Page 77 – Practical Gastro

Peter S. Francisco,Stephen M. J. Hoffman

Introduction

Hepatitis E (HEV) is a single stranded, non-enveloped RNA virus that can infect both humans and animals through fecal-oral contamination. Once infected, the incubation period can range from 2 to 8 weeks. Symptoms include myalgias, arthalgias, weakness, vomiting, jaundice, pruritus, clay-colored stools and dark urine. These symptoms can accompany elevation of liver enzymes such as transaminases, bilirubin, alkaline phosphatase and gammaglutamyltransferase. Patients infected with hepatitis E can potentially progress to fulminant hepatic failure.¹ Recently, in the United States, cases of suspected drug-induced hepatitis were ultimately deemed secondary to a hepatitis E infection.⁶ We present the case of a patient with suspected drug-induced hepatitis determined to have acute hepatitis E infection.

CASE

A 47-year-old Middle Eastern male, without significant medical history, was sent by his primary care physician (PCP) to the emergency department for evaluation. The visit with his PCP was initiated due to upper respiratory symptoms, including sinus congestion, rhinorrhea, postnasal drip and cough. He was started on medications for suspected infection, including azithromycin.

The patient subsequently had fevers and nausea with episodes of bilious emesis. Trimethoprim/ sulfamethoxazole was substituted for the azithromycin but he continued to get worse. He admitted to anorexia with approximately 10-15 pounds of unintended weight loss. He also experienced dark urine, clay-colored stools and abdominal bloating with fevers.

There was no history of exposure to herbal products, over the counter medications (including acetaminophen) or excessive vitamin use. During his trip to Bangladesh two months ago, he described a one-week history of an acute diarrheal illness.

On physical exam, scleral icterus was noted. His liver size was 12cm in the right mid-axillary line to percussion and he did not have asterixis on exam.

Laboratory tests and imaging studies revealed an aspartate aminotransferase (AST) of 1,172; alanine aminotransferase (ALT) of 2,203; alkaline phosphatase (ALP) of 239; total bilirubin of 10.4; direct bilirubin of 7.4; prothrombin time (PT) of 13.6; international normalized ratio (INR) of 1.11 on admission. His acetaminophen level was undetectable. His hepatitis profile showed prior exposure to hepatitis A but no exposure to hepatitis B or C. Hepatitis E serology was still pending upon discharge. Abdominal ultrasound showed a heterogenous pattern of the liver consistent with hepatocellular disease. There was normal flow within the hepatoportal veins on Doppler views.

The patient did well clinically through the rest of his hospital course. The etiology was presumed to be antibiotic-induced hepatotoxicity at the time of discharge. However, after discharge, his hepatitis E serology came back positive for acute hepatitis.

DISCUSSION

Although hepatitis E is found worldwide, the continents of Africa, Central America and Asia have the highest prevalence.¹ The incidence of HEV in rural

Bangladesh fluctuates with the highest occurrence

during the monsoon season because of extensive water contamination.^2,3 The virus has even been known to cause severe acute hepatitis leading to fulminant liver failure.^4,5 High morbidity and mortality has resulted in pregnant woman with HEV and decompensation of patients with underlying cirrhosis.^4,5

Treatment for acute Hepatitis E is mainly supportive since the virus is cleared spontaneously in immunocompetent patients.¹ Hepatitis E is being identified more in developed countries, such as the United States, which should alert doctors to consider the virus as a potential etiology of abnormal liver enzymes in patients with significant hepatic injury.

Unusual Causes of Abdominal Pain, #4

Unusual Causes of Abdominal Pain

Kristen Pontiff,Brannon Alberty

CASE

A 4 year old female was referred to the pediatric gastroenterology clinic with intermittent postprandial nausea and abdominal pain with varying location. The episodes, each lasting 3-5 days, have occurred several times over the past couple of years and have gradually worsened over the past few months. The parents deny that she vomits old food. Chart review reveals a waxing and waning presence of splenomegaly on abdominal exam. Prior workup by her pediatrician included a normal complete blood count (CBC) and rapid streptococcus test. Epstein-Barr virus (EBV) titers demonstrated prior infection, but were not consistent with current infection. Splenic ultrasound demonstrated an 11.2 cm spleen (normal < 9 cm) with no other focal abnormality noted. On presentation, physical examination revealed a soft, non-tender, non-distended abdomen with bowel sounds appreciated in all four quadrants. Her spleen was located in left lower quadrant. She was then sent for a computed tomography (CT) scan of the abdomen and pelvis with contrast.

ANSWER AND DISCUSSION

Wandering spleen is the displacement of the spleen from its usual position in the left upper quadrant secondary to elongation of the pedicle. The etiology is usually congenital absence or malformation of gastrosplenic or splenorenal ligaments. In adults, wandering spleen is seen in women of childbearing age secondary to hormonal changes and resulting lax abdominal musculature. Wandering spleen in children is rare and can be associated with torsion or infarct on presentation. This demonstrates the importance of high suspicion as well as the necessity of swift action. More common presentations can include nonspeciﬁc lower abdominal pain associated with back pain, nausea, vomiting and flatulence. Diagnosis can be made via ultrasound with Doppler or contrast enhanced CT. Our patient’s CT scan demonstrated ectopic positioning of a normal sized spleen in the left ﬂank, with soft tissue opacity in the left upper abdomen. A central area of increased density within the left upper abdomen was presumably related to rotation of the splenic pedicle. A possible calcified phlebolith within the splenic vein was also noted. We diagnosed the patient with wandering spleen and referred her for surgical evaluation. Splenopexy is ideal if no hemorrhage, phlebolith or other compromise to blood supply is demonstrated. Splenectomy is undertaken if the patient demonstrates infarction, potential for infarction with acute torsion or signs of frank necrosis. Splenectomy was performed secondary to a mass noted intraoperatively. Pathology later revealed benign pancreatic tissue with focal infarct. Our patient has been well to date with no further recurrence of abdominal pain since her procedure. Management of the asplenic patient includes vaccination for pneumococcus, hemophilus influenzae type B (if not already immunized fully), meningococcal group C and yearly influenza vaccine.

Antibiotic prophylaxis is given to asplenic pediatric patients to prevent sepsis and additionally instructed to seek immediate medical attention if fever develops. She was also advised to avoid contact with dogs secondary to increase in risk of canine associated bacteremias causing sepsis in asplenic patients.

Endoscopy: Opening New Eyes, Series #8

Trace Element Supplementation and Monitoring in the Adult Patient on Parenteral Nutrition

Cassandra Pogatschnik

Often overlooked by medical providers, trace elements are essential nutrients for the long-term parenteral nutrition (PN) patient. They play a significant role in human metabolism and can lead to serious complications when deficient or in excess. Individual trace element regimens are determined by patient presentation, organ dysfunction, inflammation, and patient history. In this article we emphasize awareness of the complexity of trace elements and the understanding that careful monitoring of trace element status can improve patient success on PN.

Introduction

As an integral and often life sustaining therapy, parenteral nutrition (PN) enables absorption of nutritive constituents while bypassing the gastrointestinal (GI) tract. Macronutrients sustain an individual calorically; electrolytes allow for proper electrical charge and cellular space fluid distribution; and micronutrients allow for efficient human metabolism. Often overlooked by clinicians, trace elements regulate metabolism as enzymatic cofactors that transport substrates across cell membranes.^1,2 In the United States five of nine essential trace elements are supplemented in PN. Routine addition and adjustment of chromium, copper, manganese, selenium and zinc are based upon laboratory levels, where appropriate, as well as physical and clinical symptoms of deficiency and toxicity. Specific populations, including the severely malnourished, patients with high enteral losses and those on long term home PN, require trace element monitoring.

Trace Element History

Since PN’s birth in the 1960s and its introduction to the home setting in the early 1970s, trace elements’ importance was recognized. In 1977 an expert nutrition panel from the Nutritional Advisory Group of the American Medical Association (NAG-AMA) devised the first trace element guidelines which were submitted to the Food and Drug Administration (FDA) in 1978 and were subsequently published in the Journal of American Medicine in 1979.^3,4 (See Table 1) At that time it was encouraged that single formulations of individualized trace elements be available for easier adjustment and removal as necessary.4,5 Selenium was established as essential in 1979 when supplementation eradicated Keshan Disease (a congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackie virus characterized by heart failure and pulmonary edema). This prompted selenium’s inclusion, and supported copper dosage reduction (based on copper balance studies in long-term PN patients) in the 1982 trace element review.4 Despite numerous expert panel reviews, studies, and proposals, the FDA has not yet approved a new multi-trace element formulation, a delay that may prove hazardous in some patients.³ One recent investigation performed autopsies on 8 PN dependent patients for an average duration of 14 years who had received the NAG-AMA trace element formulation. The autopsies revealed excessive tissue concentrations of chromium, copper, and manganese, which supported the need for change in multi-trace formulations today.⁶

Monitoring Trace Elements

With optimal doses under debate, PN drug shortages, a growing long-term PN population, variability of patients’ conditional requirements, and questionable laboratory testing, the task of monitoring home PN patient’s micronutrient status is difficult. Trace element lab samples are difficult to collect, handle, and are extremely susceptible to contamination, making them an infrequent and expensive physician order.² When obtained, trace element results must be interpreted with caution as some are affected by inflammatory states.² If the clinician is uncertain, but suspects an inflammatory or infectious process (such as active Crohn’s, etc.) may be present, while there are no data to support this practice, checking a C-reactive protein might be considered (See Table 2). Measurements of serum and plasma levels have demonstrated to be less indicative of body stores or nutrient adequacy in those receiving PN.6 Decreased laboratory levels may actually reflect redistribution versus true deficiency.⁷

Though whole blood and serum markers have shown unimpressive correlation to tissue levels,² they allow clinical establishment of patient baseline and trends. Suggestion for monitoring varies per clinician and home nutrition support program, however, it is suggested that trace elements be repeated at least annually. Upon trace element shortage (particularly when an individual supplement is omitted) or patient history of deficiency or toxicity, studies may be repeated every three months until levels and/or clinical symptoms improve. They may be repeated more frequently based upon clinical judgment. It is essential that clinicians confirm laboratory findings with both clinical and physical characteristics of deficiency and toxicity (See Table 3).

Chromium

Chromium is a transitional metal that is biologically active in the trivalent phase.² Considered an essential trace element due to its regulatory properties and decline with age, chromium gets incorporated into a chromodulin or “glucose tolerance factor,” promoting insulin action in peripheral tissue and reducing insulin requirements.^2,8 Transported by transferrin and albumin, it competes with iron for binding sites on transferrin.^2,8 Hemochromatosis is thought to be associated with both chromium deficiency and glucose intolerance.⁸ Deficiency symptoms include hyperglycemia, hyperlipidemia,⁸ neuropathy,⁹ and in rare cases encephalopathy.¹⁰ It is important to note, that additional chromium supplementation will not improve hyperglycemia if it is already being adequately supplemented.² No toxicities have been reported in adults;^3,9 however expert concerns arise from accumulation of high levels of chromium in the sera and tissue overtime. It has been proposed that efficient chromium dosing may be provided from alternate ingredient contamination, such as 70% dextrose solutions used for compounding PN formulations.³ Current recommended dosage of 10-15 mcg/day may be overestimated and new recommendations may be as low as 0.14-0.87 mcg/day.3 Removal from formulations may be preferred in patients with renal insufficiency as it is excreted most readily through urine.^2,3,7,8 No satisfactory test has been discovered for measurement of chromium; however, with improved analytical measurements and quality controls, serum chromium can be measured more accurately. The best way to capture deficiency may be to monitor glucose response to chromium.¹¹

Copper

Copper allows for erythrocyte synthesis, absorption and use of iron, phospholipid formation, and improves connective tissue integrity.^2,12 Transcuprein and albumin transport copper to the liver where it is incorporated into ceruoplasmin, which transports copper to peripheral tissues. Sixty to ninety-five percent of circulating copper is present in this form. Copper is not present in the blood due to poor solubility and must be drawn as a serum lab draw. Revealed during significant deficiency, and in patients with compromised GI tract with high enteric losses,¹³ symptoms include, leukopenia, hypochromic and normocytic anemia with depressed reticulocyte count.^2,10 If left untreated, patients may present with gait difficulty, resembling Vitamin B12 deficiency,^4,13 connective tissue disorders, blood vessel defects, osteoporosis, and cardiac disease.¹² Menkes Disease is defined as copper accumulation in the intestinal mucosa, which inhibits transportation of copper to the liver and tissue resulting in true deficiency, and in rare cases, causing degenerative brain disorders, severe mental retardation and in few instances, death.¹⁰ One case report revealed severe copper deficiency after a three-month intravenous multi-trace holiday due to intravenous product shortage.¹³ The multi-trace contained 0.5 mg copper/day, of which the patient received 5 days/week. Upon removal, the patient was supplemented with an oral multivitamin/mineral supplement containing 15 mg copper/day; of which she only took 1-2 doses/week due to GI intolerance. She presented with fatigue, lower extremity edema, WBC 3.1K, hemoglobin 6.5 g/dL and hematocrit of 21.3%. The patient was subsequently admitted and underwent a neurological exam and GI work-up, both of which were negative. Further labs concluded copper deficiency (Cu <3 mcg/dL, ceruloplasmin <3 mg/dL, and normal Zn of 61 mcg/dL). The patient was started on 6 mg oral copper for 1 week, 4 mg oral copper for 2 weeks, and then dosage was decreased to 2 mg/day. Two months later intravenous multi-trace was again available and was added back to the PN. Within two months all laboratory studies had normalized. Copper deficiency can manifest as early as eight to ten weeks upon withholding supplementation and with adequate repletion, can reverse hematological changes in one to two weeks.13 A case report by Spiegel et al. also demonstrated copper deficiency (confirmed by both lab and bone marrow biopsy) and pancytopenia eight weeks after intravenous copper removal.¹⁴ Repletion with copper sulfate improved the patient’s hematological and copper studies; however, the patient expired from cardiac tamponade. Interestingly no reports of human myocardial deaths caused by copper deficiency have been reported, however copper deficient rats have developed fatal cardiac diseases (ruptured arterial aneurysms and hemorrhagic pericardial tamponade) thought to be attributed to copper’s effect on elastin and collagen synthesis.¹⁴ As a trace element that is almost exclusively excreted through the bile, cholestasis can lead to copper toxicity, and toxicity can cause hepatocellular damage, accumulation and cirrhosis.^2,10 Blaszyk et al. studied long-term PN patients’ hepatic tissue copper levels and compared them to patients with alternative drug induced cholestasis. Results concluded that PN patients who had significant cholestasis accumulated high levels of hepatic copper and found that PN therapy duration alone was independent of copper toxicity.¹⁵ Renal failure and neurological disorders have also been associated with copper toxicity.² Current recommended dose is 0.5-1.5 mg/day,12 with 1 mg/day being provided in multi-trace formulations.³ The American Society for Enteral and Parenteral Nutrition (ASPEN) most recently proposed a dosage decrease to 0.3-0.5 mg/ day.³ It is suspected that requirements may increase by 0.4-0.5 mg/day in persistent malabsorptive states^12,13 and that a decrease in dosage to 0.15 mg/d or removal altogether may be required in cholestasis.¹⁶ Of note, it is necessary to monitor patients with such minute dosages as they have demonstrated pancytopenia at six weeks.⁹ Elevated bilirubin of 10.9 mg/dL and liver biopsy revealing mild steatosis, early fibrosis, and cholestasis prompted intravenous copper removal in another case report by Fuhrman et al.¹⁷ Fifteen months after removal, the patient required monthly red cell transfusions accompanied by WBC and platelet decline. Nineteen months after the copper holiday, bone marrow biopsy proved suspicion for copper deficiency etiology. Dosage of 1mg/day was again supplemented, copper levels rose and neutropenia and thrombocytopenia dramatically improved, resulting in a break from transfusions. Subsequently serum copper became elevated and was again removed. Three months later patient developed severe copper deficiency correlating again with neutropenia, thrombocytopenia, anemia, and again necessitating red cell transfusions. As a result of this experience Fuhrman et al. monitors serum copper quarterly and supplements 1 mg copper thrice weekly.¹⁷ Though serum copper and ceruloplasmin do not have high correlation with actual tissue accumulation, it is extremely important to monitor with the onset of clinical symptoms (see above). Autopsies have demonstrated copper accumulation in both liver and kidney without reflection in laboratory status.^6.9 Smoking, pregnancy, and contraception were found to alter levels.^10.11

Manganese

Manganese is a cofactor in many enzymatic systems and has roles in bone formation and metabolism of carbohydrates and cholesterol.¹⁸ This enzyme is involved in fatty acid and protein synthesis as well as melanin and dopamine production.¹⁹ After oxidation in its trivalent form, manganese is bound to transmanganin and is successfully deposited in the liver, skin, and skeletal muscle.² Deficiency has not been well detected;² however weight loss, transient dermatitis, and occasional nausea and vomiting have correlated with low manganese levels.¹⁰ Intravenous manganese administration is recommended at 60-100 mcg/day while standard multi-trace formulations contain 500-800 mcg/day. Toxicity has been reported in patients receiving long term PN. Manganese has been shown to accumulate in the basal ganglia resulting in neurotoxicity^2,9 and Parkinson’s like symptoms, hallucinations, and agitation.¹⁰ Manganese toxicity may also be associated with liver toxicity and hepatic cholestasis.^9,20 Laboratory levels often take five to six months to decrease when elevated.² One case reported an ongoing elevation of whole blood manganese for 369 days after complete removal of manganese; the patient had cholestatic disease.⁹ It has been recommended that manganese dosage be held in patients with hepatic dysfunction and cholestasis as it is almost exclusively excreted through bile;² however there is no evidence to support that manganese must be removed from PN in the setting of transient elevations of bilirubin in an acute care setting –this is not to say that evidence may be forthcoming, but clinical monitoring of these patients is essential. One study in Japan demonstrated that 55 mcg/day sustained serum manganese levels; with this evidence ASPEN supports dosage lowering to 55 mcg/day to prevent toxicity.³

Though lower than the US formulations, European dosing is 265 mcg/day and toxicity continues to exist.³ Whole blood manganese (a better representative of tissue manganese versus serum), found to be present in 60-80% of erythrocytes^2,9 may be drawn annually and more often in patients with hepato-biliary dysfunction and/or in patients exhibiting clinical signs and symptoms of deficiency and toxicity (See Table 3).

Selenium

Selenium is needed to synthesize selenocysteine, which aids in glutathione peroxidase that serves as an antioxidant, protecting cell membranes from lipid peroxidases, and free radicals. Selenium also drives endocrine enzyme function, which regulates thyroid hormone and metabolizes vitamin C.^2,21 Deficiency symptoms include macrocytic anemia, skeletal muscle pain and tenderness, arrhythmia, whitened nail beds, and loss of hair and skin pigmentation.^2,21 The development of Keshan disease (see trace element history above) is due to severe selenium deficiency, which is characterized by severe cardiomyopathy that is often irreversible or fatal.^2,4,21 Unfortunately most patients are extremely deficient prior to the appearance of clinical and physical symptoms;²¹ hence laboratory testing can be done prophylactically. The usual dose of selenium in PN is 20-60 mcg/day; however consensus is that needs are actually increased to 60-100 mcg/day.^3,9 Selenium requirements are elevated in malabsorptive states⁹ and increased dosage is controversial in critically ill, septic, and burn patients.³ Although rare,²² selenium toxicity is likely to appear when levels are tenfold higher than normal.²¹ Toxicity may cause oxidative cell and tissue death. Symptoms may include hair loss, brittle nails,²¹ skin changes, decay of teeth, and neurogenic abnormalities.¹⁰ Selenium laboratory studies lack correlation to actual selenium storage and likely reflect acute changes between tissues.⁹ Some professionals feel that erythrocyte glutathione peroxidase activity could be more reflective of selenium storage however; further studies are warranted.^9,11

Zinc

Zinc is a metalloenzyme that has roles in immune function, stress response, wound healing, and glucose control. As a cofactor, zinc also aids in the metabolism of macronutrients. Transported by plasma protein and albumin, >85% is stored in the skeletal muscle and smaller amounts in the bone, skin, liver, pancreas, kidney, and prostate.^23,24 Zinc deficiency can appear rapidly, within 14 days to 3 months of supplementation holiday,^23,24 and is often related to prolonged severe malnutrition, high enteric losses, and/or thiazide diuretic use.¹⁰ Deficiency characteristics are detectable once levels are severely low, often present with physical signs: acrodermatitis enteropathica, alopecia, hair pigmentation changes, stomatitis, glossitis, perioral ulcers, and periungual lesions.^23,24 Clinical symptoms often entail delayed wound healing, delayed sexual maturation, reduction of taste sensitivity, poor night vision and impaired immunity.¹⁰ Standard dosage administered through PN is 2.5-5 mg/day. Patient with high GI loss may require 12-17 mg/liter lost,^3,24 with a proposed upper limit of 50 mg/day.¹⁰ Some clinicians proactively supplement 10 mg/day for patients at high risk for deficiency.10 ASPEN does not have an adjustment they would like to make at this time; however, per Shike et al. average zinc dose given was 7.6 mg/day to maintain adequate zinc status, adequate for 90% of the patient population.¹² They supplemented 6.7 mg/day versus 9 mg/day in their non-short bowel as opposed to short bowel patients.¹² Rare toxicities have been detected, often expressed as dysfunction of neutrophils and lymphocytes² and have been associated with urinary tract infections.²⁵ Zinc laboratory studies have questionable accuracy as zinc is tightly regulated and reserved in the blood until supply is scarce; hence zinc deficiency may be caught late.⁹

Summary

Trace elements are essential in providing adequate PN formulations in long-term PN patients. Though infused in minute quantities, trace elements have a significant role in health and well being. However, if not carefully monitored in these patients, they can have detrimental effects. It is vital that clinicians who care for these patients understand dosages available, patients’ conditional requirements, anticipate where potential toxicities and deficiencies might occur and

the importance of dosage adjustment as appropriate. As most laboratory measures are unsatisfactory, assessment of the entire clinical picture is critical in determining the best plan of care. Develop a plan for scheduled monitoring, and if faced with product shortage, see the ASPEN website for suggestions: http://www. nutritioncare.org/news/parenteral_nutrition_trace_ element_product_shortage_considerations.

Endoscopy: Opening New Eyes, Series #8

Hemospray™ in Gastrointestinal Bleeding

Kirsten Regalia,

Alan Barkun

In this article we discuss the use of Hemospray™ (TC-325, Cook Medical Inc., Winston-Salem, NC, USA), a novel, highly adsorptive nanopowder made from a proprietary inorganic mineral blend. It has some distinct advantages over conventional endoscopic hemostatic modalities as it is easy to use and appears relatively safe and efficacious for various causes of both upper and lower gastrointestinal bleeding. It is currently licensed in Europe, Hong Kong and Canada for endoscopic hemostasis of non-variceal upper gastrointestinal bleeding and is undergoing Food and Drug Association evaluation in the United States.

Introduction

A cute upper and lower gastrointestinal bleeding are common medical emergencies with high rates of morbidity and mortality.¹ Various endoscopic hemostatic treatment modalities exist including injection, thermal and mechanical therapies. These methods have limitations, as they all require technical expertise and, in most, direct tissue contact with the bleeding vessel.² Thermal and ligation devices, such as clips, are limited by the need for en face positioning, possible difficulties in deployment and potential complications such as bleeding and perforation. Furthermore, these techniques do not provide rapid enough hemostasis in the case of massive bleeding.^3,4

Application of a hemostatic powder to the bleeding site obviates the need for direct contact of an instrument with the vessel or mucosa. Hemospray™ (TC-325, Cook Medical Inc., Winston-Salem, NC, USA) is a novel, highly adsorptive nanopowder made from a proprietary inorganic mineral blend. It contains no human or animal proteins, botanicals or allergens and is nontoxic.² It is currently licensed in Europe, Hong Kong and Canada for endoscopic hemostasis of non-variceal upper gastrointestinal bleeding^5,6 and is undergoing Food and Drug Association (FDA) evaluation in the United States (US) for similar use. It is currently only FDA approved for external traumatic uses.^7,8

Hemospray Application
Technique and Mechanism of Action

The Hemospray delivery device consists of a powder canister (which contains approximately 20 grams of TC-325 hemostatic powder), a compressed carbon dioxide propellant and a delivery catheter that is introduced through the working channel of the endoscope. Hemospray is deployed through a 7-Fr or 10-Fr catheter in short bursts (each of which contains an average of 1 to 5 grams of powder). When the powder contacts blood, it absorbs water and forms a gel, which acts both cohesively and adhesively to create a stable mechanical barrier that covers the actively bleeding site. Hemospray is neither absorbed nor metabolized by mucosal tissue and the covering formed by the powder eventually sloughs from the lesion and is eliminated via the gastrointestinal tract.^6,9,10 In vitro experiments, whereby Hemospray was added to the plasma of healthy and factor-deficient patients, suggested that Hemospray may also activate the coagulation cascade and platelet function, thereby facilitating local hemostasis.¹¹ However, these preliminary findings require confirmatory studies.

Safety and Efficacy in Animal Models

Hemostatic powders have been used efficaciously for hemorrhage control in battlefield trauma patients. Swine model studies have raised concerns about the safety of these agents when used to externally pack open vascular injuries. Local and distant thrombi, transmural vessel damage and neurovascular changes have been described with use of WoundStat (a topical hemostatic agent made of smectite granules) in swine model studies.^12,13 While these safety concerns have caused some hesitancy about the use of hemostatic powders in humans with gastrointestinal bleeding, the animal studies involved extreme vascular injury from surgically transected vessels in which the hemostatic material was firmly packed into the wounds, and therefore could have predisposed to thrombus formation.

In a swine model study by Giday et al., 6 animals underwent gastrotomy and creation of a looped vascular bundle, which was placed into the stomach lumen.² On subsequent endoscopy the transplanted vascular bundle was punctured using a needle-knife to create Forrest grade Ia (pulsatile) or Ib (oozing) bleeding gastric lesions. Hemospray was then applied. Initial hemostasis was achieved in all animals and there were no signs of re-bleeding at post-procedure day 9. There was no hemostatic powder identified grossly in any stomach specimens, nor was there histologic evidence of powder or thrombosis in any local or systemic tissue samples.

In a randomized controlled animal trial, 10 swine were randomized to endoscopic treatment with Hemospray or sham (through endoscopic monitoring only) after operative creation of gastric arterial bleeding.¹⁴ Initial hemostasis was achieved in all animals treated with Hemospray while those in the sham treatment group all succumbed to uncontrolled hemorrhage. Durable hemostasis up to 24 hours post-treatment was observed in 80% of the treatment group. There was no evidence of foreign body granuloma or embolization in the lung or brain at necropsy in any of the treatment animals sacrificed one week later.

Clinical Applications of Hemospray

A review of the literature using PubMed and Ovid up to February 2014 showed various clinical applications of Hemospray in both upper and lower gastrointestinal bleeding (summarized in Table 1).

Upper Gastrointestinal Bleeding
Various Causes of Upper GI Bleeding¹

A multicenter, international SEAL (Survey to Evaluate the Application of Hemospray in the Luminal Tract) cohort study assessed the use of Hemospray in nonvariceal upper gastrointestinal bleeding in 10 pilot sites across Europe.¹⁵ A total of 63 patients were treated with Hemospray as either primary monotherapy (in 55 patients) or combination second-line therapy (in 8 patients). The etiology of the bleeding was gastroduodenal ulcer in 48% of patients, with the remaining etiologies attributable to various other nonvariceal causes. Primary hemostasis was achieved in 85% of patients who received Hemospray monotherapy, the remainder required additional endoscopic hemostatic adjuvant interventions or angiographic embolization. Of the patients for whom initial hemostasis was achieved with Hemospray monotherapy, 15% developed re-bleeding within 7 days. Of the 8 patients treated with Hemospray when standard endoscopic therapies had failed, all 8 (100%) achieved hemostasis with Hemospray. However, 25% of these patients re-bled within 7 days. There were a total of 4 deaths within 7 days, none of which was due to bleeding. Of the patients with peptic ulcer bleeding, 36% failed to achieve either primary or sustained hemostasis with Hemospray. This is higher than expected when compared to published data from controlled studies in ulcer bleeding, but likely attributable at least in part to patient selection. While this was an uncontrolled, solely observational study with no set protocol for Hemospray use, it provides some insight into the efficacy and safety of Hemospray in non-variceal upper gastrointestinal bleeding.

Peptic Ulcer Bleeding

In a prospective, single-arm pilot clinical study by Sung et al., consecutive adults with confirmed peptic ulcer bleeding (Forrest class Ia or Ib) were treated with Hemospray.¹⁰ The majority of ulcers (70%) were located in the duodenum, while 30% were in the stomach. Routine second-look endoscopy at 72 hours post-treatment and phone follow-up at 30 days were performed in all participants. Of the 20 total patients in the study (18 men, mean age of 60 years), acute hemostasis was achieved in 95% (19/20) of patients. The one patient for whom Hemospray failed had a pseudoaneurysm that required arterial embolization (the only patient with Forrest Ia ulcer bleeding). Two patients had recurrent bleeding within 72 hours (detected clinically by hemoglobin drop), but neither had active bleeding identified at repeat endoscopy. There were no major adverse events, mortality, or treatment-related adverse events (including systemic embolization, bowel obstruction or allergic reaction) during the 30-day follow-up period. At the routine second-look endoscopy at 72 hours, Hemospray had been eliminated from the stomach and duodenum in all patients. All patients at follow-up endoscopy had clean-based ulcers, and had received high-dose proton pump inhibition co-administration.

Portal Hypertensive Bleeding
Esophageal Variceal Bleeding

A prospective, non-randomized pilot study by Ibrahim et al. evaluated the efficacy of Hemospray in 9 patients with acute esophageal variceal bleeding: 3 with active hemorrhage and 6 with stigmata of recent bleeding.¹⁶ The application of Hemospray produced hemostasis in all patients, and a second dose was required in only one case. Follow-up endoscopy was performed at 24 hours post-intervention in all patients, at which time hemostatic powder had been eliminated from the upper gastrointestinal tract in all patients, and the entire cohort then underwent elective variceal band ligation. No cases of recurrent bleeding or Hemospray-related adverse events were reported. These findings highlight Hemospray as a potential bridge to definitive therapy (either transjugular intrahepatic portosystemic shunt [TIPS] or band ligation) in acute esophageal variceal bleeding, especially in cases when immediate hemostasis is otherwise difficult to achieve. Currently, Hemospray is not recommended for use in variceal hemorrhage by the manufacturer due to theoretical concerns about possible systemic embolization.³

Gastric Variceal Bleeding

There are two case reports describing the use of Hemospray in gastric variceal bleeding, both after injection therapy with N-butyl-2-cyanoacrylate (Histoacryl™) with lipiodol failed. In one of the patients, it served as a bridge to TIPS, and in the other it was definitive therapy as TIPS was contraindicated due to underlying cardiomyopathy.^17,18

Portal Hypertensive Gastropathy

Hemospray has been used successfully in 3 patients with diffuse bleeding from portal hypertensive gastropathy.⁶

Patients on Antithrombotic Therapy

Antithrombotic therapy (ATT) includes antiplatelet therapy and anticoagulants and can give rise to life-threatening gastrointestinal hemorrhage. Holster et al. evaluated the relative efficacy of Hemospray in patients with bleeding on ATT (n = 8) compared with those without ATT (n = 8).¹⁹ Successful initial hemostasis was achieved in all 8 (100%) of the non-ATT patients and in 5/8 (63%) of the patients on ATT (p = 0.20). For the 3 patients on ATT for whom Hemospray failed, 2 had spurting arterial bleeds controlled with subsequent clipping and the other patient required angiography with coil embolization. Re-bleeding within 7 days was observed in 5 of the 16 patients (3 in the ATT group and 2 in the non-ATT group). In 2 of the 3 ATT cases, Hemospray had been applied to spurting arterial vessel bleeding, and in both of the non-ATT cases, Hemospray had been applied for peptic ulcer related arterial bleeds. No deaths occurred up to 30 days after Hemospray application in either group.

Malignant Tumor Bleeding

Both primary and metastatic tumors of the gastrointestinal tract are at risk of bleeding. Bleeding from malignancy can be induced by tumor necrosis and is often diffuse and widespread.²⁰ Conventional endoscopic hemostatic therapies (such as heater probe, electrocautery and argon plasma coagulation [APC]) are associated with high rates of recurrent bleeding compared to other non-malignant causes of gastrointestinal bleeding.²¹ Chen et al. described 5 cases in which Hemospray was used to treat upper gastrointestinal bleeding due to gastroduodenal tumors.²² Hemospray was successful in achieving immediate and sustained hemostasis in 4 of the 5 patients, but failed in a patient with severe metastatic disease and disseminated intravascular coagulation. In a study by Leblanc et al., 5 patients with active upper gastrointestinal bleeding due to malignancies of the esophagus, stomach or pancreas were treated with Hemospray.²⁰ Hemospray was used as first-line therapy in 4 of the 5 patients, and as rescue therapy in the fifth for persistent bleeding despite placement of hemostatic clips. Immediate hemostasis was successful in all 5, with recurrent bleeding in 2 patients. Figure 1 shows a gastric tumor with diffuse bleeding prior to the use of Hemospray. Figure 2 shows complete hemostasis of the same lesion following the application of Hemospray.

Post-Therapeutic Intervention Bleeding

Hemospray has been used in 12 patients who developed upper gastrointestinal bleeding after therapeutic endoscopic interventions.20 Bleeding occurred after esophageal endoscopic mucosal resection (EMR) in 5 patients, after duodenal EMR in 4 patients, after ampullary resection in 2 patients and after biliary sphincterotomy in 1 patient. Lesion diameter ranged from 10 mm to 90 mm. Hemospray was used as initial therapy in 8 of these patients and as rescue therapy (after standard hemostatic therapy failed) in 4 patients. Recurrent bleeding was suspected but not confirmed on repeat endoscopy 48 hours after Hemospray application in two of the 12 patients. No recurrent bleeding occurred in any of the 12 patients during follow-up at 7 days and 30 days post-treatment. In the only published U.S. case report of Hemospray, a young patient with a metal biliary stent placed for malignant biliary obstruction developed a bleeding duodenal ulcer from stent migration.⁸ Because of its location and anatomic distortion, conventional endoscopic hemostatic interventions failed and the patient continued to bleed despite gastroduodenal artery embolization. An investigational device exemption was approved for use of Hemospray, and hemostasis was finally achieved. The patient was discharged home 6 days later with no further bleeding episodes.

Lower Gastrointestinal Bleeding

Lower gastrointestinal bleeding accounts for 20-40% of acute gastrointestinal bleeding cases. This type of bleeding can be massive and therefore requires prompt and durable hemostasis. Conventional hemostatic modalities include clips and thermal coagulation.⁹ The role of Hemospray in lower gastrointestinal bleeding has recently been studied. In a multi-center European case series by Holster et al., nine patients with active lower gastrointestinal bleeding of various causes (post-9 patients (22%) within 7 days. Both of these patients polypectomy, colorectal anastomosis, rectal ulcer, were on aspirin and had initial pulsatile arterial bleeds. diverticular, proctitis and cecal adenocarcinoma) were Successful hemostasis was eventually achieved in these treated with Hemospray, either as initial or salvage patients with clip placement and arterial embolization. therapy.⁹ Immediate hemostasis was successful in all Soulellis et al. were the first group to report 9 patients (100%), but re-bleeding occurred in 2 of the additional clinical uses of Hemospray.²³ Indications included post-polypectomy bleeding, after conventional hemostatic therapy with clips, thermal probe, and epinephrine injection had failed. Hemospray was also used successfully in a left-sided colonic Dieulafoy’s lesion after clip placement and epinephrine injection failed. Lastly, the investigators also reported its use in radiation proctopathy after argon plasma coagulation caused more bleeding. Granata et al. described a single case report of Hemospray application for refractory cecal ulcer bleeding in a patient with influenza A (H1N1) virus who was being treated with extracorporeal membrane oxygenation for respiratory failure.²⁴ Re-bleeding had occurred after initial hemostasis with fibrin glue injection, whereas rescue therapy with Hemospray resulted in durable hemostasis.

Cautionary note and CompliCations

A recent review suggested that because the Hemospray powder only binds to actively bleeding sites, its short contact time on the lesion may limit its use as monotherapy and may contribute to re-bleeding. Feared complications of Hemospray use include bowel obstruction, systemic embolization and perforation. There have been no reports of bowel obstruction to date. Due to fear of systemic embolization, the manufacturers do not recommend use of Hemospray in variceal bleeding (where theoretically the powder could enter the venous circulation and embolize). However, some authors report that the outflow pressure of the device (when used correctly) is 12 mmHg, which should be less than intravariceal pressures, suggesting the embolization risk may be overstated.²³ In the available published literature where Hemospray was used in esophageal and gastric varices, there was no clinical evidence of systemic embolization. There has been only one reported case of perforation after endoscopic application of Hemospray in a patient with active portal hypertensive gastropathy-related bleeding. It was unclear whether the perforation was a result of endoscopy itself or directly due to the application of Hemospray.6 This potential risk is related to the requisite carbon dioxide pressure used during application, which is approximately 12 mmHg with the catheter 1 to 2 cm from the target lesion, but reaches 55 mmHg if the catheter is incorrectly placed in direct contact with the mucosa.²³

There is one report of Hemospray causing transient biliary obstruction when applied to a bleeding biliary orifice after sphincterotomy done for biliary stone removal. Biliary patency was restored with water irrigation and prodding open of the papillotomy orifice, but caution is recommended when applying Hemospray near small orifices adjacent to bowel lumen, such as a biliary or pancreatic sphincterotomy site.²⁵ In one case series, a female patient experienced abdominal pain after each burst of Hemospray application that resolved on its own post-procedure.⁹ Device-related complications have included clumping of the powder within the catheter when the biopsy port is exposed to a moist or wet environment and transient adherence of the endoscope to the mucosa.^8,15

Summary

Hemospray has some distinct advantages over conventional endoscopic hemostatic modalities. It is easy to use and appears relatively safe and efficacious for various causes of both upper and lower gastrointestinal bleeding. Based on the limited available studies, it may have reduced efficacy in spurting arterial ulcer bleeds and in patients on ATT, primarily due to delayed re-bleeding that may exceed the residency time of the product more so than failure to achieve initial immediate hemostasis. In fact, Hemospray may be the most effective product available today in achieving immediate hemostasis. Unfortunately, Hemospray has not been compared in head-to-head controlled comparisons with conventional hemostatic therapies and hence the relative efficacy of this treatment is unknown. Hemospray has been

successfully used in combination with other therapeutic modalities in some cases, and when lightly applied, the mucosal topography is preserved.

Its greatest applicability is as rescue therapy in massive hemorrhage when other therapies fail, or as a bridge to more definitive therapy (such as transferring the patient to a more specialized center, application in the context of a marked coagulopathy or in active variceal bleeding as a bridge to TIPS or band ligation under more controlled conditions). It may also be particularly adapted in diffusely bleeding lesions that involve large surface areas, especially in malignant bleeding in which the noncontact application may be particularly advantageous. While Hemospray appears promising as an adjunctive endoscopic hemostatic agent, prospective, controlled studies and resulting cost-effective analyses are urgently needed before more specific recommendations can be made regarding its use in patients with gastrointestinal bleeding.

A Case Report

Intrahepatic-Ductal Papillary Mucinous Neoplasm: A Real Disease Entity

Megha Kothari,Matthew Grossman,Gregory Haber

INTRODUCTION

A rare and recently emerging papillary subtype of biliary intraductal neoplasms is intraductal pancreatic mucinous neoplasm of the bile duct (B-IPMN). B-IPMNs have histological and clinicopathological resemblance to pancreatic IPMNs. These rare tumors represent approximately 8.3-29.9% of all biliary neoplasms and more likely to occur in males between the ages of 39 and 71. Patients most commonly experience abdominal discomfort (65%), jaundice (39%) and weight loss (35%), which are related to mass effect. In comparison to pancreatic IPMN, B-IPMN have a greater malignancy potential, 83% vs. 30%. However, they harbor a favorable outcome with aggressive surgical resection.

Case Presentation

A 67 year-old Chinese female was referred to our center with recurrent right upper quadrant abdominal pain and intermittent fevers over the past year, worsening in the last month. Her history included a cholecystectomy 16 years ago for symptomatic gallstones. The patient’s labs were within normal limits, except for an elevated carcinoembryonic antigen (CEA) level of 206 ng/ml (normal range 0-3 ng/ml). An initial abdominal ultrasound revealed a markedly dilated common bile duct (CBD) to approximately 3 cm. Magnetic resonance cholangiopancreatography (MRCP) confirmed intra and extra-hepatic duct dilatation with a fusiform CBD measuring 2.8 cm (Image 1 and 2). No intrahepatic bile duct or CBD calculi were identified. Marked saccular dilatation of intra-hepatic bile ducts was seen in the lateral segment of the left lobe (segments 2 and 3). No pancreatic mass or pancreatic ductal abnormality was noted. An endoscopic retrograde cholangiopancreatography (ERCP) with direct cholangioscopy (Spyglass, Boston Scientific) was performed. The ampulla was noted to have a classic “fish-mouth” appearance – patulous with viscous mucin extravasating from the os. ERCP revealed papillary mucosal changes in the left intrahepatic duct near the saccular dilatation (Image 3). Multiple cold-forcep biopsies were taken from the area. Pathology noted fibrous tissue with mild epithelial atypia. No carcinoma was identified. Given the findings, there was concern for an underlying papillary mucinous neoplasm and the patient was then referred for a left hepatectomy with resection of the common bile duct. Surgical pathology revealed a biliary intraductal papillary mucinous neoplasm (B-IPMN) with moderate epithelial dysplasia involving the left hepatic duct and periductal branches (Images 4-7).

Discussion

Biliary intraductal neoplasms are found to occur as either intra or extrahepatic lesions. A rare and recently emerging papillary subtype of biliary intraductal neoplasms is IPMN of the bile duct (B-IPMN). The two known subtypes are flat and papillary type.¹ However, B-IPMN have histological and clinicopathological resemblance to pancreatic IPMN. This is believed to be in part due to parallel embryological developments of the pancreatic and bile ducts from the hepato-pancreatic bud of the foregut.² B-IPMN differ from other biliary mucinous cystic neoplasms; they lack ovarian-like stroma and growth tends to occur along the biliary ducts, without confined cyst formation.³

These rare tumors represent approximately 8.329.9% of all biliary neoplasms.⁴ The wide range is likely due to variations in classification of B-IPMN.⁴ In a retrospective study of resected cholangiocarcinomas, Chu et al. found that B-IPMN are more frequently encountered in males between the ages of 39 and 71.⁴ A high correlation of B-IPMN is observed in patients with a history of choledocholithiasis, infections, pancreatic injury and biliary hyperplasia thus potentially defining some of the risk factors.¹ These lesions are thought to develop from stem cells of the bile ductules, lining of biliary epithelium glands or epithelium of peribiliary glands.⁵

Although very little is known regarding the molecular pathogenesis of the B-IPMN, the idea of microsatellite instability has been postulated. Susan at el. extracted DNA samples from B-IPMN lesions, invasive cholangiocarcinoma and normal tissue to find high occurrence microsatellite instability, particularly in B-IPMN. Importantly, they noted that the patterns of allelic shifts were different between relatively benign IPMN and invasive cholangiocarcinoma lesions, indicating a high level of genetic heterogeneity in these neoplasms.⁶ This variation may in part contribute to their difference of varying malignant potentials.

B-IPMN exhibit mucosal spread along the bile duct lumen and cause mucin hypersecretion, often resulting in polypoid or sessile growths;^3,5 therefore, ducts may exhibit marked dilatation. Tumors are often confined within the dilated part of the bile ducts.³ Occasionally, hepatic parenchymal atrophy has been observed due to long-standing elevated ductal pressures, resulting in partial obstruction.⁵ This may be accompanied by compensatory hypertrophy of a “normal” hepatic lobe.⁵ However, mass effect related symptoms may not always be present with B-IPMN. Symptoms usually appear when a mass enlarges to cause pressure on the liver capsule.⁵ Lim at al. reported that the most common symptom presentations are abdominal discomfort (65%), jaundice (39%) and weight loss (35%).⁷

In comparison to pancreatic IPMN, B-IPMN had a greater malignancy potential, 83% vs. 30%.² B-IPMN range from benign to malignant based on histological criteria. One classification scheme categorizes the tumors as adenomas, borderline tumors, carcinoma in situ or carcinomas.¹ Another classification system is based on histology and genetic expression, which has significant roles in carcinogenesis and tumor invasion. Histologically, B-IPMN can be classified as intestinal, pancreatico-biliary, gastric or oncocytic; while gene expression is classified as MUC1, MUC2, and MUC5 genes.¹ Higashi et al. found that MUC1 expression and the absence of MUC2 correlated with increased aggressiveness and subsequently a poor outcome in pancreatic ductal adenocarcinomas. Subsequently, isolated MUC2 and MUC5 expression poses a more favorable outcome for B-IPMNs.^1,5,8

Ultrasound and MRCP are the initial non-invasive studies for assessment of IPMN lesions. It is important to note that ERCP fails to delineate intraductal papillary changes along the ductal border; thus, cholangioscopy and/or intraductal ultrasonography (IDUS) are the most sensitive and specific modalities for diagnosing and localizing papillary tumors. The presence of a large amount of viscous mucin within the duct can make cholangiogram imaging difficult. Cholangioscopy proves to be better than IDUS to diagnose the extent of tumor.⁹

A recent case report presented a large B-IPMN, which was resected via a right sided trisectionectomy and caudate lobectomy.¹⁰ The authors note that complete surgical resection usually has a favorable prognosis; therefore, aggressive surgery needs to be recommended regardless of tumor size and extent.¹⁰ Favorable prognosis of B-IPMN is likely due to the theory that these tumors do not aggressively invade the bile duct wall unless there is transformation to tubular adenocarcinoma or mucinous adenocarcinoma.¹¹

CONCLUSION

In conclusion, B-IPMN are rare neoplasms which harbor a favorable outcome with aggressive surgical resection. Biliary mucinous cystic neoplasm, mass-forming type intrahepatic cholangiocarcinoma with choledochal cysts and recurrent pyogenic cholangitis with choledocholithiasis are among the differentials for B-IPMN lesions.⁹ However, biliary IPMN should be considered when bile duct dilatation and hepatic parenchymal atrophy is seen. This area warrants further investigation to devise a classification system and treatment options.

Unusual Causes of Abdominal Pain, #3

Unusual Causes of Abdominal Pain

George W. Meyer

CASE

A 44 year old man presents with a complaint of episodic abdominal pain and fever beginning at age 27. He emigrated to the United States as a young adult from his home in Catania, Sicily. Typically these episodes last roughly 24 hours and occur monthly but have recently increased in frequency. Right shoulder pain, 1-2 hours before the onset of his symptoms, would occasionally precede sudden, severe subxiphoid stabbing pain radiating to the back. Progression would include generalized abdominal pain. The associated fever would last 6-12 hours; there is no vomiting but diarrhea has occurred. When evaluated in the emergency department (ED) his white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) were both elevated. Although resolution of the fever and pain occur within 24 hours, these events cause exhaustion for the next 24 hours. A therapeutic trial was initiated.

Answer and Discussion

Familial Mediterranean Fever (FMF), inherited by autosomal recessive means, affects mostly those whose families have come from around the Mediterranean Sea, such as Sephardic Jews, Armenians, Turks, North Africans and Arabs. Greeks and Italians are less often affected. Most of those who suffer with this disorder develop symptoms in their first decade and 90% are symptomatic by the age of 20. The typical patient will develop sudden onset of fever and abdominal pain (sterile peritonitis), which may last 1-3 days and resolve spontaneously. They may also have pleuritis, synovitis, pericarditis, a skin rash that looks like erysipelas, or orchitis. The abdominal exam may simulate acute peritonitis (guarding, rebound tenderness, rigidity and ileus), leading to exploratory surgery. Abnormal lab results may include elevated WBC, ESR, and CRP. Treatment with colchicine is dramatic in ~75% of patients (fewer than 1 episode in 6 months), usually 0.6 mg per day but as high as 1.8 mg may be needed daily. At least half of non responders were noncompliant patients. The major complication of untreated FMF is amyloidosis (AA type), which may develop after several decades. Differential diagnosis, to be especially considered if the patient does not respond to colchicines, should include: tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS), hyper-IgD syndrome, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome. Genetic testing for FMF is available but is not very sensitive.

Nutrition Issues in Gastroenterology, Series #128

Nutrition Update in Hepatic Failure

Joe Krenitsky

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