Page 69 – Practical Gastro

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #11

Medicinal Plants for Digestive Disorders What Gastroenterologist Needs to Know

September 2015 • Volume XXXIX, Issue 9

Medicinal plants have been used by all cultures throughout history and still continue to be an integral part of our modern civilization. From generation to generation, various ethnic groups around the world have used a wide array of plants to treat various gastrointestinal problems. With the remarkable surge of so-called complementary and alternative medicine, or CAM (currently known by the more accurate term of Integrative Medicine), it is imperative that the gastroenterologist be aware of both the potential risks as well as the benefits of using herbal medicine in his/her modern practice.

Herbal medicine is arguably the oldest form of healthcare known to humanity. Medicinal plants have been used by all cultures throughout history and still continue to be an integral part of our modern civilization. From generation to generation, various ethnic groups around the world have used a wide array of plants to treat various gastrointestinal problems. This practice is especially common among the Hispanic communities living along the United States-Mexico border. The principal afflictions for which various plants are ingested (either taken as tea made from a single plant – or multiple combinations) range from parasitic diseases, to bloating, ulcers, nausea, dyspepsia and diarrhea, just to name a few. Plants contain a myriad of secondary metabolites or phytochemicals, which may have a role in the treatment and prevention of various digestive disorders. With the remarkable surge of so-called complementary and alternative medicine, or CAM (currently known by the more accurate term of Integrative Medicine), it is imperative that the gastroenterologist be aware of both the potential risks as well as the benefits of using herbal medicine in his/her modern practice.

Armando Enrique González-Stuart, Ph.D., Professor of Phytotherapy and Integrative Medicine, O.L.L.I. at the University of Texas at El Paso Richard W. McCallum, MD, FACP, FRACP (Aust), FACG, Texas Tech University Health and Sciences, Department of Internal Medicine, Gastroenterology, Center for Neurogastroenterology and GI Motility, El Paso, TX

INTRODUCTION

Medicinal plants, collectively comprising various species of green plants as well as fungi (mushrooms), were arguably the first therapeutic agents known to humans.¹

The use of herbs to cure diverse human and animal ailments predates recorded history. From Paleolithic cave dwellers to medieval healing monasteries as well as from Renaissance alchemists such as Paracelsus to the modern “techno era”, medicinal plants have been, and continue to have, an important part in the healing therapies applied in both human as well as veterinary medicine.²

The application of the plethora of species used in herbal treatments has been anything but haphazard. Well-known and mastered by the Hakims (physicians) of Arabic medicine as well as the Aztec and Mayan healers of ancient Mesoamerica, herbal medicine has been a part of highly systematized medical modalities throughout the orb. Such systems include, but are not limited to, Ayurveda, Siddha, and Unani-Tibb from India, Traditional Chinese herbology and Native American herbal healing (here indicating the totality of the American continent), to name only a few.^3,4

The infamous slave trade also brought diverse African food and medicinal plants to the American continent (such as okra, hibiscus and castor oil plant, for example) that both enriched and diversified the conglomerate of European, Asian and Amerindian herbal pharmacopoeias.^5,6,7

Dyspepsia

Various plants are available usually as teas or capsules, for the treatment of dyspepsia. Chamomile (German or Roman), as well as anise (green and star anise), various mints and licorice have been regarded as traditional medicine for centuries⁸ (See Table 1).

A study compared the efficacy of a ginger (Figure 1.) and artichoke supplementation compared to placebo for the treatment of dyspepsia. The design consisted of a 4-week prospective multicenter, double blind, randomized, placebo controlled, parallel- group format that compared the herbal combination versus placebo. A dose of two capsules per day was given before two meals (lunch and dinner) to the 126 participants suffering from dyspepsia. The study showed that after two weeks, only the treatment group showed a substantial decrease in symptoms of gastric discomfort including nausea, epigastric fullness, epigastric pain, and bloating. The researchers concluded that the herbal combination of ginger and artichoke leaf extracts appears safe and efficacious for the treatment of dyspepsia.⁹

Because medicinal plants usually contain hundreds of active ingredients, many are multifaceted, that is, they can be applied to various (apparently) unrelated ailments. One example is cinnamon (Cinnamomum verum), which can have both anti-flatulent as well as hypoglycemic properties.

Nausea and Vomiting

Certain medicinal plants can help to reduce nausea and vomiting due to various conditions such as motion sickness or vomiting that may accompany the early stages of pregnancy (hypermesis gravidarium). One of the plants most employed in traditional medicine against nausea and emesis is ginger (Zingiber officinalis- Zingiberaceae). The underground stem (rhizome) of this plant is considered to have “warming” properties by both Ayurvedic as well as Chinese medicine and has been recommended to treat both digestive as well as respiratory disorders throughout Asia for many centuries.

Ginger’s antiemetic effects are not completely understood, but it seems the plant’s main bioactive ingredients (gingerol and various shogaols) act directly on the gut via the peripheral nervous system but not via the central nervous system (CNS). Ginger’s phytochemicals may have beneficial anti-inflammatory actions as well as an inhibitory effect on platelet aggregation.¹⁰

Ginger can be taken as a tea or in capsules containing the dried and pulverized stem. In Europe, this plant is widely used to treat nausea and vomiting during the first trimester of pregnancy

Ginger extracts containing gingerols and shogaols exert their activity upon cholinergic and serotonergic receptors.

A systematic review of double-blind, placebo- controlled, randomized studies with ginger emphasized the possible efficacy of this plant on the prevention and treatment of nausea and vomiting of various origins. The review focused on pregnancy-induced nausea and vomiting, as well as nausea induced by chemotherapy. The authors hypothesized that ginger extracts do have a therapeutic role in the treatment of nausea and vomiting from various causes, and with minimal side effects. For this reason, the authors concluded, ginger preparations can be a potential alternative to traditional prokinetic pharmaceuticals such as domperidone, levosulpiride or metoclopramide, as well as conventional antiemetics like the phenotiazines and 5HT 3 antagonists, for example.¹¹

Diarrhea

Traditionally, plants that are rich in tannins are used for the treatment of diarrhea due to their astringent properties. Many medicinal plants may also contain additional phytochemicals, such as quercetin (a polyphenolic compound with antioxidant and anti- inflammatory properties), that maybe useful in curtailing the symptoms.

Teas made form Guava leaves are used throughout the American tropics for the treatment of diarrhea in adults and children. The plant contains tannins, quercetin and is a good source of Vitamin C.

A review of the pharmacological experiments with guava in both in vitro and in vivo models found that guava’s diverse bioactive phytochemicals include phenolic, flavonoid, carotenoid, terpenoid and triterpene compounds. Extracts obtained from the leaves and fruits possess antispasmodic and antimicrobial properties that are useful for the treatment of diarrhea (including infantile rotavirus enteritis) and dysentery.¹²

Bloating (flatulence)

In herbal medicine, the term carminative refers to a plant whose active ingredients ease flatulence and colic in the gut. This property is usually due to volatile oils, as well as other phytochemicals produced by the plant.^1,13

Some of the commonly used herbal products for treating flatulence include anise (Pimpinella anisum- Apiaceae) also known as green anise or European anise. European or green anise may be mistaken for another different spice with similar actions and flavor: star anise. Although star anise contains some of the same ingredients, it may not be safe to give to small children, since it may be neurotoxic (see Table 2 as well as description for star anise below).

Star anise (Illicium verum -Illiaceae), is also referred to as Chinese star anise (to differentiate it from the toxic Japanese star anise: I. anisatum). The fruits of this small Asian tree are used as a tea to relieve bloating and indigestion. Star anise and European (green) anise are different plants, although they contain some of the same ingredients. The fruits are star shaped (hence the vernacular name) and are rich in essential oils as well as terpenoid and phenolic compounds.

The phytochemicals act as carminatives as well as spasmolytics. The fruits’ antiseptic properties are due to anethol, since this compound has both antibacterial as well as antifungal actions. Traditionally, Star anise has been employed as a carminative as well as a eupeptic (substance that promotes good digestion). However, its use in children younger than 6 years of age should be undertaken only under the supervision of a professional due to the possibility of side effects due to the adulteration with another very similar species known as Japanese star anise, which can be very toxic to the nervous system.^{14, 15}

Constipation

Caution should be practiced recommending using certain herbs as laxatives due to their potentially irritating effects on the gastrointestinal tract (See Table 3). These plants include aloe vera (whole leaf preparations including the latex and gel), as well as any species of rhubarb root. However, certain over- the-counter (OTC) medications), such as senna leaf (sometimes sold as a proprietary laxative known as Senokot�) are generally regarded as safe to use during limited periods. Chronic use as a laxative can darken the mucosa of the colon-an endoscopic observation referred to as melanosis coli.

When constipation is due to tension or stress, the anthraquinone-containing laxatives should be avoided due to their potentially irritating action on the gastrointestinal tract.¹⁶

Medicinal Plant Use on the U.S.-Mexico Border

The U.S./Mexico border is approximately 2,000 miles in length with a population of nearly 12 million inhabitants. People of Hispanic origin (principally of Mexican ancestry) comprise approximately 80% of the population living on the U.S. side of the border. The El Paso, Texas/Ciudad Juarez, Chihuahua international community comprises the largest US/Mexico border population.¹⁷

Various parameters related to healthcare activities are unique to the bi-national border region. These include, but are not limited to, the use of so-called complementary and alternative medicine (CAM), especially employing medicinal plants, by the predominantly Hispanic population. Even though a copious amount of research has been conducted in the U.S. to determine the extent of the formerly known alternative medical therapies by the general population, far less research has taken place within the largest ethnic minority living on the southwestern border.

A dearth of studies are available but have shown a higher prevalence of medicinal plant use among the Hispanic population. Research undertaken to evaluate the use of herbs and related supplements has shown that between 13-19% of the U.S. population report taking these products.^{18, 19} A study conducted in El Paso, Texas assessed the rates and types of herbal product use among patients interviewed at local hospitals and clinics. It is worth noting the El Paso’s population is 80% Hispanic. The results of the study demonstrated that 59% of the patients mentioned using various herbal supplements within the previous year.²⁰

Plants Used in Mexican Traditional Medicine to Treat Digestive Problems

Throughout developing countries, the so-called “third world” nations, various gastrointestinal diseases continue to be one of the most challenging health issues. This is the case for various indigenous peoples of Mexico.²¹

Many of these ethnicities posses a wealth of native knowledge regarding the use of a wide array of plants to treat disease. According to the indigenous viewpoint on the healing characteristics of herbs, certain plants are employed in the treatment of a various diseases due to the particular plant’s characteristic taste or aroma.²² Healing herbs that possess astringent properties are used particularly to treat diarrhea and dysentery, while herbs with bitter and aromatic characteristics are used to treat pain and gastrointestinal cramping. For the treatment of diarrhea and dysentery, for example, plants rich in tannins are used. Many plants frequently employed in Mexican traditional medicine address bloating, diarrhea and other gastrointestinal problems. Guava (Psidium guajaba), Quassia amara, and wormseed (Dysphania ambrosioides), are good examples, but have only limited availability in the United States.²³

Potential Toxicity of Certain Herbal Products

Practitioners of modern phytotherapy are well aware that the common saying: “if it’s natural, it must be safe” is not a realistic viewpoint. Many of the most toxic substances known to man (from the carcinogenic aflatoxins from microscopic fungi to the bacterial botulism toxins, for example) are naturally occurring substances. On the other hand, this does not mean that all herbal or fungal products are inherently dangerous.

However, of special concern is the great variability in quality control among the various foreign and domestic companies that market these “natural supplements” as OTC products. Since the majority of these products are classified in the United States as nutritional supplements rather than medications, they are not required to be under the direct supervision of the FDA.

Hepatotoxicity is a Concern for Certain Herbs

Certain herbs used in traditional medicine for the treatment of various illnesses are known to harm the liver, especially if taken internally for an extended period. A few examples include Creosote bush, the so-called “Chaparral” (Larrea tridentata -Zygophyllacaeae). The leaves and twigs of this xerophytic shrub are taken either as teas or pills to treat a myriad of afflictions, ranging from venereal disease to kidney and gastrointestinal tract ailments. The pills tend to be more concentrated and thus pose a greater risk for toxicity.

Comfrey (Symphytum officinale-Boraginaceae) as well as Colt’s foot (Tussilago farfara-Asteraceae) teas can also be liver toxic due to their content of pyrrolizidine alkaloids. Additionally, there are a few cases of kava kava (Piper methysticum- Piperaceae) hepatotxicity, especially if combined with certain medications or alcoholic beverages.²⁴

Medicinal and Toxic Fungi

The use of medicinal fungi in traditional medicine is very common, especially in Oriental traditional medicine. Currently, they are available in health food stores throughout the U.S. Various species of higher fungi (“mushrooms”) are used to treat various ailments, including some types of cancer. They contain complex polysaccharides that act as immuno-modulators and may be useful as cytotoxic agents against certain cancer cell lines.²⁵

On the other hand, toxic mushroom poisonings are usually accidental and occur through careless handling and misidentification when consuming mushrooms from the wild. Some species contain poisonous cyclopeptides that are very toxic to the liver and kidneys, sometimes causing death.

Interestingly, a natural compound known as silymarin, (derived from the medicinal plant known as Milk thistle (Silybum marianum – Asteraceae), is used by physicians in Germany as an antidote for mushroom poisoning, provided it is applied intravenously within 24 hours after ingestion of the offending species.²⁶

CONCLUSION

Every day thousands of medicinal plant and fungal species are being taken by our patients to treat a wide array of ailments, from infant colic to stomach cancer. Scientific herbal medicine or phytotherapy is very commonly practiced in many regions, especially Western Europe, not only by herbalists but by physicians as well. Unfortunately, many species of plants used by indigenous traditional medicine in many developing countries have not been studied in depth. However, we have reviewed those that should be considered by gastroenterologists for incorporation into their practice regimens, in order to both enrich as well as diversify their therapeutic armamentarium. A better knowledge of the commonly used medicinal plants and their active constituents will aid the physician in more effectively communicating with the patient who may be taking some of these agents without officially informing their physician. In addition, it is important to assess the possibility of an herb-drug interaction. Overall, we can say that using certain herbal preparations for digestive problems available on the U.S. market today would have minimal to no unexpected toxic effects, apart from rare idiosyncratic allergic reactions or their proscribed use during pregnancy.

Although no official FDA approval process is currently in place, when used judiciously, a plethora of medicinal plant and fungal species can certainly add to the therapeutic repertoire of the Western physician.

We hope this review will prepare you to understand and incorporate certain herbs to improve the symptoms of patients with various entities.

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A CASE REPORT

Autoimmune Pancreatitis

August 2015 • Volume XXXIX, Issue 8

Tianna E. Johnson,Kenneth M. Sigman

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Autoimmune pancreatitis is an uncommon cause of recurrent and chronic pancreatitis. It may be characterized by clinical findings resembling pancreatic carcinoma posing a diagnostic challenge to practitioners. Misidentifying autoimmune pancreatitis as pancreatic carcinoma results in unnecessary surgeries for a condition that may be managed medically. Conversely, misdiagnosis of pancreatic carcinoma as autoimmune pancreatitis delays treatment of a potentially fatal malignancy. The pathogenesis, diagnosis and treatment of autoimmune pancreatitis are discussed in the context of a case presentation and literature review. This report summarizes the diagnostic criteria required to distinguish this disease from pancreatic carcinoma. In conclusion: 1) the diagnosis of autoimmune pancreatitis requires a multidisciplinary approach, 2) autoimmune pancreatitis should be strongly considered among the differential diagnosis in patients presenting with presumed pancreatic carcinoma and 3) thorough evaluation for this condition should be pursued to determine the most appropriate treatment and avoid unnecessary surgery.

Tianna E. Johnson, D.O., Internist Kenneth M. Sigman, M.D., Gastroenterologist Authors’ Affiliations at the Time of Article Submission: Baptist Health System and Trinity Hospital

INTRODUCTION

Autoimmune pancreatitis represents a small percentage of all forms of recurrent and chronic pancreatitis.¹ It occurs due to a primary pancreatic autoimmune process or as a secondary component of a systemic autoimmune disorder.² This condition accounts for approximately six percent of chronic pancreatitis cases in the United States.¹

There are two subtypes of autoimmune pancreatitis.³ Type 1 is typically found in elderly men and is associated with systemic disease affecting extra-pancreatic organs such as the bile duct, kidneys, lymph nodes, and salivary glands.^2,3,4 Elevated serum immunoglobulin four (IgG4) is a defining feature.^2,3 Type II autoimmune pancreatitis is typically seen one decade before type I.^2,3 It is not predominant to one gender, does not involve other organs with the exception of inflammatory bowel disease and is not linked with increased IgG4 levels.^2,3 Both subtypes demonstrate lymphoplasmacytic infiltrate upon histologic examination.

The diagnosis of autoimmune pancreatitis requires a high index of suspicion and a multidisciplinary approach involving serologic tests, radiologic imaging, endoscopic imaging with tissue sampling, and sometimes surgical biopsies.¹ The Mayo Clinic proposed the HISORt criteria to help better define and confirm the presence of this disease.

Autoimmune pancreatitis is treated with corticosteroids, typically beginning with 40 mg/d of prednisone daily for four weeks.^1,3,5 The patient’s clinical status is thereafter reassessed and serologic and radiologic studies are repeated.¹ If the response is appropriate, the dose is tapered by 5 mg/week until completion.¹ Azathioprine or rituximab are used for patients who have contraindications to taking steroids or to treat recurrent relapses.¹

A 69-year old Caucasian man presented with a 10 day history of jaundice accompanied by two weeks of dark colored urine, acholic stool and pruritus. He further admitted to resolved lower abdominal pain that lasted for two weeks and 30 pounds of intentional weight loss achieved with diet and exercise. He denied fever, chills, nausea, vomiting, dyspnea, prior jaundice, joint pain, ankle edema, dysuria and hematuria. His past medical history was pertinent for anemia, gallbladder disease and hyperlipidemia for which he had been taking lovastatin for seven years until two weeks prior to his presentation. He had no other personal or family history of gastrointestinal or autoimmune disorders or diabetes. His surgical history was significant for a cholecystectomy and Nissen fundoplication for a hiatal hernia. Social history was remarkable for smoking approximately five pipefulls per day for 53 years and consuming four beers per year plus an occasional glass of wine. He denied history of illicit or intravenous drug use, tattoos, or transfusions. He had no known drug allergies

All vital signs were within normal limits upon presentation. Physical was otherwise remarkable for jaundice with no other abnormalities.

A complete blood count revealed a hemoglobin of 12.6 (14-17 gm/dL), hematocrit of 36.9 percent (42- 52 percent) and normal white blood cell and platelet counts. A basic metabolic panel was remarkable only for a potassium of 2.8 mEq/L (3.5-5.1 mEq/L). A hepatic panel showed an alkaline phosphatase of 542 U/L (50- 136 U/L), alanine aminotransferase of 133 U/L (12-78 U/L), aspartate aminotransferase of 117 U/L (15-37 U/L), and total bilirubin of 11.2 mg/dL (0.2-1 mg/dL). Repeat total and direct bilirubin were 16.6 mg/dL and 9.8 mg/dL, respectively, within the same week. His amylase and lipase were normal. His hepatitis panel was negative. His carbohydrate antigen 19-9 (CA 19-9) was 236 U/mL (normal less than 55 U/mL). Repeat CA 19-9 less than two weeks later was 709 U/mL.

Computed tomography (CT) of the abdomen and pelvis without contrast showed a prominent common bile duct and mild edematous changes in the area of the pancreatic head with a small amount of fluid in the cul-de- sac. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a lengthy stricture in the pancreatic duct suggesting a neoplasm, a malignant appearing distal bile duct stricture and a dilated proximal bile duct. Pancreatic and bile duct brushings were obtained and were negative for malignancy. Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) of the pancreatic head was subsequently performed.

The patient’s serum IgG4 level was elevated based on hospital parameters at 138 mg/dL (2.4-121 mg/ dL). The patient’s FNA pathology report of his lymph node was benign. Two histologic specimens from the pancreatic head showed chronic active inflammation but no malignancy. One of two specimens was positive for an increased number of IgG4 cells consistent with autoimmune pancreatitis. The patient was treated with steroids and responded well to this. His CA 19-9 one month later was normal at 7 U/mL. Repeat liver enzymes were also all within normal limits after one month and remained normal six months after the patient’s biliary stent removal.

DISCUSSION

Various guidelines have been established to distinguish autoimmune pancreatitis from pancreatic carcinoma. The Mayo Clinic HISORt, Japanese Pancreas Society and Kim (Korean) criteria have emerged as leading diagnostic tools.² Each share histology, imaging and serology as key diagnostic components; however, the Mayo Clinic model places more emphasis on core biopsy and response to steroid therapy.² The Japanese strategy is more dependent upon imaging; steroid therapy is considered optionally inclusive.¹ The efficacies of these criteria are reliant on the clinicians’ expertise.¹ Both have similar trends of algorithmic progression to surgical intervention for suspected malignancy, with the Mayo Clinic and Japanese models having resection rates of 16.7% and 16.2%, respectively.¹

Autoimmune pancreatitis presents diversely. Painless obstructive jaundice is noted in approximately 70% of patients.⁶ A third of individuals report abdominal pain and weight loss.⁶ Others are asymptomatic and are incidentally found to have laboratory derangements.⁶ Extreme cachexia, anorexia, and severe pain necessitating narcotics for relief are less suggestive of autoimmune pancreatitis.² A lack of alcohol abuse or family history of pancreatitis further support the diagnosis of autoimmune pancreatitis.^7,8

Increased serum IgG4 is the best serologic diagnostic marker for autoimmune pancreatitis; however, one study reports that only 44% of patients initially presenting with this disease had elevated levels.^2,3 Serum IgG4 can also be elevated in pancreatic cancer.² Guidelines therefore endorse a level above two times the upper limit of normal as being highly suggestive of autoimmune pancreatitis.^2,3 Additionally, CA 19-9, often elevated in pancreatic cancer, may also be increased in autoimmune pancreatitis, but tends to decline with steroid treatment.² An escalating CA 19-9 suggests malignancy rather than autoimmune pancreatitis.²

Core biopsy is considered the best mode of obtaining specimens to assess for autoimmune pancreatitis while fine needle aspiration is preferred for evaluating for pancreatic carcinoma.⁶ In the absence of malignant histology, biopsy samples demonstrating lymphocytic and plasma cell infiltrates along with fibrosis support the diagnosis of autoimmune pancreatitis especially when plasma cells are positive for abundant IgG4.¹

Multiple imaging modalities have been used for the evaluation of autoimmune pancreatitis and preferences vary geographically.² CT, ERCP, MRCP (magnetic resonance cholangiopancreatography) and EUS are commonly utilized.^1,6,7 Classic findings for autoimmune pancreatitis on CT and MRCP include a pancreas that is diffusely enlarged with a rimmed capsule coupled with diffusely attenuated pancreatic duct; however, this disease can be represented by a wide radiographic spectrum.^4,7 Pancreatic cancer is more likely to have a low attenuation mass and pancreatic ductal dilatation.²

Two to five percent of patients undergoing surgical resection for presumed malignancy are later discovered to have autoimmune pancreatitis.^2,3 Some researchers propose that patients in this category have increased likelihood of postoperative complications such as diabetes and are at higher risk of needing additional invasive interventions later.^6,8 Some of the major causes for the misdiagnosis of this condition are a lack of awareness of the disease or a widely accepted consensus of diagnostic criteria.⁶

CONCLUSION

Autoimmune pancreatitis is an under-recognized form of recurrent and chronic pancreatitis that can be medically managed. Though less prevalent than pancreatic carcinoma, it must be considered among the differential diagnoses for patients with questionable malignancy as early recognition may prevent unnecessary surgeries for presumed cancer. Distinguishing autoimmune pancreatitis from pancreatic carcinoma and other causes of pancreatitis remains a diagnostic challenge that requires a high index of suspicion along with a multidisciplinary approach. New diagnostic criteria
with increased sensitivity and specificity are needed to more definitively distinguish autoimmune pancreatitis from pancreatic carcinoma and to reduce morbidity and mortality.

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UNUSUAL CAUSES OF ABDOMINAL PAIN, #9

Unusual Causes of Abdominal Pain

August 2015 • Volume XXXIX, Issue 8

Stanley Yakubov,Rabin Rahmani

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Stanley Yakubov MD, Rabin Rahmani MD, Maimonides Medical Center, Brooklyn Campus of Albert Einstein College of Medicine, Brooklyn, NY

CASE

A 43 year old male with no past medical history presented to ER complaining of right lower quadrant pain for 3 days. He described the pain as sharp, constant, 8/10 in intensity, non-radiating, localized to the right lower quadrant, associated with nausea and worsened with coughing. He denied associated fevers, vomiting, diarrhea or constipation.

Vital signs on presentation showed temperature 98.1°F, blood pressure 130/84 mmHg, heart rate 80 beats/min, and respiratory rate of 20 breaths/min. On physical examination his abdomen was tense, non- distended, and normal bowel sounds were present. Patient was tender in RLQ with positive guarding, but no rebound. He was Dunphy’s sign positive. No tenderness at McBurney’s point noted. Rovsing’s sign, Obturator sign and Psoas sign were negative. No visible or palpable hernias were noted with and without coughing. The remainder of physical examination was unremarkable. Laboratory analysis showed a white blood cell (WBC) count of 9.5 K/Ul with 39% neutrophil count. The remainder of the laboratory tests were within normal limits. CT scan of Abdomen/Pelvis with contrast confirmed the diagnosis. Patient improved with conservative treatment and NSAIDS.

ANSWER AND DISCUSSION

Around 5% of all ER visits are due to a complaint of acute abdominal pain. Epiploic appendagitis (EA) also known as appendixes epiploica, hemorrhagic epiploitis, epiplopericolitis and appendicitis epiploica, is a fairly rare, benign condition of the epiploic appendages that occurs due to torsion or spontaneous venous thrombosis of a draining vein of the epiploic appendage. The resulting strangulation and inflammation leads to localized abdominal pain.

EA most commonly occurring in the second to fifth decades of life, with slightly higher incidence in middle aged males, although, it can affect anyone including young and healthy individuals. Obesity and heavy exercise are thought to be potential risk factors. First described by Vesalius in 1543, about 100 pedunculated fatty structures, also known as epiploic appendages, protrude from the serosal surface of the colon from the cecum to the recto-sigmoid junction. The average length of epiploic appendage is 3 cm, but can be as long as 15cm in length. Clustering in the sigmoid and cecal regions is what leads to the mistaken diagnosis of diverticulitis and appendicitis when the epiploic appendages become torsed or inflamed. Patients most commonly present with acute abdominal pain, more often in the left lower than right lower quadrant, without associated leukocytosis or fever. One-third of patients will have an elevated C-reactive protein.

EA is recognized and diagnosed with the use of ultrasound or CT scan, with CT scan being more sensitive and specific. EA should be entertained when diverticulitis, appendicitis and other causes of acute abdomen are ruled out. On CT scan EA presents as an oval shaped fat density, paracolic mass with fat stranding and thickened peritoneal lining. In addition, a central hyper-attenuating dot representing an engorged or thrombosed draining vein may be seen on CT. Complete resolution of symptoms typically occurs within 2 weeks with conservative treatment, primarily anti- inflammatory agents. No hospitalization or antibiotic use is required. Improved awareness of EA presentation as an acute abdomen will prevent unnecessary medical procedures and surgical interventions.

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A CASE REPORT

Staghorn Renal Calculus with Xanthogranulomatous Pyelonephritisand Renocolic Fistula

August 2015 • Volume XXXIX, Issue 8

Risheng Xu,Khawaja Azimuddin

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Risheng Xu, DO Former Triton Hospitalists at the Houston Methodist Willowbrook Hospital, University of Texas HSC at Houston Lyndon B. Johnson Hospital Academic Hospitalist Khawaja Azimuddin, MD FACS FASCRS Northwest Colon- Rectal Surgery Physician Association, Houston, TX

Reno-colic fistula is rare, and even fewer cases were reported in association with staghorn stones and xanthogranulomatous pyelonephritis (XGP). Here we present a case of reno-colic fistula initially presented as recurrent urinary tract infections (UTI) at outside facility and empirically treated with antibiotics without improvement. Patient was admitted to us and found to have staghorn renal calculus with renocolic fistula and pathology features of XGP. Renocolic fistulas complicating staghorn calculus and in association with features of XGP are rare. Although they may present as recurrent UTIs initially, further work up to rule out a fistula should be entertained as imagine modalities are limited in initial diagnosis of fistulas. A high clinical suspicion to rule out fistula should be kept when initial imaging shows staghorn calculus with XGP features. Repeat imaging with contrast is helpful in evaluating renocolic fistulas. Treatment involves nephrectomy with partial colectomy. Post operative prognosis is generally good.

INTRODUCTION

Renocolic fistula is a rare clinical entity. The initial presentation could be abdominal pain, hematuria, pyuria and flank pain which may mimic urinary colic secondary to nephrolithiasis or urinary tract infection. Here we present a case of a female patient initially diagnosed with urinary tract infection who was later found to have obstructive hydronephrosis due to large staghorn calculus, imaging features of xanthogranulomatous pyelonephritis (XGP) and renocolic fistula. She was subsequently treated with aggressive antibiotic therapy and surgical management with excellent recovery.

Presentation of Case

A 50 year-old female with remote history of nephrolithiasis presented to our hospital with a two- week history of dysuria, hematuria and abdominal pain radiating to the left flank. A few days prior to admission, she was seen at outside facility emergency department and was diagnosed with a urinary tract infection (UTI). She was given nitrofurantoin and discharged home. The patient completed the course of antibiotics but showed no clinical improvement and subsequently presented to our hospital for reevaluation. She denied fever and her abdominal exam was normal, except for left costovertebral angle percussive tenderness. On initial check, her white blood cell count was 10,000 with no left shift, and her urinalysis revealed 3+ protein, large blood, large leukocyte esterase, >200 WBC and 177 RBC with few bacteria and many white cell clumps. The patient had a non-contrast computed tomography (CT) of the abdomen and pelvis which showed a large, 4 cm staghorn calculus within left kidney, and an enlarged left kidney with hydronephrosis. Air was noticed within the inferior pole calices with surrounding perinephric fat stranding concerning for emphysematous pyelonephritis and features of XGP. Repeat CT with intravenous contrast revealed extrarenal extension of the infection into posterior perinephric and pararenal spaces and into the quadratus lumborum muscle with an abscess of 5.3 x 2.1 x 5.7cm. A percutaneous nephrostomy tube was placed. Post procedure imaging confirmed appropriate placement of the tube but contrast was noted to be in the descending colon (Figure 1) and in the previous abscess in the posterior abdominal wall, without apparent injury from nephrostomy tube.

Urine culture yielded Proteus mirabilis, which was empirically treated with broad-spectrum antibiotics. Given the imaging findings, exploratory laparotomy with left nephrectomy and segmental left colon resection was performed. The resected left kidney eventually showed XGP features on pathology. Cultures obtained during laparotomy subsequently grew Streptococcus bovis and Bacteroides fragilis. The patient tolerated the surgical procedure well, and no postoperative complications occurred. Eventually, antibiotics were simplified to oral ciprofloxacin and metranidazole and she was discharged from the hospital in ambulatory status. The patient was doing well 6 weeks post operatively.

DISCUSSION

Renocolic fistulas complicating XGP are rare. To our knowledge, less than 10 reports have been published thus far, and there is no large case series in English medical literature. Renocolic fistulas have been described since Hippocrates’ time in 460 A.D. Since its initial description, there have been more than 100 cases described.^1,9 Many cases of renocolic fistulas were suspected to be secondary to chronic tuberculosis (TB) infections in pre-modern time.⁸ Modern cases of fistulas were associated with chronic XGP, nephrolithiasis, iatrogenic cause due to procedures, abdominal trauma and renal and colonic malignancy.^9,10 Of these suspected causes of renocolic fistula, a majority of cases were reported with presence of XGP.

Xanthogranulomatous pyelonephritis was first described in 1916 by Schlagenhaufer.⁵ It is a variant of chronic pyelonephritis and is characterized by chronic inflammatory destructions of renal parenchyma and replacement with granulomatous tissue containing histiocytes and foamy cells. The exact etiology is unknown, but XGP is suspected to be caused by UTI, chronic urinary obstruction, hyperlipidemia, altered immune response, vascular occlusion and nephrolithiasis including staghorn calculus.^1,2,3

XGP has a female prevalence, and has been reported to occur more in the 5 through 7th decades, but rarely in the pediatric population.^1,4 Malek and Elder et al. have described a classification system of XGP (Chart 1). The exact pathogenesis of XGP causing renocolic fistula is unknown. It has been postulated that the chronic inflammatory and destructive process of the renal parenchyma and eventual perforation of the renal capsule with abscess formation and direct contact with colon is the cause of renocolic fistula.⁹

The clinical presentation of XGP is variable, mostly mimicking UTI symptoms, but the presence of gastrointestinal complaints rarely exist. Urinalysis usually shows pyuria and urine culture most commonly show E. Coli and Proteus mirabilis.^1,6,7,8 Before the presence of effective tuberculosis treatment, many cases were associated with TB infection.⁹

Multiple imaging modalities have been used in the diagnosis of renocolic fistula, however yields have been limited. Intravenous pyelography (IVP) and contrast CT have been the most commonly utilized and reported imaging studies. Due to rarity and subtlety in clinical presentation, majority reported cases presented without initial radiographic evidence of fistula and XGP, and diagnosis was only confirmed on pathological tissues after nephrectomy.^6,7 Retrograde pyelography has been reported to be helpful in confirming renocolic fistula.¹² In our case, we were fortunate to have seen contrast in the perinephric space and descending colon as well as abscess formation within quadratus lumborum muscle.

The general treatment approach in patients with renocolic fistulas is to perform nephrectomy and partial colectomy simultaneously.¹ Often, as in our case, treatment with broad spectrum of antibiotics may be necessary to stabilize or transition the patient to surgery.

CONCLUSION

Renocolic fistula complicated by XGP is rarely reported. Most cases of XGP were associated with obstructive nephrolithiasis and chronic UTI, especially in the presence of staghorn formation. Renocolic fistula should be considered in patients presenting with imaging evidence of XGP and staghorn calculus with recurrent UTIs. IVP and contrasted CT imaging have been reported in making diagnosis but with limited yields. When additional imaging is needed, retrograde pyelography has been reported to be helpful in confirming renocolic fistula. Nephrectomy and partial colectomy is the treatment of choice and usually with good clinical outcomes.

Acknowledgement

We would like to thank Houston Willowbrook Methodist Hospital Department of Radiology in helping with obtaining imaging used in this report.

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GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #10

Making Sense of Patients with Gas and Bloating of Undetermined Origin

August 2015 • Volume XXXIX, Issue 8

Juan Castro-Combs,

Evelyn Eichler,

Richard W. McCallum

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Unexplained bloating is one of the most common and bothersome gastroenterology complaints in gastrointestinal (GI) specialty and primary care clinics. This article attempts to provide physicians with a simple and rational approach to unexplained abdominal bloating and to identify underdiagnosed entities that could be responsible for this symptom.

Unexplained bloating is one of the most common and bothersome gastroenterology complaints in gastrointestinal (GI) specialty and primary care clinics. Abdominal bloating is likely to present in association with other complaints including belching, flatulence, post-prandial distension, borborygmi, abdominal pain and diarrhea. Given the lack of a systematic approach to these complaints, symptomatic patients are often asked to keep a food diary and dietary modifications are suggested. If symptom resolution does not occur, further testing (blood and stool tests, imaging studies, endoscopic procedures) to rule out organic disorders is initiated. A “negative” or unremarkable work up often places patients into the “functional” GI disorder compartment. This article attempts to provide physicians with a simple and rational approach to unexplained abdominal bloating and to identify underdiagnosed entities that could be responsible for this symptom.

Juan Castro-Combs, MD¹ Evelyn Eichler MS, RD, LD² Richard W. McCallum, MD, FACP, FRACP (Aust), FACG³ ¹Texas Tech University Health and Sciences, Internal Medicine Department, Gastroenterology ²University Medical Center, Food and Nutrition Care Services ³Texas Tech University Health and Sciences, Department of Internal Medicine, Gastroenterology, Center for Neurogastroenterology and GI Motility, El Paso, TX

INTRODUCTION

Abdominal bloating is a nonspecific term whose definition varies among gastroenterologists with an even broader meaning for patients in general. Bloating can be defined as the objective abdominal distention originating from gas or as a subjective feeling of abdominal distention or abdominal wall tension without objective distension. These symptoms have been linked with different pathophysiologic mechanisms that are not fully understood. Several functional gastrointestinal disorders (functional dyspepsia,^1,2 irritable bowel syndrome (IBS),^1,2,3 functional constipation^1,2,4,5 and functional bloating⁶) have bloating as a manifestation despite the absence of a somatic abnormality.

Bloating is likely to present in association with other nonspecific GI complains including belching, flatulence, borborygmi, abdominal pain, nausea and diarrhea. Patients with such gastrointestinal (GI) symptoms, especially those with alarm symptoms, usually undergo multiple studies to rule out organic disorders. Testing includes but is not limited to blood work, stool tests, imaging studies and endoscopic procedures. When these tests fail to expose any abnormality, patients are diagnosed with functional GI disorders.

Carbohydrate intolerance or malabsorption and small bowel bacterial overgrowth (SIBO) are common problems frequently encountered in the GI and primary care clinics. These disorders are responsible for bloating as well as other unspecific symptoms. Their exact prevalence is unknown because they are poorly recognized and, as a consequence, are poorly managed. The current report attempts to provide physicians with a rational approach to address these GI symptoms and to identify underdiagnosed or underappreciated entities before patients are placed into the GI functional disorders compartment where further investigations may be limited.

Small Intestinal Bacterial Overgrowth

SIBO is the presence of excessive bacteria in the small intestine, defined as a bacterial population, possibly colonic-type species, exceeding 10⁵-10⁶ organisms/ml in jejunal fluid.^7,8 Symptoms of SIBO are nonspecific and include bloating, abdominal distension, abdominal pain or discomfort, diarrhea, constipation, fatigue and weakness. The severity of symptoms likely reflects the degree of bacterial overgrowth and the extent of mucosal inflammation.

Risk factors for SIBO include GI tract structural or anatomic abnormalities (e.g. small bowel diverticulosis, strictures), post-surgical changes (e.g. vagotomy, Bilroth I and II anastomoses, bariatric surgery, gastro- jejunostomy, colectomy with ileocecal valve resection), radiation damage to the small bowel, motility disorders (e.g. gastroparesis, small bowel dysmoltility), systemic diseases that affect bowel motility (e.g. diabetes, scleroderma, amyloidosis), IBS, cirrhosis, pancreatitis, immunodeficient states, hypochlorhydria (e.g. atrophic gastritis, proton pump inhibitor (PPI) use), advanced age which may overlap with hypochlorhydria, recurrent antibiotic use and medications that decrease motility (e.g. narcotics, anticholinergics) (Table 1).

The presenting symptoms of SIBO can sometimes also reflect the underlying cause (e.g. abdominal pain, early satiety and vomiting may point towards gastroparesis or small bowel dysmotility). Other symptoms can reflect complications of SIBO, including malabsorption, nutritional deficiencies (e.g. B12 related anemia) and metabolic bone disorders.⁹ The nonspecific nature of these complaints makes SIBO difficult to distinguish clinically from other disease entities, such as IBS, lactose intolerance and fructose intolerance.

Fructose Malabsorption

Dietary fructose intolerance (DFI), although its role is somewhat controversial, is often implicated in the causation of GI symptoms. Several studies reported a prevalence of fructose malabsorption in patients with the diagnosis of functional dyspepsia or unexplained GI symptoms between 40 and 73%.^10,11 Another study has estimated that up to one third of patients with suspected IBS had DFI.¹²

Undigested or poorly digested fructose generates an osmotic force driving water into the lumen of the small bowel and leading to decrease transit times of bowel contents which then reach the colonic flora producing fermentation of this carbohydrate.¹³ This may result in symptoms including abdominal pain, excessive gas, bloating and variable diarrhea, especially in patients with visceral hypersensitivity.¹⁴

Symptoms, and self-rated health, improve if patients are willing to adhere to a low fructose diet.¹⁵ Fructose is present in a variety of fruits, vegetables and honey but it is also produced from the digestion of high fructose corn syrup, commonly found in processed food. The amount of fructose in the diet of the average American has definitely increased during the last 50 years when high fructose corn syrup was introduced to the food industry in the late 1960s. GI symptoms might develop after the consumption of 37.5 gm of fructose per day¹⁶ (for reference, an 8 ounce can of Coca-Cola contains 25 gm of fructose). It is possible that a rise in fructose consumption in the United States (US) population has resulted in a rise in fructose malabsorption and intolerance.¹⁰

Breath Testing

Hydrogen breath tests are currently utilized as diagnostic tests to confirm or eliminate the possibility of carbohydrate malabsorption or SIBO in such patients. Currently available breath tests include: lactose, fructose (FBT), lactulose and glucose.

Lack of standardization has led to subjectivity of these tests and institutional comparisons are difficult given the variability of parameters such as the dose of substrate administered, duration of the test, the interval of breath testing and cut-off values.¹⁷

The breath tests measure hydrogen (H₂), methane (CH₄) and CO₂ present in the exhaled air. H₂ is a common gas produced by bacteria during the metabolism of these carbohydrates; conversely, methanogenic flora is far less common and has been described to be present in up to 30% of patients with Scandinavian descent and in less than 10% of US population. By adding methane measurements the sensitivity of the tests is increased. CO₂ level is determined to ensure that the sample measures actual alveolar air to assure accuracy of breath samples.

The glucose hydrogen breath test (GBT) is more acceptable for diagnosis of SIBO whereas lactose and fructose hydrogen breath tests are used for detection of lactose and fructose maldigestion respectively. Lactulose hydrogen breath test has been used for SIBO as well but glucose breath test has greater advantages over lactulose because of its higher specificity. Lactulose breath test is also used in GI motility to measure the orocecal transit time. These methods are noninvasive and inexpensive. Breath tests, though valuable tools, are underutilized in evaluating dyspepsia, functional bloating and diarrhea as well as suspected malabsorption.

Our extensive experience with glucose breath testing to rule out SIBO has indicated us that the optimal protocol should include the administration of a 100 gm oral glucose challenge with collection of breath samples every 20 minutes for 3 hours to measure hydrogen and methane concentrations. Over the last 2 two years we have performed this study in 188 patients presenting with unexplained abdominal bloating to our motility Center at University Medical Center at Texas Tech Health and Sciences, El Paso. We found that 85 of these patients were positive for SIBO representing 45% of the total of patients tested. A glucose breath test was considered to be positive if there was an increase in hydrogen concentration exceeding 20 parts per million (ppm), an increase over 10 ppm for methane or when the baseline values are >20 ppm. 38 of these patients with negative glucose breath tests and unexplained bloating underwent further testing using fructose breath tests (FBT) performed after 25 gm fructose oral administration with collection of breath samples in the same fashion. 18 out of the total 38 patients were found to be FBT positive. This represents 47% of the FBTs evaluated. The parameters utilized for a positive fructose test include H₂ or CH₄ peaks of more than 20 ppm and 10 ppm respectively. Usually these peaks occur in the range of 90 min to 3 hours after fructose intake when unabsorbed fructose is metabolized by colonic flora.18

Approach to Abdominal Bloating, Gas and Distension

Patients with abdominal distension, bloating and excess gas, with or without additional GI symptoms, often have a negative GI work up. Evaluation may include laboratory tests for hypothyroidism, stool tests for bacterial, helminthic and protozoa infections, imaging for bowel obstruction or ascites, endoscopy for common disorder such as celiac disease, H. pylori infection and lactose intolerance exclusion through a dairy free diet.

As a next step in evaluating bloating without a determined etiology, a GBT to assess for SIBO could be performed. A positive GBT may indicate the presence of excess bacteria in the small bowel requiring appropriate antibiotic treatment. Acceptable antibiotic regimes include metronidazole 500 mg PO BID, neomycin 500 mg PO BID, amoxicillin/clavulanic acid 500 mg PO BID, doxycycline 100 mg PO BID or rifaximin 400 mg PO TID (non-standard dosing)^19,20,21 for 2 to 3 weeks. (Table 2) Refractory symptoms in the setting of a repeat positive GBT may require an alternative antibiotic or combination therapy. Patients with continued symptomatic or recurrence may benefit from 1) gastric and small bowel prokinetics (eg. low dose erythromycin, metoclopramide or pyridostigmine) in settings of gastric or small bowel motility disorders, 2) treating constipation with linaclotide or lubiprostone, 3) probiotics, specifically containing bifidobacterium infantus, 4) discontinuing PPI to reduce hypochlorhydria which promotes the possibility of bacterial colonization of the small bowel and 5) stopping or decreasing doses of anticholinergic drugs and/or narcotics which reduce gut motility and enhance bacterial colonization. A negative GBT may prompt a FBT. A positive fructose test would indicate the presence of fructose intolerance and should trigger the treatment with a low fructose diet. A patient with a negative FBT on the other hand may be empirically treated with a low FODMAP diet to assess if there is any improvement of symptoms. Hence the algorithm we illustrate can unmask the presence of DFI and see if a less restrictive diet would help before recommending a more demanding low FODMAP diet (Figure 1).

Dietary Management

A low fructose diet is a less restrictive alternative than the low FODMAP diet since it only limits the consumption of fructose from some fruits (e.g. prunes, pears, cherries, peaches, apples, plums, dates, mango, watermelon) vegetables (e.g. sugar snap peas, tomatoes, corn, carrot, sweet potatoes) honey and other processed foods with fructose on the label.

FODMAPs (fermentable oligosaccharides, disaccharides, monosacharides and polyols) are osmoticaly active carbohydrates that are high in fructose (e.g. honey, peaches, dried fruits), fructans (e.g. wheat, rye, onions), sorbitol (e.g. dried fruits, sugar alcohols and sweeteners), and rafinose (e.g. lentils, cabbage, legumens). The high osmolality of FODMAPs leads to increased water in the small bowel, decreasing transit time resulting in increasing gas and colonic distention from bacterial fermentation of poorly absorbed carbohydrates.¹³ This diet limits the consumption of high fiber foods such as beans, fruits, vegetables and grains. The low FODMAP diet implementation is flexible and can be tailored to meet individual’s lifestyle and preferences.

The low FODMAP diet was developed by a research group in Australia as a new dietary management of IBS and other functional gastrointestinal disorders with bloating and abdominal pain.²² A pilot study showed that a low FODMAP diet led to sustained improvement in all gut symptoms in 86% of the patients diagnosed with IBS compared to the standard diet group of 49%.¹⁹

Subsequently several high-quality clinical studies have further confirmed that FODMAP diet allows drug-free symptom relief in many patients with IBS.^23,24,25

A typical approach in the implementation of the low FODMAP diet would involve restricting problematic (elimination diet) FODMAPs for 6 to 8 weeks, or until symptomatic control is achieved. This is performed by substituting high FODMAP foods with lower options or by reducing the total FODMAP load consumed in each meal or across the day. After this, small amounts of FODMAP-containing foods are reintroduced through challenges. The aim of challenging is to gradually increase to levels well-tolerated by the individual, while widening the diet as much as possible.

Food Sensitivity

Food sensitivity is an evolving science in nutrition, and it is different than food allergy or food intolerance. Food allergy is an IgE mediated immune response that occurs reproducibly on exposure to a given food, with a physiological response usually within 2 hours of exposure. Food intolerance can be due to lack of enzymes or bacterial changes. Food sensitivity is a reaction from an assault to the gut from food irritants, toxins (mold, pesticides), infections (SIBO), pharmacological decreases and increases in gut permeability, malabsorptions and psychological stress. True food sensitivity is a non-IgE adverse food reaction, where the individual may or may not have an initial reaction because it is usually delayed and dose dependent. Symptoms of food sensitivity can be similar to a food allergy resulting in skin changes, but it may also be systemic causing fatigue, asthma, migraines and body aches.

Serum testing for IgG and IgE antibodies to specific food antigens has been performed in the past with some degree of success. In a study in which 20 IBS patients unresponsive to standard therapy where enrolled, IgG and IgE levels to different food and mold panels were obtained. The most frequent positive serologic IgG antigen-antibody complexes in the study were: 4 or more molds, baker’s yeast, onion mix, pork and peanut. These patients underwent targeted elimination diet followed by controlled food challenges and were followed at 1 year after trial completion with a questionnaire. This approach resulted in a sustained clinical response and improvement in overall well-being and quality of life.²⁶ These specific testing and treatment for food sensitivities really comes into play where breath testing has not been fruitful and other GI medical diagnoses are excluded. Determination of IgG serum antibodies to food constituents, elimination diets and re-challenge play a role in food sensitivity approaches.

Take Home Pearls

When the standard gastrointestinal work up for bloating of undetermined origin fails to expose any abnormality, providers should consider SIBO and DFI before patients are placed into the functional GI disorder compartment. Glucose and fructose breath tests are specific and sensitive diagnostic tests that can be used to either confirm or eliminate the possibility of SIBO or fructose intolerance in such patients.

For refractory cases of SIBO, the authors recommend to improve GI motility with low dose prokinetics when gastroparesis and/or small bowel dysmotility are present; chronic constipation should be aggressively treated if present; bifidobacterium infantus containing probiotics should be started to augment host defense; PPI should be tapered or stopped when possible to improve hypochlorhydria. Additionally, stop or attempt to decrease dose of anticholinergic drugs and/or narcotics when possible.

A positive fructose test would indicate the presence of fructose intolerance and should result in treatment with a low fructose diet. A negative FBT on the other hand should lead to a trial with the low FODMAP diet to assess if there is any improvement of symptoms. Finally food sensitivity and “food allergy” are a consideration to provide a rational approach for the practitioner.

We hope this article enlightens our readers and most of all we hope it improves the caring treatment and quality of life of your patients with abdominal bloating.

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #96

Inflammatory Bowel Disease in the Elderly: Hazards of Generalizing the Evidence

August 2015 • Volume XXXIX, Issue 8

Vineet S. Gudsoorkar,

Bincy P. Abraham

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Several challenges exist in managing the geriatric population with inflammatory bowel disease (IBD). The physiology of aging affects not only disease expression, but also the treatment and surveillance strategies. The existing evidence for their treatment is extrapolated from studies that often suffer from a suboptimal representation of this patient subgroup. In this review, we discuss the existing evidence for IBD in the elderly and the potential hazards of its unchecked extrapolation to, arguably, a more fragile and susceptible population.

Vineet S. Gudsoorkar, MD, Gastroenterology Fellow, Houston Methodist Hospital. Bincy P. Abraham, MD, MS, FACG, Director, Gastroenterology Fellowship Program Director, Underwood Center – Fondren Inflammatory Bowel Disease Program, Houston Methodist Academic Gastroenterology Office, Houston, TX

The prevalence of inflammatory bowel disease (IBD) in the elderly population is on the rise. Several challenges exist in managing the geriatric population with these chronic disorders. The physiology of aging affects not only disease expression, but also the treatment and surveillance strategies. Despite such considerations, which are unique to elderly IBD patients, the existing evidence for their treatment is extrapolated from studies that often suffer from a suboptimal representation of this patient subgroup. In this review, we discuss the existing evidence for IBD in the elderly and the potential hazards of its unchecked extrapolation to, arguably, a more fragile and susceptible population.

INTRODUCTION

Ulcerative colitis (UC) and Crohn’s disease (CD) collectively referred to as inflammatory bowel disease (IBD), continue to pose significant challenges to the healthcare system. The latest estimates show that IBD affects approximately 1.2 million Americans.¹ Despite such extensive burden, our understanding of the pathogenesis of IBD remains incomplete; and although significant strides have been made in the field of therapies aimed at keeping the disease under control, no definite cure has yet been identified. With the advent of new therapies, the epidemiology of IBD appears to be changing; and with improved patient longevity, gastroenterologists are expected to encounter more and more elderly patients with IBD in their clinical practice. Yet, there remains a remarkable paucity of literature focusing primarily on the geriatric IBD patient population.

Changing Epidemiology: A Function of Overall Survival, or Missing Links in Pathogenesis?

Classically, IBD has been thought to carry a bimodal distribution of incidence with a peak in the 2nd- 4th decade of life, followed by a smaller second peak in the 6th- 7th decade. As the etiology of IBD is considered multifactorial involving interactions between environmental influences, adaptive and innate immunity, and genetics; the exact reason of such bimodal distribution is unclear.² Current epidemiologic studies demonstrate that approximately 10-15% of the newly diagnosed IBD patients are above 60 years of age.³

One such study analyzing over a decade of data in the Department of Veterans Affairs suggested that the incidence of IBD has stabilized in the USA, but there appears to be an increase in the prevalence.⁴ Considering IBD is a chronic disease without a significant direct mortality risk, this can be thought of a direct result of increased survival.

Such change in epidemiology of IBD has several direct and important implications that affect short and long-term management of the disease. In the age of evidence-based medicine, the older, and arguably more fragile patient population has the least amount of evidence on management of IBD.

IBD in the Elderly: Hazards of Generalizing the Evidence

Despite the rising prevalence of IBD in the geriatric population, evidence- based data specifically addressing the management of older IBD patients is scarce. The reasons for such scarcity are manifold, starting with the definition of the term “elderly”. In the literature, the age cut-off for defining the elderly population has been variable, ranging most commonly from 50 to 65 years of age. Without a standardized cut-off, the generalizability of evidence remains limited.

Similarly, the current opinions on the management of such patients are derived from subgroup analyses of clinical trials involving the general population. Geriatric patients are often excluded or poorly represented in such trials. A valid statistical analysis cannot be performed of the outcomes in non-predefined subgroups. Additionally, at extremes of the age distribution curve the statistical power is expected to be quite low given the low number of the patients analyzed.

Apart from statistical considerations, applying the results of clinical trials to the geriatric population would fail to take into consideration age-related physiologic changes such as alterations in pharmacokinetics of the medications, physiology of aging, presence of comorbidities and importantly, quality of life. This article aims at exploring practical considerations and caveats in application of current management principles of IBD to the geriatric population.

IBD in the Elderly:Review of Evidence and Caveats

Despite the limitations outlined above, given the lack of data addressing exclusively the geriatric population clinical decisions are often made extrapolating the current available evidence to the elderly population. The following section reviews the available evidence and problems unique to the elderly.

a) Disease Characteristics

The disease phenotype of IBD in elderly is distinct from that in the young. Several factors may account for such difference: immune senescence, less contribution of genetic influences and possibly, altered environmental factors such as the gut microbiota. Compared to the younger patients (17-59 years old), the elderly-onset patients with CD tend to have ileocolonic or colorectal involvement, less frequent involvement of the upper gastrointestinal tract, and a less aggressive disease course with relatively lower rate of progression to stricturing or penetrating disease.^5,6 Similarly, compared to the younger patients the elderly onset UC patients tend to have more limited (proctitis or left sided) colonic disease and also seem to have a less aggressive disease course.^5,6 Such key differences in epidemiology, disease phenotype and disease progression highlight the heterogeneity of the disease among the different age groups.

b) Medical Therapy: Drug Metabolism, Eficacy and Safety Considerations

Important pharmacokinetic changes in the elderly population result from the physiology of aging. These physiologic alterations include changes in body composition such as reduced lean body mass and subsequent reduction in total body water, reduced first-pass metabolism and a reduction in renal mass and glomerular filtration rate (GFR).⁶ Also, the elderly patients are frequently on a variety of other medications increasing the risk of drug-drug interactions in the setting of altered pharmacodynamics.

5-Aminosalicylic acids

Oral 5- aminosalicylic acid (5-ASA) derivatives are used in the treatment of active disease as well as for maintaining remission in CD and UC, although their therapeutic utility appears to be more evident in UC.^7,8 The safety and efficacy of the various 5-ASA formulations appear to be uniform across all patient populations without any significant age-related variations.⁹ Older data from rheumatoid arthritis patients treated with sulfasalazine suggest that the elderly patients have higher steady-state concentration of its metabolites;¹⁰ however has not been observed with the newer 5-ASA (mesalamine) formulations. Pharmacokinetics of 5-ASA may not be very relevant from an efficacy standpoint as most of its therapeutic effect is topical in nature and pharmacokinetic variations may be driven more by genetic influences (such as enzymatic polymorphism) rather than age.¹¹ Nephrotoxicity, which is perhaps the most concerning adverse effect of these compounds, occurs at an incidence of less than 1 in 500.¹¹ A recent retrospective study showed that there was a significant dose- and treatment duration- dependent decline in creatinine clearance (CrCl) in IBD patients treated with 5-ASA. Although the patient age at treatment onset did not significantly affect the CrCl, a pre-treatment renal dysfunction correlated with a greater decline in CrCl.¹² To conclude, ASA drugs remain a reasonable option in the armamentarium of clinicians treating geriatric IBD patients but close monitoring of renal function, particularly during the initiation of therapy and yearly thereafter is warranted considering the physiological decline in renal function in this age group.

Antibiotics

Antibiotics are frequently used to treat infectious complications of IBD such as abscesses, fistulizing CD, and pouchitis in UC. Metronidazole and ciprofloxacin have been the most studied in IBD. Their role in modifying the primary disease process is controversial although alteration of gut microbiota has been recently suggested as a putative mechanism for their actions. Metronidazole is eliminated mainly via hepatic metabolism. Data regarding the influence of age on its pharmacokinetics, derived mainly from non-IBD patient population, suggest a decreased renal excretion of metronidazole and its metabolites in the elderly,¹³ although age-dependent dose adjustment is not common.

Ciprofloxacin, on the other hand, is eliminated renally. While some studies have shown an increased serum concentration, slower renal clearance, and prolonged half-life of ciprofloxacin in the elderly, recommending a dose frequency of not less than every 12 hours;¹⁴ whereas others did not find such difference its elimination half-life, and attributed the higher serum concentration to a lower volume of distribution.¹⁵ Considering the physiologic decline in GFR, attention should be paid to the dosage even in the absence of overt renal insufficiency given that adverse effects of quinolones such as diarrhea can often be mistaken for a flare of the underlying IBD. Additionally, older age (>60 years) and concurrent steroid use are known risk factors for tendonopathy associated with quinolones.¹⁶

Clostridium difficile infection remains an important risk associated with antibiotic use. Other important risk factors include older age, fluoroquinolone exposure, and immunosuppression. These place the geriatric IBD patients at a significantly higher risk of acquiring C. difficile infection which, in addition to confounding the underlying disease activity assessment, is associated with a greater morbidity, mortality, healthcare costs as well as need for colectomy.¹⁷

Corticosteroids

Corticosteroids have long been used to induce remission in the treatment of IBD, which is either severe or unresponsive to 5-ASA therapy. The risks associated with prolonged steroid use in general population are well known. In the geriatric population steroids have been associated with increased relative risk for developing adverse effects such as hypertension, diabetes, altered mental status as compared to younger (< 50 years old) patients.¹⁸ Additionally the age-specific incidence rate ratio (IRR) of osteoporotic fractures is 40% higher in all IBD patients as well as the elderly subgroup (>60 years of age) compared to the age- and sex- matched general population. The incidence of fractures in IBD patients increases with age.¹⁹ Chronic use of steroids, combined with vitamin D deficiency, which is often coexistent in IBD,²⁰ further increases this risk. Age related loss of muscle mass and nutritional deficiencies may also exacerbate steroid-induced myopathy in the elderly. It has been suggested that persons above the age of 65 may have increased unbound (free) fraction of prednisolone;²¹ although it is not clear whether a dose reduction is necessary in the elderly patients.

Budesonide and budesonide MMX, synthetic corticosteroids that have linear pharmacokinetics, differential absorption when administered orally versus rectally, and fewer acute adverse effects;²² is an alternative to prednisone for elderly patients. However, it should be noted that most patients included in major trials evaluating the conventional corticosteroids as well as the formulations of budesonide were in the 3rd to 4th decade of life.^23-26 Older age and chronic steroid use have been associated as the two key risk factors for potential drug interaction.²⁷ As noted by Parian and Ha, a majority of late-onset IBD patients- including those in remission or those with mild disease activity- often receive chronic maintenance therapy with steroids and steroid-sparing therapies remain underused in these patients. Therefore, caution should be exercised in older patients on long-term steroids (typically, >7.5 mg per day of prednisone for > 1 month).

Appropriate screening including bone mineral density, vitamin D levels, electrolytes and blood glucose must be periodically performed; feasibility of a steroid-sparing regimen should be considered early; medications should be reviewed for potential drug-drug interactions and clinical predisposition for infections should be assessed frequently in older patients on steroid therapy.

Immunomodulators

Immunomodulators such as methotrexate (MTX), azathioprine (AZA), and 6-mercaptopurine (6-MP) are most commonly used as steroid-sparing agents or in combination therapy with biologic agents. AZA and 6-MP, the thiopurine compounds are catabolized by the enzyme thiopurine S-methyltransferase (TPMT). Patients with TPMT gene mutations and enzyme deficiency are at higher risk for developing severe hematological toxicity such as bone marrow suppression. While screening patients for TPMT deficiency prior to starting thiopurine therapy is standard of care, age-related variations in TPMT activity have been documented.^28,29 Although these findings suggest a multifactorial regulation and not necessarily only age related linear association of TPMT activity, clinicians should be aware of a potentially exaggerated myelosuppression in the elderly patients, particularly considering the physiological changes in the bone marrow activity with aging.³⁰

Concern exists regarding the risk of malignancy- particularly lymphomas, melanoma and non-melanoma skin cancers in association with immunomodulator therapy. Studies have shown an increased risk of lymphoma as high as fourfold with thiopurines.³¹ Of note, a German study demonstrated 18% incidence of lymphoma in IBD patients over 50 years of age, as compared to 4% incidence in those less than 50 years old, when treated with thiopurines.³² A meta-analysis of immunomodulator use with AZA/6MP/ MTX showed a bimodal risk distribution with relative risk of lymphoma being higher in patients below 35 years of age but the highest absolute lymphoma risk with a standardized incidence ratio of 4.78 (1:354 cases per patient-year) was seen in IBD patients older than 50 compared to the younger IBD population. However these observations were not reproduced when data from a previously excluded “outlier” study were included in the analysis.³³

With regards to skin cancer, a large population- based study showed an association between immunomodulatory use for more than 5 years and non- melanoma skin cancer [Odds ratio (OR) 1.78],³⁴ whereas a similar study from Olmstead County, Minnesota reported an increased risk of melanoma in patients treated with immunomodulators.³⁵ A meta-analysis addressing the association between non-melanoma skin cancers and thiopurine use demonstrated a modest risk (pooled adjusted hazard ratio 2.28), but this association lost statistical significance after excluding studies with a relatively short-term (< 3 years) follow-up. The authors concluded that there is not enough evidence to suggest that the cancer risk outweighs the treatment benefit with thiopurines.³⁶ None of these studies identified age as an independent risk modifier.

Periodic monitoring of complete blood count, liver and kidney function and skin examinations should be a part of routine surveillance of all IBD patients on immunomodulator therapy but special precautions should be taken in the elderly as they are at higher risk of the drugs adverse effects than their younger counterparts.

Biologics

The fourth major class of drugs used to treat moderate to severe IBD is biologics, either antibodies against tumor necrosis factor (TNF)-a (infliximab, adalimumab, certolizumab, golimumab), or anti-integrins (natalizumab and vedolizumab). These agents have been shown to induce and maintain remission, improve quality of life, and reduce hospitalizations for IBD patients.^37,38

An analysis of IBD patients >65 years of age treated with TNF-a inhibitors demonstrated an 11% incidence of severe infections and 10% total mortality in the elderly group- as compared to 2.6% and 1% incidence of severe infections and mortality, respectively, in the younger patients.³⁹ Another study confirmed these results with a 3 times high risk of severe adverse events in the >65 year old IBD patients compared to those <65 on anti-TNF therapy.⁴⁰ These findings further prompt concerns about the applicability of results of clinical trials to the geriatric population.

Older age has been shown to be a statistically significant predictor of suboptimal early response to anti-TNF therapy.^40,41 Additionally, Desai et al. noted a 70% discontinuation rate at the end of 2 years of anti-TNF therapy in patients > 60 years of age, and concluded that older age was a significant risk factor for discontinuation of this treatment.⁴²

Of the two anti-integrin molecules, vedolizumab was recently approved for the treatment of moderate to severe IBD. The mean age of patients in the two phase 3 randomized trials comparing vedolizumab to placebo for CD and UC was 35-40 years.^43,44 Similarly, randomized clinical trials involving natalizumab for the treatment of CD had the mean patient age of approximately 35- 40 years.^45,46 Although no age-specific differences were seen in efficacy or safety analyses in these clinical trials, surveillance strategies in patients above the age of 65 on anti-integrin therapy remain undefined as the clinical data of anti-integrin therapy in the elderly population is quite sparse.

c) Surgical Therapy: Restorative Surgery versus Permanent Ileostomy

Advanced age is a significant risk factor and predictor of outcomes for patients undergoing surgery for IBD. Advanced patient age is associated with a longer operating room time, longer length of hospitalization and higher odds for postoperative complications.⁴⁷ Ileo- pouch anal anastomosis (IPAA), being a more complex procedure was traditionally reserved for “younger” patients with IBD. In a population-based study of veterans above 50 years of age with UC, Longo et al. noted that 64% of the patients underwent proctocolectomy and permanent ileostomy.⁴⁸ However, a recent systematic review evaluating medical and surgical complications in IBD patients observed encouraging outcomes after IPAA in the elderly population. Neither was there an increase in mortality in the IPAA group compared to total proctocolectomy group regardless of age, nor an association between age and IPAA failure rates seen. The functional outcomes were also comparable between the older and younger patients with no difference in daytime functional impairment. However, an increased incidence of post-IPAA nocturnal bowel incontinence was noted in the elderly group, as well as an association between age and nocturnal bowel movements.⁴⁹ From the patient perspective, however, 89-100% reported that they would undergo their surgery again, and 93-100% reported that they would recommend it to others.⁵⁰

d) Colorectal Cancer Screening/Surveillance

While the IBD population is at a higher risk for developing colorectal cancer (CRC), the exact magnitude of this relationship is not clear. A meta- analysis from 2001 showed an increased risk for developing CRC in UC patients- 2% by 10 years, 8% by 20 and 18% by 30 years.⁵¹ In contrast, more recent data have suggested a progressive reduction in the excess CRC risk in IBD patients and that the disease extent and duration are important risk factors for developing CRC.⁵² In a case-control study, the histological inflammation score was the only significant determinant of CRC risk.⁵³ Taken together, the risk of CRC in IBD patients has reduced in magnitude but remains present as long as the patients are not in histological remission. Therefore, elderly patients- particularly the early-onset subgroup- will still carry a higher risk of progression to CRC, unless complete histological remission is achieved. This brings forward the issue of screening and surveillance strategies in the elderly subgroup. The current guidelines do not specify an upper age cutoff for endoscopic screening and surveillance in the IBD population. In general population, colonoscopy in the elderly has been shown to be associated with a lower rate of procedure completion,⁵⁴ a higher likelihood of suboptimal bowel preparation,⁵⁵ and an incremental risk of perforation with increasing age and comorbidities.⁵⁶

Although the risk of neoplasia increases with age,
overall life expectancy decreases. A study showed that
the mean extension of life expectancy in the patients
undergoing routine screening colonoscopy was 0.17
years in the healthy population between the age 75-79,
and 0.13 years in those older than 80 years of age; as
compared to 0.85 years in those between 50-54 years
of age, respectively.⁵⁷ However, data addressing this
issue specifically in the IBD are lacking, and decisions
regarding surveillance need to be individualized.

CONCLUSION

The growth of the elderly IBD population in the
upcoming decades will bring on a unique set of
management challenges. Studies evaluating this
population are disproportionally low as clinical trials
often exclude this population. Thus, extrapolating the
efficacy and risk data from the younger population
may not always accurately describe the effects that we
need to take into account for the geriatric population.
Specifically, changes in metabolism and potentially
poorer response to medications, increased risk of
infections, and lack of specific guidelines such as
colorectal cancer surveillance for this population
contributes to this challenge. At this time providers
should take into account not just physiologic age but
also comorbidities to individualize potential risks and
create a treatment plan that provides optimal benefit
for the elderly IBD population.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #144

Getting Critical About Constipation

August 2015 • Volume XXXIX, Issue 8

Jean-Louis Vincent,

Jean-Charles Preiser

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Gastrointestinal motility is a complex process, which is often altered during critical illness, an effect that can lead to constipation. There is no consensus definition for constipation and it is therefore difficult to accurately assess incidence across studies. More recently, the term “paralysis of the lower gastrointestinal tract” has been suggested. Constipation can cause abdominal distension and discomfort, and reduce tolerance to enteral feeding. It can impair respiratory function and has been associated with worse patient outcomes including prolonged ICU length of stay and prolonged mechanical ventilation. The etiology of constipation in ICU patients is multifactorial and includes immobility, fluid and electrolyte disturbances, adverse effects of medication, and sepsis. Management must focus on treating the underlying cause and re-establishing regular bowel movements.

Jean-Louis Vincent MD PhD, Jean-Charles Preiser MD PhD, Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium

INTRODUCTION

Gastrointestinal motility is a complex process regulated by a number of hormones and peptides. Constipation is a frequent problem in intensive care unit (ICU) patients,^1,2 but is often overlooked. Staff often react more quickly to diarrhea, which is usually obvious, than to constipation, which is often less apparent. The definition of constipation is not as simple as it may seem. In the general population, the Rome criteria are frequently used, assessing objective (stool frequency [<3 stool movements per week], need for manual maneuvers to defecate) and subjective (straining, hard stool, sensation of incomplete bowel movement or anorectal blockage) factors.³ However, in critically ill patients, subjective symptoms are often difficult to assess and a diagnosis of constipation essentially relies on absence of defecation, although the chosen time period varies among studies. Because of the subjective nature of constipation, some debate the use of the term “constipation” in critically ill patients and a recent Working Group on Abdominal Problems from the European Society of Intensive Care Medicine recommended that the term “paralysis of the lower gastrointestinal (GI) tract” be preferred.⁴ They defined this as “the inability of the bowel to pass stool due to impaired peristalsis” and suggested that clinical signs would include absence of stool for three or more consecutive days without mechanical obstruction regardless of bowel sounds.⁴ Indeed, whatever term is employed, bowel sounds, which have been widely used as an indicator of bowel activity, are unreliable and should not form part of the diagnostic criteria.⁵

Epidemiology

There are few published epidemiological data specifically related to constipation in critically ill patients. Constipation has been reported to occur in 5 – 90.5% of patients depending on the specific population studied and the definition used (Table 1).

Clinical Impact

Constipation can cause abdominal distension and discomfort, poor tolerance of enteral feeding, confusion, and intestinal obstruction with vomiting and risk of pulmonary aspiration (Table 2).^2,9,10,12 It may also be associated with raised intra-abdominal pressure, which can impact on respiratory function. Abdominal distension associated with constipation may be associated with bacterial overgrowth^12,13 and increased bacterial translocation. Gacouin et al. reported reduced bacterial ICU-acquired infections in patients who passed stools early (< 6 days) rather than late (> 6 days).⁹ Constipation in critically ill patients has been associated with worse outcomes including prolonged ICU length of stay and prolonged mechanical ventilation.^2,8,9,14 Patanwala et al.¹⁵ noted that patients with constipation had more severe illness, as indicated by higher APACHE II scores. Montejo et al. reported that patients with GI complications, including constipation, had longer ICU stays and higher mortality than those without GI complications.⁶

Contributing Factors

A number of factors can contribute to constipation in critically ill patients, some of which are more obvious than others, for example spinal cord injury. Recent abdominal surgery is a common cause, although the delay before first defecation in these patients can vary considerably and may be related to the effects of the anesthesia and analgesia and not just to the surgery per se. Immobility, common in ICU patients, is also an important factor in reduced gut motility and patients who are unconscious or sedated may not feel the need to defecate.

The effects of morphine and other opioids on gut motility are well known,^16,17 but opioids have other effects that also increase the risk of constipation, including reducing intestinal secretions.^16,17 Other medications that may be used in the ICU can also cause gut hypomotility, including dopamine,^18,19 phenothiazines, diltiazem, verapamil, and anticholinergic drugs.¹

Sepsis may also increase the likelihood of constipation in critically ill patients. Indeed, recent data suggest that sepsis may enhance the inhibitory effects of opioids on colonic motility via Toll-like receptor 4,²⁰ a key signaling molecule in sepsis pathogenesis.²¹

Electrolyte disturbances, including hypokalemia, hypercalcemia, and hypomagnesemia, can also reduce gut motility and increase the risk of constipation, in part via impaired smooth muscle contraction.²² Inadequate fluid administration or inappropriate use of diuretics leading to dehydration also promotes constipation, but, conversely, too much fluid can lead to splanchnic edema, impairing gut motility.

Gacouin et al.⁹ reported that hypotension, defined as a systolic blood pressure < 90 mmHg, was independently associated with late (> 6 days) passage of first stools, as was a PaO₂/FiO₂ ratio of <150 mmHg (hazard ratio 1.40 [95% confidence interval 1.06-1.60], p=0.003).

In most critically ill patients with constipation, the etiology will be the result of a combination of several of the above factors (Table 3).

Interaction with enteral feeding

The relationship between the type and delivery of enteral nutrition (EN) and constipation is interesting. On the one hand, delayed administration of EN may contribute to constipation,¹ while, on the other hand, constipation in the critically ill can be associated with an intolerance to EN.¹⁰ Early EN is recommended in critically ill patients.²³ Boelens et al.²⁴ reported that early EN was associated with a significantly shorter time to first defecation compared to early parenteral nutrition (PN) in patients undergoing major rectal surgery. Continuous EN is usually recommended to improve the delivery of nutrients. However, meals and bolus delivery of nutrients cause gastric and colonic distention, leading to increased antro-pyloric pressure waves and motility.²⁵ In a pseudo-randomized controlled trial in 30 critically ill mechanically ventilated patients receiving EN for more than 72 hr, Kadamani et al. reported that continuous EN was associated with more constipation, defined as absent bowel movements for at least three consecutive days, than bolus EN.²⁵

Management

Because of the potential complications associated with constipation listed above, appropriate treatment of constipation is important. The most important factor in treating these patients is to make it a priority to re- establish, and then maintain, regular bowel movements. In a recent prospective randomized controlled trial, de Azevedo et al. (personal communication) reported that maintenance of daily defecation resulted in an improvement in organ function, as reflected by a faster decline in sequential organ failure assessment (SOFA) scores.

Treating the Underlying Cause

Full physical examination must include rectal examination and imaging when necessary to exclude the presence of any mechanical obstruction that requires surgical management. In acute colonic pseudo-obstruction (Ogilvie’s syndrome), a therapeutic colonoscopic examination may be required to decompress the pseudo-obstruction.^26,27 Electrolyte imbalances should be corrected and fluid administration optimized. As part of routine patient management, the need for analgesic agents should be regularly reviewed.28 Fentanyl may be associated with less constipation than morphine,^29,30 but these differences may not be large, especially with short-term use. If continued opioid use is necessary, administration of opioid antagonists, such as methylnaltrexone, should be considered as this can be useful to counteract the effects of opioids on gut motility.^31,32 Methylnaltrexone is a selective opioid µ-receptor antagonist that poorly crosses the blood- brain barrier, and hence interferes with GI effects, but not the central pain-relieving actions of opioids.³³ Lubiprostone, a selective chloride channel-2 activator that acts locally in the small intestine to increase fluid secretion and improve gut motility,³³ has been recently proposed as an alternative.³⁴ The enteral administration of naloxone, which has low bioavailability when given orally, may represent a cheaper option.³⁵

Treating the Constipation
Laxatives and Enemas

There are essentially two types of treatment for constipation after efforts have been made to remove the underlying cause: oral laxatives and suppositories or enemas. Oral laxatives can be broadly divided into bulking agents, osmotic laxatives, stimulant laxatives, and stool softeners (Table 4).^12,36 The choice of laxative is largely a matter of personal preference and availability with few published recommendations, especially in the critically ill population. Lactulose is perhaps the most widely used,¹⁴ with a recommended starting dose of 10 ml twice a day increasing to a maximum of 20 ml three times daily. Lactulose use can result in production of intestinal gases with uncomfortable bloating in some patients.¹⁴ Senna (10 ml/day) is a commonly used alternative.^2,15,37 Polyethylene glycol (PEG) is also widely used and can be administered intermittently or continuously. Van der Spoel et al.¹⁴ compared administration of lactulose (13 g three times daily), PEG or placebo in patients with multiple organ failure who were receiving mechanical ventilation and intravenous circulatory support and who had had no defecation by day 3 after admission. The authors reported that lactulose and PEG were both more effective in promoting defecation than placebo. There was an increased occurrence of acute intestinal pseudoobstruction in patients receiving lactulose, possibly related to increased intestinal gas production, and PEG seemed to be more effective than lactulose in patients receiving opioids.¹⁴ Enemas are generally reserved for patients in whom orally administered laxatives do not have an effect.³⁷

Neostigmine

In severe cases of functional colonic pseudo-obstruction, after exclusion of treatable causes, administration of neostigmine, an acetylcholinesterase inhibitor, may be considered to increase peristalsis and promote gut motility. Many studies have shown the efficacy of neostigmine in this situation, including the classical study by Ponec et al.³⁸ in which 21 patients with acute colonic pseudo-obstruction with no response to > 24 hours of conservative treatment, were randomized to receive a single dose of 2 mg of intravenous neostigmine or intravenous saline. Ten of the 11 patients who received neostigmine had rapid evacuation of flatus or stool, with a median time to response of just 4 minutes, as compared with none of the 10 patients who received placebo (p<0.001). Van der Spoel et al.³⁹ randomized 24 mechanically ventilated patients with multiple organ failure and critical illness-related colonic ileus to a continuous infusion of intravenous neostigmine (0.4-0.8 mg/h over 24 h) or placebo, and again reported good efficacy with 11 of the 13 patients receiving neostigmine passing stools, compared to none of the placebo-treated patients (p < 0.001). Neostigmine can cause bradycardia and cardiac arrest has even been reported,⁴⁰ so care should be taken, especially in patients with severe cardiocirculatory problems. Neostigmine use has also been associated rarely with colonic perforation.⁴¹

Prophylaxis of Constipation

A couple of studies have suggested beneficial effects of prophylactic laxative administration in critically ill patients.^11,42 Masri et al.⁴² reported that prophylactic use of lactulose 20 ml twice daily for 3 days in critically ill ventilated patients was associated with increased incidence of bowel movement in the first 72 hours compared to no intervention (18% vs 4%, p<0.05). More recently, in a sequential phase trial, Guardiola et al. compared treatment of lower GI tract “paralysis” with prophylaxis. Patients who received PEG as prophylaxis on the first day of mechanical ventilation had more rapid resolution of the paralysis than those who received PEG as treatment on day 4.11

It is important to remember that early sitting and mobilization of patients is a cheap and effective way to stimulate gut function. See Table 5 for a summary of suggestions to prevent and treat constipation in the ICU.

CONCLUSION

Constipation is common in ICU patients. Attempts should be made to prevent and treat it when necessary to avoid complications. There are few published data to guide treatment choices in this population. When considering constipation in these patients, one can identify two vicious cycles that need to be avoided. The first is the problem of abdominal distension that can induce discomfort, which results in increased opioids for pain relief, causing more constipation, and so the cycle starts again. The second potential cycle is the development of abdominal bloating, leading to withholding of EN, which in fact can worsen constipation as EN can promote peristalsis. Indeed, although not often considered as such, EN can be considered as, perhaps the optimal form of prophylaxis against constipation! Other general patient management strategies, including ensuring adequate hydration and encouraging mobilization when possible, must not be forgotten.

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A CASE REPORT

Malignant Extrarenal Rhabdoid Tumor (MERT) of the Colon

August 2015 • Volume XXXIX, Issue 8

Deepti Dhavaleshwar,Kofi Clarke

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Ten cases of primary colonic malignant extrarenal rhabdoid tumors (MERT) have been reported. We report a case in a 31-year-old female who presented with abdominal pain, nausea and vomiting. Her initial evaluation was significant for leukocytosis and an elevated erythrocyte sedimentation rate. On colonoscopy, a 4-cm localized inflammatory-appearing lesion at the ileocecal valve was noted. Biopsies showed poorly differentiated adenocarcinoma. Surgical pathology after right hemi-colectomy revealed a malignant neoplasm with rhabdoid features. Despite aggressive chemotherapy, the patient died four months after diagnosis. MERT cases are rare and have poor prognosis. A better understanding of these tumors may help to improve outcomes.

Deepti Dhavaleshwar, MD; Kofi Clarke, MD, FRCP, Allegheny Health Network, Allegheny General Hospital, Division of Gastroenterology, Pittsburgh, PA

BACKGROUND

Malignant extrarenal rhabdoid tumors (MERT) of the gastrointestinal tract are extremely rare. To our knowledge, only 10 cases of primary colonic MERT have been reported.^1-9 We report a case of MERT involving the colon in a 31 year-old female patient.

CLINICAL CASE

A 31-year-old Caucasian female with no significant past medical or surgical history presented with right lower quadrant abdominal pain, nausea and vomiting. The pain was non-radiating, rated 10/10 in intensity and had no aggravating or relieving factors. She denied diarrhea, constipation, loss of appetite or weight changes. Her family history was significant for Crohn’s disease in a maternal aunt.

Initial work up was significant for leukocytosis of 14,000 cells/mL (normal range: 4,000-10,000 cells/ mL) and an elevated erythrocyte sedimentation rate of 44 mm/hr (normal range: 0-20 mm/hr). Computed tomography (CT) scan of the abdomen and pelvis with contrast showed small bowel obstruction (SBO), focal thickening of the terminal ileum, mesenteric engorgement and upstream inflammation with skip lesions in the distal ileum (Figure 1). Colonoscopy performed after resolution of the SBO showed a 4-cm localized inflammatory-appearing lesion at the ileocecal valve. The terminal ileum could not be intubated because of partial obstruction (Figure 2). Biopsies showed poorly differentiated adenocarcinoma (Figure 3), and the patient underwent a right hemi-colectomy. Surgical pathology revealed a poorly differentiated malignant neoplasm with rhabdoid features, and 9 out of 15 pericolonic lymph nodes were positive for metastatic malignancy. Immunostains showed the tumor cells were positive for cytoketain AE1/AE3, negative for CK7, CK20 and CDX-2. Post-operative workup including positron emission tomography (PET) CT revealed multiple fluorodeoxyglucose (FDG) avid hepatic lesions, consistent with metastatic disease. The patient underwent chemotherapy with FOLFOX (a combination of leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin), but despite the aggressive therapy, the patient succumbed to the disease four months after diagnosis.

DISCUSSION

The term malignant rhabdoid tumor (MRT) was originally used to describe a variant of pediatric renal tumor, which was clinicopathologically distinct from Wilms tumors. MRT of the kidney demonstrates a particularly aggressive growth and poor prognosis.¹⁰ Malignant tumors with similarly appearing rhabdoid cells were subsequently described at extrarenal sites, and these have been described as MERT.

There appears to be no sex predilection and overall survival is less than 12 months. MERT is derived from primitive pluripotential cells, which have the potential for a wide range of differentiation.¹¹ As such, phenotypic heterogeneity is observed in different tumors as well as in the same tumor.

Approximately 100 cases of extra renal MERT have been reported, which demonstrated partial and global rhabdoid features on conventional microscopic examinations. Colonic MERT is an extremely rare tumor that has been described in elderly individuals. It is typically located proximal to the transverse colon. To our knowledge, only 10 cases of primary rhabdoid colonic tumors (RCT) have been reported, and our patient, at 31 years of age, is the youngest (Table 1).

The two described histologic types of RCT are pure and composite. Composite refers to adenocarcinoma with rhabdoid features and has been associated with polyposis syndromes. Three RCT out of the 10 previously reported tumors were composite and associated with multiple polyposis.

Treatment of colonic MRTs is typically surgical resection without chemotherapy or radiotherapy. Prognosis is very poor in cases with metastases. Given that the tumors are so rare, no clear consensus exists about the choice of chemotherapeutic agents. Single agent chemotherapy with bevacizumab, cetuximab⁷ and multi-agent chemotherapy with capecitabin and oxaliplatin has been described.² Recent studies have suggested considering monoclonal antibodies against the epidermal growth factor receptor for RCTs that exhibit “wild type” KRAS gene,^2,4,7 however no case reports were found where this was used.

In summary, rhabdoid tumors of the gastrointestinal tract are rare and associated with a poor prognosis. They do not respond to conventional therapeutic regimens. A better understanding of the genetic and molecular basis of these tumors may help guide management to improve prognosis.

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FELLOWS' CORNER

Fellows’ Corner

July 2015 • Volume XXXIX, Issue 7

Justin Chen,

Kheng-Jim Lim,

Arkady Broder

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Justin Chen, Medical Student, Drexel University College of Medicine. Kheng-Jim Lim MD, Gastroenterology Fellow, Robert Wood Johnson Medical School, Rutgers University. Arkady Broder MD, Gastroenterology Saint, Peter’s University Hospital

CASE PRESENTATION

A 53-year-old Asian male with a history of chronic hepatitis B presents to a university hospital with jaundice for seven days. Prior to admission, he had intermittent post-prandial right upper quadrant discomfort, nausea, vomiting and jaundice and was evaluated by his primary care physician. An outpatient abdominal ultrasound found a 2 cm common bile duct (CBD) stone and a dilated CBD up to 13 mm. He did not have any fevers or abdominal pain. His only medication was entecavir for chronic hepatitis B. His vital signs were within normal limits, physical exam was notable for jaundice, a benign abdomen and Murphy’s and Courvoisier’s sign were not present. Laboratory studies were significant for alkaline phosphate (ALP) 138 U/L, aspartate and alanine aminotransferase (AST, ALT) 34, 79 IU/L, respectively, total bilirubin 14.6 mg/dL, lipase 24 U/L, CA 19-9 of 2910 U/mL, and white blood cell count (WBC) 5,500 cell/µl. Endoscopic ultrasound found choledocholithiasis and CBD dilation. Endoscopic retrograde cholangiopanctreatography (ERCP) with sphincterotomy was performed and an exudate was seen in Figure 1. Subsequently, cannulation of the ampulla demonstrated the findings in Figure 2.

1. What is the diagnosis?
2. What is the substance exuding from ampulla?
3. What are the therapeutic options?
4. What other associated illnesses need to be investigated and how?

This is a 53-year-old male with a clinical presentation, laboratory values, and imaging suggesting choledocholithiasis but on ERCP had a diagnosis of Mirizzi syndrome (MS). Upon contrast injection, ERCP revealed contrast dye only filling the cystic duct and the guide wire in the CBD (Figure 2). Further manipulation confirmed a gallstone within the cystic duct compressing the CBD (Figure 3).

Mirizzi syndrome is a complication of gallstone disease that involves obstruction of the CBD by a stone in the cystic duct. It is more predominant in women, ages 53-70 years old, with a 0.2-1.5% prevalence in individuals with gall bladder disease. There is an increased prevalence in individuals with anatomical abnormalities of the biliary tree, like the long cystic duct with low insertion of cystic duct seen in this patient.¹ The most popular classification for MS involves four types described by Csendes in 1989.² Type I: external compression of CBD due to a stone impacted at the neck of the gallbladder or at the cystic duct. Type II: presence of a cholecystobiliary fistula that affects less than 1/3 of the circumference of the CBD. Type III: presence of a cholecystobiliary fistula with erosion of the CBD that involves up to 2/3 of its circumference. Type IV: presence of a cholecystobiliary fistula with complete destruction of the entire wall of the CBD.³

MS is often misread on transabdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP) as choledocholithiasis and is ultimately diagnosed with ERCP. Transabdominal ultrasound is found to be diagnostically accurate in 29% of cases with a sensitivity of 8.3-27%. Transabdominal ultrasound classically shows dilatation of biliary system proximal to the stone and normal width of the CBD distal to the stone. MRCP has a diagnostic accuracy of 50% and can show external compression of the CBD and visualize a fistula if present for staging. ERCP can confirm or diagnose MS with a diagnostic accuracy of 55-90%. ERCP with stent placement and sphincterotomy is often performed as therapy for symptoms of jaundice and ascending cholangitis.¹

Prolonged cholestasis in this patient led to the development of “milk of calcium” or “limy bile” exuding from the ampulla after sphincterotomy. Although the pathophysiology of “milk of calcium” is not completely understood, it is believed that obstruction of the gall bladder neck, cystic duct or CBD with subsequent biliary stasis leads to precipitation of calcium carbonate crystals in the bile. The exudate manifests as a thick, radiopaque paste in the gallbladder or common bile duct.⁴ MS is typically diagnosed on imaging, including abdominal X-rays and CT scan, which shows filling of the gallbladder or CBD as if contrast was administered. Prevalence of limy bile syndrome ranges between 0.1- 1.7% of all surgeries for cholelithiasis with a male to female ratio of 1:3.⁵

The treatment for MS is typically surgical and the pre-operative diagnosis may not always be known prior to surgery. Surgical treatment options are determined by the classification of MS. Open cholecystectomy is usually performed due to inflammation that cause adhesions and distorts the anatomy increasing risk of biliary tree injury.¹ Laparoscopic surgery is controversial and reserved for Type I MS because of a high laparoscopic to open conversion and complication rate. Type I MS can be treated with total or subtotal cholecystectomy with stone extraction. Treatment for Type II MS is dependent on fistula size and can involve partial cholecystectomy, suture repair or T tube placement to repair the fistula. Type III can be treated with choledochoplasty or enterobiliary anastomosis with cholecystectomy and Type IV MS requires cholecystectomy and enterobiliary anastomosis, most commonly Roux-en Y hepaticojejunostomy.² Stone removal can be attempted with ERCP using stone removal techniques (e. g. balloon, basket, lithotripsy), but it is reserved for patients who are poor surgical candidates due to increased risk of bleeding and perforation.¹

In patients with MS, it is necessary to evaluate for gallbladder cancer preoperatively with imaging or a CA19-9 level, intraoperatively, or post operatively with pathology. Gallbladder cancer is present in 5.3%- 27.8% of patients with MS compared to 1-2% in patients with benign biliary disease.⁶ The underlying chronic cholestasis found in MS is proposed to be the risk factor for gallbladder cancer.⁷ Although the average CA19-9 is 987 units/ml in patients who had both MS and gallbladder cancer, 4.7% of patients who had cholangitis or cholestasis with no gallbladder cancer had CA19-9 levels >1000 units/ml.^7,8

As in many patients with MS, this patient was misdiagnosed initially with transabdominal ultrasound and EUS as choledocholithaisis, but later found to have MS on ERCP. An MRCP later showed no fistula and confirmed Type I MS and an open partial cholecystectomy was then performed. Post operatively, a partial gallbladder pathology showed no malignancy with evidence of chronic cholecystitis and his CA19-9 decreased from 2910 U/mL to 19 U/mL. The patient was subsequently discharged from the hospital in good health.

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A CASE REPORT

A Rare Presentation of a Common Condition: A Squamous Cell Papilloma Causing Dysphagia and Hematemesis

July 2015 • Volume XXXIX, Issue 7

Carla Duffoo,Ghassan Tranesh,Mohammed Barawi

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Carla Duffoo DO,¹ Ghassan Tranesh MD,¹ Mohammed Barawi MD¹ ¹Department of Gastroenterology, ²Department of Pathology, St. John Medical Center, Detroit, MI

INTRODUCTION

Squamous papillomas of the oral cavity are common, benign, painless lesions that arise from the squamous epithelium of the lips, tongue, pharynx, esophagus and others. They are most often found in the mucosa of the hard and soft palate, but they can also be found in the uvula. Although there is an association with the human papilloma virus (HPV), they are neither transmissible nor threatening.1 These lesions, although benign, are thought to be pre-malignant.2 They are also generally asymptomatic; only two cases of symptomatic squamous papillomas arising from the uvula have been reported in the literature.^3,4 Here we present a case of a symptomatic squamous papilloma of the oral cavity.

CASE REPORT

A 41-year-old African American woman presented to our institution with nausea, vomiting and several episodes of hematemesis. She also described a feeling that “something was stuck in the back of her throat,” and she had been able to manipulate an ‘object’ and push it to the side of her inner cheek, but on occasion this ‘object’ would protrude out of her mouth when she coughed. She reported having a choking sensation and difficulty swallowing solids but not liquids. She did not report any weight loss, odynophagia, abdominal pain, hematochezia or melena. She also denied having any previous episodes of similar symptoms and had no history of gastrointestinal bleeding. She denied any oral intake over the previous 24 hours and had no history of food impaction. The patient underwent an esophagogastroduodenoscopy (EGD) two years prior to this presentation, which only revealed the presence of gastritis. Upon presentation to the hospital, her vital signs were stable, except for mild tachycardia. Her hemoglobin was 13.2 g/dL. A computerized tomography (CT) of the neck was unremarkable except for a possible right parotid gland lymph node versus nodule. Due to her complaints of acute dysphagia and hematemesis, the patient underwent an urgent EGD. On endoscopy, a long, finger-like polypoid lesion was seen projecting from the soft palate; this lesion measured approximately 2 cm in length. The lesion had a cauliflower like tip with areas of superficial ulceration (Figures 1 (a) and (b)). The remainder of the exam was normal. It was difficult to clearly visualize the exact origin of this lesion; therefore, an otorhinolaryngology (ENT) consult was requested. The patient underwent a flexible fiberoptic evaluation, which revealed an elongated polypoid lesion arising from the uvula. She was taken to the operating room for surgical excision of the lesion. Pathology revealed a 2 cm long polypoid, pedunculated, papillary tissue that was pink-tan in color, containing a fibrovascular core consistent with a squamous papilloma with acute and chronic inflammation that was not associated with HPV (Figures 2 (a) and (b)). The patient’s postoperative course was uneventful and she reported complete resolution of her symptoms.

DISCUSSION

Squamous cell papillomas are small exophytic growths composed mostly of parakeratinized, stratified, squamous epithelium that are arranged in papillary projections, giving them a cauliflower-like appearance.⁵ They are common benign neoplasms of the oral mucosa that typically present as a single pedunculated mass and are often found on the hard and soft palate. The tongue was described as the most common site of growth in one series,⁶ while others report that the soft palate-uvula complex was the most common site.^7,5 In our patient, the lesion was seen as a long, polypoid elongation of the uvula with a cauliflower-like appearance at the tip (Figures 1 (a) and (b)). These lesions are not considered contagious or transmissible, however the literature suggests an association with HPV-6 and HPV-11.³ Squamous papillomas of the oral cavity are generally diagnosed in people ages 30 to 50 years; however, in one series, the age range was 2 to 91 years.⁵ There is conflicting information regarding the impact of gender on the predisposition for this condition, but it seems that these lesions may be more common in men. One study revealed a greater percentage of white patients, while other series did not make a reference to racial distribution.⁵ These lesions tend to be asymptomatic and are often found incidentally. There have been two case reports of symptomatic squamous papillomas, with dysphagia as the presenting symptom.^3,4 None of the cases reported hematemesis as a complaint. The cases in which the papilloma caused symptoms reported that the lesion was greater than 1 cm in length; this was the case in our patient who presented with complaints of dysphagia and hematemesis. We believe the hematemesis was due to vomiting of ingested blood as a result of mechanical trauma to the papilloma as it protruded out from the patient’s mouth when she coughed. In one series, 24% of cases (34/141) had lesions that were greater than 1 cm in length, and of those, 7.8% (11/141) were between 2 cm and 3 cm long.⁵ It is postulated that the greater the length of the papilloma, the more likely it is to cause symptoms. Squamous papillomas of the oral cavity are not typically associated with malignancy, unlike those found in the larynx,³ but surgical removal is the treatment of choice. Recurrence after excision is uncommon.

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INTRODUCTION

Dyspepsia

Nausea and Vomiting

Diarrhea

Bloating (flatulence)

Constipation

Medicinal Plant Use on the U.S.-Mexico Border

Plants Used in Mexican Traditional Medicine to Treat Digestive Problems

Potential Toxicity of Certain Herbal Products

Hepatotoxicity is a Concern for Certain Herbs

Medicinal and Toxic Fungi

CONCLUSION

INTRODUCTION

DISCUSSION

CONCLUSION

CASE

ANSWER AND DISCUSSION

INTRODUCTION

Presentation of Case

DISCUSSION

CONCLUSION

Acknowledgement

INTRODUCTION

Small Intestinal Bacterial Overgrowth

Fructose Malabsorption

Breath Testing

Approach to Abdominal Bloating, Gas and Distension

Dietary Management

Food Sensitivity

Take Home Pearls

INTRODUCTION

Changing Epidemiology: A Function of Overall Survival, or Missing Links in Pathogenesis?

IBD in the Elderly: Hazards of Generalizing the Evidence

IBD in the Elderly:Review of Evidence and Caveats

a) Disease Characteristics

b) Medical Therapy: Drug Metabolism, Eficacy and Safety Considerations

5-Aminosalicylic acids

Antibiotics

Corticosteroids

Immunomodulators

Biologics

c) Surgical Therapy: Restorative Surgery versus Permanent Ileostomy

d) Colorectal Cancer Screening/Surveillance

CONCLUSION

INTRODUCTION

Epidemiology

Clinical Impact

Contributing Factors

Interaction with enteral feeding

Management

Treating the Underlying Cause

Treating the Constipation Laxatives and Enemas

Neostigmine

Prophylaxis of Constipation

CONCLUSION

BACKGROUND

CLINICAL CASE

DISCUSSION

CASE PRESENTATION

INTRODUCTION

CASE REPORT

DISCUSSION

Treating the Constipation
Laxatives and Enemas