Erik Christensen

An Endocytic Pathway Essential for Renal Uptake and Activation of the Steroid 25-(OH) Vitamin D3

Steroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by receptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D-binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin. Endocytosis is required to preserve 25-(OH) vitamin D3 and to deliver to the cells the precursor for generation of 1,25-(OH)2 vitamin D3, a regulator of the calcium metabolism. Megalin-/- mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease.

Serum levels of YKL-40 and PIIINP as prognostic markers in patients with alcoholic liver disease

BACKGROUND/AIMS YKL-40 (growth factor) and PIIINP (N-terminal propeptide of Type III procollagen) are potential markers of liver fibrosis. The aim was to evaluate the prognostic value of serum YKL-40 and PIIINP levels in patients with alcoholic liver disease. METHODS Three hundred and seventy patients with alcoholic liver disease were studied in a trial of malotilate with a median follow-up period of 470 days; 75 patients died; 336 patients had a liver biopsy on entry. Serum levels of YKL-40 and PIIINP were determined by radioimmunoassay (RIA). RESULTS Serum YKL-40 and PIIINP were elevated in the patients compared to controls. Patients with steatosis or no fibrosis had the lowest serum levels of YKL-40 and PIIINP, whereas patients with alcoholic hepatitis and/or cirrhosis had the highest levels. Serum YKL-40 was associated with the presence of fibrosis, and serum PIIINP was also associated with the different grades of fibrosis. Patients with elevated serum YKL-40 or PIIINP had shorter survival than patients with normal serum levels of YKL-40 (P<0.0001) or PIIINP (P=0.044). High degree of fibrosis predicted shorter survival (P=0.004). CONCLUSIONS Serum levels of YKL-40 and PIIINP are elevated in alcoholic patients, related to the presence of liver fibrosis and may provide prognostic information.

Prognostic variables in patients with cirrhosis and oesophageal varices without prior bleeding.

As identification of patients at risk of bleeding or death is essential for prophylaxis, we determined the prognostic influence of various patient characteristics on the risk of bleeding and death. Fifty-five patients with cirrhosis and oesophageal varices without previous bleeding were included in the study and followed up after an average observation period of 446 days (range: 5-1211 days). A total of 55 clinical, biochemical, haemodynamic, and endoscopic variables were classified as systemic haemodynamic, portal haemodynamic, or metabolic. Using univariate analysis, the following variables showed a significant relation with an increased risk of bleeding or death: high plasma volume (p < 0.02), high azygos blood flow (p < 0.004), elevated hepatic venous pressure gradient (p < 0.02), marked prominence of varices (p < 0.05), poor nutritional status (p < 0.0001), decreased clotting factor 2,7,10 (p < 0.002), poor incapacitation index (p < 0.004), low serum albumin (p < 0.005), increased serum bilirubin (p = 0.05), elevated alkaline phosphatases (p < 0.02), low arterial oxygen saturation (p = 0.02), and encephalopathy (p < 0.007). In a Cox regression model, poor nutritional status (p < 0.00005), increased serum bilirubin (p < 0.001), short central circulation time (p < 0.03), low serum albumin (p < 0.02), and decreased clotting factor 2, 7, 10 (p < 0.05) were independently associated with a higher risk. In conclusion, the results support the prognostic value of metabolic variables as described earlier. The prognostic significance of central circulation time stresses the importance of the hyperdynamic systemic circulation in assessing the increased risk of bleeding or death.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose

Animal studies on acetaminophen toxicity suggest that chronic alcohol intake affects the outcome adversely, whereas acute alcohol intake seems protective. Few clinical data are available.

The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage

A plasma acetaminophen (INN, paracetamol) half‐life of more than 4 hours has been correlated with hepatotoxicity in acetaminophen overdosing not treated with an antidote. Acetaminophen half‐life has not been studied in patients receiving the antidote N‐acetylcysteine.

Cardiac and proinflammatory markers predict prognosis in cirrhosis

Inflammation and cardiac dysfunction plays an important role in the development of complications leading to increased mortality in patients with cirrhosis. Novel cardiac markers such as prohormone of ANP (proANP), copeptin and high‐sensitivity troponin T (hs‐TnT) and proinflammatory markers including soluble urokinase‐type plasminogen activator receptor (suPAR) and high‐sensitive C‐reactive protein (hs‐CRP) are related to these complications. We aimed to investigate if cardiac and proinflammatory markers are related to severity of liver disease, cardiac and haemodynamic changes, and long‐term survival.

A consensus conference on prognostic studies in hepatology

A PRIMARY task of the physician is to improve the patients prognosis. Assessment of the prognosis is highly relevant and necessary for rational decisionmaking concerning management and therapy, as well as providing information to be given to the patient about the prospects for the future. In hepatology a large variety of prognostic studies and models have been published over the years. In parallel, there has been a marked evolution in statistical methodology and information technology. These rapid developments have led to a need to clarify the current situation, with the purpose of providing guidelines for future prognostic studies. For these reasons, a Consensus Conference was held in Chianciano (Italy) from 27 to 30 September 19971 . Prognostic studies investigate the relation between the characteristics of the patients in a defined patient population and the occurrence of a well-defined outcome, They usually apply a regression analysis technique, and result in prognostic models. The use of standardised, generally accepted diagnostic criteria which are as unrestrictive as possible is recommended to ensure a wide applicability of the results. The time, place and route of enrolment of the patients must be described, consecutive patients fulfilling the selection criteria should be included, and the sample size should be adjusted to the number of the putative variables and to the number of the expected events. The follow-up of the patients should be as complete as possible. All variables necessary for diagnosis and for

Prediction of hepatic encephalopathy in paracetamol overdose : A prospective and validated study

BACKGROUND Paracetamol overdose may cause hepatic encephalopathy (HE). This condition demands specialized care and, in some instances, liver transplantation evaluation. No model is available for predicting HE. We aimed to set up and validate a model for predicting the occurrence of HE in paracetamol overdose. METHODS Prospectively, 161 patients with single-dose paracetamol overdose and no HE (defined as hepatic coma grade II or more) on admission were studied during a 26-month period. Patients admitted during the first 13-month period constituted a learning set to construct a model to predict the occurrence of HE. Patients admitted in the second 13-month period constituted the validation set. Serial biochemical variables (measured twice daily), the time line after the overdose, and demographic data were used for univariate testing, and significant factors were assessed in various multiple logistic regression analyses. RESULTS Thirty-two patients (20%), 15 in the first period and 17 in the second, developed HE grade II. The best model (the highest chi-square) for HE included: log10 (hours from overdose to antidote treatment), log10 (plasma coagulation factors on admission), and platelet count hours from overdose (chi-square = 41.2, P < 0.00001). In the validation set 88% (confidence interval (CI), 64%-99%) of the patients who developed HE were correctly predicted by the constructed model, whereas 90% (CI, 79%-96%) of the patients in the non-HE group were correctly predicted. CONCLUSIONS The constructed model for predicting HE in paracetamol overdose proved sensitive and accurate in the validation set and should be valuable for transferring high-risk patients to a liver intensive care unit/transplantation facility.

Mannose 6-Phosphate Receptor and Sortilin Mediated Endocytosis of α-Galactosidase A in Kidney Endothelial Cells

Prominent vasculopathy in Fabry disease patients is caused by excessive intracellular accumulation of globotriaosylceramide (GL-3) throughout the vascular endothelial cells causing progressive cerebrovascular, cardiac and renal impairments. The vascular lesions lead to myocardial ischemia, atherogenesis, stroke, aneurysm, thrombosis, and nephropathy. Hence, injury to the endothelial cells in the kidney is a key mechanism in human glomerular disease and endothelial cell repair is an important therapeutic target. We investigated the mechanism of uptake of α-galactosidase A (α-Gal A) in renal endothelial cells, in order to clarify if the recombinant enzyme is targeted to the lysosomes via the universal mannose 6-phosphate receptor (M6PR) and possibly other receptors. Immunohistochemical localization of infused recombinant α-Gal A in a renal biopsy from a classic Fabry disease patient showed that recombinant protein localize in the endothelial cells of the kidney. Affinity purification studies using α-Gal A resins identified M6PR and sortilin as α-Gal A receptors in cultured glomerular endothelial cells. Immunohistochemical analyses of normal human kidney with anti-sortilin and anti-M6PR showed that sortilin and M6PR were expressed in the endothelium of smaller and larger vessels. Uptake studies in cultured glomerular endothelial cells of α-Gal A labeled with fluorescence and 125I showed by inhibition with RAP and M6P that sortilin and M6PR mediated uptake of α-Gal A. Biacore studies revealed that α-Gal A binds to human M6PR with very high affinity, but M6PR also binds to sortilin in a way that prevents α-Gal A binding to sortilin. Taken together, our data provide evidence that sortilin is a new α-Gal A receptor expressed in renal endothelial cells and that this receptor together with the M6PR is able to internalize circulating α-Gal A during enzyme replacement therapy in patients with Fabry disease.

Outcome of acute liver failure in the elderly

Older age is considered a poor prognostic factor in acute liver failure (ALF) and may still be considered a relative contraindication for liver transplantation for ALF. We aimed to evaluate the impact of older age, defined as age ≥ 60 years, on outcomes in patients with ALF. One thousand one hundred twenty‐six consecutive prospective patients from the US Acute Liver Failure Study Group registry were studied. The median age was 38 years (range, 15–81 years). One thousand sixteen patients (90.2%) were younger than 60 years (group 1), and 499 (49.1%) of these had acetaminophen‐induced ALF; this rate of acetaminophen‐induced ALF was significantly higher than that in patients ≥ 60 years (group 2; n = 110; 23.6% with acetaminophen‐induced ALF, P < 0.001). The overall survival rate was 72.7% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 67.9% in group 1 and 48.2% in group 2 for non‐acetaminophen patients (P < 0.001). The spontaneous survival rate (ie, survival without liver transplantation) was 64.9% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 30.8% in group 1 and 24.7% in group 2 for non‐acetaminophen patients (P = 0.27). Age was not a significant predictor of spontaneous survival in multiple logistic regression analyses. Group 2 patients were listed for liver transplantation significantly less than group 1 patients. Age was listed as a contraindication for transplantation in 5 patients. In conclusion, in contrast to previous studies, we have demonstrated a relatively good spontaneous survival rate for older patients with ALF when it is corrected for etiology. However, overall survival was better for younger non‐acetaminophen patients. Fewer older patients were listed for transplantation. Liver Transpl 15:1481–1487, 2009.