 3 summarizes the established regimens for different antisecretory drugs and their monitoring parameters.

Histamine-2 Receptor Blockers

h3RBs are a good choice as initial empirical therapy for gastric acid hypersecretion, on-demand symptom/ acid control, or for the management of breakthrough acid hypersecretion. h3RBs demonstrate a dose- dependent effect in reducing gastric acid secretion.¹⁸ They are generally safe and are the only systemic drugs with an immediate onset of action in reducing gastric acid secretion. Clinical effect can be detected within 1 hour after drug administration.^19,20 These drugs are available as oral and intravenous formulations. The intravenous formulations are also compatible with most parenteral nutrition (PN) solutions, making them a very accommodating therapeutic option for patients as initial therapy after intestinal surgery. Nevertheless, the long-term effectiveness of h3RBs is limited by their relatively modest efficacy and the development of tolerance over time despite dose-escalation.

Proton Pump Inhibitors

PPIs are the most potent agents in the management of diseases requiring the reduction of gastric acid secretion and are the primary drugs used as maintenance therapy for gastric hypersecretion. PPIs are most effective when proton pumps are active, such as during meal time under normal physiology. Therefore, the best time to administer these drugs is shortly before meal time.^21,22 Maximal inhibition of acid secretion will require at least 3 to 5 days of continued therapy.^23,24 In patients with SBS, especially those receiving nutrients exclusively by PN, it is less clear how to maximize the efficacy of PPIs. Additionally, up to 30% of the patients may not show adequate clinical response to PPIs.^25,26 Poor response may be due to altered pharmacogenetics, non-adherence to therapy, and/or other physiological causes.^26-28 Therefore, PPIs may not be the best therapeutic agent for all patients.

All oral PPI products are formulated with an enteric- coating (either on the outer shell of the tablet or the cover of the granules inside the capsule) to protect the drugs from acid-mediated deactivation. Some products have additional extended-release characteristics in order to extend the duration of time the active drug is present in the body. Because PPIs are absorbed in the small intestine,²⁴ in patients with SBS, their oral bioavailability may be limited. It is unclear whether the drug is absorbed adequately in the colon. In general, the clinical efficacy of the different commercially available PPIs is considered comparable.

If there is a lack of clinical response to antisecretory therapy with an oral PPI in the early postoperative period, it is reasonable to consider a trial of IV PPI as oral drug absorption may be compromised immediately after resection of small intestine. Limited data suggest that IV PPI should be started with either a twice daily bolus regimen or as a continuous infusion. A patient can be characterized as having a positive response if clinical symptoms improve (significant decrease in stool/ostomy volume) within 5 days of the initiation of IV PPI.

With proper monitoring, PPIs are safe and effective and should be considered an integral treatment for gastric hypersecretion. In the SBS patient, a PPI should be started as soon as possible after small intestinal surgery and can generally be initiated orally for most patients. For all PPIs, it will take about one week for a clinically significant response to be seen. Since h3RBs provide a more immediate clinical response, it is not unreasonable to have concurrent treatment with a PPI and an h3RB during the initial treatment period.

Clonidine

Clonidine is a centrally acting a2-adrenergic receptor agonist approved by the Food and Drug Administration for the treatment of hypertension. The GI-related side effects of clonidine include dry mouth and constipation. The exact mechanism of clonidine in reducing gastric hypersecretion is unclear, although clonidine has been shown to reduce diarrhea in patients with proximal jejunostomy and those with diabetic diarrhea. Clonidine decreases fecal water and sodium losses and prolongs intestinal transit time in patients with chronic diarrhea.^29-33 As an antisecretory drug, clonidine can be administered orally as a tablet or as a transdermal patch, a potentially advantageous option for the patient with SBS where there may be unreliable oral absorption. The effective doses are between 0.1 to 0.4 mg per day.^29,30,32 The patch only needs to be replaced weekly.³⁴ One of the most serious side effects of clonidine is hypotension, which may be exacerbated by dehydration from chronic diarrhea, seriously limiting its use in SBS. Therefore, the dose of clonidine should be started cautiously and slowly titrated up. Patients should also be advised to remove the transdermal patch before undergoing a magnetic resonance imaging procedure as burn injuries have been reported.^34,35

Octreotide

Octreotide is a synthetic analog of somatostatin. Somatostatin decreases endocrine and exocrine secretion and blood flow, reduces gallbladder contraction, slows down GI motility and inhibits secretion of most GI hormones. Inhibition of gastrin release is likely the primary mechanism for octreotide’s benefit in the treatment of gastric hypersecretion. Octreotide is available in only two parenteral forms – octreotide acetate injectable solution, which is intended for intravenous or subcutaneous injection; and octreotide acetate injectable suspension (or LAR depot), which should only be administered as an intramuscular injection. Octreotide solution is physically compatible with most PN solutions providing additional flexibility for drug administration. When starting octreotide therapy, the injectable solution should be initiated first to allow dose titration and determination of the optimal dose based upon the clinical response. Once efficacy is established, the regimen can be converted to the injectable suspension to allow less frequent dosing. Although the use of octreotide in various types of diarrhea has been reported, its effectiveness in reducing gastric hypersecretion is highly variable and unpredictable.³⁶

The typical starting dose for octreotide is 50 or 100 mcg subcutaneously TID. The dose can be titrated up every 3 to 4 days based upon clinical response; most patients will require a total daily dose between 200 to 300 mcg to attain a clinical response.^37,38 Octreotide is not the primary therapeutic agent for acute control of GI hypersecretion given its cost, subcutaneous administration, and since it generally takes 5 to 7 days to see a clinically significant response. Importantly, in SBS, since octreotide inhibits the release and function of most GI hormones, it can negatively affect intestinal adaptation. See Table 3 for a summary of the antisecretory agents and Table 4 for potential adverse reactions.

Other Pharmacotherapies Sometimes Considered in the Treatment of SBS
Bile Acid Binders

Resection of > 100 cm of terminal ileum affects the reabsorption of bile acids into the enterohepatic circulation, hence, reducing bile acid production. Since 95% of bile salts are recirculated, the reduced bile acid absorption eventually exceeds the ability of the liver to synthesize adequate replacement. This decreased bile acid pool results in impaired micelle formation and fat digestion, and manifests clinically as steatorrhea and fat soluble vitamin deficiencies. As such, the use of bile acid sequestrants may actually worsen steatorrhea and fat-soluble vitamin losses in the SBS patient and should generally be avoided, or at most reserved for those with a colon who fail other front line agents.³⁹ The entry of bile acids into the colon also enhances water secretion and accelerated colonic motility (due to the caustic nature of bile salts on colonic mucosa), affecting the colonocytes ability to reabsorb salt and water. Although an attempt to improve the depleted bile acid pool using bile acid supplements would seem worthwhile in order to improve fat maldigestion, there are no suitable bile acids readily available that will not also aggravate stool losses. See Table 5 for the doses and monitoring parameters of different bile acid sequestrants.

Pancreatic Enzymes

SBS patients with extensive proximal small bowel resections may lose sites of secretin and cholecystokinin- pancreozymin synthesis and develop decreased pancreatic and biliary secretions;⁴⁰ fortunately, most SBS patients have extensive distal small bowel resections and demonstrate normal pancreatic enzyme and bilirubin secretion. Pancreatic function is reduced in patients on PN only when there is no concomitant enteral/oral diet and, potentially, during the hypersecretory period if no antisecretory medications are being used. Although there may be concern about a mismatch of the timing of the mixing of ingested nutrients with pancreatic enzymes due to the alterations in anatomy and small bowel transit, evidence supporting the usefulness of pancreatic enzyme supplementation in SBS is lacking (and they add yet even more to that “total pill count”).

Antimicrobials

Small intestinal bacterial overgrowth (SIBO) is common in SBS patients.⁴¹ The combination of bowel dilatation and altered transit frequently seen in SBS, together with medications commonly used in these patients (e.g., acid suppressants and antimotility agents) is thought to facilitate the development of SIBO. Excess bacteria in the small bowel can:

Induce inflammatory and atrophic changes in the gut impairing absorption
Deconjugate bile acids resulting in fat maldigestion
Consume vitamin B12 leading to deficiency
Cause a number of gas-related symptoms
Aggravate diarrhea leading to a reduction in oral intake

A number of limitations of the tests used to diagnose SIBO (i.e., small bowel aspirate with quantitative bacterial culture and hydrogen breath testing most commonly used), make securing the diagnosis of SIBO in SBS challenging. Because of the test limitations and the increased risk of SIBO in this patient population, empiric treatment is often provided. Antimicrobial treatment is generally prescribed; a variety of oral broad- spectrum antibiotics can be used (Table 6) with success being judged on improvement in symptoms, reduction in stool output and/or weight gain. The continuous use of low-dose antibiotics in SBS may be necessary in some patients. To reduce the risk of antibiotic resistance, periodic rotation of 3 or 4 antibiotics is advised.

Probiotics

While high-quality evidence supporting the use of prebiotic, probiotic and synbiotic agents in SIBO is lacking in adults, there is emerging evidence from both preclinical studies and reports in the pediatric SBS population of their benefit.⁴² It is also important to remember that probiotics are regulated as dietary supplements in the U.S. and therefore product purity and safety cannot be guaranteed. Until clear evidence is available, probiotic use cannot be recommended at this time.

Glutamine

Glutamine, a ‘conditionally essential’ amino acid, is a primary energy source for the enterocyte. Its use in SBS was popularized by a series of retrospective, open-label studies and a prospective randomized, controlled clinical trial when used in combination with human growth hormone and an optimized diet.^43,44 Nevertheless, when glutamine alone was added to an ORS provided to adult SBS patients with an end- jejunostomy, no benefit was seen in terms of fluid or sodium absorption.⁴⁵ Furthermore, in a randomized, controlled, crossover study involving eight adult SBS patients, glutamine resulted in no difference in small bowel morphology, transit time, D-xylose absorption or stool output.⁴⁶

SUMMARY

Treatment of short bowel syndrome requires aggressive use of several different pharmacological agents. To maximize their efficacy, it is important for clinicians to give thought to the site of absorption, formulation, frequency, timing of each drug and individual patient’s response to therapy. Setting and monitoring endpoints for each intervention (i.e., how long you will give each intervention time to achieve efficacy or not), is crucial in the care of the SBS population. In addition, cost considerations and availability to the patient depending on where they obtain their medications are important in order to improve medication adherence. Finally, remember that there are only 24 hours in a day, one-third or more of which is spent sleeping. It is important to periodically do a “Total Pill Count,” as not only do the prescription medications, over-the counter medications, and vitamin/mineral supplements add up (and can be quite overwhelming), the osmotic contributions of these agents, as well as the sheer volume of fluid needed to take them, can contribute to yet even more stool or ostomy output.

INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #92

The Current State of the Inflammatory Bowel Disease Drug Pipeline: A Promising Time

Jason R. Goldsmith,

Peter D.R. Higgins

The pipeline for IBD therapies has exploded in recent years, as advances in our understanding of the pathogenesis of IBD have led to new therapeutic targets. This includes multiple new mechanisms of action, ranging from biologic-based immunosuppression to mucosal barrier repair. This article reviews the promising mechanisms of action and specific agents currently in clinical trials for IBD.

Jason R. Goldsmith MD, PhD¹ Peter D.R. Higgins MD, PhD, MSc² ¹Department of Medicine, ²Department of Gastroenterology, University of Michigan, Ann Arbor, MI

BACKGROUND

In recent years, basic and translational science research into the pathogenesis of inflammatory bowel diseases (IBD) have resulted in a boom of new therapeutics for IBD. This started with the anti-TNF therapies, but has significantly broadened since. This article reviews the current state of the IBD drug pipeline (Figure 1). In this pipeline, several broad mechanisms of action (MOA) show significant promise, with multiple drugs in the pipeline, with many in late phase trials and one recent FDA approval. These MOAs include anti-adhesion therapies, anti-IL12/23 therapies, and Janus kinase (JAK) inhibitors. Other MOAs are less developed, but show promise as novel mechanisms. This includes therapies that directly modulate the immune response, therapies that alter the microbiome, and therapies that enhance/repair the intestinal barrier, as well as a new appreciation of the anti-inflammatory properties of several natural products.

Anti-Adhesion and Chemotaxis Therapies

Anti-adhesion therapies prevent the interaction between the endothelium of blood vessels and the integrins on a subset of white blood cells, preventing immune cell infiltration into organs and thus tamping down the immune response. Natalizumab (Tysabri) was the first drug in this class to be approved for use in CD, after the Phase 3 ENCORE trial demonstrated efficacy.¹ A monoclonal antibody targeting the a4 integrin subunit, it had broad effects, blocking the gut-specific a4ß7 integrin as well as the brain a4ß1 integrin. Thus, the antibody was also effective in the treatment of multiple sclerosis, by reducing immune surveillance in the brain. Unfortunately, long-term natalizumab has been associated with increased susceptibility to JC virus infection and subsequent development of progressive multifocal leukoencephalopathy (PML).²

Because of this risk of PML, development of gut-specific anti-integrin therapies were undertaken, culminating in the FDA approval of vedolizumab (Entyvio), a a4ß7-specific monoclonal antibody.³

Other second-generation anti-adhesion therapies are still in clinical trials. In phase 2 trials for UC and CD, abrilimumab (AMG181/MEDI7183) targets a4ß⁷ on WBCs like vedolizumab. Etrolizumab,⁴ which targets only the ß7 subunit on WBCs, is currently in Phase 3 trials for UC. PF-00547659,⁵ which targets enterocyte Mucosal Addressin Cell Adhesion Molecule-1, has completed phase 2 for UC and CD.

Because these second generation anti-adhesion therapies are designed to be gut-specific, there is a hypothesis that they may result in lower risk of infections (supported based on extensive impressive data with vedolizumab) than existing anti-TNF therapies. Consequently, head-to-head trials between anti-adhesion therapies and anti-TNF therapies are needed to determine whether these new therapies provide equivalent efficacy with improved safety; as it stands there is currently a set of two trials registered on clinicaltrials.gov to compare Etrolizumab vs adalimumab (Humira), but they are not yet in the recruiting phase.

In contrast to the aforementioned gut-specific injectable therapies, Ajinomoto Pharmaceutical has tested an oral small-molecule inhibitor (AJM300) of the a4 integrin subunit,6 demonstrating short-term efficacy. The authors hope that the pharmacokinetics of this drug, with its short half-life, will facilitate easy cessation should PML occur, and that the subsequent resumption of immune activity would prevent significant brain damage. However, given the significant harm caused by PML, the evidence level required for such a a4 agent to reach market will be quite high for the FDA and the European Medicines Agency. A biologic targeting a2 integrin, vatelizumab, is in Phase 2 studies for UC, but would likely encounter similar safety concerns to natalizumab and now AJM300.

A related approach involves inhibition of immune cell chemotaxis: the signaling that targets immune cells to different tissues. Several therapies are being pursued in this vein, including: 1) RPC1063, a sphingosine 1-phosphate 1 receptor modulator that inhibits lymphocyte egress from lymph nodes, which recently completed phase 2 trials for UC; 2) GS-5745, a monoclonal antibody targeting matrix metalloprotease-9 (MMP-9), a pro-inflammatory enzyme involved in wound repair and chemotaxis, in phase 1 trials for UC; 3) GSK3050002, a monoclonal antibody targeting chemokine (C-C motif) ligand 20, in phase 1 trials for UC; and 4) E6011, a monoclonal antibody inhibitor of chemotaxis being explored in Japan in Phase 1/2 trials.

Anti-IL-12/23 Therapies

Ustekinumab (Stelara) is a monoclonal antibody targeting p40, a subunit of both IL-12 and IL-23. It is on the market for psoriasis, and has proven effective in phase 3 trials for Crohn’s disease. It is believed to act through both inhibition of IL-12-mediated maturation of Th1 cells, and IL-23 mediated stimulation of Th17 cell survival and proliferation. With the completion of phase 3 trials, ustekinumab is anticipated to reach market within the next two years. Other compounds in this class include MEDI2070, an IL-23 specific agent that has finished recruitment for a phase 2 study. AMG139 is another IL-23 specific agent, which is in phase 1 dose-ranging studies for CD, and BI655066 is an IL23p19 sub-unit specific monoclonal antibody in phase 2 trials for CD. Based on the pipeline, it appears as if several therapies targeting this pathway will be available for CD in the future.

JAK Inhibitors

JAK inhibitors work by blocking the activation of the intracellular enzymes Janus Kinases 1-3, which transduce cytokine signals and generally active immune cells. The different agents under investigation vary in their selectivity for the different JAK molecules. Tofacitinib (Xeljanz) is a small-molecule oral JAK inhibitor which is FDA approved for rheumatoid arthritis, and in a head-to-head trial with adalimumab was found to be numerically superior without reaching statistical significance.7 Tofacitinib is currently in phase 3 clinical trials for UC and in phase 2 trials for CD. ASP015K/ JNJ54781532 is another JAK inhibitor (selective for JAK1/3) in phase 2 trials for UC, while GLPG0634 is a JAK inhibitor with similar selectivity in phase 2 trials for CD. Given the approval of Tofacitinib for rheumatoid arthritis (RA), it is likely that JAK inhibitors will reach the market soon, assuming they prove safe and effective in IBD. With the recent rejection of agent for RA in Europe on the basis of safety data, the fate of Tofacitinib for IBD is not a foregone conclusion in the USA.

Immune Cell Modulation

Other therapies focus on modulating the aberrant T-cell responses thought to be an important underpinning in the pathogenesis of IBD. One interesting approach being used in UC is directly tamping down the Th3-immune response believed to be involved in the pathogenesis of IBD. SB012, which is being investigated in a Phase 1/2 trial currently, is a rectally administered formulation of a DNAzyme that degrades GATA-3, a key transcription factor mediating the Th3 response. Another approach involves therapies to expand the regulatory T-cell (Treg) compartment that regulates inflammation. Low dose IL-2 has been shown to expand Treg populations and has clinical evidence supporting efficacy in auto- immune conditions, including alopecia⁸ and graft-vs- host disease.⁹ This approach is now being investigated in a phase 1&2 trials in UC and CD patients.

Similar immune modulation is being explored by Qu Biologics in phase 1/2 CD studies with a proprietary technology they have labeled site-specific immunomodulators derived from bacterial products, which are believed to alter macrophage function.

Microbiome-Targeted and Anti-Microbial Therapies

With the continuously evolving understanding of the host-microbiome interactions that underpin IBD, therapies designed to target the microbiome have received significant attention in recent years. Unfortunately, both probiotics¹⁰ and fecal microbiota transplant (FMT)¹¹ have not yielded consistent results in IBD and further work is still being undertaken. FMT in particular is seeing a large amount of continued research activity, given its low cost of acquisition and use. A phase 1 trial is ongoing in CD patients, and a phase 2/3 trial for FMT in pediatric IBD patients has been registered but is not yet open to enrollment. A phase 2 FMT trial is currently in the recruitment phase for patients with UC-associated pouchitis, and a phase 1 trial exploring pre- and post- FMT shifts in host microbiota population in patients with mild to moderate UC is also recruiting. One hypothesized problem with FMT in IBD is that the increased immune response in IBD patients may overwhelm the transplanted microbiota; to test this theory a phase 1/2 trial using serial FMTs is being pursued in CD patients. Another phase 4 study is looking at antimicrobial ablation with FMT rescue therapy in UC and Crohn’s colitis patients.

With the failure of probiotic studies in recent years, attention has shifted to prebiotics – compounds that shift the microbial composition, usually by serving as preferential metabolites for “good bacteria” to increase their relative presence. Synergy-1, a 1:1 oligosaccharide/ inulin mixture, has recently completed a Phase 2 trial in UC patients and results are pending. Unfortunately, previous pilot trials of fructo-oligosaccharides were very poorly tolerated by IBD patients due to high rates of bloating and discomfort, with 26% (vs. 8% in placebo) choosing to discontinue in the FOS arm, and additionally did not demonstrate clinical benefit.¹² In a related vein, studies of partial enteral nutrition, as a potential replacement to the poorly tolerated enteral nutrition approach, are being pursued in CD patients.

A third, perhaps more traditional approach, involves ablation of perceived “bad” gut microbiota that may be contributing to IBD. One approach being pursued in CD patients is the ablation of intra-macrophage bacteria using a combination of ciprofloxacin, doxycycline, and hydroxychloroquine. Another antimicrobial trial explores the hypothesis that CD is caused by an infection by mycobacterium avium subspecies paratubuclerosis (MAP) using a combination anti-MAP therapy of clarithromycin, rifabutin, and clofazimine.

Mucosal Barrier Enhancement

A different approach to treating IBD involves enhancing the mucosal barrier, as opposed to suppressing the immune system. The pathway with the strongest evidence using this approach is phosphatidylcholine, a key component of the mucosal barrier. Recent phase 2 trials of LT-02, a delayed release formulation of phosphatidylcholine, showed efficacy in UC patients,¹³ and phase 3 trials are being planned.

Natural Products

Herbal compounds used in other medical cultures, along with other natural products, have received increasing amounts of attention as potential therapies for IBD; especially as anti-inflammatory claims become backed by experimental evidence. Andrographis paniculata extract (HMPL-004) is a plant extract with broad anti-inflammatory properties (inhibiting TNF, NF- kB, and IL-1B)¹⁴ currently in phase 3 trials for UC as an alternative to mesalamine.^15,16 Flaxseed lignan- enriched complex (FLC), is another dietary extract with anti-inflammatory properties that is currently being investigated in phase 2 trials for UC. STW5 is an herbal preparation that has been shown to be efficacious in IBS¹⁷ and in murine colitis¹⁸ and a phase 2 trial has been registered at clinicaltrial.gov for UC patients. Tripterygium glycosides (T2), an extract of Tripterygium wilfordii Hook F, is a traditional Chinese medicine used in inflammatory conditions now being investigated in phase 2/3 trials for CD. Curcumin, a potent NF-kB inhibitor,¹⁹ is being explored alongside thiopurines in phase 3 trials to prevent post-op recurrence of CD. Milk-derived gangliosides, believed to be anti-inflammatory,²⁰ are being explored in early phase 1 trials in IBD patients.

Other Therapies

There are several other therapies in the pipeline for IBD that cover a wide range of modalities. Recruitment has opened for a Phase 2/3 clinical trial exploring hyperbaric oxygen for the treatment of UC. The mechanism of action is believed to broad anti-inflammatory properties.²¹ Other novel mechanisms of action under active clinical investigation include: 1) an oral antisense inhibitor of SMAD7 (Mongersen) which has completed phase 2 studies in CD; 2) small-molecule inhibition of toll-like receptor (TLR) 2 and TLR4 (via CD14): VB- 201, in phase 2 trials for UC; 3) umbilical cord blood stem cells (FURESTEM-CD) in phase 1/2 trials for CD; 4) placenta-derived cells (PDA001) in phase 1 trials for CD, 5) allogenic mesenchymal stromal cells in phase 1 trials in pediatric CD, and 6) AVX-470, a parenteral bovine anti-TNF that is oral bioavailable in the gut, which just completed phase 1 trials in UC patients.

CONCLUSION

The recent advances in our understanding of the pathogenesis of IBD have led to an explosion of drugs in IBD pipeline. In particular, MOA with multiple drugs in late-stage development include anti-adhesion therapies, anti-IL12/23 therapies, and JAK inhibitors. Barrier enhancing and microbiome-altering therapies are also being pursued, but these pipelines are less robust.

In addition to the aforementioned successes and promising candidates, there have also been several failures in recent years. Most notably, the recent negative trial of Trichuris suis ova appears to be the end of parasitic therapy, although the parasitic enzyme P28GST, derived from Schistosoma, is being explored as a post-resection agent in CD patients in phase 2 trials to prevent the recurrence of ileo-colonic disease. The negative trials for anti-IL-13 (tralokinumab) and anti- IL-17 (secukinumab) therapies have led to refocused basic mucosal immunology questions, continuing the feedback loop between bench and bedside research.

Additionally, phase 3 trials are limited in their ability to inform us how to best use a given therapy, demonstrating only clinical superiority to placebo. For instance, we have had access to infliximab since 1998, but we still continue to study how to best optimize its use.22,23 Currently, our approach to medical management of IBD is largely one of trial and error, starting with less potent drugs with safer side effect profiles, and escalating after clinical failure. We select more potent agents largely by fiat, as head-to-head trials of more potent agents, such as anti-TNFs or anti-TNFs and vedolizumab, are just starting to be performed. As we move forward, work is being done to move towards a more evidence-based approach. Future predictive models that could include genetic and clinical markers may be able to predict which patients are more likely to respond to or fail a given therapy, to avoid the slow, empiric approach currently being used. With increased understanding of the genetic24 and environmental factors that lead to IBD, we have come to appreciate that UC and CD likely have multiple underlying pathogenic routes which likely explain the variable responses to drugs seen between patients. As we can advance and align this knowledge with an expanding array of MOA for the treatment of IBD, one can envision that going forward, we will be able to select specific agents by MOA for a patient’s particular IBD subtype, rapidly producing better outcomes.

FRONTIERS IN ENDOSCOPY, SERIES # 16

Mirizzi Syndrome: A Rare but Relevant Biliary Entity

Kimberley Davenport,

Douglas G. Adler

Mirizzi Syndrome (MS) is a rare clinical entity that presents a formidable challenge when encountered. The constellation of a contracted gallbladder, obstructive jaundice, gallstones, pain and cholecystitis should arouse suspicion of MS. Here, we discuss the importance of a multidisciplinary team approach which includes a skilled endoscopist and surgeon. Treatment for each patient must be individualized, as specific MS types necessitate distinct surgical approaches.

Kimberley Davenport, University of Utah School of Medicine, Gastroenterology and Hepatology. Douglas G. Adler MD, FACG, AGAF, FASGE, Associate Professor of Medicine, Director of Therapeutic Endoscopy, Director, GI Fellowship Program, Gastroenterology and Hepatology, University of Utah School of Medicine, Huntsman Cancer Center, Salt Lake City, UT

CASE REPORT

A 64 year-old man presented to our facility with a one-day history of right upper quadrant pain, scleral icterus, and intermittent fever and chills. The patient’s vital signs included a temperature of 97.8, a pulse of 71, a respiration rate of 14, and a blood pressure of 124/80. On physical exam, he was mildly uncomfortable with key physical exam findings of right upper quadrant abdominal pain to palpation and on deep inspiration, scleral icterus, and jaundice. An abdominal ultrasound demonstrated mild intrahepatic biliary ductal dilation with at least one stone visualized in the gallbladder. The wall of the gallbladder was found to be slightly thickened without pericholecystic fluid and the common bile duct was measured at 11mm. A contrast-enhanced CT of the abdomen and pelvis was obtained and revealed prominent intrahepatic ductal dilation and what was interpreted as choledocholithiasis. Notably, the common bile duct had more distension proximally near the stone and less distension distally. GI and surgery consultations were obtained. A plan of preoperative ERCP followed by laparoscopic cholecystectomy was agreed upon.

ERCP revealed intrahepatic ductal dilation and proximal extrahepatic ductal dilation. Initial cholangiogram revealed what appeared to be a single, round 30 mm filling defect consistent with a stone eccentrically obstructing at the level of the CHD (Figure 1). Immediately proximal to the stone, there was visible dilation of the left and right hepatic ducts as well as the intrahepatic ducts. An inflated 15-18mm occlusion balloon could be pulled across the site of the stone without any apparent movement of the stone itself. Of note, the cystic duct was never seen to fill and was presumed to be obstructed. At this point it became apparent that the stone was actually within the cystic duct and was extrinsically compressing the CBD, consistent with a Mirizzi syndrome. An 8.5Fr x 12cm plastic biliary stent was inserted into the CBD across the site of extrinsic compression, with the proximal end of the stent in the CHD. (Figure 2) The patient improved clinically over the next 24 hours following biliary decompression. The patient was then referred for his cholecystectomy.

At surgery, the gallbladder was noted to be inflamed and adherent to the CBD, with what appeared to be a cholecystocholedocho fistula between the two at the level of the gallbladder neck/proximal cystic duct. Opening of the gallbladder revealed the impacted stone at the level of the fistula, which was then removed. Cholecystectomy was then carried out with subsequent incision of the CHD and removal of the impacted stone. The CHD was felt to have been damaged too severely by the stone/fistula combination for simple T-tube placement. The patient then underwent biliary reconstruction via a Roux-en-Y hepaticojejunostomy, although the distal CBD was left in continuity. The plastic bile duct stent was left in as a guide during surgery. The patient did well postoperatively and without complication.

A follow-up ERCP 8 weeks later demonstrated brisk flow of contrast through the biliary tree as well as a patent hepaticojejunostomy with free flowing contrast and bile into the small bowel. No filling defects were noted, indicating an absence of any residual or recurrent stones. Overall, the patient was felt to have developed a Type IV Mirizzi syndrome.

DISCUSSION

In developed countries, the incidence of gallstone disease has been rising of late with the majority of cases involving cholesterol stones. In the U.S. alone, an estimated 20 – 25 million adults suffer from some form of gallstone disease. Epidemiological studies have found that gallstone disease correlates highly with obesity, diabetes and metabolic syndrome.1 Though gallstones are understood to be multifactorial from an etiology point of view, one property these risk factors all share seems to be hypercholesterolemia: a condition that can allow supersaturation of bile by cholesterol with subsequent precipitation of gallstones.¹ Gallstones can lead to a variety of conditions including cholangitis, cholecystisis, gallstone pancreatitis, and even gallstone ileus.²

Mirizzi Syndrome (MS) is a rare complication of cholelithiasis.^3,4 Classically, the common hepatic duct (CHD) or the common bile duct (CBD) become obstructed from mechanical compression and surrounding inflammation by gallstone impaction at either the cystic duct or the gallbladder neck.^2,5 Compression by the impacted stone results in biliary obstruction which can then cause obstructive jaundice and in some patients also lead to cholangitis. ^4,6 From there, this process has the potential to further evolve into an internal biliary fistula, or even complete obliteration of the CHD.³

Overall, the incidence of Mirizzi Syndrome is rare, discovered only in 0.7 – 1.4% of patients undergoing cholecystectomy.⁷ Management has historically been difficult due to the inadequacy of pre-operative diagnosis as well as the surgical challenge it presents given the presence of active inflammation, dense adhesions, and distorted biliary ductal anatomy.^5,8

The term Mirizzi Syndrome refers to a collection of four subtypes of the disease commonly acknowledged as the Csendes Classification model.⁹ Type I is the most dominant form of MS and is characterized by extrinsic compression of the CBD due to an impacted stone at the cystic duct or the gallbladder neck. ^4,10 Types II, III and IV all include cholecystocholedochal fistulas.¹¹ Type II describes a fistula where 1/3 of the CBD circumferential wall has eroded.^4,9 Type III refers to a larger fistula with erosion of 2/3 of the circumferential wall of the CBD.^4,9 Finally, Type IV denotes a fistula that has caused circumferential damage to the CBD and thus requires reconstruction of the CBD.^4,9

Pathophysiology

Mirizzi Syndrome begins when a gallstone becomes impacted at the cystic duct or gallbladder neck and causes an inflammatory response. The offending stone then applies external pressure on the bile duct, eventually leading to erosion of the CBD with possible fistulization.¹²

Once this situation is established, episodes of biliary colic cause fibrosis and gallbladder atrophy.^12,13 Ongoing inflammation and proximity allow the gallbladder and/ or the cystic duct and/or the CBD to fuse together.¹² An impacted gallstone at this location likely causes a pressure ulcer which then develops necrosis. The necrotic tissue can enable partial stone migration into the CBD and ultimately the production of a chronic fistula.¹² Such cholecystocholedocal fistulas are the hallmark of Type II, III and IV Mirizzi Syndrome, but they are still exceedingly rare. In fact, most biliary fistulas are actually cholecystoduodenal, joining the gallbladder to the small bowel.¹¹ Despite advanced imaging, most fistulas are found intra-operatively during cholecystectomy.^4,11

Clinical Presentation

Mirizzi Syndrome is difficult to diagnose clinically because of its non-specific symptom profile.^5,6 Because MS resembles several other conditions, its differential diagnosis includes choledocholithiasis, cholecystitis, cholangitis, gallstone ileus, and gallbladder cancer.^5,11,12,14 Clinical presentation is non-specific, but obstructive jaundice is a common symptom – especially for types II, III and IV.⁴ RUQ pain is also frequently seen, along with a fever. Laboratory values often reflect elevated liver enzymes, hyperbilirubinemia, leukocytosis, and a high CA-19-9.¹²

A reported 28% of MS types II, III and IV cases also have also been found to have concurrent gallbladder cancer.^11,12 Notably, longstanding gallstones is one of the primary risk factors for both MS and gallbladder cancer.¹² Average age of onset for MS is around 61 years.⁹ Most MS patients have had gallstone disease for a mean of 29 years.¹²

Diagnosis

Lack of pathognomonic patterns or reliable clinical or laboratory indicators have made the diagnosis of MS difficult to distinguish from common choledocholithiasis.^5,15 Optimal management of MS and avoidance of iatrogenic bile duct injury during cholecystectomy depends on accurate preoperative diagnosis, although this cannot be made in all circumstances.¹⁰ Several modalities are available for biliary imaging including transabdominal ultrasound, CT, MRCP, endoscopic ultrasound (EUS) and ERCP.¹² Transabdominal ultrasound (US) is typically the initial imaging test ordered for suspected biliary disease because it is non-invasive, although it’s ability to detect choledocholithiasis is limited and the test is highly operator dependent.² US has high sensitivity to findings consistent with MS such as gallstones in the gallbladder neck, acute cholecystitis, a shrunken gallbladder and a dilated CHD.¹⁰ CT scans have the capacity to demonstrate dilated intra and extrahepatic ducts with gallstones in the biliary tree, but in general are a poor test to detect MS or choledocholithiasis.⁵ EUS is ideal for detecting choledocholithiasis but may fail to detect MS if the stone is located too proximally for the EUS transducer to visualize.¹⁶ MRCP (Magnetic Resonance Cholangiopancreotography) is noninvasive and has a high sensitivity for finding pericholicystic inflammation and cholecystobiliary fistulas.¹¹ However, ERCP (Endoscopic Retrograde Cholangiopancreotography) is the gold standard for diagnosis of MS.⁹ The sensitivity of ERCP for diagnosis of MS approaches 90%.^11,12 ERCP is both diagnostic and therapeutic.¹¹ Diagnostically, ERCP identifies ductal abnormalities and can distinguish with precision the cause, level and degree of biliary obstruction.¹⁰ Therapeutically, ERCP is used for stone clearance if the stone is endoscopically accessible.⁸ It also facilitates biliary decompression prior to cholecystectomy in patients with MS via stent placement, as was the case in our patient.^6,8 If a preoperative diagnosis of MS is not obtained, most experienced surgeons would recognize the entity in the operating room.

Treatment

The goals of treating patients with MS include: removal of the impacted stone and gallbladder, restoration of bile drainage and repair of the anatomical defect.^6,11 Preoperative ERCP can confirm the presence of MS.⁹ It also allows for placement of a temporary stent – providing critical decompression of the obstructed biliary duct.¹² Such decompression alleviates progression of any fistulas.¹⁴ Moreover, the stent will serve as a landmark in subsequent surgery to help minimize the risk of ductal injury.4 Preoperative ERCP is also a viable alternative for patients who are not candidates for open cholecystectomy (OC).¹²

Removal of the gallbladder and the impacted stone along with repair of the malformed anatomy is performed laparoscopically or by open surgery. OC has historically been the surgical standard of care for MS.⁴ However, LC is fast gaining acceptance as a viable alternative to OC.^6,11 The main advantage conferred by OC is a lower risk of iatrogenic bile duct injury than LC.¹⁴ This is large part due to the feasibility of a fundus first approach enabled by OC.17 Morbidity from OC has been reported to be 3% for MS type I. However, OC performed on types II and III correlate with a higher morbidity rate (15 – 26%) due to more complicated anatomical deformities.⁴ The biggest risk associated with OC is iatrogenic injury to the CBD.⁵ Such risk stems from the technical challenge presented by anatomical distortions, cholecystocholedocal fistulas, and adhesions in Calot’s triangle encountered in MS patients undergoing OC.^4,5 Disadvantages of OC include a larger incision which provides a higher risk of infection and wound dehiscence.⁸ Additionally, OC entails a longer recovery.⁶

Laparoscopic Cholecystectomy (LC) for treatment of MS has been somewhat controversial.¹⁰ Indeed, some surgeons still consider MS as a contraindication to laparoscopic cholecystectomy.^4,6,9 Nonetheless, LC has become a viable alternative to OC as experience and enhanced instruments continue to improve outcomes with this procedure.⁶ LC involves removal of the gallbladder, the impacted stone and suturing the biliary defect.⁸ Its advantages are that it is minimally invasive and by extension entails a lower risk of infection, produces less blood loss, and offers a shorter hospital stay.⁸ Some disadvantages are that it is technically demanding, requires a high degree of expert skill and thus a longer duration for the procedure.⁸

In general, LC is indicated for the less complicated MS as in Type I. Open surgery is indicated for higher risk cases of MS, difficult dissections (due to anatomical malformations or acute inflammation), and patients who have failed LC.⁸ In some cases, higher grades of MS: Type II, III and IV, may require open biliary-enteric bypass to repair extensive destruction of the bile ducts or strictures.¹¹ Such complete biliary reconstruction is termed a Roux-en-Y hepatico-jejunostomy and involves anastomosis of the jejunum with the fistula to close the eroded duct.¹⁸ Lastly, postoperative ERCP after complete healing of the site removes the temporary stent.⁸ The incidence of iatrogenic complications is reported to range between 0 – 14%.3 Such adverse events can be severe and include cholangitis, bile leakage from perforation of the CBD or perforation of the gallbladder, bile duct strictures from fistula repair, post-ERCP pancreatitis, and sepsis.3 Regardless of the intervention, a high risk of morbidity exists with treatment of MS.⁹

CONCLUSION

Mirizzi Syndrome is a rare clinical entity that presents a formidable challenge when encountered. The constellation of a contracted gallbladder, obstructive jaundice, gallstones, pain and cholecystitis should arouse suspicion of MS. A preoperative diagnosis is critical to optimal management and is best confirmed by cholangiography during ERCP, although not all patients have the diagnosis made prior to interventions. Once a definitive diagnosis of MS is made, a multidisciplinary team approach including a skilled endoscopist and surgeon offers the best outcome. Treatment for each patient must be individualized, as specific MS types necessitate distinct surgical approaches. Preoperative ERCP with stenting can restore bile flow and mitigate cholangitis, thus enhancing safety of subsequent surgery.

A Special Article

The City Criteria: A Review of Toponyms Used in Naming Diagnostic Guidelines

February 2016 • Volume XL, Issue 2

Alexander Gerald Chen,

Kheng-Jim Lim

Alexander Gerald Chen¹ Kheng-Jim Lim² 1Undergraduate, Columbia University, New York City, NY ²Division of Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School, New Brunswick NJ

INTRODUCTION

Based on the Greek word …t….. (kriterion), “criterion” is defined as the standard upon which a decision or judgment is based. The medical field abounds in criteria to aid in the diagnosis of diseases. Traditionally, classification schemes were named after individuals, giving rise to numerous medical eponyms (e.g. Ranson’s criteria), however, of late, eponyms have been abandoned and toponyms, names based on places, have come into vogue (e.g. the Atlanta criteria). No particular rule appears to guide this nomenclature other than the fact that a major meeting in which experts met to collaborate on the rules of the criteria. Most of the observations in modern medicine cannot be credited solely to an individual as the majority of today’s research is produced by joint effort, thus the simpler solution is use the name of the locale where the experts met and analyzed the research to formulate the guidelines.

Some of these criteria are a useful set of rules to follow in the diagnosis (e.g. the Rome Criteria) or treatment (e.g. the Toronto Consensus) of specific conditions. Similar to the utility of the instruction manual for a new piece of complex equipment, the average clinician may find the guidelines useful, as the various criteria offer a substantial road map in the diagnosis and treatment of diseases without significant deviation from the standard of good care.

The use of criteria by the practitioners of medicine is variable and depends on the popularity of the criteria and the incidence or prevalence of the disease. A criterion for diverticular disease diagnosis is thus more often used than one for endoscopic grading of esophagitis. The authors, realizing these limitations, aim to summarize the criteria in gastroenterology and assess their impact by using the citation indexing database “Web of Science” managed by Thomson Reuters.

All accompanying images are in the public domain and a world map is provided for reference.

Amsterdam Criteria for Lynch Syndrome
Rational

The authors of the Amsterdam criteria1 for hereditary non-polyposis colorectal cancer (ICG-HNPCC) or Lynch Syndrome came together with the goal of creating a simple system to help clinicians identify Lynch Syndrome for which there was little data about at the time.

Criteria

A patient is said to have Lynch Syndrome if he or she meets all the following criteria:
3 relatives with colorectal cancer (one of which is a first-degree relative of the other two)
= 2 successive generations affected
= 1 of the three diagnosed before age 50

Citation History

Citations for “Vasen HFA, Mecklin J-P, Meera Khan P, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG- HNPCC). Dis Colon Rectum 1991; 34: 424-425”

Naming

The Amsterdam Criteria was the result of the effort of 30 authorities in their respective fields from eight different countries who met in Amsterdam in 1990.

Atlanta Classification for Pancreatitis
Rational

Considering the many forms and complications of acute pancreatitis, it is no surprise that many classification systems for acute pancreatitis existed before the creation of what is now known as the Atlanta Criteria.2 This system set itself apart by being intended for clinical practicality and it defines many of the terms associated with acute pancreatitis.
Acute Pancreatitis The inflammation of the pancreas with possible involvement of other tissue or distant organ systems.
Severe Acute Pancreatitis Acute pancreatitis associated with organ failure and possibly local complications such as necrosis, abscess, or pseudocyst.
Mild Acute Pancreatitis Acute pancreatitis with minimal organ dysfunction and uneventful recovery. No indicators for severe acute pancreatitis present.
Acute Fluid Collections Occur early in acute pancreatitis, located within or close to the pancreas and always lack a wall of granulation or fibrous tissue.
Pancreatic Necrosis The diffuse or focal areas of nonviable pancreatic parenchyma, typically associated with peripancreatic fat necrosis.
Acute Pseudocysts A collection of pancreatic fluid enclosed by a wall of fibrous or granulation tissue, the result of acute pancreatitis, pancreatic trauma or chronic pancreatitis.
Pancreatic Abscess A circumscribed intra-abdominal collection of pus, usually near the pancreas, containing little or no pancreatic necrosis, the result of acute pancreatitis or pancreatic trauma.

Citation History

Citations for “Bradley EL III. A clinically based classification system for acute pancreatitis. Summary of the international symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992. Arch Surg 1993; 128: 586-90.”

Naming

This consensus was the result of the effort of 40 experts in their respective medical fields from around the world coming together in Atlanta, Georgia to decide upon these definitions.

Chicago Criteria for Achalasia
Rational

With the development of high resolution manometry (HRM), clinicians are able to more accurately measure the pressurization of the esophagus during peristalsis. However, there was no agreed upon usage of HRM to diagnosis motility disorders until the study published that is now referred to as the Chicago Criteria,3 which is summarized as follows:
Type I Minimal esophageal pressurization
Type II Absent peristalsis with esophageal pressurization
Type III Lumen destroying spasm on HRM

Citation History

Citations for “Pandolfino JE, Ghosh SK, Rice J, Clarke JO, Kwiatek MA, Kahrilas PJ. Classifying esophageal motility by pressure topography characteristics: a study of 400 patients and 75 controls. Am J Gastroenterol 2008; 108: 27-37”

Naming

The data for the study leading to the Chicago Criteria came from the Northwestern Memorial Hospital manometry laboratory located in Chicago, Illinois.

Glasgow Criteria for Pancreatitis
Rational

The Glasgow scoring system⁴ is intended to determine the severity of pancreatitis within 48 hours of a patient’s admission. It is actually a modification of a scoring system by Imrie et al.⁵ meant to increase accuracy and simplicity.

Criteria

The scoring system is a set of possible factors that the patient may exhibit. Three or more factors defines severe pancreatitis.
Age > 55
White Blood Count > 15,000/µl
Blood Glucose > 180 mg/dl
PaO2 < 60 mmhg
Serum Calcium < 8 mg/dl
Serum Albumin < 3.3 g/dl
Blood Urea Nitrogen > 45 mg/dl
Lactate Dehydrogenase > 600 U/L

Citation History

Citations for “Blamey SL, Imrie CW, O’Neill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984; 25”

Naming

This criterion was put forth by Glasgow University and the Royal infirmary of Glasgow.

Glasgow Classification of Alcoholic Hepatitis
Rational

Although grading systems for alcoholic pancreatitis have existed before the Glasgow alcoholic hepatitis score⁶, the authors of this classification system wanted to create a clinically useful system that more accurately identified patients with higher mortality risks in order to better inform treatment decisions.

Criteria

Each factor is given a score of 1, 2 or 3. Then, all the factor scores are combined for a total score. A total score greater than or equal to 9 is associated with a poor prognosis and increased risk of mortality.

Citation History

Citations for “Forrest EH, Evans CDJ, Stewart S et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut 2005; 54: 1174-9”

Naming

The data for this study was obtained from patients presenting with alcoholic liver disease to the Glasgow Royal Infirmary and the Victoria Infirmary which is also in Glasgow.

Los Angeles Criteria for Esophagitis
Rational

The creation of the Los Angeles criteria⁷ for esophagitis was intended to implement a universally accepted standard for grading the severity of gastroesophageal reflux disease (GERD). This system was intended to be easier to use and more clinically practical than the many existing classification systems for GERD.

Criteria

This system allows clinicians to interpret endoscopically observed peptic lesions and grade the severity of the GERD into one of the following categories:
Grade A 1 ≤ mucosal breaks, ≤ 5 mm long that does not extend between tops of two mucosal folds
Grade B 1 ≤ mucosal breaks, >5 mm long that does not extend between tops of two mucosal folds
Grade C 1 ≤ mucosal breaks, continuous between tops of = 2 mucosal folds but involves < 75% of esophageal circumference
Grade D 1 ≤ mucosal breaks that but involves = 75% of esophageal circumference

Citation History

Citations for “Armstrong D, Bennett JR, Blum AL., et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996; 111: 85-92”

Naming

The study leading to this criterion was performed at the symposium of the World Congress of Gastroenterology in Los Angeles, earning its name.

Marseille Classification of Pancreatitis
Rational

The main goal of the Marseille Symposium was to clarify the ambiguity in the literature concerning terms such as “Acute pancreatitis” which writers defined differently. The Marseille classification sought to solve these problems with a single well defined set of criteria for classifying pancreatitis. It has been noted in at least one study⁸ on pancreatitis how difficult it is to obtain the official Marseille publication, which was also apparent when trying to obtain an originating document for the purposes of the citation history. As a result, what seemed to be the most widely used document9 based on the Marseille classification was used for the purposes of the citation history.

Criteria

The Marseille classification of pancreatitis subdivided pancreatitis into “acute” and “chronic”
Acute Pancreatitis Defined as restitution of the pancreas when the cause of the disease is removed, such as a gallstone.
Chronic Pancreatitis Defined as the progression and or worsening of general lesions despite removing the source of the disease, such as alcoholism.

Citation History

Citations for “Sarles H, Sarles JC, Camatte R et al. Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 1965. 6; 545”

Naming

The Marseille symposium on pancreatitis took place in Marseille, Italy.

Milan Criteria for Liver Transplantation
Rational

The Milan criteria¹⁰ was developed to analyze the effectiveness of liver transplantation as a treatment for unresectable hepatocellular carcinomas in patients with cirrhosis. The need for such a criteria was recognized because of the limited supply of livers for transplantation and the uncertainty of transplantation as a viable treatment.

Criteria

The Milan criteria considers someone with unresectable hepatocellular carcinomas eligible for liver transplantation if they fall into one of these two categories: Number of Tumors Size ≤ 3 Each < 3 cm
Only 1 < 5 cm

Citation History

Citations for “Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.”

Naming

This classification system is known as the Milan criteria because multiple institutions that contributed to this study were all located in Milan, Italy. For example, the patients whose medical information was used to complete this study were all seen at the Division of Gastrointestinal Surgery of the National Cancer institute in Milan, Italy.

Milwaukee Criteria for Sphincter of Oddi Dysfunction
Rational

The Milwaukee criteria¹¹ deals with overlaps in the etiology of the motor dysfunction of the sphincter of Oddi by trying to develop patient group classifications that describe the severity of their sphincter of Oddi dysfunction.

Criteria

The Milwaukee system uses a scoring method, determining the severity of a patient’s SOD. Factors
A Biliary-like pain
B Elevated liver function tests documented = 2 times
C Delayed drainage of contrast medium at endoscopic retrograde cholangiopancreatopgraphy (ERCP)
D Dilated common bile duct with corrected diameter = 12mm at ERCP

Classification:
Type I All four factors present
Type II Factor A in addition to = 1 other factors
Type III Only factor A present

Citation History

Citations for “Hogan WJ, Greenen JE. Biliary dyskinesia. Endoscopy. 1988; 20: 179-183”

Naming

This criteria was formulated after an extensive study and a meeting of experts in Milwaukee, United States.

The Oslo Definitions for Celiac Disease
Rational

The incidence of celiac disease (CD) has been increasing in the United States over the past few decades, very often going undiagnosed.¹² With greater recognition and literature concerning CD arising, the Oslo definitions¹³ seek to create a consensus concerning the definitions for the various types of this multifaceted disorder and its related terms. The Oslo definitions came about as the result of a literature review concerning CD related terms from the database PubMed.

Criteria

The Oslo definitions cover a vast array of CD related terms, for simplicity only the definitions of different types of CD are listed here.
Celiac Disease A Chronic small intestinal immune-mediated enteropathy caused by dietary gluten in genetically pre-disposed individuals.
Typical CD Gluten-induced enteropathy with signs of malabsorption. The use of this term is discouraged because “typical” implies this form of CD is the most common when in fact the presentation of CD has changed over time to include symptoms such as anemia, fatigue and abdominal pain.
Atypical CD Used only in reference to typical CD and its use is discouraged. Traditionally, this term has been used to describe patients with gluten-induced enteropathy who do not have weight loss but may have irritable bowel syndrome symptoms, liver dysfunction or gastrointestinal symptoms.
Symptomatic CD Characterized by clinically evident gastro-intestinal and/or extraintestinal symptoms resulting from gluten consumption.
Asymptomatic CD Used to describe patients who do not present common symptoms of CD
Classical CD CD defined as showing signs and symptoms of malabsorption such as diarrhea, steatorrhea, weight loss or growth failure must be present.
Non-classical CD CD presenting without signs and symptoms of malabsorption
Silent CD Equivalent to asymptomatic CD. The use of this term is discouraged.
Subclinical CD CD below the threshold of clinical detection. Often used in reference to silent CD.
Overt CD Most often used to describe clinically evident gastrointestinal or extra-intestinal symptoms. The use of symptomatic CD is encouraged as a replacement of Overt CD.
Refractory CD Describes persistent or recurrent symptoms of malabsorption and signs of villous atrophy despite a gluten free diet for man than 12 months.
Latent CD Because the authors of the Oslo definitions found 5 different definitions for Latent CD, its use is discouraged to minimize confusion.
Potential CD Refers to people with normal small intestinal mucosa but who are at a higher risk for developing CD as indicated by positive CD serology. This term is used, however, with different definitions.

Citation History

Citations for Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for celiac disease and related terms. Gut 2013; 62: 43-52”

Naming

The team of 16 physicians from seven countries responsible for the Oslo definitions collaborated over the phone and internet but also had a meeting in Oslo, Norway.

Prague Criteria for Barrett’s Esophagus
Rational

The Prague classification system for Barrett’s Esophagus¹⁴ was developed in order to create one easily understood and effective method of describing Barrett’s Esophagus. Before this system, there was not only an absence of effective criteria but an abundance of ineffective methods for classifying Barrett’s Esophagus.

Criteria

The Prague system consists of two components, a “C” number and an “M” number.
Circumference (C) Describes the height above the gastroesophageal junction for which there is Barrett’s mucosa completely encircling the circumference of the esophagus.
Maximum (M) Describes the maximum height any “tongue” or continuation of the Barrett’s mucosa reaches in the esophagus.

Using this system, a description of a Barrett’s esophagus with a maximum circumferential height of 3cm and an absolute maximum height of 4cm can be abbreviated as “C3M4”.

Citation History

Citations for “Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: The Prague c & m criteria. Gastroenterology 2006; 131: 1392-1399”

Naming

This criterion was first put forth at the United European Gastroenterology Week in Prague, September 2004.

Rome Criteria For Irritable Bowel Syndrome
Rational

What is referred to today as the Rome Criteria has a long history¹⁵ which makes it difficult to single out one particular paper as the “originating” paper. Because of this, both the first diagnostic criteria for irritable bowel syndrome that the Rome Criteria has been based off of and the most recent Rome Criteria are presented. The evolution of the Rome criteria is conveniently laid out by W. Grant Thompson in his article Road to Rome.¹⁵

Criteria

The Manning criteria¹⁶ for IBS presents six factors of IBS, the more of which a patient presents with the more likely it is that he or she actually has IBS. The six symptoms are:
1. Abdominal distention
2. Alleviation of pain by bowel action
3. More frequent stools with onset of pain
4. Looser stools with onset of pain
5. Rectal passage of mucus
6. A sensation of incomplete evacuation

The Rome III criteria¹⁷ for Irritable Bowel Syndrome follows in the long tradition of the Rome criteria, building upon the Rome II criteria to update diagnosis and treatment recommendations. Concerning IBS, the diagnostic criteria is as follows:
Recurrent abdominal pain or discomfort at least 3 days a month in the last 3 months associated with at least 2 of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (Appearance) of stool

Citation History

Citations for “Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J 1978;2:653-654”
Citations for “Longstreth G, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130: 1480-1491”

Sendai Consensus Guidelines for Management of Intraductal Papillary Mucinous Neoplams and Mucinous Cystic Neoplams of the Pancreas
Rational

The increased recognition of two types of non- inflammatory cystic lesions of the pancreas, intraductal papillary mucionous neoplams (IPMN) and mucinous cystic neoplasms (MCN), prompted the working group of the International Association of Pancreatology to put out what is now known as the Sendai consenss guidelines¹⁸ for the management of IPMN and MCN.

Criteria

The Sendai consensus guidelines seek to answer 6 clinical questions with 18 subdivisions. Like the Sydney system, there is no practical method to summarize the Sendai consensus guidelines. Instead, the 6 areas of IPMN and MCN management it is concerned with are listed here.
1. Definition and Classification
2. Preoperative evaluation
3. Indication for resection
4. Method of resection
5. Histological questions
6. Method of follow-up

Citation History

Citations for “Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006; 6: 17-32”

Naming

The Sendai consensus guidelines were formulated during the 11th Congress of the International Association of Pancreatology which was held in Sendai, Japan.

Sydney System for the Classification of Gastritis
Rational

The Sydney Working Party developed the Sydney System¹⁹ in order to create a universal system that took into account the widespread use of endoscopic targeted biopsy and recognition of the H. pylori infection’s role in gastritis. It combines the etiology, topography and morphology of gastritis to create a working formula for its classification. It should be noted that The Sydney System was actually put fourth as six papers in the Journal Of Gastroenterology and Hepatology however for the purposes of this review, only the histological division was used for the citation history and criteria because it was the most frequently cited of the Sydney System papers.

Criteria

The Sydney System is not easily reproducible; to do so would be tantamount to including the entirety of the original paper so simply the main components of the histological division, as outlined in the paper, are named here.
Etiology Pathogenic associations
Topography Pangastritis, gastritis of antrum, gastritis of corpus
Morphology Graded variables: Inflammation, activity, atrophy, intestinal metaplasia, H. Pylori Non-Graded variable: Non- specific, specific

Citation History

Citations for “Price AB. The Sydney system: histological division. Gastroenterol. Hepatol. 1991;6: 209-22”

Naming

This criteria was the result of the efforts of the Sydney Working Party.

Toronto Consensus Guidelines for Medical Management of Nonhospitalized Ulcerative Colitis
Rational

Acknowledging the advancement of medical care for patients with Ulcerative Colitis (UC), the working group responsible for the Toronto consensus guidelines²⁰ conducted a thorough and systematic literature review in order to reevaluate the management of UC.

Consensus

The Toronto consensus guidelines include 34 statements on 5 classes of drugs, in addition to other conclusions.

Like the Sendai consensus guidelines, it would not be practical to include all the statements of the Toronto consensus here. The paper nicely summarizes its finding in a single table, whose main categories are listed here.
1. Statements regarding 5-ASA
2. Statements regarding corticosteroids
3. Statements regarding immunosuppressants
4. Statements regarding anti-TNF therapy
5. Statements regarding other agents

Citation History

Because the Toronto consensus guidelines came out last year, reporting its citation history is not practical or an accurate measure of its acceptance.

Naming

The working group met for 2 days in Toronto, Canada.