Clinical Case Summary

Stauffer's syndrome represents a rare renal cell carcinoma (RCC)-related paraneoplastic syndrome whose pathogenesis could be related to cancer cells-derived overexpression of inflammatory mediators, such as IL-6, contributing to the inhibition of multidrug resistance transporter and hepatobiliary dysfunction.
We present a 63 years-old male affected by third-line chemorefractory advanced RCC complicated by encephalic metastases. The patient was admitted to our department for fever, weight loss, acute onset severe cholestasis, and jaundice. Laboratory tests on admission revealed a compromised liver function.
Initially, all causes of acute cholestatic liver damage were excluded: the drug-induced liver injury was chronologically and etiologically-based criteria excluded; major and minor hepatotropic viruses and autoimmune panel resulted in negative.
The abdominal ultrasound with transient elastography ruled out advanced fibrosis, biliary dilatations, stones, and neoplastic lesions; the magnetic resonance cholangiopancreatography consistently excluded biliary tract diseases.
In light of these findings, paraneoplastic extra-hepatobiliary causes were considered. The dosage of serum IL-6 levels revealed a marked increase, confirming Stauffer’s syndrome suspicion.
Thereby, considering the failure of intravenous high-dose prednisone (1 mg/kg/die) administration, an off-label treatment based on the IL-6 inhibitor Tocilizumab (8 mg/kg in a single intravenous infusion) was started. During the following two weeks, a clinical and cholestasis indexes improvement was observed, and the patient was discharged. Unfortunately, 40 days after, he died due to brain metastases complications.
Stauffer’s syndrome should be suspected in advanced-stage oncological patients with unexplainable acute cholestasis and the administration of IL-6 inhibitors may represent a useful palliative approach.

References

1. Elseidy, S.A., Awad, A.K., Mandal, D. et al. Stauffer syndrome: a comprehensive review of the disease and diagnostic plan proposal. Egypt J Intern Med 34, 39 (2022). https://doi.org/10.1186/s43162-022-00128-6
2. Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome. Expert Rev Clin Immunol. 2019 Aug;15(8):813-822. doi: 10.1080/1744666X.2019.1629904. Epub 2019 Jun 20. PMID: 31219357; PMCID: PMC7936577.
3. Walther MM, Johnson B, Culley D, Shah R, Weber J, Venzon D, Yang JC, Linehan WM, Rosenberg SA. Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlate with paraneoplastic syndromes but not patient survival. J Urol. 1998 Mar;159(3):718-22. PMID: 9474133.
4. Nguyen V, Gurney H, van der Poorten D. Paraneoplastic hepatic dysfunction in metastatic prostate cancer: the role of cytokine dysregulation. J Clin Oncol 2011;29:e21–3, http://dx.doi.org/10.1200/JCO.2010.30.6522

Clinical Case Summary

For decompensated advanced chronic liver disease (dACLD) individuals, the onset of refractory ascites (RA) represents a dramatic event (6-month survival rate < 50%). In this setting, a relevant proportion of RA patients develop Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI) with limited therapeutic and survival chances.
An 81-year-old female dACLD RA patient was admitted to our department to receive large-volume paracentesis (LVP). Eradicated HCV infection, type II diabetes, and chronic obstructive pulmonary disease were her comorbidities.
The AKI onset imposed the intravenous (i.v.) human albumin (HA) (1 g/kg/die) administration, followed by the proper dosage of terlipressin (for HRS-AKI) within the first 72 hours (h), subsequently discontinued due to the persistence of anuria and the worsening of respiratory failure.
To simultaneously address uremic symptoms and facilitate ascites drainage, a Tenckhoff catheter was placed, and peritoneal dialysis (PD) started with a single icodextrin dwell, resulting in the removal of 14 L of ascites and an improvement in AKI within the subsequent 72h. After one week, she was discharged, receiving a specific PD schedule. After the readmission due to the difficulties in administering i.v. HA, we proposed administering HA via the intraperitoneal route, creating an HA-enriched PD (PD+HA) home-performable schedule by adding two vials of 100 ml of HA 20% to 800 ml of icodextrin solution (40 g in 1000 ml/die; lasting: 12 hours; frequency: every other day) (Figure 1).
The patient has been performing this PD schedule for 12 months (~0.5 L of ascites is discharged every other day before performing PD+HA dwell). During the follow-up, no PD-related complications (e.g., peritonitis) and liver-related events requiring hospitalization have been observed.
We report the first successful use of PD+HA, highlighting the cruciality of a multidisciplinary (hepatologists-nephrologists) approach in the management of dACLD-RA HRS-AKI patients.

References

1. Moreau, R.; Delègue, P.; Pessione, F.; Hillaire, S.; Durand, F.; Lebrec, D.; Valla, D.-C. Clinical Characteristics and Outcome of Patients with Cirrhosis and Refractory Ascites. Liver Int 2004, 24, 457–464, doi:10.1111/j.1478-3231.2004.0991.x.
2. Moore, K.P.; Wong, F.; Gines, P.; Bernardi, M.; Ochs, A.; Salerno, F.; Angeli, P.; Porayko, M.; Moreau, R.; Garcia-Tsao, G.; et al. The Management of Ascites in Cirrhosis: Report on the Consensus Conference of the International Ascites Club. Hepatology 2003, 38, 258–266, doi:10.1053/jhep.2003.50315.
3. Nadim, M.K.; Kellum, J.A.; Forni, L.; Francoz, C.; Asrani, S.K.; Ostermann, M.; Allegretti, A.S.; Neyra, J.A.; Olson, J.C.; Piano, S.; et al. Acute Kidney Injury in Patients with Cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) Joint Multidisciplinary Consensus Meeting. J Hepatol 2024, 81, 163–183, doi:10.1016/j.jhep.2024.03.031
4. Brown, E.A.; Blake, P.G.; Boudville, N.; Davies, S.; de Arteaga, J.; Dong, J.; Finkelstein, F.; Foo, M.; Hurst, H.; Johnson, D.W.; et al. International Society for Peritoneal Dialysis Practice Recommendations: Prescribing High-Quality Goal-Directed Peritoneal Dialysis. Perit Dial Int 2020, 40, 244–253, doi:10.1177/0896860819895364.

Clinical Case Summary

Lysosomal acid lipase deficiency (LALD) is a rare autosomal-transmitted metabolic disease in which infants and adults show uncontrolled accumulation of cholesterol esters and triglycerides, resulting in multi-organ damage and premature death. Few cases of hepatocellular carcinoma (HCC) onset in LALD-related cirrhosis have been described, while the occurrence in the earlier disease stages remains unreported.
A 49-year-old (yo) male was admitted for chronic diarrhea and recurrent abdominal pain. History collection revealed his brother's death due to cryptogenic cirrhosis complications. Comorbidities were: statin-unresponsive dyslipidemia determining an episode of juvenile (27yo) Acute Myocardial Infarction (AMI). Physical examination evidenced splenic-hepatomegaly and emaciated facies with an aquiline nose. Laboratories abnormalities highlighted mainly: alanine-aminotransferase elevation and malabsorption. Ultrasonography revealed in the bright-liver not-coarse pattern a nodule (30 mm) appearing contrast-enhanced-suspected for HCC, subsequently histologically confirmed by a percutaneous biopsy. The colonoscopy was negative for malignancies; esophagogastroduodenoscopy showed an edematous duodenal mucosa with a marked foam cell infiltrate. In light of these findings, considering also the anamnestic (familiarity), clinic (facies, unexplainable diarrhea), and biochemical data, rare lysosomal accumulation diseases were suspected.
A Dried Blood Spot test evidenced low LAL activities and the genetics confirmed the LALD diagnosis. Due to the reported hepatic disorder recurrence, liver transplantation was not indicated, and thus microwave thermoablation was performed. Twelve months later, the patient would have benefited from Sebelipasi Alpha-based enzyme replacement therapy. Unfortunately, he died after a new AMI.
LALD should be suspected and early identified. HCC occurrence in a non-cirrhotic LALD context appears possible

References

Cunha-Silva M, de França EVC, Veiga CT, Greca RD, de Moraes PBS, de Campos Mazo DF, de Ataíde EC, Perales SR, Monici LT, Sevá-Pereira T. 15-Year progression to liver cancer in the lack of treatment for lysosomal acid lipase deficiency: A case report. Medicine (Baltimore). 2022 Sep 2;101(35):e30315. doi: 10.1097/MD.0000000000030315. PMID: 36107601; PMCID: PMC9439781.

Introduction

Malnutrition, sarcopenia, and frailty constitute the three vertices of a nutrition-status-determined physio-pathological triangle constantly featuring and dramatically burdening the prognosis of advanced chronic liver disease (ACLD) patients.
Dysgeusia is defined by a distortion of the sense of taste whose prevalence, relationship with the progression of the disease, and the direct contribution to malnutrition (and consequently, sarcopenia-frailty) in ACLD have never been systematically explored.

Aims & Methods

This observational study aimed to explore the prevalence of dysgeusia in a cohort of ACLD patients and evaluate the impact of this disorder on appetite levels and nutritional status (malnutrition, sarcopenia, and frailty), as well as to prospectively estimate the repercussions of dysgeusia-induced impaired nutritional status on liver-related events (LREs) occurrence. For this purpose, 40 controls, 50 chronic-liver disease-affected individuals staging initial-mild fibrosis (<F3), and 150 ACLD patients of various etiologies were enrolled. Anthropometrical, biochemical, clinical, and nutritional [European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaire] data were collected. The opportunely modified Chemotherapy-induced Taste Alteration Scale (CITAS) questionnaire was used to assess the dysgeusia. Child-Pugh (CP) and Liver Frailty Index (LFI) calculations, Liver Stiffness Measurement (LSM), and Bioelectrical Impedance Analysis (BIA) were performed. Skeletal Muscle Mass (SMM) index (SMMI) (SMM/height²) < 7 kg/m² (male) and < 5.7 kg/m² (female) defined sarcopenia. ACLD patients were 3 years followed up semiannually and LREs (including ascites, hepatic encephalopathy, and bleeding) were collected.

Results

The prevalence of dysgeusia was significantly higher in ACLD (68%) in comparison to <F3 (8%) individuals and controls (5%) and in decompensated ACLD (dACLD) than compensated (cACLD) (54% vs 6%) patients (all p<0.0001). In line, CITAS-dysgeusia severity positively correlated with CP (R:0.81), as well as with the levels of appetite impairment (R:0.93) (both p<0.0001). Logistic regression analysis, appropriately weighted for factors notoriously impacting food intake in ACLD patients (low-sodic diet, drugs/supplements taken, physical activity frequency, occurrence of encephalopathy and ascites episodes in the previous 2 weeks), revealed the level of impairment of the appetite as a factor significantly associated with dysgeusia [HR: 2.12; p:0.02]. Compared to no-dysgeusia-affected dACLD (p:0.03), dysgeusia-affected dACLD patients (dys-dACLD) showed a decreased daily protein intake, reduced Free Fat Mass % (p<0.0001), and SMMI (p<0.0001: p:0.04), in contrast with increased LFI (p<0.0001). Consistently, dys-dACLD patients showed a higher prevalence (59% vs 39%) of sarcopenia (p:0.0002). The Kaplan-Meier Log-Rank Test analysis on LREs occurrence showed HR:3.53 [95% C.I: 1.58-4.92] for dys-dACLD individuals.

Conclusion

The prevalence of dysgeusia, increasing in parallel to the worsening of liver disease, promoted sarcopenia-frailty pictures, negatively influencing ACLD patients' outcomes.

References

1. Jafari A, Alaee A, Ghods K. The etiologies and considerations of dysgeusia: A review of literature. Journal of oral biosciences. 2021;63(4):319-26.
2. Sieber CC. Malnutrition and sarcopenia. Aging clinical and experimental research. 2019;31(6):793-8.
3. Tandon P, Montano-Loza AJ, Lai JC, Dasarathy S, Merli M. Sarcopenia and frailty in decompensated cirrhosis. Journal of hepatology. 2021;75 Suppl 1(Suppl 1):S147-s62.

Introduction

Two years after the Delphi consensus-proposed revolution in the nomenclature and diagnosis of Steatotic Liver Disease (SLD), the potential benefits of adopting Metabolic dysfunction-associated steatotic liver disease (MASLD) rather than Metabolic dysfunction-associated fatty liver disease (MAFLD) diagnostic criteria in defining the disease progression risk of SLD patients have never been systematically and longitudinally evaluated in real-life.

Aims & Methods

The present study aimed to compare MASLD and MAFLD criteria in estimating the 3-year risk of advanced fibrosis (AF) progression and Acute Cardiovascular Event (ACE) occurrence in not-lean (NL) and lean (L) SLD patients.
For this purpose, we retrospectively analyzed the anthropometrical, biochemical, clinical, and Liver Stiffness Measurement (LSM - FibroScan) data stored in the University Hospital (UH)-official Health Documents Digitization Archive of 931 SLD patients admitted to UH “Luigi Vanvitelli” (between January 2016 and May 2021), and followed up for 3 years. Based on baseline Body Mass Index (BMI), patients were subdivided into “L” (BMI <25 kg/m2) (n:134) and “NL” (n:797) and, subsequently, by applying MAFLD and MASLD criteria, in NL-MASLD (n:206), NL-MASLD/MAFLD (n:481), NL-MAFLD (n:110), and L-MASLD (n:39), L-MASLD/MAFLD (n:68), L-MAFLD (n:27). The following validated LSM cut-offs were used to identify the different liver fibrosis stages according to the Metavir score: (a) F0-F2 ≤ 9.6 kPa; (b) F3: 9.7 - 13.5 kPa; (c) F4 ≥ 13.6 kPa. AF (F3-F4) was defined by LSM values > 9.7 kPa. The transition from F0-F2 to F3-F4 defined AF progression. Retrospectively collected and documented ACEs were: (1) Acute Myocardial Infarction (IMA), (2) Acute Coronary Syndrome (ACS), (3) Ictus cerebri (IC), and (4) Transient Ischemic Attack (TIA).

Results

MASLD and MAFLD criteria similarly estimated [MASLD: OR: 2.334, C.I.95%: 1.878 - 3.028, MAFLD: OR: 2.469, C.I.95%: 1.892 - 3.668, p < 0.0001; positive predictive value (PPV), MASLD: 0.800, C.I. 95%: 0.641-0.89 vs MAFLD: 0.785, C.I. 95%: 0.604-0.897, p: 0.076)] the overall 3-year risk of AF progression in NL-SLD, whereas in L-SLD, MAFLD criteria better estimated the overall 3-year risk of AF progression [PPV, MASLD: 0.571, C.I. 95%: 0.405-0.841 vs MAFLD: 0.714, C.I. 95%: 0.558-0.794, p: 0.006].
Compared to MASLD, MAFLD diagnostic criteria better estimated the 3-year risk of ACEs occurrence in NL [HR: 1.104, C.I..95%: 0.024-1.293, p:0.025], and not in L [HR: 1.260, C.I..95%: 0.665-2.101, p:0.071] patients. Multivariate competing risk analysis (adjusted for sex, age, diabetes, steatosis, and fibrosis severity) revealed diabetes (aHR: 2.113, C.I. 95%: 1.981-2.434, p:0.001), high-sensitivity-C-reactive protein (aHR: 1.441; C.I. 95%: 1.232-1.775; p:0.02) and Homeostatic-model-assessment-for-insulin-resistance (aHR: 1.228; C.I. 95%: 1.152-1.893; p:0.03) as associated with ACE occurrence in NL-MAFLD patients.

Conclusion

MAFLD criteria better estimate the 3-year AF progression and the ACE occurrence risk in L-SLD and NL-SLD patients, respectively.

References

1. Rinella ME, and NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023 Dec;79(6):1542-1556. doi: 10.1016/j.jhep.2023.06.003. Epub 2023 Jun 24. PMID: 37364790.
2. Ramírez-Mejía MM, Jiménez-Gutiérrez C, Eslam M, George J, Méndez-Sánchez N. Breaking new ground: MASLD vs. MAFLD-which holds the key for risk stratification? Hepatol Int. 2024 Feb;18(1):168-178. doi: 10.1007/s12072-023-10620-y. Epub 2023 Dec 21. PMID: 38127259.
3. Alboraie M, Butt AS, Piscoya A, Dao Viet H, Hotayt B, Al Awadhi S, Bahcecioglu IH, Alkhalidi N, Al Mahtab M, Méndez-Sánchez N. Why MASLD Lags Behind MAFLD: A Critical Analysis of Diagnostic Criteria Evolution in Metabolic Dysfunction-Associated Liver Diseases. Med Sci Monit. 2024 Jul 30;30:e945198. doi: 10.12659/MSM.945198. PMID: 39075772; PMCID: PMC11299466.
4. De A, Bhagat N, Mehta M, Taneja S, Duseja A. Metabolic dysfunction-associated steatotic liver disease (MASLD) definition is better than MAFLD criteria for lean patients with NAFLD. J Hepatol. 2024 Feb;80(2):e61-e62. doi: 10.1016/j.jhep.2023.07.031. Epub 2023 Aug 7. PMID: 37558135.