Budd-Chiari syndrome diagnosed with pregnancy in a patient with inherited thrombophilia

Abstract

An 18-year-old primigravida was referred to our high risk pregnancy (HRP) department at 34 weeks of gestation for birth panning as she has Budd-Chiari syndrome (BCS). Her history was significant for familial thrombophilia. She had portal hypertension manifestations. Her work-up revealed factor V Leiden gene mutation, hepatic and portal vein thrombosis. A multidisciplinary team of physicians from the gastroenterology and hepatology, haematology and HRP departments puts a management plan; it culminated into safe delivery of the patient at 36 weeks of gestation. The patient was referred to a specialised BCS centre where she had successful liver transplantation done.

Background

Pregnancy is a hypercoagulable state that is known to unmask inherited thrombophilia tendency, exacerbate procoagulant factors and provoke various thromboembolic diseases like deep venous thrombosis and primary Budd-Chiari syndrome (BCS).¹ BCS is defined as posthepatic venous outflow obstruction that is not due to cardiac disease or sinusoidal obstruction syndrome of the liver. Primary BCS is most commonly due to thrombosis (figure 1), while secondary BCS is due to invasion or compression of hepatic venous outflow by a mass from outside (eg, malignancy). BCS can have an acute onset with gastrointestinal bleeding, ascites and jaundice; or chronic onset with very mild or no symptoms until liver cirrhosis occurs.² Twenty percent of cases of BCS are women who are pregnant, postpartum or on oral contraceptive pills (OCPs).³

Figure 1.

Pathophysiology of primary Budd-Chiari syndrome: hepatic vein thrombosis results in backpressure with centrilobular necrosis in hepatocytes and liver cirrhosis. It also leads to portal hypertension with consequent ascites, splenomegaly and porto-systemic shunts manifestations: oesophageal varices, caput medusa and rectal haemorrhoids.

Case presentation

An 18-year-old primigravida was referred to the high risk pregnancy (HRP) outpatient clinic (OPC) of our tertiary care obstetric centre for delivery planning. She was pregnant at 34 weeks of gestational age (GA) and she was diagnosed with primary BCS by the gastroenterology and hepatology (GE&H) department.

The patient history was remarkable for familial thrombophilia as she reported unprovoked deep venous thrombosis events in her sister and stepparent; she also gave a history of arterial thrombotic events in her father and uncle. In addition, she reported exposure to a secondhand smoke in the household since her childhood. The patient medications consisted of 60 IU two times per day of low-molecular weight heparin (LMWH) enoxaparin sodium (Clexane, Sanofi, Paris, France), 40 mg two times per day of pantoprazole (Controloc, Takeda, Tokyo, Japan), antenatal vitamins and silibinin (Silymarin, Sedico, Cairo, Egypt) (a medication used in treatment of liver cirrhosis) per day.⁴ The patient history was unremarkable for major surgeries or any other medical illnesses; she reported no allergy to any known drug or substance.

Our patient examination was only notable for abdominal distention due to ascites. Obstetric examination was normal with fundal level corresponding to GA as well as positive fetal heart sounds.

Investigations

Our patient disease first manifestation was 7 months back, when she was pregnant at 6 weeks of GA. She presented to the emergency medicine department with a sudden severe attack of haematemesis that led to haemoglobin (HB) drop to 72 g/L with vital instability. She was resuscitated and given two units of packed red blood cells (RBCs) that corrected HB to 95 g/L.^{5 6} She then had an upper gastrointestinal (GI) endoscopy that visualised grade III oesophageal varices (OVs), which were ligated with bleeding control.

After this attack, the patient had an abdominal ultrasound (US) that detected cirrhotic changes in the liver and ascites. She also had coloured duplex US study of hepatic vasculature that detected proximal hepatic venous thrombosis (figure 2). So she was diagnosed with primary BCS.

Figure 2.

Coloured duplex study of hepatic vasculature showing proximal hepatic veins (HV) thrombosis as evidenced by arrest of blood flow in HVs with discontinuity between HV and inferior vena cava (IVC). Blood flow is seen in collateral as a bypass to the obstruction in HV.

The patient had thrombophilia screening that was significant for low serum levels of antithrombin (AT) III, protein S and protein C; It also detected heterozygous mutant genotype of factor V Leiden (FVL) (G1691A:R506Q) and Methylenetetrahydrofolate reductase (MTHFR) (C677T). Autoimmune markers were only remarkable for weak positive antismooth muscle (ASM) antibodies (Abs). Other laboratory test results were only notable for anaemia and thrombocytopenia (table 1).

Table 1.

Patient labs during after the haematemesis attack during pregnancy, abnormal results are underlined

Laboratory test (unit)		Result	Reference value
LFTs and RFTs	ALT (IU/L)	21	(10–45)
	AST (IU/L)	37	<35
	Direct bilirubin (mg/dL)	0.2	<0.2
	Total bilirubin (mg/dL)	1	(0.3–1.2)
	Albumin (g/dL)	2.4	(2.5–5.2)
	Urea (mg/dL)	16	(17- 43)
	Creatinine (mg/dL)	0.5	(0.5–0.9)
CBC	Hb () (g/ L)	92	(95- 130)
	HCT (%)	29.9	(28–39)
	TLC (K/µL)	10.2	(5.6–16)
	PLT (×109/L)	96	(150–400)
Coagulation profile	INR	1.1	(0.8–1.1)
	PT (seconds)	12.9	(9.6–12.9)
	PTT (seconds)	28.5	(24.7–35)
Autoimmune markers	Anti-smooth muscle antibodies	Weak positive	Negative
	Antinuclear antibodies	Negative	Negative
	Anti-double stranded-DNA	Negative	Negative
Thrombophilia screening	FVL (G1691A:R506Q)	Heterozygous genotype	Wild genotype
	Factor VR2 (A4070G: H1299R)	Wild genotype	Wild genotype
	Factor V (A5279G:Y1702C)	Wild genotype	Wild genotype
	Factor II (Prothrombin gene G20210A)	Wild genotype	Wild genotype
	MTHFR (C677T)	Heterozygous genotype	Wild genotype
	MTHFR (A1298C)	Wild genotype	Wild genotype
	Anti-thrombin III	71	(83–111)
	Protein S	38	(70–150)
	Protein C	51	(60–130)
	Lupus anticoagulant dRVVT screen	1.1	0.85–1.17
	Lupus anticoagulant dRVVT confirm	1.2	≤1.2
	Anti cardiolipin IgM (U/Ml)	5	Negative <7
	Anti cardiolipin IgG (U/Ml)	8	Negative <10
	Anti B2-glycoprotein IgG (U/Ml)	2.5	Negative <5
Viral hepatitis markers	HbS Ag	Negative	Negative
	Anti HCV Ab	Negative	Negative

ALT, alanine transaminase; AST, aspartate transaminase; dRVVT, Dilute Russell's viper venom time; FVL, factor V Leiden; FVL, factor V leiden; Hb, haemoglobin; HbS Ag, hepatitis B surface antigen; HCT, hematocrit; HCV Ab, hepatitis C virus antibody; INR, international normalized ratio; LFTs, liver function tests; MTHFR, Methylenetetrahydrofolate reductase; PLT, platelets; PT, prothrombin time; PTT, partial thromboplastin time; RFTs, renal function tests; TLC, total leukocyte count.

Conservative management with the previously mentioned medications was started. She was scheduled for follow-up upper GI endoscopies, which detected congestive gastropathy and grade II OVs that were ligated (figure 3). She was also scheduled for abdominal US scans that followed-up progressively cirrhotic liver, splenomegaly and ascites.

Figure 3.

Follow-up upper gastointestinal endoscopy showing grade II esophageal varices that were ligated.

Obstetric US on admission showed a foetus that was small for GA (SGA) (fetal weight below 10th percentile for GA),⁷ with borderline amniotic fluid index and normally implanted placenta. Middle cerebral artery and umbilical artery pulsatile indices were within normal ranges for GA.

Treatment

With daily fetal surveillance at our department, the patient was given 24 mg of betamethasone (Betafos, Amoun, Cairo, Egypt) in two divided doses over 2 days to improve fetal lung maturity.^{8 9} GE&H recommended termination of pregnancy as early as possible through caesarean section (CS). They also recommended epidural anaesthesia and preoperative platelet count above 100×10⁹/L. The patient was then scheduled for CS at 36 weeks of GA.

Preoperative, our patient had 12 units of platelet transfused due to direct platelet count of 87×10⁹/Lwith correction to 103×10⁹/L. She also had two packed RBCs transfused for HB 92 g/L with correction to 113 g/L. LMWH was held 24 hours before surgery.¹⁰

The patient subsequently had an uncomplicated elective CS under epidural anaesthesia. She delivered a boy baby who was admitted in neonatal intensive care unit (NICU) due to respiratory distress and sepsis.

Following haematology team recommendations, the patient resumed LMWH in therapeutic doses as a bridging therapy. She started stepwise increasingly doses of daily warfarin (marevan, GalaxoSmithKline, London, UK) with international normalized ratio (INR) control until INR plateaued at 2.3, 3 weeks postpartum. LMWH was then stopped and she was discharged only on warfarin.¹⁰ Genetic counselling and serial monitoring of previously abnormal test results were recommended. She was scheduled for follow-up OPC visits, follow-up labs and radio scans.

Differential diagnosis

The patient had another coloured duplex study of the hepatic vasculature 4 weeks postpartum. It showed portal vein thrombosis (PVT) and inferior vena cava compression by enlarged caudate lobe of liver. In addition, it showed the previously detected hepatic vein thrombosis.

The patient had repeated thrombophilia and autoimmune markers testing 14 weeks postpartum. Protein C, protein S and AT III values were within normal ranges this time, while ASM Abs titre turned frankly positive. On the other hand, FVL and MTHFR C677T heterozygous gene mutations were confirmed (table 2).

Table 2.

Patient labs 14 weeks postpartum, abnormal results are underlined

Autoimmune markers	Anti-smooth muscle antibodies	Positive	Negative
	Antinuclear antibodies	Negative	Negative
	Anti-double stranded-DNA	Negative	Negative
	Serum immunoglobulin G (IgG) (mg/dL)	660	700–1400
Thrombophilia screening	FVL (G1691A:R506Q)	Heterozygous mutant	Wild genotype
	Factor VR2 (A4070G: H1299R)	Normal	Normal
	Factor V (A5279G:Y1702C)	Normal	Normal
	Factor II (Prothrombin gene G20210A)	Normal	Normal
	MTHFR (C677T)	Heterozygous mutant	Normal
	MTHFR (A1298C)	Normal	Normal
	PAI-1 (4G/5G)	Normal	Normal
	Anti-thrombin III	93	(83–111)
	Protein S	74	(70–150)
	Protein C	69	(60–130)
	Lupus anticoagulant	Negative	Negative

FVL, factor V leiden; MTHFR, Methylenetetrahydrofolate reductase; PAI-1, Plasminogen activator inhibitor-1.

This established the diagnosis that our patient has an inherited thrombophilia, due to FVL and MTHFR gene mutations, that was augmented by her long history of smoke exposure and exacerbated by her pregnancy state. These caused PVT and hepatic vein thrombosis.

Outcome and follow-up

On her discharge, our patient was offered comprehensive counselling on her inherited predisposition as well as the modifiable factors that can increase her risk of thrombosis. These include long periods of immobility, dehydration, surgeries, exposure to cigarette smoke and use of OCPs.¹¹ The patient’s husband and father were instructed to stop smoking at home.

Our patient infant was discharged from NICU 5 weeks postpartum after improvement. She did not breastfed him after discharge. He is currently normal and growing well. She came for a copper intrauterine device (Cu IUD) insertion for contraception 6 weeks postpartum.

Our patient was referred to a specialised BCS centre where she had a successful orthoptic liver transplantation done after failed transcutaneous intrahepatic portosystemic shunt two times.¹² She is currently on immunosuppressive therapy. Her condition dramatically improved after transplantation.

Discussion

BCS is any pathophysiological process that results in interruption or diminution of blood flow out of the liver (figure 1). A hypercoagulable state is identified in 80% of BCS cases. Risk of thrombosis as a cause of BCS is highest when FVL gene mutation occurs in association with another prothrombotic condition like pregnancy or smoke exposure.³ BCS is an aggressive disease, it has a 3-year survival rate of 10% without treatment.¹²

Pregnancy is a hypercoagulable state that provokes various thromboembolic diseases through augmentation of genetically inherited and acquired prothrombotic factors. Pregnancy with BCS carries substantial risks to the pregnancy as well as BCS progression. Multidisciplinary care with involvement of GE&H, haematology and HRP specialists is mandatory. Successful pregnancies with conservative management of BCS have been reported. Disease control before conception as well as anticoagulation throughout pregnancy and postpartum result in better pregnancy outcomes.¹³

FVL heterozygous gene mutation (our case) is the most common inherited thrombophilia found in Caucasian population and in individuals with venous thromboembolism (VTE). Even though it is associated with lower risk for VTE than FVL homozygous gene mutation,¹⁴ it carries much higher risk than MTHFR gene mutation. Actually, MTHFR gene mutation is becoming less important and less predictive of VTE.¹ Our lab performs it just as one of the thrombophilia screening panel tests. FVL gene mutation is associated with more VTE events than arterial thromboembolic ones.¹⁵

Ideally, screening for inherited thrombophilia should be carried out 12 weeks postpartum or after termination of breastfeeding, without the use of any form of hormonal contraception.¹ That is why values of AT III, protein C and protein S were deceptively low during pregnancy. They returned to normal ranges when repeated on week 14 postpartum with suppression of lactation.

Given the patient history of familial thrombophilia, she should have undergone thrombophilia screening prior to pregnancy or took intermediate dose of LMWH throughout her pregnancy and postpartum.¹ The latter is not an ideal but a common practice in our low resource community, as thrombophilia lab screening is costly and available only in limited places. So, prophylactic doses of LMWH or unfractionated heparin are sometimes given empirically based only on familial history and a procoagulant state like pregnancy or surgery.

Despite that our patient ASM Abs result was positive, autoimmune hepatitis was excluded by the negative viral hepatitis markers as well as the normal levels of aminotransferases, ANA and serum IgG. Serum IgG level was obtained prior to transplantation. Additionally, histopathology examination of our patient removed cirrhotic liver after transplantation showed cirrhotic changes mainly without features suggestive of autoimmune hepatitis, like ductal changes and portal area inflammatory cell infiltration.¹⁶

In our patient’s second coloured duplex study, caudate lobe was hypertrophied. This is a common finding in chronic liver cirrhosis that was caused by BCS in our case. PVT identified was not secondary to BCS; it was probably secondary to the same factor causing BCS, which is her genetic thrombophilia that was augmented by other prothrombotic factors. PVT in association with BCS was found in 14% of patients in one study.²

Thrombocytopenia discovered since the patient first presentation and until she had the transplantation was due to progressive portal hypertension (HTN) with consequent hypersplenism and platelet destruction¹⁷ (figure 1). Cu IUD was the best contraceptive choice for our patient according to centres of disease control and prevention recommendations.¹⁸

GE&H recommended termination of pregnancy as soon as possible. This is due to the fact that the increased blood volume with pregnancy can worsen portal HTN. Actually, rates of variceal bleeding are higher after second trimester. CS was recommended as straining during vaginal delivery increases the pressure in collateral veins with increased risk of variceal bleeding.¹⁹ Neuraxial anaesthesia with epidural block was recommended by the GE&H team for CS to control the postoperative pain.²⁰ Neuraxial anaesthesia is also associated with less hepatic pass and systemic effects than general anaesthesia.²¹

Eventhough epidural anaesthesia and CS can be carried out safely with platelet counts 70–100×10⁹/L,^{5 22} GE&H recommended preoperative platelet count >100 ×10⁹/L to provide an extra margin of safety given our patient bleeding history. HB optimisation to ≥ 100 g/L before CS is not an ideal but a common practice at our community; it is associated with less postpartum haemorrhage and postpartum anaemia.^{5 23} HB optimisation predelivery was achieved by blood transfusion rather than iron therapy as our patient CS was very close.

In spite of the fact that pregnancy is a procoagulant state that provokes various thromboembolic diseases, BCS in our patient could preceded pregnancy but only manifested during it. However, we could not figure this out as our patient did not have an abdominal US or duplex study done before pregnancy.

Finally, SGA was diagnosed in our patient fetus. This may be due to thrombosis and infarction in placental bed with consequent placental hypoperfusion and affection of the fetal growth. Unfortunately, we did not send the patient placenta for histopathology examination after delivery, but the aforementioned pathology (thrombosis and infarction in placental bed) was reported in a similar case of BCS with SGA.²⁴ On the other hand, it could be also constitutional,²⁵ as our patient was 162 cm long and weighted 50 Kg (BMI: 19).

Learning points.

• Pregnancy is a hypercoagulable state that is known to unmask inherited thombophilic tendency, exacerbate procoagulant factors and provoke various thromboembolic diseases like deep venous thrombosis and primary Budd-Chiari syndrome (BCS).

• Primary BCS is commonly due to hepatic vein thrombosis, it is a progressive disease that necessitates a prompt management. Pregnancy with BCS is extremely high risk; multidisciplinary team management is a must.

• Thrombophilia screening should be carried out in individuals with strong family history of thrombophilia, especially in the setting of a procoagulant state like pregnancy, surgery or malignancy.