Noncirrhotic portal hypertension: An overview

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Abbreviations

HVPG

hepatic venous pressure gradient

NCPH

noncirrhotic portal hypertension

Noncirrhotic portal hypertension (NCPH) comprises a broad group of disorders characterized by elevated portal pressures in the absence of cirrhosis.1 NCPH is an infrequent cause of portal hypertension worldwide; however, its prevalence varies widely between different geographic regions. Historically, NCPH was mainly described in developing regions, with only sporadic cases from industrialized countries reported in the literature.2 This may explain why NCPH has not received great attention as a research topic, with research in this field over the past few decades mainly conducted by few dedicated investigators around the globe. Consequently, knowledge of the mechanisms leading to development of NCPH, and a clear understanding of its natural history, have not yet been fully elucidated. Furthermore, the paucity of well‐designed, large‐scale, prospective studies dedicated to the study of NCPH has made it difficult to develop evidence‐based guidelines for diagnosis and treatment of this condition. With increasing recognition and awareness, certain forms of NCPH have been associated with poor clinical outcomes.3, 4 This observation underscores the importance of continued vigilance in identifying and developing better tools for diagnosis, staging, and management of NCPH.

This article will highlight the following aspects of NCPH: the clinical significance of NCPH; challenges and pitfalls in diagnosis; and proposal of a clinically based approach to its diagnosis and management.

What Is the Clinical Significance of NCPH?

A common misconception about NCPH is that it is generally associated with a clinically benign course. This concept has probably evolved on the basis of three clinical observations. First, the histopathologic recognition of most forms of NCPH is often made incidentally on a liver biopsy performed in an asymptomatic patient. Second, most forms of NCPH do not display impaired hepatic function despite disease progression, providing a false sense of security. Finally, survival from traditional complications of portal hypertension are generally more favorable in NCPH as compared to cirrhosis‐related liver disease (variceal bleeding is better tolerated, ascites and hepatic encephalopathy occur less commonly).

However, it should be noted that NCPH is not a benign liver disease without consequences. Progressive liver failure has been reported in children presenting with extrahepatic portal vein thrombosis and in adults with idiopathic portal hypertension. There is also increasing recognition that NCPH may be associated with serious complications other than portal hypertensive sequelae, such as failure to thrive in children, and a higher rate of fatal infections in patients with nodular regenerative hyperplasia associated with underlying immunodeficiency disorders. Thus, further research is needed to identify the mechanisms responsible for these interactions in the different forms of NCPH.

Diagnosis of NCPH—Challenges and Pitfalls

From a clinical standpoint, several challenges and pitfalls often complicate the diagnosis of NCPH. First, NCPH represents a final common pathway from a myriad of diseases, some of which are extremely rare. These do not necessarily share common risk factors or have similar clinical presentations. Second, is that in some instances, manifestations of another underlying disease can mask the known sequelae of portal hypertension, especially in the early stages of NCPH development. Third, a major diagnostic challenge of NCPH is due to the absence of reliable noninvasive tests for NCPH. Liver enzymes and bilirubin levels can vary, while markers of hepatic synthetic function are generally preserved until end‐stage. Finally, even if histology is obtained, the diagnosis may be missed as not all forms of NCPH can be diagnosed with routine histologic staining of needle biopsy specimens. Consequently, many NCPH patients are diagnosed with late‐stage disease, when overt clinical signs have already appeared.

Staging and Prognostication of NCPH—Why Is it Difficult?

Currently, no staging system exists for NCPH that can accurately determine disease severity or predict clinical outcomes. Liver biopsy can characterize specific patterns of injury and its spatial distribution (presinusoidal, sinusoidal, and postsinusoidal compartments); however, these features have not correlated with severity of portal hypertension (Fig. 1). Use of pre‐existing scoring systems such as Child‐Pugh and MELD is also unreliable, because they were developed for cirrhosis‐related liver disease and depend on hepatic synthetic markers for staging and prognostication. The hepatic venous pressure gradient (HVPG) > 10 mm Hg is a strong predictor of clinical outcomes in patients with cirrhosis; however, in patients with NCPH, hepatic hemodynamic measurements should be interpreted with caution. Because most forms of NCPH are associated with injury to presinusoidal or prehepatic structures, HVPG values tend to be normal or only slightly elevated. Furthermore, low HVPG values may result from formation of venous‐venous connections between intrahepatic hepatic vein tributaries, leading to falsely low measurements of wedge pressures.5 Overall, this results in underestimation of the true value of portal pressures, thus limiting the use of invasive hemodynamic monitoring for predicting clinically meaningful outcomes given current knowledge.

Figure 1.

Radiologic and pathologic findings in a patient with NCPH, a 10‐year‐old male with common variable immunodeficiency. (A) He initially presented with mildly elevated liver enzymes and a palpable spleen. (B) Histopathologic findings on transjugular liver biopsy were consistent with nodular regenerative hyperplasia. A HVPG of 15 mm Hg was measured; however, esophagogastroduodenoscopy was negative for gastric or esophageal varices. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

How Can We Improve Detection Rates and Management of NCPH?

Clinicians should maintain a high index of suspicion for the diagnosis of NCPH in diseases known to be associated with this condition, especially when the disease course is complicated or when response to treatment is suboptimal. Workup should also be considered when subtle changes are noted in liver enzymes, or when prothrombin time is mildly prolonged. Suspicion for NCPH should also arise when platelet levels show gradual decrease over time even if absolute counts remain within normal range.6 Importantly, the investigation of portal hypertension should not be discontinued after common causes of chronic liver disease have been ruled out, especially when clinical evaluation shows marked splenomegaly and hypersplenism in the absence of a medical explanation. When a liver biopsy is obtained, the pathologist should be alerted to the fact that NCPH is suspected, so that liver tissue will be subjected to reticulin staining and vascular components reviewed thoroughly. Ultrasound with Doppler studies of the portal and hepatic veins should be obtained to look for extrahepatic causes of NCPH. Finally, in centers where hepatic hemodynamic measurement is available, abnormally high values of free hepatic and wedge pressures should be acknowledged, even when HVPG is normal or only slightly elevated. Table 1 summarizes some of the major differences in presentation between cirrhotic portal hypertension and NCPH.

Table 1.

Differences in Presentation Between Cirrhotic and Noncirrhotic Portal Hypertension.

	Cirrhotic Portal Hypertension	NCPH
Age at Presentation	Adults	Children and adults
Diagnostic Features
Splenomegaly	+	+++
Pancytopenia	+	+++
Liver enzymes	Usually elevated	Normal/mildly elevated
Synthetic markers	Gradual worsening with disease progression	Normal in most until end‐stage disease in some
HVPG	Usually high	Usually normal or slightly elevated, can be high
Clinical Presentation
Gastroesophageal bleeding	Late presentation of disease	Common first presentation of disease
Ascites	Common in late stages	Uncommon
Encephalopathy	Common in late stages	Uncommon
Liver failure	Common in late stages	Uncommon, appears in certain forms

Management of NCPH should focus on optimizing therapy for underlying diseases and treating complications of portal hypertension. Until further evidence pertaining to NCPH becomes available, screening for and management of gastroesophageal varices should generally follow evidence‐based guidelines developed for portal hypertension associated with cirrhosis.7, 8 Nevertheless, in selected patients with NCPH, surgical shunt surgery may be the treatment of choice, because it may offer better long‐term control of variceal bleeding than band ligation or sclerotherapy. Hepatic causes of NCPH are best managed with distal‐splenorenal shunt, especially in young patients with a long life expectancy, due to the decreased risk of encephalopathy. This procedure is technically challenging; however, it offers the benefits of portal pressure reduction with minimal risk for development of hepatic encephalopathy. In addition, it may not be adequate when patients have significant ascites. The Rex shunt is the surgical treatment of choice for extrahepatic portal vein occlusion. In these patients, careful monitoring for signs of progressive liver failure is advised, with liver transplantation considered if conservative therapies fail.9

Summary

NCPH represents a diverse group of diseases sharing a final common clinical pathway. It is an under‐recognized condition that may have potentially fatal consequences. We are still in the early stages of learning about the disease, its causes, and outcomes, and better diagnostic tools are needed to assist clinicians in detection of NCPH in its preclinical stages. Perhaps even more than in other chronic liver diseases, the management of NCPH may benefit from an individualized approach in the ever‐growing field of personalized medicine.