Acute fatty liver of pregnancy

Last updated
Acute fatty liver of pregnancy
Specialty Obstetrics,
Perinatology,
Hepatology
Complications Death, Disseminated intravascular coagulation
Usual onsetThird trimester of pregnancy
Causes Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
Diagnostic method Clinical history and physical examination
Liver biopsy (rarely needed)
TreatmentPrompt delivery of the infant,
Intensive supportive care
Liver transplantation
Frequency1 in 7,000 to 1 in 15,000 pregnancies
Deaths18% [1]

Acute fatty liver of pregnancy is a rare life-threatening complication of pregnancy that occurs in the third trimester or the immediate period after delivery. [1] It is thought to be caused by a disordered metabolism of fatty acids by mitochondria in the fetus, caused by long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. [2] 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, [3] but aggressive treatment by stabilizing the mother with intravenous fluids and blood products in anticipation of early delivery has improved prognosis. [4]

Contents

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 period immediately after delivery. [1] On average, the disease presents during the 35th or 36th week of pregnancy. [5] The usual symptoms in the mother are non-specific including nausea, vomiting, anorexia (or lack of desire to eat) and abdominal pain; excessive thirst may be the earliest symptom without overlap with otherwise considered normal pregnancy symptoms; [5] however, jaundice and fever may occur in as many as 70% of patients. [1] [6]

In patients with more severe disease, pre-eclampsia may occur, which involves elevation of blood pressure and accumulation of fluid (termed oedema). [5] This may progress to involvement of additional systems, including acute kidney failure, [7] hepatic encephalopathy, [8] and pancreatitis. [9] There have also been reports of diabetes insipidus complicating this condition. [10]

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. [1] Bilirubin is almost universally elevated. Alkaline phosphatase is often elevated in pregnancy due to production from the placenta, but may be additionally elevated. [4] Other abnormalities may include an elevated white blood cell count, hypoglycemia, elevated coagulation parameters, including the international normalized ratio, and decreased fibrinogen. [1] [4] [5] Frank disseminated intravascular coagulation, or DIC, may occur in as many as 70% of people. [1]

Abdominal ultrasound may show fat deposition in the liver, but, as the hallmark of this condition is microvesicular steatosis (see pathology below), this is not seen on ultrasound. [11] Rarely, the condition can be complicated by rupture or necrosis of the liver, which may be identified by ultrasound.[ citation needed ]

Pathophysiology

Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy LCHAD deficiency.svg
Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of LCHAD deficiency, a hallmark of acute fatty liver of pregnancy

The understanding of the causes of acute fatty liver of pregnancy has been improved by advances in mitochondrial biochemistry. Deficiency of LCHAD (3-hydroxyacyl-CoA dehydrogenase) leads to an accumulation of medium and long chain fatty acids. When this occurs in the foetus, the unmetabolized fatty acids will re-enter the maternal circulation through the placenta, and overwhelm the beta-oxidation enzymes of the mother. [12] The gene responsible for LCHAD has been isolated, and the most common mutation found in acute fatty liver of pregnancy is the E474Q missense mutation. [13] LCHAD deficiency is autosomal recessive in inheritance and mothers are often found to be heterozygous for the affected mutation. [14]

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 liver may be difficult. [1] 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. [4]

A liver biopsy can provide a definitive diagnosis, [15] but is not always done, due to the increased chance of bleeding in acute fatty liver of pregnancy. [16] Often testing will be done to exclude more common conditions that present in a similar fashion, including viral hepatitis, [17] pre-eclampsia, [5] HELLP syndrome, [4] intrahepatic cholestasis of pregnancy, [1] and autoimmune hepatitis. [3]

Pathology

If a liver biopsy 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 shows a foamy appearance due to the prominence of fat. Necrosis is rarely seen. The diagnosis can be enhanced by electron microscopy which can be used to confirm the presence of microvesicular steatosis, and specifically the presence of megamitochondria and paracrystalline inclusions. [18] [19] Liver diseases with similar appearances include Reye's syndrome, drug-induced hepatitis from agents with mitochondrial toxicity, including nucleoside reverse transcriptase inhibitors used to treat HIV, [20] and a rare condition known as Jamaican vomiting sickness which is caused by the eating of the unripened Ackee fruit. [21]

Treatment

Acute fatty liver of pregnancy is best treated in a centre with expertise in hepatology, high-risk obstetrics, maternal-fetal medicine and neonatology. The physicians who treat this condition will often consult with experts in liver transplantation in severe cases. Admission to the intensive care unit is recommended. [1]

Initial treatment involves supportive management with intravenous fluids, intravenous glucose and blood products, including fresh frozen plasma and cryoprecipitate to correct DIC. The foetus should be monitored with cardiotocography. After the mother 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 may be needed. [1] 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.[ citation needed ]

The complications of acute fatty liver of pregnancy may require treatment after delivery, especially if pancreatitis occurs. [9] 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. [22]

Epidemiology

Acute fatty liver of pregnancy is a rare condition and occurs in approximately one in 7,000 to one in 15,000 pregnancies. [3] [19] 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. [1] [3] 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. [12] Mortality of the foetus has also diminished significantly, but still remains 23%, [23] and may be related to the need for premature delivery. [1]

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. [1] [24]

See also

Related Research Articles

<span class="mw-page-title-main">Hepatitis</span> Inflammation of the liver

Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

Liver function tests, also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), albumin, bilirubin, and others. The liver transaminases aspartate transaminase and alanine transaminase are useful biomarkers of liver injury in a patient with some degree of intact liver function. Most liver diseases cause only mild symptoms initially, but these diseases must be detected early. Hepatic (liver) involvement in some diseases can be of crucial importance. This testing is performed on a patient's blood sample. Some tests are associated with functionality, some with cellular integrity, and some with conditions linked to the biliary tract. Because some of these tests do not measure function, it is more accurate to call these liver chemistries or liver tests rather than liver function tests. Several biochemical tests are useful in the evaluation and management of patients with hepatic dysfunction. These tests can be used to detect the presence of liver disease. They can help distinguish among different types of liver disorders, gauge the extent of known liver damage, and monitor the response to treatment. Some or all of these measurements are also carried out on individuals taking certain medications, such as anticonvulsants, to ensure that these medications are not adversely impacting the person's liver.

<span class="mw-page-title-main">Disseminated intravascular coagulation</span> Medical condition

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 of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

<span class="mw-page-title-main">Eclampsia</span> Pre-eclampsia characterized by the presence of seizures

Eclampsia is the onset of seizures (convulsions) in a woman with pre-eclampsia. Pre-eclampsia is a hypertensive disorder of pregnancy that presents with three main features: new onset of high blood pressure, large amounts of protein in the urine or other organ dysfunction, and edema. If left untreated, pre-eclampsia can result in long-term consequences for the mother, namely increased risk of cardiovascular diseases and associated complications. In more severe cases, it may be fatal for both the mother and the fetus. The diagnostic criteria for pre-eclampsia is high blood pressure occurring after 20 weeks gestation or during the second half of pregnancy. Most often it occurs during the 3rd trimester of pregnancy and may occur before, during, or after delivery. The seizures are of the tonic–clonic type and typically last about a minute. Following the seizure, there is either a period of confusion or coma. Other complications include aspiration pneumonia, cerebral hemorrhage, kidney failure, pulmonary edema, HELLP syndrome, coagulopathy, placental abruption and cardiac arrest.

<span class="mw-page-title-main">Alcoholic liver disease</span> Medical condition

Alcoholic liver disease (ALD), also called alcohol-related liver disease (ARLD), is a term that encompasses the liver manifestations of alcohol overconsumption, including fatty liver, alcoholic hepatitis, and chronic hepatitis with liver fibrosis or cirrhosis.

<span class="mw-page-title-main">Pre-eclampsia</span> Hypertension occurring during pregnancy

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 there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances. Pre-eclampsia increases the risk of undesirable outcomes for both the mother and the fetus. If left untreated, it may result in seizures at which point it is known as eclampsia.

<span class="mw-page-title-main">Steatosis</span> Medical condition

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 disease. Steatosis can also occur in other organs, including the kidneys, heart, and muscle. When the term is not further specified, it is assumed to refer to the liver.

<span class="mw-page-title-main">Budd–Chiari syndrome</span> Medical condition

Budd–Chiari syndrome is a very rare condition, affecting one in a million adults. The condition is caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites, and liver enlargement. The formation of a blood clot within the hepatic veins can lead to Budd–Chiari syndrome. The syndrome can be fulminant, acute, chronic, or asymptomatic. Subacute presentation is the most common form.

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 feeling tired, retaining fluid, headache, nausea, upper right abdominal pain, blurry vision, nosebleeds, and seizures. Complications may include disseminated intravascular coagulation, placental abruption, and kidney failure.

<span class="mw-page-title-main">Fatty liver disease</span> Medical condition related to obesity

Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complications may include cirrhosis, liver cancer, and esophageal varices.

<span class="mw-page-title-main">Acute liver failure</span> Medical condition

Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease, and indicates that the liver has sustained severe damage. The complications are hepatic encephalopathy and impaired protein synthesis. The 1993 classification defines hyperacute as within 1 week, acute as 8–28 days, and subacute as 4–12 weeks; both the speed with which the disease develops and the underlying cause strongly affect outcomes.

<span class="mw-page-title-main">Placental abruption</span> Medical condition

Placental abruption is when the placenta separates early from the uterus, in other words separates before childbirth. It occurs most commonly around 25 weeks of pregnancy. Symptoms may include vaginal bleeding, lower abdominal pain, and dangerously low blood pressure. Complications for the mother can include disseminated intravascular coagulopathy and kidney failure. Complications for the baby can include fetal distress, low birthweight, preterm delivery, and stillbirth.

<span class="mw-page-title-main">Complications of pregnancy</span> Medical condition

Complications of pregnancy are health problems that are related to pregnancy. Complications that occur primarily during childbirth are termed obstetric labor complications, and problems that occur primarily after childbirth are termed puerperal disorders. Severe complications of pregnancy, childbirth, and the puerperium are present in 1.6% of mothers in the US, and in 1.5% of mothers in Canada. In the immediate postpartum period (puerperium), 87% to 94% of women report at least one health problem. Long-term health problems are reported by 31% of women.

<span class="mw-page-title-main">Non-alcoholic fatty liver disease</span> Excessive fat buildup in the liver not caused by alcohol use

Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), with the latter also including liver inflammation. Non-alcoholic fatty liver is less dangerous than NASH and usually does not progress to NASH. When NAFL does progress to NASH, it may eventually lead to complications such as cirrhosis, liver cancer, liver failure, or cardiovascular disease.

<span class="mw-page-title-main">Intrahepatic cholestasis of pregnancy</span> Medical condition

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 with itching and can lead to complications for both mother and baby.

<span class="mw-page-title-main">Amniotic fluid embolism</span> Potentially fatal complication of pregnancy

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Hypertensive disease of pregnancy, also known as maternal hypertensive disorder, is a group of high blood pressure disorders that include preeclampsia, preeclampsia superimposed on chronic hypertension, gestational hypertension, and chronic hypertension.

Rh factor testing, also known as Rhesus factor testing, is the procedure of determining the rhesus D status of an individual.

<span class="mw-page-title-main">Liver angiosarcoma</span> Medical condition

Liver angiosarcoma also known as angiosarcoma of the liver or hepatic angiosarcoma is a rare and rapidly fatal cancer arising from endothelial that line the blood vessels of the liver. It is a type of angiosarcoma. Although very rare with around 200 cases diagnosed each year, it is still considered the third most common primary liver cancer, making up around 2% of all primary liver cancers. Liver angiosarcoma can be primary, meaning it arose in the liver, or secondary, meaning the angiosarcoma arose elsewhere and metastasized to the liver. This article covers PHA, however much is also applicable to secondary tumors.

Hyperbilirubinemia is a clinical condition describing an elevation of blood bilirubin level due to the inability to properly metabolise or excrete bilirubin, a product of erythrocytes breakdown. In severe cases, it is manifested as jaundice, the yellowing of tissues like skin and the sclera when excess bilirubin deposits in them. The US records 52,500 jaundice patients annually. By definition, bilirubin concentration of greater than 3 mg/ml is considered hyperbilirubinemia, following which jaundice progressively develops and becomes apparent when plasma levels reach 20 mg/ml. Rather than a disease itself, hyperbilirubinemia is indicative of multifactorial underlying disorders that trace back to deviations from regular bilirubin metabolism. Diagnosis of hyperbilirubinemia depends on physical examination, urinalysis, serum tests, medical history and imaging to identify the cause. Genetic diseases, alcohol, pregnancy and hepatitis viruses affect the likelihood of hyperbilirubinemia. Causes of hyperbilirubinemia mainly arise from the liver. These include haemolytic anaemias, enzymatic disorders, liver damage and gallstones. Hyperbilirubinemia itself is often benign. Only in extreme cases does kernicterus, a type of brain injury, occur. Therapy for adult hyperbilirubinemia targets the underlying diseases but patients with jaundice often have poor outcomes.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Ko H, Yoshida EM (2006). "Acute fatty liver of pregnancy". Canadian Journal of Gastroenterology. 20 (1): 25–30. doi: 10.1155/2006/638131 . PMC   2538964 . PMID   16432556.
  2. Bellig LL (2004). "Maternal acute fatty liver of pregnancy and the associated risk for long-chain 3-hydroxyacyl-coenzyme a dehydrogenase (LCHAD) deficiency in infants". Advances in Neonatal Care. 4 (1): 26–32. doi:10.1016/j.adnc.2003.12.001. PMID   14988877. S2CID   29356240.
  3. 1 2 3 4 Mjahed K, Charra B, Hamoudi D, Noun M, Barrou L (2006). "Acute fatty liver of pregnancy". Archives of Gynecology and Obstetrics. 274 (6): 349–353. doi:10.1007/s00404-006-0203-6. PMID   16868757. S2CID   24784165.
  4. 1 2 3 4 5 Riely CA (1999). "Liver disease in the pregnant patient. American College of Gastroenterology". The American Journal of Gastroenterology. 94 (7): 1728–1732. doi: 10.1111/j.1572-0241.1999.01199.x . PMID   10406228. S2CID   36694459.
  5. 1 2 3 4 5 Riely CA (1987). "Acute fatty liver of pregnancy". Seminars in Liver Disease. 7 (1): 47–54. doi:10.1055/s-2008-1040563. PMID   3296215.
  6. Riely CA, Latham PS, Romero R, Duffy TP (1987). "Acute fatty liver of pregnancy. A reassessment based on observations in nine patients". Annals of Internal Medicine. 106 (5): 703–6. doi:10.7326/0003-4819-106-5-703. PMID   3565968.
  7. Koroshi A, Babameto A (2002). "Acute renal failure during acute fatty liver of pregnancy". Nephrology Dialysis Transplantation. 17 (6): 1110–1112. doi: 10.1093/ndt/17.6.1110 . PMID   12032205.
  8. Aggarwal R (2003). "Hepatic encephalopathy in pregnancy". Indian Journal of Gastroenterology. 22 Suppl 2: S78–80. PMID   15025263.
  9. 1 2 Moldenhauer JS, O'brien JM, Barton JR, Sibai B (2004). "Acute fatty liver of pregnancy associated with pancreatitis: a life-threatening complication". American Journal of Obstetrics and Gynecology. 190 (2): 502–505. doi:10.1016/j.ajog.2003.09.022. PMID   14981397.
  10. Kennedy S, Hall PM, Seymour AE, Hague WM (1994). "Transient diabetes insipidus and acute fatty liver of pregnancy". BJOG: An International Journal of Obstetrics and Gynaecology. 101 (5): 387–91. doi:10.1111/j.1471-0528.1994.tb11909.x. PMID   8018608. S2CID   11869406.
  11. Castro MA, Ouzounian JG, Colletti PM, Shaw KJ, Stein SM, Goodwin TM (1996). "Radiologic studies in acute fatty liver of pregnancy. A review of the literature and 19 new cases". The Journal of Reproductive Medicine. 41 (11): 839–43. PMID   8951135.
  12. 1 2 Tein I (2000). "Metabolic disease in the foetus predisposes to maternal hepatic complications of pregnancy". Pediatric Research. 47 (1): 6–8. doi: 10.1203/00006450-200001000-00005 . PMID   10625076.
  13. IJlst L, Oostheim W, Ruiter JP, Wanders RJ (1997). "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations" (PDF). Journal of Inherited Metabolic Disease. 20 (3): 420–422. doi:10.1023/A:1005310903004. PMID   9266371. S2CID   23046057.[ permanent dead link ]
  14. Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L (1999). "Disorders of mitochondrial fatty acyl-CoA beta-oxidation" (PDF). Journal of Inherited Metabolic Disease. 22 (4): 442–487. doi:10.1023/A:1005504223140. PMID   10407780. S2CID   35795159.[ permanent dead link ]
  15. Brunt EM (2000). "Liver biopsy interpretation for the gastroenterologist". Current Gastroenterology Reports. 2 (1): 27–32. doi:10.1007/s11894-000-0048-2. PMID   10981000. S2CID   39207958.
  16. Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG, McGehee WG (1996). "Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy". American Journal of Obstetrics and Gynecology. 174 (1 Pt 1): 211–216. doi:10.1016/S0002-9378(96)70396-4. PMID   8572009.
  17. Pang WW, Lei CH, Chang DP, Yang TF, Chung YT, Huang MH (1999). "Acute jaundice in pregnancy: acute fatty liver or acute viral hepatitis?". Acta Anaesthesiologica Sinica. 37 (3): 167–70. PMID   10609353.
  18. Bacq Y (1998). "Acute fatty liver of pregnancy". Seminars in Perinatology. 22 (2): 134–140. doi:10.1016/S0146-0005(98)80045-1. PMID   9638907.
  19. 1 2 Reyes H, Sandoval L, Wainstein A, et al. (1994). "Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients". Gut. 35 (1): 101–106. doi:10.1136/gut.35.1.101. PMC   1374642 . PMID   8307428.
  20. Montessori V, Harris M, Montaner JS (2003). "Hepatotoxicity of nucleoside reverse transcriptase inhibitors". Seminars in Liver Disease. 23 (2): 167–172. doi:10.1055/s-2003-39947. PMID   12800069.
  21. Hautekeete ML, Degott C, Benhamou JP (1990). "Microvesicular steatosis of the liver". Acta Clinica Belgica. 45 (5): 311–26. doi:10.1080/17843286.1990.11718105. PMID   2177300.
  22. Pereira SP, O'Donohue J, Wendon J, Williams R (1997). "Maternal and perinatal outcome in severe pregnancy-related liver disease". Hepatology. 26 (5): 1258–1262. doi: 10.1002/hep.510260525 . PMID   9362370.
  23. Fesenmeier MF, Coppage KH, Lambers DS, Barton JR, Sibai BM (2005). "Acute fatty liver of pregnancy in 3 tertiary care centers". American Journal of Obstetrics and Gynecology. 192 (5): 1416–1419. doi:10.1016/j.ajog.2004.12.035. PMID   15902124.
  24. Sheehan HL (1940). "The pathology of acute yellow atrophy and delayed chloroform poisoning". Journal of Obstetrics and Gynaecology of the British Empire. 47: 49–62. doi:10.1111/j.1471-0528.1940.tb14731.x. S2CID   72493420.