Elizabeth J. Carey

Primary biliary cirrhosis

Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.

A single-center experience of 260 consecutive patients undergoing capsule endoscopy for obscure gastrointestinal bleeding.

OBJECTIVES:Capsule endoscopy (CE) has revolutionized the evaluation of obscure gastrointestinal bleeding (OGIB) but published literature is limited to small series with heterogeneous indications. The aim of this study was to determine the findings and the diagnostic yield of CE in a large series of patients with overt and occult OGIB.METHODS:Data on 260 patients who underwent CE for overt (N = 126) or occult (N = 134) OGIB were obtained by retrospective chart review and review of an internal database of CE patients and findings.RESULTS:Visualization of the entire small bowel was achieved in 74%. The majority of exams (66%) were rated as having a good or excellent prep. Clinically significant positive findings occurred in 53%. The yield of CE in the obscure-overt group was greater than in the obscure-occult group (60% vs 46%, P = 0.03). Small bowel angioectasias were the most common finding, comprising over 60% of clinically significant lesions. The mean follow-up was 9.6 months, and there were significant reductions in hospitalizations, additional tests/procedures, and units of blood transfused after CE. Both before and after CE, patients in the overt group had more significant GI bleeding than patients in the occult group. Complications occurred in five (1.9%) cases: nonnatural excretion (four) and CE impaction at cricopharyngeus (one).CONCLUSIONS:The yield of clinically important findings on CE in patients with OGIB is 53% and is greater in patients with obscure-overt than obscure-occult GI bleeding. Angioectasias account for the majority of significant lesions in both groups. Compared with pre-CE, patients had clinical improvement post-CE in medical interventions for OGIB. Complications of CE occur in less than 2% of cases.

Six‐minute walk distance predicts mortality in liver transplant candidates

The 6‐minute walk distance (6MWD) is a simple test measuring global physical function. It is commonly used to predict mortality in patients with cardiac and pulmonary diseases, but it is also useful in assessing the functional status of patients with a variety of other medical conditions. We sought to determine (1) the characteristics of the 6MWD in patients listed for liver transplantation (LT), (2) the existence of a relationship between the 6MWD and the quality of life, and (3) the relationship between the 6MWD and survival in LT candidates. The 6MWD was prospectively measured in all patients listed for LT. The 6MWD was determined when the listed Model for End‐Stage Liver Disease (MELD) score was ≥15. Patients were followed until LT, death, removal from the wait list, or the end of the study period. Quality of life was assessed with the Short Form 36 (SF‐36). In 121 patients, the mean 6MWD was 369 ± 122 m; it was not related to age, height, weight, body mass index, albumin level, or etiology of liver disease and showed a moderate correlation with the physical component score (PCS) on the SF‐36 (r = 0.4) and a moderate inverse correlation with the native MELD score (r = −0.61). In an unadjusted analysis, a high native MELD score, a low 6MWD, and a low PCS were associated with mortality, with only the 6MWD retaining significance after adjustment for covariates. Each 100‐m increase in the 6MWD was significantly associated with increased survival (hazard ratio = 0.48, P = 0.0001), with 6MWD < 250 m being associated with an increased risk of death (P = 0.0001). In conclusion, the 6MWD is significantly reduced in patients awaiting LT and is inversely correlated with the native MELD score. A pretransplant 6MWD < 250 m is a risk for death on the wait list. Liver Transpl 16:1373–1378, 2010.

Natural History of Post-Liver Transplantation Hepatitis C: A Review of Factors That May Influence Its Course

Our aim was to assess long‐term survival in patients transplanted for HCV‐related end‐stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV‐related ESLD since the programs inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per‐protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV‐related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1‐, 5‐, and 7‐year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI ≥6 and/or fibrosis ≥2) was present in 49%, “early recurrence” (within 1 year of LT) in 30.5% and biopsy‐proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage ≥2 at 12‐month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of “rapid fibrosers” may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV‐positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV‐positive recipients. Liver Transpl 15:1872–1881, 2009.

Safety of wireless capsule endoscopy in patients with implantable cardiac defibrillators.

OBJECTIVES:Wireless video capsule endoscopy (CE) is a new technology that allows visualization of the entire small intestinal mucosa. It is indicated for the evaluation of obscure gastrointestinal bleeding (OGIB) and other disorders of the small intestine. Studies to date suggest that CE is safe and associated with few adverse events. A concern, which has not been studied, is the potential effect of CE on implanted cardiac devices such as implantable cardiac defibrillators (ICD) and other electromedical devices. We previously found CE to be safe in patients with cardiac pacemakers. The primary aim of this study was to evaluate the safety of CE in patients with ICDs who were being evaluated for OGIB. In addition, a secondary aim of the study was to determine whether ICDs had any effect on the images captured by CE.METHODS:Patients referred for the evaluation of OGIB and who also had an ICD were enrolled into the study after informed consent. Five consecutive patients (four females and one male; mean age: 72 yr; range: 60–81 yr) with ICDs were studied. All patients had transvenous endocardial ICDs located in the chest. Prior to CE, patients had a baseline electrocardiogram (ECG) and ICD interrogation. Thereafter, CE was performed in a hospital setting with telemetry monitoring performed simultaneously. A post-procedure ICD interrogation was carried out to evaluate changes in programmed parameters. A cardiologist and ICD nurse specialist together reviewed both the telemetry monitor and the post-procedure ICD interrogation on each patient. When CE studies were reviewed, observations pertaining to technical difficulties and interference with video imaging were documented.RESULTS:No arrhythmia or other adverse cardiac events were noted during capsule transmission. No interference by the ICD on the CE video images was seen.CONCLUSIONS:CE was performed safely in these five patients with ICDs, and was not associated with any adverse cardiac events. ICDs also do not appear to interfere with video capsule imaging.

Recent advances in the development of farnesoid X receptor agonists

Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.

Endoscopic capsule endoscope delivery for patients with dysphagia, anatomical abnormalities, or gastroparesis

BACKGROUND Capsule endoscopy relies on an intact swallowing mechanism and unimpeded passage of the capsule through the pylorus. A technique is described for endoscopic delivery of the capsule in patients with dysphagia, anatomical abnormality, or gastroparesis. METHODS EGD is performed with concomitant placement of an overtube. A foreign body net retrieval device is passed through the endoscope and used to grasp the activated capsule in the net. The endoscope then is advanced through the overtube, and the capsule is released in the duodenum. OBSERVATIONS Five patients underwent endoscopic placement of the capsule. Relative contraindications to peroral ingestion were the following: oropharyngeal dysphagia, pyloric stenosis (2), prior gastric surgery, and gastroparesis. Endoscopic delivery was successful in all cases and yielded positive findings in 4. There was no complication. CONCLUSIONS Endoscopic delivery of the capsule endoscope for patients with dysphagia, anatomical abnormality, or gastroparesis is safe and effective.

A multicenter study to define sarcopenia in patients with end‐stage liver disease

Sarcopenia is associated with increased wait‐list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end‐stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross‐sectional area (cm2) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait‐list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex‐specific potential cutoff values to define sarcopenia were determined with a grid search guided by log‐rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm2/m2: 50.0 in men and 42.0 in women. At a median of 8.8 months follow‐up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm2/m2; P < 0.001), and SMI was associated with wait‐list mortality (hazard ratio, 0.95; P < 0.001). Optimal search method yielded SMI cutoffs of 50 cm2/m2 for men and 39 cm2/m2 for women; these cutoff values best combined statistical significance with a sufficient number of events to detect survival differences between groups. In conclusion, we recommend that an SMI < 50 cm2/m2 for men and < 39 cm2/m2 for women be used to define sarcopenia in patients with ESLD awaiting LT. Liver Transplantation 23 625–633 2017 AASLD.

Coccidioidal Pneumonia, Phoenix, Arizona, USA, 2000-2004

A prospective evaluation identified Coccidioides spp. as frequent causes of community-acquired pneumonia.

The prevention of recrudescent coccidioidomycosis after solid organ transplantation.

Background. Coccidioidomycosis is an endemic fungal infection of the southwestern United States that causes considerable morbidity and mortality in transplant recipients, often as the result of reactivated infection. Methods. A retrospective review of the medical records of 47 patients with prior coccidioidomycosis who underwent solid organ transplantation (18 liver, 24 kidney, 3 pancreas, and 2 combined organ) at our tertiary care academic medical center. Results. Of 47 transplant recipients with a history of coccidioidomycosis, 44 had quiescent infection at transplantation. Of the three with active coccidioidomycosis at transplantation, two were taking azole prophylaxis and had no further coccidioidal infection after transplantation. One of the three had positive serologic findings identified only on the day of transplantation, and prophylaxis was initiated a few hours after surgery along with immunosuppression; nevertheless, the treatment course was complicated by disseminated coccidioidomycosis. Seven patients did not initiate or self-discontinued prophylaxis; one patient who discontinued prophylaxis experienced recurrent pulmonary infection. Conclusions. For patients undergoing transplantation in an area endemic for coccidioidomycosis, we recommend routine evaluation for evidence of prior infection and initiation of azole prophylaxis. For our patients with quiescent infection, azoles suppressed any recrudescent coccidioidomycosis after transplantation. The selection of patients who would benefit from prophylaxis and the optimal dose and duration of such prophylaxis should be studied further.