Page 25 – Practical Gastro

Clostridioides difficile is a common cause of infectious colitis, and a less recognized cause of enteritis. There have been several reported cases of C. difficile enteritis in patients who have an end ileostomy after a total colectomy. Like colitis caused by C. difficile, C. difficile enteritis can have a wide range of clinical manifestations, ranging from diarrhea to septic shock, although the most common presenting symptom is increased ileostomy output. Risk factors include recent antibiotic use, proton pump inhibitor use, inflammatory bowel disease, and immunosuppression. Diagnosis and treatment are the same as for C. difficile colitis, as diagnosis is confirmed with stool toxin assays and first line treatment is oral vancomycin. C. difficile enteritis is a rare disease that can have a fatal outcome, and thus providers must have a high index of suspicion to reduce morbidity and mortality.

INTRODUCTION

Clostridioides difficile (CD) is a Gram-positive, end-organ failure and death. Less appreciated is its spore-forming, toxin-producing bacillus, that role as a cause of small bowel enteritis in patients is the most common etiology of nosocomial who have undergone a total colectomy with an infectious diarrhea, and antibiotic-associated end ileostomy or ileal pouch-anal anastomosis.
diarrhea.¹ The incidence of C. difficile has been increasing rapidly since the early 2000s, in part due to the highly virulent NAP1/BI/027 strain.² Lower clinical cure rates, increased recurrence rates, more severe disease, and higher 14-day mortality rates have been seen in patients infected with this strain.³

C. difficile infection (CDI) is well known to affect the colon, resulting in a large range of clinical outcomes, ranging from relatively asymptomatic diarrhea, to toxic megacolon and fulminant colitis which can result in hemodynamic instability,

As CDI enteritis is rare, much of our knowledge of the disease comes from case reports, with approximately 60 cases reported in the literature to date.^2,4-22

CDI enteritis is associated with increased hospital length of stay (LOS) and health care costs, poor patient quality of life, and high mortality rate approaching 30%.^2,4 This high mortality rate is likely due to delay in diagnosis given the rarity of the illness. Unfortunately, many patients are diagnosed only at the time of autopsy where pseudomembranes are identified within the small intestine.¹⁰ Luckily, with increased recognition of the disease and early diagnosis, prognosis is improving. Here, we aim to summarize the current evidence regarding CDI enteritis, specifically in the

subset of patients who have had a total colectomy and an end ileostomy, and increase awareness of this underdiagnosed, yet potentially fatal disease. Risk Factors and Pathogenesis

Risk factors for CDI enteritis include recent antibiotic and proton pump inhibitor (PPI) use, ICU or prolonged hospital stay, increasing age, immunosuppression, history of gastrointestinal surgery of the colon, and inflammatory bowel disease (IBD).^4,14 Approximately 70% of patients have been found to have antibiotic usage in the 4 weeks prior to presentation, and approximately 35% have been found to have a medical condition that might lead to an immunocompromised state.^2,9 Similar to colonic CDI, patients with a history of IBD are also at an increased risk of developing CDI enteritis. Approximately 40-50% of patients with CDI enteritis have a history of IBD.^2,9 The abnormal gut mucosal immune response in IBD patients may play a role in increasing susceptibility to gastrointestinal infection amongst these patients.¹⁴

The pathogenesis of CDI enteritis in patients with an end ileostomy is unclear; however, several hypotheses have been suggested. There appears to be an increase in susceptibility to disease as a result of the histologic and microbiologic similarity between the small bowel and colon that may develop after a total colectomy. A competent ileocecal valve has been suggested to inhibit small bowel colonization with colonic bacterial flora. With removal of the colon and ileocecal valve, the small bowel flora changes such that the neoterminal ileum is characterized by colonic-type fecal flora, thereby making it more susceptible to overgrowth with CD.^4,14 Patients with a history of CDI colitis are more susceptible to developing CDI enteritis, especially in the early postoperative phase, as a result of bacterial migration from the colon to the small bowel.¹⁴ Patients also develop colonic-type metaplasia and partial villous atrophy of the terminal end of the ileostomy as a result of alterations in fecal flow, thereby increasing its similarity to the colonic environment.^2,4,8

Symptoms and Diagnosis

Patients with CDI enteritis may present with nonspecific symptoms. The most common presenting symptom amongst case reports is increased ileostomy output, which may lead to dehydration or acute kidney injury.¹⁴ Diagnosis is often missed in those with an ileostomy, as watery diarrhea is expected, especially in the immediate postoperative period. Additionally, increased ileostomy output could have several other causes, including infection and partial obstruction, etc. Other symptoms include ileus, fever, abdominal or pelvic pain, and abdominal cramping. Depending on the severity of disease and degree of dehydration, some patients may present with hemodynamic instability, including tachycardia and hypotension.^4,6,10 However, many patients are non-toxic with normal vital signs, and may or may not be febrile.^5,8 Physical exam findings can include diffuse tenderness without signs of peritonitis.^2,4,6 Laboratory and imaging studies may aid in the diagnosis of CDI enteritis. Patients will often have leukocytosis. In severe cases, patients may have evidence of acute kidney injury and electrolyte derangements as a result of dehydration.^12,18 A computed tomography (CT) scan can show findings of distended, fluid-filled small bowel in the presence of mesenteric fat stranding and free intraabdominal fluid suggestive of enteritis.¹⁹ Although this is also nonspecific, the combination of laboratory derangements, CT scan findings and patient’s symptoms should raise one’s clinical index of suspicion and aid in the diagnosis of CDI enteritis.

CDI enteritis should be considered in any patient with an ileostomy presenting with the aforementioned symptoms, especially if they have a history of recent antibiotic use, IBD, or immunosuppression. Diagnosis is confirmed by the presence of CD toxin in a stool sample by polymerase chain reaction (PCR) or enzyme immunoassay.¹

Management

Management of CDI enteritis parallels that of CDI colitis, and is dictated by disease severity. The first line treatment for mild/moderate disease is a 10day course of oral vancomycin or fidaxomicin. Metronidazole is a second-line agent but should be avoided in patients with associated IBD due to poor absorption. Recurrence may be treated with For a second recurrence, one should consider fidaxomicin, pulse tapered regimen of vancomycin, or rifaximin regimen following PO vancomycin.⁴ Additional recurrences may necessitate consideration of a fecal microbiota transplant administered via upper endoscopy or ileoscopy through the stoma itself.^4,24 As with CDI colitis, severe cases should be treated with antibiotics, supportive care and early consideration for surgical intervention.⁴

C. Difficile in Patients with

Ileal Pouch-Anal Anastomosis

Total colectomy with ileal pouch-anal anastomosis (IPAA), commonly referred to as a “J-pouch,” is the operation of choice for many patients with treatment-refractory ulcerative colitis, as it may cure the patient’s disease without necessitating a permanent ileostomy. Pouchitis, or inflammation of the ileal pouch, is the most common complication after IPAA, with cumulative incidence approaching 45% at 5 years.²³ It can be caused by infection, recurrence of IBD, and irritation to the pouch mucosa. CDI of the ileal pouch has been recognized as a possible cause of pouchitis. Approximately 10% of symptomatic patients seen at a tertiary referral center for pouch dysfunction are diagnosed with CDI of the pouch.²⁴

Unlike CDI enteritis, postoperative antibiotic exposure and use of immunosuppressive agents or PPIs do not appear to be associated with CDI pouchitis.²⁴ Rather, risk factors include male gender, recent hospitalization, and pre-surgery antibiotic usage.^24-26 Patients with an ileal pouch are susceptible to CDI due to similarities of the pouch with the colon at both physiological and structural levels.²⁴ Fecal stasis within the pouch promotes gut microbial dysbiosis and colonic metaplasia of the ileal mucosa, which may predispose to CDI infection and colonization.²³

Patients commonly present with abdominal

or pelvic pain and increased stool frequency.^23,27,28 Diagnosis is confirmed with stool toxin assays, and endoscopic visualization by pouchoscopy may be of value.²⁴ CDI should be considered in ileal pouch patients particularly if there is a change to their usual symptomology and if the episode of pouchitis appears to be refractory to antibiotic management.²⁴

Testing for CDI should be considered in pouch patients presenting with fever, urgency, increased stool frequency, hematochezia, incontinence, and abdominal or pelvic pain.²³

Treatment for CDI pouchitis is the same as treatment for CDI colitis and enteritis, with oral vancomycin being the first line agent. Although exploratory, fecal microbiota transplantation may be useful in severe or antibiotic-refractory cases.²⁴ Overall, the prognosis is relatively good, and most patients are successfully treated with antibiotics; however more severe cases of CDI pouchitis have also been reported. There is one case reported in the literature that required pouch excision with conversion to ileostomy,²⁹ and one case of fulminant CDI resulting pseudomonas aeruginosa septicemia, intravascular coagulopathy, acute renal failure, hemorrhagic ascites, respiratory failure, and eventual death.³⁰

SUMMARY AND RECOMMENDATIONS

Although better known for causing colitis,

Clostridioides difficile is a rare cause of enteritis, particularly in patients who have undergone a total colectomy. Physicians treating patients with end ileostomies and ileal pouch-anal anastomoses should have a high index of suspicion for C. difficile infection in any patient presenting with increased stool output, abdominal cramping, and/or fever, especially if they have a history of recent antibiotic use, PPI use, inflammatory bowel disease, or an immunosuppressed state. CDI enteritis can be a highly morbid and even fatal disease, and thus prompt recognition and initiation of treatment is imperative to improve outcomes. See Table 1 for a summary of identification and management of CDI enteritis.

References

^{Dupont HL. Diagnosis and management of Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11(10):1216-23.}
^{Dineen SP, Bailey SH, Pham TH, et al. Clostridium difficile enteritis: A report of two cases and systematic literature review. World J Gastrointest Surg. 2013;5(3):37-42.}
^{Marsh JW, Arora R, Schlackman JL, et al. Association of relapse of Clostridium difficile disease with BI/NAP1/027. J Clin Microbiol. 2012;50(12):4078-82.}
^{Aujla AK, Averbukh LD, Potashinsky A, et al. A Rare Case of Clostridium difficile Enteritis: A Common Bug in an Uncommon Place. Cureus. 2019;11(4):e4519.}
^{Causey MW, Spencer MP, Steele SR. Clostridium difficile enteritis after colectomy. Am Surg. 2009;75(12):1203-6.}
^{Freiler, JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clin Infect Dis. 2001;33(8):1429-32.}
^{Gagandeep D, Ira S. Clostridium difficile enteritis 9 years after total proctocolectomy: a rare case report. Am J Gastroenterol. 2010;105(4):962-3.}
^{Khan MS, Levy D, Mann S. Clostridium difficile infection in the absence of a colon. BMJ Case Rep. 2010 Oct 21;2010:bcr0220102728.}
^{Kim JH, Muder RR. Clostridium difficile enteritis: a review and pooled analysis of the cases. Anaerobe. 2011;17(2):52-5.}
^{Kim KA, Wry P, Hughes E, et al. Clostridium difficile small-bowel enteritis after total proctocolectomy: a rare but fatal, easily missed diagnosis. Report of a case. Dis Colon Rectum. 2007;50(6):920-3.}
^{Kurtz LE, Yang SS, Bank S. Clostridium difficile-associated small bowel enteritis after total proctocolectomy in a Crohn’s disease patient. J Clin Gastroenterol. 2010;44(1):76-7.}
^{Lundeen SJ, Otterson MF, Binion DG, et al. Clostridium difficile enteritis: an early postoperative complication in inflammatory bowel disease patients after colectomy. J Gastrointest Surg. 2007;11(2):138-42.}
^{Nasser H, Munie S, Shakaroun D, et al. Clostridium difficile Enteritis after Total Abdominal Colectomy for Ulcerative Colitis. Case Rep Crit Care. 2019;2987682.}
^{Navaneethan U, Giannella RA. Thinking beyond the colon-small bowel involvement in clostridium difficile infection. Gut Pathog. 2009;1(1):7.}
^{Peacock O, Speake W, Shaw A, et al. Clostridium difficile enteritis in a patient after total proctocolectomy. BMJ Case Rep. 2009;2009:bcr10.2008.1165.}
^{Seril DN, Shen B. Clostridium difficile infection in the postcolectomy patient. Inflamm Bowel Dis. 2014;20(12):2450-69.}
^{Tarasiuk-Rusek A, Shah KJ. Clostridium difficile ileitis in a patient, after total colectomy. BMJ Case Rep. 2016 Feb 22;2016:bcr2015214319.}
^{Vesoulis Z, Williams G, Matthews B. Pseudomembranous enteritis after proctocolectomy: report of a case. Dis Colon Rectum. 2000;43(4):551-4.}
^{Wee B, Poels JA, McCafferty IJ, et al. A description of CT features of Clostridium difficile infection of the small bowel in four patients and a review of literature. Br J Radiol. 2009;82(983):890-5.}
^{Williams RN, Hemingway D, Miller AS. Enteral Clostridium difficile, an emerging cause for high-output ileostomy. J Clin Pathol. 2009;62(10):951-3.}
^{Yafi FA, Selvasekar CR, Cima RR. Clostridium difficile enteritis following total colectomy. Tech Coloproctol. 2008;12(1):73-4.}
^{El Muhtaseb MS, Apollos JK, Dreyer JS. Clostridium difficile enteritis: a cause for high ileostomy output. ANZ J Surg. 2008 May;78(5):416.}
^{Kayal M, Tixier E, Plietz M, et al. Clostridioides Difficile Infection Is a Rare Cause of Infectious Pouchitis. Inflamm Intest Dis. 2020;5(2):59-64.}
^{Seril DN, Shen B. Clostridium difficile infection in patients with ileal pouches. Am J Gastroenterol. 2014;109(7):941-7.}
^{Li Y, Qian J, Queener E, et al. Risk factors and outcome of PCRdetected Clostridium difficile infection in ileal pouch patients. Inflamm Bowel Dis. 2013;19(2):397-403.}
^{Shen BO, Jiang ZD, Fazio VW, et al. Clostridium difficile infection in patients with ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2008;6(7):782-8.}
^{Shen B, Goldblum JR, Hull TL, et al. Clostridium difficileassociated pouchitis. Dig Dis Sci. 2006;51(12):2361-4.}
^{Mann SD, Pitt J, Springall RG, et al. Clostridium difficile infection-an unusual cause of refractory pouchitis: report of a case. Dis Colon Rectum. 2003;46(2):267-70.}
^{Martinez Ugarte ML, Lightner AL, Colibaseanu D, et al. Clostridium difficile infection after restorative proctocolectomy and ileal pouch anal anastomosis for ulcerative colitis. Colorectal Dis. 2016;18(5):O154-7.}
^{Shen B, Remzi FH, Fazio VW. Fulminant Clostridium difficileassociated pouchitis with a fatal outcome. Nat Rev Gastroenterol Hepatol. 2009;6(8):492-5.}

RE-INTRODUCTION: LIVER DISORDERS SERIES

Re-Introduction: Liver Disorders Series

Michael Babich

In 2014, Practical Gastroenterology first introduced a series of review articles with the goal of providing a detailed review of many aspects of the management of liver and biliary diseases, intended for professionals to use as reference points in their clinical practices. Today, we re-introduce a new series of liver-related articles, to continue and expand upon this purpose.

Fostering a foundation of knowledge related to liver disease management remains a highly relevant practice for all clinicians. The CDC estimates that 4.5 million adults in the United States, nearly 2% of the population, carry a diagnosis of liver disease, which is responsible for over 44,000 deaths per year.¹ The economic burden of chronic liver disease to the United States remains substantial. Considering just inpatient costs, the national hospitalization costs in patients with chronic liver disease exceeds $81 billion, while, on the ambulatory side, in considering only nonalcoholic fatty liver disease, or NAFLD, which affects roughly 100 million Americans, costs accrued by the United States healthcare system in 2018 reached $32 billion annually.^2,3 While liver diseases such as chronic hepatitis B and C and hemochromatosis are now relatively easy to control and prevent progression, or cure, current management options for alcohol use disorder and NAFLD remain suboptimal, despite the high prevalence of these diseases. Consequently, the prevalence of advanced liver disease and cirrhosis remains high, with over 600,000 patients estimated to have cirrhosis in the United States.⁴ For many patients with decompensated cirrhosis, liver transplantation remains the only option to significantly improve mortality. The total cost billed for a liver transplant from 30 days prior to transplant to 6 months after transplant was estimated to average $577,000.⁵

For a practicing clinician, having a solid understanding of the diagnosis and management of liver-related conditions is essential to optimizing the care and prognoses of their patients. In most cases, early diagnosis is optimal. The goal of this series is to provide timely and relevant reviews on a variety of liver diseases, highlighting the most recent advances and management strategies published in the medical literature. We aim to provide information, and will focus our selections of topics, so as to be relevant to general gastroenterologists and primary care providers, who are on the front lines of patient care. Our first review, appearing in this issue, will detail the diagnosis and management of autoimmune liver disease variants. Future articles in this series will address topics including acute liver failure, hepatic encephalopathy, drug-induced liver injury, intrahepatic cholestasis, dietary approaches to the management of NAFLD, evaluation of solid liver lesions, and a review of newer concepts in pre- and post-liver transplant care directed towards the primary care provider.

References

^{Summary Health Statistics Tables for U.S. Adults: National Health Interview Survey, 2018, Table A-4b, A-4c.}
^{JAMA Netw Open. 2020;3(4):e201997. doi:10.100 /jamanetworkopen.2020.1997}
^{Intermountain Medical Center. “Economic burden of fatty liver disease in US is $32 billion annually, new study finds.” ScienceDaily. www.sciencedaily.com/ releases/2018/07/180703105956.htm}
^{Journal of Clinical Gastroenterology: September 2015 – Volume 49 – Issue 8 – p
690-696}
^Google

FROM THE PEDIATRIC LITERATURE

Underreporting of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is not uncommon in children and can be associated with hepatic fibrosis with the risk of long-term associated mortality. Thus, early detection is important in order to monitor disease activity and to provide resources to improve health outcomes. Children often undergo computed tomography (CT) of the abdomen for various reasons, and the authors of this study evaluated for incidental hepatic steatosis findings in a group of children undergoing CT for nephrolithiasis.

This retrospective, single-center study included patients younger than 18 years of age who underwent abdominal CT imaging for concern of nephrolithiasis over a 5-year period. Patients with known medical conditions that could cause steatosis such as metabolic/storage diseases, Wilson disease, autoimmune hepatitis, and viral hepatitis were excluded. Patients with asplenia also were excluded. Patient parameters including height, weight, age, and standard laboratory data were obtained from the electronic medical record. Liver and spleen parenchymal attenuation were measured with moderate-to-severe steatosis defined as a histologic fat concentration greater than 30%. This value (defined as “original criteria”) was obtained by using specific parameters of liver and spleen attenuation differences calculated as Hounsfield Units on CT. Mild steatosis was defined as histologic fat concentrations ≥ 5% and was determined using mDIXON-Quant magnetic resonance imaging to calculate Hounsfield Units (defined as “secondary criteria”). These two criteria categories were compared to patients who underwent CT for nephrolithiasis who did not have hepatic steatosis. Kappa statistics were used to determine degree of agreement of imaging findings between 2 radiologists. A total of 584 patients with appropriate inclusion criteria underwent abdominal CT for a diagnosis of nephrolithiasis during this period. Most patients were non-Hispanic females, and the median age of the patients was 14.8 years. The median body mass index (BMI) was at the 73^rd percentile with 41% of patients being defined as overweight or obese. It was noted that 541 patients had no steatosis on imaging while 42 patients did have steatosis. The two CT criterium (“original” for moderate to severe; “secondary” for mild) used to determine steatosis demonstrated a prevalence rate of steatosis between 3%-35%. Kappa statistics between radiologists showed excellent correlation of findings. No significant difference in ethnicity was found between patients with or without steatosis. However, BMI percentiles and median serum alanine aminotransferase (ALT) levels were significantly higher in patients with any degree of steatosis compared to patients with no steatosis. Steatosis ranged between 6%-47% in those patients who were overweight or obese compared to 0.3%24% of patients with a normal BMI percentile. Additionally, steatosis was present in 11%-43% of patients with elevated ALT levels while steatosis was present in 0.7%-27% of patients with normal ALT levels. Finally, using a non-contrast CT liver attenuation value of less than 48 Hounsfield Units, only 12 of 42 patients (29%) had steatosis reported in the original radiology reports, and only 2 of these 12 patients had a known history of NAFLD.

This study suggests that steatosis can be found during CT imaging of the abdomen ordered for non-hepatic reasons. If steatosis is found, it is essential to have such patients be referred to pediatric gastroenterology to assist with diagnosis and treatment options to prevent the long-term complications of NAFLD.

^{Okura H, Yodoshi T, Thapaliya S, Trout A, Mouzaki M. Under-reporting of hepatic steatosis in children: a missed opportunity for early detection. Journal of Pediatrics 2021; 234: 92-98.}

FROM THE PEDIATRIC LITERATURE

Could Glucocorticoids Improve Enteral Feeding?

Short bowel syndrome (SBS) in children is a rare disease with extremely high health care costs due to long-term parenteral nutrition (PN) requirements and the potential for frequent hospitalizations. Many patients can have PN requirements reduced or can wean from PN completely if enteral nutrition can be advanced successfully. However, risk factors such as production of inflammatory mediators and bacterial overgrowth can lead to intestinal inflammation in pediatric patients with SBS, and the authors of this study looked at the potential benefit of glucocorticoids in this specific population.

This retrospective study from a medical center with expertise in pediatric intestinal rehabilitation looked at all pediatric patients with SBS at their institution who had undergone glucocorticoid therapy for intestinal inflammation diagnosed by endoscopy with biopsy. Patients on glucocorticoids for organ transplantation or food allergy therapy were excluded. Those patients with SBS and who received glucocorticoid therapy received either prednisone or budesonide. Specifically, patients with high parenteral nutrition needs initially were placed on prednisone and then tapered to budesonide with sulfasalazine. Sulfasalazine was added if colonic inflammation was present. Patients with lower parenteral nutrition needs were initially placed on budesonide and sulfasalazine, and budesonide was eventually weaned off. All patients had linear growth monitored, and bone age and bone density were checked annually. Standard laboratory data was reviewed as well.

A total of 15 patients (9 girls) were included in this study. Gastroschisis was the leading cause of SBS occurring in 10 of the patients, and the median small bowel length for this patient group was 46 centimeters with most patients having at least half of their colon length conserved. Significant bowel inflammation with associated eosinophilia was present in the biopsies of 6 patients. The median age of starting glucocorticoid therapy and the median length of time these patients were on parenteral nutrition was 3.3 years. The median time of glucocorticoid therapy was 18 months (range 1-64 months). The ability to wean parenteral nutrition occurred in 11 patients once glucocorticoid therapy was initiated, and 7 patients were able to stop parenteral nutrition. The authors noted that linear growth was not affected, and no metabolic bone disease occurred in the study group.

Although the results are encouraging, it is still unknown if glucocorticoid therapy has the potential to reduce or remove parenteral nutrition needs in pediatric patients with SBS. The exact mechanisms for improvement in such patients are unknown (including the potential of intestinal microbiome changes), and a randomized controlled trial for this type of therapy is needed.

^{Wang F, Gerhardt B, Iwansky S, Hobson B, Logan S, Mercer D, Quiros-Tejeira R. Glucocorticoids improve enteral feeding tolerance in pediatric short bowel syndrome with chronic intestinal inflammation. Journal of Pediatric Gastroenterologists and Nutrition 2021; 73: 17-22.}

FROM THE LITERATURE

Endoscopic Sleeve Gastroplasty in Treatment of NAFLD

A total of 118 patients with obesity and NAFLD (nonalcoholic fatty liver disease), underwent endoscopic sleeve gastroplasty (ESG) and were followed for 2 years. Weight loss was evaluated as percentage total body weight loss. Insulin resistance (IR) was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR).

Previously evaluated hepatic steatosis index and NAFLD fibrosis score were used to estimate hepatic steatosis and risk of fibrosis.

Lean body mass index was 40 kg/m². At baseline, 84% of patients completed 2 years of follow-up. At 2 years, the mean total body weight loss was 15.5%. Patients’ HOMA-IR improved significantly from 6.7 average to 3 average after one week from ESG performance, with continued improvement up to 2 years. Patient’s hepatic steatosis index score improved significantly, decreasing by 4 points per year. Patient’s NAFLD fibrosis score improved significantly, decreasing by 0.3 per year. A total of 24 patients (20%), improved their risk of hepatic fibrosis from F3 to F4, or indeterminate to F0 to F2, whereas only 1% experienced an increase in the estimated risk of fibrosis. It was concluded there was a significant and sustained improvement in estimated hepatic steatosis and fibrosis after ESG in patients with NAFLD and it was demonstrated early and weight-independent improvement in insulin resistance, which lasted for 2 years after the procedure.

^{Hajifathalkian, K., Mehta, A., Ang, B., et al. “Improvement in Insulin Resistance and Estimated Hepatic Steatosis and Fibrosis After Endoscopic Sleeve Gastroplasty.” Gastrointestinal Endoscopy 2021; Vol. 93, pp. 1110-1118}.

Need for Second-Look Endoscopy with an Acute Peptic Ulcer Bleed

A meta-analysis to evaluate the usefulness of routine second-look endoscopy in patients with acute upper GI bleed because of peptic ulcer disease (PUD), with evidence of hemostasis was carried out. Several databases from inception to September 15, 2020 were evaluated to identify randomized controlled trials (RCTs) that compared routine secondlook endoscopy with no planned second-look endoscopy in patients with upper GI bleed from PUD.

The outcomes of interest included recurrent bleeding, mortality, need for surgery, and mean number of units of blood transfused. For categorical variables, pooled risk ratios were calculated (RRs), with 95% confidence intervals (CIs). For continuous variables, standardized mean difference was calculated with 95% CIs. Data was analyzed using a random effects model: the grading of recommendations, assessment, development and evaluation (GRADE) framework to ascertain the quality of the evidence.

Nine RCTs were included, comprising 1452 patients; 726 patients underwent planned routine second-look endoscopy and 726 did not. There was no significant difference in recurrent bleeding, need for surgery, mortality or mean number of units of blood transfused. Quality of evidence ranged from low to moderate, based on the GRADE framework.

It was concluded that single endoscopy with complete endoscopic hemostasis is not inferior to routine second-look endoscopy in reducing the risk of recurrent bleeding, mortality, or need for surgery in patients with acute upper GI bleed from PUD.

^{Kamal, F., Han, N., Lee-Smith, W., et al. “Role of Routine Second-Look Endoscopy in Patients With Acute Peptic Ulcer Bleeding: Meta-Analysis of Randomized Controlled Trials.” Gastrointestinal Endoscopy 2021; Vol. 93, pp. 1228-1237.}

FROM THE LITERATURE

Esophageal Dysmotility in Idiopathic Pulmonary Fibrosis

To understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux – a prerequisite of aspiration), and pulmonary function in patients with IPF, 35 patients were prospectively recruited with IPF, aged 53 to 75 years and 27 of whom were men. These underwent highresolution impedance manometry and 24hour pH-impedance, together with pulmonary function assessment.

A total of 22 patients (63%), exhibited dysmotility and 16 (73%) exhibited ineffective esophageal motility (IEM); 6 (27%) exhibited esophagogastric junction outflow obstruction.

Patients with IEM have more severe pulmonary disease and more proximal reflux than patients with normal motility. In patients with IEM, intrathoracic pressure adversely correlated with the number of proximal events. Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus, whereas in patients with normal motility, it inversely correlated with a bolus exposure time and number of proximal events.

Percentage forced vital capacity in patients with IEM inversely correlated with inspiratory LESP and positively correlated with intrathoracic pressure.

The study demonstrated that pulmonary function is worse in patients with IEM, which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

Cheah, R., Chirnaksorn, S., Abdelrahim, A., et al. “The Perils and Pitfalls of Esophageal Dysmotility in Idiopathic Pulmonary Fibrosis.” American Journal of Gastroenterology, 2021; Vol. 116, pp. 1189-1200.

FROM THE LITERATURE

Adverse Event Profile in Treatment of H. Pylori

To assess the frequency, type, intensity and duration of adverse events (AEs) and their impact on compliance for the most frequently used treatments in the “European Registry on

Helicobacter Pylori Management,” a systematic, prospective, noninterventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators), on the management of H. pylori infection in routine clinical practice was evaluated.

All prescribed eradication treatments and their corresponding safety profiles were reported. AEs were classified, depending on the intensity of symptoms as mild/moderate/ severe and as serious AEs. All data was subject to quality control.

The different treatments prescribed to 22,492 patients caused at least 1 AE in 23% of the cases; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance 7%, diarrhea 7%, nausea 6%, and abdominal pain 3% were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe and only 0.8% were serious with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard, triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies.

It was concluded that HP eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance.

Nyssen, O., Perez-Aisa, A., Tepes, B., et al on behalf of the Hp-EuReg Investigators. “Adverse Event Profile During the Treatment of Helicobacter Pylori: A Real-World Experience of 22,000 Patients from the European Registry on H. Pylori Management (Hp-EuReg).” American Journal of Gastroenterology, 2021; Vol. 116, pp. 1220-1229.

FROM THE LITERATURE

PPI vs. H²RA Comparison as Potential Risk Factors for Gastric Carcinoma

Long-term use of PPIs has been suspected to have a provocative effect on gastric cancer and this study was carried out to determine the association between PPI vs. histamine-2 receptor antagonist H²RA use and the risk of gastric cancer in a region where the risk of this malignancy is high.

A population-based cohort study using the Korean National Health Insurance Service database was carried out with participants with first prescription of PPIs and H_²RA with normal endoscopy findings from 2004 through 2015 collected. Among them, 50% of participants were systematically stratified and randomly sampled. There were 122,118 users of PPIs or H_²RAs who used medication more than cumulative daily defined dose of 180 days. The users were followed up from long-term use threshold until gastric cancer, death from non-gastric cancer cause, gastric surgery, or study end (December 2017). After calculating propensity score weights, 39,799 PPI and 38,967 H_²RA users were included. Among the new PPI and H_²RA users, 411 cases of incident gastric cancer were identified from 182,643 person/years of followup observation and 397 cases from 178,846 person/years of followup observation, respectively. Compared with H_²RA users, PPI users did not experience significantly different gastric cancer incidents (HR 1.01). Sensitivity analyses confirmed that gastric cancer incidence did not differ between PPI and H_²RA users.

Shin, G., Park, J., Hong, J., et al. “Use of Proton Pump Inhibitors vs Histamine 2 Receptor Antagonist for the Risk of Gastric Cancer: Population-Based Cohort Study.” American Journal of Gastroenterology, 2021; Vol. 116, pp. 1211-1219.

FELLOWS’ CORNER

Acute Liver Failure in a Patient with Cholestatic Liver Disease and Nephrotic Syndrome

Sotirios G. Doukas,Yi-Chia Wu,Kheman Hara,Ruba Abdullah,

Arkady Broder

CASE PRESENTATION

52-year-old woman with hypertension presented to the hospital with months of poor appetite, 20-pound weight loss, and two weeks of bilateral leg swelling. She had no fever, shortness of breath, chest pain, abdominal pain, hematochezia, or melena. Prior outpatient workup included an echocardiogram, cardiac stress test, upper endoscopy, and colonoscopy, which were unremarkable. The patient had no history of alcohol, over-the-counter medication, recreational drug, or tobacco use. Family history was only significant for gastric cancer in her father. The vital signs were within normal limits on presentation, and the physical exam was unremarkable except for +3 lower extremity edema.

Labs were significant for markedly elevated alkaline phosphatase (ALP) 4018 U/L (from 160 U/L three months prior and 11 U/L ten months prior), with elevated gamma-glutamyl transferase (GGT) of 717 mg/dl, AST 176 U/L, ALT 69 U/L, and total bilirubin 1.8 mg/dL (direct bilirubin 1.0 mg/dL; total bilirubin was normal two months prior). INR was normal at 1.08. The patient also had a creatinine 2.88 mg/dL (normal at baseline 3 months prior), blood urea nitrogen 51 mg/dL, and hypoalbuminemia 1.7 g/dL. The urinalysis was notable for proteinuria >500 mg/dL. Peripheral blood smear showed Howell-Jolly bodies, suggestive of splenic dysfunction. An abdominal ultrasound showed coarse hepatic echotexture and bilateral echogenic kidneys consistent with renal disease. A computed tomography pan-scan without contrast revealed hepatomegaly, mild mesenteric panniculitis (“misty mesentery”), and mild anasarca. Her labs progressively worsened during her hospital stay, particularly the total bilirubin (peak 26.6 mg/dL), which prompted further evaluation with magnetic resonance cholangiopancreatography, which showed no choledocholithiasis and a normal biliary tree.

An extensive liver disease workup was performed. Labs were significant for positive ANA (1:600 titer) and low ceruloplasmin 4 mg/dL. Otherwise, the chronic liver disease workup was unremarkable, including viral hepatitis serologies, antimitochondrial antibody, anti-smooth muscle antibody, liver-kidney microsome type 1 antibody, soluble liver Ag IgG. Serum ferritin was 227 µg/ mL, but iron saturation was 22%, likely secondary to an acute inflammatory state. Immunoglobulin G level was normal. The liver elastography showed a METAVIR stage F3 appearance (7.6 kPa). Further diagnostic workup was pursued. Despite reaching a diagnosis and starting treatment, the patient continued to have worsening liver function and eventually developed liver failure with INR 1.61 and encephalopathy. Her kidney injury also progressed to end-stage renal disease requiring hemodialysis. Within a month of admission, the patient succumbed to her illness.

QUESTIONS

1. W hat are the differential diagnoses and what is the most likely diagnosis in this patient?

This patient had a cholestatic pattern of liver injury without evidence of apparent extrahepatic

A. Dyed with congo-red, under white light.

obstruction. In this case, we should consider other causes of cholestatic disease. Given the patient’s lack of alcohol or medication use, the suspicion for alcohol and medication-induced cholestasis is low. Therefore, intrahepatic pathology should be considered. There was suspicion for autoimmune causes such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). PSC has also been associated with mesenteric panniculitis, better known as sclerosing mesenteritis, as described in this patient’s imaging. AMA antibody was negative and IgG4 levels were normal, making the diagnosis of PBC and autoimmune cholangitis much less likely; however, small-duct PSC was still a possibility.¹ While ceruloplasmin was significantly low, one would think of Wilson’s disease (WD), however given the highly elevated ALP and nephrotic syndrome in our patient, the hypoceruloplasminemia is much less likely due to WD and more likely due to protein loss from nephrotic syndrome.

It should be noted that at this point, our patient had two end-organ injuries, including acute kidney injury with nephrotic syndrome, prompting consideration of infiltrative diseases with systemic involvement, such as sarcoidosis or amyloidosis. Hepatic sarcoidosis manifests with noncaseating liver granulomas. The lack of characteristic sarcoid pulmonary and skin involvement made this diagnosis less likely in our patient. However, considering the clinical presentation and rapid progression of the patient’s nephrotic syndrome, kidney and liver failure, amyloidosis should be strongly suspected.

Amyloid Light Chain Amyloidosis (AL) and Amyloid A (AA) are the most common types encountered in clinical practice.^2,3AA amyloidosis is commonly associated with chronic inflammatory diseases, resulting in amyloid A protein accumulation in tissues.³ Contrarywise, in AL amyloidosis, the light chain immunoglobulins are deposited in target organs such as the liver, kidney, and heart.³

The heart, kidney, and liver are the three most common organs affected by amyloidosis. Hepatic amyloid commonly presents with nonspecific symptoms of fatigue and weight loss.⁴ In cases of hepatic amyloidosis, more than 80% of the patients present with proteinuria and elevated ALP.^4,5 As seen in our case, peripheral blood smear findings suggesting hypersplenism are also common in patients with hepatic amyloidosis. Imaging can include diffuse or focal decrease in hepatic parenchymal attenuation and triangular-shaped hepatomegaly.⁵ Although hepatic involvement is encountered in about 90% of patients with AL amyloidosis, progression to acute liver failure is highly rare.⁶

2. Which test needs to be done next to confirm the diagnosis (and exclude others)?

In patients with suspected liver amyloidosis, prompt diagnosis is crucial since hepatic amyloidosis carries a poor prognosis. Among patients with primary hepatic amyloidosis, the median survival is 8-9 months without treatment.⁸ Although amyloidosis can be diagnosed with less invasive methods, in cases where the diagnosis is unclear and the differential remains broad, a liver biopsy should be performed. Characteristic histopathologic finding for liver amyloidosis is congo red staining of tissue demonstrating apple-green birefringence under polarized light.⁷

(Figure 1)

Further evaluation with immunofixation, kappa lambda ratio, cardiac assessment with troponins, B-type natriuretic peptide, and cardiac imaging to rule out cardiac amyloid involvement should also be performed in every patient with a new diagnosis of amyloidosis.²

In our case, the patient received both a liver and kidney biopsy, which showed AL amyloidosis. In addition, bloodwork showed a significantly elevated kappa lambda ratio without evidence of cardiac disease.

3. What are the treatment options for the patient’s condition? Amyloidosis is a devastating disease, and no cure exists yet. Current treatment options focus on symptomatic improvement and prolonging survival. The most successful treatment approach to date involves induction therapy followed by high dose melphalan (HDM) and Autologous Stem Cell Transplantation (ASCT) at institutions specializing in amyloidosis.⁷ Unfortunately, only 15% to 20% of patients are eligible to undergo this intensive therapeutic pathway owing to a high risk of treatment-related mortality.⁷ An alternative, highly effective regimen for newly diagnosed amyloidosis includes the combination of bortezomib, cyclophosphamide, and dexamethasone (CyBorD).^2,7 A summary of the available treatment options is outlined in Table 1.

Our patient declined transfer to a tertiary institution with amyloidosis specialization, so she was started immediately on CyBorD. Given her combined liver and renal failure, her prognosis was poor. The patient had worsening hypotension and encephalopathy, and a family discussion with Palliative Care decided to proceed to hospice care. The patient passed away within a month of her hospital admission and within four months since her first laboratory abnormalities and leg edema development.

CONCLUSION

Primary hepatic amyloidosis is a rare disease but an important one for a clinician to recognize. Hepatic amyloidosis should be suspected in cases of hepatomegaly, elevated ALP, and proteinuria, especially after ruling out other common liver diseases. Liver biopsy remains the gold standard for diagnosing amyloidosis. The treatment option for non-ASCT transplant candidates is chemotherapy. Overall, while the prognosis is poor, <12 months, and worse with concomitant renal or cardiac involvement, a prompt diagnosis may help prolong survival.

References

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FELLOWS’ CORNER FELLOWS’ CORNER
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Norero B, Pérez-Ayuso RM, Duarte I, et al. Portal hypertension and acute liver failure as uncommon manifestations of primary amyloidosis. Ann Hepatol. 2014;13(1):142-149. doi:10.1016/S1665-2681(19)30916-0
Fotiou D, Dimopoulos MA, Kastritis E. Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management. HemaSphere. 2020;4(4). doi:10.1097/ HS9.0000000000000454
Wang Y-D, Zhao C-Y, Yin H-Z, Primary hepatic amyloidosis: a mini literature review and five cases report. Annals of Hepatology. 2012; 11(5): 721-727. https://doi.org/10.1016/ S1665-2681(19)31450-4.