Clinical Case Summary

Bullous cellulitis is a type of skin infection that forms large fluid-filled blisters or bullae. It is usually caused by bacterial infections, most commonly gram-positive bacteria, and can occur anywhere on the body. It can cause pain, redness, swelling, and warmth in the affected area, as well as fever and chills in more severe cases. Hepatorenal syndrome is a form of renal impairment that occurs in patients with liver cirrhosis. Here, we present the case of a patient with liver cirrhosis who developed bullous cellulitis of the left lower limb caused by E. coli and hepatorenal syndrome. A 55-year-old male patient diagnosed with alcohol-induced liver cirrhosis and type 2 diabetes mellitus comes to the hospital due to pain in the left lower limb that started on the same day. Physical examination revealed signs of inflammation in the area, so bacterial cellulitis was suspected, cultures were taken and empirical antibiotic treatment was initiated. On the fourth day of hospitalization, a blister was observed in the affected area, and he developed anuria. Paracentesis was performed, and cultures of the affected tissue were obtained, as well as laboratory tests. The patient had total leukocytosis, elevated creatinine levels were obtained in the following days, and the patient continued to be oliguric. A renal ultrasound was performed, finding no alterations. There was no improvement with albumin and norepinephrine was started, which resulted in spontaneous diuresis recovery, the patient was discharged. Weeks later, he recovered a normal creatinine level, as well as a normal leukocyte count. In patients with cirrhosis, gram-negative infections are frequently observed. However, gram-positive cocci are typically responsible for skin infections. In cases of severe bullous cellulitis in cirrhosis patients, gram-negative bacteria should be considered as a possible cause. Prompt medical attention is important to improve outcomes and avoid complications.

References

Horowitz, Y., Sperber, A. D., & Almog, Y. (2004). Gram-Negative Cellulitis Complicating Cirrhosis. Mayo Clinic Proceedings, 79(2), 247–250. doi:10.4065/79.2.247
Gupta, K. et al. (2021) “Acute kidney injury and hepatorenal syndrome in cirrhosis,” World Journal of Gastroenterology, 27(26), pp. 3984–4003. Available at: https://doi.org/10.3748/wjg.v27.i26.3984.
Brown BD, Hood Watson KL. Cellulitis. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549770/
Horowitz, Y., Sperber, A.D. and Almog, Y. (2004) “Gram-negative cellulitis complicating cirrhosis,” Mayo Clinic Proceedings, 79(2), pp. 247–250. Available at: https://doi.org/10.4065/79.2.247.
Cirera I, Bauer TM, Navasa M, Vila J, Grande L, Taurá P, Fuster J, García-Valdecasas JC, Lacy A, Suárez MJ, Rimola A, Rodés J. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001 Jan;34(1):32-7. doi: 10.1016/s0168-8278(00)00013-1. PMID: 11211904.
Nadim, M.K. and Garcia-Tsao, G. (2023) “Acute kidney injury in patients with cirrhosis,” New England Journal of Medicine, 388(8), pp. 733–745. Available at: https://doi.org/10.1056/nejmra2215289.

Introduction

Chronic constipation (CC) is a prodromal and severe symptom in up to the 80% of Parkinson's disease (PD) patients (PD/CC) often refractory to standard laxative treatments. The molecular mechanisms underlying PD/CC are still unclear, although changes of enteric nervous system and intestinal epithelial barrier (IEB) have been thought to play a pathogenetic role.

Aims & Methods

In this study, PD/CC and chronic constipated (CCs) patients were functionally characterized, and possible abnormalities to IEB and the key neuromodulator vasoactive intestinal polypeptide (VIP) were investigated. N=12 PD/CCs (2 females; age range: 51-80 yrs), 20 CCs (15 females; 27-78; yrs) and 23 controls (Ctrls; 11 females; 32-74yrs) were enrolled. PD was diagnosed according to the United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic criteria, whereas CC was established following Rome IV criteria. Ctrls were otherwise asymptomatic subjects undergoing screening colonoscopy. Ten PD/CCs and 10 CCs were functionally characterized by anorectal manometry (AM) and transit time (TT). Colonic mucosal / submucosal biopsies were obtained in all patients / subjects and tested for gene, protein expression and localization of IEB tight junction markers claudin-4 (CLDN4), occludin-1 (OCCL-1) and zonula occludens-1 (ZO-1) and VIP, by RT-qPCR, immunoblot and immunofluorescence staining.

Results

PD/CCs were clustered in two groups: a) patients with delayed TT and altered AM (60%); b) those with altered AM only (13%). The evaluation of IEB markers on mucosal specimens showed an increase of CLDN4 mRNA in PD/CCs (1.26 ± 0.26) vs. Ctrls (1.00 ± 0.19) and CCs (0.95 ± 0.33), whereas a trend to CLDN4 protein reduction in PD/CCs (0.88 ± 0.33) vs. Ctrls (0.96 ± 0.25) and CCs (1.02 ± 0.51) was observed. Moreover, the OCCL-1 transcript was significantly increased in PD/CCs (1.36 ± 0.36) vs. Ctrls (1.05 ± 0.33) and CCs (0.81 ± 0.18). ZO-1 mRNA relative levels were consistent with those of OCCL-1 showing a significant increase in PD/CCs (1.35 ± 0.38) vs. Ctrls (1.02± 0.27) and CCs (0.85 ± 0.24). Notably, both OCCL-1 and ZO-1 showed a tendency to be reduced in CCs vs. Ctrls. Immunofluorescence highlighted a decrease in OCCL-1 immunoreactivity (IR) in PD/CCs (score= 1.5) vs. CCs and Ctrls (score= 4). Conversely, ZO-1-IR displayed an intense pattern (score=4) in both Ctrls and PD/CCs, but it was decreased in CCs (score= 2). VIP mRNA levels resulted significantly greater in CCs (3.98 ± 3.93, p<0.05) vs. Ctrls (1.52 ± 1.55) and PD/CCs (0.86 ± 1.056), whereas a decreasing trend was observed in PD/CCs vs. Ctrls (p>0.05). Both immunofluorescence and immunoblot confirmed this tendency showing a 15% drop of the VIP protein (PD/CCs 0.86 ± 0.43 vs. Ctrls 1.01 ± 0.56, p>0.05).

Conclusion

Transit and anorectal dysfunctions in PD/CCs are associated with ZO-1, OCCL-1, CLDN-4 and VIP changes, hence suggesting that a leaky IEB contributes to submucosal neurochemical abnormalities underlying PD/CC. These findings suggest that the expression of the IEB markers are subject to both transcriptional and post-translational regulatory mechanisms, presumably distinct in CC and PD/CC.

References

1. Giancola F, Torresan F, Repossi R, Bianco F, Latorre R, Ioannou A, Guarino M, Volta U, Clavenzani P, Mazzoni M, Chiocchetti R, Bazzoli F, Travagli RA, Sternini C, De Giorgio R. Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation. Neurogastroenterol Motil. 2017 May;29(5):10.1111/nmo.12995.
2. Clairembault T, Leclair-Visonneau L, Coron E, Bourreille A, Le Dily S, Vavasseur F, Heymann MF, Neunlist M, Derkinderen P. Structural alterations of the intestinal epithelial barrier in Parkinson's disease. Acta Neuropathol Commun. 2015 Mar 10;3:12.
3. Neunlist M, Toumi F, Oreschkova T, Denis M, Leborgne J, Laboisse CL, Galmiche JP, Jarry A. Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways. Am J Physiol Gastrointest Liver Physiol. 2003 Nov;285(5):G1028