Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of cholesterol, and whole body cholesterol pool size in a mouse model of CESD. In 50-day-old lal(-/-) and matching lal(+/+) mice fed a low-cholesterol diet, whole animal cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal(-/-) mice sequestered cholesterol at an average rate of 3.2 mg·day(-1)·animal(-1). The proportion of the body sterol pool contained in the liver of the lal(-/-) mice was 64 vs. 6.3% in their lal(+/+) controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal(-/-) mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal(-/-) mice, whole liver cholesterol synthesis increased 10.2-fold, resulting in a 3.2-fold greater rate of whole animal sterol synthesis compared with their lal(+/+) controls. The rate of cholesterol synthesis in the lal(-/-) mice exceeded that in the lal(+/+) controls by 3.7 mg·day(-1)·animal(-1). Fractional cholesterol absorption and fecal bile acid excretion were unchanged in the lal(-/-) mice, but their rate of neutral sterol excretion was 59% higher than in their lal(+/+) controls. Thus, in this model, the continual expansion of the body sterol pool is driven by the synthesis of excess cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal(-/-) mice was 355 days.
Abstract Background The impact of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection among pediatric solid organ transplant (SOT) recipients remains unclear. We sought to characterize the clinical epidemiology and outcomes following SARS-CoV-2 infection among pediatric SOT recipients in Dallas, TX. Methods Retrospective review of all SOT recipients with laboratory confirmed COVID-19 infection from March 1, 2020 –March 31, 2021. Demographic, clinical, and outcome data were stratified by transplant type and disease severity. Fischer’s exact test and Kruskall-Wallis test were used to evaluate risk factors for more severe disease among hospitalized children. Results Twenty-six SOT recipients with a median age of 14 years were included in the study. Fifteen (58%) were female, eighteen (69%) were Hispanic and thirteen (50%) were overweight/obese. Median time post-transplant was 3.6 years (1311 days, interquartile range (IQR) 394-2881). Fourteen patients were liver recipients, seven kidney, three heart, and two multiorgan. The majority of patients (65%) had a known community exposure and presented with fever (50%), cough (38%) and GI symptoms (19%). Half of all cases were hospitalized (n=13), with 2 requiring intensive care unit (ICU) admission, but no patients required positive pressure ventilation. Median hospital stay was 3 days. Five of the thirteen hospitalized patients were categorized as having moderate disease. No patients developed severe disease and there were no deaths. Older children, as well as children with multiple co-morbidities were noted on univariate analysis to be at higher risk for moderate, as compared to mild, disease. Conclusion SARS-CoV-2 infection among pediatric SOT recipients are at increased risk for hospital admission but demonstrate an overall mild /moderate disease course. Larger studies are required to elucidate the risk of morbidity between pediatric SOT recipients and immunocompetent children with SARS-CoV-2. Disclosures Amal Aqul, MD, Albireo pharma Inc. (Consultant)
Objectives: The aim of the study was to evaluate whether liver stiffness measurement (LSM), determined by transient elastography, correlates with presence and severity of liver disease in children and young adults with cystic fibrosis (CF). Methods: Subjects underwent LSM at routine CF visits. Presence and severity of cystic fibrosis liver disease (CFLD) was determined by clinical parameters. Subjects were classified as no CFLD, CFLD without portal hypertension (PHTN), and CFLD with PHTN. LSM was compared with aspartate aminotransferase/platelet ratio index (APRI) as a correlate to severity of CFLD. Results: A total of 249 subjects (53% boys; mean age 14 ± 7 years; 7 [3%] <2 years and 74 [30%] 18–25 years) underwent LSM. Subjects were classified as 158 (64%) with no CFLD, 73 (29%) CFLD without PHTN, and 18 (7%) CFLD with PHTN. The median (interquartile range) LSM was different among the 3 groups: 4.4 (3.8–5.4), 5.1 (4.4–6.3), and 14.1 (8.8–24.8) kPa, respectively, with all pairwise comparisons different from one another ( P < 0.0001). Similarly, median (interquartile range) APRI was different in groups 1 and 2 compared with CFLD with PHTN: 0.22 (0.17–0.27), 0.24 (0.17–0.33), and 0.53 (0.24–0.84), respectively ( P < 0.01). Analysis of receiver operating characteristics for discriminating CFLD with PHTN from the other groups resulted in cut‐points at 6.2 kPa (LSM) and 0.35 (APRI). LSM was superior to APRI in discriminating CFLD with PHTN from other groups, with areas under the curve 0.91 (LSM) versus 0.78 (APRI) ( P = 0.05). Conclusions: Liver stiffness, as determined by transient elastography, correlates with the presence and severity of CFLD. Although APRI provided some information regarding severity of liver disease, LSM performed better than APRI in this population.
Purpose of review Long-term survival is now the rule rather than the exception for infants and children who undergo liver transplantation for end-stage liver disease, metabolic liver conditions and a variety of other indications. Pediatricians and primary care providers play vital roles in the care and management of this patient population. The purpose of this review is to highlight key aspects important to the care of the pediatric liver transplant recipient. Recent findings Significant advances in immunosuppressive therapies and surgical techniques have contributed to improved graft and patient survival rates, shifting the focus beyond immediate survival to strategies to minimize comorbidities related to long-term immunosuppression during growing years, attend to patient and parent-reported outcomes and enhance quality of life. A multidisciplinary approach allows for monitoring and surveillance of both routine (growth, nutritional rehabilitation, cognitive development, mental and psychosocial health, contraception and daily activities) and transplant-related (adverse effects of immunosuppression, susceptible infections, extra-hepatic systems, transition from childhood to adolescence to adulthood) themes. Summary Effective communication between the primary care physician and the transplant team is imperative for optimizing best outcomes. The primary care provider should be aware of the multifacet nature of posttransplant management, which includes medication regimens, common complications and infections.
Introduction: Pediatric patients with metabolic diseases are listed so that livers are preferentially allocated to them, having the option of receiving very high quality organs. We examined outcomes of these livers in comparison to livers with marginal characteristics to see if a pediatric metabolic recipient should wait for a prime organ. Methods: The UNOS database was queried to examine outcomes in all pediatric liver transplant recipients (<18 years) who were transplanted between 1987 - 2018. Living donor and multi-organ recipients were excluded. Patients with a diagnosis of glycogen storage disease (GSD) type I, GSD type IV, homozygous hypercholesterolemia, tyrosinemia, hyperoxaluria, maple syrup urine disease, and “other” metabolic diseases were included for analysis. A marginal liver was defined as one with any of the following characteristics: donor age > 60 years, terminal transaminases > 500 U/L, biopsy proven macrosteatosis > 30%, cold ischemia time (CIT) > 8 hours, donation after cardiac death (DCD) donor, or HBV core Ab +/HCV Ab + donor. Donor and recipient demographic data were examined, as were survival and outcomes. A p-value of <0.05 was considered to be significant. Results: There were 1342 metabolic pediatric patients who underwent liver transplantation; 926 received a high quality (HQ) liver; 416 received a marginal (MARG) liver. The MARG donor was significantly younger (9.9 vs. 12.9 years), had a lower BMI (18.9 vs. 20.0 kg/m2), a higher SGPT (64.2 vs. 53.1) and SGOT (107.6 vs. 70.9), longer CIT (11.0 vs. 5.5 hours), and higher DCD percentage (1.0% vs. 0%). Recipients of MARG livers were not significantly different in age (4.8 vs. 4.5 years), BMI (18.7 kg/m2vs. 18.7 kg/m2), final MELD/PELD score (2.8 vs. 1.8), or wait time (150.2 vs. 168.6 days). MARG liver recipients were more likely to be on life support (8.9% vs. 6.0%, p<0.05), and trended to having a longer length of stay (45.1 vs. 24.4 days, p=0.05). Outcomes showed similar or improved outcomes when examining causes of allograft failure including primary nonfunction, acute or chronic rejection, and thrombotic events. When allograft survival was examined, there was no difference when comparing HQ vs. MARG livers (Figure 1).Conclusions: Livers with marginal characteristics have similar allograft outcomes and survival when compared to high quality livers that are transplanted into pediatric metabolic recipients. Rather than waiting for the perfect liver, it should be strongly considered to transplant a liver with expanded criteria characteristics into these patients as long-term allograft survival does not suffer.
INTRODUCTION The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in coronavirus disease 2019 (COVID-19) continues to cause a worldwide pandemic. Recognized clinical presentations of COVID-19 have evolved beyond solely respiratory symptoms. We report a 13-year-old girl with severe abdominal pain who was found to have chylous ascites, cardiac dysfunction, and multiple thrombi 10 weeks following a COVID-19 infection. Informed consent was obtained from the family before the submission of this article. CASE REPORT A 13-year-old girl with a history of Ewing Sarcoma diagnosed in 2009, post left leg amputation and rotationplasty in remission since 2010 acutely developed nausea, nonbilious, nonbloody emesis, and severe cramping right lower quadrant abdominal pain, prompting admission for evaluation. Ten weeks before admission, she had tested positive for SARS-CoV-2 on real-time reverse transcription-polymerase chain reaction via nasopharyngeal swab when she had presented with fever, fatigue, and cough. Laboratory findings on admission were remarkable for leukocytosis, thrombocytosis, elevated inflammatory marker, low albumin, elevated aminotransferases, and prolonged prothrombin time (Table 1). Electrolytes were normal. Computed tomography (CT) abdomen revealed moderate free abdominal fluid and right-sided pleural effusion. Liver ultrasound with Doppler showed mild hepatomegaly, thickened gallbladder wall, normal spleen, and patent hepatic artery, hepatic and portal veins, and inferior vena cava. TABLE 1. - Laboratory results at admission and during hospitalization Laboratory measures HD 0 HD 5 HD 16 Reference range White blood cell count, 1000/mm3 14.6 12.8 11.2 4.5–11.0 Lymphocytes, % 24.9 31.0 30.9 24.0–44.0 Neutrophils, % 63.1 62.1 54.2 36.0–66.0 Hemoglobin, g/dL 12.2 11.7 11.0 12.0–15.0 Platelet count, 1000/mm3 572 279 678 150–450 Albumin, g/dL 3.1 2.9 3.3 3.6–5.0 Triglycerides, mg/dL 112 Prothrombin time, s 20.5 18.1 13.5 12.0–15.0 International normalized ratio 1.7 1.5 1.0 Total bilirubin, mg/dL 1.6 0.6 0.3 0.1–1.3 Direct bilirubin, mg/dL 0.7 0.4 0.1 0.1–0.3 Alanine aminotransferase, U/L 174 531 37 10–50 Aspartate aminotransferase, U/L 176 327 15 10–45 C-reactive protein, mg/dL 2.3 6.9 0.7 0–1.0 Lipase, units/L 24 31–93 D-dimer, mcg/mL 10.0 8.64 1.50 0–0.5 ESR, mm/h 3.0 16.0 44.0 0–20.0 Troponin, ng/mL 0.016 1.060 <0.100 BNP, pg/mL 1437.7 1316.30 <100.0 BNP = B-type natriuretic peptide; ESR = erythrocyte sedimentation rate; HD = hospital day. Due to the severity of abdominal pain, ascites, and history of Ewing sarcoma, she underwent diagnostic laparoscopy, which revealed a large amount of ascites and patchy inflamed and ischemic appearance of the liver (Fig. 1A). The remainder of the abdominal inspection was unremarkable, and a peritoneal drain was placed. The initial ascitic fluid analysis revealed triglycerides (TGs) 75 mg/dL with normal bilirubin. Cytopathology of the peritoneal fluid showed predominantly foamy, nonpigmented macrophages. No infectious organisms or malignant cells were visualized, and cultures were negative. Liver biopsy demonstrated central lobular congestion suggestive of veno-occlusive disease and vascular compromise without signs of malignancy or inflammation (Fig. 1B). On hospital day (HD) 2, her peritoneal fluid became milky in appearance with elevated TG (219 mg/dL).FIGURE 1.: Gross and histopathologic findings of the liver at time of diagnostic laparoscopy. A) Patchy, inflamed appearance of the liver with a large amount of thick, yellow ascites visualized in the upper abdomen on diagnostic laparoscopy. B) Biopsy of the liver showing centrilobular (zone 3) sinusoidal dilatation and congestion with rare zone 3 hepatocyte dropout. Periportal (zone 1) hepatocytes show feathery degeneration and balloon change.Additional tests for congestive hepatopathy revealed elevated B-type natriuretic peptide (1437 pg/mL) and an abnormal echocardiogram with severely depressed systolic function (ejection fraction [EF] 28%) and large thrombi in the right atrium and left ventricle (Fig. 2). The patient had a history of doxorubicin exposure; however, her last surveillance echocardiogram 3 months before demonstrated normal biventricular systolic function. Hematology consults led to findings of elevated D-dimer levels and factor VIII 241% (normal: 53%–131%). Inherited (factor V Leiden and prothrombin G20210A gene mutation, protein C and S activity, and antithrombin III activity) and acquired thrombophilia (lupus anticoagulant screen, anticardiolipin antibodies, and anti-B2 glycoprotein) were negative. Ultrasound of upper and lower extremities showed no clots. She was admitted to the cardiovascular intensive care unit on milrinone and heparin drip. On HD 9, cardiac MRI revealed myocardial scarring in the anterior segments of the subendocardium characteristic of an ischemic cause. Lobar pulmonary emboli with two pulmonary infarcts were also visualized bilaterally on CT angiography. She was transitioned to aspirin and enoxaparin before discharge. Repeat echocardiogram obtained on HD 16 revealed improvement in EF (38%). She was discharged on carvedilol, digoxin, enalapril, and furosemide. On HD 10, the patient's SARS CoV-2 IgG returned elevated at 5.07.FIGURE 2.: Echocardiogram demonstrating (A) an echogenic mass (2.3 × 1.5 cm) in the right atrium and (B) another echogenic mass (0.7 × 1.6 cm) in the left ventricle.At a 6-month follow-up, she was clinically well without cardiac symptoms or abdominal pain. However, her systolic function remained depressed (~30%). Liver enzymes and bilirubin had normalized. CT heart demonstrated resolution of the intracardiac and pulmonary thrombi. DISCUSSION The COVID-19 pandemic continues to cause catastrophic disease in the USA. Increasing cases of COVID-19 have been documented in children and adolescents. The presence of gastrointestinal symptoms in children with COVID-19 has been well described (1). Abnormalities in liver chemistries have been reported in 20%–30% of cases with COVID-19 (2). This is in contrast to adults who may present primarily with respiratory symptoms and infrequently with gastrointestinal involvement. The symptoms of nausea, vomiting, abdominal pain, or diarrhea can be mistaken for more common etiologies including gastrointestinal infections or inflammatory bowel disease. Multisystem inflammatory syndrome in children (MIS-C) has been described with associated fever, elevated inflammatory markers, and multi-organ involvement (3,4). However, our patient did not fit the case definition for MIS-C based on Centers for Disease Control criteria and had a prolonged time passage from COVID-19 infection. It is not uncommon for patients with COVID-19 infection to have multi-organ dysfunction in the acute setting. In a multi-center series of 186 pediatric patients infected with SARS-CoV-2, 92% had gastrointestinal involvement, 80% had cardiovascular involvement, and 76% had hematologic involvement (3). Reports have also outlined greater thrombotic risk for patients with COVID-19 such as venous thromboembolism, pulmonary thrombosis, and myocardial infarction (5–7). However, few patients present with this degree of severe multi-organ disease weeks following primary COVID-19 infection. The rapid progression to decompensated heart failure following our patient's COVID-19 infection raises suspicion for viral myocarditis as a possible etiology. Her initial presenting symptom of abdominal pain was ultimately attributed to ischemia caused by systolic heart failure. Congestive heart failure has been reported to lead to the development of chylous ascites and may have been the trigger in our patient's case (8–10). Heart failure leads to elevated central venous pressures which can increase capillary filtration and induce abdominal lymph production, increased peritoneal lymphatic pressure, and leakage of lipid-rich lymph into the peritoneal cavity (11). Although the level of TGs in our patient's initial ascitic fluid does not meet diagnostic criteria (TG content >200 mg/dL), it is important to note that our patient had poor oral intake and malnutrition in the weeks from her COVID-19 test to the presentation. This may have led to a falsely low or normal TG content in her ascitic fluid. This is the first reported case of systolic heart failure leading to severe abdominal pain and chylous ascites in the setting of prior SARS-CoV-2 infection. As we continue to witness the spread of COVID-19, it is important to think broadly about our differential diagnosis for a patient presenting with primarily gastrointestinal symptoms. Our patient's case emphasizes the need to consider multisystem involvement, especially in pediatric patients with a history of SARS-CoV-2 infection.
