Clinical Case Summary

Hematopoietic stem cell transplantation (HPSCT) is associated with multiple complications, such as hepatic sinusoidal obstruction syndrome (SOS) (hepatomegaly, ascites, jaundice, and thrombocytopenia) and graft-versus-host disease (GVHD) (skin, gastrointestinal tract and liver are the main targets). These entities may present overlapping clinical findings, being considered differential diagnoses. Coexistence is rare.
A 29-year-old man undergoes HPSCT for acute myeloid leukemia. On day(D)+20, he presents with hyperbilirubinemia (HBR), pleural effusion, ascites, painful hepatomegaly. Ultrasound is suggestive of SOS – Defibrotide was initiated. On D+44, acute cutaneous, intestinal and hepatic GVHD develops. He started methylprednisolone, with analytical improvement. On D+132, worsening cholestasis and abdominal pain. MRCP revealed caliber compromise in several segments of the intrahepatic bile ducts and wall irregularity of the main bile duct. Due to clinical and analytical worsening, he was admitted to the ICU. As he maintained total HBR (30mg/dL) and thrombocytopenia (30,000cell/uL), he underwent an hepatic hemodynamic study (hepatic venous pressure gradient of 10 mmHg) and a transjugular liver biopsy that showed canalicular hepatic cholestasis, bile duct injury and focal hepatocellular necrosis - probable GVHD – and injury to centrilobular veins and centrilobular necrosis - possible SOS. Mycophenolate mofetil was started, but on D+195 the patient died.
This case is notable for its complexity and for demonstrating the rare co-existence of histological aspects of SOS (several weeks after its diagnosis and clinical resolution) and GVHD. Although the clinical and analytical findings may be sufficient for the diagnosis, it is important to highlight the importance of transjugular liver biopsy in patients with severe thrombocytopenia for the characterization and histological confirmation of cholestatic hepatitis, especially when the etiology may be multifactorial.

References

- Ramachandran V, Kolli SS, Strowd LC. Review of Graft-Versus-Host Disease. Dermatol Clin. 2019 Oct;37(4):569-582. doi: 10.1016/j.det.2019.05.014.
- Fan C, Crawford J. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol. 2014 Dec;4(4):332-46. doi: 10.1016/j.jceh.2014.10.002.
- Matsukuma K, Wei D, Sun K, Ramsamooj R, Chen M. Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD). J Gastrointest Oncol. 2016 Apr;7(Suppl 1):S21-31. doi: 10.3978/j.issn.2078-6891.2015.036.
- Tuncer H, Rana N, Milani C, Darko A, Al-Homsi S. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012 Apr 28;18(16):1851-60. doi: 10.3748/wjg.v18.i16.1851.
- Corbacioglu S, Jabbour EJ, Mohty M. Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome. Biol Blood Marrow Transplant. 2019 Jul;25(7):1271-1280. doi: 10.1016/j.bbmt.2019.02.018.

Introduction

Acute kidney injury (AKI) in cirrhosis manifests as pre-renal azotemia (PRA), hepatorenal syndrome (HRS), or acute tubular necrosis (ATN), each with distinct prognosis ⁽¹⁾. Early subtype classification and outcome prediction are critical. In Decompensated Cirrhosis patients with AKI, urine NGAL (UNGAL) and urine IL-18 (UIL-18) have been evaluated for differentiating between ATN and non-ATN AKI (PRA and HRS) with conflicting results ^(2,3). The present study compared the diagnostic accuracy of UNGAL and UIL-18 for predicting ATN AKI, AKI resolution and in-hospital mortality.

Aims & Methods

Present study was conducted at a tertiary care hospital (GIPMER, India) from July 1, 2023 to December 31, 2024. Patients with Decompensated Cirrhosis having AKI stage IB or higher were included, while advanced chronic kidney disease, Hepatocellular carcinoma prior liver transplant were excluded. The AKI was diagnosed as per International Club of Ascites Consensus (2015) and classified as per clinical adjudication after volume expansion with injection Human Albumin (20%, 1 g/kg body weight) on day 3 ⁽⁴⁾. Urine NGAL (sandwich ELISA) and IL-18 (sandwich ELISA) were measured after 48 hours of volume expansion, that is on day 3 of AKI diagnosis. The primary outcome was prediction of ATN-AKI on day 3 and secondary outcomes were prediction of AKI resolution at discharge and in-hospital mortality. The Receiver-operator curve (ROC) and multivariate logistic regression were used for analysis and p value <0.05 considered statistically significant.

Results

Total of 81 Decompensated Cirrhosis patients with AKI were enrolled in study. The aetiology of AKI was 24 (29.5%) PRA, 37 (45.7%) HRS and 20 (24.7%) ATN respectively. Mean MELD Na score was 28.4+7.3 and majority (82.7%) were CTP-C. Mean Serum Creatinine was 2.85+0.95 mg/dl. Mean UNGAL was 109.7 (PRA), 206.6 (HRS) and 396.4 (ATN) ug/g Creatinine (p<0.001). Mean UIL-18 was 39.8 (PRA), 85.6 (HRS) and 139.3 (ATN) pg/ml (p<0.001). AUROC for differentiation of ATN from non-ATN for urine NGAL was 0.9 (best cut-off 236.3 ug/g Creat) and urine IL-18 was 0.88 (best cut-off 108.75 pg/ml). AKI resolution occurred in 95.8% (PRA), 81% (HRS), and 40% (ATN). Mortality was highest in ATN (50%), vs PRA (16.7%) and HRS (8.1%). AUROC of UNGAL was 0.211 and UIL-18 was 0.185 for predicting AKI resolution. AUROC of UNGAL was 0.654 and UIL-18 was 0.641 for predicting in-hospital mortality (AUROC: NGAL 0.654, IL-18 0.641). Urine NGAL ( and urine IL-18 failed to predict AKI resolution (p 0.14 and 0.27) and in-hospital mortality (p 0.06 and 0.07) in multivariate regression analysis.

Conclusion

Urine NGAL and IL-18 had good diagnostic accuracy in predicting ATN-AKI in patients with Decompensated Cirrhosis, however do not independently predict resolution of AKI and in-hospital mortality.

References

1. Tariq R, Hadi Y, Chahal K, Reddy S, Salameh H, Singal AK. Incidence, mortality and predictors of acute kidney injury in patients with cirrhosis: A systematic review and meta-analysis. J Clin Transl Hepatol. 2020;8(2):135.
2. Puthumana J, Ariza X, Belcher JM, Graupera I, Ginès P, Parikh CR. Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2017;15(7):1003-13.
3. Huelin P, Solà E, Elia C, Solé C, Risso A, Moreira R, et al. Neutrophil gelatinase-associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study. Hepatology.2019;70(1):319–33.
4. Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and
management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64(4):531–7.

Introduction

Cirrhotic cardiomyopathy (CCM), cardiac dysfunction in liver cirrhosis of any aetiology in the absence of a primary cardiac cause predisposes to morbidity and mortality before and after Liver Transplantation (LT). Global longitudinal strain (GLS) measurement is included in the updated CCM criteria to detect subclinical myocardial dysfunction. Myocardial work (MW) is a novel echocardiographic measure, combining GLS with simultaneous blood pressure measurements has been found to correlate well with invasively measured global myocardial function. MW is not reported in cirrhosis and CCM.

Aims & Methods

The primary aim was to evaluate global cardiac function in decompensated cirrhosis using advanced echocardiographic parameters at rest and with dobutamine stress echo (DSE), and to study their association with development of a composite clinical outcome including acute kidney injury/hepatorenal syndrome, refractory ascites, cardiac failure and death over the subsequent 12 months. The secondary aims were to report the prevalence of CCM and to assess its association with the study outcome; to assess the diagnostic utility of cardiac biomarkers (NT-pro-BNP and cardiac troponin T) in CCM, and re-assess cardiac function at 12 months of successful LT.
Prospective study of cirrhotic patients with ascites or undergoing LT assessment from January 2021 to August 2022, with 12-month follow-up. After a written consent, clinical profile, Model for End-stage Liver Disease sodium (MELD Na) score, and cardiac biomarkers were evaluated. Transthoracic echo and DSE measured GLS and calculated MW (GWI (global work index), GCW (global constructive work), GWE (global work efficiency) and GWW (global wasted work). Statistical analysis was conducted using SPSS IBM Statistics version 29. Difference in estimated marginal mean difference in MW between baseline and DSE were obtained using repeated measures of ANOVA. Univariate analysis of clinical, echocardiographic and demographic features on the study outcome was assessed using either independent t-test or chi-squared test as appropriate. Significant predictors from the univariate analysis (p<0.05) were included in multivariate Cox regression analysis.

Results

96 patients with mean±SD age 56±11 years; (58% male; 59% alcohol misuse) were studied. The mean±SD MELD Na was 17±11. 16 patients underwent LT; 53 developed the composite clinical outcome. MELD Na, troponin, LVEF, rest and peak GLS, rest and peak GWI, peak GWE and E/e’ were significantly higher in patients meeting study outcome in univariate analysis. MELD Na and E/e’ were positively associated in multivariate analysis with HR (95%CI)=1.075:1.018–1.135; p=0.009 and HR=1.179; 1.037–1.340; p=0.012 respectively. There was a significant decrease in GLS and MW on DSE. There was a significant correlation between MELD Na and rest GLS (r=0.30, p<0.001). Based on new CCM criteria, systolic dysfunction was detected in 17% and diastolic dysfunction in 13% and CCM in 27%. There was no association between CCM and the composite study outcome. Median (IQR) troponin was 13.5 ng/ml (7.0–24.0) and BNP was 189 (pg/ml) (53.0–374.0). There was no association between these biomarkers and CCM. Ten patients evaluated post LT, demonstrated significant improvements in GLS, MW and LVEF.

Conclusion

In our patients with advanced cirrhosis, the study revealed increased myocardial work without any augmentation on DSE. CCM observed in a quarter of patients, had no impact on clinical course before/ after LT. Further studies are warranted to validate the updated CCM criteria and improve its clinical utility.

Disclosure

no cnfict t if interest