Protein-losing Enteropathy as a Complication and/or Differential Diagnosis of Common Variable Immunodeficiency.

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4+: p = 0.005; CD8+: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.

Protein-losing gastroenteropathy complicated with asymptomatic primary biliary cholangitis, refractory to immunosuppressant, and improved by Helicobacter pylori eradication: a case report.

BACKGROUND: Protein-losing gastroenteropathy (PLGE) is a syndrome with a chief complaint of hypoalbuminemia, which occurs due to plasma protein leakage in the gastrointestinal tract, leading to general edema, ascites, and pleural effusions. CASE PRESENTATION: A 71-year-old woman visited another hospital for evaluation of hypoalbuminemia and systemic edema. She was hospitalized for a close inspection of hypoalbuminemia and was diagnosed with PLGE. Steroid and azathioprine therapy was prescribed; however, hypoalbuminemia did not improve, and the patient's condition worsened due to anasarca. As hospitalization was prolonged, the patient was transferred to our hospital. She was infected with Helicobacter pylori, and we performed H. pylori eradication. Following H. pylori eradication, her edema improved remarkably. CONCLUSION: We present the first case wherein H. pylori eradication successfully improved protein leakage in the lower gastrointestinal tract in a patient diagnosed with PLGE complicated with refractory to immunosuppressant treatment. H. pylori eradication should be considered in patients with PLGE complicated with H. pylori infection, without specific endoscopic finding or refractory to immunosuppressants.

The Lymphatic System in the Fontan Patient-Pathophysiology, Imaging, and Interventions: What the Anesthesiologist Should Know.

The Fontan surgery was developed as a palliative intervention for congenital heart disease (CHD) patients with single-ventricle physiology who are not candidates for a biventricular repair. Improvements in the surgery and medical management of these patients have increased survival, yet this population remains at risk for complications and end-organ dysfunction due to Fontan failure. Lymphatic vessels maintain a fluid balance within the extracellular space, participate in fat reabsorption from the small intestine, and play an important role in the body's immune response. Altered Starling forces at the capillary level, capillary leak, and lymphatic obstruction contribute to lymphatic dysfunction in patients with Fontan physiology. These lymphatic complications include edema, pleural effusions, plastic bronchitis (PB), and protein-losing enteropathy (PLE). Over the past decade, there have been innovations in lymphatic imaging. These new imaging techniques include noncontrast magnetic resonance (MR) lymphangiography, intranodal lymphangiography (IL), dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL), and liver lymphangiography. These imaging techniques help in delineating anatomy and guiding the appropriate therapeutic approach. Lymphatic interventions then may be performed to decompress the lymphatic system or to identify and occlude abnormal lymphatic vessels and drainage pathways. The anesthesiologist should have an understanding of the effects of lymphatic disorders on the Fontan circulation and apply appropriate management techniques for the associated interventions. The Fontan surgery was developed as a palliative intervention for CHD patients with single-ventricle physiology who are not candidates for a biventricular repair. The surgery creates a series systemic and pulmonary circulation with the energy necessary to provide gradient-driven pulmonary blood flow generated by the ventricle.1 In the past decades, improvements in the surgery and medical management of these patients have increased survival, with 30-year survival rates close to 85%.2 Despite these improvements, this population remains at risk for complications and end-organ dysfunction due to Fontan failure, which is characterized by elevated systemic venous pressures and low cardiac output. These complications include arrhythmias, cardiac dysfunction, ascites, liver fibrosis/cirrhosis, renal dysfunction, pulmonary failure, and lymphatic complications such as edema, pleural effusions, PB, and PLE. Complications ultimately contribute to increased risk for hospitalization, death, and need for heart transplantation.3,4 For this reason, there has been increasing interest in the role of abnormal lymphatic circulation in the genesis of Fontan failure. The authors characterize the lymphatic pathophysiology associated with Fontan physiology and review the imaging and interventional strategies used to treat these patients.

Venous Properties in a Fontan Patient with Successful Remission of Protein-Losing Enteropathy.

We present the case of a 1-year-old boy who developed protein-losing enteropathy (PLE) within 2 months of a fenestrated Fontan procedure. His fenestration rapidly closed despite bilateral pulmonary stenosis (BPS). Subsequent to PLE onset, both fenestration and the bilateral pulmonary artery were reconstructed, and the patient's PLE had been in remission, with additive use of medications, for more than 2 years. Notably, although fenestration closed again and central venous pressure (CVP) reduction was minimal, the surrogates of venous return resistance were markedly suppressed as shown by increased blood volume, reduced estimated mean circulatory filling pressure, and suppressed CVP augmentation against a contrast agent. Taken together, dynamic characteristics of venous stagnation, rather than the absolute value of CVP, were ameliorated by the pulmonary reconstruction and use of medications, suggesting a significant role of venous property in the physiology of PLE. In addition, simultaneous measures of CVP and ventricular end-diastolic pressure during the abdominal compression procedure suggested a limited therapeutic role of fenestration against PLE in this patient.

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

Glycomacropeptide Ameliorates Indomethacin-Induced Enteropathy in Rats by Modifying Intestinal Inflammation and Oxidative Stress.

Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is considered a serious and increasing clinical problem without available treatment. Glycomacropeptide (GMP) is a 64-amino acid peptide derived from milk κ-casein with numerous biological activities. The aim of this study was to investigate the protective effect of GMP on NSAID enteropathy in rats. Enteropathy was induced by seven days oral indomethacin administration. Rats were orally GMP treated from seven days previous and during the establishment of the enteropathy model. Changes in metabolism, hematological and biochemical blood alterations, intestinal inflammation and oxidative damage were analyzed. Integrity barrier markers, macroscopic intestinal damage and survival rate were also evaluated. GMP treatment prevented anorexia and weight loss in animals. Furthermore, prophylaxis with GMP ameliorated the decline in hemoglobin, hematocrit, albumin and total protein levels. The treatment had no therapeutic efficacy on the decrease of occludin and mucin (MUC)-2 expression in intestinal tissue. However, GMP markedly decreased neutrophil infiltration, and CXCL1, interleukin-1ß and inducible nitric oxide synthase expression. Nitric oxide production and lipid hydroperoxide level in the small intestine were also diminished. These beneficial effects were mirrored by preventing ulcer development and increasing animal survival. These results suggest that GMP may protect against NSAID enteropathy through anti-inflammatory and antioxidant properties.

Steroid-resistant protein-losing gastroenteropathy complicated with Sjögren's syndrome successfully treated with mizoribine.

A 64-year-old woman with leg edema was diagnosed with protein-losing gastroenteropathy and Sjögren's syndrome. Central venous nutrition led to infection of her catheter, ascites, and deep vein thrombosis. Following successful treatment of these conditions with antibiotics and anticoagulants, she was treated unsuccessfully with prednisolone and steroid pulse therapy. Mizoribine add-on markedly reduced edema and normalized serum albumin. This is the first report of a steroid-resistant protein-losing gastroenteropathy patient with Sjögren's syndrome successfully treated with mizoribine.

Gastrointestinal haemorrhage due to lymphangiectasia caused by protein-losing enteropathy in the Fontan circulation.

We report the case of a 14-year-old boy with severe protein-losing enteropathy after Fontan surgery that led to lymphangiectasia, which caused gastrointestinal haemorrhage and required invasive treatment to stop the bleeding. Through this case and a review of the literature on protein-losing enteropathy after Fontan surgery, we highlight a rare and serious presentation of the disease and the difficulties of diagnosis and management.

Multiple small intestinal ulcers associated with protein-losing enteropathy secondary to cholesterol crystal embolism:a case report.

A 78-year-old man with hypertension, nephrosclerosis, and angina pectoris visited his family doctor with a history of fatigue and leg edema. He had a history of percutaneous coronary intervention 5 years prior, and was taking low-dose aspirin. Blood tests revealed hypoalbuminemia, gastrointestinal 99mTc-HSA scintigraphy was positive, and alpha-1 antitrypsin clearance was high;therefore, the hypoalbuminemia was thought to be secondary to a protein-losing enteropathy. A small bowel series revealed multiple, ring-shaped, longitudinal ulcers in the ileum. Balloon-assisted enteroscopy from the anus showed severe stenosis with an ileal ulcer. Since we were not able to diagnose the ulcers, mesalazine and supplemental nutritional care were provided. Four years after the hypoalbuminemia had been diagnosed, the patient died because of pulmonary congestion secondary to renal failure. An autopsy revealed severe atherosclerosis in his aorta and multiple cholesterol embolisms in his small intestine, kidney, stomach, colon, liver, and spleen. The multiple ulcers in the small intestine were thought to be caused by cholesterol crystal embolism, which should be considered in the differential diagnosis of small intestinal ulcers in elderly men or patients after cardiovascular intervention.

[Protein-losing enteropathy]. / Enteropatiya s poterei belka.

Protein-losing enteropathy (PLE) is a rare complication of intestinal diseases. Its main manifestation is hypoproteinemic edema. The diagnosis of PLE is based on the verification of protein loss into the intestinal lumen, by determining fecal α1-antitrypsin concentration and clearance. The localization of the affected colonic segment is clarified using radiologic and endoscopic techniques. The mainstay of treatment for PLE is a fat-free diet enriched with medium-chain triglycerides. Surgical resection of the affected segment of the colon may be the treatment of choice for severe hypoproteinemia resistant to drug therapy.

Case studies of patients successfully and unsuccessfully managed pre- and post-Fontan procedure.

As a result of advances and modifications in surgical procedures and the development of drugs for pulmonary arterial hypertension, many patients who have undergone Fontan procedures are able to enjoy good quality of life, without pulmonary arterial hypertension and severe complications. In Shizuoka Children's Hospital, drugs for pulmonary arterial hypertension have long been given to Fontan candidates and patients with established Fontan circulation to maintain sufficient pulmonary blood flow and suppress pulmonary arterial hypertension. We present three typical cases that were treated with anti-pulmonary hypertensive drugs before or after Fontan procedure. The first case had asplenia syndrome, and a single ventricle with major aortopulmonary collateral arteries. Anti-pulmonary hypertensive therapy permitted a Fontan procedure and maintained a good long-term quality of life. The second case was a Down syndrome patient who had progressive cyanosis after a Fontan operation. Anti-pulmonary hypertensive therapy improved cyanosis. The third case suffered from protein-losing enteropathy, for which all procedures and medical therapies were ineffective. Fontan candidates and patients with Fontan circulation have varied anatomical backgrounds and pulmonary properties. We must identify the conditions that lead to successful Fontan procedure and Fontan circulation correction, as well as conditions that result in failed Fontan procedure and poorly-controlled Fontan circulation.

Clinical experience of more than 2 months usage of extracorporeal membrane oxygenation (Endumo(®)4000) without circuit exchange.

A 5-year-old girl with right atrial isomerism, complete atrioventricular septal defect, hypoplastic left ventricle, double outlet right ventricle, and mixed-type total anomalous pulmonary venous connection with totally occluded left pulmonary veins presented at our center for fenestrated total cavo-pulmonary connection with an extra cardiac conduit at the age of 3 years. Eleven months after the Fontan completion, she developed protein-losing enteropathy (PLE). Spontaneously closed fenestration was thought to be the cause of the PLE, and she underwent revision of fenestration at the age of 5 years. After the operation, PLE did not improve, and newly developed hypoxemia impaired her systemic ventricular function, leading to the initiation of veno-arterial extracorporeal membrane oxygenation (ECMO) with the Endumo(®) system 18 days after the operation to treat her hemodynamic instability. Although the ECMO circuit was changed three times during the first 8 days, the fourth circuit could be used for 74 days without hemolysis and serum leakage, until the patient unfortunately died 82 days after the operation due to multi-organ failure.

Contractility-afterload mismatch in patients with protein-losing enteropathy after the Fontan operation.

This study aimed to clarify the relationship between onset of protein-losing enteropathy (PLE) and Fontan circulation, with special reference to the development of contractility-afterload mismatch. The PLE group comprised 9 patients who experienced PLE after undergoing the Fontan operation, and the control group consisted of 32 patients had did not experienced PLE more than 10 years after the Fontan operation. The study compared the pre- and postoperative values of arterial elastance (Ea), end-systolic elastance (Ees), and contractility-afterload mismatch (Ea/Ees). Furthermore, the variations in the values were examined during the preoperative, postoperative, and midterm postoperative periods in seven PLE patients who underwent cardiac catheterization at the onset of PLE and during the pre- and postintervention periods in three PLE patients who underwent surgical intervention to improve the Fontan circulation after the onset of PLE. Comparison of the values obtained before and after Fontan operations showed that the Ea values increased significantly in the PLE group. However, the pre- and postoperative Ees values did not differ in the two groups. During the postoperative period, Ea/Ees increased significantly, and the Ea and Ea/Ees values increased continuously until the onset of PLE in the PLE group. In the patients who underwent surgical intervention to improve the Fontan circulation after the onset of PLE, the Ea/Ees decreased significantly, and the serum albumin levels improved after the intervention. Contractility-afterload mismatch, mainly caused by the increase in the afterload of the systemic ventricle, may have an important role in the development of PLE after the Fontan operation.

Seizure caused by Hypocalcemia as a Rare Manifestation in an Infant with Eosinophilic Gastroenteritis.

Eosinophilic gastroenteritis (EGE) can occur throughout the gastrointestinal tract, from the stomach to the colon. Typical known symptoms are abdominal pain, nausea, vomiting, and diarrhea. In addition, lesions in the intestinal mucosa may cause weight loss, protein-losing enteropathy (PLE), and other problems. A 6-month-old girl with no previous medical history was brought to our hospital after an afebrile 1-min clonic seizure. Blood tests showed low concentrations of serum calcium and albumin. After the correction of hypocalcemia with gluconic acid, there was no recurrence of seizure. Technetium-99m scintigraphy showed slight leakage of protein from the intestinal tract, which led us to conclude that the hypocalcemia and hypoalbuminemia were caused by PLE. Gastrointestinal endoscopy and biopsy performed to detect the cause of PLE revealed the presence of EGE. After starting administration of an amino acid-based formula, gastrointestinal symptoms of diarrhea or vomiting did not reappear. The serum albumin concentration normalized, and her weight gain improved. We report the first case of EGE in an infant who was diagnosed based on seizure. This case shows that infants with EGE may present with seizure resulting from hypocalcemia caused by PLE.

Clinical characteristics of concurrent and sequentially presented lupus-related protein-losing enteropathy: what are their differences?

Our objective was to compare patients with concurrent and sequentially presented systemic lupus erythematosus (SLE)-related protein-losing enteropathy (PLE). Patients with history of SLE admitted for PLE were selected and their clinical, laboratory, endoscopic and imaging characteristics, treatment and outcome were analyzed. From 2001 to 2010, 21 and 27 patients had concurrent and sequentially presented SLE-related PLE, respectively, and their clinical characteristics were comparable except the following: the concurrent group had more pleural effusion (P < 0.01), cutaneous (P < 0.03), neurological (P = 0.02) manifestations, higher creatine phosphokinase (127.6 IU/L vs. 105.7 IU/L, P < 0.05) and lactate dehydrogenase (504.0 IU/L vs. 422.2 IU/L, P < 0.05); whereas the sequential group had higher anti-double strand DNA titer (179.8 vs. 100.4, P < 0.05), 24-h urine protein excretion (1.1 g/d vs. 0.6 g/d, P < 0.05) and increased proteinuria after onset of PLE (0.21 g/d vs. 1.1 g/d, P < 0.04). The endoscopic, histological and radiological features were comparable between the two groups. More patients from the sequential group required more potent immunosuppressive therapy for induction (55.6% vs. 14.3%, P = 0.002) and maintenance (48.2% vs. 9.5%, P < 0.01).The concurrent group associated with better treatment outcomes, with requiring shorter mean time (4.5 months vs. 7.9 months, P = 0.03) for normalbuminemia and more individuals (90.5% vs. 63%, P < 0.02) achieving normalbuminemia in first year. The complications were infrequent: two drug-related adverse events from each group, one patient each from the concurrent group developed shingle and SLE nephropathy. PLE associated with concurrent and sequentially presented of SLE are comparable in clinical behavior; and the immunosuppressive therapy is generally well-responded and tolerated. However, the concurrent group is associated with better disease activity control.

CD55 Deficiency With Budd-Chiari Syndrome Treated by Liver Transplantation and Eculizumab.

We report the case of a male patient who had a history of early-onset protein-losing enteropathy, chronic diarrhea, and repeated thrombotic events since early childhood. He developed Budd-Chiari syndrome with consequent acute liver failure that required liver transplantation when he was 12 years old. The initial graft failed to function and he required retransplantation. Steroid-resistant rejection complicated the clinical course after the second transplant. Treatment with antithymocyte globulin stabilized graft function but abdominal symptoms and enteral protein loss persisted. The patient remained dependent on intravenous albumin and immunoglobulin. Extended work-up for thrombophilia was unremarkable. Flow cytometry analysis of the peripheral blood cells revealed an unexplained CD55 deficiency. By sequencing of CD55 and, later, exclusion of alternative rare diseases by whole-exome sequencing, we discovered a novel, likely pathogenic homozygous splice-site variant in CD55 c.578 + 5G>A, NM_000574.4, OMIM 125240. The staining of liver and colon biopsies revealed a lack of CD55 protein expression. After initiation of treatment with eculizumab, the patient achieved and has maintained a complete clinical remission throughout 56 months of follow-up. We recommend testing for CD55 deficiency in patients with protein-losing enteropathy. In addition, CD55 deficiency should be considered in the differential diagnosis of patients with Budd-Chiari syndrome in whom an underlying cause is uncertain.

Protein-Losing Enteropathy and Plastic Bronchitis Following the Total Cavopulmonary Connections.

BACKGROUND: We aimed to evaluate incidence, outcomes, and predictors of protein-losing enteropathy (PLE) and plastic bronchitis (PB) in a cohort of total cavopulmonary connection (TCPC). METHODS: We included 620 consecutive patients undergoing TCPC between 1994 and 2021. Prevalence and predictors for onset of PLE/PB were evaluated. Death and heart transplantation after onset of PLE/PB were examined. RESULTS: A total of 41 patients presented with PLE/PB (31 with PLE, 15 with PB, and 5 developed both PLE and PB). Their median age at TCPC was 2.2 (interquartile ranges [IQRs], 1.7-3.7) years, and time period to onset for PLE was 2.6 (IQR: 1.0-6.6) years and for PB was 1.1 (IQR: 0.3-4.1) years after TCPC. Independent factors for developing PLE/PB were dominant right ventricle (RV, hazard ratio [HR], 2.243; 95% confidence interval [CI], 1.129-4.458, P = .021) and prolonged pleural effusion after TCPC (HR, 2.101; 95% CI, 1.090-4.049, P = .027). In PLE/PB population, freedom from death or transplantation after PLE/PB diagnosis at 5 and 10 years were 88.7% and 76.4%, respectively. Eleven surgical interventions were performed in 10 patients, comprising atrioventricular valve repairs (n = 4), Fontan pathway revisions (n = 2), pacemaker implantation (n = 2), secondary fenestration (n = 1), diaphragm plication (n = 1), and ventricular assist device implantation (n = 1). In nine patients, a recovery from PLE with the resolution of PLE symptoms and normal protein levels was achieved. Eight patients died and the remaining continued to have challenging protein loss. CONCLUSIONS: Protein-losing enteropathy and PB remain severe complications in the cohort of TCPC. Patients with dominant RV, and prolonged pleural effusions, were at risk for PLE/PB.