Linda Skibsted Kornerup

Background/Objectives: Small quantities of gastric parietal cell-derived Intrinsic Factor (IF) are present in circulation. Here, we explore circulating concentrations of IF in different medical conditions affecting the stomach, anticipating finding both low and high concentrations depending on the state of the parietal cells. Methods: We measured serum IF in (I) patients before and after bariatric surgery; (II) patients diagnosed with portal hypertension; and (III) patients with suspected pernicious anemia referred for measurement of IF autoantibodies. Results: Patients undergoing bariatric surgery (n = 25) showed a significant drop in serum IF following surgery. Their median serum IF declined from 5.1 pmol/L (pre-surgery) to 3.3 pmol/L (two months post-surgery), and nine out of 25 patients showed serum IF concentrations below reference interval (1.7–11.6 pmol/L). Most patients with portal hypertension (n = 18) showed normal serum IF concentrations, but with unexpectedly high concentrations up to 30 pmol/L in a few patients. Out of 120 patients referred for measurement of IF autoantibodies, 10 patients showed IF concentrations below the reference interval. Three out of four patients with IF autoantibodies showed low concentrations of circulating IF. Conclusions: Our study shows a decline in circulating IF following bariatric surgery consistent with the known decline in vitamin B12 uptake in these patients. Both high and low concentrations were observed in the other two groups. Future longitudinal studies are needed to illuminate possible usefulness for measurement of circulating IF.

Objective: Carcinoid heart disease (CHD) is a severe fibrotic complication affecting cardiac valves in patients with neuroendocrine neoplasms (NENs). Early detection is crucial to improve prognosis. The value of the recommended screening biomarker, NT-proBNP, is uncertain. Biomarkers reflecting extracellular matrix (ECM) remodeling may capture early fibrogenesis. We aimed to evaluate circulating ECM biomarkers for the detection of CHD and to compare their performance with NT-proBNP. Design and methods: In this cross-sectional study, we prospectively included patients with disseminated small intestinal NENs (siNENs). We performed transthoracic echocardiography (TTE) for CHD diagnosis, and blood samples were analyzed for 10 ECM biomarkers. Biomarker levels were compared between patients with and without CHD, and diagnostic performance was assessed using the area under the receiver operating characteristic (AUROC) curve. Results: Among 98 patients, 16 (16%) had CHD. PRO-C3 levels were significantly elevated in patients with CHD compared with patients without CHD (median: 19.3 ng/mL (IQR: 15.6–24.0) vs 14.3 ng/mL (IQR: 12.4–17.5), P = 0.002). The AUROC curve of PRO-C3 for CHD detection was 0.77 (95% CI: 0.64–0.90). At a cutoff level of 15.4 ng/mL, the sensitivity was 85%, the specificity was 56%, the positive predictive value was 27%, and the negative predictive value was 95%. In the direct comparison between PRO-C3 and NT-proBNP, PRO-C3 did not outperform NT-proBNP (P = 0.09). Conclusion: PRO-C3, reflecting collagen type III formation, demonstrated good performance in CHD detection and may represent a complementary or potentially earlier marker than NT-proBNP. However, the performance of PRO-C3 was insufficient as a stand-alone tool, and further evaluation and exploration of new biomarkers in larger cohorts is required.

Background: Thyroid hormone levels are associated with HCC in animal studies. We examined HCC risk and prognosis in patients with thyroid disease. Methods: We included all Danish citizens with a hospital diagnosis for thyroid disease after January 1, 1980, and/or a filled prescription for thyroid medication after 1995. They were 1:10 age-matched, sex-matched, and calendar year–matched with population comparators without thyroid disease diagnoses. All were followed through 2021 for HCC diagnosis and death. Results: We included 529,330 patients, followed for up to 42.0 years. Among those with hyperthyroid disease, a current low TSH was associated with lower HCC incidence (adjusted HR: 0.66, 95% CI: 0.29–1.47). Nontoxic goitre was associated with lower mortality after HCC diagnosis (adjusted HR: 0.77, 95% CI: 0.59–1.00), corresponding to an estimated 6 months’ increased survival. Those with hypothyroid disease and a high current TSH had a higher HCC incidence (adjusted HR: 2.07, 95% CI: 1.03–4.18). Conclusions: Overall, in this large population-based study, a suppressed TSH level was associated with either lower HCC incidence or longer survival, while an elevated TSH level was associated with higher HCC incidence. Interpreted by TSH level, this suggests that an excess of thyroid hormones protects against HCC and that a deficit in thyroid hormones increases the HCC risk. The therapeutical implications are uncertain.

Introduction: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. Method: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-Dotatate or ⁹⁰Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8–14-week intervals. Results: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15–76) years. The median follow-up time was 31 (IQR 17–37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). Conclusions: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to ¹³¹I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Introduction: The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels. Methods: We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation. Results: We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51–70)] and 47 patients with incident PBC [77% women, median age 60 y (49–67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77–4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83–5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages. Conclusion: In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment. Export

Introduction: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide. Recent animal studies suggest that thyroid hormone treatment improves HCC prognosis. The aim of this study was to describe the association between thyroid disease and HCC prognosis in humans. Methods: We performed a nationwide cohort study including all persons with an HCC diagnosis from 2000 to 2018. Patients’ age, sex, HCC treatment, and diagnoses of thyrotoxicosis, nontoxic goiter, and myxedema were obtained from Danish national healthcare registries. We used regression models to examine the association between thyroid disease and mortality hazard and restricted mean survival time after HCC diagnosis, adjusting for confounding by sex and age. Results: We included 4,812 patients with HCC and 107 patients with thyroid disease. Median follow-up time was 5 months (total 5,985 person-years). The adjusted mortality hazard ratio was 0.68 (95% CI: 0.47–0.96) for thyrotoxicosis and 0.60 (95% CI: 0.41–0.88) for nontoxic goiter. The restricted mean survival time during the 5 years following HCC diagnosis was 6.8 months (95% CI: 1.1–12.6) longer for HCC patients with thyrotoxicosis than for patients without thyroid disease, and it was 6.9 months (95% CI: 0.9–12.9) longer for HCC patients with nontoxic goiter than for patients without thyroid disease. Conclusions: In this large nationwide cohort study, thyrotoxicosis and nontoxic goiter were associated with prolonged HCC survival.

Liver transplantation (LT) represents the definitive treatment for end-stage liver disease. Cognitive impairment following LT is frequent, referred to as postliver transplant encephalopathy (PLTE). LT removes the underlying chronic liver disease, and until recently hepatic encephalopathy (HE) was assumed to be fully reversible after LT. However, increasing evidence indicates that some degree of cognitive impairment may be present after LT. To which extent PLTE reflects cognitive impairment caused by residual HE (RHE) or the combined effect of other factors affecting brain function before, during, and after LT is not clarified. None of the available psychometric and neurophysiological tests used for detecting HE is shown to be able to distinguish between etiologies. The available, mostly retrospective, clinical studies indicate a high prevalence of abnormal psychometric tests after LT, and not all seem to recover completely. The patients with earlier HE show the most marked improvements, suggesting that the clinical picture of the early PLTE, in fact, represents RHE. Other early post-LT etiologies for PLTE comprise cerebral ischemia, critical illness encephalopathy, and immunosuppressive therapy. Late-onset etiologies comprise diabetes and hypertension, among others. PLTE regardless of etiology is a worrying issue and needs more attention in the form of mechanistic research, development of diagnostic/discriminative tools, and standardized prospective clinical studies.