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)

GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome is a recessively inherited lethal disease characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. We previously localized the causative gene to a 1.5-cM region on chromosome 2q33-37. In the present study, we report the molecular defect causing this metabolic disorder, by identifying a homozygous missense mutation that results in an S78G amino acid change in the BCS1L gene in Finnish patients with GRACILE syndrome, as well as five different mutations in three British infants. BCS1L, a mitochondrial inner-membrane protein, is a chaperone necessary for the assembly of mitochondrial respiratory chain complex III. Pulse-chase experiments performed in COS-1 cells indicated that the S78G amino acid change results in instability of the polypeptide, and yeast complementation studies revealed a functional defect in the mutated BCS1L protein. Four different mutations in the BCS1L gene have been reported elsewhere, in Turkish patients with a distinctly different phenotype. Interestingly, the British and Turkish patients had complex III deficiency, whereas in the Finnish patients with GRACILE syndrome complex III activity was within the normal range, implying that BCS1L has another cellular function that is uncharacterized but essential and is putatively involved in iron metabolism.
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PMID:GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. 1221 68

GRACILE syndrome (Fellman syndrome, MIM 603358), an autosomal recessive metabolic disorder of the Finnish disease heritage, has been diagnosed in 25 infants of 18 families. The incidence is at least 1/47,000 in Finland. The main findings are fetal growth retardation, Fanconi type aminoaciduria, cholestasis, iron overload (liver hemosiderosis, hyperferritinemia, hypotransferrinemia, increased transferrin iron saturation, and free plasma iron), profound lactic acidosis, and early death. The pathophysiology of the metabolic disturbance is unsolved. No significant deficiency of complex III activity of respiratory chain has been found, although we recently showed that the underlying genetic cause is a missense mutation (S78G) in the BCS1L gene and other mutations in that gene have been associated with complex III deficiency. BCS1L encodes a mitochondrial protein, acting as a chaperone in the assembly of complex III. Iron accumulation in liver, a typical feature being less abundant with increasing age, might be a primary abnormality or a secondary phenomenon due to liver dysfunction. In order to decrease the iron overload, three infants have been repeatedly treated with apotransferrin followed by exchange transfusion. Improvement in iron biochemistry occurred, but no clear beneficial effect on the clinical condition was found. Further studies will elucidate the role of iron in the pathophysiology of the disease.
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PMID:The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload. 1254 34

It is established that mexidol (3-hydroxy-6-methyl-2-ethylpyridine succinate) influences the state of homeostasis in guinea pigs intoxicated with paracetamol. Paracetamol administered in toxic doses disturbs the functions of liver and kidneys, violates the lipid, carbohydrate, and mineral metabolism, activates the lipid peroxidation (LPO) process, and decreases the level of antioxidant protection. Treatment of the test animals with mexidol (25 mg/kg) decreases the cytolysis of hepatocytes, the development of cholestasis, the degree of hepatocellular insufficiency, the growth of endogenous intoxication, the drop of calcium content, the growth of iron content in the blood serum, and the content of final LPO products. The mexidol treatment activated the enzymatic chain of the antioxidant system.
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PMID:[Effect of mexidol on the homeostasis and lipid peroxidation in paracetamol poisoning]. 1259 35

In a previous study, we identified Pistacia lentiscus was worthy for further laboratory evaluation because an aqueous extract of the plant suppressed iron-induced lipid peroxidation in rat liver homogenates without affecting mitochondrial respiration in cultured HepG2 and PC12 cells. The present study was undertaken to evaluate the efficacy of an aqueous extract prepared from the dried leaves of Pistacia lentiscus in a rat model of hepatic injury caused by the hepatotoxin, thioacetamide. We assessed the impact of daily dosing on biochemical and morphological indices and the extent of oxidative stress in the livers of healthy and thioacetamide-treated rats. In healthy rats, long-term administration of the extract induced hepatic fibrosis and an inflammatory response, mild cholestasis and depletion of reduced glutathione associated with an increase in its oxidized form. In thioacetamide-treated rats, long-term administration of extract aggravated the inflammatory and fibrotic and glutathione depleting responses without affecting the extent of lipid peroxidation. Although our previous in vitro study established that extracts prepared from the leaves of Pistacia lentiscus had antioxidant activity, this in vivo study establishes these extracts also contains hepatotoxins whose identity may be quite different from those compounds with antioxidant properties. The results of this study suggest complementing in vitro experiments with those involving animals are essential steps in establishing the safety of medicinal plants. Furthermore, these data confirm that complete reliance on data obtained using in vitro methodologies may lead to erroneous conclusions pertaining to the safety of phytopharmaceuticals.
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PMID:The effects of aqueous extracts prepared from the leaves of Pistacia lentiscus in experimental liver disease. 1605 33

Hepcidin is a proposed mammalian host defense peptide that was identified on the basis of its antimicrobial activity, but it was later shown to be a crucial regulator of iron homeostasis and a mediator of the anemia of chronic inflammation. Hepcidin and stainable iron expression in biliary atresia (BA) were investigated in this study. Fresh liver tissues were obtained from 10 patients in the early stage of BA when they underwent Kasai's procedure, 9 in the late stage of BA when they received liver transplantation and 5 controls receiving liver resection for benign lesions other than cholestasis or fibrosis. Real-time quantitative reverse-transcription PCR (QRT-PCR), immunohistochemical staining and ELISA were performed to gauge hepcidin mRNA and protein expression in liver and plasma. Archival liver specimens from patients in the early and late stages of BA were treated with Perls' acid ferrocyanide technique for hepatic stainable iron. The results demonstrated that liver hepcidin mRNA expression was 100-fold lower in late-stage BA than in the early stage by QRT-PCR. Significantly weaker liver hepcidin immunostaining and lower plasma hepcidin levels were found in late-stage BA than in the early stage. There was also significantly lower stainable iron in the liver of late-stage BA. The major site of stainable iron was in Kupffer cells. The results support a role for hepcidin as a key regulator of mammalian iron metabolism and chronic inflammation, whose expression correlates with the degree of stainable iron in BA.
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PMID:Liver hepcidin and stainable iron expression in biliary atresia. 1662 78

In a study of 22 patients receiving total parenteral nutrition (TPN), we found that iron-deficient patients were less likely to develop cholestasis than patients with normal iron stores. The mean and S.D. of serum iron, total iron binding capacity and percent saturation in the 12 patients developing cholestasis were 12.7 +/- 5.2 micromol/L, 37.1 +/- 8.5 micromol/L and 37 +/- 24% whereas in the 10 patients who did not develop cholestasis, the values were 7.3 +/- 3.6 micromol/L, 54.8 +/- 17.9 micromol/L and 14 +/- 7% respectively. All differences were statistically significant. The relationship between iron stores and TPN-associated cholestasis deserves further study.
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PMID:Relationship between iron deficiency and cholestasis associated with parenteral nutrition. 1682 45

Liver pathology occurring in patients with sickle cell disease is commonly related to viral hepatitis or hepatic iron deposition due to repeated transfusions; cholestasis and cirrhosis may also occur. Consequently, the differential diagnosis of abnormal liver tests in patients with sickle cell anemia is often complicated. We report the case of a patient presenting with jaundice and abnormal liver biochemistries, without typical evidence of the liver diseases associated with sickle cell anemia. Biochemical markers for viral hepatitis were negative. CT scan only showed hepatomegaly. The liver biopsy revealed marked sinusoidal congestion with red blood cells without significant steatosis or increased iron deposition. The patient's medical history corroborated with biochemical tests and histological examination of the liver suggested that worsening hemolysis related to increased sickling of erythrocytes intrahepatically led to sinusoidal dilatation and probably caused the abnormal liver tests.
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PMID:Exacerbation of sickle cell disease itself as a cause of abnormal liver chemistry tests. 1717 33

Schistosomiasis mekongi was shown to be endemic, along the Mekong River, in northern Cambodia, affecting many patients with portal hypertension. Surgical procedures were proposed to some patients with digestive haemorrhage history to avoid fatal recurrence. The aim of our study was to evaluate the intensity of the liver fibrosis among these patients. During surgical treatment, liver biopsies were collected, fixed in Bouin or in formalin and processed at the Institut Pasteur of Cambodia. Sections were stained by H&E, Masson's trichrome, PAS, Ziehl-Neelsen's method and Congo Red. A total of six biopsies from patients aged 16-36 were analysed. There was complete disorganization of hepatic architecture with fibrous enlargement of portal tracts and some portal-portal bridging fibrosis, but there was no cirrhosis. In portal areas, there was blood vessel congestion and thrombosis with inflammation. Bile ducts were normal. In the parenchyma, congestion of sinusoidal capillaries was combined with focal mononuclear inflammatory infiltrate. There was no steatosis, no necrosis, no cholestasis, no iron accumulation and no amyloidosis. Numerous eggs of Schistosoma mekongi were observed in five cases, mostly in fibrous areas and more rarely in the parenchyma. Eggs were round or oval, measuring 60 x 40 microns with an acid-fast thin hyaline wall. Some eggs were surrounded by epithelioid and giant cell reaction. In conclusion, our findings illustrated a surprisingly high degree of fibrosis among young adults which contrasts with other schistosomiasis.
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PMID:[Histology of liver lesions due to Schistosoma mekongi. About six cases with severe portal hypertension operated in Cambodia]. 1725 54

Liver function tests include biochemical parameters (AST, ALT, GGT or Alkaline phosphatase), bilirubin and albumin levels and coagulation tests as prothrombin activity. These tests are commonly used in the routine screening even in symptomatic as in asymptomatic patients, and the right evaluation of the results is of vital importance. Cytolytic elevation in serum aminotransferases: In mild chronic elevation pharmacological toxicity, viral hepatitis, alcoholic and non-alcoholic fatty liver disease and hemochromatosis, should be excluded. Cholestatic elevation os serum enzymes: The first option should be to establish the origin of the alkaline phosphatase elevation, with the evaluation of the GGT levels to confirm the hepatic origin. The next step should be to distinguish the presence of an extrahepatic (biliary obstruction) or intrahepatic (PBC, PSC, drugs, etc) cholestasis, in these cases the most important test should be the abdominal ultrasound, in order to evaluate the biliary system. Hyperbilirubinemia: Non conjugated hyperbilirubinemia (hemolysis, ineffective erythropoiesis, Gilbert or Criggler-Najjar syndromes) and conjugated hyperbilirubinemia, an unusual situation in which Rotor and Dubin-Johnson Syndromes should be considered. The evaluation of albumin and prothrombin levels evaluates the hepatic function per se, allowing to differentiate between acute and chronic diseases. At present, there are not prospective studies to evaluate the efficacy of the liver function tests. To carry out a complete medical history, an appropriate physical examination and the appropriate application of non-invasive diagnostic tests (serology, iron levels, autoimmunity or abdominal ultrasound) allow to perform a right diagnosis in most patients, making more complex tests, including liver biopsy, secondary.
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PMID:[Utility of analytical parameters in the diagnosis of liver disease]. 1737 60

Liver fibrosis and cirrhosis are predisposing factors for the development of hepatocellular carcinoma (HCC). Hemosiderosis has also been described to trigger carcinogenesis. A significant iron overload, as found in hereditary hemochromatosis (HHC), is a risk factor for HCC and may also promote the symptoms of porphyria cutanea tarda (PCT). A 68-year old male patient presented to our clinic with a suspected HCC, elevated alpha-fetoprotein but normal liver function tests. He reported a 25 year-old history of vitiligo upon exposure to sunlight. The patient underwent an extended left hemihepatectomy, and the recovery was uneventful, with the exception of a persistent hyperbilirubinemia. Perfusion problems and extrahepatic cholestasis were ruled out by CT-scan with angiography and MR-cholangiopancreatography. However, MRI showed an iron overload. Histology confirmed the HCC (pT3, pN0, G3, R0) and revealed a portal fibrosis and hemosiderosis. Based on the skin lesions we suspected a PCT that was confirmed by laboratory tests showing elevated porphyrin, uroporphyrin, coproporphyrin and porphobilinogen. Concurrently, molecular diagnostics revealed homozygosity for the C282Y mutation within the hemochromatosis HFE gene. After phlebotomy and normalization of liver function tests the patient was discharged. This is the first case ever showing the unusual combination of HCC in a fibrotic liver with HHC and PCT. This diagnosis not only warrants oncological follow-up but also symptomatic therapy to normalize iron metabolism and thereby improve liver function and alleviate the symptoms of HHC and PCT. Thus progression of fibrosis may be prevented and liver regeneration supported.
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PMID:An unhappy triad: hemochromatosis, porphyria cutanea tarda and hepatocellular carcinoma-a case report. 1746 5


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