Hypoechoic Liver: A Promising Soft Marker in Screening for Trisomy 21

Abstract

Objectives

Hypoechoic liver, although a known association in Down syndrome fetuses, is scarcely reported in prenatal literature. This article examines the incidence of hypoechoic liver in Down syndrome fetuses and correlates its association with the presence of other established second-trimester soft markers for trisomy 21.

Methods

Retrospective analysis of 547 high-risk cases for aneuploidy where invasive testing was done between 16 and 22 weeks of gestation was included in the study. Fetal liver was evaluated in the coronal or parasagittal sections of the fetus, using a routine convex probe (1–5 MHz). The liver was considered hypoechoic when its echogenicity was less than that of the adjacent lung and bowel, with conspicuous visualization of the diaphragm.

Results

Out of the 45 cases of proven trisomy 21, 55.5% had hypoechoic liver, 62% had absent nasal bone (NB), and 48.8% had increased nuchal translucency (NT)/nuchal fold thickness (NFT). The other soft markers were identified in less than 10% of trisomy 21 cases. Hypoechoic liver was coexistent with absent NB in 20/25 (80%) and increased NT/NFT in 15/25 (60%) of trisomy 21 cases, the two being the most common associations. Hypoechoic liver was not identified as an isolated marker in Down syndrome fetuses. Hypoechoic liver was seen only in 4/469 (0.8%) of the normal fetuses.

Conclusion

The presence of hypoechoic liver in more than 50% of the cases with trisomy 21 appears to be a significant association. Further prospective studies are required to assess the potential of hypoechoic liver as a soft marker in Down syndrome screening.

Keywords

hypoechoic liver - trisomy 21 - Down syndrome - soft markers - prenatal ultrasound

Introduction

Trisomy 21 (Down syndrome) is the most common karyotypic abnormality in live-born infants, with an incidence of 1 per 850 to 900 live births[1] and is a leading cause of intellectual impairment. Prenatal detection of Down syndrome is a major challenge faced by maternal and fetal medicine specialists, as many of these fetuses do not present with detectable structural malformation. Screening for prenatal detection of Down syndrome has evolved over the years, with several soft markers being reported, of which unossified nasal bone (NB) has the highest likelihood ratio in the second trimester, followed by the aberrant right subclavian artery, ventriculomegaly, hyperechoic bowel, mild hydronephrosis, and an echogenic intracardiac focus in order of decreasing significance.[2] Increased nuchal translucency (NT) is one of the strongest standalone markers for Down syndrome in the first trimester. Hypoechoic liver, although a known association in Down syndrome fetuses, is scarcely reported in prenatal literature. We observed a significant association of Down syndrome fetuses with hypoechoic liver in our case series.

Methods

The primary objective of our study was to identify the association of hypoechoic liver in Down syndrome fetuses and to correlate its association with the presence of other known second-trimester soft markers for trisomy 21.

This is a retrospective study of a cohort of 547 patients identified as high risk for aneuploidy based on their first-trimester ultrasound and screening results across two centers in South India. Fetal liver was evaluated in stored coronal or parasagittal sections, which were acquired by using a convex probe (1–5 MHz). The liver was considered hypoechoic when its echogenicity was less than that of the adjacent lung and bowel, with conspicuous visualization of the diaphragm. [Figs. 1] and [2] show the subtle transition from the lung to the liver echogenicity at 16 and 21 weeks of gestation, respectively. [Fig. 3] shows hypoechoic liver parenchyma across varying gestational ages. Due to the subjective nature of the finding, images of hypoechoic liver parenchyma were retrospectively analyzed by two independent operators, and consensus was obtained.

Fig. 1 Normal echogenicity of liver parenchyma at 16 weeks in (A) sagittal section and (B) coronal section.

Fig. 2 Normal echogenicity of liver parenchyma at 21 weeks in (A) sagittal section and (B) coronal section.

Fig. 3 Hypoechoic liver at various gestation ages: (A, B) 15 weeks, (C, D) 16 weeks, (E, F) 17 weeks, and (G, H) 18 weeks of gestation.

Results

Of the 547 patients who underwent amniocentesis between 16 and 22 weeks of gestation over a period of 1 year, chromosomal abnormalities were seen in 14% (78/547) cases. Among these, trisomy 21 was the most common abnormality seen in 58% (45/78) of aneuploid fetuses.

Hypoechoic liver was seen in 55.5% (25/45) of Down syndrome fetuses (p-value < 0.00001). In 45 cases, the distribution of soft markers was as follows: absent NB and increased NT/nuchal fold thickness (NFT) were observed in 62% (28/45) and 48.8% (22/45), respectively. Other soft markers, such as hyperechoic bowel and an aberrant right subclavian artery, were observed in fewer than 10% of trisomy 21 cases.

Analyzing the presence of coexisting soft markers in cases with hypoechoic liver parenchyma, the results are as follows: hypoechoic liver coexisted with absent NB in 80% (20/25) of cases ([Fig. 4]) and with increased NT/NFT in 60% (15/25) of cases ([Fig. 5]), representing the most prevalent associations. Hypoechoic liver was not identified as an isolated marker in Down syndrome fetuses. Among 469 fetuses with normal karyotype, only 4 had hypoechoic liver on prenatal ultrasound. The positive predictive value of hypoechoic liver for Down syndrome is 86.2%.

Fig. 4 (A) Unossified nasal bone, (B) and (C) hypoechoic liver at 13 weeks of gestation.

Fig. 5 (A) Increased nuchal fold and (B) hypoechoic liver at 22 weeks.

Discussion

Chromosomal abnormalities occur in 0.1 to 0.2% of live births, with the most common being Down syndrome. Down syndrome is characterized by the presence of an extra copy of chromosome 21. The most common cause is meiotic nondisjunction during gametogenesis; other causes include balanced translocation involving chromosome 21, ring chromosome, or mosaicism.[3]

Screening for Down syndrome has become the standard of care in the prenatal period. Sonographic findings in fetuses with Down syndrome include both structural and nonstructural abnormalities or “soft markers.” Less than 25% of trisomy 21 fetuses have major structural abnormalities, while soft markers are seen in at least 50% of cases. Screening tests using sonographic soft markers alone had a sensitivity ranging from 49 to 89%, depending on whether individual markers or their combinations were used.[4] This has led to the development of a variety of screening methods that combine maternal age, biochemical markers, and prenatal sonographic markers. First-trimester combined screening tests carry a detection rate of around 90%[5] and quadruple screening in the second trimester carries a detection rate of 70%.

The landmark discovery of noninvasive prenatal testing is a major breakthrough in prenatal screening for Down syndrome since it has a sensitivity of 99.2%. It is considered the most accurate screening test for trisomy 21.[6] However, its role as a primary screening modality is restricted in developing countries due to cost factors and the need for further invasive testing for 100% accuracy. Hence, the role of ultrasound in aneuploidy screening is still considered irreplaceable.

Hypoechoic liver in association with Down syndrome has not been much reported in prenatal literature.[7] [8] [9] Reported ultrasound findings in the fetal liver in trisomy 21 fetuses include hypoechoic liver, hepatomegaly, low resistance flow in the hepatic artery (HA), and high resistance flow in the ductus venosus (DV).[10]

Liver hypoechogenicity and hepatomegaly are significant but easily missed findings on antenatal ultrasound, mainly because they are subjective assessments and hence are underreported in the literature. Evaluation of the fetal liver in longitudinal and coronal planes, in addition to the routine axial plane, is essential to identify this finding.

Liver echogenicity is assessed by comparison with adjacent lung and bowel. However, as this marker is subjective, it is prone to interobserver variation. As echogenic bowel is also a marker for Down syndrome, comparison of liver echogenicity with bowel may lead to overreporting of this finding. Hence, it is ideal to compare the liver parenchyma with the echogenicity of the lung parenchyma, and if the liver is hypoechoic, the diaphragm becomes conspicuous.

Hypoechoic liver in trisomy 21 is often linked to abnormal liver hemodynamics and transient abnormal myelopoiesis (TAM). TAM is usually seen in the third trimester in Down syndrome fetuses, caused by early-onset leukocytosis with blast cells, extramedullary hematopoiesis, and absence of leukemic infiltration. The abnormal extramedullary hematopoiesis observed in the fetal liver may correlate with hypoechoic hepatomegaly, potentially due to an increased hepatic blood volume due to hepatic congestion similar to that in congenital cardiac failure.[7] Autopsy findings in Down syndrome fetuses frequently reveal TAM and significant hepatomegaly, with a mean liver weight of 64.5 g. This is attributed to congestion and infiltration of CD61-positive blast cells in the vascular lumina and periluminal areas, accompanied by fibrotic changes.

Hamada et al presented two case reports of prenatally reported hypoechoic hepatomegaly due to Down syndrome with TAM. Both of them died in the postnatal period from liver failure, even when TAM did not progress to leukemia.[7] A case series by Kikuchi et al reported four cases of hypoechoic hepatomegaly, of which three were diagnosed to have trisomy 21 and one isolated TAM.[8] Kim and Lee presented an isolated case report of Down syndrome with TAM in a fetus with hypoechoic hepatosplenomegaly associated with cerebral ventriculomegaly that resulted in intrauterine fetal demise at 29 weeks of gestation.

It has been hypothesized that fetuses with TAM and hypoechoic liver parenchyma tend to have a poor prognosis. A retrospective study by Hojo et al reported seven cases of Down syndrome with TAM, of which six were diagnosed prenatally. All six cases had hepatomegaly and were associated with either splenomegaly, hydrops, or cardiac defects. Four cases with hydrops had a fatal outcome in the intrauterine period due to coagulopathy resulting from liver failure.[11]

Studies in literature report the presence of hypoechoic liver in cases with trisomy 21, even in the absence of TAM. It is also postulated that hepatomegaly in trisomy 21 fetuses with TAM is different from Down syndrome without TAM, possibly due to leukostasis causing leukemic infiltration or local hypoxemia.[12]

Omar et al reported three cases of Down syndrome in which a hypoechoic liver was found in the second trimester but without evidence of TAM, suggesting that the hypoechogenicity may be secondary to hemodynamic disturbances. All three cases had negative first-trimester Down syndrome screening, and one case was detected solely because of the isolated finding of hypoechoic liver, highlighting its diagnostic significance.[9]

Dysfunction in angiogenesis is proposed to be one of the etiologies for hepatomegaly in Down syndrome fetuses, including umbilico-portal anomalies.[13] The abnormal liver hemodynamics hypothesis is supported by prospective studies conducted by Bilardo et al and Zvanca et al, which noted low-resistance, high-velocity hepatic arterial flow in a significant number of aneuploid fetuses in the late first trimester.[10] [14] This was noted in association with increased NT and abnormal DV; DV-pulsatility index (PI) and HA-PI are inversely related, possibly due to the same underlying pathology and considered to be an unfavorable prognostic factor.

Other etiologies for hypoechoic fetal liver include storage and deposition disorders, myeloproliferative disorders, fetal anemia, and infections.[15] This retrospective analysis had been done in the period of the coronavirus disease pandemic and hence the theoretical possibility of fetal infection was not been accounted for in this study.

Nevertheless, the finding of hypoechoic liver would have the inherent limitations of it being a subjective marker and will always be prone to both over- and underreporting. In spite of the subjective nature of the marker, the association of hypoechoic liver in Down syndrome fetuses needs to be taken into consideration. In future, newer methods would evolve in standardizing reporting of hypoechoic liver.

Moreover, the prevalence of hypoechoic liver in healthy fetuses is very low, and it is an uncommon observation in the general population. Its diagnostic value increases when combined with other soft markers, although its significance in isolation is yet to be evaluated. Hypoechoic liver demonstrated a strong association with absent NB ([Fig. 4]) and increased NT/NFT ([Fig. 5]) in trisomy 21 fetuses.

Conclusion

This study reports a significant association of hypoechoic liver in Down syndrome fetuses, which promotes the inclusion of hypoechoic liver as an additional soft marker in screening for Down syndrome fetuses. The presence of a hypoechoic liver in addition to other markers strongly warrants further genetic testing. As an isolated finding, it should alert the physician to thorough screening for trisomy 21, given the association. Further large-scale prospective studies are required to establish the strength of this association and predict the likelihood ratios to incorporate this finding as a soft marker in Down syndrome screening.

Conflict of Interest

None declared.

Ethical Approval

This retrospective study was conducted in accordance with the ethical principles of the Declaration of Helsinki and utilized only previously collected, anonymized data.

Authors' Contributions

S.B., A.M.R., S.A.R., P.P., H.R., S.R.L.: Involved in all stages of the study, including conceptualization, data collection, analysis, and preparation of original and manuscript revision. V.T.J.: Preparation, analysis, revision of the original draft, editing, and reviewing.

All authors read and approved the final manuscript.

Presentation

This article has been presented as an abstract in the 32nd International Society of Ultrasound in Obstetrics and Gynecology World congress with the abstract number EP15.04 https://doi.org/10.1002/uog.25389.

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Publication History

Article published online:
05 February 2026