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Acute fatty liver during pregnancy constitutes a rarely clinical entity with unknown pathogenesis and etiology. Its clinical picture is similar to preeclampsia including liver failure manifestations. Here in me expose a clinical case of a young woman 35 week first pregnancy with mild preeclampsia symptoms. We include a review of the literature.
We treated a patient with idiopathic fatty liver of pregnancy and a subsequent uncomplicated pregnancy. She experienced general fatigue, nausea, vomiting and jaundice, and renal failure occurred in the third trimester of her first pregnancy. Liver biopsy revealed swollen hepatocytes with microvesicular changes in the cytoplasm. A diagnosis of idiopathic fatty liver of pregnancy was made. Following delivery of a dead fetus, she recovered completely and was discharged on the 30th hospital day. Eighteen months later, she became pregnant again and was delivered of a healthy male baby in the 39th week of gestation. Total bilirubin and transaminase levels were normal, and renal function tests revealed no significant changes during the course of the pregnancy. However, cholinesterase activity increased progressively from the 7th month, thereby suggesting a predisposition to idiopathic fatty liver of pregnancy.
Human liver fatty acid-binding protein (L-FABP) has been efficiently expressed in Escherichia coli. The cDNA encoding human liver FABP was under the control of T7 RNA polymerase promoter in the expression vector pET-3b. Expression required overnight induction with isopropyl beta-D-thiogalactopyranoside in the presence of the bacterial RNA polymerase inhibitor, rifampicin. The protein could be purified by (NH4)2SO4 fractionation, anion-exchange and gel filtration chromatography, and was recognized by anti-(human L-FABP) antiserum. The binding characteristics of delipidated recombinant human L-FABP and muscle FABP (M-FABP) for fatty acids of different chain length and saturation grade, and for various hydrophobic ligands, were determined by radiochemical analysis and also by fluorescence for L-FABP. The apparent binding affinity of the ligands was calculated by using displacement curves of oleic acid and dansylamino-undecanoic acid (DAUDA). L-FABP showed a preference for the binding of long-chain saturated and unsaturated fatty acids up to C24:1, whereas the M-FABP has a preference for unsaturated fatty acids, especially those with 18 C atoms. L-FABP also binds palmitoyl derivatives and many other hydrophobic ligands--however, generally with a lower affinity than fatty acids. M-FABP binds--besides with fatty acids--only with oestradiol and testosterone with high affinity. Fatty acids with fluorescent reporter groups are also more tightly bound by L-FABP. A direct assay and displacement study of oleic acid gave the same Kd value of DAUDA for L-FABP. Fluorescence enhancement and displacement studies indicate that the binding of fluorescent fatty acids is determined by both the fluorescent reporter group and the acyl carbon chain.
The purpose of this study was to assess changes in the degree of fatty acid unsaturation in rat liver after partial hepatectomy. This is the first study in which liver fatty acid unsaturation has been analyzed over a long period of regeneration until day 28 after operation. The relationship between changes in unsaturation and fatty acid composition in the regenerating liver were also investigated in this study. Proton nuclear magnetic resonance spectroscopy revealed significantly elevated levels of unsaturation with a maximum on day 5 after partial hepatectomy, compared with untreated controls (11.72+/-0.55 vs. 11.05+/-0.26%, P < 0.05). No significant changes in unsaturation were found in day 1 regenerating liver, which is rich in absolute amounts of fatty acids. Based on gas-liquid chromatography, the relative amounts of oleic acid (18:1n-9) and linoleic acid (LA; 18:2n-6) were increased, while polyunsaturated fatty acids such as arachidonic acid (20:4n-6) and docosahexaenoic acid (DHA; 22:6n-3) were decreased on day 1. On the other hand, on day 5 of regeneration, while most fatty acids were returning to their preoperative control levels, only DHA was higher than the control value (7.69+/-0.58 vs. 5.57+/-0.37%, P < 0.001). The high levels of unsaturation on day 5 were found to be partly due to the increase in DHA. The findings suggest that some significant signals are transmitted during the regeneration process owing to alterations in the membrane structure by the high levels of fatty acid unsaturation and the increase in DHA levels on day 5 after partial hepatectomy.
Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation.
The diagnostic evaluation of nonalcoholic fatty liver disease (NAFLD) relies on the initial detection of hepatomegaly or elevated serum aminotransferases by the primary care provider. In this investigation, the aptitude of the primary care provider to identify children with hepatomegaly and initiate an evaluation for NAFLD is determined. The physical examination findings and requests for diagnostic testing of 18 primary care physicians (and pediatric gastroenterologists) on 11 obese school-aged children, including a subset of children with hepatomegaly and NAFLD, were analyzed. In children with NAFLD, clinicians detected hepatomegaly in 1.4% of encounters and requested serum liver chemistries in 12.5% of encounters. Hepatomegaly is detected poorly in obese children by primary care physicians and thereby increases the likelihood of a delayed or omitted evaluation for NAFLD.
Liver-fatty acid binding protein (L-FABP) is an abundant intracellular lipid-carrier protein. The hypothesis that perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and certain related perfluorooctanesulfonamide-based fluorochemicals (PFOSAs) can interfere with the binding affinity of L-FABP for fatty acids was tested. The relative effectiveness of PFOA, PFOS, N-ethylperfluorooctanesulfonamide (N-EtFOSA), N-ethylperfluorooctanesulfonamido ethanol (N-EtFOSE), and of the strong peroxisome proliferator Wyeth-14643 (WY) to inhibit 11-(5-dimethylaminonapthalenesulphonyl)-undecanoic acid (DAUDA) binding to-L-FABP was determined. The dissociation constant (Kd) of the DAUDA-L-FABP complex was 0.47 nM. PFOS exhibited the highest level of inhibition of DAUDA-L-FABP binding in the competitive binding assays, followed by N-EtFOSA, WY, and, with equal IC(50)s, N-EtFOSE and PFOA. The in vitro data presented in this study support the hypothesis that these fluorochemicals may interfere with the binding of fatty acids or other endogenous ligands to L-FABP. Furthermore, this work provides evidence to support the hypothesis that displacement of endogenous ligands from L-FABP may contribute to toxicity in rodents fed these fluorochemicals.
Although native rat liver fatty acid binding protein (L-FABP) is composed of isoforms differing in isoelectric point, their comparative structure and function are unknown. These properties of apo- and holo-L-FABP isoforms were resolved by circular dichroism, time-resolved fluorescence spectroscopy, and binding/displacement of fluorescent ligands. Both apo-isoforms had similar hydrodynamic radii of 18.5 A, but apo-isoform I had a greater alpha-helical content and exhibited a longer Tyr lifetime, indicative of secondary and tertiary structural differences from isoform II. Isoforms I and II both had two fatty acid or fatty acyl CoA binding sites. Ligand binding decreased the isoform hydrodynamic radii by 3-4 A and increased Tyr rotational motions in a more restricted range. Fatty acyl CoAs were more effective than fatty acids in altering the isoform structures. Scatchard analysis showed that both isoforms bound cis- parinaric acid with high affinity (Kd values 41 and 60 nM, respectively) and bound trans-parinaric acid with 2- and 7-fold, respectively, higher affinity than for cis-parinaric acid. In contrast, isoform I had higher affinity for cis- and trans-parinaroyl CoAs (Kd values of 33 and 14 nM) than did isoform II (Kd values of 110 and 97 nM), thereby resulting in biphasic plots of parinaroyl-CoA binding to native L-FABP. Finally, displacement studies indicated that each isoform displayed distinct specificities for fatty acid/fatty acyl CoA chain length and unsaturation. Thus, rat L-FABP isoforms differ markedly in both structure and ligand binding function.
Highly purified rat liver fatty acid synthetase is completely inhibited when assayed in the presence of a coenzyme A-depleting system such as that catalyzed by phosphotransacetylase, acetyl-CoA synthetase, or ATP citrate lyase. The addition of free CoA causes a reversal of this inhibition. The requirement of free CoA is the same whether acetyl-CoA or butyryl-CoA serves as the primer for fatty acid synthetase. The CoA-depleted and thus inactive fatty acid synthetase system can be reactivated by the addition of a rat brain thioesterase or a rat mammary gland thioesterase II preparation. This reactivation appears to occur in the absence of free CoA. Long chain fatty acids (mainly palmitate) are formed by the thioesterase reactivated system. These results suggest that CoA is required for the termination of the fatty acid synthetase reaction. Possible mechanisms are discussed.
The present study was aimed at demonstrating the effects of exercising in water at two different temperatures on lipid-lipoprotein metabolism in experimental fatty liver rats. The rats were fed a high fat, high cholesterol (CHL) diet for 6 weeks, then returned to standard chow. The fatty liver rats were then divided at random into three groups, two for swimming in 20 degrees C (20SWG) and 30 degrees C (30SWG) water, 5 days/week, 30 min/day for 6 weeks, and a sedentary control group (SG). The concentrations of serum triglyceride (TG) and CHL were significantly lower (p less than 0.01) in both the 20SWG and 30SWG than in the SG. The serum concentration of very low density lipoprotein (VLDL)-CHL was clearly less in the 20SWG than in the SG (p less than 0.05) or the 30SWG (p less than 0.01). Compared to the SG, the two swimming groups had significantly lower levels (p less than 0.01) of low density lipoprotein (LDL)-CHL. The LDL-CHL in the 30SWG was significantly lower (p less than 0.01) than that in the 20SWG. There were no significant differences among the three groups in high density lipoprotein (HDL)/CHL. However, the ratio of HDL to CHL was over 10% greater in the two swimming groups than in the SG. Hepatic CHL ester and TG were significantly lower (p less than 0.05) in the 20SWG than in the SG. These results indicate that swimming in water at the lower temperature was more stimulating to lipid-lipoprotein metabolism in fatty liver than swimming in the higher temperature water.
Liver basic fatty acid (FA)-binding protein (Lb-FABP) cDNA was cloned from the livers of laying Tsaiya ducks and used to generate probes for quantification of the Lb-FABP mRNA in Tsaiya ducks. The full-length Lb-FABP cDNA of the Tsaiya duck was highly homologous with that of the mallard (99%), chicken (88%), and iguana (73%). The amino acid sequence was also highly homologous to Lb-FABP found in birds and reptiles, indicating a similar function of the Tsaiya duck Lb-FABP to those species. The calculated molecular weight for the cloned duck Lb-FABP was 14,043g/mol. The Lb-FABP was highly expressed in the liver of laying Tsaiya ducks and not detectable in heart, ovary, intestine, or adipose tissues. The expression of Tsaiya duck Lb-FABP in the skeletal muscle was also detected, and the sequence was confirmed. The greater expression of the hepatic Lb-FABP in the egg-laying Tsaiya ducks than the prelaying ducks paralleled the higher FA use by the laying ducks. These results suggest that hepatic Lb-FABP may be needed for egg production when FA metabolism is high for the ducks. Feeding laying Tsaiya ducks with diets enriched with 2% docosahexaenoic acid (DHA) oil for 2 wk significantly increased hepatic DHA content compared with in ducks fed a 2% butter basal diet. There was no effect of dietary DHA enrichment on the expression of Lb-FABP in the liver of Tsaiya ducks. The results suggest that even though the Lb-FABP may be involved in hepatic FA metabolism, the effect of individual FA on liver Lb-FABP in laying Tsaiya ducks needs to be further studied.
The treatment of non-alcoholic fatty liver disease may be worthwhile to prevent progression to advanced liver failure, but no therapy is definitely evidence-based. Weight loss or lifestyle modifications remain the primary line of intervention, particularly in overweight or obese subjects. In adult non-alcoholic fatty liver disease, they are effective in the short-term, but require a multidisciplinary team approach that is rarely available in liver units. Insulin-sensitizing agents are probably the treatment of choice. They definitely reduce the insulin resistance that promotes steatosis. Several uncontrolled and controlled studies have documented an improvement in liver biochemistry and in histology, but the long-term results remain unsettled. This is an area where significant advances are expected in the next few years.
OBJECTIVE: The present study was designed to assess the pharmacokinetics of propiverine after single and multiple dosing in patients with and without fatty liver disease. METHODS: The serum concentration-time curves of propiverine and its main metabolite propiverine-N-oxide were investigated in 12 patients with mild to moderate impairment of liver function (mean antipyrine clearance 26.0 ml x min(-1)) and in 12 controls (antipyrine clearance 42.8 ml x min(-1)). Subjects were treated orally with propiverine hydrochloride (Mictonorm) for 5 days (15 mg t. i. d.) to reach steady state. RESULTS: No significant differences were observed for propiverine and its main metabolite with regard to peak serum concentration (Cmax), area under the serum concentration-time curve (AUC) and elimination half-life (t1/2). Adverse events were reported by 12 patients. Five patients with fatty liver disease and seven patients with normal liver function complained of dry mouth and/or blurred vision. All adverse events reported were transient and mild. CONCLUSION: No pharmacokinetic differences relevant for safety were observed, comparing patients with and without fatty liver disease following repeated oral administration of propiverine. Thus there seems to be no need to adjust the dose in patients with mild to moderate impairment of liver function.
Rats fed a diet varying in the amount of fat, infused with ethanol, were studied to determine the relationship among diet, degree of fatty liver, and development of necrosis, inflammation, and fibrosis. Three groups of experimental animals, male Wistar rats, were fed diets containing 25% fat, 35% fat, and 32% fat with low protein. Morphologic assessment of liver injury was performed monthly by obtaining liver biopsies. The greatest degree of fatty infiltration at 1 month was seen in the high fat-low protein group, the mean fat score (3.8 +/- 0.37) was significantly higher than in the other two groups (P less than 0.05 and P less than 0.01). When the subsequent development of necrosis, inflammation, and fibrosis was related to the degree of fatty infiltration at 1 month, a significant relationship was seen between the number of animals developing these pathologic lesions and the severity of fatty liver. Our results show that the degree of fatty infiltration of the liver, influenced by the dietary intake of both fat and protein, is related to the subsequent development of necrosis, inflammation, and fibrosis in our intragastric feeding model for alcoholic liver disease.
Acute fatty liver is a rare but fatal complication of pregnancy. Here we describe a patient presenting with stupor and jaundice after aspirin intake at 35 weeks of gestation. Supportive management and delivery resulted in uneventful discharge of the patient and the newborn. Differential diagnosis and management of this condition are discussed.
A community health survey of 923 residents aged 30 years or more was performed in Putai Township of Taiwan. To elucidate the relationships between hepatitis C virus (HCV) and surrogate tests for non-A, non-B hepatitis in hyperendemic areas of hepatitis B virus (HBV) serum levels of alanine aminotransferase (ALT), triglycerides, cholesterol, hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) were examined. Glucose tolerance tests and the history of diabetes treatment were used to define the diabetes status. Fatty liver was diagnosed by sonography. The prevalence of anti-HCV was 2.6% (95% confidence interval, 1.6-3.6%). Elevated ALT and fatty liver were significantly associated with anti-HCV in univariate analysis. Anti-HCV was not an associated factor for fatty liver after adjusting for serum triglycerides and cholesterol, sex, body mass index and diabetes status through multiple logistic regression. However elevated ALT was still associated with anti-HCV after adjusting for serum triglycerides, sex, body mass index, HBsAg and age through multiple linear regression. The anti-HCV prevalence was similar between HBsAg-positive and negative subjects. Aggregation of HCV infection was found among spouses. It was concluded that elevated ALT and intimate contact with HCV carriers might be associated factors for HCV infection, and that HBV infection and fatty liver were not related to HCV infection in Taiwan.
Increased esterification of fatty acids to triglyceride is common to most of the mechanisms proposed to explain the causation of alcoholic fatty liver. However, it is unclear whether this is caused by increased substrate supply or whether direct stimulation of the enzymes of the esterification pathway occurs after excessive alcohol intake. The rate-limiting step in triglyceride synthesis is catalyzed by the enzyme phosphatidate phosphohydrolase, which is present in the cytosol and microsomes and is sensitive to inhibition by N-ethylmaleimide. This enzyme is physically distinct from a second form of phosphatidate phosphohydrolase that is located predominantly in the plasma membrane, is insensitive to N-ethylmaleimide inhibition and has a putative role in cell-signaling. We have investigated whether the activity of the N-ethylmaleimide-sensitive ("metabolic") form of phosphatidate phosphohydrolase is increased in patients with alcoholic liver disease and whether any increased activity correlates with the severity of steatosis. N-ethylmaleimide-sensitive and -insensitive phosphatidate phosphohydrolase activities were measured in needle liver biopsy specimens from 42 alcoholic patients and 6 patients with primary biliary cirrhosis and in wedge biopsy specimens from 6 normal patients undergoing routine cholecystectomy. Steatosis was "scored" on coded slides from 0 to 3. N-ethylmaleimide-sensitive activity was higher in alcoholic biopsy specimens scoring 3 (3.25 +/- 0.4 units/mg protein, n = 10) than in those scoring either 0 (1.21 +/- 0.2, n = 14) or 1 to 2 (1.58 +/- 0.2, n = 18), and it was also higher than in biopsy specimens from normal and primary biliary cirrhosis patients (1.65 +/- 0.3, n = 12; p < 0.0001, analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND/AIMS: Hepatitis C and nonalcoholic fatty liver disease (NAFL) are the two most common forms of liver disease in the United States. Recently, obesity and its associated risk factors have been suggested to enhance HCV-related fibrosis. The aim of this study was to assess the impact of hepatic steatosis, steatohepatitis, and its associated risk factors on HCV-related fibrosis. METHODS: Patients with untreated, biopsy-proven, chronic hepatitis C (6/97-3/99) were included. Clinical and demographic data at the time of liver biopsy were obtained from chart review and verified by telephone survey. One hepatopathologist reviewed all pathologic specimens, using the modified histological activity index score and the Ishak staging for fibrosis and a NAFL pathologic protocol. RESULTS: One hundred and seventy patients with hepatitis C were included [age: 48.7+/-9.33 (years), body mass index (BMI): 28.1+/-5.7 (kg/m2) and type 2 diabetes mellitus (DM): 14%]. Of these, 77 (45.3%) had no or mild fibrosis and 93 (54.7%) had advanced fibrosis. Hepatic steatosis was seen in 90 (52.9%) patients. The grade of steatosis was associated with markers of obesity only. Age (p=0.002), type 2 DM (p=0.04), and superimposed steatohepatitis (p=0.047) were independently associated with advanced fibrosis. Superimposed nonalcoholic steatohepatitis (NASH) was seen in 17 (10%) patients. Patients with superimposed NASH were mostly obese (76.5%), males (62%) with 16% having type 2 diabetes and a BMI 33.8+/-7.12. CONCLUSION: In patients with chronic hepatitis C, type 2 DM and superimposed steatohepatitis are independently associated with advanced fibrosis.