Helicobacter pylori infection is not associated with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an autoinflammatory disease caused by genetic susceptibility and environmental triggers, which include infectious agents. Helicobacter pylori, a bacterium that frequently colonizes the stomach, is associated with the development of certain autoinflammatory disorders. This study examined a possible association between H. pylori infection and RA. METHOD: This cohort study was performed in the Central Denmark Region. Patients were enrolled from primary healthcare centres after a urea breath test (UBT) for H. pylori and followed for a median of 8 years. Nationwide administrative registries provided information about the patients' diagnoses, country of birth, and gender. Comorbidity was determined using the Charlson Comorbidity Index. We compared the prevalence of RA via odds ratios (ORs) and incidences using Cox regression to calculate the hazard ratios (HRs) by comparing H. pylori-positive and H. pylori-negative individuals and adjusting for confounding variables. RESULTS: A total of 56 000 people diagnosed as H. pylori positive or negative had similar rates of comorbidity. No link was found between H. pylori and RA. There was no difference in RA prevalence until time of UBT [OR = 0.91, 95% confidence interval (CI) 0.70-1.19)] or incidence of new RA cases after UBT (HR = 0.80, 95% CI 0.56-1.13) between H. pylori-positive and -negative subjects. Validation via four other RA definitions provided similar results. CONCLUSION: This study found no association between H. pylori infection and RA. This result does not support the involvement of H. pylori in a gut-joint axis of importance for RA development.

Effects of common chronic medical conditions on psychometric tests used to diagnose minimal hepatic encephalopathy.

Many chronic medical conditions are accompanied by cognitive disturbances but these have only to a very limited extent been psychometrically quantified. An exception is liver cirrhosis where hepatic encephalopathy is an inherent risk and mild forms are diagnosed by psychometric tests. The preferred diagnostic test battery in cirrhosis is often the Continuous Reaction Time (CRT) and the Portosystemic Encephalopathy (PSE) tests but the effect on these of other medical conditions is not known. We aimed to examine the effects of common chronic (non-cirrhosis) medical conditions on the CRT and PSE tests. We studied 15 patients with heart failure (HF), 15 with end stage renal failure (ESRF), 15 with dysregulated type II diabetes (DMII), 15 with chronic obstructive pulmonary disease (COPD), and 15 healthy persons. We applied the CRT test, which is a 10-min computerized test measuring sustained attention and reaction time stability and the PSE test, which is a paper-pencil test battery consisting of 5 subtests. We found that a high fraction of the patients with HF (8/15, 0.002) or COPD (7/15, p = 0.006) had pathological CRT test results; and COPD patients also frequently had an abnormal PSE test result (6/15, p < 0.0001). Both tests were unaffected by ESRF and DMII. Half of the patients with HF or COPD had psychometrically measurable cognitive deficits, whereas those with ESRF or DMII had not. This adds to the understanding of the clinical consequences of chronic heart- and lung disease, and implies that the psychometric tests should be interpreted with great caution in cirrhosis patients with heart- or lung comorbidity.

Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests.

Minimal hepatic encephalopathy (MHE) is a frequent complication to liver cirrhosis that causes poor quality of life, a great burden to caregivers, and can be treated. For diagnosis and grading the international guidelines recommend the use of psychometric tests of different modalities (computer based vs. paper and pencil). To compare results of the Continuous Reaction time (CRT) and the Portosystemic Encephalopathy (PSE) tests in a large unselected cohort of cirrhosis patients without clinically detectable brain impairment and to clinically characterize the patients according to their test results. The CRT method is a 10-minute computerized test of a patient's motor reaction time stability (CRTindex) to 150 auditory stimuli. The PSE test is a 20-minute paper-pencil test evaluating psychomotor speed. Both tests were performed at the same occasion in 129 patients. Both tests were normal in only 36% (n = 46) of the patients and this group had the best quality of life, a normal CRP, a low risk of subsequent overt HE, and a low short term mortality. Either the CRT or the PSE test was abnormal in a total of 64% of the patients (n = 83), the CRT in 53% (n = 69) and the PSE in 34% (n = 44). All these patients had a poorer quality of life, low-grade CRP elevation, moderate risk for subsequent overt HE, and a higher than 20% short term mortality. Both tests were abnormal in 23% (n = 30) of the patients and this group had more advanced cirrhosis and a 40 % short-term mortality. One of the tests was abnormal in the majority of the patients but concordant in only 60%. Most cirrhosis patients seem to have impairments of different cognitive domains and more domains with advancing disease. Two abnormal tests identified patients with an increased risk of overt HE and death.

The continuous reaction times method for diagnosing, grading, and monitoring minimal/covert hepatic encephalopathy.

Existing tests for minimal/covert hepatic encephalopathy (m/cHE) are time- and expertise consuming and primarily useable for research purposes. An easy-to-use, fast and reliable diagnostic and grading tool is needed. We here report on the background, experience, and ongoing research regarding the continuous reaction times (CRT) method. The method has been in clinical use for decades in Denmark for the stated purpose. The method is a 10-minutes, computerised registration of a series of motor reaction times to an auditory stimulus, with results reported as the CRTindex (50 percentile/(90-10) percentile) as a parameter of reaction time variability. The index is a measure of alertness stability and is used to assess attention and cognition deficits. The CRTindex identifies half of patients in a Danish cohort with chronic liver disease, as having m/cHE, a normal value safely precludes HE, it has a broad outcome span reflecting the degree of brain impairment, it shows no learning effect, and it is independent on age and gender. The CRTindex is, therefore, a candidate tool for routine screening, detecting, grading, and monitoring m/cHE. Still, however, further methodological and clinical validation trials are required and are currently being conducted.

Hospital admission for non-fatal poisoning with weak analgesics and risk for subsequent suicide: a population study.

BACKGROUND: Poisoning with weak analgesics is a major public health problem because of easy accessibility of the compounds; however, few studies have investigated their influence on subsequent suicide in the context of subjects' psychiatric status and other factors. METHOD: This nested case-control study was based on the entire Danish population including all 21,169 suicide cases and 423,128 matched population controls. Data on hospital admissions for poisoning and confounding factors were retrieved from national medical and administrative registries. Conditional logistic regression was used to compute relative risk. RESULTS: A prior hospital admission for poisoning with weak non-opioid analgesics significantly increased the risk of subsequent suicide [crude incidence rate ratio (IRR) 24.7, 95% confidence interval (CI) 22.1-27.6], and the effect of paracetamol poisoning was substantially stronger than that of poisoning with salicylates or non-steroidal anti-inflammatory drugs (NSAIDs). This association could not be explained by confounding from socio-economic or psychiatric factors. The elevated risk was extremely high during the first week following the overdose (adjusted IRR 738.9, 95% CI 173.9-3139.1), then declined over time but still remained significantly high 3 years later (adjusted IRR 4.2, 95% CI 3.5-5.0). Moreover, a history of weak analgesic poisoning significantly interacted with a person's psychiatric history, increasing the risk for subsequent suicide substantially more for persons with no history of psychiatric hospitalization than did it for those with such a history. CONCLUSIONS: A history of non-fatal poisoning with weak analgesics is a strong predictor for subsequent suicide. These results emphasize the importance of intensive psychiatric care of patients following overdose.

FDG-PET improves management of patients with colorectal liver metastases allocated for local treatment: a consecutive prospective study.

BACKGROUND AND AIM: Colorectal cancer is a common cancer in the Nordic countries and 50% of the patients develop liver metastases. Liver resection may result in long term survival. Proper staging is therefore essential and CT is the standard imaging modality. We examined whether additional FDG-PET improves therapeutic management of patients with colorectal liver metastases. PATIENTS AND METHODS: Fifty-four consecutive patients were enrolled. Each patient had a treatment plan made based on our standard evaluation. The patients then had a PET scan and the treatment plan was re-evaluated, taking these results into account. RESULTS: In 76% of the cases, PET did not change the treatment plan due to complete concordance with CT. In another 19% of the cases, the plan was altered due to finding of more liver lesions by PET than by CT (four patients), fewer or no liver lesions (three patients), and extrahepatic lesions not visible on CT (three patients). In 5% of the cases, non-concordance between PET and CT did not change the therapeutic plan. CONCLUSION: Pre-treatment FDG-PET, used supplementary to CT, improved the treatment plan in one fifth of the patients with colorectal liver metastases.

The continuous reaction time test for minimal hepatic encephalopathy validated by a randomized controlled multi-modal intervention-A pilot study.

BACKGROUND: Minimal hepatic encephalopathy (MHE) is clinically undetectable and the diagnosis requires psychometric tests. However, a lack of clarity exists as to whether the tests are in fact able to detect changes in cognition. AIM: To examine if the continuous reaction time test (CRT) can detect changes in cognition with anti-HE intervention in patients with cirrhosis and without clinically manifest hepatic encephalopathy (HE). METHODS: Firstly, we conducted a reproducibility analysis and secondly measured change in CRT induced by anti-HE treatment in a randomized controlled pilot study: We stratified 44 patients with liver cirrhosis and without clinically manifest HE according to a normal (n = 22) or abnormal (n = 22) CRT. Each stratum was then block randomized to receive multimodal anti-HE intervention (lactulose+branched-chain amino acids+rifaximin) or triple placebos for 3 months in a double-blinded fashion. The CRT is a simple PC-based test and the test result, the CRT index (normal threshold > 1.9), describes the patient's stability of alertness during the 10-minute test. Our study outcome was the change in CRT index in each group at study exit. The portosystemic encephalopathy (PSE) test, a paper-and-pencil test battery (normal threshold above -5), was used as a comparator test according to international guidelines. RESULTS: The patients with an abnormal CRT index who were randomized to receive the active intervention normalized or improved their CRT index (mean change 0.92 ± 0.29, p = 0.01). Additionally, their PSE improved (change 3.85 ± 1.83, p = 0.03). There was no such effect in any of the other study groups. CONCLUSION: In this cohort of patients with liver cirrhosis and no manifest HE, the CRT identified a group in whom cognition improved with intensive anti-HE intervention. This finding infers that the CRT can detect a response to treatment and might help in selecting patients for treatment.

The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis.

BACKGROUND: Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM: To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can predict portal hypertension in patients with cirrhosis. METHODS: We measured sCD163 and the ELF components (hyaluronic acid, tissue inhibitor of metalloproteinase-1 and procollagen-III aminopeptide) in two separate cohorts of cirrhosis patients that underwent hepatic vein catheterisation. To test the predictive accuracy we developed a CD163-fibrosis portal hypertension score in an estimation cohort (n = 80) and validated the score in an independent cohort (n = 80). A HVPG ≥10 mmHg was considered clinically significant. RESULTS: Both sCD163 and the ELF components increased in a stepwise manner with the patients' Child-Pugh score (P < 0.001, all), and also with increasing HVPG (P < 0.001). receiver operator characteristics (ROC) analyses showed that each one of the individual components predicted a HVPG >10 mmHg with AUROC's of approximately 0.80. The combined score optimised by logistic regression analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short-term mortality. CONCLUSIONS: The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted significant portal hypertension in patients with cirrhosis. This score may prove useful for screening purposes and highlights the importance of both the inflammatory and the fibrotic components of cirrhotic portal hypertension.

Reduced sCD36 following weight loss corresponds to improved insulin sensitivity, dyslipidemia and liver fat in obese children.

BACKGROUND/OBJECTIVES: Childhood obesity is a major health problem with serious long-term metabolic consequences. CD36 is important for the development of obesity-related complications among adults. We aimed to investigate circulating sCD36 during weight loss in childhood obesity and its associations with insulin resistance, dyslipidemia, hepatic fat accumulation and low-grade inflammation. SUBJECTS/METHODS: The impact of a 10-week weight loss camp for obese children (N=113) on plasma sCD36 and further after a 12-month follow-up (N=68) was investigated. Clinical and biochemical data were collected, and sCD36 was measured by an in-house assay. Liver fat was estimated by ultrasonography and insulin resistance by the homeostasis model assessment (HOMA-IR). RESULTS: Along with marked weight loss, sCD36 was reduced by 21% (P=0.0013) following lifestyle intervention, and individual sCD36 reductions were significantly associated with the corresponding decreases in HOMA-IR, triglycerides and total cholesterol. The largest sCD36 decrease occurred among children who reduced HOMA-IR and liver fat. After 12 months of follow-up, sCD36 was increased (P=0.014) and the metabolic improvements were largely lost. CONCLUSIONS: Weight-loss-induced sCD36 reduction, coincident with improved insulin resistance, circulating lipids and hepatic fat accumulation, proposes that sCD36 may be an early marker of long-term health risk associated with obesity-related complications.

Single-centre experience of the macrophage activation marker soluble (s)CD163 - associations with disease activity and treatment response in patients with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is characterised by liver inflammation with reversibility upon anti-inflammatory treatment. Soluble (s)CD163, a specific macrophage activation marker, is associated with inflammation in other liver diseases, but never investigated in AIH. AIM: To investigate sCD163 in patients with acute AIH and in complete and incomplete responders to standard anti-inflammatory pharmacotherapy, and during follow-up in treatment naive patients. METHODS: In a cross-sectional design, we studied 121 AIH patients (female/male 89/32, median age 49 years); of these, we prospectively studied 10 treatment naïve AIH patients during prednisolone treatment and tapering. Twenty patients had variant syndromes of AIH and primary biliary cholangitis or primary sclerosing cholangitis. sCD163 was compared with markers of disease activity, severity and treatment response. RESULTS: In the patients with acute AIH (n = 21), sCD163 was sixfold increased compared with the normalised levels in patients (n = 32) with complete response to standard treatment [9.5 (3.3-28.8) vs. 1.6 (0.8-3.2) mg/L, P < 0.01)], while the patients (n = 27) with incomplete response had higher sCD163 [2.2 (1.3-7.9), P < 0.05] than the complete responders. sCD163 was positively associated with ALAT, IgG and bilirubin (rho: 0.45-0.59, P < 0.001, all), and negatively to external coagulation factors (rho:-0.34, P < 0.001). In the treatment naïve patients, sCD163 fell during high-dose prednisolone treatment and tapering. Immunohistochemical staining confirmed increased CD163 expression in liver biopsies from patients with acute AIH. CONCLUSIONS: sCD163 was markedly elevated in AIH in the acute phase, normalised by successful treatment in complete responders, but remained higher in the incompletely responding cases. Our results demonstrate macrophage activation in AIH paralleling disease activity, severity and treatment response, suggesting a role for macrophage activation in AIH.

Glucagon immunoneutralization in diabetic rats normalizes urea synthesis and decreases nitrogen wasting.

To study the effect of glucagon neutralization on urea synthesis in diabetic rats, animals with newly induced (75 mg/kg streptozocin) experimental diabetes mellitus were divided into two groups. One group was given one weekly injection of nonimmune rabbit serum (n = 6), and the other group was given one weekly injection of a specific high-titer antibody against pancreatic glucagon (n = 6). Four weeks later, serum-treated diabetic rats had fasting glucagon concentrations 2-3 times higher than nondiabetic controls given one weekly injection of saline (control). Plasma glucagon binding capacity of diabetic rats given glucagon antibodies was 10-15 times higher than the glucagon concentration. A second group of nondiabetic controls were given nonimmune serum. Blood glucose concentration and urinary glucose output were identical in both groups of diabetic animals. Food intake doubled in both groups of diabetic rats. In control rats, the accumulated nitrogen balance, determined weekly for 4 wk, was positive at 81 +/- 3.1 mmol/96 h; in serum-treated diabetic rats, the accumulated nitrogen balance was negative, -8.3 +/- 2.4 mmol/96 h throughout the 4 wk, whereas it was higher at 4.7 +/- 2.3 mmol/96 h in the glucagon antibody-treated diabetic rats (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A nationwide study of the incidence and 30-day mortality rate of pyogenic liver abscess in Denmark, 1977-2002.

BACKGROUND: Pyogenic liver abscess is a life-threatening disease. Accurate data on incidence and prognosis are important, but scarce. AIM: To examine changes in the incidence and 30-day mortality rate of patients with pyogenic liver abscess in Denmark. METHODS: Using nationwide administrative registers, we identified all patients diagnosed with pyogenic liver abscess in Denmark, 1977-2002, and their dates of death. We computed annual standardized incidence and 30-day mortality rates, and used Poisson regression to adjust gender-specific mortality rates for year-by-year differences in age at diagnosis. RESULTS: We identified 1448 patients with pyogenic liver abscess, of whom 54% were men. The crude incidence rate for the entire study period was 11.8 per 1,000,000 for men and 9.7 per 1,000,000 for women. Between 1977 and 2002, the incidence rate increased from 6 to 18 per 1,000,000 for men and from 8 to 12 per 1,000,000 for women. The cumulative 30-day mortality rate was 15% for men and 23% for women. The adjusted 30-day mortality rate decreased from 40% for men and 50% for women to around 10% for both genders. CONCLUSIONS: In this large nationwide study spanning a 26-year period, we found an increasing incidence rate and a decreasing mortality rate of pyogenic liver abscess. We believe that these changes are primarily explained by more sensitive diagnostic tools.

The association between admission for poisoning with paracetamol or other weak analgesics and subsequent admission for psychiatric disorder: a Danish nationwide case-control study.

BACKGROUND: Many cases of paracetamol poisoning are with suicidal intent, but the association between paracetamol poisoning and subsequent psychiatric disorder is unknown. AIM: To examine the association between poisoning with paracetamol or other weak analgesics and subsequent psychiatric disorder. METHODS: The study was set in a nested case-control design and based on nationwide Danish registers. We identified all patients diagnosed with schizophrenia, affective disorder or eating disorder in 1994-1998 and matched population controls. We estimated the relative risk of these psychiatric disorders after admission for paracetamol or nonparacetamol poisoning, adjusting for income, employment and marital status. RESULTS: We included 12,603 cases with psychiatric disorder, and 1.2% had a diagnosis of poisoning compared with 0.2% of the 252,060 matched population controls. Compared with those with no diagnoses of weak analgesic poisoning, the risk of schizophrenia increased 3.9-fold after paracetamol poisoning, and 2.0-fold after nonparacetamol poisoning. The risk of affective disorder increased 12.2-fold after paracetamol poisoning and 2.6-fold after nonparacetamol poisoning. The risk of eating disorder increased 5.0-fold after paracetamol poisoning, and 2.2-fold after nonparacetamol poisoning. The risk of a diagnosis of psychiatric disorder was very high immediately after poisoning and remained increased for more than 10 years. CONCLUSIONS: Paracetamol poisoning is a strong risk marker for psychiatric disorder, particularly affective disorders.

The macrophage activation marker sCD163 is associated with changes in NAFLD and metabolic profile during lifestyle intervention in obese children.

BACKGROUND: Obesity is associated with metabolic derangement and non-alcoholic fatty liver disease (NAFLD). Macrophages are involved in liver inflammation and fibrosis, and soluble (s)CD163 is a macrophage activation marker. OBJECTIVES: To associate sCD163 with parameters of paediatric obesity and NAFLD, as well as changes in these parameters during lifestyle intervention. METHODS: We studied 117 obese children during a 10-week lifestyle intervention; 71 completed the 12-month follow-up. We recorded clinical and biochemical data, and performed liver ultrasonography. RESULTS: Baseline sCD163 was higher in children with elevated alanine transaminase (ALT) (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1), P = 0.03), steatosis (2.3 ± 0.7 vs. 2.0 ± 0.6 mg L(-1), P = 0.01) and high paediatric NAFLD fibrosis index (2.3 ± 0.7 vs. 1.9 ± 0.6 mg L(-1) , P = 0.03). Baseline sCD163 was independently associated with ALT, cholesterol and high-sensitivity C-reactive protein (hs-CRP). The change in sCD163 during lifestyle intervention was associated with changes in ALT, homeostatic model assessment of insulin resistance (HOMA-IR), hs-CRP and cholesterol, and inversely associated with the change in high-density lipoprotein cholesterol. CONCLUSION: sCD163 was associated with markers of liver injury and metabolic parameters in obese children, and changes in these parameters during lifestyle intervention. This may suggest that activated macrophages play a role in NAFLD and sCD163 may serve as a marker of liver disease severity and treatment effect.

Loss of nitrogen from organs in rats induced by exogenous glucagon.

Rats weighing 220 g were injected sc with zinc protamin glucagon 20 micrograms once daily (recurrent hyperglucagonemia) and zinc protamin glucagon 60 micrograms three times daily (chronic hyperglucagonemia); the controls received the vehicle three times daily. In the first group blood glucagon rose to above 200 ng/liter for 5 h every day; in the second group it constantly stayed above 600 ng/liter. After both 2 (n = 5) and 14 (n = 5) days treatment the control total blood alpha-amino-nitrogen (AAN) concentration was 4.3 +/- 0.1 mmol/liter, and the urea nitrogen synthesis rate was 4.9 +/- 0.4 mumol/(min.100 g BW) (mean +/- SEM) in controls. In recurrent hyperglucagonemic rats, treated for both 2 (n = 5) and 14 (n = 5) days, total AAN was 3.6 +/- 0.2 mmol/liter (P less than 0.05 vs. control) and urea nitrogen synthesis rate 4.5 +/- 0.8 mumol/(min.100 g BW). In chronic hyperglucagonemic, treated for both 2 (n = 5) and 14 (n = 5) days, total AAN was 2.2 +/- 0.1 mmol/liter (P less than 0.05 vs. control) and UNSR 7.9 +/- 0.8 mumol/(min.100g BW) (P less than 0.05 vs. control). The urea excretion was identical in controls and during recurrent hyperglucagonemia, but it was increased by 50% during chronic hyperglucagonemia. Food intake was the same in all groups. N Balances decreased from 10 mmol/24 h to 5 mmol/24 h (P less than 0.05) by chronic hyperglucagonemia. The total organ N content did not change by recurrent hyperglucagonemia, but in chronic hyperglucagonemia it decreased to 65-85% (P less than 0.01) in carcass, intestines, liver, and kidneys. In conclusion chronic but not recurrent hyperglucagonemia increases the rate of urea synthesis and decreases the blood amino acid concentration. This is suggested to be a reason for the loss of N from organs by chronic hyperglucagonemia.

Somatostatin-stimulated insulin-like growth factor binding protein-1 release is abolished by hyperinsulinemia.

It was demonstrated recently that administration of lanreotide and octreotide, two somatostatin octapeptide analogs, increased circulating insulin-like growth factor binding protein 1 (IGFBP-1) levels. The present study demonstrates that native somatostatin 14 shares this ability and that the increase in abolished by concomitant hyperinsulinemia within the physiological range. Five fasting healthy volunteers underwent a hyperinsulinemic as well as a normo-insulinemic (i.e. basal insulinemic) euglycemic clamp lasting 8 h (serum insulin levels remained constant, about 570 vs. 16 pmol/L). Immediately before the clamps, a somatostatin infusion (500 micrograms/h) was started and continued throughout. During normo-insulinemia, IGFBP-1 levels increased slowly from 6.3 +/- 6.2 to 36.1 +/- 14.8 micrograms/L (P < 0.05) reaching maximum after 7 h constant somatostatin infusion, whereas hyperinsulinemia induced a significant decrease from basal levels (from 4.7 +/- 5.4 to 1.1 +/- 1.5 micrograms/L) after 8 h (mean +/- SD, n = 5). These results may indicate hitherto unnoticed interactions of somatostatin and insulin on IGFBP-1 release with possible impact on IGF-I action at the cellular level.

Dose-dependent stimulation of insulin-like growth factor-binding protein-1 by lanreotide, a somatostatin analog.

It was recently reported that octreotide, besides its many, almost obligatory, inhibitory actions, stimulates the release of insulin-like growth factor-binding protein-1. The present study sought to exclude the possibility that the inescapable preceding somatostatin analog-induced reduction in serum insulin participated in the observed effect. We, therefore, administered sc two clinically relevant doses (5 and 80 micrograms/kg) of lanreotide, another somatostatin octapeptide analog, which induced identical 60% initial suppressions of serum insulin. In spite of this, clear dose-dependent increases in insulin-like growth factor-binding protein-1 were observed, starting between 1-2 h after administration of lanreotide, and levels were still elevated several-fold 5 h after administration of 80 micrograms/kg lanreotide. In addition, we found that infusion of amino acids had no discernible effect on binding protein-1 release. The changes found in immunoreactive binding protein-1 were confirmed employing Western ligand blotting. The data indicate that the lanreotide-induced increase in binding protein-1 levels in serum is not due to the changes in circulating insulin. The magnitude and duration of the increase raise the possibility that the stimulation may have clinically relevant implications in somatostatin analog treatment.

Effects of growth hormone (GH) administration on functional hepatic nitrogen clearance: studies in normal subjects and GH-deficient patients.

A decline in serum urea levels and urinary urea excretion is usually seen after GH administration in humans, indicating overall protein anabolism. Whether this reflects the diminished supply of alpha-amino acids for urea synthesis or a substrate-independent hepatic mechanism is unknown. To pursue this we measured the urea nitrogen synthesis rate (UNSR) and blood alanine levels before, during, and after a 4-h constant iv infusion of alanine (2 mmol/kg BW.h). UNSR was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in total body water. The slope of the linear relationship between UNSR and circulating alanine levels represents the hepatic components of conversion of amino nitrogen and is denoted the functional hepatic nitrogen clearance (FHNC). Eight male volunteers were randomly investigated on three occasions: 1) after 12-h iv saline infusion, 2) after 12-h iv GH infusion (1 IU/h), and 3) after 2-day sc GH treatment (8 IU/day), followed by 12-h iv infusion of GH (1 IU/h). The UNSR (millimoles per h) during alanine infusion was significantly lower when the subjects were receiving GH therapy [maximum +/- SE, 133.0 +/- 6.9 (saline) vs. 96.7 +/- 11.1 (12-h GH; P < 0.01) vs. 106.5 +/- 7.5 (2-day GH; P < 0.05)]. FHNC (liters per h) was similar in all three studies [30.3 +/- 1.2 (saline) vs. 26.6 +/- 3.4 (12-h GH) vs. 27.0 +/- 2.6 (2-day GH)]. Six GH-deficient adult patients were randomly studied twice: 1) on regular daily (at 2000 h) sc GH therapy (3 IU/m2.day), and 2) after discontinuation of GH for 2 days. The UNSR during alanine infusion was likewise significantly lower when the patients were receiving GH therapy [147.7 +/- 11.7 mmol/h (no GH) vs. 123.9 +/- 9.1 mmol/h; P < 0.01]. FHNC (liters per h) values were similar in the two studies [29.2 +/- 3.8 (GH) vs. 27.5 +/- 4.5 (no GH)]. Our data confirm the anabolic action of GH and show that short term GH deprivation is associated with catabolism in terms of increased UNSR. The finding of unaltered FHNC suggests a GH-induced extrahepatic regulation of amino nitrogen conversion, rather than a substrate-independent hepatic mechanism.

Alcohol consumption and serum liver-derived enzymes in a Danish population aged 30-50 years.

BACKGROUND: Based on the increased consumption of alcohol in Denmark the aim of this study was to measure prevalence of abnormal liver-derived enzymes in a homogeneous Danish population and possible associations with alcohol consumption, smoking and body mass index (BMI). METHOD: In a representative population sample of 905 people (aged 30-50) from the baseline survey of the Ebeltoft Health Promotion Project in Denmark, we examined prevalence of abnormal liver-derived enzymes and its possible association with self-reported alcohol consumption, smoking and BMI, applying logistic regression analyses. RESULTS: In a significant proportion, 12% (women 8%; men 16%) of the cohort we found raised levels of liver-derived enzymes associated with moderate self-reported alcohol intake adjusted for BMI and smoking. If the intake was higher than moderate, i.e. > 28 units per week (one unit equals 12 g of alcohol), the odds ratio (OR) for raised liver enzymes increased further; S-gamma-glutamyltransferase (GGT) (OR: for women 24.4; men 18.4). S-aspartate-aminotransferase (ASAT) (24.2; 5.8) and S-alanine-aminotransferase (ALAT) (27.2; 3.0). Furthermore, daily smoking increased the risk of raised liver enzymes in women (OR: 3.4-4.2), and obesity (BMI > or = 30 kg/m2) in men showed a positive association with all three enzymes (OR: 3.0-9.0). CONCLUSIONS: The occurrence of raised liver-derived enzymes was frequent in the Danish population sample and associated with moderate self-reported alcohol consumption adjusted for BMI and smoking.

Hormonal and neural blockade prevents the postoperative increase in amino acid clearance and urea synthesis.

The combined effect of continuous blockade of glucagon and cortisol by somatostatin and etomidate and thoracic epidural analgesia on hepatic conversion of amino nitrogen was studied in eight patients who underwent elective cholecystectomy on day 1 after operation and was compared with 16 patients who underwent operation without blockade. Surgery increased the plasma clearance of total alpha-amino nitrogen from 5.2 +/- 0.3 to 6.6 +/- 0.3 ml/sec (mean +/- sem; p less than 0.05). This increase was due to increased elimination by the liver, because the hepatic effectiveness for amino nitrogen conversion measured by the functional hepatic nitrogen clearance increased from 9 +/- 2 to 16 +/- 4 ml/sec (p less than 0.05). In contrast, during the combined neural and hormonal blockade, surgery decreased the plasma clearance of amino nitrogen from 5.3 +/- 0.3 to 3.9 +/- 0.3 ml/sec (p less than 0.05), and the blockade prevented the postoperative increase in functional hepatic nitrogen clearance. The results suggest that glucagon, cortisol, and afferent neural reflexes are mediators of the hepatic contribution to catabolism after operation.