Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann-Pick-Disease Type C1.

Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-ß-cyclodextrin (HPßCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPßCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1-/- mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., pparα and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα- and acox1-associated lipolysis/ß-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPßCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.

Infant with hepatomegaly and hypoglycemia: A setting for fatty acid oxidation defects.

Fatty acid oxidation defects (FAOD) are one of the commonest metabolic liver diseases (MLDs) that can have varied presentations in different age groups. An infant presented with short history of jaundice and irritability, examination showed soft hepatomegaly. Investigations revealed non-ketotic hypoglycemia suggesting FAOD which was later confirmed as carnitine uptake defect with gas chromatography and mass spectrometry and mutation analysis. Patient improved with acute management of metabolic crisis, carnitine supplementation and corn starch therapy with reversal of encephalopathy, reduction in hepatomegaly, maintenance of euglycemia and improvement in liver function tests and creatine phosphokinase on follow up. Non-ketotic hypoglycemia is a characteristic finding in FAODs. Early diagnosis and appropriate management can result in excellent outcomes in patients with FAODs.

Omega-6 and omega-3 oxylipins are implicated in soybean oil-induced obesity in mice.

Soybean oil consumption is increasing worldwide and parallels a rise in obesity. Rich in unsaturated fats, especially linoleic acid, soybean oil is assumed to be healthy, and yet it induces obesity, diabetes, insulin resistance, and fatty liver in mice. Here, we show that the genetically modified soybean oil Plenish, which came on the U.S. market in 2014 and is low in linoleic acid, induces less obesity than conventional soybean oil in C57BL/6 male mice. Proteomic analysis of the liver reveals global differences in hepatic proteins when comparing diets rich in the two soybean oils, coconut oil, and a low-fat diet. Metabolomic analysis of the liver and plasma shows a positive correlation between obesity and hepatic C18 oxylipin metabolites of omega-6 (ω6) and omega-3 (ω3) fatty acids (linoleic and α-linolenic acid, respectively) in the cytochrome P450/soluble epoxide hydrolase pathway. While Plenish induced less insulin resistance than conventional soybean oil, it resulted in hepatomegaly and liver dysfunction as did olive oil, which has a similar fatty acid composition. These results implicate a new class of compounds in diet-induced obesity-C18 epoxide and diol oxylipins.

Primary Carnitine Deficiency - A Rare Treatable Cause of Cardiomyopathy and Massive Hepatomegaly.

Systemic primary carnitine deficiency (CDSP) is a rare autosomal recessive disorder caused by a defect in plasma membrane uptake of carnitine due to SLC22A5 gene mutations. A nine-mo-old boy presented with hypertrophic cardiomyopathy, massive hepatomegaly and jaundice. Metabolic testing revealed very low free carnitine levels. Genetic analysis using Sanger sequencing method revealed compound heterozygous mutations in SLC22A5 gene, c. 1354 G > A (p. Glu452Lys, previously reported) and c.231_234del (novel frame-shift). Oral carnitine supplementation resulted in improved clinical outcome with ejection fraction to 75 % and normalization of liver size and enzymes after 3 mo.

[Malignant infantile osteopetrosis revealed by choanal atresia: A case report]. / Ostéopétrose maligne infantile révélée par une atrésie des choanes : à propos d'un cas.

Malignant infantile osteopetrosis is a rare genetic disease characterized by increased bone density due to osteoclastic dysfunction. We report on the case of a 3-month-old girl who was referred to our hospital by the ENT department for severe anemia in the context of bilateral choanal atresia. Clinical examination showed failure to thrive, anemia, respiratory distress, bilateral choanal atresia, and chest deformation. The abdomen was soft with large hepatosplenomegaly. We noted a lack of eye tracking, no optical-visual reflexes, and left nerve facial paralysis. The blood count showed normocytic normochromic anemia with severe thrombocytopenia. The infectious work-up and blood smears were negative. The skeleton X-ray showed diffuse bone densification of the skull, long bones, pelvis, vertebrae, and ribs. The facial bone CT confirmed membranous choanal atresia. The molecular biology search for the TCIRG1 gene mutation was not available. The patient had supportive treatment (transfusion, oral steroid, vitamin D, oxygen, nutrition). Bone marrow transplantation was indicated but not available. She died at 6 months in a context of severe anemia and bleeding. Malignant infantile osteopetrosis is rare and symptoms are nonspecific. Diagnosis should be considered in young infants presenting refractory anemia, particularly in the context of choanal atresia. Bone marrow transplantation remains the only curative treatment.

Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis.

Ginkgo biloba extract (GBE) is commonly used as a herbal supplement. The National Toxicology Program (NTP) study of GBE reported clear evidence of hepatocarcinogenicity in mice. To clarify the mode of action (MOA) for hepatocarcinogenesis by GBE, we investigated the involvement of the constitutive androstane receptor (CAR) in hepatocarcinogenesis induced by GBE using CAR-knockout (CARKO) and wild type (WT) mice. We used the same lot of GBE that was used for the NTP study. In 1-week GBE dietary treatment, hepatocellular DNA replication was increased in WT mice but not in CARKO mice. In 4- or 13-week treatment, greater hepatic Cyp2b10 induction and hepatocellular hypertrophy were observed in WT mice, whereas these effects of GBE were much smaller in CARKO mice. In a two-stage hepatocarcinogenesis model initiated by diethylnitrosamine, 27-week treatment with GBE resulted in an increase of eosinophilic altered foci and adenomas in WT mice. By contrast, foci and adenomas were clearly less evident in CARKO mice. These results indicate that GBE-induced hepatocarcinogenesis is mainly CAR-mediated. Since CAR-mediated MOA for hepatocarcinogenesis in rodents is considered to be qualitatively implausible for humans, our findings would be helpful to evaluate the carcinogenic characterization of GBE to humans.

Budd-Chiari syndrome secondary to toxic pyrrolizidine alkaloid exposure.

In this report, we describe a case of pyrrolizidine alkaloid-related Budd-Chiari syndrome in Hong Kong. A 10-month-old boy presented with ascites, right pleural effusion, and hepatomegaly after consumption of herbal drinks for 3 months. His clinical (including imaging) features were compatible with Budd-Chiari syndrome. Budd-Chiari syndrome is a rare disease entity in paediatric patients. In our case, extensive workup performed to look for the underlying cause of Budd-Chiari syndrome was unrevealing, except for toxic pyrrolizidine alkaloid exposure in his herbal drinks.

Neonatal jaundice.

Neonatal jaundice lasting greater than 2 weeks should be investigated. Pale stools and dark or yellow urine are evidence of liver disease, which should be urgently investigated. The neonatal hepatitis syndrome has many causes, and a structured approach to investigation is mandatory. It should be possible to confirm or exclude biliary atresia within one week, so that definitive surgery is not delayed unnecessarily. Babies with the neonatal hepatitis syndrome should have vigorous fat-soluble vitamin supplementation, including parenteral vitamin K if coagulation is abnormal. The prognosis for infants with idiopathic neonatal hepatitis and multifactorial cholestasis is excellent.

Gaucher disease due to saposin C deficiency, previously described as non-neuronopathic form--no positive effects after 2-years of miglustat therapy.

Gaucher disease occurs mainly as a result of a deficiency of the lysosomal enzyme beta-glucocerebrosidase activity. A rare variant form of Gaucher disease is known in which saposin C required for glucosylceramide degradation is deficient. In an earlier paper we described the first cases of two siblings with the non-neuronopathic form of Gaucher disease caused by saposin C deficiency [Tylki-Szymanska et al., 2007]. In this article, we present a follow up of clinical and biochemical findings in one patient who has been treated with miglustat for two years. We observed that administration of miglustat failed to exert any favorable effect on the clinical condition, haematological parameters and glucosylceramide level in the serum. In two individuals (described in this article) very slow deterioration of the peripheral and central nervous systems was observed.

Preoperative liver reduction utilizing a novel nutritional supplement.

BACKGROUND: One of the most common reasons for conversion in bariatric surgery is hepatomegaly caused by inadequate exposure of the proximal stomach. This study utilizes a novel nutritional supplement with a calorie-restricted diet to reduce liver volume preoperatively. METHODS: A consecutive series of morbidly obese patients consumed a nutritional supplement called Nuvista(®) for 4 weeks preoperatively. Preoperatively, each patient completed baseline demographics, blood work, urine ketone analysis, ultrasonography of the left lateral segment, and multiple questionnaires. At the time of surgery, these studies were repeated. Data were analyzed using a paired t-test and bivariate analysis where appropriate. A P<.05 was considered significant. RESULTS: Four men and 17 women were recruited with a mean preoperative weight and body mass index of 122.7±15.9 kg and 44.5±3.9, respectively. Mean preoperative liver volume of the left lateral segment was 562.5±291.3 cm(3). After 4 weeks of Nuvista, the mean weight and body mass index decreased significantly to 118.9±15.5 kg and 43.1±3.4, respectively (P<.001). The mean liver volume of the left lateral segment was significantly reduced to 299.9±162.1 cm(3) (P<.001). Mean liver reduction was 43.4%±17.2% (13.6%-81.9%, P<.05). Urinary ketone scores did not show any evidence of starvation. No preoperative factors correlated with liver volume reduction. CONCLUSION: Utilizing Nuvista, as part of a preoperative 4-week calorie-restricted regimen, significantly reduced lateral segment liver volume by 43.4%. This preoperative regimen incorporates healthy behavioral changes that are necessary to sustain long-term weight loss.

Glycogen storage disease type III with hypoketosis.

A rare case of glycogen storage disease type III with unusually absent ketone body production during hypoglycemia is presented. A 10-month-old boy presented with asymptomatic hepatomegaly. GOT/GPT 2555/1160 IU/L, CK 302 IU/L, triglycerides 1223 mg/dL, cholesterol 702 mg/dL and uric acid 7.9 mg/dL. After a 9-hour fast, glucose was 27 mg/dL and adequate lipolysis without ketogenesis was observed (total/free carnitine 34.5/20 micromol/L, free fatty acids 1620 micromol/L and beta-hydroxybutyrate 172 micromol/L). Result of MCT (medium-chain triglycerides) load test: basal hydroxybutyrate 29 micromol/L rose to 5748 micromol/L. Treatment with a fat-restricted diet supplemented with formula containing MCT was initiated and the patient presented a satisfactory initial evolution. Three months later, CK were 3000 IU/L. Muscle biopsy was diagnostic of glycogenosis. Enzymatic activity in skin fibroblasts was 0% for amylo-1,6-glucosidase. The diagnosis of glycogenosis type III was established. Echocardiography performed at that time showed non-obstructive ventricular hypertrophy. Until now hypoketosis during hypoglycemia has only been described in glycogenosis type I.

Intoxicación pediátrica por fósforo blanco (saltapericos): supervivencia a ingesta de dosis potencialmente letal / Pediatric poisoning with white phosphorus (saltapericos): survival after potentially lethal ingestion

El saltapericos es un juego pirotécnico a base de fósforo inorgánico, cuyo uso está prohibido porque causa daño hepático agudo. Se reporta un caso de intoxicación severa en una niña sobreviviente, quien ingirió una dosis potencialmente letal y recibió asistencia médica tardía. El protocolo terapéutico que se siguió en el presente caso clínico, permitió el logro de una evolución satisfactoria; este tratamiento consistió en descontaminación interna con agua oxigenada y aceite mineral, exsanguinotransfusión y fármacos hipoamonemizantes.

Saltapericos is a pyrotechnic firework containing inorganic phosphorus whose use is banned since causes acute liver damage. A case of severe poisoning is reported in a girl, who consumed a potentially lethal dose and received late medical care. The therapeutic protocol followed in the present clinical case led to a positive outcome; this treatment consisted of internal decontamination with hydrogen peroxide and mineral oil, exchange transfusion and hypoammonemic drugs.

Paciente con fiebre y exantema / Patient with fever and rash

Presentamos el caso de una paciente de 23 años de edad,con fiebre, cefalea, inyección conjuntival bilateral, hepatomegaliadolorosa y exantema macular generalizado con elevaciónde enzimas hepáticas. Se realizó un estudio serológicoque confirmó la sospecha diagnóstica de infección agudapor el virus del sarampión (AU)

We report the case of a 23-year old woman with fever, headache,bilateral conjunctival injection, painful hepatomegalyand generalized macular rash with elevated liver enzymes.Acute measles infection was suspected based on the clinicalfindings and was serologically confirmed (AU)

Complicated sigmoid diverticulitis.

In medical practice, the colonic diverticulitis diagnosis is easy, based especially on a barium enema and an inferior digestive endoscopy, but the diverticulitis complications, especially metastatic infections, raise serious positive and differential diagnosis problems. We present the case of a 51 year old male who comes with hepatomegaly and multiple hepatic formations, in deteriorating clinical condition, context suggestive of secondary metastasis, but after investigation it was demonstrated they were of infectious nature, from a sigmoidian diverticulitic abscess. In this case, the hepatic biopsy was appropriate and it represented an important moment in the management of the patient.

Fanconi-Bickel syndrome.

We present here the first case of Fanconi-Bickel syndrome, a rare type of glycogen storage disease, from India. A 17-month-old female child presented with severe growth retardation and abdominal distention. Clinical examination revealed a "doll-like" face, massive hepatomegaly, and rickets. Laboratory investigations confirmed severe hypophosphatemic rickets and proximal renal tubular dysfunction. Liver biopsy showed glycogen accumulation in the hepatocytes.

Progressive liver fibrosis in late-onset argininosuccinate lyase deficiency.

A 4-month-old boy, with late-onset argininosuccinate lyase (ASL) deficiency with hepatomegaly, was treated by protein restricted diet and arginine supplementation; he was followed for 3 years. Hepatomegaly and mild liver dysfunction persisted without significant hyperammonemia. He maintained normal psychomotor development to the age of 12 months, but, at 3 years of age, his developmental status is in the borderline normal range. Liver biopsy performed at 12 months of age demonstrated swollen and pale hepatocytes with abnormal glycogen deposition and mild periportal fibrosis. A subsequent liver biopsy at 3 years of age showed progressive liver fibrosis in the periportal and central areas, which extended into the liver lobule. These findings suggest that liver impairment in ASL deficiency may advance without significant hyperammonemia and underline the importance of repeated liver biopsy in this disorder, even when the plasma ammonia level is well controlled.

Glicogenosis hepáticas: diagnóstico clínico y manejo nutricional / Glycogen storage disease: clinical diagnosis and nutritional management

Las glicogenosis hepáticas son errores congénitos del metabolismo, secundarios a deficiencia en alguna de las vías de la síntesis o degradación del glicógeno. Objetivo: evaluar los hallazgos clínicos, de laboratorio e histopatológicos de 6 pacientes diagnosticados entre los 13 y los 52 meses de edad con glicogenosis tipo III, IV y IX y describir los resultados iniciales de la terapia nutricional. Cinco niños fueron referidos para evaluación de hepatomegalia masiva, y uno, por presentar una convulsión asociada a hipoglicemia. El diagnóstico fue confirmado mediante una prueba de carga de glucosa oral, en la que todos presentaron una hiperlactacidemia postprandial, una biopsia hepática que confirmó la acumulación intracelular de glicógeno y en tres niños mediante análisis enzimático. Todos tenían elevación de enzimas hepáticas e hiperlipidemia al momento del diagnóstico. Se inició un tratamiento nutricional que, después de al menos 6 meses, resultó en una mejoría del perfil lipídico, con reducción de los niveles de colesterol total en 19 por ciento y elevación del colesterol HDL en 55 por ciento con respecto a los valores iniciales. Conclusiones: las glicogenosis hepáticas deben considerarse dentro del diagnóstico diferencial en niños con hepatomegalia crónica, aparentemente asintomática, sobre todo en presencia de hiperlipidemia. El uso adecuado de exámenes de laboratorio relativamente simples como la prueba de carga de glucosa permitió confirmar la sospecha de estas condiciones y reducir el uso de exámenes invasores, y la dieta permitió una disminución significativa del colesterol total y HDL

Case of sepsis caused by Bifidobacterium longum.

We report a case of sepsis caused by Bifidobacterium longum in a 19-year-old male who had developed high fever, jaundice, and hepatomegaly after acupuncture therapy with small gold needles. Anaerobic, non-spore-forming, gram-positive bacilli were isolated from his blood and finally identified as B. longum. He recovered completely after treatment with ticarcillin and metronidazole. To our knowledge, this is the first report of incidental sepsis caused by B. longum.