Fibroblast growth factor 23 and its role in bone diseases.

Fibroblast growth factor 23 (FGF23) has been casually linked to numerous hypophosphatemic bone diseases, however connection with bone loss or fragility fractures is still a matter of debate. The purpose of this review is to explore and summarise the known actions of FGF23 in various pathological bone conditions. Besides implication in bone mineralisation, elevated FGF23 showed a pathological effecton bone remodelling, primarily by inhibiting osteoblast function. Unlike the weak association with bone mineral density, high values of FGF23 have been connected with fragility fracture prevalence. This review shows that its effects on bone are concomitantly present on multiple levels, affecting both qualitative and quantitative part of bone strength, eventually leading to impaired bone strength and increased tendency of fractures. Recognising FGF23 as a risk factor for the development of bone diseases and correcting its levels could lead to the reduction of morbidity and mortality in specific groups of patients.

Liver transplantation in hepatocellular carcinoma - should we perform downstaging?

AIM: To compare the long-term outcomes between liver transplant (LT) recipients with hepatocellular carcinoma (HCC) who were downstaged with transarterial-chemoembolization (TACE) to the Milan criteria (MC) and those initially meeting the MC. METHODS: This retrospective study enrolled 198 patients with HCC: 38 were downstaged and 160 patients initially met the MC. Post-LT survival and HCC recurrence-free survival were evaluated. We assessed the association of death and HCC recurrence with TACE, baseline (age, sex, disease etiology, Model of End-stage Liver Disease, tumor number and the sum of maximum tumor diameters, waiting time, alpha-fetoprotein level) and explant characteristics (tumor number and the sum of maximum tumor diameters, micro- and macrovascular invasion). RESULTS: The recipient survival rates one, three, and five years after LT were 88.2%, 80.1%, and 75.9%, respectively. HCC recurrence-free probabilities were 92.3%, 87.9%, and 85%, respectively. The outcomes were comparable between the groups. In multivariate analysis, the number of tumors on the explant, age, and tumor recurrence were independent risk factors for death. Only the sum of maximum tumor diameters on the explant was an independent risk factor for HCC recurrence. CONCLUSIONS: Patients successfully downstaged with TACE to the MC can achieve post-LT recipient and HCC recurrence-free survival comparable with patients initially within the MC. Good response to TACE as a criterion for LT may be a method of selecting patients with favorable biological characteristics.

Relationship between coffee consumption, sleep duration and smoking status with elastographic parameters of liver steatosis and fibrosis; controlled attenuation parameter and liver stiffness measurements.

AIM: our aim was to explore the association between life habits and the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) as the surrogate markers of liver steatosis and fibrosis in a large cohort of non-alcoholic fatty liver disease (NAFLD) patients. METHODS: In this prospective, cross-sectional study we had analysed 1998 patients with diagnosed NAFLD. Sleeping duration was categorised in three groups: short (S) (<6 hours), moderate (M) (6-8 hours) and long (L) (>8 hours) sleep duration. Coffee drinking was categorized into no (0), moderate (1-2) and frequent (≥3) consumption (in cups/day). Smoking was categorised as yes versus no. RESULTS: Frequent coffee consumers had the lowest prevalence of obesity, hypertension, dyslipidaemia and diabetes. Furthermore, coffee non-consumers had highest values of hepatic enzymes, CAP and LSM. Moderate sleep duration was associated with lower values of CAP and LSM. Coffee consumption was associated with lower CAP in all the multivariate models (CAP unadjusted and model 1, 2 and 3), with largest effect in most frequent coffee consumers (≥3, model 3). Also, most frequent coffee consumers were associated with lower LSM in unadjusted model, model 1 and 2, while this was not the case for model 3 and those who consumed 1-2 cups of coffee per day. Reduced sleeping was confirmed as risk factor for elevated CAP in most of the models (unadjusted and model 1 and 2). Also, negative association of LSM was also confirmed in unadjusted model and model 2. Patients which slept 6-8 hours per day were mostly associated with lower CAP and LSM. Smoking status was not associated with CAP or LSM values. CONCLUSION: Coffee consumption has beneficial effect on CAP and LSM and this effect is dose dependent since and independent of a variety of relevant confounders. We have shown that moderate sleep duration has also beneficial effect on CAP and LSM.

Small intestinal bacterial overgrowth and non-alcoholic fatty liver disease diagnosed by transient elastography and liver biopsy.

BACKGROUND: We aimed to determine if there was a higher incidence of small intestinal bacterial overgrowth (SIBO) in non-alcoholic fatty liver disease (NAFLD) than in patients without NAFLD. Moreover, we assessed whether patients with significant fibrosis (SF) had a higher incidence of SIBO compared with patients with non-significant or no liver fibrosis. METHODS: NAFLD was diagnosed in 117 patients by using Fibroscan with a controlled attenuation parameter (CAP) as well as liver biopsy (LB). SIBO was defined by esophagogastroduodenoscopy with an aspiration of the descending duodenum. RESULTS: Patients with non-alcoholic steatohepatitis (NASH) and those with SF on LB had a significantly higher incidence of SIBO than patients without NASH and those without SF, respectively (P < .05). According to histological characteristics, there was a higher proportion of patients in the SIBO group with higher steatosis and fibrosis grade, lobular and portal inflammation, and ballooning grade (P < .001). In multivariate analysis, significant predictors associated with SF and NASH were type 2 diabetes mellitus (T2DM) and SIBO. Moreover, in multivariate analysis, significant predictors that were independently associated with SIBO were T2DM, fibrosis stage and ballooning grade (OR 8.80 (2.07-37.37), 2.50 (1.16-5.37) and 27.6 (6.41-119), respectively). The most commonly isolated were gram-negative bacteria, predominantly Escherichia coli and Klebsiella pneumoniae. CONCLUSION: In this relatively large population of patients, we used a gold standard for both SIBO (quantitative culture of duodenum's descending part aspirate) and NAFLD (LB), and we demonstrated that NASH patients and those with SF had a higher incidence of SIBO. Moreover, significant predictors independently associated with SIBO were T2DM, fibrosis stage and ballooning grade. Although TE is a well-investigated method for steatosis and fibrosis detection, in our study, independent predictors of SIBO were histological characteristics of NAFLD, while elastographic parameters did not reach statistical significance.

Liver transplantation in patients with neuroendocrine tumors: a case series and literature review.

Neuroendocrine tumors (NET) are a rare and heterogeneous group of neoplasms with variable biological behavior. They frequently metastasize to the liver, requiring active, multimodality treatment. Surgical resection, possible in only a minority of cases, was until recently the only potentially curative option. For unresectable NET with liver metastases, liver transplantation (LT) emerged as a potential curative treatment due to relatively slow growth and indolent behavior of the metastases. In this case series with literature review, we retrospectively analyzed the characteristics of 12 highly selected patients with metastatic NET disease as an indication for LT treated in our center. We also summarized the proposed prognostic factors, and evaluated and compared the existing selection criteria. The main poor prognostic factors in our patients were high grade NET and primary tumor in the pancreas. Inconsistent liver transplantation outcome parameters make it difficult to standardize patient selection criteria. There is a need for further studies that would fully elucidate the curative potential of LT in patients diagnosed with NET.

CROATIAN GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF NONALCOHOLIC FATTY LIVER DISEASE.

Nonalcoholic fatty liver disease (NAFLD) is a term describing excessive accumulation of fat in hepatocytes, and is associated with metabolic syndrome and insulin resistance. NAFLD prevalence is on increase and goes in parallel with the increasing prevalence of metabolic syndrome and its components. That is why Croatian guidelines have been developed, which cover the screening protocol for patients with NAFLD risk factors, and the recommended diagnostic work-up and treatment of NAFLD patients. NAFLD screening should be done in patients with type 2 diabetes mellitus, or persons with two or more risk factors as part of metabolic screening, and is carried out by noninvasive laboratory and imaging methods used to detect fibrosis. Patient work-up should exclude the existence of other causes of liver injury and determine the stage of fibrosis as the most important factor in disease prognosis. Patients with initial stages of fibrosis continue to be monitored at the primary healthcare level with the management of metabolic risk factors, dietary measures, and increased physical activity. Patients with advanced fibrosis should be referred to a gastroenterologist/hepatologist for further treatment, monitoring, and detection and management of complications.

Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: A randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the effects of vitamin D on transient elastography (TE, FibroScan) indices of liver steatosis (controlled attenuation parameter [CAP]) and fibrosis (liver stiffness measurement [LSM]) in adults with non-alcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: In this randomized (2:1), double-blind, single-centre, 12-month trial, patients with NAFLD were treated with vitamin D (1000 IU/day) (n = 201) or a matching placebo (n = 110). Two co-primary outcomes were changes in CAP and LSM after 360 days of treatment versus baseline. Two main secondary outcomes were CAP/LSM changes after 180 days of treatment. RESULTS: Both CAP and LSM gradually decreased in vitamin D-treated patients and slightly increased in the placebo arm. Vitamin D was superior to placebo for both primary outcomes (mean differences in CAP and LSM changes (-49.5 dB/m [95% CI -59.5 to -39.4] and -0.72 kPa [95% CI -1.43 to 0.00], respectively) and both secondary outcomes (-22.1 dB/m [-32.1 to -12.1] and -0.89 kPa [-1.61 to -0.17], respectively). Of a number of exploratory outcomes (change at 12 months vs. baseline), vitamin D reduced serum uric acid (-17.9 µmol/L [-30.6 to -5.2]), gamma-glutamyltransferase (-8.9 IU/L [-15.5 to -2.3)] and fasting serum insulin levels (-5.1 pmol/L [-9.3 to -0.8]) as well as the homeostatic model assessment of insulin resistance index (-1.6 [-3.1 to -0.2]) (false discovery rate [5%]-adjusted P-values between .0572 and .0952). CONCLUSION: Low-medium dose supplementation of vitamin D (1000 IU/day) over 12 months reduces TE indices of liver steatosis (CAP) and fibrosis (LSM) in NAFLD patients.

Epidemiological and clinical features of primary biliary cholangitis in two Croatian regions: a retrospective study.

AIM: To assess the measures of disease frequency and determine the clinical features of primary biliary cholangitis (PBC) in two Croatian regions. METHODS: Databases of two tertiary hospitals, one located in the continental and one in the coastal region of Croatia, were retrospectively searched for PBC patients diagnosed from 2007 to 2018. Epidemiologic data analysis was restricted to patients from each hospital's catchment area. We analyzed factors related to response to therapy and event-free survival (EFS), defined as absence of ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma, liver transplantation (LT), or death. In addition, we determined clinical and demographic data of transplanted PBC patients. RESULTS: Out of 83 PBC patients, 86.7% were female, with a median age at diagnosis of 55 years. Average PBC incidence for the 11-year period was 0.79 and 0.89 per 100000 population, whereas the point prevalence on December 31, 2017 was 11.5 and 12.5 in the continental and coastal region, respectively. Of 76 patients with complete medical records, 21% had an advanced disease stage, 31.6% had an associated autoimmune condition, and all received ursodeoxycholic acid. EFS rate at 5 years was 95.8%. In an age and sex-adjusted multivariate Cox regression model, the only factor significantly associated with inferior EFS was no response to therapy (HR=18.4; P=0.018). Of all Croatian patients who underwent LT, 3.8% had PBC, with the survival rate at 5 years after LT of 93.4%. CONCLUSION: This study gives pioneer insights into the epidemiological and clinical data on PBC in Croatia, thus complementing the PBC map of Southeast Europe.

Liver elastography malignancy prediction score for noninvasive characterization of focal liver lesions.

BACKGROUND & AIMS: To analyse elastographic characteristics of focal liver lesions (FLL)s and diagnostic performance of real-time two-dimensional shear-wave elastography (RT-2D-SWE) in order to differentiate benign and malignant FLLs. METHODS: Consecutive patients diagnosed with FLL by abdominal ultrasound (US) underwent RT-2D-SWE of FLL and non-infiltrated liver by intercostal approach over the right liver lobe. The nature of FLL was determined by diagnostic work-up, including at least one contrast-enhanced imaging modality (MDCT/MRI), check-up of target organs when metastatic disease was suspected and FLL biopsy in inconclusive cases. RESULTS: We analysed 196 patients (median age 60 [range 50-68], 50.5% males) with 259 FLLs (57 hepatocellular carcinomas, 17 cholangiocarcinomas, 94 metastases, 71 haemangiomas, 20 focal nodular hyperplasia) of which 70 (27%) were in cirrhotic liver. Malignant lesions were stiffer (P < .001) with higher variability in intralesional stiffness (P = .001). The best performing cut-off of lesion stiffness was 22.3 kPa (sensitivity 83%; specificity 86%; positive predictive value [PPV] 91.5%; negative predictive value [NPV] 73%) for malignancy. Lesion stiffness <14 kPa had NPV of 96%, while values >32.5 kPa had PPV of 96% for malignancy. Lesion stiffness, lesion/liver stiffness ratio and lesion stiffness variability significantly predicted malignancy in stepwise logistic regression (P < .05), and were used to construct a new Liver Elastography Malignancy Prediction (LEMP) score with accuracy of 96.1% in validation cohort (online calculator available at http://bit.do/lemps). CONCLUSION: The comprehensive approach demonstrated in this study enables correct differentiation of benign and malignant FLL in 96% of patients by using RT-2D-SWE.

Liver Disease During Pregnancy: A Challenging Clinical Issue.

One of the least studied topics in the field of obstetrics is liver disease during pregnancy, which creates a challenge for both gynecologists and hepatologists. Approximately 3% of pregnant women are affected by some form of liver disease during pregnancy. Some of these conditions can be fatal for both the mother and child. In addition, 3 types of liver disease need to be differentiated during pregnancy. One type is liver disease directly related to pregnancy, which can occur at a specific time during pregnancy. Another type is liver disease not related to pregnancy, which can occur at any time, such as viral- or drug-induced hepatitis. Furthermore, pregnancy can occur in women with pre-existing liver disease. It is essential that the clinicians are familiar with this disorder so they can respond promptly and appropriately in all of these situations, especially when emergency delivery is needed and must not be postponed.

Percutaneous Endovascular Treatment for Hepatic Artery Stenosis after Liver Transplantation: The Role of Percutaneous Endovascular Treatment.

BACKGROUND: To retrospectively analyze the outcomes of interventional radiology treatment of patients with hepatic artery stenosis (HAS) after liver transplantation at our Institution. MATERIAL/METHODS: Hepatic artery stenosis was diagnosed and treated by endovascular technique in 8 (2.8%) patients, who underwent liver transplantation between July 2007 and July 2011. Patients entered the follow-up period, during which we analyzed hepatic artery patency with Doppler ultrasound at 1, 3, 6, and 12 months after percutaneous endovascular treatment (PTA), and every six months thereafter. RESULTS: During the 12-month follow-up period, 6 out of 8 patients (75%) were asymptomatic with patent hepatic artery, which was confirmed by multislice computed tomography (MSCT) angiography, or color Doppler (CD) ultrasound. One patient had a fatal outcome of unknown cause, and one patient underwent orthotopic liver retransplantation (re-OLT) procedure due to graft failure. CONCLUSIONS: Our results suggest that HAS angioplasty and stenting are minimally invasive and safe endovascular procedures that represent a good alternative to open surgery, with good 12-month follow-up patency results comparable to surgery.

Influence of donor age on liver transplantation outcomes: A multivariate analysis and comparative study.

BACKGROUND: The growing disparity between the rising demand for liver transplantation (LT) and the limited availability of donor organs has prompted a greater reliance on older liver grafts. Traditionally, utilizing livers from elderly donors has been associated with outcomes inferior to those achieved with grafts from younger donors. By accounting for additional risk factors, we hypothesize that the utilization of older liver grafts has a relatively minor impact on both patient survival and graft viability. AIM: To evaluate the impact of donor age on LT outcomes using multivariate analysis and comparing young and elderly donor groups. METHODS: In the period from April 2013 to December 2018, 656 adult liver transplants were performed at the University Hospital Merkur. Several multivariate Cox proportional hazards models were developed to independently assess the significance of donor age. Donor age was treated as a continuous variable. The approach involved univariate and multivariate analysis, including variable selection and assessment of interactions and transformations. Additionally, to exemplify the similarity of using young and old donor liver grafts, the group of 87 recipients of elderly donor liver grafts (≥ 75 years) was compared to a group of 124 recipients of young liver grafts (≤ 45 years) from the dataset. Survival rates of the two groups were estimated using the Kaplan-Meier method and the log-rank test was used to test the differences between groups. RESULTS: Using multivariate Cox analysis, we found no statistical significance in the role of donor age within the constructed models. Even when retained during the entire model development, the donor age's impact on survival remained insignificant and transformations and interactions yielded no substantial effects on survival. Consistent insignificance and low coefficient values suggest that donor age does not impact patient survival in our dataset. Notably, there was no statistical evidence that the five developed models did not adhere to the proportional hazards assumption. When comparing donor age groups, transplantation using elderly grafts showed similar early graft function, similar graft (P = 0.92), and patient survival rates (P = 0.86), and no significant difference in the incidence of postoperative complications. CONCLUSION: Our center's experience indicates that donor age does not play a significant role in patient survival, with elderly livers performing comparably to younger grafts when accounting for other risk factors.

Fragility spinal fractures among cirrhotic liver transplant candidates in Croatia.

INTRODUCTION: Existing data on fragility spinal fractures prevalence in liver transplant candidates are scarce and inconsistent. This may be due to other comorbidities, besides hepatic osteodystrophy (HO), that contribute to bone loss and fragility fracture prevalence in chronic liver disease (CLD). OBJECTIVES: The aim of this study was to investigate the prevalence of spinal thoracic and lumbar fragility fractures among cirrhotic, non-chronic kidney disease (CKD), non-diabetic liver transplant candidates and to explore their relationship with clinical characteristics, laboratory markers and dual-energy x-ray absorptiometry (DXA) results. MATERIAL AND METHODS: This cross-sectional observational study was conducted at Merkur University Hospital, Croatia, between February 2019 and May 2023. Adult patients with liver cirrhosis referred for liver transplantation were included. Patients with acute infection, CKD, diabetes mellitus, malignancies, inflammatory bone diseases and those on corticosteroid or antiresorptive therapy were excluded. Clinical, laboratory and radiological assessment was carried out and patients were accordingly allocated into non-fractured and fractured group for the purpose of statistical analysis. RESULTS: A total of 90 patients were included in the study. There was 123 fractures, 87 (70.7 %) in the thoracic and 36 (29.3 %) in the lumbar region. Eighty-nine (72.4 %) fractures were grade 1, 31 (25.2 %) were grade 2 and 3 (2.4 %) were grade 3. Patients in the fractured group were significantly older (p < 0.001). No significant differences between fractured and non-fractured group according to laboratory and DXA parameters were noted. Subgroup with lumbar fractures had significantly lower bone mineral density values at L1-L4 region. Statistically significant negative correlation between bone specific alkaline phosphatase (BALP) and hip total BMD (rho = -0.414, p < 0.001) and spine total BMD (rho = -0.258, p = 0.014) values was found. CONCLUSION: Present study confirmed detrimental impact of CLD and HO on bone strength. DXA measurement correlated with the presence of lumbar fragility fractures. A combination of standard X-ray imaging and DXA is needed for adequate bone evaluation in pretransplant period and BALP could be useful for detecting HO in CLD. Searching for other risk factors and implementing bone turnover markers and additional imaging techniques for bone loss evaluation in liver transplant candidates is needed.

The Outcomes of Liver Transplantation in Severe Metabolic Dysfunction-Associated Steatotic Liver Disease Patients.

The increasing prevalence of diabetes mellitus, obesity, and metabolic syndrome in the population can lead to metabolic dysfunction-associated steatohepatitis (MASH) and metabolic dysfunction-associated steatotic liver disease (MASLD). In Western industrialized countries, this has become a major problem with significant socioeconomic impacts. MASH is now a leading cause of liver transplantation (LT), especially in developed countries. However, the post-transplant outcomes of such patients are a major concern, and published data are limited and extremely variable. In this article, we discuss graft and patient survival after LT, complications, the recurrence of MASH, and MASH appearing de novo after transplantation. Recent studies suggest that patients with MASH have slightly worse short-term survival, potentially due to increased cardiovascular mortality. However, most studies found that longer-term outcomes for patients undergoing LT for MASH are similar or even better than those for other indications. Hepatocellular carcinoma due to MASH cirrhosis also has similar or even better outcomes after LT than other etiologies. In conclusion, we suggest questions and topics that require further research to enhance healthcare for this growing patient population.

Use of machine learning models for identification of predictors of survival and tumour recurrence in liver transplant recipients with hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation (LT) however, selection criteria remain controversial. We aimed to identify survival factors and predictors for tumour recurrence using machine learning (ML) methods. We also compared ML models to the Cox regression model. Methods: Thirty pretransplant donor and recipient general and tumour specific parameters were analysed from 170 patients who underwent orthotopic liver transplantation for HCC between March 2013 and December 2019 at the University Hospital Merkur, Zagreb. Survival rates were calculated using the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards regression model. Data was also processed through Coxnet (a regularized Cox regression model), Random Survival Forest (RSF), Survival Support Vector Machine (SVM) and Survival Gradient Boosting models, which included pre-processing, variable selection, imputation of missing data, training and cross-validation of the models. The cross-validated concordance index (CI) was used as an evaluation metric and to determine the best performing model. Results: Kaplan-Meier curves for 5-year survival time showed survival probability of 80% for recipient survival and 82% for graft survival. The 5-year HCC recurrence was observed in 19% of patients. The best predictive accuracy was observed in the RSF model with CI of 0.72, followed by the Survival SVM model (CI 0.70). Overall ML models outperform the Cox regression model with respect to their limitations. Random Forest analysis provided several relevant outcome predictors: alpha fetoprotein (AFP), donor C-reactive protein (CRP), recipient age and neutrophil to lymphocyte ratio (NLR). Cox multivariate analysis showed similarities with RSF models in identifying detrimental variables. Some variables such as donor age and number of transarterial chemoembolization treatments (TACE) were pointed out, but these were not influential in our RSF model. Conclusions: Using ML methods in addition to classical statistical analysis, it is possible to develop sufficient prognostic models, which, compared to established risk scores, could help us quantify survival probability and make changes in organ utilization.

Acute Liver Failure Caused by Secondary Hemophagocytic Lymphohistiocytosis After COVID-19 Vaccination - Case Report and Literature Review.

Hemophagocytic lymphohistiocytosis (HLH) is a congenital or acquired hyperinflammatory syndrome, in some cases accompanied by acute liver failure. We present a case report of acute liver failure associated with HLH after COVID-19 vaccination and bring a literature review of the connection between HLH and COVID-19 vaccination. HLH has significant mortality rate, and liver transplantation is not a therapeutic option. Therefore, early recognition and timely conservative treatment are corner stones in reducing HLH-related morbidity and mortality.