Factors associated with diabetic foot ulcers and lower limb amputations in type 1 and type 2 diabetes supported by real-world data from the German/Austrian DPV registry.

AIMS: Diabetic foot ulcer (DFU) is a leading cause of lower limb amputations in people with diabetes. This study was aimed to retrospectively analyze factors affecting DFU using real-world data from a large, prospective central-European diabetes registry (DPV [Diabetes-Patienten-Verlaufsdokumentation]). MATERIALS AND METHODS: We matched adults with type 1 (T1D) or type 2 diabetes (T2D) and DFU to controls without DFU by diabetes type, age, sex, diabetes duration, and treatment year to compare possible risk factors. Cox regression was used to calculate hazard ratios for amputation among those with DFU. RESULTS: In our cohort (N = 63 464), male sex, taller height, and diabetes complications such as neuropathy, peripheral artery disease, nephropathy, and retinopathy were associated with DFU (all p < .001). Glycated hemoglobin (HbA1c) was related to DFU only in T1D (mean with 95% confidence interval [CI]: 7.8 [6.9-9.0] % vs 7.5 [6.8-8.5] %, p < .001). High triglycerides and worse low-density lipoprotein/high-density lipoprotein ratio were also associated with DFU in T1D, whereas smoking (14.7% vs 13.1%) and alcohol abuse (6.4% vs 3.8%, both p < .001) were associated with DFU in T2D. Male sex, higher Wagner grades, and high HbA1c in both diabetes types and insulin use in T2D were associated with increased hazard ratios for amputations. CONCLUSIONS: Sex, body height, and diabetes complications were associated DFU risk in adults with T1D and T2D. Improvement in glycemic control and lipid levels in T1D and reduction of smoking and drinking in T2D may be appropriate interventions to reduce the risk for DFU or amputations.

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria.

BACKGROUND: The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany. METHODS: German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared. RESULTS: Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT's albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible. CONCLUSIONS: Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review.

Chronic liver disease (CLD), manifested as hepatic injury, is a major cause of global morbidity and mortality. CLD progresses to fibrosis, cirrhosis, and-ultimately-hepatocellular carcinoma (HCC) if left untreated. The different phenotypes of CLD based on their respective clinical features and causative agents include alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD), and drug-induced liver injury (DILI). The preferred treatment modality for CLD includes lifestyle modification and diet, along with limited pharmacological agents for symptomatic treatment. Moreover, oxidative stress (OS) is an important pathological mechanism underlying all CLD phenotypes; hence, the use of antioxidants to manage the disease is justified. Based on available clinical evidence, silymarin can be utilized as a hepatoprotective agent, given its potent antioxidant, antifibrotic, and anti-inflammatory properties. The role of silymarin in suppressing OS has been well established, and therefore silymarin is recommended for use in ALD and NAFLD in the guidelines approved by the Russian Medical Scientific Society of Therapists and the Gastroenterology Scientific Society of Russia. However, to discuss the positioning of the original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies, an expert panel of international and Russian medical professionals was convened on 11 November 2020. The panel reviewed approaches for the prevention and treatment of OS, existing guidelines for patient management for CLD, and available evidence on the effectiveness of silymarin in reducing OS, fibrosis, and hepatic inflammation and presented in the form of a narrative review. Key messagesAn expert panel of international and Russian medical professionals reviewed existing guidelines for ALD, NAFLD, MAFLD, and DILI to establish consensus recommendations that oxidative stress is the common pathophysiological mechanism underlying these conditions.The panel also discussed the positioning of original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies.The panel reviewed the effectiveness of 140 mg original silymarin three times a day in reducing oxidative stress in chronic liver diseases such as ALD, NAFLD, MAFLD, and DILI.

Response to peginterferon plus ribavirin and subsequent retreatment with telaprevir-based triple therapy in a patient with chronic lymphocytic leukaemia and chronic HCV genotype 1b infection.

BACKGROUND: Case-controlled studies have clearly demonstrated a link between chronic hepatitis C infection (CHC) and B cell non-Hodgkin lymphoma (NHL). To our knowledge, this is the first case report of outcome in a patient with CLL and chronic HCV infection treated with PEG-IFN/RBV and subsequent retreated with triple therapy. FINDINGS: We report the case of a 54-year old, caucasian woman with a history of elevated liver enzymes diagnosed with chronic lymphocytic leukaemia (CLL) detected during investigation for hepatitis C (HCV) infection. The patient showed a haematological response following initially successful anti-HCV therapy with peginterferon plus ribavirin (PEG-IFN/RBV), with normalization of leukocyte and lymphocyte counts. She subsequently showed a late virological relapse at week 24, and was successfully retreated with telaprevir-based triple therapy. Despite an increase in leucocyte and lymphocyte count compared to baseline following triple therapy, to date there is no evidence of progression of CLL and the patient remains asymptomatic. CONCLUSION: Patients with CLL may experience haematological response following successful anti-HCV therapy using IFN-based regimens. Re-treatment with triple therapy including telaprevir following late virological relapse was successful, was not associated with any unexpected safety issues, and did not adversely affect CLL status.

Biliary cytokeratin expression but not CD56 (N-CAM) expression aids in the differential diagnosis of non-neoplastic bile duct diseases.

Non-neoplastic bile duct diseases include several entities with a variety of clinical and histopathologic features. In needle biopsies, however, these may overlap. Here, auxiliary diagnostic markers would be helpful. CD56 (N-CAM) has been reported in bile duct development, liver regeneration, and different liver diseases. This study was performed to evaluate the diagnostic value of CD56 immunohistochemistry compared to biliary cytokeratins in the diagnosis of non-neoplastic biliary liver diseases in liver needle biopsies. Thirty-eight cases (10× PSC; 10× PBC; 10× obstruction; 8× drug-induced liver disease [DILD]) were analyzed using antibodies against CD56/NCAM, CK7, and CK19. Twenty-three of all cases (63.9%) showed a positive CD56 reaction (PSC 6/10; PBC 9/10; obstruction 5/10; DILD 3/8) with no statistical significance between the groups. Biliary cytokeratins visualized the bile ducts in all cases. CK7 highlighted cholangiolar metaplasia in seven cases (3× PSC; 1× PBC; 3× DILD). CD56 cannot be used as a supplementary tool in the differential diagnosis of non-neoplastic biliary diseases. CK7 should be included in the routine assessment of liver biopsies in these settings. Further research is needed to find better targets for immunohistochemical determination of the etiology of bile duct damage.

Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma.

AIM: To investigate the role of tumor infiltrating lymphocytes (TIL) in primary hepatocellular and cholangiolar carcinomas of the liver. METHODS: Immunohistochemical analysis was performed including antibodies to CD3, CD4, CD8, CD20, CD56 and TIA-1 in formalin-fixed and paraffin-embedded tissue of 35 liver resection specimens of hepatocellular or cholangiocellular carcinomas. Semiquantitative evaluation was performed with emphasis on the area of the tumor itself and of the tumor/liver interface. RESULTS: All hepatocellular carcinomas showed infiltration of lymphocytes predominantly around the tumor in the tumor/liver interface consisting mainly of CD3+ CD4+ T lymphocytes [164.3/10 high power fields (HPF)] and in the tumor itself of CD8+ cells (54.9/10 HPF). Cholangiocarcinomas contained a heterogeneous amount of TIL, composed mainly of CD3+ T cells with a predominance of CD8+ cells in the tumor tissue (52.6/10 HPF) and of CD4+ cells in the interface region (223.1/10 HPF). CD56+ cells of the innate immune system were scarce. There was no significant difference between hepatocellular or cholangiolar carcinoma. No correlation with the clinicopathological data was seen. CONCLUSION: Liver TIL consists of intratumoral CD8+ T cells and peritumoral CD4+ T cells independent of histogenetic origin. Different functions of lymphocytes in these regions seem possible.