Fedja A. Rochling

Current management of short bowel syndrome.

ntestinal failure refers to a condition that results from obstruction, ysmotility, surgical resection, congenital defect, or disease-associated oss of absorption and is characterized by the inability to maintain rotein-energy, fluid, electrolyte, or micronutrient balance. The short owel syndrome (SBS) is a type of intestinal failure caused by intestinal esection leading to a shortened intestinal remnant and is characterized by he inability to maintain protein-energy, fluid, electrolyte, or micronutrint balances when on a conventionally accepted, normal diet. SBS ccounts for approximately three-fourths of intestinal failure patients in dults and more than one half in children. The pathophysiologic changes hat occur in SBS relate primarily to the loss of intestinal absorptive urface and more rapid intestinal transit. The consequences of malabsorpion of nutrients include malnutrition, diarrhea, steatorrhea, specific utrient deficiencies, and fluid and electrolyte imbalance. These patients re at risk for other specific complications, which include an increased ncidence of cholelithiasis, gastric hypersecretion, nephrolithiasis, and iver disease. The history of SBS is one of long-standing interest but more recent dvancements. Koeberle reported the first patient surviving massive esection of the small intestine in 1880. The clinical consequences of iarrhea and malabsorption were described by Senn in 1888. Mall eported using reversed intestine segments to improve these symptoms in 896. Functional adaptation after massive resection was well documented y Flint in 1912. In 1935, Haymond reviewed 257 cases of extensive 8 feet resected) intestinal resection. He found that only 50 (20%) urvived for more than 1 year and further suggested that loss of 50% of he intestine was the upper limit of safety. Simons and Jordan reported 0 SBS patients ( 4 feet remaining small intestine) in 1969. Mesenteric ascular disease was the most common diagnosis and mortality remained igh. An important milestone was the demonstration by Wilmore and udrick in 1968 that parenteral nutrition (PN) would support nutritional

Current Management of the Short Bowel Syndrome

Short bowel syndrome is a challenging clinical problem that benefits from a multidisciplinary approach. Much progress has recently been made in all aspects of management. Medical intestinal rehabilitation should be the initial treatment focus, and several new potential pharmacologic agents are being investigated. Surgical rehabilitation using nontransplant procedures in selected patients may further improve intestinal function. Intestinal lengthening procedures are particularly promising. Intestinal transplantation has increasingly been used with improving success in patients with life-threatening complications of intestinal failure.

Maintenance of parenteral nutrition volume reduction, without weight loss, after stopping teduglutide in a subset of patients with short bowel syndrome.

BACKGROUND Teduglutide was discontinued after being tested for ≥ 24 weeks in patients with parenteral nutrition (PN) -dependent short bowel syndrome in a clinical trial for efficacy to reduce PN volume. This study was describes change in body mass index (BMI) and PN volume over 12 months in patients who stopped drug after the clinical trial. METHODS Prescribed PN volume, weight, and complications were reported. Patients with stable (NEUT, n = 15) or decreased (DEC, n = 7) PN volume by 12 months after stopping drug (NEUT/DEC, n = 22) were compared to those who had increased PN volume (INC, n = 15). With drug response defined by ≥ 20% reduction from pre-drug PN volume to end of drug therapy, 12 INC and 13 NEUT/DEC patients were drug responders. RESULTS Eleven of 20 eligible sites reported data for 39 of 53 eligible study participants, with follow-up data for 37. INC patients had shorter colon and less frequently had colon in continuity than NEUT/DEC. BMI was decreased at 3, 6, and 12 months relative to the first off-drug visit in INC patients (P = .001), but not in NEUT/DEC patients. Change in BMI off-drug was predicted by colon and small bowel length, baseline BMI, and on-drug change in PN volume (adjusted R2 = 0.708). CONCLUSIONS Gastrointestinal anatomy, baseline BMI, and PN volume reduction on-drug predicted change in BMI off-drug. Whether this response would be maintained for a longer time or in the context of a challenging clinical situation has not been evaluated.

A 25-year experience with postresection short-bowel syndrome secondary to radiation therapy.

BACKGROUND Short-bowel syndrome (SBS) can be caused by abdominal and pelvic malignancies treated by radiation therapy (XRT). The management and long-term outcome of these patients is poorly defined. METHODS This was a retrospective observational study. We reviewed 48 adults developing postresection SBS after XRT over a 25-year period. There were 36 women and 12 men ranging from 19 to 78 years. Follow-up evaluation ranged from 1 to 360 months. RESULTS The underlying cancer in women included rectum (n = 13), ovary (n = 8), uterus (n = 7), and cervix (n = 6). In men, rectal cancer (n = 4) was most common. The interval to SBS was 1 to 234 months, with 16 (33%) patients developing SBS within 12 months. The indication for surgery was intestinal obstruction in 35, fistula in 9, perforation in 5, and ischemia in 2. Thirty-four (71%) patients underwent multiple resections and residual radiation enteritis was present in 34 (71%). Thirty-six (75%) patients also underwent colectomy and 28 (58%) had an ostomy. Intestinal remnant length was 60 cm or less in 11 patients, 60 to 120 cm in 16 patients, and 120 to 180 cm in 21 patients. Parenteral nutrition was weaned in 9 (19%) patients, and 30 (62%) patients remain on parenteral nutrition. Up to half (48%) of the patients had further intestinal procedures, including 2 liver-small-bowel transplants. Mortality during the follow-up period was 35%, with 8 patients dying within 12 months. CONCLUSIONS Postresection SBS develops within months to years after XRT for mainly gynecologic and rectal malignancies. Intestinal obstruction is the most common reason for surgery. Multiple resections, colectomy, and ostomy are performed frequently. Long-term survival is possible in many patients although further surgical intervention, including transplantation, can be performed safely.

Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study

BACKGROUND Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING CymaBay Therapeutics.

Management of Ascites

The development of ascites indicates a pathological imbalance between the production and resorption of intraperitoneal fluid. The appearance and composition of ascites are variable, based on the underlying pathophysiology. Most commonly, ascites develops in the setting of decompensated cirrhosis, peritoneal infection, carcinomatosis, congestive heart failure or a combination (mixed ascites). The diagnosis can be difficult in some patients. Management options for ascites from decompensated liver disease focus on low-sodium diets and diuretics supplemented by large-volume paracentesis, transvenous intrahepatic portosystemic shunts and liver transplantation. The development of refractory ascites, hepatic hydrothorax, hyponatraemia or hepatorenal syndrome presents unique challenges to the provider and the patient. In some of these patients, therapy with liver transplantation will be the only viable therapeutic option. The diagnosis of infectious ascites, such as tuberculosis, and carcinomatous ascites remain diagnostic and therapeutic challenges for the clinician.

Radiation therapy increases the risk of hepatobiliary complications in short bowel syndrome

UNLABELLED Patients developing short bowel syndrome (SBS) are at risk for hepatobiliary complications. Radiation enteritis and radiation-induced liver disease are potential complications of radiation therapy (XRT). The authors hypothesized that SBS patients with a history of abdominal XRT would be at increased risk for hepatobiliary complications. METHODS The authors reviewed 92 adult patients developing SBS as a complication of operation for malignancy (n = 37) and/or XRT (n = 55). Hepatobiliary disease was evaluated by liver function tests, radiologic imaging, endoscopy, and histologic studies. RESULTS Rectal cancer was the most frequent tumor in both groups (36% vs 35%). There were significantly more ovarian cancers (18% vs 3%, P < .05) in the radiation group and fewer desmoid tumors (0% vs 24%, P < .05). Intestinal remnant length was similar, but radiation patients more frequently had colon present (87% vs 62%, P < .05) and were less likely to have type I anatomy (33% vs 65%, P < .05). Radiation patients were less likely to be weaned off parenteral nutrition (PN; 16% vs 41%, P < .05). Cirrhosis/portal hypertension was more frequent in the radiation group (35% vs 11%, P < .05). Radiographic evidence of fatty liver, end-stage liver disease and the risk of cholelithiasis post-SBS were similar in both groups. CONCLUSIONS SBS patients with a history of XRT were more likely to develop cirrhosis and portal hypertension than SBS patients with malignancy alone. Radiation SBS patients were less likely to wean from PN despite more favorable intestinal anatomy.

Preresection Obesity Increases the Risk of Hepatobiliary Complications in Short Bowel Syndrome

Patients developing the short bowel syndrome (SBS) are at risk for hepatobiliary disease, as are morbidly obese individuals. We hypothesized that morbidly obese SBS individuals would be at increased risk for developing hepatobiliary complications. We reviewed 79 patients with SBS, 53 patients with initial body mass index (BMI) < 35 were controls. Twenty-six patients with initial BMI > 35 were the obese group. Obese patients were more likely to be weaned off parenteral nutrition (PN) (58% vs. 21%). Pre-resection BMI was significantly lower in controls (26 vs. 41). BMI at 1, 2, and 5 years was decreased in controls but persistently increased in obese patients. Obese patients were more likely to undergo cholecystectomy prior to SBS (42% vs. 32%) and after SBS (80% vs. 39%, p < 0.05). Fatty liver was more frequent in the obese group prior to SBS (23% vs. 0%, p < 0.05) but was similar to controls after SBS (23% vs. 15%). Fibrosis (8% vs. 13%) and cirrhosis/portal hypertension (19% vs. 21%) were similar in obese and control groups. Overall, end stage liver disease (ESLD) was similar in obese and control groups (19% vs. 11%) but was significantly higher in obese patients receiving PN (45% vs. 14%, p < 0.05). Obese patients developing SBS are at increased risk of developing hepatobiliary complications. ESLD was similar in the two groups overall but occurs more frequently in obese patients maintained on chronic PN.

Practice, Knowledge, and Barriers for Screening of Hepatocellular Carcinoma Among High-Risk Chinese Patients

BACKGROUND Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths in China. Considering its poor prognosis when diagnosed late, Chinese guidelines recommend biannual screening for HCC with abdominal ultrasound and serum α-fetoprotein (AFP) test for high-risk populations. OBJECTIVES To investigate the practice, knowledge, and self-perceived barriers for HCC screening among high-risk hospital patients in China. METHODS An interview-based questionnaire was conducted among Chinese patients with chronic hepatitis B and/or chronic hepatitis C infection from outpatient clinics at 2 tertiary medical institutions in Shanghai and Wuhan, China. FINDINGS Among 352 participating patients, 50.0% had routine screening, 23.3% had irregular screening, and 26.7% had incomplete or no screening. Significant determinants for screening included higher level of education, underlying liver cirrhosis, a family history of HCC, and better knowledge concerning viral hepatitis, HCC, and HCC screening guidelines. Moreover, factors associated with better knowledge were younger age, female gender, urban residency, education level of college or above, annual household income of greater than 150,000 RMB, and longer duration of hepatitis infection. The 3 most common barriers reported for not receiving screening were not aware that screening for HCC exists (41.5%), no symptoms or discomfort (38.3%), and lack of recommendation from physicians (31.9%). CONLUSIONS Health care professionals and community leaders should actively inform patients regarding the benefits of HCC screening through design of educational programs. Such interventions are expected to increase knowledge about HCC and HCC screening, as well as improve screening adherence and earlier diagnosis.

Risk of Intestinal Malignancy in Patients With Short Bowel Syndrome

Background: Postresection intestinal adaptation is an augmented self-renewal process that might increase the risk of malignant transformation in the intestine. Furthermore, patients with short bowel syndrome (SBS) have other characteristics that might increase this risk. Our aim was to determine the incidence of new intestinal malignancy in SBS patients. Methods: We reviewed the records of 500 adult SBS patients identified from 1982–2013. There were 199 men and 301 women ranging in age from 19–91 years. Follow-up from the time of diagnosis of SBS ranged from 12–484 months. A total of 186 (37%) patients were followed >5 years. Results: The cause of SBS was postoperative in 35% of patients, malignancy/radiation in 19%, mesenteric vascular disease in 17%, Crohn’s disease in 16%, and other in 13%. Twenty-eight (6%) patients received growth stimulatory medications. Fifteen percent of patients had a prior total colectomy. Twenty-eight (6%) patients underwent intestinal transplantation, and 115 (23%) patients had a previous abdominal malignancy, including colorectal cancer in 43 patients. Thirty-six (7%) received radiation therapy. Recurrent colon cancer was found in 2 patients, one at a stoma and the other with lung metastases. New colon cancer was found in 1 patient (0.2%), a 62-year-old woman with long-standing Crohn’s disease. Conclusion: The incidence of colon cancer in this heterogenous group of patients with SBS was similar to that of the normal population. This suggests that the risk of developing a new colon cancer in patients with SBS is not increased.