Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homozygosity for alpha 1-antitrypsin deficiency, usually of the genotype PIZZ, is one of the more common single gene defects in infants of European origin, occurring in about 1 in 2000 to 1 in 7000 of the newborn population. About 17% of such infants present with neonatal hepatitis and a small number with intracranial haemorrhage thought to be caused by vitamin K deficiency associated with cholestasis. At least 3% of PIZZ infants will die of cirrhosis in later childhood unless successfully treated by liver transplant. The pathogenesis of the liver disease is not understood and this is unsatisfactory both for treatment and for genetic counselling. The locus coding for alpha 1-antitrypsin (alpha 1AT) is designated PI for proteinase inhibitor. Careful study of the genotypes at this locus in neonatal disease shows that the only certain association is with the homozygous PIZZ genotype. The mutation results in a normal rate of synthesis of a polypeptide that becomes entrapped in the endoplasmic reticulum of the hepatocyte. Some other factor (or factors), as yet unidentified, determines whether severe liver damage results. The low level of alpha 1AT in the plasma seems unlikely to be the primary cause of damage but may play a secondary role. There is some evidence that the other factor(s) may be familial since in one study, though not in all, a high correlation for severity of liver disease was found between PIZZ siblings. The heterogeneity of the clinical course does not result from heterogeneity of PIZ alleles and there is no evidence that it is determined by variation in other related genes on chromosome 14. Only two possible clues have emerged so far. There is some evidence of a protective effect of breast-feeding, and a recent study has found the HLA class II DR3 antigen to be more common than expected in children with alpha 1-antitrypsin deficiency and liver disease. Accumulation of alpha 1AT protein in the hepatocytes may predispose them to some unidentified alteration of the immune response. It is possible that lack of antiprotease activity in the plasma might exacerbate the original damage, so the possibility of useful therapy with alpha 1AT cannot be ruled out entirely. At present, there is no valid way of predicting the severity of disease in a PIZZ child; hence, it is common for parents of a severely affected child to wish to terminate any future PIZZ pregnancy. The most direct method to diagnose the PIZZ genotype of a chorion villus sample is by allele-specific hybridization or sequencing of amplified DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetics of alpha 1-antitrypsin deficiency in relation to neonatal liver disease. 218 61

On the basis of an inquiry held in Switzerland in May 1988, over 99% of all newborn receive vitamin K prophylaxis, 59% orally and 41% intramuscularly. In the previous 2 1/2 years, ten cases of bleeding due to vitamin K deficiency had been observed, of which two were inadequately documented. In two children there was early haemorrhage and late haemorrhage in eight. The latter were all exclusively breast-fed and had received oral vitamin K prophylaxis. Seven presented with vitamin K deficiency due to cholestasis or chronic diarrhea. The only "idiopathic" case is insufficiently documented. The advantages and disadvantages of oral and intramuscular prophylaxis are discussed. A definite stand in favour of the one route or the other is not possible at present. However, the continuation of general prophylaxis is undoubtedly necessary.
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PMID:[Neonatal vitamin K prophylaxis and vitamin k deficiency hemorrhages in Switzerland 1986-1988]. 320 22

We measured serum levels of vitamins A, E, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D, as well as levels of abnormal (des-gamma-carboxy) prothrombin, in 52 patients with primary biliary cirrhosis. Decreased serum levels of retinol (vitamin A) and 25-hydroxyvitamin D and elevated levels of abnormal prothrombin were common in these patients and correlated with the histologic stage of the disease and with the clinical severity of disease as judged by elevated serum bilirubin levels and decreased serum albumin levels. The increased levels of abnormal prothrombin were due primarily to vitamin K deficiency but also, in part, to the severity of the liver disease itself. Vitamin E deficiency was rare. Only 1 patient had clinical manifestations of fat-soluble vitamin deficiency, night blindness, and gastrointestinal bleeding related to a marked prolongation of the prothrombin time. Deficiencies of fat-soluble vitamins are most likely to be present in jaundiced patients with long-standing, severe cholestasis. We suggest that fat-soluble vitamin status be determined in all patients with primary biliary cirrhosis by appropriate blood tests and that vitamin supplements be given only to those patients who require them.
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PMID:Fat-soluble vitamin nutriture in primary biliary cirrhosis. 339 23

Four cases of extrahepatic biliary atresia are reported. Each of these infants presented with haemorrhagic phenomena rather than with prolonged jaundice. The increased bleeding tendency was due to a vitamin K deficiency, probably caused by cholestasis-induced malabsorption. Therefore extrahepatic biliary atresia should be considered in each infant with a bleeding diathesis.
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PMID:Bleeding as the first symptom of extrahepatic biliary atresia. 349 31

A male born to first cousins presented at 12 months with hypocalcemic convulsions, rickets, epistaxis due to vitamin K deficiency, and extremely low serum levels of beta-carotene and vitamin A. Liver function was altered moderately (glutamic-oxaloacetic transaminase, 55 U/L; glutamic-pyruvic transaminase, 37 U/L; lactate dehydrogenase, 255 U/L; alkaline phosphatase, 437 U/L). To correct the deficiencies, 8,000 IU vitamin D/day, 10,000 IU vitamin A/day, and intramuscular administration of vitamin K1 were required. At 9 years, he presented signs of neuromuscular affection, and the serum vitamin E level (measured for the first time) was extremely low. Classic lipid malabsorption syndromes (abetalipoproteinemia, chronic cholestasis, mucoviscidosis, coeliac disease, Whipple's disease) were excluded by appropriate examinations. Composition of duodenal bile acids was characterized by undetectable levels of cholic acid metabolites, and only chenodeoxycholic acid metabolites were present. Serum total bile acid concentration was normal, with an atypical low cholic acid/chenodeoxycholic acid ratio and abnormal presence of 3 beta-OH-delta 5-cholenic acid and 6-OH-bile acids. Urinary bile acid composition was also characterized by elevated 6-OH-bile acids. Known enzymopathies of the bile acid synthetic pathway were excluded (cerebrotendinous xanthomatosis, cerebro-hepato-renal syndrome of Zellweger, coprostanic acidemia). Bile acid pool sizes were determined by using stable isotopes: cholic acid pool size [2.90 (N, 32 +/- 16) microM/kg] and chenodeoxycholic acid pool size [10.8 (N, 32.6 +/- 9.9) microM/kg] were extremely low; fractional turnover rates of both bile acids were in a normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Malabsorption of liposoluble vitamins in a child with bile acid deficiency. 379 31

In vitamin K deficiency or treatment with vitamin K antagonists, a precoagulant of prothrombin (Factor II) called preprothrombin has been established. We measured preprothrombin with Clarke-Freeman electrophoresis in 26 patients with acute viral hepatitis (21 HBS-AG positive) who did not suffer from vitamin K deficiency. Prothrombin and the vitamin-K dependent Factors VII, IX, and X were determined by standard coagulometric methods. Prothrombin was additionally estimated by immunoelectrophoresis according to Laurell. Three patients with acute HBS-AG positive hepatitis showed preprothrombin in their plasma. The activity of Factors II, VII, IX, and X was slightly below normal with normal concentration of Factor II in the immunoelectrophoresis. Liver parenchymal damage and cholestasis were slight; the pseudocholinesterase showed subnormal levels in all three patients. Possible causes for the appearance of preprothrombin in the peripheral blood in acute viral hepatitis and the possible connections with liver cell damage are discussed.
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PMID:[Preprothrombin in acute viral hepatitis B]. 717 63

Liver chemistry was studied in fifteen patients with vitamin K deficiency in infancy (VKDI). All except 2 were exclusively breast fed and 4 of the 15 infants had received intramuscular vitamin K prophylaxis. A high incidence of hepatic dysfunction was found during long term follow-up in patients with VKDI. Abnormal aminotransferase was noted either at the time of onset (n = 6) or during the ensuing few weeks (n = 6). Cholestasis was documented in six cases at onset and another two in a later period. Most cases had increased serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), or bile acid levels regardless of hepatic enzymes and bilirubin levels. The abnormal enzymes returned to normal after 5 weeks to 23 months. This study demonstrates a close relationship between hepatic dysfunction and VKDI. Liver function impairment other than cholestasis may play some role in the pathogenesis of VKDI, but the cause of hepatic dysfunction can not be defined. Follow-up of liver chemistry is recommended in patients with VKDI. Parenteral vitamin K prophylaxis at birth may not give sustained protection against VKDI, especially in those with underlying liver disease.
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PMID:Liver function in patients with vitamin K deficiency in infancy. 783 84

Intra-hepatic cholestasis of pregnancy (ICP) is a specific liver disease that occurs in the third trimester of pregnancy (less frequently in the second trimester) and disappears quickly after delivery. Cholestasis can occur in pregnancy in three situations: a chronic liver disease brought out during pregnancy, intercurrent liver disease or ICP. The serum levels of alanine aminotransferase (ALT) and total bile salts are the most sensitive tests for diagnosing cholestasis in pregnancy. Collaboration between the obstetric team and the liver doctor is needed to find a cause or a factor that increases the risk of cholestasis. Urinary tract infections should always be ruled out. Oral hormonal treatments in pregnancy have not been clearly established as a cause and further investigations are continuing. The maternal prognosis is excellent, but it is important to monitor the prothrombin time and treat any vitamin K deficiency. On the other hand, the fetal prognosis is less good and there is an increase in prematurity and intra-uterine fetal death. When a diagnosis of cholestasis has been confirmed we advise immediately cessation of hormone treatments including natural progesterone. We describe the principals of medical and obstetric management.
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PMID:[Intrahepatic cholestasis in pregnancy. The hepatologist's point of view]. 822 18

Fat-soluble vitamin deficiency is known to result in various complications that may be prevented if the problem is recognized and managed appropriately. In infants and children with chronic cholestasis, replacement therapy of the fat-soluble vitamins, vitamins A, D, E, and K, may prove extremely difficult because low concentrations of intraluminal bile acids lead to malabsorption of these compounds and other fat-soluble substances. Recent progress in the use of a water-soluble form of vitamin E, d-alpha-tocopheryl polyethylene glycol-1000 succinate, has enabled correction of vitamin E-deficiency states in these patients. It has also allowed for the admixture and coadministration of other fat-soluble vitamins and compounds in d-alpha-tocopheryl polyethylene glycol-1000 succinate to enhance their absorption. For managing vitamin K deficiency, similar success has been achieved using a vitamin K compound solubilized in glycocholate and lecithin. Vitamin A deficiency has been implicated in the higher incidence of childhood mortality and morbidity in Third World countries. Increased risk of childhood cancer has recently been associated with intramuscular injection of vitamin K to newborns. Finally, it is worth noting that among the pediatric population, exclusively breastfed infants, in general, are at risk for hypovitaminosis D, and at even greater risk in the absence of adequate exposure to sunlight or when the maternal diet is not sufficient to provide for vitamin D requirements.
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PMID:Fat-soluble vitamin deficiency in infants and children. 828 79

Four infants with conjugated hyperbilirubinemia who were brought for treatment primarily because of a hemorrhage are reported. Underlying disorders included extrahepatic biliary atresia, choledochal cysts, and alpha 1-antitrypsin deficiency. Prodromal signs of disturbed coagulation and diminished bile excretion were not recognized. The increased bleeding tendency was probably caused by vitamin K deficiency, resulting from a combination of cholestasis-induced fat malabsorption, absence of vitamin K supplementation after birth, and low vitamin K intake as a result of breast feeding.
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PMID:Bleeding as presenting symptom of cholestasis. 841 Mar 91


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