Graziella Privitera

Adrenocortical dysfunction in liver disease: A systematic review

In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term “hepato‐adrenal syndrome” was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250‐μg adreno‐cortico‐tropic‐hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies. (HEPATOLOGY 2012)

Assessment of adrenocortical reserve in stable patients with cirrhosis

BACKGROUND & AIMS Adrenal insufficiency (AI) is reported in critically ill patients with cirrhosis and is associated with increased mortality. It is unclear if AI is an underlying condition or triggered by critical events (e.g. sepsis). We investigated AI in cirrhosis without infection or hemodynamic instability. METHODS A total of 101 consecutive patients with cirrhosis were studied. AI was defined by a total serum cortisol (TC) <18 μg/dl at 20 or 30 min after injection of 1 μg of tetracosactrin. Transcortin, calculated free cortisol (cFC), and free cortisol index (FCI) were assessed in a subgroup of 41 patients, with FCI>12 representing normal adrenal function. RESULTS AI was present in 38 patients (38%). Child score (median, 10 vs 7, p<0.0001), MELD score (median, 17 vs 12, p<0.0001), ascites (68% vs 37%, p<0.01), basal TC (median,7.6 vs 14.9 μg/dl, p<0.001), albumin (28 ± 0.8 vs 33 ± 0.7 g/L, p<0.0001), INR (median, 1.6 vs 1.2, p<0.0001), total bilirubin (median, 51 vs 31 μmol/L, p<0.05), total cholesterol (median, 120 vs 142, p<0.05), and LDL (median, 76 vs 81, p<0.05) were significantly different between those with and without AI. ROC curves showed a basal TC ≤ 12.8 μg/dl to be a cut-off value closely associated with AI. The cFC was significantly related to TC for baseline values (R=0.94, p<0.0001), peak values (R=0.90, p<0.0001), and delta values (R=0.95, p<0.0001), in patients with and without AI. However, no patient had a FCI<12. CONCLUSIONS AI defined by an abnormal response to 1 μg tetracosactrin is frequent in stable patients with cirrhosis, in the absence of infections or hemodynamic instability and is related to the severity of liver disease. However, evaluation of the true incidence of AI should comprise direct assays of free cortisol. Clinical consequences of AI need to be explored.

Apolipoprotein AI and HDL are reduced in stable cirrhotic patients with adrenal insufficiency: A possible role in glucocorticoid deficiency

Abstract Backgrounds and aims: Adrenal insufficiency (AI) has been reported in patients with stable cirrhosis. A lack of substrates has been suggested as a possible contributing pathogenic mechanism leading to glucocorticoid deficiency in these subjects. To better explore this hypothesis, we studied lipoproteins in cirrhotics with and without AI. Methods. A total of 81 cirrhotic patients and 30 normal volunteers were enrolled. The severity of liver disease was graded by Child-Pugh score. Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and apolipoprotein AI (Apo-AI) levels were evaluated. HDL subfractions were measured by gradient gel electrophoresis. Adrenal function was assessed by the Low-Dose Short Synacthen Test. Results. Cirrhotic patients showed a significant reduction of TC, HDL, LDL, TG, and Apo-AI levels compared with controls. HDL3 was significantly lower, while HDL2 was higher, in cirrhotics compared with the controls. AI was observed in 26 patients. TC, TG, HDL, and Apo-AI were significantly reduced in cirrhotics with AI compared with those with normal adrenal function. HDL2 and HDL3 did not differ between these two groups. Delta cortisol was related to TC (r = 0.30, p < 0.01), TG (r = 0.22, p = 0.05), and Apo-AI (r = 0.37, p < 0.001). Multivariate analysis revealed that Apo-AI and HDL were independently associated with AI. Conclusion. Our study shows that TC, TG, HDL, and Apo-AI are reduced in cirrhotics with AI. In particular, because both HDL and Apo-AI play a primary role in providing substrates for steroidogenesis to adrenal cells, this deficiency may contribute to the pathogenesis of AI in these patients.

Abnormalities of Lipoprotein Levels in Liver Cirrhosis: Clinical Relevance

Progressive lipoprotein impairment occurs in liver cirrhosis and is associated with increased morbidity and mortality. The present review aims to summarize the current evidence regarding the prognostic value of lipoprotein abnormalities in liver cirrhosis and to address the need of a better prognostic stratification of patients, including lipoprotein profile assessment. Low levels of lipoproteins are usual in cirrhosis. Much evidence supports the prognostic role of hypolipidemia in cirrhotic patients. In particular, hypocholesterolemia represents an independent predictor of survival in cirrhosis. In cirrhotic patients, lipoprotein impairment is associated with several complications: infections, malnutrition, adrenal function, and spur cell anemia. Alterations of liver function are associated with modifications of circulating lipids. Decreased levels of lipoproteins significantly impact the survival of cirrhotic patients and play an important role in the pathogenesis of some cirrhosis-related complications.

Guidelines on the management of atrial fibrillation in the emergency department: a critical appraisal

Several guidelines often exist on the same topic, sometimes offering divergent recommendations. For the clinician, it can be difficult to understand the reasons for this divergence and how to select the right recommendations. The aim of this study is to compare different guidelines on the management of atrial fibrillation (AF), and provide practical and affordable advice on its management in the acute setting. A PubMed search was performed in May 2014 to identify the three most recent and cited published guidelines on AF. During the 1-week school of the European School of Internal Medicine, the attending residents were divided in five working groups. The three selected guidelines were compared with five specific questions. The guidelines identified were: the European Society of Cardiology guidelines on AF, the Canadian guidelines on emergency department management of AF, and the American Heart Association guidelines on AF. Twenty-one relevant sub-questions were identified. For five of these, there was no agreement between guidelines; for three, there was partial agreement; for three data were not available (issue not covered by one of the guidelines), while for ten, there was complete agreement. Evidence on the management of AF in the acute setting is largely based on expert opinion rather than clinical trials. While there is broad agreement on the management of the haemodynamically unstable patient and the use of drugs for rate-control strategy, there is less agreement on drug therapy for rhythm control and no agreement on several other topics.

Emerging hepatic syndromes: pathophysiology, diagnosis and treatment

Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions.

Hypothalamus-pituitary dysfunction is common in patients with stable cirrhosis and abnormal low dose synacthen test

BACKGROUND Adrenal insufficiency is often present in cirrhosis. We hypothesize that a prolonged adrenocorticotropic hormone (ACTH) stimulus can restore cellular capacity of adrenal glands to secrete cortisol. Aim of our study was to assess adrenal responsiveness to prolonged ACTH stimulation in cirrhotics. METHODS Prospective observational study in 121 consecutively admitted cirrhotic patients undergoing a low dose short synacthen test and plasma ACTH measurement using a chemiluminescence immunoassay. Long synacthen test was performed if the low dose was abnormal. RESULTS 46 patients had abnormal low dose short test (38%), and 29 underwent the long test: 41% showed normal response (Group 1), 55% showed delayed response (Group 2) and 1 had abnormal response (4%). Baseline ACTH levels did not significantly differ between the two groups. Median basal cortisol was higher in Group 1 (296 vs. 198 nmol/L; p=0.02). Using ROC curve basal cortisol <254 nmol/L was associated with a delayed long synacthen test response (AUC 0.78, p=0.001) with good accuracy (sensitivity 67%, specificity 81%). CONCLUSION A delayed cortisol response after a prolonged ACTH stimulation is found in over fifty percent of cirrhotics with abnormal low dose short synacthen test, confirming that the mechanism of hypoadrenalism in these patients could be related both to adrenal cellular dysfunction and hypothalamus-pituitary adrenal axis impairment.

OC-35 Hypothalamus-pituitary dysfunction accounts for adrenal insufficiency in cirrhosis

Background: Little is known on changes of replication of HCV replication during chemotherapy and on correlated hepatic flares. Aims: To evaluate changes in HCV-RNA load in plasma and PBMC of patients with onco-hematological diseases (OHD) during and after chemotherapy (CT). Methods: Thirty-six consecutive patients with OHD (21 with B-cell nonHodgkin Lymphoma, 9 chronic lymphocytic leukemia, 5 multiple myeloma and 1 Hodgkin Lymphoma), naive for CT, were enrolled: 8 were antiHCV/HCV-RNA positive (HCV-POS group) and 28 anti-HCV negative (HCV-NEG group). Twenty-three patients, 7 in HCV-POS and 16 in HCVNEG group, received Rituximab-based CT for 4-6 months. HCV-RNA was searched by a ultra-sensitive real time RT-PCR in Light Cycler 1.5 on plasma and PBMC samples collected before, during and after CT. Results: In all the 7 patients treated with Rituximab-based CT in the HCVPOS group, an increase in HCV load of at least of 1.5 log in plasma and of 1.1 in PBMC was observed during CT. A hepatic flare (increase in ALT> 4 times the previous values) occurred after CT discontinuation in these 7 patients; in the patient with cirrhosis the hepatic flare was associated with decompensation. The remaining patient in the HCV-POS group receiving Rituximab-sparing CT for chronic lymphocytic leukemia had cirrhosis, but she did not show an increase in HCV load, both in plasma and in the PBMC, nor a hepatic flare nor decompensation of liver disease. HCV-RNA was never detected in plasma and PBMC samples of the 28 patients in HCV-NEG group neither before, during nor after CT. Conclusion: HCV-RNA positive OHD patients treated with Rituximab show a consistent increase in HCV load under CT and develop a hepatic flare, lifethreatening in cirrhotic patients. None of 28 anti-HCV/HCV-RNA negative OHD patients became HCV-RNA positive during or after CT, excluding in patients under a consistent immune-suppression a reactivation and probably the presence of the so called “occult HCV replication”. OC-35