GI Grand Rounds

Johanna Chan, PGY-5 FellowBaylor College of Medicine2/13/2014

Mentor: Dr. Waqar QureshiWith thanks to Dr. Rise Stribling and Dr. Norman Sussman

No conflicts of interestNo 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: NKDASocHx– 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% RAGen: NAD, AAOx4, fatigued-appearing, jaundicedHEENT: +scleral icterus, PERRL, EOMI, MMM, OP clearCV: RRR no m/r/gChest: CTAB no wheezes, slight crackles at basesAbd: soft, nontender, NABS, +gravid uterusExt: WWP, no clubbing or cyanosis, +generalized swelling of BLE without pittingNeuro: oriented x4, fatigued, conversational

Labs on admission

MCV 9679% PMNs

128

5.4 14

104 21

2.6163 7.84

38.5

13.3138

INR 2.2PTT 58.4D-dimer >20Fibrinogen 60LDH 1575Haptoglobin 63

Total prot 5.8Albumin 2.6Total bili 6.3Direct bili 5.1Alk phos 394GGT 49ALT 351AST 504

7.31/24/144Lactate 5.1

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 trendHD #0 Immediate

post-op8 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 pregnancyCauses of liver disease during pregnancy

Liver diseasesunique to pregnancy•Cholestasis of pregnancy (ICP)•Hyperemesis gravidarum•Pre-eclampsia•HELLP syndrome•Acute fatty liver of pregnancy (AFLP)

Liver diseasesunique to pregnancy•Cholestasis of pregnancy (ICP)•Hyperemesis gravidarum•Pre-eclampsia•HELLP syndrome•Acute fatty liver of pregnancy (AFLP)

Coincidentalliver diseases•Viral hepatitis•Herpes hepatitis•Gallstones•Budd-Chiari syndrome•Drug-induced

Coincidentalliver diseases•Viral hepatitis•Herpes hepatitis•Gallstones•Budd-Chiari syndrome•Drug-induced

Chronic liverdiseases•Chronic hepatitis B or C•Autoimmune hepatitis•Wilson disease•Cirrhosis of any cause

Chronic liverdiseases•Chronic hepatitis B or C•Autoimmune hepatitis•Wilson disease•Cirrhosis of any cause

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 HELLPStander 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 pre-eclampsia• 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

ruptureHay, J. Hepatology. 2008; 47(3):1067-76. 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.

Vigil de Gracia P. Int J Gynaecol Obstet. 2001 Jun;73(3):215-20.

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?