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

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.

Comparison of total cortisol, free cortisol, and surrogate markers of free cortisol in diagnosis of adrenal insufficiency in patients with stable cirrhosis.

BACKGROUND & AIMS: Measurements of serum levels of total cortisol can overestimate the prevalence of adrenal dysfunction in patients with cirrhosis because they have low concentrations of corticosteroid-binding globulin and albumin. We used measurements of serum total cortisol and serum free cortisol after the low-dose short Synacthen test (LDSST) to assess adrenal dysfunction. METHODS: We studied 79 patients with stable cirrhosis; adrenal dysfunction was defined by peak concentrations of total cortisol ≤494 mmol/L and/or peak concentrations of free cortisol ≤33 nmol/L after the LDSST. We determined free cortisol index (FCI) scores and calculated free cortisol levels by using Coolens' equation. The Cox regression model was used to assess the relationship between adrenal dysfunction and outcomes (death or liver transplant). RESULTS: On the basis of measurement of total cortisol, 34% of patients had adrenal dysfunction, and on the basis of measurement of free cortisol, 29% had adrenal dysfunction. There was agreement between total cortisol and free cortisol levels in 22% of patients; in 13%, adrenal dysfunction was diagnosed only on the basis of total cortisol and in 6% only on the basis of free cortisol (κ coefficient, 0.56; P < .01). Low concentrations of corticosteroid-binding globulin (21 vs 54 µg/mL, P < .01) led to an overestimation of adrenal dysfunction that was based on measurement of total cortisol. Measurements of calculated free cortisol constantly overestimated free cortisol concentrations, with variations as large as 87% for baseline values and up to 84% after stimulation. Adrenal insufficiency, defined by FCI scores <12, was detected in 30% of patients; among them, 23% also had subnormal peak levels of free cortisol (κ coefficient, 0.70; P < .001). Adrenal dysfunction was not significantly associated with patient outcomes, on the basis of Cox model analysis. CONCLUSIONS: Adrenal insufficiency, defined by LDSST, is frequent in patients with stable cirrhosis, on the basis of measurements of total and free cortisol. FCI scores are better than measurement of total cortisol in assessing adrenal function in patients with cirrhosis. We did not associate adrenal dysfunction with outcome, but further studies are needed.

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.

Hypereosinophilic Syndrome Following the BNT162b2 (BioNTech/Pfizer) Vaccine Successfully Treated with Mepolizumab: A Case Report and Review of the Literature.

Although an increasing number of real-life data confirm large-scale clinical trial findings on the efficacy and safety of SARS-CoV-2 vaccines, rare but severe adverse reactions have begun to emerge. Here, we report a full-blown hypereosinophilic syndrome (HES) following a BNT162b2 (BioNTech/Pfizer) vaccine. A 48-year-old man developed, 5 days after the first shot of the SARS-CoV-2 vaccine, erythematous and painful nodular lesions in the lower and upper limbs accompanied by widespread itching, acrocyanosis with gangrenous lesions at the tips of the first and fourth fingers of the right hand, as well as paresthesia in the right hand and foot. Investigations revealed isolated eosinophilia, occlusion of the right ulnar artery, and electromyography alteration compatible with multifocal sensory neuropathy, as well as minimal accentuation of the interstitial texture with some ground glass appearance. Despite treatment with prednisone in combination with warfarin, he developed thrombosis of the left ulnar artery. Therefore, therapy with an IL-5 inhibitor and acetylsalicylic was successfully added. Given the time interval between the onset of clinical manifestations and the vaccine shot, we believe that the mRNA vaccine triggered the eosinophilic response. This case evidences a possible link between HES and the SARS-CoV-2 vaccination. Mepolizumab, an IL-5 inhibitor, might be considered in steroid refractory cases.

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.

Cardiovascular dysfunction in patients with liver cirrhosis.

Hyperdynamic syndrome is a well-known clinical condition found in patients with cirrhosis and portal hypertension, characterized by increased heart rate and cardiac output, and reduced systemic vascular resistance and arterial blood pressure. The leading cause of hyperdynamic circulation in cirrhotic patients is peripheral and splanchnic vasodilatation, due to an increased production/activity of vasodilator factors and decreased vascular reactivity to vasoconstrictors. The term "cirrhotic cardiomyopathy" describes impaired contractile responsiveness to stress, diastolic dysfunction and electrophysiological abnormalities in patients with cirrhosis without known cardiac disease. Underlying circulatory and cardiac dysfunctions are the main determinant in the development of hepatorenal syndrome in advanced cirrhosis. Moreover, the clinical consequences of cirrhosis-related cardiovascular dysfunction are evident during and after liver transplantation, and after transjugular intrahepatic portosystemic shunt insertion. Cardiovascular complications following these procedures are common, with pulmonary edema being the most common complication. Other complications include overt heart failure, arrhythmia, pulmonary hypertension, pericardial effusion, and cardiac thrombus formation. This review discusses the circulatory and cardiovascular dysfunctions in cirrhosis, examining the pathophysiologic and clinical implications in light of the most recent published literature.

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.

Corticosteroid replacement therapy in hepatoadrenal syndrome: case report with a review of the literature.

In liver cirrhosis, hepatoadrenal syndrome has been described recently as a progressive impairment in the adrenocortical reserve, with deficient production or action of glucocorticoids resulting in adrenal insufficiency. Data on the treatment of this syndrome are scarce. We report a case of a 60-year-old male patient referred to our hospital because of rectal bleeding and bilateral leg swelling. He complained of marked weakness, bilateral leg swelling, and shortness of breath with exertion for the last 2 months. Biochemistry and imaging indicated liver cirrhosis. Because of the weakness and persistent hypotension, we performed a low-dose synacthen test, which indicated adrenal insufficiency (baseline cortisol level 1.8 µg/dl, increasing to 3.5 and 3.7 µg/dl at 20 and 30 min, respectively). The patient's general condition improved promptly after corticosteroid supplementation.