Updates in noncirrhotic portal hypertension

Abstract

Cirrhosis is the commonest cause of portal hypertension (PH).¹ However, the development of PH in the absence of cirrhosis is frequent and is termed “noncirrhotic PH.” This entity includes diverse conditions based on the resistance locations along the portal inflow and outflow tract (Figure 1).² In this review, we discuss idiopathic noncirrhotic portal hypertension (INCPH) and extrahepatic portal vein obstruction (EHPVO) in detail.

FIGURE 1.

Classification of noncirrhotic PH according to the site of resistance. Abbreviations: EHPVO, extrahepatic portal vein obstruction; HVOTO, hepatic venous outflow tract obstruction; INCPH, idiopathic noncirrhotic portal hypertension; NCPF, noncirrhotic portal fibrosis; PBC, primary biliary cholangitis; PH, portal hypertension; PSC, primary sclerosing cholangitis; WHVP, wedge hepatic venous pressure.

IDIOPATHIC NONCIRRHOTIC PORTAL HYPERTENSION

Nomenclature

Several nomenclatures and descriptions have emerged as the initial seminal reports. While terminologies such as idiopathic portal fibrosis and noncirrhotic portal fibrosis were more commonly used in Japan and India, the Western literature frequently described the entity as obliterative portovenopathy or hepatoportal sclerosis. Numerous other terminologies have been used, essentially connoting similar entities of PH without cirrhosis conglomerated under the term INCPH (Figure 2).³ More recently, portosinusoidal vascular disorder has been proposed to include all the specific and nonspecific portal tract and sinusoidal abnormalities with or without clinical manifestations of PH meriting liver biopsy to exclude cirrhosis.^4,5 Subtle differences between Eastern literature and Western literature exist (Table 1).

FIGURE 2.

Various nomenclatures used for INCPH. PSVD does not require manifestations of PH. Abbreviations: INCPH, idiopathic noncirrhotic portal hypertension; PH, portal hypertension; PSVD, portosinusoidal vascular disorder.

TABLE 1.

Difference between Eastern and Western noncirrhotic PHs

Variables	Eastern	Western
Nomenclature	INCPH/NCPF	IPH/PSVD
Sex dominance	Male > female	Female > male
Age	Third decade	Fifth decade
Symptoms and signs of portal hypertension	Always present	May or may not be present
Usual presentation	Well-tolerated variceal bleed	Anemia, splenomegaly, or incidentally diagnosed when evaluated for abnormal liver function tests
Obliterative portal venopathy	70%	80%
Nodular regenerative hyperplasia	18%	10%
Cause	Usually unknown	Known trigger
Concomitant autoimmune disease	Rare	Common
Coexisting liver disease	Rare	Common
Elevated liver chemistries	Uncommon	Common
Ascites	Transient during variceal bleed	Common and sign of worsening disease
Anorectal varices	Uncommon but seen	Unknown
Nonvariceal portosystemic collaterals	More frequent	Less frequent
HVPG	Normal-slightly high (upto 8 mm Hg)	Normal
Mortality	Usually liver related	Related to underlying disease > liver related

Abbreviations: INCPH, idiopathic noncirrhotic portal hypertension; IPH, idiopathic portal hypertension; NCPF, noncirrhotic portal fibrosis; PH, portal hypertension; PSVD, portosinusoidal vascular disorder.

Epidemiology

Approximately 30%–40% of PH cases in the east (India and Japan) are due to INCPH, whereas the prevalence in the west is only 3%–5%.⁶

Etiopathogenesis

The exact pathogenesis of INCPH still lies undetermined, justifying its “idiopathic” nomenclature. However, the pathophysiology revolves around insults (Figure 3) that lead to portal venous attenuation, subsequent phlebosclerosis, and the development of aberrant vasculature.⁷

FIGURE 3.

Proposed etiological factors involved in the pathogenesis of INCPH and EHPVO. Abbreviations: EHPVO, extrahepatic portal vein obstruction; INCPH, idiopathic noncirrhotic portal hypertension.

Histopathological signatures

Histologically, the hallmark of INCPH is the obliteration of the main portal vein (PV) (obliterative portal venopathy), sclerosed walls (phlebosclerosis), thrombotic changes in medium and small PV branches, and random nonzonal sinusoidal dilation.⁴ In addition to these, there are nonspecific changes that have emerged in the backdrop of the heterogeneity in INCPH descriptions. Specific and nonspecific histologic features are elaborated on in Table 2.

TABLE 2.

Histological features in INCPH (PSVD) with description and alternative terminologies⁴

Serial number	Specific features	Alternative names	Description
1	Obliterative portal venopathy	Phlebosclerosis, PV obliteration, PV stenosis, hepatoportal sclerosis	Incomplete or complete luminal narrowing of PV branches along with PV wall thickening and fibrosis
2	Nodular regenerative hyperplasia	—	Micronodular changes of hepatic parenchyma without any significant fibrosis
3	Incomplete septal fibrosis/cirrhosis	—	Fine fibrous septa that arise from a PT and terminate blindly within a hepatic lobule without any definitive bridge to central veins or other PT
	Nonspecific features	Alternative names	Description
1. PT abnormalities	Herniated PV	Aberrant vessels, shunt vessels	A PV branch originating from PT abutting the adjacent hepatic parenchyma without a rim of intervening connective tissue
	Periportal abnormal vessels	Aberrant vessels, cavernous transformation, periportal shunting vessels	Single or multiple thin-walled vascular channels of variable caliber in close contact with the PT but not within
	Hyper-vascularized PT	Multiplicity of PVs, PT angiomatosis, angiomatoid lesion, angiomatous transformation of PT	Increased number of PV branches within PT
2	Architectural disturbance	—	Irregular distribution of PTs and central veins
3	Nonzonal sinusoidal dilatation	—	Sinusoidal lumen (nonzonal) wider than a single liver cell plate
4	Mild perisinusoidal fibrosis	—	Fibrosis around the sinusoids

Abbreviations: INCPH, idiopathic noncirrhotic portal hypertension; PSVD, portosinusoidal vascular disorder; PT, portal tract; PV, portal vein.

Approach to diagnosis and management

Clinical presentation: INCPH usually presents with episodes of well-tolerated variceal hemorrhage (VH) and symptoms of hypersplenism in young to middle-aged (third to fourth decades) males. In Japanese literature and Western literature, the disease has a female predilection (fifth decade) and presents with hepatosplenomegaly, variceal bleeding, and ascites with/without mild alterations in liver chemistries.² Imaging features reveal splenomegaly with a large patent hepatic artery and PV with smooth or mildly nodular liver-surface area. Various clinical and noninvasive diagnostic features have been discussed in Table 3.

TABLE 3.

Clinical features and diagnosis of INCPH

Clinical presentation
Age/sex	Usually young to middle age with a male predilection (third to fourth decade) in Indian studies and a female predilection (fifth decade) in studies from Japan and western literature2
Hypersplenism	Pain abdomen, early satiety, postprandial fullness, cytopenias (usually asymptomatic recurrent infections are rare)
Portal hypertension	Well-tolerated episodes of VH Transient ascites (in <1/3) during VH, PVT and infection. Ascites can also be noted in patients with parenchymal extinction and those who develop cirrhosis due to recurrent transfusion-related viral hepatitis (HBV/HCV)
Noninvasive tests
Liver function and coagulation tests	Usually normal until parenchymal extinction. Mild alterations in liver enzymes and serum bilirubin can be noted
Endoscopy	Esophageal, gastric, and ectopic varices
Radiologic findings	Spleen-enlarged PV and hepatic artery-patent and enlarged. Liver-surface smooth or mildly nodular. Hypertrophy of the caudate lobe and segment IV. (In cirrhosis there is hypertrophy of caudate lobe and atrophy of segment IV) Thickened hyperechoic walls or reduced caliber or occlusive thrombosis of intrahepatic portal branches
Transient elastography	Liver stiffness lower than those with cirrhosis but higher than normal individuals, with values between 7 and 12 kPa suggestive of INCPH8,9

Abbreviations: INCPH, idiopathic noncirrhotic portal hypertension; PSVD, portosinusoidal vascular liver disorder; PV, portal vein; VH, variceal hemorrhage.

The 2 key areas of treatment are managing acute episodes of VH and complications of hypersplenism. Medical and endoscopic management of VH is similar to patients with cirrhosis. For secondary prophylaxis, a single randomized trial indicates equal efficacy with endoscopic therapy and nonselective beta-blockers.¹⁰ The literature on noninvasive methods to stratify variceal screening, follow-up endoscopic recommendations, and primary prophylaxis strategies are unclear in INCPH. Interventional radiologic procedures, including transjugular intrahepatic portosystemic shunts for refractory VH and splenic artery embolization for hypersplenism-related pancytopenia, have been performed with variable success.² Splenectomy with devascularization can be performed for patients with refractory variceal bleeds and/or symptomatic hypersplenism as the lifespan of transjugular intrahepatic portosystemic shunt is shorter (for a disease of the young patient), and a splenic abscess is not uncommon with splenic artery embolization. Liver transplantation has also been performed in such younger patients with excellent outcomes for refractory ascites, HE, hepatopulmonary syndrome, and refractory bleeding from ectopic varices although recurrence of disease is well known.^11,12

Prognosis

INCPH has traditionally been considered a nonprogressive disease although quality studies on natural history are limited. Patients with INCPH have a higher risk of VH and PVT than those with compensated cirrhosis, thus mandating a relook on the benign nature of the disease and justifying PVT screening.¹³

EXTRAHEPATIC PORTAL VEIN OBSTRUCTION

Nomenclature

In contrast to INCPH, EHPVO refers to a more homogenous entity of a vascular disorder characterized by obstruction of the extrahepatic PV with or without the involvement of intrahepatic PV, splenic, or superior mesenteric veins.¹⁴ The cavernoma formation is a hallmark of EHPVO and is unique and distinct from the natural history of those with cirrhosis and PVT.²

Epidemiology

EHPVO has been more frequently reported from the East, constituting 15%–20% of PH cases compared with 5%–10% in the West. In children, EHPVO is the commonest cause of PH (80%–85%).

Etiopathogenesis

The exact pathogenesis of EHPVO remains debatable. However, the presence of prothrombotic states and local abdominal inflammatory conditions that lead to PV injury are well-known risk factors (Figure 3). The plausible natural course of EHPVO is depicted in Figure 4.

FIGURE 4.

Natural history of extrahepatic portal vein obstruction. Created with Biorender.com.

Approach to diagnosis and management

In children, EHPVO has a bimodal presentation, with those secondary to umbilical sepsis (rarely noted now) presenting as early as 3 years whereas those with unnoticed inciting events presenting as late as 8 years to early adolescence. Well-tolerated VH is the most common presentation, along with moderate splenomegaly and growth retardation. Unlike noncirrhotic portal fibrosis, liver biopsy is not required for the diagnosis of EHPVO. However, the developments of ascites, jaundice, symptomatic biliopathy, encephalopathy, and parenchymal failure are not uncommon. The differences between INCPH, EHPVO, and cirrhosis are detailed in Table 4. Imaging differences between these are depicted in Figure 5. The endoscopic presence of varices with a high preponderance of anorectal varices and colopathy is a hallmark, along with portal cavernoma in Doppler studies.² The endoscopic and medical management of bleeding events is similar to cirrhotic PH. The role of beta-blockers remains unclear. Apart from splenectomy with devascularization and shunt operations, transjugular intrahepatic portosystemic shunt has also been performed for EHPVO through the transsplenic route.¹⁵

TABLE 4.

Key differences among INCPH, EHPVO, and cirrhosis^2–4

Parameter	INCPH	EHPVO	Cirrhosis
Primary site of portal flow resistance	Hepatic (presinusoidal)	Extrahepatic	Hepatic (sinusoidal)
Pressure hemodynamics
FHVP	Normal	Normal	Normal
WHVP	Normal/near normal	Normal	High
RAP	Normal	Normal	Normal
HVPG	Near normal-high	Normal	High
Usual age of presentation	third–fifth decade	first–second decade	Variable depending on etiology
Sex predilection	India: males > females; Japan and West: females > males	Usually females > males	Nonspecific except for certain aetiologies
Usual clinical presentation	Variceal bleed Hypersplenism (symptomatic > asymptomatic)	Variceal bleed Hypersplenism (asymptomatic > symptomatic) Obstructive jaundice	Symptoms and signs of liver cell failure
Development of ascites	Uncommon	Rare	Common
Jaundice	Rare (unless progression to parenchymal extinction)	Uncommon but may occur with development of biliopathy or parenchymal extinction	Common
PCC (%)	10–40	80–100	<10
HE	Rare	Presence of minimal HE not uncommon (shunt related)	Common
Splenomegaly	Massive	Mild–moderate	Mild–moderate
Liver function	Normal to slightly elevated liver chemistries	Normal (in the absence of PCC/extinction)	Usually abnormal
Hepatopulmonary syndrome	Rare	Uncommon	Common
Growth retardation	Rare	Common	Rare
Antiendothelial cell antibodies	Common	—	—
Concomitant extrahepatic autoimmune features	Usual	Never	Depending on the etiology
Quality of life	Good (similar to child A cirrhosis)	Fair	Poor
Long term outcomes	Favorable	Favorable	Variable depending on stage, etiology and degree of portal hypertension

Abbreviations: EHPVO, extrahepatic portal vein obstruction; FHVP, free hepatic venous pressure; INCPH, idiopathic noncirrhotic portal hypertension; PCC, portal cavernoma cholangiopathy; RAP, right atrial pressure; WHVP, wedge hepatic venous pressure.

FIGURE 5.

Computed tomographic scans of INCPH, EHPVO, and cirrhosis. Abbreviations: CBD, common bile duct; EHPVO, extrahepatic portal vein obstruction; IHBRD, intrahepatic biliary radicle dilatation; INCPH, idiopathic noncirrhotic portal hypertension.

The development of portal cavernoma cholangiopathy (PCC) due to both the mechanical impact of cavernoma and chronic ischemia deserves special mention.^16,17 PCC is defined as abnormalities in the extrahepatic biliary system, including the gallbladder and cystic duct, with or without abnormalities in the I and II generation biliary ducts in a patient with portal cavernoma. It is seen in 80%–100% of the cases, and a subgroup becomes symptomatic with jaundice, biliary colic, and recurrent cholangitis. Therefore, jaundice in a patient with EHPVO can be due to PCC, gall stones, parenchymal extinction, or concomitant development of cirrhosis due to transfusion-related hepatitis (HBV/HCV). The management of biliopathy involves endoscopic retrograde cholangiopancreatography–based interventions, percutaneous transhepatic biliary drainage, and shunt operations.^17,18

Pregnancy and noncirrhotic portal hypertension

Patients with noncirrhotic PH have preserved fertility. Few patients are incidentally diagnosed to have noncirrhotic PH (either INCPH or EHPVO) during pregnancy. Conflicting reports of increased risk of VH, cholangitis, and poor maternal and fetal outcomes have been suggested. However, multidisciplinary team management and the safety of endoscopic procedures during pregnancy have certainly improved the outcomes. A pregnancy reaching 20 weeks usually ends in a live birth.¹⁹

CONCLUSION

INCPH encompasses a diverse group of disorders. Despite varied associations, the exact aetiopathogenesis remains unclear. VH and features of hypersplenism are the cardinal symptoms. INCPH requires a liver biopsy with specific histopathological features, while demonstrating cavernoma with or without biliopathy is central to EHPVO. The prognosis of these patients is dependent on the development of acute splenoportal and mesenteric venous thrombosis, parenchymal extinction and liver failure, the development of ascites, recurrent bleeds from ectopic varices, and PCC. Management of these diseases is largely supportive and centers around endoscopic management, requiring biliary interventions and shunt operations in selected cases of biliopathy and refractory VH (Figure 6).

FIGURE 6.

Management of INCPH and EHPVO. Indications for shunt operation include refractory variceal bleeds, symptomatic hypersplenism, symptomatic portal cavernoma cholangiopathy, ectopic variceal bleeds, growth retardation despite nutritional rehabilitation, uncommon blood group, and poor access to endoscopic therapy. Abbreviations: EHPVO, extrahepatic portal vein obstruction; INCPH, idiopathic noncirrhotic portal hypertension; PCC, portal cavernoma cholangiopathy; SAE, splenic artery embolization; TIPSS, transjugular intrahepatic portosystemic shunt; VH, variceal hemorrhage.