Review of Sarcopenia and Testosterone Deficiency With Chronic Liver Disease and Postoperative Liver Transplant Utility of Short-Term Testosterone Replacement Therapy.

OBJECTIVES: Chronic liver disease is often associated with testosterone deficiency. However, testosterone replacement does not improve hepatic function or survival with diseased liver. So far, to our knowledge, testosterone replacement therapy after successful livertransplantforfunctional sarcopenia has not been studied. We had 3 goals: (1) define postoperative functional sarcopenia afterlivertransplant with serum testosterone level; (2) examine the role of short-term testosterone replacement therapy with active in-bed exercise of upper and lower extremity joints; and (3) correlate functional sarcopenia with skeletal muscle index and skeletal muscle density in relation to ascites, pleural effusion subtracted body mass index. MATERIALS AND METHODS: We evaluated 16 liver transplant recipients who had been receiving posttransplanttestosterone replacementtherapy with functional sarcopenia. Preoperative and postoperative demographics and laboratory and radiological data were retrieved; body mass index, skeletal muscle index, and skeletal muscle density were calculated. For this retrospective study, institutional review board approval was obtained before the electronic database was reviewed and analyzed. RESULTS: Mean testosterone level was 28.3 ng/dL (<5% of expected). Twelve patients received 1 dose, and the remaining 4 patients received >1 dose oftestosterone cypionate, 200 mg. Mean hospital stay was 26 days. Seven patients were discharged home, with the remaining patients to a rehabilitation facility or nursing home. One patient died from a cardiac event, and another patient died from recurrent metastatic malignancy. The 1-year and 5-year actuarial patient and graft survival rates were 93.8% and 87.5%, respectively. Overall, 5 patients were sarcopenic by skeletal muscle index, and 6 patients had poor muscle quality by skeletal muscle density. CONCLUSIONS: Testosterone deficiency after liver transplant exists with functional sarcopenia. Two- thirds of such recipients have low skeletal muscle index and/or have low skeletal muscle density. Short- term testosterone replacement therapy with in-bed active exercise provides 5-year patient and graft survival of 87.5%.

Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.

BACKGROUND: Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. METHODS: The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. RESULTS: We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) versus 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. CONCLUSION: Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Incidence of Post-Liver Transplant Hepatic Dysfunction After Sustained Virologic Response Following Direct-Acting Anti-Hepatitis C Therapy.

OBJECTIVES: Newly developed, direct-acting antiviral therapy is effective in over 90% of cases to eradicate hepatitis C virus infection. Direct-acting antiviral therapy is also effective in liver transplant recipients with recurrent hepatitis C virus infection. However, hepatic function after sustained virologic response in transplant recipients is unknown. Here, we aimed to uncover the incidence of hepatic dysfunction in this patient group at our center. MATERIALS AND METHODS: Our study included 40 consecutive (January 2014 to February 2016) and compliant posttransplant recipients who achieved sustained viral response from direct-acting antiviral therapy. Patients were investigated for incidence and causes of hepatic dysfunction. RESULTS: In our patient group, 4 (10%) experienced hepatic dysfunction with stable baseline immunosuppression, with 2 having drastic increases in alanine aminotransferase at 15 and 32 weeks after direct-acting antiviral therapy. Biopsies showed hepatitis, and both patients were treated with hydrocortisone, which increased their baseline immunosuppression. The 3rd patient had an increase in bilirubin at 21 weeks posttherapy, with biopsy showing macrovascular steatosis. The 4th patient had a rapid increase in bilirubin at 7 weeks after direct-acting antiviral therapy, with biopsy showing significant duct loss. CONCLUSIONS: During the study period, 10% of patients experienced hepatic dysfunction after sustained viral response. Presumed causative factors included partial immune reconstitution and nonalcoholic fatty liver disease.

A Developmental Approach to Internal Medicine Residency Education: Lessons Learned from the Design and Implementation of a Novel Longitudinal Coaching Program.

BACKGROUND: Resident physicians' achievement of professional competencies requires reflective practice skills and faculty coaching. Graduate medical education programs, however, struggle to operationalize these activities. OBJECTIVE: To (1) describe the process and strategies for implementing an Internal Medicine (IM) resident coaching program that evolved in response to challenges, (2) characterize residents' professional learning plans (PLPs) and their alignment with EPAs, and, (3) examine key lessons learned. DESIGN: The program began in 2013 and involved all postgraduate years (PGY) residents (n = 60, 100%), and 20 faculty coaches who were all IM trained and practicing in an IM-related specialty. One coach was linked with 3-4 residents for three years. Through 1:1 meetings, resident-coach pairs identified professional challenges ('disorienting dilemmas' or 'worst days'), reviewed successes ('best days'), and co-created professional learning plans. Typed summaries were requested following meetings. Coaches met monthly for professional development and to discuss program challenges/successes, which informed programmatic improvements; additionally, a survey was distributed after three program years. Data were analyzed using quantitative and qualitative methodologies. RESULTS: Disorienting dilemmas and professional learning plans mapped to all 16 EPAs and four additional themes: work-life balance, career planning, teaching skills, and research/scholarship. The most-frequently mapped topics included: PGY1 - leading and working within interprofessional care teams (EPA 10), research and scholarship, and work-life balance; PGY2 - improving quality of care (EPA 13), demonstrating personal habits of lifelong learning (EPA15), and research and scholarship; PGY3 - lifelong learning (EPA15); career planning was common across all years. CONCLUSIONS: Lessons learned included challenges in coordination of observations, identifying disorienting dilemmas, and creating a shared mental model between residents, faculty, and program leadership. The coaching program resulted in professional learning plans aligned with IM EPAs, in addition to other professional development topics. Operationalization of aspects of these results can inform the development of similar programs in residency education.

Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy?

BACKGROUND: Recently, a controversy has emerged: is the rate of recurrence of hepatocellular carcinoma (HCC) higher following treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapy? However, the risk of HCC recurrence has not been studied in liver transplant (LTx) recipients who received DAA therapy. The aim of the present study is to compare the rate of HCC recurrence in LTx recipients who did or did not receive DAA therapy. PATIENTS AND METHODS: Sixty-three patients received LTx with HCC. Twenty-seven (42.9%) with HCV received DAA therapy (Group A), 20 (31.7%) with HCV did not receive DAA therapy (Group B), and 16 (25.4%) did not have HCV (Group C). RESULTS: In group A, three (11%), in group B, one (5%), and in group C, none had recurrence of HCC. Actuarial 4-year recurrence-free survival was 88.9, 95, and 100% in group A, B, and C, respectively (p = 0.37). Group A was subdivided into two groups for comparison with Group B: A1 included five patients who had end of treatment response (ETR) without sustained virological response (SVR), and A2 included 20 patients who achieved SVR. Three patients from A1 had HCC recurrence and no patients from A2 had HCC recurrence. (p = 0.0038; group A1, A2, and B). CONCLUSIONS: The rate of HCC recurrence in LTx patients with DAA therapy was significantly higher with ETR, without SVR, after DAA therapy compared to patients with SVR or patients who did not receive DAA therapy. LTx recipients with HCC receiving DAA therapy requires further studies.

Pulse Oximetry Is Insensitive for Detection of Hepatopulmonary Syndrome in Patients Evaluated for Liver Transplantation.

Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2 ), arterial blood gas, spirometry, and contrast-enhanced echocardiography (CE). HPS was defined as an alveolar-arterial gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%-25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c-statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51-0.66). An SpO2 <96%, recommended by practice guidelines as a threshold to require further testing, had low sensitivity (28%; 95% CI, 18%-28%). The c-statistic of SpO2 in discriminating HPS with a partial pressure of oxygen (PaO2 ) <60 mm Hg (eligible for LT exception points) was 0.76 (95% CI, 0.46-1.00). An SpO2 cutoff of <96% had higher sensitivity for detecting HPS with PaO2 <60 mm Hg (71%; 95% CI, 38%-100%) but was still inadequate. Conclusion: Pulse oximetry is not sufficiently sensitive to screen for HPS in LT candidates. Arterial blood gas and CE are required in LT candidates for diagnosis of HPS.

Frontiers in Gastrointestinal Oncology: Advances in Multi-Disciplinary Patient Care.

Cancers of the digestive system remain highly lethal; therefore, the care of patients with malignant diseases of the digestive tract requires the expertise of providers from multiple health disciplines. Progress has been made to advance the understanding of epidemiology and genetics, diagnostic and screening evaluation, treatment modalities, and supportive care for patients with gastrointestinal cancers. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference at the Hershey Country Club in Hershey, Pennsylvania on 29 September 2017, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this oncological specialty. In this continuing medical education-certified conference, updates on the population sciences including health disparities and resistance training were presented. Progress made in various diagnostic evaluation and screening procedures was outlined. New developments in therapeutic modalities in surgical, radiation, and medical oncology were discussed. Cancer genetic testing and counseling and the supportive roles of music and arts in health and cancer were demonstrated. In summary, this disease-focused medical conference highlighted the new frontiers in gastrointestinal oncology, and showcase the multi-disciplinary care provided at the Penn State Cancer Institute.

Esophageal capsule endoscopy is not the optimal technique to determine the need for primary prophylaxis in patients with cirrhosis.

INTRODUCTION: Capsule endoscopy has been suggested as a potential alternative to endoscopy for detection of esophagogastric varices and severe portal hypertensive gastropathy (PHG). The aim of the study was to determine whether PillCam esophageal capsule endoscopy could replace endoscopy for screening purposes. MATERIAL AND METHODS: Sixty-two patients with cirrhosis with no previous variceal bleeding had PillCam capsule endoscopy and video endoscopy performed on the same day. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of capsule endoscopy were compared to endoscopy for the presence and severity of esophageal and gastric varices, PHG and the need for primary prophylaxis. Patients' preference was assessed by a questionnaire. RESULTS: Four (6%) patients were unable to swallow the capsule. Sensitivity, specificity, PPV and NPV of capsule endoscopy for detecting any esophageal varices (92%, 50%, 92%, 50%), large varices (55%, 91%, 75%, 80%), variceal red signs (58%, 87%, 69%, 80%), PHG (95%, 50%, 95%, 50%), and the need for primary prophylaxis (91%, 57%, 78%, 80%) were not optimal, with only moderate agreement (κ) between capsule and upper GI endoscopy. Had only a capsule endoscopy been performed, 12 (21.4%) patients would have received inappropriate treatment. Capsule endoscopy also failed to detect (0/13) gastric varices. The majority of patients ranked capsule endoscopy as more convenient (69%) and their preferred (61%) method. CONCLUSIONS: Despite the preference expressed by patients for capsule endoscopy, we believe that upper GI endoscopy should remain the preferred screening method for primary prophylaxis.

Hepatic hydrothorax.

Hepatic hydrothorax is defined as a transudative pleural effusion, usually greater than 500 mL, in patients with portal hypertension without any other underlying primary cardiopulmonary cause. It develops most likely because of diaphragmatic defects that allow for passage of fluid from the peritoneal space to the pleural space. Because of the mechanical constraints of the thoracic cavity, this complication of portal hypertension can be challenging to treat because patients will become symptomatic when as little as 500 mL of fluid is present in the pleural space. Treatments include salt restriction, diuretics, thoracentesis, transjugular intrahepatic portosystemic shunt, video-assisted thoracoscopy, and pleurodesis. It is important to note that a chest tube is not a potential treatment option; a hepatic hydrothorax should not be treated with a chest tube unless there is frank pus in the pleural fluid or a pneumothorax is present. The ultimate treatment is a liver transplant; the development of a hepatic hydrothorax thus warrants a referral to a liver transplant center.

Endoscopic management of biliary complications after liver transplantation.

Complications of the biliary tract are an important cause of morbidity and mortality after liver transplantation. The most frequent complications are anastomotic biliary tract strictures, bile leaks, and bile duct stones. The estimated incidence of these complications ranges between 5% and 25%, although rates have been decreasing in recent years. Most complications can be managed successfully with endoscopic retrograde cholangiography. This article reviews the various biliary complications after liver transplantation (both deceased donor and living-related donor) and their endoscopic management.

Insulin resistance and microalbuminuria are associated with microvascular disease in patients with cirrhosis.

Cardiovascular (CV) disease has a significant impact on post-liver transplantation (LT) survival. Finding surrogate markers for occult CV disease would improve CV assessment in the LT evaluation. This study was designed to determine the prevalence of microvascular disease (MVD) and the utility of both microalbuminuria and the homeostatic model for insulin resistance (HOMA-IR) for assessing the presence of MVD in potential LT recipients. In this study, we examined the prevalence of MVD in 72 diabetics and 71 nondiabetics; both groups were matched for age, sex, race, and etiology of cirrhosis while awaiting LT. We prospectively collected data including fasting serum insulin and glucose levels, urine creatinine and microalbumin, and macrovascular and microvascular complications. MVD was present in 58 (40.5%) patients; MVD was more common in diabetics (n = 45, 62.5%) than nondiabetics (n = 13, 18.3%). The presence of diabetes mellitus (DM; P = 0.03), insulin use (P = 0.002), and duration (months) of DM (85.3 +/- 96.1 versus 22.1 +/- 46.3, P < 0.0001), hypertension (51.3 +/- 101.5 versus 22.7 +/- 58.2, P = 0.03), and hypertriglyceridemia (7.2 +/- 17.4 versus 3.8 +/- 18.5, P = 0.04) were associated with MVD. Significant microalbuminuria had a sensitivity of 85%, a specificity of 100%, and a positive predictive value of 100% for the presence of MVD. HOMA-IR also was associated with MVD (P = 0.0001). In conclusion, at our center, 62.5% of DM patients and 18% of non-DM patients awaiting LT have MVD. Patients with DM, significant microalbuminuria, or an elevated HOMA-IR should undergo rigorous CV assessment prior to LT.

Management of autoimmune and cholestatic liver disorders.

The management of autoimmune and cholestatic liver disorders is a challenging area of hepatology. Autoimmune and cholestatic liver diseases represent a comparatively small proportion of hepatobiliary disorders, yet their appropriate management is of critical importance for patient survival. In this article, management strategies are discussed, including the indications and expectations of pharmacologic therapy, endoscopic approaches, and the role of liver transplantation.

Lymphadenopathy, elevated liver function tests and weight loss in a 68-year-old man.

A 68-year-old man presented to the hospital with fevers, weight loss, lymphadenopathy and abnormal liver-associated enzymes. After a thorough workup, a liver biopsy demonstrated histiocytes with phagocytosis of the lymphocytes and a positive immunostain for S-100. The diagnosis of Rosai-Dorfman disease was made. This case report will discuss the patient's presentation as well as the diagnosis and treatment of this rare, non-malignant disorder, which only rarely affects the liver.

Trends in post-liver transplant survival in patients with hepatitis C between 1991 and 2001 in the United States.

It has been suggested that the post-liver transplantation (LT) survival rate of patients with hepatitis C virus infection (HCV) has declined in recent years. To compare the outcome of LT in patients with HCV at various time intervals between 1991 and 2001, we used United Network for Organ Sharing data to compare the post-LT survival of adult patients (age >18 years) with HCV with those without HCV. Of the 37,101 patients who underwent LT during the study period, 28,193 patients (HCV 7,459 and 20,734 non-HCV) were eligible for the study. On the basis of the time of transplantation, patients were divided into 3 groups: 1991-1993 (period 1), 1994-1997 (period 2), and 1998-2001 (period 3). The patient and graft survival rates were adjusted for other known confounding variables that influenced outcomes. The 3-year patient survival rate was lower in HCV patients compared with non-HCV recipients (78.5% vs. 81.4%, hazard ratio 1.14, 95% confidence interval 1.05-1.23, P = 0.001). The graft (72.8%, 71.0%, and 69.8%) and patient (77.4%, 79.6%, and 78.5%) survival of HCV patients remained unchanged during study periods 1-3, respectively. However, the graft and patient survival rates of non-HCV recipients improved markedly during study periods 2 and 3 compared with period 1. The graft and patient survival has remained unchanged between 1991 and 2001 in HCV recipients, but during the same period, there was a great improvement in survival among non-HCV recipients.