Dan Ivanov
Forum Senior
Topics: 14
Posts: 106
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Hi, I found in BRS this disease, but it doesnt say who makes the disease: mother of fetus? (I suppose mother, but I want to be sure). Pls help
Thx
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Dan
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| Anno Domini
Moderator
Topics: 293
Posts: 727
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Do you think the Reye syndrom.That is very rare disease and its patogenesis is incopletely understood.It is probably caused by mitohondrial dysfunction , ocurring alone or in combination with viral infection.
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| Yulia
Forum Elite
Topics: 19
Posts: 240
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Hi Dan,
About fatty liver of pregnancy... I've read that in some cases it has been associated with defect in fatty acid oxidation pathway...Mothers were heterozygous, so I would imagine they make less normal amount of enzyme, and fetuses had no enzyme activity whatsoever. So, it takes two  The enzyme deficient is long-chain 3-hydroxyacyl-coenzyme A dehydrogenase. It normally functions in mitochondrial beta-oxidation process. Anyway, I am not sure that it accounts for 100% of cases but in some patients they have found these defects.
As for Reye syndrome, I thought it was occurring mainly in children, and associated with viral illness treated with ASA... But pathology will look similar - microvesicular steatosis.
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| rajeev
Forum Junior
Topics: 5
Posts: 62
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fatty liver of pregnancy ..what the ? where the ?
holy smoke .. never heard of that one ..
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| Yulia
Forum Elite
Topics: 19
Posts: 240
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It's a rare one, fortunately.. Don't think they will ask about that, pathogenesis is unclear...
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| Dan Ivanov
Forum Senior
Topics: 14
Posts: 106
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Ok, Thx Yulia for this complete answer. Anno, Fatty liver of pregnancy and Reye syndrome has the same pathologic view (microvesicular fatty liver), but they are two different diseases. :!:
Thx to all
Dan
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Dan
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| cjwhite
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What connection does fatty liver have to Reye Syndrom? My son has fatty liver and also had a terrible case of chicken pox with very high fever, hallucinations, disorientation (could he of had Reye Syndrom and they not diagnos it and that cause the fatty liver? Can fatty liver be reversed?
"rajeev" wrote:
fatty liver of pregnancy ..what the ? where the ?
holy smoke .. never heard of that one .. [QUOTE]
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| EMI777LY
Forum Senior
Topics: 14
Posts: 135
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Hi Dan,
you was right about mather :!: Acute fatty liver of pregnancy is a syndrome that occurs late in pregnancy and is often associated with jaundice and hepatic failure. In half the cases it is associated with preeclampsia.If diagnosed in time, the disease usually resolves with termination of the pregnancy. Baby involve to just becouse without pregnancy it will be no acute fatty liver of Pregnancy
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Emily
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| EMI777LY
Forum Senior
Topics: 14
Posts: 135
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What connection does fatty liver have to Reye Syndrom? My son has fatty liver and also had a terrible case of chicken pox with very high fever, hallucinations, disorientation (could he of had Reye Syndrom and they not diagnos it and that cause the fatty liver? Can fatty liver be reversed?
you can read this at harrison's principleas of internal medicine under infiltrative and metabolic ds affecting the liver
reye's syndrome
the onset usually follows an upper resp tract inf
especially influenza and chickenpox=>persistent vomiting, stupor=>convulsions =>coma
liver is ^
blood ^ ATF,PT, hypoglycemia,MA acidosis,^ammonia.
The mortality rate in Reye;s 50%,
Chronic liver disease had not been reported in survivors
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Emily
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| Hollygolightly
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I experienced AFLP in the last trimester of my third and last pregnancy (at about 37 weeks gestation). It was also accompanied by disseminated intravascular coagulation (DIC). This was back in 1974, at a time when most doctors were not even familiar with AFLP. My baby (son) and I were, indeed, fortunate to have survived this terrible illness. (The doctors later told me that it was a miracle that I survived and even more of a miracle that my baby survived). I was given platelets and whole blood transfusions to treat the DIC, followed by C-section shortly afterward. An open liver biopsy was performed at the time of my C-section, followed by a closed (punch) biopsy about one week later. My second biopsy showed marked improvement. There is much to write about my experience and my feelings about this nasty (to put it mildly) syndrome; however, I'll try to be as brief as possible. To continue, I had no lasting effects as a result of AFLP and, in fact, when I had a laparoscopic procedure for gallbladder removal five years ago, one of my doctors also asked that I agree to a liver biopsy during my surgery. (This was the same doctor, a gastroenterologist, who had been called in as a consultant by my OB-GYN during my 1974 AFLP pregnancy). The results of this most recent biopsy were completely normal and I was told that my liver was in exceptionally healthy condition. Although my son had no problems after his birth as a result of my illness, he was diagnosed with Gilbert's Syndrome about ten years ago and I am now curious to learn if there is a common denominator between the two illness--AFLP and Gilbert's. We are of French ancestry and the incidence of Gilbert's Syndrome seems to run higher in those who are French, so this might be just a coincidence. Anyway, I had hoped that a definitive cause/prevention/treatment of AFLP would have been discovered after all these years. I know that researchers feel that the cause might be from a mitochondrial defect, but much more all-encompassing research needs to be done, i.e., individual researchers should share their discoveries with one another, in order to advance their knowledge about this condition, so as to prevent this from happening to other women. I feel that this condition is not as rare as some doctors/researchers would think. I feel that the condition is being more accurately diagnosed now, but also think that the condition is on the rise. I've been following various research studies and it is my conclusion that there are varying degrees of this condition and "slight" cases of AFLP might be being overlooked. In conclusion, I would like to add that my daughter had complications toward the end of her two pregnancies and her symptoms were indicative of early AFLP, but this was never looked into because she gave birth to her babies very shortly after the symptoms began to make themselves known. Therefore, I feel that the cause of AFLP has a genetic component, which can be transferred to female offspring. As a side note, after I recovered from AFLP, my doctors told me that they had found only 8 cases (worldwide) of AFLP and that of these, only 3 of these mothers and only 2 of the offspring survived this illness. Any comments to what I have written here will be appreciated.
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| Hollygolightly
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'Sorry, an addition to my previous post about Acute Fatty Liver of Pregnancy: One week after I was released from my three week hospitalization because my AFLP, I appeared at Grand Rounds at my doctors' request. At G.R., my case was presented, along with a slide presentation which compared my Acute Fatty Liver of Pregnancy biopsy to a Reye's Syndrome biopsy and a discussion followed as to whether or not there was a relationship between the two conditions. No final conclusion was drawn either way, but opinions were expressed that both AFLP and Reye's Syndrome cases seemed to increase with higher than normal outbreaks of Chicken Pox, viral infections, and influenza. Curiously enough and at this same time period in 1974, there was a marked increase of cases of Reye's Syndrome occurring in our area (Illinois) and across the country. In fact, this increased presence of Reye's did much to raise general awareness of the condition, both in the medical community and in the general public. (Some doctors at the time were not even aware of Reye's Syndrome). Now, it has been determined that the use of aspirin during or after a viral infection may be the cause Reye's Syndrome in certain children, but also in some adults as well. Has a genetic link been found to exist between these two illnesses? Your comments, please. [B] :?:
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| Katie
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Dear HG, I've been searching the internet for current information on AFLP and stumbled upon your message. I suffered from AFLP 2 years ago when I delivered my first child (a boy - nov. 2001). The physicians had no idea what was wrong with me for several days after my delivery. I was 5 days past due when I arrived at the hospital in labor (slightly jaundiced). Two days earlier I had shown no signs whatsoever of AFLP at my check up (though no bloodwork on the liver was done...not routine). I had a completely healthy pregnancy (never high bloodpressure, no vomiting (until in labor)), delivered a healthy baby, and then it went downhill immediately from there. Acute liver failure, acute renal failure, DIC, etc. Four days after my delivery the physicians had no choice but to operate (had to remove a large hematoma) - I was losing more blood than they could give me (they had put off surgery since my liver was failing). Like you, I was lucky to survive and recover completely (2 weeks in the hospital; probably 6 months to get to 100%). I was the first case they had ever heard of to show absolutely no signs of AFLP coming on. There is more to discover about this disease, and I agree with you - I think it is not so rare as they say. When my son was 3 months old, we read online about the link between AFLP and LCHAD. This was more frightening to me than when I was sick. Our son was tested by a genetisist at Emory and the results were negative (he was tested again one year later when he had his first fever - to test his body 'under stress' and this came back negative as well - whew). Now that I have spent 2 years enjoying a beautiful boy, I am wanting another child. My question to you is - did you have more children after your first experience? Do you know the risks involved? I am crazy for evening considering this?
Also, there's something tugging at me to do more to educate the public - maybe a website devoted excusively to AFLP with helpful links or an AFLP non-profit org to educate, raise $ for research, etc. Is there one already out there? If not, are you interested in joining me? I have no clue where to begin.
Your fellow survivor,
Katie
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| Ouli Maty
Forum Elite
Topics: 33
Posts: 275
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Dear Katie and Hollygolightly, I am very please to see you sharing your own experiences on this web site. You brought the reality of a disease into light. It is no longer a material to study for the exam, but something to be aware off for the rest of my life.
As a women I support your fight and congratulate you for winning over this deadly disease.
Thank you.
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deep breathing...
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| mapetrsn
Forum Newbie
Topics: 5
Posts: 18
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I believe it is also a possible side effect of doxycycline
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| Hollygolightly
Forum Newbie
Topics: 0
Posts: 1
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Following article appeared in the New England Journal of Medicine. For full text/graphics/references, go to Webpage: http://content.nejm.org/cgi/content/full/340/22/1...
Volume 340:1723-1731 June 3, 1999 Number 22
A Fetal Fatty-Acid Oxidation Disorder as a Cause of Liver Disease in Pregnant Women
Jamal A. Ibdah, M.D., Ph.D., Michael J. Bennett, Ph.D., Piero Rinaldo, M.D., Ph.D., Yiwen Zhao, B.S., Beverly Gibson, B.S., Harold F. Sims, B.A., and Arnold W. Strauss, M.D.
ABSTRACT: Background Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in women whose fetuses are later found to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This enzyme resides in the mitochondrial trifunctional protein, which also contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase. We undertook this study to determine the relation between mutations in the trifunctional protein in infants with defects in fatty-acid oxidation and acute liver disease during pregnancy in their mothers.
Methods In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutations in the {alpha} subunit of the trifunctional protein. We then correlated the results with the presence of liver disease during pregnancy in the mothers.
Results Nineteen children had a deficiency only of long-chain 3-hydroxyacyl-CoA dehydrogenase and presented with hypoketotic hypoglycemia and fatty liver. In eight children, we identified a homozygous mutation in which glutamic acid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the {alpha}-subunit gene and a different mutation in the other allele. While carrying fetuses with the Glu474Gln mutation, 79 percent of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome. Five other children, who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein (loss of activity of all three enzymes). None had the Glu474Gln mutation, and none of their mothers had liver disease during pregnancy.
Conclusions Women with acute liver disease during pregnancy may have a Glu474Gln mutation in long-chain hydroxyacyl-CoA dehydrogenase. Their infants are at risk for hypoketotic hypoglycemia and fatty liver.
Acute fatty liver of pregnancy is a devastating disorder associated with substantial maternal and neonatal morbidity and mortality.1,2,3,4 The HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) is a more common maternal illness of late pregnancy and is associated with a better prognosis.2,5 The clinical and biochemical features of these two disorders overlap, suggesting that their underlying pathophysiologic mechanisms may be similar.
Long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase catalyzes the third step in the ß-oxidation of fatty acids in mitochondria (Figure 1). The active site of this enzyme is located in the C-terminal domain of each of the four {alpha} subunits of the trifunctional protein that is associated with the inner mitochondrial membrane.6,7 The N-terminal domain of each of the {alpha} subunits is the site of long-chain 2,3-enoyl-CoA hydratase activity. The active site of long-chain 3-ketoacyl-CoA thiolase is in the four ß subunits of the protein; this enzyme catalyzes the last step in the ß-oxidation of fatty acids. The formation of a stable trifunctional-protein complex and the expression of all three enzymes require the presence of intact {alpha} and ß subunits. The genes that encode the {alpha} and ß subunits are closely linked on chromosome 2.8,9,10
Figure 1. Biochemical Pathway of Mitochondrial Fatty-Acid Oxidation.
The four reactions of the pathway are shown in a clockwise loop. R represents the variable length of the fatty-acid chain; for example, palmitate, a typical long-chain substrate, contains 13 CH2 groups. FAD denotes flavin adenine dinucleotide, FADH2 the reduced form of FAD, and NAD+ nicotinamide adenine dinucleotide. Bars indicate the blockage of reactions as a result of isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or complete deficiency of the trifunctional protein. In the oxidation of long-chain fatty acyl–CoA substrates that are 10 to 18 carbon residues in length, the trifunctional protein catalyzes the second, third, and fourth reactions (enclosed in the box) in the pathway. The second and third reactions are catalyzed by long-chain 2,3-enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase, respectively, which reside in the {alpha} subunit of the trifunctional protein. The fourth step, catalyzed by long-chain 3-ketoacyl-CoA thiolase, occurs on the ß subunit of the trifunctional protein. The products of one cycle through the pathway are NADH, FADH2, acetyl-CoA, and a fatty acyl–CoA shortened by two carbon residues. NADH and FADH2 carry electrons to the respiratory chain (mitochondrial oxidative phosphorylation complexes) to generate ATP, and acetyl-CoA enters the citric-acid cycle. The shortened fatty acid reenters the fatty-acid oxidation spiral. Thus, in the oxidation of palmitate, seven rounds of the cycle produce eight acetyl-CoA molecules.
Patients with either an isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or complete deficiency of the trifunctional protein (a loss of activity of all three enzymes) have been described.7,11 Several months after birth, children with these recessively inherited disorders present with nonketotic hypoglycemia during fasting and hepatic encephalopathy, which may progress to coma and death; cardiomyopathy; slowly progressive peripheral neuropathy; skeletal myopathy; or sudden, unexpected death.12 Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase has been found in the children of women who had acute fatty liver of pregnancy or the HELLP syndrome during pregnancy.13,14,15,16,17,18 We have identified a mutation involving a change from glutamic acid to glutamine at amino acid residue 474 (Glu474Gln) of the {alpha} subunit of the trifunctional protein in three unrelated children whose mothers had acute fatty liver of pregnancy or the HELLP syndrome during pregnancy.8
However, not all women carrying fetuses with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or trifunctional-protein deficiency have liver disease.19,20,21 Furthermore, liver disease in pregnant women occurs most often when the deficiency of enzymatic activity in the fetus is severe, although acute fatty liver of pregnancy has been reported in two women who subsequently had healthy children with intermediate levels of long-chain 3-hydroxyacyl-CoA dehydrogenase, as determined by enzyme assay.18 The incidence of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency among the fetuses of women with acute fatty liver of pregnancy is unknown; some reports suggest that the association is rare.20,21 A recent review of liver disease during pregnancy2 did not mention the relation between severe liver diseases in pregnant women and this fatty-acid oxidation disorder in their children.
Because the association between these two disorders is not well recognized2,3 and because it has important implications for mothers and their children,8,15,16 we examined the association between a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or the trifunctional protein in children and severe liver disease in their mothers during pregnancy. We studied the frequency and molecular basis of this association in 24 families to correlate various genotypes to the clinical manifestations in the mothers and children.
We studied 24 families in which one child had clinical features suggestive of defects in fatty-acid oxidation, such as hypoketotic hypoglycemia; sudden, unexplained death with fatty liver at autopsy; or cardiomyopathy and abnormal biochemical or enzymatic findings7,10,12,13,14,15,16,22 consistent with an isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or complete deficiency of the trifunctional protein. Acute fatty liver of pregnancy or the HELLP syndrome was diagnosed by referring obstetricians according to standard criteria.1,2,3,4,5 This study was approved by the institutional review boards of Washington University and Wake Forest University, and informed consent was obtained from the adult subjects and parents of the children.
Biochemical Studies
The activities of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase were measured in crude extracts of cultured skin fibroblasts or liver tissue, as previously described.8,19,23 Because the active sites of these two enzymes are in the {alpha} and ß subunits, respectively, of the trifunctional protein, a deficiency of both activities is always associated with a lack of activity of long-chain 2,3-enoyl-CoA hydratase, whose active site is in the {alpha} subunit.7,9,23 A marked reduction in long-chain 3-ketoacyl-CoA thiolase activity, which is contained in the ß subunit of the trifunctional protein, distinguishes the biochemical phenotypes of isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and complete trifunctional-protein deficiency.8,23 Thiolase activity is very low (0 to 20 percent of normal levels) in patients with trifunctional-protein deficiency but is relatively preserved in those with isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (40 to 80 percent of normal levels).
Molecular Studies
DNA was isolated from cultured skin fibroblasts, frozen tissue, or peripheral-blood leukocytes from 24 children and various family members by means of alkaline lysis and protease digestion.24 RNA was isolated from cultured skin fibroblasts or homogenized tissue according to a standard protocol.19 Polymerase-chain-reaction (PCR) amplification of the 20 exons of the gene encoding the {alpha} subunit and the 50 to 100 bp of flanking sequence was performed8 with [32P]deoxycytosine triphosphate and 27-to-33-bp intronic primers designed on the basis of the previously identified genomic sequence8 (and unpublished data). The amplified fragments were then analyzed for single-strand conformation polymorphisms.25
The Glu474Gln mutation was identified by PstI digestion8,10,26 of the PCR-amplified product of exon 15. Nucleotide sequences were determined by the dideoxy chain-termination method, either manually with sulfur-35 radiolabeling or with an automated sequencer (model 373A, Applied Biosystems, Foster City, Calif.), with amplified exonic fragments by direct sequencing or after subcloning.
Dietary Treatment
Children were treated with frequent feedings of a low-fat diet in which the fats were medium-chain triglycerides. This regimen often prevents hypoketotic hypoglycemic liver dysfunction in patients with fatty-acid oxidation disorders.12
Results
The clinical abnormalities and molecular mutations in 23 children who had isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or complete deficiency of the trifunctional protein and their mothers are shown in Table 1 and Table 2. In Family 9, diagnosis of acute fatty liver of pregnancy in the mother prompted the analysis of the family members; the child subsequently had severe hepatic and cardiac dysfunction, and deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase was documented.
Table 1. Clinical Manifestations of a Deficiency of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase or Trifunctional Protein in 24 Children.
Table 2. Mutations in the a Subunit of the Trifunctional Protein and Clinical Abnormalities in the 24 Children and Their Mothers.
Clinical Abnormalities
The 24 children with a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or the trifunctional protein presented at a mean age of 7.6 months (range, birth to 60 months) with predominantly hepatic, cardiac, or neuromuscular abnormalities7,8,10,11,12,13,14,15,16,17,18,19,27,28 (Table 1). Seven of the children died very soon after presentation, and one died 18 months later despite treatment. The remaining 16 children were being treated with a modified diet at the most recent follow-up visit.12 At that time, eight of the surviving children were older than five years, and retinitis pigmentosa had developed in six.29 Examination of the family histories revealed unexplained deaths in six siblings of the 24 children.
Nineteen children (79 percent) presented with acute hepatic dysfunction: 18 had hypoketotic hypoglycemia, hypotonia, hepatomegaly, hepatic encephalopathy, and high serum aminotransferase concentrations, and 1 had cholestasis of unknown cause and hypocalcemia due to vitamin D deficiency; this child later died unexpectedly. The acute hepatic dysfunction progressed to coma and death in five children. Autopsies in two of these five children revealed massive hepatic steatosis, with necrosis, regenerative changes, and early nodules in one child. Two of the 19 children with acute hepatic dysfunction also had severe cardiomyopathy, and 1 had chronic myopathy. Four of these children have been described previously.8,17
Three of the 24 children presented primarily with dilated cardiomyopathy in the first month of life. One, in whom complete deficiency of the trifunctional protein was diagnosed, had dramatic improvement when an appropriate diet and treatment for congestive heart failure were given but died suddenly at the age of 18 months during an episode of mild gastroenteritis.19 The second child died at the time of presentation; the third recovered completely and had normal cardiac function at the age of 10 years.
Two previously described27,28 children who had complete trifunctional-protein deficiency were first seen at the age of 18 months with hypotonia but no liver or cardiac involvement. Each child had slowly progressive peripheral neuropathy and myopathy.
Obstetrical and Family Histories
During their pregnancies with affected fetuses, 15 of the 24 women (62 percent) had acute fatty liver of pregnancy or the HELLP syndrome (Table 2); the other 9 women had normal pregnancies. In all 15 women with liver disease during pregnancy, the disorder developed during the third trimester, at a mean of 33.5 weeks of gestation. The HELLP syndrome was the initial diagnosis in three women. Severe acute fatty liver of pregnancy was the initial diagnosis in nine women and was proved by liver biopsy in two of them. Three other women presented with signs of the HELLP syndrome, but the diagnosis was later changed to acute fatty liver of pregnancy. In one woman with acute fatty liver of pregnancy, anoxic brain damage developed, which progressed to coma, a chronic vegetative state, and death. The other 14 women recovered quickly after emergency delivery.
Five of the 15 women with acute fatty liver of pregnancy or the HELLP syndrome (33 percent) were affected during their first pregnancy. In the other 10 women, liver disease was diagnosed during a second or later pregnancy, and their fetuses were found to have long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. These 10 women had had a total of 15 previous pregnancies, 3 of which had been complicated by acute fatty liver of pregnancy, and in all 3 cases the child had died suddenly and without explanation during infancy. One woman had had a miscarriage during the first trimester. The remaining 11 pregnancies had been normal, and the offspring were healthy.
Biochemical Abnormalities in the Children
The mean (±SE) 3-hydroxyacyl-CoA dehydrogenase activity measured with palmitoyl-CoA substrate in the 24 children was 26±9 percent of normal levels, a finding similar to that reported for other children with these deficiencies.7,8,9,10,11,20,23 All 19 children with acute hepatic dysfunction had isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase and only partial loss of long-chain 3-ketoacyl-CoA thiolase activity (40 to 70 percent of normal). The children with cardiomyopathy or peripheral neuropathy and skeletal myopathy had complete deficiency of the trifunctional protein, with marked reduction of long-chain 3-ketoacyl-CoA thiolase activity (mean level of activity, 4 percent of normal).
Molecular Abnormalities
We used PCR amplification of all 20 exons of the {alpha} subunit gene and single-strand conformation polymorphism analysis to screen the 24 children for differences in genetic sequences.8,25 Mutations were detected on 47 of 48 alleles. Results in Families 5 and 9 (Figure 2, Figure 3A, and Figure 3B) illustrate this approach. The child in Family 5 presented at the age of eight months with severe myocardial dysfunction, left ventricular hypertrophy, hypoketotic hypoglycemia, and metabolic acidosis. His mother had had the HELLP syndrome during the pregnancy. The child was treated with a modified diet and inotropic drugs and was asymptomatic at the most recent follow-up visit, at the age of five years. These findings were consistent with homozygosity for the Glu474Gln mutation,8,26 which was confirmed by sequence analysis (data not shown).
Figure 2. Results of Single-Strand Conformation Polymorphism Analysis in Family 5 and a Normal Subject.
Genomic DNA from exon 15 was extracted from blood leukocytes of the affected child, his parents, an apparently healthy sibling, and an unrelated normal subject, amplified,8 and analyzed by single-strand conformation polymorphism analysis as described previously.25 In lane 1, the two normal bands represent the normal sequence. Lanes 2, 3, and 5 show two normal bands and two aberrantly migrating bands, representing DNA subsequently proved by sequence analysis to contain the Glu474Gln mutation. The parents and brother were therefore heterozygous for this mutation. Lane 4 shows only the two aberrant bands, and sequence analysis confirmed that the child was homozygous for the Glu474Gln mutation. His mother had had the HELLP syndrome during two pregnancies, one with the affected child and one with an older brother, who died unexpectedly at the age of five months. Her pregnancy with the healthy sibling was uncomplicated. No DNA from the presumably affected brother was available for analysis.
Figure 3. Results of Single-Strand Conformation Polymorphism Analysis in Family 9 (Panel A) and Sequence Analysis in the Affected Child (Panel B).
Genomic DNA from the affected child, her parents, and an unrelated normal subject was amplified with oligonucleotides flanking exon 4 and analyzed by single-strand conformation polymorphism analysis25 (Panel A). Lane 1 shows the normal bands, a pattern also found in DNA from the child's mother (lane 3). The patterns for the affected child (lane 2) and her father (lane 4) reveal the two normal bands and two additional, aberrantly migrating bands, consistent with heterozygosity for a sequence mutation. While carrying the affected child, the mother had acute fatty liver of pregnancy. Sequence analysis (Panel B) revealed a 5-bp deletion ({Delta}271–275), which results in a premature termination codon at position 67 (Asp) of the mature {alpha} subunit. Amplified exon 4 genomic DNA from the affected child was subcloned, and eight clones were sequenced. The antisense sequences are shown. The five nucleotides marked by asterisks at normal positions 271 through 275 are deleted in the mutant allele. Heterozygosity for this mutation was confirmed by similar sequence studies in the father.
Family 9 was tested solely because the mother had acute fatty liver of pregnancy with hepatic coma and renal failure. After emergency delivery and despite slight asphyxia during birth, the infant recovered. At the age of nine weeks, while molecular studies were under way, the infant had acute hypoketotic hypoglycemia and cardiogenic shock. In both the child and the father, exon 4 of the {alpha} subunit was found to be abnormal on single-strand conformation polymorphism analysis (Figure 3A), a finding consistent with heterozygosity. This mutation (Figure 3B) is a 5-bp deletion ({Delta}271 through 275) that causes a frame shift and generates a premature termination codon at position 67 (aspartic acid) in the mature {alpha} subunit. The mother was heterozygous for the Glu474Gln mutation in exon 15.
Among the 24 children with a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or of the trifunctional protein, we identified 17 different mutations involving 11 exons and affecting all domains of the {alpha} subunit gene (Table 2). Only 27 of the 47 abnormal alleles (57 percent) carried the Glu474Gln mutation; the other 20 alleles carried 16 different mutations. Thus, there was substantial heterogeneity among the {alpha} subunit mutations, in contrast to results reported previously.10,16,20
Correlation of the Children's Genotypes with Liver Disease in Their Mothers
All 19 children with an isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase had the Glu474Gln mutation on at least one allele. Eight unrelated children were homozygous for this mutation. The other 11 children were compound heterozygotes, with nine other known mutations, affecting exons 4, 5, 6, 9, 12, 15, 16, and 18. Of these mutations, three destroy a consensus splice site at an intron–exon junction and probably cause missplicing; four introduce a premature termination codon within an exon; and two, identified in three children, are deletions that alter the reading frame and introduce premature termination codons downstream.
All 15 mothers in whom acute fatty liver of pregnancy or the HELLP syndrome developed carried fetuses that were either homozygous for the Glu474Gln mutation or compound heterozygotes, with one allele carrying this mutation and a premature termination codon or splice-site mutation on the other allele. Messenger RNA containing the Glu474Gln mutation is stably expressed,8,10 and in the resulting mutant protein the activity of long-chain 3-hydroxyacyl-CoA dehydrogenase is markedly reduced. In contrast, mutations introducing premature termination codons and splice-site mutations often result in low cytoplasmic concentrations of the corresponding messenger RNA.8,17 Of the 15 women who had liver disease during pregnancies with the affected children, only 10 had the Glu474Gln mutation; the other mothers had mutations causing premature termination codons (Families 10, 11, 12, and 17) or an unknown mutation (Family 19). Thus, the maternal genotype does not correlate with the development of acute fatty liver of pregnancy or the HELLP syndrome (Table 2).
Mutation analysis in six older siblings who were born after uncomplicated pregnancies revealed heterozygosity for the Glu474Gln mutation in four and a normal genotype in two. This result suggests that heterozygosity in the fetus is not associated with maternal liver disease during pregnancy.
Among the five children with complete deficiency of the trifunctional protein (Table 2), three splice-site mutations, four missense mutations, and one termination-codon mutation were found, revealing the heterogeneity of genotype associated with this deficiency. None of these children had the Glu474Gln mutation. Two children (from Families 21 and 23), whose parents were consanguineous, were homozygous. One had an alteration in the consensus splice site preceding exon 7, in which the adenine at sequence position –2 was changed to guanine. The other had a missense mutation, a change from valine to aspartic acid at position 246, in exon 9. The other three children were compound heterozygotes. The first (from Family 20) had two different consensus splice-site mutations, one in exon 3 of each allele. The second (from Family 22) had two different mutations in the codon for arginine at residue 640. The third (from Family 24) had a missense mutation, a change from isoleucine at residue 269 to asparagine, and a termination mutation, both in exon 9. None of the mothers of these five children had liver disease while pregnant with the affected children. All five children with complete trifunctional-protein deficiency had cardiomyopathy or neuromuscular abnormalities; none had hepatic dysfunction.
Discussion
Our results provide strong evidence that a fetal–maternal interaction can cause life-threatening hepatic disease in a woman who is carrying a fetus with isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, a recessively inherited disorder of mitochondrial fatty-acid oxidation. Specifically, a woman whose affected fetus has the Glu474Gln mutation on one or both alleles of the {alpha} subunit of the trifunctional protein is likely to have acute fatty liver of pregnancy or the HELLP syndrome. In our study, none of the mothers had either of these disorders while carrying a fetus with one or two wild-type alleles of the {alpha} subunit or with complete trifunctional-protein deficiency.
Little is known about the mechanism of the association between isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase in a fetus with the Glu474Gln mutation on at least one allele and liver disease in the mother during the pregnancy. We hypothesize that in the presence of the Glu474Gln mutation, long-chain 3-hydroxyacyl metabolites produced by the fetus or placenta accumulate in the mother and are highly toxic to the liver; this reaction is perhaps exaggerated by the decreased metabolic utilization of fatty acids during pregnancy.30
In contrast to previous reports10,16,20 indicating that 90 to 100 percent of abnormal alleles of the gene encoding the {alpha} subunit of the trifunctional protein had the Glu474Gln mutation, we found 17 different mutations among the 24 children in our study. In the 19 children with isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, 71 percent of alleles had the Glu474Gln mutation, and none of the 10 alleles (all of which were abnormal) in the 5 children with trifunctional-protein deficiency had this mutation. Clearly, mutations in the genes encoding trifunctional protein are heterogeneous.
In a molecular-screening study8 of 351 normal subjects, we found that 2 were heterozygous for the Glu474Gln mutation. If this group of subjects is representative of the general population, then isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase would occur once in every 62,000 pregnancies, and either trifunctional-protein or long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency would occur once in 38,000 pregnancies.
The morbidity and mortality associated with liver disease in pregnant women are substantial.1,2,3,4,5,16 Our results indicate that fetal deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase is one cause of these maternal diseases. Because this disorder is recessive, one in four fetuses will be affected, and the rate of recurrence of maternal liver disease will be 15 to 25 percent16 (and unpublished data). Prenatal diagnosis by enzyme assay of amniocytes has been described,31 and we have performed molecular diagnoses by analyzing DNA from chorionic-villus samples (unpublished data).
The mortality rate among children with a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase or complete deficiency of the trifunctional protein has been reported to be 75 to 90 percent.9,10,16,20 In contrast, 67 percent of the affected children in our study were alive and receiving dietary treatment at the most recent follow-up, and most were able to attend school. Dietary treatment of children with fatty-acid oxidation disorders dramatically reduces morbidity and mortality.12 In Family 9, examination and prospective diagnosis of fetal long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency were prompted solely by the presence of acute fatty liver of pregnancy in the mother.
These results strongly suggest that all women with acute fatty liver of pregnancy or the HELLP syndrome, as well as their partners and children, should undergo molecular diagnostic testing. Because these women may have one of a variety of mutations, testing only for the Glu474Gln mutation in women with acute fatty liver of pregnancy21 is not sufficient to rule out long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency in the fetus or other family members. However, because their fetuses always have at least one allele with the Glu474Gln mutation, testing of both the mother and the father or of the newborn infant is sufficient to diagnose the deficiency.
In summary, we have determined the molecular basis of a fetal–maternal interaction that causes liver disease in pregnant women whose fetus has a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. Deficiency of this enzyme creates a life-threatening situation for both fetus and mother. Women with acute fatty liver of pregnancy or the HELLP syndrome, as well as their partners and children, should undergo molecular testing for the Glu474Gln mutation of the {alpha} subunit of the trifunctional protein. Prospective diagnosis of this deficiency should allow proper genetic counseling about the risk of occurrence of severe liver disease in the mother and lifesaving therapy for the affected child.
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| bertluchies
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My wife suffered from AFLP 7 months ago when she delivered our first child, a boy. The physicians first thought it was a HELLP syndrome. She had a completely healthy pregnancy. Four days after her delivery the physicians send her to another hospital, for they were unable to treat her. There they diagnosed AFLP. Acute liver failure, acute renal failure, no blood clotting, and she had a coma for 2 days .She was lucky to survive and stayed for 2 months in hospital. Our son was tested by a genetisist for LCHAD and the results were negative. We would like to talk to people who had the same experience.
Bert & Dorien Lüchies
The Netherlands
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| kgroya
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Bert, your wife's experience sounds similar to mine. I gave birth to twin boys in March 04 and immediately after delivery, my health deteriorated very quickly. They thought I had HELLP at first as well, and then they determined I had AFLP. I was rushed to a major hospital in Chicago, put in ICU and put on the liver transplant list. They found a liver for me within a few days but just then my liver started to slowly improve. I didn't need a transplant but spent a month in the hospital recovering. I also had a severe case of pancreatitis and renal failure due to the AFLP. Our boys do not have LCHAD either, thank God. What are your doctors telling you in terms of subsequent pregnancies? My doctors are giving us conflicting information. We most likely will not try to get pregnant again because it is just too risky. Best of luck to you and your family! I do wish there was more information out there for those of us who have suffered from this rare complication of pregnancy.
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