David N. Assis

The role of macrophage migration inhibitory factor in autoimmune liver disease

The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional −794 CATT5‐8 microsatellite repeat (rs5844572) and a −173 G/C single‐nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high‐expression −794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme‐linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. Conclusions: These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases. (Hepatology 2014;59:580–591)

Successful treatment of a bleeding umbilical varix by percutaneous umbilical vein embolization with sclerotherapy.

Bleeding caused by ectopic varices is an uncommon but important and life-threatening complication of portal hypertension. Spontaneous external hemorrhage from a recanalized umbilical varix is an extremely rare source of ectopic variceal bleeding. We report on the acute presentation of a patient with a bleeding umbilical varix and successful treatment with percutaneous umbilical vein embolization with sclerotherapy. This previously unreported technique is described, which adds a new therapeutic option for the management of this challenging clinical dilemma. A discussion on the recognition and management of ectopic varices is also provided.

Combination Therapy of All-Trans Retinoic Acid With Ursodeoxycholic Acid in Patients With Primary Sclerosing Cholangitis: A Human Pilot Study

Goals: To perform an exploratory pilot study of all-trans retinoic acid (ATRA) combined with ursodeoxycholic acid (UDCA) in patients with primary sclerosing cholangitis (PSC). Background: PSC is a progressive disorder for which there is no accepted therapy. Studies in human hepatocyte cultures and in animal models of cholestasis indicate that ATRA might have beneficial effects in cholestatic disorders. Study: ATRA (45 mg/m2/d, divided and given twice daily) was combined with moderate-dose UDCA in patients with PSC who had incomplete response to UDCA monotherapy. The combination was administered for 12 weeks, followed by a 12-week washout in which patients returned to UDCA monotherapy. We measured alkaline phosphatase (ALP), alanine aminotransferase (ALT), bilirubin, cholesterol, bile acids, and the bile acid intermediate 7&agr;-hydroxy-4-cholesten-3-one (C4) at baseline, week 12, and after washout. Results: Fifteen patients completed 12 weeks of therapy. The addition of ATRA to UDCA reduced the median serum ALP levels (277±211 to 243±225 U/L, P=0.09) although this, the primary endpoint, did not reach significance. In contrast, median serum ALT (76±55 to 46±32 U/L, P=0.001) and C4 (9.8±19 to 7.9±11 ng/mL, P=0.03) levels significantly decreased. After washout, ALP and C4 levels nonsignificantly increased, whereas ALT levels significantly increased (46±32 to 74±74, P=0.0006), returning to baseline. Conclusions: In this human pilot study, the combination of ATRA and UDCA did not achieve the primary endpoint (ALP); however, it significantly reduced ALT and the bile acid intermediate C4. ATRA appears to inhibit bile acid synthesis and reduce markers of inflammation, making it a potential candidate for further study in PSC (NCT 01456468).

Gastrointestinal Disorders in Cystic Fibrosis

Gastrointestinal (GI) manifestations commonly complicate the care of patients with cystic fibrosis (CF). Despite recent approval of CF transmembrane conductance regulator modulating agents that can improve pulmonary function, GI disorders continue to be relevant and require innovative therapies. This article discusses the most common GI complications of CF, including reflux, pancreatic insufficiency, small bowel intestinal overgrowth, distal intestinal obstruction syndrome, and GI malignancy, with emphasis on clinical presentation and management.

The clinical significance of the MIF homolog d-dopachrome tautomerase (MIF-2) and its circulating receptor (sCD74) in burn

BACKGROUND We reported earlier that the cytokine macrophage migration inhibitory factor (MIF) is a potential biomarker in burn injury. In the present study, we investigated the clinical significance of the newly discovered MIF family member d-dopachrome tautomerase (DDT or MIF-2) and their common soluble receptor CD74 (sCD74) in severely burned patients. METHODS DDT and sCD74 serum levels were measured 20 severely burned patients and 20 controls. Serum levels were correlated to the abbreviated burn severity index (ABSI) and total body surface area (TBSA) followed by receiver operating characteristic (ROC) analysis. Data were supported by gene expression dataset analysis of 31 burn patients and 28 healthy controls. RESULTS CD74 and DDT were increased in burn patients. Furthermore, CD74 and DDT also were elevated in septic non-survivors when compared to survivors. Serum levels of DDT showed a positive correlation with the ABSI and TBSA in the early stage after burn, and the predictive character of DDT was strongest at 24h. Serum levels of CD74 only correlated with the ABSI 5 days after injury. CONCLUSIONS DDT may assist in the monitoring of clinical outcome and prediction of sepsis during the early post-burn period. Soluble CD74 and MIF, by contrast, have limited value as an early predictor of death due to their delayed response to burn.

The interpretation of hepatic venous pressure gradient tracings ‐ Excellent interobserver agreement unrelated to experience

The hepatic venous pressure gradient (HVPG) plays an important role in the diagnosis, prognosis and therapy of patients with cirrhosis and portal hypertension. One barrier to its widespread use is the potential for a low reproducibility. We aimed to evaluate the interobserver agreement in the interpretation of optimally acquired HVPG tracings from patients with cirrhosis and different degrees of portal hypertension.

Gallbladder and bile duct disease in Cystic Fibrosis

Cystic fibrosis (CF) is a multi-organ, clinically diverse disorder caused by mutations in the cystic fibrosis transmembrane conductance receptor (CFTR). Awareness of extra-pulmonary manifestations, including gastrointestinal and hepatobiliary disturbances, is an increasingly important part of providing high-quality care to patients with CF. Furthermore, biliary disorders, including gallbladder and bile duct disease, are common complications of CF. Therefore, a thorough understanding and efficient clinical evaluation of the gallbladder and biliary tree is an important aspect of integrated care for the patient with CF in order to prevent progression of undetected pathology. This best practice article summarizes the basis for gallbladder and bile duct pathology, describes the context and clinical presentation of biliary disease, and provides recommended approaches to delivery of high-quality care for patients with CF.

Primary Sclerosing Cholangitis Is Not Rare Among Blacks in a Multicenter North American Consortium

Primary sclerosing cholangitis (PSC) is a progressive autoimmune liver disease characterized by bile duct inflammation and fibrosis. Our understanding of PSC is shaped largely from populations in Europe and the US that almost exclusively included white patients of Northern European descent.1–5 In an ongoing NIH-sponsored PSC cohort study of 1,000 patients, only 5% of subjects are non-Caucasian.6 As a result, little is known about PSC in minority populations in the US, particularly patients of black race, and it is unknown if PSC is a rare disease in patients of black race, or reflects selection bias of sampled cohorts.

Editorial: environmental risk factors for PSC with and without IBD--the story unfolds.

fetoprotein levels were very high (range 1086– 179 430 ng/mL) in 13/16 cases. The non-invasive diagnostic criteria were fulfilled in all. No coexistent risk factors for HCC such as smoking, alcohol or hepatitis B/C infections (all viral markers including anti-HBc were negative) were present in the HVOTO patients. Drs Parikh and Fontana stated that, ‘Important inferences from this study include the much lower annual incidence of HCC in this large cohort of HVOTO patients (0.35%) compared to prior estimates (2–50%) reported in a recent metaanalysis.’ The meta-analysis quoted in the editorial provides data on the prevalence of HCC among HVOTO and does not provide data on the incidence of HCC among HVOTO. This variable prevalence of 2.0–46.2% has already been compared with low prevalence of 1.9% in the present study by us in the discussion section of the manuscript. For incidence rate, this probably is the solitary cohort study documenting the cumulative incidence of HCC (3.5% in 10 years, CI 1.3–9.2%; figure 4, page 6 in the manuscript) which shows progressive increase over time. We acknowledge that over 10 years of follow-up data on incident HCC on all patients would be desirable but would like to clarify that we had 10 years of follow-up data on at least 17% (70/413) of patients (survival curve, figure 4). To conclude, we agree that the incidence of HVOTOHCC is low. Patients with long segment IVC block or combined IVC and HV block may be vulnerable to develop HCC if the obstruction is unrelieved, and progressive liver damage ensues resulting in development of HCC in the damaged liver.

The role of macrophage migration inhibitory factor in autoimmune liver disease: Assis et al.

The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional −794 CATT5‐8 microsatellite repeat (rs5844572) and a −173 G/C single‐nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high‐expression −794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme‐linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. Conclusions: These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases. (Hepatology 2014;59:580–591)