Birgitta Strandvik

Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase.

Liver transplantation is the only effective treatment for hereditary tyrosinaemia type I (McKusick 276700). We have treated one acute and four subacute-chronic cases with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27), to prevent the formation of maleylacetoacetate and fumarylacetoacetate and their saturated derivatives. The oral daily dose was 0.1-0.6 mg/kg. The excretion of succinylacetoacetate and succinylacetone decreased from 15-103 mmol/mol creatinine to the detection limit or slightly above (ie, to 20-150 mumol/mol creatinine). The concentration of succinylacetone in plasma decreased from 5.8-43 mumol/l to the detection limit (0.1 mumol/l) over 2-5 months of treatment. The almost complete inhibition of porphobilinogen synthase in erythrocytes was abolished and the excretion of 5-aminolevulinate decreased to within or slightly above the reference range. The concentration of alpha-fetoprotein decreased in four patients to 1.3-7.5% of initially high values over 6-8 months. Improved liver function was reflected by normal concentrations of prothrombin complex and in decreased activities of alkaline phosphatase and gamma-glutamyltransferase in serum. Computed tomography revealed regression of hepatic abnormalities in three patients. One patient developed rickets 6 months before treatment and had excreted high concentrations of markers of tubular dysfunction--after 3 weeks of treatment, this excretion had disappeared. No side-effects were encountered. Inhibition of 4-hydroxyphenylpyruvate dioxygenase may prevent the development of liver cirrhosis and abolish or diminish the risk of liver cancer. Normalisation of porphyrin synthesis will eliminate the risk of porphyric crises. This type of treatment may thus offer an alternative to liver transplantation in hereditary tyrosinaemia.

Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease

Approximately 5-10% of cystic fibrosis (CF) patients develop multilobular cirrhosis during the first decade of life. Most CF patients later develop signs of portal hypertension with complications, mainly variceal bleeding. Liver failure usually occurs later, after the paediatric age. Annual screening for liver disease is recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt disease progression. Liver disease should be considered if at least two of the following variables are present: abnormal physical examination, persistently abnormal liver function tests and pathological ultrasonography. If there is diagnostic doubt, a liver biopsy is indicated. All CF patients with liver disease need annual follow-up to evaluate the development of cirrhosis, portal hypertension or liver failure. Management should focus on nutrition, prevention of bleeding and variceal decompression. Deterioration of pulmonary function is an important consideration for liver transplantation, particularly in children with hepatic dysfunction or advanced portal hypertension.

European Epidemiologic Registry of Cystic Fibrosis (ERCF) : Comparison of major disease manifestations between patients with different classes of mutations

Summary. By August 1997, 11,749 patients with cystic fibrosis had been enrolled in the European Epidemiologic Registry of Cystic Fibrosis (ERCF). Genotype analysis had been performed on 8,963 (76%) of these patients, and the majority had one or two identifiable mutations. Patients with known mutations were classified according to the type of mutation (Classes I‐V), and were grouped according to the class of mutation on both chromosomes. This resulted in six subgroups, including all patients homozygous for Class I (I/I, n = 72), for Class II (II/II, n = 5,020), and for Class III mutations, (III/III, n = 23). Since there were only 23 patients homozygous for Class III mutations, a fourth group was made up of patients who were compound heterozygous for a Class II and III mutation (II/III, n = 265). There were only five patients homozygous for Class IV mutations, and consequently a fifth group was made up of all patients carrying at least one Class IV mutation, regardless of the nature of the mutation on the other chromosome (IV/any, n = 187). None were homozygous for Class V mutations; consequently, a sixth group consisted of patients carrying at least one Class V mutation (V/any, n = 22).

The Transfer of Immunity from Mother to Child

Abstract: The newborns immune system grows fast from a small size at birth by exposure primarily to the intestinal microflora normally obtained from the mother at and after birth. While building up its immune system, the infant is supported by the transplacental IgG antibodies, which also contain anti‐idiotypic antibodies, possibly also actively priming the offspring. The second mode of transfer of immunity occurs via the milk. Numerous major protective components, including secretory IgA (SIgA) antibodies and lactoferrin, are present.

Breast‐feeding, a complex support system for the offspring

The newborn has an immune system, very limited in size at birth and its postnatal expansion and maturation takes time. In the meantime the transplacental IgG antibodies from the mother play an important role for the protection of the infant. However, these antibodies act in tissues and induce inflammation and are energy‐consuming. In contrast, the milk secretory IgA antibodies stop microbes already on the mucosa preventing infection, tissue engagement and energy loss. In addition, the milk contains many protective factors such as lactoferrin and oligosacharides functioning as analogues for microbial receptors preventing mucosal attachment, the initial step of most infections. As a result, breast‐feeding significantly reduces the risk of neonatal septicemia, respiratory tract infections, otitis media, diarrhea, urinary tract infections, infection‐induced wheezing and necrotizing enterocolitis. Via several mechanisms it seems that human milk can actively stimulate the immune system of the breast‐fed infant. This reduces the risk of infections like otitis media, respiratory tract infections, diarrhea and infection‐induced wheezing for several years after the termination of breast‐feeding. Furthermore, it seems that breast‐feeding decreases the risk of attracting celiac disease and allergic diseases. The latter has been much debated, but a recent critical review of published reports gives good support for long‐term protection of allergic diseases, especially in high‐risk children.

Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents

OBJECTIVE Compared to normal weight adolescents, obese adolescents have lower serum omega-3 (n-3) polyunsaturated fatty acid (PUFA) concentrations, augmented inflammatory activity and endothelial dysfunction. We wanted to assess whether n-3 supplementation increases the serum n-3 PUFA concentration, improves vascular function and morphology, and lowers inflammation in obese adolescents. METHODS Twenty-five obese adolescents (14 females, 11 males, age 15.7±1.0 years, BMI 33.8±3.9) were randomized to receive capsules containing either 1.2g/day n-3 or placebo for 3 months. The study was performed using a double-blind, cross-over design with a 6-week washout period. Anthropometry, blood pressure measurements and fasting blood samples were obtained before and after each treatment period. The vascular structure and function was measured after each treatment period. RESULTS The serum n-3 PUFA concentration increased with n-3 treatment. The reactive hyperemia response improved with n-3 treatment compared to placebo (p<0.01). N-3 supplementation also decreased the lymphocyte, monocyte, TNF-α, IL-6 and IL-1β levels. No difference was found in the total cholesterol, triacylglycerol, HDL cholesterol, anthropometry, blood pressure, pulse wave velocity or vascular structure between the two treatment groups. CONCLUSION Daily supplementation with n-3 capsules increases the serum n-3 PUFA concentration, improves vascular function, and lowers the degree of inflammation in obese adolescents.

Fatty acid metabolism in cystic fibrosis.

Despite identification twenty years ago of the gene responsible for cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis (CF), research of this monogenetic disease has not provided an explanation for the divergent symptoms, and a treatment breakthrough is still awaited. This review discusses different aspects of disturbances in lipid metabolism seen in CF. These include increased release of arachidonic acid (AA) from cell membrane phospholipids and a low status of linoleic and docosahexaenoic acids. Recent research has explored more complicated lipid associations. Disturbances in annexins and ceramides might act in concert to explain the impact on inflammation and AA release. The connections to CFTR and between the disturbances in essential fatty acid metabolism are reviewed. The metabolic interactions, some of which might be compensating, possibly explain the difficulties in understanding the fatty acid disturbances in relation to different symptoms and their relation to the defective CFTR.

Serum Phospholipid Fatty Acids, Adipose Tissue, and Metabolic Markers in Obese Adolescents

Objective: Fatty acid (FA) composition has a role in adipogenesis. The objective was to study serum phospholipid (PL) FAs in adolescents and their relation to abdominal adipose tissue (AT) compartments and metabolic markers.

Prostanoid biosynthesis in patients with cystic fibrosis

The urinary excretion rate (ng/h/1.73 m2) of prostanoids was determined with a capillary gas-liquid chromatographic mass spectrometric method in 19 patients with cystic fibrosis (CF) aged 1-29 years. Patients with CF showed an increased excretion of prostaglandin E2 metabolites (PGE-M) and thromboxane B2 and its metabolites at all ages. An imbalance in the excretion pattern of thromboxane B2 metabolites also suggested a relative impairment of beta-oxidation. There was no increased excretion of dinor-6-keto-PGF1 alpha, indicating normal prostacyclin biosynthesis. No correlation was found to genotype, clinical score, lung function or bacterial colonization but a significant negative relation was found between the main prostanoids in the urine and serum phospholipid levels of essential fatty acids. The results show that, contrary to the generally accepted decrease of prostanoid excretion in essential fatty acid deficiency, patients with CF increase their production parallel to the development of the deficiency. Since prostanoid synthesis is rate limited by arachidonic acid release, our data support a previously presented hypothesis about a pathological regulation of the release of arachidonic acid in CF.

BILE ACIDS AND PANCREATIC ENZYMES DURING ABSORPTION IN THE NEWBORN

Many investigations have shown that the fat absorption coefficient is low in the newborn, i.e. 80-90% (11, 27, 32). It gradually rises during the first year of life (8, 13, 31), is higher than 90% in infants older than 9-10 months. Provided that the intestinal mucosa functions normally in the newborn, the impaired absorption of fat might be due to a low lipase activity or low concentration of bile acids in the intestinal content. The concentrations of lipase and bile acids in the intestine during a meal have so far not been investigated in the newborn. Studies on autopsy material have revealed that the concentration of bile acids in the bile is lower in the newborn than in children and adults (2). Investigations of intestinal content, carried out after choleretic stimulation with magnesium sulfate confirmed these findings (6). Without previous stimulation, the concentration of bile acids was found to be the same as that in children and adults (7, 24). The purpose of the present investigation was to investigate in the newborn the concentration of bile acids and bilirubin in the intestinal content during and after a test meal consisting of breast milk to which polyethyleneglycol 4000 (PEG) was added as a marker enabling to assess the rate of the passage of the breast