Fig. 27.1
Imbalance of vasoconstrictors and vasodilators in cirrhosis
The second contributing factor to portal hypertension results from increased portal-collateral blood flow. The hyperdynamic circulatory state in cirrhosis was first described in 1953 by Abelmann and Kowaski [3]. They demonstrated that patients with alcoholic cirrhosis presented with increased cardiac output and reduced peripheral vascular resistance. Vasodilation of the splanchnic circulation was later demonstrated and found to be a result of increased systemic levels of vasodilator substances and local hyporesponsiveness to vasoconstrictors. The increase of blood flow into the portal system is responsible for maintenance and further aggravation of portal hypertension.
Neoangiogenesis—formation of new blood vessels—, resultant of vascular endothelial growth factor (VEGF) release, also plays a major role in the development of a hyperkinetic state and the formation of porto-systemic collaterals. Unfortunately, these collaterals are not able to fully accommodate the excess flow or alleviate the portal pressure and they lead to one of the most dreaded complications of portal hypertension, the development of esophageal varices .
Assessment of Portal Hypertension
The direct measurement of portal pressure, which in normal individuals ranges from 7 to 12 mmHg [4], can be accomplished via transhepatic or transvenous catheterization of the portal vein. However these methods harbor a significant risk of complications, including intraperitoneal bleed, and are no longer performed, except in selected cases [5]. In recent years, many advances have been made in the assessment of portal hypertension with the goal of identifying less-invasive and reproducible diagnostic methods. Below we review the currently used methods and future directions.
Hepatic Venous Pressure Gradient
Portal hypertension can be accurately determined by the pressure gradient between the portal vein and the inferior vena cava, measured by the hepatic venous gradient pressure (HVPG). This gradient represents the actual liver portal perfusion pressure, which in normal individuals ranges from 1 to 5 mmHg [1].
The HVPG measurement is a safe and reproducible technique performed under local anesthesia and conscious sedation. Under fluoroscopic guidance a balloon-tipped catheter is advanced into the main right hepatic vein via the internal jugular, antecubital, or femoral vein. HVPG is then calculated as the difference between the wedged (WHVP) and the free (FHVP) hepatic venous pressures. The WHVP is an indirect measurement of the hepatic sinusoidal pressure which provides a good estimate of the portal vein pressure in cirrhotic patients [6–8]. The WHVP is obtained by inflating the balloon at the tip of the catheter and occluding the hepatic vein. FHVP is measured by maintaining the tip of the catheter floating freely in the hepatic vein, about 2–4 cm distal to the IVC.
Accuracy in HVPG measurement is extremely important and therefore several recommendations have been published to assure adequate measurements [9]. The operators should wait for stabilization of the venous pressures, at 60 s for WHVP and 20 s for FHVP. All measurements should be permanently recorded or printed to allow for later review of the tracings. Also important is to obtain at least duplicate and ideally triplicate measurements, to ensure accurate results. Significant variability is suggestive of errors.
As mentioned above, HVPG measurement is a safe procedure with no absolute contraindications. Caution should be exerted in patients with a history of cardiac arrhythmias when moving the catheter through the right atrium. Also, coagulopathies are common in cirrhotic patients and may require correction prior to the procedure according to individual center’s guidelines. Allergy to iodine contrast is not a contraindication as CO2 may be used or patients may be premedicated with systemic steroids. The risk of complications is small (<1 %) and are usually related to the venous puncture site. The use of ultrasound assistance helps to decrease the risk of complications [10].
HVPG is considered the gold standard test for diagnosis of portal hypertension. Recently, HVPG has been also utilized for prognostic evaluation, monitoring response to therapy and determining the etiology or classification of portal hypertension.
HVPG and Diagnosis of Portal Hypertension
As mentioned earlier, the HVPG in normal subjects ranges from 1 to 5 mmHg. HVPG values greater than 10 mmHg correspond to clinically significant portal hypertension, characterized by the development of esophageal varices and/or ascites. Values between 6 and 9 mmHg correspond to subclinical portal hypertension [11]. Unfortunately, HVPG is not widely available and therefore, it is not utilized routinely in most centers for the sole diagnosis of portal hypertension. The exception are patients undergoing a transjugular liver biopsy, where the HVPG can be easily obtained with little added cost or risks.
HVPG and Classification of Portal Hypertension
In addition to cirrhosis, portal hypertension can be caused by myriad conditions which can be classified according to their anatomical location: prehepatic, intrahepatic, or posthepatic (Table 27.1). Intrahepatic portal hypertension, most commonly caused by cirrhosis, presents with elevated HVPG, resultant of increased WHVP and normal FHVP. In prehepatic or presinusoidal portal hypertension both the WHVP and the FHVP are normal resulting in a normal HVPG. Whereas, in posthepatic portal hypertension, both the WHVP and FHVP are elevated.
Table 27.1
Hepatic venous pressure gradient in the classification of portal hypertension
Types of portal hypertension | Wedged (WHVP) | Free (FHVP) | Gradient (HVPG) |
|---|---|---|---|
Prehepatic | Normal | Normal | Normal |
Intrahepatic | |||
Pre-sinusoidal | Normal | Normal | Normal |
Sinusoidal | Increased | Normal | Increased |
Post-sinusoidal | Increased | Normal | Increased |
Posthepatic | Increased | Increased | Normal |
HVPG and Prognosis in Portal Hypertension
Several studies have correlated the HVPG values with different outcomes in portal hypertension secondary to cirrhosis. The development of gastroesophageal varices is noted when HVPG values are above 10 mmHg, whereas variceal bleeding typically ensues when HVPG is above 12 mmHg [12–14]. HVPG has also been shown to be a good predictor of survival, with values above 16 mmHg in alcoholic cirrhosis associated with increased mortality [15]. HVPG above 20 mmHg within 48 h of an acute variceal bleed episode was also associated with poor outcomes and low 1-year survival [16]. When adjusted by MELD score, presence of ascites, encephalopathy, and age, HVPG remained as an independent prognostic variable with an increased in mortality risk of 3 % for each 1 mmHg increase in the gradient [17]. HVPG has also been studied in preoperative risk assessment of hepatic decompensation in patients undergoing hepatoma resection. HVPG levels above 10 mmHg were associated with persistent decompensation 3 months after surgery [18].
Acute alcoholic hepatitis leads to a significant temporary rise in portal pressure, likely driven by a robust inflammatory response [19, 20]. HVPG values greater than 22 mmHg were independently associated with higher in-hospital mortality [21]. Finally, HVPG has also been found to be an independent predictor of the development of hepatocellular carcinoma, when values are above 10 mmHg [22].
HVPG and Treatment Response in Portal Hypertension
The use of pharmacological therapy to prevent recurrent variceal bleeding was first demonstrated in 1984 by Lebrec et al. [23]. They found that daily administration of propranolol, a nonselective beta-blocker, at doses reducing the heart rate by 25 %, was able to consistently decrease the HVPG values compared to placebo [24]. HVPG has since been used in clinical studies to assess the effects of vasoactive drugs in portal hypertension.
A clinically significant hemodynamic response has been defined by a reduction of HVPG by at least 20 % from baseline or to values below 12 mmHg. When at least one of these goals are achieved, either with pharmacological therapy [25] or spontaneously [26], the risk of first or recurrent variceal bleed decreases to less than 10 %, compared to 20–50 % in nonresponders. In addition to variceal bleed prevention, studies have demonstrated a significant reduction in ascites and spontaneous bacterial peritonitis when these hemodynamic parameters are reached [27, 28]. Finally, the effect of hemodynamic response on improvement of survival has been well demonstrated and adjusted for improvement in liver function [27, 29, 30].
The timing and frequency of HVPG monitoring, however, has not been well established. Most studies have repeated HVPG measurement in 1–3 months after a bleeding episode, whereas the highest risk for rebleeding is within the first several days. Therefore a high proportion of patients (30–40 %) had to be excluded from the studies due to early death or rebleeding. Also, repeated measurements of HVPG have been suggested not to be a cost-effective approach in clinical practice [31].
Endoscopic Assessment of Portal Hypertension
Given limited availability, cost and invasiveness of HVPG measurement, esophagogastroduodenoscopy (EGD) or upper endoscopy remains the most widely used test in clinical practice for assessment of portal hypertension and its complications, including esophageal varices, gastric varices, and portal hypertensive gastropathy (PHG). The role of endoscopy in the diagnosis and management of gastroesophageal varices will be reviewed in later chapters. At the present time, endoscopy is still recommended at diagnosis of cirrhosis although esophageal varices are present in only approximately 30–40 % of patients with compensated cirrhosis [32]. In the future, less-invasive and inexpensive methods may become available and validated for assessment of portal hypertension and risk stratification. In that case, we may be able to determine which patients may benefit from endoscopic assessment of varices based on the presence and/or severity of portal hypertension.
Physical Examination
On first assessment of patients with chronic liver disease, the physical examination may provide diagnostic clues for the presence of portal hypertension and cirrhosis. The findings of splenomegaly, telangiectasias, abdominal wall varicosities (caput medusae), encephalopathy (e.g. asterixis), and ascites are highly specific (range 75–98 %) but have low sensitivity (range 15–68 %) for diagnosis of cirrhosis, especially in the compensated state [33]. The presence of telangiectasias or spider angiomata, in addition to laboratory parameters discussed below, was a fair predictor of the presence of esophageal varices in compensated cirrhosis [34].
Biochemical Parameters
Laboratory studies have been extensively investigated, either isolated or in combination with other parameters, in the assessment of portal hypertension and gastroesophageal varices. The combination of serum albumin, bilirubin, and INR, as used in the Child-Turcotte-Pugh score have been shown to correlate with HVPG levels greater than 20 mmHg [35]. A model combining serum albumin, ALT, and INR was able to predict the presence of clinically significant portal hypertension (HVPG > 10 mmHg) with 93 % sensitivity and 61 % specificity, and an area under the curve (AUC) of 0.952. Otherwise, thrombocytopenia (with platelet count less than 88,000) has been the only parameter most frequently associated with the presence of large esophageal or gastric varices [36]. Several different combinations of laboratory markers have been evaluated to determine the presence or stage of liver fibrosis. The aspartate aminotransferase/platelet ratio index (APRI), a well validated noninvasive tool for diagnosis of liver fibrosis/cirrhosis, has been recently tested in the assessment of clinically significant portal hypertension. APRI greater than 1.09 demonstrated 66 % sensitivity and 73 % specificity for predicting clinically significant portal hypertension (HVPG > 12 mmHg) and an area under the curve (AUC) of 0.716 [37].
Other fibrosis markers , including the presence of circulating endothelial cells (CEC) and CEC/platelet count index, have not been specifically evaluated in the assessment of portal hypertension however they may have a role also in this setting [38, 39]. Serum laminin levels have been shown to correlate well with HVPG values; however its diagnostic accuracy for HVPG greater than 12 mmHg was only 70 % [40]. Similar results have been obtained with measurement of serum hyaluronic acid levels [41].
FibroTest, a commercially available panel of biochemical markers of fibrosis, has also been shown to correlate well with HVPG [42]. However the area under the receiver operating characteristic curves (AUROC) for the diagnosis of severe portal hypertension (HVPG greater than 12 mmHg) was only 0.79, equivalent to that of platelet count and Child-Turcotte-Pugh score.
Abdominal Imaging
Imaging studies, such as ultrasound, magnetic resonance imaging, or computed tomography, are able to identify morphologic features of liver cirrhosis and signs of portal hypertension. While splenomegaly is a sensitive sign of portal hypertension, it markedly lacks specificity [34]. Contrastingly, the presence of portal-systemic collaterals, such as paraumbilical vein recanalization, spleno-renal collaterals, and dilated left short gastric veins, are virtually a 100 % specific for clinically significant portal hypertension, however their sensitivity is limited, especially in compensated cirrhosis [43, 44].
Liver Stiffness
Assessment of liver stiffness, mainly by transient elastography, has been demonstrated to correlate with the presence of portal hypertension [45]. Liver stiffness is mainly determined by the presence of fibrosis, which in turn leads to development of portal hypertension by increasing the intrahepatic resistance to portal blood flow. Recently, liver stiffness, measured by magnetic resonance elastography, has been directly correlated with elevated portal pressure, in the absence of fibrosis, in an animal model of posthepatic portal hypertension [46].
Transient elastography (TE) has been first demonstrated to correlate with HVPG in patients with viral hepatitic C recurrence post liver transplantation [47]. The AUROCs for the diagnosis of portal hypertension (HVPG > 6 mmHg) and clinically significant portal hypertension (HVPG > 12 mmHg) were 0.93 and 0.94, respectively. Interestingly, the correlation of liver stiffness and HVPG was only significant for values below 12 mmHg [48]. This suggests that further increase in portal pressure, becomes almost independent from fibrosis progression as assessed by liver stiffness. A recent meta-analysis including 18 studies and 3644 patients, demonstrated TE to be a good screening tool for diagnosis of clinically significant portal hypertension (HVPG > 10 mmHg) with 90 % sensitivity and 79 % specificity. The role of TE in diagnosis of esophageal varices, however, was not as promising with a sensitivity of 87 % but specificity of only 53 % [49]. Finally, TE cannot be obtained or provides unreliable results in 3–16 % of cases, mostly due to obesity or presence of ascites [50].
Magnetic resonance elastography (MRE) has become a safe, noninvasive, and reliable tool in predicting advanced fibrosis or cirrhosis [51]. Its use in the assessment of portal hypertension has not been extensively explored; however recent studies have suggested a correlation of liver MRE with HVPG results [52].
Finally, the combination of different noninvasive tests, including liver stiffness, spleen diameter, and platelet count, has been proposed with promising results. The portal hypertension risk score was calculated with the formula: 5.953 + 0.188 × liver stiffness + 1.583 × sex (1: male; 0: female) + 26.705 × spleen diameter/platelet count ratio. In patients with compensated cirrhosis, this model demonstrated an AUROC of 0.935 [44].
Spleen Stiffness
Splenomegaly is a specific feature of portal hypertension, and therefore spleen stiffness has recently been explored as a new noninvasive tool for estimating portal pressure. Measurement of spleen stiffness by transient elastography was superior to liver stiffness, liver stiffness-spleen diameter to platelet count ratio and platelet count to spleen diameter ratio, in both the assessment of clinically significant portal hypertension and the presence of gastroesophageal varices [53]. Finally, assessment of viscoelastic parameters of the spleen by MRE was superior to liver MRE in detection of severe portal hypertension (HVPG > 12 mmHg) with an AUROC of 0.81 [52].
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