Page 60 – Practical Gastro

Nutrition Issues In Gastroenterology, Series #163

Pancreatogenic Type 3c Diabetes – Underestimated, Underappreciated and Poorly Managed

May 2017 • Volume XLI, Issue 5

Type 3c diabetes, also known as pancreatogenic diabetes, refers to diabetes resulting from pancreatic disease, including pancreatitis, cystic fibrosis and pancreatic cancer. It is difficult to diagnose, and for many, management is challenging due to erratic swings from hypoglycemia to hyperglycemia caused by metabolic abnormalities due to pancreatic tissue damage. This review aims to describe the disease along with its characteristics, diagnosis, complications, and management.

Sinead N. Duggan RD PhD, Research Fellow, 1.29 Department of Surgery. Professor Kevin C. Conlon MD, Professor of Surgery, 1.36 Department of Surgery, Trinity Centre for Health Sciences,Tallaght Hospital, Trinity College Dublin, Tallaght, Ireland

CLINICAL CASE 1

A 42 year old male with an eight-year history of alcohol-induced chronic pancreatitis was admitted from the ER. His current weight was 61Kg as opposed to his usual weight of 67Kg; his appearance was cachectic. He reported abdominal pain, intermittent diarrhea/steatorrhea along with periods of constipation, cramping, flatulence and poor appetite. He was not compliant with prescribed pancreatic enzyme replacement therapy (PERT), was still abusing alcohol, and was a heavy smoker for many years. He took opiates for relief of chronic, constant abdominal pain. His dietary intake was minimal over the past week and poor for several years. He was admitted and re-educated regarding adequate dietary intake, prescribed oral nutritional supplements, and counselled on adequate and appropriate usage of PERT. Blood work revealed low levels of serum vitamins (25 OHD, vitamin E and vitamin A), normal fasting glucose and HbA1c. He was discharged after 3 days once he was established on adequate oral diet, micronutrient supplementation, PERT, and his pain medication had been adjusted. He was readmitted three weeks later with dehydration, fatigue, excess thirst and blurred vision. Fasting glucose was measured and was elevated at 250 mg/dl (13.9 mmol/L), therefore new diabetes mellitus (DM) was diagnosed. A referral was made to the endocrinology service for further evaluation.

CLINICAL CASE 2

A 37 year old female with a five-year history of type 2 diabetes mellitus (T2DM) presented to the gastroenterology outpatient clinic complaining of a 6 month history of diarrhea (3-4 times per day), flatulence and bloating. She had taken anti-diarrheal medication with limited effect. She reported that the diarrhea tended to occur post-prandially, and was worse with larger, ‘richer’ meals. She reported that she could see visible oil in the toilet pan after defecating, requiring several flushes. She also had a history of three episodes of hypertriglyceridemia-induced acute pancreatitis. On one occasion the acute pancreatitis had been deemed ‘severe’ and she was hospitalized for several weeks, including one week in the critical care unit requiring enteral feeding. She was 88Kg (BMI 30.4 Kg/M2). Given her history of acute pancreatitis, and the oily nature of her stools, pancreatic exocrine insufficiency (PEI) was suspected and a fecal elastase-1 test ordered. Results showed faecal elastase-1 of 95µg /g (indicating severe PEI). She was referred to a pancreatologist for further workup and pancreatic imaging.

INTRODUCTION

According to the American Diabetes Association (ADA), there are four DM subgroups. Most are familiar with type 1 diabetes (T1DM), an immune- mediated condition associated with beta-cell destruction leading to absolute insulin deficiency. T2DM is well recognized as a spectrum involving varying degrees of peripheral insulin resistance and beta cell dysfunction. Type 4 DM refers to gestational or pregnancy-related diabetes.¹ This review will focus on Type 3 DM, categorized by the ADA as ‘other specific types of diabetes’. In particular we will focus on type 3c diabetes (T3cDM), which refers to DM arising from diseases of the exocrine pancreas. T3cDM is also referred to as pancreatogenic or apancreatic DM. A study from Europe on the reclassification of nearly 2,000 patients with DM reported that 8% of patients should have been diagnosed with T3cDM, rather than T1DM or more usually, T2DM.² Three-quarters of the patients reclassified as having T3cDM had chronic pancreatitis, while the rest had haemochromotosis, cystic fibrosis, or were pancreatic cancer patients. Therefore, this study showed that T3cDM was reasonably common. Several clinical and biochemical indices distinguish T3cDM from T1DM and T2DM (see Table 1). Due to its association with pancreatic disease, patients are more likely to be undernourished or have nutrient deficiency.³ Pancreatic exocrine insufficiency (PEI) will also be a feature resulting in fat malabsorption. The management of patients with T3cDM is challenging due to a number of metabolic features (especially low glycogen stores due to malnutrition making counter- regulation difficult, normal glycated hemoglobin due to long standing poor nutrient absorption, then sudden nutrient utilization once PERT initiated, exaggerated response to smaller doses of insulin to name a few) resulting in severe swings in glucose levels from hypoglycemia to hyperglycemia, which in its most severe form is termed, ‘brittle diabetes’.

PREVALENCE OF T3cDM

While the study from Germany by Ewald and colleagues found that 8% of all diabetes patients had T3cDM, most of which had chronic pancreatitis, the occurrence of T3cDM in this disease actually ranges widely from 5% to more than 80%. It is higher in patients who have undergone surgical resection, especially of the distal pancreas.⁴ Smoking,^5-7 longer duration of disease,^4,8 and the presence of pancreatic calcifications^4,9,10 increases the likelihood of developing DM in chronic pancreatitis. In general, it is thought that T3cDM is vastly underestimated. With the increased rates of pancreatic surgery and pancreatectomy, the increasingly higher survival of cystic fibrosis patients, and the increasing prevalence of chronic pancreatitis world-wide, T3cDM is of growing importance.¹¹

DIAGNOSIS AND DIFFERENTIATION OF T3cDM

Initial diagnosis of T3cDM (as for types 1 and 2), includes measurement of fasting glucose and glycated hemoglobin (HbA1c or A1c), repeated annually for those with pancreatitis. Equivocal results should arguably be investigated further by means of an oral glucose tolerance test.¹² The ADA guidelines state that fasting plasma glucose of >126 mg/dl (>7mmol/L) or HbA1c of >48 mmol/mol (6.5%) are diagnostic of DM, while a fasting glucose of 100-125 mg/dl (5.5-6.9mml/L) or HbA1c of 39-46 mmol/mol (5.7- 6.4%) are indicative of prediabetes.^1,13 However, differentiating T3cDM from T1DM and T2DM is not always straightforward.¹⁴ Destruction of the islet cells by pancreatic inflammation differs from that in T1DM as there is also a loss of glucagon and pancreatic polypeptide (PP) from the islet alpha cells and PP cells (as well as the loss of insulin from the islet beta-cells). Additionally, nutrient maldigestion and malabsorption lead to impaired incretin secretion and therefore diminished release from the remaining beta cells. Although circulating insulin levels are known to be low in T3cDM, along with a compensatory increase in peripheral insulin sensitivity, there is a decrease in hepatic insulin sensitivity (and unsuppressed hepatic glucose production), which drives hyperglycemia (see Table 1). The impairment of hepatic insulin sensitivity and persistent hepatic glucose production is associated with the reduction in pancreatic PP secretion.¹¹ Therefore, the DM associated with pancreatic disease is erratic in nature, characterized by significant swings in blood glucose from hypoglycemia to hyperglycemia in a manner which is difficult to control.

Ewald and Hardt¹⁴ devised diagnostic guidelines for T3cDM, providing useful major and minor criteria which suggest a diagnosis of T3cDM. Major criteria which must be present include:

1. Pancreatic exocrine insufficiency
2. Pathological pancreatic imaging
3. Absence of T1DM-associated auto-antibodies.

The minor criteria were absent PP secretion, impaired incretin secretion, absence of excessive insulin resistance, impaired beta-cell function, and low serum levels of fat-soluble vitamins.

Assessment and monitoring of patients with pancreatic disease should include body mass index, diabetes-associated antibodies (to out rule T1DM), and glucose to c-peptide ratio which estimates beta- cell area.¹² Insulin resistance is measureable by the homeostasis model assessment, which estimates steady state beta-cell function and insulin sensitivity as percentages of a normal reference range. This is calculated based on fasting plasma glucose and insulin values. Unlike T2DM patients, those with T3cDM will not normally have excess insulin resistance. The absence of (or reduced) PP secretion following ingestion of glucose or a mixed meal may also be indicative of T3cDM.¹⁴ However, these guides require the measurement of incretin, PP and c-peptide levels, among others, which in everyday practice is unlikely to occur. Table 1 compares the clinical and laboratory characteristics of T3cDM with that of T1DM and T2DM, which is an expansion of earlier versions by Slezak and Andersen15 and Cui and Andersen.¹¹

While T3cDM has features which overlap with both T1DM and T2DM, it is clinically and metabolically distinct from both, having unique characteristics and specific management priorities requiring tailored therapy. The additional complication of nutrient malabsorption, and frequently poor oral diet (to avoid symptoms), including chronic pain; smoking and/or alcoholism), renders the T3cDM patient at high risk of undernutrition and critical hypoglycemia. In clinical case 1, the patient did not present with gross steatorrhea as one might expect in advanced chronic pancreatitis (but remember one has to eat fat to malabsorb it – often intake can be so poor, this is another reason why it is missed), therefore it might be perceived that the small amounts of PERT taken was adequate to counteract PEI. However, once normal diet resumed and PERT dosage/administration were optimized (allowing optimal absorption of nutrients including carbohydrate), there was an ‘unmasking’ of his DM. In patients who already have a diagnosis of DM, there may be a profound worsening of hyperglycemia. Where patients take opiates due to chronic pain, constipation may be a surprising feature of chronic pancreatitis, leading the clinician to believe that PERT is adequate or unnecessary, contributing to undernutrition and nutrient deficiency. In clinical case 2, our patient with DM had undiagnosed PEI demonstrating that altered pancreatic function should be considered in diabetic patients with intractable gastro-intestinal symptoms, particularly those with a history of pancreatic disease.

COMPLICATIONS OF T3cDM

Retinopathy, renal dysfunction, neuropathy and microangiopathic complications appear to occur as frequently in T3cDM as in T1DM and T2DM.^16-19 It is thought that macrovascular complications occur less frequently due to chronic malabsorption and commonly- occurring undernutrition, however research and long- term studies are lacking and the risks are incompletely understood.

PHARMACOLOGICAL TREATMENT OF T3cDM

There are few, if any, studies on the pharmacological treatment of T3cDM. In fact, patients with T3cDM were specifically excluded from many large-scale DM studies due to their unique, eccentric clinical and metabolic characteristics. In chronic pancreatitis, for those with severe undernutrition, insulin is usually required to control blood glucose levels. Notably, Cui et al. have cautioned against using insulin in chronic pancreatitis (calling it a ‘pre-malignant condition’).¹¹ It should be noted that the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial,²⁰ which included patients with impaired fasting glucose, impaired glucose tolerance and T2DM, showed that there was no increase in incident cancers for those on insulin glargine versus standard care. The risk of developing pancreatic cancer for those with chronic pancreatitis is higher than the general population, and for those with T2DM, the risk of developing pancreatic cancer is twice that of the general population. However, those with T2DM are at a higher risk for many cancer types, so the risk is not confined to pancreatic cancer alone.²¹ In fact, many will require insulin to control rampant hyperglycemia, and its anabolic effects are welcome in those with undernutrition. For those with more mild hyperglycemia and concomitant insulin resistance, metformin could be used if not contraindicated, although it may cause gastrointestinal side-effects such as nausea and diarrhea, unwelcome additions in pancreatic disease. Even where insulin therapy is required, metformin and other oral hypoglycemic agents could be used to reduce the requirement for large amounts of insulin.²²

NUTRITIONAL MANAGEMENT OF T3cDM

The PancreasFest Working Group²³ were the first to provide a diagnostic and management framework for T3cDM in chronic pancreatitis. They recommended that patients with T3cDM should be treated with specifically-tailored medical nutrition, and that the primary goals are to prevent or treat malnutrition, control symptoms of the steatorrhea, and to minimize meal-induced hyperglycemia. Cui and Andersen stated that initial therapy should begin with correction of lifestyle factors which contribute to hyperglycemia and malignancy, including reinforcing weight loss for the obese, daily exercise, and limited carbohydrate, along with recommending abstinence of alcohol and smoking cessation at every medical visit.¹¹

A recent review by Duggan et al. aimed to provide detailed dietary guidelines.¹² In the first instance, dietary management should prioritize the prevention of hypoglycemic events and the provision of education regarding hypoglycemia symptoms and treatment (Table 2). A regular meal plan with specified, controlled amounts of starchy carbohydrate should be provided. Blood glucose should be monitored regularly (Table 3), with self-monitoring recommended especially for those on intensive insulin regimens. This is based on the ADA recommendations for T1DM and T2DM patients on intensive insulin regimens. The ADA did not provide a guide specifically for T3cDM, but given the risks of hypoglycemia and the difficulties in management, such a monitoring regimen could be implemented if tolerated by the patient. According to the ADA, such intensive monitoring regimes are probably not required for those on basal insulin plans, or for those taking oral hypoglycemic agents.

Those with ‘brittle’ DM in particular should maintain a record of blood glucose values, dietary intake, physical activity, and PERT usage to aid in dietary review and assessment.¹² Continuous Glucose Monitoring (CGM) may have an important role in patients with brittle diabetes. The recently Food and Drug Administration (FDA)-approved DEXCOM (www.dexcom.com; San Diego, CA) G5 mobile CGM system is externally-worn glucose sensor which reports values every 5 minutes. This allows for the prediction of imminent hypo- or hyperglycemia, and reduces the requirement for multiple fingerstick blood glucose testing. The DEXCOM system uses algorithmic signal processing to convert raw electrochemical blood glucose values. Therefore the CGM system may allow for a reduction in HbA1c, without an increased risk of hypoglycemia.²⁴

Alcohol, which will exacerbate hypoglycemia, should be avoided or minimized. The second priority is to reduce the frequency and extent of hyperglycemic events to minimize the risk of diabetes-associated complications. This includes minimizing simple sugar sources, especially in liquid form, and following a low- glycemic diet, where feasible. ‘Diabetic’ foods, which are expensive and may have a laxative effect in large quantities due to sorbitol (and other sugar alcohols) content, are generally not recommended. Adequate PERT, taken appropriately, is crucial to ensure nutrient absorption. Education around malabsorptive symptoms and dose titration should be provided.¹² Management of T3cDM in pancreatic disease represents just one of the challenges in the nutritional management of this complex patient group. In both chronic pancreatitis and cystic fibrosis, regular anthropometric assessment, biochemical workup, and evaluation of bone health should accompany endocrine, exocrine and dietary evaluation.^25,26 The ADA recommended that an individualized medical nutrition therapy program be established by a registered dietitian; specifically they recommended that an individualized eating plan be established. This recommendation, again, was for patients with T1DM and T2DM, but would also be vital in T3cDM.

CONCLUSION

In summary, T3cDM is a clinically important disease, which has to date been underestimated and underappreciated, and thus, tends to be poorly managed. As yet, there remain many research gaps regarding its diagnosis and management. Close, careful glycemic control, optimization of intestinal absorption and nutritional status, as well as to account for the complex array of factors contributing to this challenging condition.

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Duodenal Post-Transplant Lymphoproliferative Disorder (PTLD) with History of Heart Transplant

April 2017 • Volume XLI, Issue 4

Karen Tsai,Thomas Coppola,Raluca Vrabie

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Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy in adult transplant recipients. We present a case of PTLD in the duodenum in a 48-year-old, Epstein-Barr virus positive female who underwent remote heart transplant due to postpartum cardiomyopathy. Her PTLD manifested as acute onset hypoalbuminemia and severe diarrhea. The diagnosis was made from duodenal biopsies, which looked mildly nodular. Remission of PTLD and symptom resolution were seen with reduction of tacrolimus and increase in valacyclovir doses. Although a rare entity, PTLD is a relevant clinical diagnosis in solid organ transplant patients who have unexplained diarrhea.

Karen Tsai, BA, MD Candidate¹ Thomas Coppola, DO, Gastroenterology Fellow² Raluca Vrabie, MD Director of the Center for Inflammatory Bowel Diseases² ¹Stony Brook University School of Medicine, Stony Brook, NY, ²Winthrop University Hospital, Department of Gastroenterology, Mineola, NY,

INTRODUCTION

Post-transplant lymphoproliferative disorder (PTLD) is a serious and potentially fatal complication after solid organ transplant. It is the most common malignancy post solid organ transplant in adults and occurs in up to 10% of patients.¹ With increasing number and improving survival of solid organ transplantations, clinicians should be aware of post-transplant complications. PTLD is an entity that is usually seen within the first few years post-transplant, mediated by the degree of immunosuppression and the EBV status of the patient. Clinical symptoms of PTLD can be highly variable, ranging from acute viral illness mimicking infective mononucleosis to organ-specific symptoms often making the diagnosis challenging.

Presentation

A 48-year-old female with a history of heart transplant 16 years ago from Coxsackie-induced postpartum cardiomyopathy presented to the hospital with complaints of fatigue and severe diarrhea for the past month. Her diarrhea was watery, non-bloody, occurring six times a day and unrelieved by intermittent loperamide use. She denied any sick contacts or recent travel. Her medical history consisted of renal insufficiency secondary to chronic tacrolimus toxicity, anal squamous cell cancer diagnosed two years ago (treated with surgery, Nigro chemotherapy and radiation), Epstein-Barr virus (EBV) infection, genital herpes and Kaposi sarcoma (excised). Her home medications included tacrolimus for transplant immunosuppression and valacyclovir.

On exam, she demonstrated whole body anasarca, abdominal ascites and 3+ pitting edema in her lower extremities bilaterally up to the knees and lower back. Her labs were significant for hypoalbuminemia (2.1g/dL; normal 3.5-4.8g/dL), and hypereosinophilia (absolute eosinophil 1.4K/uL; normal 0-0.5K/uL). Urinalysis was negative for hematuria and proteinuria. Tacrolimus level was 9.9ng/mL (normal 5-20ng/mL). An infectious gastroenteritis workup including ova and parasites, stool culture including Salmonella, Shigella, Campylobacter and Clostridium difficile was negative. Serum tissue transglutaminase and stool lactoferrin, pancreatic elastase and calprotectin were unremarkable. Liver enzymes were within normal limits.

The patient underwent upper endoscopy and colonoscopy with biopsies. The endoscopy was largely normal, with mildly nodular mucosa in the duodenal bulb (Fig. 1). The colonoscopy was grossly unremarkable. Pathology results from the duodenal bulb showed atypical lymphoid infiltrates consistent with PTLD and atypical cells that expressed CD20, CD79a and BCL-2 and were negative for CD10 (Fig. 2a, 3a). Small bowel mucosa showed eosinophilia and scattered cells tested positive for EBV (Fig. 2b). This atypical lymphoid infiltrate showed a kappa to lambda ratio of 8:1, which was consistent with her serum monoclonal gammopathy.

Her tacrolimus dose was decreased due to the development of PTLD. Her symptoms markedly improved, and she was discharged with repeat endoscopy and colonoscopy six months later. Repeat endoscopy with biopsies showed remission of PTLD (Fig. 3b). The patient continued to follow with her transplant physician and oncologist who recommended continuing the current dose of tacrolimus , evaluating the therapeutic level biweekly. Her valacyclovir was increased. After these medication adjustments, her albumin increased from 2.1g/dL to 3.7g/dL and she had complete resolution of diarrhea and anasarca.

Discussion

PTLD is a well-recognized complication that occurs after solid organ transplantation. It is primarily caused by a B-cell proliferation due to therapeutic immunosuppression after organ transplantation. Tacrolimus suppresses T cell immunosurveillance, which in certain circumstances can cause the EBV virus to proliferate in immunogenic tissues. Due to its high content of immunogenic tissue, the gut provides an ideal location for the proliferation of PTLD.

The prevalence of PTLD differs with different organ allografts, with the highest prevalence in multivisceral transplant recipients (13%-33% of cases), followed by bowel (7%-11%), heart-lung (9.4%), lung (1.8%-7.9%), heart (3.4%), liver (2.2%) and kidney (1%) recipients.² PTLD can occur years after transplantation with no inciting factor. Risk factors of PTLD include previous EBV infection, recipient age (<10 and >60 years-old show greater risk), degree of immunosuppression and host genetic factors.³

Known manifestations of PTLD include gastrointestinal bleeding, weight loss, abdominal discomfort, nausea and diarrhea. Protein-losing enteropathy with hypoalbuminemia is the most sensitive sign of gastrointestinal PTLD.⁴ The duration of the post-transplant period is important because PTLD is most likely to develop in the first year following transplantation, with an incidence of 224 per 100,000 in the initial year, decreasing to 54 per 100,000 in the second year and 31 per 100,000 in the sixth year.⁵ Our patient’s presentation of PTLD happened 16 years after transplant which was quite unusual.

After tacrolimus and valacyclovir dose adjustments, our patient’s symptoms improved markedly. Although no standard formula exists, decreasing tacrolimus or cyclosporine by 50% is often recommended.⁶ Approximately 40% of patients respond to reduction in immunosuppression alone.⁷ It is important to note is that although her tacrolimus levels were not elevated at time of presentation, she still developed PTLD.

Antivirals such as valacyclovir can possibly reduce the incidence of PTLD by lowering EBV viral loads, especially since EBV infection is associated with PTLD in up to 8% of transplant recipients.8 Since the patient was taking valacyclovir for her genital herpes, this may help explain the late PTLD presentation. Current treatments, such as rituximab-based regimens, are starting to become more defined in B-cell lymphoproliferative disorders because they express CD20 and treatment with rituximab is considered to be relatively non-toxic compared with traditional chemotherapeutic agents.³ Currently, primary prevention of PTLD includes EBV vaccination and chemoprophylaxis via antivirals such as acyclovir or ganciclovir.⁸

PTLD is a serious and feared complication in the post-transplant patient. This case is unique because of the patient’s late presentation, dramatic response to adjustments in tacrolimus and valacyclovir and the fact that the patient developed PTLD in the setting of normal tacrolimus levels. Understanding PTLD and having a greater awareness is crucial due to its high mortality rate and late diagnosis. Further research on PTLD can focus on exploring universal screening techniques and defining preventative strategies and optimal therapy.

Learning Points

Consider PTLD in a patient with gastrointestinal symptoms with history of solid organ transplant
Diagnosis of PTLD is made by endoscopy and colonoscopy with biopsies so gastroenterologist consultation should not be delayed when there is suspicion of PTLD

Acknowledgements

We would like to thank Dr. Kristin Sticco from the Winthrop University Hospital Department of Pathology for providing the images.

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Dispatches From The Guild Conference, Series #3

Detecting and Managing Dysplasia in Inflammatory Bowel Disease: 5 Key Tips

April 2017 • Volume XLI, Issue 4

Fernando Velayos

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The field of IBD-related CRC prevention is evolving. Fortunately, important advances in disease management to control inflammation (primary prevention) as well as improved detection of precancerous lesions (secondary prevention) have transformed how we think about colorectal cancer and how we detect and manage dysplasia today even compared to 10 years ago. The following review discusses 5 key tips for detecting and managing dysplasia in patients with IBD today.

Fernando Velayos, MD, MPH, Professor of Medicine Co-Medical Director, Center for Crohn’s and Colitis University of California, San Francisco, CA

INTRODUCTION

Colorectal cancer (CRC) is a feared complication of inflammatory bowel disease (IBD). Long- standing inflammation of the colon, a feature of both ulcerative colitis (UC) and Crohn’s disease (CD) of the colon, can cause genetic and epigenetic changes that lead to neoplastic transformation called dysplasia. If dysplastic lesions are allowed to continue, they ultimately progress to cancer. It is well known that the risk of CRC is driven primarily by extent and duration of inflammation. Except for histological inflammation at colonoscopy, most other risk factors are not potentially modifiable such as family history of colon cancer, presence of pseudopolyps, primary sclerosing cholangitis and of course extent and duration of disease. Some of these non-modifiable risk factors therefore serve as ways of identifying at risk patients who should undergo screening and surveillance colonoscopy.

The field of IBD-related CRC prevention is evolving. Fortunately, important advances in disease management to control inflammation (primary prevention) as well as improved detection of precancerous lesions (secondary prevention) have transformed how we think about colorectal cancer and how we detect and manage dysplasia today even compared to 10 years ago.¹ The following review discusses 5 key tips for detecting and managing dysplasia in patients with IBD today.

1. Look for Dysplasia in the Right Patient

Several published guidelines recommended colon cancer screening and surveillance in patients with inflammatory bowel disease. Although the data demonstrating cancer screening in IBD reduces CRC mortality are limited, they are balanced by data demonstrating reduction in CRC risk over time in surveillance programs.² Three United States (US) based major gastrointestinal societies, American Gastroenterological Association (AGA),³ American College of Gastroenterology (ACG)⁴ and American Society of Gastrointestinal Endoscopy (ASGE)⁵ all endorse colonoscopy-based screening and surveillance in patients with IBD (Table 1).

The first key thing to note is that while patients with IBD may get frequent colonoscopy, this often occurs in the setting of active disease and work up of symptoms. In contrast, colonoscopy performed for the purpose of screening should occur when disease is quiescent and otherwise would not have been performed. Although obviously “opportunistic screening” can occur during a symptom-indicated colonoscopy, analogous to removing a polyp in the work-up of a non-IBD patient who has diarrhea or abdominal pain, the fact is that these should not be considered pure screening. Symptom-based colonoscopies performed in patients with IBD or those with active inflammation should not be considered strictly screening unless inflammation is minimal as inflammation can obscure the presence of dysplastic lesions.

Regardless of the guideline used, the three US- based guidelines all make a recommendation for a first screening colonoscopy and then a recommendation for subsequent colonoscopies assuming no dysplasia is found. Almost all recommend performing the first screening colonoscopy within 8-10 years after diagnosis or alternatively, symptom onset, in all patients regardless of extent. The exception is in patients diagnosed with primary sclerosing cholangitis where it should occur immediately after the diagnosis of PSC. The latter recommendation is based on epidemiologic data showing a significantly increased colon cancer incidence in patients with PSC and that PSC patients often have occult low-grade clinical inflammation, therefore making assessment of disease duration a challenge. Biopsies should be taken in the right and left colon as well as the rectum, as subsequent intervals should be based on the degree of histological inflammation.

Assuming the colonoscopy did not detect dysplasia, guidelines vary with regard to the next colonoscopy, but they all recommend more frequent colonoscopy than the general population. Patients with isolated proctitis, Crohn’s involving less than one third of the colon, or isolated small bowel Crohn’s, do not need subsequent intense surveillance as their risk of colon cancer approximates that of the general population. For all other patients, the intervals between colonoscopies for IBD patients vary between one and three years depending on the guideline with wide latitude regarding criteria for the subsequent interval. The British society of Gastroenterology Guidelines, not included in the table, risk stratifies subsequent colonoscopies based on degree of inflammation and other risk features so that patients with the lowest risk features may not need the next colonoscopy for five years. Such an extension to five years for surveillance has not formally entered into US-based guidelines, although not unreasonable for low risk patients with no evidence of pseudopolyps and no symptoms or evidence of inflammation on colonoscopy over many years.

2. Focus on Mucosal Abnormalities, Not Simply Random Biopsies During Colonoscopy

The classic technique for performing screening and surveillance involves taking 33 random biopsies throughout the colon. This approach is quite different to what we do during screening colonoscopies in patients without IBD. This unique approach for screening and surveillance in patients with IBD was based on the common notion nicely summarized in a 1995 review article that 95% of dysplastic foci occurred in patients in flat mucosa and was essentially invisible and only occasionally visible macroscopically.⁶ With improved resolution colonoscopes, cables and monitors over the past decade, this notion has changed. More recent data suggest that most dysplasia is visible, not invisible, and the overall yield of random biopsies is low. Even so, other studies show nearly 25% of dysplasia discovered on colonoscopy is from random biopsies and not visible.⁷ As the need and value of random biopsies is debated, the more relevant question is whether these invisible lesions are truly invisible or simply hard to see. Recent data suggest strategies for enhancing dysplasia detection may be useful for detecting these “invisible” lesions, perhaps obviating the need for random biopsies.

Introduction of enhanced dysplasia detecting techniques such as chromoendoscopy as well as data showing each additional minute of withdrawal time increased the flat dysplasia rate by 3.5% suggests these strategies may help reduce the invisible dysplasia rate even further and potentially eliminate the need for random biopsies. An important take home is that even when the dysplasia is visible, it may not look like a classic polyp. The 1995 review that reported that 95% of dysplasia is not visible endoscopically, also noted that when it is seen, it may be subtle, such as an irregularity, discoloration or nodularity that could be obscured by inflammation. This description of what subtle dysplasia looks like is probably still relevant today. What has changed is that likely what we thought was invisible dysplasia is now at least partly visible with better control of inflammation, technologic improvement of scopes and monitors and better appreciation of subtle findings on colonoscopy.

Thus, besides trying to reduce inflammation as much as possible when performing surveillance, it is important to focus and biopsy anything that may look different than its neighbor or catches one’s attention. If a lesion looks particularly concerning, marking the area with India Ink will be helpful for finding the lesion in the future should the biopsies show dysplasia. Despite this, we must still recognize that lesions can be missed because they can be subtle and blend easily with the surrounding inflammation.

3. Chromoendoscopy but Not Virtual Chromoendoscopy Improves IBD Dysplasia Detection Rate

Chromoendoscopy involves the application of dilute methylene blue or indigo carmine during colonoscopy to the mucosa of the colon with the goal of improving visualization of dysplasia. This is achieved by enhancing contour differences between the lesion and the surrounding mucosa as well as differential uptake of stain between normal and dysplastic tissue. Several studies have now shown this strategy improves detection of dysplasia in IBD patients over white light, particularly when using standard definition colonoscopes. So called “virtual chromoendoscopy” on the other hand is alteration of the image by the processor to create a pseudocolorized image designed to enhance the detection of subtle colonic lesions. These are often proprietary technologies such as narrow band imaging (Olympus) or iscan (Pentax) to name two. However, despite the utility of these technologies to better define lesions, clinical trials have not shown that they improve the detection of dysplastic lesions over white light colonoscopy. Thus, if one wanted to engage in an evidence-based enhanced dysplasia detection technique that contains the word “chromo”, dye needs to be sprayed on the colon.

A recent review on the how to perform chromoendoscopy is a useful reference for those who want to learn the technique.⁸ It is important that the patient is well prepared to perform chromoendoscopy. The dye is diluted and can be applied via spray catheter or foot pump. Recommended is to exchange the water irrigation with contrast solution if using the foot pump once the cecum is reached. The dye should be applied circumferentially while withdrawing, spraying on the anti-gravity side. Typically, the colon is examined in 20-30 cm segments, once with white light, then reinserting and applying the dye and examining a second time after the dye has been applied. Suspicious areas showed be targeted for biopsies or if resectable, removed endoscopically.

4. Avoid Older Terms like DALM and ALM to Describe and Manage Dysplasia

The traditional description of dysplasia involved such terms such as flat dysplasia, dysplasia associated lesion or mass (DALM), adenoma like lesion or mass (ALM) and adenomatous polyps. The problem with these terms is that the definitions were quite vague. For example, the ALM and adenomatous polyp were often indistinguishable clinically. The difference between the DALM and ALM was a functional one, where the DALM was a lesion that could not be resected endoscopically or biopsies surrounding the lesion showed evidence of dysplasia whereas the ALM could be resected endoscopically or had no dysplasia on biopsies surrounding the lesion. Flat dysplasia also produced semantic problems it was it was not always clear if what was meant was visible lesions that were wider than tall or those not seen visually but detected on random biopsies during colonoscopy. Although there is no formal consensus on the optimal way to describe dysplasia in IBD, consensus is to abandon the use of terms such as DALM, ALM and flat dysplasia for terminology already in use for patients without IBD.

What has been proposed is to first dichotomize dysplasia into visible or invisible dysplasia (the latter detected solely on random biopsies).⁹ Visible dysplasia should be defined into one of 3 categories of lesions that should be familiar to practicing gastroenterologists: 1) pedunculated (lesion attached to mucosa by a stalk); 2) sessile (lesion not attached to mucosa by stalk, entire based is contiguous); and 3) non-polypoid (lesion <2.5 mm above the mucosa with little or no protrusion above the mucosa. Non-polypoid dysplasia perhaps is the term least used by gastroenterologists but it is easy to define: 2.5mm is the half the height of the cup of a closed biopsy forceps.

Once defied this way, one can apply more standard principles of polyp/dysplasia management that are familiar to most gastroenterologists. For example, when managing dysplastic lesions in patients without IBD (such as a tubular adenoma), the first step in management is to define whether the lesion is discreet and endoscopically resectable either by the gastroenterologist performing the procedure or by someone else employing advanced endoscopic technique. One distinction to note is that in patients with IBD, the disease itself can cause scarring in the underlying mucosa, so lesions may be more difficult to lift and resect than the same lesion in a patient without IBD. If marking the lesion with India Ink, it is helpful to pick the wall opposite the lesion, especially if referring to someone else, as the India Ink itself can cause scarring if injected nearby the lesion. This approach of defining management of visible dysplastic lesions in IBD based on the same principles of endoscopic management in patients without IBD represents a further evolution of managing dysplasia in IBD with less surgery that has been occurring over the past 15-20 years. Even so, it is important to note that this strategy, while reasoned and based on experience and some evidence, has not been validated.

5. Most IBD Patients with Dysplasia Do Not Need Surgery, but Some Do

Two seminal studies published in the late 1990s changed our thinking on the need for surgery on most patients with IBD and visible dysplasia. These studies ushered in the term “ALM” and suggested that these discrete polyps called “ALMs” with no surrounding dysplasia can be managed with polypectomy alone and did not need surgery. Another seminal study published in 2004 demonstrating that most dysplasia (roughly 75%) was visible, further moved the needle that perhaps if the lesion could be seen, even more patients could be eligible for polyp resection. This thinking was in contrast to the thinking just a decade before that most (95%) dysplasia in IBD was invisible and even when visible, appeared to be ill-defined lesions that could not be resected (Table 2).

That being said, the decision of how to manage any dysplastic lesions found on colonoscopy in a patient with IBD has to be individualized based on the appearance of the lesion, resectability of the lesion, degree of symptoms and inflammation and cannot be generalized into a single summary as to whether IBD dysplasia is managed surgically or endoscopically. Despite advances in optics and techniques, the fact is that even in the 2004 article that first observed that most IBD dysplasia was visible, one of 25 of the “invisible” dysplastic lesions were actually a cancer. Among the visible lesions, six of 85 were cancers but only one could be confirmed histologically at colectomy. Table 2 shows how the proportion of patients who may need surgery has changed. The management of invisible low-grade dysplasia (previously called flat) has been controversial, with the most recent 2010 AGA guidelines proposing an insufficient data to provide a recommendation regarding surgery vs. ongoing surveillance.3 The 2015 SCENIC consensus statement recommended performing a colonoscopy with chromoendoscopy in these patients and include extensive random biopsies in the area of interest to at least determine whether the “invisible” lesion can be visualized with dye spray.9

CONCLUSION

The field of inflammatory bowel disease dysplasia is changing and studies suggest advances in reducing CRC risk in IBD likely due to improved control of inflammation (primary prevention) and surveillance colonoscopy (secondary prevention). Despite limitations in data, surveillance colonoscopy is a currently practiced strategy for IBD patients to prevent colon cancer. By following these 5 tips (choosing the right patient for surveillance, focusing on mucosal abnormalities not random biopsies, incorporating chromoendoscopy in the right patient, abandoning older terms to describe dysplasia and knowing that most patients do not need surgery when dysplasia is found but some do) the hope is to simplify and improve our ability to detect and manage dysplasia in patients with IBD and prevent mortality from colorectal cancer.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #22

Understanding the Etiology and Spectrum of Idiopathic Gastroparesis

April 2017 • Volume XLI, Issue 4

Danny J. Avalos,

Pratik Naik,

Richard W. McCallum

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Gastroparesis is a debilitating disease of delayed gastric emptying (GE) which affects approximately 10 million people in the United States. Diabetes-related and post-surgical gastroparesis are well-known entities, but the majority of patients with gastroparesis have no identifiable etiologies and are labeled as idiopathic (IG). Although post-infectious causation has been implicated in IG, the pathophysiology of IG remains elusive. Vagal nerve impairment, changes in enteric neurons, and depletion of interstitial cells of Cajal have been demonstrated. The diagnosis of IG is based on clinical symptoms and an abnormal scintigraphic gastric emptying study. This article aims to review new discoveries in idiopathic gastroparesis and update entities that may be incorrectly labeled idiopathic gastroparesis.

Danny J. Avalos, MD, GI Fellow, PGY-4, TTUHSC Pratik Naik, MD, GI Motility Fellow, TTUHSC Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Gastroparesis (GP) is a disease of delayed gastric emptying where mechanical obstruction of the upper gastrointestinal tract has been excluded. Often, disordered gastric emptying is accompanied by post-prandial nausea, vomiting, early satiety, bloating and abdominal pain. Estimated to occur in 10 million (3%) people in the Unites States, gastroparesis can be categorized into diabetic (DG), post-surgical (PSG) and idiopathic (IG). Idiopathic gastroparesis accounts for up to 50-60% of cases and primarily affects females (88%) with an average age of onset of 41 years.¹ Case reports and case series have linked an infectious prodrome (gastroenteritis or flu-like symptoms) to IG, and this particular sub-category is termed post-infectious GP. It had previously been reported that post-infectious GP accounts for approximately 21% of all IG cases,² however, this number will be higher with new data. Also, post-infectious GP patients seem to have a higher likelihood for spontaneous recovery.²

The majority of the data for understanding IG comes from the NIDDK Gastroparesis Clinical Research Consortium (GpCRC), a collaborative effort from experts at a few specialized academic motility centers in the U.S. The consortium has led multiple studies with the aim of improving the understanding of the pathophysiology, clinical presentation, and response to therapy in GP. Symptoms of nausea, vomiting, and abdominal pain have been associated with a poor quality of life among all GP patients.^3,4 Data from the NIDDK Gastroparesis Registry revealed that among 159 patients with gastroparesis (107 IG, 52 DG), nausea was the predominant symptom in both groups, vomiting was more common in DG (81% vs. 57% p=0.004),⁵ and abdominal pain was more common in IG.⁶ Also, psychological profiles have identified depression along with physical and sexual abuse as present in up to 62% of the female patients with IG.⁷ These factors contribute to visceral hypersensitivity and could help explain the higher prevalence of abdominal pain in IG. The limited understanding about the pathogenesis in IG has led to a non-tailored approach in the management of symptoms. Additionally, many entities (i.e scleroderma), which can cause delayed GE, may be inappropriately labeled as IG. Knowledge of this evolving field will lead to a more focused approach to treatment. The goal of this article is to review this entity of “idiopathic gastroparesis” while also emphasizing these other diagnoses that may mimic IG.

Methods

Pubmed (MEDLINE) was searched using the MESH and non-MESH search terms: “idiopathic”, “post- infectious”, “autoimmune”, “connective tissue diseases”, “paraneoplastic syndromes”, “eating disorders”, “delayed gastric emptying”, “gastroparesis” and “diagnosis”. This search was complemented by the extensive clinical experience of the Center for Neurogastroenterology and GI Motility at Texas Tech University Medical Center in El Paso.

Pathophysiology

Although the pathophysiology of idiopathic gastroparesis remains unclear, some mechanisms and explanations are evolving (Figure 1). Vagal function and regulation have been shown to be impaired among patients with DG, however, to a lesser extent in IG.^8,9 Also, the role of the vagus nerve in ghrelin secretion has been proposed. Ghrelin is released mainly by neuroendocrine cells in the gastric fundus and duodenum and has been suggested to function as an appetite-stimulating hormone acting centrally through vagal afferent pathways.⁸ Ghrelin also has also been shown to stimulate gastric contractility and improve meal related symptoms and gastric emptying (GE) in IG patients.¹⁰

Full thickness gastric biopsies in patients with gastroparesis (compared to matched-controls) revealed that nNOS expression was more frequently decreased in IG than in DG (40% vs 20%). Increased connective tissue stroma, however, was visualized in both IG and DG via electron microscopy.¹¹ Loss of interstitial cells of Cajal (ICC) has been a predominant finding among patients with both DG and IG,¹¹ being present in up to 50% of cases and has been correlated with delayed gastric emptying in DG.¹² Interstitial cells of cajal are regarded as the origin of the gastric electric activity and the loss of ICC impairs and disorganizes the electrical signal resulting in reduced peristalsis. Previous studies revealed differences in gastric myoelectrical patterns among patients with IG and non-GP as assessed by electrogastrography (EGG). Idiopathic gastroparesis patients had a more irregular EGG pattern, with reduced 3-cycles-per-minute (cpm) EGG activity, whereas patients with mechanical pyloric outlet obstruction had high-amplitude, regular 3 cpm EGG patterns.^13,14 In patients with IG, clinical severity and nausea has been associated with immune-mediated infiltration of the myenteric plexus.¹⁵ Evidence of ganglionitis in full thickness gastric biopsies infers a diagnosis of IG. There is also an evolving role of pyloric pathophysiology in the development of GP. Loss of ICC in the pylorus occurs twice as commonly as in the antrum, and fibrosis in pyloric smooth muscle is three times more common than in the antrum on biopsies of patients undergoing gastric electric stimulation with pyloroplasty.¹⁶ Therefore, one unifying concept is that gastroparesis has similarities to “achalasia”. In achalasia, there is both denervation of the esophageal body producing loss of peristalsis, in addition to a non-relaxing lower esophageal sphincter (LES) resulting in esophageal obstruction. In GP, there is impairment of the enteric neurons, ICC loss in the smooth muscle of the antrum, and an impaired relaxation/compliance of the pyloric sphincter resulting in retention of a meal. One of these “dual mechanisms” may be more dominant in an individual GP patient, but both need to be considered and addressed when planning therapies.

How to Diagnose IG: Re-visiting the Gastric Emptying (GE) Diagnostic Criteria

Grading for severity of delayed gastric emptying, adopted from the consensus paper of a Joint Report of the Society of Nuclear Medicine and the American Neurogastroenterology and Motility Societies, is based on the percentage of gastric retention at 4 hours. The following grading system has been proposed: grade 1 (mild): 11-20% retention at 4 h; grade 2 (moderate): 21-35% retention at 4 h; grade 3 (severe): 36-50% retention at 4 h; and grade 4 (very severe): >50% retention at 4 h.¹⁷ A recent study by the NIDDK GP Research consortium suggests that the severity of gastric retention significantly correlated with the severity of symptoms when there was more than 35% retention of isotope at 4 hours. This correlation was not significant in the large number of patients with retention of 11-34%.¹⁸ To readdress normal gastric emptying criteria (since the original “egg meal” dates back 20 years ago), we recently studied the range of gastric emptying in 25 healthy individuals aged to 30 to 70 years, both male and female, with equal distribution for each decade. Four-hour retention values of up to 17% can be observed in asymptomatic healthy volunteers.¹⁹ Therefore, in interpreting the current “gold standard” meal for GE, we recommend that gastric retention > 15% at 4 hours should be considered the appropriate criteria to apply the label of “gastroparesis” and not the >10% standard currently used. Hence the term “idiopathic” gastroparesis needs to be applied with more rigorous GE criteria. Patients with symptoms of postprandial distress and normal GE are generally regarded as having functional dyspepsia (FD). There is more attention being directed to the role of impaired fundic accommodation and rapid filling of the antrum in explaining symptoms of early satiety, fullness, abdominal pain and nausea, which may be more dominant in some patients, categorized as having FD.

Pharmacologic Explanation for Delayed GE

Effect of Marijuana on GE

Cannabis has been shown to delay GE in previous studies. In the first study investigating the effect of delta-9-tetrahydrocannabinol (THC) on gastric emptying, smoking THC was shown to significantly delay GE compared to placebo in normal volunteers who did achieve symptoms of being “high”. The mean percentage of retention was significantly greater in the THC group compared to placebo at all times from 30 min to 2 hours after the test meal.20 Chronic (daily) marijuana use has been linked to the newly recognized syndrome of cannabis hyperemesis and patients may be misdiagnosed as having gastroparesis as a cause of vomiting. More recently, use of recreational marijuana has been approved in many states. It is important to take a careful history and stop all marijuana use for at least 72 hours prior to GE being studied.¹⁷

Effect of Medications on GE

There are many classes of medications that can slow GE. In this article, we will emphasize the most commonly encountered medications (Table 1).

Opioids are the most commonly associated medication inducing delayed GE. A randomized controlled trial evaluating 75mg of Tapentadol immediate-release (IR) TID or 5mg Oxycodone IR TID vs. placebo revealed a significant delay in GE with narcotics compared to placebo.²¹ Medications used for the management of hyperglycemia in type 2 diabetics including Pramlintide,²² an amylin analogue, and Exenatide,²³ a GLP-1 agonist, have been associated with delayed GE due to inhibition of vagal function.

Proton pump inhibitors can mildly delay GE to solids by impairment of the acid-dependent peptic activity, which interferes with trituration of ingested food.²⁴

Table 1 lists all the classes of medications that should be considered as possibly slowing GE and emphasizes that a detailed social and medication history is paramount when IG is in the differential.

Hypothesized Etiologies for IG

Post-Infectious Gastroparesis

Post-infectious GP has been reported in both pediatric and adult populations and it has been linked to various pathogens. The pathophysiology of post-infectious GP could be neuropathic or myopathic in origin. The proposed mechanism is believed to be due to inflammation, an immune-mediated phenomenon or an exacerbation or unmasking of an underlying dysmotility.²⁵ There is also literature suggesting possible viral mediated damage to the ICC.¹³

Viral Pathogens Linked to IG

In the pediatric literature, reports have linked rotavirus to IG. Two cases series reported that among children with post-viral GP, positive for rotavirus, all had full recovery of their gastric emptying over 6-24 months.^15,26

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) have been linked to gastroparesis. In a large cohort of 143 adult patients with IG, 11 patients were identified with a post viral etiology of which four had antibody titers against CMV and two against EBV, while the remaining five had a clinical history and presentation consistent with viral etiology based on an illness consistent with gastroenteritis.² Seven patients (age three months to 47 years old) with a viral prodrome prior to development of GP revealed CMV and EBV as culprits in two cases.¹³ CMV was also linked to GP in an immunosuppressed patient who developed neurological symptoms and delayed gastric emptying with confirmatory CSF PCR positivity for CMV. This patient later had clinical improvement with ganciclovir.²⁷

Enterovirus (EV) has been linked as a possible causative etiology in IG.²⁸ Seventeen adult patients reported having flu-like symptoms or gastroenteritis prior to diagnosis of IG and 11 subjects had immunoperoxidase staining for EV on mucosal gastric biopsies. Nine patients had active EV infection as noted on endoscopic gastric biopsies and eight patients underwent treatment with antivirals and/or immune therapy. Four out of the eight patients treated experienced symptomatic improvement.

Among other viral etiologies, Norwalk virus and Hawaiian virus have been associated with IG in up to 50% of patients thought to be affected with the viruses.²⁹ Varicella-Zoster has also been associated with IG in a setting of a 52 year-old male with Ramsay-Hunt syndrome who developed GP and had symptomatic improvement with metoclopramide.³⁰

A case series of three adolescent female patients also revealed viral gastroenteritis as a possible culprit for GP.²⁵ Viral GP was identified in seven out of 103 GP cases from the Mayo Clinic. Among the seven cases (three male, four female), the mean age was 26.9 years and symptoms experienced prior to onset of GP included, low-grade fever, fatigue, myalgia with or without diarrhea. A mean follow-up of 32.3 months revealed complete resolution of gastroparetic symptoms in five of the seven subjects while the remaining two had significant improvement in symptoms³¹ suggesting that post-infectious GP appears to have an overall good prognosis. Neither article specified the pathogens, but it was presumed to be viral as per clinical presentation.

Medical Entities that May be Un-recognized and Inappropriately Labeled as “Idiopathic Gastroparesis”

Connective Tissue Disorder

The esophagus, small intestine and colon are commonly affected in patients with systemic sclerosis (SSc).³³ Approximately 47-66% of patients with SSc have delayed gastric emptying to solids.^33,34 Dyspeptic symptoms such as nausea, vomiting and epigastric fullness are often observed in SSc patients.³³ In one study, 80% patients with abnormal esophageal motility also had significantly delayed GE.³³ Similarly, delayed GE with liquids was seen via ultrasonography in 20 patients with SSc vs 20 healthy controls.³⁵ It is hypothesized that collagen replacement of the gastric smooth muscle may lead to subsequent stomach hypomotility in SSc.³⁶

Autoimmune Diagnosis

Gastroparesis in patients with myasthenia gravis with subacute autonomic failure shows clinical improvement after administration of an acetylcholinesterase inhibitor.³⁸ In this report seven patients had antibodies against muscle AChR, and three had antibodies against neuronal ganglionic AChRs (all had thymoma). Autoimmune autonomic neuropathy in association with ganglionic neuronal acetylcholine receptor and N-type voltage-gated calcium channel autoantibodies was also reported in a 60 year-old non-diabetic woman with a 15-year history of GP.³⁹ Patients with Sjogren’s syndrome who have serum antimuscarinic antibodies (IgG) can also have delayed GE.³⁷

Demyelinating Diseases

Acute demyelinating disease is a rare cause of GP, but it should be suspected when symptoms of GP are associated with neurological deficits. Antibodies against the water channel protein aquaporin (AQP)-4 can cause a spectrum of inflammatory, demyelinating, central nervous system disorders termed neuromyelitis optica spectrum disorders (NMOSDs) which can present with GI symptoms similar to GP with intractable nausea, vomiting and hiccups. However, AQP4-IgG positive patients have not demonstrated delayed GE.⁴⁰ In a case report, a 31-year-old female with acute gastroenteritis developed gastroparesis and suffered a cardiac arrest during the hospitalization. A post- mortem autopsy revealed decreased myelinated axons with vacuolar degeneration consistent with Guillain- Barre syndrome.⁴¹ Two cases of patients with focal deficits and demyelinating disease, seen on magnetic resonance imaging (MRI), have also been associated with abnormal GES. Both patients improved with intravenous corticosteroids and one of the patients later developed multiple sclerosis.⁴²

Multiple sclerosis (MS) is a demyelinating disease, which damages the brain and spinal cord. Similar to IG, more patients with MS are women. The most common GI complaints reported in MS patients are diarrhea or constipation and dysphagia.⁴³ Previous studies have demonstrated delayed GE in MS patients. In a study of 49 patients with defined MS and 20 controlled subjects, 47.7% demonstrated slow emptying, 34.1% normal and 18.2% had rapid emptying compared with controls.43 In other reports, the complaints reported in MS patient who presented with symptoms of delayed GE were mainly a sense of fullness, nausea, persistent vomiting, recurrent hiccups and gastroesophageal reflux.⁴⁴ However, there has been no correlation noted between the severity of MS and gastric emptying abnormalities.

Paraneoplastic Syndrome

Paraneoplastic syndrome can be manifested as esophageal dysmotility (pseudoachalasia), gastroparesis, intestinal pseudo-obstruction or constipation.45 Factors related to cachexia have been theorized as an explanation for paraneoplastic syndrome. Inflammatory lymphocytic and plasma cell infiltrate of the myenteric plexus as well as loss of ganglion cells can be seen on full thickness biopsy in patients with paraneoplastic dysmotility of the GI tract.⁴⁵

Gastroparesis was reported to be the most common paraneoplastic syndrome associated with type 1 antineuronal nuclear (ANNA-1, also called anti-Hu) antibodies, and small cell lung cancer (SCLC) of the lung is the most common tumor expressing this antibody.45 Plasmapharesis was effective in overcoming the antibodies. The second most common antibody in paraneoplastic syndrome and GP is the P/Q-type calcium channel antibodies, which are predominately seen in patients with Lambert Eaton myasthenic syndrome (LEMS) in association with SCLC.⁴⁶ Patients with LEMS can present with proximal muscle weakness, depressed tendon reflexes, post-tetanic potentiation and autonomic changes, which can be similar to that of myasthenia gravis. Similarly, a ganglionic acetylcholine receptor antibody has been associated with GP in a patient with bladder cancer but also in patients with no underlying cancer.⁴⁷

Pancreatic cancer has also been associated with GP. A cohort of 15 patients with pancreatic carcinoma without invasion or obstruction revealed that nine (60%) patients had delayed solid-food GE. Symptoms of nausea and/or vomiting were more frequent among patients with delayed GE as opposed to those with normal GE.⁴⁸ Other tumors that have been linked with delayed gastric emptying include cholangiocarcinoma,⁴⁹ as well as intestinal50 and retroperitoneal leiomyosarcoma.⁵¹ In the two cases where leiomyosarcoma was linked to delayed GE, both patients had resolution of symptoms after tumor resection.

CNS Degenerative Diseases

Patients with Parkinson’s disease (PD) have been noted to have delayed gastric emptying to solids.⁵² In a randomized study, 80 patients with untreated PD were compared to 40 healthy controls with solid or liquid gastric emptying. A total of 88% of PD patients had delayed GE with solids and 38% with liquids. Abnormal gastric myoelectrical activity in untreated Parkinson’s disease may be responsible for delayed GE.⁵³ Lewy bodies have also been identified in the smooth muscle and enteric neurons of Parkinson’s disease patients.⁵⁴ In an animal study, 6-hydroxy-dopamine (6-OHDO) was unilaterally injected into the substantia nigra pars compacta of mice. The mice developed delayed gastric emptying four weeks after a 6-OHDO injection, as measured by a [13C]-octanoic acid breath test. Thus, the authors postulated a neurofunctional and neuroanatomical alteration of the brain-gut axis as a potential etiology for delayed GE in PD.⁵⁵

Dopamine agonists used in the treatment of PD have been regarded as being a risk for delaying GE. However, treatment with the dopamine agonist as a transdermal patch, rotigotine, has recently shown improvement in gastric emptying.⁵⁶

Functional Dyspepsia

Approximately 40% of patients with the working diagnosis of functional dyspepsia (FD) may have delayed GE as the explanation for their symptoms.⁵⁷ Idiopathic gastroparesis patients are more likely to have frequent nausea and vomiting, whereas FD patients have postprandial distress syndrome manifested by early satiety and abdominal discomfort. A meta-analysis of 17 studies with 868 dyspectic subjects and 397 controls revealed that GE was delayed with a relative risk of 1.46 (CI 1.23-1.69).⁵⁷ Recent reports of duodenal eosinophilia in a subgroup of dyspepsia patients may be another marker for separating FD from GP where eosinophilia in the duodenum was infrequent among the latter group.⁵⁸

Gastroesophageal Reflux

Delayed GE has been reported in 28 to 56% of the patients with gastroesophageal reflux (GERD) and is a co-existing entity, which can exacerbate GERD symptoms.⁵⁹ Theoretically, the slow GE induces gastric distention, which increases the frequency of transient lower esophageal sphincter relaxation increasing GERD. A gastric emptying study should be considered in patients whose heartburn is resolved with anti-reflux medication but who continue to report persistent nocturnal regurgitation.

Anorexia Nervosa/Bulimia

Anorexia and bulimia have been associated with dyspeptic symptoms and delayed gastric emptying. In a study of 16 female patients with anorexia nervosa, GE of solid food phase was significantly delayed in 80% of patients.⁶⁰ In this study, patients with anorexia nervosa were observed to have better tolerance to liquid diet compared to solid meals. Patients with bulimia have had conflicting results. Two studies reported normal GE to solids and liquids,^61,62 however, a cohort of female patients with bulimia revealed delayed GE in 38% of the patients.⁶³

Anorexia nervosa in childhood or early adulthood results in an unused or atrophic gastric emptying function, where despite subsequent improvement of eating habits, it does not lead to recovery of the “gastric atrophy.” In another scenario, some patients may still be “closet anorexics” and have hidden their eating behaviors. Some important clues suggesting an eating disorder are excessive dental caries, finger excoriations and unexplained hypokalemia. Another possible explanation for delayed GE could be secondary to endocrine dysfunction (i.e hypoadrenalism) observed in patients with eating disorders.

Celiac Axis Injury or Compression

Compression or injury to the celiac plexus ganglion can affect parasympathetic signaling to the stomach, resulting in loss of myenteric coordination. Compression of the celiac axis by a fibrous band (the median arcuate ligament) connecting the diaphragmatic crura is called median arcuate ligament syndrome (MALS) which is characterized by abdominal pain, nausea and vomiting. A case report of a patient presenting with postprandial epigastric pain, weight loss, gastroparesis and gastric dysrhythmias was diagnosed with MALS and had significant improvement of symptoms and GE after surgical decompression of the celiac axis. The patient was able to return to a full diet within four weeks without nausea or vomiting.⁶⁴ This entity is not explained by vascular insufficiency but by compression of the celiac ganglion via the the fibrous ligament. Clinical clues include nausea, vomiting and upper abdominal pain which is out of proportion to abdominal examination

Hypermobility Syndrome

Joint hypermobility syndrome (JHS), a type of Ehlers- Danlos Syndrome (EDS) (formally called type III), is a new addition to an association with GI symptoms. Patients with JHS have hypermobility of the joints, skin hyper extensibility and easy brushing. In a case- controlled study of the 336 patients with functional gastrointestinal disorder (FGID), 39% were also diagnosed with JHS. More specifically 51% of the FGID patients whose predominant symptom was postprandial distress were diagnosed with JHS.⁶⁵ Postural orthosthetic tachycardia syndrome (POTS), caused by dysfunctional autonomic control mechanism, is accompanied by JHS in up to 60% of patients.⁶⁶ In a large cohort study of 163 patients with POTS, 34% had normal, 18% has delayed and 48% had rapid GE.⁶⁷ In JHS patients, autonomic dysfunction and decrease in compliance of the gut wall may influence GE. Review of literature suggests that rapid gastric is more common in JHS patient with POTS but in absence of POTS, occurrence of rapid and delayed GE were similar.⁶⁸

Miscellaneous Causes for Delayed GE

Cystic fibrosis (CF) can be associated with GI dysmotility including GP, GERD and chronic constipation. The average life span of patients with CF who live to adulthood is 37 years. In a systemic review, patients with CF had a high frequency of GP (38%) and it was more prevalent among patients older than 18 years of age.⁶⁹ The co-existence of GP and CF may pose significant nutritional challenges.

Cases of GP in patients receiving abdominal, pelvic and total spine radiation have also been documented.⁷⁰ There is also a report of GP in patients who received high dose chemotherapy and stem cell transplant.⁷¹ Post- chemotherapy treatment GP is rare and pathophysiology behind the process is not well established but could relate to being part of the paraneoplastic syndrome or neuropathy from the chemotherapy agent. ¹

Delayed solid emptying is also noted in atrophic gastritis with or without pernicious anemia,⁷² which is explained, by a combination of achlorhydria and thinning of smooth muscle. Other diseases associated with delayed GE include mastocytosis⁷³ and eosinophilic gastroenteritis.⁷⁴

TAKE HOME POINTS

A wide spectrum of contributing factors and unappreciated entities can result in the label of “idiopathic gastroparesis”. Idiopathic gastroparesis is also a term that may be overused as the etiology for unexplained upper gastrointestinal symptoms. The diagnosis of IG must be rigorously made with particular attention to the interpretation of a scintigraphic GE study, where abnormal should be >15% retention at 4 hours, not the current >10%. Medications, specifically opioids and marijuana, are key factors to consider in interpreting a gastric emptying study. This article helps the reader gather enough data to differentiate idiopathic gastroparesis from other diagnoses while at the same time emphasizing the importance of a thorough evaluation of the patients’ history for factors that can have a long term effect on gastric motility and present as gastroparesis. In the future, the diagnostic approach will benefit from a non-surgical way of obtaining gastric smooth muscle tissue to examine enteric neurons, and ICC, which will be achieved by endoscopic ultrasound- guided biopsies of gastric antrum smooth muscle. Patients with suspected post-infectious gastroparesis appear to have an overall good chance of recovery. Idiopathic gastroparesis, the most common subset of gastroparesis patients, remains a challenging diagnostic and clinical entity. We hope this article will give you new expertise in addressing this in your practices.

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Nutrition Issues In Gastroenterology, Series #162

Protein Losing Enteropathy: Diagnosis and Management

April 2017 • Volume XLI, Issue 4

Andrew P. Copland,

John K. DiBaise

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Protein losing enteropathy (PLE) is an uncommon etiology of hypoproteinemia. It is caused by protein loss from compromised gastrointestinal (GI) mucosa as a result of GI mucosal diseases, GI tract infections, as well as from disruptions of venous and lymphatic outflow. The prevalence of PLE is poorly understood given the wide variety of causes of both hypoalbuminemia and PLE, and due to a lack of systematic screening. The evaluation of a potential PLE patient includes a careful assessment for alternative causes of hypoalbuminemia and a measurement of GI tract protein loss. This review provides the clinician with diagnostic criteria, as well as management and nutrition support options.

Andrew P. Copland, MD¹ John K. DiBaise, MD² ¹Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA ²Division of Gastroenterology and Hepatology, Mayo Clinic in Arizona, Scottsdale, AZ

INTRODUCTION

Protein-losing enteropathy (PLE), sometimes referred to as protein-losing gastroenteropathy, is an unusual cause of hypoproteinemia and is characterized by the shedding of large quantities of protein from the gastrointestinal (GI) mucosa. PLE may result from a wide variety of etiologies and can be both a diagnostic and therapeutic challenge to the practicing gastroenterologist. The clinical presentation of PLE may also be complicated by micronutrient deficiencies related to the underlying etiology of the PLE. In some cases, we have noted significant vitamin deficiencies and deficiency of essential fatty acids complicating the care of these patients. Through the use of a case illustration, we will explore a practical approach to the evaluation and management of PLE.

In early 2016, a 51 year-old woman presented to the GI clinic upon referral by a hematologist because of the development of progressive hypoalbuminemia (albumin 2.6 g/dL) which had been identified approximately 1 year earlier. She described one normal appearing stool per day, denied any GI complaints, and her physical examination was entirely normal.

PLE is generally considered to be a rare condition; however, given a lack of systematic screening and a wide variety of causes of hypoalbuminemia, its prevalence is poorly understood. There are robust data describing an incidence of up to 18% among survivors of the Fontan procedure, used as treatment of the univentricular congenital heart; however, data are much more limited for other causes of PLE.¹ A 2-3% prevalence of PLE has been reported among Asian patients with systemic lupus erythematosus (SLE).² In a study of 24 patients with ileal Crohn’s disease in clinical remission, all had laboratory evidence of PLE (although none had clinical signs), suggesting that the prevalence of PLE may be significantly underrecognized.³ Similarly, in a study from 1975, 22% of 55 patients with primary lymphedema who were screened for PLE were found to have evidence of protein wasting from the GI tract.⁴

Despite the poor understanding of its prevalence, PLE should be a consideration in the evaluation of patients who present with moderate to severe hypoalbuminemia (serum albumin <3.0 g/dL), particularly those who present with edema. Although some patients with PLE present with severe GI symptoms such as diarrhea, which can take on a secretory character, it is important to recognize that not all patients suffering from PLE will exhibit overt GI symptoms. In fact, the key clinical characteristic of PLE is symptomatic hypoalbuminemia which manifests most commonly as edema. Other clinical manifestations generally reflect the underlying disease responsible for PLE.

Pathophysiology

The protein loss in the bowel typically results in serum albumin levels <3.0 g/dL, and frequently <2.0 g/dL. In the normal GI tract, only 1-2% of total daily protein is lost through active intestinal secretions and mucosal turnover.⁵ This is significantly different from the dramatic protein losses from the GI tract seen in PLE, which can result in daily loss of as much as 60% of the total serum protein. ⁶ Because albumin contributes about 80% of the total colloidal osmotic effect of human serum due to its oncotic effect and affinity for sodium ions, loss of serum albumin results in third-spacing of fluid and generally manifests clinically as peripheral edema, ascites, and pleural effusions.⁷ In addition to symptomatic hypoalbuminemia, patients presenting with PLE may be at increased risk of infection and thrombosis due to concomitant stool loss of serum immunoglobulins and key anticoagulant proteins respectively, although neither occurs commonly.

In the context of increased serum protein loss, the body will attempt to compensate by increasing protein synthesis. As such, serum levels of rapid turnover proteins including prealbumin, immunoglobulin E (IgE), and insulin may remain normal.⁸ In contrast, insufficient compensatory protein production and low serum level is more often seen with slower turnover proteins such as albumin, ceruloplasmin, fibrinogen, transferrin, and immunoglobulins (other than IgE), as the body has a less robust capacity to increase daily production.⁵ Albumin in particular is a slow turnover protein with a half-life of about 25 days; there is also evidence that the liver is unable to fully compensate for sustained albumin losses.⁷ Decreased serum levels of lipids and trace elements have also been reported in PLE, as has the presence of lymphopenia, particularly in the setting of lymphatic obstruction or malnutrition. The reduction of serum proteins other than albumin seldom causes clinically significant problems.

Her past medical history was notable for remote peptic ulcer disease, hyperlipidemia, seasonal allergies and persistent unexplained peripheral eosinophilia first discovered in 2010. In 1989, she underwent a vagotomy and pyloroplasty for gastric outlet obstruction due to peptic ulcer disease. Extensive evaluations of the eosinophilia by specialists in infectious diseases, hematology, allergy, immunology, and rheumatology were unsuccessful in identifying an etiology.

Alternative causes of hypoalbuminemia

Other causes of hypoalbuminemia are diverse and warrant careful thought when evaluating the hypoalbuminemic patient. In particular, fluid overload (e.g., congestive heart failure), reduced protein synthesis (e.g., chronic liver disease), and other sources of serum protein losses (e.g., nephrotic syndrome) are important to consider. This evaluation should include a careful history and physical examination, as well as standard evaluations of other causes of hypoalbuminemia noted in Table 1.

A diagnostic evaluation revealed no evidence of chronic liver disease, nephrotic syndrome or congestive heart failure. Alpha-1-antritrypsin clearance was found to be 341 mL/24 hours (normal, < 27 mL/24 hr), consistent with PLE.

Testing to Confirm a Diagnosis of PLE

The primary diagnostic test for PLE is stool testing for the presence of alpha-1-antritrypsin (A1AT) (Table 2). A1AT is a protein that suffers minimal degradation or active secretion in the GI tract and is of similar molecular weight as albumin. By measuring A1AT levels in both serum and a 24-hour stool collection, A1AT clearance can be calculated as follows:

A1AT clearance = [(mL Stool) x (stool A1AT mg/ dL)] / [serum A1AT mg/dL]

An elevated A1AT clearance >27 mL/day reflects a general state of GI protein loss and has a sensitivity of approximately 80%.⁷ Diarrhea from any cause, however, results in some obligate A1AT loss and, thus, a higher threshold (>56 mL/day) may be required for the diagnosis of PLE in this situation.^9,10 A1AT is also sensitive to degradation by acid so, in the setting of a hypersecretory state, this test is optimally performed while the patient is receiving acid suppression.¹¹ Finally, A1AT testing of a spot stool specimen may also show elevated levels in PLE, but this is a less sensitive approach and is not recommended in the initial diagnosis.¹⁰ Use of a random stool A1AT level coupled with serum A1AT level, however, may serve as a convenient surveillance method for patients with known PLE undergoing treatment or in remission.

There are a number of other methods to search for protein loss in the GI tract, albeit none as widely available or as safe as the A1AT clearance. Historically, the gold standard test for PLE has been the fecal excretion of ⁵¹Cr labelled albumin, which requires collection of stool for a minimum of 4 days.⁷ It is not only challenging for patients to complete a 4-day stool collection but it exposes them to radiation and it is not widely available. The ⁵¹Cr-albumin clearance may be useful when there is a high clinical suspicion in the context of a negative A1AT clearance given its higher sensitivity. An alternative is technetium 99m-labelled human serum albumin (HSA) scintigraphy. This test has demonstrated superior sensitivity and negative predictive value compared to A1AT clearance for the diagnosis of PLE and has the added benefit of not requiring a prolonged stool collection.¹² These tests may also be used to monitor response to treatment.

Upper endoscopy was subsequently performed and was notable for patchy gastric erythema with an atrophic appearance to the stomach. Biopsies from the second portion of the duodenum demonstrated patchy eosinophilia while biopsies from the duodenal bulb were normal. Random biopsies from the stomach showed marked eosinophilia without other abnormalities (Figure 1). Based on the peripheral eosinophilia and presence of eosinophils on the biopsy, the patient was suspected to have eosinophilic gastroenteritis. Interestingly, in 2010, she had undergone upper endoscopy and colonoscopy to evaluate iron deficiency anemia. While both examinations were grossly normal, random biopsies from the stomach revealed a similar intense eosinophilic inflammatory infiltrate throughout the mucosa and submucosa. Biopsies from the duodenum, terminal ileum and colon were normal.

Evaluating Confirmed PLE

When a diagnosis of PLE has been determined, additional testing is necessary in order to identify the underlying cause and help direct treatment. PLE is associated with a diverse set of diseases often affecting multiple organ systems and can be divided into GI and non-GI causes (Table 3). GI sources can be further divided into erosive and nonerosive diseases of the bowel that result in protein loss across the mucosal membrane of the intestine and are detailed in Table 3.

Circulatory dysfunction from cardiac pathology such as congestive heart failure (CHF), constrictive pericarditis, and congenital heart disease can lead to PLE. The most common cardiac cause of PLE occurs in adults with congenital heart disease, a functional single ventricle, treated as a child with a palliative Fontan operation.¹ Post-Fontan patients make up the largest cohort of patients with PLE described in the literature.

PLE is associated with a significant morbidity and mortality depending upon the underlying cause. The five-year mortality after diagnosis of PLE in the setting of a Fontan procedure approaches 50%; however, recent data suggest that advances in our understanding of the disease may have improved this rather dismal outlook.¹³ While data on morbidity and mortality associated with PLE related to other causes are more limited, malnutrition, volume overload, thrombophilia, and secondary immunodeficiency, likely have a significant impact on long-term outcomes.

Because the management of PLE is closely tied to treating the underlying disease, when PLE is identified, a thorough evaluation should be undertaken to better characterize the state of the GI tract mucosa, lymphatic system, and cardiovascular system. This is best approached through upper and lower GI endoscopy with mucosal biopsies as well as infectious studies (focusing on chronic intestinal infections). If conventional endoscopy does not yield a diagnosis, video capsule endoscopy or small bowel enteroscopy have been shown to be useful in patients with known PLE.¹⁴ Cross-sectional imaging of the abdomen and pelvis, echocardiogram, lymphatic/hematologic tests and, sometimes, diagnostic laparoscopy may also be useful depending on the clinical presentation.

Mechanisms Causing PLE

As our understanding of PLE has improved, it has become increasingly clear that a common link between the various etiologies of the disease involves injury to, or breakdown of, the GI epithelium causing increased permeability. Conceptually, this pathology is clear when considering PLE caused by mucosal diseases such as inflammatory bowel disease, eosinophilic gastroenteritis, and microscopic colitis, for example. Poor lymphatic drainage from congenital defects or from significant lymphatic obstruction may cause loss of lymphatic fluid into the GI tract through direct hydrostatic forces.¹⁵ Although the mechanism responsible for PLE in systemic autoimmune disease is unclear, it has been hypothesized that it results from mucosal or capillary inflammation caused by:

1. local vascular injury mediated by complement or vasculitis
2. lymphatic damage through mesenteric inflammation, or
3. increased endothelial permeability through the effect of inflammatory cytokines.¹⁶

The cause of PLE associated with cardiovascular diseases such as CHF and the Fontan procedure is generally considered to be increased hydrostatic pressure from venous hypertension which, at least in part, results in loss of protein into the GI tract.¹ Interestingly, these patients do not have significantly elevated venous hypertension relative to similar patients without PLE making the exact pathophysiologic process less clear.¹ Some of these patients seem to respond to treatments based at the level of the mucosal membrane, implying that perhaps mucosal injury is again a primary root cause. Some hypothesize that hemodynamic changes associated with the Fontan procedure result in increased mesenteric vascular resistance as a compensatory mechanism to poor cardiac output.¹⁷ This may in turn damage the mucosal epithelium, increase permeability and engorge intestinal lymphatics with an appearance histologically similar to congenital intestinal lymphangiectasia. There are also data to suggest that patients with univentricular-type congenital heart disease may have increased protein loss in the GI tract prior to the Fontan procedure; this may reflect either a response to the initial circulatory dysfunction of the congenital heart disease or concurrent congenital malformation of some component of the GI tract itself.¹⁸ Others have attempted to strengthen the argument for mucosal injury by demonstrating that patients who have undergone a Fontan procedure typically have elevated inflammatory markers.

The patient was placed on prednisone for suspected eosinophilic gastroenteritis with rapid normalization of her serum albumin and eosinophils and more gradual normalization of the A1AT clearance. With weaning of the prednisone, an increase in peripheral eosinophils and decrease in albumin occurred prompting initiation of oral cromolyn and budesonide. Thereafter, she was able to eliminate prednisone use. Repeat upper endoscopy approximately one year later was normal including duodenal and gastric biopsies. Interestingly, biopsies from the upper esophagus demonstrated marked eosinophilia consistent with eosinophilic esophagitis. Notably, she denied dysphagia or any other esophageal symptoms.

Management of PLE

Because PLE is a rare disease with a variety of seemingly disparate causes, there are limited data on its optimal treatment. As such, no single treatment reliably improves PLE in all patients. A core principle is to treat the underlying disease which, if successful, should generally result in improvement in the PLE. Fortunately, most causes of PLE can be readily diagnosed and treated. Examples might include optimization of the management of eosinophilic gastroenteritis as demonstrated in our case illustration, or fenestration of the Fontan heart to improve cardiac output.²⁰

A number of PLE-specific strategies have been described and include dietary, pharmacological or surgical interventions. No controlled studies, however, have been performed to demonstrate the utility of these approaches. It is also important to recognize that there is often a substantial delay in clinical response to treatment of PLE, which may take months to display a measurable response. Nutritional strategies focusing on protein deficiency are important. A high protein diet is recommended in patients with PLE and may require significantly greater protein intake (2.0-3.0 g/ kg/day) than normal (0.6-0.8 g/kg/day) to remain in a positive nitrogen balance.⁶ In patients with associated fat malabsorption, primary or secondary intestinal lymphangiectasia or other lymphatic disorders causing PLE, a lowering of fat intake may decrease pressure on the lymphatics and limit protein leakage.¹⁵ To replace these lost fats, medium-chain triglycerides can be tried as these provide a source of energy rich fats and are absorbed largely via the portal vein rather than the lymphatics.¹⁵ However if a very low fat diet is used > 3 weeks, a source of essential fatty acids will be necessary and fat soluble vitamins may need to be monitored.21 If oral intake is inadequate, enteral feedings should be considered. If fat malabsorption has been demonstrated based on a quantitative fecal fat collection with fat ingested or infused enterally, then a semi-elemental or elemental product should be used. If the patient fails enteral, then parenteral will be necessary.

Although dietary modification may not produce obvious benefit in terms of symptoms or degree of protein wasting, the optimization of the PLE patient’s nutritional status is important to the success of other therapies and the patient’s overall outcome.

Direct replacement of serum albumin by infusion is not a useful long-term strategy as it provides only short-term benefit, is expensive, and does not reverse the underlying pathophysiology. In the acute setting, albumin infusion may help patients suffering from severe third-spacing of fluid due to marked hypoalbuminemia as a bridge to more durable therapies.²²

Supportive measures to avoid complications resulting from fluid retention contribute meaningfully to PLE patients’ quality of life. Use of compression stockings may help decrease edema and improve functional status. Careful skin care along with edema management is important to avoid pressure ulcerations and other complications of skin breakdown.

Although there are a number of anecdotal case reports and small case series of medical therapies for patients with specific causes of PLE, there are no high quality randomized controlled trials of any therapy in PLE (see Table 4). In some cases, a surgical approach to the primary underlying GI pathology is necessary. In inflammatory bowel disease, for example, this might result in resection of active bowel affected. Gastrectomy may prove curative for patients with Ménétrier’s disease.

Practical approach to PLE

Given the rarity of the PLE and the lack of rigorous supportive data, the treatment of PLE can be a puzzle to the clinician. The initial step in the evaluation of hypoalbuminemia is to exclude other, more common, causes such as liver and renal diseases. When concern over PLE remains, the A1AT clearance test is recommended as the test of choice given its reliability, relative inexpense, and wide availability. After a diagnosis of PLE has been made, the following approach is suggested:

1. Aggressive pursuit to identify the underlying disease responsible for PLE and treat accordingly while encouraging a high protein diet and supportive measures for fluid retention when present. A low-fat diet and supplementation with medium chain triglyceride supplementation should be considered on an individual basis. Monitoring and treatment of any associated malnutrition and/or micronutrient deficiencies, when present, is also important. In certain conditions where severe symptoms prevent adequate oral intake, occasionally use of either enteral or parenteral support may be needed.
2. If cardiac disease is an underlying etiology, addition of diuretic regimen including spironolactone should be considered. The chronic use of diuretics in other settings, while commonly attempted, is otherwise generally discouraged as is the long-term use of intermittent albumin infusions. The use of other “heart failure” medications in order to optimize cardiac output in those with cardiac etiologies of PLE may also be pursued.
3. A trial of pharmacological agents such as corticosteroids, heparin, and octreotide may be considered in patients who have not responded to other measures, but should not be considered primary therapeutic agents for PLE. The use of cetuximab and everolimus should be considered based upon its reported use in relevant underlying diseases. If a trial of budesonide 9mg daily results in clinical improvement, a gradual taper over several months is recommended, recognizing that recurrence is common after discontinuation. Subcutaneous heparin or octreotide may be used in combination with oral or intravenous corticosteroids.
4. Periodic monitoring of the degree of PLE is advised, for example, by using A1AT clearance, after treatment is initiated. Similarly, periodically monitoring the serum albumin level is recommended with the assessment of other serum chemistries and micronutrients on a case-by-case basis.

CONCLUSION

The patient described in our case illustration represents a typical case of PLE with a GI etiology with the exception of an absence of edema. It highlights the need to recognize PLE as a cause of unexplained hypoalbuminemia even in the absence of GI symptoms or evidence of fluid retention. PLE can occur in the context of a myriad of diseases ranging from primary GI mucosal disorders, to malignancies, to lymphatic disorders, to congenital heart disease. Diagnosis is most commonly confirmed by the A1AT clearance test. The care of the patient with PLE can be challenging and often requires a multidisciplinary approach. While the evidence regarding the management of PLE is limited, treatment primarily focuses of the underlying disease with the addition of supportive measures to manage complications such as edema.

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Frontiers In Endoscopy, Series #35

Endoscopic Ultrasound Guided Gastroenterostomy for the Treatment of Gastroduodenal Outlet Obstruction

April 2017 • Volume XLI, Issue 4

Emmanuel Coronel,

Uzma D. Siddiqui

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Here we discuss EUS-guided gastroenterostomy (EUS-GE) as a novel, minimally invasive technique that can be used to palliate the symptoms of gastroduodenal outlet obstruction due to benign or malignant conditions. Due to the risk for serious adverse events, no current standardized technique and limited published data, this endoscopic technique should only be undertaken by experienced endosonographers. Early results show promise in the treatment of gastric outlet obstruction.

Emmanuel Coronel, MD Uzma D. Siddiqui, MD, FASGE, Center for Endoscopic Research and Therapeutics (CERT), Chicago, IL

BACKGROUND

The term gastric outlet obstruction has been used broadly to define any mechanical obstruction impairing gastric emptying into the small bowel. The area of obstruction can be in the distal stomach or proximal duodenum, and can be due to an intraluminal lesion or from extrinsic compression, most commonly from malignancy. Patients often present with early satiety, nausea, vomiting (usually undigested food contents) and weight loss. Upper endoscopy and cross- sectional imaging, such as an upper gastrointestinal series with oral contrast or a contrast-enhanced computerized tomography (CT), are necessary not just to confirm the diagnosis but also to evaluate the location and severity of the obstruction. Interestingly, until the 1970?s, the most common cause of gastric outlet obstruction was pyloric stenosis associated with peptic ulcer disease. Since the introduction of effective acid suppressive medications and the identification of Helicobacter pylori as one of the main drivers of peptic ulcer disease, severe peptic stricture has become rare. Currently, the most common etiology of gastric outlet obstruction has become pancreatic cancer.¹ However, although less common, gastric outlet obstruction can arise from duodenal compression caused by chronic pancreatitis.

Many patients with gastric outlet obstruction are not ideal candidates for surgical resection of the obstructing tumor due to the presence of advanced malignancy. Therefore, these patients are managed with palliative interventions such as surgery (open or laparoscopic gastroenterostomy) or endoscopy, traditionally via enteric stent placement. These patients are frequently debilitated and have a poor performance status and while surgery, when successful, offers better long term outcomes it is associated with much higher rates of morbidity and mortality when compared to minimally invasive interventions such as endoscopic stenting. Endoscopic stenting is safe and effective for symptom palliation in gastroduodenal outlet obstruction. In a retrospective study comparing its outcomes against surgery, endoscopic stenting had significantly less complications and patients had shorter hospitals stays but had a higher re-intervention rate and overall charges.² Enteral stents are designed for patients with malignancy and may not be ideal for use in benign conditions.³

Endoscopic ultrasound (EUS) was initially utilized as a diagnostic modality in pancreatic diseases dating back to the 1980?s where a radial echoendoscope allowed detailed imaging to be obtained due to scope proximity to the pancreas while sitting in the gastrointestinal tract. In the 1990?s, the linear echoendoscope with an accessory channel was developed which allowed for therapeutic interventions. This included pancreatic sampling (fine needle aspiration and fine needle biopsy) and drainage of multiple types of lesions (pseudocysts, bile ducts, and pancreatic ducts).

More recently, with the advent of lumen apposing metal stents (LAMS), EUS guided placement has been used in the creation of luminal anastomoses. The idea of creating a luminal anastomosis between the stomach and small bowel (EUS-guided gastroenterostomy) using a stent was initially developed in animals. In 2012, Binmoeller and Shah showcased the results of this technique using a porcine model.⁴ The procedure was performed using an anchor wire to appose the lumen of the small bowel to the stomach and a biflanged lumen apposing metal stent (LAMS) was deployed under ultrasound guidance to create the anastomosis. The procedure was technically successful in all four animals without complications. Another animal study from Japan performed by Itoi et al.⁵ showed similar results with a successful creation of a gastroenteric anastomosis and no adverse events. In this study, the authors used different devices such as a novel double balloon enteric tube to access the small bowel and a different lumen apposing metal stent.

In the United States, a cautery-enhanced (CE) LAMS system allows for direct puncture through the stomach and into the small bowel and obviates the need for tract dilation prior to stent deployment. Furthermore, the single-step access to the small bowel may minimize the chance for separation between the stomach and small bowel. The biphalanged design of the stent reduces the risk of migration and we would advocate using the 15mm diameter size. However, the use of CE-LAMS for gastroenterostomy is an off-label indication.

Endoscopic Technique

EUS-guided gastroenterostomy (EUS-GE) using LAMS was developed as a way to bypass the obstructed proximal duodenum with direct placement of the stent between the stomach and more distal duodenum or proximal jejunum. This new endoscopic technique continues to evolve as endosonographers gain more clinical experience and as more devices are developed for the creation of endoscopic anastomosis. There is no ?ideal method? of how to perform this procedure and the technique itself has multiple steps that require an expert operator when performing this procedure.

The basic principles include filling the small bowel with contrast to distend it for better apposition with the gastric wall, puncture into the small bowel, and then stent deployment with the distal flange in the small bowel and the proximal flange in the stomach. This can be performed using different approaches.

The initial access can be performed by using a 19-gauge needle and advancing a guidewire into the small intestine or can be performed directly ?freestyle? using the cautery enhanced (CE) LAMS delivery system.

It is of utmost importance to ensure adequate visualization and distention of the small bowel prior to puncture. Depending on the degree of lumen obstruction, every effort should be made to infuse a large volume of dilute contrast into the small bowel. Small amounts of methylene blue can be added to the diluted contrast to help confirm appropriate access after stent deployment. A case series from Japan used a double balloon enteric tube to access the small bowel and distend the bowel distal to the ligament of treitz.⁶ In two other case series the visualization of the small bowel was performed using biliary or luminal dilation balloons advanced over a guidewire under fluoroscopic guidance.^7,8 In this approach, the balloon in the small bowel can serve as target for the 19-gauge needle to puncture. Our preference when using the balloon- assisted technique is the longer length dilation balloons since they provide a larger target for needle puncture.

One major pitfall in this technique is the difficulty in obtaining reliable apposition of the small bowel wall to the gastric wall to prevent misdeployment of the stent into the peritoneum. Currently available LAMS have a 1cm length and therefore the walls must be in close proximity for proper deployment. Some endoscopists theorize that once the small bowel is punctured with the 19-gauge needle and guidewire is passed, it may push the small bowel away from the stomach. Therefore, they advocate for the direct puncture technique using CE-LAMS. Meanwhile, puncture using a 19-gauge needle and passage of a guidewire over which CE- LAMS can be passed allows maintenance of access and potential for ?rescue? placement of a longer fully covered biliary stent to serve as a bridge in cases of LAMS misdeployment.⁸

Careful stent deployment is critical. In our experience, applying gentle traction is useful to ensure appropriate deployment of the proximal phalange, but care must be taken not to apply too much traction that can cause migration of the distal flange out of the small bowel and into the peritoneum. Once the LAMS has been deployed, careful balloon dilation of the stent lumen can be performed. We suggest dilating to just below the diameter of the stent (i.e. 12mm if 15mm LAMS used). The anastomosis created by the stent can be seen endoscopically and by fluoroscopy. Contrast can also be seen passing through the LAMS from the small bowel and into the stomach under fluoroscopy when placement is correct.

To help illustrate this technique we have added a series of figures on an EUS-GE performed at our institution in a patient with severe gastroduodenal outlet obstruction due to chronic calcific pancreatitis. (Figures 1-6.) The patient has previously had a metal biliary stent placed at an outside hospital for a benign biliary stricture and jaundice. In our case, we used the dilation balloon over a guidewire technique. First, we injected copious amounts of dilute contrast into the small bowel and advanced an 0.035mm guidewire under fluoroscopic and endoscopic guidance (Figure 2). After removing the endoscope, a 20-mm through the scope dilation balloon was passed over the guidewire under fluoroscopic guidance and inflated with contrast. Next, the EUS linear scope was passed down and the dilation balloon was visualized in the small bowel with the scope tip in the stomach (Figure 3). We then used a 19-gauge needle to puncture the balloon in the small bowel and advanced a second 0.035 guidewire deeper into the small bowel. The needle was then exchanged for a 15mm CE-LAMS that was deployed successfully. (Figures 4-6). Finally, the LAMS was dilated using a 12mm balloon allowing contrast from the small bowel to enter the stomach.

Our patient was started on a full liquid diet the next day and then advanced to a low residue diet. He was discharged 48 hours after the procedure, gained 40lbs in 8 weeks and continues to do well 6 months after the procedure. Currently, there are no data to suggest optimal time for stent removal but there are anecdotal reports of gastroenterostomy tract closure after LAMS removal.

Safety and Efficacy of EUS-GE

Since this is a new technique, the data evaluating its efficacy and safety is limited to a few small studies. The data includes patients with benign and malignant gastric outlet obstruction and reported the results of ten patients,⁷ twenty patients6 and twenty-six patients,8 describing 90% technical success rates, and clinical success rates of 90%6,7 and 85%.⁸

By analyzing these studies, even though the number of patients is limited, the rate of adverse events was low (less than 5%). Nonetheless, it is important to note that when complications happen these are not trivial. Khashab et al.⁷ reported one case of stent misdeployment that ultimately resulted in conversion to a surgical gastrojejunostomy. The case series by Itoi et al.6 reported two stent misdeployements and the multicenter study published by Tyberg et al.⁸ reported one case of bleeding, one case of post procedural pain and one patient who developed peritonitis and died the following day after the procedure. Therefore, close collaboration with surgery and review of the technique is key to ensure success during this intervention.

CONCLUSION

EUS-guided gastroenterostomy (EUS-GE) is a novel, minimally invasive technique that can be used to palliate the symptoms of gastroduodenal outlet obstruction due to benign or malignant conditions. Due to the risk for serious adverse events, no current standardized technique and limited published data, this endoscopic technique should only be undertaken by experienced endosonographers. Furthermore, use of CE-LAMS for EUS-GE is not currently an FDA approved indication. Multidisciplinary care is strongly encouraged, incorporating surgeons, radiologists and gastroenterologists to ensure proper patient selection. EUS-GE remains to be prospectively evaluated, but early results show promise in the treatment of gastric outlet obstruction. This technique may be of particular interest for benign indications where long-term stent patency is desired but more study is warranted.

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A Case Report

Dysphagia Aortica, an Extrinsic Cause of Dysphagia

March 2017 • Volume XLI, Issue 3

Giulio Quarta,David M. Poppers

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The etiologies of dysphagia are myriad, including intrinsic disorders of the esophagus, such as neoplasia, stricture, severe reflux disease and motility disorders. Extrinsic etiologies of dysphagia include compression from adjacent lymph nodes or vascular structures. The importance of extrinsic compression is emphasized in this case of a patient presenting with the acute onset of dysphagia to solids, found to have compression of the esophagus secondary to a tortuous aorta. Despite a relatively normal endoscopic exam, this patient demonstrated significant pathology during follow up barium esophagram. Clinical signs and symptoms cannot reliably distinguish extrinsic from intrinsic causes of dysphagia and thus dysphagia aortica, which can be associated with imminent aneurysmal rupture, should be considered in elderly patients with acute onset dysphagia.

Giulio Quarta MD, David M. Poppers MD, PhD, NYU School of Medicine, NYU Langone Medical Center, New York NY, Division of Gastroenterology

INTRODUCTION/PRESENTATION

Extrinsic and intrinsic causes of dysphagia are challenging to distinguish from one another, as they often present with similar signs and symptoms. Dysphagia due to any anomaly of the aorta is called dysphagia aortica. In this case we highlight the importance of contrast-enhanced esophagram in an elderly patient presenting with acute onset dysphagia.

A 91 year-old man with a history of gastroesophageal reflux, hyperlipidemia and coronary artery disease presented with the abrupt onset difficulty swallowing solids, associated with an unintentional weight loss of seven pounds over two months. Solid foods such as bread and potatoes were associated with intermittent symptoms. He denied odynophagia, distracted eating and did not wear dentures. Laboratory analysis, including serum hemoglobin and iron studies, was unremarkable.

Initial evaluation included an upper endoscopy which demonstrated a normal caliber esophagus and unremarkable squamocolumnar junction at 43cm from the incisors. The gastric mucosa in the antrum showed a patchy erythematous pattern; biopsies revealed reactive gastropathy without intestinal metaplasia or Helicobacter pylori. Chest X-ray revealed a prominent thoracic aorta with widening of the cardiac silhouette. A single-contrast barium esophagram revealed a dilated esophagus with extrinsic narrowing by a tortuous aorta and delayed esophageal emptying in the semi-upright position. Of note, cross sectional abdominal imaging revealed a normal aorta and branches.

Discussion

Pape first described dysphagia aortica in 1932, affecting women with short stature, old age, hypertension and kyphosis.¹ Compression of the esophagus can originate from tortuosity, dilation or aneurysm of an atherosclerotic aorta. Barium esophagram has been shown to be the most reliable method of diagnosis of this condition, and thoracic computed tomography (CT) facilitates early diagnosis. On endoscopy, pulsatile extrinsic compression resulting in stenosis with proximal esophageal dilation is considered diagnostic. Manometry can reveal local high-pressure regions associated with cardiac pulsation.² In cases of thoracic aortic aneurysm, endovascular repair is associated with significant improvement in symptoms and morbidity.³ Mild cases of dysphagia aortica are typically treated conservatively, and patients who are not surgical candidates may be managed with insertion of a percutaneous gastrostomy tube.² Dysphagia aortica is rarely considered in the differential diagnosis of dysphagia. Vascular extrinsic esophageal conditions such as dysphagia lusoria, in which esophageal compression from an aberrant right subclavian artery may produce a similar clinical presentation, should also be considered. Lack of awareness can lead to a significant diagnostic delay. Fatal cases of thoracic aorta aneurysmal rupture have been reported,⁴ especially when associated with alarm features such as chest or back pain. However, intrinsic etiologies of dysphagia, such as esophageal spasm or invasive esophageal cancer, may also be associated with similar symptoms, often confounding and delaying timely diagnosis and intervention. Routine imaging such as chest X-ray or thoracic CT can quickly and non-invasively be diagnostic. In elderly patients with kyphosis and hypertension presenting with dysphagia, we suggest that such conditions be entertained in the differential diagnosis, and that timely use of imaging studies be utilized to evaluate for extrinsic causes of dysphagia.

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Gastrointestinal Motility And Functional Bowel Disorders, Series #21

Belching, Aerophagia and Rumination: Not Just Refractory Gastroesophageal Reflux Disease

March 2017 • Volume XLI, Issue 3

Il J. Paik,

Craig R. Gluckman

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High-resolution manometry and impedance studies have allowed physicians to now more confidently identify subtle differences between belching, aerophagia and rumination. Here, we discuss our increased ability to diagnose and differentiate patients with these and other related conditions and to treat often closely related entities.

Il J. Paik, MD, Assistant Professor of Medicine- Gastroenterology. Icahn School of Medicine at Mt Sinai. Director, Swallowing Center of the Mt Sinai Health System Digestive Disease Institute Director, Center for GI and Motility Disorders. Mt Sinai St Luke’s and Mt Sinai West Hospitals. Craig R. Gluckman, MBBCh, Gastroenterology Fellow, Mount Sinai Beth Israel, New York, NY

Widespread availability and utilization of esophageal impedance recording and pH monitoring in specialized motility centers has improved our understanding of belching, aerophagia and rumination. This new understanding has increased our ability to diagnose and differentiate patients with these and other related conditions. As the pathophysiology of these heterogeneous group of disorders becomes clearer, our ability to treat often closely related entities continues to improve. This benefits patients, who have often gone undiagnosed or incorrectly labelled, as well as the primary care doctors and gastroenterologists caring for these patients. Impedance studies, differentiating and diagnosing these very different conditions, has improved our understanding of gastroesophageal reflux (GERD) and its relationship to these disorders. High-resolution manometry and impedance studies have allowed physicians to now more confidently identify subtle differences between belching, aerophagia and rumination resulting in the correct treatment options being applied to these patients.

BELCHING
Introduction

Excessive belching has become one of the most common chief complaints that physicians address. Patients often present after an unremarkable endoscopic evaluation and clinical failure on multiple regimens of proton pump inhibitors (PPIs) and other acid- suppressing medicines. Historically, the diagnosis of excessive belching required a careful history and close observation during physical examination. Patients often describe a variety of symptoms and sensations to explain the act of belching as a primary symptom or in association with other upper gastrointestinal symptoms. This has led to a discrepancy between the subjective symptoms described by the patient and the ability of the clinician to make an objective diagnosis. An incomplete understanding of the pathophysiology of belching, aerophagia and rumination and the lack of diagnostic tests may have led to this discrepancy.

Currently, newer esophageal impedance testing now allows more accurate differentiation between these various conditions. Specifically, differentiating between various types of belching and correctly identifying it as an isolated condition or as a concomitant symptom in patients with GERD or functional dyspepsia is possible. This testing allows clinicians to improve their evaluation of patients with symptoms such as dysphagia, epigastric pain, persistent reflux and heartburn.

Belching (eructation) is the oral expulsion of a gas bolus from the upper gastrointestinal tract; this release can be audible or occur silently.¹ Gases, a normal constituent of the gastrointestinal tract, enter the esophagus and moves to the stomach with each swallow. Gases can also be released in the stomach by ingested food and drink. In the small intestines and colon, gases are produced by bacterial fermentation of luminal contents. These gases are released from the gastrointestinal tract proximally in the form of a belch and distally as flatus.²

Many patients with belching may not initially present to a healthcare provider. However, patients are likely to seek attention if their belching is responsible for a decreased quality of life or at the request of friends, family or co-workers. Patients with GERD and functional dyspepsia frequently complain of belching, but other symptoms usually predominate. Studies show that an excess of air swallowing and belching in these patients is a response to uncomfortable gastrointestinal sensations.³ Treatment with a PPI reduces the number of air swallows in patients with GERD but not in other subjects, which suggests that the unpleasant sensation of heartburn stimulates patients to swallow more air.⁴ So, belching is the physiological venting of excessive gastric air.⁵

Pathophysiology of Belching

The mechanism of belching has further been elucidated through the use of manometric studies and esophageal electrical impedance monitoring. (Figure 1) Air and saliva are pushed down through the esophagus into the stomach by peristalsis as the lower esophageal sphincter (LES) relaxes. Gastric air causes dilation of the proximal stomach and activates a vaso-vagal reflex. A belch begins with a transient lower esophageal relaxation (TLESR) triggered by distension of the fundus from this intragastric air and movement of air begins from the stomach into the distal esophagus. This is then followed by reflex relaxation of the upper esophageal sphincter (UES) as air moves up towards the proximal esophagus and then expelled orally. This physiological response of venting excessive gastric air is what the patient will perceive as a belch. This gastric belch reflex releases the uncomfortable sensation associated with gastric distension and is the gaseous equivalent of gastroesophageal reflux as both occur in the setting of a spontaneous and not swallow-induced TLESR. This gastric belch reflex is lost following a fundoplication procedure done for anti-reflux surgery as the ability for proximal stomach distension and TLESR are decreased. These patients are physically unable to belch and are often left with the uncomfortable sensations of bloating, flatulence and abdominal distension⁶, often referred to as the post-fundoplication gas-bloat syndrome.

This gastric belch needs to differentiated from a second type of belch identified in patients with isolated excessive belching. Initially detected in the 1990s with the use of intraluminal esophageal impedance monitoring of the flow of fluid and air in the esophagus, a new mechanism of belching was described. Now known as a supragastric belch, this second type of belching, which is physiologically different from a gastric belch, is characterized by air rapidly brought into the esophagus and immediate, rapid, oral expulsion without ever reaching the stomach. Combined use of high resolution manometry and impedance monitoring has discovered that this belch may be initiated by air which is sucked into the esophagus by creating a negative intrathoracic pressure or less commonly by pushed or injected air from an increase in pharyngeal pressures.⁷ This also identified patients with repetitive and multiple, instantaneous supragastric belches as only occurring in patients with supragastric belches and not with gastric belches.⁸

Impedance studies, with or without manometry, can now accurately differentiate patients with gastric belching from supragastric belching and other mimickers. From these studies, a supragastric belch has been defined as a rapid anterograde movement of gas (impedance >1000Ω), followed by its quick retrograde expulsion with a return to baseline impedance. (Figure 2) The incidence of air-containing swallows and gastric belches is similar in patients and controls but supragastric belches occur exclusively in affected patients.⁹

Initially a supragastric belch represents a voluntary response to an unpleasant gastrointestinal sensation, but over time patients may no longer be aware that their belches are under voluntary control, thus becoming excessive and repetitive. Supragastric belches almost always cease at night suggesting the presence of a behavioral disorder.¹⁰ Additional studies have shown that patients with excessive belching who were unaware that they were being studied or were distracted during the study had significantly reduced numbers of belches.¹¹ Typically, a patient belches while the physician is asking the questions, whereas a patient does not belch while responding to these questions.¹² These studies support the rationale for behavioral therapy as a method of treatment.

The estimated prevalence of supragastric belching in a tertiary referral population is 3.4% in patients being investigated with upper gastrointestinal symptoms.¹³ Not all patients diagnosed with supragastric belching report belching as their predominant symptom and, conversely, many patients who report excessive belching are not in fact belching by current manometric criteria.

Patients with esophageal hypomotility on high resolution manometry demonstrate an increase in the frequency of supragastric belching compared to the patients with normal motility.¹⁴ It is unclear whether the hypomotility led to supragastric belching or if some factor in patients with supragastric belching affected motility patterns. Further studies are needed to investigate this possible association.

Belching in Patients with GERD

Estimates of 40-49% of patients with GERD experience belching.¹⁵ Air swallowing promotes belching but does not facilitate acid reflux.¹⁶ Similarly, supragastric belching was more frequent in patients with typical reflux symptoms than in healthy subjects. Supragastric belches occur immediately prior (<1s) to the onset of the reflux episode suggesting that the supragastric belching occurs in response to the unpleasant sensation felt in those with reflux.¹⁷ Patients with severe reflux symptoms have more supragastric belching and subsequently more severe belching complaints. Thus, it has been suggested that GERD patients with troublesome belching symptoms could also be treated with speech therapy aimed at reducing the incidence of supragastric belches.¹⁸

Treatment of Belching

Supragastric belching is associated with significant reduction in quality of life and distressing psychosocial repercussions.¹⁹ Given that supragastric and excessive belching are likely behavioral disorders, cognitive behavioral therapy can be used as a treatment strategy. The primary step in treatment is offering reassurance and a thorough explanation of the cause of the belching. Speech therapy and breathing exercises can be utilized. Patients should be educated on modifying their habits, as supragastric belching is a self-induced, learned behavior.²⁰ For example, breathing exercises with the emphasis on abdominal breathing reduce the belching episodes through behavior modification.

Gum chewing has no effect on the frequency of gastric or supragastric belches, but in fact may exacerbate belching disorders by increasing the amount of air and saliva swallowed.²¹ Simethicone and similar drugs have not been found to be beneficial in patients with belching. Baclofen, a GABA_B receptor agonist, used in patients with refractory GERD to decrease TLESR, has been studied for its use in patients with belching. It was found to be effective in reducing both supragastric belching and aerophagia²² thus providing complementary therapy to behavioral modification.

Aerophagia

It may be difficult to differentiate aerophagia (Greek for ‘air eating’) and excessive belching. However, these two conditions are very different in terms of the direction of air movement in and out of the mouth and esophagus. Patients with aerophagia swallow air too often and in large quantities. In aerophagia, peristalsis of the esophagus actively moves air down the esophagus into the stomach, whereas in supragastric belching there is no esophageal peristalsis. Furthermore, a supragastric belch is completed within one single second, in contrast to aerophagia.²³ Intraluminal impedance monitoring has allowed accurate differentiation of these two conditions. (Figure 3) Supragastric belching is not a predominant symptom in patients with aerophagia but they do experience gastric belching episodes. Patients with aerophagia have symptoms of bloating, distension and flatulence. An abdominal X-ray may show increased intragastric and intra-intestinal air. The management of aerophagia is based on expert and local opinion as no standard treatment exists. Consideration of speech therapy could be considered, but no published reports exist.²⁴

Rumination

Rumination is an eating disorder characterized by recurrent regurgitation of recently ingested food or liquid into the mouth, followed by re-chewing, re- swallowing or expulsion. The effortless regurgitation of these recently ingested gastric contents occurs within 15-20 minutes of intake. The event is often proceeded by belching before fluid and food are regurgitated.²⁵ This condition was thought to predominantly occur in adults and children with developmental delay, but it also occurs in otherwise healthy people. Rumination was traditionally diagnosed based on the history provided by the patient, but esophageal manometry and impedance studies can be used to confirm the diagnosis. The characteristic manometric pattern of rumination shows an abrupt rise in intragastric pressure followed by an increase in intra-esophageal pressure in all channels. (Figure 4) This pressure rise has been referred to as the “R” wave, and occurs when the patient is asked to drink a liquid or swallow food. The importance of a diagnostic test in rumination syndrome is to exclude other conditions that present with postprandial vomiting and regurgitation such as achalasia and GERD. The mainstay of treatment for this condition is a thorough explanation of the disorder followed by behavioral therapy and breathing exercises to distract the patient while eating. In addition, rumination syndrome is associated with the setting of great stress and emotional factors, therefore often requiring concomitant care with a psychologist or counselling. Tricyclic antidepressants are also very helpful during the breathing and relaxation/ distraction approach.²⁶

CLINICAL PEARLS

Major advancements have been made in recognizing and differentiating belching, aerophagia, rumination and GERD as distinct clinical entities largely through the use of esophageal impedance. Supragastric belching differs from gastric belching in terms of its pathophysiology and often becomes a behavioral response to some ongoing, unpleasant gastrointestinal sensation like GERD. Reflux symptoms occur more commonly in patients with supragastric belching than in healthy controls. Patients with aerophagia have gastric belching due to excessive air swallowing. Rumination syndrome can be accurately diagnosed with impedance studies. Breathing exercises to distract the patient as well as behavioral therapy are the mainstay of treatment. It is hoped that as our understanding of these conditions continues to evolve, newer treatment options will also become available for these patients.

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Nutrition Issues In Gastroenterology, Series #161

Lactic Acidosis: A Lesser Known Side Effect of Thiamine Deficiency

March 2017 • Volume XLI, Issue 3

Kelly O’Donnell

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A lesser known cause of elevated lactate levels in the critically ill patient is thiamine deficiency. Thiamine is a water soluble vitamin essential for carbohydrate metabolism. Given limited stores along with daily requirements, thiamine deficiency may occur quickly in patients presenting with persistent vomiting, malnutrition and alcoholism. The purpose of this paper is to help identify those patients at risk for thiamine deficiency and recognize signs and symptoms of deficiency including, but not limited to, elevated lactate levels.

INTRODUCTION

Lactate, produced by most tissues in the body, is an end product of anaerobic metabolism. Reasons for elevated lactate levels include, sepsis, shock or tissue hypoperfusion, ischemic bowel, uncontrolled source of infection, liver dysfunction, medications and thiamine deficiency, to name a few. Lactate is often used as a marker of illness severity with elevated levels associated with adverse outcomes and mortality as high as 80%.¹

Thiamine is a water-soluble vitamin with limited tissue storage. When oral intake is reduced, stores may be consumed in as quickly as 18-20 days.² Thiamine is a cofactor for pyruvate dehydrogenase during aerobic metabolism (glycolysis), facilitating the conversion of pyruvate to acetyl-CoA within the mitochondria. If a thiamine deficiency exists, pyruvate is unable to enter the citric acid cycle, instead being converted to lactate, which may lead to lactic acidosis.^3,4

Thiamine deficiency is largely a clinical diagnosis and if left untreated, may result in irreversible neurologic damage. Therefore, waiting for lab confirmation to confirm a deficiency is not advised. Moreover, plasma and serum thiamine levels have a low sensitivity and specificity, and are decreased in critically ill trauma patients and those requiring continuous renal replacement therapy.^3,5 Whole blood assays may be a better reflection of total body stores, but are impractical in an acute care setting due to cost or long turnaround time which can take up to 2 weeks. Additionally, there is not a specific blood level that correlates with the appearance of signs and symptoms of deficiency. Identifying patients with risk factors such as alcoholism, persistent emesis, and malnutrition is the key to detecting thiamine deficiency.^3,5-7 (see Table 1).

There are two major clinical manifestations of thiamine deficiency: Dry beriberi, which includes peripheral neuropathy and gait ataxia; more advanced symptoms include Wernicke’s encephalopathy with its classic triad of ataxia, confusion and ocular changes.^3,5,8 Wet beriberi includes high output heart failure, cardiac hypertrophy (especially of the right ventricle), lactic acidosis, and edema in lower extremities.^3,5,8,9 (See Table 2).

Case

A 35-year-old female with a history of bipolar disorder and prior self-inflicted abdominal injury, resulting in exploratory surgery and bowel resection, recently presented to surgery clinic for evaluation of her ongoing abdominal pain, daily vomiting and reflux symptoms. She was referred to gastroenterology and underwent esophagogastroduodenoscopy and manometry, which showed:

LA Grade C reflux esophagitis
Hiatal hernia
Erythematous duodenopathy
Lower esophageal sphincter hypotension

The hiatal hernia was felt to be contributing to her gastroesophageal reflux disease and esophagitis, as well as cholelithiasis precipitating her biliary colic. She was subsequently admitted to the hospital and underwent an elective laparoscopic Nissen fundoplication, hiatal hernia repair and cholecystectomy. In the operating room, she was noted to have significant steatosis with hepatomegaly. Despite this, her operation was completed successfully and she was transferred to the regular surgical floor post-operatively. When questioned about the appearance of her liver, the patient acknowledged a “few drinks” per week. A nutrition evaluation revealed that the patient had suffered a severe weight loss of 26 pounds (180 down to 154 lbs. or a 15% loss over the previous 3 months) from frequent vomiting and an inability to eat. This prompted the initiation of 100 mg of intravenous (IV) thiamine per day starting on post- operative day (POD) 1; a clear liquid diet was begun and intravenous normal saline continued. Liver function tests peaked on POD 2 with alkaline phosphatase rising to 22 U/L (40-150 U/L), ALT 62 U/L (<55 U/L) and AST 329 U/L (<35 U/L). During this time, lactic acid ranged from 1.0 to 1.3 mmol/L (0.5-2.2 mmol/L).

On POD4, she experienced confusion and dyspnea with a chest x-ray demonstrating bilateral pulmonary infiltrates suggestive of acute respiratory distress syndrome. She was transferred to the intensive care unit (ICU) and intubated. Her course was further complicated by severe lactic acidosis requiring a bicarbonate drip, sepsis requiring high dose vasopressors, and renal failure requiring continuous renal replacement therapy (CRRT). Low calorie parenteral nutrition with an additional 200 mg thiamine to avoid refeeding syndrome was initiated upon transfer to the ICU. She also continued to receive 100 mg IV thiamine. Although broad spectrum antibiotics were started, all percutaneous and central line blood cultures continued to be negative. A transthoracic echocardiogram showed a mildly dilated right ventricle.

On POD6, given persistent lactic acidosis and unable to identify a source of her sepsis, the patient returned to the operating room where she underwent a diagnostic laparoscopy converted to exploratory laparotomy with findings of 20-30 cm of dusky, dilated jejunum, but no evidence of spillage, injury, or septic source within the abdomen.

At this time, the patient’s family was again questioned about her alcohol use and it was revealed that the patient engaged in heavy drinking of 5-6 drinks per day up until the time of hospital admission. Based on this new information, as well as the preoperative excessive weight loss with persistent vomiting, a mildly dilated right ventricle, in addition to her lactic acidosis of unclear etiology, it was presumed the patient was thiamine deficient and thiamine was repleted aggressively with 500 mg IV three times per day over the next 3 days, followed by 250 mg IV thiamine daily for four more days.

Results

Supplementation with high dose IV thiamine was associated with a rapid reversal of lactic acidosis and a greater than 50% decrease in lactic acid levels within 8 hours (14.0 to 6.1 mmol/L) (see Table 4). Normalization of lactic acid levels occurred within 18 hours (POD7). Three days later, on POD10, she was weaned off pressor support and continuous renal replacement therapy was discontinued. She was extubated on POD 14. The patient subsequently underwent fascial closure, placement of retention sutures and was eventually discharged to a rehabilitation facility. Although liver failure and shock liver were considered as potential causes of her lactic acidosis, they typically take many days to weeks to correct.

DISCUSSION

Elevated lactate levels are often used as a prognostic tool in critical illness. There are many causes of lactic acidosis including sepsis, systemic hypoperfusion, medications and thiamine deficiency. Thiamine is essential for producing energy from glucose in the glycolytic pathway, but if a deficiency exists, pyruvate is instead converted to lactate (see Figure 1).

There is large variability in thiamine prescribing practices, most revolving around the treatment of alcoholics. Only one randomized, double blind study using different doses of parenteral thiamine exists to date.¹⁰ A therapeutic effect was seen with the 200 mg dose of intramuscular thiamine in alcoholic patients taking a memory test. However, the sample size was small, there was a high rate of non-completion and thiamine administration was of short duration (2 days).

Thiamine is both inexpensive and safe. Because of the potentially devastating effects of undertreating thiamine deficiency, recommendations of higher doses have appeared in the literature.¹¹ In the United Kingdom, 500 mg IV thiamine 3 times daily is prescribed followed by 250 mg IV or IM for 5 days.¹² The European Guidelines suggest 200 mg IV three times daily until symptoms resolve.¹³ American guidelines suggest the lowest amounts of thiamine, ranging from 50-100 mg IV daily for a period of at least 3 days.¹¹ (see Table 3).

Thiamine deficiency as a cause of lactic acidosis in the critical care setting may be undiagnosed or misdiagnosed as a symptom of sepsis or hypoperfusion. In a prospective, observational study, Donnino and colleagues found that 10% of septic ICU patients (n = 30) had thiamine deficiency on admission, and an additional 10% developed a deficiency within 72 hours, yet only one of the 6 deficient patients received thiamine during their hospitalization. According to the authors, this was due to a lack of clinical recognition. Overall, there was no correlation with thiamine and lactate levels, however, when patients with acute liver injury were excluded, there was a significant negative correlation between thiamine and lactic acidosis.⁴

Two recent reports involving lactic acidosis due to thiamine deficiency were attributed to parenteral nutrition with limited or no multivitamins.^14,15 All patients were admitted to the ICU and treated with 100 mg IV thiamine and within hours experienced a rapid decrease in lactate levels and ultimately a full recovery. In another case report, a 56-year-old alcohol misuser with recent weight loss and mild malnutrition was admitted to the ICU with lactic acidosis.¹⁶ He was treated with 300 mg IV thiamine and lactate levels normalized rapidly. This patient, however, experienced persistent cognitive deficits.

Of note, thiamine may be lost in critically ill patients receiving continuous renal replacement therapy (CRRT). In a prospective randomized crossover trial by Berger, et al., 11 intensive care patients on CRRT had trace element and thiamine levels analyzed during CCRT. Trace elements including copper, selenium, and zinc, as well as thiamine, were found in the effluent of each patient. Hence, patients on CRRT may need higher doses of thiamine, especially if they are malnourished or alcohol misuers prior to the initiation of CRRT.¹⁷

CONCLUSION

Elevated lactate levels are often found in critically ill patients, most often due to hypoperfusion. Thiamine deficiency as a cause of lactic acidosis in the critical care setting may be underdiagnosed. This particular case study patient was admitted to the hospital with 3 major risk factors for thiamine deficiency including alcoholism, persistent vomiting, and severe malnutrition. Upon transfer to the ICU, she exhibited symptoms of wet beriberi including dyspnea, respiratory distress, oliguria, mild right ventricular hypertrophy and lactic acidosis. No source of sepsis was ever identified. It is unknown whether thiamine supplementation is solely responsible for the decrease in lactate levels; however the rapid drop after intravenous administration is consistent with other case studies in the literature. At the very least, it was thought to have been an important component of her clinical response. In retrospect, it would have been ideal to have obtained a baseline plasma thiamine level to compare to the patient’s risk factors, signs and symptoms, the caveat being that waiting for blood draw results did not delay empiric treatment. Curiously, 100 mg of thiamine did not appear adequate to prevent lactic acidosis and only with the delivery of higher doses did this malnourished alcohol misuser respond. In addition, it may be that the CRRT pulled off a portion of the thiamine she received. Current guidelines for thiamine deficiency are not specific for the treatment of severe, life-threatening complications and more evidence is needed to clarify the appropriate dosage. Although most critical care practitioners would assume this case was a result of either septic shock lactic acidosis (∼ 25% of septic shock cases a source for infection is not found, nor do cultures grow anything), lactic acidosis from bowel ischemia (with the dusky bowel), lactic acidosis from poorly functioning liver and kidneys, or a combination of all three. However, in unexplained cases of lactic acidosis in a patient not responding as expected, consider thiamine deficiency. It is inexpensive and easy to treat.

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Dispatches From The Guild Conference, Series #2

Pregnancy and Inflammatory Bowel Disease

March 2017 • Volume XLI, Issue 3

Abhik Roy,

Uma Mahadevan

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While IBD increases the risk of certain pregnancy complications and adverse pregnancy outcomes, active disease further increases these risks while sustained remission maximizes maternal and fetal health. A multidisciplinary team emphasizing the importance of medication adherence to achieve preconception disease control and maintain remission throughout pregnancy is recommended. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease. The mode of delivery is determined by obstetrical indications, except for women with active perianal disease who should consider cesarean delivery.

Women with inflammatory bowel disease (IBD) often deal with the illness and its consequences during their childbearing years. Most will have safe pregnancies and healthy children, but there remains significant anxiety and misperceptions about fertility, pregnancy complications and medication toxicities. While IBD increases the risk of certain pregnancy complications and adverse pregnancy outcomes, active disease further increases these risks while sustained remission maximizes maternal and fetal health. A multidisciplinary team should emphasize the importance of medication adherence to achieve preconception disease control and maintain remission throughout pregnancy. Most medications, including aminosalicylates, thiopurines, and biologic agents, are low risk during pregnancy and compatible with breastfeeding. Medication adjustments to reduce fetal exposure may be considered on an individualized basis in quiescent disease. The mode of delivery is determined by obstetrical indications, except for women with active perianal disease who should consider cesarean delivery.

INTRODUCTION

The incidence of inflammatory bowel disease (IBD) peaks during the childbearing years, and the complexities of family planning and IBD management often coincide. Although most patients with IBD have successful pregnancies, anxiety and misconceptions about fertility, medication safety and the potential for adverse pregnancy outcomes are very common. Knowledgeable providers can positively impact IBD pregnancy outcomes by optimizing disease control, reducing medication-related risks and enhancing patient education. As always, a multidisciplinary team including the primary care provider, gastroenterologist, obstetrician, colorectal surgeon and pediatrician should be involved in the care of pregnant women with IBD.

FERTILITY

Though fear of infertility is common among IBD patients, women with quiescent disease and no prior pelvic surgery actually have similar infertility rates to the general population. Active disease, however, impairs fertility through a variety of mechanisms including pelvic inflammation, decreased ovarian reserve, poor nutrition, decreased libido, dyspareunia and depression. One well-established risk factor for infertility is prior pelvic surgery – which results in both scarring and adhesions. The post-operative infertility rate in ulcerative colitis patients who have undergone an ileal pouch anal anastomosis (IPAA) surgery is 48%, threefold higher than the 15% rate in medically treated patients.¹ Compared to open surgery, laparoscopic total proctocolectomy with IPAA may preserve fertility. Women of childbearing potential should be aware of the infertility risk of IPAA, and less invasive procedures may be considered.

Women who experience spontaneous abortion or difficulty conceiving should be assessed for other known risk factors for infertility, including vitamin D deficiency and celiac disease. If a woman remains unable to conceive after six months of calculated attempts, a reproductive endocrinology referral is warranted.

Less is known about male fertility in IBD, although certain medications have been shown to affect sperm quantity and quality. Sulfasalazine causes reversible infertility due to dose-dependent oligospermia and altered sperm motility and morphology. Methotrexate may reduce sperm quality, though this is reversible when the drug is discontinued. We recommend that men stop methotrexate at least 3 months before attempting conception though there have been no association with birth defects when the male has taken methotrexate prior to conception.

COMPLICATIONS

Women with IBD, independent of disease activity, experience higher rates of adverse pregnancy outcomes compared to age matched controls. A meta-analysis including more than 15,000 women with IBD found increased odds of preterm birth, small for gestational age infants and still birth.² Multiple population-based studies, however, have not detected an increased risk of congenital anomalies in IBD pregnancies. IBD is associated with higher rates of labor and delivery complications, including pre-eclampsia, preterm premature rupture of membranes and venous thromboembolism. Inadequate maternal weight gain has been identified as a predictor of adverse outcomes, and factors such inflammation, anemia, hypoalbuminemia and poor nutrition may also increase risk. Based on these findings, a maternal-fetal medicine specialist should monitor all pregnant patients with IBD, and serial ultrasonography for the assessment of fetal growth should be considered in the third trimester.

The Impact of Disease Activity on Pregnancy

Disease activity is the strongest predictor of adverse pregnancy outcomes. Active disease at conception increases the risk of spontaneous abortion and preterm birth, and disease flares during pregnancy increase the risk of preterm birth, still birth and low birth weight. An ulcerative colitis flare doubles the risk of low birth weight, and a Crohn’s flare triples it. These observations emphasize the critical importance of maintaining remission throughout pregnancy, beginning in the preconception period.

When patients conceive during disease remission and maintain quiescent disease throughout pregnancy, the risks of preterm birth and low birth weight are similar to matched non-IBD controls. Therefore, it is recommended that women achieve and sustain remission for at least three to six months before conception to maximize the chances of a successful and healthy pregnancy. Disease remission should be confirmed prior to conception using laboratory analysis, a fecal calprotectin and/or a colonoscopy or flexible sigmoidoscopy.

The Impact of Pregnancy on Disease Activity

It is unclear whether pregnancy itself adversely affects the course of IBD. Among women in remission at conception, the risk of subsequent disease exacerbation during pregnancy is higher in ulcerative colitis (33%) than in Crohn’s disease (20%).³ The reason for the higher rate of flare in ulcerative colitis is unclear, although overlapping immune pathways and less-aggressive disease management may contribute. A meta-analysis of more than 1,700 IBD patients found that disease activity at conception is strongly correlated with more flares during pregnancy.⁴ In this analysis, disease flares affected nearly half of pregnancies conceived during active disease, compared with approximately one- quarter of pregnancies conceived during remission.

It is important to note that inappropriate discontinuation of maintenance medications during pregnancy and the post-partum period increases the risk of disease flare. Patients should be educated about the importance of medication adherence to optimize preconception disease control and maintain remission throughout pregnancy.

Mode of Delivery

The mode of delivery in IBD pregnancies should largely be determined by patient preference and obstetric indications. Multiple studies have shown that cesarean delivery is more common among women with IBD compared to the general population due to concerns that vaginal delivery might trigger perianal disease. In reality, there is no association between mode of delivery and IBD natural history, and cesarean delivery should typically be recommended only for women with active perianal disease. While some colorectal surgeons also recommend cesarean delivery following IPAA to protect the pouch and preserve anal sphincter integrity, this has not fully been supported by the literature.

With regards to the risk of childhood IBD, there appears to be no link to the mode of delivery. Rather, studies estimate that a child has a 2-5% chance of developing IBD if a single parent has the disease and a 36% chance when both parents have IBD.^5-6

TREATMENT

Prior to initiating IBD therapy in a woman of childbearing age, the patient’s plans for pregnancy should be discussed and considered. Women should be aware that the dangers of active disease outweigh the risk of IBD therapies, and preconception counseling about the low risk of most medications may improve medication adherence during pregnancy. With the exception of methotrexate and thalidomide, most medications used to treat IBD are considered low risk and may be continued during pregnancy and breastfeeding. In accordance with recent FDA labeling revisions, the following discussion avoids the previously used pregnancy categories (A, B, C, D, X) in favor of a narrative risk summary, clinical considerations and a brief description of supporting data for the most commonly used IBD therapies.

Managing IBD Exacerbations in Pregnancy

In each trimester of pregnancy, patients (especially those with high-risk disease features) should be monitored for evidence of disease activity and poor nutrition using tools such as fecal calprotectin, serum inflammatory makers (though these may be unreliable in pregnancy) and gestational weight gain. Active disease during pregnancy commonly responds to standard medical therapy, and evaluation and treatment algorithms are the same as for the non-pregnant patient. There are, however, several considerations that are unique to pregnancy (Table 1).

Corticosteroids may be used to treat disease flares, though their use may be associated with an increased risk of pregnancy complications, including gestational diabetes, preterm birth, low birth weight and a possible increase in infant infections in the first four months of life.⁷ Although the benefits of controlling active disease likely outweigh these risks, corticosteroid use during pregnancy should be limited to the lowest effective dose for the shortest duration. Further, steroids should not be used as planned maintenance therapy during pregnancy. Both prednisone and budesonide are compatible with breastfeeding, though avoiding breastfeeding for three to four hours after ingestion of prednisone may limit the amount received by the infant.

The two most commonly used antibiotics in IBD management are ciprofloxacin and metronidazole. While quinolones have been shown to have no association with an increased risk of adverse pregnancy outcomes and are considered compatible with breastfeeding, metronidazole use is more controversial. Metronidazole use in the first trimester has been associated with a possible increased risk of orofacial clefts, and it is incompatible with breastfeeding due to potential toxicities. Amoxicillin-clavulanic acid is the preferred antibiotic during pregnancy, with a favorable safety profile and breastfeeding compatibility.

Indications for surgery do not differ in the pregnant patient and include bowel obstruction, perforation, and medically refractory disease. Non-emergent surgery should preferentially be performed during the second trimester.

5-Aminosalicylates

The 5-aminosalicylates (balsalazide, mesalamine, olsalazine and sulfasalazine) are considered safe in pregnancy, though two points should be kept in mind. First, the coating of delayed release Asacol HD contains dibutyl phthalate (DBP), which has been associated with congenital anomalies in animals at doses much higher than the therapeutic human dose. Asacol HD should therefore be discontinued in favor of alterative mesalamines during pregnancy. Second, women taking sulfasalazine should receive supplemental folic acid 2 mg daily to prevent folate deficiency. Though aminosalicylates enter breast milk, they are considered compatible with use during breastfeeding.

Methotrexate

Methotrexate is an abortifacient, teratogenic inhibitor of DNA synthesis and is contraindicated during conception and pregnancy. It has been associated with a constellation of congenital limb and craniofacial anomalies as well as developmental delay. Given the long half-life of the drug, women should not attempt conception within 3-6 months of methotrexate use. Furthermore, methotrexate should only be given to those women of childbearing potential who are adherent with one to two methods of contraception and take supplemental folic acid. Despite low levels of excretion in breast milk, methotrexate is also contraindicated during breastfeeding as it may accumulate in neonatal tissue. Though less is known about the impact of methotrexate use among men, we recommend stopping therapy at least three months prior to attempts at conception.

Thiopurines

Like methotrexate, thiopurines (azathioprine and 6-mercaptopurine) inhibit DNA synthesis, and at high doses are teratogenic in animals. While previous meta-analyses have shown thiopurine treatment to be associated with preterm delivery and an increased risk of congenital anomalies compared to healthy women (though not to unexposed IBD controls), many of the included studies were confounded by unmeasured disease activity.^8-9 In studies that have attempted to account for disease activity, the results have been mixed. While one has shown an increased risk of preterm delivery irrespective of disease activity,10 several have failed to detect an elevated risk of pregnancy complications or congenital anomalies.^11-14 However, infections at 9-12 months of age have been showed to be more common among infants exposed to thiopurine plus biologic therapy.¹² Given the overall body of evidence, we feel that it is reasonable to continue thiopurine monotherapy during pregnancy to maintain remission, as the risks associated with thiopurine use are likely outweighed by the risks of active disease. Due to the potential for delayed infant infections, women in deep remission with adequate trough biologic levels who are on combination thiopurine/biologic therapy may consider stopping the thiopurine before conception. Starting thiopurines for the first time during pregnancy should be discouraged due to their slow onset of action and unpredictable adverse events (bone marrow suppression and pancreatitis).

With regards to breastfeeding, clinically insignificant thiopurine concentrations have been found to peak in breast milk within 4 hours of maternal ingestion. Lactating mothers may consider avoiding breastfeeding during this interval.

Anti-tumor necrosis factor (TNF) Agents

The available data on the anti-TNF class suggest overall low risk for use during pregnancy, though the long term implications of intrauterine exposure remain unknown – particularly with regards to the development and function of the infant immune system.

Series of hundreds of women exposed to infliximab, adalimumab and certolizumab pegol have shown no adverse effect on pregnancy outcomes or congenital anomalies, and this has been confirmed in a systematic review including more than 1,500 anti- TNF exposed pregnancies.¹⁵ A recent meta-analysis also showed a similar rate of unfavorable pregnancy outcomes between women taking anti-TNF therapy and unexposed controls, including preterm delivery, low birth weight, and congenital anomalies.¹⁶ With the exception of certolizumab pegol, the anti-TNF agents are actively transported across the placenta (along with other maternal antibodies) beginning in the second trimester. With a majority of transfer occurring in the third trimester, cord blood infliximab and adalimumab concentrations at birth exceed maternal levels by up to fourfold and remain detectable in infants for over nine months.¹⁷ This raises concern about potential adverse effects on neonatal immune system development. While the ongoing prospective, multicenter Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry of more than 1475 pregnant women with IBD has shown that third trimester anti-TNF exposure does not detrimentally affect infant growth rate, immune development, number of infections or achievement of developmental milestones, it is reasonable for women in sustained remission to consider third trimester dosing adjustments to reduce neonatal exposure (Table 2). Therapeutic drug monitoring with trough serum concentrations in the late second or early third trimester may help guide this pre-delivery dosing. Stopping anti-TNF therapy in the second trimester is not supported by the current data given the low risk of continuing therapy and potential risk of disease flare in the pregnancy and post-partum as well as the development of immunogenicity.

Infants exposed to anti-TNF agents should not receive live vaccines for at least the first nine months of life or until drug levels are undetectable. All other vaccinations may be given on schedule. This recommendation does not apply to certolizumab pegol, which is not actively transported across the placenta and does not reach significant levels in the infant. Pediatricians should be aware of intrauterine anti- TNF exposure so that vaccinations can be appropriately managed.

Combination therapy with an anti-TNF and thiopurine during pregnancy may be associated with a higher risk of preterm birth and any pregnancy complication, in addition to the risk of delayed infant infections (previously described).

There is clinically insignificant anti-TNF excretion into breast milk, with milk concentrations less than 1% of maternal plasma concentrations.

Non anti-TNF Therapies

The anti-integrin agents natalizumab and vedolizumab are both monoclonal antibodies that would be expected to actively cross the placenta. There has been no observed increased risk of preterm birth, low birth weight, or congenital anomalies among hundreds of women (most with multiple sclerosis) treated with natalizumab during pregnancy. Vedolizumab pregnancy safety data are extremely limited, though pregnant women treated with vedolizumab are being followed in several registries.

The newest FDA approved therapy for Crohn’s disease is the anti-interleukin 12-23 agent ustekinumab. A series of 26 exposed pregnancies reported a spontaneous abortion rate similar to the general population.¹⁸

Lastly, tofacitinib (an oral janus kinase inhibitor) has showed efficacy in ulcerative colitis in phase II trials, but human pregnancy outcome data are sparse.

BREASTFEEDING

As discussed previously, most IBD medications are compatible with breastfeeding. Though women are commonly concerned about drug transfer to the infant via breast milk, the PIANO registry found no increased risk of infection or developmental delay among nursing infants whose mothers were being treated with thiopurines or anti-TNF agents. Furthermore, there may be a protective effect of breastfeeding for mothers, as studies have shown a decrease in disease flares in the first postpartum year among mothers who were breastfeeding.¹⁹ LactMed is a free online database sponsored by the U.S. National Library of Medicine that provides reliable information on drugs and lactation.

SUMMARY

Women with IBD are at risk for pregnancy complications and adverse outcomes, and they should be managed as high-risk obstetric patients by a multidisciplinary team. Counseling about the importance of medication adherence to optimize and maintain disease control should begin in the preconception period. Disease activity is the strongest predictor of adverse pregnancy outcomes, and sustained remission maximizes the chance of a successful and healthy pregnancy. With the exception of methotrexate, most medications are low risk for continued use during pregnancy and lactation. On a case-by-case basis, medication adjustments to reduce fetal exposure can be considered. This includes thiopurine withdrawal from combination therapy and third trimester biologic dosing adjustments.

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CLINICAL CASE 1

CLINICAL CASE 2

INTRODUCTION

PREVALENCE OF T3cDM

DIAGNOSIS AND DIFFERENTIATION OF T3cDM

COMPLICATIONS OF T3cDM

PHARMACOLOGICAL TREATMENT OF T3cDM

NUTRITIONAL MANAGEMENT OF T3cDM

CONCLUSION

INTRODUCTION

Presentation

Discussion

Learning Points

Acknowledgements

INTRODUCTION

1. Look for Dysplasia in the Right Patient

2. Focus on Mucosal Abnormalities, Not Simply Random Biopsies During Colonoscopy

3. Chromoendoscopy but Not Virtual Chromoendoscopy Improves IBD Dysplasia Detection Rate

4. Avoid Older Terms like DALM and ALM to Describe and Manage Dysplasia

5. Most IBD Patients with Dysplasia Do Not Need Surgery, but Some Do

CONCLUSION

INTRODUCTION

Methods

Pathophysiology

How to Diagnose IG: Re-visiting the Gastric Emptying (GE) Diagnostic Criteria

Pharmacologic Explanation for Delayed GE Effect of Marijuana on GE

Effect of Medications on GE

Hypothesized Etiologies for IG Post-Infectious Gastroparesis

Viral Pathogens Linked to IG

Other Pathogens Linked to IG

Medical Entities that May be Un-recognized and Inappropriately Labeled as “Idiopathic Gastroparesis” Connective Tissue Disorder

Autoimmune Diagnosis

Demyelinating Diseases

Paraneoplastic Syndrome

CNS Degenerative Diseases

Functional Dyspepsia

Gastroesophageal Reflux

Anorexia Nervosa/Bulimia

Celiac Axis Injury or Compression

Hypermobility Syndrome

Miscellaneous Causes for Delayed GE

TAKE HOME POINTS

INTRODUCTION

Pathophysiology

Alternative causes of hypoalbuminemia

Testing to Confirm a Diagnosis of PLE

Evaluating Confirmed PLE

Mechanisms Causing PLE

Management of PLE

Practical approach to PLE

CONCLUSION

BACKGROUND

Endoscopic Technique

Safety and Efficacy of EUS-GE

CONCLUSION

INTRODUCTION/PRESENTATION

Discussion

BELCHING Introduction

Pathophysiology of Belching

Belching in Patients with GERD

Treatment of Belching

Aerophagia

Rumination

CLINICAL PEARLS

INTRODUCTION

Case

Results

DISCUSSION

CONCLUSION

INTRODUCTION

FERTILITY

COMPLICATIONS

The Impact of Disease Activity on Pregnancy

The Impact of Pregnancy on Disease Activity

Mode of Delivery

TREATMENT

Managing IBD Exacerbations in Pregnancy

5-Aminosalicylates

Methotrexate

Thiopurines

Pharmacologic Explanation for Delayed GE

Effect of Marijuana on GE

Hypothesized Etiologies for IG

Post-Infectious Gastroparesis

Medical Entities that May be Un-recognized and Inappropriately Labeled as “Idiopathic Gastroparesis”

Connective Tissue Disorder

BELCHING
Introduction