Systemic disease associated with noncirrhotic portal hypertension

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Abbreviations

EHPVO

extrahepatic portal vein obstruction

HVPG

hepatic venous pressure gradient

INCPH

idiopathic noncirrhotic portal hypertension

NCPH

noncirrhotic portal hypertension

NRH

nodular regenerative hyperplasia

TIPS

transjugular intrahepatic portosystemic shunt

Introduction and Definition of Noncirrhotic Portal Hypertension

Development of portal hypertension most often occurs in the context of liver cirrhosis. However, noncirrhotic portal hypertension (NCPH) can be a complication of different systemic, primarily extrahepatic, diseases. NCPH is defined as a syndrome with a portal‐caval pressure gradient exceeding 5 mm Hg in the absence of cirrhosis.1 This review will focus on NCPH in systemic diseases along with idiopathic NCPH (INCPH). NCPH associated with extrahepatic portal vein obstruction (EHPVO) or portal vein thrombosis will be discussed in accompanying articles.2, 3

Overview of Systemic Diseases Associated With NCPH

The numerous intra‐ and extrahepatic causes of NCPH can be classified according to the site of vascular resistance into prehepatic, hepatic (presinusoidal, sinusoidal, postsinusoidal) and posthepatic forms (Table 1). Although schistosomiasis is the most common cause of NCPH worldwide, a wide spectrum of systemic diseases ranging from infections to malignancies can lead to development of NCPH (Table 2). From a pathophysiological point of view, there are different suggested mechanisms leading to the development of hypertension in the portal system, ie, by increased vascular resistance (sinusoidal compression, sinusoidal occlusion/infiltration, vascular remodeling) or by increased flow through arterio‐portal shunts (Tables 2 and 3).

Table 1.

Causes of Noncirrhotic Portal Hypertension (adapted from Schouten et al1)

PRESINUSOIDAL

Developmental abnormalities

Adult polycystic disease

Hereditary hemorrhagic telangiectasia

Arterio‐portal fistulas

Congenital hepatic fibrosis

Idiopathic noncirrhotic portal hypertension

Nodular regenerative hyperplasia

Biliary diseases

Primary biliary cirrhosis

Autoimmune cholangiopathy

Primary sclerosing cholangitis

Toxic (vinyl chloride)

Neoplastic occlusion of the portal vein

Lymphoma

Epithelioid hemangioendothelioma

Epithelial malignancies

Chronic lymphocytic leukemia

Granulomatous lesions

Schistosomiasis

Mineral oil granuloma

Sarcoidosis

SINUSOIDAL

Fibrosis of space of Disse

Drug‐induced (methotrexate, amiodarone)

Alcoholic liver damage

Toxic (vinyl chloride, copper)

Metabolic (NASH, Gaucher's disease, Zellweger syndrome)

Inflammatory (viral hepatitis, chronic Q fever, healed cytomegalovirus)

Amyloid or light‐chain deposition in space of Disse

Early noncirrhotic alcoholic liver disease (defenestration of sinusoidal lining)

Destruction or collapse of sinusoids (acute necroinflammatory diseases)

Infiltrative diseases

Mastocytosis

Agnogenic myeloid metaplasia

Gaucher's disease

Hypertrophy of Kupffer cells

Parasites (visceral leishmaniasis)

Metabolic (Gaucher's disease)

Compression of sinusoids by markedly hypertrophied hepatocytes

Microvesicular steatosis (alcohol, acute fatty liver of pregnancy)

POSTSINUSOIDAL

Veno‐occlusive disease

Acute radiation injury

Toxic injury

Drug‐induced injury

Phlebosclerosis of hepatic veins

Alcoholic liver disease

Chronic radiation injury

Hypervitaminosis A

E‐ferol injury

Primary vascular malignancies

Epithelioid hemangioendothelioma

Angiosarcoma

Granulomatous phlebitis

Sarcoidosis

Mycobacterium avium / M. intracellulare

Lipogranulomas

Mineral oil granuloma

Table 2.

Pathophysiological Mechanisms Leading to NCPH in Systemic Diseases

Sinusoidal compression (ie, sarcoidosis)

Sinusoidal occlusion/infiltration (ie, metastatic disease)

Vascular remodeling in nodular regenerative hyperplasia (ie, systemic lupus erythematosus)

Defenestration of sinusoidal lining (ie, early alcoholic disease)

Arterio‐portal shunting (ie, hereditary hemorrhagic telangiectasia)

Table 3.

Systemic Diseases Associated With Noncirrhotic Portal Hypertension With Hypothesized Underlying Pathophysiology (adapted from Reshamwala et al6)

Infectious

HIV (INCPH, NRH)

Tuberculosis (sinusoidal compression, NRH)

Schistosomiasis (sinusoidal compression)

Visceral leishmaniasis (sinusoidal compression)

Mycobacterium avium / M. intracellulare (sinusoidal compression)

Rheumatological

Rheumatoid arthritis (NRH)

Systemic lupus erythematosus (INCPH, NRH)

Felty's syndrome (NRH)

Polyarteritis nodosa (NRH)

Progressive systemic sclerosis (NRH)

Antiphospholipid syndrome (NRH)

Hematological

Idiopathic thrombocytopenic purpura (NRH)

Polycythemia vera (NRH)

Essential thrombocytosis (NRH)

Sickle cell anemia (NRH)

Macroglobulinemia (NRH)

Myeloid metaplasia (NRH)

Neoplastic

Chronic myelogenous leukemia (sinusoidal occlusion, NRH)

Chronic lymphocytic leukemia (sinusoidal occlusion, NRH)

Hodgkin's lymphoma (sinusoidal occlusion, NRH)

Non‐Hodgkin's lymphoma (sinusoidal occlusion, NRH)

Angiosarcoma (sinusoidal occlusion)

Epithelioid hemangioendothelioma (sinusoidal occlusion)

Genetic

Hereditary hemorrhagic telangiectasia (arterio‐portal shunts)

Common variable Immunodeficiency (NRH)

Adenosine deaminase 2 mutation (NRH)

Gaucher's disease (sinusoidal compression)

Zellweger Syndrome (sinusoidal compression)

Other

Sarcoidosis (sinusoidal compression)

Celiac disease (INCPH, NRH)

Generalized essential telangiectasia (NRH)

Abbreviations: INCPH, idiopathic noncirrhotic portal hypertension; NRH, nodular regenerative hyperplasia.

Diagnosis of NCPH

Depending on the underlying systemic disease and the extent of portal hypertension NCPH may remain undiagnosed (ie, in malignancy) or identified with delay. No single test is sufficient to diagnose NCPH, and even the “gold standard” for the assessment of portal hypertension (hepatic venous pressure gradient) is often misleading due to a presinusoidal component of the vascular resistance.1, 4, 5 Diagnosis of NCPH is therefore challenging and mainly a diagnosis of exclusion. Schouten et al have recently proposed diagnostic criteria for INCPH with a stepwise approach (Table 4)1: All 5 criteria (clinical signs of portal hypertension, liver histology without cirrhosis, fibrosis or other explanation for portal hypertension, patency of portal and hepatic veins) must be fulfilled to diagnose idiopathic NCPH. Other forms of NCPH can be diagnosed using the same criteria except for criterion 4 (Table 4).

Table 4.

Diagnostic Criteria for Idiopathic Noncirrhotic Portal Hypertension^a (adapted and modified from Schouten et al1)

1) Clinical signs of portal hypertension (any one of the following b)

Splenomegaly/hypersplenism

Esophageal varices

Ascites (nonmalignant)

Increased hepatic venous pressure gradient

Portovenous collaterals

2) Exclusion of cirrhosis on liver biopsy

3) Exclusion of chronic liver disease causing cirrhosis or noncirrhotic portal hypertension due to hepatic fibrosis or inflammatory infiltration c

Chronic viral hepatitis B and/or C

Nonalcoholic steatohepatitis/alcoholic steatohepatitis

Autoimmune hepatitis

Hereditary hemochromatosis

Wilson's disease

Primary biliary cirrhosis

4) Exclusion of conditions causing other forms of noncirrhotic portal hypertension

Congenital liver fibrosis

Sarcoidosis

Schistosomiasis

5) Patent portal and hepatic veins (Doppler ultrasound or computed tomography scanning)

^aAll five criteria must be fulfilled to diagnose idiopathic noncirrhotic portal hypertension. Criteria 1, 2, 3, and 5 must be fulfilled to diagnose other forms of noncirrhotic portal hypertension.

^bSplenomegaly must be accompanied by additional signs of portal hypertension to fulfill this criterion.

^cChronic liver disease must be excluded, because severe fibrosis might be understaged on liver biopsy.

Liver biopsy is central in the workup of suspected NCPH and serves to exclude advanced fibrosis and cirrhosis. On the other hand, specific histological findings (ie, granulomas, malignant infiltration, nodular transformation of the hepatic parenchyma, dilated sinusoids, luminal narrowing or obliteration of small portal venous branches) can help to establish the diagnosis of many forms of NCPH such as nodular regenerative hyperplasia (Fig. 1) and are discussed in a separate accompanying review. Percutaneous liver biopsies are preferred over transjugular liver biopsies due to larger specimens, which are less prone to sampling error and understaging.

Figure 1.

Liver biopsy (magnification 100×, Novotny staining) showing nodular regenerative hyperplasia in a patient with generalized essential telangiectasia suffering from severe noncirrhotic portal hypertension complicated by varices and ascites (adapted and modified from Rothweiler et al7). Arrows indicate compressed regions at the periphery of nodules; further histological findings show dilated sinusoids (arrowheads) and absence of fibrosis.

Clinical Manifestations of NCPH

Similar to portal hypertension in cirrhosis, increases in portal pressure in patients with NCPH may remain clinically asymptomatic or lead to the development of collateral circulation, ascites, and splenomegaly with or without hypersplenism. Splenomegaly is often more pronounced in NCPH than in cirrhosis.1, 2, 4, 6 Other complications such as hepatic encephalopathy, ascites, decreased liver synthetic function, hepatorenal syndrome, and hepatopulmonary syndrome are found less frequently in NCPH. Jaundice might occur due to portal biliopathy (ie, in hereditary hemorrhagic telangiectasia). Peripheral stigmata of chronic liver disease are usually missing.

In contrast to portal hypertension in cirrhosis, there is a lack of prospective studies on NCPH. However, clinical manifestations of patients with NCPH related to idiopathic NCPH (reviewed by Bodh and Chawla2 in an accompanying CLD article) and to nodular regenerative hyperplasia have been studied in more detail. In Western countries, the initial presentation in most patients with INCPH is splenomegaly and/or increased liver function tests.1, 7, 8 In contrast, patients with INCPH from India were found to present primarily with gastrointestinal bleeding.1, 2

Nodular regenerative hyperplasia (NRH) is the most frequent cause for NCPH in the Western world and is associated with several systemic diseases (Table 3). NRH can only be diagnosed by liver biopsy and is characterized by diffuse nodular transformation of the hepatic parenchyma into small, regenerative nodules with no or minimal fibrosis (Fig. 1). NRH is an underdiagnosed condition due to its asymptomatic and benign course in most patients.6, 7, 8 However, autopsy studies have shown NRH in 2.6% of autopsy livers with higher prevalence (5.6%) in patients aged >80 years.6, 9 Portal hypertension is the main complication in patients with NRH, and patients can present with various complications (ie, variceal bleeding, ascites). However, severe portal hypertension is rare in NRH. Typically, portal hypertension is presinusoidal with hepatic venous pressure gradient (HVPG) measurements being falsely low (<10 mm Hg) in 70% of patients.5 A transjugular intrahepatic portosystemic shunt (TIPS), if needed, is in general well tolerated in patients with NRH without the development of hepatic encephalopathy. Liver transplantation is rarely necessary in NRH, showing similar patient and graft survival rates as in other liver transplant recipients.10

Follow‐up of Patients With NCPH

The prognosis of patients suffering from NCPH is primarily determined by the underlying disease. For instance, patients with chronic granulomatous disease and NCPH have increased mortality, whereas in sporadic cases, survival seems not to be affected.11 Due to the lack of clinical studies, there are no evidence‐based recommendations for prevention, treatment, and follow‐up of patients with NCPH. Complications of portal hypertension (ie, ascites, varices) should be treated in analogy to treatment in patients with cirrhosis (ie, diuretics in ascites, nonselective beta‐blockers, and/or band ligation for varices).