basically about liver diseases unique to pregnancy

1. LIVER DISEASE IN PREGNANCY
Dr. Arshad Abbasi MRCP UK ESEGH (European Board ) FCPS (Med) FRCP (Edin)
Associate Professor of Medicine AJKMC Muzaffarabad

3. Introduction
Nearly 3 percent of pregnancies are complicated with
liver disorders and sever pregnancy related liver
disease
Med Sci Monit; 2018: 24 4080-4090

4. Normal Physiological Changes

10. INTRAHEPATIC CHOLESTASIS OF PREGNANCY

11. EPIDEMIOLOGY
• ICP is significantly more frequent in South Asian (0.8%-1.46%) and South
American populations (e.g., Chile and Bolivia) (9.2%-15.6%).
Tan LK. Obstetric cholestasis: current opinions and management. Ann Acad Med Singapore 2003; 32: 294-298.

12. • The etiology of ICP is multifactorial, and involves genetic, hormonal, and
environmental factors
Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol 2014; 124: 120-133
Soroka CJ, Boyer JL. Biosynthesis and trafficking of the bile saltexport pump, BSEP: therapeutic implications of BSEP mutations.Mol Aspects Med
2014; 37: 3-14
Invernizzi P. Intrahepatic cholestasis of pregnancy: a furtherimportant step in dissecting its genetic architecture. Dig Liver Dis 2013; 45: 266-267
PATHOPHYSIOLOGY

13. • Higher incidence of ICP in winter.
Diken Z, Usta IM, Nassar AH. A clinical approach to intrahepatic cholestasis of pregnancy. Am J Perinatol 2014
• Seasonal variations of the disease have been attributed to dietary factors
related with high maternal levels of copper and low levels of selenium and
zinc.
Reyes H, Sjövall J. Bile acids and progesterone metabolites in intrahepatic cholestasis of pregnancy. Ann Med 2000; 32: 94-106

14. INTRAHEPATIC CHOLESTASIS OF PREGNANCY

15. LABORATORY FINDINGS
• Exclusion of other clinical entities
• Elevated total bile acid levels of up to 10- to 25-fold, which may be the first, or
indeed only, laboratory abnormality observed.
• A significant rise in cholic acid and a decline in chenodeoxycholic acid levels
• A reduced glycine/taurine ratio may also be present
• ALT and AST levels rarely exceed two times the upper limits of normal
Bacq Y. Liver diseases unique to pregnancy: a 2010 update. Clin Res Hepatol Gastroenterol 2011; 35: 182-193

16. MATERNAL OUTCOME
• Maternal outcome is usually benign
• Proper attention should be provided for fatigue, anxiety, and malabsorption of
fat and fat-soluble vitamins
• Persistent cholestasis may result in vitamin K deficiency, leading to
intrapartum and postpartum hemorrhage
Boregowda G, Shehata HA. Gastrointestinal and liver disease in pregnancy. Best Pract Res Clin Obstet Gynaecol 2013; 27: 835-853

17. FETAL OUTCOME
• ICP poses a significant risk for the fetus in terms of perinatal morbidity-
mortality, preterm delivery, fetal distress, and meconium staining
Wikström Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal
outcomes: a 12-year population-based cohort study. BJOG 2013; 120: 717-723

18. FETAL OUTCOME
• Serum Bile Acid measurements exceeding 40micromole /L are associated with
increased risk of fetal outcome including prematurity, neonatal distress and
elevated stillbirth rate.
• Adverse outcome are rarely reported if level is below 40 micromole/L
• Glantz et al.Intera hepatic cholestasis of pregnancy –Relationship between serum bile acid level and fetal complication
.Hepatology2004 40(2) 467-474

19. TREATMENT

20. • The general agreement suggests that delivery should not be delayed after 37-
38 wk of gestation in patients with ICP
Puljic A, Kim E, Page J, Esakoff T, Shaffer B, LaCoursiere DY, Caughey AB. The risk of infant and fetal death by each additional week of expectant
management in intrahepatic cholestasis of pregnancy by gestational age. Am J Obstet Gynecol 2015; 212: 667.
Arthur C, Mahomed K. Intrahepatic cholestasis of pregnancy: diagnosis and management; a survey of Royal Australian and New Zealand College of
Obstetrics and Gynaecology fellows. Aust NZ J Obstet Gynaecol 2014; 54: 263-267

21. C.ACUTE FATTY LIVER OF PREGNANCY
• Fatty infiltration were first described>150 years ago.
Tarnier. Note sur l’etat graisseux du foie dans la fievre puerperale. C R Soc Biol (Paris) 1857;3: 209-14
• Earlier recognition of AFLP has the best maternal and fetal
outcomes.
Nelson DB, Yost NP, Cunningham FG. Acute fatty liver of pregnancy: clinical outcomes and expected duration of recovery. Am J
Obstet Gynecol2013;209

23. C.Etiology
• AFLP is regarded as mitochondrial cytopathy.
• Inherited fetal defects of mitochondrial beta oxidation.
• Approximately 20 %neonates born to mother with AFLP have defect in long-
chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) due to mutation in 1 or
both alelle
• Ibda JA et al A fetal faty acids oxidation disorder as a cause of liver disease in pregnant women N Engl J
Med 1999 340(22)

24. C.ACUTE FATTY LIVER OF PREGNANCY

26. • About 50% of patients with AFLP have preeclampsia, and there is some
overlap with the HELLP syndrome.
J. Eileen Hay. Liver Disease in Pregnancy. Hepatology. 2008 Mar;47(3):1067-76

27. NelsonDB,YostNP
,CunninghamFG.Acutefattyliverofpregnancy:clinicaloutcomesandexpectdurationofrecovery.AmJObstetGynecol2013;209:456.

29. LIVER BIOPSY
• Usually unnecessary but shows pathognomic findings of AFLP i.e microvesicular fatty
infiltration of the liver that is most prominent in hepatocytes surrounding central veins (zone

30. MANAGEMENT
• Maternal stabilization and prompt delivery of the fetus, regardless of
gestational age
• Maternal stabilization requires glucose infusion and reversal of coagulopathy
(eg, administration of fresh frozen plasma, cryoprecipitate, packed red blood
cells and platelets)
• Attention should be paid to the woman's overall fluid status because the low
plasmatic oncotic pressure can lead to pulmonary edema

31. • Combining a serum lactate of greater than 2.8mg/dL with
the presence of any grade of encephalopathy, indicate poor
prognosis in both AFLP and HELLP syndrome and should
be a trigger to consider liver transplantation.
• Westbrook RH,Yeoman AD Joshi D et al. Outcomes of sever pregnancy related Liver Diseases refining the role of transplantation AM J
transplant 2010 10(11)

32. Recovery and Recurrence
• Patients recover and have no sequelae of the liver disease itself
Nelson DB, Yost NP, Cunningham FG. Acute fatty liver of pregnancy: clinical outcomes and expected duration of recovery. Am J Obstet Gynecol 2013;
209:45
• Acute fatty liver of pregnancy can recur in subsequent pregnancies, , the exact risk of
recurrence is unknown
Barton JR, Sibai BM, Mabie WC, Shanklin DR. Recurrent acute fatty liver of pregnancy. Am J Obstet Gynecol 1990; 163:534.
Visconti M, Manes G, Giannattasio F, Uomo G. Recurrence of acute fatty liver of pregnancy. J Clin Gastroenterol 1995; 21:243.

33. HELLP Syndrome
• HELLP is a severe variant of preeclampsia and complicates
around 20% of preeclampsia cases.
Baxter JK, Weinstein L. HELLP syndrome: the state of the art. Obstet Gynecol Surv 2004;59:838-45
• As many as 15 to 20 percent of patients with HELLP syndrome do not have
antecedent hypertension or proteinuria
Reubinoff BE, Schenker JG. HELLP syndrome--a syndrome of hemolysis, elevated liver enzymes and low platelet count--
complicating preeclampsia-eclampsia. Int J Gynaecol Obstet 1991; 36:95
• The HELLP syndrome is characterized by hemolytic anemia,
increased liver enzymes, and low platelets.

34. RISK FACTORS
• A previous history of preeclampsia or HELLP, advance maternal age,
Multiparity, HTN DM and Obesity
• Sisters and offspring of women with a history of HELLP syndrome are also at
increased risk of developing the syndrome
Lachmeijer AM, Arngrímsson R, Bastiaans EJ, et al. A genome-wide scan for preeclampsia in the Netherlands. Eur J Hum Genet 2001; 9:758.

35. Etiology
Abnormal placentation, defective arterial perfusion and release of NO PGs
and endothelin
Inaproperiate activation of coagulation cascade
• Microangiopathic hemolytic anemia
• Vascular endothelial injury
• Fibrin deposition in blood vessels, and platelet activation with platelet
consumption, resulting in small to diffuse areas of hemorrhage and necrosis
dissecting from zone 1 to involve the whole lobule, leading to large
hematomas, capsular tears, and intraperitoneal bleeding.
Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol
2004;103:981-991.

36. Clinical Features
• Upper abdominal pain and tenderness, nausea and vomiting, malaise,
headache, edema and weight gain, hypertension, and proteinuria;
• jaundice is uncommon (5%); some patients have no obvious preeclampsia
J. Eileen Hay. Liver Disease in Pregnancy. Hepatology. 2008 Mar;47(3):1067-76
• Mistaking abdominal pain, nausea, vomiting, and malaise for viral illness is a common pitfall
that has resulted in maternal death or severe morbidity
Isler CM, Rinehart BK, Terrone DA, et al. Maternal mortality associated with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am
J Obstet Gynecol 1999; 181:924.
Catanzarite VA, Steinberg SM, Mosley CA, et al. Severe preeclampsia with fulminant and extreme elevation of aspartate aminotransferase and lactate
dehydrogenase levels: high risk for maternal death. Am J Perinatol 1995; 12:310

38. • Liver imaging with computed tomography scan (limited views) or magnetic
resonance imaging should be done to identify hepatic complications of
infarction, liver parenchymal hemorrhage, or subcapsular hematoma, because
ultrasound is not a reliable tool for identifying these complications
S. Shekhar, G. Diddi .Taiwanese Journal of Obstetrics & Gynecology 54 (2015) 475-482

39. Management
• The patient with HELLP must be hospitalized for antepartum stabilization of
hypertension and DIC, for seizure prophylaxis, and fetal monitoring.
Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome. Clin Pernatol 2004;31:807-833.
• Delivery is the only definitive therapy, and for patients with severe HELLP there is progressive
and often sudden maternal deterioration
Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol
2004;103:981-991

40. • At greater than 34 weeks’ gestation if there is any evidence of
multiorgan dysfunction, DIC, renal failure, abruptio placentae, or
fetal distress, there is consensus that immediate delivery should
be effected.
• <34 weeks of gestation — When both the maternal and fetal
status are reassuring, administer a course of corticosteroids
before delivering pregnancies complicated by HELLP syndrome
at less than 34 weeks of gestation
American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy.
Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol
2013; 122:1122
• A short delay in delivery for corticosteroid administration
appears to be safe
Fitzpatrick KE, Hinshaw K, Kurinczuk JJ, Knight M. Risk factors, management, and outcomes of hemolysis, elevated liver enzymes,
and low platelets syndrome and elevated liver enzymes, low platelets syndrome. Obstet Gynecol 2014; 123:618.

41. • Management of HELLP syndrome remote from term with fetal
lung immaturity and stable maternal condition is controversial
Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome. Clin Perinatol 2004;3. 807-33
Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis,elevated liver enzymes, and low platelet count. Obstet
Gynecol2004;103:981-91.

42. • Most cases with longer conservative therapy will deteriorate in 1 to 10 days
after diagnosis, with a high risk of fetal loss
J. Eileen Hay. Liver Disease in Pregnancy. Hepatology. 2008 Mar;47(3):1067-76
• In about 25% of cases, HELLP will develop in the postpartum period, and therapy is the same
as antepartum.

43. • Hepatic hemorrhage without rupture is managed conservatively in a
hemodynamically stable patient
Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Am J Obstet Gynecol 1996;
174:1820.

44. • Percutaneous embolization of the hepatic arteries is a reasonable first-line
therapy of hepatic rupture in women who are hemodynamically stable
Grand'Maison S, Sauvé N, Weber F, et al. Hepatic rupture in hemolysis, elevated liver enzymes, low platelets syndrome. Obstet Gynecol 2012; 119:617.
• Surgical intervention is indicated if there is hemodynamic instability, persistent bleeding,
increasing pain, or continued expansion of the hematoma
Wilson RH, Marshall BM. Postpartum rupture of a subcapsular hematoma of the liver. Acta Obstet Gynecol Scand 1992; 71:394.

45. • Maternal mortality from hepatic rupture remains very high at 50%, and
perinatal mortality rates are 10%-60%
• Indications to proceed with liver transplantation are very limited—persisting
bleeding from a hematoma or hepatic rupture or liver failure from extensive
necrosis.
Shames BD, Fernandez LA, Sollinger HW, Chin LT, D’Alessandro AM, Knechtle SJ, et al. Livetransplantation for HELLP syndrome. LiverTranspl
2005;11:224-228

46. Recurrence of HELLP
• Subsequent pregnancies in patients with HELLP syndrome carry a high risk of
complications— pre-eclampsia, recurrent HELLP, prematurity, Intrauterine
growth retardation, abruptio placentae, and perinatal mortality.
Baxter JK, Weinstein L. HEELP syndrome: the state of the art. ObstetGynecol Surg 2004;59:838-845.
van Oostwaard MF, Langenveld J, Schuit E, et al. Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis. Am J Obstet
Gynecol 2015; 212:624.