Nutrition Issues In Gastroenterology, Series #153

Vitamin D Deficiencies in Patients with Disorders of the Digestive System: Current Knowledge and Practical Considerations

July 2016 • Volume XL, Issue 7
Zhiyong Han,Samantha L. Margulies,Divya Kurian,Mark S. Elliott

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There is a considerably high prevalence of vitamin D deficiency in patients with various disorders of the digestive system, including cystic fibrosis, acute and chronic pancreatitis, celiac disease, short bowel syndrome and inflammatory bowel disease. In this article, we discuss the different causes of the vitamin D deficiency and the different strategies for normalization of the vitamin D status in patients.

There is a considerably high prevalence of vitamin D deficiency in patients with various disorders of the digestive system, including cystic fibrosis, acute and chronic pancreatitis, celiac disease, short bowel syndrome and inflammatory bowel disease. There are different causes of the vitamin D deficiency, and accordingly, there are different strategies for normalization of the vitamin D status in patients. In general, vitamin D normalization is beneficial for most patients. However, because there is evidence suggesting that vitamin D may be a negative acute-phase reactant, and as such is down-regulated during acute pancreatitis, it may be prudent to hold off on supplementing during the acute phase (and perhaps wait until the acute phase passes before checking levels) until there is evidence supporting benefit.

Zhiyong Han PhD1 Samantha L. Margulies2 Divya Kurian2 Mark S. Elliott PhD1 1Department of Biochemistry and Molecular Medicine, 2MD Class of 2016, The George Washington University School of Medicine and Health Sciences, Washington, DC

BRIEF INTRODUCTION TO VITAMIN D METABOLISM

Vitamin D had been considered as a dietary essential nutrient for the human body until it became obvious that it is a natural hormone of the human body. That is, vitamin D is synthesized in the human body and acts in ways that are no different from a steroid hormone.1

However, vitamin D synthesis is unique in that it depends on the irradiation of the epidermis of the skin by UV-B (ultraviolet B) light. Briefly, the energy of UV-B photons causes a structural change in 7-dehydrocholesterol, yielding pre-vitamin D3. The pre-vitamin D3 then spontaneously isomerizes to vitamin D3 (also called cholecalciferol). Vitamin D3 is exported to the blood circulation from the skin and is sequentially metabolized to:

  • 25(OH)D3 (25-hydroxyvitamin D3, or calcidiol) mainly by the enzyme, CYP2R1 (25-hydroxylase), in the liver
  • then to 1,25(OH)2D3 (1,25-dihydroxyvitamin D3, also called “calcitriol”) by the enzyme, CYP27B1 (1-α-hydroxylase), in the epithelial cells of the proximal convoluted tubules in the kidney.1

Of the different forms of vitamin D, only 1,25(OH)2D3 has biological activity.1 The 1,25(OH)2>D3

Vitamin D Deficiencies in Patients with Disorders of the Digestive System

in the blood circulation acts as an endocrine hormone to stimulate vitamin D receptor (VDR)-dependent gene regulation for intestinal absorption of Ca2+ and renal reabsorption of Ca2+ for the maintenance of a healthy blood Ca2+ level.1 PTH (parathyroid hormone) and reduced serum ionized calcium concentration induce renal CYP27B1 activity, thereby stimulating the renal production of 1,25(OH)2D3; increased concentrations of 1,25(OH)2D3, serum calcium or phosphorus have the opposite effect (reduce CYP27B1 activity).1Similar to other hormone systems, 1,25(OH)2D3 has a negative feedback effect on PTH production. Therefore, patients with chronic kidney disease have reduced production of 1,25(OH)2D3 and are likely to have increased PTH secretion and secondary hyperparathyroidism.

Although proximal tubules of the kidneys are the primary site of 1,25(OH)2D3 production, activated macrophages in extrarenal tissues have also been shown to possess CYP27B1.2 Thus conditions such as sarcoidosis can result in increased production of 1,25(OH)2D3 in macrophages which can lead to hypercalcemia.2 The 1,25(OH)2D3 produced in these tissues acts locally in an intracrine or paracrine fashion to stimulate VDR-dependent expression of genes to affect the functions of these cells.2 This explains the potential immunomodulatory effects of VDR-activating synthetic vitamin D analogs shown in some studies.3,4 The production of 1,25(OH)2D3 in extrarenal tissues is independent of the blood levels of Ca2+ and PTH.

Vitamin D Deficiencies in Patients with Disorders of the Digestive System

The 25(OH)D3 circulates in the blood at ng/mL concentrations with a half-life of approximately 15 days whereas the 1,25(OH)2D3 circulates at pg/mL concentrations with a half-life of approximately 15 hours.5 Therefore, blood levels of 25(OH)D3 are commonly used for the determination of vitamin D status in the body because of convenience for technique reasons. Although controversy exists in the literature, vitamin D status is defined by the Endocrine Society as follows:

  • Vitamin D deficiency is defined by a serum 25(OH)D3 level of ≤20 ng/mL
  • Vitamin D insufficiency by a serum 25(OH) D3 level of 21-29 ng/mL
  • Vitamin D sufficiency by a serum 25(OH) D3 level of ≥30 ng/mL.6

Given the above definition of vitamin D deficiency, vitamin D deficiency occurs in 40-60% of patients with various intestinal disorders, including celiac disease, short bowel syndrome, cystic fibrosis, Crohn’s disease and ulcerative colitis.7 In addition, up to 70% patients with acute or chronic pancreatitis develop vitamin D deficiency.8-11 Strikingly, it appears that over 40% of the patients with acute pancreatitis at the time of admission had severe vitamin D deficiency – that is, their serum levels of 25(OH)D3 were less than 10 ng/ml.10,11

The high rates of vitamin D deficiency in patients with intestinal disorders and chronic pancreatitis are closely correlated with increased incidence of osteopenia and osteoporosis or low-trauma fracture .7,12

Except in cases of acute pancreatitis, the causes of vitamin D deficiency in patients with disorders of the digestive system appear to include:

  • 1. Insufficient cutaneous synthesis of vitamin D
  • 2. Hyperparathyroidism secondary to hypocalcemia that results from calcium wasting
  • 3. Inflammation-associated conversion of 25(OH)D3 to 1,25(OH)2D3 (Table 1).7

However, vitamin D deficiency in patients with acute pancreatitis at the time of admission is likely an acute event caused by an as-of-yet unidentified mechanism that actively down-regulates the blood 25(OH)D3 level during pancreatic inflammation.10,11

Insufficient cutaneous synthesis of vitamin D in patients due to inadequate solar UV-B exposure is a major cause of vitamin D deficiency.7 The rate of pre- vitamin D synthesis in the epidermis is inversely related to the amount of melanin in the skin as melanin is an excellent UV-B absorbent, hence, the rate of vitamin D deficiency is higher in patients with darker skin than in those with fair skin in the same season (Table 1). Furthermore, since the solar UV-B doses are substantially reduced in geographical locations of high latitudes (>35o North [ex. Albuquerque, Memphis, Charlotte] or < 35o South [Adelaide, Auckland, Melbourne]) in the winter as a result of the solar zenith angle,13 the rate of vitamin D deficiency is much higher during the winter months than during the summer months of the same patient population.7 The significance of solar UVB exposure for the maintenance of a sufficient serum level of 25(OH)D3 is further highlighted by the fact that sunlight exposure, but not fat malabsorption, is a more important determinant of vitamin D levels in preadolescent children with cystic fibrosis,7 and that the amount of sunlight exposure, but not even an oral supplementation of up to 800 IU vitamin D/day, was the key determinant to the serum vitamin D level over a period of four years in a cohort of patients with cystic fibrosis.14

Hyperparathyroidism secondary to hypocalcemia, which can result from gastrointestinal loss of calcium, often develops in patients with celiac disease and gastrectomy,7 and possibly in others with steatorrhea. Thus, excessive renal conversion of 25(OH)D3 to 1,25(OH)2D3 due to hyperparathyroidism can cause a reduction in the serum levels of 25(OH)D3 in patients with celiac disease and gastrectomy.7

Active intestinal conversion of 25(OH)D3 to 1,25(OH)2D during an inflammatory flare is independent of blood levels of PTH and calcium and appears to be primarily induced by the inflammatory cytokine, TNFa, because neutralization of TNFa with therapeutic antibody can effectively restore the blood level of 25(OH)D3 in individuals with different inflammatory conditions.7 Thus, conversion of 25(OH)D3 to 1,25(OH)2D3 in the inflamed intestine “drains” 25(OH) D3 from the blood circulation to the inflamed intestine, and hence reduces the blood 25(OH)D3 level. The significance of the intestinal production of 1,25(OH)2D during an inflammatory flare is that 1,25(OH)2D3 acts locally to activate a biofeedback mechanism to enhance antimicrobial activity of macrophages and promote the intestinal epithelial barrier and tissue healing,15 and additionally, to cause suppression of the activities of pro-inflammatory T helper cells (i.e., Th1 and Th17 cells) in the intestine to prevent excessive inflammatory damage to the intestine.2

The severe vitamin D deficiency in patients with acute pancreatitis10,11 deserves special attention. In an observational study, 74.4% (58/78) of patients admitted with acute pancreatitis were found to be vitamin D deficient (< 20ng/mL) the first 2 days of their admission.10 In a prospective study, patients not only had documented vitamin D deficiency at the time of admission, there was a progressive decrease in the blood level of 25(OH)D3 from day 0 to day 2 as a result of pancreatic inflammation.11 Given that inflammation is known to cause macrophage-mediated conversion of 25(OH)D3 to 1,25(OH)2D3,2 which may lead to hypercalcemia,16 which can cause acute pancreatitis,117 it seems active down-regulation of the blood 25(OH)D3 level is beneficial for patients with acute pancreatitis: it would reduce the substrate available for the production of 1,25(OH)2D3 to a level that is high enough to cause hypercalcemia, which can exacerbate acute pancreatitis. Thus, it is reasonable to suspect 25(OH)D3 as a negative acute-phase reactant, specifically during the process of acute pancreatitis.

Normalization of Vitamin D Status in Patients with Disorders of the Digestive System

Not counting vitamin D supplements, there are two sources of vitamin D for the human body: vitamin D present in foods and vitamin D3 synthesized in the epidermis upon UV-B irradiation. Most natural foods, except certain fatty fish (e.g. salmon, bluefish, mahi-mahi and swordfish) and a few species of edible mushroom, are poor sources of vitamin D.7 There are few types of vitamin D-fortified food, such as milk, orange juice and breakfast cereals.7 Given the fact that a minimal daily intake of 600 IU of vitamin D is needed for individuals with minimal sunlight exposure to maintain vitamin D,18 it is unrealistic for many to rely on eating vitamin D-fortified foods to acquire adequate vitamin D3.

Therefore, it is important to inform patients that having sufficient solar UV-B exposure can result in cutaneous synthesis of the amount of vitamin D that the body needs. For the determination of sunlight exposure time to avoid sun burn, physicians could teach patients how to use the solar UV-B calculator (http://zardoz.nilu. no/∼olaeng/fastrt/VitD_quartMED.html) developed by Webb and Engelsen.19 Alternatively, physicians could use short-term UV-B light therapy to stimulate cutaneous synthesis of vitamin D in patients.20,21 However, the UV-B light treatment seems ineffective for patients with chronic pancreatitis;22 in addition, patients should be warned that UV-B exposure has added health risks, such as skin cancer.

Vitamin D absorption occurs mainly in the jejunum and terminal ileum.23 Therefore, patients with ulcerative colitis, which rarely involve the small intestine, may still have normal intestinal vitamin D absorption capacity. However, patients with active Crohn’s Disease or short bowel syndrome have reduced intestinal surface area for vitamin D absorption (Table 2). Patients with cystic fibrosis and chronic pancreatitis have fat maldigestion and malabsorption and consequently malabsorption- and diarrhea-mediated wasting of vitamin D (Table 2). The reduced intestinal absorption of vitamin D or wasting of vitamin D explains why daily intake of up to 800 IU vitamin D is ineffective in normalization of the vitamin D status in these patients,14 and it also explains why normalization of the vitamin D status in these patients require long term treatments with higher doses of oral vitamin D3 supplementation (Table 3).

In addition to vitamin D3 supplements, vitamin D2 (ergocalciferol) supplements are also widely used by patients. However, the blood level of 25(OH)D2 (25-hydroxyvitamin D2) cannot be accurately measured by certain commonly used methods, and thus the effect of vitamin D2 treatment on the blood vitamin D level cannot be accurately determined.24 In addition, it has been suggested that the use of vitamin D3 is preferable because vitamin D2 treatment is considered by some investigators to be less effective than vitamin D3 treatment.25

The Cystic Fibrosis Foundation guideline recommends that all patients maintain a serum 25(OH) D level of at least 30 ng/ml.26 Hall et al. reviewed available evidence and recommend to treat patients with cystic fibrosis less than five years old with 12,000 IU vitamin D3 bi-weekly and for older patients with 50,000 IU vitamin D3 bi-weekly.27

For most patients with celiac disease, adhering to gluten-free diets for 6 months or longer can result in the normalization of the vitamin D status (Table 3).7,28

For patients with chronic pancreatitis, long-term supplementation of extremely high oral doses of vitamin D, 20,000 – 60,000 IU/week or even 140,000 IU/week (20,000 IU/day), are required (Table 3).8

For patients with short bowel syndrome, very high doses of vitamin D3 may be needed. In addition, an intake of 1,500 mg calcium/day should be considered if the patients develop bone metabolic disorders (Table 3).29,30

For patients with Crohn’s disease, it is recommended that the blood level of 25(OH)D3 be raised to above 30 ng/ml.31,32 Numerous studies have demonstrated that treatment of patients with 2000 IU vitamin D3/day over a prolonged period of time is necessary to raise the blood levels of 25(OH)D3 to above 30 ng/ml (Table 3).7 In particular, the study by Raftery and colleagues31 demonstrated that if the blood level of 25(OH)D3 in patients with Crohn’s disease in remission is raised to above 30 ng/ml, it can reduce the rate of relapse and promote the maintenance of intestinal permeability and cause elevated serum levels of LL-37 (cathelicidin, an antimicrobial peptide that promotes intestinal healing and reduces intestinal inflammation) and higher quality of life score.

However, it should be noted that normalization of the vitamin D status in some patients may not be achieved even with super high oral doses of vitamin D3 supplementation (e.g., 10,000 to 50,000 IU vitamin D3 daily). Therefore, the symptoms of vitamin D deficiency of these patients may be treated with calcitriol (0.5 mg) or synthetic, biologically active vitamin D analogs, such as paricalcitol (1 mg) twice daily, daily or less frequently.3,4,33 However, there is no guarantee that calcitriol and vitamin D analogs would be easier to absorb. Also, it would be prudent for physicians to monitor the blood levels of calcium, phosphate and PTH in patients to prevent possible development of hypercalcemia.

CONCLUSION

It appears that elevation of the blood levels of 25(OH) D3 to >30 ng/ml is beneficial to patients with various disorders of the digestive system. To achieve this, it is reasonable to first start patients on clinically tried regimens, depending on the disorder, for 2-3 months (Table 3). If the treatment fails to achieve the goal, then different forms such as tablets (crushed), liquid, or higher doses and longer treatment may be needed; intramuscular injections of high-dose vitamin D3 (“Arachitol”, Solvay Pharmacia) may also be considered.34-36 Nevertheless, patients must be individually monitored on a regular basis to ensure that adjustment of dose, form, or route of administration of vitamin D is made in a timely manner.

Finally, even though it is not conclusive at the present time that 25(OH)D3 is truly a negative acute- phase reactant in the context of acute pancreatitis, given that inflammation-associated production of 1,25(OH)2D3 can cause hypercalcemia,16 which is an established cause of acute pancreatitis,17 it is critical that physicians conduct thorough investigations before deciding to give patients with acute pancreatitis vitamin D replacement therapy simply because their serum 25(OH)D3 levels are low at the time of admission.

Acknowledgement

We wish to thank the Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences for providing support.

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FRONTIERS IN ENDOSCOPY, SERIES #54

Clinical Update on the Endoscopic Management of Ampullary Adenoma

August 2019 • Volume XLIII, Issue 8
Douglas G. Adler,Gandhi Lanke

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Gandhi Lanke1 MD, MPH Douglas G. Adler MD, FACG, AGAF, FASGE2 1Plains Regional Medical Center, Clovis, NM 2University of Utah School of Medicine, Gastroenterology and Hepatology, Salt Lake City, UT.

Ampullary adenomas (AA) are benign, and if untreated, can undergo malignant transformation in to ampullary adenocarcinoma. AA can occur sporadically or associated with familial adenomatous polyposis (FAP). The incidence of AA is increasing due to more frequent use of imaging and endoscopy. Management of AA includes Endoscopic ampullectomy (EA), local surgical excision and pancreaticoduodenectomy, depending on the size, lymph node involvement, ingrowth in to bile or pancreatic duct and presence or absence of advanced duodenal polyposis. Accurate preoperative diagnosis and staging is essential in the management of AA. Endoscopic ultrasound (EUS) can aid in preoperative risk stratification of size, regional nodal metastasis and ductal and vascular invasion in high risk ampullary lesions.

INTRODUCTION
The incidence of ampullary adenoma (AA) is increasing with the ever-more-frequent use of imaging and endoscopy. (Figure 1) AA can occur sporadically or in the context of genetic syndromes such as familial adenomatous polyposis (FAP).1 Adenocarcinoma of the ampulla of vater (AV) is relatively uncommon and it accounts for 0.2% of gastrointestinal cancers.2 Ampullary adenoma can transform in to ampullary adenocarcinoma. Intestinal mucosa near the ampulla is more prone to neoplastic transformation than any other site in the small intestine as there is a transition from pancreaticobiliary epithelium to small intestinal epithelium and it is constantly irritated chemically and mechanically.3 According to SEER data base, the incidence of ampullary cancer (AC) was 0.59 per 100,000 per year and more common in males than females.2 Accurate staging is important in preoperative assessment of adenoma. Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) can aid in the preoperative staging for AA. Endoscopic ampullectomy (EA) can be safe and effective in experienced endoscopist hands and can avoid surgical intervention in patients without ductal extension. This review article focuses on pathogenesis, diagnosis, indications, technique and outcomes of endoscopic management of AA.

ANATOMY
The AV is a spherical structure formed by the confluence of common bile duct (CBD), pancreatic duct (PD) and the distal aspect of the sphincter of oddi muscle. The duodenal papilla is a nipple-like structure located on the medial aspect of the second portion of the duodenum. The ampullary region is a transition from pancreaticobiliary epithelium to small intestinal epithelium.3 The AV is located behind the major duodenal papillae and is covered by small intestinal-type epithelium. The entry of bile in to the second portion of the duodenum is controlled by the smooth muscle fibers of the sphincter of oddi that open at the duodenal papilla and allows bile to flow in to the small intestine. Periampullary tumors can originate from pancreas, duodenum, distal CBD or structures of AV. Ampullary carcinoma can arise from within the AV.

Clinical Presentation
AA is usually found incidentally, and they are asymptomatic. However, they can present with jaundice, pruritus, abdominal pain, nausea, vomiting, anorexia, malaise, dyspepsia and melena.4 Obstructive jaundice is usually caused by compression of the distal bile duct by the tumor. Jaundice at initial presentation with pancreatic invasion and superior mesenteric lymph node can predict advanced stage ampullary carcinoma with poor prognosis.5 Iron deficiency anemia with blood loss can occur secondary to ulceration from ampullary tumors.6 Acute or recurrent pancreatitis can occur with the obstruction of pancreatic duct from ampullary tumor.7

Pathogenesis
AC develops from preexisting adenomas or flat preneoplastic lesions. Most AA develop sporadically. Patients with familial adenomatous polyposis (FAP) are more prone to colorectal adenoma and AA.8 Yamaguchi and Enjoji, defined three macrotypes of AC based on macroscopic appearance. Intramural protruding (intraampullary), extramural protruding (periampullary) and ulcerating AC.9 The common channel is formed by the intestinal mucosa of the ampulloduodenum and mucosa of the ampullo-pancreatico-biliary duct. Histologically, AC has 2 main types, which includes the intestinal type and the pancreaticobiliary type. The intestinal type resembles tubular adenocarcinoma of stomach or colon and the pancreaticobiliary type is characterized by papillary growth with scant fibrous cores.10 The AA of intestinal type can be tubular, villous or tubulovillous and closely resemble adenoma of the intestine.

Diagnosis
Accurate preoperative diagnosis and staging is essential in the management of AA. The side- viewing endoscope (SVE) allows better visualization of the morphological features of ampullary lesion and aids in acquisition of the tissue for biopsy during the procedure. To improve accuracy of diagnosis, atleast six biopsies from the ampulla and biopsy after several days of endoscopic sphincterotomy (ES) has been recommended by some authors, although in practice this does not always occur.11-13 Also, to prevent pancreatitis from forceps biopsy, the forceps should be directed away from the pancreatic duct orifice to avoid papillary edema (although in practice this is not always possible and pancreatitis can result even if biopsies are performed in this manner).14 Preoperative forceps biopsy with SVE can miss AC in about 15-60% of AA as high percentage of AA contain small foci of invasive adenocarcinoma.15-18 Endoscopic retrograde cholangiopancreatography (ERCP) can assess for the presence and extent of any intraductal extension, aids in prophylactic pancreatic duct stent to prevent post ampullectomy pancreatitis and allows biliary stenting to treat obstructive jaundice.19

Endoscopic ultrasound (EUS) aids in the assessment of depth of mucosal invasion, infiltration of the periampullary wall layers and pancreatobiliary ducts preoperatively. The role of routine EUS preoperatively when the size of the AA is less than 1 cm or no suspicious signs of malignancy like ulceration, induration or bleeding is not clear but is often performed per protocol at many centers.20 EUS has modest sensitivity of 77% and specificity of 78% for T1 lesions; sensitivity of 70% and specificity of 74% for nodal invasion.21 Many endoscopists use EUS universally before performing ampullectomy to evaluate the lesion thoroughly, others use it selectively, and some others do not use it at all.

Intraductal ultrasound (IDUS) allows EUS from inside the biliary and pancreatic ducts. IDUS probes can be inserted through the accessory channel of a duodenoscope during ERCP into either the biliary or the pancreatic duct. IDUS is superior to EUS in visualization of tumors of major duodenal papillae with accuracy of 100 % vs 59.3% (IDUS vs EUS); Sensitivity of 100% vs 75% (IDUS vs EUS) and specificity of 62.5% vs 50% (IDUS vs EUS) respectively.22 Despite these benefits, IDUS is rarely performed given the additional cost and the need for a second EUS processor. Computed tomography (CT) and transabdominal ultrasound (US) are not adequate for staging for ampullary tumors but they can identify biliary and pancreatic duct dilation.23 CT can also identify locoregional lymph nodes and distant metastasis. Magnetic resonance cholangiopancreatography (MRCP) can assess the extent of intraductal involvement non-invasively and identify pancreas divisum, in addition to the identification of biliary and pancreatic dilation but small ampullary lesions are often missed on MRI with MRCP.19

Management and Ampullectomy Technique:
Management of AA depends on the size, presence of concurrent duodenal adenomatosis, characteristics of the adenoma, endoscopic expertise and willingness of the patient to undergo surveillance after papillectomy. In general, AA less than 2-3 cm are more amenable to endoscopic removal, but there are case reports of EA for lesions less than 4.5 cm if there is no intraductal growth or malignancy.24-26 Endoscopic characteristics of the AA including firmness, ulceration, and non-lifting after submucosal saline injection are suggestive of possible malignancy and patients with these findings may not be candidates for endoscopic removal.25

The goal of endoscopic management of patients with AA should be complete excision of all adenomatous tissue when feasible. (Figure 2) En bloc or piecemeal resection may be performed. The advantages of en bloc excision include accurate histological assessment because of clear margins, an increased likelihood of complete removal of the AA, and potentially decreased procedural time.19 However, for large AA or lesions with limited endoscopic accessibility, en-bloc resection may not be feasible. Piecemeal excision is usually performed in these cases.

The equipment used includes thin wire snare of approximately 0.3mm size and microprocessor-controlled electrosurgical generator. There is no specific type of snare that is universally recommended when performing EA. Many snares have been used to perform ampullectomy. Snare size should fit the size of the target lesion, if possible. Depending on the size and morphological characteristics of the lesion, a variety of stiff-type snares can be used.27 The Spiral snare (20-mm spiral SnareMaster; Olympus, Tokyo, Japan) is preferred by some endoscopists to enable more tissue capture. The mini oval Acusnare (15 x 30-mm mini oval, Cook Medical, Brisbane, Australia) can be used to remove the residual tissue from the margin. For large exophytic lesions, Acusnare (25 x 55-mm AcuSnare [standard oval], Cook Medical, Brisbane, Australia) can be used. The use of thin wire snare maximizes the current density for swift transection and minimizes the risk of dispersion of the energy to the pancreatic orifice and thereby theoretically reduces the risk of late stenosis.28 Final snare selection is left to the endoscopist.

The role of submucosal injection of saline in EA is not clear. The anatomy is such that, the duodenal papilla is continuous with the AV and the AV is a confluence of the terminal part of the pancreatic and common bile duct that extends deep in to the muscularis propria layer of the duodenum. As a result, when submucosal saline injection is used for excision of the duodenal papilla, there can be tethering of the duodenal papilla to the ductal structures and can theoretically lead to incomplete resection as the ampullary lesion may not lift as expected which can make effective snare placement for enbloc resection difficult.29 However, many authors prefer to perform submucosal injection of saline prior to ampullectomy as it may reduce the risk of perforation and facilitate tissue removal. Most centers use normal saline, although some can add indigo carmine (0.04%) and epinephrine (1:100000) for submucosal injection. 28

All specimens after EA should be ideally retrieved for histological evaluation. Anti-peristaltic agents like glucagon or hyoscine butylbromide can be used to prevent migration of the specimen into the intestine.19 Commercially available retriever net or endoscopic suction can be used to retrieve the tissue but aspiration through accessory channels of duodenoscope can lead to fragmentation of tissue. However, sometimes the specimen may be lost if it rapidly passes beyond the reach following ampullectomy. Pinning of the specimen after flattening on to cork board or polysterene block can prevent curling of the specimen and can aid the pathologist for accurate assessment of lateral and deep margins.28 The duodenoscope is typically reintroduced after retrieving the specimen to examine for any signs of bleeding stigmata or active bleeding and residual adenomatous tissue. Ablation therapies including monopolar coagulation, bipolar coagulation, Nd:YAG laser, photodynamic therapy and Argon plasma coagulation (APC) can be used to treat residual adenomatous tissue based on the institutional availability and preference of the endoscopist.19,30 The benefit of ablation therapy is controversial, and some authors prefer APC than other modalities as it can limit the depth of tissue injury with the setting of 40-50 W. In general, APC is the most commonly used ablation method given its ease of use through the duodenoscope and widespread availability.

The role of routine prophylactic pancreatic stenting after ampullectomy to prevent pancreatitis is also not clear. Some authors advocate pancreatic stenting with 5 French stents only if pancreatic orifice is not visible after EA. Harewood et al. showed in a randomized study that patients who underwent pancreatic duct (PD) stenting after EA had decreased rates of post-ampullectomy pancreatitis when compared to those who did not undergo PD stenting.31 To prevent cholangitis from hemobilia when there is major bleeding and to ensure bile drainage, when there is concern for retroduodenal perforation, biliary stenting is recommended.28,32 To minimize the risk of pancreatic ductal injury after ampullectomy, the pancreatic stent should be removed in relatively short timeframe.28 Also, any residual visible adenomatous tissue can be removed at the time of pancreatic stent removal. While pancreatic duct stents are widely used when performing ampullectomy, not all endoscopists use them in this context.

Complications
Common early complications after EA include pancreatitis, bleeding, perforation, and cholangitis. Late complications include papillary stenosis, pancreatic duct stricture, bile duct stricture, and adenoma recurrence. Outcomes of EA are discussed in detail in Table 1. Pancreatitis can develop in up to 3-30% following EA.33,34 Prophylactic pancreatic duct stent can reduce the risk of developing pancreatitis and can reduce the severity of pancreatitis if it develops. Routine prophylactic pancreatic duct stent placement is advocated by some authors to prevent pancreatitis after EA, although some studies showed no difference among patients who underwent EA with or without a pancreatic stent.31,35 As EA constitutes a high-risk ERCP, rectal indomethacin is recommended unless the patient has a contraindication.36,37

Bleeding can be intraprocedural or delayed and it accounts for 2-30% of adverse events following EA.30,38 Intraprocedural bleeding can usually be controlled with adrenaline injection, balloon tamponade, coagulation forceps, stenting, and/ or hemoclip placement. Delayed bleeding can be mild and self-limited or severe and life threatening, however endoscopic intervention might be needed when there is hemodynamic compromise. Massive bleeding unresponsive to endoscopic intervention usually warrants angiographic embolization.

Perforation can be guidewire-induced, periampullary during sphincterotomy or luminal (usually occurring during the actual ampullectomy maneuver) and accounts for 2-10% of EA resections.34,38 Guidewire perforations are usually not causes of significant clinical injury. Early recognition of perforation and conservative management with intravenous (IV) antibiotics, bowel rest, and IV fluids are often all that is needed in the case of small perforations, and many of these can be managed nonoperatively. Most perforations are small and retroperitoneal, and do not warrant surgery. In some cases, endoscopic closure can be accomplished with endoscopic clips. Surgical intervention is required if the patient shows signs of acute abdomen or decompensation. For distal common bile duct (CBD) or periampullary injuries, fully covered Self- expandable metal stent (SEMS) can be beneficial. 39

Cholangitis is uncommon after ampullectomy if a biliary stent is placed and can be managed with IV antibiotics. ERCP with stent placement or replacement may be necessary for biliary drainage if conservative management fails. Papillary stenosis (2-17%) is usually a late complication after EA and it includes biliary and pancreatic duct stenosis.40,41 Papillary stenosis can arise as a consequence of scarring from the ampullectomy procedure itself. The treatment of papillary stenosis includes sphincterotomy, stent placement and balloon dilation. Catalano et al. showed in their study that papillary stenosis was seen more in patients who did not have pancreatic duct stent and they recommended prophylactic pancreatic duct stent to prevent post EA pancreatitis and pancreatic duct stenosis.30

Recurrence Rates and Follow Up Recurrence rates after EA vary from 11-30%.25,42 Risk factors for recurrence include large size, genetic predisposition, possibly absence of adjuvant thermal ablation (laser, APC) during initial EA to treat residual tissue.30 Recurrence is usually treated with endoscopy and if there is intraductal invasion or cancer, then surgical intervention is recommended. (Figure 3)

There are no specific guidelines on the follow up after EA, however there is some consensus on initial follow up endoscopy at 3 months and once every 6 months for a period of 2 years. Once there is complete eradication or no recurrence after 2 years of follow up, yearly endoscopy afterwards is recommended.43,44 Some authors recommend that after 2 years of initial endoscopy follow up, FAP patients should undergo endoscopic surveillance every 2-3 years for the rest of the life as there is 100-330 fold of developing duodenal cancer.45 For sporadic AA, endoscopic surveillance can be performed as clinically indicated.25 In patients with genetic predisposition like FAP or Gardner syndrome, the goal of surveillance is to detect high grade dysplasia and large lesions are more likely to have high grade dysplasia and in patients with sporadic AA, the goal of surveillance is to detect recurrence at the excision site.46 The severity of duodenal adenomatosis is graded by spigelman (0-IV) and with grade III, IV, there is more risk of recurrence of AA and high-grade dysplasia which makes endoscopic papillectomy less feasible.41 In patients with complex histories or unusual situations, follow up can be individualized.

CONCLUSION
Endoscopic management of AA is safe and effective when appropriately selected in the hands of experienced advanced endoscopist. A multidisciplinary team including gastroenterology, radiology, pathology, oncology and surgery is key in management of AA. Surveillance for recurrence should be individualized based on pathology, risk factors like large size and genetic predisposition. Surgery is recommended when there is intraductal extension in to common bile duct and/or pancreatic duct with invasive cancer on biopsy or large ampullary lesions that cannot be endoscopically treated.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #189

The Specific Carbohydrate Diet in Inflammatory Bowel Disease: The Evidence and Execution

August 2019 • Volume XLIII, Issue 8
Maithili V. Chitnavis,Kimberly L. Braly

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Maithili V. Chitnavis, MD Virginia Tech Carilion School of Medicine, Carilion Clinic Gastroenterology, Roanoke, VA. Kimberly L. Braly, RD, CD, CNSC Kimberly Braly Nutrition Services, Seattle Children’s Hospital Division of Gastroenterology Seattle, WA.

Nutrition, specifically exclusive enteral nutrition, has long been considered a therapeutic option in patients with inflammatory bowel disease; less is known, however, about the specific carbohydrate diet (SCD). The SCD supports avoidance of certain complex carbohydrates (thought to be pro-inflammatory in nature), thus promoting intestinal healing. Traditionally, a step-wise or staged approach has been used for SCD initiation, with progression from the most easily digestible foods to more complex foods over time. Close monitoring of laboratory parameters and anthropometrics is recommended. A multidisciplinary approach to the SCD is ideal, with access to a registered dietitian who is trained in, or has experience with, the SCD.

INTRODUCTION
Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, and in some, debilitating conditions that can affect any portion of the gastrointestinal (GI) tract in CD and the length of the colon in UC, and can be associated with disease relapse and progression. While many providers take a multidisciplinary approach to the care and treatment of patients with IBD, the focus of therapy for patients with IBD, particularly in the adult IBD population, remains largely based on pharmacologic options. Even so, many patients are eager to try alternative and complementary medicine as a therapeutic option for IBD.
Exclusive enteral nutrition (EEN) can be used for inducing and maintaining remission in both the pediatric and adult IBD populations, but adherence remains very challenging.1,2,3,4 and relapse becomes likely upon resumption of a normal diet.5 The specific carbohydrate diet (SCD) remains one such alternative, which allows for patients to eat “real food” and thus has piqued the interest of both patients and researchers. Fear of long-term consequences, lack of efficacy, and adverse reactions to medical therapy are often cited as reasons for patients to pursue the SCD; some perceive a greater benefit of the SCD compared to medical therapy.6,7

Nutritional books and the internet are filled with successful anecdotes of how the SCD has changed the lives of patients and has resulted in symptomatic remission, often in children, but results from large-scale clinical trials are lacking.2 For example, one online survey of 51 IBD patients revealed that 84% of patients experienced symptomatic remission on the SCD, with 61% of all patients off of all medical therapy.8 To date, only seven clinical trials researching the SCD subject are registered with ClinicalTrials.gov.

The “Specific Carbohydrate Diet” was published by Drs. Sidney and Merrill Haas in 1951, who found that taking a dietary approach to celiac disease and cystic fibrosis with pancreatic insufficiency resulted in complete disappearance of GI symptoms in their patients suffering from these conditions.9 However, Dr. Sidney Haas had been using the SCD to treat his patients for decades before this. The parent of one of his patients with ulcerative colitis, Elaine Gottschall, became a proponent of the diet as a treatment option for patients suffering from intestinal diseases, and popularized the SCD in her book, Breaking the Vicious Cycle: Intestinal Health Through Diet.

The SCD can be well balanced, but is very specific in the types of sugars and starches that are allowed (Table 1). The natural SCD aims to permit single sugars, or monosaccharides, such as those found in some fruits, certain vegetables, and honey, as opposed to disaccharides (sucrose, for example) and complex polysaccharides (starches) as shown in Table 2. Even so, certain starches such as those found in dried beans and lentils may be consumed as they have been tolerated by many patients.9 Research is ongoing as to what foods on the SCD are permissible and not permissible and the mechanism of action as to why these foods may be beneficial or harmful.

Carbohydrate intolerance is central to the basis behind the SCD. The concept of the SCD aims to promote strict avoidance of those foods which trigger gut inflammation by avoiding certain types of carbohydrates, noted above, as these are thought to exert the most influence over the intestinal microbiome.4,9 By avoidance of these carbohydrates, small bowel mucosal injury and bacterial overgrowth can be reduced, thereby preventing downstream effects such as diarrhea and malabsorption. In addition to the traditionally proposed mechanism of action behind the SCD, researchers are also investigating whether food additives and preservatives may play a role in the inflammatory process.

The Evidence
 As previously mentioned, large-scale clinical trial data on the SCD in IBD is lacking,2 but several studies have explored the role of the SCD in IBD, particularly in pediatric patients.1,10-13 Suskind and colleagues conducted a retrospective study of seven pediatric patients with Crohn’s disease, excluding those on immunosuppressants, and found that all patients experienced symptom remission within three months of initiating the SCD, with either normalization or improvement in laboratory parameters such as CRP, hemoglobin, albumin, and fecal calprotectin.11

The same group conducted an internet-based survey of 417 pediatric and adult respondents with CD, UC, and indeterminate colitis and demonstrated that the majority reported achieving clinical remission of IBD on the SCD, with 33% of patients reporting clinical remission at two months after initiation of the SCD and 42% of patients reporting clinical remission at 6 and 12 months after continuation of the SCD.6 While this was based on survey data, it highlights the importance of the patient perspective and a perceived benefit for patients trying the SCD, many of whom were having symptoms such as abdominal pain, diarrhea, bloody stools, and limitations in their activity levels prior to initiation.6

Burgis and colleagues from Stanford conducted a retrospective study investigating the effects of the SCD in maintenance of remission in pediatric patients with CD over a one-year period.1 They found significant improvements in lab parameters (hemoglobin, albumin, ESR) with implementation of the SCD in patients who were treated with and without immunomodulatory therapy, and overall patient height and weight also improved. All effects persisted with liberalization of the diet, with the exception of weight gain (50% of patients lost weight when SCD was liberalized). While the study was small (n = 11 patients), this was the first study investigating liberalization of the SCD.

Another survey-based case series of 50 patients with UC, CD, or indeterminate colitis from Rush University Medical Center demonstrated that 66% of patients reported complete resolution of IBD symptoms on the SCD after an average of 9.9 months.7 The majority of these patients were adults, but pediatric patients were also included. On average, the diet was also rated to be 91.3% effective in controlling acute flare symptoms and 92.1% effective in maintenance of remission of IBD.

Although patients may experience symptomatic remission and improvement in laboratory parameters with dietary changes, the target of anti-inflammatory treatments in IBD remains mucosal healing. Studies investigating mucosal healing on the SCD are limited to the pediatric population, and although only small numbers of patients have been included, results are conflicting. Wahbeh and colleagues demonstrated a lack of mucosal healing in a retrospective study including 7 pediatric patients with Crohn’s disease on a modified SCD (e.g. permitting some foods normally restricted on the SCD), with a median duration of 26 months on the diet.12 Although one patient had mucosal healing on ileocolonoscopy, this patient had persistence of upper GI Crohn’s disease.

In contrast, Cohen and colleagues demonstrated small bowel mucosal healing on capsule endoscopy in a cohort of 10 pediatric patients with active Crohn’s disease who were started on the SCD.13 Interestingly, mucosal healing as measured by the mean Lewis score for capsule endoscopy was seen at 12 weeks, but did not persist at 52 weeks. Only four out of the 10 patients had normal-appearing small bowel at 12 weeks as measured by the Lewis score. Other parameters of clinical disease activity (Harvey-Bradshaw Index, Pediatric Crohn’s Disease Activity Index) also improved significantly at 12 weeks, and effects were also noted to persist up to 52 weeks.

Results of the DINE-CD study (Trial of Specific Carbohydrate and Mediterranean Diets to Induce Remission of Crohn’s Disease), a multicenter randomized, open-label trial headed by researchers at the University of Pennsylvania, should provide more evidence of the utility of the SCD in the adult Crohn’s disease population.14 Both symptomatic remission and reduction of bowel inflammation as measured by fecal calprotectin are the primary outcome measures in this study, which is scheduled to complete in mid-2019 and will be the largest investigation into the application of the SCD in IBD patients to date.

In many instances, nutrition has taken a “backseat” in the care of IBD patients in the United States, particularly in the adult population. In Europe and Asia, EEN is a first-line therapy in many instances. Future research on the SCD may allow dietary modification to come to the forefront of therapy options alongside pharmacologic therapy.

Nutritional Adequacy of the SCD
While the SCD is based on exclusion of carbohydrates, it has been shown to be nutritionally adequate in comparison to healthy peer reference diets; even so, certain deficiencies, particularly calcium and vitamin D, can occur.10 In a study by Braly and colleagues at the University of Washington which included eight pediatric IBD patients, the majority (64%) exceeded 100% of their recommended daily allowance for energy intake and all individuals consumed approximately three times the RDA for protein. Six out of the eight patients were able to gain weight during the study. However, 100% of patients had intakes below the RDA for vitamin D, and 75% of patients’ daily intakes were less than the RDA for calcium.10

Background and Diet Implementation
Traditionally, the SCD has been introduced using a step-wise or staged approach. Food introduction begins with the most easily digestible foods, advancing to more complex foods including raw fruits, vegetables, legumes and specific dairy products over a variable time period. Researchers are looking into expediting food introduction given the diet can be nutritionally lacking until the full SCD is reached (PRODUCE study15). Many pediatric GI providers do not currently use the staged approach as the evidence is lacking as to its efficacy over initiation of the full SCD.

For patients with IBD initiating the SCD, a multidisciplinary approach to their care, with access to a registered dietitian, is recommended to ensure adequate micro- and macronutrient content in diet and proper education on the SCD. Without proper nutrition counseling, the diet can be lacking in essential nutrients.10 Supplementation with an SCD multivitamin and/or vitamin D has also been suggested.10 A food journal detailing snacks and meals can also be helpful for patients working with dietitians. It is easy for foods with hidden prohibited ingredients to make their way into the diet without close monitoring. These hidden ingredients are typically found in pre-made foods, spices, and seasoning mixes. It is not recommended that patients who follow a vegan diet use the SCD as part of their therapy regimen given the difficulty in achieving adequate caloric and nutrient intake with the combined limited food options; however, vegetarians can have a nutritionally complete diet on the SCD. Additional resources regarding SCD-approved supplements, ingredients to be avoided, and meal/snack ideas can be found on the PRODUCE website .

When first presenting the SCD to a patient and family, diet implementation is most successful when the patient is on board with the diet and the whole family participates as much as able. Encourage patients to transition to the full SCD within a two-week time period, as they will need to prepare a pantry of new food items and purge foods that are not allowed on the SCD. In order to prevent inadequate nutritional intake, it is important to discuss and adhere to a timeline over which the full SCD can be initiated.
All diets can alter the microbiome; however, the ideal composition of beneficial versus harmful bacteria is yet to be determined. Research on microbiome modulation through diet in IBD is ongoing.15,16 An important aspect of the SCD is restoration of “good gut bacteria” in the form of a varied diet and the addition of probiotics through certain allowable fermented foods, and in particular, the SCD homemade yogurt. This yogurt is fermented for 24 hours, allowing for fermentation of the sugar, lactose. For this reason, many who are lactose intolerant tolerate the SCD yogurt in moderation. Yogurt-making instructions can be found on the PRODUCE website (see above). The SCD yogurt also provides calcium and vitamin D when cow’s milk is used and can be an excellent calorie source for patients struggling with low weight. It can be made with whole milk or even a mixture of half and half with whole milk. The SCD yogurt can be made with homemade nut milk or goat’s milk as well, but the nutritional content of these vary considerably.17

Providing nutritional supplementation when indicated, tips for social situations, weight loss prevention strategies, and resources that patients can reference for meal and snack ideas encourages diet adherence and success (see Tables 1-3).

Clinical Pearls for Frequently Asked Questions
Pre-made foods
SCD patients and families frequently ask about SCD convenience foods that come pre-made in order to save time. While some “convenience” SCD foods exist, the premise of the diet is centered upon more basic, whole foods. Additionally, many companies can change ingredients in their products allowing for proscribed ingredients to make their way into the diet unbeknownst to the patient. Therefore, intake of these foods on a regular basis is discouraged when the diet is being used as a treatment modality.

Probiotics
Families frequently inquire about supplementation with a probiotic. A varied diet with fresh fruits and vegetables, legumes, various proteins and healthy fats is one of the best sources of prebiotics and probiotics, which can help stimulate the growth of the intestinal microbiome. Additionally, on the SCD, the SCD yogurt can be a beneficial source of probiotics. Some patients dislike the taste of the yogurt alone, so it is recommended to add the SCD yogurt to smoothies, various dishes and baked goods.

Organic and/or Grass-Fed Meats
Patients are encouraged to select organic products whenever possible. Certified organic is a third-party certification that must meet USDA criteria. Organic foods cannot be irradiated, genetically modified or grown using synthetic fertilizers, chemicals, or sewage sludge. The organic label on meat and poultry means that it was not treated with hormones or antibiotics and was fed only organically grown feed (with no animal byproducts). Animals raised for organic meat must have access to the outdoors, and grass-eating animals must have access to pasture. Antibiotic resistance with eating high amounts of meat from non-organic sources remains a concern amongst providers.

Tips for produce include selecting organic options, when available, for foods listed on the “Dirty Dozen,” (a list of fruits and vegetables with the highest pesticide residues), published annually by the Environmental Working Group (https://www.ewg.org/foodnews/dirty-dozen. php). Conversely, selecting organic varieties of the produce on the “Clean Fifteen” list is not necessary, as these non-organic fruits and vegetables are least likely to contain pesticide residues according to the Environmental Working Group .

On the SCD, dietitians recommend that patients consume a balance between plant and animal-based proteins.

Monitoring
Like medication therapy, it is essential to monitor symptoms, laboratory parameters and anthropometrics to assess efficacy of the diet.

Labs
Inflammatory markers, stool calprotectin, hemoglobin/hematocrit, and vitamin D should be followed at the provider’s discretion.

Anthropometrics
Clinically monitoring weight changes, height velocity in children, and BMI is important in the setting of IBD, and while on an elimination diet.

Weight loss or linear growth deceleration can indicate inadequate caloric intake or may suggest ongoing inflammation.

Long-Term Outlook
Prospective studies are underway looking at the possibility of a more liberalized SCD as treatment in comparison to the traditional SCD in hopes that some patients may tolerate a more lenient diet while still maintaining remission of their disease (PRODUCE15).

CONCLUSIONS
The SCD has had significant support among patients with IBD and other GI disorders since it was popularized by Elaine Gotschall.9 While small studies have demonstrated nutritional adequacy, symptomatic remission, and improvement in laboratory parameters among IBD patients on the SCD, the studies have mainly been limited to the pediatric population, and these findings and others (e.g. mucosal healing) remain to be demonstrated in large-scale clinical trials. Increased awareness of SCD among patients, providers and dietitians has fueled an interest in more research into this dietary option, which may become an integral part of a multidisciplinary approach to IBD patient care in the near future.

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FELLOW"S CORNER

Acute Colitis in a Recent Immigrant from the Philippines

August 2019 • Volume XLIII, Issue 8

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Paris Charilaou MD1 Devendra Enjamuri MD1 Andrew Korman MD2 1Gastroenterology & Hepatology Fellows, 2Gastroenterology & Hepatology Attending, Director of Advanced Therapeutic Endoscopy, Division of Gastroenterology & Hepatology Department of Medicine Saint Peter’s University Hospital/Rutgers, RWJ Medical School, New Brunswick, NJ

CASE PRESENTATION/INTRODUCTION
A previously healthy 38 year-old male from the Philippines immigrated to the United States months prior to presenting to the emergency department with a three-month history of diarrhea and diffuse, crampy abdominal pain associated with tenesmus and hematochezia. The diarrhea has been progressive with up to 10 watery, small-volume bowel movements a day. He has experienced a 20-pound weight loss over that period. There was no nausea, vomiting, fever, rash or arthralgias. He had not been taking any non-steroidal anti-inflammatory medications or antibiotics. On further history, he disclosed that he was homosexual. He had no family history of malignancy or inflammatory bowel disease. He did not smoke, drink alcohol or used illicit drugs.

His physical exam was unremarkable, other than severe pain and nodularity of the rectal mucosa, without blood or other palpable masses, on rectal exam.

Basic laboratory testing included a normal complete blood count and a comprehensive metabolic panel. Initial routine stool studies, including ova and parasites, were negative.

On colonoscopy, there were multiple erosions in the terminal ileum and multiple well-demarcated ulcers throughout the colon (Figure 1, blue arrows). Several nodules were found in the anus and rectum. Moderate architectural distortion with acute and chronic inflammation, reactive epithelial changes, with intracytoplasmic and intranuclear inclusions were seen on histopathology. (Figure 2)

QUESTIONS
Question 1. What is the most likely diagnosis?
Question 2. What is the next step in the management of this patient?
Question 3. What is the most important consultation you should consider at this time?
Question 4. What are the other gastrointestinal manifestations of this pathogen?

Answer 1.
In this adult patient with chronic diarrhea, we need to consider infectious and inflammatory bowel disease as the top two diagnostic categories. Considering the complete history and presentation of this patient, including his immigrant status, sexual practices and weight loss, human immunodeficiency virus (HIV) infection, and its potential complications, should be entertained. In doing so, one should consider the different entities that may be encountered depending on whether a patient has received highly active anti-retroviral therapy (ART) or not (see Table 1).1,2 Our patient was found to be HIV positive, with a CD4+ count of 69/µL, consistent with acquired immunodeficiency syndrome (AIDS).During the post-ART era, complications encountered are usually medication-associated adverse effects (Table 1).1,2 The pre-ART complications that need to be considered in an AIDS patient with chronic diarrhea include cytomegalovirus (CMV) colitis, cryptosporidiosis, microsporidiosis, mycobacterium avium complex (MAC), Shigella, Campylobacter jejuni, Clostridium difficile.2 Idiopathic AIDS-related enteropathy should also be considered if all diagnostic studies are negative. The most likely diagnosis at that time was CMV colitis, as it is the most common pathogen leading to chronic diarrhea in patients with AIDS and a CD4+ < 100/µL. The colonic biopsies stained positive for CMV and a diagnosis of CMV colitis was made.

CMV serum antigen, antibodies and polymerase chain reaction (PCR) cannot be used to determine invasive gastrointestinal CMV infection.3,4 Most patients have already been colonized by CMV and have seroconverted. The clinical picture,

endoscopic and pathologic findings are indicative of an invasive CMV infection that warrants treatment. CMV DNA levels have been shown to predict disease severity but do not play a role in diagnosing active gastrointestinal disease.3 In patients with diarrhea on ART, medications such as protease inhibitors, nucleoside reverse transcriptase inhibitors, delavirdine, maraviroc, raltegravir, cobicistat, and elvitegravir/cobicistat have been implicated and should be considered as potential etiologies1.

Answer 2.
The patient should be started on treatment for invasive CMV infection (Table 2) and also on ART for HIV. His diarrhea resolved after approximately three weeks of valganciclovir, while receiving ART.

Answer 3.
Every patient diagnosed with CMV infection should have fundoscopy to exclude CMV retinitis. Thus, an ophthalmology consult is mandated. CMV retinitis, if present, needs close follow-up to ensure remission and to prevent blindness.

Answer 4.
CMV can affect multiple gastrointestinal (GI) organs, most commonly in immunocompromised patients. CMV esophagitis, gastritis and enteritis are other luminal, gastrointestinal manifestations. Esophagitis usually presents with odynophagia (rather than dysphagia) and endoscopy may reveal multiple, shallow ulcers, which can be confirmed with biopsies taken from their center. At least three biopsies can have a sensitivity of 80%, reaching 98% with 10 biopsies.5 The differential diagnosis of CMV esophagitis includes HIV-associated idiopathic ulcers and herpes simplex (HSV) esophagitis. Gastritis will often present with non-specific symptoms of epigastric pain, nausea and vomiting. A specific, yet less common presentation, is that of postural epigastric pain with relief in supine position.6 Endoscopy may reveal ulcerations with erythematous mucosa in the antro-pyloric region. Enteritis, including duodenitis, may present with severe diarrhea, especially in post-transplant patients. Differential diagnosis includes lymphoma and graft-vs-host disease, which requires serial biopsies to differentiate from the latter.7 Potentially fatal complications include perforation and peritonitis.

CMV hepatitis may be seen in immunocompetent patients, commonly presenting as subclinical liver enzyme elevation, typically as a hepatocellular pattern. In symptomatic cases, liver enzyme elevations will be more severe, with signs of hepatic dysfunction and even portal vein thrombosis.8 Differential diagnosis should include hepatic granulomas, especially in patients with prolonged unexplained fevers. In post-liver transplant patients, CMV hepatitis from reactivation can lead or resemble acute allograft rejection, especially in sero-mismatched donor/recipient pairs (i.e. CMV-positive donor with CMV-negative recipient).9

CONCLUSION
In patients with chronic diarrhea and a clinical suspicion for HIV/AIDS, CMV colitis should be suspected as it is the most common pathogen implicated in these cases. Once the diagnosis is made and treatment is started, the patient should be referred to an ophthalmologist to rule out retinal involvement, which would otherwise necessitate close follow-up during the treatment period.

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BOOK REVIEWS

ASPEN Enteral Nutrition Handbook, 2nd edition

August 2019 • Volume XLIII, Issue 8

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Editors: Ainsley Malone, MS, RD, CNSC, FAND, FASPEN; Liesje Nieman Carney, RD, CSP, LDN; Amy Long Carrera, MS, RD, CNSC, CWCMS; Andrew Mays, PharmD, BCNSP, CNSC
Publisher and Year: American Society for Parenteral and Enteral Nutrition, 2019
Print ISBN: 978-1-889622-39-2
eBook ISBN: 978-1-889622-40-8
Price: $84.95 (print, spiral-bound paperback)
$79.95 (eBook)

For all those clinicians who have read practice guidelines and thought, “Just tell me what to do!” the second edition of the ASPEN Enteral Nutrition Handbook answers those questions. The book is not quite a pocket guide, not quite a textbook, and not quite a set of guidelines, but instead spans the gap between all three. Clearly written for healthcare providers currently engaged in enteral nutrition (EN), this book provides practical advice without delving too deeply into background explanations or a review of literature. Generally, throughout the book, the assumption is made that the reader knows a significant amount about nutrition and needs only the nuts and bolts of how to properly deliver EN to patients, so it may be less helpful to a student or new practitioner who has no background nutrition knowledge.

Following the mission of the American Society for Parenteral and Enteral Nutrition (ASPEN), the Enteral Nutrition Handbook is not expressly written for a single profession but instead includes information that would be of interest and utility for pharmacists, physicians, dietitians, and nurses. This text is written, reviewed, and edited mostly by current practitioners in a variety of settings across the country; for a practicing clinician, reading it feels like consulting an experienced colleague on how to implement the ASPEN guidelines. Research findings are integrated into the text, but limited to a sentence or less to keep the focus on practice recommendations. For the readers who want more explanation, many chapters end with practice resources and suggested readings in addition to the extensive references.

The second edition includes chapters on nutrition assessment; patient selection for EN; access devices; formulas for both adults and pediatrics; EN orders; preparation, labeling, and dispensing EN (new to this edition); administration and monitoring; complications; medication administration; and home EN. Each chapter covers both pediatric and adult nutrition issues and includes plentiful and helpful tables and figures for reference. While pocket-sized, this book is likely not a text that a practitioner really would carry around in a pocket during patient care, but instead is an excellent reference for clinicians who want useful advice to improve their practice.

Leah Hoffman, PhD, RD/LD, CNSC,
Assistant Professor, Director, Coordinated Program for Master of Arts in Dietetics
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma

FROM THE PEDIATRIC LITERATURE

Foreign Bodies During the Holidays

August 2019 • Volume XLIII, Issue 8

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Pediatric injuries in the United States, in general, increase during summer holidays (such as Labor Day) but decrease during seasonal holidays (such as Thanksgiving and Christmas). Since the winter holiday, Christmas, is associated with potential ingestible foreign bodies (such as Christmas ornaments) the authors of this study looked at trends of accidental foreign body ingestions in children during this specific holiday. The National Electronic Injury Surveillance System (NEISS) database was searched for specific foreign body ingestions that were related to Christmas items (Christmas tree lights, Christmas decorations) and that presented to the emergency department (ED) from 1997 to 2015. Subjects were included in the study if they were between 0 to 17 years old, had an injury documented as “ingestion/internal”, and the ingested object could be identified from the NEISS coding manual. National estimation of ingestions was determined by Taylor series linearization, and the Cochran Armitage test of trend was used to look for seasonal differences.

During the 18 year time period, it was estimated that 22,224 children presented to the ED with a Christmas-related foreign body ingestion (CFBI) which equaled 1235 encounters annually. Children who were 2 years of age or younger accounted for 84% of ingestions, and 60% of ingestions occurred in males. CFBI was noted to increase in a 7-week period around Christmas with a peak ingestion period occurring at a median of 13 days before or after Christmas (interquartile range 4-23 days). No increase in total foreign body ingestions (CFBI plus all other ingestions) was noted during this 7-week period. When ED visits associated with CFBI were evaluated monthly, a significant seasonal trend was noted during the winter holiday months. The most common CFBI were nonelectric Christmas decorations, and 95.8% of CFBI involved simple triage and discharge from the ED. A significantly lower percentage of CFBI required an escalation of care (defined as hospital admission or transfer from the ED to another hospital) compared to all other foreign bodies. This study demonstrates that medical providers should have increased awareness of the risk of foreign body ingestion during the Christmas holiday season which should translate into increased education and anticipatory guidance to parents, especially parents of young children.

Reeves P, Krishnamurthy J, Pasman E, Nydlund C. Pediatric ingestions of Christmas past, present, and future: a review of holiday trends, 1997 to 2015. Clinical Pediatrics 2019; 58: 571-577.

FROM THE PEDIATRIC LITERATURE

Genetics in Hirschsprung Disease

August 2019 • Volume XLIII, Issue 8

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Hirschsprung’s disease (HD) is due to a congenital absence of ganglion cells (aganglionosis) in the colon leading to difficult-to-treat constipation as well as the potential for life-threatening enterocolitis from colonic inflammation. A total of 17 genes are associated with HD, with these mutations affecting the RET proto-oncogene encoding the tyrosine kinase receptor and G-protein–coupled receptor EDNRB which are involved in neurogenesis. The authors of this study looked at the phenotypic variation of HD based on these genetic mutations.

Whole exome sequencing was performed in 190 patients with HD and 47 relatives (36 first-degree relatives), and results were compared to a well-described control group from the 1000 Genomes Project and the National Institute of Mental Health Repository to look for differences in sequence variants (via single nucleotide polymorphism or SNP arrays). Three SNPs associated with HD in RET (rs2435357, rs7069590, and rs2506030) and one SNP associated with HD in SEMA3 (rs11766001) involved in the G-protein–coupled receptor EDNRB were used as markers for common noncoding variants (missense and nonsense). Potential HD-associated genes were defined as having more unique pathogenic alleles in the HD cohort compared to the control group. In order to see if a genetic mutation was associated with HD, reverse-transcriptase polymerase chain reaction (RT-PCR) testing was performed to evaluate RNA expression in human embryonic gut samples and in developing mouse gut.

Patients with 5 or more alleles showing mutations in RET and SEMA3 increased the risk of having HD, and the population frequency of HD increased with increasing numbers of risk alleles. The effect of pathogenic allele enrichment then was determined by analysis of 15,963 SNPs in 4027 genes in patients with HD and controls. Interestingly, besides RET and EDNRB mutations associated with neurogenesis, 7 new genetic mutations were found (ACSS2, ADAMTS17, ENO3, FAM213A, SH3PXD2A, SLC27A4, and UBR4). These genes also were expressed in human and mouse embryonic samples during embryogenesis and in zebrafish as markers of cell migratory defects. A larger number of coding copy variants, as opposed to noncoding copy variants, increased the risk of HD. It was noted that 8.9% of the 190 patients with HD had a genetic syndrome, and 16 copy number variants (14 not previously described) were noted in those patients who had both a genetic syndrome and HD. The most common syndrome associated with these variants was Trisomy 21.

In total, 72.1% of HD patients had some type of identified genetic risk factor with a large number of these patients having 5 or more noncoding, rare coding, or copy number variants, and the risk of HD increased in the population as the number pathogenic alleles increased. No genotype-phenotype relationship existed between HD and sex, length of HD segment, family history, or presence of a genetic syndrome. This study provides more much needed information about the genetics and subsequent pathophysiology of HD. In particular, determining the presence and copy number of alleles may be helpful in determining the risk of developing HD in families or during pre-natal screening.

Tilghman J, Ling A, Turner T, Sosa M, Krumm N, Chatterjee S, Kapoor A, Coe B, Nguyen K, Gupta N, Gabriel S, Eichler E, Berrios C, Chakravarti A. Molecular genetic anatomy and risk profile of Hirschsprung’s disease. New England Journal of Medicine 2019; 380: 1421-1432

Nutrition Issues In Gastroenterology, #150

Pancreatic Resection Operations Contribute Significantly to Both Macro-Nutrient and Micro-Nutrient Malabsorption

March 2016 • Volume XL, Issue 3
Mary E. Phillips

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Patients suffer both short term and long term deficiencies and are prone to other gastro-intestinal conditions with similar symptoms. Identifying the cause of their symptoms is challenging and requires careful follow up in a multi- professional setting. This paper discusses these issues and the importance of patient access to specialist dietetic support and routinely assessing endocrine function following all pancreatic resection.

Mary E. Phillips BSc (Hons) RD DipADP, Advanced Specialist Dietitian (Hepato-pancreatico-biliary surgery) Department of Nutrition and Dietetics, Royal Surrey County Hospital, Surrey, England

Pancreatic resection is carried out for benign and malignant diseases of the pancreas, duodenum and distal common bile duct. These operations contribute significantly to both macro-nutrient and micro-nutrient malabsorption. Pancreatic enzyme supplements are underused and should be administered routinely to all patients who have had a pancreatic head resection. Patients suffer both short term and long term deficiencies and are prone to other gastro-intestinal conditions with similar symptoms. Thus, identifying the cause of their symptoms is challenging and requires careful follow up in a multi-professional setting. Vitamin and mineral deficiencies are common and weight loss, abdominal symptoms and diabetes have a significant impact on quality of life and survival. Patients should have access to specialist dietetic support and endocrine function should be assessed routinely following all pancreatic resection. Assessment of vitamin and mineral status should be carried out in patients who have undergone curative resection or who have benign disease.

INTRODUCTION

Types of pancreatic resections vary considerably; each having a different impact on the digestive system and therefore on the patient’s nutritional status. Poor nutritional status is associated with poor quality of life,1 and reduced survival.2 Pancreatic exocrine insufficiency (PEI) is common and undertreated3 and there is a lack of funding for dietetic support for this patient group.4

Survival with malignant pancreatic disease remains poor, but some pancreatic resections are carried out for benign disease, and long term implications must be considered in all patients with benign disease, and those who have had surgery with curative intent.

Fat, carbohydrate and protein malabsorption all occur in PEI;5-7 yet historical treatment has focused on fat malabsorption. This results in many patients following unnecessary dietary fat restrictions and not receiving appropriate enzyme supplementation or dietary advice. Pancreatic cancer and chronic pancreatitis are both progressive diseases, and consequently the severity of both exocrine and endocrine dysfunction can worsen with time.

preserving in nature, or include a distal gastrectomy. There is a high incidence of PEI following this resection, documented in as many as 98% of patients.1,8-10 Furthermore, the presence of a blind loop of bowel predisposes the patient to small intestinal bacterial overgrowth (SIBO). The asynchrony of the delivery of bile, precipitation of bile salts and resection of the gallbladder results in a higher risk of bile acid malabsorption (BAM). A lower incidence of PEI (12- 80%)11-13 is reported in central pancreatectomy and distal pancreatectomy, but there is massive variation between studies.10

Procedures carried out in patients with chronic pancreatitis to relieve ductal obstruction and remove calcification within the gland, such as Frey, Beger, Peustow and longitudinal pancreatico-jejunostomy (LPJ) procedures are associated with damage due to obstruction of the pancreatic duct prior to surgery. Consequently there is a high incidence of PEI and type 3c diabetes, and this has an impact on survival.2, 3, 14

Malabsorption

Pancreatic exocrine insufficiency is common after all pancreatic resections.10 and often undertreated. Diagnostic tests have low sensitivity in this setting1 and markers of nutritional status have links with PEI, but are not diagnostic in their own right.15

The aetiology of PEI and malabsorption is multifactorial with the type of surgery, reconstruction, and concurrent use of inhibitory medications, all contributing to malabsorption (Table 1). Thus, the quantity of residual pancreas may not predict the severity of PEI.

Clinical symptoms of malabsorption are listed in Table 2. Severe malabsorption can occur in the absence of abdominal symptoms.5 Due to the high cost of pancreatic enzymes in the United States, patients need to demonstrate a clinical need. Assessment takes place in the form of coefficient of fat absorption, the presence of weight loss in the setting of adequate oral intake or non-infective diarrhoea. Other tests available include the faecal elastase (FE1) or C13 mixed trigylceride breath tests. The prescription of pancreatic enzyme replacement therapy (PERT) is occasionally challenged due to the lack of a reliable measure of exocrine function. FE1 is poorly correlated with fat malabsorption after PD,1 but coefficient of fat malabsorption is an unpleasant test requiring a 48-72 hour stool collection whilst consuming a 100g fat per day diet. Some clinicians empirically will start PERT and monitor clinical response; others consider this test controversial for diagnostic purposes.17 C13 mixed triglyceride breath tests are not routinely available in the United States or the United Kingdom.

Studies that use symptoms of steatorrhoea to determine PEI report a much lower incidence compared to those using formal diagnostic tests.8,12 It is widely accepted that steatorrhoea is a late symptom of malabsorption.18 This, along with the influence of low fat diets, constipating medication, and the poor specificity of diagnostic tests, means that sometimes the only option to confirm the diagnosis may be a trial on PERT.

These issues and the lack of ability to definitively determine the need for PERT, can make it difficult to obtain the funding for the use of these medications.

Pancreatic Enzyme Replacement Therapy (PERT)

Pancreatic enzyme replacement therapy takes many forms. Enteric coated mini-microspheres are most commonly used, but tablets, granules and powdered forms are available in some countries.

PERT should be prescribed with all meals and snacks. The dose varies and should be adjusted to each individual patient. The PERT dose also needs to be higher with higher energy meals, and should be prescribed alongside nutritional supplements and sip feeds (Table 4).

Patients requiring enteral feeding should be prescribed a semi-elemental peptide, medium chain triglyceride based feed, and PERT may need to be administered alongside enteral feeds. However, depending on the tube size, this may result in clogging if the patient does not receive clear information.19 Alternatively, a strict elemental formula can be used without the need for pancreatic enzymes.

PERT should be swallowed with a cold drink and stored out of extreme heat. Storage temperatures vary between products, but range from 15-25 degrees centigrade. Patients should be taught how to adjust their own enzyme dose, specifically to increase their dose with larger meals and to spread their capsules out throughout their meals. This is especially important for long duration meals, such as meals with several courses. Patients should also be advised on managing potential side effects, which include nausea and constipation.

Gastric acid suppression may be of benefit to prevent acid denaturing of the enzymes,20 which require a pH of > 5.5 for activation, but are irreversibly denatured in very acidic environments. Bicarbonate secretion from the pancreas is reduced in pancreatic failure, which may result in a change in pH within the gut. A more acidic environment in the proximal small bowel can result in delayed enzyme release from the enteric-coated PERT and destabilize bile salts altering micelle formation.

Each PERT product differs in efficacy at different acidity levels and have different activation times, varying from 30 to 120 minutes at pH’s from 4.5 to 5.6.22,23 So it may be assumed that some products may work better in some patients than others. There are no trials directly comparing products in different clinical situations such as delayed gastric emptying or dumping syndrome, but theoretically there could be a benefit to trialling different products in different clinical situations. Consequently, if a patient does not see significant benefit with the first brand of enzyme prescribed, a trial on an alternative product is recommended.

Nutritional therapy

Historically malabsorption has been treated with low fat diets. This will minimize symptoms of steatorrhoea, but will not correct malabsorption of nutrients, merely mask it. Experienced clinicians recommend that low fat diets are not used in the management of PEI due to the negative impact on nutritional status.24

Patients who are nutritionally compromised should be encouraged to consume high energy meals with food fortification advice including the use of nutritional supplements and sip feeds as deemed necessary by a specialist dietitian.

Constipation

Constipation can occur alongside PERT therapy, and often complicates management, as PERT doses are often reduced in an effort to control constipation. The concurrent use of laxatives and other methods of correcting constipation are more appropriate than inducing malabsorption in an effort to control bowel function.

Vitamin and Minerals

Data on vitamin and mineral status is limited, however deficiencies in zinc, selenium, iron and vitamins A, D, E, and K in both resection of pancreatic cancer and in chronic pancreatitis are reported.25,26 The duodenum plays a key role in absorption of vitamins and minerals, and is removed in PD resections. This, in combination with malabsorption and increased metabolic demand, results in increased risk of micronutrient deficiencies. Routine supplementation of fat soluble vitamin and trace elements are recommended following resection.25

Differential Diagnosis of Failure to Thrive

Reoccurrence of tumor and benign strictures can cause narrowing of the gastro-jejunostomy resulting in delayed gastric emptying or gastric outflow obstruction. Tumors can infiltrate the mesentery, including the portal vein. This or the development of liver metastases can cause ascites. All of these issues reduce oral intake and worsen gut function.

Bile acid malabsorption (BAM) and SIBO are common in chronic pancreatitis, pancreatic cancer and following pancreatico-duodenectomy31 and the symptoms of these are difficult to distinguish from PEI. Patients who do not respond to PERT should be investigated for BAM and SIBO.

Diabetes

Type 3c or pancreaticogenic diabetes occurs in patients with pancreatic disease.14 This type of diabetes is more brittle than type 1 or type 2 diabetes; patients often require insulin therapy and are prone to significant episodes of hypoglycaemia due to the reduction in glucagon secretion.30 There are specific hormonal differences between type 1, 2 and 3c diabetes, including low pancreatic polypeptide, insulin and glucagon levels in type 3c diabetes.31

When PERT is commenced in a patient with pre- existing diabetes, blood glucose levels should rise and oral hypoglycaemic agents or insulin therapy may need to be adjusted accordingly. Similarly, commencing PERT may unmask diabetes in a patient not yet diagnosed.32 Consequently, glucose levels should be checked before and after commencing PERT, as well as periodic glycosylated hemoglobin levels.

Annual Screening

Nutritional status should be assessed regularly, and PERT doses adjusted as required. All patients with pancreatic disease should be regularly screened for diabetes, regardless of underlying pathology. Vitamin and mineral screening and bone density scans should take place in all patients with benign pancreatic disease26,33,34 and those who have had surgery with curative intent.

CONCLUSION

PEI is common before and after pancreatic resection, but remains difficult to diagnose and undertreated. Patients should be referred to a specialist dietitian and undergo regular screening for diabetes in addition to vitamin and mineral deficiencies. Adequate doses of PERT are an essential part of patient management, and doses should be reviewed regularly as they may need to be increased over time. Failure to respond to PERT should result in investigations for other gastrointestinal pathology (Table 4).

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Nutrition Issues In Gastroenterology, #149

Wernicke’s Encephalopathy: Under Our Radar More Than it Should Be?

February 2016 • Volume XL, Issue 2
Guillermo E. Solorzano,Rahul Guha

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Historically, thiamine deficiency has been associated with alcoholism, but there are several other populations that are at risk including post-operative gastrointestinal surgery patients and those on parenteral nutrition. The clinical manifestation of thiamine deficiency is often classified as Wernicke’s Encephalopathy. It is identified as a triad of mental status changes, eye movement abnormalities and unsteadiness of gait with poor balance. This article describes the clinical features of thiamine deficiency, its manifestations, and the use of thiamine supplementation as treatment for this condition.

Thiamine (Vitamin B1) is a vital cofactor in the metabolism of glucose. Thiamine deficiency leads to a specific constellation of central and peripheral nervous system dysfunction. Historically, thiamine deficiency has been associated with alcoholism, but there are several other populations that are at risk including post-operative gastrointestinal surgery patients and those on parenteral nutrition. The clinical manifestation of thiamine deficiency is often classified as Wernicke’s Encephalopathy. It is identified as a triad of mental status changes, eye movement abnormalities and unsteadiness of gait with poor balance. This article describes the clinical features of thiamine deficiency, its manifestations, and the use of thiamine supplementation as treatment for this condition.

Guillermo E. Solorzano, MD, MSc, Assistant Professor Rahul Guha, MD, Neurology Resident University of Virginia Department of Neurology, Charlottesville, VA

CLINICAL CASE

A30 year old woman presented with abdominal sepsis due to choledocholithiasis to an outside hospital. Her hospitalization was complicated by post-endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis with infected peri- pancreatic fluid collections. As a consequence of poor oral intake due to persistent nausea, vomiting and abdominal pain, parenteral nutrition (PN) was initiated. Several attempts were made to restart oral nutrition, but were unsuccessful. Despite appropriate antimicrobial coverage and drainage of her complex intra-abdominal infections, her mental status deteriorated. On the day of transfer to our center she was not oriented to person, place or time. Her pupils were miotic and she had roving eye movements. She was intubated and underwent an MRI of the brain that showed T2/FLAIR hyperintensities along the medial thalami and periaqueductal region (see Figure 1). A lumbar puncture performed was unremarkable for infection. CSF Herpes Simplex PCR was negative. Serum copper, TSH, B12, Zinc and pyridoxine were within normal limits. Thiamine was found to be low. The neurology consult service reviewed the PN formulation she received at the outside hospital with the nutrition support service and found thiamine had not been included for unclear reasons. She was treated with intravenous thiamine 500 mg three times daily for three days and then switched to oral replacement 50 mg daily. She slowly improved to the point of independence for her activities of daily living, although ataxia and memory issues persisted 2 months later.

INTRODUCTION

Wernicke’s Encephalopathy (WE) is a severe neurological syndrome due to deficiency of thiamine (vitamin B1). It was first described by Carl Wernicke in 1881 in a paper depicting three patients presenting with eye movement abnormalities, ataxia and mental status changes, in addition to retinal hemorrhages and optic disk swelling.1 Since that first report, WE has been associated with alcohol misuse. However, only two of the three patients described by Wernicke fell into that category. The first case described is of a young woman with persistent vomiting due to pyloric stenosis following sulphuric acid ingestion.1

Untreated WE is fatal. The three patients initially described by Wernicke died within weeks of onset of the syndrome.1 In subsequent publications there have been case reports and case series devoted to the clinical manifestations and treatment for WE. Despite over a century of reports about this condition, diagnosis is not uncommonly delayed, if not missed altogether. It is important to note that there are no large scale, class I studies on WE, so we are left to rely mostly on Class IV evidence for management and diagnosis. The purpose of this report is to give the general practitioner a review of the protean manifestations of this condition, identifying those at risk, its diagnosis, and treatment.

Epidemiology

The specific prevalence or incidence of WE is not accurately known. Our knowledge of the prevalence of this condition comes from autopsy reports. The prevalence ranges from 0.8-2.8% of autopsy cases.2 Based on one review, the predicted clinical prevalence was of 0.04-0.13%.3 From other case series, the incidence is reported as high as 1.9% of autopsies.4 Autopsy confirmed WE was missed by clinical examination in 75-80% of cases in one series.3 WE is more common in the setting of alcohol misuse or abuse. However, other conditions have been associated with its onset (Table 1).

Clinical Manifestations of Thiamine Deficiency in Non-Alcoholic Patients

In susceptible patients, like the case in question where persistent vomiting and diarrhea led to the use of PN, consideration of the triad of Wernicke’s disease (eye movement abnormalities, ataxia, and mental status changes) is a useful diagnostic tool. Unfortunately, the likelihood of each symptom varies. Thirty-to- forty percent of patients with thiamine deficiency will have only one of the symptoms or signs of the triad.5 The complete triad is only present somewhere between 5-16% of patients with thiamine deficiency.2,3,5 Interestingly, in some reports the triad has been noted to be more common in alcoholics than in non-alcoholics with WE,2 while other reports do not see a difference between alcohol related and non-alcohol related WE.5 In non-alcoholics, dietary deficiency and a history of vomiting were more frequent than in alcoholics with WE.2

Given the seemingly rare presentation of the “classic” triad, it is of utmost importance to identify the various presentations of this condition and discuss them separately. Additionally, in the post-surgical or PN- related WE, it might be useful to discuss the timeline in which it may develop. Thiamine deficiency leads to brain lesions in susceptible regions with high thiamine turnover in 2-3 weeks.3 Therefore, it stands to reason that in a patient with malnutrition, or improper thiamine intake, symptoms would emerge in this timeframe. Case reports support this concept where patients on PN (without thiamine or with inadequate thiamine along with poor endogenous stores) complain of double vision, vertigo unsteady gait and postural tremors within 11 days to two weeks following the initiation of PN.6-8

Additional signs of thiamine deficiency that may present with encephalopathy include heart failure (wet beriberi) leading to peripheral and pulmonary edema and orthopnea.3 A rarer manifestation is hypotension and lactic acidosis without edema.3 Seizures have also been reported, but are also rare.3

Clinical Features of the Wernicke’s Encephalopathy Triad
Alteration in Mental Status

Alteration in mental status is the most common feature of thiamine deficiency present in 70-80% of patients according to one autopsy series.2 Specific manifestations can include apathy towards the examination, an inability to answer questions of orientation, or to follow multiple step commands. Poor concentration as manifested by a diminishing ability to remember and repeat a series of numbers (an individual should be able to recite 5 to 7 digits within a minute of being presented with such a series) is also seen.2 At its most severe form an alteration in mental status can manifest as coma.2 As patients recover with treatment (discussed below), they may describe a distorted account of the events. This confabulation can occur in the acute phase of WE, but also in a more delayed fashion in Wernicke-Korsakoff syndrome. Progression to coma is gradual. Although patients appear somnolent during the examination they can be easily aroused. Coincident toxicities or alternative causes should be considered concomitantly. Given the relatively common finding of delirium in the inpatient setting, consideration for WE should be included in the differential and workup of a delirious or encephalopathic patient.

Abnormal Eye Movements

In thiamine deficiency, nystagmus is the most common eye movement abnormality (at least in alcoholic-related disease),4 and it can be present in the horizontal or vertical planes. Patients may also complain of double vision. This is a consequence of two abnormalities:

  • 1. The first is weakness of the lateral rectus muscles that are responsible for eye abduction. This can affect either side and vary in intensity.
  • 2. There may also be difficulty with conjugate gaze (coordination of both eyes to simultaneously focus on a target). Ophthalmoplegia (a lack of any eye movement) is also possible.

Ocular abnormalities occur in about a third of patients,3 but others note that non-alcohol related disease has a greater proportion of eye abnormalities.5 More rare ocular abnormalities include unequal pupillary size and “light-near dissociation”.3 In light-near dissociation, the pupil constricts when focusing on a nearby object, but does not constrict in response to direct light. As in the initial reports, visual disturbances due to optic disc edema or retinal hemorrhages can occur.3

Gait Ataxia

Thiamine deficient patients may be non-ambulatory. If they can walk, they take short steps and display gait unsteadiness. They maintain a broad stance to support themselves. In milder cases, the only way to provoke this ataxia is by having the patient walk with one foot in front of the other or to rub one heel along the front of the opposite leg’s shin from the knee down to the ankle in one swift movement. Ataxia is present in anywhere from 23-60% of patients.3,5 Careful consideration of a superimposed polyneuropathy should be investigated. Thiamine deficiency leads to a large fiber peripheral neuropathy manifesting with preferential weakness of the lower extremities and an inability to sense the position of limbs in space (proprioception) that is most notable when the eyes are closed. This loss of position sense tends to be more pronounced than pain.9

Korsakoff’s Syndrome

Once the acute encephalopathy of thiamine deficiency resolves, the enduring problem with learning and memory is classified as Wernicke-Korsakoff syndrome. The defining feature of Korsakoff Syndrome is memory impairment out of proportion to other aspects of cognition in an otherwise alert patient. The timeline of development of Korsakoff’s psychosis after Wernicke’s encephalopathy is not always clear.

Diagnosis

A clinical history and neurological examination are sufficient to make the diagnosis of WE as it remains a clinical diagnosis. Measurement of serum thiamine via high-performance liquid chromatography can help in the diagnosis of thiamin deficiency; however, it often takes over a week for the results to return.3 Given the potential for long term neurological harm and even death, waiting for lab results is not practical and is unsafe; treatment should begin after the lab draw. Additional ancillary testing can also include magnetic resonance imaging (as was done in the case discussed above). MRI brain findings of WE include abnormalities in and around the cerebral aqueduct, third ventricles and in the mamillary bodies, tectal plate, dorsal medulla and medical thalamus.10 In our case, the MRI was significant for signal abnormalities along the medial thalami (which can appear within a week of symptom onset) (Figure 1). The sensitivity of MRI is reported as 53% with a specificity of 93% and a positive predictive value of 89%.11 Therefore, imaging can help in excluding the diagnosis, but as noted earlier, clinical suspicion is most important.

Treatment

Treatment of WE, or suspected WE, once identified, consists of intravenous (IV) thiamine replacement (see Table 2). The exact dose of thiamine needed to effectively treat this condition has not been extensively studied; doses as low as 50 mg IV have been successfully used to treat WE.7 Other treatment paradigms suggest 200 mg IV in 100 ml of normal saline or 5% glucose over 30 minutes three times a day until symptoms resolve.2 It is ideal to give IV thiamine over 30 minutes as the infusion can be very painful at the site. Alternatively, the Royal College of Physicians recommends using 500 mg IV three times a day for three days followed by 250 mg IV daily for 5 days or until clinical improvement is no longer noted.12 This recommendation is based on patients with evidence of alcohol misuse. It is advisable to draw a thiamine level prior to the first dose, but once the level is drawn, BEGIN TREATMENT. Additionally, thiamine infusion should precede or be given along with intravenous glucose, as glucose can precipitate WE in thiamine-deficient individuals.3 Intravenous thiamine has rare adverse side effects, but anaphylaxis is possible.3 For WE, risk of the medication is low. The benefit can be argued to be rather high as will be discussed in the next section. At our institution and based on the pharmacy purchasing information, a day’s worth of therapy costs approximately $120 (personal communication). Following the completion of a course of parenteral administration of thiamine, oral thiamine at 30 mg twice a day is recommended for as long as the nutritional risk factor is present. The prophylactic course may be indefinite for the most vulnerable patients.3

Expected Clinical Course

Based on case series of alcohol-related Wernicke’s Encephalopathy, the first symptoms that respond to thiamine are the eye movement abnormalities, which resolve within hours-to-days.4 Confusion may persist despite treatment for days-to-weeks, but should gradually improve.4 As mental status clears, however, long-term deficits in memory may become more obvious. Korsakoff Syndrome, a condition of persistent impaired memory (loss of recent memories and inability to form new memories) can occur as a sequela of WE.4 In WE not related to alcohol, 25% of patients were noted to have Korsakoff’s Syndrome.5 Interestingly, in a large case series of patients with alcohol abuse, 84% were felt to have Korsakoff’s Syndrome, 21% of them had complete resolution in time, while 26% had no recovery.4 According to a large case series, ataxia improves in 2-4 weeks.4 In those that had resolution (38%), it occurred in days; however, approximately one-third of the patients had no improvement in their ataxia.

CONCLUSION

WE is a rare, but treatable, condition that often goes underdiagnosed. It has been associated with alcohol use and abuse, but there are other patient populations at risk. Patients with recent GI surgery, malnutrition or in need of parenteral nutrition are at higher risk. Symptoms can start within 10 to 20 days of parenteral nutrition and can progress rapidly in this population if thiamine is not included. The triad of eye movement abnormalities, ataxia and alteration in mental status is not present in all patients with WE. In vulnerable patients, a screening examination of mental status with focus on attention span and concentration, along with a thorough assessment of ocular motility is useful. Evaluation for truncal and limb ataxia is also key, but clinicians must be aware of the possibility of a superimposed peripheral neuropathy. Neuroimaging can be useful in the diagnosis, but clinicians should rely on the patient’s clinical presentation/history and their own clinical acumen. Clinicians should be vigilant in vulnerable populations and, given the relatively low cost and risk of parenteral thiamine, should highly consider empiric treatment at one of the doses described above.

In our experience, we opt for the higher 500 mg IV TID for three days given the low risk profile. Outcomes can vary and, despite treatment, irreversible disability is not uncommon. Appropriate counseling to patients and their families about the course of the disease is warranted.

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Nutrition Issues In Gastroenterology, #148

Nutritional Implications of GI-Related Scleroderma

January 2016 • Volume XL, Issue 1
Soumya Chatterjee

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Scleroderma (SSc) is an autoimmune disease characterized by progressive fibrosis of skin and various internal organs, including the lungs, heart, kidneys, and the gastrointestinal (GI) tract. Effective collaboration with gastroenterologists in the evaluation and management of SSc in a multispecialty partnership model has the potential to produce better outcomes. This article discusses the nutritional implications and current evidence-based management recommendations for the wide range of GI manifestations in SSc.

Scleroderma (SSc) is an autoimmune disease characterized by progressive fibrosis of skin and various internal organs, including the lungs, heart, kidneys, and the gastrointestinal (GI) tract. Second only to skin disease, GI tract involvement is the next most common manifestation of SSc. Any part of the GI tract may be affected, leading to considerable impairment of quality of life. When GI involvement is extensive, severe malnutrition can occur and it can even result in death in about 20% of patients. Early recognition and management may alter the long-term outcome. Effective collaboration with gastroenterologists in the evaluation and management of SSc in a multispecialty partnership model has the potential to produce better outcomes and improve survival in these patients. This article discusses the nutritional implications and current evidence-based management recommendations for the wide range of GI manifestations in SSc.

Soumya Chatterjee, MD, MS, FRCP, Associate Professor of Medicine, Staff, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH

INTRODUCTION

Scleroderma, or systemic sclerosis (SSc), is an autoimmune disease of unclear etiology, characterized by progressive fibrosis of skin and various internal organs, an ongoing occlusive microvasculopathy, and abnormalities of the immune system. There is wide variability in the prevalence of SSc worldwide. In the United States, about 250 cases per million Americans are afflicted with this disease. Progressive skin thickening is an integral part of the disease, explaining how the term ‘scleroderma’ was originally coined (Gr., ‘skleros’ = thickening, ‘dermos’ = skin). There are two main subtypes of SSc, based on the extent of skin hardening:

  • limited SSc (lcSSc, formerly CREST syndrome) only involving the distal extremities (beyond elbows and knees) and face.
  • diffuse SSc (dcSSc), where skin tightening is widespread, including the trunk and proximal extremities.

SSc, both limited and diffuse, can also affect multiple internal organ systems, including the lungs, heart, kidneys, and the gastrointestinal tract. Next only to skin involvement, the gastrointestinal (GI) tract is the second most commonly involved organ system, with over 90% of patients experiencing symptoms pertaining to the GI tract.

The management of SSc remains one of medicine’s most formidable challenges. So far, no effective disease modifying therapy has been developed that effectively reverses, halts, or even slows down the natural progression of the disease process.

SSc can involve any part of the GI tract – i.e. oral aperture, mouth and oral cavity, oropharynx, esophagus, stomach, small intestine, large intestine, and even rectum and anal canal (Table 1). GI manifestations of scleroderma are very common, and can be a source of significant morbidity and even mortality, especially when the entire GI tract is involved.1 Patients are also at risk of malnutrition (15%-58%),1,2 that can even lead to death in about 20% patients.2 Fat malabsorption has been found to occur in 43% of SSc patients, along with reduced serum levels of copper, selenium, carotene, and ascorbic acid.3 Whether these specific nutrient deficiencies are solely a result of reduced oral intake is unclear at this time.

The main pathological findings of GI involvement in SSc are smooth muscle atrophy and enteral wall fibrosis. Involvement can generally involve either the entire GI tract or any part of it. The muscle atrophy in the gut wall is thought to be either a result of involvement of the vasa nervorum (one of the manifestations of widespread scleroderma microvasculopathy), or due to perineural wrapping of collagen (which is formed in excess in scleroderma), leading to impaired denervation of the smooth muscle cell layer of the GI tract.

This article will discuss the nutritional implications of GI involvement in SSc and will emphasize specific management recommendations. Due to space constraints, detailed discussion of the investigations is beyond the scope of this article. Therefore, for investigations, please refer to the article by Kirby4 and the other annotated references.

GI MANIFESTATIONS OF SCLERODERMA
Oral

Thickening of perioral skin and fibrosis of perioral tissue leads to a narrow oral aperture (microstomia).

This results in significant problems during brushing and flossing of teeth and professional dental cleaning. For the same reason, fitting an adult mouthpiece during the recommended annual spirometry becomes difficult, leading to unreliable readings due to air leak around the mouthpiece. Hence, SSc patients often have to resort to a pediatric mouthpiece during spirometry. Patients are also prone to develop considerable dryness of the mouth, due to secondary Sjogren syndrome, seen in about 14%-20% patients.5,6 Sjogren syndrome is associated with dental problems, periodontal disease, and oral candida infections.

Oropharynx

Oropharyngeal dysphagia has been found to occur in up to 25% patients.7,8 This is particularly true in patients with concomitant polymyositis (known as scleromyositis), seen in about 3% of patients with SSc,9 where the striated muscle of the oropharynx and upper esophagus may be affected by an inflammatory process. In patients with advanced and long-standing SSc, the entire esophagus may be involved, as well as the oropharynx. Laryngopharyngeal reflux has been associated with nocturnal cough, distressing sour eructations (oral regurgitation of gastric acid), bronchospastic disease, and intermittent hoarseness of voice.

Esophagus

Esophageal dysmotility much more commonly affects the lower two-thirds of the esophagus leading to dysphagia (predominantly to solids), but also to liquids in advanced cases. Over time, the entire esophagus becomes patulous and aperistaltic. In addition, the lower esophageal sphincter becomes incompetent, encouraging gastro-esophageal reflux disease (GERD) – often seen as an early manifestation of SSc. The problem seems to be more troublesome at night when the patient lies down and the benefit of gravity, which normally keeps food down in the stomach, is lost. There is impaired clearance of the refluxed acidic gastric contents due to esophageal dysmotility, aggravating esophageal irritation, especially at the gastro-esophageal junction and the lower esophagus. This chronic irritation predisposes to ulcerative esophagitis. If not recognized and managed in a timely manner, chronic esophagitis predisposes to esophageal stricture and even metaplastic and dysplastic changes close to the gastro-esophageal junction (where normal stratified squamous epithelium is replaced by columnar epithelium), leading to Barrett’s esophagus (Figure 1). Barrett’s esophagus in turn predisposes to esophageal adenocarcinoma. Hence, surveillance endoscopies need to be performed routinely. Studies have shown that about 25% of patients presenting with adenocarcinoma have no prior history of GERD or Barrett’s esophagus, indicating that GERD can be subclinical and asymptomatic in a substantial number of patients. Patients with esophageal dysmotility and aperistalsis are also more prone to develop “pill esophagitis”; therefore, certain medications (Table 2) should be swallowed with extreme caution with at least 8 ounces of water, to ensure that their esophageal transit is complete.

Stomach

Gastric dysmotility can lead to gastroparesis in 27%- 38% of SSc patients.10,11 Symptoms include bloating, flatulence, early satiety, nausea and vomiting. It can aggravate malnutrition and weight loss. Moreover, gastroparesis can also worsen GERD, as the stagnant food is not propelled through the antrum, causing further gastric distension and enhancing reflux through the incompetent lower esophageal sphincter.

Another curious complication of SSc is gastric antral vascular ectasias (GAVE, also known as watermelon stomach). Dilated blood vessels (vascular ectasias) appear in the gastric antrum. The appearance of GAVE resembles the stripes of a watermelon (Figure 2). In addition, isolated mucosal telangiectasias can appear in the stomach, as well as the remaining GI tract. These lesions (GAVE and telangiectasias) can rupture inside the lumen causing acute blood loss or chronic iron deficiency anemia. Bleeding from these lesions cannot be controlled with proton pump inhibitors or other acid reducing agents.

Small Intestine

Symptomatic involvement of the small intestine is not common, occurring in about 15% of patients.12 However, when it occurs, it is a cause of major morbidity. This problem, known as chronic intestinal pseudo-obstruction (CIPO), leads to severe constipation. There is smooth muscle atrophy, predominantly of the longitudinal muscle layer, leading to a slowing or absence of peristalsis. Malabsorption can occur due to fibrosis of the gut lymphatics. Moreover, slow intestinal transit sets the stage for significant small intestinal bacterial overgrowth (SIBO). This can lead to severe diarrhea, abdominal pain and distension, sometimes episodic and sometimes more continuous. Malabsorption and malnutrition from significant intestinal involvement portends an extremely poor prognosis in SSc and is often a challenging problem to manage.

Large Intestine

Collagen deposition and neuronal damage causes hypomotility of the large intestine in about 50% of scleroderma patients.13 This results in severe constipation and patients have to resort to laxatives and stool softeners, often with suboptimal response.

Anal Canal

Fecal incontinence, resulting from an incompetent anal sphincter, is not uncommon in SSc. This becomes a social nuisance, especially when patients are also having diarrhea, and can lead to fecal soilage. Patients may become homebound. Fecal incontinence has a major psychological impact and significantly impairs quality of life.

CLINICAL IMPLICATIONS AND MANAGEMENT
Diet and Nutrition

The North American Expert Panel convened by the Canadian Scleroderma Research Group (comprised of gastroenterologists, dietitians, speech pathologists, and rheumatologists) advocates screening all SSc patients for malnutrition and involving a multidisciplinary team (including gastroenterologists and dietitians) in those diagnosed with malnutrition.14 SSc patients should be encouraged to record monthly weights and report significant changes in their weight to their provider.2

Oral Diet

Dietary modification is helpful in mild cases of intestinal involvement in SSc. A balanced healthy diet should be continued as long as possible. Intake of fats or sugars should not be restricted.3 Malabsorption and occult GI blood loss leads to vitamin B complex deficiency and iron deficiency. As a result, glossitis, cheilosis, angular stomatitis, and oral ulcers can develop. These nutritional deficiencies should be recognized and corrected as well. If gastroparesis develops, frequent, small, low-fiber, and lower fat meals with higher liquid content should be encouraged.2

Theoretically, restricting simple carbohydrates, fruit juices, sugar alcohols, and fiber (especially fiber bulking agents in those with constipation), may decrease fermentation and thus alleviate symptoms of bacterial overgrowth. Secondary lactose intolerance often develops, which may require additional dietary adjustments. If SIBO becomes a major problem, where possible, patients should be advised to reduce acid lowering agents to allow gastric acid to help keep SIBO at bay. However, this may be problematic in SSc patients, as GERD also needs to be effectively controlled to reduce its complications.

Enteral Nutrition

When severe esophageal dysmotility and aperistalsis makes oral feeding difficult, gastric or jejunal feeding through a percutaneous or surgically placed tube needs to be considered. In one small study of SSc patients, PEG tube feeding was reported to cause successful weight gain and improvement in quality of life.15

In patients with severe gastroparesis or GERD, nasojejunal tube feedings may be tried temporarily.16 If the procedure provides symptomatic relief along with improvement in nutritional status, a percutaneous or surgically placed jejunal tube may be an effective and durable solution in carefully selected patients.17 In refractory gastroparesis, a feeding jejunostomy sometimes needs to be combined with a decompression gastrostomy.18

Parenteral Nutrition

When malabsorption from CIPO and subsequent SIBO becomes severe and intractable, symptoms may prevent enteral feeding in maintaining adequate nutrition. This is uncommon, but may occur in a small number of SSc patients. In this situation, parenteral nutrition (PN) may need to be considered. It has become an evolving route of alimentation for SSc patients with severe protein calorie malnutrition.3 Home PN has recently gained considerable attention as an effective means of maintaining adequate nutrition in patients with chronic intestinal failure from intractable scleroderma enteropathy. Its acceptance is based on the cumulative success observed in several retrospective case series each involving a relatively small number of SSc patients.19-23

Pharmacological Agents

Prokinetic agents such as erythromycin (which stimulates motilin receptors in the intestine), domperidone, and even daily subcutaneous injections of octreotide (Sandostatin®)17 have been used with some success.

Prokinetic Agents

Prokinetic agents such as cisapride (Propulsid®) and tegaserod maleate (Zelnorm®) are no longer available in the US, but linaclotide (Linzess®),24 has been tried with variable degrees of success in improving lower GI tract motility and regulating bowel movements. Prucalopride.15,26 (sold as Resolor® in Europe and as Resotran® in Canada) is in the same class as tegaserod, but does not share the same arrhythmogenic risk of Zelnorm® that led to its withdrawal from the US market. However, it is not available in the US.

Somatostatin Analogue

The somatostatin analogue, octreotide (Sandostatin®),17 increases the mean frequency of intestinal migratory motor complexes and thus stimulates intestinal motility. Octreotide can also reduce SIBO.17 It was shown to improve nausea, vomiting, flatulence and abdominal pain in SSc patients with CIPO.17

Antibiotics

SIBO, leading to episodic diarrhea, gas, bloating, and abdominal distension, can either be controlled with cyclical antibiotics, 7-10 day courses as necessary, or continuously in more severe cases (i.e. those with chronic diarrhea from SIBO) (Table 3). For the latter, rotating three or four antibiotics (Table 3) may be effective and help to reduce development of antibiotic resistance. Furthermore, there is some evidence on the benefit of long-term use of oral probiotics such as Bifidobacterium infantis (Align®) or Lactobacillus GG (Culturelle®).4

MOUTH CARE

If there is problem chewing or swallowing, dietary modifications are helpful, e.g. resorting to a soft moist diet, and avoiding dry items such as bread and those that require a lot of chewing such as meat. In addition, it is important to maintain good oral hygiene. If screening reveals poor oral health, a dentistry evaluation is appropriate.27 Secretagogues (Table 4) are helpful in increasing saliva flow. Artificial saliva preparations that have earned ADA (American Dental Association) seal of acceptance can be used as necessary and can be helpful in lubricating the mouth. Oral candida (due to lack of protective saliva) is very common and should not be overlooked, treated when found (Table 4).

OROPHARYNGEAL DYSPHAGIA

When oropharyngeal dysphagia develops, referral to a speech pathologist is prudent.3 Aspiration precautions are particularly important in this subgroup of patients, as aspiration pneumonia not only worsens hypoxia in a SSc patient with pre-existing interstitial lung disease (ILD), but repeated micro-aspirations have also been implicated in accelerating the rate of progression of ILD in SSc. When oropharyngeal and upper esophageal striated muscles are involved in scleromyositis (discussed above), since this is an inflammatory process, there may be a role for immunosuppressive therapy. Thus, in our practice, selected patients with this problem have benefitted from glucocorticoids and other immunomodulatory agents such as methotrexate, azathioprine or intravenous immunoglobulin.

ESOPHAGEAL PROBLEMS

Although the mainstay of therapy for GERD in SSc is the use of pharmacologic agents, some of the common and simple non-pharmacologic measures that will help manage acid reflux are listed below4:

  • Frequent small meals
  • Avoiding lying down for 1-2 hours after the last meal at night
  • Avoiding certain food items (items that are known to relax the lower esophageal sphincter further) such as chocolate, caffeine, mint, fruit juices, fatty foods, etc.
  • Avoiding smoking and alcohol, especially before going to bed at night
  • Avoiding tight undergarments
  • Avoiding weight gain
  • Use of liquid medications when pills cannot be taken safely
  • Elevating the head end of the bed by 6-8 inches (using wooden blocks) or a wedge pillow
  • Assuming a left lateral decubitus position at night. This recommendation is being made based on studies that have demonstrated that a sleep device that maintains recumbent horizontal position with left lateral decubitus position considerably reduces recumbent esophageal acid exposure28 and symptoms of nocturnal acid reflux.29

Acid Reducing Agents

Among pharmacologic agents, proton pump inhibitors (PPI) are by far the most effective acid-reducing agents that should be used on a long-term basis (Table 5). Sometimes the patient might need a higher than usual dose, and even twice daily in recalcitrant cases. The concerns about bone loss, increased risk of serious GI infections (including C. difficile colitis), enhanced proliferation of SIBO, and nutritional deficiencies (iron, calcium, magnesium, vitamin C, and vitamin B12), are real, but if the physician is cognizant of these potential complications of long-term PPI use, and deals with them appropriately, as they occur, the benefits of long- term PPI use in an SSc patient can far outweigh the risks. For breakthrough heartburn even with continuous PPI use, antacids (preferably in a liquid form such as Gaviscon®, Maalox ® or Mylanta®) can be used for immediate symptomatic relief. If PPIs are not tolerated or ineffective for any reason, the next option is to use an h3 receptor antagonist (Table 5).

Prokinetic Agents

Prokinetic agents such as metoclopramide (Reglan®) or domperidone (Motilium®) may be helpful in the early stages of esophageal dysmotility in SSc. Many gastroenterologists prefer the latter, as unlike metoclopramide, it does not significantly cross the blood brain barrier and thus cannot cause the extra-pyramidal side effects that can occur with metoclopramide. However, it is not readily available in the United States, and may need to be obtained from other parts of the world (e.g. buying it online at: www.medisave.ca). Moreover, there is no published evidence about its efficacy in patients with SSc.

Cisapride (Propulsid®), proven to be a very effective prokinetic agent, was withdrawn from the US market in July 2000, due to its risk of inducing QT-prolongation, torsades-de-pointes and sudden cardiac death. However, in cases of severe and intractable SSc associated GERD, it may still be available from the manufacturer through a limited-access compassionate use program under an ‘investigational new drug’ mechanism (Protocol CIS-USA-154: Cisapride access to adult patients with GERD, gastroparesis, pseudo-obstruction or severe chronic constipation disorders who have failed standard therapy). However, as interactions with CYP3A4 inhibitors (azole antifungals, macrolide antibiotics and grapefruit juice) increase arrhythmogenic risk, these agents should not be co-administered. As the disease progresses, in patients with extensive smooth muscle atrophy and fibrosis, prokinetic agents may eventually become ineffective.

Procedural and Surgical Interventions

For peptic stricture of the esophagus (seen in 20% of patients with GERD), periodic esophageal dilation (using a dilator or bougie) is necessary.

If Barrett’s esophagus is present, periodic (at least annual) endoscopic surveillance is necessary. Some newer forms of therapy have led to a breakthrough in the management of this once incurable condition.4 These procedures can be successfully used to eradicate, and thus cure Barrett’s esophagus, e.g. radiofrequency ablation or photodynamic therapy.

In appropriate patients, small foci of in-situ adenocarcinoma arising from Barrett’s mucosa can be removed with radiofrequency ablation or endoscopic mucosal resection. Preferably, these patients should be referred to centers that have expertise in such therapy.4 Once invasive adenocarcinoma develops, the prognosis is poor and treatment may require extensive surgery, radiation and/or chemotherapy, especially for metastatic disease.

Sometimes permanent surgical procedures such as 270? Nissen fundoplication or even roux-en-Y gastric bypass are performed for intractable GERD and recurrent bouts of aspiration pneumonia. These procedures may also be performed in some selected patients in order to qualify for a lung transplant for severe lung disease associated with SSc, or sometimes after the lung transplant, to prevent aspiration induced lung injury.30 However, fundoplication should preferably be avoided in SSc-associated GERD, as it is likely to worsen severe dysphagia (by inducing further mechanical obstruction in an already dysmotile esophagus), and thus aggravate the risk of malnutrition that these patients are already prone to develop.

GASTROPARESIS

Similar to esophageal dysmotility, prokinetic agents such as metoclopramide (Reglan®) or domperidone (Motilium®) may be helpful in the early stages of gastroparesis in SSc. As mentioned earlier, the latter is preferred by many gastroenterologists, but is not available in the US. Patients who may benefit from nutrition support should undergo a nasogastric or nasojejunal feeding trial before considering permanent enteral access. In those who do not tolerate it, it saves them from undergoing a procedure they do not need; for those ultimately needing parenteral support, it may be required for insurance coverage purposes, before approval. However, it has to be kept in mind that when gastroparesis develops in SSc, bypassing the stomach is often not a solution, because the rest of the GI tract is also likely to be similarly affected by dysmotility. Nevertheless, sometimes a PEG tube needs to be inserted for intermittent gastric decompression when gastric distension from severe gastroparesis causes considerable discomfort, and substantially increases the risk of reflux and aspiration.

GAVE

For GAVE (Figure 2) and isolated gastro-intestinal telangiectasias, several ablative procedures have been used with success.4 The preferred endoscopic method is argon plasma coagulation (APC), as the lesions induced by cauterizing the bleeding vessels by APC are more superficial (compared to the other methods) and therefore they lead to minimal scarring of the antrum – a complication that can worsen gastric dysmotility, particularly when the patient has concomitant gastroparesis.

CONCLUSION

GI tract involvement is the most common extra- cutaneous manifestation of SSc. Any part of the GI tract from the mouth to the anal canal may be affected, potentially causing significant malnutrition, impairment of quality of life and in severe cases, even death. Early recognition and management of GI complications of SSc may favorably alter the long-term outcome. The durable benefits of parenteral nutrition in SSc enteropathy are beginning to emerge. A multidisciplinary approach including rheumatologists, gastroenterologists with expertise in gastrointestinal dysmotility and early involvement of a dietitian familiar with the disease is paramount in producing better outcomes and improving survival in these patients.

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