Portal hypertension commonly accompanies cirrhosis and may cause significant complications, including variceal hemorrhage, ascites, hepatopulmonary syndrome, portopulmonary hypertension, and hepatic encephalopathy. The severity of portal hypertension can be evaluated by measurement of the hepatic venous pressure gradient (HVPG), an indirect measure of portal venous pressure that is valid in predicting clinical outcomes, and guiding therapeutic decisions in cirrhotic adults (1).
HVPG is obtained by cannulation of the hepatic vein and measurement of the difference between the “free” hepatic vein pressure (FHVP) and the “wedged” hepatic vein pressure (WHVP) (Fig. 1) (2). Occlusion of blood flow in a hepatic vein by balloon or when the catheter is wedged creates a static column of blood that transmits the pressure from the preceding vascular territory (ie, the portal vein) to the catheter (3). Normal HVPG values range from 1 to 5 mmHg in adults. In studies of adults primarily with cirrhosis caused by alcoholic liver disease or hepatitis C, complications of portal hypertension occur when HVPG measurements are >10 mmHg (1,4,5). An HVPG >20 mmHg correlates with variceal bleeding, rebleeding, and increased mortality (6). In cirrhotic adults given propranolol to treat portal hypertension, a reduction of the HVPG to <12 mmHg or by >20% of baseline significantly reduces the risk of variceal bleeding and rebleeding, ascites, spontaneous bacterial peritonitis, and death (7–9). Measurement of HVPG in cirrhotic adults is therefore now recommended as part of routine clinical practice to aid in determining prognosis and choosing optimal prophylactic therapy (2,10).
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FIGURE 1: Schematic representation of the measurement of hepatic venous pressure gradient. A, Measurement of free hepatic venous pressure. B, Measurement of wedged hepatic venous pressure. HV = hepatic vein; IVC = inferior vena cava; PV = portal vein.
On the contrary, there is a paucity of data to guide the management of complications of portal hypertension in cirrhotic children. To our knowledge, there is only 1 published study that reported HVPG measurements in a small number of children with chronic liver disease (11). In addition, portal pressure gradient data are available from reports of placement of transjugular intrahepatic portosystemic shunts in children with portal hypertension, in which the portal-systemic venous pressure gradient typically ranges from 12 to 35 mmHg before placement of the transjugular intrahepatic portosystemic shunts and falls to 5 to 15 mmHg afterward (12,13).
Therefore, we aimed to determine the feasibility and safety of HVPG measurements in children with liver disease by reviewing the retrospective experience with this test in our institution. We anticipate that our results will help to inform the design of future studies of the management of portal hypertension in children.
METHODS
We searched the database of procedures performed by the Image Guided Therapy (interventional radiology) Department at The Hospital for Sick Children for patients who had undergone HVPG measurements between January 2000 and December 2011. We then reviewed the medical charts of these patients and retrieved clinical, procedural, and outcome details, which included demographic data, anesthetic and procedural records, endoscopy studies, imaging studies, and pathology reports.
HVPG measurement was performed under general anesthesia after fasting, and all of the procedures were performed by experienced interventional radiologists. Measurements were completed as part of routine clinical care at the discretion of the interventional radiologist during a procedure primarily undertaken to obtain a transjugular liver biopsy (n = 47), to define venous anatomy with venography, or solely to evaluate portal hypertension. We generally aim to include a liver biopsy in the diagnostic investigation of children attending our institution with acute liver failure, which the treating physician decides on a case-by-case basis.
Informed consent was obtained from all of the patients. Infusions of platelets and/or fresh frozen plasma were used in patients with severe coagulation defects. Blood transfusion was provided before the procedure if necessary. Anesthesia was provided according to the clinical practice of the anesthetist, usually including administration of propofol. The right internal jugular vein was punctured under ultrasound guidance and an angiography catheter was advanced into a hepatic vein. Intralumenal pressure was measured in the right atrium, the inferior vena cava and with the catheter free in the hepatic vein (FHVP). Pressure measurements were calibrated to the height of the right atrium. The catheter was then advanced to a wedged position in the hepatic vein, its position confirmed by the appropriate change in pressure waveform, and the WHVP measured after the pressure tracing had stabilized. After all measurements were completed in duplicate, hepatic venography and other angiographic assessments were undertaken as indicated. The HVPG was calculated by subtracting the FHVP from the WHVP.
Outcomes up to 1 year after the HVPG measurement were recorded from the charts for all of the patients. The outcomes recorded included adverse events during or immediately following the procedure (including bleeding, liver capsule tear, anesthetic complications) and later outcomes related to the underlying disease (including variceal bleeding, death, liver transplantation). The study was approved by the research ethics board of the Hospital for Sick Children, Toronto, Ontario, Canada.
RESULTS
Forty-nine children underwent 52 HVPG measurements during the time interval studied. For 3 children who underwent measurements twice, only the first HVPG values are included here, although safety and outcomes data from the subsequent measurements are also included. Patient details are provided in Table 1.
TABLE 1: Details of patients
Thirty-nine patients had a history of clinical events attributable to portal hypertension: 19 patients had varices documented at endoscopy or portal-systemic collaterals on abdominal imaging, 34 had ascites, 27 had splenomegaly on ultrasound imaging, and 4 patients had encephalopathy. Twenty-eight patients had a platelet count <100 × 109 cells/L, 20 had an international normalized ratio >1.3, and 14 patients had previous or presently documented gastrointestinal bleeding. Fifteen patients were in the critical care unit before the time of the procedure.
HVPG measurements were undertaken during procedures primarily undertaken for transjugular liver biopsy (n = 47) or for venography to evaluate intrahepatic vascular abnormalities or portal hypertension. In children after liver transplantation, HVPG measurements were undertaken at the time of transjugular liver biopsy in children with chronic graft injury, portal hypertension, thrombocytopenia, and/or other coagulopathy. Measurements were successfully completed in all of the patients. No complications were documented to have occurred. HVPG values ranged between 0 and 28 mmHg, median 9.0 mmHg, and were elevated >6 mmHg in 30 patients (Table 2 and Fig. 2).
TABLE 2: HVPG measurements in 49 children with liver disease
FIGURE 2: Hepatic venous pressure gradient (HVPG) values in 49 children with acute and chronic liver diseases.
Among the 7 patients with cirrhosis, 6 had clinical complications of portal hypertension (ascites 1, varices 1, varices and ascites 2, variceal bleeding 1, variceal bleeding and ascites 1). HVPG in these 6 patients ranged from 10 to 20 mmHg (median 13 mmHg). HVPG was 12 mmHg in the 1 cirrhotic patient without complications of PHT. In the year following the HVPG measurement, 2 of the cirrhotic patients underwent liver transplantation, 3 had persistent or recurrent complications of portal hypertension managed with medical therapy, 1 remained stable without recurrent complications, and 1 was lost to follow-up. No relation between initial HVPG and outcome was identified.
Fifteen patients had acute liver failure and their HVPG ranged from 0 to 14 mmHg (median 9 mmHg). Median HVPG in the 7 patients with recovery from acute liver failure was 4 mmHg (range 0–13 mmHg) compared with 10.5 mmHg (range 0–13 mmHg) in the 8 patients who underwent liver transplantation or died, with significant overlap between the 2 groups.
HVPG was measured in 9 patients after bone marrow transplantation, including 3 with sinusoidal obstruction syndrome (median HVPG 24 mmHg, range 15–28 mmHg) and 4 with graft-versus-host disease (GVHD, median HVPG 7.5 mmHg, range 2–12 mmHg).
DISCUSSION
In this study, we have shown that measurement of HVPG is feasible in children with acute and chronic liver disease. The procedure can be completed safely, with no major or minor complications documented in the 49 patients included in this retrospective review.
A previous report found HVPG measurements to be feasible in a study of 20 children with chronic liver disease, including 10 with biliary atresia (11). Our patient population included those experiencing acute liver failure as well as chronic liver disease, but none had biliary atresia. The wide range of other conditions in our patients enables us to suggest that HVPG is safe and feasible in a variety of circumstances.
Patients included in our study generally had severe disease, as documented by markers of severity such as coagulopathy and present admission to the critical care unit. The absence of complications attributable to the HVPG measurement suggests that the procedure is also safe and feasible in patients who are critically ill and with increased bleeding risk.
HVPG was elevated in all of the children with cirrhosis we evaluated, although the small number of children precluded comparison of HVPG between those with and without complications of portal hypertension such as variceal bleeding and ascites. Miraglia et al (11) documented that HVPG values were elevated in all but 3 of 20 children with chronic liver disease and splenomegaly, ranging between 2 and 33 mmHg (mean 11.3 ± 7.2 mmHg). They found that several children with biliary atresia had veno-venous shunts, which can lead to an underestimation of portal pressure by HVPG measurement (11). This finding was not identified in any of the patients in our study.
Patients with acute liver failure in our study underwent HVPG measurements at the discretion of the interventional radiologist during the performance of a transjugular liver biopsy procedure. Elevated HVPG in acute liver failure may reflect portal hypertension because of the effects of acute swelling of the liver causing increased vascular resistance or to direct vascular damage or vasoconstriction. To our knowledge, there are no published data that have examined this mechanism or that have provided information about HVPG in acute liver failure in adult or pediatric populations. In our study, it is not possible to examine correlations between HVPG and other potential predictors of outcome in the children with acute liver failure because of the retrospective study design, the variation in detail provided in pathology reports, and the variable administration of fresh frozen plasma and other blood products before and after the HVPG measurement.
Our data also suggest that HVPG measurements may help to distinguish sinusoidal obstruction syndrome from GVHD in children following bone marrow transplantation. The less pronounced elevation of HVPG seen in children with GVHD is in keeping with the expected effects of primarily the biliary GVHD pathology with associated portal tract inflammation (14). The elevation of HVPG in sinusoidal obstruction syndrome has been previously described in a single study reporting measurements in adults (15). If further validated in an adequately powered and designed future study, this novel finding would have clinical use for those patients in whom the differential diagnosis between GVHD and sinusoidal obstruction syndrome remains challenging after standard clinical testing.
The limitations of our study include a small sample size and no control group for HVPG measurement in healthy children. Furthermore, the retrospective design means that the approach to the procedures was not standardized, being performed by different (although all experienced) radiologists and having various combinations of anesthetic agents. This highlights the importance for future research of the potential effects of anesthetic agents and intravenous fluid therapy on HVPG measurements in children, who, unlike adults, require general anesthesia for this procedure. Future pediatric studies must also carefully standardize measurement technique (2).
In conclusion, we found that measurement of HVPG was feasible and safe in a mixed group of children with acute and chronic liver disease, including those who were critically ill. Further studies are needed to evaluate the reliability and reproducibility of HVPG measurements in children and to identify relations between HVPG and the complications of portal hypertension in children with cirrhosis.
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