Emergency Radiology

, Volume 14, Issue 5, pp 323–329

Vitamin K deficiency bleeding with intracranial hemorrhage: focus on secondary form

Authors

    • Department of RadiologyNational Center for Child Health and Development
  • Shunsuke Nosaka
    • Department of RadiologyNational Center for Child Health and Development
  • Hirokazu Sakai
    • Department of Anesthesia and ICUNational Center for Child Health and Development
  • Yoshiyuki Tsutsumi
    • Department of RadiologyNational Center for Child Health and Development
  • Masayuki Kitamura
    • Department of RadiologyNational Center for Child Health and Development
  • Osamu Miyazaki
    • Department of RadiologyNational Center for Child Health and Development
  • Ikuko Okusu
    • Department of RadiologyNational Center for Child Health and Development
  • Kyoko Kashima
    • Department of RadiologyNational Center for Child Health and Development
  • Reiko Okamoto
    • Department of RadiologyNational Center for Child Health and Development
  • Chihiro Tani
    • Department of RadiologyNational Center for Child Health and Development
  • Yoshiyuki Okada
    • Department of RadiologyNational Center for Child Health and Development
  • Hidekazu Masaki
    • Department of RadiologyNational Center for Child Health and Development
Original Article

DOI: 10.1007/s10140-007-0632-y

Cite this article as:
Miyasaka, M., Nosaka, S., Sakai, H. et al. Emerg Radiol (2007) 14: 323. doi:10.1007/s10140-007-0632-y
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Abstract

Non-accidental trauma is the leading cause of intracranial hemorrhage (ICH) in infancy. In contrast, ICH as a part of vitamin K deficiency bleeding (VKDB) secondary to hepatobiliary disease is rare, but encountered even in the era of vitamin K (VK) prophylaxis. During 43 months, six cases with ICH were diagnosed as an initial presentation of VKDB. Clinical features and imaging findings of them were retrospectively reviewed. All cases were breastfed and received oral VK prophylaxis. Liver dysfunction was found in five. Brain CT showed hemorrhage in subdural and subarachnoid space in six, parenchyma in three, and ventricle in one. Abdominal ultrasound was positive in four with final diagnoses of biliary atresia in two, neonatal hepatitis in one, and milk allergy in one. Two cases with negative ultrasound were diagnosed as idiopathic VKDB. In conclusion, ICH with secondary VKDB is rare, but important in infancy in the era of VK prophylaxis.

Keywords

Vitamin K deficiency bleedingIntracranial hemorrhageBiliary atresiaNeonatal hepatitisBrain CTAbdominal ultrasound

Introduction

Non-accidental trauma is the leading cause of intracranial hemorrhage (ICH) in infancy. In contrast, ICH due to vitamin K deficiency bleeding (VKDB), as one of coagulopathy, is rarely present in early infancy [1, 2].

VKDB is a coagulopathy caused by a decrease in vitamin K-dependent coagulation factors (II, VII, IX, X) [36]. A diagnosis of VKDB can be made when there is elevated PIVKA-II (protein induced in vitamin K absence -II), prolonged prothrombin time (PT), and rapid improvement of PT, and/or cessation of bleeding after administration of vitamin K [35, 7]. VKDB has been categorized into two forms, idiopathic and secondary. Causes of secondary VKDB include biliary atresia, neonatal hepatitis, antibiotic therapy, and chronic diarrhea [5, 79]. Early diagnosis of secondary VKDB is essential to achieve appropriate treatment.

In 1981 in Japan, a recommendation was made for oral administration of vitamin K prophylaxis at birth, at the 6th day, and 1 month after birth. Since then, the incidence of VKDB has decreased. However, it is still present, even in infants receiving the prophylaxis [10]. During 43 months, we experienced six cases with VKDB who initially presented with ICH. Of those, secondary VKDB was diagnosed in four cases. To our knowledge, there were few reports of diagnostic imaging findings of VKDB in the past radiological literatures [11, 12]. The purpose of this study is to review the clinical features and diagnostic imaging findings of mainly focusing on secondary VKDB.

Materials and methods

Between March 2002 and October 2005, there were 155 cases in whom an emergency brain CT was obtained in an infant 6 months of age or younger. Among these 155 cases, six cases (4%) were diagnosed as having ICH caused by vitamin K deficiency. These six cases were five boys and one girl with a mean age of 56 days (ranging from 35 to 74 days). In all cases, pregnancy and delivery were uneventful, and all cases had no history of trauma.

We retrospectively reviewed the following factors: (1) clinical features, (2) diagnostic imaging findings, and (3) neurological outcomes. Clinical features included symptoms, physical examinations, nutritional history, history of vitamin K prophylaxis, and laboratory data on admission. Diagnostic imaging findings included those of the initial brain CT, follow-up brain CT or MRI, and abdominal ultrasound (US); other diagnostic imaging included hepatobiliary scintigraphy and intraoperative cholangiography.

Results

  1. (1)
    Clinical features
    1. (a)

      Symptoms and physical examinations (Table 1)

      Patients had several symptoms at the time of admission. The most common symptoms were vomiting and seizures.

      Physical examinations on admission revealed fontanel bulging in three cases and bleeding from puncture sites in two cases.

       
    2. (b)

      History of nutrition and vitamin K prophylaxis

      All cases were exclusively breastfed infants and had been given vitamin K prophylaxis.

       
    3. (c)

      Laboratory data on admission (Table 2)

      All cases had severe anemia. Among them, case no. 1 received intravenous administration of vitamin K at our facility. The five remaining cases (case nos. 2 to 6) were transferred to our facility from neighboring hospitals, where the babies had received administration of vitamin K immediately prior. At 24 h after administration of vitamin K, PT values were normal in all cases. Elevation of PIVKA-II was confirmed in all cases. All cases had bilirubinemia, and five cases had mild to severe liver dysfunction.

       
     
  2. (2)
    Diagnostic imaging findings
    1. (a)

      Initial brain CT and follow-up brain CT or MRI findings (Table 3)

      Initial brain CTs showed subdural hematoma (SDH) and subarachnoid hemorrhage (SAH) in all cases. In addition to SDH and SAH, there was intraventricular hemorrhage (IVH) in one case, intraparenchymal hemorrhage (IPH) in two cases, and both IVH and IPH in one case. The locations of the bleeding varied including bilateral involvement in four cases and unilateral involvement in two cases. In cases with bilateral involvement, the distribution of the hemorrhage was asymmetric. The infratentorial region, however, was not involved in our series. There were findings associated with midline shift in five cases and low density areas (LDA) in three cases. Surgical removal of hematoma was performed in all cases.

      On the 1-month follow-up CT or MRI, encephalomalacia was seen in four cases. Of these four cases, LDA was seen on the initial CT. The two remaining cases appeared to be normal on follow-up CT.

       
    2. (b)

      Abdominal US findings (Table 4)

      All six cases underwent abdominal US because of bilirubinemia and/or liver dysfunction. Of these six cases, abnormal findings were recognized in four. These abnormal findings were triangular cord sign, absence of gallbladder, gallbladder sludge, and gallbladder wall thickening.

       
    3. (c)

      Other diagnostic imaging findings (Table 4)

      Following US, three cases underwent hepatobiliary scintigraphy. The findings of hepatobiliary scintigraphy were abnormal in all three cases including absence of intestinal excretion of radiotracer in two cases, and intestinal excretion of radiotracer with slow hepatic clearance in one case.

      Two of these three cases underwent laparotomy with intraoperative cholangiography followed by Kasai procedure. Intraoperative cholangiography showed absence of a biliary tree in case no. 3 and a hypoplastic biliary tree in case no. 4 (Fig. 1).

      In summary, secondary VKDB was diagnosed in four cases including two cases of biliary atresia, one case of milk allergy, and one case of neonatal hepatitis (Fig. 2). The two remaining cases were diagnosed as having idiopathic VKDB (Fig. 3).

       
     
  3. (3)

    Neurological outcomes (Table 5)

    All patients were observed for a mean period of 19 months ranging from 2 to 33 months. Four cases with encephalomalacia have had some degree of handicap. The other two cases are developing normally.

     
Table 1

Symptoms and physical examinations

Case no.

Age(day)/sex

Symptoms

Physical examinations

1

54/M

Vomiting

Pallor

2

35/M

Hypoactivity, seizure

Bulging of fontanelle

3

62/M

Poor sucking, Seizure

Pallor, bulging of fontanelle

4

60/F

Vomiting, Jaundice

Hepatomegaly

5

74/M

Vomiting

Pallor

6

52/M

Vomiting, seizure

Pallor, bulging of fontanelle

Table 2

Laboratory data

Case no.

RBC (X104μl)

Hb (g/dl)

PT on admission (second)

PT 12–24 h after vitaminK (second)

PIVKA-II

T-Bil (mg/dl)

D-Bil (mg/dl)

GOT (IU/l)

GPT (IU/l)

1

281

8.2

100

13.5

Elevated

5.5

2.7

78

56

2

192

5.6

22

13.2

Elevated

2.2

1.4

160

172

3

196

5.8

12.8

11.0

Elevated

7.3

4.9

82

62

4

285

8.3

17.7

11.7

Elevated

7.8

4.7

107

69

5

418

5.6

20.5

12

Elevated

1.2

0.7

79

56

6

212

6.6

17.1

12.9

Elevated

6.5

2.6

33

28

RBC red blood count, Hb hemoglobin, PT prothrombin time, PIVKA-II protein induced in vitamin K-II, T-Bil serum total bilirubin, D-Bil serum direct bilirubin, GOT glutamic oxaloacetic transaminase, GPT glutamic pyruvic transaminase

Table 3

Initial and follow-up brain imaging findings

Case No.

Initial brain CT

Follow up brain imagings after 1mo.

SDH

SAH

IPH

IVH

Midline shift

LDA

locations

1

+

+

+

Rt.>>Lt. temporal

Normal

2

+

+

+

+

+

Rt. frontal

Encephalomalacia

3

+

+

+

+

+

+

Rt.>>Lt. temporal

Encephalomalacia

4

+

+

+

Lt. >>Rt. parieto-temporal

Normal

5

+

+

+

+

Rt. >>Lt. fronto-parietal

Encephalomalacia

6

+

+

+

+

+

Lt. patrieto-temporal

Encephalomalacia

SDH subdural hematoma, SAH subarachnoid hemorrhage, IPH intraparenchymal hemorrhage, IVH intraventricular hemorrhage, LDA low density area, Rt. Right, Lt. Left,

Table 4

US and other diagnostic imaging findings

Case no.

US findings

Hepatobiliary scintigraphy

Intraoperative cholangiography

Final diagnosis

1

No abnormality

Idiopathic

2

No abnormality

Idiopathic

3

Absence of gallbladder

No excretion of radiotracer into the bowel

Absence of biliary tree

Biliary atresia

4

Triangular cord

No excretion of radiotracer into the bowel

Hypoplastic biliary tree

Biliary atresia

5

Gallbladder sludge

Milk allergy

6

Thickening of gallbladder wall

Excretion into the bowel, but slow clearance

Neonatal hepatitis

study not performed

https://static-content.springer.com/image/art%3A10.1007%2Fs10140-007-0632-y/MediaObjects/10140_2007_632_Fig1_HTML.jpg
Fig. 1

Case 4: 60-day-old girl presented with vomiting and jaundice. Initial axial CT image (a) shows SDH and SAH in left cerebral hemisphere with midline shift. LDA is not associated. Transverse images (b) of the hepatic hilum, however, reveal an echogenic cord anterior to the portal vein, which was determined to be a triangular cord (arrows). Hepatobiliary scintigraphy at 24 h (c) shows no intestinal excretion of the radiotracers. Intraoperative cholangiography (d) reveals hypoplastic biliary tree and absence of the common bile duct. Therefore, diagnosis of biliary atresia was made. Follow-up brain CT images (e) appear to be normal. The girl has no neurological sequelae

https://static-content.springer.com/image/art%3A10.1007%2Fs10140-007-0632-y/MediaObjects/10140_2007_632_Fig2_HTML.jpg
Fig. 2

Case 6: 52-day-old boy presented with vomiting and seizure. Initial CT images (a, b) show massive SDH extending over the left side in association with SAH and IPH of the left parietal lobe. In addition, associated midline shift and LDA of the left cerebral hemisphere are obvious. Longitudinal sonographic image of the right upper abdomen (c) shows gallbladder wall thickening. Hepatobiliary scintigraphy at 24 h (d) shows excretion of the radiotracer into the bowel, but slow clearance of the hepatic parenchyma. Therefore, the diagnosis of neonatal hepatitis was made. Follow-up brain MRI after 1 month with T2-weighted axial image (e) shows encephalomalacia involving bilateral hemispheres with a speared area in the right occipital lobe. He is severely handicapped

https://static-content.springer.com/image/art%3A10.1007%2Fs10140-007-0632-y/MediaObjects/10140_2007_632_Fig3_HTML.jpg
Fig. 3

Case 2: 35-day-old boy had symptoms with hypoactivity and seizure. Initial brain CT (a) shows massive IPH in the right frontal lobe with SDH and SAH. Midline shift and diffuse LDA of bilateral cerebral hemispheres were seen. Follow-up brain CT (b) after 1 month shows diffuse encephalomalacia. He is severely handicapped

Table 5

Neurological outcomes

Case no.

Neurological Outcome

1

Normal

2

Epilepsy, spastic tetraparesis

3

Developmental delay

4

Normal

5

Epilepsy

6

Microcephalus, epilepsy, hemiparesis

Discussion

Most ICH in infants less than 1 year old is due to non-accidental trauma [1, 2]. It is generally accepted that SDH is highly specific feature of non-accidental trauma [13]. However, ICH due to vitamin K deficiency is rarely present in early infancy. In infants with non-accidental trauma, coagulation studies and liver function are usually normal at presentation [1].

Incidence of VKDB in early infancy is 25 per 100,000 births in Japan, whereas the rate in UK and Germany is in only 5 per 100,000 births [4, 7, 9, 10].

Causes of VKDB are described in two forms, idiopathic and secondary. Idiopathic VKDB has several characteristic features; namely, it (1) is more common in Asian babies and in boys, (2) occurs in early infants between 2 and 12 weeks of life, (3) is common in exclusively breastfed infants, and (4) entails a high incidence of ICH [6, 7]. Idiopathic VKDB is considered to result from the lower content of vitamin K in breast milk than in formula and from the inefficiency of the intestinal flora of breastfed infants in absorbing vitamin K [5, 6]. On the other hand, causes of secondary VKDB include biliary atresia, antibiotic therapy, chronic diarrhea, and other conditions [5, 7, 8]. The bleeding tendency in patients with biliary atresia is caused by vitamin K deficiency resulting from a combination of cholestasis-induced fat malabsorption and low vitamin K intake due to breast-feeding [1416]. The same mechanism is recognized in neonatal hepatitis, choledochal cyst, and alpha-1-antitripsin deficiency [1416].

The symptoms described in past reports vary [5, 6, 8]. These symptoms were nonspecific. Our results were similar to those of the previous reports.

Considering laboratory data of VKDB, liver dysfunction and/or bilirubinemia have been reported in some of the literatures [47]. In our results, all six cases had bilirubinemia and/or liver dysfunction.

A high incidence of mild to severe neurological sequelae was identified in the past reports [5, 6, 8] (Table 6). Our results were similar. In our cases, patients with neurological handicaps showed LDA of cerebral parenchyma on initial CT. It was thought that the mass effect, elevated intracranial pressure and acute hemispheric swelling caused ischemic brain damage [17]. Therefore, prompt diagnosis and treatment of ICH in early infants is mandatory.
Table 6

Summary of reported cases of ICH caused by VKDB

 

Chaou WT, et al. 1984, Florida

Aydinli N, et al. 1998, Turkey

Demiroren K, et al. 2004, Turkey

Presented data

Number of cases

32

11

19

6

Age of onset

10–40 days

32–80

31–67

35–74

Breastfed

27/32 cases

All cases

All cases

All cases

VK prophylaxis

1/32 cases

none

11/19

All cases

ICH: SAH

90.6%

46%

47%

100%

ICH: SDH

37.5%

27%

42%

100%

ICH:IPH

31.3%

91%

47%

50%

ICH: IVH

12.5%

27%

26%

33%

Neurological sequela

97%

73%

84%

67%

Secondary VKDB

3%a

none

16%b

66%c

aSecondary VKDB included one case of Hirschsprung disease

bSecondary VKDB included four cases of antibiotic therapy, one case of alpha-1 antitripsin deficiency, and one case of unknown cholestatic jaundice.

cSecondary VKDB included two cases of biliary atresia, one case of neonatal hepatitis, and one case of milk allergy

VKDB is manifested by ICH, gastrointestinal, or skin bleeding. In the literature, ICH is the most common presentation and accounts for approximately 50% of cases [5, 79]. The reports [5, 6, 8] in the non-radiological literatures are summarized in Table 6. In these past reports [5, 6, 8] and our cases, ICH occurred in early infancy under 3 month of age and different types of bleeding were recognized. In our cases, the most common types of hemorrhage were SDH and SAH. Chaou et al. reported that the infratentorial region was involved in 9.4% cases [6]. Our cases had no infratentorial involvement. According to these past reports and our results, it may be considered that ICH due to vitamin K deficiency is characterized by a variable combination of different types of bleeding and occurs in early infancy under 3 month of age, regardless of an idiopathic or secondary VKDB.

In contrast to the reports of Aydinli et al., secondary VKDB was presented in our cases and those of Demiroren et al. (Table 6) [5, 6, 8]. In our results, secondary VKDB occurred in four out of six cases (66%), despite vitamin K prophylaxis. Vitamin K prophylaxis reduces the incidence of idiopathic VKDB; however, secondary VKDB is relatively predominate.

One of the major causes of secondary VKDB is biliary atresia. Biliary atresia is usually presented with prolonged jaundice [14]. ICH, however, occurs in 1–6% of infants with biliary atresia in Japan [14]. It is well known that early diagnosis and the timing of surgery for biliary atresia are important for achieving a good prognosis [14]. Decision on the timing of surgical intervention for biliary atresia is difficult in patients with ICH [14]. Okada et al. [14] reported the usefulness of abdominal US for investigating possible causes, such as biliary atresia. US findings of biliary atresia have triangular cord sign, small or absent gallbladder [18]. Our two cases with triangular cord sign or absence of gallbladder were suggested of having biliary atresia. Following US results and clinical course, hepatobiliary scintigraphy was added to diagnose whether it was biliary atresia or not. Three cases underwent hepatibiliary scintigraphy. Of these three cases, there were preoperatively diagnosed biliary atresia in two and neonatal hepatitis in 1. In our cases, the clinical features and the initial brain CT findings were similar in all six cases regardless of idiopathic or secondary VKDB. All four cases with secondary VKDB, however, had abnormal US results, while remaining two cases with idiopathic VKDB had normal US results.

Considering of diagnostic imaging results of our data, the role of diagnostic imaging for VKDB are summarized as follows: (1) initial brain CT is useful to diagnose ICH and to decide the therapeutic strategy, (2) follow up CT or MRI is useful expecting the neurological sequela. (3) US is a valuable non-invasive imaging modality detecting the causes of secondary VKDB. When abnormal US results are recognized, hepatobiliary scintigraphy is necessary.

Our study was limited with the small series in one institution. Therefore, further investigation is required in the near future. To our knowledge, there were few reports of diagnostic imaging findings of VKDB in the past radiological literatures [11, 12]. VKDB is not familiar to radiologist, because VKDB is diagnosed clinically. When an initial brain CT may requested and may demonstrate ICH unknown ICH. Therefore, the radiologist must consider that ICH in early infancy alert one to the likelihood of secondary VKDB in the era of vitamin K prophylaxis.

In conclusion, although it is important to consider non-accidental trauma when ICH is seen in infants, it is also important to consider VKDB as a cause. Most ICH caused by vitamin K deficiency occurs in infancy under 3 month of age. And ICH was a variable combination of different types of bleeding. When bilirubinemia and/or liver dysfunction are present or ICH due to vitamin K deficiency is diagnosed, it must be considered as a sign of the possibility of secondary VKDB, regardless of vitamin K prophylaxis. In that situation, abdominal US can be a diagnostic adjunct for the further investigation and to decide therapeutic strategy.

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© Am Soc Emergency Radiol 2007