Friday, March 31, 2023
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Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine
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Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine
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HVPG and endoscopy are current gold-standard techniques to assess portal hypertension and esophageal varices. However its use is limited by their invasiveness. Patients would undoubtedly benefit from noninvasive tests that are able to provide similar information. As any diagnostic test, noninvasive techniques should be safe, easy to perform, inexpensive, accurate and reproducible. Ideally, such tests should be predictive of long-term clinical outcomes.
In the absence of anamnestic data, the cheapest and most immediate information on presence of portal hypertension is that provided by physical examination; splenomegaly, spider nevi, presence of abdominal wall collateral circulation and ascites (±edema) are highly specific of the syndrome,[48] but the sensitivity of physical signs is low in patients with compensated cirrhosis. In a recent study in patients with well-compensated cirrhosis, spider nevi were independent predictors of esophageal varices.[49]
A further step is represented by laboratory tests, having the advantage of being inexpensive and independent of expertise. Albumin, bilirubin, international normalized ratio (INR) or their combination in the Child–Pugh score correlate with HVPG[21,50] and with the prevalence and grade of esophageal varices in cirrhotic patients. In a study from our group in patients with compensated cirrhosis, a model combining albumin, ALT and INR had an area under the curve (AUC) of 0.952 in predicting clinically significant portal hypertension (CSPH; HVPG >10 mmHg).[49] Thrombocytopenia is the single laboratory test most frequently associated with the presence of varices and of large esophageal varices.[51]
Most serum fibrosis markers have not been specifically studied in predicting portal hypertension but some data suggest that they might be useful. Fibrotest showed a good accuracy in one study,[52] but as 92% of the studied population had CSPH its specificity is questionable. YKL-40 and collagen propeptide PIIINP were predictive of short-term survival and increased relative-risk of death in patients with alcoholic liver disease;[53] hyaluronic acid had a predictive value equivalent to Child–Pugh score in a cohort of patients with HCV-related cirrhosis followed-up for a median of 38 months.[54]
Transient elastography (TE; Fibroscan®, Echosens, Paris, France) is a well-validated technique for the noninvasive assessment of liver fibrosis.[55] Measurements are performed with an ultrasound transducer built on the axis of a vibrator; a vibration of mild amplitude and low frequency is transmitted, inducing a wave that propagates through the liver tissue, and pulse-echo acquisitions are performed to measure the velocity of propagation of the wave, which is directly related to tissue stiffness. Since fibrosis is the main determinant of tissue stiffness and of hepatic resistance to portal blood flow (the major determinant of portal pressure in early stages of portal hypertension), TE has been tested in recent years as a novel way of obtaining numerical, objective and operator-independent noninvasive surrogate data of HVPG.[55]
In a study performed in patients with hepatitis C recurrence after liver transplantation, LS showed a good linear correlation with fibrosis and HVPG;[56] specifically, a LS ≥8.74 kPa had a sensitivity and specificity of 90 and 81%, respectively, for the diagnosis of HVPG >6 mmHg in this population. Five subsequent studies provided evidence of a good accuracy (AUC range: 0.77–0.99) of TE for diagnosing and ruling-out CSPH (HVPG >10 mmHg) in patients with cirrhosis ( Table 3 ),[57] LS showing a significant linear correlation with HVPG (R range: 0.55–0.86). The cutoff for predicting CSPH varies across studies, mainly due to differences in the choice of sensitivity or specificity. This limitation is largely overcome by applying a pragmatic rule, choosing a very sensitive cutoff to rule-out CSPH and a very specific cutoff to rule it in. In doing so, a LS <13.6 kPa confidently rules-out CSPH, while LS ≥21.1 kPa accurately diagnoses it. Interestingly, a recent study[58] showed that both HVPG ≥10 mmHg and LS ≥21.1 kPa were good predictors of clinical decompensation, with substantially equal discriminative ability (AUC: 0.815 vs 0.837; not significant). On the other hand, patients with intermediate values (LS between 13.6 and 21.1 kPa) cannot be easily classified as having or not having CSPH. This was also shown recently in patients with potentially resectable hepatocellular carcinoma, indicating that TE might be used to rule-out or confirm CSPH, and thus for indicating or contraindicating surgery[59] whenever HVPG is not available.
On the other hand, it should be underlined that above the threshold value of 13.6 kPa the correlation of LS and HVPG is less accurate,[60] probably reflecting that at HVPG >10 mmHg development of portals–systemic collaterals and increased portal–collateral blood flow means that fibrosis is no longer the main mechanism responsible for portal hypertension.[60] This also partially explains why TE is not accurate enough to predict the presence and size of esophageal varices (accuracy does not exceed 65–75% in the published studies with adequate sample size). In summary, TE can be very useful to rule out or rule in CSPH, but there is a considerable ‘gray zone’ (between 13.6 and 21.1 kPa) and the technique is not accurate enough to substitute HVPG to quantify the exact severity of portal hypertension. Major technical limitations of TE include the lack of visualization of the parenchyma in the region of interest and failure to obtain any measurement or unreliable results in 3–16% of cases[61] mostly because of obesity or presence of ascites. Moreover, the influence of the etiology of cirrhosis (e.g., alcoholic vs viral cirrhosis) on the cutoffs of TE for CSPH have not been specifically studied, and should be addressed by future studies.
Newer methods for estimating LS include magnetic resonance imaging elastography (MRE)[62] and ultrasound-based (sonoelastography) methods (strain ratios, acoustic radiation force impulse imaging [ARFI] and shear-wave velocity estimation). While MRE is accurate but too costly to be routinely used, sonoelastography is increasingly used, as it can be implemented on ultrasound equipment and overcome technical limitations of TE. Among sonoelastography methods ARFI (Virtual Touch™ Tissue Quantification; Siemens Healthcare, Erlangen, Germany) is the best validated so far. ARFI uses mechanical excitation of the tissue using short-duration (262 µ) that propagate shear waves and generate localized, µ-scale displacements in tissue. The shear-wave velocity (expressed in m/s) is measured in a 10-mm long and 6-mm wide region that can be chosen by the operator on real-time imaging. ARFI has already shown to hold a similar accuracy as TE in predicting significant fibrosis and cirrhosis[63] and preliminary data in assessing the consequences of portal hypertension suggest similar results. An important limitation that is probably inherent to all elastography techniques is that LS can increase independent of fibrosis due to food ingestion, inflammation, cholestasis and liver congestion.
Spleen stiffness. Since splenomegaly in cirrhosis is a direct consequence of portal hypertension, spleen stiffness has been recently proposed as a new noninvasive parameter with better accuracy than LS for predicting CSPH and esophageal varices. Data obtained by MRE,[64] TE,[65] real-time elastography[66] and ARFI appear promising, and future studies assessing the performance of noninvasive predictors of portal hypertension should include this parameter.
Ultrasonography (US) is the first-line imaging technique recommended for the diagnosis and follow-up of patients with portal hypertension,[67] since it is noninvasive, cheap and can be performed at bedside. US is highly specific for the diagnosis of cirrhosis and portal hypertension, but its sensitivity is relatively low in compensated patients. Diagnosis of cirrhosis on conventional US is based on changes in liver morphology and signs of portal hypertension.[67] The most accurate single US sign for the diagnosis of cirrhosis is nodularity of liver surface. This should be specifically investigated using high-frequency transducers, with better diagnostic performance than conventional abdominal US probes. The combination of nodular liver surface and portal flow mean velocity <12 cm/s has 80% accuracy discriminating patients with chronic hepatitis with severe fibrosis from those with cirrhosis and its combination with TE allows an optimal accuracy in ‘difficult’ patients.[68] In patients with known cirrhosis, US-Doppler has >80% specificity diagnosing CSPH, but sensitivity does not exceed 40–70%, particularly in compensated patients.[67] While the presence of one or more signs allows establishment of a robust diagnosis, their absence cannot exclude CSPH. The presence of portal–systemic collaterals (patent paraumbilical vein, spleno–renal collaterals, dilated left- and short-gastric veins), and inversion of flow within the portal system are 100% specific of CSPH. Some collaterals, such as left-gastric vein >3 mm and short-gastric veins, strongly suggest the presence of esophageal varices, and their development/increase in number have been associated with a greater proportion of variceal formation and growth.[67,69]
On the other hand, it should be underlined that US and Doppler-US are very accurate for detecting portal vein and hepatic veins thrombosis.[70] As portal vein thrombosis often takes place in patients with cirrhosis and hepatocellular carcinoma, which can be detected by US, and can aggravate a previously stable condition, US should be routinely performed to rule-out these complications in patients with cirrhosis presenting a new clinical event.[67]
Splenomegaly is the most common and sensitive sign of portal hypertension. It is an independent predictor of esophageal varices, and is a marker of CSPH in compensated cirrhotic patients. Progressive spleen enlargement has been shown to predict variceal formation and growth, and is associated with a higher probability of clinical decompensation.[67,69]
Other US and Doppler-US signs of CSPH include dilatation of portal vein (diameter >13 mm); lack or reduced respiratory variations of splenic and superior mesenteric vein diameter; reduced portal vein velocity; increased ‘congestion index’ of portal vein; altered hepatic vein Doppler pattern; increased intraparenchymal hepatic and splenic artery resistance and pulsatility index; increased intraparenchymal renal artery resistance and pulsatility index and reduced mesenteric artery resistance and pulsatility index.[67,69] While US signs can reliably indicate CSPH, the correlation of HVPG with these parameters is unsatisfactory; thus US signs can not be used as surrogates of HVPG.
US are highly sensitive in diagnosing ascites, which is the most common clinical decompensation of cirrhosis and holds a severe prognostic significance. Also, increased intrarenal arteriolar resistance index correlates with renal vasoconstriction in patients with cirrhosis; it is observed in about 40% of patients with ascites and is accurate in detecting hepatorenal syndrome. Small liver size, splenomegaly >14.5 cm, mean portal vein velocity below 10 cm/s and loss of pulsatility of hepatic veins have been all associated with higher mortality on follow-up in patients with compensated cirrhosis.[67,69]
US-Doppler is useful in the noninvasive follow-up of TIPS.[71] However, US-Doppler is insufficiently accurate to be used as a surrogate of changes of HVPG during medical therapy of portal hypertension.[67,69]
CT and MRI allow a very accurate visualization of the portal venous system. Single detector and multidetector CT scanning are reliable in detecting large esophageal varices (specificity: 90–100%; sensitivity: 84–100%), with moderate interobserver variability; however, the sensitivity in detecting small varices is lower. CT screening of varices was more cost-effective than endoscopy screening and than CT followed by endoscopy in patients with small varices on CT. However, CT scan implies substantial irradiation, which should be carefully considered in risk–benefit assessment. Dynamic contrast-enhanced single-section CT scans and compartmental analysis of time/intensity curves of liver MRIs after injection of a gadolinium chelate allow a quantitative measurement of portal and azygos blood flow.[72] Portal fraction of liver perfusion and mean transit time on MRI show a moderate correlation with HVPG.[73]
CT and/or MRI should be used in clinical situations requiring a detailed assessment of the portal venous system, such as to assess the extent of thrombosis; to detect portal cholangiopathy in patients with a portal cavernoma; to map collateral circulation in patients with ectopic variceal bleeding, and before TIPS placement, especially in ‘difficult’ patients, such as those with Budd–Chiari syndrome.
The combination of different methods provides theoretical advantages over the use of a single method, since falsely positive and/or negative results of one method may be overcome by the use of another, and complementary information may lead to more robust predictions.
There are scarce data on the prediction of CSPH (as assessed by HVPG) by a combination of tests. A study performed before TE showed that the combination of simple laboratory tests (INR, albumin and ALT) allowed predicting CSPH in patients with compensated viral cirrhosis,[49] but external validation showed less accuracy than that observed in the original series. As for the prediction of varices, platelet count and spleen diameter are almost invariably found among the combinations tested in cirrhosis. Platelet count to spleen diameter ratio improves the predictive ability of the two tests as assessed separately and values >909 had 100% negative-predictive value for the presence of esophageal varices in the original study,[74] suggesting that endoscopy could be avoided in these patients. However, subsequent independent series showed a quite lower predictive value. Other models for predicting varices of any size or large varices included portal vein diameter and prothrombin time.[38] Again, while initial prospective studies in compensated cirrhosis suggested good discriminating ability, validation series failed to confirm adequate predictive accuracy.
A recent study in patients with compensated hepatitis B cirrhosis suggested that the combination of LS, spleen size and platelet count in the so-called LSPS (LS × spleen size/platelet count) is very accurate in predicting the presence of varices, high-risk varices and variceal bleeding.[75] This promising noninvasive approach should be validated by further studies, including other etiologies of cirrhosis, before its use can be recommended in clinical practice.
