Page 78 – Practical Gastro

Advancements in the understanding of malnutrition and the limitations of traditional nutrition assessment have spurred the development of new methods of evaluating nutrition status that are particularly applicable to patients with cirrhosis. Here we discuss the importance of successfully combating malnutrition through the efforts of the entire healthcare team to educate patients and families, and the need for adequately designed research to investigate the effects of providing additional nutrition to cirrhotic patients with malnutrition on quality of life and other outcomes.

Incidence and Causes of Malnutrition

Malnutrition as a consequence of cirrhosis has been reported for more than 50 years. Although the incidence of malnutrition described has varied widely based on the severity of liver disease and the definition of malnutrition used, there is agreement that malnutrition occurs commonly in cirrhosis.^1-4 More than 60% of patients with end-stage liver disease are malnourished, and nearly all patients with decompensated liver disease that are transplant candidates have some element of malnutrition.^1-4 Cirrhosis can be considered a form of “accelerated malnutrition.”⁴ Inadequate ability to store liver and muscle glycogen, combined with increased insulin resistance leads to rapid breakdown of muscle and fat stores after short periods without food in patients with cirrhosis.⁴ Breakdown of muscle for fuel leads to severe muscle wasting (sarcopenia) which contributes to decreased strength, loss of functional status and may compromise quality of life.^{5, 6} Patients with cirrhosis have alterations in serum biologic mediators such as leptin, tumor necrosis factor (TNF) and adiponectin that accelerate muscle wasting and also cause anorexia.¹

Decreased food intake is the most obvious source of malnutrition in cirrhosis.^2,7 Patients with more severe disease have been reported to have a greater reduction in nutrition intake, compared to patients with less serious cirrhosis.^2,7 In addition to anorexia caused by alterations in cytokines and other circulating factors, patients with cirrhosis have an increased incidence of delayed gastric emptying and small bowel bacterial overgrowth that can affect food intake.^8,9 Ascites is a major source of anorexia and early satiety in patients with decompensated disease.^1,2,8 Patients with ascites frequently eat better in the hospital after paracentesis, but then experience a progressive decrease in food intake at home as the ascitic fluid re-accumulates. Food intake, nutrition status and body composition improve after resolution of ascites post transjugular intrahepatic portosystemic shunt (TIPS).¹⁰

Nutrition Assessment

Nutrition assessment in liver disease has traditionally relied on measurement of serum proteins such as albumin, prealbumin or transferrin. However, the best available evidence indicates that serum protein levels are not accurate measures of nutrition status.^11,12 Those serum proteins that were erroneously thought to reflect nutrition status are inverse acute phase reactants, which rapidly decrease in infection, injury or other physiologic stress, and then begin to increase as the stress resolves independent of changes in nutrition intake.^11,12 Serum proteins are also affected by a plethora of non-nutritional factors including synthetic function of the liver, hydration status, renal failure, corticosteroid administration (prealbumin) and iron status (transferrin).¹¹

In many patient populations, weight loss is the most useful indicator of malnutrition. However, patients with decompensated cirrhosis who have ascites often gain weight even when oral intake is poor and advanced malnutrition is present. A modified body mass index (BMI) has been proposed for patients with cirrhosis, and to provide an index for underweight in patients with ascites.¹ A BMI < 18.5 kg/m² is usually considered underweight, but in patients with cirrhosis a BMI < 20 kg/m² was associated with increased mortality. A BMI < 23 kg/m2 may indicate underweight in patients with mild ascites, while BMI < 25 kg/m2 may be underweight for patients with severe or tense ascites.¹ Alternatively, adjustments to actual weight can be made based on the severity of ascites (see Table 1). Conversely, patients without cirrhosis may have substantial loss of muscle, but maintain, or even increase fat stores with no net change in body weight.

Physical examination to investigate possible muscle wasting in the extremities and temporal muscle should be part of routine nutrition assessment in patients with cirrhosis. Studies of body composition using ultrasound, bioimpedance or CT scan have identified severe muscle wasting as a common occurrence in cirrhosis, and the degree of sarcopenia may even be a prognostic indicator for some cirrhotic populations.^3,5,6,13 A new study identified that pre-transplant muscle mass was associated with post-transplant outcomes including duration of ICU stay and days of mechanical ventilation.⁶ In men, muscle mass was a significant predictor of survival and ability to be discharged to home (rather than discharged to a transitional facility).⁶ Further research is needed to define standards of muscle mass for different age and disease categories, and to standardize technology and techniques for measurement of muscle mass before routine use is indicated in the clinical setting.

Research also indicates that changes in functional status may be one of the better indicators of alterations in nutrition status. Measurement of handgrip strength has been used as surrogate a marker for functional status in some studies.³ Obviously, measurement of handgrip strength is not feasible in patients that are sedated, critically ill or have severely altered mental status. However, handgrip strength appears to be able to predict decline in nutrition status before other signs of clinical compromise are apparent.¹⁴ When measurement of handgrip strength is not feasible, discussions with patients and the patient’s family or caregivers about possible changes in a patient’s functional status can provide insights into overall nutrition status.

Evaluation of recent oral intake remains one of the most valuable components of nutrition assessment in patients with cirrhosis. A reliable history that documents poor oral intake may be all that is needed to appreciate a patient’s nutrition status. A more detailed interview can be helpful to assess diet quality, variety of intake and investigate the source of limitations to oral intake. Patients that are not meeting basic calorie and protein requirements are also likely not receiving sufficient vitamin and minerals (unless they consistently take vitamin/mineral supplements).⁷ Nutrition deficiencies do not normally occur in isolation, and detection of any nutrition inadequacies should be a reminder to consider other possible vitamin and mineral deficiencies.

Nutrition Needs: Calories

Patients with cirrhosis do not have substantially greater total calorie requirements than other populations.^1,2 Adult patients that are bedbound or have minimal physical activity frequently require 25-30 kcals/kg, while patients with moderate physical activity may be maintained on 30-35 kcals/kg.⁷ Patients with increased physical activity and those who need to gain weight may require in excess of 40 kcal/kg to maintain or improve nutrition status.^7,15 Adequate calorie intake is important to help prevent dietary or body protein from being used to meet energy needs. However, excessive calorie provision can cause or accelerate hepatic lipid accumulation, especially in critically ill patients. Patients with obesity, especially those with non-alcoholic fatty liver disease or insulin resistance, may benefit from slightly hypocaloric nutrition. Patients with severe malnutrition or those who have had an extended period of decreased oral intake should have reduced calorie provision for the first several days to minimize electrolyte changes associated with refeeding syndrome. Estimation of euvolemic weight in patients with ascites is helpful to avoid overfeeding (see Table 1).

There are a number of formulas to help estimate calorie expenditure, however, no data exists demonstrating improved outcomes from the use of any particular method. Considering the wide daily variability of calorie expenditure and intake, a time efficient method such as calories per kilogram, to prevent gross underfeeding or overfeeding is generally sufficient (see Table 2). Monitoring actual nutrition intake is far more important than the accuracy of the initial calorie goal.

Protein

Prior to the development of medications to treat hepatic encephalopathy, restricting dietary protein was often used in an attempt to control symptoms. However, there is no data in humans to support the use of dietary protein restriction in significantly increased breakdown of body proteins with no advantage in treating encephalopathy, compared to patients receiving 1.2 gm protein/kg.¹⁶ Three groups have reported that increasing protein to 1.2-1.5 gm/kg resulted in more rapid improvement in encephalopathy scores, compared to patients receiving reduced amounts of protein.17-19 Considering that inadequate protein intake only results in muscle protein breakdown, it is not surprising that protein restriction has no clinical benefit. Unfortunately, there are no randomized studies that have investigated the ideal protein intake, or the upper limits of recommended intake in this population.

There is sufficient evidence to support a protein intake of 1.2g/kg in most patients, with intakes up to 1.5 gm protein/kg in malnourished or acutely ill adults.¹⁵ There is extensive evidence that malnutrition is deleterious in cirrhosis. In view of the advantages of adequate protein intake on overall nutrition status and faster improvement of encephalopathy scores, plus the absence of any human data demonstrating a benefit of protein restriction, a protein intake below 1.0 gm/ kg should be discouraged in patients with cirrhosis. Our experience with those rare patients who have been described as protein intolerant is that symptoms have ultimately resolved upon discovery of an occult infection, GI bleeding, medication noncompliance or substance abuse. Unfortunately, there appears to be an “educational inertia” regarding the use of protein restriction in cirrhosis. Despite the lack of any evidence to support the use of protein restriction, and the data demonstrating the benefits of adequate protein, many textbooks and academic programs continue to propagate disproven notions of reduced protein intake in these patients.

Nutrition Intervention

Nutrition therapy for patients with hepatic failure should focus on preventing or reversing malnutrition. Maintaining adequate food intake, with frequent feedings should be a priority. Caregivers can help identify and manage the “rate limiting” factors that impede nutrition intake. Small, frequent meals and oral liquid supplements may be helpful if patients experience fullness or early satiety. Medication adjustments may help if patients are fearful of eating due to frequent bowel movements related to disaccharide (lactulose) therapy for encephalopathy. Food should be appropriate for a patient’s dentition, especially during a hospital admission. Due to the inefficiency in storing glycogen and rapid oxidation of muscle protein between meals, every effort should be made to minimize time without nutrition.^1,2,4 Patients that require frequent hospitalizations often experience multiple interruptions in diet for altered mental status, procedures or diagnostic tests. Although the duration of each time period without food may be relatively brief, the cumulative effect of repeated bouts without nutrition can contribute to net loss of muscle and decreased functional status. In view of the limited capacity to enhance synthetic function and difficulties in rebuilding muscle mass, maximum efforts should be made to avoid catabolism where possible. If patients must remain npo, adding 5% dextrose to IV fluids will provide some short-term protein-sparing.

A late evening snack appears to be the single most effective intervention to help combat sarcopenia in patients with cirrhosis.^1,2,20 A snack containing both carbohydrate and protein prior to bedtime delays the onset of fat and muscle protein breakdown overnight.²⁰ A review of 15 studies of late evening snack in cirrhosis documents improvements in nitrogen balance and fat-free mass.¹⁹ One substantial obstacle is the difficulty of convincing patients and families that frequent small meals and a late-evening snack containing both carbohydrate and protein are a vital part of care. Longterm studies of late evening snack document limited compliance after discharge.²⁰ It is not unexpected that advice regarding a peanut butter sandwich or cereal with milk may seem too mundane to be consistently followed. One study reported that when nutrition advice for patients with cirrhosis was reinforced during clinic visits by physicians and other members of the healthcare team, survival and quality of life were improved compared to nutrition counseling alone.²¹

Low sodium diets are routinely used to help manage ascites in patients with decompensated cirrhosis. There is limited research on the effectiveness or long term outcomes with different degrees of sodium restriction. One older study reported no significant advantage from sodium restriction,²² but another study described faster resolution of ascites when a sodium restriction was added to diuretics.²³ In practice, a 2-3 gm sodium restriction is common, but the ideal level of sodium in the diet for management of ascites and optimized outcomes in cirrhosis has not been adequately studied. It is also conceivable that a strict sodium restriction alone can contribute to decreased food intake in some patients. Hospitalized patients with minimal oral intake generally do not require any diet restrictions. Regular diets in most hospitals provide a 3-4gm sodium restriction if 100% of all foods are consumed. Adding a diet restriction to any patient who is eating < 50% of their hospital meals is redundant. The education of patients and families about the sodium content of foods is much more important prior to hospital discharge where fast foods, frozen meals and canned meats and meals can provide excessive sodium. Oral Liquid Nutrition Supplements Liquid oral nutrition supplements can be useful adjuncts to increase calorie, protein and vitamin-mineral intake in selected patients. Patients that have early satiety or otherwise have difficulty with eating full meals can often meet needs with oral liquid supplements. Two meta-analysis have evaluated studies of oral supplements in patients with cirrhosis.^24,25 One meta-analysis reported reduced occurrence of ascites and infections with improved resolution of hepatic encephalopathy.²⁴ The other meta-analysis reported significantly decreased mortality with oral nutrition supplements in patients with cirrhosis.²⁵ Although long term compliance and cost may limit the effectiveness of oral supplements for some patients, overall, they can be an effective component of nutrition therapy for many patients with cirrhosis. See Table 3 for a summary of suggested nutrition interventions. Branched Chain Amino Acids (BCAA)

Serum levels of the branched chain amino acids (leucine, isoleucine and valine) are decreased in cirrhosis. Research with parenteral BCAA infusions reported improvements in symptoms of encephalopathy.^1,2 However, research with enteral BCAA feedings and supplements have produced mixed results. Most studies that have described beneficial effects of BCAA supplements generally did not provide isocaloric and isonitrogenous control supplements.²⁶ Furthermore, many patients in past studies were inappropriately maintained on reduced protein diets at baseline, and supplementing any additional amino acids or feedings to help reverse protein malnutrition and support hepatic synthetic function may be of benefit. BCAA products are significantly more expensive than conventional foods or nutrition supplements; palatability and compliance are also limiting factors. A well controlled study of BCAA supplements did not report any significant improvement in overall patient 52 outcomes.²⁷ Nonetheless, those patients who remained compliant with long term BCAA supplements had decreased frequency of hospitalizations compared to patients that received protein supplements.²⁷ The effects of BCAA supplements on encephalopathy appear modest and there is insufficient data to know if BCAA supplements would provide benefits above and beyond those patients receiving full nutrition (frequent feedings with a bedtime snack). Glutamine

One amino acid that should not be supplemented in increased amounts in patients with cirrhosis is glutamine. Glutamine is metabolized to glutamate and ammonia, and supplemental glutamine can cause an exacerbation of hepatic encephalopathy. Oral glutamine supplements used as a “challenge” to help diagnose patients suspected to have minimal hepatic encephalopathy, acutely increased serum ammonia and overt encephalopathy symptoms.²⁸ Vitamin and Mineral Supplementation

Patients with cirrhosis are at risk for multiple nutrient deficiencies.^1,2,7 A multi-vitamin with minerals can be useful for patients that are not meeting micronutrient needs. However, supplements that contain iron and copper should be avoided until hemochromatosis and Wilson’s disease as a cause of cirrhosis have been ruled out.

Patients with cholestatic disease or a biliary disorder such as primary sclerosing cholangitis or primary biliary cirrhosis, are at increased risk for fat-soluble vitamin deficiencies.^1,2 Vitamins A, E and D should be monitored and provided at increased doses if deficiencies occur. Due to the risk of hepatic toxicity and long-bone fractures with increased vitamin A supplementation, serum levels should be checked before high-dose supplementation is initiated. In those patients with severe cirrhosis, it is unclear whether vitamin A stores can be mobilized from the liver as alterations in serum proteins make serum vitamin A results difficult to interpret.

Patients with cirrhosis are at risk for osteopenia, osteoporosis and fractures.²⁹ Vitamin D should be monitored and replaced in all patients with liver disease.

Zinc is an essential cofactor for enzymes in the urea cycle and throughout the body. Patients with cirrhosis are particularly susceptible to zinc deficiency due to increased losses from diuretics, increased stool output, decreased food intake, or if patients have been told to limit meat.^30,31 Treating a zinc deficiency is advisable, but routine zinc supplementation in patients with decompensated cirrhosis did not improve encephalopathy.³¹ Long term zinc supplementation should be avoided due to the risk of inducing a deficiency of other trace minerals that compete with zinc for absorption. Some populations may be at increased risk for urinary tract infections with chronic zinc supplementation.³² Serum levels of zinc are unreliable as serum levels are decreased in conditions of stress, injury or infection and hypoalbuminemia. One clinical approach if a zinc deficiency is suspected is to provide 25 – 50 mg of elemental zinc/day for a limited time (2-3 weeks) and then discontinue the supplement.

Nutrition Support
Enteral Nutrition (EN)

Placement of a feeding tube to provide EN is indicated when patients with cirrhosis are unable to meet nutrition needs with oral intake alone. Considering the difficulties with maintaining and restoring nutrition status in patients with cirrhosis, patients should not be permitted to go extended periods without adequate nutrition. Small bore nasogastric (NG) placement is feasible in most patients, even those with recent GI bleeding.³³

Patients with altered mental status are at risk for frequent displacement of NG feeding tubes. Securing the feeding tube with a nasal bridle (http://www. amtinnovation.com/bridle.html) has been shown to help maintain NG placement and increase nutrition delivery.³⁴ Careful patient selection for placement of a nasal bridle and feeding tube is essential because patients with cirrhosis may be at higher risk for bleeding. Placement of mitts and/or temporary restraints in addition to a nasal bridle may be required to safely maintain NG access in some patients. Multidisciplinary engagement and a dedication to maintain nutrition as a basic component of care for patients with cirrhosis is often required for successful EN. Standard calorie-dense, polymeric EN formulas are tolerated by most patients. Placement of long-term percutaneous enteral feeding access is associated with significantly increased complications in patients with cirrhosis, and is generally considered contraindicated in patients with ascites.³⁵ Social embarrassment and discomfort generally limit the ability to maintain NG access in the outpatient setting for any duration.

There is a need for additional research to examine the role of EN in patient outcomes for patients with cirrhosis.24, 25 EN provided to patients with advanced cirrhosis with jaundice for 4 weeks did not improve mortality at one year, but the potential role of EN for patients with less advanced disease has not been adequately studied.³⁶

Parenteral Nutrition (PN)

The indications for PN in patients with hepatic failure are similar to any other disease process; yet it also increases the risk for infectious complications and is more expensive, compared to EN.³⁷ PN also requires a greater fluid volume, compared to calorie-dense EN.

PN that provides lipid emulsion > 1 gm/kg in adults is associated with increased incidence of hepatic compromise.³⁸ However, increased carbohydrate loads that would be necessary for patients receiving very low fat PN have also been implicated in hepatic compromise.³⁸ PN that provides fat, calories and protein similar to a healthy diet and EN formulas, without an excessive amount of any single nutrient, may be the best approach until further data is available. Lipid emulsions made from fish oils have demonstrated potential to prevent or even reverse PN-associated liver disease in neonates and pediatric patients.³⁹ However, there is limited data to know if fish-oil containing lipid emulsions are effective in adults with PN-induced liver disease.

CONCLUSIONS

Malnutrition is a serious problem in cirrhosis that leads to muscle wasting, compromised quality of life and increased complications. Successfully combating malnutrition requires the efforts of the entire healthcare team to educate patients and families that frequent feedings and an evening snack are an important part of their care. Education efforts must also include “mythbusting” the outdated, mistaken and potentially deleterious notions about restricting protein intake in patients with cirrhosis. Enteral nutrition support is useful for hospitalized patients to help minimize the cumulative nutrition deficit that frequently occurs in patients with cirrhosis. However, further research is required to understand if there are outcome advantages of longer periods of nutrition support in malnourished patients with cirrhosis, especially those preparing for transplant.

Epidemiology of Gastrointestinal Cancers, #3

Gastric Cancer: A Global Perspective

Febin John,

Janeesh Sekkath Veedu,

C.S. Pitchumoni

Wide geographic variation exists in the incidence of Gastric Cancer, with a high incidence in the eastern parts of Asia and Europe, but rare in North America and Western Europe. Here we discuss dietary practices, effective Helicobacter pylori eradication, early diagnosis, endoscopy and target biopsies coupled with effective surgical procedures and their affect on outcomes.

Gastric cancer (GC) is the fifth most common cancer worldwide, following lung, breast, prostate and colon cancers. It accounts for about 8% of the total cancer cases and 10% of cancer related deaths.^1-3 The 5 year survival is low (≤20 %) except in countries like Korea (> 60%) and Japan where type of cancer is biologically different and early screening is in effect.^4-6

Wide geographic variation exists in the incidence of GC, with a high incidence in the eastern parts of Asia and Europe, but rare in North America and Western Europe. Healthy dietary practices and effective Helicobacter pylori (H. pylori) eradication probably explains the decreasing incidence. Early diagnosis is a challenge with absence of classical symptoms and paucity of molecular markers.⁷ Endoscopy and target biopsies coupled with effective surgical procedures have improved outcomes marginally.⁸

A recent trend shows rise in GC in the cardia as opposed to non-cardia cancers, with a shift in the histology as well. The intestinal type of gastric adenocarcinoma is decreasing compared to the diffuse type.9 An increasing incidence has been reported among the indigenous populations (Maori in New Zealand and Inuit in North America) compared to others inhabiting the same geographical region.^10,11

GLOBAL EPIDEMIOLOGY

Distribution of GC is wide but occurs predominantly (>70%) in the developing countries¹² with Eastern Asia, Korea, Japan and China being highly endemic areas (Fig-1).¹ Incidence within a region/ country also varies as in China and India (higher in the North-eastern and Southern states). A different pattern of incidence exists in migrant populations compared to the natives living in endemic regions, pointing to environmental influences.

CHINA

Forty two percent of all cases worldwide are in China, partially attributed to its large population.¹³ GC is the second most frequently diagnosed cancer in China and the third leading cause of cancer related death.¹ The incidence is declining both in rural and urban areas but slower than in the Western world.^10,11

There is an increased prevalence among adolescents and young adults in Shanghai, which is postulated to be related to consumption of food rich in salted pork and to H. pylori and genetic polymorphisms.^14,15 In Shandong province, nutritional deficiencies from childhood to adolescence during the famine (1959–1961) might have played a role in the risk for GC. Famine exposure in early life caused gastric mucosal damage leading to intrusion of carcinogens (H. pylori, N-nitrosamines and acetaldehyde) coupled with mutations.¹⁶ The use of refrigerators, improved hygiene and antibiotics are factors in the drastic reduction in chronic H. pylori infection, which is the strongest risk factor.^17-19 A 50% increased risk for GC in those consuming pickled vegetables/foods suggests the existence of causes other than H. pylori.²⁰ Higher intake of cruciferous vegetables was identified as protective against non-cardia GCs.²¹ However, the incidence has been projected to increase in the next 40 years as a consequence of population growth and aging.²²

JAPAN

GC is the second most frequently diagnosed cancer after colorectal cancer and the second leading cause of cancer death (15%) in Japan.^1,13,23 The highest mortality rates were seen among those born towards the end of the nineteenth century and in females, risk being higher than that of USA, UK, France and Korea.²⁴

Environmental factors, including diet, and H. pylori infection are the main risk factors.^25,26 Protective role for green tea, the most commonly consumed beverage worldwide, is controversial.^27,28 The prevalence of H. pylori negative GC in Japan is less than 1%.²⁹ A synergistic effect of high dietary vitamin A intake and H. pylori infection on malignant alterations in the gastric mucosa through oxidative stress is postulated.²⁶ Reduced intake of vitamin A together with H. pylori eradication may be an effective strategy to reduce the risk of GC.^26,29

KOREA

GC has been the most frequently diagnosed cancer in men and ranks fourth in women, after thyroid, breast and colorectal cancer.¹ Incidence increases with age and is rare below 30 years; the crude mortality rate was 28.5 in men and 15.7 in women (per 100,000) in 2012.^1,30,31 The 5-year survival rates have however dramatically increased from 43.0% to 63.8% in men and 42.6% to 61.6% in women since 1995.³⁰

The prevalence of the more aggressive H. pylori negative cancers is 5.4% in South Korea.³² There is an increased prevalence of obesity among patients with gastric cardia cancers.³³ Renal transplant patients had a higher risk for GC and Epstein- Barr virus (EBV) was the principal etiologic agent than H. pylori.³⁴ High prevalence of autoimmune gastritis (40.7%) with intestinal metaplasia (12.5%) was one major histological risk factor. Autoimmune gastritis, the host and environmental factors such as increased consumption of dairy products were identified as risk factors for intestinal metaplasia.³⁵

INDIA

In India, GC is the most fatal cancer in men after lung with a mortality rate of 11.4%.^1,36 The highest incidence rate is in the Northeastern areas. The age attributable risk (AAR) among the Bhutia population in Sikkim (60.4 in men and 29.4 in women per 100000) was the highest among the Population Based Cancer Registries in India in 2010 which was the highest in the world.³⁷ The age-adjusted incidence rate in men was the highest in the Chennai registry in South India (11.1 per 100000) during 2003-2005.^38,39 The state of Jammu and Kashmir has a high incidence of gastrointestinal tract cancers which accounts for about 50% of all cancers.⁴⁰ GC is one of the top five cancers in the valley, with a 3.1:1 male: female ratio.

Although the prevalence of H. pylori is very high, the incidence of GC is low in India and Africa which is a paradox, often referred to as the Indian/ African enigma.^41-43 The protective role of diet (curcumin in turmeric powder), host inflammatory polymorphisms (IL-1), dissimilarity in bacterial strain and the predominant immune response (protective Th 2 vs Th 1) are suggested explanations.^41-43

Although H. pylori infection is the cause of at-least 80% of cases and other factors including diet, lifestyle, especially tobacco use, genetic and socioeconomic conditions, have a considerable role.^7,44 Other suspected etiologies include excessive consumption of pickles, rice, high-temperature foods, smoke-dried salted meat and fish and overuse of baking soda, spices and chilies.^7,45,46 Certain occupations with exposure to high temperature and dusty environments (miners, farmers, cooks, machine operators in timber and rubber industry) increased the risk of GC especially diffuse type of adenocarcinoma.⁷ There is a decreasing trend in the incidence over the past decades which is in concordance with the global scenario.³⁹

EUROPE

GC is the fifth most common cancer in males and seventh in females with a male: female ratio 1.5:1.^1,47 There is a fourfold difference in incidence across countries in the European Union with the highest incidence and mortality rates in Belarus, Albania and Russian Federation.¹ Belarus for males and Albania for females mark the areas of highest incidence.^1,48 Central and Eastern European countries have higher incidence rates when compared to Western or Northern European countries. Sweden was the country with the lowest incidence and the rate in UK was below EU average.⁴⁸

A significant association between alcohol consumption and risk of GC was seen in Lithuania and accounted for about 8% of the total cases. The possible explanation was the presence of contaminants like acetaldehyde, a human carcinogen.⁴⁹ Similar to the trend worldwide, the incidence of gastric non-cardia cancers has decreased attributed to the improvement in socioeconomic conditions and consequent decrease in H. Pylori prevalence in the younger population.^43,50 Furthermore, H. pylori eradication therapy has augmented the decline in incidence and mortality rates.⁵¹

FINLAND

Finland has a higher incidence of GC compared to other Scandinavian countries. It is the sixth common cause of cancer death in men and seventh in women.¹ Increased intake of salt, decreased consumption of fruits and vegetables and alcoholism are notable associations with no association with high coffee consumption.^52-54 The high prevalence of H. pylori infection in the lower socioeconomic strata is a strong association for the increased incidence of distal tumors.⁵⁵ The need for prompt eradication of H. pylori with proper follow-up in patients with precancerous lesions is stressed.⁵⁶ This endogenous infection, heavy drinking and smoking along with ALDh3 deﬁciency posed the greatest risk for GC.^57,58

USA

GC in US ranks fifteenth in incidence and fourteenth in mortality.¹ There is a rising trend in the incidence of reflux related gastric cardia and gastro-esophageal cancers in the past 50 years.^59,60 The incidence of GC among Caucasians is only half of that among Asian Americans, Paciﬁc Islanders, African Americans, and Hispanics.¹² This ethnic disparity could be due to migration from endemic regions.³ The increased incidence in the Hispanic population has been attributed to a high prevalence of H. pylori.⁵⁹ Increasing age, non-white ethnicity, poor education and low-income groups are the factors other than H. pylori causing distal tumors.^61,62 Distal tumors were common in the eastern coast, large urban centers and teaching hospitals.⁶³ The overall incidence of GC is decreasing. The reason for a slight rise among the younger population (25-39 years) is not well understood.³

SOUTH AMERICA

The distribution of GC varies widely in this continent. Higher incidence rates are seen in the Western coast compared to the Caribbean, Amazonia and Eastern coast while mortality rates are the highest in the mountainous regions (along the pacific coast). The incidence in Peru, which has the largest Native American population in the region, is about five times that of the US and twice that of Brazil and accounts for the highest mortality among all cancers.^1,64

Brazil has a very high incidence with an estimated risk of 13 and 6 new cases (per 100,000) in men and women respectively.^1,65,66 The prevalence of highly conducive conditions for H. pylori infection i.e. poor sanitation, overcrowding and dietary factors such as reduced fruit and vegetable intake together with restricted access to refrigeration are the possible factors.^67,68

High altitude regions such as Columbia have a higher GC incidence and mortality, which could be due to clustering of genetic risk factors and H. pylori virulent strains.^69,70 Improper diet practices such as increased intake of processed meat and environmental conditions also contribute to this.⁷¹ In Uruguay, maté drinking (caffeine-rich infused drink) was associated with increased risk of upper aerodigestive tract cancers.⁷²

Although the incidence has been decreasing, there are reports suggesting an approximate 300% rise in proximal tumors as well as diffuse type of adenocarcinoma in some parts of this continent.^73,74 Nevertheless, GC incidence is predicted to rise in the coming years.

CHILE

GC is second most common cancer in men and sixth in women.1 The incidence and mortality rates for GC are one of the highest in the world.^75,76 A higher prevalence of H. pylori virulent strains (with cagA, vacA and babA2 genes) together with poverty, poor sanitation, high alcoholism, smoking and decreased fruits and vegetables consumption contribute to burden despite recent socioeconomic advances.^77,78

IRAN

GC is the most frequent cancer in men while it is third in women and the most common cause of cancer related death.^1,79-82 Incidence over the past decades has risen slowly with a relative increase in proximal tumors.^83-86

The geographical distribution varies between regions with a high prevalence in the northern and north-western parts (along the border of Caspian Sea) compared to the Persian Gulf and the desert areas.⁸⁷ The Persian and Arabs with better socioeconomic conditions occupy the deserts including the Persian gulf which explain the decreased prevalence in these areas.⁸⁰ Consumption of smoked fish in coastal areas, smoking, high salt intake, increased prevalence of H. pylori infection, poor socioeconomic background and genetic predisposition is responsible for the high rates.88,89 Selenium levels were much lower in inhabitants of endemic areas with an inverse association with GC.^87,90 Unlike other parts of the world, endemic regions in Iran have predominance of gastric cardia cancers.^87,91 Overall, the incidence is decreasing.⁹² GIST and Gastric lymphoma will be discussed in another paper in this series.

ETIOLOGICAL FACTORS FOR GASTRIC CANCER
H. pylori

The association of this ancient bacterium with GC came into light only since its discovery in 1982.⁹³ H. pylori have been documented to produce gastritis, peptic ulcer, gastric carcinoma and lymphoma including the MALT type. The infection was found more among people with lower socioeconomic status, poor educational background and higher BMI. H. pylori prevalence is higher among foreign-born Hispanics compared to non-Hispanic whites.⁹⁴

Infection with virulent H. pylori strains (CagA positive) together with a permissive environment in a genetically susceptible host is essential for the occurrence of GC.7 H. pylori breach the gastric barrier and trigger a sequence of events starting from acute gastritis, chronic gastritis, atrophic gastritis, intestinal metaplasia and dysplasia finally leading to carcinoma.¹⁸ But only about 5% of people infected with H. pylori develop cancer highlighting the need for a permissive environment for the organism. H. pylori eradication strategies have resulted in a drastic reduction in prevalence among subsequent generations.⁹⁴

DIETARY FACTORS

Most of the observations about diet and GC are speculative. A high consumption of salted food, red meat and starch based low in protein diet increases the risk for GC while consumption of fruits and vegetables decreases the risk.^3,7,39,95 High salt intake, alcohol men.^7,97 Endogenous production by bacteria/activated consumption and smoking induced mucosal damage macrophages and conversion of dietary nitrates in is proposed as a facilitating factor for H. pylori that the acidic gastric environment are other sources for lead to epithelial cell proliferation, parietal cell loss NOC. Heme-iron content of the meat influences the and progression to premalignancy.^3,7,46,52 Other dietary endogenous formation of NOC in the lower GI tract.⁹⁷ risk factors are given in Table 1.

Scientific explanation for the role of diet is a relationship between N-nitroso compounds (NOC) and GC. NOC can be found in some vegetables (cabbage, cauliflower, carrot, celery, radish, beets, spinach), cereals and beer.96 Preformed NOC is seen in cured meat, dried milk, dried coffee and instant soups. Broiling meat, grilling and baking in open furnaces, sun drying, salting and pickling increase the formation of NOC which increase proximal gastric tumors and esophageal squamous cell carcinoma in men.^7,97 Endogenous production by bacteria/activated macrophages and conversion of dietary nitrates in the acidic gastric environment are other sources for NOC. Heme-iron content of the meat influences the endogenous formation of NOC in the lower GI tract.⁹⁷ Refrigeration was found to decrease the bacterial burden in food thereby decreasing the formation of nitrates. Improved methods of food preservation have dramatically decreased the dietary risk and mortality from GC.^7,59

SMOKING AND ALCOHOL

Smoking is attributed to about 11-29% of GC.^10,105-107 The highest occurrence of cancer is seen among current as well as former smokers in males while only among current smokers in females.¹⁰⁸ A dose-response relationship has not been established so far.¹⁰⁵ But there is a risk reduction after abstinence, which is related to the duration since quitting. The risk is much less in those who quit smoking ?21 years (17% higher than non-smokers) compared to those who quit within the last 10 years (69% more than non-smokers).¹⁰⁸ A greater association of smoking with proximal tumors than distal ones was noted.108 Cigarette smoke, which contains many carcinogens such as N-nitroso-compounds, can directly damage the gastric mucosa and affect gastric prostaglandin synthesis.^7,108,109 It was also found to decrease the efficacy of H. pylori eradication leading to persistence of the bacteria resulting in dysplasia/ metaplasia of the gastric mucosa.¹¹⁰ Studies have shown that smoking reactivates EBV- positive cell lines (Akata and B95-8).¹¹⁰

Alcohol use has a strong association with gastric noncardia cancer.¹¹¹ Unlike smoking, abstinence from drinking has not shown to reduce the risk, which could be due to the chronic histological damage caused by heavy drinking and intestinal metaplasia. Beer consumption had the highest association for cancer in one study, which was explained by the presence of nitrosamines (N-nitrosodimethylamine), a potent animal carcinogen.¹¹² Acetaldehyde, the metabolite of alcohol metabolism is a carcinogen.¹¹² H. pylori strains possessing aldehyde dehydrogenase activity produce acetaldehyde from ethanol under micro-aerobic conditions.¹¹³ Alcohol also induces cytochrome P4502E1 that could play an important role in carcinogenesis by formation of reactive oxygen species.¹¹²

OBESITY

Obesity is emerging as a risk factor for GC, in particular proximal gastric lesions.^94,114 The increased incidence of gastro-esophageal reflux could be a possible cause. Adiponectin, leptin, insulin resistance, insulin-like growth factors and obesity-related inflammatory markers are also incriminated in the etiology of cancer.¹¹⁴

ETHNICITY

The incidence of GC tends to vary among ethnicities. In US, the incidence among Caucasians is about half when compared to the rest (Hispanics, African Americans and Asian Pacific islanders).^3,7,115 A higher incidence of GC among blacks of Caribbean descent compared to other races was recently reported from UK.^116,117 Despite these strong ethnic factors, environmental factors play a major role in gastric carcinogenesis. Japanese settled in the US have a much lower incidence compared to native Japanese and an inverse trend among African-Americans compared to the native African population provide evidence for this.^3,7

Foreign-born Hispanics (>60%) had a higher incidence of GC than those born in the US.¹¹⁵ The intestinal type of adenocarcinoma decreased among foreign-born Hispanics with an increase in the incidence of diffuse-type.¹¹⁵ Hispanics were younger (P <.01) and had greater proportion of distal tumors compared to whites at the time of diagnosis.^94,118 Hispanics and African- Americans often presented with advanced disease compared to Asia/Pacific Islanders (P < .01).^59,118 Asian race, female sex, distal tumors and care at a teaching hospital had favorable outcomes.¹¹⁸ The overall median survival was over 1 year among patients with Asian descent while all other ethnicities had less than a year.¹¹⁸

GENETICS

Multiple genetic and epigenetic alterations are involved in the gastric carcinogenesis. Microsatellite instability (MSI), chromosomal instability (CIN), activation/ suppression of oncogenes and tumor suppressor genes as well as cell cycle regulators are implicated in the etiology.⁷

MSI, a genomic defect that represents defects in DNA replication (hMLH 1 – mismatch repair gene) accounts for about 13-44% of GCs, which are of intestinal type, distally located with better prognostic factors.¹¹⁹ MSI is also implicated in intestinal metaplasia, a premalignant condition.¹²⁰ A decreased tendency for invasion and nodal metastasis is seen in MSI due to mutations in TGF-β, IGFⅡ and BAX genes.^7,119 CIN plays a major role in sporadic GCs. Several factors from N-nitroso compounds, smoking and H. pylori to DNA repair mechanisms and defects in cell cycle regulation contribute towards CIN. Erb-B2 oncogene activation has a role in intestinal-type of gastric adenocarcinoma while c-met (proto-oncogene that codes HGFR) and FGFR2 gene amplification (via Erb-B3/PI3 over-expression) plays a role in diffuse type of cancer.^7,121 Inactivation of p53 gene has been found in about 60% of the cancers while APC gene mutations are seen only in a small proportion of early cancers. K ras gene mutations are rare and seen only in stage 4 diseases.¹²¹ E-cadherin a product of CDH1 gene is found to be associated with advanced disease and has poor prognosis.^7,121 Similarly Cell cycle regulator (Cyclin E and CDK) abnormalities coupled with alterations in tumor suppressor gene expression also have poor prognosis.^7,122 There is evidence from literature that genes linked to inflammatory mediators (interleukin, toll-like receptor 4, human leukocyte antigen, metabolic phase I enzyme etc.) are also involved in carcinogenesis.³⁹

PERNICIOUS ANEMIA AND EBV

GC is a rare complication of Pernicious Anemia (PA).¹²³ Multifocal atrophic gastritis not confined to the body of stomach has a higher risk.¹²³ Intestinal type of adenocarcinoma and distal tumors are common, with the risk proportional to the duration of the disease.¹²⁴ The increased pH that allows chronic H. pylori infection could be a possible cause.¹²⁵ In Common Variable Immune Deficiency, seen in 10% of patients with PA, the normal mucosal defense mechanisms are weak to contain H. pylori infection aggravating the risk for GC.¹²⁶

EBV could be a possible etiology for GC in PA attributable to about 9% of cases.^3,127,128 The lack of acidic environment coupled with damaged gastric mucosa (due to chronic inflammation) favour EBV colonozation. EBV is known to involve in the earlier stages of mucosal transformation based on the presence of monoclonal viral episomes in EBV positive tumor cells.¹¹⁰ An increased risk for EBV induced GC is seen in smokers (RR=2.4).¹¹⁰ EBV positive tumors tend to occur in the gastric cardia and more frequently in post-surgical patients.¹¹⁰

CONCLUSION

(See the Key Points Table)
The overall incidence of GC is decreasing but the incidence of gastric cardia cancer is increasing with a noted association with obesity. The screening strategies adopted by countries like Japan and Korea helped to bring down the burden of this disease to a great extent and reduce the mortality. H. pylori prevalence in developing countries need to be tackled with adequate eradication measures coupled with early screening together with healthy dietary practices.

A Case Report

Drainage of a Symptomatic Pancreatic Pseudocyst via a Fully Covered Self Expanding Metal Stent (FCSEMS)

Douglas G. Adler

INTRODUCTION

Symptomatic pancreatic pseudocysts often require treatment with options including endoscopic drainage, surgical drainage, or catheter drainage via interventional radiologists. No approach is universally accepted as ideal for all patients. This case describes the drainage of a symptomatic pancreatic pseudocyst via endoscopy using a fully covered self-expanding metal stent (FCSEMS).

Case Report

An 81 year-old man underwent a laparoscopic left hemicolectomy for a history of recurrent diverticulitis and diverticular bleeding. During the surgery, the pancreas was accidentally traumatized by a surgical trocar. Following the operation, the patient developed acute pancreatitis and a large pseudocyst in the body of the gland. The cyst caused signiﬁcant extrinsic compression on the stomach with resulting gastric outlet obstruction. The patient was only able to be fed via a nasojejunal tube (Figure 1). Following eight weeks of tube feeding, a computed tomography (CT) scan showed no interval improvement in the overall size of the cyst and the patient was referred for endoscopic drainage.

The cyst was identiﬁed by endoscopic ultrasound (EUS) and a 19 gauge ﬁne-needle aspiration (FNA) needle was used to access the cyst (Figure 2). A 0.035” biliary guidewire was passed through the lumen of the needle and looped in the cyst. The cystgastrostomy site was dilated with an 8 mm biliary dilating balloon (Figure 3); the location was veriﬁed by the ﬂow of cystic ﬂuid into the stomach. A 10 mm x 80 mm fully covered Viabil stent (WL Gore and Associates, Flagstaff, AZ) was then advanced over the guidewire through the EUS scope and deployed across the cystgastrostomy. One half of the stent was deployed in the pseudocyst, and the other half was deployed in the stomach. At this point copious cyst contents drained into the stomach. Guidewire access to the cyst was then obtained again using a duodenoscope to pass the guidewire through the metal stent and into the cyst. A 7 Fr double pigtail stent was then deployed across the cystgastrostomy, through the metal stent, to serve as an anchor and to reduce the risk of metal stent migration (Figure 4). The patient tolerated the procedure well.

Repeat CT scan obtained four weeks later demonstrated complete resolution of the pseudocyst, with the metal stent/plastic stent complex still in good position (Figure 5). The patient underwent upper endoscopy soon thereafter conﬁrming correct positioning of the stents within a well healed cystgastrostomy site (Figure 6). The plastic stent/metal stent complex was removed in a single pull via rat tooth forceps (Figure 7). The patient has experienced resolution of his gastric outlet obstruction and has no evidence of recurrence of his pseudocyst.

Discussion

Endoscopic drainage of symptomatic pancreatic pseudocysts is widely performed. Cystgastrostomy can be created via endoscopic retrograde cholangiopancreatography (ERCP), EUS, or a combined approach. To date, no ideal approach for all lesions has been identified.,^{1, 2, 3} Most endoscopists who perform these procedures place two or more double pigtail plastic stents across the cystgastrostomy. Plastic stents are inexpensive, and allow the pseudocyst contents to drain both through and between the stents.

The idea of using a metal stent to drain a symptomatic pancreatic pseudocyst is a relatively new concept. Previously, uncovered stents were rarely used for this purpose as there was a fear that such an uncovered device could imbed itself across the cystgastrostomy and might be difﬁcult to remove. The advent of covered biliary metal stents allowed new consideration of using these devices in this context. Metal stents have the advantage of providing a greater diameter through which cyst contents (both solid and liquid) can drain and they offer the beneﬁt of being removable. However, metal stent usage may be limited due to their increased cost.

In a series of ten patients treated with EUS-guided pseudocyst drainage via metal stents, Berzosa et al reported success in nine patients.⁴ Weilert et al used FCSEMS in 18 patients with pancreatic ﬂuid collections, although they were only left in place for 7-10 days, after which they were removed and replaced with double pigtail stents. Patients in this study had inderterminate adherence of the cyst to the gut lumen and one patient did experience dehiscence of the cystgastrostomy. Overall success in this series was 78% cyst resolution.⁵

The notion of using a covered metal stent to drain a pseudocyst has been extended by some to include walled off pancreatic necrosis. The size of a metal biliary stent may allow an endoscope to pass into the cyst to facilitate endoscopic necrosectomy. Early reports and series using these types of devices are available and are very encouraging.^6,7

Recently, dedicated metal stents designed to facilitate endoscopic drainage of pancreatic ﬂuid collections have become available and the limited data available for these devices is encouraging. These stents have a dumbbell shape to provide ﬂared ends on each side of the cystgastrostomy thus reducing the risk of migration and promoting ﬁxation between the ﬂuid collection and the gut lumen.8,9 Itoi et al reported on the use of one of these lumen apposing metal stents to drain 15 patients with symptomatic pancreatic pseudocysts via an EUS-guided approach. In this study, all stents were successfully deployed with a median dwell time of 35 days. One of the metal stents migrated into the stomach, but the others remained in situ across the cystgastrostomy site. All patients had resolution of their pseudocysts.10

It is difficult to state at this time that metal stents are superior to plastic stents for the drainage of pancreatic pseudocysts and other pancreatic fluid collections.¹¹ Both approaches offer advantages and disadvantages. Migration of a metal stent into a pseudocyst or out into the gut lumen remains a significant risk, and in the case presented above a single double pigtail stent was placed through the metal stent to minimize this risk, although the metal stent used did have antimigration struts built into its matrix. Metal stents can be placed quickly and provide a larger overall lumen for cyst contents to drain, but come at increased cost overall. Removal of both metal and plastic stents appears to be equally easy and straightforward.

The data on using plastic stents to drain pancreatic pseudocysts is far more robust and features large studies to support their use in this context. The data for metal stents in this role is still developing, and it seems likely that larger studies of metal stents in this context will be forthcoming. A randomized trial comparing the two seems would be helpful, and a study comparing plastic stents, biliary metal stents, and specifically designed dumbbell shaped metal stents would be ideal.

Conclusion

The use of fully covered metal stents to drain symptomatic pancreatic pseudocysts is becoming more common, and this trend will likely continue to accelerate in clinical practice. FCSEMS appear to be safe and effective in this context, but formal comparisons with plastic stents would be beneficial. Lumen apposing stents are beginning to become more widely available, and it seems likely that these will play a role in any future studies of metal stents in this context.

Frontiers in Endoscopy, Series #10

Evaluation and Management of Pancreatic Pseudocysts

Matthew E. Feurer,

Douglas G. Adler

The management of pancreatic pseudocysts is complex and can range from simple observation to aggressive endoscopic and surgical interventions to treat symptomatic lesions. This manuscript will review the current evaluation and treatment of pancreatic pseudocysts.

INTRODUCTION

Case Report

Discussion

Endoscopic drainage of symptomatic pancreatic pseudocysts is widely performed. Cystgastrostomy can be created via endoscopic retrograde cholangiopancreatography (ERCP), EUS, or a combined approach. To date, no ideal approach for all lesions has been identiﬁed.1, 2, 3 Most endoscopists who perform these procedures place two or more double pigtail plastic stents across the cystgastrostomy. Plastic stents are inexpensive, and allow the pseudocyst contents to drain both through and between the stents.

In a series of ten patients treated with EUS-guided pseudocyst drainage via metal stents, Berzosa et al reported success in nine patients.4 Weilert et al used FCSEMS in 18 patients with pancreatic ﬂuid collections, although they were only left in place for 7-10 days, after which they were removed and replaced with double pigtail stents. Patients in this study had inderterminate adherence of the cyst to the gut lumen and one patient did experience dehiscence of the cystgastrostomy. Overall success in this series was 78% cyst resolution.5

It is difficult to state at this time that metal stents are superior to plastic stents for the drainage of pancreatic pseudocysts and other pancreatic fluid collections.11 Both approaches offer advantages and disadvantages. Migration of a metal stent into a pseudocyst or out into the gut lumen remains a significant risk, and in the case presented above a single double pigtail stent was placed through the metal stent to minimize this risk, although the metal stent used did have antimigration struts built into its matrix. Metal stents can be placed quickly and provide a larger overall lumen for cyst contents to drain, but come at increased cost overall. Removal of both metal and plastic stents appears to be equally easy and straightforward.

Conclusion

Fellows’ Corner

Giant Paraumbilical Veins/Caput Medusae

Amulya Belagavi,Lisa Meringer

Case Presentation

A 48-year-old woman who was initially diagnosed with Hepatitis C, subsequently developed compensated cirrhosis of liver and portal hypertension with a complication of hepatocellular carcinoma. She presented to the hospital with lower abdominal pain. On examination, vitals were stable. She was noted to have massive splenomegaly, without hepatomegaly, hepatic bruit, ascites or pedal edema. In the periumbilical region were distended superficial veins similar in appearance to caput medusae, but without any bruit around the umbilicus. The CT of the abdomen is as shown in Images 1 and 2.

What is the abnormality seen?
What are the implications of the abnormality and treatment options?
What is the diagnosis if there was an additional finding of a bruit around the umbilical area?

DISCUSSION

Caput medusae are a network of dilated veins around the umbilicus and are one of the manifestations of portal hypertension from cirrhosis of the liver. The term is Latin for Head of Medusa and originates from its similarity to Medusa’s hair.

Caput medusae may be left alone. Embolization or transjugular intrahepatic portosystemic shunt may be used to decompress the collateral route in cases of hemorrhage. Knowledge of the other collaterals is essential since they may undergo spontaneous hemorrhage or bleeding from disruption of these vessels during surgical procedures.¹ They also had lesser episodes of bleeding from esophageal varices. At times this could be mistaken for paraumbilical hernia.

Cruveilhier-Baumgarten (CB) syndrome, described by Cruveilhier (1835) and Baumgarten (1908), refers to a murmur over the umbilicus often in the presence of caput medusae, resulting from portal hypertension, usually with hepatic cirrhosis. Recanalization of the umbilical vein with reverse blood flow from the liver into the abdominal wall veins creates the murmur.²

Embryologically, the left umbilical vein undergoes gradual atrophy to form the ligamentum teres in the falciform ligament. A small portion of the umbilical vein at its junction with the left portal vein may remain patent throughout life. CB syndrome represents spontaneous portosystemic collateralization between the paraumbilical vein and the veins of the anterior abdominal wall in a patient with portal hypertension.

A Case Report

Hepatic Abscesses Caused by a Rare Fistulous Tract

Neha Sahni,Dhiraj Gulati,Kamran Heydarpour

Introduction

We present a case of a fistula, between the portal vein and the left hepatic duct, discovered during an endoscopic retrograde cholangiopancreatography (ERCP). Fistulas between the portal vein and biliary tract are rare and occur in less than 1 % of patients with biliary tract disease.¹ Current literature reports that portobiliary fistulas may occur spontaneously, after biliary stent placement, following biliary surgery, after trauma, post trasjugular intrahepatic portosystemic shunt (TIPS) placement and also following liver biopsies;^{1 ,2,3,7,8} the case we present was likely a complication of cholangitis. A literature review accompanies this case.

CASE REPORT

A 79 year-old African American female with a history of cebrovascular accident, hypertension, congestive heart failure and hyperlipidemia presented to the hospital after having been found at home on the floor with altered mental status. Upon initial evaluation, she complained of vague chest pain and right upper quadrant abdominal pain. On physical examination, her temperature was 100.9 degrees; her blood pressure, heart and respiratory rates were normal. The remainder of the physical examination was unremarkable.

Initial blood tests were as follows: aspartate aminotransferase, 267 IU/L (<33 IU/L), alanine aminotransferase, 105 IU/L (<32 IU/L), total bilirubin of 2.1 mg/dl (0.0-1.5 mg/dl), direct bilirubin 1.3 mg/ dl (0.0-0.3 mg/dl), alkaline phosphatase 397 IU/L (35105 IU/L), international normalized ratio (INR) of 2.0, and a prothrombin time of 17.2 sec (10.6-13.4 sec). The complete blood count revealed a white cell count of 15.3 (4.8-10.8 k/mm cu) and a hemoglobin of 9.3 (12-16 g/dl). A CT of the abdomen revealed multiple hypodense nodules throughout the liver (Figure 1) with a dilated common bile duct. An ERCP was performed for suspicion of acute cholangitis. The common bile duct was injected and a ﬁlling defect in the gallbladder was noted to be consistent with a large gallstone. As the biliary tree branches were completely ﬁlled (Figure 2), there was a ﬂuid accumulation at the proximal portions of the biliary tree suggesting abscesses. These ﬂuid collections were draining through a ductal structure completely different from that of the biliary tree. Thus, a fistula between the biliary tree and the ductal structures was exposed. Further evaluation revealed that the ductal structure was, in fact, the portal vein. A 7-French 10-cm stent was placed to assure adequate drainage of the bile duct (Figure 3). A CT guided biopsy of the liver lesions demonstrated acute cholangitis with microabscesses. The patient was successfully treated with intravenous antibiotics. The follow-up ERCP performed two months later revealed complete resolution of the fistula.

DISCUSSION

This case is a good demonstration of a rare ﬁstula in the gastrointestinal (GI) tract. Portobiliary ﬁstulas can occur spontaneously, following biliary stent placement, biliary surgery, trauma, post TIPS placement, as a result of liver biopsy ^1,2,3,7,8,10 and, in our case, as an unusual complication of ascending cholangitis. Repeated inﬂammation, with development of scar tissue between adjacent organs, can cause the formation of ﬁstulas.^1,5 In this patient, it was the upsurge of pressure in the hepatic duct from prolonged cholangitis that led to an outpocketing and an eventual ﬁstulous tract between the hepatic duct and portal vein, which lie in close proximity. Per previous case reports, portobiliary ﬁstulas may present with right upper quadrant pain, hemobilia and bleeding per rectum resulting in anemia.^1,4,6,9 The pathophysiology of rectal bleeding is that leakage of blood from the portal vein into the hepatic duct, common bile duct and then to the GI tract occurs. The lack of bleeding in the patient presented above can be explained by Figures 4 and 5. Magnetic resonance imaging (MRI) revealed a thrombus in the portal vein, proximal to the fistula, blocking the vein from bleeding into the GI tract. It was also suspected that the thrombus contributed to the fistula formation by eroding the portal vein wall.

Given the elevated liver enzymes, INR and bilirubin and the hepatic nodules seen on the abdominal CT, cancer was highly suspected. Liver biopsy confirmed cholangitis and ruled out malignancy. Blood cultures were positive for Staphylococcus simulans and Enterococcus species, most likely starting in the biliary ducts spreading through the fistula into the portal vein to the liver creating abscesses.

Ultimately, a stent was placed to maintain drainage of the duct as well as relieve the high pressures in the duct due to the cholangitis. It was the relief of this pressure that allowed for the natural closure of the fistula, as proven by the repeat ERCP done two months later. Treatment may also have included surgical resection of the fistula had it not resolved.

Unusual Causes of Abdominal Pain, #2

Unusual Causes of Abdominal Pain

George W. Meyer

CASE

A 12 year old girl presents with a several month history of daily episodes of abdominal pain with some diarrhea (loose bowel movements). Her bowel movements were 3-4 per day without nocturnal defecation. She had no weight loss and her growth and Tanner development were normal compared to an older sister. She has complained of daily headaches without aura since age 8. She also gave a history of motion sickness, especially in automobiles. On physical examination her vital signs were normal and there were no abnormalities in the physical examination. A therapeutic trial was initiated.

Answer and Discussion

This young person had abdominal migraine. She responded to Inderal 10 mg by mouth thrice daily. Not only did her abdominal pains find relief but she no longer complained of headaches. Ninety percent of recurrent abdominal pain in pediatrics is functional, the farther from the umbilicus, the greater the chance for significant disease. The differential diagnosis includes cyclic vomiting, tachygastria, and, perhaps, abdominal epilepsy. Abdominal migraine is said to affect 2-4 % of children, 60 % are female, with the age of onset between 2 and 10 years. The pain is associated with other complaints, such as anorexia, nausea, vomiting, and pallor. Sixty percent of children are said to have a family history of migraines. Most children outgrow their abdominal pains but they may develop or continue to have migraine headaches. Propanolol and cyproheptadine have been described as beneficial in preventing these episodes. During the acute episode some find that acetaminophen or ibuprofen may be helpful; anti-nausea medications such as triptans are best administered rectally; intravenous valproic acid has been reported to be successful in the Emergency Department.

Inflammatory Bowel Disease: A Practical Approach, Series #88

Hepatobiliary Disease and Inflammatory Bowel Disease

Emily Schonfeld,

James S. Park,

Seymour Katz