INTRODUCTION

Alejandro Del Cerro Rondon,

Majd Michael,

Darine Kassar,

Richard W. McCallum

Oculopharyngeal muscular dystrophy (OPMD) is rare, adult-onset, familial muscular dystrophy, which has been mainly characterized clinically by progressive dysphagia and ptosis. Dysphagia determines prognosis due to an increase in the risk of aspiration pneumonia and also poor nutrition. OPMD is suspected clinically in older adults with the combination of ptosis and dysphagia. A positive family history may be obtained. Impairments in cricopharyngeal relaxation and hypertonicity of the upper esophageal sphincter (UES) can be best documented through a modified barium swallow. Molecular genetic testing confirms the diagnosis. Treatment options include cricopharyngeal myotomy, cricopharyngeal dilatation and cricopharyngeal botulinum toxin injection. Dilatation of the upper esophageal sphincter by the gastroenterologist is a safe and effective procedure. It has the advantage that can be repeated over the years and complications are rare. Cricopharyngeal (UES) myotomy is the most common surgical intervention. Improvement is seen immediately after surgery, but high recurrence rates and the procedure itself leave the patient at risk for aspiration pneumonia. Botulinum toxin injection has limited literature support and unclear outcomes. We present our experience with three patients with OPMD and the challenges in the diagnosis and treatment.

Alejandro Del Cerro Rondon, MD, PGY-1 Internal Medicine Resident, Department of Internal Medicine Majd Michael, MD, PGY-3 Internal Medicine Resident, Department of Internal Medicine Darine Kassar, MD, Assistant Professor, Department of Neurology, Texas Tech University Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

CASE 1

A 71-year old female with past medical history of asthma, diabetes, hypertension, hypothyroidism, rheumatoid arthritis, obstructive sleep apnea, gastroesophageal reflux disease (GERD) and a surgical history significant for cardiac pacemaker was referred for progressive dysphagia over the past ten years. The dysphagia was initially to solids, worsening in the last three years and now is to both solids and liquids. The patient also noticed hoarseness. She developed bilateral ptosis four years ago, and at that time underwent blepharoplasty. The patient also reported difficulty climbing stairs.

On physical exam, the patient had bilateral ptosis with normal extraocular muscles movement, mild hoarseness and weakness of deltoid, supraspinatus and iliopsoas muscles bilaterally. The patient demonstrated a steady gait.

Initial evaluation for dysphagia utilizing a modified barium swallow study showed irregular filling in the piriform sinus esophageal stenosis at the C5-C6 level, cricopharyngeus hypertrophy and silent aspiration. Upper endoscopy revealed a normal esophagus, thrush in the oropharynx, non-bleeding gastric erythema and normal duodenum. High-resolution esophageal manometry documented decreased lower esophageal sphincter pressure with adequate relaxation. Findings of normal peristalsis in smooth muscle portion of the esophagus as well as striated muscle weakness were noted. Also, pharyngeal contractions and esophageal mobility at cervical level appeared reduced.

Laboratory workup results were negative for acetylcholine receptor antibodies, muscle-specific kinase (MuSK) antibodies, myeloperoxidase antibodies, and antineutrophil cytoplasmic antibodies (ANCA) profiles also came back negative.

Modified barium swallow showed a weak oropharyngeal phase of swallowing with significant pooling of contrast in the piriform sinuses and vallecula. Silent aspiration was also noted (Figure 1). The patient was referred to speech therapy, and, after a few sessions of exercise to improve swallowing, she continued to have aspirations that resulted in pneumonia.

The decision was made to dilate the upper esophageal sphincter to facilitate emptying and decrease aspiration risk. The dilation was performed utilizing a balloon through the scope to a maximum balloon size of 20 mm. Dilation was tolerated with no complications. However, her dysphagia did not improve so the decision was made to undergo a second esophagogastroduodenoscopy (EGD). This time a mild, benign-appearing, intrinsic stenosis was found in the upper third of the esophagus and was dilated utilizing a Savary dilator method over a guidewire with fluoroscopy monitoring with no resistance at 18, 19 and 20 mm. The dilation site was re-examined and showed mild improvement in luminal narrowing (Figures 2 and 3).

The patient reported improvement of the dysphagia after the second dilation and started a diet of pureed food. Genetic confirmatory testing for oculopharyngeal muscular dystrophy (OPMD) was ordered.

CASE 2

A 71-year-old woman with a past medical history of hypothyroidism and dyslipidemia experienced difficulty with swallowing starting at 40 years of age. Also, around same time noticed bilateral ptosis requiring blepharoplasty twice. She reported a family history of similar symptoms in her mother, maternal grandmother and three siblings. On physical exam, there was weakness in orbicularis oculi muscles bilaterally with limitation in extraocular muscles movements. Muscular strength of upper and lower extremities was adequate. The DNA test came back positive for 9 GCG repeat expansion in PABP2 gene confirming OPMD.

A modified barium swallow showed increased pooling in the vallecula, accumulation of contrast in the piriform sinus with penetration and aspiration of liquids. The patient started working with speech therapy weekly. Esophageal upper sphincter dilation was performed twice using a through the endoscope balloon technique with a minor improvement of the dysphagia.

CASE 3

A 70-year-old man with a past medical history of hypertension and hyperlipidemia presented to the clinic for evaluation of muscle weakness. He reported difficulties using the stairs for the last 10 years. Also, in the previous five years, he noticed a change in his voice and swallowing problems when eating solids. Multiple family members from his mother side have similar symptoms including his mother, three aunts, one uncle and a grandmother. On physical exam, weakness of the orbicularis oculi muscles was remarkable. Extraocular movements were intact. Proximal lower extremity muscle weakness was noted. A modified barium swallow showed a marked deficiency of the swallow mechanism with increased pooling in the vallecula and piriform sinus. Penetration and aspiration were present. DNA test was ordered and came back positive for 9 GCG repeat expansion in PABP2 gene confirming OPMD. The patient refused treatment for dysphagia and also percutaneous endoscopic gastrostomy (PEG) tube placement.

Discussion

Oculopharyngeal muscular dystrophy (OPMD) is rare, adult-onset, familial muscular dystrophy which has been mainly characterized clinically by progressive dysphagia and ptosis due to an involvement of the pharyngeal and palpebral musculature, respectively. E. W. Taylor first described it in 1915 emphasizing the unusual combination of ptosis and pharyngeal palsy in a family of French-Canadian descent. However, Taylor believed that the cause of this rare entity was a degeneration of vagus and glossopharyngeal nuclei. He called it progressive vagus-glossopharyngeal paralysis with ptosis. It was not until 1951 after the observations of Kiloh and Nevin of cases with similar symptoms but also had involvement of limb and trunk muscles suggesting the myopathic nature of the disease. In 1962, Victor et al. reported three cases in Jewish family from eastern Europe with a dominant mode of inheritance with clinical features of progressive dysphagia and ptosis in the late life and named the disease oculopharyngeal muscular dystrophy.¹

Cases of patients with OMPD have been reported in numerous countries in all five continents. The most significant clusters of patients are in Quebec of French-Canadian origin,² in Israel from Bukhara Jewish immigrants³ and in Hispanics living in New Mexico.⁴

The mean age of onset for ptosis is 48 years and for dysphagia is 50 years. Dysphagia determines prognosis due to an increase in the risk aspiration pneumonia and also poor nutrition. As the disease progresses, there are other signs like hoarseness, weakness of the tongue, facial muscles and proximal upper and lower extremities. Involvement of the central nervous system (CNS) also has been reported.⁵ Severe OPMD represents five to 10% of all cases and is characterized by symptoms before age 45 years and incapacitating proximal leg weakness before age 60 years.⁶

The mechanisms contributing to dysphagia in OPMD patients include reduced lingual pressure generation, impairments in cricopharyngeal relaxation and hypertonicity of the UES and incomplete laryngeal vestibule closure and subsequent airway compromise. Swallowing efficiency and safety are affected and is a significant determinant of prognosis due to an increase in the risk aspiration pneumonia and also poor nutrition. In the end stages of disease is recommended the use of PEG tubes to address both malnutrition and aspiration risks.⁷ Swallowing-related quality of life is moderately impacted characterized by prolonged mealtime durations and increased burden that contribute to social withdrawal and decrease enjoyment of meals in these patients.⁸

OPMD is suspected clinically with a combination of ptosis, defined as either vertical separation of at least one palpebral fissure measuring less than eight mm at rest or previous corrective surgery and dysphagia, characterized by a swallowing time greater than seven seconds when drinking 80 ml of ice-cold water. Modified barium swallow (MBS) using applesauce, cereal, liquids and videofluoroscopic swallowing study (VFSS) are essential to document aspiration and dysfunction of the pharyngeal muscles and upper esophageal sphincter (UES).⁶ Standard esophageal motility studies to analyzed upper esophageal sphincter function have not been rewarding or diagnostic.

Molecular genetic testing confirms the diagnosis with a detection of an expansion of a GCN trinucleotide repeat in the first exon of PABPN1 (previously named PABP2). Normal alleles contain 10 GCN 6 GCG trinucleotide repeats. Autosomal dominant alleles range in size from 12 to 17 GCN repeats. Patients with longer PABPN1 expansion and homozygotes are, on average, diagnosed at an earlier age, the disease is more severe and shows a faster progression.⁹

Autosomal recessive alleles comprise 11 GCN repeats and present later in life usually after the six decades.^6,10,11

Muscle biopsy is only necessary if suspicion of the disease exists and there is a presence of two normal PABPN1 alleles. The biopsy of muscle shows in some patients with OPMD, intranuclear inclusions of tubular filaments that are 250 nm in length, dystrophic changes such as atrophic muscle fibers of different width, ragged red fibers, and rimmed vacuoles. Electromyography (EMG) is not specific or necessary for OPMD diagnosis and often shows signs of myopathic changes that could also be related to age. Serum creatine kinase (CK) concentrations are usually in range or twice the upper limit. CK level is not sensitive or specific for the diagnosis of OPMD.⁶

Differential Diagnosis

Facioscapulohumeral dystrophy (FSHD) symptoms usually begin in the 2nd decade, in contrast to OPMD that presents later in life. The muscular weakness has a different distribution than OPMD with facial, scapular, abdominal upper and lower extremities affected. Facial muscles weakness is milder compared to OPMD. Dysphagia is rare in this entity.¹²
Myotonic dystrophy presents with different genotypes and onset of presentation. There is a combination of proximal and distal weakness. Myotonia and muscle pain are cardinal symptoms, and both are absent in OPMD.¹³
Mitochondrial myopathies have variable clinical expression. Myopathy could be a major or a minor clinical feature depending on presentation. Muscles symptoms range from fatigue, myalgia and exercise intolerance. Other associated features are retinitis pigmentosa, ataxia. These are not present in OPMD patients. The inclusion body myositis found in mitochondrial myopathies are 15-18 nm filaments compared to 250 nm filaments in OPMD.¹⁴
Myasthenia Gravis usually presents with ptosis, diplopia and bulbar involvement as dysarthria, dysphagia, generalized weakness and positive test results for anti-AChR or anti-MuSK antibodies. These serologic markers are negative in patients with OPMD.¹⁵

Treatment

The treatment in OPMD patients is supportive in most cases. Avoiding secondary complications such as aspiration pneumonia, malnutrition and social withdrawal is the primary focus. Blepharoplasty is the treatment of choice for ptosis. Surgery is usually done for cosmetic reasons and is recommended when it affects vision in the central position of gaze and neck pain due to retroflexion of the neck.^16,17 It has been hypothesized that this compensatory position also affects dysphagia in OPMD patients.¹⁸ Exposure keratitis is a known complication of this surgery.¹⁶

Cricopharyngeal (UES) myotomy is the most common surgical treatment for dysphagia. Clinical improvement is seen immediately after surgery, but long-term follow-up shows a decrease in success due to the progression of the myopathic process in the pharyngeal muscles, making early diagnosis and treatment necessary. This procedure also carries the increased risk of aspiration when gastroesophageal reflux occurs in the setting of weakened pharyngeal protection.^19-21

Botulinum toxin injections for dysphagia are another alternative to treatment. Safety and efficacy of this intervention is dose-dependent, requires frequent retreatment and is expensive. Higher doses have led to worsening of the dysphagia and also dysphonia due to diffusion of neurotoxins in nearby muscles.^24,25

Dilatation of the UES through an upper GI endoscope is a relatively safe, well-tolerated procedure that is usually performed as an outpatient and only requires moderate sedation. The Savary dilatation method is recommended where a guidewire is passed and dilatation with increasing sizes is performed under fluoroscopic monitoring. This procedure can be repeated throughout the years and complications are rare and include perforation or hemorrhage. This technique has a reasonable success rate in improving dysphagia, weight maintenance, prolongation of oral feedings and avoidance of necessity for PEG which is an option.^22,23

The Microbiome And Disease, Series #4

The Microbiome and the Heart

Alon Steinberg,

Sabine Hazan

In this article, we discuss further understanding the gut microbiome along with its effect on metabolites and cardiovascular health. This understanding will give us opportunities to develop new test and therapeutic approaches to arteriosclerosis. In the future, stool transplantation with lean or low risk for cardiovascular disease microflora may be a way of treating patients who are susceptible to arteriosclerosis.

Alon Steinberg MD, Cardiology Associates Medical Group, Ventura Clinical Trials, expertcardiologist.com Sabine Hazan, MD, Gastroenterology/Hepatology/ Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center, Ventura, CA

Despite great focus and multiple treatments for coronary artery disease and its risk factors, the residual number of deaths is very large. Cardiovascular disease is the number one cause of death in the world.¹ Our well-known risk factors for arteriosclerosis do not always explain the degree of cardiovascular disease development and risk of myocardial infarction and death. Researchers and physicians are looking to uncover novel reasons and risk factors in hopes to explain why patients develop arteriosclerosis and ruptured plaque. There has been an interest in inflammation including obesity and metabolic syndrome as contributing factors. As eloquently summarized in last issue of Practical Gastroenterology,² the microbiome may contribute significantly to these risks.

Humans have a symbiotic relationship with our gut microflora. The gut microbiome helps metabolize fuels, aids with absorption and helps create important vitamins and amino acids. The microbiota breaks down toxins and is a barrier against invading bacteria. What we eat has a large impact on the development of heart disease. Can the study of the microbiome help us understand why we develop heart disease? Can we can work to manipulate the microbiome to prevent heart disease?

There appears to be lean and obese microbiota.³ In study with mice, lean and obese donors had their cecal microbes transplanted to germ-free recipients. Those mice colonized with obese microbiome developed obesity while those with lean donors remained lean. This documents that our microbiome can affect what we absorb and is a factor in our metabolism. This study also showed that this may be transmissible and changed.³ In a human study, stool transplant from lean donors to obese recipients with metabolic syndrome showed significant and persistent improvement in insulin sensitivity.⁴ This shows that changing gut microorganisms can alter mechanisms that can transform and improve metabolism. Further understanding hopefully with can lead to developing intestinal microbiota as a therapeutic agent to reduction of obesity, metabolic syndrome, inflammation and cardiovascular disease.

There is a saying that the best way to a man’s heart is through his stomach. But we now know that is not just what you eat but what your gut microbiome lets pass and creates. Metobolomic studies have now revealed effective routes linked to cardiovascular disease. Metabolites choline, TMAO, and betaine were shown to predict risk for cardiovascular disease in an independent large clinical cohort.⁵ These metabolites are linked to lecithin (or phoshaphatidylcholine) metabolism. Our Western diet is full of lecithin. Gut microbes use lecithin to create trimethylamine (TMA) which gets absorbed by the gut. While in blood circulation, the liver then converts TMA to TMAO.

Dietary supplementation with these metabolites in mice showed an upregulation of multiple macrophage scavenger receptors and creation of foam cells and arteriosclerosis. When these diet supplements were given to mice with gut free of flora, dietary metabolites were not created and thus did not promote arteriosclerosis.5 In a human study, suppression of intestinal microbiota with oral broad-spectrum antibiotics showed plasma levels of TMAO were markedly suppressed. TMAO rise reappeared after withdrawal of antibiotics.⁶

Further testing has been done with Trimethylamine N-oxide (TMAO). Increased levels of TMAO were associated with an increased risk of major adverse cardiovascular events6 and may be a stronger risk factor than LDL and C-reactive protein. A recent meta-analysis showed TMAO increased cardiovascular risk and mortality.⁷ This gut metabolite that has been associated with accelerated arteriosclerosis, enhanced platelet hyper-reactivity and thrombosis risk.⁸

One way to control TMAO levels is diet. Vegetarians, vegans and those on Mediterranean diet⁹ are associated with lower TMAO levels. TMAO decrease may explain the reduction in cardiovascular risk with the Mediterranean diet.

Another way to target TMAO is antibiotics. Prior antibiotic trials for prevention of coronary disease events have been disappointing. It is thought that a possible and intriguing risk factor for development of arteriosclerosis is inflammation due to infectious disease (e.g. chlamydia). Randomized trials with antibiotics in humans targeting certain bacteria have not shown to have a significant effect on cardiovascular outcomes and may cause increased risk.¹⁰ These trials were targeting specific organisms and not on adjusting the makeup of intestinal microbiota. The risks of microflora change (and QT prolongation) did not outweigh of the benefits. Future studies with antibiotics aiming at reducing TMAO may be in order but other therapeutic approaches may be better.

We need to further understand the gut microbiome better along with its effect on metabolites and cardiovascular health. This understanding will give us opportunities to develop new test and therapeutic approaches to arteriosclerosis. Medications can be developed against microbial enzymes creating dangerous metabolites like TMA and TMAO, blocking diet induced arteriosclerosis. Stool transplantation with lean or low risk for cardiovascular disease microflora may be a way in the future of treating patients who are susceptible to arteriosclerosis.

Frontiers In Endoscopy, Series #42

Endoscopic Ultrasound-Guided Gallbladder Drainage

Douglas G. Adler,

Judith Staub

Here we discuss EUS-GBD, an evolving technique that can be an alternative to PTGBD when treating acute or chronic cholecystitis in high-risk surgical patients, and also has promising results when used for long-term or definitive treatment.

Judith Staub, MD Douglas G. Adler, MD, FACG, AGAF, FASGE, Division of Gastroenterology and Hepatology, Utah School of Medicine, Salt Lake City, UT

CASE REPORT

An 81 year old man with metastatic pancreatic cancer, diabetes mellitus, and other comorbidities developed fever, right upper quadrant pain with a serum bilirubin of 9.8 mg/dL, an alkaline phosphatase of 770 U/L, and an AST of 110 U/L. His white blood count was 15,000/uL. CT scan showed findings consistent with a malignant biliary obstruction and acute cholecystitis. The gallbladder was enlarged and distended with a thickened wall and dense internal contents. General surgery evaluated the patient and felt that he was not a candidate for cholecystectomy. The therapeutic service was consulted to perform ERCP and to place a transmural gallbladder stent to decompress both the biliary tree and gallbladder in one procedure.

At ERCP, a malignant appearing stricture was seen in the mid common bile duct. This was stented with an 8x10mm uncovered metal biliary stent (Alimaxx-B, Merit Endotek, South Jordan, Utah) (Figure 1). After the ERCP, a linear echoendoscope was used to evaluate the gallbladder. The gallbladder had a thick wall, pericholecystic fluid, and dense fluctuant appearing contents (Figure 2). Using a freehand technique, an electrocautery- enhanced, 15mm wide x 10mm long lumen apposing metal stent (Axios, Boston Scientific, Natick, MA) was used to access the gallbladder in a transgastric manner (Figure 3). The stent was deployed without difficulty with one flange in the gallbladder and one in the stomach (Figure 4). There was copious drainage of purulent gallbladder contents and sludge into the stomach. The lumen of the stent was dilated with a 13.5mm esophageal dilation balloon to good effect (Figure 5). A 7Fr double pigtail stent was then placed across the stent with one pigtail in the gallbladder and one in the stomach (Figure 6). The patient tolerated the procedure well and there were no complications. The patient’s laboratory studies normalized and he had a rapid improvement in his clinical symptoms. The patient was discharged to hospice and passed away several months later without recurrence of biliary symptoms.

Overview and Efficacy of EUS Guided Gallbladder Drainage

Laparoscopic cholecystectomy is the definitive treatment of choice for acute cholecystitis. Patients who are poor surgical candidates or have severe sepsis at presentation often undergo percutaneous transhepatic gallbladder drainage (PTGBD) for second line primary therapy or as a bridge to surgery. However, hospital readmissions and adverse events associated with using external drainage catheters such as pneumothorax, peritonitis, bleeding and dislodgement are reported in up to 12% of cases. Endoscopic ultrasound- guided transmural gallbladder drainage (EUS- GBD) has emerged as a promising alternative that allows for minimally invasive, internal drainage of the gallbladder in the setting of acute and chronic cholecystitis in high-risk patients. Using EUS guidance, transmural stents can be placed via a transgastric or transduodenal approach.

Several studies have described the advantages of EUS-GBD over PTGBD, which include fewer adverse events, decreased cost, and fewer re-interventions. EUS-GBD has several other distinct advantages. For example, placement of lumen-apposing metal stents (LAMS) creates a portal between the gallbladder and the luminal GI tract that can allow, in some cases, for spontaneous passage of stones and further advanced endoscopic evaluation.⁵ Complete clearance of gallbadder stones with LAMS has been reported in up to 88% of patients. EUS-GBD has also been shown to be safe and effective in patients with coagulopathy or that require anticoagulation.

Several large studies have looked at outcomes for patients who have received EUS-GBD for acute cholecystitis and have had very positive results. Tyberg et al. performed a retrospective review comparing 42 patients who underwent EUS-GBD with 113 patients who underwent PTGBD. This study found similar technical success between the two (95.3 vs. 99%), but patients with EUS-GBD required fewer repeat procedures (9.5% vs. 27.7%) and had fewer hospital readmission (14.3% vs. 23.9%). Further, clinical success was higher EUS- GBD vs. PTGBD (95% vs. 86%).

Teoh et. al. performed a matched cohort study of 118 patients comparing EUS-GBD (59 patients) with PTGBD (59 patients).⁶ This study found similar rates of technical and clinical success, but, similar to the study by Tyberg et al., patients who underwent EUS-GBD had decreased hospital readmission rates (6.8% vs. 71.2% respectively) and no significant difference in 30-day adverse events. Critically, 95.2% of the readmissions were related to tube dislodgement in the PTGBD group. Finally, Dollhopfet et al. recently performed a multicenter retrospective review of 75 patients who underwent EUS-GBD for acute cholecystitis with a novel LAMS with an electrocautery enhanced delivery catheter (ECE-LAMs). The procedure had very high rates of clinical and technical success (98.7% and 95.9% respectively), with a rate of adverse events of 10.7%. This study also found that using the electrocauteryenhanced device led to significantly decreased stent deployment times. These studies demonstrate that EUS-GBD has similar efficacy to PTGBD, but fewer hospital readmissions and adverse events related to external tube dysfunction.

Adverse Events

Adverse events associated with EUS-GBD have been reported to occur in 6.3% to 32.2% for patients who have undergone the procedure for acute cholecystitis, but this rate has declined as endoscopic experience with the technique has grown.^8,11 Immediate adverse events include bleeding, bile leak and stent migration. Stent migration can be both into the luminal GI tract and into the gallbladder, and is more common when plastic stents are used. Notably, the progression from plastic stents to SEMS and LAMS has reduced the incidence of stent migration and bile leak by anchoring the stent on the apposing organs of the newly created fistulous tract. However, procedure and stent related adverse events associated with LAMS use have been reported up to 13%, suggesting a high level of endoscopic expertise is pivotal.¹³ Delayed adverse events include abscess formation and recurrent cholecystitis.⁷ Interestingly, the rate of recurrent cholecystitis in EUS-GBD is about 4%, compared to up to 22% after 151 days from drain removal for PTGBD.¹¹ The reduced rate of recurrent cholecystitis may be related to clearance of stones through the fistulous tract over time.^8,11,13

Long Term Management

Several studies have performed long-term evaluation of SEMS or LAMS kept in place for up to 3 years.¹³ Reasons for foregoing stent removal in these studies include poor clinical condition, patient refusal, and tissue overgrowth. A recent study by Walter et al. in which patients had LAMS in place for up to 364 days found that 10% of patients studied had significant tissue overgrowth of their LAMS that precluded stent removal. However, no LAMS-related complications had occurred by long-term follow up. Choi et al. used partially covered SEMS with large bilateral flares (BONA-AL stent, Standard Sci Tech Inc., Seoul, Korea) and found that complete distal migration of the stent had occurred in 3.6% of patients at long-term follow up, but interestingly had no recurrence of cholecystitis occurred, suggesting full maturation of the cholecysto-enteric fistulous tract. These studies suggest that EUS-GBD may serve as not only an effective treatment for acute cholecystitis, but also definitive management in a select group of patients who remain poor surgical candidates over time due to malignancy or other significant medical comorbidities.

CONCLUSION

EUS-GBD is an evolving technique that can be an alternative to PTGBD when treating acute or chronic cholecystitis in high-risk surgical patients, and also has promising results when used for long- term or definitive treatment. Current research suggests that the two procedures appear to have similar technical and clinical efficacy, however it may not be valid to extrapolate this data to centers without high levels of endoscopic expertise.

Dispatches From The Guild Conference, Series #11

How to Grade IBD Disease Activity in Your Daily Practice

Trilokesh D. Kidambi,

Fernando Velayos

A clear understanding of disease activity can facilitate better care for IBD patients by addressing the impact of disease as well as risk of progression. The aim of this review is to discuss accessible measures of disease activity in IBD that can be used regularly in the office with the goal of facilitating consistent clinic care, use of a shared vocabulary for IBD activity and to provide an objective basis for treatment and assessment of treatment response.

Trilokesh D. Kidambi MD¹ Fernando Velayos MD, MPH² ¹Clinical Fellow Gastroenterology, Division of Gastroenterology, University of California San Francisco, San Francisco, CA ²Professor of Medicine, University of California; Regional Director-Kaiser Northern California Inflammatory Bowel Disease Program Division of Gastroenterology, Kaiser Permanente San Francisco, San Francisco, CA

Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by immune dysregulation. Measurement of disease activity, which refers to the inflammatory burden and its impact on the patient at any one point in time, is a crucial step in the assessment of patients and factors into decision making regarding therapy. Categorizing disease activity into three domains – quality of life, clinical symptoms and endoscopic inflammation – can help the clinician follow disease activity using objective and standardized grading systems. This in turn can help assess response to treatment, which is increasingly important as the paradigm of management in IBD shifts to a “treat-to-target” approach. A clear understanding of disease activity can facilitate better care for IBD patients by addressing the impact of disease as well as risk of progression. The aim of this review is to discuss accessible measures of disease activity in IBD that can be used regularly in the office with the goal of facilitating consistent clinic care, use of a shared vocabulary for IBD activity and to provide an objective basis for treatment and assessment of treatment response.

INTRODUCTION

Inflammatory bowel disease (IBD), a progressive and chronic condition, is driven by immune dysregulation of the digestive tract which results in chronic inflammation and disease activity.^1,2 A significant challenge is how to describe disease activity and severity in a way that is reproducible and actionable. An additional challenge is determining if disease activity and severity is best described using symptoms, colonoscopy findings, or impact of the disease on quality of life. The aim of this review is to discuss accessible measures of disease activity in IBD that can be used regularly in the office with the goal of facilitating consistent clinic care, use of a shared vocabulary for IBD activity and to provide an objective basis for treatment and assessment of treatment response.

Disease Activity Versus Severity in IBD

A fundamental, though often misunderstood, concept in the understanding of IBD disease scoring is the difference between disease activity and severity. Disease activity refers to a measure of the inflammatory burden and its impact at any one point in time and disease severity is a measure of the cumulative impact of the inflammatory burden over time.4 While disease activity and severity can be related, they are separate concepts that should not be used interchangeably. The focus of this article will be on disease scoring and tracking disease activity as it influences daily care by aiding in decisions for management and monitoring response to treatment.

Three Domains of Disease Activity A recent review divides disease activity into three domains: quality of life (QOL), clinical symptoms, and inflammation⁵ as shown in Table 1. Each domain has specific measures for ulcerative colitis (UC) and Crohn’s disease (CD). It is useful to think of these domains separately, though admittedly they overlap and are interrelated. However, considering them separately allows for a standardized approach to disease activity scoring.

Quality of Life

Quality of life (QOL) is a critical component of disease activity as it evaluates the patient’s social and emotional well-being, behavior and attitudes, and physical disease related symptoms and is the ultimate goal of therapy.5 Because many QOL measures are lengthy and cumbersome, we recommend only measures which are fast to complete, valid, reliable, and acceptable to patients. Measurement tools for QOL in IBD fall into three categories: psychological distress, disease adaptation and global QOL.

Measures of psychological distress are not IBD-specific and include the Patient Health Questionnaire-9 (PHQ-9) and the Hospital Anxiety and Depression Scale. The PHQ-9 was validated for diagnosing and monitoring major depressive disorder, but is easy to use in a clinical setting and given the high prevalence of comorbid depression in IBD6 is relevant. The Hospital Anxiety and Depression Scale was validated to screen for depression, anxiety and emotional distress in the outpatient setting utilizing just 14 questions and is commonly used, though never validated, in IBD-related research. A recent study confirmed prevalent depression and anxiety in IBD patients, but recognition of the symptoms by gastroenterologists was only fair.7 We believe routine use of a standardized measure will help in the identification of patients who would benefit from addressing their comorbid psychiatric conditions. to capture important changes that are difficult to otherwise to identify. The Brief Illness Perception Questionnaire is one such measure with nine items that has the added benefit of being positively associated with medication adherence8 and thus serves as a potential target to improve outcomes.

The Short Inflammatory Bowel Disease Questionnaire is an IBD-specific measure of global QOL that consists of 10 items that address bowel symptoms, emotional health, systemic symptoms and social function. It is easy to use, validated, reproducible and responsive and correlates well with longer IBD-specific questionnaires.9 It is subject to license so does require a fee to use.

Clinical Symptoms

In clinical practice, assessment of symptoms predominates patient encounters and thus it is crucial to objectively assess symptoms as they relate to disease activity to guide precision in decision making.¹⁰ There are over 20 indices of clinical symptoms in UC and CD, some of which are cumbersome to use in clinical practice and require complex calculations like the Crohn’s Disease Activity Index. We present the indices we have found to be straight-forward and easy to integrate into daily practice.

An important first step in clinical symptom assessment is determining disease extent in UC patients and the phenotype of CD patients as this helps understand the cause of symptoms or guide investigation into complications that may be driving the onset of new symptoms. The Montreal Classification is a simple tool that categorizes UC patients based on disease extent – E1 disease is limited to the rectum (proctitis), E2 disease is limited to the splenic flexure (left- sided) and E3 disease extends beyond the splenic flexure (extensive).11 Similarly, CD is categorized based on age of disease onset (A1: ≤ 16 years, A2: 17-40 years, A3 >40 years), location (L1: ileal, L2: colonic, L3: ileocolonic, L4: isolated upper gastrointestinal), and behavior (B1: non-stricturing, non-penetrating, B2: stricturing; B3: penetrating, +p if perianal disease present).

We recommend use of the Harvey Bradshaw Index (HBI) for symptom assessment in CD given it is simple to use and correlates well the complex Crohn’s Disease Activity Index, which has been an outcome measure in many of the studies of treatments for CD. The HBI has five variables and items are scored based on the previous making it easy to use as shown in Table 2. The major limitation is that perianal disease is a low contributor to the total score, which may underestimate the more severe phenotype. HBI scores greater than 16 are consistent with severe disease activity, whereas scores between 5-7 suggest mild activity and 8-16 suggest moderate activity. Response to therapy is defined by a reduction in the score by 3 points or more.5,12,13 As shown in Table 3, the Simple Clinical Colitis Activity Index (SCCAI) is an easy to use index for the assessment of clinical symptoms in UC. This can be filled out by patients without the need for lab values, endoscopy results or physician assessment, making it our preferred measurement tool for clinical symptoms in UC. It includes nocturnal bowel movements and urgency to defecate which are omitted in other indices, but, in our experience, are vitally important to patients. It is the best non-invasive index for validity, reliability, feasibility with the added benefit of being able to measure responsiveness, or change in disease activity.^5,14 A score of two or less on the SCCAI indicates remission.

Inflammation

Inflammation is closely linked to progression of disease and therefore impacts severity of disease; it is one of the hallmarks of IBD disease activity and the gold-standard for measurement is endoscopy. Complementary measures of inflammation include histology (which is obtained via endoscopy), imaging (such as magnetic resonance and computed tomography imaging) and biomarkers (such as C-reactive protein and fecal calprotectin). Various endoscopic scoring symptoms exist and are specific for UC and CD, which will be the focus of this review.

We recommend use of either the UC Endoscopic Index of Severity15 (UCEIS) or the Mayo endoscopic sub-score to assess inflammation activity in UC. The UCEIS is the only validated endoscopic index in UC, is simple to use, and has high inter-observer reproducibility. The endoscopist grades the inflammation, without considering disease extent, based on the most severe area in three categories: vascular pattern, bleeding, and erosions and ulcers as shown in Table 4. While the UCEIS does not further classify the activity as mild, moderate, or severe, the target score for remission is one or less.^3,5,16 An alternative endoscopic index for UC that is commonly utilized in clinical practice is the endoscopic sub-score of the Mayo index, which is simple to use but lacks strong inter-observer reliability and is not a validated measure of mucosal healing.3,5,16 Endoscopic activity is graded in each segment of the examined colon as normal (Mayo 0), mild (Mayo 1: erythema, mild friability and loss of vascular pattern), moderate (Mayo 2: presence of erosions and marked erythema, friability) and severe (Mayo 3: spontaneous bleeding and ulcers). Endoscopic remission corresponds to a Mayo 0 or 1. In our endoscopy unit, the Mayo endoscopic sub-score is widely used to grade disease activity to standardize assessment across physicians.

The gold-standard for the endoscopic assessment of disease activity in CD is the CD Endoscopic Index of Severity (CDEIS), which is reproducible, validated and used extensively in clinical trials.^4,5,17 However, because it is cumbersome to use we don’t routinely measure it as part of clinical care in our practice. Instead, we recommend measurement of the Simple Endoscopic Score for CD (SES-CD), which is validated, correlates with the CDEIS and is easier to use, though admittedly still takes time. Each part of the colon as well as the ileum are graded on four categories (size of ulcers, ulcerated surface area, affected surface area and presence of narrowing) and the total score correlates with remission (0-2), mild (3-6), moderate (7-16), and severe (>16) as shown in Table 4. A response is defined by at least 50% reduction in the score.^3,18 In post-operative CD patients, the Rutgeert’s post- operative endoscopic score is an important activity index because it correlates with risk of recurrence and thus helps inform decision-making regarding post-operative treatment of CD.¹⁹ The Rutgeert’s grade (i0-i4), as shown in Table 5, is based on the number and nature of ulcers at the neoterminal ileum and i0 and i1 grades are considered remission given the low risk of recurrence at five years.

Integrating Assessment of Disease Activity into Clinical Practice

Armed with an accurate, objective and reproducible assessment of disease activity in IBD, the clinician is able to understand the risks and benefits of continuing or changing therapies for their patients. Recently, an evidence-based expert consensus process was conducted to examine potential treatment targets in IBD with a focus on a “treat- to-target” clinical management strategy and the results of their discussions were published as the Selective Therapeutic Targets in IBD (STRIDE) recommendations.¹² The rationale behind a “treat- to-target” approach is to focus on achieving remission and low disease activity; accordingly, physicians and patients should discuss the targets and work to achieve them within set time frames in order to improve outcomes (in all domains of disease activity, as previously described).

In UC, the STRIDE recommendation is to treat to a target of clinical symptomatic remission and patient reported outcomes as well as endoscopic remission (UCEIS ≤ 1 or Mayo endoscopy sub- score of ≤ 1). Clinical symptoms and QOL should be assessed at least every three months during active disease and endoscopic evaluation should be performed every three months until remission. For CD, similarly the target was clinical remission (defined by clinical symptoms and QOL indices) as well as endoscopic remission or resolution of inflammation objectively documented on cross- sectional imaging. As in UC, clinical symptoms of QOL should be assessed at least every 3 months, but endoscopic evaluation can be performed in 6-9 month intervals until resolution.

The Role of Disease Severity

The STRIDE recommendations did not specify treatment modalities and instead focused on treatment targets. Decisions on which treatment to choose in IBD is complex and requires an understanding of both disease activity as well as severity since an assessment of current and prior activity as well as prognostication for long-term complications factors into risk assessment of patients with low and high severity of disease.

CONCLUSION

The three domains of disease activity (quality of life, clinical symptoms, and inflammation) present an opportunity to capture activity longitudinally to help care for IBD patients. Using a standardized approach to measurement of disease activity allows objective assessment of response to treatment and standardizes practice and facilitates comparisons between endoscopies and treating physicians with the ultimate goal of providing better care for IBD patients by addressing not only impact of the disease but also the risk of progression.

A Case Report

Leiomyosarcoma of the Inferior Vena Cava

Murali Dharan,Bhavtosh Dedania,Nayla Ahmed

Leiomyosarcomas (LMS) of the inferior vena cava (IVC) are rare and comprise less than 1% of all soft tissue sarcomas. Patients usually present in the fifth or sixth decade of life with back pain and/or increased abdominal girth. The diagnosis is usually made with noninvasive imaging [computed tomography (CT) or magnetic resonance (MRI)] or by invasive methods such as endoscopic ultrasound (EUS) with biopsy. We report the case of a 76 year-old female with a chief complaint of vague intermittent abdominal pain. CT scan revealed a mass possibly arising from the pancreas. She underwent a diagnostic EUS which confirmed that the mass was retroperitoneal in origin compressing the IVC; fine needle aspiration (FNA) showed spindle cells. The patient underwent laparotomy and pathology revealed a leiomyosarcoma of the IVC.

Nayla Ahmed, Academic Hospitalist, Dartmouth Hitchcock Hospital, Lebanon, NH Bhavtosh Dedania, GI Fellow, UT Health Sciences Center, Houston, TX Murali Dharan, St. Francis Hospital, Hartford & University of Connecticut, Hartford, CT

CASE PRESENTATION

A76-year-old Caucasian woman with a past medical history of coronary artery disease, diabetes mellitus, gastroesophageal reflux disease and anxiety presented with a two month history of progressively worsening sharp lower quadrant abdominal pain radiating to her right upper quadrant. She denied associated fever, chills, weight loss, night sweats, nausea, vomiting, constipation, diarrhea, melena or hematochezia. Initial laboratory evaluation showed mild kidney injury and normal CEA (1.3 ng/ml) and CA 19-9 (30 U/ml). Computed tomography (CT) scan of her abdomen and pelvis showed a 2.3 cm x 2.4 cm hypoechoic, retro-peritoneal mass between the pancreas and inferior vena cava (IVC). Magnetic resonance imaging (MRI) confirmed a solid mass along the posterior head of the pancreas and anterior to the IVC at the origin of renal veins. There was compression of the IVC however there was no thrombus or invasion.

Endoscopic ultrasound (EUS) confirmed a peri-duodenal, peri-pancreatic diffusely hypoechoic, heterogeneous retroperitoneal mass, measuring 3 cm x 2.8 cm x 2.4 cm. Fine needle aspiration (FNA) revealed spindle cells. The positron emission tomography (PET) scan showed increased metabolic activity in the proximal duodenum or pancreatic head, without loco-regional or distant spread. At laparotomy, a 5.0 cm x 4.0 cm x 3.0 cm mass extending from anterior aspect of the IVC was noted, and en- bloc resection performed. Pathology revealed spindle cell proliferation with atypical features without necrosis or increased mitotic activity. Immunohistochemistry was positive for vimentin, desmin, actin, myosin and negative for CD117 (ckit) and S-100 with a Ki67 proliferative index of 40 to 60%. Findings were consistent with high grade, poorly differentiated leiomyosarcoma [Stage 2a (T1bN0M0), Grade 3].

Adjuvant radiotherapy was administered, and outpatient follow up revealed recurrence-free survival at 36 months.

Discussion

Vascular leiomyosarcomas (LMS) are rare soft tissue sarcomas and account for 2% of all leiomyosarcomas¹ and 0.7% of all soft tissue sarcomas in adults.² Over half of these vascular LMS arise from the IVC. Patients usually present in the fifth or sixth decade of their lives with a male to female ratio of 1:4.³ Clinical symptoms are vague and include back pain, increasing abdominal girth, weight loss and abdominal pain.⁴ The tumor commonly grows extra-luminally (in more than 60%)⁵ and hence pedal edema is not a common presentation. Clinical presentation depends on location and luminal versus extraluminal growth. Segment I (infra-renal involvement) occurs in 36% and can present as lower extremity edema, deep vein thrombosis (DVT) and abdominal mass. Segment II involvement (hepatic to renal veins) is the most common (up to 44%) and can present as abdominal pain, nephrotic syndrome and hypertension. Segment III involvement (right atrium to hepatic veins) is least common and can cause cardiac arrhythmias and Budd-Chiari syndrome. Liver involvement by direct contiguity or metastases is less common but has been noted (up to 20%).⁶ These tumors tend to metastasize primarily to lung and liver and occasionally to bone and brain.^7,8

Tumors originating from segment II respond better to therapy.^3,4 Other prognostic factors include tumors arising from tunica media and absence of palpable abdominal mass. Presence of abdominal pain (which occurs earlier in segment II involvement due to rich innervation) portends better prognosis. Improved survival rates are noted with early detection, surgery and neoadjuvant therapy.

Surgical resection is the treatment of choice. The most important predictor of 5-year survival is complete resection of the lesion.^3,9 Other important prognostic factors include the histopathological grade ¹⁰ and location of the tumor.¹⁰ Data regarding prognostic value of tumor size are conflicting.^10,12 Median time to recurrence is 8 to 27 months.¹³ Adjuvant radiotherapy is indicated for high grade tumors and margin-positive resections.⁹

Very little literature is available on the role of EUS in the diagnostic work up of this tumor. To the best of our knowledge, there is one case report of EUS-FNA diagnosis of IVC LMS during evaluation of a large right retro-peritoneal tumor.¹⁴ EUS can be very useful in confirming relation of tumor to IVC and providing tissue diagnosis – as was the case in this patient. It?s role in diagnosis of incidental finding of IVC LMS during EUS for other indications needs to be ascertained. It is likely that EUS is perhaps most helpful in segment II lesions.

CONCLUSION

LMS of the IVC is a rare tumor that presents a diagnostic challenge. It should be considered in the differential of retro-peritoneal tumors, as survival improves with early detection and resection. EUS can be helpful in the diagnostic evaluation.

The Microbiome And Disease, Series #3

The Microbiome and Obesity

Sabine Hazan,

Daniel Frochtzwajg,

Skylar Steinberg

There is a growing body of research suggesting that obesity, metabolic syndrome, and insulin resistance are associated with predictable phyla and gene level compositional changes in the intestinal microbiome of humans and mice. With a better understanding of these changes, we can develop new, robust therapeutic strategies. In this article, we will briefly discuss some of the definitive research related to the microbiome and its impact on obesity and other metabolic derangements.

Sabine Hazan, MD, Gastroenterology/Hepatology/ Internal Medicine Physician, CEO, Ventura Clinical Trials, CEO, Malibu Specialty Center Daniel Frochtzwajg, DO, Research Assistant, Ventura Clinical Trials Skylar Steinberg, BS, Health Promotion and Disease Prevention, Research Assistant, Ventura Clinical Trials, Ventura, CA

In 2016, the World Health Organization (WHO) estimated that, globally, over 1.9 billion adults and 340 million children and adolescents (between the ages of 5 and 19 years), were overweight or obese. Since 1975, the worldwide prevalence of obesity has tripled, and, currently, the majority of the world?s population lives in countries where being overweight or obese kills more than being underweight.²¹ An increased body mass index (BMI) is a risk factor for cardiovascular disease, musculoskeletal disorders, diabetes, and a number of malignancies, including endometrial, breast, ovarian, prostate, liver, gallbladder, kidney, and colon cancers.²¹ Traditional weight loss therapies have proven largely ineffective, and given the dire consequences of obesity on general health, the development of better treatment modalities has become a scientific imperative. There is a growing body of research suggesting that obesity, metabolic syndrome, and insulin resistance are associated with predictable phyla and gene level compositional changes in the intestinal microbiome of humans and mice; ^8,9 with a better understanding of these changes, we can develop new, robust therapeutic strategies. In this article, we will briefly discuss some of the definitive research related to the microbiome and its impact on obesity and other metabolic derangements.

Contemporary, culture-independent techniques for microbial DNA sequencing have identified four dominant bacterial phyla which reside in the mammalian gut.¹⁷ They are the Gram-negative Bacteroidetes and Proteobacteria and the Gram- positive Actinobacteria and Firmicutes.¹⁷ In two foundational studies, one by Ley et al. and another by Turnbaugh et al., researchers used 16S rRNA gene sequencing to demonstrate that the microbial composition of the distal gut of leptin-deficient ob/ob mice was reduced in Bacteroidetes and enriched in Firmicutes when compared to their lean ob/+ and wild-type siblings, despite being fed the same diet.1^5,17,19 In subsequent research, Ley et al. corroborated the findings in the murine studies, observing a similar increase in the Firmicute/Bacteroidetes ratio in obese humans.^13,14,18 However, other researchers have not noted the same pattern of colonization and more recent literature stresses biomarker composition and host-microbe genetics over phyla level profiles.^10,16

One way by which the microbiome affects body weight is through its link to fat storage and energy extraction. For example, Flint et al. showed that the gut microbiota enables energy extraction from otherwise indigestible polysaccharides.¹² Backhed et al. demonstrated that germ-free mice, once conventionalized, exhibited increased triglyceride content in their livers and adipose tissue, as well as increased luminal monosaccharide uptake.⁴ They hypothesized that this change was due to the microbial modulation of Fiaf, also known as angiopoietin-like protein 4, and its inhibitory effect on lipoprotein lipase (LPL). LPL is an enzyme that increases cellular uptake of fatty acids. During feeding, Fiaf is induced in germ- free mice; however, in conventionalized mice, it is functionally suppressed.^1,4 Years later, Backhed et al. shed light on another possible mechanism of microbe-mediated energy capture. They identified Ampk as a “fuel gauge” enzyme and found that the phosphorylated form was increased in the skeletal muscle of lean, germ-free mice.^3,17 Yet another pathway of the microbiome’s influence on host metabolism is through its production of hydrolases, which digest carbohydrates to short-chain fatty acids (SCFA). SCFAs like acetate and propionate are not only energy sources, but also interact with G protein-coupled receptors in the gut, altering motility and affecting inflammatory pathways.^15,17

In addition to the direct effects on host metabolism, it has been proposed that the microbiota composition may cause low-grade, systemic inflammation and play a role in the development of insulin resistance.1,7 Researchers have determined that lipopolysaccharide (LPS), a proinflammatory molecule, derived from Gram-negative bacteria in the mammalian microbiome is increased in the plasma of mice on a high-fat diet; this has also been observed in human studies.^1,7 Furthermore, it has been noted that the gut permeability of obese mice is increased secondary to expressional changes in tight-junction proteins. This, coupled with increased LPS production, elucidates a possible pathway to the generalized inflammation associated with metabolic diseases.^1,5,6,7 From a microbial ecology perspective, there has been an association of diabetic patients with a core microbiota rich in Proteobacteria.¹ Vrieze et al. found that the introduction of intestinal microbes from lean donors resulted in temporary improvements in insulin sensitivity in patients with metabolic syndrome.^1,20 This would lead one to think that fecal microbiota transplantation (FMT) is not a modality restricted to the treatment of C. difficile infection, but could possibly be used to treat obese and/or diabetic patients as well. As we discuss various biomarker-disease associations, it is appropriate to point to a microbiome classification paradigm associated with microbiota composition and biomarker levels. Arumugam et al. found that three energy-modulating molecules correlate with a host’?s BMI, which may mean that there are common microbiome compositions associated with various disease states; this would potentially enable intervention through diet, pre- and probiotics, and medication.^1,2 Lastly, more recent literature has highlighted the interaction between host genes and the microbiome, noting the relationship between leptin (“the satiety hormone”) and commensal bacterial populations, the declines and rises in various bacteria associated with the apolipoprotein A1 gene, and the phospholipase D1 gene, which may offer insight into host genotypic effects on microbiome.¹¹

Obviously, there is a strong body of science linking obesity and other metabolic disease states to changes in the gut microbiome; however, our understanding of the relationship between microbe and host must continue to be refined. Expanding research and interest in the human microbiome could lead to improved treatment strategies for obesity and its long list of comorbidities. With the increasing complexity of the microbe-host relationship, new ground must be broken with new ideas.

Food For Thought - Importance Of Nutrition In Alcoholic Hepatitis

Food For Thought – Importance Of Nutrition In Alcoholic Hepatitis

Ariel W. Aday,

Mack C. Mitchell

Acute alcoholic hepatitis (AAH) is the most severe form of alcoholic liver disease, yet many patients suffering from this syndrome are not diagnosed or are inadequately treated. Nutritional support is an essential component of treatment as malnutrition has been associated with poorer outcomes. The role of adjunctive nutritional support, including enteral feeding and specific supplemental micronutrients, needs to be better delineated as it relates to altering clinical outcomes. Here, we review the nutritional aspects of patients with AAH and the effect implementation of various dietary interventions have on clinical outcomes of this frequently deadly condition.

As alcohol consumption increases worldwide, so does the prevalence of various clinical manifestations of alcohol-related liver disease. Acute alcoholic hepatitis (AAH) is the most severe form of alcoholic liver disease, yet many patients suffering from this syndrome are not diagnosed or are inadequately treated. Morbidity and mortality are high in patients with severe AAH. Unfortunately, available therapeutic regimens remain few and far between. Nutritional support is an essential component of treatment for AAH as malnutrition has been associated with poorer outcomes. The role of adjunctive nutritional support, including enteral feeding and specific supplemental micronutrients, needs to be better delineated as it relates to altering clinical outcomes. We review the nutritional aspects of patients with AAH and the effect implementation of various dietary interventions have on clinical outcomes of this frequently deadly condition.

Ariel W. Aday, MD Department of Internal Medicine, Division of Digestive & Liver Diseases. Mack C. Mitchell, MD, Nancy S. and Jeremy L. Halbreich Professor, Executive Vice Chairman, Interim Executive Vice President for Health System Affairs, Department of Internal Medicine, Division of Digestive & Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX

INTRODUCTION

Alcoholic liver disease (ALD) refers to a spectrum of diseases including asymptomatic steatosis, alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis, and hepatocellular carcinoma. In its most severe form, AAH refers to decompensation of liver function on a background of heavy alcohol use and chronic ALD. This syndrome is characterized by several clinical features including malaise, anorexia, jaundice, tender hepatomegaly, and features of the systemic inflammatory response syndrome (SIRS) such as fever, tachycardia, and leukocytosis. This syndrome increases catabolism by up to 60% energy expenditure with increasing nutritional requirements necessary to support this state.^1,2 Patients with ALD are prone to a wide range of nutritional issues including direct consequences such as protein/calorie malnutrition and deficiencies in many micronutrients; indirect consequences are often due to other environmental factors largely associated with lifestyle changes.

Therapeutic Approach

Goals of treatment are to reduce short- term morbidity and mortality by utilizing a combination of intensive supportive care and adjuvant pharmacological therapies. Abstinence from alcohol is the cornerstone of therapy that is integral to long-term survival. The currently accepted pharmacological standard of care in treatment of severe AH is glucocorticoid therapy, although the optimal duration of therapy remains unclear.³ Several randomized control trials (RCTs) have demonstrated conflicting results regarding survival benefit. Glucocorticoids have been shown to improve short term mortality at 28 days, but long-term mortality benefits are unproven.^4,5 The efficacy of pentoxifylline for improving mortality is not supported.⁴ Adequate intake of both calories and nutrients is an essential component of intensive supportive care⁶ and has become an area of focus given the lack of other effective treatment modalities.

Nutrition Support

Numerous factors contribute to poor overall nutritional status that is commonly observed in patients with AAH (Table 1). These long- standing observations are a major reason that nutrition support is viewed as an essential part of the standard care for AH. Not surprisingly, patients with malnutrition are at increased risk for impaired recovery from AAH.⁶ Several studies have documented an association between protein- calorie malnutrition and higher short and long-term mortality rates in patients with severe AH.^7,8

Oral Nutrition

Multiple studies have shown that low daily caloric intake is associated with increased mortality in severe AH.9-12 The degree of protein-calorie malnutrition is directly related to mortality with a rate that approaches 80% in those patients who are characterized as severely malnourished.⁹ Patients with severe ALD often have reduced hepatic glycogen stores that result in hypoglycemia and accelerated catabolic breakdown of muscle to support gluconeogenesis.¹⁰ Reducing the length of time without oral calories with an emphasis on eating breakfast and a bedtime snack, as well as avoiding prolonged fasting during hospitalization or for diagnostic testing (i.e., add D5 to IV fluids where possible), may reduce the adverse impact of reduced hepatic glycogen stores.^11,12

Standard per oral dietary intake is often impaired in these patients for a multitude of reasons,¹³ including delayed gastric emptying and prolonged small bowel transit times resulting in early satiety.¹⁴ Furthermore, ascites can result in impaired gastric accommodation leading to postprandial discomfort.¹⁵ In addition to the mental status changes that can be seen in hepatic encephalopathy (HE) limiting ability to eat, HE also contributes to impaired appetite, and in some more covert forms, leading to an overall malnourished state. Finally, the use of lactulose (a non absorbable, but highly fermentable synthetic sugar) in treatment of encephalopathy can contribute to symptoms of bloating and discomfort, thus exacerbating impaired per oral intake.¹⁶ Patients who develop HE are at risk of undernutrition and enteral access may be indicated.^26,27 Normal- to high-protein diets are safe and do not increase the risk of encephalopathy in alcoholic hepatitis.⁶

Enteral Nutrition Support

In the most severe forms of AAH, patients may be intubated or obtunded to the point where conventional nutrition is not an option and enteral nutrition (EN) must be considered. Whether or not NG tubes should be recommended to provide EN remains controversial given potential feeding tube complications seen in some trials,^17,21 although the risk/benefit seems to weigh in favor of providing nutrition in these individuals.

Data suggest that the optimal nutrition goals for recovery are 1.5 g of protein/kg body weight and 30 ? 40 kcal/kg of body weight per day and should be initiated as soon as impaired per oral intake is noted.¹⁸ The American Society for Parenteral and Enteral Nutrition (ASPEN) suggest using an estimated euvolemic weight or usual weight for these calculations rather than actual weight in patients with cirrhosis and hepatic failure given complications of hypoalbuminemia, edema, intravascular depletion, and ascites that are often present in this patient population masking the patient?s true weight.¹⁹ EN is the preferred modality for providing nutrition in these patients unable to tolerate per oral intake based on expert consensus from ASPEN, and the American Gastroenterological Association.^18,19

In a systematic review assessing effects of nutritional intervention for patients with AH or cirrhosis, analysis of 13 randomized controlled trials suggested that nutritional therapy may have beneficial effects on clinical outcomes and mortality yet, given the high risk of bias in all the studies included, the need for higher quality trials was again underscored.²⁰ Several RCTs have shown that EN was comparable with glucocorticoids in reducing 28-day mortality and more effective in reducing long-term mortality. Another study suggested that combining intensive EN via nasogastric (NG) tube with glucocorticoids was not more effective than glucocorticoids alone, but the study was limited by lack of power and a higher than expected rate of NG tube complications in 7.4% of patients including aspiration pneumonia, poorly controlled hyperglycemia, and worsening HE. Premature feeding tube withdrawal was noted in 48.5% of patients predominantly due to intolerance and noncompliance.²¹ Importantly, regardless of the study arm, nutritional intake was found to be an important determinant of mortality, with those patients consuming < 21.5 kcal/kg/day having lower survival. Another study investigated combining EN with corticosteroids revealed improved survival, suggesting a complementary mechanism with these two therapies. Of note, corticosteroids were tapered when serum bilirubin and prothrombin time decreased by 50%, suggesting that a more individualized approach to duration of steroid therapy is key.²² The Lille model is useful to predict mortality rates in patients with severe alcoholic hepatitis treated with steroids and should be utilized to avoid extending therapy in those who are unlikely to respond, thereby reducing the risk of complications of glucocorticoid therapy.²³

In general, EN is preferable to parenteral nutrition support because delivery of nutrition to the gut strengthens gut mucosal immunity and subsequently decreases endotoxemia that may play a role in the pathogenesis of alcoholic hepatitis; it is also a less expensive option with far fewer complications.²⁴ Those patients with hepatic encephalopathy should be treated with nonabsorbable disaccharides, such as lactulose; rifaximin can be added if this treatment is not effective after 24-48 hours.²⁵

Parenteral Nutrition Support

Many randomized control trials have been performed comparing parenteral nutrition (PN) to enteral feeding in hospitalized patients with AAH and ALD. PN was shown in one of these studies to decrease serum bilirubin more rapidly and improve nitrogen balance, one measure of improved nutritional status.²⁸ However, PN did not significantly improve mortality or hepatic encephalopathy and was associated with increased risk of line infections and other complications such as thrombophlebitis. Furthermore, a Cochrane review of 37 RCTs studying therapeutic effects of PN, EN, and nutritional supplements, found no significant difference in mortality. However, all but one of the included trials had a high risk of systematic error highlighting the need for better designed and higher powered randomized trials to prove efficacy of various nutritional therapies.²⁹ Given the known hepatic complications associated with PN including sepsis, coagulopathy, and death in addition to worsening of existing liver disease and steatohepatitis, this modality is not recommended as preferential therapy.³⁰

Supplements

In addition to a high prevalence of severe protein- calorie malnutrition in heavy alcohol users, numerous micronutrient deficiencies including zinc, folate, thiamine, pyridoxine, vitamins A, B12, D, and E, have been reported in patients with heavy alcohol use and ALD.^31-33 These nutritional deficiencies are not solely related to poor intake, but also to impaired absorption placing these patients at risk of osteoporosis, myopathy, insulin resistance, and dyslipidemia, as well as increase the risk of developing alcohol-induced liver injury. Factors contributing to these deficiencies include:

impaired hepatic production of carrier proteins;
decreased bile acid synthesis and their small bowel delivery as a result of cholestasis leading to fat malabsorption.³⁴

Zinc supplementation may attenuate alcohol-induced liver injury and prevent hepatic encephalopathy through several mechanisms including the improvement of intestinal barrier function, decreasing proinflammatory cytokines, oxidative stress, and endotoxinemia, as well as offsetting hepatocyte apoptosis.^35,36 The recommended dose of zinc used for treatment of liver disease is usually 50 mg of elemental zinc (220 mg of zinc sulfate) taken once daily with a meal to decrease possible nausea. Of note, long term zinc supplementation can be associated with copper deficiency due to competition at the brush border for absorption. The duration of supplementation requires further investigation.

Obesity

Obesity and excess body weight have been associated with increased risk of development of ALD.^37,38 It is proposed by some experts that preexisting fatty liver due to obesity provides the necessary milieu to potentiate additional injury from alcohol,18 thus explaining the increased risk of AH in these patients. Recent data has also shown that there is increased gut permeability in patients with obesity and hepatic steatosis, which likely plays a role in the development of alcoholic liver disease.³⁹

Microbiome

Newer research suggests that the intestinal dysbiosis induced by alcohol ingestion is integral to the development of alcoholic-induced liver injury, further emphasizing the role of the gut- liver axis in disease development. The ?leaky gut? phenomenon is supported by numerous human and animal studies, which suggest alcohol intake causes impaired intestinal barrier function allowing for bacterial transport across the intestinal basement membrane into systemic circulation.^40-42 One study using a murine model showed that acute on chronic alcohol ingestion led to alterations in gut microbiota.⁴³ Treatment with antibiotics prevented neutrophilic infiltration mimicking acute steatohepatitis in human patients, as well as reduced the expression of several proinflammatory markers and reduced steatosis.⁴³ Other human studies have shown a high level of endotoxinemia associated with chronic alcohol use.⁴⁴ These observed changes in the gut microbiome have spurred investigations into possible interventions, which may normalize alcohol-induced intestinal dysbiosis. One study showed that rats consuming alcohol who were later fed with Lactobacillus- containing probiotics or prebiotic oats achieved similar microbiota compositions to the control mice.⁴⁵ Similar results have been seen in human studies,^46,47 suggesting that probiotics may improve clinical outcomes in patients with AH by reversing dysbiosis. Evidence also suggests that probiotics may prevent or decrease intestinal hyperpermeability thus decreasing intestinal oxidative stress and proinflammatory cascade^48-50 which could potentially ameliorate development of alcoholic liver disease. Although probiotics are not considered a standard of care in the treatment of AAH, several RCTs are underway to study potential benefits of probiotic therapy in patients with moderate AAH (clinicaltrials.gov).

CONCLUSION

Nutritional intake is an essential component in recovery from AAH. Protein-calorie malnutrition is associated with significantly higher short and long- term mortality. Existing data favor early initiation of EN during this critical illness, however, more robust data supporting provision of EN when per oral intake is inadequate is needed. The role of specific therapies, particularly zinc and probiotics, in addition to clear recommendations on optimizing nutritional supplementation in this patient population also needs further study. Table 2 provides suggested nutrition interventions for clinicians in patients with AAH based on available evidence.

Dispatches From The Guild Conference, Series #10

A New Model of Specialty Care -The Inflammatory Bowel Disease Medical Home

Benjamin Click,

Miguel Regueiro

In this manuscript, we review the concept of patient-centered specialty medical homes, potential reimbursement methods, implementation requirements and potential challenges. We also present the process and considerations of developing a specialty medical home, and review our experience with an IBD specialty medical home. We further discuss other alternative value-based IBD models being studied across the country.

Benjamin Click MD, Fellow in Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA Miguel Regueiro MD, Division of Gastroenterology, Hepatology and Nutrition. University of Pittsburgh School of Medicine, Professor of Medicine, University of Pittsburgh School of Medicine Medical Director, Inflammatory Bowel Disease Center Co-Director, Total Care-IBD Division of Gastroenterology, Hepatology & Nutrition University of Pittsburgh Medical Center Senior Medical Lead of Specialty Medical Homes, UPMC Health Plan.Conflict of Interest: Miguel Regueiro serves as a consultant and advisory boards for Abbvie, Janssen, UCB, Takeda, Miraca, Pfizer, Celgene, and Amgen. He also receives research support from Abbvie, Janssen, and Takeda. Benjamin Click serves as consultant for Janssen.

Healthcare costs in the United States are escalating at a staggering rate. New models of healthcare delivery have emerged, including patient-centered medical homes, to improve the patient experience, enhance healthcare quality and decrease costs. Previously employed in primary care, such models have not been tested in specialty patient populations. In collaboration with a large integrated healthcare system, we established a specialty medical home for inflammatory bowel disease (IBD). In this manuscript, we review the concept of patient-centered specialty medical homes, potential reimbursement methods, implementation requirements and potential challenges. We also present the process and considerations of developing a specialty medical home, and review our experience with an IBD specialty medical home. We further discuss other alternative value-based IBD models being studied across the country.

HEALTHCARE IN THE UNITED STATES

The United States spends more than any other country on healthcare, estimated at $3.3 trillion in 2016, accounting for 17.9% of the gross domestic product according to the Centers for Medicare and Medicaid Services. Healthcare spending is expected to continue rising by 5.6% per year through 2025. Chronic disease management accounts for the majority of healthcare expenditures. Despite this spending, the U.S. often fails to provide high-quality and efficient care. With an aging population, we can only expect this economic burden to swell.

New Models of Care

Over the past decade, new models of healthcare delivery have emerged that seek to address the growing healthcare economic burden by transitioning away from traditional fee-for-service, volume-incentivized reimbursement towards value-based care. Including accountable care organizations and patient-centered medical homes, these models seek to improve patient experience, enhance healthcare delivery and outcomes, and reduce costs by emphasizing care quality. Placing the patient at the center of the healthcare universe, a patient-centered medical home seeks to provide whole-person care to individuals by utilizing a small team of providers to coordinate all of the patient?s healthcare needs. Initially trialed in the primary care setting, patient-centered medical home results are mixed. A systematic review of 19 comparative studies demonstrated that patient-centered medical home interventions had a small positive effect on patient experiences and small-to-moderate positive effects on the delivery of preventive care services with modestly improved staff experiences.¹ Among older adults, there was a reduction in emergency department visits (risk ratio, 0.81 [95% confidence interval, 0.67-0.98]) but not in hospital admissions (risk ratio, 0.96 [95% confidence interval, 0.84-1.10]) in this patient population. Overall, however, there was no evidence for cost savings. The lack of clear success and cost savings with primary care-based patient centered medical home models has been attributed to multiple factors including caring for an older patient population with multiple chronic diseases, variability in patient-centered medical home design and structure, minimal reporting of financial plans utilized, and potential evaluation by entities that do not routinely publish in peer-reviewed journals (e.g., consulting firms).

Specialty Medical Homes – An Ideal Target Disease

Inflammatory bowel diseases (IBD) are life- long, chronic inflammatory conditions affecting the gastrointestinal tracts of approximately 1.6 million Americans, with a rising incidence rate, and are generally diagnosed in young adulthood. IBD is estimated to account for between $14- 31 billion in both direct and indirect costs from complex care needs and associated morbidity. IBD patients require integrated medical and surgical management with often costly pharmaceutical and procedural requirements. Additionally, IBD patients have higher rates of behavior comorbidities, which can impact healthcare adherence, medical response, unplanned healthcare utilization, and quality of life. These complex factors can result in fragmented care between multiple providers sometimes in different healthcare systems. Such segmented and fractionated healthcare falls short of seamless integrated care. Due to typical younger age and lack of other medical comorbidities, IBD patients often rely on a gastroenterologist as their primary healthcare coordinator. Thus, IBD may be uniquely situated as a chronic disease with a high economic burden and more focused medical needs to potentially benefit from a patient-centered medical home model.

A Break from Tradition

Patient-centered medical care is unique, especially when considering a specialty population with specialty providers. In traditional specialty care, a provider collaborates with a hospital or medical center, is referred patients by other providers and serves as a consultant, focuses mostly on the specific disease, is reimbursed through a relative value unit (RVU)-, volume-based payment structure, and receives institutional support from downstream revenue such as surgery, pathology, radiology, or infusions. In comparison, in a patient-centered specialty care model, the provider collaborates with a payer(s) and is referred patients by the payer to provide care for all patients with a certain disease in a population. The provider works with an interdisciplinary team to address all healthcare needs of each patient and is reimbursed through a value- based approach, focusing on implementing quality care, preventative medicine, and incorporating tele- or other tech-oriented medicine. The payer partner provides up-front support to develop this multidisciplinary team and resources in hopes of improved value and reduced costs.

SMH Requirements and Challenges

Instituting a SMH requires a significant change and deviation from traditional specialty healthcare. We acknowledge that resources for developing such alternative systems varies from region to region. We previously detailed the necessary factors to implement a specialty medical home.^2,3 These include a willing payer(s), a large enough IBD patient population, a physician champion, and goals with metrics of success. It is likely best if there is one or a few larger payers in the region to approach for potential collaboration. This will maximize the potential benefits and buy-in from the payer(s). As for patient population, we estimate that the smallest necessary IBD population for such an approach to be successful is approximately 500 active patients. The SMH system can be scaled to larger populations. Transitioning to patient-centered medical care is a departure from traditional specialty practice. In addition to addressing the biologic disease, the emphasis is on whole-patient care ? preventive care, behavioral medicine, socioeconomic factors, and provision or coordination of care for non-gastrointestinal symptoms and diseases. In a SMH, the specialist must be willing to incorporate and address all facets of healthcare, addressing unmet needs to improve patient outcomes.

Reimbursement Model

Due to the novelty of SMH, the ideal reimbursement model has yet to be defined. Considerations include a shared-savings or global cap approach with emphasis on total cost of care reduction. This will require particular attention to accrued costs, not only by care for the IBD itself, but also for the total care. While biologic medications incur a significant expense, and will likely continue to increase, this should not deter appropriate utilization in patients that may experience improved IBD outcomes, decreased healthcare use, and optimized work and life productivity from these medications. Leveraging the pharmaceutical negotiating power of payer partners may be able to reduce some of the cost impact. Ultimately, the SMH must work together with its partners to achieve high quality care at a lower cost.

UPMC-Total Care IBD as a New Model of Specialty Care

The University of Pittsburgh Medical Center (UPMC) is a large integrated healthcare delivery and finance system that operates both a large academic health system as well as a health insurance plan and currently covers over 3 million individuals, predominantly in Western Pennsylvania. In collaboration with an integrated healthcare delivery network, we formed an IBD specialty medical home (SMH), termed UPMC- Total Care IBD. Incorporating multidisciplinary care, open-access scheduling, and telemedicine, we have enrolled over 650 IBD patients to the SMH to date. Recognizing the complex medical, behavioral, surgical, and socioeconomic factors that influence IBD patients’? healthcare requirements, we implemented a multidisciplinary team including gastroenterologists, a psychiatrist, a social worker, a nutritionist, schedulers, nurse coordinators, and advanced practice providers. The gastroenterologist becomes the principal care provider for this patient cohort and coordinates the total care of each patient. UPMC-Total Care IBD also coordinates with colorectal surgeons and chronic pain specialists for direct care collaboration. Additional support is provided by the UPMC Health Plan (HP). Health coaches work directly with patients on lifestyle modifications including smoking cessation. UPMC HP also provides operational support in the form of data analytics, collaborative interpretation of data, program publicity, and IBD medication approval facilitation through their pharmacy department.

Patient Enrollment

UPMC-Total Care IBD initiated patient enrollment and care delivery in July 2015. Patients are eligible for enrollment in UPMC-Total Care IBD if they were between 18 and 50 years old and carry a clinical diagnosis of IBD. Initially after launch, the target patient population for UPMC-Total Care IBD were the highest healthcare utilizer patients. Thus, an initial criterion of greater than 25% of medical expenditures in the prior year were related to IBD. After several months of enrollment, to expand the patient population, this requirement was dropped and we now enroll any patient with UPMC HP insurance who has IBD.

Data Collection

At the initial visit, patient demographics and disease characteristics are collected. Prior IBD medications are also reviewed and recorded. At each visit, patient-reported interim healthcare utilization including emergency department visits, hospitalizations, radiographic studies, and endoscopies are documented. IBD medications as well as opiate and antidepressant use are reviewed and updated. Additionally, patient-reported disease activity indices (Harvey-Bradshaw Index [HBI] for CD and ulcerative colitis activity index [UCAI] for UC), disease-related quality of life (QoL) metric (short inflammatory bowel disease questionnaire [SIBDQ]), depression and anxiety screening metrics (patient health questionnaire [PHQ]-9 and generalized anxiety disorder [GAD]-7 respectively) are prospectively collected.

Individualized Treatment Plan

All patients are initially evaluated by the gastroenterologist, dietician, social worker, advanced practice provider, and registered nurse. If scores on mental health metrics indicate a potential mental health issue, the social worker or psychiatrist perform a full evaluation for comorbid behavioral health disorders. Patients requiring further individual psychiatric treatment are scheduled for additional clinical sessions and telemedicine as indicated. Prior to each clinic session, the UPMC-Total Care IBD team meets to discuss individual patients and determine active factors or issues requiring attention. Based on these discussions, the team allots differential amounts of time for the team member(s) addressing those issues. Figure 1. depicts key personnel, patient flow, data collection, and collaboration in UPMC-Total Care IBD.

One Year Outcomes

In the first year, UPMC-Total Care IBD enrolled nearly 350 patients. Enrolled patients experienced significant reduction in both emergency room visits by nearly one-half and hospitalizations by approximately one-third. This was accompanied by significant improvement in disease activity scores, quality of life, and mental health metrics. Patients in the most extreme quartiles of these metrics demonstrated the most improvement. Retention in UPMC-Total Care IBD was high, with over 90% patients staying actively engaged at the end of one year. To date, over 650 patients are now actively participating in UPMC-Total Care IBD with ongoing enrollment. Limitations of this initial evaluation include the lack of a standardized control cohort and relatively short-term follow-up. Creation of a comparable control population and longer-term follow-up are underway.

Other Experimental Models

Other centers are also experimenting was variations of value-based care and patient-centered approaches in IBD. The Division of Digestive Disease at UCLA has introduced a comprehensive, integrated, and holistic approach to the management of IBD, incorporating value-based care (the “value quotient”) and cost-effective IBD management.4-7 The Illinois Gastroenterology Group developed a care management system for patients with IBD utilizing nurse care managers and physician medical directors in a team approach, along with clinical decision support and patient engagement, and has recently partnered with a national payer to create a specialist intensive medical home.^8-10

CONCLUSION

Healthcare spending in the United States is growing exorbitantly and cannot be sustained. Alternative healthcare delivery models are being explored in an attempt to reduce costs of care while improving outcomes, quality of life, and patient experience. IBD is uniquely situated to benefit from a value- based coordinated care model due to the younger patient population affected by a chronic illness requiring multidisciplinary care with a high economic impact. In collaboration with a large integrated healthcare delivery and finance system, we formed a patient-centered specialty medical home for inflammatory bowel disease patients. After one year of enrollment, treatment, and follow- up, we observed a significant reduction in emergent and inpatient healthcare utilization with concordant improvement in disease activity, quality of life, and mental health metrics. This model of caring for IBD patients shows promise in improving outcomes while reducing spending. Extension to other chronic disease models is underway and further evaluation of these alternative models of care will be critical to addressing the future of healthcare in the U.S.

Introduction: Dispatches From The Guild Conference 2018

Dispatches from the GUILD Conference 2018

Uma Mahadevan

Uma Mahadevan MD, Professor of Medicine, Medical Director, UCSF Center for Colitis and Crohn’s Disease

Dear Reader: As Chairman of the GUILD (Gastroenterology Updates, IBD, Liver Disease) Conference (guildconference.com), I would like to welcome you to the second annual series “Dispatches from the GUILD Conference.” The GUILD conference is a 4 day, high impact course held in Maui, HI, focusing on inflammatory bowel disease (2 days), liver disease (1 day) and a fourth day of rotating hot topics in gastroenterology. Continuing medical education (CME) and maintenance of certification (MOC) points are offered. The course features the nation’s top faculty and innovative presentation formats in a relaxed setting conducive to interactive learning, networking and camaraderie. GUILD and Practical Gastroenterology have teamed up to bring you the highlights from GUILD. Mahalo and enjoy!

Sincerely,
Uma Mahadevan, MD

Nutrition Issues In Gastroenterology, Series #172

Amyloid – A Wolf in Sheep’s Clothing

February 2018 • Volume XLII, Issue 2

Hassan Tariq,

Muhammad Umar Kamal,

Ariyo Ihimoyan

Amyloidosis is a complex group of diseases associated with variable presentations characterized by excessive deposition of the misfolded, abnormal, and insoluble proteins in different organs of the body. The goal of management in amyloidosis is to inhibit the excessive production of amyloid fibrils and control symptoms. This article highlights classification, etiologies, diagnosis, and management of amyloidosis, in particular, the management of GI symptoms and malnutrition.

Hassan Tariq, MD, Muhammad Umar Kamal, MD, Ariyo Ihimoyan, MD, Bronx Lebanon Hospital Center, Department of Medicine, Bronx, NY

INTRODUCTION

Amyloidosis is a complex and rare group of diseases associated with diverse etiologies and variable presentations. It is neither a malignancy nor an autoimmune disorder, but it can occur in response to, and along with, chronic infectious and inflammatory diseases. It is characterized by excessive deposition of misfolded, abnormal, and insoluble proteins in different organs of the body resulting in structural change and altered function.¹ The incidence or prevalence is not well known due to the wide spectrum of presentations increasing the chance of under-diagnosis or even missing the diagnosis, resulting in confounding statistics of occurrence. In 1992, Kyle and colleagues reviewed a 40-year data set of primary amyloidosis in Minnesota and reported the overall prevalence of Amyloid light chain (AL) amyloidosis of about 6-10 cases per million person-years (MPY).² This corresponds to disease burden of approximately 2200 cases in the U.S. annually. The prevalence may have increased over the years due to newer diagnostic and therapeutic interventions for chronic infectious and inflammatory diseases contributing to increased morbidity. A recent cohort study of Latin America has reported incidence by describing the disease burden of 6.13 cases per MPY for AL and 1.21 cases per MPY for amyloid A (AA) amyloidosis.³ Given its complicated clinical course, amyloidosis poses diagnostic and therapeutic challenges for the clinicians. In this article, we aim to review the basic pathophysiology, clinical presentations, diagnostic dilemma and treatment hurdles, especially focusing on the management of gastrointestinal (GI) amyloidosis and nutritional implications.

Types of Amyloidosis

The group of diseases that fall under “amyloidosis” can be either genetic or acquired. Genetic/hereditary manifestations are due to mutations in specific genes. Acquired occurs in response to malignancies or chronic inflammatory and infectious states. Amyloid protein production starts in response to these conditions and has the propensity to deposit in certain organs or spread systemically and manifest with localized or systemic disease. The most common type of systemic amyloidosis is primary amyloidosis or, Amyloid light chain (AL).⁴ Other types include secondary amyloidosis (serum amyloid AA),^2,5 dialysis-related (b-2 microglobulin),⁶ senile (Alzheimer?s related apolipoprotein E), and familial amyloidotic polyneuropathy (transthyretin, apolipoprotein AL). Different types are described in Table 1. Primary amyloidosis AL has been described in association with plasma cell disorders like multiple myeloma.4 Secondary AA development occurs in the setting of chronic inflammatory/infectious disorders such as autoimmune diseases, persistent or longstanding microbial infections (leprosy, tuberculosis, bronchiectasis), and various cancers (carcinoma of the GI tract, kidneys, pulmonary, genitourinary system, or skin), etc. The proteolysis of serum amyloid A (acute phase reactant) results in the deposition of AA protein in various organs.^6-8 In familial amyloid polyneuropathy, the mutated transthyretin and apolipoprotein can deposit in any tissue resulting in malfunction, but has a high predisposition towards the liver.^4,9 Senile amyloidosis, commonly seen in the elderly, affects the heart, pancreas, prostate, and brain. Disease is confirmed with congo-red staining of biopsied specimens of above-mentioned organs. The involvement of the brain is considered as one of the etiologies of Alzheimer?s disease in the elderly.⁹ Familial amyloidosis is an autosomal dominant disease caused by abnormal deposition of serum amyloid P in mucosal or neuromuscular regions and results in disruption of tissue structure and function.^6,10

Pathophysiology

The amyloid protein develops in response to chronic inflammatory/infectious disorders including cancers and is deposited in various organs of the body most specifically, heart, kidneys, liver, bowel, skin, etc. depending on the type of amyloidosis. Tissue specimen can be obtained from any organ suspected/confirmed to have amyloidosis. In patients suspected of amyloidosis, subcutaneous (SC) fatty tissue biopsies (usually from the abdomen) are taken and can be stained with different stains like Congo red (appears green under polarizer), hematoxylin eosin (appears red) or thioflavin T (appears yellow green), but the Congo red staining is the most specific for diagnosis.^4,11

Clinical Presentation

The clinical findings of amyloidosis depend on the areas of involvement of the amyloid deposition. General symptoms include weight loss, fatigue, dizziness, and generalized or pedal edema.^4,12

Each type of amyloid has a predisposition to deposit in different organs and infiltration of the amyloid fibrils, commonly seen in kidney, heart, peripheral nerves, and GI tract, lead to the symptoms observed.¹³ Table 2 shows the percentage of organ involvement depending on the type of amyloidosis.

Initial findings of kidney involvement include proteinuria, followed by azotemia and renal failure depending on the underlying cause and severity of disease. Infiltration of the heart can manifest with symptomatology of restrictive cardiomyopathy, which can progress to heart failure or fatal cardiac arrhythmias.4⁴

The amyloid deposition in the GI tract effect the myopathic and neuromuscular function by involving the muscularis mucosae, and gradually damaging blood vessels, nerves and nearby structures.¹⁴ The consequence of which is impaired GI motility leading to gastroparesis with nausea and heartburn, anorexia, and constipation; severe disease might lead to pseudo-intestinal paralysis. Diarrhea occurring in GI amyloidosis can be due to autonomic dysfunction, enteritis, or excessive bacterial overgrowth in the small bowel.^15-17 GI bleeding is a fearsome presentation of systemic amyloidosis seen in 57% patients and can occur anywhere in the GI tract; the cause of which can be ulceration or erosion.¹⁸

Interestingly, AA amyloidosis exhibited the highest percentage of GI findings in the range of 10%-70%; AL amyloidosis is associated with fewer extrahepatic GI symptoms.⁴ The amyloid deposition in the liver occurs in stellate cells resulting in fibrogenesis¹⁹ and subsequently mechanical and functional tissue disruptions. It does not suddenly derange liver function, but initially causes symptoms like weight loss, abdominal pain, decreased appetite and fatigue. Jaundice is rare in amyloidosis, but if present, is associated with an increased mortality rate.^20,21 Macroglossia and clinical splenomegaly have also been described in patients with systemic amyloidosis.²²

DIAGNOSIS

Patients with amyloidosis might undergo a battery of tests due to complex clinical presentations before the final diagnosis is made. Therefore, when suspected, relevant imaging and laboratory testing and appropriate tissue collection is necessary for the definitive diagnosis. It is ideal to biopsy the organ affected as it increases the diagnostic yield, but commonly SC fat tissue is biopsied usually from the abdominal wall, due to less risk of complications; however, any other site of adipose tissue can be biopsied depending on the availability of subcutaneous fatty tissue. Tissue biopsy is under local anesthesia with 2% solution of lidocaine subcutaneously; then using a scalpel, a cutaneous resection of 3-4mm length of skin is done; followed by clipping of subcutaneous fatty tissue with a Kocher and the material is separated with a scalpel. Biopsy site is wrapped with clean dressing for a couple of days. Some recent studies have reported a wide range (13-73%) of sensitivity of SC tissue biopsy, but specificity was 100%.^23-24 The variable sensitivity is due to different types of amyloidosis. Rectum is the next common site of biopsy with sensitivity of 75-85%.²⁵ Other organs may be biopsied when involved, but hepatic biopsy is usually not recommended given high risk of bleeding.^4,26 In patients with systemic AA or AL amyloidosis, the diagnostic sensitivity of whole-body 123I-labeled serum amyloid P (SAP) scintigraphy was 90%. It showed the amount of amyloid infiltrated in the all the affected organs except the heart.²⁷ It is very important to screen other organs such as heart, kidney, bone marrow, GI etc. for amyloidosis if the disease is suspected or confirmed anywhere in the body.^11,12,28

The radiological imaging is usually nonspecific, but can be helpful in leading towards diagnosis. Radiographs, barium studies, CT, and MRI are utilized to evaluate the abnormalities. The findings on imaging of the GI tract include mucosal irregularities, thickened mucosal folds, rough mucosal surface with multiple nodular densities, polyps, narrowed lumen, thickened intestinal wall, etc. They are most prevalent in the small intestine (SI).^29-32 Sometimes thickened and dilated SI can be visualized on the CT.³¹ Laboratory results revealing proteinuria, and abnormal serum protein electrophoresis may suggest the existence of amyloidosis in the patient.¹² These tests provide a clue for further assessment of a patient having an obscure diagnosis.

Alarming GI symptoms warrants endoscopy, which helps in revealing the site of involvement. In the GI tract, the small intestine is mostly affected.^13,33 Studies have reported polypoid appearance and thickened intestinal folds in AL seen during endoscopy that can lead to intestinal obstruction and constipation. A diffuse granular appearance is seen endoscopically in AA and clinically manifests as bleeding, diarrhea, and malabsorption.^12,30,34,35 Gastric findings include submucosal masses, erosions, ulcers, thickened rugae and hemorrhages.³⁶

Management

The goal of management in amyloidosis is to inhibit the excessive production of amyloid fibrils. It includes treating the underlying etiologies of acquired amyloidosis like cancers, chronic infections and auto-immune diseases.³⁷

Plasma cell proliferative disorders causing AL amyloidosis and affecting organ system warrant further investigation. This includes further evaluation by an oncologist for possible chemotherapy or stem cell transplantation (SCT).^37,38 Similarly, patients suspected of having AA amyloidosis are managed by addressing the underlying etiology like chronic infectious or inflammatory disorders and/or malignancies. This is because targeting the underlying cause for AA amyloidosis will halt and prevent the progression of disease. Sometimes it can be difficult to elicit the cause of AA amyloidosis requiring frequent physician visits and extensive diagnostic work up. Studies have reported efficacy with the use of biologics³⁹ i.e., interleukin-6 inhibitors/anti-tumor necrosis factor agents (TNF) for the treatment of rheumatic diseases,⁴⁰ and anti-tumor necrosis factor agents (TNF) for management of inflammatory bowel disease.41⁴¹

Symptoms

The GI symptoms can result in poor intake, nutritional deficiencies, and malabsorption. Initial management of patient requires control of symptoms such as persistent nausea and vomiting with anti-emetics. This includes treating symptomatic diarrhea with antidiarrheal or antisecretory agents, and diarrhea due to small bowel bacterial overgrowth with antibiotics.⁴² Prokinetics like metoclopramide or erythromycin may be tried for gastroparesis or dysmotility.^13,43

Nutritional Considerations

Malnourishment in amyloidosis is multifactorial and requires regular nutrition assessment. Malnutrition should be corrected by managing symptoms and providing nutritional support, as well as vitamin and mineral supplementation when needed. Early nutritional referral and consultation is recommended.^4,44 Patients with mild to moderate involvement of the bowel will benefit from enteral feeding if oral intake is inadequate. In patients with severe malnutrition, severe GI involvement with worsening GI symptoms or pseudo- obstruction, total parenteral nutrition (TPN) may be considered.44 However, TPN is associated with increased risk of infections and edema in these patients, so caution is necessary.⁴⁴ These patients need to be closely monitored to decide if and when to start more aggressive management like TPN, but only after enteral feeding has failed. Intake of various supplements has shown to influence the disease activity in animals, but studies in humans are lacking.^45-47

The response to treatments in AL amyloidosis can be assessed by monitoring the amount of amyloid deposits via serum amyloid P scintigraphy and functional status of organs via laboratory tests and imaging as required.⁴⁸

Prognosis

The survival in these patients depends on the type of amyloidosis and the severity of organ damage. AL amyloidosis has a poor prognosis due to its association with malignancy, even if the patient is undergoing chemotherapy alone. In patients undergoing chemotherapy and stem cell transplantation (SCT), the calculated 5 year survival is approximately 60%.³⁷ Treatment of underlying disorders in AA amyloidosis is associated with regression of amyloid deposits and improvement in mortality.⁴⁹ In addition, the survival of patients also coordinates serum amyloid P concentrations that can be monitored with SAP scintigraphy. This is of utmost importance in targeted management of serum amyloid P for the treatment of amyloidosis by monitoring SAP levels during therapy.⁵⁰ A recent study by Lim et al reported median overall survival of 15.84 months in AL amyloidosis patients without GI involvement and 7.95 months in patients with GI involvement. GI involvement is associated with poor prognosis.51⁵¹

SUMMARY

Amyloidosis usually manifests in a discreet sequela, which include non-specific symptoms such as weight loss, autonomic dysfunction, fatigue, and GI symptoms. Patient with chronic diseases and cancers should be suspected to have amyloidosis if presenting with nonspecific symptoms. The evaluation includes laboratory testing and imaging, and if necessary, biopsy of the organ involved which is the gold standard for diagnosis.