GI Grand Rounds
Johanna Chan, PGY-5 Fellow
Baylor College of Medicine
2/13/2014
Mentor: Dr. Waqar Qureshi
With thanks to Dr. Rise Stribling and Dr. Norman Sussman
No conflicts of interest
No financial disclosures
HPI
• Reason for consult: abnormal liver function tests
• 26yo G2P1001 healthy woman at 32w0d
gestation with quadriamniotic quadruplets
• Conceived with clomifene
• Uncomplicated pregnancy, routine prenatal care
• Presented to obstetrics clinic at 32 wks GA with
bilateral leg swelling, malaise, nausea, and poor
oral intake x 4-5 days
• After labs, admitted directly from clinic to PFW
PMHx
– No known prior liver
disease
– Gestational DM2 (1st
pregnancy)
– Uncomplicated SVD
2009 at 40w2d
Medications: MVI
PSHx: Cerclage, 16 weeks
FamHx
– Mother: DM2
– Father: HTN
– No liver disease or
autoimmune disease
Allergies: NKDA
SocHx
– Never EtOH
– No prior IVDA, nasal
cocaine, blood transfusions,
tattoos
– Never smoker
– Stay-at-home mother
– No recent travel, antibiotics,
unusual food exposures
Physical Exam
T 98.6, BP 116/56, HR 112, RR 12, O2 sat 98% RA
Gen: NAD, AAOx4, fatigued-appearing, jaundiced
HEENT: +scleral icterus, PERRL, EOMI, MMM, OP clear
CV: RRR no m/r/g
Chest: CTAB no wheezes, slight crackles at bases
Abd: soft, nontender, NABS, +gravid uterus
Ext: WWP, no clubbing or cyanosis, +generalized
swelling of BLE without pitting
Neuro: oriented x4, fatigued, conversational
Labs on admission
128
104
5.4
14
21
2.61
63
13.3
7.84
38.5
79% PMNs
Total prot 5.8
Albumin 2.6
Total bili 6.3
Direct bili 5.1
Alk phos 394
GGT 49
ALT 351
AST 504
7.31/24/144
Lactate 5.1
138
MCV 96
INR 2.2
PTT 58.4
D-dimer >20
Fibrinogen 60
LDH 1575
Haptoglobin 63
Additional labs
Hepatitis A Ab (−)
Hepatitis B sAb (+)
Hepatitis B sAg (−)
Hepatitis C Ab (−)
HCV RNA (−)
U/A: dark yellow, cloudy, 1+
bilirubin, trace blood, 2+
protein, neg nitrite, neg leuk
Blood cultures (−)
Urine culture (−)
Imaging
• CXR normal
• RUQ U/S on admission
– Liver 13.7cm, normal in morphology and
echotexture, no focal mass
– Gallbladder contracted, 4mm wall
– CBD 6mm
– Portal vein diameter 14mm
– Ascites: none
Clinical course
• Immediate C-section
• No unusual degree of blood loss
• GI evaluation immediately post-op:
intubated/sedated on fentanyl but following
commands, no bleeding
Lab trend
HD #0
Immediate
post-op
8 hours
post-op
HD #1
HD #2
Total bili
8.2
6.1
5.8
5.4
5.9
Alk phos
394
255
188
196
163
ALT
370
220
150
92
74
AST
530
292
221
179
140
WBC
8.4
9.6
13.4
12.6
10.2
Platelets
138
113
118
156
134
INR
2.2
1.7
1.4
2.2
2.5
Creat
2.61
2.73
2.50
2.71
2.60
Clinical course
• Hospital day #1
– Extubated
– Fever 101.5
– “Lethargic, but arousable” after holding sedation x
7 hours, follows commands but seems confused
– No asterixis, but ammonia 76
• Hospital day #2:
– Obvious further decline in mentation, no longer
following commands, nonverbal
– Transferred to Houston area hospital
Acute fatty liver of pregnancy
(AFLP)
Clinical questions
• What are clinical and pathophysiologic
characteristics of AFLP?
• How can we distinguish clinically from HELLP?
• What are prognostic indicators and outcomes
of AFLP?
Causes of liver disease during pregnancy
Coincidental
liver diseases
•Viral hepatitis
•Herpes hepatitis
•Gallstones
•Budd-Chiari syndrome
•Drug-induced
Chronic liver
diseases
•Chronic hepatitis B or C
•Autoimmune hepatitis
•Wilson disease
•Cirrhosis of any cause
Liver diseases
unique to
pregnancy
•Cholestasis of
pregnancy (ICP)
•Hyperemesis
gravidarum
•Pre-eclampsia
•HELLP
syndrome
•Acute fatty liver
of pregnancy
(AFLP)
Courtesy of Dr. Waqar Qureshi
Clinical questions
• What are clinical and pathophysiologic
characteristics of AFLP?
• How can we distinguish clinically from HELLP?
• What are prognostic indicators and outcomes
of AFLP?
AFLP: Clinical presentation
• 1 in 7,000 to 1 in 16,000 pregnancies
(retrospective)
• UK-based prospective study (UKOSS), 229
centers: 57 confirmed cases in 1,132,964
pregnancies
• Third trimester
• 40-50% nulliparous
• Increased incidence in twin pregnancies or
multiple pregnancies
Hay, J. Hepatology. 2008; 47(3):1067-76.
Kaplan MM. N Engl J Med 1985; 313: 367-70.
Knight M et al. Gut 2008; 57:951-56.
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
AFLP: Clinical presentation
• 1934: Stander and Cadden, “acute yellow atrophy
of the liver”
• 1-2 weeks: anorexia, N/V, RUQ pain
• Ill-appearing: jaundice, edema, ascites, +/encephalopathy
• Liver dysfunction: hypofibrinogenemia,
hypoalbuminemia, coagulopathy
• Renal failure and hyperuricemia common
• 50% have pre-eclampsia, and symptoms/labs may
mimic HELLP
Stander H, Cadden B. Am J Obstet Gynecol 1934; 28:61-69.
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
AFLP: Swansea diagnostic criteria
(Six or more in the absence of other explanation)
• Vomiting
• Abdominal pain
• Polydipsia/polyuria
• Encephalopathy
• High bilirubin > 15 micromol/L
• Hypoglycemia < 4 mmol/L
• High uric acid > 340 micromol/L
• Leukocytosis > 11 x 106/L
• Ascites or bright liver on ultrasound
• High AST/ALT > 42 micromol/L
• High ammonia > 47 micromol/L
• Renal impairment with creatinine > 150 micromol/L
• Coagulopathy PT > 14 sec
• Microvesicular steatosis on liver biopsy Ch’ng CL et al. Gut 2002; 51(6): 876-80.
Goel A et al. Gut 2011; 60(1): 138-9.
AFLP: Clinical complications
• Early complications of AFLP
–
–
–
–
–
Acute renal failure
Acute pancreatitis
Hypoglycemia
Infection
Hepatic encephalopathy
• Late complications
– Cerebral edema, seizures
– Coagulopathy, GI hemorrhage
– Hepatic failure
AFLP: Pathophysiology
• Fetal long-chain 3-hydroxyacyl coenzyme A
dehydrogenase (LCHAD) deficiency
• LCFA accumulate in mother  incorporate in
TGs within hepatocytes
• Microvesicular fat deposition, zone 3
• Histologically and clinically similar to Reye’s
syndrome and Jamaican Vomiting Sickness
(both diseases of microvesicular fatty
infiltration)
Hay, J. Hepatology. 2008; 47(3):1067-76.
Joshi D et al. Lancet. 2010; 375(9714): 594-605.
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
Joshi D et al. Lancet. 2010; 375(9714): 594-605.
Clinical questions
• What are clinical and pathophysiologic
characteristics of AFLP?
• How can we distinguish clinically from HELLP?
• What are prognostic indicators and outcomes
of AFLP?
HELLP
•
•
•
•
First described in 1982 by Weinstein
1 in 1,000 to 6 in 1,000 pregnancies
Second or third trimester, postpartum possible
Risk factors: advanced maternal age,
multiparity, and white ethnicity
• “Pro-inflammatory and pro-coagulant” state:
alterations in platelet and cytokine activation,
segmental vasospasm, vascular endothelial
damage
Hepburn IS. Dig Dis Sci. 2008; 53:2334-2358.
Than NN and Neuberger J. Best Pract Res Clin Gastroenterol.
2013;27(4):565-75.
Weinstein L. Am J Obstet Gynecol 1983; 142: 159-67.
HELLP: Clinical presentation
• Hemolysis (microangiopathic hemolytic anemia),
Elevated Liver enzymes, and Low Platelets
• RUQ pain, N/V, malaise, and peripheral edema
• Hemolysis  unconjugated bilirubin and LDH
elevations
• Intravascular fibrin deposition, vasoconstriction
of hepatic vascular bed, and increased sinusoidal
pressure
 mild-moderate ALT/AST increase, mild bilirubin elevation
Hepburn IS. Dig Dis Sci. 2008; 53:2334-2358.
Than NN and Neuberger J. Best Pract Res Clin Gastroenterol. 2013; 27(4):565-75.
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
HELLP: Clinical presentation
• 5-15% of pre-eclampsia cases develop HELLP
• 70-80% of HELLP cases co-exist with preeclampsia
• Most frequent complication is DIC (30%)
• Other complications:
–
–
–
–
–
abruptio placentae (16%)
acute renal failure (7%)
eclampsia
pulmonary edema/ARDS, severe ascites
hepatic infarction, subcapsular hematoma or hepatic
Hay, J. Hepatology. 2008; 47(3):1067-76.
rupture
Hepburn IS. Dig Dis Sci. 2008; 53:2334-2358.
Joshi D et al. Lancet. 2010; 375(9714): 594-605.
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
Joshi D et al. Lancet. 2010; 375(9714): 594-605.
AFLP vs. HELLP
AFLP
HELLP
% of pregnancies
0.005% - 0.01%
0.2% - 0.6%
Onset/trimester
3 or postpartum
3 or postpartum
Family history
Occasionally
No
Presence of pre-eclampsia 50%
Yes
Clinical features
Liver failure
Hemolysis, thrombocytopenia
Aminotransferases
300-500 typical, +++
10-20 fold elevation
Bilirubin
<5 mg/dL, higher if severe
<5 mg/dL unless massive necrosis
Platelets
Low-normal
Low (<100,000/mm3)
INR
High
Normal
Fibrinogen
Low
Normal-increased
Glucose
Low
Normal
Renal failure
Yes
+/-
Histology
Microvesicular fat, zone 3
Patchy/extensive necrosis, hemorrhage
Hepatic imaging
+/- fatty infiltration
Hepatic infarcts, hematoma, rupture
Hay, J. Hepatology. 2008; 47(3):1067-76.
Hepburn IS. Dig Dis Sci. 2008; 53:2334-2358.
AFLP vs. HELLP
• In comparison with HELLP…
• AFLP patients more likely to have liver failure
– coagulopathy, hypoglycemia, encephalopathy, DIC,
and renal failure
• DIC present in >75% of AFLP cases and only
20-40% of HELLP cases
• AFLP patients less likely to have
thrombocytopenia
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
AFLP vs. HELLP
• DDx AFLP
– HELLP
– fulminant hepatic
failure 2/2 acute viral
hepatitis
– drug toxicity
• DDx HELLP
– AFLP
– acute viral hepatitis
– gastroenteritis
– appendicitis
– cholecystitis
– ITP
– SLE
– TTP/HUS
Clinical questions
• What are clinical and pathophysiologic
characteristics of AFLP?
• How can we distinguish clinically from HELLP?
• What are prognostic indicators and outcomes
of AFLP?
AFLP Prognosis and Management
• Hypoglycemia and PSE: poor prognostic sign
• Estimated maternal mortality of around 10-20%
and a perinatal mortality of 20-30%
• Prompt delivery of fetus and supportive care
• Limited case report/series data for
plasmapheresis
• Liver transplantation for ALF
• Spontaneous survivors have no long-term
sequelae; liver function normalizes 1-4 weeks
after delivery
Hay, J. Hepatology. 2008; 47(3):1067-76.
Jin F et al. Discovery Medicine. 2012(13): 369–373, 2012.
Steingrub JS. Crit Care Clin 2004; 20: 763-776.
Seyyed Majidi MR et al. Case Rep Obstet Gynecol. 2013; 615975.
Lee WM et al. Hepatology 2008; 47: 1401-15.
Survival ALF Study Group
Lee WM et al. Hepatology 2008; 47: 1401-15.
Clinical update
• Quadruplets were born healthy and are doing
well at TCH
• Babies should be screened for LCHAD
deficiency
• Mother at Hermann reportedly has severe
pancreatitis, persistent eclampsia with
seizures, liver function guarded but stable
• She is undergoing plasmapheresis
Take home points
• Early recognition of both HELLP and AFLP are
critical
• Management is prompt delivery of fetus (as
well as placenta for HELLP) and supportive
care
• Clinical distinction between HELLP and AFLP
may be subtle
– Close postpartum monitoring
– Maintain high level of suspicion for AFLP and liver
failure
References
•
•
•
•
•
•
•
•
•
•
•
Ch’ng CL et al. Prospective study of liver dysfunction in pregnancy in South Wales. Gut
2002; 51(6): 876-80).
Ch’ng CL et al. Acute fatty liver of pregnancy in South Wales. Gastroenterology 2002;
123(Supple 1): 53.
Goel A et al. How accurate are the Swansea criteria to diagnose acute fatty liver of
pregnancy in diagnosing microvesicular steatotis? Gut 2011; 60(1): 138-9.
Hay, J. Liver disease in pregnancy. Hepatology. 2008 Mar;47(3):1067-76.
Hepburn IS. Pregnancy-associated liver disorders. Dig Dis Sci. 2008 53:2334-2358.
Ibdah JA et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in
pregnant women. N Engl J Med 1999; 340: 1723-31.
Jin F et al. Therapeutic effects of plasma exchange for the treatment of 39 patients with
acute fatty liver of pregnancy. Discovery Medicine, vol. 13, no. 72, pp. 369–373, 2012.
Joshi D et al. Liver disease in pregnancy. Lancet. 2010 Feb 13; 375(9714): 594-605.
Kaplan MM. Acute fatty liver of pregnancy. N Engl J Med 1085; 313: 367-70.
Knight M et al. A prospective national study of acute fatty liver of pregnancy in the UK.
Gut 2008; 57:951-56.
Lee WM et al. Acute liver failure: summary of a workshop. Hepatology 2008; 47:
1401-15.
References (continued)
•
•
•
•
•
•
•
•
•
Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association
for the Study of Liver Diseases Position Paper on acute liver failure 2011.
Hepatology. 2012;55:965-967.
Seyyed Majidi MR et al. Plasmapheresis in acute fatty liver of pregnancy: an
effective treatment. Case Rep Obstet Gynecol. 2013; 615975.
Reyes H. Acute fatty liver of pregnancy. Clin Liver Dis 1999;3:69-81.
Reyes H et al. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11
patients. Gut 1994; 35:101-106.
Stander H, Cadden B. Acute yellow atrophy of the liver in pregnancy. Am J Obstet
Gynecol 1934; 28:61-69.
Steingrub JS. Pregnancy-associated severe liver dysfunction. Crit Care Clin 2004;
20: 763-776.
Than NN and Neuberger J. Liver abnormalities in pregnancy. Best Pract Res Clin
Gastroenterol. 2013 Aug;27(4):565-75.
Vigil de Gracia P. Acute fatty liver and HELLP syndrome: two distinct pregnancy
disorders. Int J Gynaecol Obstet. 2001 Jun;73(3):215-20.
Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet
count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol
1983; 142: 159-67.
Questions or comments?