BOOK REVIEWS

ASPEN Enteral Nutrition Handbook, 2nd edition

August 2019 • Volume XLIII, Issue 8

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

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

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

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

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

FROM THE PEDIATRIC LITERATURE

Foreign Bodies During the Holidays

August 2019 • Volume XLIII, Issue 8

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

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

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

FROM THE PEDIATRIC LITERATURE

Genetics in Hirschsprung Disease

August 2019 • Volume XLIII, Issue 8

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

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

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

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

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

Nutrition Issues In Gastroenterology, #150

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

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

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

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

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

INTRODUCTION

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

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

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

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

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

Malabsorption

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

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

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

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

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

Pancreatic Enzyme Replacement Therapy (PERT)

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

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

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

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

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

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

Nutritional therapy

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

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

Constipation

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

Vitamin and Minerals

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

Differential Diagnosis of Failure to Thrive

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

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

Diabetes

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

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

Annual Screening

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

CONCLUSION

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

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Nutrition Issues In Gastroenterology, #149

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

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

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

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

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

CLINICAL CASE

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

INTRODUCTION

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

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

Epidemiology

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

Clinical Manifestations of Thiamine Deficiency in Non-Alcoholic Patients

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

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

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

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

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

Abnormal Eye Movements

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

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

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

Gait Ataxia

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

Korsakoff’s Syndrome

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

Diagnosis

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

Treatment

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

Expected Clinical Course

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

CONCLUSION

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

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

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Nutrition Issues In Gastroenterology, #148

Nutritional Implications of GI-Related Scleroderma

January 2016 • Volume XL, Issue 1
Soumya Chatterjee

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

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

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

INTRODUCTION

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

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

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

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

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

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

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

GI MANIFESTATIONS OF SCLERODERMA
Oral

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

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

Oropharynx

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

Esophagus

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

Stomach

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

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

Small Intestine

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

Large Intestine

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

Anal Canal

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

CLINICAL IMPLICATIONS AND MANAGEMENT
Diet and Nutrition

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

Oral Diet

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

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

Enteral Nutrition

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

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

Parenteral Nutrition

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

Pharmacological Agents

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

Prokinetic Agents

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

Somatostatin Analogue

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

Antibiotics

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

MOUTH CARE

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

OROPHARYNGEAL DYSPHAGIA

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

ESOPHAGEAL PROBLEMS

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

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

Acid Reducing Agents

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

Prokinetic Agents

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

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

Procedural and Surgical Interventions

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

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

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

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

GASTROPARESIS

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

GAVE

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

CONCLUSION

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

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Nutrition Issues In Gastroenterology, Series #169

A Clinician’s Guide to Defining, Identifying and Documenting Malnutrition in Hospitalized Patients

November 2017 • Volume XLI, Issue 11
Wendy Phillips,Maria Browning

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As our understanding of the effects of malnutrition on outcomes and hospital stays has evolved, it has become increasingly important for the Registered Dietitian Nutritionist (RDN) to consistently identify and communicate the degree of malnutrition present in any patient who meets criteria, in order to set up a timely treatment plan. The clinical nutrition team is positioned to spearhead the education of all appropriate providers to ensure consistent use of the approved criteria throughout the facility. This article aims to provide practical guidance for clinicians to do just that.

Malnutrition has been associated with trends toward higher acuity, higher health care cost, and poor patient outcomes. However, until recently no universal definition of malnutrition was available. As our understanding of the effects of malnutrition on outcomes and hospital stays has evolved, it has become increasingly important for the Registered Dietitian Nutritionist (RDN) to consistently identify and communicate the degree of malnutrition present in any patient who meets criteria, in order to set up a timely treatment plan. Adopting and imbedding standard language related to malnutrition in the electronic medical record (EMR) can lead to more consistent coding and tracking.

Wendy Phillips, MS, RD, CNSC, CLE, FAND, Division Director of Clinical Nutrition, Morrison Healthcare, St. George, UT Maria Browning MS, RD, CNSC, Quality Expert, Charge Management Surgical Charge Optimization Revenue Cycle Services, IU Health Methodist Hospital, Indianapolis, IN

INTRODUCTION

Most healthcare professionals will agree that malnutrition can be simply defined as inadequate calories, protein, and micronutrients required for proper tissue growth, maintenance, and repair.1 The causes of malnutrition can be multifactorial including, but not limited to: poor nutrient intake, malabsorption, poor nutrient utilization (hyperglycemia), and/or hypercatabolism. Historically, malnutrition has had various descriptions in the literature due to the lack of a universally accepted definition. Therefore, the prevalence of malnutrition in hospitalized patients has been reported to be anywhere between 16-68%.2-7 Regardless of the definition used, malnutrition is associated with poorer outcome,8 specifically: longer hospital length of stay,4-14 more readmissions within 30 days,14-29 more nosocomial infections,16-29 and more pressure injuries.24-27 Unfortunately, due to the various definitions found in the literature describing the prevalence of, and complications associated with, malnutrition, the true prevalence and consequences are still unknown.

The Academy of Nutrition and Dietetics (Academy) and the American Society for Enteral and Parenteral Nutrition (A.S.P.E.N.) joined forces to develop a consensus statement for the identification of adult malnutrition in 20121 and for pediatric malnutrition in 2014.28 Clinicians and researchers are encouraged to use the criteria set forth from these documents to identify malnutrition in an effort to inform facility policies, interventions, and resource allocations. It would help the process of standardizing definitions of malnutrition if each facility reviews and approves the Academy/A.S.P.E.N. criteria for malnutrition assessment and diagnosis by all key players: clinical nutrition team, LIPs, and coders. The clinical nutrition team is positioned to spearhead the education of all appropriate providers to ensure consistent use of the approved criteria throughout the facility. This article aims to provide practical guidance for clinicians to do just that.

Malnutrition Coding: Beyond the Money

Understanding the Medicare payment structure for hospital admissions is necessary to understand the importance of adequately diagnosing malnutrition and translating the malnutrition diagnosis into International Classification of Disease (ICD), 10th revision (ICD- 10) codes.30 Medicare is the largest funding source for most hospitals, and some commercial insurance companies structure their payment system similar to Medicare. Medicare does not pay hospitals directly for each expense incurred to care for patients, but rather categorizes patients into a Diagnosis Related Grouping (DRG) based on the principle diagnosis precipitating hospitalization.31 Payment is then based on an annual analysis of the average resources required to care for patients admitted for the same or similar principle diagnoses. Additional stratification occurs when the patient is further categorized into tiers within the DRG based on the presence of secondary diagnoses. This stratification is known as the Medicare Severity-DRG (MS-DRG) – some DRGs have one or two tiers, but the majority have three. Secondary diagnoses are those impacting clinical evaluation, therapeutic treatment or diagnostic procedures, and extend the length of stay or increase the nursing care required. They can be coded as co-morbidities or complications (CCs) or major co-morbidities or complications (MCC). See Table 1 for definition of terms. CCs and MCCs can raise the assigned tier within the DRG for the patient’s principle diagnosis. Medicare reimbursement increases to the hospital for higher tiered patient stays in order to cover the increased cost of care. Since the higher tiers have a higher relative weight (RW) assigned by Medicare, this also influences the case mix index (CMI).31 The CMI is an average of all of the RWs of patients with discharges within a specified time interval, and provides an index of the severity level of the patient population receiving care at that hospital. The CMI will also influence the base rate for that hospital for Medicare payment in subsequent years.

Secondary diagnoses count as CCs or MCCs and influence payments for hospital stays under Medicare’s MS-DRG Inpatient Prospective Payment System only if several conditions are met and documented in the licensed independent practitioner (LIP) progress notes.31 The secondary diagnosis cannot be an integral part of the principle admitting disease process itself and must affect the care provided during that hospital admission. For example, severe protein-calorie malnutrition cannot be considered a MCC for the principle diagnosis of “Failure to Thrive” because the two conditions are too similar. For principle diagnoses in which severe protein-calorie malnutrition could be listed as a MCC, there must be documentation demonstrating additional nursing care or other resources required for the patient (such as enteral or parenteral nutrition support). While clinicians recognize malnourished patients require additional resources and nursing care, this is not always clearly stated in the medical record, nor historically been adjusted for in terms of hospital reimbursement. Secondary diagnoses must be listed in the final diagnostic statement by the provider using whatever method the facility has designated (such as the problem list or the discharge History and Physical). For example, a patient may be admitted with community-acquired pneumonia as the principle diagnosis precipitating hospitalization. Secondary diagnoses may include acute respiratory failure (requiring the intervention of mechanical ventilation) and severe protein-calorie malnutrition (requiring the intervention of enteral nutrition). The acute respiratory failure and severe protein-calorie malnutrition would be listed as secondary diagnoses by the LIP in the final diagnostic statement and coded to be included in the MS-DRG assignment.

Although both acute respiratory failure and severe protein-calorie malnutrition are MCCs, only one MCC is required to increase the severity tier of the DRG. Therefore, the malnutrition cannot be considered a diagnosis that increases reimbursement in this patient, because the acute respiratory failure would have already increased the DRG and the reimbursement, even if malnutrition had not been documented and coded. However, both should be documented and coded. Beyond potentially increasing the reimbursement for providing care, the accurate identification, documentation, and coding of malnutrition is important for many other reasons. First, it encourages an increased awareness and focus on malnutrition that requires a specific intervention during that encounter and throughout the transition of care. When malnutrition is documented as a medical diagnosis and communicated through the discharge summary alerting clinicians at the next care site (such as a rehabilitation or long term care facility), prompt attention to nutrition care needs will be more likely to occur within that next setting.

Additionally, the expected length of stay (LOS), severity of illness (SOI), and risk of mortality (ROM) increase as the secondary diagnoses are coded as CCs or MCCs and the patient moves to a higher tier within the MS-DRG.31 This provides more realistic survival expectations for Medicare and other payers who use a method similar to the MS-DRG classifications. “Grades” that are given to a hospital and individual providers based on patient outcomes are adjusted for SOI, ROM, and CMI. The adjustment process is too complicated to explain in this article; a basic explanation is that coding for all applicable secondary diagnoses (like malnutrition) can make the hospital or provider’s grades better with the same outcomes because of the associated expected SOI and ROM. A good grade with a high CMI is an overt indication that the facility successfully cares for very ill patients. Poor grades may cause payers to remove the hospital or LIP as a provider for certain payment plans. This data is also publicly available, and patients may not seek care from institutions whose survival rates are below what is expected for a particular diagnosis. Diligence in documenting an MCC such as severe protein-calorie malnutrition not only can move the patient’s stay to a higher tier within the MS-DRG, which has the potential to direct nutrition intervention as well as help recover revenue for services, but also better represents SOI, ROM, and the resources required to care for the patient.

Finally, large-scale epidemiological studies require accurate diagnosis data available in discrete fields in the electronic medical record (EMR) that can be queried by automated data mining programs. Standardized language to describe the diagnosis of malnutrition with associated signs and symptoms ensures the interoperability and communication for that diagnosis with different EMRs, billing systems, and data mining programs used for research. An example of discrete fields would be the utilization of flow sheets with drop-down boxes that have been pre-populated with standardized language that can be clicked indicating the presence and degree of malnutrition.

Malnutrition Treatment: It Takes a Healthcare Village

The first step in identifying malnutrition in the hospitalized patient is through adequate nutrition risk screening, which is usually conducted by the registered nurse as part of the admission screening process. A validated nutrition screening tool appropriate for the patient population is recommended, such as the Malnutrition Screening Tool,32 the Malnutrition Universal Screening Tool,33 or the Nutrition Risk Screening (NRS) 2002.34 Periodically, the accuracy of the screening tool and the workflow process to notify the RDN should be reevaluated to ensure patients requiring full nutrition assessment and interventions are being identified.35,36

Once a patient is identified as at-risk for malnutrition, or frankly malnourished, either through the nutrition screening process or other method, a referral needs to be placed to a registered dietitian nutritionist (RDN) to complete a full nutrition assessment and implement a nutrition care plan in partnership with the patient/ caregiver, physician, nurses, and other healthcare team members. RDNs rely heavily on nursing documentation to evaluate the parameters described in the malnutrition clinical characteristics consensus statements published by the Academy/A.S.P.E.N.1,28 The RDN must communicate the presence of malnutrition and the associated signs and symptoms to the LIP responsible for the care of the patient; this will need to be included as a medical diagnosis by the LIP. This crucial step ensures the diagnosis is communicated from one care setting to the next so that nutrition intervention continues until the malnutrition is resolved.

The nutrition interventions in the care plan should specifically address the etiology, as well as signs and symptoms of the malnutrition. Often, nursing and food service staff will assist with the actual implementation of the nutrition interventions designed by the RDN, with nursing staff providing valuable documentation in the medical record about the patient’s response to care.

In some facilities, the LIP will need to place orders for at least some of the nutrition interventions per facility policy. The RDN will monitor, evaluate, and document the patient’s response to care, progress towards defined goals, making alterations to the nutrition care plan as needed, and finally document and coordinate the discharge nutrition needs to ensure appropriate nutrition follow-up after leaving the hospital.

Physicians continue to be responsible for documenting all diagnoses affecting the hospitalization or influencing the principle diagnosis causing the patient’s admission. If a patient is malnourished, this will affect the course of the hospital stay, the resources necessary to care for the patient, and the length of hospitalization required.9-14 Therefore, malnutrition should be documented by the LIP responsible for the care of the patient whenever it has been identified by the RDN as a nutrition diagnosis.

Likewise, medical billing specialists are required to code for all diagnoses affecting the care of the patient and/or their prognosis during that hospital stay, regardless of whether or not doing so will influence reimbursement for the stay. If the RDN has provided written information about the malnutrition as a nutrition diagnosis, but the LIP has not added it also as a medical diagnosis, then the billing specialist should query the LIP to check for agreement with the RDN. He/she may also query the RDN for documentation clarification if necessary.

Documentation Guidance for RDNs and LIPs

Since the malnutrition diagnosis must be documented by the LIP for it to become part of the official record of care from one healthcare facility to the next, RDNs need effective communication strategies to notify the LIP when a patient is identified as malnourished. Ideas to accomplish this are included in Table 2. A suggested sample charting template for RDNs is included in Table 3 with ideas on how this can coordinate with the LIP’s documentation. Documentation must be sufficiently detailed and measurable, and specific to the patient to support Medicare billing compliance audits that may be conducted by Medicare’s Recovery Audit Contractors or the Office of the Inspector General. See Table 4 with examples for specific and measurable documentation.

Building the Foundation: Success Story of Documentation

Streamlining and standardizing the documentation process as described above can lead to drastic improvements in identifying all degrees of malnutrition within the hospital setting. In 2013, Indiana University (IU) Health identified a significant opportunity to improve the diagnosis of malnutrition at their Adult Academic Health Center (AHC). The AHC consists of 2 major hospitals including: level one trauma services, comprehensive transplant services, the largest neurosurgery center in the state, and destination care for all ranges of oncology services, as well as many others. Despite providing high-level care for acute and chronically ill patients, in 2013, malnutrition was coded as a secondary diagnosis in only 5.5% of patients discharged from the 2 facilities combined.37 As a process improvement intervention, standardized language using the malnutrition clinical characteristics criteria from the consensus statement1 was developed and imbedded within the EMR in 2014 allowing the clinical nutrition team to unify their approach to the diagnosis of malnutrition Additionally, with the support of IU Health Information Services and the Statewide Advanced Provider Team, approval was gained to allow for RDN documentation to automatically populate LIP documentation. Within the first year of implementation, total patients discharged with a diagnosis of malnutrition increased from 2900 to 4969 encounters, a 71% increase. More specifically, severe protein-calorie malnutrition diagnoses increased from 459 to 2081 encounters, a 353% increase. Ultimately, the end result was an increase in total discharges with a malnutrition diagnosis from 5.5% to 10%.37

The increased number of discharges with a malnutrition diagnosis led to improved communication of the nutritional state of the patient and required interventions implemented to remedy the malnutrition in the transition of care from the acute care hospital to home, long term care facility, or inpatient rehabilitation facility.

Consistent with previous studies,7,12 the costs associated with treating malnourished patients were higher in IU Health’s population. Despite making up only 6% of the population, patients diagnosed with malnutrition made up nearly 12% of the total variable direct cost for patients admitted during a 30-day period (Table 5). Therefore, increasing awareness of the prevalence of malnutrition and the associated necessary interventions to treat it is an important step towards reducing overall healthcare costs.

CONCLUSION/CALL TO ACTION

Focusing on nutrition assessment, diagnosis, documentation, and intervention led to a significant improvement in identifying patients at nutrition risk requiring intervention at IU Health. Continued attention must be given by the entire healthcare team to ensure ongoing success. It is essential for RDNs to be diligent in their role to identify malnutrition, communicate with the LIP and other healthcare team members, and most importantly, implement meaningful interventions. Patients identified with malnutrition during their hospital stay should have clear instructions for continued nutrition repletion communicated to all appropriate healthcare team members and documented in the discharge summary. Standardizing how malnutrition is defined and documented with details specific to the individual patient will help facilities move towards meaningful and effective assessment, diagnosis, and intervention. In order to conduct studies within and beyond our own institutional walls, RDNs should agree to use the standards as defined by the Academy/A.S.P.E.N. Consensus Statements of 2012 (adults)1 and 2014 (pediatrics)28 and build this into daily practice. First and foremost the goal is to improve care and patient outcomes, benefiting not only the patient and families, but also the providers and institutions. Consistent documentation and coding leads to a better understanding of disease through the ability to mine large amounts of data to determine which diagnoses are most often comorbidities of each other and the related implications. Correlating malnutrition with quality metrics such as length of stay, blood stream infections, wound healing, anthropometrics, readmission and mortality will allow for improved understanding of implications and lead to more targeted therapy. An understanding of population health determinants requires appropriate documentation and coding of protein-calorie malnutrition to inform populated based interventions. Acknowledements A special thank you to Kate Willcutts, DCN, RD, CNSC, University of Virginia Medical Center, Charlottesville, VA and Terese Scollard, MBA RDN LD FAND, Providence Health and Services, Portland, Oregon, for their expertise and editorial suggestions.

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Nutrition Issues In Gastroenterology, Series #168

Nutritional Approaches to Chronic Nausea and Vomiting

October 2017 • Volume XLI, Issue 10
Nitin K. Ahuja

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In addition to a relative lack of definitive diagnostics and effective therapies, maintenance of adequate nutritional intake can represent a significant challenge for patients with chronic nausea and vomiting. This brief review will consider the existing evidence basis for nutritional approaches to a variety of non-structural causes of chronic nausea and/or vomiting, including gastroparesis, chronic nausea and vomiting syndrome, functional dyspepsia, cyclic vomiting syndrome, and rumination syndrome.

Nitin K. Ahuja, MD, MS, Assistant Professor of Clinical Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

INTRODUCTION

For a variety of reasons, chronic nausea and vomiting can be difficult complaints to manage clinically. In cases of severe or refractory symptoms, quality of life can be markedly diminished, which often corresponds with significant healthcare resource utilization.1 Objective testing modalities beyond endoscopy and scintigraphy are also limited, leading to a sometimes frustrating lack of etiologic specificity and often empiric patterns of therapeutic decision-making.

Regardless of governing diagnosis, the role of nutrition in the setting of chronic nausea and vomiting can be vital. Given a tendency within this patient population toward postprandial symptom exacerbation, there is keen interest in potentially mitigating dietary strategies. Chronic nausea and vomiting also may limit the adequacy of nutritional intake, which can necessitate consideration of enteral or parenteral feeding alternatives. While several options exist for pharmacologic and mechanical intervention among patients with chronic nausea and vomiting, this review will focus on nutrition-based approaches to their longitudinal support.

Etiology and Nomenclature

Recognizing the diverse and often overlapping diagnostic categories for chronic nausea and vomiting is a useful preface to considering nutritional management in the face of these symptoms (Table 1). Gastroparesis, defined as a clinical syndrome of gastric retention with objective evidence of delayed gastric emptying, is a commonly suspected etiology. When gastric emptying time is normal, however, and mucosal abnormalities, mechanical gastric outlet obstruction, and metabolic disturbances have been excluded, a diagnosis often relies on clinical patterns. With its latest iteration of diagnostic criteria (Rome IV), the Rome Foundation offered a revised classification for this latter set of patients, combining “chronic idiopathic nausea” and “functional vomiting” into the single category of “chronic nausea and vomiting syndrome (CNVS).” CNVS is formally defined as bothersome nausea or episodic vomiting, either of which must occur at least once weekly, at the exclusion of regurgitation, rumination, disordered eating behaviors, and underlying structural or systemic processes.2

Some investigators have questioned the importance of distinguishing gastroparesis from chronic nausea and vomiting with a normal gastric emptying time (sometimes called “chronic unexplained nausea and vomiting” or “vomiting of unexplained etiology”) given that the clinical presentation and management of these two entities are often strikingly similar.3 Functional dyspepsia (FD), a related Rome IV diagnosis that emphasizes post-prandial pain or fullness as the primary complaint, also includes the possibility of co-morbid chronic nausea (though usually without significant vomiting). Alternative nomenclature, including “gastroparesis-like syndrome” and “gastric neuromuscular dysfunction,” has been proposed to reflect the possibility that, along a spectrum of transit time measurements, patients with chronic nausea (with or without associated bloating, abdominal pain, subjective fullness, and early satiety) may reflect common pathophysiologic mechanisms.43

Other potential explanations for chronic nausea and vomiting, such as cyclic vomiting syndrome (CVS), abdominal migraine, and rumination syndrome, have distinct historical features, but are likewise limited by a lack of clear objective metrics. CVS is defined according to Rome IV clinical criteria as episodes of vomiting stereotyped by acute onset and short duration with absence of vomiting between episodes. On the basis of phenomenological similarities and associations with migraine headaches, abdominal migraine is hypothesized as a close relative of CVS, the former typified more prominently by pain than by nausea. Rumination syndrome is a behaviorally mediated disorder defined by Rome IV criteria as the persistent regurgitation of recently ingested food, often within 30 minutes of meal completion; regurgitation, in turn, is qualitatively distinguished from vomiting by its effortless quality and usual dissociation from prodromal retching.2 Chronic nausea and vomiting complaints might also reflect disordered eating, excessive cannibis use, or dysmotility processes distal to the stomach (e.g. intestinal pseudo-obstruction).

Gastroparesis and Chronic Nausea and Vomiting Syndrome

Gastroparesis is usually thought to arise from autonomic nerve injury related to diabetes, surgery, or antecedent infections, though the largest disease subcategory remains idiopathic.5 Aside from the need for blood glucose optimization in patients with diabetes, nutritional recommendations in gastroparesis tend not to be etiologically specific. Indeed, some practitioners regard these recommendations as broadly relevant enough to apply, at least in part, to patients with symptoms of gastroparesis and a normal gastric emptying time, though specific data are lacking regarding optimal nutritional strategies within this population.6

Dietary Symptom Management

American College of Gastroenterology (ACG) guidelines advocate dietary interventions as the first- line strategy for gastroparesis management (Table 2). Traditional dietary recommendations to minimize symptoms and maximize tolerance of oral intake include: small, frequent meals (=4/day) given the tendency toward gastric retention; an emphasis on liquid nutritional sources given relative preservation of liquid emptying function in gastroparesis; restriction of excess fat intake with solid meals given its deleterious effects on stomach emptying; and restriction of fiber intake given the risk of bezoar formation.7 The narrowness of these restrictions is often organized in a stepwise manner in accordance with symptom severity, such that patients are ideally graduated from thin liquids to tolerable solids as their symptoms improve.8

Despite the longstanding nature of these recommendations, they are largely rooted in physiologic models and expert opinion rather than direct, trial- based observation.9 A recent study of 12 patients with gastroparesis demonstrated increased post-prandial symptom severity with high-fat versus low-fat meals and with solid meals versus liquid meals.10 A slightly larger study by the same group inventoried specific foods in a cohort of 45 patients with gastroparesis, identifying a trend toward fatty, spicy, acidic and roughage-based foods as reliable symptom triggers, while bland, sweet, salty, and starchy foods were comparatively well tolerated.11

Relatively newer strategies for oral nutrition in patients with gastroparesis include the small particle size diet, which emphasizes food that is easily mechanically processed to the consistency of a mashed potato. Within this framework, easily digestible foods include, for example, avocados, processed cheese, and other foods that can be pureed, mixed, or cooked to the consistency of mashed potatoes. Poorly digestible foods, by contrast, include seeds, grains, and fibrous, unpeeled fruits and vegetables. A randomized controlled trial of the small particle size diet among patients with diabetic gastroparesis demonstrated significant reductions in the severity of nausea/vomiting symptoms (as well as postprandial fullness and bloating) relative to a traditional diabetic diet. These symptom reductions were noted despite a significantly higher amount of fat in the intervention diet, suggesting that, with further study or in particular patient subsets, some nutritional recommendations may take priority over others.12

Other investigators have considered the utility of reducing fermentable carbohydrate loads (e.g. fermentable oligo-, di-, monosaccharides and polyols; FODMAPs) among patients with gastroparesis, particularly in light of the benefits such diets yield in the context of irritable bowel syndrome.13 Retrospective, questionnaire-based analysis has suggested an association between high FODMAP intake in gastroparesis and increased abdominal pain and reduced quality of life, though no significant trend was noted with respect to nausea and vomiting.14

Table 3 offers more targeted recommendations based on the broad strategies outlined above (but should be supplemented with other published materials and consultation with a dietitian for the purposes of patient counseling). Dietary strategies may also include the consumption of herbal compounds with previously demonstrated antiemetic properties. While ginger preparations have not been rigorously studied in the context of gastroparesis or CNVS, they have demonstrated benefit in chemotherapy-induced nausea and hyperemesis gravidarum, with a putative mechanism related to accelerated gastric emptying and increased antral contractions.15-16 Researchers have tended to study ginger as a powdered extract in dose ranges of 250-1,000 mg, though anecdotal benefits have also been reported from a variety of commonly available ginger products, including raw and crystallized ginger as well as ginger ale.11 A separate compound of nine herbal extracts called STW5 (marketed from Germany as Iberogast) has demonstrated the ability to promote antral contractions and increase proximal gastric volume, suggesting a possibly beneficial role in gastroparesis, though it has not been formally studied in this population.17

Nutritional Support

The propensity toward malnutrition among patients with gastroparesis is well established with regard to overall caloric intake as well as vitamins and minerals. Data suggest that particularly common micronutrient deficiencies include iron, folate, thiamine, calcium, magnesium, phosphorus, zinc, and Vitamins B12, C, D, E, and K.18-19 Importantly, overweight status precludes neither the diagnosis of gastroparesis nor the possibility of malnutrition, as recent research indicates that weight gain may be due to significantly reduced energy expenditure in this population relative to healthy controls.20

Among patients in whom oral feeding is deemed inadequate, enteral supplementation is preferred to parenteral supplementation due to the former’s relative safety, lower costs, and ease of use. Common thresholds for considering the initiation of enteral therapy include: unintentional, progressive weight loss (e.g. greater than 5-10% over 3-6 months, or consistently below agreed upon goals); frequent hospitalizations for dehydration or metabolic disarray; an inability to reliably take oral medications; and an otherwise unsustainably low quality of life or failure to thrive. The vast majority of patients will tolerate standard enteral formulations, though hospitalization is usually required for initiation of feedings, particularly among patients with labile blood glucose control or acutely severe symptoms.21

ACG guidelines for gastroparesis management recommend a trial of nasojejunal feedings prior to placement of a percutaneous feeding tube terminating in the jejunum in order to bypass the stomach. Keeping a jejunal tube in an appropriate position can be a challenge, however, particularly in patients with persistent vomiting. Anecdotal strategies to avoid displacement include minimizing the pre-pyloric distance traversed by the tube and locating its tip as distally as possible, though even with optimal initial positioning, endoscopic or fluoroscopic replacement may become necessary. Direct jejunostomy placement can also mitigate the likelihood of tube displacement but is relatively more technically challenging and precludes the possibility of gastric venting.7 Little data is available regarding preferred enteral supplementation strategies in symptomatic patients with a normal gastric emptying time. In practice it may be more difficult to make the case for jejunal tube placement in patients without a formal diagnosis of gastroparesis, though cohort studies acknowledge the potential need for enteral feeding in this population as well.22

Other Causes of Chronic Nausea and Vomiting
Functional Dyspepsia

Similar food-based symptom triggers (fried, fatty, spicy foods, along with carbonated beverages) have been identified in the gastroparesis and FD populations.23 While the mechanistic relationship between these two conditions is not yet definitively established, intriguing arguments have been made regarding the likely interplay among dietary fat, gastrointestinal signaling hormones, and aberrant gastroduodenal bolus transit giving rise to distressing visceral sensations in FD.24-25 These hypotheses may have relevance for other chronic nausea syndromes as well. Recently published ACG guidelines do not recommend routine use of complementary and alternative modalities such as herbal preparations for FD, citing insufficient evidence.26

Cyclic Vomiting Syndrome (CVS) and Abdominal Migraine

While CVS manifestations can be marked by significant heterogeneity, diet plays a significant role in a subset of patients with this disorder. Potential triggers of stereotyped vomiting episodes can include prolonged fasting and catabolism associated with interceding illness, in which case prophylactic nutritional recommendations include supplemental carbohydrates between meals, before exercise, and at bedtime. Specific food-related triggers sometimes attributed to CVS include chocolate, cheese, caffeine, and monosodium glutamate (MSG), which, once identified in a given patient, should be avoided.27 Such recommendations are sometimes broadened to exclude all foods generally implicated in migraine provocation (including citrus, pork, shellfish, game, gravies, yeast extract, and alcohol), attesting to the putative clinical proximity of CVS and abdominal migraine.28 Interest in the dietary management of these conditions spans several decades; a low-oxalate diet (e.g. avoidance of carrots, onions, rhubarb, spinach, chocolate, and tea) was once advised in the 1970s for CVS and abdominal migraine, which at the time were deemed synonymous.29

Rumination Syndrome

While the therapeutic mainstay for rumination syndrome is behavioral, many experts advocate a multidisciplinary team of providers, particularly in severe cases. As with chronic nausea and vomiting of any etiology, the perspective of a dietitian can be quite valuable for accurately assessing caloric deficits and goals. The use of temporary enteral feeding modalities (e.g. nasogastric or nasoduodenal tubes) can also help meet patients’ nutritional needs while targeted behavioral interventions are being pursued.30

CONCLUSION

Formalized dietary recommendations for patients with chronic nausea and vomiting hinge on diagnostic categories whose boundaries have been subject to ongoing revision. The clinical relevance of gastric emptying delay, in particular, has been called into question, suggesting that oral feeding recommendations for gastroparesis may be at least partially applicable to symptomatic patients with normal scintigraphic results. Enteral supplementation is preferred when oral nutrition is deemed inadequate, with post-pyloric feedings perhaps easier to rationalize in the setting of documented gastroparesis. Particular foods have been identified as typical symptom triggers in gastroparesis, FD, CVS, and abdominal migraine, and avoidance of these foods can be considered on an empiric basis. Areas ripe for further study include the precedence of dietary content versus consistency in the management of gastroparesis; optimal thresholds and locations for enteral feeding in various patient subsets; and any relevant distinctions between gastroparesis, FD, and CNVS that might impact individual strategies of dietary optimization.

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Frontiers In Endoscopy, Series #37

Melanoma Metastatic to the Ampulla of Vater Diagnosed via EUS-Guided Core Biopsy

July 2017 • Volume XLI, Issue 7
Zoey Bridges,Isaac Lloyd,Douglas G. Adler

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In this article, we discuss a rare presentation of metastatic melanoma to the ampulla where an endoscopy and endoscopic ultrasound were vital in evaluating the patient and obtaining core biopsies of the lesion. Proper tissue acquisition was made possible with EUS-FNB for pathology interpretation, showing the value of this technique.

Zoey Bridges,1 Isaac Lloyd MD,2 Douglas G. Adler MD, FACG, AGAF, FASGE1 1University of Utah School of Medicine, Department of Internal Medicine, Division of Gastroenterology and Hepatology, 2University of Utah School of Medicine, Department of Anatomic Pathology, Huntsman Cancer Center, Salt Lake City, UT

CASE HISTORY

A 69 year old female had a history of a metastatic melanoma to the left groin without identification of a primary site 4 years prior to presentation. The groin lesion was resected and one out of 14 nodes was positive for melanoma, and the patient was ultimately staged as having pTx N1b M0 stage IIIC melanoma. At that time, she was treated with ipilumimab.Three years prior to presentation she developed a left inguinal lymph node recurrence, which was resected. This year, the patient underwent a surveillance CT scan which revealed a generous ampulla and elevated serum liver chemistries and was referred to endoscopy. At endoscopy, the ampulla was generous without obvious mucosal neoplasia. (Figure 1) Endoscopic ultrasound revealed a hypoechoic, 15x19mm mass lesion in the ampulla below the mucosa. (Figure 2) The lesion compressed the CBD, but the duct was still patent. The lesion was sampled via EUS-guided core biopsy using a 22 gauge core needle. Pathologic analysis revealed metastatic melanoma. (Figure 3). The patient was referred back to oncology and initiated treatment with pembrolizumab.

Discussion

Malignant melanoma develops from melanocytes mainly present in the skin, eyes, meninges and gastrointestinal (GI) mucosa, which can arise anywhere from the mouth to the anus. Melanoma is rare, comprising only 1-3% of all tumors.1 While the primary site of melanoma is the skin, it is known that melanoma can metastasize to the GI tract.2,3 The propensity of a primary malignant tumor to metastasize depends on the Clark staging, with >70% of Clark level III and Clark level IV lesions involving the GI tract.6 Metastatic melanoma has been seen in the esophagus, stomach, small intestines, and colon. 1-4% percent of patients with malignant melanoma show clinically apparent gastrointestinal tract involvement during the course of their disease and are diagnosed ante mortem, while up to 60% of all patients with melanoma are found to have metastases at autopsy.4 Due to these findings, some have recommended that all patients with known melanoma should be screened to rule out any gastrointestinal spread.4

The clinical presentation for patients with metastatic melanoma can be asymptomatic or can include the following: abdominal pain, upper or lower GI tract bleeding, anemia, weight loss, intestinal obstruction, perforation, or intussusception.1,5 The anorectal region is the most common site for primary gastrointestinal melanomas, due to the presence of melanocytes.7 On the other hand, metastases of the GI tract are seen more frequently in the small intestines (35% to 97%).6,7 Reports on the prevalence of metastatic melanoma in the gastrointestinal tract show 0.1-0.5% cases in the esophagus, 5%-50% cases in the stomach and duodenum, and 5%-32% cases in the colon.7 When examining these rates separately, reports found 12%-19% occurrence of malignant melanoma in the duodenum and 24%-26% in the stomach.8 The average time from initial diagnoses to the finding of intestinal metastases ranges from 21.6 months to 54 months.7

While primary GI and biliary melanomas are rare, it can be difficult to distinguish between a primary mucosal, metastatic GI, and biliary melanoma from an unknown or regressed primary site.9 If a primary lesion has already been diagnosed, the clinician can usually determine that the melanoma in the GI tract is in fact metastatic.9 This particular patient did have a prior history of melanoma that had metastasized to other areas. Metastases of the GI tract often occur late in the history of the disease and have an overall poor prognosis.10 Once melanoma has metastasized to the GI tract and other visceral sites, the median survival is four to nine months for these patients.11

While it is uncommon to find metastatic melanoma in the biliary tree it has been previously documented.10 Unfortunately, the incidence of isolated metastases to the ampulla is far less known with only a few reports to analyze.10,11,12 The literature separates the cases of primary biliary tract melanomas and ampullary melanomas. One publication suggests that many of the ampullary melanomas may have metastasized from cutaneous or vaginal primary melanoma.9 Metastatic melanoma to the common bile duct can present itself as a lesion located above the ampulla. One study reported the metastatic melanoma of the common bile duct extending to the ampulla and involving the gall bladder.9 This particular case found the patient’s lesion in the ampulla compressing her CBD. At postmortem examinations, 6% of patients with a known malignant melanoma have unexpected bile duct involvement while 15% with metastatic melanoma have gallbladder involvement.11 Melanoma metastatic to the ampulla is rare and can cause biliary obstruction.10,11 Patients diagnosed with metastatic melanoma of the ampulla presented symptoms of nausea, vomiting, cholestasis, and melena.10

The appearance of metastases during an endoscopy may take the form of ulcers, nodules, or polyps, which may be pigmented or amelanotic.6 Diagnostic yield of biopsy from the margins of these ulcerations or lesions is >90%.6 The 15x19mm mass lesion found in the patient’s ampulla below the mucosa was analyzed and a EUS-guided fine needle biopsy was taken. The 22 gauge needle used to collect the biopsy is specifically used in diagnosing pancreatic and non-pancreatic lesions where the tip of a fine needle aspiration (FNA) is not optimal.

Recent months have seen the development of biopsy needles designed for core tissue acquisition that provide sufficient tissue for histologic evaluation.13 One multicenter study on EUS-FNB reported on the histological specimens being adequate in 89.47% of the patients and having a diagnostic yield of 92.9% of patients.16 Core EUS-FNB needles can provide higher histologic yield despite requiring fewer needle passes compared to the standard EUS-FNA needles.14 The endoscopist, for this particular case, saw it beneficial to use a EUS-FNB, with a 22-gauge needle, to sample the lesion on the patient’s ampulla.

EUS-FNB needles can come in a variety of gauge sizes, including 19, 22, and 25 gauge. While the larger diameter needles may provide more tissue, there can be instances where 19 gauge needles are associated with an increase in blood and cellular debris contamination, adverse events, or technical failures.15,16 A prospective study comparing of a 25-guage and 22-gauge FNB needles found the diagnostic accuracy of the two were 98% and 95%, respectively. While the 25-gauge needle produced adequate core biopsies for histological examination in 87.5% lesions in comparison to 82.1% of lesions that were sampled with a 22-gauge needle.15 A study on EUS guided fine needle biopsy (FNB) sampling compared a forked-tipped biopsy needle to a FNA needle found that the FNB needle provided a higher yield of core tissue with fewer passes.13 This particular study found histology cores in 95% of the fine needle biopsy samples in comparison to only 59% of the fine needle aspirate samples. The median number of passes for FNB needles during this study was two while four passes remained the median for FNA needles.13 Another result of this particular study was that the authors found a diagnosis of a specific lesion type was obtained with no more than two passes in 80% of the FNB group but only in 14% of the FNA group.

Another study analyzed two specific core needles; one with a reverse-bevel design and another with a 6-cutting edge and opposing bevel design. In this study, 99% of the specimens obtained with the opposing bevel needle were adequate for histopathologic interpretation in comparison to only 87% of the samples obtained from the needle with the reverse bevel.14 This study also found the opposing bevel tipped needle providing higher sensitivity (90.1% vs 71.1%) and overall accuracy (92% vs 74%) than the reverse bevel needles. The FNB needle used during our patient’s EUS provided adequate core biopsies for pathologists to complete a histopathologic interpretation. The sufficient amount of core collected aided the pathologists in diagnosing the lesion as metastatic melanoma in the ampulla.

While endoscopy can help identify any ulceration or lesion, metastatic melanoma may be completely amelanotic with a variable cytological appearance. In order to confirm the diagnosis of malignant melanoma immunhistochemical stains are needed; the S100 sensitivity varies between 33-100%, HMB-45 antibodies has sensitivity between 80-97%, but the specificity is high (100%).1,10 Proper tissue acquisition is important in diagnosing these lesions because an adequate sample must be obtained for the immunohistochemical stains. The EUS-guided core biopsies collected in this case were more than for diagnosing the patient’s lesion as metastatic melanoma and provided tissue for both cytologic and histologic analysis.

Overall, metastatic melanoma in the GI tract is often times asymptomatic or not discovered until autopsy. This patient had a rare presentation of metastatic melanoma to the ampulla. An endoscopy and endoscopic ultrasound were all vital in evaluating the patient and obtaining core biopsies of the lesion in her ampulla. Proper tissue acquisition was made possible with EUS-FNB for pathology interpretation, showing the value of this technique.

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Nutrition Issues In Gastroenterology, Series #182

Revisiting Vitamin B12 Deficiency: A Clinician’s Guide For the 21st Century

December 2018 • Volume XLII, Issue 12
Andrew P. Copland,Brian J. Wentworth

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Vitamin B12 (cobalamin) deficiency is a common disorder encountered across various medical and surgical disciplines. Traditional diagnosis has relied on serum cobalamin quantification; however, accumulating evidence suggests that a significant proportion of cases are missed without additional workup. This review discusses the various etiologies of B12 deficiency, provides a practical approach to diagnosis, and summarizes the available nutritional and medical literature regarding management.

Brian J. Wentworth MD, Fellow Physician, PGY-4, University of Virginia Health System, Division of Gastroenterology & Hepatology Andrew P. Copland MD, Assistant Professor of Medicine, University of Virginia Health System, Division of Gastroenterology & Hepatology, Charlottesville, VA

INTRODUCTION

Vitamin B12 (cobalamin) is a water-soluble vitamin that serves as cofactor for three major cellular reactions converting:

  • 1. Methylmalonic acid (MMA) to succinyl coenzyme A,
  • 2. Homocysteine to methionine, and
  • 3. 5-methyltetrahydrofolate to tetrahydrofolate.

The first reaction is a key step in the tricarboxylic acid (TCA) or Krebs cycle within the mitochondria to generate energy (adenosine triphosphate), while the latter two reactions ensure unimpeded DNA synthesis. In addition, vitamin B12 (B12) is essential for myelin synthesis and maintenance within the nervous system and also plays a role in bone marrow erythropoiesis.1,2

B12 deficiency is quite common. Estimates range from 40% to 80% in developing nations;3 surprisingly, approximately 6% of people aged less than 60 years and nearly 20% of adults older than 60 years are B12 deficient in the United Kingdom and the United States.4 Despite its high prevalence, however, B12 deficiency often remains undiagnosed and may present subtly in patients. An understanding of the basic physiology of B12 absorption will help the clinician contextualize how deficiency may develop. Appreciating the limitations of current diagnostic strategies is key to effective clinical practice.

Physiology

Vitamin B12 is one of the essential vitamins as it cannot be synthesized by human metabolism. Bacteria and archaebacteria synthesize B12 through aerobic and anerobic pathways, respectively.5 Human colonic flora are also able to produce B12, yet its location distal to the terminal ileum prevents absorption.6 To achieve an adequate daily intake of 2.4µg for adults (2.6µg for pregnant women and 2.8µg for lactating women), humans must obtain B12 from animal products including meat, seafood, dairy, and fortified cereals.7 Interestingly, ≤1% of free cobalamin is absorbed at the epithelial border in the terminal ileum. The remainder is stored in the liver and muscles, with a half-life of 1-4 years.6

In food, B12 is protein-bound. As food reaches the stomach, gastric parietal cells secrete pepsinogen and intrinsic factor (IF). Pepsin, the activated form of pepsinogen, cleaves food-bound B12 allowing it to bind to haptocorrin (R-binder). In the small bowel, pancreatic proteases break this B12-haptocorrin complex, forming a new B12-IF complex. The B12-IF complex travels to the terminal ileum where it is absorbed via the receptor complex cubam.6,8 After absorption, B12 binds to either haptocorrin for transport to the liver, or transcobalamin to form holotranscobalamin, which facilitates incorporation into cells.8 In contrast, synthetic or unbound B12 does not require pepsin to bind to IF and 1-2% can be passively absorbed throughout the GI tract without intrinsic factor or the presence of an ileum.9

Both enteral nutrition (EN) and parental nutrition (PN) are able to provide adequate daily requirements for B12, assuming the patient is on daily PN10 or receives the volume of EN needed to provide the daily requirement. A recent review of 62 enteral formulas determined on average each product provided > 200% of the recommended daily amount (doses of 1500 and 2000 Kcal/day).11 Although jejunal feeding bypasses the stomach, the passively absorbed synthetic B12 in commercial products is adequate to prevent deficiency.8

Pathophysiology

In addition to inadequate B12 intake, there are numerous steps in the B12 absorptive pathway where disease may strike (Table 1). Gastric parietal cell loss secondary to autoantibodies (autoimmune gastritis) or surgical removal causes loss of hydrochloric acid and intrinsic factor production.12 Autoimmune gastritis (AIG) has a prevalence of 2.5-12% without sex preference; all ages may be affected,13 but a large series reported a median age range of 70-80 years. It is associated with the presence of autoantibodies to parietal cells and/or intrinsic factor. Risk factors for development of AIG include a history of autoimmune disease (particularly thyroid disorders), northern European heritage, HLA DRB1*03 and DRB1*04 genotypes, and age over 30.14 Over time, pernicious anemia may develop, which is defined as the presence of anemia, low serum B12, gastric body atrophy (with resultant atrophy of oxyntic glands and hypochlorhydria), and the presence of autoantibodies. The duration from onset of AIG to development of pernicious anemia is not well described in the literature, but some reports suggest a latency of as long as 20 years.2

Intestinal malabsorption of food-bound B12 has several physiologic mechanisms, including ileal resection or active inflammation, pancreatic insufficiency, congenital defects (Table 1), and an altered intestinal microbiome.4 Small-intestinal bacterial overgrowth (SIBO) has increased in prevalence over time and may interfere with protein-bound B12 absorption due to competitive inhibition by abnormal ileal flora.15

Some medications can also interfere with B12 absorption. Chronic use (2+ years) of acid-suppressing medications, including h3 receptor antagonists (h3RAs) and proton-pump inhibitors (PPIs), are associated with a higher likelihood of deficiency. The proposed mechanism involves a loss of gastric acid required to activate pepsinogen to pepsin in the stomach, disabling the cleavage of B12 from its associated R-protein.16 Long-term metformin use has also been associated with B12 deficiency; however, a true estimate of effect size remains elusive.17 Unlike acid suppressants, the mechanism for B12 deficiency is less well understood for metformin, and may relate to interference of calcium-dependent membrane action necessary for B12-IF complex absorption in the terminal ileum.18 Recreational nitrous oxide (N2O) use in adolescent and young adult population may also precipitate B12 deficiency with high dose or chronic abuse. N2O irreversibly oxidizes the cobalt ion of B12, interfering with its ability to be a cofactor to methionine synthase, leading to downstream impairment of myelin production.19

Clinical Manifestations

The sequelae of B12 deficiency in adults ranges widely in severity. Given the hepatic storage of inactive B12, onset to overt deficiency may take up to 10 years.2 Mild deficiency may present only as fatigue. As B12 deficiency becomes more severe, skin hyperpigmentation, glossitis, cardiomyopathy and infertility can be seen.2,4 Thrombosis, including atypical presentations such as cerebral venous sinus thrombosis, may occur as a result of hyper-homocysteinemia induced by severe B12 deficiency.20 Bone marrow involvement is common and pancytopenia may develop in severe deficiency. Megaloblastic anemia is most frequently seen, although patients with AIG may initially demonstrate iron deficiency (gastric acid is necessary for duodenal iron absorption), before B12 deficiency is diagnosed.20 Neurologic dysfunction is not uniform and can present with demyelination of the posterior and lateral tracts of the spinal cord. Demyelination of these neurons causes both peripheral and truncal weakness as well as paresthesias and a loss of vibration, pressure, and touch sensation. Progressive neurologic damage with untreated B12 deficiency includes spastic ataxia, anosmia, ageusia, and optic atrophy.4,20 Peripheral neuropathy may also be seen, and in those with diabetes, it can be difficult to distinguish from diabetic polyneuropathy.21 Finally, at its most severe, B12 deficiency may cause a dementia-like presentation termed “megaloblastic madness” with depression, mania, irritability, paranoia, delusions, and frank psychosis with hallucinations.4,20 Clinicians need to be aware that concomitant anemia in the presence of neurologic signs may be absent in up to 20% of cases and delayed diagnosis can lead to progressive and irreversible damage.4

Diagnosis

Making the diagnosis of B12 deficiency requires attention to the limitations of current laboratory assays. Serum B12 levels are often the first test performed, however these are subject to both false negatives and false positives. A severely low level (<100 µg/mL) is often associated with signs and symptoms of deficiency. Significant variation exists between various laboratory assays and B12 levels may be spuriously normal or falsely high in patients with anti-intrinsic factor antibodies as intrinsic factor is often used in the U.S. as the assay-binding protein.20 Thus, clinicians should consider the clinical context when interpreting serum levels and be careful to avoid direct comparison between two different values from independent laboratories (Table 2).

Elevated B12

An elevated serum B12 level is common. Prevalence ranges from 7-18% in hospitalized patients22 and does not necessarily exclude an underlying deficiency. The principle reason for a high level typically stems from an imbalance in B12 plasma binding proteins (haptocorrin, transcobalamin) related to either increased synthesis or decreased clearance. In liver disease, damaged hepatocytes release B12 in addition to abnormal hepatic clearance of haptocorrin. Elevated B12 levels may be seen in various solid and hematological cancers, mostly secondary to high haptocorrin production. Additionally, renal dysfunction leads to poor B12 clearance.8,22

Methylmalonic Acid and Homocysteine

When clinical manifestations are subtle, measurement of serum methylmalonic acid (MMA) and homocysteine (HCys) can be helpful as they reflect key cellular pathways involving B12. Both MMA and HCys are elevated in >98% of patients with B12 deficiency; HCys will also be elevated in folate deficiency. Both levels decrease rapidly after treatment and can be used to ensure adequate B12 supplementation.20 Limitations of MMA and HCys include falsely elevated levels in the presence of renal dysfunction.20 variation in pregnancy without validated reference ranges,24 and short-term fluctuations of MMA and HCys in both normal and deficient individuals.25 There also is new evidence that polymorphisms in the gene HIBCH affect MMA levels irrespective of B12 status.24

Determining Etiology

Identifying the cause of B12 deficiency aids in directing treatment. A detailed clinical history often reveals an obvious etiology such as vegetarian or vegan diets or patients with either gastric or ileal resections. The cumbersome Schilling test, involving administration of radioactive B12 and measuring fractional urine excretion, has been phased out. Non-invasive assessment for AIG currently relies on detection of serum autoantibodies to parietal cells (PCAs) and intrinsic factor (IFAs). The combination of PCA and IFA often improves the characteristics of this testing12 (Table 3). However, the gold standard for diagnosis of AIG is endoscopy with biopsy. Elevated fasting serum gastrin and low serum pepsinogen may also be used to support diagnosis if uncertainty remains.14

Screening

No guidelines exist to assist clinicians with identification of patients at increased risk for deficiency and guide screening intervals. Nonetheless, clinicians should be aware of the high prevalence in certain key patient populations (Table 4). Expert opinion regarding several of these conditions suggests annual screening with a CBC and possibly serum B12, MMA, and HCys.

Management

Treatment of B12 deficiency has traditionally centered on increasing oral intake of food-bound B12 and intramuscular (IM) injection of the synthetic vitamin. Cyanocobalamin is the preferred form of B12 in the U.S., while hydroxocobalamin is primarily used in Europe; the latter formulation has been noted to have better retention and thus may be dosed less frequently.24 Both are readily converted to the biologically active adenosylcobalamin and methylcobalamin.24 Approximately 10-15% of a standard 1000µg IM B12 injection is retained, allowing for rapid replacement.24,26 Guidelines from the British Society for Haematology recommend thrice weekly injections for two weeks in patients without neurologic deficits, with extension to three weeks or until clinical improvement if neurologic symptoms are present.2 Injections may then be tapered to weekly for a month, then monthly in perpetuity if an irreversible cause is present. Improvement in MMA and HCys levels is seen within one-week; neurologic symptoms may take 6-12 weeks (sometimes with transient paradoxical worsening). Hematologic abnormalities may take up to eight weeks to normalize.2,20

Oral replacement has become more popular in recent years given the cost, convenience, and pain associated with injection. For a similar 1000µg dose (as compared to IM), only 0.5-4% is absorbed.24 A Cochrane review of the available evidence found no difference between serum B12 levels in patients taking either IM or oral formulations (most commonly 1000µg/day). Outcomes related to signs and symptoms of deficiency or quality of life were not reported in the trials reviewed.26 Oral supplementation should ideally be administered in a fasting state as it is less effectively absorbed when taken with a meal.

Although there is some evidence for high dose oral supplementation in patients with known malabsorption or severe deficiency, most experts recommend IM administration. Treatment should be continued indefinitely if the etiology of malabsorption is irreversible – in patients with pernicious anemia who discontinue supplementation, neurologic symptoms recur as soon as 6 months; megaloblastic anemia can return within a few years.24,27 A prophylactic daily oral dose of 1000µg B12 may be reasonable for patients having undergone bariatric surgery; in fact, this is recommended by the American Society for Metabolic and Bariatric Surgery.2 Interestingly, despite the high prevalence in Crohn’s disease, the recent American College of Gastroenterology28 and American Gastroenterology Association guidelines29 do not address specific recommendations regarding B12 deficiency.

Other less common administration routes include sublingual30 and intranasal,31 although the data supporting these modalities is derived from small cohorts of patients without severe clinical manifestations (or anemia in the sublingual cohort). There is anecdotal experience with successful subcutaneous (SQ) administration, however rigorous comparisons to IM have not been published. SQ injection is a preferred administration route by some patients at our institution, as they report less injection site pain as compared to IM. Table 5 provides a condensed summary of B12 repletion strategies.

CONCLUSION

B12 deficiency is common, yet under diagnosed, as clinical manifestations may be subtle. Serum B12 levels can be problematic and clinicians should consider obtaining MMA and HCys to assist with diagnosis. Treatment can prevent irreversible neurologic damage. Fortunately, there are many therapeutic options for treating B12 deficiency and maintaining adequate B12 reserves.

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