Page 53 – Practical Gastro

Dispatches From The Guild Conference, Series #18

Novel Therapies for Primary Sclerosing Cholangitis

November 2018 • Volume XLII, Issue 11

Primary sclerosing cholangitis (PSC) is chronic, cholestatic liver disease that progresses to advanced liver disease and cirrhosis. PSC is strongly associated with inflammatory bowel disease (IBD). In this article we present new studies, clinical trials and novel therapies for the treatment PSC.

Manan A. Jhaveri MD, MPH Kris V. Kowdley MD, FACP, FAASLD Liver Care Network and Organ Care Research, Swedish Medical Center Seattle, WA

INTRODUCTION

Primary sclerosing cholangitis (PSC) is chronic, cholestatic liver disease that progresses to advanced liver disease and cirrhosis. It is characterized by inflammation and fibrosis of both intra and extra hepatic bile ducts leading to the formation of multiple bile duct strictures resulting into chronic cholestasis. This may eventually develop into cirrhosis with subsequent portal hypertension and hepatic decompensation.^1,2 The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 people per year and 0 to 16.2 per 100,000 people, respectively. The estimated median survival from the time of PSC diagnosis until liver transplantation or mortality related to liver disease is 12 to 15 years.¹ Roughly 65% of PSC patients are male. PSC is strongly associated with inflammatory bowel disease (IBD), as the prevalence of IBD in PSC is 60-80%.³ The typical PSC patient is a male in their fourth or fifth decade of life presenting with a diagnosis of ulcerative colitis (UC) or Crohn’s colitis and abnormal liver biochemistries.^4,5 The IBD associated with PSC is unusual in that it is usually pancolitis with right sided predominance, backwash ileitis and rectal sparing.^6,7

PSC is associated with an increased risk of biliary and colorectal cancer; patients with concomitant UC and PSC have a much higher risk compared with patients with UC or PSC alone.^8,9 Surveillance colonoscopy, from the time of diagnosis of PSC, cannot be stressed enough. Patients with small duct PSC disease have an improved survival and lower risk of cholangiocarcinoma as comparted to patients with large duct PSC.^8,10 Patient who demonstrate a significant reduction in serum alkaline phosphatase (ALP) in a median time of two years following diagnosis have an improved transplant-free survival and reduced risk of cholangiocarcinoma.¹¹ PSC is also associated with increased frequencies of multiple gall bladder abnormalities including cholecystitis, cholelithiasis, benign lesions and malignancies.¹² Gallbladder lesions have been found in about 5% of patients with PSC, with half of these being malignant. Gallbladder polyps are significantly associated with high risk of malignancy, so cholecystectomy is recommended even if the lesion is less than 1 cm.^13,14

Pathogenesis

The exact pathogenesis of PSC is unknown. Multiple studies have supported an autoimmune etiology given the presence of concurrent autoimmune disease in up to 25% of PSC patients as well as strong linkage of PSC to human histocompatibility complex genes.⁴ The involvement of gut microbiota has been evaluated in PSC. Several in vitro studies have demonstrated that small bowel bacterial overgrowth may cause cholangitis and liver lesions similar to those seen in PSC. Subsequent antimicrobial therapy leads to an improvement in these lesions. The strong HLA associations suggest that adaptive innate responses are also involved in the pathogenesis of PSC. IgG4 (immunoglobulin-G4) related disease is a systemic disease characterized by extensive IgG4 plasma cells and T-lymphocyte infiltration of various organs including pancreas (autoimmune pancreatitis) and bile ducts (IgG associated cholangitis, IAC). It is important to distinguish between IAC and PSC with elevated IgG4 as cholangiographic changes of IAC may resolve completely after corticosteroids treatment. PSC patients with elevated IgG4 are less responsive to corticosteroids and also multiple studies have demonstrated that these patients may progress rapidly and have more severe liver disease.^15,16

Diagnosis

The diagnosis of PSC is made in patients with cholestatic liver test abnormalities and characteristic stricturing of the intrahepatic and/or extrahepatic bile ducts with segmental dilatation on cholangiography [e.g., magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERC) or percutaneous transhepatic cholangiography (PTC)] after excluding secondary causes of sclerosing cholangitis.^4,17 The preferable test for making a diagnosis of PSC is MRCP, which has acceptable sensitivity and specificity of 86% and 94% respectively. Small duct PSC is a disease variant characterized by cholestasis and histological features of PSC with normal bile ducts cholangiogram; liver biopsy is required for diagnosis in these cases.¹⁷ Secondary sclerosing cholangitis is characterized by multiple biliary strictures due to recognizable causes such as infection, inflammation and long-term biliary obstruction that leads to destruction of bile ducts. PSC overlap syndromes are conditions with features of PSC and other autoimmune liver diseases such as autoimmune hepatitis (AIH) and autoimmune pancreatitis. PSC-AIH overlap syndrome is characterized by clinical, biochemical, and histological features of AIH along with cholangiographic findings similar to PSC. However, current understanding is that rather than reflecting a separate entity, the observed features of autoimmune hepatitis in PSC, including elevated transaminases and IgG, may also be due to biliary disease. Autoimmune pancreatitis (AIP) is characterized by stricturing of pancreatic duct, raised IgG4 level, a lymphocytic infiltrate and response to corticosteroid therapy. AIP in association with stricturing of bile ducts similar to PSC is termed as autoimmune pancreatitis – sclerosing cholangitis (AIP-SC). It is important to note that alkaline phosphatase levels fluctuate in PSC patients and may be normal or only mildly elevated in a significant proportion of PSC patients.^4,8,9

Management

Managing patients with PSC is complicated, as it requires management of primary disease and also coexisting conditions and complications from end stage liver disease. Currently there is no medical therapy that will halt the progression of liver disease in PSC patients, despite numerous clinical trials over the past two decades. This is due to uncertainty regarding the pathophysiology of PSC and also lack of reliable diagnostic markers.

Ursodeoxycholic Acid

Multiple clinical trials have studied the efficacy and safety of ursodeoxycholic acid (UDCA) in PSC patients. UDCA is the most commonly prescribed drug for PSC, as it is effective in other cholestatic liver diseases, specifically primary biliary cholangitis (PBC). However, the role of UDCA in clinical improvement is questionable. UDCA reduces hydrophobicity of bile acid and also affects adaptive immunity by inhibiting dendritic cell response.^18,19 The initial placebo controlled clinical trials of low dose UDCA conducted in early 1990s demonstrated improvement in clinical symptoms, liver biochemistries and histological features. However, its clinical significance was limited due to small sample size.^20,21 A large, placebo-controlled clinical trial of low dose UDCA (13-15 mg/kg/day) in PSC demonstrated improvement in serum liver biochemistries but no effect on patient’s clinical symptoms or time to liver transplantation. ²² A large, multicenter, randomized, placebo-controlled trial treated 219 PSC patients with moderate doses of UDCA (17-23 mg/kg/day) and followed them for five years. Improvement in liver biochemistries with UDCA treatment was seen, but there was no statistically significant effect on survival, time to liver transplantation or prevention of cholangiocarcinoma.²³ Pilot clinical trials with a higher dose of UDCA (28-30 mg/kg/day) demonstrated clinical improvement in liver biochemistries as well as Mayo risk score.^24,25 However, the largest clinical trial of high dose UDCA26 was terminated at five years due to an increased risk of progression to liver transplantation, cirrhosis, gastric or esophageal varices and cholangiocarcinoma compared to placebo.²⁶ It has been demonstrated that an increased serum lithocholic acid concentration, a potent hydrophobic bile acid in patients receiving high dose of UDCA, may be responsible for these adverse outcomes.²⁷ A meta-analysis of nine randomized control trials (RCTs)²⁸ concluded that UDCA at any dose showed no significant improvement in symptoms, histological progression, mortality or cholangiocarcinoma. Similarly, a systematic review of eight RCTs ²⁹ showed improvement in liver biochemistries but no significant reduction in the relative risk of death, varices, ascites or encephalopathy. Due to variable doses of UDCA, different treatment time course, follow up and end points, the treatment guidelines for UDCA in PSC are conflicting. The two major United States (US) societies including the AASLD (American Society for the Study of Liver Diseases)17 and the ACG (American College of Gastroenterology)³⁰ do not support the use of ursodeoxycholic acid; however the EASL (European Association for the Study of the Liver)³¹ recommends the use of low dose UDCA (13-15 mg / kg / day).

Novel Treatment in PSC
Farnesoid X Receptor Ligands

The Farnesoid X receptor (FXR) plays an important role in bile acid homeostasis. The natural ligands for FXR are bile salts. The key role of FXR is to down regulate the cytochrome P4507A1, the rate limiting enzymes in bile acid synthesis.³² Obeticholic acid (OCA), a semisynthetic analogue of chenodeoxycholic acid and an FXR agonist with anti-fibrotic properties has been approved by the US Food and Drug Administration for the treatment of primary biliary cholangitis (PBC).³³ A clinical trial of obeticholic acid in patients with primary sclerosing cholangitis is underway (clinicaltrials.gov identifier, NCT02177136). The results from a phase 2 randomized, double blind, placebo controlled trial (AESOP) evaluating the safety and efficacy of OCA compared to placebo in 77 patients with PSC were presented at the annual meeting of the AASLD in 2017. Patients were randomized to placebo, OCA 1.5 – 3 mg, and OCA 5 – 10 mg (with dose titration occurring at the 12 week midpoint). By 24 weeks, ALP increased by 1% in placebo group and decreased by 22% in both OCA 1.5 – 3 and OCA 5 – 10 mg groups. In AESOP, about 46 – 48% of patients in each group were receiving UDCA at baseline. Results from a post-hoc analysis showed that improvement in serum ALP were observed with OCA regardless of treatment with UDCA. Pruritus is the common symptom of PSC and was the most common adverse event observed, occurring in 46%, 60% and 67% of patients in the placebo, OCA 1.5 – 3 mg and OCA 5 – 10 mg groups, respectively.³⁴

Role of Antibiotics in PSC

Multiple in-vitro studies demonstrated a link between the intestinal microbiota and biliary inflammation in PSC. The use of vancomycin in PSC showed improvement in liver biochemistries, however the long-term outcome is still unclear. The safety and efficacy of oral vancomycin and metronidazole were evaluated as well. Patients in the vancomycin arm achieved the primary end point (a decrease in alkaline phosphatase at 12 weeks) with less adverse effects.³⁵

Simtuzumab

Lysyl oxidase homolog 2 (LOKL2) catalyzes the first step in the formation of cross links in collagen and elastin and is associated with progression of liver disease. Pre-clinical models (e.g., MDR2 knock out mice), inhibition of LOKL2 improves fibrosis. In addition, serum and tissue LOXL2 levels are elevated in PSC and correlated with fibrosis stage. A clinical trial evaluating the safety and efficacy of simtuzumab (SIM, a humanized IgG4 monoclonal antibody against LOXL2) in PSC was conducted. In a phase 2b clinical trial (results were presented at the EASL International Liver Congress 2017, Amsterdam), 234 patients with PSC were randomized to receive weekly subcutaneous injections of SIM 75 mg, SIM 125 mg or placebo for 96 weeks. The authors concluded that neither dose of SIM lead to significant reduction in mean hepatic collagen content, change in Ishak fibrosis stage, serum alkaline phosphatase concentration or progression of cirrhosis.³⁶

Norursodeoxycholic Acid

24-Norursodeoxycholic acid is a synthetic bile acid and C23 homolog of ursodexoycholic acid. It reduces inflammation and improves fibrosis as well as liver function tests in rodent model of sclerosing cholangitis. Results from a phase 2 clinical trial evaluating the safety and efficacy of norursodeoxycholic in patients with PSC were presented at the EASL ILC in 2016;³⁷ 59 PSC patients were randomized to 500, 1000, and 1500 mg of norursodeoxycholic for 12 weeks. The authors concluded that PSC patients treated with norursodeoxycholic demonstrated significant reduction in serum ALP levels within 12 weeks of treatment in all groups (12.3%, 17.3% and 26%, respectively). A long term clinical trial will determine the effect of norursodeoxycholic acid on clinical outcomes of PSC such progression of disease to cirrhosis, time to liver transplantation and liver related mortality.³⁷

ASBT Inhibitor

Interruption of intestinal bile acid circulation might have therapeutic benefit in PSC. The active absorption of bile acids in the terminal ileum is mediated by Apical Sodium Dependent Bile Acid Transporter (ASBT). ASBT inhibition reduced cholestatic liver injury and fibrosis by increasing fecal excretion of bile acids, lowering hydrophobic biliary bile acid concentrations. Lopixabat, an ASBT inhibitor is currently being evaluated in patients with PSC.³⁸

Cenicriviroc

Cenicriviroc, a dual chemokine receptor (CCR) 5 and CCR2 antagonist is currently being studied for PSC. CCR5 and CCR2 are involved in the inflammatory and fibrogenic pathways that cause fibrosis and often lead to cirrhosis and liver cancer.³⁹

NGM282

NGM282 is a variant of the human hormone FGF19 that reduces liver fat content, reverses fibrosis and improves liver function. Results from a phase 2 clinical trial evaluating the safety and efficacy of NGM282 in patients with PSC were recently presented at the EASL ILC 2018; 62 PSC patients with elevated ALP were randomized to receive daily subcutaneous injection of NGM282 1mg or 3 mg or placebo. The primary end point was the change in ALP from baseline to week 12. The study did not meet the primary end point. However, significant reductions in serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) were observed in 3 mg cohort at week 12. Also markers of fibrosis and bile acid synthesis were significantly reduced in both NGM282 cohorts at week 12 as compared to placebo group.⁴⁰

CONCLUSION

PSC, a disease with complex pathophysiology, results in morbidity and mortality due to liver disease. No therapy thus far has been effective to slow the progression of disease and complications from cirrhosis in PSC. UDCA has been evaluated in depth in PSC, but even though it improves liver biochemistries, there is no significant improvement in clinical outcomes of PSC such as cirrhosis, time to liver transplantation and mortality from liver disease. Multiple novel therapeutic agents beyond UDCA are now targeting bile acid homeostasis and are currently being evaluated in patients with PSC.

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Frontiers In Endoscopy, Series #47

Current Management of Ascending Cholangitis

November 2018 • Volume XLII, Issue 11

Dan McEntire,

Douglas G. Adler

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If not recognized and treated appropriately, ascending cholangitis can pose significant morbidity to affected patients. Accurate diagnosis and assessment of disease severity is essential to guide selection of antimicrobials, timing of biliary decompression, and selection of a decompression technique. This article reviews the current literature related to ascending cholangitis management, in conjunction with current international guidelines.

Dan McEntire MD, Douglas G. Adler MD, University of Utah School of Medicine, Gastroenterology and Hepatology, Salt Lake City, UT

INTRODUCTION

Ascending cholangitis (AC) is an infection of the biliary tract. The normal biliary tree is near-sterile secondary to constant drainage, bacteriostatic bile salts, and mucosal immune mechanisms. Biliary obstruction disrupts these processes and causes elevated intraductal pressure with increased bile duct permeability, which permits endotoxin and bacterial translocation into lymphatic and portosystemic circulation.¹ Biliary obstruction is most frequently caused by biliary stones, though there are many causes including mass effect of malignancy, benign and malignant strictures, parasites (e.g., Ascaris), and iatrogenic causes (e.g., biliary stenting, surgery).¹ (Figures 1 and 2)

The organisms implicated in AC originate from enteric flora, and cultures are usually polymicrobial.² The most frequently isolated Gram-negative organisms are E. coli and K. pneumoniae, with Enterococcus species being the most common Gram-positive organism.^3,4 Anaerobes, primarily Bacteroides and Clostridium, are relatively infrequently isolated.^3,4

Accurate diagnosis and assessment of severity are fundamental to guide appropriate therapy. In additional to clinical support and resuscitation, antibiotic administration and biliary decompression represent the central components of AC management. This article presents current data pertinent to these areas.

Diagnosis of Ascending Cholangitis

The classic clinical characteristics of AC are fever, right-upper-quadrant (RUQ) abdominal pain, and jaundice (Charcot’s triad). More severe cases may present with hypotension and altered mental status (Reynold’s pentad). However, because few cases present with all of these features, standardized criteria were recently developed.^5,6

The current Tokyo Guidelines 2018 (TG18) diagnostic criteria for AC are based on evidence of systemic inflammation, cholestasis, and biliary obstruction. The presence of systemic inflammation is defined as fever >38°C, shaking chills, leukocyte count <4,000/µL or >10,000/µL, or C-reactive protein (CRP) ≥1 mg/dL. Cholestasis is defined as clinical jaundice, total bilirubin ≥ 2 mg/dL, or alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, or gamma-glutamyltransferase >1.5 times the upper limit of normal. The presence of biliary dilatation, or evidence of the etiology (e.g., stone, stricture), indicates obstruction. A definitive diagnosis is made when at least one criterion is met in each of the three categories. A suspected diagnosis is made when one criterion is met in the systemic inflammation category, plus one item in either the cholestasis or imaging categories. One study found that the diagnostic criteria successfully identified 90% (73.1% definitive, 16.9% suspected) of cases.⁷ The remaining undiagnosed 10% were mild cases that lacked systemic inflammation. This suggests reasonable performance of criteria, especially for moderate to severe disease.

Imaging is necessary to make a definitive diagnosis of cholangitis (though clinical suspicion may be high in known cases of preexisting pancreaticobiliary disease). Abdominal ultrasound (US) is the suggested first step due to its wide availability, noninvasive nature, and low cost. US is well suited to visualize the proximal common bile duct (CBD) and common hepatic duct, but visualization of the distal CBD is typically limited. Computed tomography (CT) and magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) can be performed. MRI/MRCP is favored given the high-resolution imaging of the common bile duct that is possible. Invasive endoscopic or percutaneous imaging options, discussed below, can be both diagnostic and therapeutic.

Severity Grading of Ascending Cholangitis

TG18 includes a severity grading system that has prognostic value and may help to guide appropriate intervention timing.⁵ Grade III (severe) cholangitis is manifested by evidence of organ dysfunction. Organ dysfunction is defined as the presence of cardiovascular dysfunction requiring intravenous dopamine >5µg/kg/min or any dose of norepinephrine, neurologic dysfunction (i.e., disturbance of consciousness), respiratory dysfunction (PaO2/FiO2 <300), renal dysfunction (oliguria or serum creatinine >2mg/dL), hepatic dysfunction (INR >1.5), or hematologic dysfunction (platelet count <100,000/µL). Grade II (moderate) cholangitis is defined by the presence of high fever (>39°C), leukocyte count <4,000/µL or >12,000/µL, advanced age (>75 years), or hypoalbuminemia (<70% lower limit of normal). Grade I (mild) cholangitis lacks the aforementioned criteria. A large study that stratified patients by severity grade found 5.1%, 2.6%, and 1.2% 30-day mortality in patients with Grade III, II, and I disease, respectively.⁷

Antibiotics

Initiation of antibiotics should occur within one hour in cases of sepsis, or within six hours for all other cases.^4,8 Prescribing adequate empiric coverage is becoming increasingly difficult due to antibiotic resistance patterns.^2,9 Appropriate selection of empiric coverage is also made with consideration given to comorbidity, allergy, or other factors.

General recommendations for empiric coverage include intravenous treatment with a third-generation cephalosporin or a penicillin derivative/beta-lactamase inhibitor combination.⁴ TG18 and the Surgical Infection Society/Infectious Disease Society of America (SIS/IDSA) guidelines recommend to consult local antibiograms and administer alternative medications if community pathogen resistance exceeds 10-20%.4,10 Ampicillin-sulbactam and fluoroquinolones are not recommended for empiric use due to widespread E. coli resistance, but are frequently used in clinical practice.^2,4,9,10 Antipseudomonal agents can be reserved for severe cases and healthcare-associated infection.^3,4 Coverage of Enterococcus species with vancomycin is recommended in severe or healthcare-associated disease, or in immunocompromised patients.4,10 Anaerobic coverage with metronidazole is recommended in patients with a surgical history of biliary enteric anastomosis or for general prophylaxis.^4,10 This is due to a relative scarcity of anaerobe isolation in AC, and reports that anaerobic coverage for other indications does not improve outcomes.^2,3,11,12,13

Antibiotic treatment can be adjusted based on patient response and pathogen susceptibility data. TG18 and SIS/IDSA guidelines recommend a total of 4-7 days of therapy after source control is obtained, obstruction removed, and assuming absence of local complications (e.g., liver abscess).^4,10 In the presence of Gram-positive bacteremia, 2 weeks of therapy is recommended.⁴

Timing of Biliary Decompression

Several studies, mostly related to ERCP, have assessed clinical outcomes in AC patients with regards to time-to-intervention but a clear consensus has not been well defined. Based on findings of improved mortality in patients with Grade II (moderate) disease that received biliary drainage within 48 hours, TG18 generally recommends decompression within 48 hours in patients.^5,7 In practice, however, sometimes patients are too unstable to undergo a drainage procedure and require more time before biliary decompression. The recommendation for 48 hours as a general cutoff is supported by investigators who found worse outcomes (persistent organ failure, longer hospitalization, relapse, or mortality) in patients with further delayed decompression.^{14, 15, 16, 17, 18} In contrast, other accounts favor decompression within 24 hours, mostly on the basis of shorter hospitalization.^{16,17,19,20,21} A recent study describes outpatient management of AC after endoscopic drainage, suggesting that early intervention in mild to moderate disease can prevent hospitalization altogether.²² Patients with septic shock or critical illness appear to warrant early decompression after appropriate resuscitation, with significantly improved mortality reported when decompressed before 12 or 24 hours, respectively.^23,24

Biliary Drainage Techniques

Biliary drainage is recommended for all cases of AC, irrespective of severity.²⁵ Techniques for biliary decompression are broadly categorized into endoscopic, percutaneous, and surgical.

Endoscopic Biliary Drainage

ERCP biliary decompression by direct cannulation of the major duodenal papilla is the gold standard for acute cholangitis.^25,26 This is due to high success rates, minimally invasive nature, and fewer adverse events compared to percutaneous or surgical procedures.^26,27,28,29 Disadvantages, however, include need for sedation.³⁰ Endoscopic duct clearance by sphincterotomy, balloon extraction, and/or endoscopic stenting for strictures is performed as needed. Patients in whom stone extraction cannot be performed can simply undergo stent placement. An additional adjunctive technique is direct cholangioscopy with lithotripsy. Nasobiliary drains are rarely used in modern practice.^26,27,31 Balloon-assisted enteroscopy ERCP (BE-ERCP) is recommended in cases of altered postoperative anatomy.²⁵ Endoscopic ultrasound biliary drainage (EUS-BD) is a relatively new and developing technique, though current data are largely related to obstructive jaundice generally, and not specific to cholangitis. Several studies indicate that EUS-BD, in the hands of experienced endoscopists, is an effective alternative after failed ERCP and may outperform percutaneous drainage.^{32,33,34,35,36,37,38} EUS-BD may also represent a feasible approach in patients with surgically altered anatomy.³⁹ Research into the optimal tools and techniques to perform EUS-BD is ongoing.

Percutaneous Biliary Drainage

Percutaneous techniques include percutaneous transhepatic biliary drainage (PTBD) and percutaneous cholecystostomy (PC). PTBD is currently the recommended alternative to traditional ERCP drainage and may be required when endoscopy is unavailable or contraindicated (e.g., unusual anatomy) or after failed ERCP.25 PTBD usually involves local anesthesia, puncture of an intrahepatic duct with a fine needle under US or fluoroscopy, and placement of a drain. Successful needle placement requires ample intrahepatic ductal dilatation.⁴⁰ PTBD is second-line to ERCP due to invasiveness, common requirement for additional procedures, and higher rate of adverse events.25,29,37 PTBD is primarily used to provide biliary drainage, whereas stone removal is much less commonly performed via this route. Patients with stones and AC often require ERCP at a later time to remove the stones from the biliary tree, usually via sphincterotomy and balloon/basket extraction. PC, though rarely used for this indication, can be a useful alternative to PTBD, especially if intrahepatic duct dilation is insufficient to allow a successful transhepatic approach.^41,42

Surgical Biliary Drainage

Surgical drainage of the biliary ducts is generally thought of as the last option after unsuccessful endoscopic or percutaneous intervention.²⁵ This is primarily due to high success rates of less invasive techniques and observations of higher mortality compared to other less invasive methods.^1,25,28

CONCLUSION

Ascending cholangitis is a treatable illness with practice guidelines in place to assist in guiding diagnosis, severity grading, antibiotic selection, and therapeutic intervention. Use of the diagnostic and severity grading criteria reliably identifies patients and provides prognostic information. Antimicrobial selection is based on community isolate resistance patterns. ERCP remains the most common procedure selected for biliary drainage. PTBD is an acceptable alternative, with EUS-BD gaining acceptance as experience broadens.

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A Case Report

Single Cause, Dual Presentation: Inferior Pancreatico-Duodenal Artery Pseudoaneurysm as a Cause of Acute Gastrointestinal Bleeding and Obstructive Jaundice

October 2018 • Volume XLII, Issue 10

Mir Adil Shamim,Rupinder Mann,Steven Lichtenstein

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Pseudoaneurysms of the inferior pancreaticoduodenal artery are rare. We report a case of chronic pancreatitis-related inferior pancreaticoduodenal artery pseudoaneurysm that resulted in obstructive jaundice and life-threatening bleeding. This case highlights both of these complications, and it also reflects on the importance of a multidisciplinary and multimodal approach to diagnosis and management. Anticipating potential complications and intervening at the right time can prevent fatal consequences in such patients.

INTRODUCTION

Inferior pancreaticoduodenal artery pseudoaneurysms are rare. The most common causes include abdominal trauma, acute or chronic pancreatitis, septic emboli and laparoscopic cholecystectomy. This is in contrast to true aneurysms which are caused by arteriosclerosis, congenital disease or stenosis of celiac trunk.¹ Pseudoaneurysm rupture is more likely to cause gastrointestinal (GI) bleeding whereas true aneurysm rupture mostly causes a retroperitoneal bleed.¹ We present a case of a life-threatening GI bleed from a pseudoaneurysm of the inferior pancreaticoduodenal artery, also causing obstructive jaundice by virtue of its size and location. Case

A 45-year-old male with past medical history of chronic pancreatitis from alcohol use presented with severe right upper quadrant abdominal pain. On exam, he had exquisite right upper quadrant abdominal tenderness and scleral icterus. Vitals signs were stable on initial presentation (Blood pressure: 144/68mmHg, Pulse: 74/min, Resp: 18/min, O2 sat: 100% on room air). Labs revealed microcytic hypochromic anemia (Hb: 6.1, Hct: 20.3, RDW: 25.2), and abnormal liver enzymes with a cholestatic pattern (alkaline phosphatase 416 [reference range {RR} 45-115 U/L], gamma glutamyl transferase (GGT) 230 (RR 10-66)U/L, aspartate aminotransferase (AST) 76 (RR 8-40)U/L , alanine aminotransferase (ALT) 132 (RR 7-60)U/L, total serum bilirubin 4.4 (RR 0.2-1.2)mg/dL, direct bilirubin 3.4 (RR 0-0.3) mg/dL.

Computed tomography (CT) scan of the abdomen with intravenous contrast (Image 1a and 1b) showed a pseudoaneurysm measuring 65 x 41 mm arising from the inferior pancreaticoduodenal artery. In addition to evidence of acute on chronic pancreatitis, there was obstruction of the biliary tree due to mass effect from pseudoaneurysm, new marked intra and extrahepatic biliary dilation (common bile duct measuring up to 17 mm) and gallbladder distension. Mesenteric angiography (Image 2) also revealed the aneurysm but was felt not to be amenable to embolization. Overnight, the patient became hypotensive and his abdominal pain worsened. Stat CT angiography of the abdomen showed an increase in size of the pseudoaneurysm to approximately 67 x 43 mm. Hyperdense material was noted within a moderately distended stomach and dilated small bowel loops, new from the most recent previous CT, concerning for GI hemorrhage. After initial stabilization, the patient underwent exploratory laparotomy with distal gastrectomy along with duodenotomy with suturing of the pseudoaneurysm with anterior abdominal closure.

Following the procedure, his liver enzymes trended to normal. The course was complicated by delirium, multi-organ failure, pneumonia, prolonged ventilator dependent respiratory failure, severe protein-calorie malnutrition requiring total parenteral nutrition and tube feedings via jejunostomy tube. The patient was eventually discharged to a long-term acute care facility.

DISCUSSION

A bleeding pseudoaneurysm is a rare and potentially life threatening complication of chronic pancreatitis.² As a complication of chronic pancreatitis, pseudoaneurysms most commonly occur in the splenic artery, followed by the gastroduodenal, pancreaticoduodenal and hepatic arteries.⁹ Given the history of chronic pancreatitis with multiple severe acute exacerbations, it is the most likely cause of the pseudoaneurysm (of inferior pancreaticoduodenal artery) in our patient. Once formed, they can cause direct pressure over the pancreaticobiliary ducts, leading to recurrent bouts of acute pancreatitis and jaundice.

Some proposed mechanisms for pseudoaneurysmformation due to pancreatitis include: severe inflammation contributing to local spread of proteolytic enzymes causing auto digestion of pancreatic or peripancreatic arterial tissue, weakening of the vessel wall, producing arterial disruption and erosion of a long standing pseudocyst directly into a visceral artery potentiated by virtue of the enzymatic content of fluid especially if there is communication with the pancreatic ductal system.^2,3,4 Risk factors include necrotizing pancreatitis, sepsis, multi-organ failure, previous history of procedures such as necrosectomy, Whipple procedure or underlying vasculitis.⁸ Pseudoaneurysm formation after a surgical procedure is a late complication, mostly occurring days to weeks after the procedure.⁸

Abdominal computed tomography (CT) is the most commonly used noninvasive test for diagnosing pseudoaneurysms with a sensitivity of 80-100%. It can detect partial thrombosis or the effect on adjacent viscera, however, carries risks of exposure to ionizing radiation and intravenous iodinated contrast. Abdominal ultrasound (US) has limited ability to detect aneurysms.10 Mesenteric angiography is the gold standard diagnostic test that precisely identifies the feeding artery.^1,5,8 It has a sensitivity of 100% in detecting arterial bleeding due to pseudoaneurysms.^8,6 Smaller lesions which could be missed on other imaging modalities can also be identified.⁸ A fatal complication of pseudoaneurysms is acute hemorrhage. The mortality is 90-100% in untreated patients and remains 12-50% even with aggressive treatment.⁵ Pseudoaneurysms may bleed into the gastrointestinal tract, retroperitoneum, biliary tree (hemobilia), pancreatic ducts (hemosuccus pancreaticus), peritoneal cavity and pseudocysts, resulting in massive hemorrhage.⁸ Clinically, ruptured pseudoaneurysms present as abdominal pain, anemia or gastrointestinal (GI) bleeding. Bleeding can be chronic or acute leading to hemorrhagic shock.^5,6,7 Local inflammation or mechanical compression by virtue of the size of the aneurysm may lead to biliary and/or pancreatic duct compression resulting in obstructive jaundice and/or acute pancreatitis. Similarly, compression of the adjacent portal system may lead to variceal formation and eventual hemorrhage.⁸ Our patient had developed common bile duct obstruction and features of obstructive jaundice from the recent increase in the size of the aneurysm.

Two major treatment modalities (radiologic and surgical) are available, based on the location of pseudoaneurysm and hemodynamic stability. These include angiographic embolization and surgical treatment. Angiographic therapy has been reported to have a high success rate, ranging from 79-100% and has been associated with shorter lengths of stay as compared to surgery.⁸ Real time ultrasound guided thrombin injections have been reported to be of value, however, the efficacy is not well established. Surgical ligation of the feeding vessel can be attempted, however, if this fails, pancreatectomy may be required. A Whipple procedure may be needed for pseudoaneurysms near the pancreatic head.⁸ In general, this potentially lethal complication of chronic pancreatitis should be treated as an urgent situation, and a multidisciplinary approach covering diagnostic and therapeutic interventions including angiography, surgery and endoscopy may be needed to manage it optimally.

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Liver Disorders, Series #8

Approach to Liver Disease in Pregnancy

October 2018 • Volume XLII, Issue 10

Hamza Arif,

Helen Lee,

Cristina Strahotin

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Liver disease in pregnancy is a rare phenomenon, but its presence represents a challenging scenario as it can have harmful effects on both the mother and the fetus. Certain liver diseases are unique to pregnancy only, including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and acute fatty liver of pregnancy. In this article we discuss the management of these disorders as imperative to avoid development of maternal and fetal complications.

Hamza Arif, MD¹ Helen Lee, MD² Cristina Strahotin, MD³ ¹Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA ²Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA ³Division of Gastroenterology, Hepatology and Nutrition, Allegheny Health Network, Pittsburgh, PA

INTRODUCTION

Liver disease in pregnancy is a rare phenomenon, occurring in 2-3% of pregnancies.¹ The presence of liver disease, however, can represent a challenging scenario as it can have harmful effects on both the mother and the fetus.² Certain liver diseases are unique to pregnancy only; these include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Concurrently, pregnant patients remain susceptible to acquiring liver disorders that may be encountered in general population including viral hepatitis or gallstones, whereas some diseases may predate pregnancy such as autoimmune hepatitis or Wilson disease.

Normal Physiology

Heart rate and cardiac output increase in pregnancy but systemic vascular resistance is reduced. Overall, these physiological changes lead to lowering of systemic blood pressure and a hemodynamic state mimicking decompensated liver disease.³ Elevation of alkaline phosphatase due to additional production from placenta may be observed as a normal change in liver enzymes in pregnancy. Conversely, increase levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and bilirubin may suggest a pathological process.⁴

Liver Diseases Unique to Pregnancy

Liver diseases unique to pregnancy can be divided by their predominance in a particular trimester. It must be noted that although some of these liver disorders may be specific to a one trimester, most overlap between trimesters and may even be present post-partum.

First Trimester
Hyperemesis Gravidarum (HG)

Hyperemesis gravidarum (HG) usually presents in the first half of pregnancy and typically resolves within 4-6 weeks of the second trimester. It has an incidence of 0.3-2% and with predisposition in pregnant females with increased body-mass index, molar pregnancy, multiple pregnancies and patients with co-morbid conditions such as diabetes.⁵ Clinical features include intractable vomiting that can result in dehydration and ketosis.

Mild elevation of serum bilirubin and aminotransferases is common while other biochemical abnormalities, likely related to the underlying symptoms, may also be observed including hypokalemia, hypomagnesemia and elevation of serum creatinine. Vomiting may be severe enough to cause weight loss along with ketonuria that is a diagnostic finding. Viral hepatitis should be ruled out during the workup as it may also present with similar clinical features.

HG is associated with premature delivery, low birth weight and small for gestational age babies but is not linked with perinatal death.⁶ Management is supportive with anti-emetics and intravenous (IV) fluids. Thiamine supplementation is necessary to prevent Wernicke’s encephalopathy.⁷ Recurrence of HG is common, with a risk of 15% in the second pregnancy compared to 0.7% without a prior history of hyperemesis.⁸

Second and Third Trimester
Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease unique to pregnancy. It is more common in multiple gestation pregnancies, with prevalence of 0.4 – 5%.^9,10 ICP typically presents in the second half of pregnancy but can even occur in the first trimester. Patients present with pruritus, usually involving the palms and the soles of the feet, which may be worse at night. Jaundice can also occur but is not as common as pruritus. ICP is characterized by elevation of serum aminotransferases, up to 10 to 25 times upper limit of normal (rising to >1,000 U/L), and bile acids. Fat-soluble vitamin deficiencies may also be observed, which can lead to reduction of vitamin K-dependent coagulation factors and subsequent elevation of prothrombin time. Bile acid levels of >10 µmol/l is diagnostic of ICP but levels of >40 µmol/l are associated with adverse outcomes in pregnancy and fetal complications such as spontaneous preterm deliveries, asphyxia events and meconium staining of amniotic fluid, placenta and membranes.¹¹

Management focuses on both controlling the symptoms and preventing complications along with close monitoring of the fetus. First-line treatment is ursodeoxycholic acid (UDCA), given at 10-15mg/kg maternal body weight. UDCA not only improves pruritis, but also improves bile acid levels and serum aminotransferases. Most importantly, this decrease in bile acid levels can lead to reduction in adverse fetal outcomes such as prematurity and fetal distress.¹² S-adenosyl methionine (SAMe), a glutathione precursor that results in excretion of biliary salts by methylation of hormone metabolites, has also been used as a treatment modality.¹³ However, a meta-analysis revealed that SAMe alone was not as effective as UDCA in improvement of pruritus, serum ALT levels or total bile acids.¹⁴ Dexamethasone may improve lung maturity in the fetus but does not have a significant role in treatment of ICP. Delivery at 37 weeks is recommended to avoid the risk of intra-uterine death.¹⁵ Adequate nutritional status maintenance is important, particularly in patients with severe steatorrhea.

Pruritus usually resolves within a few days of delivery followed by normalization of elevated liver enzymes and bile acids. These tests may be repeated 6-8 weeks after delivery. Elevated bilirubin levels at the time of diagnosis or failure of resolution of cholestasis should prompt further investigation into alternative causes. Rarely, such as in familial cases, ICP will lead to chronic liver disease after delivery with cirrhosis and fibrosis.¹⁴ Therefore, patient follow-up after delivery should be continued in the outpatient setting. Recurrence of ICP is common, in up to 60-70% of subsequent pregnancies.

Preeclampsia

Hypertension in pregnancy, defined as blood pressure of ≥140/90 mmHg, has been associated with adverse outcomes in both the pregnant mother and the fetus. Preeclampsia is now described by International Society for the Study of Hypertension in Pregnancy (ISSHP) as de-novo hypertension present after 20 weeks gestation combined with proteinuria (≥300 mg/24h), other maternal organ dysfunction, including liver involvement, renal insufficiency, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction.¹⁶ Complications of the liver include hepatocellular injury, hepatomegaly and hepatic rupture.

Risk factors for this disorder include extremes of age (less than 16 years old or greater than 45 years old), nulliparity, prior history of hypertension, previous preeclampsia episode or positive family history of preeclampsia.³ Although clinical presentation is variable, patients are mostly asymptomatic, but they may present with right-sided abdominal pain, nausea and vomiting along with headaches and visual disturbances. Liver enzymes may be deranged with elevation of serum aminotransferases predominantly.

Although hypertension control is important, delivery is the definitive treatment. This should be urgent if diagnosis is made at >34 weeks to prevent further complications such as eclampsia or hepatic rupture.¹⁷ For a fetus of less than 34 weeks, corticosteroids may be indicated to improve the maturity of fetal lung followed by delivery.

The United States Preventive Services Task Force (USPSTF) recommends using low-dose aspirin (81 mg/d) after 12 weeks of gestation in women who are at high risk for preeclampsia as a preventive medication (grade B recommendation).¹⁸ They define high risk factors as hypertensive disease during prior pregnancy, chronic kidney disease, autoimmune disease, type 1 or type 2 diabetes, chronic hypertension or multiple pregnancies. Of note, however, the American College of Gastroenterology (ACG) and American Association for the Study of Liver Diseases (AASLD) currently do not endorse this recommendation.

Abnormal liver enzymes tend to resolve within a couple of weeks after delivery. Patients should be followed-up regularly with yearly observation of their blood pressure as well as blood glucose and lipid profile.

Hemolysis, Elevated Liver Enzymes and Low Platelets (HELLP) Syndrome

Hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome characterizes severe features of preeclampsia. It manifests in 0.1 – 0.9% of pregnancies but may lead to complications in up to 20% of patients with preeclampsia.¹⁹ HELLP syndrome typically occurs after 20 weeks of gestation and but nearly one third of cases can occur post-partum.²⁰ Risk factors for HELLP syndrome are comparable to preeclampsia including nulliparity, prior history of hypertension or previous episode of HELLP syndrome. Clinical features of HELLP syndrome may also be similar to preeclampsia. Patients may have epigastric or right upper quadrant abdominal pain, nausea and vomiting as well as occasional headaches and visual disturbances. Hypertension may be present but HELLP syndrome can also occur in normotensive patients.

Complications of HELLP syndrome include development of renal failure, pulmonary edema, disseminated intravascular coagulation (DIC), and maternal death.^20,21 Subcapsular liver hematomas may be present in 0.9% of patients with HELLP syndrome.²⁰ Hepatic rupture can occur in 1-in-45,000 to 1-in-225,000 deliveries with associated maternal mortality rates of 60-86%.²² Perinatal mortality due to maternal complications and prematurity has also been reported in up to 70% of cases.¹⁹ The diagnosis of HELLP syndrome is established when a patient has hemolytic anemia, with lactate dehydrogenase (LDH) of > 600 U/L, elevation of liver enzymes including serum aminotransferase and reduced platelet counts of <100 k/mcL.^23,24 Increase in serum bilirubin levels may also be present. DIC should be considered in the presence of elevated prothrombin time and low fibrinogen levels. Hepatic imaging using computed tomography (CT) or magnetic resonance imaging (MRI) is preferred over ultrasonography to detect hepatic hematoma, infarction or rupture.²⁵ Imaging should be performed in all patients with HELLP syndrome that present with abdominal, neck or shoulder pain or elevation of aminotransferase of > 1,000 U/l to rule out hepatic complications.²³

Patients with HELLP syndrome need to be closely monitored. The plan should include stabilizing the mother while assessing for fetal distress and determining if urgent delivery is indicated. Just as with preeclampsia, in a pregnancy with >34 weeks of gestation, the decisive treatment is delivery. A fetus of <34 weeks of gestation, in the absence of complications, may benefit from glucocorticoids to improve fetal lung maturity after the mother has been stabilized, but delivery should not be delayed beyond 48 hours of presentation. Small or contained hematomas may be managed with supportive treatment but in patients with hepatic rupture who are hemodynamically stable, percutaneous embolization of hepatic artery may be preferred.^25,26 Surgery is reserved for hemodynamically unstable patients or those with persistent bleeding.

Patients with HELLP syndrome tend to improve after delivery but a small risk of recurrence persists in subsequent pregnancies. Liver enzymes tend to normalize 48 hours postpartum.

Acute Fatty Liver of Pregnancy (AFLP)

Acuter fatty liver of pregnancy (AFLP) is a rare but lethal phenomenon that generally presents in the third trimester, occurring in 1 in 10,000 pregnancies.²⁷ Risk factors for AFLP include multiple gestations and underweight women.²⁸

AFLP has been linked to an inherited defect in mitochondrial beta-oxidation. This fetal mitochondrial beta-oxidation defect, specifically, in the enzyme long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD), results in the accumulation of fatty acids in hepatocytes and maternal circulation.^29,30 This eventually leads to hepatic failure and encephalopathy.

Patients may have complaints of epigastric pain, nausea and vomiting. However, they could also present with serious complications of AFLP such as pulmonary edema, renal or liver failure, proteinuria or DIC. Laboratory work may reveal hypoglycemia as well as elevated serum aminotransferases, bilirubin, ammonia and serum creatinine. Liver biopsy, although not usually performed, may show microvesicular fatty infiltration. The Swansea Criteria has been validated for diagnosis of AFLP. It requires six or more positive clinical or laboratory findings in the absence of another cause (Table 2). It has a positive predictive value of 85% and negative predictive value of 100%.³¹

AFLP is associated with fatal outcomes for the fetus and the mother, and maternal mortality rates of 12.5% have been reported.2,27 Like HELLP, treatment of AFLP requires stabilization of the mother, including resuscitation, as well as immediate delivery. Symptoms and laboratory abnormalities usually improve thereafter, but the patient may require monitoring in the postpartum period. Fulminant liver failure from AFLP may necessitate the need for liver transplant.³² Infants born to mothers with AFLP should undergo testing for LCHAD deficiency mutation. Recurrence of AFLP can manifest in future pregnancies if a patient has a mutation for LCAHD deficiency, but it may also occur in those patients without this specific mutation.³³

Liver Diseases Not Unique to Pregnancy
Cirrhosis and Portal Hypertension

Pregnancy is less common in patients with cirrhosis because of decreased fertility due to derangements in metabolic and hormonal balances that may result in anovulation. Gonadotrophin release is reduced in cirrhosis secondary to hypothalamic-pituitary dysfunction. This, combined with increased serum estradiol and testosterone levels in portosystemic shunts, can result in low fertility.³⁴

A pregnant cirrhotic mother presents a unique challenge as these patients are at a higher risk of developing complications that can affect both the mother and the fetus. These patients remain at risk for liver decompensation, including variceal bleeding, encephalopathy and ascites. There is also an increased risk of preterm labor and spontaneous loss of pregnancy.³⁵ Maternal mortality rates remain elevated at 18-50% from gastrointestinal bleeding.³⁶ These numbers have improved recently due to more urgent management of variceal bleeding and liver failure.³⁵

As the plasma volume expands in pregnancy, patients with portal hypertension may develop variceal bleeding, observed in nearly 30% of pregnant cirrhotic patients.37 Although no formal guidelines exist for screening prior to pregnancy, it is reasonable to perform pre-conception screening for varices just like for other cirrhotic patients.^38,39 Patients should also undergo repeat screening in the second trimester if varices were not observed on preconception screening esophagogastroduodenoscopy (EGD) given the increased variceal bleeding risk in pregnancy.⁴⁰ Varices observed on EGD should be treated with endoscopic variceal ligation. Non-selective beta-blockers, such as propranolol, are also indicated in management of esophageal varices in pregnancy despite potential adverse effects such as hypoglycemia, retardation of intrauterine growth and neonatal bradycardia.

Treatment of an acute variceal bleed is similar in both pregnant and non-pregnant females. Patients should receive IV fluids resuscitation and appropriate transfusion of blood products, antibiotic prophylaxis, octreotide and endoscopic therapy to achieve hemostasis. TIPS and liver transplant have also been described in patients with severe variceal bleeding, but this is not commonly practiced. As prolonged vaginal delivery is also associated with an increased risk of variceal bleeding, a short second stage of labor in vaginal delivery is preferable.⁴⁰ Cesarean section may also be considered but it is associated with increased bleeding risk. Further studies are still needed to determine the safest mode of delivery. Other complications of cirrhosis, including ascites and hepatic encephalopathy may also be observed in pregnancy but they are managed the same as in non-pregnant patients.³⁸

Viral Hepatitis

Viral hepatitis in a pregnant patient may be acute or chronic. These viral infections may account for up to 40% of jaundice in pregnant patients.⁴¹ The presence of hepatitis B virus (HBV) poses no risk to mother unless cirrhosis is present. However, the number of at-risk infants is increasing with an estimated 25,000 infants at risk for vertical transmission of HBV in the United States.⁴² The American College of Obstetricians and

Gynecologists (ACOG) recommends screening all pregnant women for hepatitis B at the first pre-natal visit.⁴³ Management with antivirals is avoided in women of childbearing age or in the first trimester of pregnancy as exposure to the medical treatment can result in adverse effects on organogenesis in the fetus. If the pregnant patient is known to have cirrhosis or fibrosis, however, the treatment may be initiated or continued. AASLD and ACG guidelines recommend antivirals in the third trimester of pregnancy if patients have positive hepatitis B surface antigen (HBsAg) and subsequent HBV DNA >200,000 IU/mL.^40,44 The treatment should continue until birth or three months postpartum. Perinatal transmission of hepatitis B when HBV DNA < 200,000 IU/mL has not been reported. Although positive hepatitis B e antigen (HBeAg) has also been linked to increased rate of transmission, the presence of HBV DNA is the most important predictor of persistent infection in the infant.⁴⁵ Tenofovir and telbivudine are first-line therapies for HBV infection. A high-risk pregnant patient with negative hepatitis B surface antibody (HBsAb) may be vaccinated safely during pregnancy. Infants born to HBV-infected mothers should receive both hepatitis B immune globulin (HBIG) and the hepatitis B vaccination series, which provide passive and active immunization respectively. The first dose of the vaccine should be delivered within 12 hours of delivery while the additional two doses are administered within 6-12 months. These interventions appear to have reduced the rate of transmission from more than 90% to less than 10% presently.⁴⁴ Current guidelines do not favor one mode of delivery over the other; therefore, elective cesarean section and vaginal delivery both remain an option. Breastfeeding is supported regardless of the mother’s treatment status.

Hepatitis C virus (HCV) infection, similarly to HBV, does not pose a risk to the mother unless she is cirrhotic. However, HCV was associated with a higher risk for preterm births in a meta-analysis.⁴⁶ Unlike HBV, current guidelines recommend screening for HCV in only those pregnant women with risk factors for HCV. Overall, mother-to-child transmission rates of up to 5% have been reported in HCV positive mothers but some co-morbidities are associated with an increase the rate of transmission.⁴⁷ Vertical transmission of HCV virus is enhanced to 19.4% if human immunodeficiency virus (HIV) co-infection exists, whereas intravenous drug use increases the rate of transmission to 8.6%.⁴⁷ Other risk factors that have been associated with increased risk of transmission include a viral load of more than 2.6 million and invasive procedures in pregnancy. Treatment of HCV is generally not pursued, as it usually does not require urgent therapy. Additionally, ribavirin is teratogenic and the new antivirals have not been well studied in pregnant patients thus far. Cesarean section and vaginal delivery both are an option for the patient as there are no guidelines favoring one mode of delivery to another. Breastfeeding is not discouraged if there is no skin breakdown or cracked nipples.

Acute hepatitis A virus (HAV) infections occur at the same frequency in pregnant and non-pregnant patients. HAV infection may increase gestational complications, including preterm labor, but overall, no differences in maternal and fetal outcomes has been observed.⁴⁸ Treatment is supportive, but it is recommended that a neonate receive HAV immunoglobulin if the mother has HAV infection within two weeks of delivery.⁴⁰

Acute hepatitis E virus (HEV) infection is the most common viral cause of acute liver failure in pregnancy.⁴⁹ Maternal and fetal mortality, as well as obstetrics complications, are significantly elevated in the presence of HEV infection. Fulminant liver failure has a reported mortality of 10-25% in pregnant women with HEV.⁵⁰ Therefore, all pregnant females presenting with acute hepatitis should have HEV-IgM levels checked. Management is supportive, although a successful liver transplant has been reported in a patient with acute liver failure from HEV infection.⁵¹

Herpes simplex virus (HSV) infection is a rare cause of liver failure in pregnancy even though pregnant females are at an increased risk of developing serious infections.⁹ Mortality has been reported to be as high as 74% in patients with HSV hepatitis,⁵² which should be suspected in patients who present with fever and elevated LFTs in the absence of jaundice. Pathognomonic mucocutaneous lesions are seen in <50% of the patients making the diagnosis challenging. HSV PCR is recommended to diagnose HSV infection due to the poor sensitivity and specificity of HSV-IgM testing. Nonetheless, as the results of HSV PCR may not be known immediately, if HSV infection is suspected, treatment with acyclovir should be promptly initiated. Acyclovir appears to be safe in pregnancy without an increased risk of birth defects in patients who have received this medication.⁵³

Gallstones

There is an increased risk for gallstone formation in pregnancy due to supersaturation of cholesterol, particularly in the second and third trimester of pregnancy. Decreased motility of the gallbladder in pregnancy and stasis of bile also promote lithogenicity. Gallstones can result in biliary colic, acute cholecystitis, or acute gallstone pancreatitis. Ultrasonography is a safe imaging modality that can be used to detect acute cholecystitis with a sensitivity of 85-95% and specificity of 95%.⁵⁴ In the past, conservative management with intravenous (IV) fluids, antibiotics and bed rest was the standard of care for pregnant patients with acute cholecystitis. Surgery was reserved for only those patients that failed conservative management. However, currently, it is recommended to perform laparoscopic cholecystectomy for symptomatic cholecystitis as this appears to be a safe procedure in pregnant patients.⁵⁵ Surgical interventions are also necessary in patients with intractable biliary colic and acute gallstone pancreatitis. As pregnant mothers with symptomatic cholelithiasis are at an increased risk of recurrent gallstones later in pregnancy, patients with episodes associated with severe complications should also undergo cholecystectomy.⁵⁶

Endoscopic retrograde cholangiopancreatography (ERCP) may be indicated for treatment of symptomatic choledocholithiasis, cholangitis, or biliary pancreatitis.48, 57 It is a safe procedure to perform in pregnancy, especially if exposure of fluoroscopy is minimized.⁵⁷ Complications of ERCP during pregnancy include post-ERCP pancreatitis, post-ERCP bleeding and pre-term births.^58,59

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) may worsen in pregnancy or in the postpartum period.⁶⁰ Completion of pregnancy is possible if a patient’s disease is well managed but poor control of AIH is associated with prematurity.⁶¹ If a patient has a history of AIH, their maintenance medications should be continued during pregnancy. Azathioprine has the best safety data when compared to other immunosuppressants. While congenital malformations have been described in pregnant mice from azathioprine, it is associated with favorable outcomes in pregnancy in humans.⁶² Flares of the disease during pregnancy are usually treated with corticosteroid monotherapy,⁴⁰ but these flares can lead to hepatic decompensation and need for liver transplant or even death.

Wilson Disease

Wilson disease (WD) is an autosomal recessive disorder that affects biliary copper excretion resulting in deposition of copper in the brain, liver and kidneys. Patients typically present with elevated serum aminotransferases, hyperbilirubinemia and hemolytic anemia. Alkaline phosphatase levels may be low. Treatment should be maintained during pregnancy as interruptions can lead to liver failure.⁶³ Management of WD in pregnancy usually consists of zinc sulfate or chelating agents, penicillamine and trientine. AASLD recommends continuing zinc sulfate at the same dosage but the chelating agents should be dose-reduced by 25-50% to promote wound healing if cesarean section becomes necessary.⁶⁴ Patients on D-penicillamine are discouraged from breastfeeding due to concern for potential harm to the infant. Spontaneous abortions have been attributed to WD, particularly if it is poorly controlled.⁶⁵

Liver Transplant

Most patients with liver transplant have fertility restored within 6-12 months post-transplant, but higher rates of preeclampsia, preterm births and cesarean sections have been observed in these patients.⁶⁶ With the use of immunosuppressive medications including azathioprine, cyclosporine, tacrolimus and steroids, pregnant patients with history of a liver transplant can have a good quality of life.⁶⁷ Mycophenolic acid is avoided in pregnancy due to its association with congenital malformations and embryopathy.⁶⁸ Pregnancy should be avoided for at least one year following transplant to optimize graft function and subsequently, permit the use of a lower dose of immunosuppressive medications.³

Thrombosis

Pregnant women are at an increased risk for venous thromboembolism with an estimated incidence of 0.76 to 1.72 per 1000 pregnancies.⁶⁹ Pregnancy is associated with an increase in fibrinogen and clotting factors levels.⁷⁰ When thrombosis is observed, it is imperative to search for additional causes of hypercoagulable states due to a high recurrence risk.⁷⁰

Budd-Chiari syndrome (BCS) can be triggered by pregnancy. It is characterized by obstruction of hepatic venous outflow. Patients may complain of right upper quadrant pain, abdominal distention and jaundice. Ascites and icterus may be evident on examination. Although hepatic failure and portal hypertension are both common complications of BCS,⁷¹ anticoagulation therapy has improved fetal and maternal mortality.

Patients with a prior history of thrombosis should continue anticoagulation. Women on warfarin should be switched to low molecular weight heparin (LMWH) prior to conception due to the teratogenic effects of warfarin. Direct oral anti-coagulants (DOACs) are also teratogenic; therefore, these medications should be discontinued in pregnancy in favor of LMWH.⁷²

Medications and Pregnancy

Previously, medications used in pregnancy were assigned a risk category defined by the Food and Drug Administration (FDA) as A, B, C, D and X based on limited research data on their safety derived from animal and human studies. As this classification system was not able to completely elicit the risks versus the benefits of medical therapy and provided limited information on the medication’s effects in labor or lactation, the FDA introduced a new labeling system in June 2015. The new pregnancy and lactation labeling system includes narratives with general pregnancy information, fetal risk summary, clinical considerations and data on human and animal studies.⁷³

CONCLUSION

Pregnancy is associated with various physiological changes, affecting many organs, including the liver. It is important to differentiate between physiological and pathological processes in pregnancy to ensure timely diagnosis and management, particularly for the diseases unique to pregnancy. However, chronic liver diseases may present differently in pregnancy and that can pose a diagnostic and therapeutic dilemma.

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The Microbiome And Disease, Series #6

Probiotics: What Do We Know So Far?

October 2018 • Volume XLII, Issue 10

Skylar Steinberg,

Sabine Hazan

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Probiotic is a general term for live, nonpathogenic microorganisms, many of which exist in a symbiotic relationship within the normal human gut flora. Here we discuss their growth in popularity, their use in treating Gastrointestinal (GI) and non-GI medical conditions, and the data demonstrating their effectiveness.

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

Probiotics have grown in popularity in recent years, marketed as a healthy dietary supplement and placed in popular foods such as yogurt, kombucha, kimchi and more. In 2014, Sales of probiotics in the United States exceeded more than $1 billion, constituting a $25 billion market worldwide.¹ The media and proclaimed health magazines have been quick to push the consumption of these products into our everyday lifestyle and diet. However, there is some confusion on the background and potential risks involved with an increased intake of probiotics that needs to be addressed. Furthermore, “probiotic,” has become increasingly misused, with many companies exploiting the term’s popularity without meeting the requisite criteria.

Probiotic is a general term for live, nonpathogenic microorganisms, many of which exist in a symbiotic relationship within the normal human gut flora.¹ They have been used to treat Gastrointestinal (GI) and non-GI medical conditions, but data demonstrating their effectiveness has been conflicting. The Federal Drug Administration also views probiotics as a health food, not a drug, and does not regulate these products.¹ One major issue is the fact that selection and dosing vary among products and the specific, beneficial effects of each probiotic strain cannot be generalized.¹ Not all species of probiotics are a part of the normal human gut bacteria and the benefits associated with one strand cannot be generalized to others.¹ Therefore, not all brands should promise equal effectivity and choosing a probiotic can be incredibly confusing and potentially harmful,¹ especially in immunosuppressed individuals or critically ill patients. For example, two cases of Lactobacillus Bacteremia during probiotic treatment of short gut syndrome have been discovered demonstrating that probiotics may not be as benign a treatment as generally thought.² Yet, as a result of media and marketing, most consumers now believe that probiotics are key to helping remedy a variety of health issues, keeping the demand for these products high.¹

Evidence has shown, however, that probiotics have been beneficial for the treatment of acute diarrhea, pouchitis, atopic eczema, and some genitourinary infections.¹ A 2010 analysis of 63 studies, totaling 8014 participants, concluded that probiotics helped decrease the duration and severity of acute infectious diarrhea.³ In fact, Irritable Bowel Syndrome (IBS) is one of the most common reasons that probiotics are consumed in clinical practice and also one of the most commonly studied with over 80 clinical trials of probiotics for IBS. The main reason for use of probiotics for both IBS constipation or IBS diarrhea is lack of pharmacologic treatment options.⁴

There has been no evidence or even weak evidence that probiotics help in conditions of Crohn’s disease or ulcerative colitis.^5,6,7 In fact, Rolfe et. al. in 2006 showed that out of 160 participants with Crohn’s disease, probiotics were not superior to a placebo or aminosalicylates for the maintenance of remission in patients.⁸ In 2007, Lirussi et al. conducted further studies on liver disease that showed no benefit or harm from probiotics in patients with end-stage liver disease.⁹ However, Xu and al. showed probiotics “significantly reduced the development of overt hepatic encephalopathy” in patients with liver cirrhosis.¹⁰

With regards to metabolic diseases, probiotics have shown to significantly decrease plasma glucose and glycosylated hemoglobin. However, there is no agreement that they reduce blood insulin levels in diabetes patients.^{11,12,13,14,15} For patients with cardiovascular and cholesterol conditions, studies found that probiotics decreased LDL, but did not raise HDL. Although Cho and Kim, like several others, emphasized, “both the efficacy of probiotics for cholesterol lowering and safety should be investigated further in well-designed clinical trials.”^16,17,118,19

When looking at the role of probiotics in GI infections like Helicobacter pylori and Clostridium difficile, the data has been controversial. Chao et al. in 2016 showed that probiotics, plus standard therapy, did not improve the eradication rate of H.pylori compared to placebo, however, probiotics did improve the side effects of diarrhea and nausea from the antibiotics.²⁰ When given with antibiotics, probiotics did decrease the risk of developing CDAD by 64%.²¹

There is also inadequate evidence recommending probiotics for respiratory tract infection,²² Bacterial vaginosis,^23,24 UTI,²⁵ or chronic periodontitis.²⁶ Overlooking the literature, it is evident that some effects of probiotics are well-documented, and their use alone or in combination with other therapies can be considered “evidence-based,” such as antibiotic-associated diarrhea, and C. diff-associated diarrhea, and yield positive results. In other conditions, however, further studies are crucial to determine the benefits of probiotics, because the available evidence is insufficient to show the efficacy of probiotics themselves and the studies included a wide swath of participants with varying degrees of ailments. Careful trials are needed to validate the effects of particular strains of probiotics given at specific dosages and for specific durations²⁷ but more importantly, probiotics need to be specific to the individual because, clearly, microbiome profiling has demonstrated species-specific patterns.^28,29

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Nutrition Issues In Gastroenterology, Series #180

Conventional, Complementary, and Controversial Approaches to Small Intestinal Bacterial Overgrowth

October 2018 • Volume XLII, Issue 10

Amisha Ahuja,

Nitin K. Ahuja

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Small intestinal bacterial overgrowth (SIBO), classically understood as an excess of bacteria and their associated byproducts in the small bowel, has become in recent years a progressively credible explanation for a variety of gastrointestinal symptoms. At the same time, clinical presentations associated with this entity are wide-ranging and overlap substantially with other heterogeneous diagnoses like irritable bowel syndrome. This ambiguity is compounded by a lack of standardized testing and treatment modalities, which can be frustrating for providers and patients alike. Herein we outline a contemporary understanding of SIBO pathophysiology, diagnosis, and therapy, with particular attention to their interface with diet and nutrition.

Amisha Ahuja, MD, Resident, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA Nitin K. Ahuja, MD, MS, Assistant Professor of Clinical Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA

Once a highly contested diagnosis, small intestinal bacterial overgrowth (SIBO) has gained traction over the past several years as a reasonable explanation for a variety of gastrointestinal symptoms. This traction is attributable not only to an accumulating foundation of empiric evidence, but also to a growing general interest in the role of gut microbiota in health and illness. At the same time, persistent ambiguities surrounding SIBO with respect to clinical hallmarks, diagnostic testing, and preferred treatment approaches leave providers vulnerable to setting thresholds of suspicion that may be too high or too low. Likewise, patients frustrated by a lack of definitive answers may be prone to perseverating upon this clinical entity given its elusive, protean, and faddish qualities.

Classically, the pathophysiology of SIBO has been understood as an excess of bacteria in the small intestine beyond the conventional cutoff value of 10⁵ colony forming units per milliliter (CFU/mL). This excess of bacteria, along with their associated metabolic processes and byproducts, leads in theory to various forms of maldigestion. More recent refinements in the SIBO disease model suggest that it may also involve the presence of inappropriate microbial species in particular regions of the small intestine. In a healthy state, proximal small intestinal microbiota are comprised primarily of Gram-positive aerobes, whereas the distal small bowel favors mostly facultative anaerobes in a gradient leading toward to the dense and almost exclusively anaerobic population of the colon.¹ Alongside bacterial overgrowth in absolute numbers, then, disturbances in these usual ratios have been suggested as potentially problematic.

Recent work has also focused on delineating qualitative distinctions among the various microbiota that might account for SIBO symptoms in any given individual. Elaborations in breath testing modalities have facilitated scrutiny of organisms producing methane and hydrogen sulfide as metabolic byproducts in response to an oral carbohydrate load, though the quantitative parameters for identifying them are subject to ongoing refinement.² Recognizing that bacteria are not the only microorganisms present in the body, some investigators have suggested that a parallel process of small intestinal fungal overgrowth (SIFO) may account for the persistence of symptoms in patients treated adequately for SIBO.^3,4 While such added layers of detail represent exciting avenues for future research, these distinctions remain difficult to draw clinically and thus, as speculation, can be clarifying and confounding in equal measure.

Clinical Features

Still, amidst these controversies, clinical patterns do exist to guide thinking about SIBO rationally. According to aggregated case series, among patients with SIBO, the most commonly reported symptoms tend to be diarrhea, abdominal pain, and abdominal bloating.⁵ In large individual studies, however, symptom prevalence and severity have been shown to be poor predictors for the presence of SIBO as defined by hydrogen breath testing. Such analyses have considered a wide variety of gastrointestinal symptoms, including heartburn, chest pain, nausea, bloating, belching, flatulence, abdominal pain, constipation, and diarrhea, suggesting that while none is predictive of SIBO, any might in theory be associated with it.⁶ That said, attention to alternative fermentative byproducts has yielded more significant associations. Methane production, for instance, is tied to constipation, perhaps by virtue of delayed gut transit.⁷ Recently presented data on hydrogen sulfide production, meanwhile, suggest an association with diarrhea and abdominal pain.⁸

The overlapping presentations of irritable bowel syndrome (IBS) and SIBO have been scrutinized heavily, and the shifting relationship between these two categories can contribute to uncertainty on the part of both patients and providers. Recognizing that IBS is a diagnosis predicated on clinical criteria, SIBO is likely a mechanism contributing to symptoms in a subset of IBS cases, though not necessary an exclusive explanation. Prevalence data vary widely, with a recent meta-analysis suggesting that approximately one-third of IBS patients tested positive for SIBO by conventional, non-invasive methods.⁹ SIBO has also been hypothesized to contribute to other clinically defined diagnoses, like functional dyspepsia, though experimental data to prove this link are thus far limited.¹⁰

Risk factors for excessive or otherwise altered small bowel microbiota include disturbances of small bowel anatomy or motility, predisposing in turn to bacterial stasis (including diverticula, post-operative adhesions, blind limbs, chronic opiate use, diabetic enteropathy, or underlying connective tissue disease such as systemic sclerosis) and impairments in the normal biochemical clearance mechanisms for bacteria in the small bowel (including hypochlorhydria mediated by proton pump inhibitors, for example, or reduced pancreaticobiliary secretions in the setting of chronic pancreatitis) (Table 1). Incompetence or surgical absence of the ileocecal valve has also been studied as a potential risk factor for SIBO, presumably by virtue of inappropriate reflux of colonic microbiota into the small intestine.¹¹ Given the imperfect nature of available diagnostics, as will be discussed below, recognizing clinical risk factors becomes a valuable means of establishing pre-test probability for SIBO before committing to a potentially protracted series of iterative therapies.

Diagnostic Evaluation

There are multiple modalities available for SIBO testing, though all are subject to important limitations. Quantitative culture of aspirated small bowel fluid is formally considered to be the diagnostic gold standard, though cost, invasiveness, and technical limitations (including variations in bacterial concentration according to the region of small bowel sampled) make it impractical for routine clinical use.¹² By virtue of its relative convenience, breath testing has become a much more widespread surrogate technology for establishing a diagnosis of SIBO, though debate continues to surround basic questions of methodology and interpretation.

Breath tests are performed by asking patients to ingest a pre-specified carbohydrate substrate before quantifying exhaled gases at regular intervals as an indirect measure of small bowel bacterial metabolism. The choice of substrate is an important variable, since glucose is natively absorbed by the small bowel whereas lactulose is not; as such, glucose can be predisposed to more false negative results, while lactulose can lead to more false positives.¹³ A recently published North American consensus document has formalized cutoff values for abnormality with regard to exhaled hydrogen and methane, a helpful frame of reference for an often subjective study.¹⁴ A number of experts explicitly disagree with these values, however, citing conflicting data, flawed assumptions about carbohydrate transit through the small intestine, and the lack of a reliable diagnostic gold standard.¹⁵

Supportive data can be gathered from other laboratory parameters, most of which surround the nutritional implications of SIBO. Severe SIBO is classically associated with reductions in Vitamin B12, due to either competitive bacterial uptake or inhibited absorption, and excesses in folate, a byproduct of bacterial metabolism.¹⁶ While certain bacterial species produce Vitamin B12, the majority are consumers, leading to a functional state of Vitamin B12 malabsorption.¹⁷ In certain circumstances, elevations of methylmalonic acid may be a useful surrogate biomarker of SIBO even when the serum Vitamin B12 level is normal.¹⁸ Fat malabsorption and deficiencies in the fat-soluble vitamins (Vitamins A, D, E, and K) have also been rarely reported, sometimes with clinically significant implications, including reduced bone density, night blindness, neuropathy, and coagulopathy.¹⁹ These metrics are neither sensitive nor specific in isolation, of course, but can be useful points to remember with respect to pattern recognition.

Conventional Therapy

Given the inherent limitations of the tests discussed above, many providers consider empiric treatment for SIBO as a diagnostic modality in its own right. In this context, the most common approach is to utilize a course of antibiotics to reduce bacterial burden and evaluate for symptom improvement thereafter. This strategy errs on the side of overtreatment; however, increasing the number of patients exposed to the potential risks of antibiotic therapy, including medication side effects, precipitation of C. difficile colitis, and the development of resistant organisms.

A variety of antibiotics have been studied with roughly equivalent rates of success, suggesting that targeting specific bacteria may not always be necessary to facilitate the collapse of synergistic, polymicrobial colonies.²⁰ The studied dosages and durations of these antibiotics have also varied. Recent practice has favored the use of rifaximin, a poorly absorbed antibiotic, in part due to its reduced toxicity profile and in part due to a relatively more robust base of evidence, including randomized controlled trial evidence for its utility in IBS with diarrhea, a diagnosis that is often simultaneously entertained.^21,22 For methane-predominant SIBO, certain investigators have advocated using a combination of neomycin and rifaximin, which small data sets suggest is superior in this context to either antibiotic alone.²³

Underlying risk factors for SIBO will predispose to recurrence after a successful course of antibiotic therapy and thus should be mitigated wherever possible. Such maneuvers might include optimizing blood glucose control, withdrawing gut-slowing or acid-suppressing medications, and perhaps even selectively instituting prokinetic drugs.²⁴ Even common risk factors can be potentially significant; some estimates suggest that proton pump inhibitors at daily dosing increase the small intestinal bacterial burden by 50- to 100-fold.²⁵ In situations where risk factors are significant and cannot be reversed, SIBO treatment may obligate the indefinite long-term use of multiple antibiotics in cycling fashion.

Alternative and Nutritional Therapy

A variety of alternative management options for SIBO have been proposed from within and beyond the physician community (Table 2). Among patients with a high threshold of suspicion for SIBO who are intolerant of, or unresponsive to, antibiotic medications, alternative interventions may be seen as attractive options despite a relative paucity of supporting data. Likewise, given the frequent link between food intake and symptom exacerbation, nutrition can be an avenue of native interest for patients with SIBO, though again the available evidence for any individual dietary strategy is sparse. Diets proposed for SIBO tend to focus on reducing or eliminating foods easily fermented by bacteria and leading in turn to gaseous and osmotically active metabolic byproducts. The low FODMAP (fermentable oligo-, di-, monosaccharides and polyols) diet is perhaps the best known of these diets, but it should be noted that its effectiveness has been studied particularly in the context of IBS, not SIBO. Extrapolation regarding the potential benefit of this diet in SIBO rests on the known overlap between these two clinical entities, but to our knowledge, the evidence to support this extrapolation remains largely anecdotal.²⁶ Other popular diets proposed for bacterial overgrowth, under names like “the biphasic diet,” “the fast tract diet,” and “the SIBO specific diet,” among others, are even less driven by published data but seem to function as ad hoc variations on the same basic theme of reducing intake of highly fermentable carbohydrates.

The identification and elimination of dietary triggers may be viewed as a relatively low-harm exercise to the extent that patients with SIBO understand that it represents a short-term and essentially palliative maneuver. Misapprehensions that dietary modification can treat bacterial overgrowth, or that dietary indiscretion can lead to worsening dysbiosis, should be avoided. Symptoms may be mitigated, but the underlying risk factors for SIBO remain. Providers should also counsel patients to keep their exclusions temporary and minimally restrictive, given the risk of developing disordered eating habits (that is, “orthorexia nervosa”) and the potentially deleterious effects of carbohydrate restriction on the gut microbiome overall.^27,28 Registered dietitian involvement can be instrumental in facilitating healthful approaches to dietary optimization, including the identification and repletion of developing micronutrient and macronutrient deficiencies.

Beyond dietary modification, nutritional supplements have also been explored as alternative therapies for SIBO. A recent meta-analysis suggested that probiotics trend toward effectiveness in reducing bacterial burden and symptoms associated with SIBO, though interpretation is limited by heterogeneity in study methodology and the probiotic products under investigation.²⁹ By way of caution and contrast, however, a recent small study suggested that symptomatic SIBO could in fact be provoked by probiotic supplementation.⁴ Herbal compounds for the treatment of SIBO are widely available, and at least one study has suggested comparable efficacy with rifaximin as measured by a negative follow-up breath test.³⁰ Again, however, variations in the composition of these commercial preparations limit the extent to which these findings are clinically actionable.

CONCLUSION

Approaching the question of SIBO responsibly requires acknowledging the persistent ambiguities surrounding the clinician’s standard diagnostic and therapeutic tools. Recognizing clinical patterns can help determine how aggressively to query for SIBO when initial diagnostic and therapeutic modalities are unproductive. Furthermore, literacy with alternative strategies promoted to general audiences can facilitate more meaningful counseling in recognition of patients’ pre-existing health attitudes and behaviors.

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Frontiers In Endoscopy, Series #46

A Review of Lithotripsy Applications in Gastroenterology

October 2018 • Volume XLII, Issue 10

Praneeth Kudaravalli,

Bilal Aslam,

Moamen Gabr

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Lithotripsy has been a principle technique in the field of urology for four decades but was not implemented in the field of gastroenterology until the mid-1980s. In this article we discuss some of the commonly used lithotripsy methods in gastroenterology, such as mechanical lithotripsy, laser lithotripsy, electrohydraulic lithotripsy and extracorporeal shockwave lithotripsy.

Lithotripsy has been a principle technique in the field of urology for four decades but was not implemented in the field of gastroenterology until the mid-1980s. Large in vivo stones are often challenging to extract so lithotripsy is performed to assist in fragmenting or removing stones. Lithotripsy is used for various gastrointestinal conditions like common bile duct stones, pancreatic duct stones, gallstone ileus, Bouveret’s Syndrome, and in the management of some cases of calcified, impacted or occluded stents. Mechanical lithotripsy, laser lithotripsy, electrohydraulic lithotripsy, and extracorporeal shockwave lithotripsy are some of the commonly used lithotripsy methods in gastroenterology.

Praneeth Kudaravalli MD, Department of Internal Medicine, University of Kentucky, Bilal Aslam MD, Department of Digestive Diseases and Nutrition, University of Kentucky, Moamen Gabr MD, MSc, Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY

INTRODUCTION

Lithotripsy is being increasingly used in gastroenterology for fragmentation of stones prior to extraction as large stone removal is technically difficult and failure is associated with increased risk of complications including infection and stone impaction.¹ Surgical techniques are invasive and often associated with significant morbidity and mortality compared to endoscopic procedures. Most stones can be successfully removed by conventional endoscopic techniques alone, however larger stone size, impaction, the location of stone and presence of stricture can limit endoscopic success.^2,3 Lithotripsy in conjunction with conventional endoscopic techniques increases the rate of successful stone removal.

Mechanical lithotripsy for common bile duct (CBD) stones was first described in 1982 by Riemann et al.⁴ and is one of the most commonly used techniques for fragmentation of large CBD stones. Other types of lithotripsy techniques have been developed and used as an alternative to mechanical lithotripsy in patients with refractory stones which include electrohydraulic lithotripsy, laser lithotripsy, and extracorporeal shockwave lithotripsy. In addition to large gallstone management, lithotripsy is employed in other gastrointestinal conditions including chronic calcific pancreatitis caused by pancreatic duct calculi obstructing the main pancreatic duct, gallstone ileus with large stones impacting the duodenum or ileocecal valve, and calcified or occluded pancreatic duct stents.^5-7 This review focuses on endoscopic lithotripsy techniques and their applications in various gastrointestinal conditions.

Lithotripsy Techniques
Mechanical Lithotripsy (ML)

First introduced in 1982, it is one of the most commonly used lithotripsy methods due to cost, simplicity, and availability; and is the initial modality of lithotripsy used for almost all GI lithiasis. ML uses a large, strong basket to capture the stone, and a crank handle (Figure 1.A) to apply tension to the basket wires to crush the stone. ML baskets are of two types: through the scope and a second type called the salvage device. The first uses a 3-piece pre-assembled basket (Figure 1.B) fitted through an inner plastic and outer metal sheath. This apparatus is inserted through the accessory port of the endoscope, and the stone is trapped using the basket and plastic sheath. The metal sheath is then advanced over it and tension is applied to crush the stone using a crank handle (wheel or a caulk gun design). The latter salvage design (LithoCrushV – Olympus America Inc.) is generally used for the emergent treatment of an unexpected broken basket or stone impaction. Hard stones can sometimes break the basket and wires resulting in impaction. A study by Thomas M et al.⁸ with 712 ML cases showed the incidence of trapped/broken basket (N = 18), wire fracture (N = 12), and broken handles (N = 12) for overall biliary and pancreatic procedures. The salvage procedure is performed by removing the endoscope as well as the crank handle from the patient, and then a spiral metal sheath is glided over the bare basket wires with fluoroscopic assistance. The crank handle (Figure 1.C) is then connected, and the stone is crushed. Later both the broken basket and stone are retrieved. Newer techniques now allow passing a smaller sheath through the scope without having to remove the duodenoscope.⁹ A success rate of up to 90% has been reported with this technique.¹⁰ However, this is influenced by several factors including stone composition, size, shape, number, the diameter and tortuosity of the bile duct with or without the presence of stricture, broken lithotripter baskets, stone engagement by lithotripter and impaction.^11-13 Complications like basket impaction, broken handle, bile duct perforation, and pancreatic duct leak are seen with approximately 4% of ML procedures.8 ML is also an acceptable modality of endoscopic treatment for pancreatic duct stones with favorable outcomes.¹⁴ However, rates of complications are three-fold higher than in biliary applications.⁸

Electrohydraulic Lithotripsy (EHL)

After successful animal and corpse experiments, this industrial mining tool was introduced in the late 1970’s by Koch for the management of large bile duct stones in humans.¹⁵ EHL (Northgate Technologies, Inc, Elgin, IL, USA) uses a mother-baby endoscopy system, and a cholangioscope (Figure 2.A) is inserted through the instrument port of a larger duodenoscope. Under direct visualization or fluoroscopic guidance, a bipolar probe connected to a generator (Figure 2.B) is deployed through the instrument channel of the cholangioscope close to the stone, and continuous irrigation is performed to create an aqueous medium. The bipolar probe then creates high-frequency hydraulic pressure waves leading to stone fragmentation.¹⁶ Traditionally, two endoscopists were required to perform this procedure, one to maneuver the duodenoscope and a second to operate the cholangioscope. In addition, older systems had other technical limitations such as fragile scopes and reduced steerability. In 2015, a single-operator cholangiopancreatoscopy system – SpyGlass DS (Legacy and DS; Boston Scientific, Boston, Mass) was introduced with improved operating characteristics and higher image resolution thus overcoming the limitations of older systems.^17,18 EHL has been shown to have a stone fragmentation rate of 96% and final clearance of 90% for gallstones and 83% fragmentation rates for pancreatic duct calculi. Complications are seen in 7-9% of patients with the most common being cholangitis and ductal perforation.¹⁷ A study by Arya N et al.¹⁹ with 111 patients showed complications such as cholangitis (13 patients), hemobilia (1 patient), post-ERCP pancreatitis (1 patient) and biliary leak (1 patient) post-EHL. A multi-center retrospective study of 224 patients by Alder DG et al.²⁰ undergoing a single operator cholangiopancreatoscopy reported adverse events including post ERCP pancreatitis, cholangitis, bleeding and perforation in 3.9%, 1.4%, 1% and 0.7% of cases respectively.

Laser Lithotripsy (LL)

In 1986, endoscopic retrograde laser lithotripsy was used for the first time in the treatment of problematic large bile duct stones.²¹ Numerous types of laser technologies are employed, such as pulsed dye laser lithotripsy, a rhodamine-6G dye laser with an integrated stone-tissue detection system, holmium laser lithotripsy, and Double Pulse Nd: YAG (FREDDY) laser.^22-25 LL (Lumenis Ltd. Israel) (Figure 3.) is performed by direct visualization using a cholangioscope, or under fluoroscopic guidance. A tissue-stone recognition system developed in 1993 identifies gallstones, and the tip of the probe is placed on the surface of the stone using the helium-aiming beam. Laser light initiates plasma formation at the stone surface, and a short, very high-intensity pulse heats the plasma which causes expansion and contraction of the stone leading to fragmentation. Fragments are later extracted with a dormie basket or balloon catheter.²⁴ Alternatively, the stone can first be captured using a double lumen basket, with LL performed subsequently.²⁶ LL is also used for pancreatic duct calculi when conventional methods fail. EUS-guided pancreaticogastrostomy with a self-expanding stent is used to access the main pancreatic duct, and LL is performed on pancreatic duct stones.²⁵ Stone fragmentation rates of 80-90% with a ductal clearance of 64-97% are reported. Adverse events like pancreatitis, hemobilia, and cholangitis have been observed in a trivial number of patients.²⁴

Extracorporeal Shockwave Lithotripsy (ESWL)

This well-established treatment technique for urolithiasis has been extrapolated for the management of gallstones and pancreatic duct stones. It was first used in 1985 to treat difficult gallstones using a kidney lithotripter.²⁶ Stones are targeted with fluoroscopy after injection of contrast medium via nasobiliary catheter or ultrasound guidance, and shock waves are generated by an electromagnetic lithotripter (Delta Compact, Dornier Medtech, Wessling, Germany). These high-pressure shock waves through liquid or tissue medium are then fixated on to a target by elliptical transducers. First generation ESWL required immersion of patients in water and obligated use of general anesthesia. Newer machines do not require immersion and can be used with sedation only.^28,29 Stone clearance rates were as high as 90% for gallstones and 71% for pancreatic duct stones. Complications are seen in about 10-15% of patients, with patients experiencing cardiac arrhythmia, hemobilia, cholangitis, pancreatitis, and hematuria. A prospective study involving 283 patients by Tandan M et al.³⁰ showed complications such as mild hemobilia (12% cases), cholangitis (3.8% cases), and post-ERCP pancreatitis (3.5% cases). Other rare incidents reported include bowel perforation and splenic rupture.^28,31 ESWL is successful and well tolerated by patients, and the equipment is easily available at most institutes as they are the same ones used for renal stones. However, LL has been shown to have better outcomes compared to ESWL in terms of stone-free rates (97% vs. 73%) and number of sessions needed for stone clearance (1.2 vs. 3 respectively).³²

Lithotripsy Applications
Common Bile Duct Stones

Approximately 10% of the US population is diagnosed with gallstones, and 10-20% of these patients develop choledocholithiasis. 35% of patients with gallstones will ultimately become symptomatic and will require cholecystectomy. Of these, 3-10% of patients are found to have CBD stones.³³ CBD stones can vary in size from 1-2 mm to as large as 3 cm or more. CBD stones up to 1.5 cm can be treated with conventional techniques like endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy and basket or balloon extraction. However, conventional endoscopic techniques fail in 10-15% of patients, because the stones are too large or impacted, or due to challenging bile duct access or intrahepatic stones.¹² In such cases, stone fragmentation is required prior to extraction using techniques like lithotripsy. ML technique is very effective in the management of large bile duct stones, but in frail patients or in select high-risk groups, peroral cholangioscopy guided laser or electrohydraulic lithotripsy is safer for fragmentation and ductal clearance.29 EHL has also provided treatment for symptomatic cholelithiasis for high-risk surgical candidates such as patients with end-stage liver disease.³⁴

Chronic Calcific Pancreatitis

Pain in chronic pancreatitis is caused by a wide variety of factors, but the main pancreatic duct obstruction due to stones or strictures resulting in increased duct pressure and pain is well established.³⁵ Stones are observed in as many as 90% of patients with chronic alcoholic pancreatitis. ERCP with sphincterotomy and balloon or basket stone removal after mechanical lithotripsy have been validated with reasonable outcomes. The success of these procedures is limited when the size of the pancreatic duct stone is > 5mm, or in the setting of strictures or impaction. Surgery carries a risk of 5% mortality and has not been shown to achieve long-term pain relief.³¹ Bekkali et al.¹⁷ described ductal clearance for pancreatic duct stone when using SpyGlass-assisted pancreatography with EHL which obviated the need for surgery; similar results have been reproduced by other groups.³⁶ ESWL has been shown to be effective in patients who failed conservative pain management in several retrospective and prospective studies. A study by Tandan et al. showed 84% pain relief at 6 months follow up post ESWL. In a subsequent study, 68.7% of patients at 24-60 months and 60.3% at > 60 months showed the absence of pain after ESWL and ERCP.30,35 A meta-analysis of 27 studies on ESWL showed 52.7% pain relief, quality of life improvement in 88.2% and ductal stone clearance in 70.7% of patients.31 Alternative therapies with LL or EHL for patients who failed ESWL or with hereditary pancreatitis are also available, but experience with these techniques is limited.³⁷

Gallstone Ileus and Bouveret’s Syndrome

Large gallstones can rarely migrate through a cholecystoduodenal or choledochoduodenal fistula and cause obstruction of the gastric outlet, duodenum or ileum.³⁸ Endoscopic treatment with or without lithotripsy is now the first line management for this disorder. A comprehensive review of 61 cases by Dumonceau showed successful treatment by mechanical lithotripsy (40% of cases), EHL (21% of cases), LL (15% of cases), and ESWL (4% of cases).³⁹

Calcified or Occluded Pancreatic Stents

One of the main indications for pancreatic duct stent placement is pain secondary to obstruction from strictures or stones. Several studies have shown a success rate of 75-100% pain relief after stent placement.^40,41 However, the benefit is only short term due to a common phenomenon of stent clogging at 9-12 weeks making regular stent exchange inevitable. ESWL is used effectively to cleanse clogged stents with success in as many as 80% of cases thus increasing exchange intervals.⁷ Stent exchanges can be complicated by calcified stents making them difficult to retrieve by snares or forceps during ERCP; ESWL has been used in such cases where lithotripsy is performed prior to ERCP making stent exchange successful.⁴²

CONCLUSION

In conclusion, given high rates of morbidity and mortality associated with surgical methods, endoscopy with lithotripsy has become the primary modality of treatment in the past few years for difficult to treat gastrointestinal lithiasis. Recent advances in endoscopy techniques with newer ultrathin endoscopes, and single operator cholangioscopes have made these procedures safer and more reliable. In addition, patients prefer alternative non-surgical approaches. Future studies should focus on quality, safety, efficacy and best modalities of lithotripsy for a specific gastrointestinal condition.

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Dispatches From The Guild Conference, Series #17

Managing Severe Ulcerative Colitis in the Hospitalized Patient

October 2018 • Volume XLII, Issue 10

Edward V. Loftus

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Studies tell us that the first year after diagnosis of ulcerative colitis (UC) is associated with the highest colectomy rate and it’s severity can be defined by a combination of clinical and objective parameters. In this article we discuss the management of severe UC in the hospitalized patient.

Esophageal adenocarcinoma is increasing in frequency in the United States. Barrett’s esophagus is the strongest risk factor for esophageal adenocarcinoma making evaluation for Barrett’s esophagus of utmost importance. Currently screening and surveillance are accomplished with regular white light endoscopy; however, new advances in both population screening and surveillance are being developed. This review will cover selecting the appropriate patient population for Barrett’s esophagus screening, available and upcoming technologies for screening and surveillance, and lastly treatment of Barrett’s esophagus.

One of the true “emergencies” in inflammatory bowel disease (IBD) is the management of the patient with acute severe colitis. Natural history studies tell us that the first year after diagnosis of ulcerative colitis (UC) is associated with the highest colectomy rate. Ulcerative colitis severity can be defined by a combination of clinical and objective parameters. The Truelove and Witts Severity Index, developed over 60 years ago, still holds up as a good approximation of disease activity.¹ Patients with severe ulcerative colitis tend to have more than six bowel movements per day, frequent blood in stool, a body temperature >37.5 degrees Celsius, heart rate >90 beats per minute, hemoglobin that is <75% of normal (i.e., <9 g/dL for women, <10 g/dL for men) and erythrocyte sedimentation rate >30 mm per hour.¹

On day one of hospitalization, abdominal film should be obtained to exclude toxic megacolon. Clostridium difficile superinfection should be excluded. The patient should be given intravenous fluids and corticosteroids. Patient expectations should be set. The colorectal surgeon should be consulted. Subcutaneous heparin should be administered for deep venous thrombosis prophylaxis, as patients have an elevated risk due to activation of the coagulation cascade due to systemic inflammation. Narcotics should be avoided as they can further slow gut motility and potentially precipitate toxic megacolon. In anticipation that the patient might require immunosuppression (either infliximab or a calcineurin inhibitor), thiopurine methyltransferase, interferon gamma release assay for tuberculous antigens and hepatitis B virus serologies should be obtained.

Numerous studies have documented the increasing prevalence and severity of Clostridium difficile infection, particularly in patients with inflammatory bowel disease.² These infections can lengthen hospital stay as well as increase in-hospital colectomy rates and mortality. Another superinfection to exclude is cytomegalovirus (CMV) infection, which is diagnosed by flexible sigmoidoscopy and biopsy, asking the pathologist to obtain CMV immunostains (this should be obtained within 48 hours of admission). The density of CMV inclusions in the biopsy fragments will help determine whether the CMV is an “innocent bystander” (generally <5 inclusions per biopsy) or an actual pathogen (generally >5 inclusions per biopsy).³ Multiple studies have demonstrated that antiviral therapy with intravenous (IV) ganciclovir followed by oral valganciclovir can reduce colectomy rates in UC patients who are refractory to intravenous corticosteroids and who have CMV colitis.

Intravenous corticosteroid doses should be equivalent to methylprednisolone 60 mg daily. There is no evidence that steroid doses higher than the equivalent of methylprednisolone 60 mg daily are more efficacious-indeed, a meta-regression of multiple studies correlated colectomy rates with corticosteroid dose and found no reduction in colectomy rates beyond 60 mg daily.⁴ The original “Oxford regimen” for acute severe colitis included not only intravenous fluids, electrolytes and corticosteroids, but also intravenous antibiotics, blood transfusion, bowel rest and corticosteroid enemas.⁵ Although bowel rest is appealing (less antigenic stimulation, less luminal secretion, etc.) there are at least two controlled trials showing that total parenteral nutrition and bowel rest was no more effective in reducing colectomy rates compared to offering the patient a general diet. Therefore, routine bowel rest and total parenteral nutrition for acute severe colitis is not advocated; however, total parenteral nutrition (TPN) may be indicated for severe malnutrition. Similarly, several controlled trials have not demonstrated a benefit for intravenous antibiotics in acute severe colitis, but there may be a role for broad spectrum antibiotics in selected patients with fulminant colitis.

A number of studies have attempted to prognosticate risk of colectomy in patients with acute severe colitis.6,7 The best indices seem to incorporate serum C-reactive protein concentration and stool frequency on the third day of hospitalization. For example, having >8 stools daily, or 3 to 8 stools daily in combination with a CRP >45 mg/L on day three, is approximately 85% predictive of requiring colectomy. Thus, by day three the provider has a good idea as to whether or not salvage therapy with infliximab or a calcineurin inhibitor will need to be implemented at day five.

The best study demonstrating the efficacy of infliximab in the setting of severe ulcerative colitis was a European study by Jarnerot and colleagues.⁸ A total of 45 patients were randomized to infliximab 5 mg/kg versus placebo. Two thirds of the infliximab-treated patients were able to avoid colectomy as compared to only 29% in the placebo-treated group. A subgroup analysis of the Active Ulcerative Colitis Trials (ACT) showed that survival free of colectomy was significantly higher among patients randomized to the infliximab group compared to that of the placebo group.⁹ Adverse events associated with anti-tumor necrosis factor (TNF) alpha agents have been well described over the past 20 years. These events include granulomatous and fungal infections, other serious infections, infusion reactions, drug-induced lupus, demyelination syndromes, congestive heart failure, hepatotoxicity and an increased risk of lymphoma and skin cancer.

The use of infliximab in the acute severe colitis setting is challenging in that infliximab is a protein and severe UC patients generally have a protein-losing colopathy (which in part explains their hypoalbuminemia). It has been shown that patients who are not experiencing clinical or endoscopic response in the acute severe colitis setting have higher levels of fecal infliximab than those responding.¹⁰ Higher doses of infliximab, or an accelerated dosing regimen, might reduce the colectomy rate. However, this has been surprisingly difficult to prove. One retrospective study of 50 hospitalized UC patients who were steroid-refractory received either standard induction dosing or accelerated dosing (three doses within a median interval of 24 days).¹¹ In the short term, patients receiving accelerated dosing were significantly less likely to require colectomy during induction (6.7% versus 40%); however, by two years out, the colectomy rates were not significantly different. The experience with accelerated dosing of infliximab in severe UC by the IBD group at the University of Michigan has been published in preliminary form.¹² They instituted in 2013 a protocol whereby the second dose of infliximab 5 mg/kg was given early if the CRP level had not dropped by 7 mg/L. Surprisingly, the colectomy rate among the accelerated group was significantly higher (47.1%) than among the group receiving standard dosing (12.4%).¹² At this point in time, an accelerated dosing regimen would not be considered “standard of care.”

The landmark trial demonstrating the short-term efficacy of intravenous cyclosporine in the acute severe colitis setting was published in 1994 (82% response rate with cyclosporine vs. 0% placebo, 18% vs. 44% colectomy rate).¹³ Further randomized controlled trials showed that cyclosporine was at least as effective as corticosteroids,¹⁴ and that a 2 mg/kg infusion was as effective as 4 mg/kg.¹⁵ The long-term efficacy remains unclear. This appears to be a good option in a patient na�ve to thiopurines, because one then can use cyclosporine as a bridge to thiopurines. Cyclosporine might make more sense in a patient with marked hypoalbuminemia/protein-losing colopathy. Serious infections including fatal infections (1.4%-2.8%) have been described with the use of cyclosporine.^16-18

A randomized clinical trial comparing cyclosporine to infliximab in 110 patients with acute severe colitis refractory to steroids was performed by the GETAID group.¹⁹ Treatment failure was defined as a composite of no clinical response at day seven, inability to achieve steroid-free remission by day 98, a clinical relapse between days 7 and 98, colectomy, or death. Rates of treatment failure were similar-54% for the infliximab group versus 60% for the cyclosporine arm.¹⁹ The authors concluded that cyclosporine was not superior to infliximab. Colectomy rates at day 98 were very similar-18% in the cyclosporine group versus 21% in the infliximab-treated arm. Over the longer term, colectomy rates up to seven years out from initiation in the trials were similar.²⁰ Thus, it is reasonable to consider either option as salvage therapy in steroid-refractory severe ulcerative colitis patients. The sequential use of cyclosporine followed by infliximab or vice versa is generally not recommended, because such a strategy does not improve colectomy-free survival, and it appears to be associated with a high rate of serious adverse events including serious and sometimes fatal infections.²¹

Tacrolimus, which has better oral bioavailability than cyclosporine, may be a reasonable alternative to the aforementioned options. In a Japanese randomized trial comparing low-trough level tacrolimus (5-10 ng/mL) to high-trough level tacrolimus (10-15 ng/mL) and to placebo, the rates of clinical improvement, clinical remission, endoscopic improvement, and endoscopic remission were significantly higher for the treatment arm randomized to the high-trough level arm.²²

Surgical options for ulcerative colitis include total proctocolectomy with Brooke ileostomy and total proctocolectomy with ileal pouch-anal anastomosis. In the acute severe colitis setting, the latter is typically offered as a 3-stage rather than 2-stage procedure. Such an approach is associated with reduced postoperative complications. Disappointingly, colectomy rates in the acute severe colitis setting have not changed over the past 40 years (since the advent of the Oxford regimen). A 2007 meta-regression of numerous studies of severe UC found that the mean weighted colectomy rate was 27% and there had been no change over time.⁴ The mortality rate for acute severe colitis was 1%. A landmark study of the Nationwide Inpatient Sample by Kaplan and coworkers found that only about 30% of the colectomies performed in U.S. hospitals for ulcerative colitis were proctocolectomies with ileal pouch-anal anastomosis (IPAA), and this was most frequently performed at centers with the highest volume of colectomies.²³ In that same study, it was noted that there was an inverse relationship between postoperative mortality and colectomy volumes. Centers with the lowest volume of colectomies had a postoperative mortality of 4%, whereas the highest volume centers had a postoperative colectomy mortality of only 0.7%. Emergency or urgent colectomy had a postoperative mortality of 5.4%, while mortality associated with elective colectomy was 0.7%.²³ We presented our experience at Mayo Rochester with severe ulcerative colitis in preliminary form.²⁴ Between 1997 and 2006, a total of 281 patients were hospitalized with acute severe colitis. The in-hospital colectomy rate was 44%. In multivariate analysis, predictors of colectomy included prior hospitalization for UC, previous need for steroids, a hemoglobin on admission of <12 g/dL, endoscopic severity with a Baron score of 3 or 4, and body mass index of <25 kg/m2.²⁴ Only 30% of those treated with cyclosporine were able to avoid colectomy, whereas 63% of those treated with infliximab could avoid in-hospital colectomy.

Putting this all together, one should exclude superinfections early on, get the colorectal surgeon involved early, treat with intravenous corticosteroids, assessing response at day three with a view to initiating salvage therapy or proceeding with colectomy if no clinical response by day five.^25,26

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A Special Article

Chromoendoscopy in Community Practice

October 2018 • Volume XLII, Issue 10

Samir A. Shah

Early detection of dysplastic tissue during colonoscopy allows early intervention and may decrease colon cancer and improve survival. Studies from several academic centers have demonstrated chromoendoscopy increases diagnostic yield for intraepithelial neoplasia in inflammatory bowel disease (IBD) compared with white-light colonoscopy (WLE). The feasibility of this technique, however, has not been adequately studied in the community setting. Our study evaluates a single physician’s experience with chromoendoscopy in patients with IBD.

Mohd Amer Alsamman, MD¹ Niren Jasutkar MD, PharmD² Steven E. Reinert³ Murray Resnick MD, PhD⁴ Jude Fleming MD⁵ Samir A. Shah MD⁶¹ ¹Internal Medicine, Alpert Medical School, Brown University, The Miriam Hospital, Providence, RI ²Riverside Medical Group, Secaucus NJ ³Lifespan Information Services, Lifespan Hospital System, Providence, RI ⁴Department of Pathology, Alpert Medical School, Brown University, The Rhode Island Hospital, Providence, RI ⁵Internal Medicine, Columbia University, New York, NY ⁶Division of Gastroenterology, Alpert Medical School, Brown University, The Miriam Hospital, Gastroenterology Associates Inc., Providence, RI

Background: Patients with inflammatory bowel disease (IBD) have increased risk of developing colorectal neoplasia associated with chronic inflammation. Surveillance colonoscopy for longstanding disease is the standard of care. Typically, conventional white light endoscopy (WLE) is used with random biopsies; however, studies from several academic centers have demonstrated chromoendoscopy increases diagnostic yield for intraepithelial neoplasia in (IBD) compared with (WLE).

Aims:
Compare the feasibility and yield of chromoendoscopy vs WLE surveillance colonoscopy in a community based practice.

Methods:
A retrospective review of surveillance colonoscopies performed by one physician in a community based private practice with and without chromoendoscopy in patients with IBD between January 2005 & August 2012. Demographic data, time for procedure, number of biopsies, number of jars, and yield of dysplastic lesions were obtained.

Results:
25 dysplastic lesions were found in 64 procedures with chromoendoscopy (39.1%) versus only 8 in 120 procedures (6.9%) with WLE (p<0.001).

Conclusions:
Chromoendoscopy is feasible in community private practice. Compared to WLE, chromoendoscopy yields a higher rate of dysplastic lesions, similar to the increased yield reported from academic centers.

INTRODUCTION

Early detection of dysplastic tissue during colonoscopy allows early intervention and may decrease colon cancer and improve survival.¹ Studies from several academic centers have demonstrated chromoendoscopy increases diagnostic yield for intraepithelial neoplasia in inflammatory bowel disease (IBD) compared with white-light colonoscopy (WLE).^2,3,4 The feasibility of this technique, however, has not been adequately studied in the community setting. Our study evaluates a single physician’s experience with chromoendoscopy in patients with IBD.

Background

Patients with Crohn’s and ulcerative colitis have increased risk of developing colorectal neoplasia associated with chronic colonic inflammation. This risk rises with duration and extent of disease and other factors including primary sclerosing cholangitis (PSC), family history of colon cancer, and histologic disease activity. Current ASGE guidelines recommend surveillance colonoscopy every 1 to 3 years starting approximately 8 years after onset of left sided colitis and Crohn’s disease involving at least 1/3 of the colon, and annually in cases of PSC with IBD (starting at time of PSC diagnosis).^5,6 Most endoscopists will take random four quadrant biopsies from every 10 cm of the colon with the aim of collecting at least 32 biopsies to maximize sensitivity in detecting dysplastic lesions. This approach relies on sampling luck and may overlook early neoplasia. In addition, previous studies have shown poor adherence in obtaining 32 biopsies. Furthermore, the yield of random biopsies is exceedingly low.^7,8 Dysplastic lesions often have flat or subtle borders and early lesions may not be detected by conventional standard definition or even high definition white light endoscopy (WLE).

Over the past decade, numerous studies from tertiary academic centers have established the advantage of chromoendoscopy over WLE.^9,10,11 The use of chromatographic dyes to better visualize colonic mucosa allows for easier detection of subtle dysplastic tissue. Contrast dyes, such as indigo carmine, coat the surface of gastrointestinal mucosa highlighting pit pattern of normal mucosa.12 Absorptive dyes, such as methylene blue, are taken up by normal mucosa, leaving dysplastic tissue unstained.^13,2 Irrespective of the dye utilized, chromoendoscopy facilitates targeted biopsy or lesion removal by highlighting the borders of flat or subtle neoplastic tissue. Previous studies have reported a 3 to 6 fold increase in number of lesions detected using chromoendoscopy with increase in sensitivity and specificity of detecting dysplastic tissue.^14,15

The feasibility and practicality of this technique in the community setting has not been adequately studied. There is a significant increase in length of procedure which some argue may make chromoendoscopy prohibitive in a private practice setting. However, if targeted biopsies have higher efficiency in detecting dysplasia, random biopsies may be avoided which would result in greater savings from pathology costs as well as keep procedure time comparable to conventional colonoscopy. Other barriers may include lack of exposure to chromoendoscopy during GI fellowship or afterwards, unfamiliarity with the Kudo pit classification, cost and availability of dyes for chromoendoscopy, lack of additional compensation for performing chromoendoscopy lack of specific billing code for chromoendoscopy, and finally lack of data showing reduction of incidence and death from colorectal cancer as a result of utilizing chromoendoscopy.

Methods

We performed a retrospective review of surveillance colonoscopies with and without chromoendoscopy in patients with IBD between January 2005 & August 2012. The choice of using chromoendoscopy (indigo carmine 0.1 to 0.4%) for a surveillance exam was at the discretion of the endoscopist (SAS) and was not randomized. Procedure reports and pathology were reviewed. On the procedure reports, a detailed description of the polyp detection before or after chromoendoscopy was specifically noted by the physician (SAS) performing all the surveillance colonoscopies. This was done with the anticipation of analyzing whether the extra time spent in doing chromoendoscopy would be justified by an increased yield. The scopes used transitioned from standard definition to high definition during the study period (2010 in the outpatient ambulatory center and 2006 at the hospital). Demographic data (age, gender), diagnosis (Crohn’s, ulcerative colitis, inflammatory bowel disease unspecified), smoking and family history, history of polyps, length of time for colonoscopy (defined as scope insertion to scope removal), complications from procedure, location & number of biopsies, and final tissue diagnosis from pathology were collected. The Lifespan/Rhode Island Hospital Institutional Review Board reviewed and approved the study protocol.

Results

A total of 184 colonoscopies were evaluated. Of these, 64 were performed using chromoendoscopy with indigo carmine dye. Cases comprised 118 individual patients, 64 males and 54 females, with a mean age of 51.6 years. There were no adverse events associated with colonoscopy with or without chromoendoscopy in the study population. These demographics are outlined in Table 1.

The average length of procedure was 38.8 [34.1, 43.4] minutes for chromoendoscopy, and 20.5 [18.1, 22.9] minutes without (p<0.001). Chromoendoscopy yielded an average of 42.0 [38.0, 46.0] biopsies in 13.1 [12.4, 13.86] jars per case, while white-light averaged 34.9 [32.4, 37.3] biopsies in 10.0 [9.68, 10.44] jars (p<0.001) per case.

White light colonoscopy found 87 polyps and chromoendoscopy found 157 polyps. An average of 2.4 [1.9, 3.0] polyps were resected per case during chromoendoscopy while white-light yielded 0.7 [0.5, 1.0] polyps per case on average (p<0.001). Chromoendoscopy led to discovery of 25 dysplastic lesions in 64 colonoscopies at a rate of 0.39 [0.23, 0.55] per case compared to 8 dysplastic lesions in 120 colonoscopies at a rate of 0.07 [0.02, 0.11] per case with WLE (p<0.001), (Figure 1). Of all polyps discovered via chromoendoscopy, 31% were dysplastic lesions. With white light, 7% (p=0.002) of all polyps resected were dysplastic. In our study, there was only one case, which found low grade dysplasia on a random biopsy; otherwise all remaining dysplastic lesions were resected polyps.

We divided our study population based on extent of disease, into left sided colitis, ileocolitis, and pancolitis. On analyzing different groups, percentages of dysplastic lesions found were 16.2%, 6.5%, and 77.3% respectively. We looked at the following variables, extent of disease, age, gender, family history, and, smoking in relation to total number of dysplastic lesions, using t test; P values, were 0.71, 0.74, 0.41, 0.75, 0.26, respectively. A previous personal history of polyps was significantly associated with subsequent dysplastic polyp detection (p = 0.001). These results are presented in Table 2.

Discussion

Chromoendoscopy allows for increased recognition of dysplastic polyps especially in higher risk populations such as patients with IBD.^16,17 Our analysis is consistent with published data from tertiary academic centers and demonstrates that chromoendoscopy can be done safely in a community private practice setting and with increased yield for dysplastic lesions.

In our study colonoscopy time was prolonged by an average of 18 minutes per procedure with chromoendoscopy, which is higher than the 11 minute average reported by Subramanian.¹⁷ This is at least in part due to the endoscopist still doing random biopsies with chromoendoscopy. Since early 2014, the endoscopist has given up random biopsies with chromoendoscopy and switched to chromoendoscopy for all surveillance in IBD with only targeted biopsies. For the few patients with co-existing PSC, a previous history of dysplasia on random biopsies, or multiple pseudopolyps, random biopsies in addition to chromoendoscopy is still employed. A review of the last 20 cases with chromoendoscopy from October 2017 to February 2018 showed an average time of 29.6 minutes per case and 5.7 jars per case and included several patients with multiple pseudopolyps in whom multiple random biopsies were taken. Thus with this approach most cases are done under 30 minutes making it practical from a scheduling and community practice perspective. In addition, all colleagues within the same community practice have adopted chromoendoscopy into their practice for selective cases without difficulty.

The technique allowed for a five-fold higher rate of detection of dysplastic lesions compared to white light colonoscopy. This correlates with published data citing a 3 to 5 fold difference.^10,18 Our experience is consistent from the “real world” experience from a multicenter study in Spain with 350 IBD patients from 2012-2014 who underwent WLE followed by chromoendoscopy with indigo carmine. In this study, 41.5% of the procedures were with standard definition scopes and 58.5% were with high definition. A total of 94 dysplastic (1 Cancer, 5 HGD, 88 LGD) lesions were found with a dysplasia miss rate 40/94 (57.4% incremental yield with chromoendoscopy). No significant learning curve was observed, no difference was noted between experts and non-experts in chromoendoscopy and increased yield with chromoendoscopy was seen regardless of whether standard or high definition scopes used. The authors concluded that any endoscopist can do chromoendoscopy and it works better than WLE high definition or standard definition. In contrast, a recent single center, prospective study in Calgary Canada randomized 270 patients with longstanding IBD 1:1:1 to surveillance dye spray chromoendoscopy, high definition WLE and “virtual chromoendoscopy” using the Pentax iScan technology. All of the procedures were performed by a single highly experienced endoscopist with only targeted biopsies for all cases. Initially for dye spray chromoendoscopy 0.4% indigo carmine was used and later .03% methylene blue due to shortage of indigo carmine. No difference in dysplastic lesion detection between the three techniques arguing against chromoendoscopy.

In our population, random biopsy yielded low grade dysplasia in only one patient. This patient has chosen to not have colectomy and remains under surveillance with annual chromoendoscopy without further dysplasia detected with the exception of a few visible dysplastic polyps seen with chromoendoscopy. Thus, the yield of random biopsies finding dysplasia was approximately 1 in 6,600. This is consistent with other studies^19,7 that the utility and cost effectiveness of random biopsies is exceedingly low. Furthermore, the 32 random biopsies are estimated to sample only 0.03% of the mucosal surface. Two studies concluded that even with standard white light endoscopy, most dysplastic lesions found were endoscopically visible.^8,20 These studies reported that 73-77% of dysplastic lesions and 89-100% of invasive cancers in UC patients were detectable endoscopically with white light colonoscopy.

The expense from random biopsy must also be taken into account. The most recent Medicare fee-schedule lists an average pathology cost of $73 per specimen jar submitted for gross and microscopic examination (laboratory processing and pathologist reading). As for private insurance, one commercial insurer in our region pays $150 per specimen jar (personal communication, James Carlsted, MD). As chromoendoscopy yielded 13.1 jars per case the average pathology cost was $956.3 for patients who had Medicare and $1,965 for private insurers. On the other hand, WLE yielded 10 jars per case resulting in $750 for Medicare and $1,500 for private insurance. However, chromoendoscopy cases in our analysis averaged a higher number of biopsy jars compared to WLE, but these included both targeted as well as random biopsies. While it was outside the scope of our study, abandoning the practice of random biopsy and performing targeted biopsies alone would significantly reduce the pathology cost associated with surveillance over the lifetime of a patient with IBD. We estimate that the number of jars with targeted biopsies with chromoendoscopy would average 4 (sampling for disease activity and removal of visualized lesions). The estimated cost saving in terms of pathology costs would be $438 for Medicare patients and $900 for commercially insured patients per case. This is particularly important in showing value in the current MACRA/MIPS view of physician services. Furthermore, since a negative chromoendoscopy colonoscopy is associated with a lower risk of colectomy for dysplasia/cancer the interval between surveillance may be increased based on other risk factors leading to further cost savings.¹⁸ In line with this, the British Society guidelines²¹ suggest 5 year intervals for low risk IBD patients.

There are several limitations to the generalizability of our study. All procedures were performed by a single endoscopist. Patient selection toward chromoendoscopy was not random and patients with longer duration of disease, history of dysplastic findings or other risk factors may have generated a higher index of suspicion to select use of chromoendoscopy and hence yield of dysplastic polyps. Over the time period of our analysis, newer generation high-definition endoscopes were introduced which was not factored into our study design. The absence of statistically significant relation between variables known to be associated with risk such as FH, smoking, gender, and number of dysplastic polyps detected is not surprising given the sample size, and retrospective non-randomized design.

Our data adds to growing body of literature supporting the practice of chromoendoscopy as an effective tool in detecting dysplastic lesions and thereby preventing colorectal cancer. It should be utilized more frequently in patients with IBD undergoing surveillance colonoscopy. Our experience shows it can be performed successfully and safely in the community practice setting.

All authors contributed substantially to the manuscript and approved the final manuscript. The study was conceived by SAS. NJ and SAS wrote the protocol for IRB approval with input from MR. NJ did the initial chart reviews and collection of data. JF and MAA performed a critical review of the previous data and focusing on risk factors for colon cancer and filling in gaps in missing data. SR performed all the statistical analysis with input from SAS, NJ and MAA. The bulk of the manuscript was written by NJ, MAA and SAS with critical input from all the authors. Each author read and approved the final, submitted manuscript.

There was no grant support or other assistance.

There were no conflicts of interest on behalf of all authors.

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A Case Report

Autoimmune Enteropathy: An Uncommon Presentation

September 2018 • Volume XLII, Issue 9

Alan Naim,Kaivan Salehpour,Camron Kiafar

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Alan Naim MD,^1,3 Kaivan Salehpour MD,² Camron Kiafar DO, AGAF, FACG^1,3 ¹Department of Gastroenterology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ ²Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ ³Department of Gastroenterology, Phoenix VA Health Care System, Phoenix, AZ

INTRODUCTION

Diarrhea is a common gastrointestinal complaint, with infection, irritable bowel syndrome, inflammatory bowel disease (IBD) and malabsorption syndromes (such as lactose intolerance and celiac disease) being the most common etiologies. We report a case of a 70-year old male with a two-month history of profuse, watery diarrhea. An abdominal computerized tomography (CT) scan on initial presentation revealed pneumatosis intestinalis. Extensive workup that included enteroscopy and colonoscopy revealed histology suggestive of autoimmune enteropathy. Anti-enterocyte antibodies confirmed the diagnosis. Although rare, autoimmune enteropathy (AIE) represents an important consideration in the differential diagnosis of intractable diarrhea in adults.

Presentation

A 70-year old male with a history of resected Meckel’s diverticulum and acid reflux was admitted for profuse, frequent, watery diarrhea and hypotension. Two months prior, he had presented to an outside hospital with similar symptoms including mild abdominal pain; he was found to be severely dehydrated with associated acute kidney injury. At that time, a computed tomography (CT) of the abdomen and pelvis revealed pneumatosis intestinalis of the small intestine and colon. Due to his presentation and CT findings, the patient underwent an exploratory laparotomy. There was no evidence of ischemia, perforation or necrotic bowel noted during laparotomy. Subsequent colonoscopy at the outside hospital was normal. However, random biopsies were suggestive of lymphocytic colitis for which the patient was discharged on budesonide therapy along with total parenteral nutrition (TPN). He presented to our hospital with ongoing intractable diarrhea despite compliance to his medication therapy.

At the time of presentation, he endorsed greater than 15 watery stools per day with nocturnal symptoms. A gluten-free and lactose-free diet failed to improve his symptoms. He had lost nearly 20 pounds in the last two months. He denied recent travel or sick contacts. He had no history of autoimmune disease as well as no family history of gastrointestinal or autoimmune disease. He had a longstanding smoking history but denied alcohol or drug use.

Vital signs were all within normal limits. On physical exam, his findings were only significant for a deconditioned gentleman as well as rectal exam showing peri-anal excoriations. Laboratory studies demonstrated a normocytic anemia, elevated creatinine, and low albumin level of 2.5 gm/dL (nl 3.4-5.0 gm/dL). Human immunodeficiency virus (HIV) status as well as stool studies, which included stool culture with Shiga toxin, Clostridium difficile toxin B PCR, giardia antigen, ova and parasites, fecal lactoferrin and fecal leukocyte testing were all negative. Serum tissue transglutaminase Ab IgA was undetectable with a normal IgA level. CT abdomen/pelvis imaging findings at our institution again demonstrated pneumonitis intestinalis of the small intestine and colon (Figure 1).

Given his non-response to budesonide therapy, and in consideration for an alternative diagnosis, the decision was made to undergo upper enteroscopy and repeat colonoscopy. Esophagogastroduodenoscopy (EGD) and upper enteroscopy findings were normal and random biopsies of the duodenum and jejunum were taken. The colonoscopy showed boggy, edematous appearing mucosa. Random biopsies of the colon were taken as well. Small bowel biopsies all indicated moderate to severe villous blunting, with marked lamina propria infiltrate (plasma cells and lymphocytes) (Figure 2). No goblet or paneth cells were identified. There was marked crypt apoptosis. Colon biopsies exhibited active colitis with preserved crypt architecture. Markedly increased crypt apoptosis was again demonstrated (Figure 3). No goblet or paneth cells were visualized.

Serum Anti-Enterocyte IgG antibodies were present in elevated titers and demonstrated positive linear periapical staining of the enterocytes and staining in the goblet cells. Anti-enterocyte IgA antibody also demonstrated positive linear periapical staining of enterocytes in elevated titers.

When the diagnosis of autoimmune enteropathy was established, he was placed on intravenous methylprednisolone. Shortly after, he was started on TPN for nutritional support. The patient began responding positively to intravenous steroids on the third day of treatment, resulting in a decrease in frequency and volume of bowel movements. As he clinically improved, he was transitioned to oral prednisone and discharged with a steroid taper for outpatient gastroenterology follow-up.

Discussion

Autoimmune enteropathy is a rare cause of intractable diarrhea in children and an even rarer cause in adults. It is best defined as a presentation of chronic diarrhea, malabsorption, with specific small intestinal histologic features and is typically confirmed by the presence of circulating auto-enteric antibodies. Extraintestinal manifestations may include hypothyroidism, nephrotic syndrome, autoimmune hemolytic anemia, and rheumatoid arthritis.^1-3 A lack of response to a gluten-free diet or other dietary exclusions is also described, as is a predisposition to other autoimmune diseases.^1-3 The disease was first described in 1982 in London in a 15 month-old child with protracted diarrhea and weight loss. Since that time, only a handful of adult cases of AIE have been reported with the largest case series from Mayo Clinic Rochester comprising of 15 patients.¹

AIE is histologically characterized by findings including: villous blunting, increased mononuclear inflammation in the lamina propria, lymphocytic infiltration into deep crypt epithelium with a relative decrease of surface lymphocytosis (< 40 lymphocytes per 100 epithelial cells), as well as the presence of increased crypt apoptotic bodies.¹ Mononuclear infiltrates are comprised of both plasma cells and lymphocytes. Colon histopathology shows similar histologic abnormalities to those seen in the small bowel. Gastric biopsies not uncommonly demonstrate an autoimmune atrophic gastritis as well.¹ CT findings are typically non-diagnostic.¹ This is the first known case to report the findings of pneumatosis intestinalis in autoimmune enteropathy.

The presence of anti-enterocyte or anti-goblet cell antibodies is supportive of the diagnosis of AIE, although the detection of these antibodies has been described as “observer dependent.” The significance of circulating auto-enteric antibodies in regards to pathology has not been fully delineated. Akram et al. did not show association between the clinical course, intestinal histology, and the type of circulating auto-enteric antibodies.¹ While anti-enterocyte antibodies have not been reported in celiac disease and inflammatory bowel disease, anti-goblet antibodies have been reported in patients with chronic inflammatory bowel disease, as well as in their asymptomatic first-degree relatives.^4,7,8 Despite concerns regarding their sensitivity and specificity, anti-enterocyte antibodies aid in establishing a diagnosis of AIE in cases with protracted diarrhea and malabsorption.

Much of the pathophysiology behind autoimmune enteropathy is unknown, but some studies have pointed to a deficiency or dysfunction in CD4+ and CD25+ regulatory T cells which are involved in the down-regulation of a variety of bodily immune responses.5 Mutation in the FOXP3 gene (forkhead box p3) in T cells, for instance, has been found in inherited forms of autoimmune enteropathy such as the rare X-linked recessive disorder of early childhood known as IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome.^2,5,6

Scarce data exists regarding epidemiology, disease course, and treatment options for AIE. Anecdotal experience guides a number of treatment decisions including use of corticosteroids as well as immunosuppressive drugs such as azathioprine, cyclophosphamide, tacrolimus, cyclosporine and infliximab. In a retrospective study, over half of the patients responded to steroid therapy. However, two-thirds of these patients either became steroid-dependent or refractory requiring additional immunomodulating or biologic therapy for maintenance of remission.¹

CONCLUSION

Autoimmune enteropathy represents a rare and important consideration in the differential diagnosis of intractable diarrhea in adults. It should be especially sought out in cases of malabsorption and small bowel villous atrophy not responding to a gluten-free diet. This disorder may also be considered in patients presenting with pneumatosis intestinalis when other common causes have been excluded. Treatment can be challenging and often requires both nutritional support with immunosuppressive medications.

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INTRODUCTION

Pathogenesis

Diagnosis

Management

Ursodeoxycholic Acid

Novel Treatment in PSC Farnesoid X Receptor Ligands

Role of Antibiotics in PSC

Simtuzumab

Norursodeoxycholic Acid

ASBT Inhibitor

Cenicriviroc

NGM282

CONCLUSION

INTRODUCTION

Diagnosis of Ascending Cholangitis

Severity Grading of Ascending Cholangitis

Antibiotics

Timing of Biliary Decompression

Biliary Drainage Techniques

Endoscopic Biliary Drainage

Percutaneous Biliary Drainage

Surgical Biliary Drainage

CONCLUSION

INTRODUCTION

DISCUSSION

INTRODUCTION

Normal Physiology

Liver Diseases Unique to Pregnancy

First TrimesterHyperemesis Gravidarum (HG)

Second and Third TrimesterIntrahepatic Cholestasis of Pregnancy

Preeclampsia

Hemolysis, Elevated Liver Enzymes and Low Platelets (HELLP) Syndrome

Acute Fatty Liver of Pregnancy (AFLP)

Liver Diseases Not Unique to Pregnancy Cirrhosis and Portal Hypertension

Viral Hepatitis

Gallstones

Autoimmune Hepatitis

Wilson Disease

Liver Transplant

Thrombosis

Medications and Pregnancy

CONCLUSION

Clinical Features

Diagnostic Evaluation

Alternative and Nutritional Therapy

CONCLUSION

INTRODUCTION

Lithotripsy Techniques Mechanical Lithotripsy (ML)

Electrohydraulic Lithotripsy (EHL)

Laser Lithotripsy (LL)

Extracorporeal Shockwave Lithotripsy (ESWL)

Lithotripsy Applications Common Bile Duct Stones

Chronic Calcific Pancreatitis

Gallstone Ileus and Bouveret’s Syndrome

Calcified or Occluded Pancreatic Stents

CONCLUSION

INTRODUCTION

Background

Methods

Discussion

INTRODUCTION

Presentation

Discussion

CONCLUSION

Novel Treatment in PSC
Farnesoid X Receptor Ligands

First Trimester
Hyperemesis Gravidarum (HG)

Second and Third Trimester
Intrahepatic Cholestasis of Pregnancy

Liver Diseases Not Unique to Pregnancy
Cirrhosis and Portal Hypertension

Lithotripsy Techniques
Mechanical Lithotripsy (ML)

Lithotripsy Applications
Common Bile Duct Stones