Noncirrhotic portal hypertension

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2016. | This topic last updated: Sep 01, 2015.

INTRODUCTION — Portal hypertension is defined by a pathologic increase in the pressure of the portal venous system. Cirrhosis is the most common cause of portal hypertension, but it can also be present in the absence of cirrhosis, a condition referred to as "noncirrhotic portal hypertension."

This topic will review the differential diagnosis of noncirrhotic portal hypertension and will discuss in detail two of the disorders associated with noncirrhotic portal hypertension, schistosomiasis, and idiopathic noncirrhotic portal hypertension. Other causes of noncirrhotic portal hypertension are discussed elsewhere.

●(See "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management".)

●(See "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management".)

●(See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)".)

●(See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis".)

●(See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis".)

●(See "Diagnosis of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following hematopoietic cell transplantation".)

●(See "Extrarenal manifestations of autosomal dominant polycystic kidney disease", section on 'Hepatic cysts' and "Diagnosis and management of cystic lesions of the liver", section on 'Polycystic liver disease'.)

●(See "Acute fatty liver of pregnancy".)

●(See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

●(See "Drug-induced liver injury".)

●(See "Major side effects of amiodarone", section on 'Hepatotoxicity'.)

●(See "Hepatic granulomas".)

 

●(See "Constrictive pericarditis".)

●(See "Definition and classification of the cardiomyopathies", section on 'Restrictive cardiomyopathy'.)

 

ETIOLOGY — The disorders associated with noncirrhotic portal hypertension can be categorized based on their site of involvement (extrahepatic or intrahepatic). Intrahepatic causes can be subcategorized as presinusoidal, sinusoidal, and postsinusoidal (table 1). In some cases, a given disorder may affect multiple sites (eg, vinyl chloride toxicity, Gaucher disease, alcoholic liver disease).

Extrahepatic causes — Disorders affecting the prehepatic or posthepatic vascular system may result in noncirrhotic portal hypertension. Prehepatic causes include portal or splenic vein thrombosis, splanchnic arteriovenous fistulas, and splenomegaly (eg, due to lymphoma or Gaucher disease). Posthepatic causes include obstruction of the hepatic veins or the inferior vena cava (eg, from Budd-Chiari syndrome) and cardiac diseases (eg, constrictive pericarditis and restrictive cardiomyopathy).

Intrahepatic causes — The intrahepatic causes of noncirrhotic portal hypertension may be presinusoidal, sinusoidal, or postsinusoidal.

Presinusoidal causes — Presinusoidal causes of noncirrhotic portal hypertension include [1]:

●Developmental abnormalities (eg, adult polycystic liver disease, congenital hepatic fibrosis, arteriovenous fistulas)

●Biliary diseases (eg, biliary cirrhosis, autoimmune cholangiopathy, primary sclerosing cholangitis, toxic biliary injury from vinyl chloride)

●Neoplastic occlusion of the intrahepatic portal vein (eg, due to lymphoma, epithelioid hemangioendothelioma, epithelial malignancies, chronic lymphocytic leukemia)

●Granulomatous liver lesions (eg, schistosomiasis, mineral oil granuloma, sarcoidosis)

●Idiopathic noncirrhotic portal hypertension

 

Sinusoidal causes — Sinusoidal causes of noncirrhotic portal hypertension include [1]:

●Fibrosis of the space of Disse, which may be metabolic (eg, nonalcoholic fatty liver disease, Zellweger syndrome), inflammatory (viral hepatitis, chronic Q fever, prior cytomegalovirus, schistosomiasis), or induced by drugs or toxins (eg, amiodarone, methotrexate, alcohol, vinyl chloride, copper) [2-5]

 

●Amyloid or light-chain deposition in the space of Disse

 

●Defenestration of the sinusoidal lining in early alcoholic liver disease

 

●Sinusoidal destruction or collapse in the setting of acute hepatic injury

 

●Infiltrative diseases such as mastocytosis, Gaucher disease, and agnogenic myeloid metaplasia

 

●Compression of sinusoids by markedly hypertrophied hepatocytes, which may be seen with microvesicular steatosis

 

Postsinusoidal causes — Postsinusoidal causes of noncirrhotic portal hypertension include [1]:

●Sinusoidal obstruction syndrome (venoocclusive disease)

●Budd-Chiari syndrome

●Phlebosclerosis of hepatic veins (eg, due to alcoholic liver disease, chronic radiation injury, hypervitaminosis A)

●Primary vascular malignancies (eg, epithelioid hemangioendothelioma, angiosarcoma)

●Granulomatous phlebitis (eg, from sarcoidosis, Mycobacterium avium or M. intracellulare infection)

●Lipogranulomas (eg, mineral oil granuloma)

 

SCHISTOSOMIASIS — Schistosomiasis is one of the most common causes of noncirrhotic portal hypertension worldwide [6]. Of the three main Schistosoma species, S. japonicum and S. mansoni are known to cause liver disease. S. hematobium affects mainly the urinary tract, although at advanced stages the liver can develop portal fibrosis. The acute stage of schistosomiasis mimics acute bacterial infection and is accompanied by marked eosinophilia. Chronic hepatic schistosomiasis is characterized by features of portal hypertension: esophageal varices, hepatomegaly, and splenomegaly with hypersplenism. The diagnosis of schistosomiasis can be made by the detection of schistosomal ova in the stool. Management includes treating underlying parasitic infection and preventing or treating the consequences of portal hypertension. (See "Epidemiology, pathogenesis, and clinical manifestations of schistosomiasis" and "Diagnosis of schistosomiasis" and "Treatment and prevention of schistosomiasis".)

S. japonicum is distributed widely throughout the world, predominantly in Asia. S. mansoni is endemic in Egypt, Africa, the Middle East, and South America. Two other species (S. mekongi and S. intercalatum) also cause hepatic infections in endemic areas in Southeast Asia and Western Africa, respectively.

Pathophysiology — The infection occurs when the schistosomal cercariae enter the body through the skin. Adult worms eventually find their way to inhabit tributaries of the inferior (S. mansoni) or superior (S. japonicum) mesenteric veins, where they produce hundreds to thousands eggs per day for several years before the end of their lifespan (figure 1). Some of these eggs pass through the intestinal mucosa and are excreted in the urine or feces to continue their life cycle. Others flow into the portal vein tributaries and become trapped in the terminal portal venules, where they induce chronic inflammation that is subsequently followed by marked fibrosis. S. japonicum is capable of producing far more eggs than S. mansoni and thus causes more severe liver disease [7,8]. (See "Epidemiology, pathogenesis, and clinical manifestations of schistosomiasis".)

In the early stages of infection, the portal resistance is mainly presinusoidal. However, as the fibrotic changes in the portal tracts progress, lobular distortion at the sinusoidal level occurs. This results in an increase in resistance to portal venous flow, as evidenced by an increased wedged hepatic venous pressure in advanced cases [9]. Hemodynamic studies in patients with hepatic schistosomiasis have demonstrated a hyperdynamic systemic and splanchnic circulation with normal hepatic venous pressure gradient and total hepatic blood flow [7,10,11]. (See "Portal hypertension in adults", section on 'Hepatic venous pressure gradient'.)

Clinical features — Chronic hepatic schistosomiasis is characterized by features of portal hypertension: esophageal varices, hepatomegaly, and splenomegaly with hypersplenism. In children, chronic infection is associated with growth retardation. Many patients with mild fibrosis are asymptomatic during the earlier phases of their disease. (See "Epidemiology, pathogenesis, and clinical manifestations of schistosomiasis", section on 'Hepatosplenic schistosomiasis'.)

Underlying hepatic function remains preserved in hepatic schistosomiasis, and hepatic encephalopathy, ascites, and liver failure are uncommon. Patients with hepatic schistosomiasis tolerate episodes of acute variceal bleeding well compared with patients with cirrhosis because of their preserved liver function. In advanced cases, hepatic decompensation may develop, with hypoalbuminemia and chronic ascites. However, this tends to occur in patients with coexisting liver disease such as chronic viral hepatitis B or C infection or alcoholic liver disease. These coexisting liver diseases have been found to aggravate the course of hepatic schistosomiasis, changing its natural history [12-14]. Extrahepatic manifestations, such as pneumonia and pulmonary hypertension, have been described in S. mansoni infection [15]. (See"Epidemiology, pathogenesis, and clinical manifestations of schistosomiasis", section on 'Hepatosplenic schistosomiasis'.)

Diagnosis — The diagnosis of schistosomiasis can be made by the detection of schistosomal eggs in the stool (picture 1). As an alternative, it can be demonstrated in biopsies of the rectal mucosa (picture 2) or the liver. Because the worms concentrate more densely in the distal colon, the rectal mucosa has a heavy load of schistosomal eggs. The diagnosis can also be made using various immunologic assays [16]. (See "Diagnosis of schistosomiasis".)

Management — Praziquantel and oxamniquine are active against all forms of human schistosomiasis and are effective in eradicating the worms in the acute stage of the disease. Cure rates vary from 60 to 90 percent for S. mansoni and 60 to 80 percent for S. japonicum [17,18]. Even if treatment does not kill all the worms, it will result in a sharp reduction in egg laying. In patients with chronic schistosomiasis, the worms no longer lay eggs and the patient may not require any specific antihelminthic treatment. (See "Treatment and prevention of schistosomiasis", section on 'Treatment'.)

In addition to treating the underlying parasitic infection, management should be aimed at preventing or treating the consequences of portal hypertension (predominantly variceal bleeding). Only a few studies have described treatment options in these patients. As a result, patients are typically managed similarly to patients with varices in the setting of cirrhosis [19]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Complications of portal hypertension'.)

Treatment for acute variceal bleeding includes early pharmacologic treatment with vasoactive drugs, early endoscopic control of bleeding, careful blood product replacement, and prophylactic antibiotics. (See"General principles of the management of variceal hemorrhage".)

Primary and secondary prevention of variceal bleeding includes the use of nonselective beta blockers and endoscopic variceal ligation. (See 'Management' below and "Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis" and "Prevention of recurrent variceal hemorrhage in patients with cirrhosis".)

Surgery has been used for patients with noncirrhotic portal hypertension from schistosomiasis who have recurrent variceal bleeding despite medical and endoscopic treatment [20]. Surgical options included splenectomy with esophagogastric devascularization or selective shunts (eg, distal splenorenal shunts) [21]. Nonselective shunts (eg, proximal splenorenal shunts) are not recommended because they are associated with high rates of hepatic encephalopathy, hemolysis, and death [22]. Transjugular intrahepatic portosystemic shunt placement may be an alternative to surgery, but also puts patients at risk for hepatic encephalopathy [21]. (See "Role of transjugular intrahepatic portosystemic shunts in the treatment of variceal bleeding".)

IDIOPATHIC NONCIRRHOTIC PORTAL HYPERTENSION (INCLUDING NODULAR REGENERATIVE HYPERPLASIA) — Idiopathic noncirrhotic portal hypertension has been referred to by several different names, including nodular regenerative hyperplasia. It is characterized by portal hypertension in the absence of liver cirrhosis, with histologic features of dense portal fibrosis, marked phlebosclerosis, and dilated sinusoids. It typically has a more benign course than portal hypertension that develops in the setting of cirrhosis, though patients may present with complications such as variceal bleeding. The diagnosis is made by ruling out other causes of portal hypertension. Management is primarily aimed at decreasing the risk of variceal bleeding (eg, with beta blockers or variceal banding).

Terminology — Noncirrhotic portal hypertension without an identifiable cause has been referred to by various names. We, as well as others, prefer to use the term idiopathic noncirrhotic portal hypertension [1,23].

Other terms that have been used for idiopathic noncirrhotic portal hypertension include [24-31]:

●Nodular regenerative hyperplasia

●Noncirrhotic portal fibrosis

●Idiopathic portal hypertension

●Hepatoportal sclerosis

●Incomplete septal cirrhosis

●Obliterative portal venopathy

●Benign intrahepatic portal hypertension

●Idiopathic presinusoidal portal hypertension

●Partial nodular transformation

 

In the past, it was thought that these entities represented different disorders. However, the clinicopathologic features are sufficiently similar that they are now considered to be the same disease. While differences in epidemiology, hepatic pressure gradients, and proposed etiology have been described in reports from different geographical areas, the differences likely reflect the varied spectrum of this disease and not separate disease entities [1]. (See 'Liver pathology' below.)

Epidemiology — The incidence of idiopathic noncirrhotic portal hypertension varies worldwide. Studies from the 1980s and 1990s suggested it accounts for approximately 23 percent of cases of portal hypertension in India [32,33], whereas older studies suggested it accounts for 3 to 5 percent of cases of portal hypertension in Western countries [34]. Among Western patients, it is thought to account for 14 to 27 percent of cases of noncirrhotic portal hypertension [35-37]. However, over time, fewer cases have been reported, suggesting that the incidence may now be much lower [1,33].

In Eastern countries, the disease is often encountered in patients who are socioeconomically disadvantaged [38]. Slight differences in the sex and age distribution have been reported from different countries [39,40]. The reason for this is not clear, but differences in socioeconomic status, living conditions, pathogen exposure, average life span, and ethnicity may play a role. In Japan, the incidence of idiopathic noncirrhotic portal hypertension has declined in recent decades, possibly because of improvements in hygiene and living standards [40].

Pathophysiology — The etiology of idiopathic noncirrhotic portal hypertension is unknown. However, several pathophysiologic mechanisms are believed to be involved, including chronic or recurrent infections, exposures to drugs or toxins, immunologic disorders, genetic disorders, and hypercoagulability. A large number of disorders, medications, and toxins have been associated with idiopathic noncirrhotic portal hypertension (table 2).

●Chronic or recurrent infections – Repeated episodes of umbilical sepsis, bacterial infections, and diarrhea in early childhood (all relatively common in socioeconomically disadvantaged populations) are believed to lead to portal pyemia and pylephlebitis, which may subsequently cause vascular endothelial injury, microthrombosis, sclerosis, and obstruction of small- and medium-sized portal vein radicals. This may subsequently lead to the development of idiopathic noncirrhotic portal hypertension in early adulthood [41]. Supporting this hypothesis, animal studies involving repeated injections of Escherichia coli into the portal system of rabbits resulted in the development of noncirrhotic portal fibrosis [42].

 

●Drugs and toxins – Drugs and toxins may induce fibrosis in the space of Disse, leading to idiopathic noncirrhotic portal hypertension [1]. Drugs associated with idiopathic noncirrhotic portal hypertension include azathioprine and several cytotoxic drugs.

 

●Human immunodeficiency virus (HIV) infection – There have been consistent reports of patients with HIV infection who develop variceal bleeding due to underlying noncirrhotic portal hypertension [43-48]. The pathogenesis is thought to be related to the effect of highly active antiretroviral treatment (particularly long-term exposure to didanosine) on the microvasculature of the liver or the direct effect of the HIV itself [45,49]. The discontinuation of didanosine has been reported in some studies to reduce the progression of idiopathic noncirrhotic portal hypertension [50,51].

 

●Altered immune response – Several alterations in the immunologic response have been described in patients with idiopathic noncirrhotic portal hypertension [52,53]. In addition, different autoimmune diseases are frequently associated with idiopathic noncirrhotic portal hypertension (table 2) [54-56]. Anti-DNA antibodies are demonstrable in more than 65 percent of Japanese women with idiopathic noncirrhotic portal hypertension [54]. Studies have also reported the presence of idiopathic noncirrhotic portal hypertension and portal systemic collaterals in some patients with severe primary antibody deficiencies [57].

 

●Genetic predisposition – A genetic basis for idiopathic noncirrhotic portal hypertension has not been identified. However, familial aggregation of idiopathic noncirrhotic portal hypertension and a high frequency of HLA-DR3 have been observed among Indian patients [58].

 

●Hypercoagulability – Some studies have suggested an association of idiopathic noncirrhotic portal hypertension with a hypercoagulable state. A study of idiopathic noncirrhotic portal hypertension in 28 Western patients found evidence of various prothrombotic disorders in 50 percent of patients [59]. Over the course of follow-up, 13 patients developed portal vein thrombosis within a median of 7.6 years (range 1 to 21 years). The authors advocated anticoagulant therapy in patients with idiopathic noncirrhotic portal hypertension found to have a prothrombotic disorder. Similarly, a report from Turkey described extrahepatic portal vein thrombosis in 7 of 34 (20 percent) patients with idiopathic noncirrhotic portal hypertension over a five-year follow-up period [60].

 

●Miscellaneous – Preliminary observations have described a role for endothelin-1, nitric oxide, and connective tissue growth factor in development of idiopathic noncirrhotic portal hypertension [61-65].

 

It has been proposed that a central event in the development of idiopathic noncirrhotic portal hypertension is portal venopathy caused by thrombosis or obliteration due to hypercoagulability, endothelial injury, or autoimmune injury (from immune complex deposition, autoantibodies, or activated T cells) [35,66-70].

A vascular cause of idiopathic noncirrhotic portal hypertension is supported by experimental studies in animals and histologic findings in humans. Blockage of the portal veins decreases blood flow to the liver, resulting in ischemia of the supplied hepatic parenchyma [71]. Ischemia leads to atrophy of the more vulnerable regions of the liver around the central vein and compensatory hypertrophy of the less vulnerable periportal areas [72]. Studies of human livers from patients with acute or chronic portal vein thrombosis have demonstrated apoptosis, atrophy, and the development of nodules [71]. In some cases, the primary insult to the liver was arterial rather than venous. The resulting periportal inflammation eventually leads to portal venopathy [66-68,71-74].

T cell-induced autoimmune mechanisms have also been implicated in the development of the portal vein injury [75]. In one report, sinusoidal infiltration with CD 8+ cytotoxic T cells was observed in 14 of 44 patients (32 percent) [69]. The T cells were located mainly in the atrophic areas and were adjacent to endothelial cells exhibiting evidence of apoptosis. The authors speculated that transient T cell-induced endothelial injury may be the trigger for the development of idiopathic noncirrhotic portal hypertension. Another study found that 77 percent of patients with idiopathic noncirrhotic portal hypertension had antiphospholipid antibodies, possibly indicating an antibody-dependent autoimmune mechanism [76].

Clinical manifestations — As the name implies, idiopathic noncirrhotic portal hypertension is characterized by portal hypertension. Typically, liver function is preserved, even when portal hypertension is clinically evident. Liver failure with ascites and/or encephalopathy is rare [68,71,77]. (See "Portal hypertension in adults", section on 'Clinical manifestations'.)

The most common clinical presentation is variceal bleeding, which (in contrast to variceal bleeding in cirrhosis) is often relatively well tolerated due to the preserved liver function. In the late stages of the disease or following an episode of gastrointestinal bleeding, patients will occasionally develop jaundice, ascites, or hepatic encephalopathy. Hepatopulmonary syndrome has been described and reverses after liver transplantation [78-80]. Development of portal vein thrombosis is a frequent event during the natural course of the disease, particularly in patients with associated HIV infection [81].

On clinical examination, massive splenomegaly (>10 cm below the left subcostal margin) is present in more than 95 percent of patients. Dilated superficial abdominal veins can be seen in 15 percent of patients, and mild hepatomegaly (<4 cm below the right subcostal margin) can be found in 50 percent of patients [32]. Other stigmata of chronic liver disease are usually absent.

Liver biochemical tests are usually normal or nearly normal [37,68,71]. Anemia, leukopenia, and thrombocytopenia are common because of hypersplenism. (See "Approach to the adult patient with splenomegaly and other splenic disorders", section on 'Hypersplenism' and "Approach to the adult patient with splenomegaly and other splenic disorders", section on 'CBC and peripheral smear'.)

Imaging findings that have been described in patients with idiopathic noncirrhotic portal hypertension include:

●Ultrasonography: Isoechoic nodules. The nodules can also be hypoechoic, often with a hypoechoic rim, features that can mistakenly suggest hepatic metastases [35,82].

 

●Computed tomography (CT) scanning: Nonspecifically hypodense nodules on CT [35,82].

 

●Magnetic resonance imaging (MRI): Isointense nodules on T2-weighted images that contain foci of high intensity on T1-weighted images [35,83-85].

 

Diagnosis — The diagnosis of idiopathic noncirrhotic portal hypertension is based on the presence of unequivocal portal hypertension, histologic exclusion of cirrhosis, and exclusion of other disorders that may cause noncirrhotic portal hypertension [86]. (See 'Etiology' above.)

Patients who have histologic findings consistent with idiopathic noncirrhotic portal hypertension, but who do not have evidence of portal hypertension, are not considered to have idiopathic noncirrhotic portal hypertension. In a series of 2500 autopsies, histologic findings consistent with idiopathic noncirrhotic portal hypertension were found in 3 percent. However, of that 3 percent, only 5 percent had evidence of portal hypertension.

Diagnostic approach — The diagnostic approach in a patient suspected of having idiopathic noncirrhotic portal hypertension includes the following: laboratory tests to rule out other causes of liverdisease/noncirrhotic portal hypertension, history of drug or toxin exposure, hepatic imaging to rule out portal or hepatic vein occlusion, and liver biopsy to rule out cirrhosis.

To aid with the identification of patients with idiopathic noncirrhotic portal hypertension, diagnostic criteria have been proposed. A diagnosis of idiopathic noncirrhotic portal hypertension requires that all of the following criteria be met [1]:

●Clinical signs of portal hypertension (at least one of the following) must be present:

 

•Splenomegaly/hypersplenism in conjunction with another sign of portal hypertension

•Esophageal and/or gastric varices

•Ascites (nonmalignant)

•Increased hepatic venous pressure gradient

•Portovenous collaterals

 

●Exclusion of cirrhosis on liver biopsy

 

●Exclusion of chronic liver disease that may cause either cirrhosis or noncirrhotic portal hypertension:

 

•Chronic hepatitis B or C virus infection (see "Diagnosis of hepatitis B virus infection" and "Diagnosis and evaluation of chronic hepatitis C virus infection", section on 'Diagnostic tests')

•Nonalcoholic steatohepatitis (see "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Diagnosis')

•Alcoholic steatohepatitis (see "Clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic cirrhosis", section on 'Diagnosis')

•Autoimmune hepatitis (see "Autoimmune hepatitis: Clinical manifestations and diagnosis")

•Hereditary hemochromatosis (see "Approach to the patient with suspected iron overload", section on 'Making the diagnosis of iron overload')

•Wilson disease (see "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnosis')

•Primary biliary cirrhosis (see "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Diagnosis')

 

●Exclusion of other conditions that may cause noncirrhotic portal hypertension:

 

•Congenital liver fibrosis

•Sarcoidosis (see "Clinical manifestations and diagnosis of pulmonary sarcoidosis")

•Schistosomiasis (see 'Schistosomiasis' above)

 

●Imaging showing patent portal and hepatic veins

 

Patients should be evaluated for the disorders associated with idiopathic noncirrhotic portal hypertension (table 2) if they have signs or symptoms of any of the conditions, hematologic manifestations of a myeloproliferative disease on the complete blood count and differential, prior thrombotic events that might reflect an underlying hypercoagulable state, or manifestations suggestive of a systemic disease associated with vascular injury (eg, vasculitis, lupus). (See "Overview of the myeloproliferative neoplasms", section on 'Diagnosis' and "Evaluating patients with established venous thromboembolism for acquired and inherited risk factors" and 'Etiology' above.).

Laboratory tests — A report has suggested that serum vitamin B12 levels are significantly lower in patients with idiopathic noncirrhotic portal hypertension than in patients with cirrhosis and may be useful in distinguishing between the two entities [87]. However, the potential diagnostic role of serum vitamin B12 levels has not been validated. Similarly, it has been suggested, but not yet validated, that a group of serum metabolites detected by metabolomics may aid with diagnosing idiopathic noncirrhotic portal hypertension [88].

Imaging — An imaging test is required to evaluate the liver parenchyma and circulation. The portal and hepatic veins in idiopathic noncirrhotic portal hypertension should be patent on imaging by Doppler ultrasound, CT angiography, or MRI angiography, though patients with advanced disease may have secondary portal vein thrombosis. Secondary portal vein thrombosis may then be misdiagnosed as primary extrahepatic portal vein thrombosis or thrombosis secondary to underlying cirrhosis. The clinical history, liver stiffness values, and liver biopsy findings may help to differentiate between these entities.

Liver stiffness — A patient with idiopathic noncirrhotic portal hypertension should have a liver stiffness value on transient elastography that is far below what would be expected in a patient with cirrhosis. This can be helpful in differentiating patients with primary extrahepatic portal vein thrombosis due to cirrhosis from those with secondary portal vein thrombosis in the setting of idiopathic noncirrhotic portal hypertension [48]. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography", section on 'Transient elastography'.)

Liver pathology — From a clinical perspective, the most important reason to obtain a liver biopsy in the evaluation of idiopathic noncirrhotic portal hypertension is to exclude the presence of cirrhosis and other specific disease entities that could account for the development of portal hypertension. Percutaneous or transjugular biopsy may not be sufficient because of the sampling variability, so patients suspected of having idiopathic noncirrhotic portal hypertension who have an unrevealing core needle biopsy may require an open or laparoscopic biopsy [71,72,75,89,90]. (See "Percutaneous, fine-needle aspiration, and laparoscopic liver biopsy".)

Gross pathology of the liver surface in patients with idiopathic noncirrhotic portal hypertension is normal in most patients, but it is markedly nodular in 10 to 15 percent of patients, with nodularity confined to the liver's surface [39]. The portal vein and its branches are prominent with sclerosed walls. Autopsy specimens often demonstrate the presence of thrombi in the small and medium portal vein branches [91].

Historically, idiopathic noncirrhotic portal hypertension was classified into one of four histologic categories: idiopathic portal hypertension, nodular regenerative hyperplasia, partial nodular transformation, and incomplete septal cirrhosis:

●Idiopathic portal hypertension was defined by the presence of fibrotic portal tracts and thin fibrous septa without evidence of cirrhosis.

 

●Nodular regenerative hyperplasia was defined by micronodular transformation of the liver parenchyma, with central hyperplasia, an atrophic rim, and no fibrosis.

 

●Partial nodular transformation was characterized by noncirrhotic, grossly visible parenchymal nodules that are located in the perihilar region of the liver around the large portal tracts.

 

●Incomplete septal cirrhosis was defined by slender, incomplete septal fibrosis that demarcates the liver parenchyma into nodules. The portal tracts are hypoplastic and hepatocytes are hyperplastic.

 

However, it is now appreciated that patients often have features of more than one classification. Some of the variability in histologic findings among patients may be the result of heterogeneity in the disease and its severity and because of sampling variability on liver biopsy specimens (table 3) [36,39,59,92].

A common finding associated with idiopathic noncirrhotic portal hypertension is obliteration of small portal venules (occlusive venopathy) that may lead to impairment in the intrahepatic portal perfusion and parenchymal atrophy. Other typical histological findings include an "obliterative portal venopathy of liver" (characterized by irregular sclerosis of the portal vein wall), fibrosis of the portal tract, dilatation of sinusoids due to increased portal pressure, and emergence of new aberrant portal channels (picture 3A-B) [93]. In advanced cases, parenchymal atrophy in the subcapsular regions may lead to collapse [36,92,94,95]. Uncommon histologic features include pseudonodules, piecemeal necrosis, and regenerative activity [91]. Regenerative nodules may develop near the hilum of atrophic livers in advanced cases. Electron microscopy has revealed widening of the space of Disse with fibrogenesis in the perisinusoidal space leading to capillarization of the sinusoids in some patients [42].

Hemodynamics — Intrasplenic and portal vein pressures are markedly elevated in patients with idiopathic noncirrhotic portal hypertension [96,97]. The wedged hepatic vein pressure (WHVP) is normal or slightly elevated in approximately half of patients. The WHVP, along with the free hepatic venous pressure (which reflects intraabdominal pressure), are used to determine the hepatic venous pressure gradient (HVPG), which estimates the severity of portal hypertension. Despite unequivocal signs of portal hypertension such as large esophageal varices and splenomegaly, HVPG values in patients with idiopathic noncirrhotic portal hypertension are much lower than the cutoff for clinically significant portal hypertension in cirrhosis [98]. In addition, hepatic vein-to-vein communications are frequently seen during venography in idiopathic noncirrhotic portal hypertension. In the presence of these intrahepatic venous communications, the WHVP almost always underestimates the true portal pressure because communications between the hepatic veins often preclude correct positioning and occlusion of the balloon catheter [99,100]. Demonstration of such communication during hepatic venography is supportive of the diagnosis. (See "Portal hypertension in adults", section on 'Hepatic venous pressure gradient'.)

Differential diagnosis — The differential diagnosis includes portal hypertension due to cirrhosis of any etiology and a variety of pre-, intra-, or postsinusoidal disorders associated with portal hypertension (table 1). The diagnosis of idiopathic noncirrhotic portal hypertension includes ruling out these other disorders. (See 'Etiology' above and 'Diagnostic approach' above.)

Management — The key issues in the management of patients with idiopathic noncirrhotic portal hypertension are related mainly to management and prevention of variceal hemorrhage. While data are limited in this population regarding the best approach to management [81,101-105], patients are typically managed in the same manner as those with portal hypertension due to cirrhosis. A cohort study of patients with idiopathic noncirrhotic portal hypertension reported good long-term outcomes using a management strategy based on current management guidelines for varices in the setting of cirrhosis [81]. Other elements of the management include withdrawing any drugs associated with idiopathic noncirrhotic portal hypertension and treating any associated medical conditions (table 2). As an example, biochemical and histologic improvement or reversibility has been reported after stopping azathioprine in organ transplantation recipients [83,106]. In addition, patients should be screened for portal vein thrombosis (eg, with Doppler ultrasonography every six months [107]). (See 'Etiology' above.)

Treatment for acute variceal bleeding includes early pharmacologic treatment with vasoactive drugs, early endoscopic control of bleeding, careful blood product replacement, and prophylactic antibiotics. (See"General principles of the management of variceal hemorrhage".)

Primary and secondary prevention of variceal bleeding includes the use of nonselective beta blockers and endoscopic variceal ligation. Shunt surgery is an effective alternative in patients who fail to respond to endoscopic therapy [108,109]. However, shunt surgery has largely been replaced by transjugular intrahepatic portosystemic shunting. Splenectomy has been described in patients with symptomatic hypersplenism (spontaneous bleeding episodes, severe transfusion-dependent anemia, or repeated splenic infarcts) [39]. Case reports of patients with idiopathic noncirrhotic portal hypertension have also described splenic embolization and percutaneous transhepatic obliteration [105,110]. (See "Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis" and "Prevention of recurrent variceal hemorrhage in patients with cirrhosis".)

Prognosis — Because of preserved liver function, the prognosis of patients with idiopathic noncirrhotic portal hypertension is better than that of patients with cirrhosis who have a similar degree of portal hypertension. However, a subgroup of patients progresses to develop advanced hepatic insufficiency, eventually requiring liver transplantation [111,112]. These patients generally have nodular transformation of the liver with extensive subhepatic and portal fibrosis. A few case reports have suggested an association between idiopathic noncirrhotic portal hypertension and hepatocellular carcinoma, but whether other risk factors may have accounted for the observation is unclear [113,114]. Currently, screening for hepatocellular carcinoma is not recommended for these patients.

There are very few studies evaluating the long-term prognosis of patients with idiopathic noncirrhotic portal hypertension:

●One cohort study of Western patients suggested that overall survival was poorer compared with that of the general population, with a transplant-free survival of only 40 percent at 10 years [115]. However, the increased mortality in this study was related to non-liver related conditions and not to complications of portal hypertension or liver failure. Only 4 of 62 patients (6.5 percent) died from liver-related conditions.

 

●By contrast, another study reported good long-term outcomes in patients with biopsy-proven idiopathic noncirrhotic portal hypertension, with a 10-year transplant-free survival rate of 82 percent [81].

 

In both studies, the development of ascites was identified as a poor prognostic factor in patients with idiopathic noncirrhotic portal hypertension. In the latter study, the presence of a severe associated disorder (immunological disease or malignancy) was also identified as a poor prognostic factor [81].

SUMMARY AND RECOMMENDATIONS

●Cirrhosis is the most common cause of portal hypertension, but portal hypertension can also be present in the absence of cirrhosis, a condition referred to as "noncirrhotic portal hypertension." The causes of noncirrhotic portal hypertension can be divided into prehepatic, intrahepatic (presinusoidal, sinusoidal, and postsinusoidal), and posthepatic causes (table 1). (See 'Etiology' above.)

 

●Schistosomiasis is one of the most common causes of noncirrhotic portal hypertension worldwide [6].

 

•Chronic hepatic schistosomiasis is characterized by features of portal hypertension: esophageal varices, hepatomegaly, and splenomegaly with hypersplenism. (See 'Clinical features' above.)

 

•The diagnosis of schistosomiasis can be made by the detection of schistosomal eggs in the stool. (See 'Diagnosis' above.)

 

•In addition to treating the underlying parasitic infection, management is aimed at preventing or treating the consequences of portal hypertension (predominantly variceal bleeding). (See 'Management'above and "Treatment and prevention of schistosomiasis", section on 'Treatment' and "General principles of the management of variceal hemorrhage" and "Methods to achieve hemostasis in patients with acute variceal hemorrhage" and "Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis".)

 

●Idiopathic noncirrhotic portal hypertension has been referred to by several different names, including nodular regenerative hyperplasia. It is characterized by portal hypertension in the absence of liver cirrhosis, with histologic features of dense portal fibrosis, marked phlebosclerosis, and dilated sinusoids.

 

•The most common clinical presentation is variceal bleeding, which is often relatively well tolerated due to the preserved liver function. Development of portal vein thrombosis is a frequent event during the natural course of the disease, mainly in those with associated human immunodeficiency virus infection. (See 'Clinical manifestations' above.)

 

•The diagnostic approach in a patient suspected of having idiopathic noncirrhotic portal hypertension includes the following: laboratory tests to rule out other causes of liver disease/noncirrhotic portal hypertension, hepatic imaging to rule out portal or hepatic vein occlusion, and liver biopsy to rule out cirrhosis. The differential diagnosis includes portal hypertension due to cirrhosis of any etiology and a variety of pre-, intra-, or postsinusoidal disorders associated with portal hypertension (table 1). (See 'Etiology' above and 'Diagnosis' above.)

 

•As with noncirrhotic portal hypertension due to schistosomiasis, management is aimed at preventing or treating the consequences of portal hypertension (predominantly variceal bleeding). While data are limited in this population regarding the best approach to management, patients are typically managed in the same manner as those with portal hypertension due to cirrhosis. Patients should also undergo screening for portal vein thrombosis (eg, with Doppler ultrasonography every six months). (See 'Management' above and "Treatment and prevention of schistosomiasis", section on 'Treatment'and "General principles of the management of variceal hemorrhage" and "Methods to achieve hemostasis in patients with acute variceal hemorrhage" and "Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis".)

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