GRAND

ROUNDS
Progressive Splenomegaly and Hypersplenism: An Unusual Case of Splenic
Vein Stenosis with Histologic Findings of Hepatoportal Sclerosis
Ben Freiberg, MD1, Sukru Emre, MD2, Raffaella Morotti, MD3, Brian Dillon, MD4, Alexander Koral, MD1,
Shilpa M. Hattangadi, MD5, and Pamela L. Valentino, MD, MSc, FRCP(C)1

A
palpable spleen is a relatively common finding on 1.8  1.6  2.7-cm fluid-filled structure thought to represent
physical examination.1-5 Because it typically repre- a cyst was found abutting the caudate lobe of the liver and the
sents an underlying pathology, all cases of spleno- gastroesophageal junction. This was suspected to be related
megaly should be evaluated systematically for hematologic, to her previous intestinal surgery. The MRI was not timed
oncologic, and hepatic disorders, as well as for infections, in- to interrogate the portal or splenic vasculature.
flammatory conditions, and primary splenic causes.6-10 A Over the course of the next 6 months, she underwent
thorough history and physical examination along with blood extensive evaluation by hematology, infectious diseases,
work and imaging can help to guide clinicians toward the and cardiology to determine the source of her splenomegaly
diagnosis. We present an unusual case of splenomegaly and continuing weight loss. Liver biochemistry and synthetic
owing to splenic vein stenosis and propose a stepwise function remained normal (alanine aminotransferase, 9 U/L;
approach to evaluating splenomegaly based on our experi- aspartate aminotransferase, 19 U/L; total bilirubin, 0.3 mg/
ence and a review of the literature. dL; gamma-glutamyl transferase, 10 U/L; international
normalized ratio, 1.04; albumin, 4.5 g/dL). She continued
Case Presentation to have iron deficiency anemia (hemoglobin, 10.2 g/dL;
mean corpuscular volume, 72.7 fL; absolute reticulocyte
A 12-year-old girl presented to her primary care physician count, 0.0507  106 cells/mL [normal]; iron 39, mg/dL; iron
with left-sided abdominal pain and early satiety. On exami- saturation, 9%) and thrombocytopenia (134  103/mL “giant
nation, she was found to have significant splenomegaly platelets”) without leukopenia (white blood cell count,
without hepatomegaly. She reported a history of abdominal 8.7  103/mL, normal differential). There was no evidence
surgery in another country at 3 years of age for intestinal of hemolysis on blood smear; the haptoglobin (69 mg/dL)
perforation secondary to malrotation and volvulus, as well and lactate dehydrogenase (174 U/L) were both normal; there
as a history of pulmonary hypertension and cardiomyopathy was no abnormal osmotic fragility. Given her progressive
while living at a high altitude (medical records unavailable). weight loss, she was evaluated for an oncologic process via
She had been otherwise healthy since coming to the United a bone marrow aspirate, which did not demonstrate a malig-
States with only mild aortic insufficiency as seen on echocar- nant process (normocellular marrow; increased eosinophils;
diogram. absent lymphoid aggregates and granulomas).
Initial investigations performed by her primary care physi- The infectious disease workup was expanded to include
cian demonstrated normal liver biochemistry (alanine parvovirus, toxoplasma, Bartonella henselae, B quintana,
aminotransferase, 8 U/L; aspartate aminotransferase, 14 U/ strongyloides, paracoccidioidomycosis, and toxocara, which
L; total bilirubin, 0.4 mg/dL; direct bilirubin, 0.1 mg/dL; al- were all negative. Owing to eosinophilia on the blood smear,
bumin, 4.4 g/dL), microcytic anemia (hemoglobin, 11.1 g/ a stool sample for ova and parasites was obtained and was
dL; mean corpuscular volume, 70.1 fL), and thrombocyto- negative.
penia (116  103/mL) without leukopenia (white blood cell She was evaluated by cardiology for right-sided cardiac
count, 8.3  103/mL, normal differential). C-reactive protein disease as a source for possible portal hypertension leading
was normal (<0.10 mg/dL). Infectious workup was negative to splenomegaly. An electrocardiogram and echocardiogram
for Epstein-Barr virus, cytomegalovirus, and viral hepatitis did not demonstrate signs of pulmonary hypertension or
A, B, and C. She had a speckled antinuclear antibody pattern increased right atrial pressure.
with a titer of 1:40. Ultrasound (US) examination without Hepatology was consulted during a hospital admission
Doppler demonstrated a homogeneous spleen without focal 8 months after her initial presentation. She had continued
defects. Magnetic resonance imaging (MRI) was performed
to evaluate a mass seen adjacent to the liver on US
examination, and it demonstrated splenomegaly (16 cm)
From the 1Department of Pediatrics, Section of Pediatric Gastroenterology and
without hepatomegaly. Notably, a well-circumscribed Hepatology, 2Department of Surgery, Section of Transplantation and Immunology,
3
Department of Pathology, 4Department of Radiology and Biomedical Imaging,
Division of Pediatric Radiology, and 5Department of Pediatrics, Section of
Hematology and Oncology, Yale University School of Medicine, New Haven, CT
The authors declare no conflicts of interest.
MRI Magnetic resonance imaging
US Ultrasound 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jpeds.2019.11.018

222

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 Volume 218  March 2020

early satiety, but no bruising, jaundice, or pruritus. On exam- tal vein thrombosis in the right upper quadrant. Notably, a
ination she was well-appearing, weighing 44.1 kg (32nd previous Roux jejunojejunostomy was confirmed in the epi-
percentile), a decrease of 2 kg over the prior 3 months, gastrium, which was the unknown cystic structure visualized
with a body mass index of 18 kg/m2 (35th percentile). on the abdominal MRI. The liver appeared grossly normal.
Abdominal examination revealed a soft liver edge at the sub- An intact 311 g, 18.0  7.9  2.8-cm spleen without signifi-
costal margin and a spleen edge 17 cm inferior to the left cant abnormalities was removed.
costal margin but not crossing the midline. Laboratory inves- Postoperatively, she demonstrated almost immediate
tigations continued to demonstrate normal liver biochemical improvement in appetite and resolution of abdominal pain,
and synthetic function, iron deficiency anemia, and wors- with a subsequent 5 kg weight gain over the following
ening thrombocytopenia to 66  103/mL. The US examina- 12 months. Her thrombocytopenia resolved (389  103/
tion was repeated, this time with Doppler, to evaluate the mL). There were no postoperative complications or infec-
portal, hepatic, and splenic vasculature. Worsening spleno- tions. To maintain shunt patency, she was treated with
megaly to 24 cm was identified with normal liver echogenic- 3 months of anticoagulation (enoxaparin), and 6 months
ity. Doppler imaging revealed normal portal venous and of antithrombotic therapy (aspirin). Given the increased
hepatic venous flow, without any signs of thrombus or risk for sepsis from encapsulated organisms in patients
cavernous transformation. The splenic vein was not visual- with asplenia, she received the meningococcal B vaccine
ized immediately proximal to the superior mesenteric vein/ immediately after the splenectomy. Because she had received
splenic confluence; there was slow flow and the suggestion the pneumococcal polysaccharide vaccine (PPSV23) before
of splenic varices at the splenic hilum. This constellation of the splenectomy, the pneumococcal conjugate vaccine
findings was suspicious for chronic thrombosis or occlusion (PCV13) was given immediately after the splenectomy with
of the splenic vein. A portal venous-timed MRI demonstrated the recommendation to administer the PPSV23 6-12 months
evidence for splenic vein narrowing just proximal to its later and then every 5 years. Penicillin V prophylaxis was
confluence with the superior mesenteric vein (Figure 1, A; administered for 1 year. She was counselled to obtain the
available at www.jpeds.com). annual influenza vaccine.
A transjugular liver biopsy was obtained by interventional
radiology. The microscopy was notable for mildly dilated Discussion
branches of the portal vein with dilatation and extension
into the periportal sinusoids, consistent with hepatoportal The Spleen and Its Vascularity
sclerosis (Figure 1, B). There were no signs of cirrhosis, The spleen is a highly vascularized organ divided into 2 com-
nodular regenerative hyperplasia, or congenital hepatic partments based on morphology and function: the red and
fibrosis. During the same procedure, transjugular hepatic white pulp.11 The red pulp serves as a blood filter where mac-
venous pressure measurements were obtained to evaluate rophages remove foreign material, pathogens, cellular debris,
the hepatic outflow and hepatic venous pressure gradient and aging erythrocytes from circulation.11 This region also
across the liver. The pressure in the hepatic vein was 6 mm acts as a storage site for iron, erythrocytes, and platelets.11
Hg, and the hepatic venous pressure gradient was 1 mm The white pulp is a highly organized lymphoid region
Hg (normal <5 mm Hg). An upper endoscopy was composed of B and T lymphocytes regulated by macrophages
performed to evaluate for complications of portal and B lymphocytes in the surrounding marginal zone.11
hypertension and was significant for type 1 isolated Segmental branches of the splenic artery divide into arteri-
gastric varices (Figure 1, C), without esophageal varices oles surrounded by the white pulp, which end in cords within
(Figure 1, D). the red pulp.11 These cords drain into venous sinuses that
Based on the entirety of her investigations, the cause of her merge and join to form the splenic vein which exits the spleen
splenomegaly was suspected to be splenic vein stenosis at the hilum.11 Tributaries of the splenic vein include the
causing a splenic venous outflow obstruction, possibly a pancreatic, short gastric, and left gastroepiploic veins.12,13
complication of her prior intestinal surgery or past intestinal The inferior mesenteric vein typically flows into the splenic
disease. We evaluated her suitability for a splenic vein dila- vein, but anatomic variations exist.13,14 The splenic and supe-
tion procedure with interventional radiology. However, we rior mesenteric veins merge to form the portal vein.14
deemed this to be too high risk for hemorrhagic complica-
tions owing to the splenic vein’s retroperitoneal location Left-Sided Portal Hypertension
and the uncertainty surrounding her anatomy after the pre- Left-sided portal hypertension is a localized form of extrahe-
vious abdominal surgery. After discussion with the hepato- patic portal hypertension.13,15 Splenic vein occlusion leads to
biliary surgeon, the patient, and her mother, a decision was splenomegaly as well as isolated gastric varices without
made to perform a splenectomy with creation of a proximal esophageal varices, as seen in the case presented here. This
splenorenal shunt. Intraoperatively, extensive vascular collat- is due to the increased blood flow to the short gastric and
erals were identified in the left side of the abdomen in an area left gastroepiploic veins, with subsequent engorgement of
proximal to the splenic vein stenosis, which was consistent the submucosal veins in the stomach which can hemor-
with the splenic vein stenosis and isolated type 1 gastric vari- rhage.13,15,16 Although multiple causes have been described,
ces. There were no signs of collateralization secondary to por- the majority of cases reported in adults are of splenic vein
223

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THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 218

thromboses secondary to pancreatic disorders, owing to the directed laboratory investigations and US examinations. A
splenic vein’s close proximity to the pancreas.13,15,16 suggested systematic approach is presented in Figure 2.
Based on the history and physical examination, the
Splenomegaly and Hypersplenism
clinician may narrow down the differential diagnosis
Since the early 1900s, it has been reported that splenomegaly
(Table). Systemic complaints such as fevers, night sweats,
is not typically due to a primary splenic disease.6 Studies of
or weight loss are nonspecific for infectious, hematologic,
patients of all ages with splenomegaly from various hospitals
or malignant causes, and rashes or joint swelling may
in California as well as from the Danish National Registry of indicate a rheumatologic disease. Physical examination
Patients have demonstrated that the overarching causes of
findings of lymphadenopathy may suggest an infection or
splenomegaly are extensive and include hematologic disor-
malignancy, and hepatomegaly may indicate liver disease.
ders (16%-66%), hepatic diseases (9%-41%), infections
Jaundice may reflect an underlying hemolytic disorder or
(9%-36%), inflammatory (2%-5%), primary splenic causes
liver disease. Petechiae may be a sign of thrombocytopenia
(1%-6%), and idiopathic/unknown (1%-25%).7-10 Because
from hypersplenism or hematologic malignancy.
of this, detection of splenomegaly should be considered
Laboratory investigations are important in the evaluation
potentially pathologic and warrants further evaluation.
of splenomegaly. Initial testing should be geared toward
Splenomegaly may progress to hypersplenism, a disorder narrowing down the list of overarching categories. These
where the enlarged spleen traps platelets and becomes a reser-
include a complete blood count with differential, reticulo-
voir for circulating neutrophils and red blood cells.17,18 This
cyte count, blood smear, liver biochemistry (alanine amino-
condition leads to thrombocytopenia and/or anemia with
transferase, aspartate aminotransferase, gamma-glutamyl
subsequent bone marrow hyperplasia.18-20 The cytopenias
transferase, and total and direct bilirubin), liver synthetic
typically resolve with resolution of splenomegaly or following
function (international normalized ratio, albumin), and
splenectomy, if indicated.
Epstein-Barr virus, cytomegalovirus, and parvovirus
Approach to Splenomegaly serology. Other laboratory investigations, such as autoim-
Identifying the underlying cause of splenomegaly starts with mune markers, can be considered based on the history
a thorough history and physical examination followed by and physical examination findings.

Figure 2. Systematic approach for the evaluation of splenomegaly. ab, antibody; ALT, alanine aminotransferase; ANA, anti-
nuclear antibody; AST, aspartate aminotransferase; CBC, complete blood count; CMV, cytomegalovirus; dsDNA, double
stranded DNA; EBV VCA, Epstein-Barr virus viral-capsid antigen; EKG, electrocardiogram; GGT, gamma-glutamyl transferase;
IR, interventional radiology; LDH, lactate dehydrogenase; RF, rheumatoid factor; sAg, surface antigen.

224 Freiberg et al

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March 2020 GRAND ROUNDS

Table. Differential diagnosis of splenomegaly

Infectious Hepatic disorders

 Viral: Hepatitis A/B/C/E, cytomegalovirus, Epstein-Barr virus, herpes  Cirrhosis with portal hypertension
simplex virus, HIV  Autoimmune hepatitis
 Bacterial: Bartonellosis, brucellosis, Lyme disease, salmonellosis,  Congenital hepatic fibrosis
tularemia, tuberculosis, subacute bacterial endocarditis, syphilis  Hepatoportal sclerosis
 Other: Schistosomiasis, Rocky Mountain spotted fever, disseminated  Nodular regenerative hyperplasia
histoplasmosis, malaria, toxoplasmosis, leishmaniasis, echinococcosis  Storage diseases and inborn errors of metabolism: Lipidoses (Gaucher
Hemolytic disorders disease, Niemann-Pick disease), mucopolysaccharidoses, defects in
 Hemolytic anemia carbohydrate metabolism (galactosemia, fructose intolerance), sea-blue
 Hemoglobinopathy: Thalassemia, sickle cell disease histiocyte syndrome
 Myelofibrosis Anatomic
 Myeloid metaplasia  Vascular abnormalities: portal or splenic venous obstruction/thrombosis
 Thrombocythemia  Cysts or pseudocysts
Malignancy  Hamartomas
 Leukemia, lymphoma  Hemangiomas
 Angiosarcoma  Lymphangioma
 Histiocytosis  Hematoma
 Metastatic diseases  Peliosis
Autoimmune/inflammatory disorder Other
 Juvenile rheumatoid arthritis  Elevated right-sided heart pressures, congestive heart failure
 Systemic lupus erythematosus
 Sarcoidosis

Imaging is a useful adjunct to the physical examination to or travel, infectious diseases should be consulted early after
assess the anatomy. US examination is often the first modal- presentation. Finally, rheumatology can provide insight on
ity used because it is quick, noninvasive, and does not expose autoimmune conditions that can cause nonspecific enlarge-
the patient to ionizing radiation. The normal spleen will ment of the spleen. If no one overarching diagnosis can be as-
appear homogeneous on US imaging, mildly hyperechoic certained, a multidisciplinary team should collaboratively
compared with the kidney, and isoechoic to mildly hypere- guide further investigations.
choic compared with the liver.21 Expected splenic dimen-
sions on US examination have been reported by age.22,23 Hepatoportal Sclerosis
Doppler imaging is useful to evaluate the hepatic artery, he-
patic vein, portal vein, and splenic vein vasculature as well as Hepatoportal sclerosis was first described in patients with
the presence of collateral blood flow. With any vascular ab- portal hypertension whose liver histology was notable for
normalities, computed tomography scans or MRI sequences dilated portal vascular spaces and thickened or sclerotic por-
can be used, with contrast timed to highlight the vessel(s) in tal veins with herniation, without the presence of cirrhosis.26
question.21 Although the pathophysiology is unknown, hepatoportal
The involvement of subspecialists is typically helpful in the sclerosis has been associated with immunologic diseases,
diagnosis and management of splenomegaly. Hematology/ chronic infections, medication or toxin exposure, genetic dis-
oncology is frequently consulted as cytopenias develop with orders, and prothrombotic conditions.25 It is unclear if the
splenomegaly and can evaluate for underlying blood disor- histologic changes predate the portal hypertension, as specu-
ders such as hemolytic anemias and hemoglobinopathies lated in a case series of pediatric patients.27 This finding
that can cause splenomegaly. Furthermore, the presence of would be consistent with the theory that damage to the portal
constitutional symptoms necessitates an evaluation for ma- venous microcirculation leads to increased intrahepatic resis-
lignancy. With hepatomegaly or elevated liver biochemistry, tance and portal hypertension.28,29 Conceivably, it is also
further hepatologic evaluation should be performed. Howev- possible that decreased portal venous blood flow, as from a
er, it should be noted that noncirrhotic portal hypertension, portal vein thrombus, could contribute to the development
such as hepatoportal sclerosis, congenital hepatic fibrosis, or of hepatoportal sclerosis, similar to the sinusoidal dilation
nodular regenerative hyperplasia, may present without hepa- observed with impaired portal perfusion, such as with portal
tomegaly or elevated liver biochemistry, and may only be vein insufficiency.30,31
diagnosed on liver histopathology.24,25 Thus, without an The overall survival of patients with hepatoportal sclerosis
obvious source for splenomegaly, hepatology or clinicians seems to be good,32 with surveillance and treatment geared
knowledgeable in hepatologic diseases should be consulted, toward preventing its complications. It has been suggested
even in the setting of normal liver biochemistry and no hepa- that management of esophageal variceal bleeding may be
tomegaly. With splenic vascular abnormalities or focal similar to that for patients with cirrhosis and portal hyper-
splenic anatomic abnormalities on imaging, such as splenic tension, although data supporting this practice are scarce.28
cysts, hepatology, pediatric surgery, or interventional radi- There is a paucity of data for the use of anticoagulation to
ology consultation should be sought. With a history of fever manage hepatoportal sclerosis, but this may be considered.25

Progressive Splenomegaly and Hypersplenism: An Unusual Case of Splenic Vein Stenosis with Histologic Findings 225
of Hepatoportal Sclerosis
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THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 218

Liver transplant can be considered in the setting of unman- evaluate splenomegaly. Repeat imaging or other modalities
ageable portal hypertension and the rare instances of progres- may be required if there is inadequate visualization.
sive end-stage liver disease.25 There is some evidence to Our patient’s initial presentation of splenomegaly demon-
suggest that splenectomy may not only treat the symptoms strates the diagnostic challenges faced by clinicians. Given the
of hypersplenism caused by hepatoportal sclerosis, but may broad differential, it is important to have a systematic
also lead to disease remission.33-35 Surveillance can include approach to evaluation. Initial investigations should be
serial physical examination measurements of the enlarged geared toward the most common causes of hematologic, he-
spleen, liver biochemistry, and synthetic function, as well as patic, infectious, and anatomic etiologies. A multidisci-
the platelet counts. There is no evidence to support liver elas- plinary team approach is essential to direct further
tography in this setting because validated reference values are investigations to elucidate and manage the underlying diag-
not available for this condition but serial elastography may be nosis. To our knowledge, this is the first case of splenic
considered to track changes in liver stiffness over time to alert vein stenosis associated with hepatoportal sclerosis. n
the clinician of worsening hepatic fibrosis.
We thank our multidisciplinary team at Yale New Haven Children’s
Therapeutic Options and Splenectomy Hospital. We also thank our patient and her family for entrusting
Because the differential diagnosis of splenomegaly is wide, in- our team with her medical care and participating in this journey
with us.
vestigations to understand the underlying pathology is key to
direct treatment. Managing the underlying cause can lead to Submitted for publication Aug 13, 2019; last revision received Oct 18, 2019;
resolution of splenomegaly and hypersplenism with normal- accepted Nov 11, 2019.
ization of platelet count. As in our patient, splenectomy may Reprint requests: Ben Freiberg, MD, 333 Cedar Street, PO Box 208064, New
be required on a case-by-case basis. A distal splenorenal Haven, CT 06520. E-mail: [email protected]
shunt was not preformed owing to the suspicion of splenic
vein stenosis and its unknown exact location. As such, a prox- References
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Progressive Splenomegaly and Hypersplenism: An Unusual Case of Splenic Vein Stenosis with Histologic Findings 227
of Hepatoportal Sclerosis
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THE JOURNAL OF PEDIATRICS  www.jpeds.com Volume 218

Figure 1. Investigations to evaluate the etiology of splenomegaly and consequences of portal hypertension. A, MRI. Axial T1-
weighted volumetric interpolated breath-hold (VIBE) fat-saturated subtracted postcontrast sequence. The arrow denotes the
stenosis of the splenic vein just proximal to the portosplenic confluence. B, Portal tract demonstrating dilated branches of portal
vein, herniating toward the lobule (stain: hematoxylin and eosin; orginal maginication  200). C, Endoscopic view in retroflexion
of the gastric fundus demonstrating isolated type 1 gastric varices (arrows). D, Endoscopic view of lower esophagus demon-
strating absence of esophageal varices.

227.e1 Freiberg et al

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