Acute fatty liver of pregnancy is a rare life-threatening complication of

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

that occurs in the third trimester or the immediate period after delivery. It is thought to be caused by a disordered metabolism of

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

s by

mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

in the fetus, caused by long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. This leads to decreased metabolism of long chain fatty acids by the feto-placental unit, causing subsequent rise in hepatotoxic fatty acids in maternal plasma. The condition was previously thought to be universally fatal, but aggressive treatment by stabilizing the mother with

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

fluids and

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

products in anticipation of early delivery has improved

prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain sta ...

Signs and symptoms

Acute fatty liver of pregnancy (or hepatic lipidosis of pregnancy) usually manifests in the third trimester of pregnancy, but may occur any time in the second half of pregnancy, or in the

puerperium The postpartum (or postnatal) period begins after childbirth and is typically considered to end within 6 weeks as the mother's body, including hormone levels and uterus size, returns to a non-pregnant state. The terms puerperium, puerperal perio ...

, the period immediately after delivery. On average, the disease presents during the 35th or 36th week of pregnancy. The usual symptoms in the mother are non-specific including

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenter ...

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

(or lack of desire to eat) and abdominal pain; excessive thirst may be the earliest symptom without overlap with otherwise considered normal pregnancy symptoms; however,

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

and

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

may occur in as many as 70% of patients. In patients with more severe disease,

pre-eclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...

may occur, which involves elevation of blood pressure and accumulation of fluid (termed oedema). This may progress to involvement of additional systems, including

acute kidney failure Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both. Causes of AKI are c ...

hepatic encephalopathy Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stage ...

, and

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic p ...

. There have also been reports of

diabetes insipidus Diabetes insipidus (DI), recently renamed to Arginine Vasopressin Deficiency (AVP-D) and Arginine Vasopressin Resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced ...

complicating this condition. Many laboratory abnormalities are seen in acute fatty liver of pregnancy. Liver enzymes are elevated, with the AST and ALT enzymes ranging from minimal elevation to 1000 IU/L, but usually staying in the 300-500 range.

Bilirubin Bilirubin (BR) ( Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from t ...

is almost universally elevated.

Alkaline phosphatase The enzyme alkaline phosphatase (EC 3.1.3.1, alkaline phosphomonoesterase; phosphomonoesterase; glycerophosphatase; alkaline phosphohydrolase; alkaline phenyl phosphatase; orthophosphoric-monoester phosphohydrolase (alkaline optimum), systematic ...

is often elevated in

due to production from the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

, but may be additionally elevated. Other abnormalities may include an elevated

white blood cell count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and ...

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

, elevated coagulation parameters, including the international normalized ratio, and decreased

fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...

. Frank

disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts ...

, or DIC, may occur in as many as 70% of people. Abdominal

ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

may show fat deposition in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

, but, as the hallmark of this condition is

microvesicular steatosis Steatosis, also called fatty change, is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver – the primary organ of lipid metabolism – where the condition is commonly referred to as fatty liver dis ...

(see pathology below), this is not seen on ultrasound. Rarely, the condition can be complicated by rupture or

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...

of the

, which may be identified by

Pathophysiology

The understanding of the causes of acute fatty liver of pregnancy has been improved by advances in mitochondrial

biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...

. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain

s. When this occurs in the

foetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

, the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother. The

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

. LCHAD deficiency is

autosomal recessive In genetics, dominance is the phenomenon of one variant ( allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...

in inheritance and mothers are often found to be

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. ...

for the affected mutation.

Diagnosis

The diagnosis of acute fatty liver of pregnancy is usually made on clinical grounds by the treating physician, but differentiation from other conditions affecting the

may be difficult. The diagnosis of acute fatty liver of pregnancy is suggested by jaundice with a lesser elevation of liver enzymes, elevated white blood cell count, disseminated intravascular coagulation, and a clinically unwell patient. A

liver biopsy Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment. Medica ...

can provide a definitive diagnosis, but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy. Often testing will be done to exclude more common conditions that present in a similar fashion, including

viral hepatitis Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form. The most common causes of viral hepatitis are the five unrelated hepatotropic vi ...

HELLP syndrome HELLP syndrome is a complication of pregnancy; the acronym stands for hemolysis, elevated liver enzymes, and low platelet count. It usually begins during the last three months of pregnancy or shortly after childbirth. Symptoms may include feelin ...

intrahepatic cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, cholestasis of pregnancy, jaundice of pregnancy, and prurigo gravidarum, is a medical condition in which cholestasis occurs during pregnancy. It typically presents wi ...

, and

autoimmune hepatitis Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the live ...

Pathology

If a liver

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...

is needed for diagnosis of the condition, the mother should be appropriately stabilized and treated to reduce bleeding related complications. The diagnosis can be made by a frozen-section (as opposed to a specimen in formalin) that is stained with the Oil red O stain, that shows microvesicular steatosis (or small collections of fat within the liver cells). The microvesicular steatosis usually spares zone one of the liver, which is the area closest to the hepatic artery. On the regular trichrome stain, the liver cell

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

shows a foamy appearance due to the prominence of fat.

Necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...

is rarely seen. The diagnosis can be enhanced by

electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

which can be used to confirm the presence of microvesicular steatosis, and specifically the presence of megamitochondria and paracrystalline inclusions. Liver diseases with similar appearances include

Reye's syndrome Reye syndrome is a rapidly worsening brain disease. Symptoms of Reye syndrome may include vomiting, personality changes, confusion, seizures, and loss of consciousness. While liver toxicity typically occurs in the syndrome, jaundice usually doe ...

, drug-induced hepatitis from agents with mitochondrial toxicity, including nucleoside reverse transcriptase inhibitors used to treat HIV, and a rare condition known as

Jamaican vomiting sickness Jamaican vomiting sickness, also known as toxic hypoglycemic syndrome (THS), acute ackee fruit intoxication, or ackee poisoning, is an acute illness caused by the toxins hypoglycin A and hypoglycin B, which are present in fruit of the ackee tree ...

which is caused by the eating of the unripened

Ackee The ackee, also known as ankye, achee, akee, ackee apple or ayee (''Blighia sapida'') is a fruit of the Sapindaceae ( soapberry) family, as are the lychee and the longan. It is native to tropical West Africa. The scientific name honours Captain ...

fruit.

Treatment

Acute fatty liver of pregnancy is best treated in a centre with expertise in

hepatology Hepatology is the branch of medicine that incorporates the study of liver, gallbladder, biliary tree, and pancreas as well as management of their disorders. Although traditionally considered a sub-specialty of gastroenterology, rapid expansi ...

, high-risk

obstetrics Obstetrics is the field of study concentrated on pregnancy, childbirth and the postpartum period. As a medical specialty, obstetrics is combined with gynecology under the discipline known as obstetrics and gynecology (OB/GYN), which is a sur ...

, maternal-fetal medicine and

neonatology Neonatology is a subspecialty of pediatrics that consists of the medical care of newborn infants, especially the ill or premature newborn. It is a hospital-based specialty, and is usually practised in neonatal intensive care units (NICUs). The ...

. The physicians who treat this condition will often consult with experts in liver transplantation in severe cases. Admission to the

intensive care unit 220px, Intensive care unit An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensi ...

is recommended. Initial treatment involves supportive management with

fluids, intravenous

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

and blood products, including

fresh frozen plasma Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the re ...

and

cryoprecipitate Cryoprecipitate, also called cryo for short, is a frozen blood product prepared from blood plasma. To create cryoprecipitate, fresh frozen plasma thawed to 1–6 °C is then centrifuged and the precipitate is collected. The precipitate is r ...

to correct DIC. The

should be monitored with

cardiotocography Cardiotocography (CTG) is a technique used to monitor the fetal heartbeat and the uterine contractions during pregnancy and labour. The machine used to perform the monitoring is called a cardiotocograph. Fetal heart sounds was described as earl ...

. After the

mother ] A mother is the female parent of a child. A woman may be considered a mother by virtue of having given birth, by raising a child who may or may not be her biological offspring, or by supplying her ovum for fertilisation in the case of ges ...

is stabilized, arrangements are usually made for delivery. This may occur vaginally, but, in cases of severe bleeding or compromise of the mother's status, a

caesarian section Caesarean section, also known as C-section or caesarean delivery, is the surgical procedure by which one or more babies are delivered through an incision in the mother's abdomen, often performed because vaginal delivery would put the baby or ...

may be needed. Often AFLP is not diagnosed until the mother and baby are in trouble, so it is most likely that an emergency C-section is needed. The complications of acute fatty liver of pregnancy may require treatment after delivery, especially if pancreatitis occurs. Liver transplantation is rarely required for treatment of the condition, but may be needed for mothers with severe DIC, those with rupture of the liver, or those with severe

encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...

Epidemiology

Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies. The mortality from acute fatty liver of pregnancy has been reduced significantly to 18%, and is now related primarily to complications, particularly DIC (Disseminated Intravascular Coagulation) and infections. After delivery, most mothers do well, as the stimulus for fatty acid overload is removed. The disease can recur in future pregnancies, with a calculated genetic chance of 25%; the actual rate is lower, however. Mortality of the foetus has also diminished significantly, but still remains 23%, and may be related to the need for premature delivery.

History

The disease was first described in 1940 by H. L. Sheehan as an "acute yellow atrophy" of the liver, then thought to be related to delayed chloroform poisoning.

References

External links

{{DEFAULTSORT:Acute Fatty Liver Of Pregnancy Diseases of liver Autosomal recessive disorders Maternal disorders predominantly related to pregnancy Fatty-acid metabolism disorders