Introduction

A plethora of findings suggests the correlation between Metabolic-(Dysfunction)Associated Fatty Liver Disease (MAFLD) and long-term incorrect lifestyle behavior. The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2) pandemic lockdown represented a unique event forcing the entire population to suddenly change their lifestyle, favoring a drastic reduction in physical activity and an improper diet, with consequences on metabolic homeostasis never experienced before. In this study, we aimed to investigate the effects of the SARS-CoV-2 confinement and related lifestyle changes on MAFLD evolution.

Aims & Methods

A cohort of 222 MAFLD patients was followed two years before, two years during, and one year after the pandemic. At four time points [January 2018: T0; January 2020: T1; January 2022: T2; January 2023: T3], anthropometrical, biochemical, nutritional, bioelectrical impedance analysis (BIA) data, non-invasive tools for disease staging and hepatocellular carcinoma (HCC) occurrence were collected.

Results

At T2 an increase in fats and carbohydrate intake consistently with impaired weekly physical activity was demonstrated, associated with an increase in body mass index and waist-to-hip ratio (p<0.0001 for all), as well as a worsening in levels of total cholesterol, low/high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance and transaminases (insulin: p=0.0003, glucose: p=0.0007; p<0.0001 for the others). Non-invasive tools assessments revealed a NAFLD fibrosis score, Liver Stiffness Measurement (LSM), and Controlled Attenuation Parameter impairment at T2 (p<0.0001 all). In comparison with T0 and T1, the BIA evidenced at T2 an increase in Fat Mass (FM) and a reduction of Free Fat Mass (FFM), Body Cell Mass (BCM), and Extracellular Mass (ECM). During the confinement period, the overall HCC and Milan-out staged HCC occurrence revealed HR:2.521, p=0.01, and HR:13.78, p=0.0009 respectively. Contrariwise to the modifications of the biochemical parameters, a significant association between body composition parameters modification during the study evaluations with HCC overall and HCC Milan-out criteria occurrence was highlighted (ΔFFM pre- vs during pandemic, OR: 0.704; ΔFM pre- vs during-pandemic, OR: 1.531; p <0.0001).
Receiving operator curve (ROC) analysis identified respectively -0.92 Kg (AUC:0.86) and -1.90 Kg (AUC:0.90) for FFM and +1.35 Kg (AUC:0.87) and +1.51 Kg (AUC:0.94) for FM as the best cut-off (BCO) variations (pre-pandemic vs pandemic) in the prediction of HCC overall and HCC Milan-out staged occurrence during the confinement. Time-to-time analysis revealed a higher incidence of HCC overall occurrence along the pandemic period in MAFLD patients presenting the following body modification composition “combined pattern” (BMCC) [BCO FFM decrease + BCO FM increase] in comparison to individuals presenting only one of two variations (p:0.025). At T3, compared to the pandemic period, simultaneously with improvement in physical activity as well as a decrease in fats and carbohydrate intake, the insulin levels, CAP, and FM were significantly decreased (p<0.001). Relevantly, a higher incidence of HCC overall occurrence even after the pandemic period in BMCC-MAFLD patients (p:0.048) was observed.

Conclusion

The confinement-related lifestyle changes impacted MAFLD evolution via body composition modifications, negatively influencing the HCC occurrence even after the pandemic period and the restoration of pre-existing life habits, as we are still observing the consequences of the confinement-induced "damages".

References

1. Taheri E, Bostick RM, Hatami B, et al. Dietary and Lifestyle Inflammation Scores Are Inversely Associated with Metabolic-Associated Fatty Liver Disease among Iranian Adults: A Nested Case-Control Study. J Nutr 2022;152:559-567.
2. Dallio M, Romeo M, Gravina AG, et al. Nutrigenomics and Nutrigenetics in Metabolic- (Dysfunction) Associated Fatty Liver Disease: Novel Insights and Future Perspectives. Nutrients 2021;13.
3. Ariya M, Koohpayeh F, Ghaemi A, et al. Assessment of the association between body composition and risk of non-alcoholic fatty liver. PLoS One 2021;16:e0249223.
4. Fujii H, Nakamura N, Fukumoto S, et al. Lifestyle changes during the coronavirus disease 2019 pandemic impact metabolic dysfunction-associated fatty liver disease. Liver Int 2022;42:995-1004.

Clinical Case Summary

A 64-year-old male patient presented with acute epigastric pain over 7 days, worsening after meals, nausea, vomiting 2 times without signs of bleeding, diarrhea 5-6 times/day, high blood pressure 180/100 mmHg. He had a 6-year history of recurrent epigastric pain, after multiple EGDSs was diagnosed as gastric ulcer and atrophic gastritis. The patient had undergone HP eradication and received standard anti-ulcer therapy several times, with no clinical improvement. On physical examination, the patient appeared pale. The abdomen was soft, without pain, guarding or rebound tenderness. The patient's medical history was significant for arterial hypertension. Lab abnormalities included WBC 16.32-10x10⁹/L, ESR 94mm/sec, CRP at 184.3 mg/L, FBG 767 mg, Total protein 50.9 g/L, CREA 147 mmol/L, Urea 13.42 mmol/L, Na 129 mmol/L. Intestinal infections were negative. New EGDS revealed an ulcerative lesion with 0.8cm diameter, in the region from antrum to greater curvature, covered with fibrin. Colonoscopy was normal. Duplex ultrasound revealed a 70% stenosis of the celiac trunk and superior mesenteric artery, with atherosclerotic wall deformation and intima-media thickening. A thrombosis was detected in the region of the aortic bifurcation. CT angiography revealed up to 70% stenosis of the suprarenal abdominal aorta, no contrast enhancement was observed in the origins of the celiac trunk, superior mesenteric artery, left renal artery (left kidney appeared atrophic), total occlusion of bilateral common, external, and internal iliac arteries.
Conclusion: Gastric ulcers are mostly associated with HP. However, in rare cases, underlying vascular pathology may be critical in their pathogenesis. This case highlights an overlooked cause of gastric ulcers, particularly in patients with atherosclerotic risk factors. In patients with persistent symptoms despite medical therapy ischemic ulceration should be included in the differential diagnosis.

Clinical Case Summary

Background: Syphilis is a chronic systemic infection caused by the spirochete Treponema pallidum, often referred to as "the great imitator" due to its ability to affect nearly any organ. Syphilitic hepatitis, or "luetic jaundice," is a rare manifestation, indicating spirochete dissemination to the liver.
Case Report: A 26-year-old female was admitted to the hospital with fever (39.5 °C), fatigue, sweating, tremor, dark urine, pale stools, and significant weight loss (15 kg over two months). She also reported lower extremity muscle and joint pain, cough and slowing of speech. On examination, she had icteric skin, a generalized maculopapular rash, and enlarged cervical lymph nodes. No history of alcohol or drug use was noted.
Laboratory tests revealed elevated levels of both cytolytic and cholestatic liver enzymes, along with increased bilirubin an elevated C-reactive protein.
Abdominal ultrasound and contrast CT showed hepatomegaly, hilar and retroperitoneal lymphadenopathy and splenomegaly.
Viral hepatitis markers (HBsAg, HBV PCR, HCVAb, HCV PCR, anti-HAV IgM, anti-HEV IgM) and antibodies for CMV, EBV, HIV, HSV-1,2 were negative. Wright-Hedelson test for brucellosis and serological markers for autoimmune hepatitis were negative while IgG and cerulopasmin levels were within normal range. Given systemic findings and history, syphilis was considered. Serologic tests were positive for Treponema pallidum (ELISA, TPHA, MRP). Liver biopsy revealed mild active hepatitis. The diagnosis of ^secondary syphilitic hepatitis was made. The patient was started on antimicrobial therapy. During follow-up, liver function tests normalized, and systemic symptoms resolved.
Conclusion: This case underscores the importance of considering syphilis in the differential diagnosis of unexplained hepatitis. Although rare, syphilitic hepatitis should be considered in patients with liver enzyme elevations and nonspecific symptoms, particularly when no clear alternative diagnosis is found.

References

1) Malvar G, Cardona D, Pezhouh MK, Adeyi OA, Chatterjee D, Deisch JK, Lamps LW, Misdraji J, Stueck AE, Voltaggio L, Gonzalez RS. Hepatic Secondary Syphilis Can Cause a Variety of Histologic Patterns and May Be Negative for Treponeme Immunohistochemistry. Am J Surg Pathol. 2022 Apr 1;46(4):567-575. doi: 10.1097/PAS.0000000000001848. PMID: 34864775.
2)Supronowicz Ł, Rogalska M. Syphilitic hepatitis. Clin Exp Hepatol. 2024 Mar;10(1):9-13. doi: 10.5114/ceh.2024.136235. Epub 2024 Mar 12. PMID: 38765910; PMCID: PMC11100338.
3)Al Dallal HA, Narayanan S, Alley HF, Eiswerth MJ, Arnold FW, Martin BA, Shandiz AE. Case Report: Syphilitic Hepatitis-A Rare and Underrecognized Etiology of Liver Disease With Potential for Misdiagnosis. Front Med (Lausanne). 2021 Nov 29;8:789250. doi: 10.3389/fmed.2021.789250. PMID: 34912834; PMCID: PMC8666961.
Figure 1: Histological images of the liver biopsy
Figure 2: Abdominal CT images
Figure 3: Images of maculopapular rash

Introduction

Functional dyspepsia (FD) is a common gastrointestinal disorder with limited treatment options. Itopride, a compound that combines dopamine D2 receptor antagonism with inhibition of acetylcholinesterase, may offer benefits over other prokinetics.

Aims & Methods

This meta-analysis evaluates the therapeutic efficacy of Itopride compared to placebo and other prokinetic agents in managing FD symptoms.
A total of 19 randomized controlled trials were included in the analysis, comprising six placebo-controlled studies (n=1981, 976 on placebo and 1005 on Itopride) and 13 trials comparing Itopride to another prokinetic (n=1077, 515 on Itopride and 562 on control prokinetics including mosapride citrate, levosulpiride, metoclopramide, domperidone, and cisapride). Meta-analyses were conducted using a random-effects (DerSimonian and Laird) model. Outcome measures included overall responder rate and symptom assessment, comparing Itopride to 1) all prokinetics and 2) placebo. In addition, Itopride was compared to placebo and domperidone for symptom scores of epigastric pain and early satiation. Results are presented as Cohen’s d (95% CI) or odds ratios(OR) (95% CI).

Results

Analysis of responder rates from seven placebo-controlled and nine active comparator studies showed a statistically significant benefit of Itopride over placebo (OR=1.25, 1.07 to 1.45, p=0.01), with no significant difference when compared to other prokinetics (OR=1.11, 0.93 to 1.34).
When assessing overall symptom scores, three placebo-controlled and four prokinetic-controlled trials were analyzed. Itopride showed a moderate effect size compared to other prokinetics (Cohen’s d=0.51, 0.13 to 0.88, p=0.01) and a large but not statistically significant effect compared to placebo (Cohen’s d=1.14, -0.43 to 2.71).
Early satiation was assessed in six domperidone-controlled trials, yielding a significant odds ratio of 1.37 (1.02 to 2.67, p=0.04). A large but not statistically significant difference was found compared to placebo (two trials, Cohen’s d=1.10, -0.47 to 2.67). For epigastric pain, a moderate but not statistically significant difference was found with placebo (two trials, Cohen’s d=0.68, -0.01 to 1.38) or domperidone (four trials, OR=0.85, 0.63 to 1.16).

Conclusion

This meta-analysis suggests that Itopride provides significant symptom relief in patients with FD compared to placebo, particularly in overall responder rates. While Itopride’s benefits over other prokinetics were modest in general symptom relief, it demonstrated a statistically significant advantage over domperidone for early satiation.