Rieko Sakamoto

Plasma exchange and chelator therapy rescues acute liver failure in Wilson disease without liver transplantation.

Wilson disease (WD) in patients with a New Wilson Index (NWI) score ≥ 11 is fatal, and these patients are good candidates for liver transplantation (LT). However, plasma exchange and chelator therapy are indispensable and effective even for WD with a score ≥ 11. Moreover, continuous hemodiafiltration (CHDF) with these treatments is essential for acute liver failure (ALF) in WD with hepatic encephalopathy because CHDF can exclude toxic metabolites that may cause damage to the brain. Here, we describe four rescued patients presenting with ALF in WD and discuss the available treatment options.

Liver transplantation may prevent neurodevelopmental deterioration in high-risk patients with urea cycle disorders

UCDs are among the most common inherited metabolic diseases in Japan. We investigated the clinical manifestations, treatment, and prognoses of 177 patients with UCDs who were evaluated and treated from January 1999 to March 2009 in Japan, using a questionnaire survey. Among these 177 patients, 42 (seven with carbamoyl phosphate synthetase 1 deficiency, 27 with ornithine transcarbamylase deficiency, seven with argininosuccinate synthetase deficiency, and one with arginase 1 deficiency) underwent living‐donor LT. Although this study was retrospective and included limited neurodevelopmental information before and after LT, we evaluated whether LT could improve neurodevelopmental outcomes in patients with UCDs. The neurodevelopmental outcomes of patients with a MAC of <300 μmol/L at the time of onset were not significantly different between the LT and non‐LT groups (P=.222). LT may have prevented further neurodevelopmental complications in children with MAC ≥300 μmol/L (P=.008) compared with non‐transplant management. Therefore, Liver transplant should be considered in patients with UCD with a MAC of ≥300 μmol/L at the time of disease onset.

Improvement in the prognosis and development of patients with methylmalonic acidemia after living donor liver transplant

Liver transplant is a treatment option for patients with MMA‐emia. While this therapy does not bring about a complete cure, it is expected to prolong survival and improve the QOL of patients. The aim of this study was to evaluate the significance of LDLT for patients with MMA‐emia in Japan. Clinical information on 13 patients with MMA‐emia who underwent LDLT was acquired using a self‐developed questionnaire sent to the doctors who provided medical care to patients with MMA‐emia after LDLT. Almost all of the patients continued on a protein‐restricted diet, and the number of acidosis attacks had significantly decreased. Physical growth had recovered to within the normal range by 2.5 years after LDLT, especially in patients who underwent LDLT before the age of 1 year. The average propionyl carnitine (C3) level had significantly decreased after LDLT, and the DQs had not worsened. Liver transplant should be performed for MMA‐emia in early life. This can be expected to maintain neurological development and improve the growth and QOL of patients. However, LDLT is not a curative treatment for MMA‐emia. A protein‐restricted diet should be continued, and renal function should be monitored closely, with consideration of a renal transplant.

Fatal graft‐versus‐host disease after living‐donor liver transplantation from an HLA‐DR‐mismatched donor

Acute GVHD is a rare complication after liver transplantation that has a high mortality rate. We experienced an infant case complicated with acute GVHD. An 8‐month‐old infant with biliary atresia underwent LDLT with a graft obtained from his mother. Their HLAs showed a donor‐dominant one‐way match, not at HLA‐DR but at HLA‐A, HLA‐B, and HLA‐C (recipient; A 31/33, B 51/54, C 1/14, DR 9/11, donor; A 31/‐, B 51/‐, C 14/‐, DR 8/11). The patient exhibited a high fever, skin rash, and diarrhea, and was diagnosed with acute GVHD based on the blood chimerism test. Despite immunosuppression treatment with prednisolone and tacrolimus, plasma exchange, blood transfusion including cord blood transplantation, and antibiotics, the child died on postoperative day 126. Donor‐dominant one‐way matching at HLA class 1 can be a high‐risk factor for acute GVHD despite HLA class 2 mismatching.

Antibody-mediated rejection after ABO-incompatible pediatric living donor liver transplantation for propionic acidemia: A case report.

We herein present the case of a four‐yr‐old boy with PA who developed AMR after ABO‐incompatible LDLT despite undergoing B cell desensitization using rituximab. Although the CD19+ lymphocyte count decreased to 0.1% nine days after the administration of rituximab, he developed a high fever which was accompanied by arthralgia due to a streptococcal infection 13 days after rituximab prophylaxis. After the clearance of the infection, he underwent ABO‐incompatible LDLT 36 days after the administration of rituximab. The CD19+ lymphocyte count just prior to LDLT was 1.2%. He developed AMR five days after LDLT, and the antidonor‐type IgM and IgG antibody titers increased to 1:1024 and 1:1024, respectively. He was treated by plasma exchange, IVIG, steroid pulse therapy, and rituximab re‐administration; however, his liver dysfunction continued. Despite intensive treatment, he died due to complicated abdominal hernia, acute renal failure, and ARDS. This case suggests that a streptococcal infection may induce the activation of innate immune responses; thus, additional desensitization therapy should be considered prior to ABO‐incompatible LDLT if B cell reactivation is suspected.

Liposteroid and methylprednisolone combination therapy for a case of idiopathic lung hemosiderosis

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease in children, with unknown etiology. The classical clinical triad is hemoptysis, hypochromic anemia and diffuse parenchymal infiltrations on chest X-ray. Liposteroid dexamethasone palmitate, which was developed in Japan, has shown good efficacy for IPH. We present the case of a patient with IPH, who suffered from a life-threatening respiratory dysfunction, and was rescued by a trial administration of liposteroid with methylprednisolone (mPSL). A 6-year-old girl was admitted to our hospital for repeated dyspnea and blood-stained sputum. She was diagnosed with IPH at the age of three-months by iron staining of gastric fluid and sputum studies. Her cumulative dose of steroids (equivalent to prednisolone (PSL)) was 1062 mg/kg. However, she could not achieve remission. We decided to initiate liposteroid therapy. We administered an infusion of liposteroid 0.8 mg/kg intravenously, for three consecutive days as a therapy for acute bleeding. After administration of liposteroid, she developed high fever with CRP elevation. We suspected that the inflammation was caused by palmitate, which is present as a lipo base in liposteroid. Hence, we added 2 mg/kg mPSL per day for 1 week. As a maintenance treatment, a single infusion of liposteroid was administered followed by mPSL administration for 6 days in every week. Her respiratory condition slowly improved. Tracheostomy was performed for airway management. She was shifted out of the ICU on the 34th day. Steroid is a key therapy for hemosiderosis. When IPH is diagnosed, oral prednisone therapy is initiated. Although this is effective, there are limitations due to significant adverse effects. Maintaining drug therapy is very important for IPH patients to keep the disease under control. Liposteroid has the same mechanism of action as dexamethasone. It has a Lipo-base, palmitate, which could induce pro-inflammatory cytokine activation. We used mPSL to inhibit the inflammation following liposteroid administration. This was effective. A combination of liposteroid and mPSL administration was useful method of treatment for the patient.

Recovery of severe acute liver failure without transplantation in patients with Wilson disease

Wilson disease (WD) is a disorder of copper metabolism that leads to liver cirrhosis. WD patients with a NWIS > 11 should receive LT; however, we encountered 2 WD patients with an NWIS > 11 who recovered from ALF without LT. The present report aimed to analyze cases of WD patients with a high NWIS who recovered from severe ALF and to discuss the clinical manifestations of the patients and the effects of treatments, including zinc (Zn) therapy, chelator therapy, PE, CHDF, and LT. We retrospectively evaluated the medical records of five patients (male, 2; female, 3) diagnosed with WD along with severe ALF. In cases 1, 2, and 3, complete recovery from ALF was noted without LT. In case 4, initial recovery from ALF was noted without LT; however, ALF worsened owing to bleeding from the esophageal varix. Thus, the patient eventually needed LT. In case 5, recovery from ALF was noted with LT. All cases, except case 2, showed ALF with maximum PELD/MELD scores ≥26 and NWISs ≥ 11, and had indications for LT. In cases of severe ALF with grade I or II encephalopathy, we recommend evaluations of the effects of Zn and chelator treatments while preparing for LT, as the condition may not improve without LT, and pediatricians or physicians can ask transplant surgeons to perform LT urgently if required.

Pulmonary artery hypertension in methylmalonic acidemia

Methylmalonic acidemia (MMA) is an autosomal recessive disorder that can be classified into two types: (1) vitamin B12‐responsive and (2) vitamin B12‐non‐responsive. In MMA cases with long‐term survival, renal failure is often a problem, and timing for kidney transplantation for MMA is controversial. We encountered a vitamin B12‐non‐responsive MMA case for which regular hemodialysis for renal failure was initiated; the patient was 16 years old when she first received regular hemodialysis and 35 years old when she developed pulmonary artery hypertension (PAH). PAH can complicate regular hemodialysis; however, PAH in this case was considered to be a complication of MMA because it was responsive to medical treatment and reversible. In this report, we discuss the role of regular hemodialysis in MMA and the causal relationship between MMA and regular hemodialysis for PAH.